Drug Interaction Report

GENERALLY AVOID: Coadministration with drugs that cause moderate induction of CYP450 2C9 and strong induction of CYP450 3A4 may decrease the plasma concentrations of siponimod, which is primarily metabolized by these isoenzymes. This interaction includes concomitant use of siponimod with a moderate CYP450 2C9/strong CYP450 3A4 dual inducer or a moderate CYP450 2C9 inducer in combination with a separate strong CYP450 3A4 inducer. In CYP450 2C9*1/*1 genotype subjects, coadministration of a moderate CYP450 2C9/strong CYP450 3A4 dual inducer (rifampin 600 mg daily) and siponimod (2 mg daily) resulted in 57% and 45% decreases in siponimod steady-state AUC and Cmax, respectively. According to in silico (computer-based) evaluation, use of rifampin and efavirenz (moderate CYP450 3A4 inducer) resulted in decreases up to 78% and up to 52%, respectively, of siponimod steady-state AUC across CYP450 2C9 genotypes. The CYP450 2C9 genotype influences the fractional contributions of CYP450 2C9 and 3A4 to overall elimination. If the metabolic activity of CYP450 2C9 is decreased, a larger contribution of CYP450 3A4 can be anticipated.

MANAGEMENT: Concomitant use of siponimod and drugs that cause moderate induction of CYP450 2C9 and strong induction of CYP450 3A4 (e.g., carbamazepine, enzalutamide, rifampin) is not recommended for all patients. Concomitant use of siponimod and moderate or strong CYP450 3A4 inducers (e.g., apalutamide, bosentan, dabrafenib, dexamethasone, efavirenz, eslicarbazepine, etravirine, fosphenytoin, lorlatinib, lumacaftor, mitotane, modafinil, nafcillin, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, sotorasib, St. John's wort) is not recommended for patients with CYP450 2C9*1/*3 and *2/*3 genotypes.

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.