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FDA Updates Plavix Labeling to Warn Against Co-Administration with Other CYP2C19 Inhibitors

NEW YORK (GenomeWeb News) – The US Food and Drug Administration has updated the labeling for Plavix to warn consumers and doctors about the concomitant use of the anti-platelet agent and CYP2C19-inhibiting agents, such as the proton pump inhibitor Prilosec and others.

This week's labeling change follows an earlier update from the agency, informing healthcare providers of studies indicating poor CYP2C19 metabolizers have limited response to Plavix. At the time, the agency also said it was awaiting results from ongoing studies before making pharmacogenetically-guided dosing recommendations.

The more recent labeling update includes data from a new study conducted by Plavix developer Sanofi-Aventis. The sponsor conducted the study at the request of the FDA. Sanofi-Aventis and Bristol-Myers Squibb co-market Plavix in the US.

The new label notes: "Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole (Prilosec), esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.

The cross-over clinical study submitted by Sanofi-Aventis involved 72 subjects who received Plavix alone and then with Prilosec for five days. The results of the study showed that exposure to Prilosec worsened participants' response to Plavix.

"The exposure to the active metabolite of clopidogrel was decreased by 46 percent (Day 1) and 42 percent (Day 5) when Plavix and omeprazole were administered together," the new label informs. "Mean inhibition of platelet aggregation was diminished by 47 percent (24 hours) and 30 percent (Day 5) when Plavix and omeprazole were administered together."

Currently the labeling update is just for Plavix, however the FDA is considering whether to include the Plavix warning on the labeling of other CYP2C19 inhibitors.

In a call announcing the labeling update, Mary Ross Southworth, deputy director for safety in FDA's Division of Cardiovascular and Renal Products, noted that the agency is still awaiting data from ongoing studies. The agency doesn't yet know if the diminished response seen with the co-administration of Plavix and CYP2C19-inhibiting agents is a cause for concern in all patients or only for those who have certain CYP2C19 mutations.

"When we make these recommendations we look at totality of evidence," Ross Southworth said.

In its note to healthcare providers and the public, the FDA said it is "aware there are studies, such as the Clopidogrel and Optimization of Gastrointestinal Events (COGENT) study, that might provide information about the effect of this interaction on clinical outcome.

"Although the FDA has not fully reviewed the [COGENT] study results, the applicability of these data is limited because of the study design and follow-up," the agency noted. "Therefore, based on the current scientific information, the clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact with clopidogrel in the same way."

Ross Southworth noted that Sanofi-Aventis is conducting additional studies looking into the clinical and genetic factors that impact Plavix response.

Instead of a CYP2C19-inhibiting heartburn treatment, the FDA recommends patients use H2 blockers, such as ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), or over-the-counter antacids. However, the agency warns against simultaneously using Plavix and cimetidine (Tagamet and Tagamet HB) as it is a CYP2C19 inhibitor; or antacids that interfere with the anti-clotting activity of clopidogrel.


A more detailed report on this labeling update will be available in GenomeWeb Daily News sister publication Pharmacogenomics Reporter.

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