EVRYSDI

EVRYSDI- risdiplam powder, for solution
Genentech Inc.

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Dose Preparation

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 [see Instructions for Use].

Instruct patients or caregivers to prepare the dose using the reusable oral syringe provided.

EVRYSDI 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.

Dose Administration

EVRYSDI is taken orally once daily after a meal at approximately the same time each day.

In infants who are breastfed, EVRYSDI should be administered after breastfeeding. EVRYSDI cannot be mixed with formula or milk.

Instruct patients to drink water after taking EVRYSDI to ensure the drug has been completely swallowed.

If the patient is unable to swallow and has a nasogastric or gastrostomy tube, EVRYSDI can be administered via the tube. The tube should be flushed with water after delivering EVRYSDI [see Instructions for Use].

2.2 Dosing Information

​ EVRYSDI is administered orally once daily. The recommended dosage is determined by age and body weight (see Table 1).

Table 1 Adult and Pediatric Dosing Regimen by Age and Body Weight

​ Age and Body Weight	Recommended Daily Dosage
​ Less than 2 months of age	0.15 mg/kg
​ 2 months to less than 2 years of age	0.2 mg/kg
​ 2 years of age and older weighing less than 20 kg	0.25 mg/kg
​ 2 years of age and older weighing 20 kg or more	5 mg

2.3 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.

2.4 Preparation of 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 [see Instructions for Constitution].

Caution should be exercised in the handling of 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.

1. Gently tap the bottom of the closed glass bottle to loosen the powder.
2. Remove the cap. Do not throw away the cap.
3. 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.
4. 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.
5. 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.
6. 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.
7. Put the bottle back in its original carton.
8. ​ 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.
9. 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.

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.

3 DOSAGE FORMS AND STRENGTHS

EVRYSDI for oral solution: 60 mg as a light yellow, pale yellow, yellow, greyish yellow, greenish yellow, or light green powder for constitution. Following constitution, the volume of the greenish yellow to yellow solution is 80 mL, providing 60 mg/80 mL (0.75 mg/mL) risdiplam.

4 CONTRAINDICATIONS

None.

6 ADVERSE REACTIONS

6.1 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.

In clinical trials including patients with infantile-onset SMA, later-onset SMA, and pre-symptomatic SMA, a total of 483 patients (50% female, 74% Caucasian) were exposed to EVRYSDI for up to a median duration of 22.8 months (range: 0.5 to 46.9 months), with 221 patients receiving treatment for more than 24 months. At the time of first EVRYSDI dose, 90 (19%) patients were 18 years and older, 119 (25%) were 12 years to less than 18 years, 189 (39%) were 2 years to less than 12 years, 67 (14%) 2 months to less than 2 years, and 18 (4%) were less than 2 months.

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 the first dose.

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

Adverse Reaction	EVRYSDI(N = 120)%	Placebo(N = 60)%
* Includes pyrexia and hyperpyrexia. † Includes rash, erythema, rash maculo-papular, rash erythematous, rash papular, dermatitis allergic, and folliculitis. ‡ Includes urinary tract infection and cystitis.
Fever *	22	17
Diarrhea	17	8
Rash †	17	2
Mouth and aphthous ulcers	7	0
Arthralgia	5	0
Urinary tract infection ‡	5	0

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)]. The patient population ranged in age from 2 to 7 months at the time of the first EVRYSDI dose (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 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 (Study 3) [see Clinical Studies (14.3)]. At the time of interim analysis, the study had enrolled 18 patients with pre-symptomatic SMA between 16 and 40 days of age at the time of the first dose (weight range 3.1 to 5.7 kg). The median exposure duration was 8.7 months (range: 0.5 to 22.8 months). 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.