FDA: Effect of clopidogrel reduced when used with omeprazole

Yesterday, the FDA announced that new data have confirmed an early communication issued in January that suggested the coadministration of the anticoagulant clopidogrel and the proton pump inhibitor omeprazole resulted in a loss of anticlotting efficacy.

In January, the FDA alerted health care professionals that published reports revealed that clopidogrel (Plavix; Sanofi Aventis, Bristol-Myers Squibb) is less effective in some patients. At the time, the agency said it was working with the drug’s manufacturers to determine the cause, whether genetic or due to concomitant use with certain proton pump inhibitors.

Since then, studies conducted by the manufacturers have confirmed that coadministration of omeprazole and clopidogrel leads to decreased levels of clopidogrel’s active metabolite by inhibiting the CYP2C19 enzyme, thereby reducing clopidogrel’s anticlotting effect.

The studies compared the amount of clopidogrel’s active metabolite in the blood and its effect on platelets in patients who received clopidogrel plus omeprazole vs. those who received clopidogrel alone. Researchers found about a 45% reduction in active metabolite levels for patients who received clopidogrel and omeprazole. The effect of clopidogrel on platelets was reduced by nearly 47% in patients receiving the two drugs together. The researchers found these reductions whether the drugs were taken simultaneously or 12 hours apart.

Sanofi Aventis and Bristol-Myers Squibb are updating clopidogrel’s labeling with the study details and are conducting follow-up studies to further investigate drug interactions with clopidogrel.

A statement from the American College of Cardiology and American Heart Association cautioned that the new data "are not yet peer reviewed and published; however, the FDA recommends that patients who are using clopidogrel should consult with their health care provider if they are currently taking or considering taking omeprazole, including over-the-counter Prilosec.

"The FDA's statement is not based on any new published, peer-reviewed clinical trials showing changes in cardiovascular outcomes outcomes," the statement reads.

FDA recommendations

Other drugs that are potent inhibitors of CYP2C19 are expected to have a similar effect, and the FDA suggested they should also be avoided in combination with clopidogrel. These include esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole (VFEND, Pfizer), etravirine (Intelence, Tibotec), felbamate (Felbatol, Meda Pharmaceuticals), fluoxetine, fluvoxamine, and ticlopidine. The FDA stressed that other stomach acid-reducing drugs, including ranitidine, famotidine, nizatidine and antacids, are not likely to interfere with the effectiveness of clopidogrel because they do not inhibit CYP2C19 activity.

At this time, the FDA said it does not have enough information about drug interactions between clopidogrel and proton pump inhibitors other than omeprazole and esomeprazole to advise on their use together. The agency said that patients receiving clopidogrel should consult with health care providers if they are also currently prescribed omeprazole or are considering the drug.

The FDA acknowledged that studies including the Clopidogrel and Optimization of Gastrointestinal Events (COGENT) study might provide information about the effect of the interaction on clinical outcome, but said the applicability of the data is limited because of study design and follow-up. The agency is investigating other drug interactions with clopidogrel and plans to present the issue at the next meeting of the Drug Safety Oversight Board this month. The FDA said it will communicate any further recommendations or conclusions when additional information becomes available.