Drug Interactions between Prograf and ubrogepant

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

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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 moderate CYP450 3A4 inhibitor verapamil during in vivo studies, ubrogepant peak plasma concentration (Cmax) and systemic exposure (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. Per the manufacturer, when coadministered with grapefruit or grapefruit juice, the initial ubrogepant dose should be 50 mg, and if needed, a second ubrogepant dose should be avoided within 24 hours of the initial dose.

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