Plavix-Prilosec interaction warning

January 15, 2010

FDA has announced that concomitant use of omeprazole (Prilosec, AstraZeneca, and Prilosec OTC, Procter & Gamble) and clopidogrel (Plavix, Sanofi Aventis/Bristol-Myers Squibb) can reduce the anti-clotting effectiveness of clopidogrel.

Key Points

Patients taking clopidogrel (Plavix, Sanofi Aventis/ Bristol-Myers Squibb) and their pharmacists have a new worry. The Food and Drug Administration (FDA) warned late last year that concomitant use of omeprazole (Prilosec, AstraZeneca, and Prilosec OTC, Procter & Gamble) can reduce the anti-clotting effectiveness of clopidogrel.

The FDA said recent data submitted by drugmakers' studies show that use of omeprazole reduces serum levels of clopidogrel's active metabolite by 45 percent and reduces anti-clotting activity by up to 47 percent. Similar reductions were seen whether clopidogrel and omeprazole were taken at the same time or as much as 12 hours apart.

"Plavix is a critical therapy, preventing stroke, preventing myocardial infarct," said Cynthia Reilly, director of practice development for the American Society of Health System Pharmacists. "Anything that reduces the effectiveness of therapy has to be looked at very cautiously and carefully."

Omeprazole inhibits the drug-metabolizing enzyme CYP2C19, which is responsible for the conversion of clopidogrel into its active metabolite. CYP2C19 is part of the cytochrome P450 system, which affects the metabolism of multiple pharmaceutical agents. FDA cautioned that other drugs that are potent inhibitors of the CYP2C19 enzyme should also be avoided in combination with clopidogrel.

These other agents include cimetidine (Tagamet and Tagamet HB, GlaxoSmithKline), esomeprazole (Nexium, AstraZeneca), fluconazole (Diflucan, Pfizer), ketoconazole (Nizoral, McNeil), voriconazole (Vfend, Pfizer), etravirine (Intelence, Tibotec), felbamate (Felbatol, Meda), fluoxetine (Prozac, Lilly; Sarafem, Warner Chilcott; and Symbyax, Lilly), fluvoxamine (Luvox, Solvay), and ticlopidine (Ticlid, Roche).

The American College of Cardiology (ACC), the American Heart Association (AHA), and the American College of Gastroenterology (ACG) recommend use of gastroprotective agents, specifically proton pump inhibitors (PPIs) such as omeprazole, in patients receiving aspirin, a thienopyridine such as clopidogrel, or both. Other acid suppressives can be used, including misoprostol, sucralfate, histamine H2-receptor antagonists, and over-the-counter antacids, but PPIs have become a common adjunct to clopidogrel therapy.

The FDA warning evoked a storm of reaction in the cardiovascular community. Peter Berger, MD, associate chief research officer at Geisinger Medical Center, Danville, Pennsylvania, told reporters he was shocked by the FDA alert. Christopher Cannon, MD, associate professor, Harvard Medical School, Cambridge, said FDA's interpretation of the interaction oversteps the evidence.

Reilly was less surprised. An article in the December 2009 American Journal of Health System Pharmacy concluded that observational studies and prospective trials suggest a clinically significant interaction between clopidogrel and PPIs.

The Society for Cardiovascular Angiography and Interventions issued a similar warning against combining PPIs and clopidogrel in mid-2009. The group was reacting to the Clopidogrel Medco Outcomes Study finding that patients on both clopidogrel and a PPI had a 50 percent increased risk of hospitalization for heart attack, stroke, unstable angina, or repeat revascularization.

The Journal of the American Medical Association reported last year (JAMA, May 27, 2009) that use of PPIs and other acid-suppressive agents in hospitals is associated with 30 percent increased odds for hospital-acquired pneumonia.

Between 40 percent and 70 percent of hospital patients receive some sort of acid suppression, Reilly noted. About half of patients are given discharge orders for continuing acid suppression. But up to 70 percent of inpatient use of acid-suppressive medications has not been studied or is not supported by evidence.

"A great first step is to ensure that patients really need these acid-suppressive agents," she said. "If they do, then there are alternatives to PPIs."

FDA noted that acid-suppressive drugs that do not inhibit CYP2C19 activity are not expected to affect the anti-clotting activity of clopidogrel. These agents include ranitidine (Zantac, GlaxoSmithKline), famotidine (Pepcid, Johnson & Johnson/Merck), nizatidine (Axid, GlaxoSmithKline), and antacids.