Drug Interaction Report

ADJUST DOSE: Coadministration with inducers of CYP450 2C8 and/or uridine diphosphate glucuronosyltransferase (UGT) 1A3 and/or 2B7 enzymes may reduce the plasma concentrations and therapeutic effects of selexipag and its active metabolite. Following concomitant use with rifampin, an inducer of CYP450 2C8 and UGT enzymes at a dose of 600 mg once daily, systemic exposure to selexipag was not altered; however, exposure to the active metabolite was reduced by 50%.

MANAGEMENT: Caution and clinical monitoring should be considered whenever a CYP450 2C8, UGT 1A3, and/or UGT 2B7 inducer is added to or withdrawn from therapy, and the selexipag dosage adjusted as necessary. Some authorities recommend increasing the selexipag dose up to 2-fold when coadministered with rifampin (US). Patients receiving selexipag with a CYP450 2C8, UGT 1A3, and/or UGT 2B7 inducer should be monitored for reduced efficacy.

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.

Food prolongs the gastrointestinal absorption of selexipag. When taken with food, the time to peak concentration (Tmax) was delayed and peak plasma concentration (Cmax) was approximately 30% lower. Selexipag systemic exposure (AUC) and that of its active metabolite did not significantly change, however. Selexipag may be taken with or without food. Tolerability may be improved when taken with food.