Evrysdi Drug Information

EVRYSDI is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.

Dosing Information EVRYSDI is administered orally once daily with or without food at approximately the same time each day. The recommended dosage is determined by age and body weight (see Table 1 ). EVRYSDI tablets are available for patients prescribed the 5 mg dose.

Table 1 Adult and Pediatric Dosing Regimen by

Important Administration Instructions It is recommended that a healthcare provider discuss with the patient or caregiver how to prepare the prescribed daily dose prior to administration of the first dose. EVRYSDI for Oral Solution In infants who are breastfed, EVRYSDI for oral solution can be administered before or after breastfeeding. EVRYSDI cannot be mixed with formula or milk.

Instruct patients or caregivers to administer the dose using the reusable oral syringe provided. EVRYSDI for oral solution must be taken immediately after it is drawn up into the oral syringe. If EVRYSDI is not taken within 5 minutes, EVRYSDI should be discarded from the oral syringe, and a new dose should be prepared.

Instruct patients to drink water after taking EVRYSDI for oral solution to ensure the drug has been completely swallowed. EVRYSDI for oral solution can be administered via a nasogastric or gastrostomy tube. The tube should be flushed with water after delivering EVRYSDI for oral solution.

EVRYSDI Tablets Swallow EVRYSDI tablets whole with water. Do not chew, cut, or crush the tablets. Alternatively, the EVRYSDI tablet can also be dispersed in one teaspoon (5 mL) of room temperature non-chlorinated drinking water (e.g., filtered water).

EVRYSDI tablets must not be dispersed in any liquid other than non-chlorinated drinking water. Do not expose the prepared dispersion to sunlight. Swirl the small cup gently for up to 3 minutes until fully mixed (though some particles will remain).

Administer the dispersed tablet immediately. To ensure no particles are left in the small cup, refill it with at least one tablespoon (15 mL) of non-chlorinated drinking water, swirl, and administer immediately again. EVRYSDI must be taken immediately after it is dispersed in non-chlorinated drinking water.

Discard the prepared dispersion if it is not used within 10 minutes of adding non-chlorinated drinking water. The dispersed EVRYSDI tablet can be administered via a nasogastric or gastrostomy tube that is 8 French or higher. Flush the tube with the non-chlorinated drinking water used to rinse the dispersion cup.

Missed Dose If a dose of EVRYSDI is missed, EVRYSDI should be administered as soon as possible if still within 6 hours of the missed dose, and the usual dosing schedule can be resumed on the next day. Otherwise, the missed dose should be skipped, and the next dose should be taken at the regularly scheduled time on the next day. If a dose is not fully swallowed or vomiting occurs after taking a dose of EVRYSDI, another dose should not be administered to make up for the lost dose.

The patient should wait until the next day to take the next dose at the regularly scheduled time.

Preparation of Powder for Oral Solution by Healthcare Provider EVRYSDI powder must be constituted to the oral solution by a pharmacist or other healthcare provider prior to dispensing to the patient. Preparation of the EVRYSDI Oral Solution 0.75 mg/mL The EVRYSDI " Instructions for Constitution " booklet contains more detailed instructions on the preparation of the oral solution. Caution should be exercised when handling EVRYSDI powder for oral solution.

Avoid inhalation and direct contact with skin or mucous membranes with the dry powder and the constituted solution. If such contact occurs, wash thoroughly with soap and water; rinse eyes with water. Wear disposable gloves during the preparation and cleanup procedure.

Gently tap the bottom of the closed glass bottle to loosen the powder. Remove the cap. Do not throw away the cap.

Carefully pour 79 mL of purified water into the EVRYSDI bottle to yield the 0.75 mg/mL oral solution. Do not mix EVRYSDI with formula or milk. Insert the press-in bottle adapter into the bottle opening by pushing it down against the bottle lip.

Ensure it is completely pressed against the bottle lip. Re-cap the bottle tightly and shake well for 15 seconds. Wait for 10 minutes.

You should have obtained a clear solution. If not, shake well again for another 15 seconds or until you have obtained a clear solution. Write the date of expiration of the constituted oral solution (calculated as 64 days after constitution) and the lot number on the bottle label.

Peel off the part of the bottle label that has the expiration date of the powder. Put the bottle back in its original carton. Select the appropriate oral syringes (1 mL, 6 mL, or 12 mL) based on the patient's dosage and remove the other oral syringes from the carton.

Dispense with the " Instructions for Use " and FDA-approved patient labeling. Alert patients to read the important handling information described in the Instructions for Use. Storage Keep the constituted oral solution of EVRYSDI in the original amber bottle to protect from light.

Store in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard any unused portion 64 days after constitution.

Keep the bottle in an upright position with the cap tightly closed. If refrigeration is not available, EVRYSDI can be kept at room temperature up to 40°C (up to 104°F) for a combined total of 5 days. EVRYSDI can be removed from, and returned to, a refrigerator.

The total combined time out of refrigeration should not exceed 5 days.

Clinical Trials Experience

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

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 reported in ≥ 10% of patients were: upper respiratory tract infection (including nasopharyngitis, rhinitis), lower respiratory tract infection (including pneumonia, bronchitis), constipation, vomiting, and cough. Clinical Trial in Pre-Symptomatic SMA The safety of EVRYSDI therapy for pre-symptomatic SMA is based on data from an open-label, single-arm study in 26 patients (Study 3).

The safety profile of EVRYSDI in pre-symptomatic patients in Study 3 is consistent with the safety profile for symptomatic SMA patients treated with EVRYSDI in clinical trials.

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, 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.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to EVRYSDI during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-760-1098 or visiting https://www.evrysdipregnancyregistry.com. 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. 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 respectively.

Based on animal data, advise pregnant women of the potential risk to the fetus. Data Animal Data Oral administration of risdiplam 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 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. When risdiplam 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.

Pediatric Use The safety and effectiveness of EVRYSDI in pediatric patients (neonates and older) have been established. Use of EVRYSDI for SMA is supported by evidence from adequate and well-controlled studies of EVRYSDI in patients 2 months of age and older with SMA. Use of EVRYSDI for SMA in patients 2 months of age and younger is supported by pharmacokinetic and safety data from pediatric patients 16 days and older, and pharmacokinetic modeling and simulation to identify the dosing regimen.

Juvenile Animal Toxicity Data Oral administration of risdiplam 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 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.