Drug Interaction Report

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4, breast cancer resistance protein (BCRP), and/or P-glycoprotein (P-gp) may increase the plasma concentrations of ubrogepant based on in vivo and in vitro data. The proposed mechanism involves enhanced oral bioavailability as well as reduced clearance of ubrogepant due to inhibition of CYP450 3A4-mediated metabolism and BCRP/P-gp-mediated efflux in the intestine and liver. When ubrogepant was administered with the potent CYP450 3A4 inhibitor ketoconazole during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 5.3- and 9.7-fold, respectively. When administered with the moderate CYP450 3A4 inhibitor verapamil, ubrogepant Cmax and AUC increased by 2.8- and 3.5-fold, respectively. Dedicated drug interaction studies have not been conducted to assess concomitant use of ubrogepant with weak CYP450 3A4 inhibitors and inhibitors of BCRP or P-gp transporters. Ubrogepant exposure is not expected to increase by more than 2-fold when used with weak CYP450 3A4 inhibitors per a conservative prediction from the manufacturer.

MANAGEMENT: The recommended dose of ubrogepant is 50 mg during concomitant treatment with weak CYP450 3A4 inhibitors and/or inhibitors of BCRP or P-gp. If needed, a second 50 mg ubrogepant dose may be administered at least 2 hours after the initial dose.

ADJUST DOSE: Grapefruit and grapefruit juice may increase the plasma concentrations of ubrogepant. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit but has been reported for other CYP450 3A4 inhibitors. When ubrogepant was administered with the potent CYP450 3A4 inhibitor ketoconazole during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 5.3- and 9.7-fold, respectively. When administered with the moderate CYP450 3A4 inhibitor verapamil, ubrogepant Cmax and AUC increased by 2.8- and 3.5-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

When administered with a high-fat meal, ubrogepant time to maximum plasma concentration (Tmax) was delayed by 2 hours, which resulted in a 22% decrease in Cmax and no change in AUC. Ubrogepant was administered without regard to food in clinical efficacy studies.

MANAGEMENT: Ubrogepant may be administered with or without food. When coadministered with grapefruit or grapefruit juice, the manufacturer recommends an initial ubrogepant dose of 50 mg. A second dose, if needed, should not be administered within 24 hours of the initial dose.