Chemical: Prodrug
clopidogrel

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Prescribing Info (5) Drug Labels (4) Clinical Annotations (44)

Available Prescribing Info

Dosing Guidelines

Annotation of CPIC Guideline for clopidogrel and CYP2C19
Annotation of DPWG Guideline for clopidogrel and CYP2C19

last updated 03/15/2017

1. Annotation of CPIC Guideline for clopidogrel and CYP2C19

Summary

The CPIC Dosing Guideline for clopidogrel recommends an alternative antiplatelet therapy (e.g., prasugrel, ticagrelor) for CYP2C19 poor or intermediate metabolizers if there is no contraindication.

Annotation

This annotation is based on the CPIC® guideline for clopidogrel and CYP2C19.

September 2013 Update

Advance online publication May 2013.

The 2013 update of CPIC guidelines regarding clopidogrel have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Literature published between 1966 to January 2013 was reviewed. The updated therapeutic recommendations are more focused to patients with acute coronary syndromes undergoing percutaneous coronary intervention (ACS/PCI) than the original guideline, with additional updates involve refined recommendations for variant and novel CYP2C19 alleles beyond *2.
At the time of the development of this recommendation, there are no data available on the possible role of CYP2C19 in clopidogrel response in pediatric patient populations; however, there is no reason to suspect that CYP2C19 variant alleles would affect clopidogrel metabolism differently in children as compared with adults.
Download and read:
- Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update
- 2013 supplement

Table 1: Antiplatelet therapy recommendations based on CYP2C19 status when considering clopidogrel for ACS patients undergoing PCI

Adapted from Tables 1 and 2 of the 2013 guideline manuscript.

Likely phenotype	Genotypes	Examples of diplotypes	Implications for clopidogrel	Therapeutic recommendations	Classification of recommendations
Ultrarapid metabolizer (UM) (~5-30% of patients)	An individual carrying two increased activity alleles (17) or one functional allele (1) plus one increased activity allele (*17)	1/17, 17/17	Increased platelet inhibition; decreased residual platelet aggregation ¹	Clopidogrel - label recommended dosage and administration	Strong
Extensive metabolizer (EM) (~35-50% of patients)	An individual carrying two functional (*1) alleles	1/1	Normal platelet inhibition; normal residual platelet aggregation	Clopidogrel - label recommended dosage and administration	Strong
Intermediate metabolizer (IM) (~18-45% of patients)	An individual carrying one functional allele (1) plus one loss-of-function allele (2-8) or one loss-of-function allele (2-8) plus one increased activity allele (17) ²	1/2, 1/3, 2/17	Reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular events	Alternative antiplatelet therapy (if no contraindication); e.g., prasugrel, ticagrelor	Moderate
Poor metabolizer (PM) (~2-15% of patients)	An individual carrying two loss-of-function alleles (2-8)	2/2, 2/3, 3/3	Significantly reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular events	Alternative antiplatelet therapy (if no contraindication); e.g., prasugrel, ticagrelor	Strong

¹ The CYP2C19*17 allele (rs12248560) may be associated with increased risk of bleeding.

² The predicted metabolizer phenotype for *2-*8/*17 genotypes are provisional classifications. The currently available evidence indicates that the *17 gain-of-function allele is unable to completely compensate for the *2 loss-of-function allele [Article:20492469]; however, this data has not been consistently replicated and is therefore a provisional classification (Table S5).

An important caveat for all genotyping tests is that the "wild-type" (*1) status is reported if all other alleles that are measured are absent. Some genotype tests do not interrogate the rare loss of function alleles and therefore, if present, they may be erroneously reported as "wild type". Furthermore, in human DNA, it is always possible that a new, previously undiscovered (and therefore un-interrogated) site of variation may confer altered enzyme function in an individual, and thus lead to the rare possibility of a loss-of-function allele being erroneously called as "wild-type" (*1). The guidelines do not focus on demographic and other clinical variables, such as adherence to therapy, age, diabetes mellitus, obesity, smoking, and concomitant use of other drugs that may influence clopidogrel efficacy and clinical decision making.

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.

August 2011

Advance online publication June 2011.

Guidelines regarding the use of pharmacogenomic tests in dosing for clopidogrel were published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Download and read:
- Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy
- 2011 supplement

last updated 08/10/2011

2. Annotation of DPWG Guideline for clopidogrel and CYP2C19

Summary

The Dutch Pharmacogenetics Working Group Guideline for clopidogrel recommends to consider an alternative drug for CYP2C19 poor or intermediate metabolizers, because of increased risk for reduced response to clopidogrel. Prasugrel might be associated with an increased bleeding risk compared to clopidogrel.

Annotation

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.

Phenotype (Genotype)	Therapeutic Dose Recommendation	Level of Evidence	Clinical 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 clopidogrel	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 (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 clopidogrel	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 (statistically significant difference): death; arrhythmia; unanticipated myelosuppression
CYP2C19 UM (17/17)	None	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 (statistically significant difference): QTc prolongation (<450 ms female, <470 ms male); international normalized ratio increase < 4.5 Kinetic effect (statistically significant difference)

*See Methods or [Article:18253145] for definition of "good quality."
#wherever one or more of the "good quality" criteria was missing, the quality of the study was considered to be "moderate"

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Annotated Labels

Annotation of FDA Label for clopidogrel and CYP2C19
Annotation of EMA Label for clopidogrel and CYP2C19
Annotation of PMDA Label for clopidogrel and CYP2C19
Annotation of HCSC Label for clopidogrel and CYP2C19

last updated 10/03/2016

1. Annotation of FDA Label for clopidogrel and CYP2C19

On FDA Biomarker List

Actionable PGx

Summary

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 suggests that a different platelet P2Y12 inhibitor be used in patients identified as CYP2C19 poor metabolizers.

There's more of this label. Read more.

last updated 10/25/2013

2. Annotation of EMA Label for clopidogrel and CYP2C19

Actionable PGx

Summary

The EMA European Public Assessment Report (EPAR) contains information regarding a diminished response to clopidogrel in CYP2C19 poor metabolizers. It also precautions the use of concomitant drugs that are CYP2C19 inhibitors.

There's more of this label. Read more.

3. Annotation of PMDA Label for clopidogrel and CYP2C19

Actionable PGx

Summary

The PMDA package insert for clopidogrel states that in clinical pharmacological studies, CYP2C19 poor metabolizers had diminished inhibition of platelet aggregation.

There's more of this label. Read more.

4. Annotation of HCSC Label for clopidogrel and CYP2C19

Actionable PGx

Summary

The product monograph for clopidogrel (PLAVIX) states that CYP2C19 poor metabolizers may be at increased risk for experiencing cardiovascular events when taking the drug at recommended doses as compared to normal CYP2C19 metabolizers, and that an alternative treatment or treatment strategies should be considered in these patients.

There's more of this label. Read more.

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.