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: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.