EVRYSDI Film-coated tablet Ref.[116429] Active ingredients: Risdiplam

Potential embryo-foetal toxicity

Embryo‑foetal toxicity has been observed in animal studies (see section 5.3). Patients of reproductive potential should be informed of the risks and must use highly effective contraception during treatment and until at least 1 month after the last dose in female patients, and 4 months after the last dose in male patients. The pregnancy status of female patients of reproductive potential should be verified prior to initiating risdiplam therapy (see section 4.6).

Potential effects on male fertility

Based on observations from animal studies, male patients should not donate sperm while on treatment and for 4 months after the last dose of risdiplam. Prior to initiating treatment, fertility preservation strategies should be discussed with male patients of reproductive potential (see sections 4.6 and 5.3). The effects of risdiplam on male fertility have not been investigated in humans.

Excipients

Sodium

Evrysdi contains less than 1 mmol sodium (23 mg) per 5 mg dose, i.e. is essentially 'sodium-free'.

Effects of other medicinal products on risdiplam

Omeprazole had no impact on the pharmacokinetics of risdiplam administered as a tablet. The risdiplam tablet may therefore be administered concomitantly with medication that increases the gastric pH (proton pump inhibitors, H2 antagonists, and antacids).

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 C_max). No dose adjustments are required when risdiplam 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%; C_max 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.

Patients of reproductive potential

Contraception in male and female patients

Male and female patients of reproductive potential should adhere to the following contraception requirements:

• Female patients of childbearing potential should use highly effective contraception during treatment and for at least 1 month after the last dose.
• Male patients, and their female partners of childbearing potential, should both ensure that highly effective contraception is achieved during treatment and for at least 4 months after the last dose.

Pregnancy testing

The pregnancy status of female patients of reproductive potential should be verified prior to initiating risdiplam therapy. Pregnant women should be clearly advised of the potential risk to the foetus.

Pregnancy

There are no data from the use of risdiplam in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Risdiplam is not recommended during pregnancy and in women of childbearing potential not using contraception (see section 4.4).

Breast-feeding

It is not known whether risdiplam is excreted in human breast milk. Studies in rats show that risdiplam is excreted into milk (see section 5.3). As the potential for harm to the breastfed infant is unknown, it is recommended not to breastfeed during treatment.

Fertility

Male patients

Male fertility may be compromised while on treatment, based on nonclinical findings. In rat and monkey reproductive organs, sperm degeneration and reduced sperm numbers were observed (see section 5.3). Based on observations from animal studies, the effects on sperm cells are expected to be reversible upon discontinuation of risdiplam.

Male patients may consider sperm preservation prior to treatment initiation or after a treatment-free period of at least 4 months. Male patients who wish to father a child should stop treatment for a minimum of 4 months. Treatment may be re-started after conception.

Female patients

Based on nonclinical data (see section 5.3), an impact of risdiplam on female fertility is not expected.

Risdiplam has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

In infantile-onset SMA patients, the most common adverse reactions observed in risdiplam clinical studies were pyrexia (54.8%), rash (29.0%) and diarrhoea (19.4%).

In later‑onset SMA patients, the most common adverse reactions observed in risdiplam clinical studies were pyrexia (21.7%), headache (20.0%), diarrhoea (16.7%), and rash (16.7%).

The adverse reactions listed above occurred without an identifiable clinical or time pattern and generally resolved despite ongoing treatment in infantile‑onset and later‑onset SMA patients.

Tabulated list of adverse reactions

The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Adverse drug reactions from clinical studies (Table 1) are listed by MedDRA system organ class.

Table 1. Adverse drug reactions occurring in patients with infantile-onset and later-onset SMA based on risdiplam clinical studies and postmarketing experience:

^* Includes dermatitis, dermatitis acneiform, dermatitis allergic, erythema, folliculitis, rash, rash erythematous, rash maculo-papular, rash papular
^** Cutaneous vasculitis was reported during post‑marketing experience. Symptoms recovered after permanent discontinuation of risdiplam. The frequency cannot be estimated based on available data.

Safety profile in pre-symptomatic patients

Based on the primary analysis of RAINBOWFISH, the safety profile of Evrysdi in pre‑symptomatic patients is consistent with the safety profile of symptomatic infantile‑onset and later‑onset SMA patients. The RAINBOWFISH study enrolled 26 patients with pre‑symptomatic SMA between 16 and 41 days of age at the time of the first dose (weight range 3.1 to 5.7 kg). The median exposure duration was 20.4 months (range: 10.6 to 41.9 months). Limited post‑marketing data are available in neonates <20 days of age.

Safety profile in patients previously treated with other SMA‑modifying therapies

The safety profile of risdiplam in SMA treatment non-naive patients (including those previously treated with nusinersen or with onasemnogene abeparvovec) is consistent with the safety profile in SMA treatment-naive patients treated with risdiplam in the FIREFISH, SUNFISH and RAINBOWFISH clinical studies (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.