Drug Interaction Report

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. No data are available for levoketoconazole, which is an enantiomer of ketoconazole, but a similar interaction should be expected.

MANAGEMENT: The concomitant use of itraconazole or ketoconazole with alprazolam, oral midazolam, and triazolam is considered contraindicated. Some authorities consider concomitant administration of triazolam or oral midazolam and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole. 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.

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ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.

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GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.

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