Drug Interactions between clopidogrel and lansoprazole / naproxen

MONITOR CLOSELY: The coadministration of clopidogrel with naproxen resulted in occult gastrointestinal blood loss in healthy volunteers. The mechanism has not been described, but may be due to additive platelet inhibition. The coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) and clopidogrel should be undertaken with extreme caution. Additionally, some NSAIDs are substrates for the CYP450 isoenzyme 2C9. Clopidogrel inhibits this isoenzyme and therefore may lead to decreased metabolism of these NSAIDs. The clinical magnitude of this interaction is not known.

MANAGEMENT: Close observation for increased NSAID toxicity is recommended if these agents are coadministered with clopidogrel. Patients should also be advised to promptly report any signs of GI bleeding to their caregiver, including pain, swelling, dizziness, weakness, bloody or coffee-ground emesis, or red or black stools, and to avoid any over-the-counter NSAID products.

GENERALLY AVOID: Theoretically, proton pump inhibitors may decrease the gastrointestinal absorption of enteric-coated naproxen, which requires an acidic environment for dissolution. The proposed mechanism is an increase in gastric pH (i.e. decreased gastric acidity) induced by proton pump inhibitors. In patients treated with proton pump inhibitors, the possibility of a reduced or subtherapeutic response to enteric-coated naproxen should be considered.

MANAGEMENT: Concomitant use of these drugs is generally not recommended.

MONITOR: Coadministration of clopidogrel with lansoprazole does not appear to significantly alter the systemic exposure to the active metabolite of clopidogrel or the drug's effect on platelet inhibition. The bioactivation of clopidogrel is mediated in part by CYP450 2C19. Since lansoprazole has been shown to inhibit CYP450 2C19 in vitro, an interaction is theoretically possible leading to reduced formation of the active metabolite of clopidogrel and reduced therapeutic efficacy. In a study of 40 healthy subjects who were CYP450 2C19 extensive metabolizers, administration of clopidogrel 75 mg once daily in combination with lansoprazole 30 mg for 9 days resulted in an approximately 14% decrease in mean systemic exposure (AUC) to the active metabolite compared to administration of clopidogrel alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear. Nevertheless, observational studies have reported that PPIs as a class may reduce the cardioprotective effects of clopidogrel. In a population-based nested case-control study among patients aged 66 years or older who started clopidogrel after treatment of acute myocardial infarction, concomitant use of PPIs was associated with a significantly increased short-term risk of reinfarction. No association was found with more distant exposure to PPIs or with current exposure to H2-receptor antagonists. In a stratified analysis of the type of PPIs used, pantoprazole was not associated with recurrent myocardial infarction among patients receiving clopidogrel. However, the number of patients receiving pantoprazole in the study was relatively small. Compared with no treatment, the other proton pump inhibitors (lansoprazole, omeprazole, rabeprazole) were collectively associated with a 40% increase in the risk of recurrent myocardial infarction within 90 days of initial hospital discharge. In the Clopidogrel Medco Outcomes Study, a retrospective analysis of 16,690 patients taking clopidogrel for a full year following coronary stenting revealed that patients who also took a PPI (esomeprazole, lansoprazole, omeprazole, or pantoprazole) for an average of nine months experienced a 50% increase in the combined risk of hospitalization for heart attack, stroke, unstable angina, or repeat revascularization. Specifically, use of a PPI was associated with a 70% increase in the risk of heart attack or unstable angina, a 48% increase in the risk of stroke or stroke-like symptoms, and a 35% increase in the need for a repeat coronary procedure. The event rates for the individual PPIs are esomeprazole 24.9%, lansoprazole 24.3%, omeprazole 25.1%, and pantoprazole 29.2%, compared to 17.9% for the no-PPI control group. In a study of 105 consecutive high-risk coronary angioplasty patients receiving aspirin and clopidogrel, PPI users had a significantly lower antiplatelet response to clopidogrel than nonusers as measured by the VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay, which provides an index of platelet reactivity to clopidogrel. No significant differences in antiplatelet response were found for users of statins, ACE inhibitors, angiotensin II receptor antagonists, and beta-blockers compared to nonusers.

MANAGEMENT: According to the product labeling for lansoprazole, no dosage adjustment of clopidogrel is necessary when administered with an approved dosage of lansoprazole. However, it may be advisable to closely monitor the therapeutic efficacy of clopidogrel during concomitant treatment. An H2-receptor antagonist may be substituted if an interaction is suspected.