Drug Interactions between fluconazole and rifampin

MONITOR CLOSELY: Coadministration with rifampin may decrease the plasma concentrations of fluconazole. The precise mechanism of interaction has not been established, but may involve rifampin induction of fluconazole metabolism via CYP450 isoenzymes, although fluconazole is not extensively metabolized but is primarily (approximately 80%) eliminated unchanged by the kidney. Two pharmacokinetic studies--one in healthy volunteers and one in AIDS patients with cryptococcal meningitis--demonstrated less than 25% decreases in mean fluconazole systemic exposure (AUC) during coadministration with rifampin 600 mg daily. The clinical significance of these changes is uncertain. In the study with AIDS patients, no significant differences in clinical outcomes were observed between the group that received fluconazole (400 mg/day) with rifampin and the group that received fluconazole without rifampin. However, serum concentrations of fluconazole were generally lower than the minimum inhibitory concentration for Cryptococcus neoformans in the rifampin group when fluconazole dosage was subsequently reduced to 200 mg/day for maintenance therapy, which could theoretically diminish its efficacy in the long-term prevention of recurrence. A more recent study conducted in Ugandan HIV patients treated with fluconazole 800 mg/day for cryptococcal meningitis found no difference in mean steady-state fluconazole plasma levels in patients who received concomitant rifampin therapy relative to those who did not. Nonetheless, there have been isolated reports of suspected interaction in the medical literature describing diminished therapeutic effects of fluconazole in the presence of rifampin, including clinical relapse of cryptococcal meningitis following the addition of rifampin in three HIV patients treated with fluconazole 400 mg/day. Another report describes 2 critically ill patients receiving concomitant fluconazole (100 and 200 mg/day) and rifampin therapy (1200 mg/day) whose fluconazole AUC was 52% lower than in 3 ICU patients given similar dosages of fluconazole without rifampin. Likewise, in a study of azole antifungal agents with various CYP450 inducers, a 44% reduction in fluconazole AUC was observed in a single patient receiving fluconazole 100 mg with rifampin 1200 mg daily. One study also suggests that the decrease in fluconazole concentrations with concurrent rifampin therapy is associated with a decrease in the efficacy of fluconazole in the treatment of oral candidiasis in AIDS patients. Based on available data, it would appear that the risk of a clinically significant interaction may be increased in patients receiving lower dosages of fluconazole and/or higher dosages of rifampin.

MANAGEMENT: Closer clinical monitoring of fluconazole therapy may be warranted whenever starting, stopping, or increasing the dosage of rifampin. Depending on clinical circumstances, consideration should be given to increasing the dosage of fluconazole.