Omeprazole Decreases Effectiveness of Clopidogrel, FDA Says

Kate Traynor

BETHESDA, MD 17 November 2009—Patients who are taking clopidogrel should avoid the concomitant use of omeprazole, a proton-pump inhibitor (PPI), because the latter drug diminishes the antiplatelet effects of clopidogrel, FDA announced today.

The announcement is a follow-up to recommendations FDA made in January, when the agency alerted the public to the possible adverse drug interaction. At that time, FDA asked prescribers to reevaluate whether patients who use clopidogrel can do without a PPI to relieve stomach irritation.

FDA pharmacist Mary Ross Southworth, deputy director for safety at the agency's Center for Drug Evaluation and Research, told reporters today that the adverse interaction has been observed with omeprazole and esomeprazole. But FDA does not know whether other PPIs also interfere with the actions of clopidogrel.

"We don't have enough information about other members of this class in order to make recommendations" about the PPIs as a whole, she said.

But she said the interaction is most likely related to the inhibitory effects of omeprazole and esomeprazole on the cytochrome P-450 isoenzyme 2C19 (CYP2C19)-mediated conversion of clopidogrel to its active metabolite.

For this reason, FDA has warned against the concomitant use of clopidogrel and other strong inhibitors of CYP2C19, including cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.

New data about the interaction between clopidogrel and omeprazole are included in revised labeling for clopidogrel, which is marketed as Plavix by Bristol-Myers Squibb and Sanofi Pharmaceuticals.

The labeling describes two small studies conducted in healthy volunteers given clopidogrel alone or in combination with omeprazole. Southworth said the studies were conducted by the manufacturers at FDA's request.

"What we found was fairly significant reductions in active metabolite levels of clopidogrel and significant reductions in antiplatelet aggregation activity when the two drugs were given together," Southworth said. "That same magnitude of interaction was seen whether the drugs were given at the same time of day or whether they were given 12 hours apart."

FDA stated that patients who need clopidogrel therapy should be asked about their prescription and nonprescription drug use to in order to avoid medication combinations that could reduce the anticlotting drug's effectiveness.

The agency stated that in general, drugs other than CYP2C19 inhibitors that patients take to reduce stomach acid are not believed to interact with clopidogrel.

FDA is further investigating whether other drugs interact adversely with clopidogrel. Southworth said the agency expects to have additional study data within a few months.