ORLANDO -- The FDA has issued a public health advisory warning patients and physicians that concomitant use of clopidogrel (Plavix) and omeprazole (Prilosec and Prilosec OTC) blunts the antiplatelet effect of clopidogrel, so the combination should be avoided.
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.
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, Mary Ross Southworth, PharmD, a deputy director of the FDA's Center for Drug Evaluation and Research said in a press conference.
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The FDA said the drugmaker conducted the as-yet-unpublished study at the request of the FDA.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.
And in updated guidelines for percutaneous coronary interventions and ST-elevation myocardial infarction released today by the ACC and AHA, there is this 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 here at the American Heart Association.
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."
The FDA said it is still reviewing the results of the 3,600 patient COGENT study, which was reported at the TCT meeting, but Southworth indicated that the agency was not impressed with those findings.