Drug Interaction Report

ADJUST DOSING INTERVAL: Coadministration with moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of rimegepant. According to the prescribing information, rimegepant is primarily metabolized by CYP450 3A4 and to a lesser extent by CYP450 2C9. In a dedicated drug interaction study, concomitant administration of a single 75 mg dose of rimegepant with fluconazole, a moderate CYP450 3A4 and 2C9 inhibitor, increased rimegepant systemic exposure (AUC) by 1.8-fold without any relevant effect on the peak plasma concentration (Cmax). Based on these results and other available pharmacokinetic data, coadministration of rimegepant with a moderate inhibitor of CYP450 3A4 may be expected to increase rimegepant exposures by less than 2-fold, while coadministration with a weak CYP450 3A4 inhibitor or a lone CYP450 2C9 inhibitor is not expected to have a clinically significant impact on rimegepant exposures.

MANAGEMENT: The manufacturer recommends avoiding another dose of rimegepant within 48 hours when coadministered with a moderate CYP450 3A4 inhibitor.

ADJUST DOSING INTERVAL: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of rimegepant. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Concomitant administration of a single dose of rimegepant (75 mg) with itraconazole, a strong CYP450 3A4 inhibitor, at steady state increased the systemic exposure (AUC) and peak plasma concentration (Cmax) of rimegepant by 4-fold and approximately 1.5-fold, respectively. The manufacturer also states that concomitant administration of rimegepant with a moderate CYP450 3A4 inhibitor may increase rimegepant AUC by less than 2-fold. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MONITOR: When administered with a high-fat meal under fed condition, Tmax was delayed by 1 hour, which resulted in a 42% to 53% reduction in Cmax and a 32% to 38% reduction in AUC. However, the impact of this reduction on rimegepant efficacy remains unknown.

MANAGEMENT: Rimegepant may be administered with or without food. Until more information is available, patients receiving rimegepant may want to avoid the regular consumption of grapefruits and grapefruit juice to prevent undue increases in plasma levels and systemic effects of rimegepant. If grapefruit or grapefruit juice is consumed concomitantly with rimegepant, the manufacturer recommends avoiding another dose of rimegepant within 48 hours.