Drug Interactions between amoxicillin / clarithromycin / lansoprazole and Plavix

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

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.

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.

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.