New warnings added to Plavix (clopidogrel) label

Several new warnings have been added to the Plavix (clopidogrel) label. The new warnings are for reduced effectiveness due to impaired CYP2C19 function and for co-adminstration of the drug with omeprazole, which can reduce the pharmacologic activity of clopidogrel.

The label changes took place on November 12 according to the drug’s approval history on the FDA website. Previously there was only one item– for thrombotic thrombocytopenic purpura– in the labels warnings section.

Sanjay Kaul expressed surprise at the label changes. Here is his comment:

The body of evidence informing the interaction between clopidogrel and
PPIs is derived from several platelet function and observational
studies, one prospective RCT–the COGENT trial–that was unfortunately
terminated prematurely and the results of which have been presented
but not published yet, and post hoc analyses of two RCTs (CREDO and
TRITON). While the results of laboratory and observational studies
generally yield a positive association, none of the RCTs have
substantiated the presence of clopidogrel interaction with PPIs,
including omeprazole. The relationship between ex vivo platelet assays
and clinical outcomes is unclear and the potential for misleading
information from observational studies that are typically confounded
by bias cannot be completely ruled out. Similar limitations apply to
the evidence linking genetic variations in CYP2C19 and clopidogrel
response. Thus, given the totality of the evidence (and unless I am
missing something), I am somewhat surprised at the labeling revision
by the FDA. In my opinion, the key question is whether the regulatory
agencies should change the label given the uncertainty in evidence!

Click here for the new label posted on the product’s website.

Here is the text of the new warnings:

WARNINGS

Reduced effectiveness due to impaired CYP2C19 function

The inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. Clopidogrel is metabolized to this active metabolite in part by CYP2C19. This metabolism can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19. Avoid use of PLAVIX in patients with impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity.

Genetic variations

Patients with genetically reduced CYP2C19 function have diminished antiplatelet responses and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function (see CLINICAL PHARMACOLOGY: Pharmacogenetics).

Drug interactions

Co-administration of PLAVIX with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of PLAVIX if given concomitantly or if given 12 hours apart. There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers (except cimetidine, which is a CYP2C19 inhibitor) or antacids interfere with the antiplatelet activity of clopidogrel (see PRECAUTIONS: Drug Interactions).

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  1. […] regarding an interaction between clopidogrel (Plavix) and omeprazole. The label change was first reported publicly by CardioBrief […]

  2. […] New warnings added to Plavix (clopidogrel) label (November 16, 2009) […]

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