The Food and Drug Administration updated the labeling for clopidogrel to emphasize that new data definitively shows that the drug is less effective—and may not work at all—in patients defined as “poor metabolizers.”
The agency is notifying physicians that testing is available for the genotypes that are associated with poor metabolism, but it stopped short of recommending that all patients receive such testing before starting a course of clopidogrel (Plavix).
About 2%-14% of the population probably have those alleles and are poor metabolizers, with the rate varying by racial background, according to the FDA.
The issue of reduced metabolism was first highlighted in the clopidogrel label in May 2009. But the agency decided to add a stronger, boxed warning to clopidogrel because of the mounting evidence about poor metabolizers, including a required postmarketing study conducted by the drug's manufacturer, Sanofi-Aventis, that was submitted to the FDA, said Mary Ross Southworth, Pharm. D., a clinical analyst in the Division of Cardiovascular and Renal Products in the FDA's Center for Drug Evaluation and Research, in a briefing with reporters.
That 40-patient study confirmed that patients with the *2 and *3 alleles of the CYP2C19 liver enzyme were likely to be poor metabolizers. The *4, *5, *6, *7 and *8 alleles are associated with little to no metabolism of clopidogrel but occur less commonly than *2 and *3 alleles.
In acute situations, such as during a MI or coronary angioplasty, waiting for test results won't be reasonable, said Dr. Robert Temple, deputy director for clinical science in FDA's Center for Drug Evaluation and Research, in the briefing.
For chronic use of clopidogrel in poor metabolizers, the FDA is urging physicians to consider use of other antiplatelets, such as ticlopidine (Ticlid) or prasugrel (Effient), or potentially increasing the clopidogrel dose.
Ms. Southworth and Dr. Temple acknowledged that physicians would likely have to test patients to determine first if they were poor metabolizers, but said that there are not enough data to say that testing should be required.
Only one diagnostic for liver enzyme metabolism—the Amplichip, made by Roche—has been approved, and it is not specifically approved for CYP2C19, said Dr. Courtney Harper, director of the division of chemistry and toxicology devices at the FDA's Center for Devices and Radiologic Health. Roche cannot promote the test, since it would be an off-label use.