Drug Interaction Report

MONITOR: Apalutamide and enzalutamide may reduce the effects of oral midazolam. The mechanism may be due to enhanced gut and liver metabolism of midazolam (via CYP450 3A4 enzyme induction). Coadministration of enzalutamide with a single oral dose of midazolam in prostate cancer patients led to an 86% reduction in the systemic exposure (AUC) of midazolam. Likewise, apalutamide decreased the AUC of a single oral dose of midazolam by 92%.

MANAGEMENT: Patients receiving this combination should be monitored for clinical response. Alternative oral sedative hypnotics may be preferable in patients receiving enzalutamide.

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.