Drug Interactions between amoxicillin / clarithromycin / lansoprazole and oxcarbazepine

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 oxcarbazepine may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is accelerated clearance due to induction of CYP450 3A4 activity by oxcarbazepine. In one study, administration of a single 600 mg dose of oxcarbazepine to eight healthy male volunteers had no effect on the pharmacokinetics of the CYP450 3A4 substrate felodipine (10 mg once daily), while repeated doses (450 mg twice a day) reduced the felodipine peak plasma concentration (Cmax) and systemic exposure (AUC) by 34% and 28%, respectively. Likewise, in a case study of a kidney transplant patient receiving cyclosporine 270 mg/day, investigators reported that cyclosporine trough concentrations declined to subtherapeutic levels approximately two weeks after the addition of oxcarbazepine. Trough concentrations returned to therapeutic range following an increase of the cyclosporine dosage to 290 mg/day and a reduction of the oxcarbazepine dosage from 750 mg/day to 600 mg/day. These results indicate that enzymatic induction occurs after multiple doses of oxcarbazepine.

MANAGEMENT: Caution is advised if oxcarbazepine must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oxcarbazepine is added to or withdrawn from therapy. When initiating treatment or changing the dosage, it may take 2 to 3 weeks to reach the corresponding level of induction. Similarly, the induction is expected to gradually decrease over 2 to 3 weeks following discontinuation of oxcarbazepine.

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MONITOR: Coadministration with oxcarbazepine may increase the plasma concentrations of drugs that are substrates of the CYP450 2C19 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2C19 activity by oxcarbazepine and its active metabolite 10-monohydroxy derivative, or MHD. In vivo, the plasma levels of phenytoin, a CYP450 2C19 substrate, increased by up to 40% when oxcarbazepine was given at dosages above 1200 mg/day.

MANAGEMENT: Caution is advised if higher dosages of oxcarbazepine must be used concurrently with medications that undergo metabolism by CYP450 2C19, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oxcarbazepine is added to or withdrawn from therapy.

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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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