Drug Interaction Report

GENERALLY AVOID: Coadministration of pretomanid with strong or moderate CYP450 3A4 inducers may decrease the plasma concentrations and antimicrobial effects of pretomanid, which has been shown to be a substrate of the isoenzyme. Following 7 days of concomitant administration, rifampin (600 mg daily) decreased systemic exposure (AUC) and peak plasma concentration (Cmax) of pretomanid by 66% and 53%, respectively. In another 7-day study, efavirenz (600 mg daily) decreased mean AUC and Cmax of pretomanid (200 mg daily) by 35% and 28%, respectively.

MANAGEMENT: The use of pretomanid with strong or moderate CYP450 3A4 inducers should be avoided. Dosage adjustments as well as clinical and laboratory monitoring of pretomanid should be considered whenever a strong or moderate CYP450 3A4 inducer is added to or withdrawn from therapy.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of combination drug regimens that include pretomanid.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of pretomanid. The mechanism has not been reported. Compared with the fasted state, oral administration of pretomanid with a high-fat, high-calorie meal (approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) increased mean systemic exposure (AUC) and peak plasma concentration (Cmax) of pretomanid by 88% and 76%, respectively.

MANAGEMENT: Patients should avoid alcohol use during treatment with pretomanid. In addition, to ensure maximal oral absorption, pretomanid should be administered with food. Tablets should be swallowed whole.