Drug Interactions between amoxicillin / clarithromycin / lansoprazole and digitoxin

MONITOR: Macrolide antibiotics that inhibit P-glycoprotein may increase the plasma concentrations of digoxin. The proposed mechanism is inhibition of the P-glycoprotein-mediated intestinal efflux and/or renal tubular secretion of digoxin. The interaction has been described in numerous case reports in the medical literature, the majority of which involved clarithromycin, a potent P-glycoprotein inhibitor. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Exposure to macrolides, specifically clarithromycin, azithromycin and erythromycin, has been identified as a risk factor for digoxin toxicity. A population-based, case-control study using records from Ontario, Canada's administrative health databases from 1994 to 2000 identified 1051 case patients who had been hospitalized with digoxin toxicity. These patients were about 12 times more likely to have received a prescription for clarithromycin in the previous week compared to controls without digoxin toxicity (n=51,896). Overall, 27 of the case patients (2.6%) had been exposed to clarithromycin within the previous week, compared to 101 controls (0.2%), which represented an adjusted odds ratio of 11.7. Fifty-five patients (5.2%) had been exposed to clarithromycin within the preceding 3 weeks, compared to 274 controls (0.5%), representing an adjusted OR of 8.5. A subsequent study using data from 1993 to 2008 from the same databases and focusing specifically on macrolide-induced digoxin toxicity found that the risk was significantly higher in patients who had received clarithromycin within the previous 2 weeks than in controls who did not receive antibiotics (adjusted OR=14.8). The risk of digoxin toxicity was 4 times higher following treatment with clarithromycin than with azithromycin or erythromycin (adjusted OR=3.71 and 3.69, respectively). Although little data exist, the interaction may also occur with digitoxin. Two cases of suspected azithromycin-induced digitoxin toxicity have been reported in the literature.

MANAGEMENT: Caution is advised when digoxin or digitoxin is used in combination with macrolide antibiotics that are inhibitors of P-glycoprotein. Serum digitalis levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of the macrolide in patients who are stabilized on their digitalis regimen. Patients should be advised to notify their physician if they experience signs of digitalis toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.

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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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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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