Clopidogrel receives boxed warning for reduced benefit in poor metabolizers

March 12, 2010

Silver Spring, MD - The US Food and Drug Administration (FDA) today announced it is requiring a boxed warning to be added to the anticoagulant clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) to caution that poor metabolizers of the drug may not receive its full benefits[1].

The boxed warning also states that tests are available to determine the genetic profile of a key liver enzyme and predict whether a patient will ineffectively convert clopidogrel to its active form. It advises clinicians to consider other antiplatelet medications or alternative dosing strategies for clopidogrel in poor metabolizers.

However, the FDA noted that while higher doses of clopidogrel increase antiplatelet response in poor metabolizers, an appropriate dose regimen for these patients has not been established in a clinical-outcomes trial.

A liver enzyme called CYP2C19 is primarily responsible for converting clopidogrel into an active metabolite that will protect patients from blood clots. Some patients, however, have alleles, or variations, that code for alternate versions of this enzyme that can't metabolize the drug.

Roughly 3% of the population are poor clopidogrel metabolizers, according to a press release issued today by Sanofi-Aventis and Bristol-Myers Squibb[2]. However, this metabolism inefficiency varies by ethnicity, affecting 2% of whites, 4% of blacks, and 14% of Chinese, the companies reported.

The requirement for the boxed warning comes after the FDA added information about poor metabolizers to the clopidogrel label in May 2009, as reported by heartwire . The impetus for the boxed warning came from a study sponsored by the two drug manufacturers—and requested by the FDA—that involved 40 healthy individuals.

A group of poor metabolizers in the study had a worse antiplatelet response than the others when the loading dose was 300 mg followed by 75 mg per day. Their antiplatelet response improved, however, when both the loading dose and the daily dose were doubled.

Last November, the FDA issued a similar warning about poor metabolism of clopidogrel when the drug was taken together with the proton pump inhibitor omeprazole (Prilosec, Proctor & Gamble). The FDA said at the time that omeprazole inhibited the CYP2C19 enzyme.

Test of key liver enzyme would be an off-label use

At a FDA press conference Friday, Dr Courtney Harper, director of the division of chemistry and toxicology division at the FDA's Center for Devices and Radiological Health, said that genetic tests to determine a patient's CYP2C19 status are widely available and usually cost less than $500. Depending on the particular test, said Harper, the results may come back in a few hours or a few weeks. Roche Diagnostics sells a test that can identify the most common alleles of the CYP2C1P enzyme that can't metabolize clopidogrel, Harper noted. Because the FDA has not yet cleared the test for clopidogrel dosing, physicians would need to employ it on an off-label basis, she said. "At this point, we would leave it up to the physician's discretion."

Commenting on the new labeling for heart wire , Dr Eric Topol (Scripps Clinic, La Jolla, CA) called it "great for patients. . . . It is terrific that the FDA has upgraded the label to reflect the important genotype data. It helps validate the approach we initiated at Scripps last September based on the totality of data."

More information is available on the FDA website.

To report adverse events related to clopidogrel bisulfate, contact MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

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