Drug interactions between alprazolam and Diflucan

GENERALLY AVOID: Coadministration with azole antifungal agents may significantly increase the plasma concentrations and pharmacologic effects of benzodiazepines that are primarily metabolized by CYP450 3A4. The mechanism is increased bioavailability and/or decreased clearance due to inhibition of intestinal and hepatic CYP450 3A4 by azole antifungal agents. In pharmacokinetic studies, itraconazole (200 mg/day) and ketoconazole (400 mg/day) individually increased the systemic exposure (AUC) of a single 0.25 mg oral dose of triazolam and a 7.5 mg oral dose of midazolam by more than 22-fold and 10-fold, respectively, compared to placebo. The AUC of a single 2 mg IV dose of midazolam increased 5-fold after pretreatment with ketoconazole. Itraconazole and ketoconazole increased the AUC of alprazolam (0.8 and 1 mg single oral dose) 2.5- and 4-fold, respectively, compared to placebo. Fluconazole, a weaker CYP450 3A4 inhibitor, increased the AUC of a single 0.25 mg oral dose of triazolam by 1.6-, 2.1- and 4.4-fold at dosages of 50 mg, 100 mg and 200 mg once a day, respectively, relative to placebo. A single oral dose of fluconazole 150 mg plus midazolam 10 mg resulted in only modest increases in midazolam plasma concentrations and pharmacologic effects. Overall, pharmacodynamic changes associated with the interaction include increased and prolonged sedation, enhanced benzodiazepine-related EEG effects, and increased impairment of psychomotor performance. The interaction is subject to a high degree of interpatient variability.

MANAGEMENT: Although clotrimazole, fluconazole, miconazole, and voriconazole are weaker inhibitors of CYP450 3A4 than itraconazole and ketoconazole, product labelings for alprazolam and triazolam recommend against use with any azole antifungal agent. The same precaution probably applies also to oral midazolam and high dosages of intravenous midazolam. Terbinafine may be an appropriate alternative, as it is not an inhibitor of CYP450 3A4 and has been shown to have no effect on the pharmacokinetics of midazolam and triazolam. Alternatively, benzodiazepines that are not metabolized by CYP450 3A4 (e.g., lorazepam, oxazepam, temazepam) may be considered in patients requiring treatment with azole antifungal agents. Limited data suggest that fluconazole given intermittently (e.g., 150 mg once or once a week) may be safely administered in combination with midazolam and possibly other benzodiazepines.