FDA: Early communication issued about safety of clopidogrel bisulfate

The FDA announced it is conducting an ongoing safety review of clopidogrel bisulfate after receiving reports that the pro-drug, which is metabolized in the body before becoming active, may be less effective in patients with genetic differences or assigned to certain drugs that interfere with metabolism.

Specifically, some reports have suggested that use of proton pump inhibitors may make clopidogrel (Plavix; Sanofi Aventis, Bristol Myers Squibb) less effective by inhibiting the enzyme that converts clopidogrel to the active form of the drug; however, other reports have not suggested this effect. PPIs are commonly prescribed with clopidogrel to reduce stomach irritation.

Currently, no evidence suggests that other drugs that reduce stomach acid interfere with the antiplatelet activity of clopidogrel.

Sanofi Aventis and Bristol Myers Squibb have agreed to work with the FDA to conduct studies to obtain additional information and characterize the effects of genetic factors and other drugs on the effectiveness of clopidogrel.

The release of this information does not mean that the FDA has concluded a cause and effect relationship between the drug products and the emerging safety issue. The FDA is not advising health care professionals to discontinue prescribing these products.

Until further information is available FDA recommends the following:

Health care providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to heart attack or stroke.
Health care providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC (AstraZeneca), in patients taking clopidogrel.
Patients taking clopidogrel should consult with their health care provider if currently taking or considering taking a PPI, including Prilosec OTC.

The FDA urged health care professionals and patients to report adverse effects from the use of clopidogrel to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/medwatch/report.htm. – by Leah Lawrence

In the next few months, we are going to see a large number of studies examining whether there is any sort of clinically important interaction between clopidogrel and proton pump inhibitors. I worry, however, that these non-randomized studies will not be definitive, with some finding an interaction and others finding no interaction. Additionally, several genetic studies of cytochrome P450 polymorphisms will also come out, similar to the recent publications in The New England Journal of Medicine and The Lancet. The challenge will remain how to use this information about polymorphisms that appear to affect clopidogrel's metabolism. Although scientifically very appealing, polymorphisms that affect warfarin have not really caught on in clinical practice, so it is uncertain what actual role clopidogrel-related polymorphisms may have.

– Deepak L. Bhatt, MD

Director, Integrated Interventional Cardiovascular Program
Brigham and Women's Hospital and the VA Boston Healthcare System