Evrisdi^® (Powder) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

F. Hoffmann-La Roche, Ltd (Switzerland)

Packaging and Quality Control Release

F.Hoffmann-La Roche, Ltd (Switzerland)

Or

DOBROLEK, LLC (Russia)

ATC Code

M09AX10 (Risdiplam)

Active Substance

Risdiplam (Rec.INN registered by WHO)

Dosage Form

Evrisdi®

Powder for oral solution 0.75 mg/1 ml: vial 2 g

Dosage Form, Packaging, and Composition

Powder for oral solution or powder with lumps from light yellow to yellow with a grayish or greenish tint, or light green with a yellowish tint (at release); powder or powder with lumps, or caked powder from light yellow to yellow with a grayish or greenish tint, or light green with a yellowish tint (during shelf life); prepared (reconstituted) solution is clear, from greenish-yellow to yellow in color.

1 ml of prepared (reconstituted) solution contains 0.75 mg of risdiplam.

Excipients: mannitol – 1344.7 mg, isomalt – 237.25 mg, strawberry flavor (corn maltodextrin, modified waxy corn starch (E1450), flavoring components) – 150 mg, tartaric acid – 120.5 mg, sodium benzoate – 30 mg, macrogol/polyethylene glycol 6000 – 20 mg, sucralose – 16 mg, ascorbic acid – 14.1 mg, disodium edetate dihydrate – 7.45 mg.

2 g – dark glass vials (1) complete with a bag containing an adapter, 2 oral syringes with a capacity of 6 ml (in a separate labeled bag), 2 oral syringes with a capacity of 12 ml (in a separate labeled bag) – cardboard packs with first-opening control (protective holographic stickers or first-opening control labels).
2 g – dark glass vials (1) complete with a bag containing an adapter, 2 oral syringes with a capacity of 1 ml (in a separate labeled bag), 2 oral syringes with a capacity of 6 ml (in a separate labeled bag), 1 oral syringe with a capacity of 12 ml (in a separate labeled bag) – cardboard packs with first-opening control (protective holographic stickers or first-opening control labels).

Clinical-Pharmacological Group

Gene therapy drug used for spinal muscular atrophy

Pharmacotherapeutic Group

Other agents for the treatment of musculoskeletal system diseases

Pharmacological Action

Risdiplam is a modifier of the splicing of the precursor messenger ribonucleic acid (pre-mRNA) of the survival motor neuron 2 (SMN2) gene, developed for the treatment of spinal muscular atrophy (SMA), which is caused by mutations in chromosome 5q, leading to a deficiency of the SMN protein.

Deficiency of the functional SMN protein is the pathophysiological mechanism of development of all types of SMA. Risdiplam corrects SMN2 splicing by shifting the balance from exclusion of exon 7 to inclusion of exon 7 in the mRNA transcript, leading to the production of a functional and stable SMN protein. Thus, Risdiplam treats SMA by increasing and maintaining levels of the functional SMN protein.

Risdiplam is evenly distributed throughout the body, including the CNS, penetrating the blood-brain barrier and accordingly leading to an increase in the level of the SMN protein in the CNS and throughout the body. Concentrations of risdiplam in plasma and the SMN protein in blood reflect the distribution and pharmacodynamic effects of risdiplam in tissues, namely in muscle tissue and brain tissues.

In all clinical studies, the use of risdiplam led to a sustained and long-term increase in the level of the SMN protein. Within 4 weeks after the start of treatment, the median level of the SMN protein was more than 2 times higher compared to the baseline value, according to measurements in blood. The increase in the level of the SMN protein persisted throughout the treatment period of <2 years in patients with infantile-onset SMA and in patients with later-onset SMA.

Pharmacokinetics

After oral administration of risdiplam as a solution, the pharmacokinetics were approximately linear between 0.6 mg and 18 mg. The pharmacokinetics of risdiplam were best described by a population pharmacokinetic model with absorption with three transit compartments, a two-compartment distribution, and first-order elimination.

Risdiplam was rapidly absorbed when taken on an empty stomach, with T_max in plasma varying from 1 to 4 hours. A high-fat meal did not have a significant effect on the exposure of risdiplam. The established population pharmacokinetic parameters were 98 L for the apparent central V_d, 93 L for the peripheral volume, and 0.68 L/h for the intercompartmental clearance. Risdiplam was predominantly bound to serum albumin without any binding to α1-acid glycoprotein, the free fraction was 11%.

Risdiplam is mainly metabolized by flavin-containing monooxygenase 1 and 3 (FMO 1 and 3), as well as by the isoenzymes CYP1A1, CYP2J2, CYP3A4, and CYP3A7. The pharmacologically inactive metabolite M1 was identified as the main circulating metabolite.

Population pharmacokinetic analysis established the apparent clearance of risdiplam as 2.6 L/h. The effective T_1/2 of risdiplam was approximately 50 hours in patients with spinal muscular atrophy. Approximately 53% of the dose (14% unchanged risdiplam) is excreted in feces and 28% in urine (8% unchanged risdiplam). The original Risdiplam was the main component in plasma (83% of the total drug components in the bloodstream).

Indications

Treatment of spinal muscular atrophy in adults and children from 2 months of age.

ICD codes

Dosage Regimen

Administer orally once daily after a meal.

Establish the daily dose based on the patient’s age and body weight.

For patients 2 months to less than 2 years of age, the recommended daily dose is 0.15 mg/kg.

For patients 2 years and older weighing less than 20 kg, the recommended daily dose is 0.20 mg/kg.

For patients 2 years and older weighing 20 kg or more, the recommended daily dose is 5 mg.

Reconstitute the powder with 120 ml of water to prepare the oral solution.

Shake the vial vigorously for 30 seconds to ensure complete dissolution.

Use the provided adapter and oral syringe to withdraw the prescribed dose.

Discard any remaining reconstituted solution 64 days after preparation.

Regularly monitor liver function tests during treatment.

Adverse Reactions

Gastrointestinal system very common – diarrhea.

Skin and subcutaneous tissue very common – maculopapular rash, erythema, dermatitis, allergic dermatitis, papular rash, folliculitis.

Contraindications

Hypersensitivity to risdiplam; pregnancy, breastfeeding period; children under 2 months of age.

Use in Pregnancy and Lactation

Use during pregnancy and breastfeeding is contraindicated.

Use in Hepatic Impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment. Use in patients with severe hepatic impairment has not been studied.

Use in Renal Impairment

No dose adjustment is necessary in patients with renal impairment.

Pediatric Use

Contraindicated for use in children under 2 months of age.

Special Precautions

Embryo-fetal toxicity was observed in animal studies of the drug. Patients with reproductive potential should be informed of the risk and the need to use highly effective methods of contraception during treatment and for at least 1 month after the last dose of risdiplam for female patients and for at least 4 months after the last dose of risdiplam for male patients.

A reversible effect of risdiplam on male fertility was shown in an animal study. In this regard, male patients should not donate sperm during treatment and for 4 months after the last dose of risdiplam.

Drug Interactions

No clinically significant interaction with other medicinal products has been established.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.