Drug Interactions between amoxicillin / clarithromycin / lansoprazole and tretinoin

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: Coadministration with potent inhibitors of CYP450 2C8, 2C9, and/or 3A4 may increase the plasma concentrations and toxicities of tretinoin, which is a substrate of these isoenzymes. There have been isolated reports of pseudotumour cerebri, hypercalcemia, and acute renal failure in patients receiving tretinoin with fluconazole, itraconazole or voriconazole, all of which are considered potent inhibitors of at least one CYP450 isoenzyme involved in the metabolism of tretinoin. The conditions resolved following interruption of tretinoin therapy and/or discontinuation of the azole antifungal agent. As tretinoin is thought to undergo autoinduction of its own metabolism, CYP450 inhibitors have been investigated for use to boost plasma tretinoin concentrations and to overcome treatment resistance that often occurs with continued tretinoin therapy. In a study of two patients with acute promyelocytic leukemia, tretinoin systemic exposure (AUC) was found to be reduced significantly from baseline after one week of treatment. Following two daily doses of fluconazole administered 1 hour before tretinoin, the AUC of tretinoin increased by about 2- to 4-fold compared to day eight of tretinoin treatment alone, but similar to AUCs reported at baseline. In 13 patients who had received tretinoin daily for 4 consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hour before the tretinoin dose on day 29 led to a 72% increase in tretinoin mean plasma AUC. Likewise, in 6 patients with lung cancer, a single 400 mg dose of ketoconazole (but not a 200 mg dose) one hour before tretinoin on day 29 increased tretinoin AUC by 115% compared to day 28 when tretinoin was given alone. No effect was observed when ketoconazole was given on day 2 relative to tretinoin alone on day one. By contrast, one study showed that prolonged ketoconazole administration (400 mg initially, then 200 mg daily for 14 days) in patients receiving tretinoin (45 mg/m2 twice daily for 14 days) had no effect on tretinoin auto-induction, but was associated with more vomiting.

MANAGEMENT: Caution is advised when tretinoin is prescribed in combination with potent inhibitors of CYP450 2C8, 2C9, and/or 3A4. Patients should be closely monitored and advised to seek medical attention immediately if they develop early symptoms of pseudotumour cerebri such as headache, nausea, vomiting, visual disturbances, photosensitivity, and tinnitus.

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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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