Drug Interaction Report

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.

GENERALLY AVOID: Concomitant administration of fluconazole has been shown to increase the maximum serum concentration of rifabutin and to decrease rifabutin clearance. The mechanism is inhibition of CYP450 3A4 hepatic microsomal enzymes. Additionally, rifabutin may increase the metabolism of fluconazole due to induction of CYP450 metabolism. Subtherapeutic levels of the azole may result.

MANAGEMENT: Concomitant use of fluconazole and rifabutin should generally be avoided, if concomitant use is necessary, patients should be monitored for rifabutin toxicity (e.g., neutropenia, uveitis). Antimicrobial activity should be monitored, and dosages should be adjusted as needed.