Drug Interaction Report

MONITOR: Coadministration with tecovirimat may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. Tecovirimat is a weak inducer of CYP450 3A4. In a drug interaction study involving 24 healthy subjects, a single 2 mg dose of midazolam was coadministered with tecovirimat (600 mg twice daily), and the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 39% and 32%, respectively.

MANAGEMENT: The potential for diminished pharmacologic effects of CYP450 3A4 substrates should be considered during coadministration with tecovirimat.

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.

ADJUST DOSING INTERVAL: Food may increase the extent of tecovirimat absorption following oral administration. When the recommended oral dose of tecovirimat (600 mg every 12 hours) was administered with a meal (approximately 600 calories and 25 g of fat) in healthy adults weighing less than 120 kg, tecovirimat absorption increased by 39% relative to fasting.

MANAGEMENT: Oral tecovirimat should be taken within 30 minutes after a full meal containing moderate or high fat (approximately 600 calories and 25 g of fat) with 6 to 8 ounces of water.