Risdiplam
FDA Drug Information • Also known as: Evrysdi
- Brand Names
- Evrysdi
- Drug Class
- Survival of Motor Neuron 2 Splicing Modifier [EPC]
- Route
- ORAL
- Dosage Form
- POWDER, FOR SOLUTION
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION EVRYSDI for oral solution and EVRYSDI tablets for oral use contain risdiplam, which is a survival of motor neuron 2 (SMN2)-directed RNA splicing modifier. The chemical name of risdiplam is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8 dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido-4H-[1,2-a]pyrimidin-4-one. Risdiplam has a molecular weight of 401.46 g/mol. Risdiplam demonstrates pH-dependent aqueous solubility; the greatest solubility is at low pH, and solubility decreases with increasing pH. Risdiplam has a pKa 1 of 3.78 (base) and pKa 2 of 6.62 (base). The molecular formula of risdiplam is C 22 H 23 N 7 O and the chemical structure is shown below. EVRYSDI for oral solution is supplied as a powder in an amber glass bottle. Each bottle contains 60 mg of risdiplam. The inactive ingredients of EVRYSDI are: ascorbic acid, disodium edetate dihydrate, isomalt, mannitol, polyethylene glycol 6000, sodium benzoate, strawberry flavor, sucralose, and tartaric acid. The powder is constituted with purified water to yield 60 mg/80 mL (0.75 mg/mL) of risdiplam after constitution [see Dosage and Administration (2.4) ]. Each EVRYSDI tablet contains 5 mg of risdiplam. The inactive ingredients of EVRYSDI tablet are colloidal silicon dioxide, crospovidone, mannitol, microcrystalline cellulose, polyethylene glycol 3350, polyvinyl alcohol, sodium stearyl fumarate, strawberry flavor, talc, tartaric acid, titanium dioxide, and yellow iron oxide. Chemical Structure
What Is Risdiplam Used For?
1 INDICATIONS AND USAGE EVRYSDI is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. EVRYSDI is a survival of motor neuron 2 (SMN2) splicing modifier indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Administer once daily with or without food per the table below ( 2.1 ): Age and Body Weight Recommended Daily Dosage Dosage Form Less than 2 months of age 0.15 mg/kg EVRYSDI for Oral Solution 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 EVRYSDI for Oral Solution or EVRYSDI Tablet Swallow EVRYSDI tablet whole with water or dispersed in non-chlorinated drinking water (e.g., filtered water). ( 2.2 ) Administer EVRYSDI for oral solution with the provided oral syringe. ( 2.2 ) EVRYSDI for oral solution must be constituted by a healthcare provider prior to dispensing. ( 2.4 ) See Full Prescribing Information for important preparation and administration instructions. ( 2.2 , 2.4 ) 2.1 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 Age and Body Weight Age and Body Weight Recommended Daily Dosage Dosage Form Less than 2 months of age 0.15 mg/kg EVRYSDI for Oral Solution 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 EVRYSDI for Oral Solution or EVRYSDI Tablet 2.2 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 [see Instructions for Use for EVRYSDI for Oral Solution and EVRYSDI Tablets and Patient Information ]. 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 [see Instructions for Use ]. 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...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The most common adverse reactions in later-onset SMA (incidence at least 10% of patients treated with EVRYSDI and more frequent than control) were fever, diarrhea, and rash. ( 6.1 ) The most common adverse reactions in infantile-onset SMA were similar to those observed in later-onset SMA patients. Additionally, adverse reactions with an incidence of at least 10% were upper respiratory tract infection, lower respiratory tract infection, constipation, vomiting, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 491 patients (51% female, 74% Caucasian) were exposed to EVRYSDI for up to a median duration of 48.1 months (range: 0.6 to 63.4 months), with 231 patients receiving treatment for more than 24 months. At the time of first EVRYSDI dose, 90 (18%) patients were 18 years and older, 119 (24%) 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 26 (5%) 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) % Fever Includes pyrexia and hyperpyrexia. 22 17 Diarrhea 17 8 Rash Includes rash, erythema, rash maculo-papular, rash erythematous, rash papular, dermatitis allergic, and folliculitis. 17 2 Mouth and aphthous ulcers 7 0 Arthralgia 5 0 Urinary tract infection Includes urinary tract infection and cystitis. 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 in 26 patients (Study 3) [see Clinical Studies (14.3) ] . The patient population ranged in age from 16 to 41 days at the time of the first dose (weight range: 3.1 to 5.7 kg). 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.
Drug Interactions
7 DRUG INTERACTIONS Avoid coadministration with drugs that are substrates of multidrug and toxin extrusion (MATE) transporters. ( 7.1 ) 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.
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 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 [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...
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 EVRYSDI for Oral Solution How Supplied Each amber glass bottle of EVRYSDI for oral solution is packaged with a bottle adapter, two 1 mL reusable oral syringes, two 6 mL reusable oral syringes, and one 12 mL reusable oral syringe. EVRYSDI for oral solution is a light yellow, pale yellow, yellow, greyish yellow, greenish yellow, or light green powder. Each bottle contains 60 mg of risdiplam (NDC 50242-175-07). Storage and Handling Store the dry powder at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature] . Keep in the original carton. 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) [see Dosage and Administration (2.4) ]. 16.2 EVRYSDI Tablets How Supplied Pale yellow film-coated tablet, round and curved, with EVR debossed on one side; available in HDPE bottles of 30 tablets with a child-resistant cap (NDC 50242-202-01). Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Keep in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.