Drug interactions between ketoconazole and Xanax

CONTRAINDICATED: Coadministration with itraconazole or ketoconazole 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 the azole antifungal agents. In pharmacokinetic studies, itraconazole (200 mg/day) and ketoconazole (400 mg/day) individually increased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and elimination half-life (T1/2) of a single 0.25 mg oral dose of triazolam by more than 3-, 22- and 6-fold, respectively, compared to placebo. Similarly, Cmax, AUC and T1/2 of a single 7.5 mg oral dose of midazolam were more than 3,- 10- and 3-fold higher, respectively, during coadministration of itraconazole or ketoconazole relative to placebo. The AUC of a single 2 mg IV dose of midazolam increased 5-fold after pretreatment with ketoconazole. The results for alprazolam have been less dramatic, presumably due to limited first-pass metabolism in the intestine. In separate studies, itraconazole and ketoconazole increased the AUC of alprazolam (0.8 and 1 mg single oral dose) by 2.5- and 4-fold, respectively, compared to placebo, while Cmax was not significantly affected. 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: The concomitant use of itraconazole or ketoconazole with alprazolam, oral midazolam, and triazolam is considered contraindicated. Fluconazole and miconazole are weaker inhibitors of CYP450 3A4 but may still cause the interaction, while terbinafine 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 itraconazole or ketoconazole.