New black box warning for clopidogrel: "Poor metabolizers" of the drug may remain at risk for heart attack, stroke, and cardiovascular death

On March 12, 2010, FDA announced that the manufacturers of clopidogrel, an antiplatelet agent given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease, will be placing a new black box warning into the drug's prescribing information.

Key Points

On March 12, 2010, FDA announced that the manufacturers of clopidogrel, an antiplatelet agent given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease, will be placing a new black box warning into the drug's prescribing information. This black box warning will caution healthcare providers of the reduced effectiveness of clopidogrel in patients who are poor metabolizers of the drug, and suggests that they consider the use of other antiplatelet medications or alternative dosing strategies for clopidogrel in patients identified as poor metabolizers.

For clopidogrel to exert its pharmacological effect, the liver's cytochrome P-450 isoenzyme system (particularly CYP2C19) must metabolize and activate the drug. It is estimated that anywhere from 2% to 14% of the US population are "poor metabolizers" (patient with 2 loss-of-function alleles, typically CYP2C19*2 and *3), with the rate varying by race (*2 and *3 alleles account for 85% of Caucasian and 99% of Asian patients classifed as poor metabolizers). It is expected that poor metabolizers will observe decreased benefit from clopidogrel.

The safety announcement released by FDA specifically refers to the results of a crossover pharmacokinetic and antiplatelet response study in 40 healthy volunteers receiving clopidogrel.

"In May 2009, the FDA added this warning to the drug's label," noted agency officials. "After reviewing more data, the agency felt it was important to highlight this risk in a boxed warning."

The same study also demonstrated that when poor metabolizers received the 600-mg loading dose followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300-mg loading dose and 75-mg daily regimen.

FDA officials commented that despite the findings of this study, "Healthcare professionals should note that an appropriate dose regimen for patients who are poor metabolizers has not been established in clinical outcome trials."

CONSIDER USE OF OTHER ANTIPLATELET MEDICATIONS

Officials further emphasized the importance of healthcare providers being aware that tests are available to determine patients' CYP2C19 status and that they should consider use of other antiplatelet medications in patients identified as poor metabolizers.

FDA is cautioning patients not to stop taking clopidogrel unless told to do so by their healthcare provider, and if they have concerns, to talk with their healthcare provider to see if metabolizer status testing is appropriate.

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.

SOURCES

FDA. FDA Drug Safety Communication: Reduced Effectiveness of Plavix (Clopidogrel) in Patients Who Are Poor Metabolizers of the Drug. March 12, 2010. Available at: http://www.fda.gov/drugs/drugsafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed March 15, 2010.

FDA. FDA Announces New Boxed Warning on Plavix Alerts Patients, Health Care Professionals to Potential for Reduced Effectiveness. March 12, 2010. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm204253.htm. Accessed March 13, 2010.

FDA. Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). November 17, 2009. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Accessed March 13, 2010.

Plavix [package insert]. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership: Bridgewater, NJ; 2010.