New black-box warning for clopidogrel

May 5, 2010

FDA announced that clopidogrel, an antiplatelet agent given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease, will require a new black-box warning about its reduced effectiveness in patients who are poor metabolizers of the drug.

On March 12, 2010, FDA announced that clopidogrel, an antiplatelet agent given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease, will require a new black-box warning about its reduced effectiveness in patients who are poor metabolizers of the drug. It suggests that healthcare providers consider the use of other antiplatelet medications or alternative dosing strategies for clopidogrel in patients identified as poor metabolizers.

For clopidogrel to exert its effect, the liver's cytochrome P-450 isoenzyme system (particularly CYP2C19) must metabolize and activate the drug. Estimates suggest that anywhere from 2% to 14% of the U.S. population are "poor metabolizers," with the rate varying by race. The expectation is that poor metabolizers will observe decreased benefit from clopidogrel.

The FDA announcement refers to the results of a crossover pharmacokinetic and antiplatelet response study in 40 healthy volunteers receiving clopidogrel. This study evaluated 10 volunteers in each of 4 CYP2C19 metabolizer groups (ultra-rapid, extensive, intermediate, and poor) randomly assigned to receive either a 300-mg loading dose of clopidogrel followed by 75 mg/day or a 600-mg loading dose followed by 150 mg/per day, each for a total of 5 days. After a washout period, volunteers were crossed over to the alternate regimen. This study demonstrated decreased active metabolite exposure and decreased platelet aggregation in the poor metabolizer group compared with the other groups.

It is important that healthcare providers be aware that tests are available to determine patients' CYP2C19 status, officials emphasized.

This is the second warning to healthcare providers regarding clopidogrel and its metabolism released by FDA in the past 6 months. In late 2009, the agency also warned providers about the co-administration of clopidogrel with the acid-reducer omeprazole and other drugs that inhibit the CYP2C19 isoenzyme system.