Major
Clopidogrel × Omeprazole
Antiplatelet agents – P2Y12 receptor inhibitors×Proton pump inhibitors
Mechanism
Clopidogrel is a prodrug. It must be converted in the liver via CYP2C19 into its active antiplatelet metabolite. Omeprazole strongly inhibits CYP2C19: active metabolite levels drop by 45% and platelet inhibition weakens. The FDA issued a dedicated warning about this pair in 2009.
Symptoms
The patient feels no symptoms – the weakened antiplatelet effect is silent. The combination raises the risk of recurrent myocardial infarction, stent thrombosis, and stroke in patients with prior stenting or acute coronary syndrome.
Management
Replace omeprazole with pantoprazole, which has minimal effect on CYP2C19. Among other proton pump inhibitors, rabeprazole is an alternative. If a PPI is not required, switch to famotidine (an H2-blocker that does not affect CYP2C19) or stop acid suppression altogether.
Sources
- Lexicomp: Lexicomp Drug Interactions (2024)– Wolters Kluwer Clinical Drug Information, Inc. Lexi-Interact Online, 2024
- FDA: FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug (2010)– FDA Drug Safety Communication, November 17, 2010
- COGENT Investigators: Clopidogrel with or without Omeprazole in Coronary Artery Disease (2010)– N Engl J Med 2010;363(20):1909–1917
- FDA: FDA Drug Safety Communication: Reduced effectiveness of Plavix in CYP2C19 poor metabolizers (2010)