Drug Interaction Report

MONITOR: Coadministration with pretomanid may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP1B3), and/or P-glycoprotein (P-gp). The proposed mechanism, based on in vitro data, is decreased clearance due to pretomanid-mediated inhibition of BCRP, OATP1B3, and/or P-gp. The clinical significance is unknown as data are limited and conflicting.

MANAGEMENT: Until more information is available, the manufacturers of pretomanid recommend that clinicians should be aware of the potential for enhanced pharmacologic effects with drugs that are substrates of BCRP, OATP1B3, and/or Pg-p, particularly those with a narrow therapeutic range, when pretomanid is coadministered. Dosage adjustments as well as clinical and laboratory monitoring of the BCRP, OATP1B3, and/or P-gp substrate drug should be considered whenever pretomanid is added to or withdrawn from therapy with these drugs. Patients should be monitored for the development of adverse effects.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the serum concentrations of colchicine. Clinical toxicity including myopathy, neuropathy, multiorgan failure, and pancytopenia may occur. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism and P-glycoprotein efflux in the gut wall by certain compounds present in grapefruits. A published case report describes an eight-year-old patient with familial Mediterranean fever who developed acute clinical colchicine intoxication after ingesting approximately one liter of grapefruit juice per day for two months prior to hospital admission while being treated with colchicine 2 mg/day. Her condition progressed to circulatory shock and multiorgan failure, but she recovered with supportive therapy after 24 days in the hospital. In a study of 21 healthy volunteers, administration of 240 mL grapefruit juice twice a day for 4 days was found to have no significant effect on the pharmacokinetics of a single 0.6 mg dose of colchicine. However, significant interactions have been reported with other CYP450 3A4 inhibitors such as clarithromycin, diltiazem, erythromycin, ketoconazole, ritonavir, and verapamil.

MANAGEMENT: Patients treated with colchicine should be advised to avoid the consumption of grapefruit and grapefruit juice, and to contact their physician if they experience symptoms of colchicine toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paresthesia, and numbness.

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.