Drug Interaction Report

Coadministration with remdesivir may increase the plasma concentrations of drugs metabolized via CYP450 3A4, but many sources indicate that clinically significant interactions are unlikely. The proposed mechanism is inhibition of CYP450 3A4 by remdesivir. Two drug interaction studies were conducted using the sensitive CYP450 3A4 substrate, midazolam. In the first study, healthy volunteers (n=19) received a single dose of remdesivir (200 mg) and a single dose of midazolam (2.5 mg), which resulted in midazolam's maximum concentration (Cmax) and systemic exposure (AUC) increasing by 29% and 20%, respectively. In the second study, healthy volunteers (n=14) received remdesivir (200 mg once, followed by 100 mg daily) for a total of 10 doses and a single dose of midazolam (2.5 mg) administered with the last dose of remdesivir. Midazolam's Cmax and AUC increased by 45% and 30%, respectively. Both studies indicated that remdesivir is a weak in vivo inhibitor of CYP450 3A4; however, some authorities consider these findings to be clinically insignificant.

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.