FDA Drops Clopidogrel Bomb at AHA

The FDA has issued a public health advisory warning patients and physicians that concomitant use of clopidogrel (Plavix) and …

The agency said the combination reduces the activity of clopidogrel by about half. Such a reduction could theoretically increase the risk of myocardial infarction and stroke, although there are no clinical data to support that hypothesis.

Mary Ross Southworth, PharmD, a deputy director of the FDA’s Center for Drug Evaluation and Research said in a press conference that, “The decision to require a change to the clopidogrel label warning of the interaction was based on the agency’s analysis of new data from drugmaker sanofi Aventis.”

She said lab tests from 150 healthy volunteers provided evidence that omeprazole, which inhibits CYP2C19, “reduces the pharmacological activity of [clopidogrel] if given concomitantly or if given 12 hours apart.”

The FDA said the drugmaker released the as-yet-unpublished study at the request of the FDA.

A joint statement issued by the American College of Cardiology and the American Heart Association pointed out that the FDA action was “not based on any new published, peer-reviewed clinical trials showing changes in cardiovascular outcomes.”

The ACC and AHA released the following statement:

“Although there are studies that show a pharmacodynamic interaction on ex vivo platelet function testing, to date there are no convincing randomized clinical trial data for an important clinical drug-drug interaction.”

The label change states that, “There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers (except cimetidine, which is a CYP2C19 inhibitor) or antacids interfere with the antiplatelet activity of clopidogrel.”

Concerns about the combination of clopidogrel and omeprazole had been building since last spring, but two recent reports — one at the European Society of Cardiology meeting and another at the Transcatheter Cardiovascular Therapeutics meeting in late September — suggested that those concerns were overstated.

Against that background, the FDA announcement struck many as odd, especially since many cardiologists are focused on digesting research being reported at the American Heart Association meeting.

But the label change was discovered by one blog, CARDIOBRIEF.org, which reported the new label language yesterday.

Although not included in the label change, the FDA said the following drugs — which are also CYP2C19 inhibitors — should also not be used in combination with clopidogrel: esomeprazole (Nexium), cimetidine (which is available by prescription as Tagamet and OTC as Tagamet HB), fluconazole (Diflucan), ketoconazole (Nizoral), voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol), fluoxetine (Prozac, Serafem, Symbyax), fluvoxamine (Luvox), and ticlopidine (Ticlid).

In its public health advisory, the FDA suggested that patients who need an acid reducer should switch to “antacids (such as Maalox or Mylanta) and most acid reducers, such as Zantac (ranitidine), Pepcid (famotidine), or Axid (nizatidine) because the FDA does not believe that these medicines will interfere with the anticlotting activity of clopidogrel.”