Drug Interactions between amoxicillin / clarithromycin / omeprazole and fluconazole

ADJUST DOSE: Coadministration with fluconazole may significantly increase the plasma concentrations of omeprazole and other proton pump inhibitors (PPIs). The proposed mechanism is fluconazole inhibition of PPI metabolism via CYP450 2C19 and 3A4. In 18 healthy volunteers, administration of a single 20 mg oral dose of omeprazole on day 5 of multiple once daily dosing of fluconazole 100 mg resulted in approximately 2.4- and 6.3-fold increases in omeprazole peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of omeprazole alone. Terminal half-life of omeprazole was increased from 0.85 hour to 2.59 hours by fluconazole. Since all PPIs are metabolized by CYP450 2C19 and 3A4, a similar interaction with fluconazole should be expected. Omeprazole does not appear to affect the gastrointestinal absorption of fluconazole like it does some other azole antifungal agents. In a study of 12 healthy volunteers, omeprazole 20 mg/day for 7 days increased median gastric pH from 1.1 to 4.7, but had no effect on the Cmax or AUC of a single 100 mg oral dose of fluconazole. The median bioavailability ratio of fluconazole before and after omeprazole treatment was 1.00.

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 fluconazole. However, it may be necessary in patients receiving higher dosages, such as those with Zollinger-Ellison syndrome. Patients should be monitored for potentially increased adverse effects of PPIs during coadministration with fluconazole. The same precaution may be applicable to other PPIs.

Fluconazole may increase plasma concentrations of clarithromycin when coadministered. The mechanism of the interaction is unknown. The clinical significance of the elevation appears to be minimal in healthy subjects. Observation for clarithromycin adverse effects is recommended if these drugs are given together.

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.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.