Drug Interactions between carbamazepine and rimegepant

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

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.