EVRYSDI Oral solution Ref.[10192] Active ingredients: Risdiplam

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials including patients with infantile-onset SMA and later-onset SMA, a total of 337 patients (52% female, 72% Caucasian) were exposed to EVRYSDI for up to a maximum of 32 months, with 209 patients receiving treatment for more than 12 months. Forty-seven (14%) patients were 18 years and older, 74 (22%) were 12 years to less than 18 years, 154 (46%) were 2 years to less than 12 years, and 62 (18%) 2 months to less than 2 years.

Clinical Trial in Later-Onset SMA

The safety of EVRYSDI for later-onset SMA is based on data from a randomized, double-blinded, placebo-controlled study (Study 2 Part 2) in patients with SMA Type 2 or 3 (n=180) [see Clinical Studies (14.2)]. The patient population in Study 2 Part 2 ranged in age from 2 to 25 years at the time of treatment start.

The most common adverse reactions (reported in at least 10% of patients treated with EVRYSDI and at an incidence greater than on placebo) in Study 2 Part 2 were fever, diarrhea, and rash. Table 2 lists the adverse reactions that occurred in at least 5% of patients treated with EVRYSDI and at an incidence ≥5% greater than on placebo in Study 2 Part 2.

Table 2. Adverse Reactions Reported in ≥5% of Patients Treated with EVRYSDI and with an Incidence ≥5% Greater Than on Placebo in Study 2 Part 2:

* Includes pyrexia and hyperpyrexia.
^† Includes rash, erythema, rash maculo-papular, rash erythematous, rash papular, dermatitis allergic, and folliculitis.
^‡ Includes urinary tract infection and cystitis

Clinical Trial in Infantile-Onset SMA

The safety of EVRYSDI therapy for infantile-onset SMA is based on data from an open-label study in 62 patients (Study 1) [see Clinical Studies (14.1)]. In Study 1 Part 1 (n=21) and Part 2 (n=41), 62 patients received EVRYSDI for up to 30 months (31 patients for more than 12 months). The patient population ranged in age from 2 to 7 months at the time of treatment start (weight range 4.1 to 10.6 kg).

The most frequent adverse reactions reported in infantile-onset SMA patients treated with EVRYSDI in Study 1 were similar to those observed in later-onset SMA patients in Study 2. Additionally, the following adverse reactions were reported in ≥10% of patients: upper respiratory tract infection (including nasopharyngitis, rhinitis, respiratory tract infection), pneumonia, constipation, and vomiting.

7.1 Effect of EVRYSDI on Substrates of Multidrug and Toxin Extrusion (MATE) Protein Transporters

Based on in vitro data, EVRYSDI may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K [see Clinical Pharmacology (12.3)], such as metformin. Avoid coadministration of EVRYSDI with MATE substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug (based on the labeling of that drug) if needed.

Risk Summary

There are no adequate data on the developmental risk associated with the use of EVRYSDI in pregnant women. In animal studies, administration of risdiplam during pregnancy or throughout pregnancy and lactation resulted in adverse effects on development (embryofetal mortality, malformations, decreased fetal body weights, and reproductive impairment in offspring) at or above clinically relevant drug exposures [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Based on animal data, advise pregnant women of the potential risk to the fetus.

Data

Animal Data

Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal structural variations at the highest dose tested, which was not associated with maternal toxicity. The no-effect level for adverse effects on embryofetal development (3 mg/kg/day) was associated with maternal plasma exposure (AUC) approximately 2 times that in humans at the maximum recommended human dose (MRHD) of 5 mg.

Oral administration of risdiplam (0, 1, 4, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in embryofetal mortality, fetal malformations (hydrocephaly), and structural variations at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development (4 mg/kg/day) was associated with maternal plasma exposure (AUC) approximately 4 times that in humans at the MRHD.

When risdiplam (0, 0.75, 1.5, or 3 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, gestation was prolonged in the dams, and delayed sexual maturation (vaginal opening) and impaired reproductive function (decreased numbers of corpora lutea, implantation sites, and live embryos) were observed in female offspring at the highest dose. The no-effect dose for adverse effects on pre- and postnatal development in rats (1.5 mg/kg/day) was associated with maternal plasma exposure (AUC) similar to that in humans at the MRHD.

Risk Summary

There are no data on the presence of risdiplam in human milk, the effects on the breastfed infant, or the effects on milk production. Risdiplam was excreted in the milk of lactating rats orally administered risdiplam.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EVRYSDI and any potential adverse effects on the breastfed infant from EVRYSDI or from the underlying maternal condition.

Studies of risdiplam in juvenile and adult rats and in monkeys demonstrated adverse effects on the reproductive organs, including germ cells, in males at clinically-relevant plasma exposures [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.1)].

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating EVRYSDI [see Use in Specific Populations (8.1)].

Contraception

EVRYSDI may cause embryofetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Female Patients

Advise female patients of reproductive potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after her last dose.

Infertility

Male Patients

Male fertility may be compromised by treatment with EVRYSDI [see Nonclinical Toxicology (13.1)].

Counsel male patients of reproductive potential receiving EVRYSDI about the potential effects on fertility. Male patients may consider sperm preservation prior to treatment.

The safety and effectiveness of EVRYSDI in pediatric patients 2 months of age and older have been established [see Clinical Studies (14)]. Safety and effectiveness in pediatric patients below the age of 2 months have not been established [see Clinical Pharmacology (12.3)].

Juvenile Animal Toxicity Data

Oral administration of risdiplam (0, 0.75, 1.5, 2.5 mg/kg/day) to young rats from postnatal day (PND) 4 through PND 31 resulted in decreased growth (body weight, tibia length) and delayed sexual maturation in males at the mid and high dose. The skeletal and body weight deficits persisted after cessation of dosing. Ophthalmic changes consisting of vacuoles in the anterior vitreous were seen at the high dose. Decreases in absolute B lymphocyte counts were observed at all doses after cessation of dosing. Decreases in testis and epididymis weights, which correlated with degeneration of the seminiferous epithelium in the testis, occurred at the mid and high doses; the histopathology findings were reversible, but organ weight persisted after cessation of dosing. Impaired female reproductive performance (decreased mating index, fertility index, and conception rate) was observed at the high dose. A no-effect dose for adverse developmental effects on preweaning rats was not identified. The lowest dose tested (0.75 mg/kg/day) was associated with plasma exposures (AUC) lower than that in humans at the maximum recommended human dose (MRHD) of 5 mg/day.

Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg/day) to young rats from PND 22 through PND 112 produced a marked increase in micronuclei in the bone marrow, male reproductive organ histopathology (degeneration/necrosis of the seminiferous tubule epithelium, oligo/aspermia in the epididymis, spermatic granulomas), and adverse effects on sperm parameters (decreased sperm concentration and motility, increased sperm morphology abnormalities) at the highest dose tested. Increases in T lymphocytes (total, helper, and cytotoxic) were observed at the mid and high doses. The reproductive and immune effects persisted after cessation of dosing. The no-effect dose (1 mg/kg/day) for adverse effects on postweaning juvenile rats was associated with plasma exposures (AUC) lower than that in humans at the MRHD.

Clinical studies of EVRYSDI did not include patients aged 65 years and over to determine whether they respond differently from younger patients.

The safety and efficacy of EVRYSDI in patients with hepatic impairment have not been studied. Because risdiplam is predominantly metabolized in the liver, hepatic impairment may potentially increase the exposures to risdiplam [see Clinical Pharmacology (12.3)]. Avoid use of EVRYSDI in patients with impaired hepatic function.