Drug Interaction Report

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.

GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

The coadministration with grapefruit juice may delay the absorption and increase the bioavailability of oral scopolamine. The proposed mechanism is delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In an open-label, crossover study consisting of 14 subjects, the consumption of grapefruit juice (compared to water) was associated with a 30% increase in mean systemic bioavailability and a 153% increase in time to reach peak serum concentration (Tmax) of scopolamine. However, the perceived pharmacodynamic effect of the drug, as measured by % change in subjective alertness compared to baseline, was similar after coadministration with water and grapefruit juice. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of of scopolamine but may delay its onset of action following oral administration. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability.