Risdiplam

Risdiplam and its metabolite are in vitro inhibitors of the multidrug and toxin extrusion (MATE)1 and MATE2-K transporters. 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 coadministration cannot be avoided, drug-related toxicities should be monitored and dosage reduction of the co-administered medicinal product should be considered if needed.

Patients with severe hepatic impairment have not been studied and may have increased risdiplam exposure.

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. 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.

There are no data from the use of risdiplam in pregnant women. Studies in animals have shown reproductive toxicity.

Risdiplam is not recommended during pregnancy and in women of childbearing potential not using contraception.

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

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.

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. 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, 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.

Based on the primary analysis of RAINBOWFISH, the safety profile of risdiplam 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.

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). Adverse drug reactions from clinical studies are listed by MedDRA system organ class.

Adverse drug reactions occurring in patients with infantile-onset and later-onset SMA based on risdiplam clinical studies:

^* Includes dermatitis, dermatitis acneiform, dermatitis allergic, erythema, folliculitis, rash, rash erythematous, rash maculo-papular, rash papular

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

Based on the primary analysis of the JEWELFISH study, the safety profile of risdiplam in SMA treatment non-naive patients who received risdiplam for up to 59 months (including those previously treated with nusinersen [n=76] or with onasemnogene abeparvovec [n=14]) is consistent with the safety profile in SMA treatment-naive patients treated with risdiplam in the FIREFISH, SUNFISH and RAINBOWFISH studies.

Post-marketing experience

Cutaneous vasculitis was reported during post-marketing experience. Symptoms recovered after permanent discontinuation of risdiplam. The frequency cannot be estimated based on available data.