Drug Interactions between amoxicillin / clarithromycin / omeprazole and clopidogrel

GENERALLY AVOID: Coadministration with proton pump inhibitors (PPIs) may reduce the cardioprotective effects of clopidogrel. The proposed mechanism is PPI inhibition of the CYP450 2C19-mediated metabolic bioactivation of clopidogrel. This is consistent with studies that reported decreased effectiveness of clopidogrel and poorer clinical outcome in patients who have common genetic polymorphisms of CYP450 2C19 resulting in reduced or absent enzyme activity. 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. A subsequent study conducted by the same investigators reported similar results when omeprazole (20 mg/day) or placebo was given for seven days to 140 coronary artery stent patients receiving aspirin and clopidogrel. In contrast, a study of 300 consecutive patients with coronary artery disease undergoing PCI found that esomeprazole or pantoprazole use did not impair the response to clopidogrel as measured by VASP assay or ADP-induced platelet aggregometry. More recent studies have also found no significant effect of dexlansoprazole, lansoprazole, or pantoprazole on the pharmacokinetics or pharmacodynamics of clopidogrel, and that increasing gastric pH did not influence platelet inhibition by clopidogrel.

MANAGEMENT: Until further data are available, empiric use of proton pump inhibitors should preferably be avoided in patients treated with clopidogrel. PPIs should only be considered in high-risk patients such as those receiving dual antiplatelet therapy, those with a history of gastrointestinal bleeding or ulcers, and those receiving concomitant anticoagulant therapy, and then only after thorough assessment of risks versus benefits. If a PPI is required, dexlansoprazole, lansoprazole, or pantoprazole may be safer alternatives. Otherwise, H2-receptor antagonists or antacids should be prescribed whenever possible.

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MONITOR: The concomitant administration of some macrolide antibiotics may reduce the metabolic activation of the prodrug clopidogrel and its antiplatelet effects. The proposed mechanism is inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of clopidogrel to its active metabolite. After coadministration of erythromycin stearate 250 mg four times a day and clopidogrel 75 mg/day to healthy subjects (n=9), the percent platelet aggregation was 42% with clopidogrel alone, 55% with clopidogrel plus erythromycin, and 93% at baseline. After coadministration of single doses of troleandomycin 500 mg and clopidogrel 450 mg, the percent platelet aggregation was 45% with clopidogrel alone, 78% with clopidogrel plus troleandomycin, and 93% at baseline. Clarithromycin also inhibits CYP450 3A4 activity and is also expected to affect clopidogrel metabolism.

MANAGEMENT: Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if a macrolide is coadministered with clopidogrel. Azithromycin and dirithromycin do not inhibit CYP450 3A4 and are theoretically not expected to interact with clopidogrel.

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Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

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