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Risdiplam is primarily metabolized by hepatic enzymes flavin monooxygenase 1 and 3 (FMO1 and 3), and also by cytochrome P450 enzymes (CYPs) 1A1, 2J2, 3A4, and 3A7. Risdiplam is not a substrate of human multidrug resistance protein 1 (MDR1).
Effects of other medicinal products on risdiplam: Co-administration of 200 mg itraconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 6 mg risdiplam did not exhibit a clinically relevant effect on the PK parameters of risdiplam (11% increase in AUC, 9% decrease in Cmax). No dose adjustments are required when Evrysdi is co-administered with a CYP3A inhibitor.
No drug-drug interactions are expected via the FMO1 and FMO3 pathway.
Effects of risdiplam on other medicinal products: Risdiplam is a weak inhibitor of CYP3A. In healthy adult subjects, oral administration of risdiplam once daily for 2 weeks slightly increased the exposure of midazolam, a sensitive CYP3A substrate (AUC 11%; Cmax 16%). The extent of the interaction is not considered clinically relevant, and therefore no dose adjustment is required for CYP3A substrates.
In vitro studies have shown that risdiplam and its major human metabolite M1 are not significant inhibitors of human MDR1, organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter 1 and 3 (OAT 1 and 3). However, risdiplam and its metabolite are in vitro inhibitors of the human organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion (MATE)1 and MATE2-K transporters. At therapeutic drug concentrations, no interaction is expected with OCT2 substrates. The effect of co-administration of risdiplam on the pharmacokinetics of MATE1 and MATE2-K substrates in humans is unknown. Based on in vitro data, risdiplam may increase plasma concentrations of medicinal products eliminated via MATE1 or MATE2-K, such as metformin. If co-administration cannot be avoided, drug-related toxicities should be monitored and dosage reduction of the co-administered medicinal product should be considered if needed.
There is no efficacy or safety data to support the concomitant use of risdiplam and nusinersen.
The potential for synergistic effects of concomitant administration of risdiplam with retinotoxic drugs has not been studied. Therefore, caution in using concomitant medications with known or suspected retinal toxicity is recommended.
