Drug Interactions between amoxicillin / clarithromycin / lansoprazole and Onmel

MONITOR: Coadministration of itraconazole and the macrolide antibiotics may result in elevated plasma concentrations of itraconazole. The mechanism is decreased clearance of itraconazole due to competitive inhibition of CYP450 3A4 enzymatic activity by the macrolide agents. According to the manufacturer, the administration of a single dose of erythromycin ethyl succinate (1 gram) increased the mean peak plasma concentration and area under the concentration-time curve of itraconazole (200 mg) by 44% and 36%, respectively. Likewise, in a small number of HIV-infected patients, clarithromycin also increased the plasma levels of itraconazole. The effect of itraconazole on erythromycin and clarithromycin is uncertain, although elevated plasma clarithromycin concentrations have been reported in 3 patients treated for pulmonary Mycobacterium avium complex (MAC) and aspergillosis coinfections.

MANAGEMENT: Caution is advised if itraconazole must be used concomitantly with erythromycin or clarithromycin. Patients should be advised to notify their physician if they experience possible symptoms of itraconazole toxicity, such as nausea, vomiting, diarrhea, abdominal pain, or headache. Alternative macrolide antibiotics such as azithromycin or dirithromycin, which do not inhibit CYP450, may be appropriate.

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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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GENERALLY AVOID: Proton pump inhibitors may decrease the gastrointestinal absorption of the azole antifungal agents, itraconazole and ketoconazole, both of which require an acidic environment for dissolution. By increasing gastric pH and reducing the acidity, proton pump inhibitors can decrease bioavailability of the azoles by 75% to 80%.

MANAGEMENT: If coadministration is necessary, an acidic pH may be produced with two capsules of glutamic acid hydrochloride administered 15 minutes before the azole dose. Administration with an acidic beverage such as Coca-Cola(R) or Pepsi(R) may also help. However, clinicians should still consider the possibility of a reduced or subtherapeutic antifungal effect. It may be appropriate to switch to an agent like fluconazole or terbinafine whose absorption is not affected by stomach pH.

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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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