New Boxed Warning for Clopidogrel Addresses Pharmacogenomics

Cheryl A. Thompson

BETHESDA, MD 12 March 2010—Health care professionals planning to prescribe clopidogrel should consider using "alternative treatment or treatment strategies" in patients identified as poor metabolizers of the prodrug, according to the new boxed warning in the medication's FDA-approved labeling.

The boxed warning, however, does not instruct health care professionals to determine a patient's cytochrome P-450 isoenzyme 2C19 (CYP2C19) genotype before prescribing clopidogrel.

CYP2C19 is known to help convert clopidogrel to its active metabolite, which inhibits platelet activation and aggregation. A warning that was added to the medication's labeling in May 2009 said genetic variations in CYP2C19 can impair the conversion of clopidogrel to the active metabolite.

Clopidogrel is given to certain patients with acute coronary syndrome or myocardial infarction, patients who have recently had a myocardial infarction or stroke, and patients with established peripheral arterial disease.

Studies have shown that the drug can reduce the rate of cardiovascular death, myocardial infarction, or stroke.

The labeling that FDA said it approved today describes a study of 40 healthy people who took 300 mg of clopidogrel followed by 75 mg/day for five days. Those known to be poor metabolizers had less exposure to the active metabolite and less inhibition of platelet aggregation than did the intermediate, extensive, and ultrarapid metabolizers.

Similar results occurred when the participants received clopidogrel 600 mg followed by 150 mg/day for five days, but the poor metabolizers had greater active-metabolite exposure and antiplatelet response than when they took the lower-dosage regimen.

Clopidogrel's labeling recommends the 300-mg/75-mg regimen for patients receiving the drug because of non-ST-elevation acute coronary syndrome. The labeling also states that an appropriate regimen for poor metabolizers has not been established in "clinical outcome trials."

Whether using patients' CYP2C19 genotype to tailor the clopidogrel regimen affects clinical outcomes has not been studied, FDA's Mary Ross Southworth, from the division of cardiovascular and renal drug products, told reporters in a briefing.

"These recommendations [in the boxed warning] are based on pharmacokinetic and pharmacodynamic information," she said.

Robert J. Temple, director of the Office of Medical Policy in FDA's Center for Drug Evaluation and Research, said there is some evidence showing that poor metabolizers of clopidogrel "do worse" on the standard dosage.

"It's not the kind of data you'd really wish you had, but there's some evidence to that effect," he said. "What there hasn't been is a clear test of whether you can take people who are poor metabolizers, double their dose, and do just as well.

"We have some information about what that does to their platelet inhibition—that it gets them closer to where you want to be—not quite identical to where you want to be, but closer," he continued. "And since the mechanism of how these drugs work is presumably by inhibiting platelets, that is cause for some optimism that adjusting the dose might work."

Ticlopidine and prasugrel work similarly to clopidogrel, Temple said.

Although ticlopidine is not a prodrug and thus does not depend on CYP2C19, the drug has caused life-threatening neutropenia and aplastic anemia. A boxed warning in the drug's labeling describes these adverse reactions, which cannot be reliably predicted.

Prasugrel is a prodrug, but the conversion of prasugrel to its active metabolite does not depend heavily on CYP2C19. The drug's labeling states that genetic variation in the enzyme has "no relevant effect" on the active metabolite's pharmacokinetics or inhibition of platelet aggregation.