The labeling of the antiplatelet drug clopidogrel (Plavix) has been revised to include information on a serious potential interaction with the proton pump inhibitor omeprazole (Prilosec, Prilosec OTC, Zegerid, Zegerid OTC) that decreases clopidogrel's therapeutic effect. The revision was made following a January 2009 Food and Drug Administration (FDA) safety alert that warned of the possible interaction between these two often concurrently prescribed drugs (see Drug Watch, June 2009).
Clopidogrel, which inhibits platelet aggregation, can prevent the formation of blood clots and cardiovascular events and is prescribed in patients who have had a recent myocardial infarction, stroke, or acute coronary syndrome, and as prophylaxis in peripheral arterial disease. Omeprazole is a proton pump inhibitor that decreases gastric acidity and is used in the treatment of gastroesophageal disease and stomach ulcers.
Clopidogrel can cause gastrointestinal distress (dyspepsia and diarrhea), possibly, although not commonly, posing the risk of gastric ulceration. Because proton pump inhibitors decrease gastric acidity and are useful in the treatment of gastroesophageal disease and stomach ulcers, they're often prescribed for the treatment or prevention of gastrointestinal distress in patients taking clopidogrel. Omeprazole is also available in an over-the-counter (OTC) formulation that patients can use to treat heartburn or acid reflux.
Clopidogrel is a "prodrug," meaning that it must be metabolized through the cytochrome P450 (CYP) isoenzyme system (specifically, isoenzyme CYP2C19) before it can be converted into its active form. However, omeprazole inhibits CYP2C19, thereby diminishing that conversion. Recent studies have shown that if a patient takes both clopidogrel and omeprazole, even 12 hours apart, clopidogrel's effect on platelet aggregation decreases by 47%, which can significantly increase the patient's risk of developing a life-threatening blood clot. The degree of CYP2C19 inhibition is not the same for all proton pump inhibitors, and the effect that those other than omeprazole might have on clopidogrel's therapeutic effect is not known. The only other proton pump inhibitor specifically identified in the revised labeling is esomeprazole (Nexium), a chemical component of omeprazole. Concurrent use of clopidogrel and esomeprazole, therefore, should also be avoided.
Patients who need gastric acid inhibition while taking clopidogrel may be treated with a histamine2-receptor antagonist, such as ranitidine (Zantac), famotidine (Pepcid), or nizatidine (Axid), but not cimetidine (Tagamet and Tagamet HB), which is also a CYP2C19 inhibitor. Antacids are also safe to take concurrently with clopidogrel. In addition to esomeprazole and cimetidine, other drugs that should be avoided in combination with clopidogrel because of a possible CYP isoenzyme system interaction include fluconazole (Diflucan), ketoconazole (Nizoral), voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol), fluoxetine (Prozac, Sarafem, Symbyax), fluvoxamine (Luvox), and ticlopidine (Ticlid). Nurses should closely monitor patients who decide to continue proton pump inhibitor use for diminished efficacy of clopidogrel. Nurses should also advise patients not to take OTC omeprazole or OTC cimetidine with clopidogrel.