Drug Interaction Report

MONITOR: Theoretical concerns exist that oculotoxic effects of risdiplam, observed in monkeys, may be additive with those of other drugs that are associated with retinotoxicity. Chronic treatment of monkeys with risdiplam showed photoreceptor degeneration starting in the periphery of the retina. Upon cessation of treatment, the effects on the retinogram were partially reversible but the retinal degeneration, with peripheral photoreceptor loss, was irreversible. A no-effect dose for the retinal findings (1.5 mg/kg/day) in monkeys was associated with plasma exposures (AUC) like that in humans at the maximum recommended human dose (MRHD) of 5 mg. However, the potential for synergistic effects of concomitant administration of risdiplam with retinotoxic drugs has not been studied.

MANAGEMENT: Some authorities (AU) recommend caution when risdiplam is used concomitantly with known or suspected retinotoxic drugs. These drugs may include infigratinib, selumetinib, cobimetinib, vigabatrin, chloroquine, hydroxychloroquine, thioridazine and deferoxamine.

ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of trametinib. In study subjects, administration of a single dose of trametinib with a high-fat, high-calorie meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 70% and 24%, respectively, and delayed Tmax by approximately 4 hours compared to administration in the fasted state.

MANAGEMENT: Trametinib should be taken at least 1 hour before or 2 hours after a meal.