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monitoring of pretomanid should be considered whenever a strong or moderate CYP450 3A4 inducer is added to or withdrawn from therapy.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: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

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.