Drug Interaction Report

GENERALLY AVOID: Coadministration with conivaptan may significantly increase the plasma concentrations and pharmacologic effects of midazolam, alprazolam and triazolam. The mechanism is conivaptan inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these benzodiazepines. Intravenous conivaptan 40 mg/day has been reported to cause a 2- and 3-fold increase in midazolam systemic exposure from a 1 mg intravenous and 2 mg oral dose of midazolam, respectively.

MANAGEMENT: Given the potential for prolonged and/or increased sedation and respiratory depression associated with excessive benzodiazepine blood levels, midazolam, alprazolam and triazolam should preferably be avoided in patients treated with conivaptan. Patients currently receiving these agents should consider an interruption during administration of conivaptan, and allow an appropriate amount of time following completion of conivaptan therapy before resuming these medications. Conivaptan is not expected to interact with lorazepam, oxazepam, and temazepam, which are hepatically conjugated and not significantly metabolized by CYP450 3A4.

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.