Drug Interactions between amoxicillin / clarithromycin / lansoprazole and voriconazole

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: Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. The risk of an individual agent or a combination of these agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution and clinical monitoring are recommended if multiple agents associated with QT interval prolongation are prescribed together. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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ADJUST DOSE: Coadministration with voriconazole may significantly increase the plasma concentrations of omeprazole and other proton pump inhibitors (PPIs). The proposed mechanism is voriconazole inhibition of PPI metabolism via CYP450 2C19 and 3A4. In healthy volunteers, administration of omeprazole 40 mg once daily with voriconazole 200 mg twice daily for 7 days increased steady-state omeprazole peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 2- and 4-fold, respectively, compared to omeprazole administered alone. Since all PPIs are metabolized by CYP450 2C19 and 3A4, a similar interaction with voriconazole should be expected.

MONITOR: Omeprazole and possibly other PPIs may also increase the plasma concentrations of voriconazole. The proposed mechanism is PPI inhibition of voriconazole metabolism via CYP450 2C19 and 3A4. In 18 healthy volunteers, administration of voriconazole 200 mg twice daily with omeprazole 40 mg once daily for 10 days increased the steady-state Cmax and AUC of voriconazole by an average of 15% and 41%, respectively, compared to administration with placebo. These changes are not generally considered clinically significant. However, an observational study of 52 voriconazole patients who received therapeutic drug monitoring reported that 5 out of 16 patients with voriconazole trough levels above 5.5 mg/L after one week of therapy experienced serious neurological adverse events (compared to none of the patients with lower trough levels), and 7 of the 16 were on concomitant omeprazole. Additionally, a suspected interaction between omeprazole and voriconazole was cited as a possible cause, or at least a contributing factor, in the development of torsade de pointes and cardiac arrest in the case of a young girl with congenital long QT syndrome.

MANAGEMENT: According to the manufacturers, dosage adjustment of omeprazole is not normally required when used with dual inhibitors of CYP450 2C19 and 3A4 such as voriconazole. However, it may be necessary in patients receiving higher dosages, such as those with Zollinger-Ellison syndrome. Voriconazole product labeling suggests reducing the omeprazole dosage by one-half upon initiation of voriconazole therapy in patients who are receiving omeprazole dosages of 40 mg/day or higher. Dosage adjustment recommendations for other PPIs are not available. Patients receiving PPIs with voriconazole should be monitored for potentially increased adverse reactions to both the PPI and voriconazole.

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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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