Drug Interactions between amiodarone and ubrogepant

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg/kg single dose) by 84% and 50%, respectively, compared to water. Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited. Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ. In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.

ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone. The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation. In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions. The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption. Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.

MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice. In addition, oral amiodarone should be administered consistently with regard to meals.

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.