Drug Interactions between amoxicillin / clarithromycin / lansoprazole and dabigatran

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.

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MONITOR: Patients with gastrointestinal conditions may have an increased risk of gastrointestinal bleeding during concomitant treatment with dabigatran etexilate and proton pump inhibitors or H2 blockers. In addition, pantoprazole resulted in an approximately 30% decrease in dabigatran systemic exposure (AUC). Diminished clinical effect may occur, although no dosage adjustment is recommended for dabigatran etexilate. The pharmacokinetics of pantoprazole were not significantly altered by dabigatran. Pantoprazole and other proton pump inhibitors were also coadministered with dabigatran in clinical trials for the prevention of venous thromboembolic events after hip- or knee-replacement surgery, and no effects on bleeding or efficacy were observed. Ranitidine had no significant effects on the absorption of dabigatran.

MANAGEMENT: Patients should be monitored for signs of gastrointestinal bleeding and advised to promptly report any symptoms to their physician, such as abdominal pain, dizziness, lightheadedness, vomiting blood, anorexia, and/or black, tarry stools.

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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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Coadministration with clarithromycin may slightly increase the bioavailability of dabigatran following oral administration of dabigatran etexilate. The proposed mechanism is clarithromycin inhibition of the P-glycoprotein efflux transporter, of which dabigatran etexilate is a substrate. When dabigatran etexilate was coadministered with clarithromycin 500 mg twice a day in healthy volunteers, increases in dabigatran peak plasma concentration (Cmax) by about 15% and systemic exposure (AUC) by about 19% were observed without any clinical safety concern. Dabigatran had no significant effect on the pharmacokinetics of clarithromycin. No dosage adjustment for dabigatran etexilate is recommended during coadministration with clarithromycin, but caution may be advisable.

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