Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A1 inducers (e.g., rifampicin, phenytoin, carbamazepine), may decrease the systemic exposure of ponesimod. Experiments with human liver preparations indicate that metabolism of ponesimod to inactive metabolites occurs through a combination of non-CYP450 oxidative enzymes, multiple CYP450 (2J2, 3A4, 3A5, 4F3A, and 4F12) enzymes, and direct glucuronidation (mainly UGT1A1 and UGT2B7). Limited clinical data are available, and it is unclear whether this decrease in ponesimod systemic exposure would be considered of clinical relevance.

MANAGEMENT: Until more information is available, concomitant use of ponesimod with potent CYP450 3A4 and UGT1A1 inducers should generally be avoided.

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.