GENETIC TEST FOR PLAVIX POOR METABOLIZERS

March 12, 2010 — The US Food and Drug Administration (FDA) today announced it is requiring a boxed warning for the anticoagulant clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership) to caution that poor metabolizers of the drug may not receive full protection from heart attacks, stroke, and cardiovascular death.

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 patients who are poor metabolizers.

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

The liver enzyme 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, of this enzyme and cannot metabolize the drug to its active form.

Roughly 3% of the population are poor clopidogrel metabolizers, according to a press release issued today by Sanofi-Aventis and Bristol-Myers Squibb. However, this metabolism inefficiency varies significantly by race.

Boxed Warning Follows Earlier Yellow Flags About Poor Metabolism of Clopidogrel

The requirement for the boxed warning comes after the FDA added information about poor metabolizers to the clopidogrel label in May 2009. The impetus for the boxed warning came from a cross-over study requested by the FDA and sponsored by the 2 drug manufacturers evaluating pharmacokinetic and antiplatelet response in 40 healthy individuals. Ten participants from each of 4 metabolizer groups (ultrarapid, extensive, intermediate, and poor) were randomly assigned to 2 treatment regimens: 300 mg loading dose followed by 75 mg/day, and 600 mg loading dose followed by 150 mg/day.

The 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/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 heartburn medicine omeprazole (Prilosec, Proctor & Gamble). The FDA said at the time that omeprazole inhibited the CYP2C19 enzyme.

Roche Diagnostics Test of Key Liver Enzyme Would Be an Off-Label Use

At an FDA press conference today, Courtney Harper, PhD, director of the Division of Chemistry and Toxicology Devices 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 Dr. Harper, the results may come back in a few hours or a few weeks.

Dr. Harper noted that Roche Diagnostics sells a test that can identify the most common alleles of the CYP2C1P enzyme that cannot metabolize clopidogrel. 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."

More information is available on the FDA Web site.