Evrysdi (Risdiplam)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Spinal muscular atrophy (SMA) | Pediatric (neonates and older) and adult patients | Monotherapy (disease-modifying) | FDA Approved |
| SMA — infantile-onset (Type 1) | Studied in infants 2–7 months at first dose (FIREFISH) | Monotherapy | FDA Approved |
| SMA — later-onset (Type 2 / non-ambulant Type 3) | Studied in patients 2–25 years (SUNFISH) | Monotherapy | FDA Approved |
| SMA — pre-symptomatic infants | Studied in infants up to 6 weeks of age at first dose, with genetic SMA diagnosis (RAINBOWFISH) | Monotherapy (early intervention) | FDA Approved |
Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier indicated for the treatment of 5q-linked spinal muscular atrophy in pediatric and adult patients. It is the first orally available disease-modifying therapy for SMA, joining nusinersen (intrathecal antisense oligonucleotide) and onasemnogene abeparvovec (one-time gene replacement) in the modern SMA armamentarium. The FDA originally approved risdiplam in August 2020 for patients aged 2 months and older. The label was subsequently expanded to include infants under 2 months on the basis of pharmacokinetic and safety data in patients 16 days and older together with PK modeling. A 5 mg film-coated tablet was approved by the FDA in February 2025 for patients 2 years or older weighing at least 20 kg, providing an alternative to the constituted oral solution.
Combination with anti-myostatin therapy — combined use with the investigational anti-myostatin agent GYM329 (RG6237) is being evaluated in the MANATEE phase II/III trial in patients aged 2–10 years; not currently approved. Evidence quality: very low (trial in progress).
Use after onasemnogene abeparvovec gene therapy — risdiplam is being studied in HINALEA 1 and HINALEA 2 (phase IV) in patients under 2 years who received SMN1 gene replacement either pre- or post-symptomatically. Sequential or combination use is increasingly seen in clinical practice but is formally investigational. Evidence quality: low (ongoing trials and observational data).
Dosing
Dosing is age- and weight-driven and is administered once daily, ideally at the same time each day, with or without food. The constituted oral solution must be prepared by the pharmacist (final concentration 0.75 mg/mL) and is stable in the refrigerator for 64 days. Patients aged 2 years or older weighing 20 kg or more may use the 5 mg tablet, which has been shown to be bioequivalent to the 5 mg dose of the oral solution in adult healthy volunteers.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| SMA, infant < 2 months of age | 0.15 mg/kg | 0.15 mg/kg once daily | 0.15 mg/kg/day | Oral solution only at this age Recalculate dose at every weight check |
| SMA, 2 months to < 2 years of age | 0.20 mg/kg | 0.20 mg/kg once daily | 0.20 mg/kg/day | FIREFISH-validated dose for symptomatic infantile-onset SMA Recalculate at every weight check |
| SMA, ≥ 2 years and < 20 kg | 0.25 mg/kg | 0.25 mg/kg once daily | 0.25 mg/kg/day | Tablet not authorised at this weight — continue oral solution Recalculate at every weight increment |
| SMA, ≥ 2 years and ≥ 20 kg | 5 mg | 5 mg once daily | 5 mg/day | Fixed dose; 5 mg tablet may be swallowed whole or dispersed in 5 mL non-chlorinated drinking water and given within 10 minutes Bioequivalent to oral solution; transition possible without titration |
| Missed dose ≤ 6 hours from usual time | Same dose | Resume schedule | — | Take as soon as remembered; resume usual time the next day |
| Missed dose > 6 hours | Skip | Resume next day | — | Take next dose at the regular time the next day; do not double-dose |
| Dose not fully swallowed or vomiting after dose | Do not redose | — | — | Wait until the next regularly scheduled dose the following day |
Population-Specific Adjustments
| Population | Adjustment | Rationale |
|---|---|---|
| Mild hepatic impairment (Child–Pugh A) | No adjustment | AUC ~20% lower, Cmax ~5% lower vs healthy controls — not clinically meaningful |
| Moderate hepatic impairment (Child–Pugh B) | No adjustment | AUC ~8% higher, Cmax ~20% higher vs healthy controls — not clinically meaningful |
| Severe hepatic impairment (Child–Pugh C) | Not studied | Pharmacokinetics and safety in this population have not been characterised |
| Renal impairment | No adjustment expected | Renal impairment is not expected to alter risdiplam exposure (per FDA PI) |
| Geriatric (≥ 65 years) | Not studied | Clinical trials did not include patients aged 65 years and older |
The oral solution must be taken from the supplied oral syringe within 5 minutes of being drawn up; if delay occurs, discard and prepare a fresh dose. Drink water afterwards to ensure complete swallowing. Do not mix with formula or milk. Tablets dispersed in non-chlorinated drinking water must be administered within 10 minutes of dispersion and must not be administered via nasogastric or gastrostomy tubes — for tube administration, use the oral solution. Avoid skin and eye contact with the powder or dispersion; wash with soap and water if contact occurs.
Pharmacology
Mechanism of Action
Spinal muscular atrophy is caused by biallelic loss-of-function variants in the SMN1 gene, which normally encodes survival of motor neuron (SMN) protein. A paralogous gene, SMN2, produces only a small fraction of full-length functional SMN protein because of a splicing defect that leads to skipping of exon 7 in most transcripts. Risdiplam is a small-molecule splicing modifier that increases inclusion of exon 7 in SMN2 mRNA transcripts, thereby increasing production of full-length, functional SMN protein from the patient’s own SMN2 gene copies. In clinical trials in both infantile-onset and later-onset SMA, treatment produced a greater than two-fold median increase in blood SMN protein within four weeks, sustained throughout follow-up. In vitro and animal data also indicate that risdiplam can cause alternative splicing of additional genes (including FOXM1 and MADD), which has been considered a potential contributor to non-clinical adverse effects.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Median Tmax 3.3–4 h fasted (delayed up to 1 h with food); high-fat, high-calorie meal has no relevant effect on overall exposure; tablet bioequivalent to oral solution in adult volunteers | Can be given with or without food; switching between oral solution and tablet does not require titration |
| Distribution | Apparent Vd at steady state ~190 L (31.3 kg patient); free fraction 11% (predominantly albumin-bound, no binding to alpha-1 acid glycoprotein); crosses blood–brain barrier in non-clinical studies | CNS penetration supports motor neuron effect; no clinically relevant displacement interactions expected |
| Metabolism | Primarily by FMO1 and FMO3, with minor contributions from CYP1A1, 2J2, 3A4, 3A7. Inactive M1 metabolite is the major circulating metabolite (parent drug accounts for ~83% of drug-related material in plasma) | FMO is not commonly inhibited by other drugs — the interaction profile is favourable; severe hepatic impairment unstudied |
| Elimination | Terminal t½ ~50 h in healthy adults; CL/F ~2.45 L/h (31.3 kg patient); after an 18 mg dose, ~53% excreted in feces (14% unchanged) and ~28% in urine (8% unchanged) | Long half-life supports once-daily dosing; minor renal clearance of unchanged drug means significant accumulation in renal impairment is not expected |
Population pharmacokinetic analysis identified body weight and age as significant determinants of risdiplam pharmacokinetics. Mean steady-state AUC0–24h exposures across age cohorts are deliberately matched (~1900–2100 ng·h/mL): pre-symptomatic infants 1–2 months at 0.15 mg/kg, infantile-onset patients 2–7 months at 0.20 mg/kg, and patients aged 2–25 years at 0.25 mg/kg (< 20 kg) or 5 mg fixed (≥ 20 kg).
Side Effects
The risdiplam adverse-event profile differs by age cohort. In symptomatic infants with Type 1 SMA (FIREFISH), respiratory and infectious events dominate and substantially overlap with the natural history of advanced disease. In patients aged 2–25 years with Type 2 or non-ambulant Type 3 SMA (SUNFISH Part 2, n = 120 risdiplam vs n = 60 placebo), most adverse reactions occurred at rates similar to placebo. The figures below are drawn from the FDA prescribing information’s Adverse Reactions section (Table 2) and from the published FIREFISH and SUNFISH manuscripts; the source is identified for each value.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Pyrexia (later-onset, SUNFISH) | 22% | 17% in placebo arm — modest excess; symptomatic management with antipyretics |
| Diarrhea (later-onset, SUNFISH) | 17% | 8% in placebo arm; usually mild and transient — maintain hydration |
| Rash (later-onset, SUNFISH) | 17% | 2% in placebo arm; includes erythema, maculo-papular rash, dermatitis allergic, folliculitis |
| Upper respiratory tract infection (infantile, FIREFISH Part 2) | ~54% | Most common AE in n=41 cohort; reflects baseline SMA respiratory vulnerability as much as drug effect |
| Lower respiratory tract infection (infantile) | ≥10% (FDA PI) | Specific incidence not reported in the PI; includes pneumonia and bronchitis |
| Constipation (infantile) | ≥10% (FDA PI) | Counsel caregivers on routine bowel regimen and adequate fluid intake |
| Vomiting (infantile) | ≥10% (FDA PI) | If vomiting occurs after a dose, do not redose — wait until the next scheduled administration |
| Cough (infantile) | ≥10% (FDA PI) | Reflects underlying weakness of cough mechanism in Type 1 SMA |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Mouth and aphthous ulcers (later-onset, SUNFISH) | 7% | 0% in placebo arm; inspect oral cavity at routine visits — supportive care usually sufficient |
| Arthralgia (later-onset, SUNFISH) | 5% | 0% in placebo arm; reported predominantly in older paediatric and adult cohorts |
| Urinary tract infection (later-onset, SUNFISH) | 5% | 0% in placebo arm; standard work-up and treatment — not a reason to interrupt risdiplam |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Pneumonia (serious AE) | 39% in FIREFISH Part 2 (Type 1 infants); 8% vs 2% placebo in SUNFISH Part 2 | Any time; risk highest during respiratory illness | Admit, broad-spectrum antibiotics, respiratory support; risdiplam typically continued |
| Respiratory distress (Type 1 SMA) | ~7% (3 of 41 in FIREFISH Part 2) | Often during respiratory infection | Multidisciplinary respiratory escalation; consider non-invasive ventilation |
| Embryofetal toxicity | Animal data only; human risk unquantified | Throughout pregnancy | Document negative pregnancy test before initiation; counsel on contraception during therapy and for ≥ 1 month after the last dose |
| Death due to underlying SMA (Type 1 cohort) | 6 of 62 patients in FIREFISH (per FDA PI); not attributed by investigators to risdiplam | Mostly within first 3 months of treatment | Reflects natural history of advanced Type 1 SMA; multidisciplinary palliative care planning where appropriate |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Disease-related death (Type 1 SMA) | 6 of 62 in FIREFISH | Reflects natural course of severe SMA, not drug toxicity |
| Permanent ventilation (Type 1 SMA) | 4 of 62 by Month 24 | Defined as tracheostomy or > 21 consecutive days of NIV ≥ 16 h/day or intubation |
| Confirmed pregnancy | Rare | Discussion of risk–benefit and probable discontinuation pending counselling |
Rash (17%) and oral ulceration (7%) are the most clearly drug-attributable adverse events in the SUNFISH cohort, given the wide separation from placebo (2% and 0% respectively). Most cases are mild and respond to symptomatic measures (emollients, gentle oral hygiene, soft diet). Persistent or severe lesions warrant temporary dose hold and dermatology referral; permanent discontinuation is rarely necessary.
Drug Interactions
Risdiplam has a narrow interaction profile because its dominant metabolic pathway is FMO1/FMO3, an enzyme system with few clinically relevant inhibitors or inducers. The single labelled interaction concern is that risdiplam and its M1 metabolite are in vitro inhibitors of the renal organic-cation transporters MATE1 and MATE2-K. The 2025 FDA prescribing information directs prescribers to avoid coadministration with MATE substrates, and if avoidance is not possible, to monitor for substrate-related toxicity and consider a dose reduction of the coadministered drug. Risdiplam is also a weak in vivo CYP3A inhibitor, but the magnitude (~11% AUC increase in midazolam) is not considered clinically relevant.
The MATE recommendation in the 2025 FDA prescribing information is to avoid coadministration of EVRYSDI with MATE substrates rather than to monitor empirically. For patients already taking metformin or another MATE substrate, the decision to continue therapy, switch to an alternative, or accept the interaction with monitoring should involve the prescriber and the relevant specialist (endocrinology, cardiology, or oncology).
Monitoring
The FDA prescribing information does not mandate routine laboratory monitoring for risdiplam. The principal monitoring focus is on disease response (motor function, respiratory and nutritional status), pregnancy status in females of reproductive potential, and weight-driven dose recalculation in growing children.
-
Body Weight
At every visit; minimum every 3 months in children
Routine Recalculate mg/kg dose at every weight change in children < 20 kg. Once weight reaches 20 kg and the child is ≥ 2 years, transition to fixed 5 mg/day. -
Motor Function
Every 6–12 months
Routine Use age- and ability-appropriate scales (e.g., CHOP-INTEND or BSID-III gross motor for non-sitters; HFMSE or RULM for sitters; MFM-32 for ambulant patients). Document attainment of new motor milestones. -
Respiratory Function
Every 6 months (more often in Type 1 SMA)
Routine Spirometry (FVC) where developmentally feasible; track time on non-invasive ventilation; cough-assist effectiveness; pulse oximetry during illness. -
Nutrition / Swallowing
Each clinic visit
Routine Weight-for-age, feeding tolerance, video-fluoroscopic swallow study if clinical concern; involve dietitian and SLT. -
Pregnancy Test
Before initiation in females of reproductive potential
Routine Confirm negative serum or urine βhCG. Counsel on effective contraception during therapy and for at least 1 month after the final dose. -
Skin and Oral Mucosa
Each visit
Routine Inspect for rash, mouth ulcers; document any new lesions and severity. Photograph if needed for longitudinal comparison. -
Liver Function Tests
If clinical signs of hepatic dysfunction
Trigger-based No routine LFT requirement, but consider ALT, AST, bilirubin if jaundice, fatigue, or abdominal pain develops or before adding hepatically cleared concomitant therapy. -
MATE Substrate Surveillance
If coadministration is unavoidable
Trigger-based Per the FDA PI, avoid coadministration with MATE substrates. If unavoidable, monitor for drug-related toxicity (e.g., metformin tolerance, eGFR, lactate) and consider substrate dose reduction. -
Pregnancy Registry
If conception occurs on therapy
Trigger-based Encourage enrolment in the EVRYSDI Pregnancy Registry (1-833-760-1098) to collect long-term outcome data.
Contraindications & Cautions
Absolute Contraindications
- None — the FDA prescribing information lists no contraindications (Section 4).
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment (Child–Pugh C) — pharmacokinetics and safety in this population have not been studied. The decision to initiate or continue therapy should involve hepatology and the SMA team.
- Pregnancy — animal data show embryofetal mortality, malformations (including hydrocephaly in rabbits), decreased fetal body weights, and reproductive impairment in offspring at clinically relevant exposures. There are no adequate human data. If pregnancy is confirmed on therapy, treatment should be paused pending an individualised risk–benefit conversation with the patient and the SMA team.
- Females of reproductive potential without effective contraception — pregnancy testing is recommended before initiation, and effective contraception should be in place during treatment and for at least 1 month after the last dose.
Use with Caution
- Mild–moderate hepatic impairment (Child–Pugh A or B) — no dose adjustment required; routine clinical observation suffices.
- Concurrent MATE-substrate drugs (metformin, dofetilide, cisplatin, procainamide) — coadministration should be avoided; if unavoidable, monitor for substrate toxicity and consider substrate dose reduction.
- Male patients of reproductive potential — non-clinical data indicate possible adverse effects on male reproductive organs and germ cells at clinically relevant exposures. Counsel on the potential for compromised fertility; sperm preservation may be considered before initiation.
- Breastfeeding — risdiplam is excreted in the milk of lactating rats; human data are unavailable. Balance the developmental and health benefits of breastfeeding against the unknown infant exposure on a case-by-case basis.
- Patients receiving prior or concurrent SMA disease-modifying therapy — combination or sequential use with nusinersen or onasemnogene abeparvovec is not FDA-approved and is being studied prospectively (HINALEA). Specialist oversight is essential.
- Geriatric patients (≥ 65 years) — clinical trials did not include this age group; clinical experience is limited.
Based on animal studies, EVRYSDI may cause fetal harm when administered during pregnancy. In animal reproduction studies, oral risdiplam produced embryofetal mortality, fetal malformations (including hydrocephaly in rabbits), decreased fetal body weights, and reproductive impairment in offspring at exposures within or above the clinically relevant range. There is no boxed warning for this drug; the pregnancy risk is communicated through Section 8.1 of the prescribing information.
Verify pregnancy status in females of reproductive potential before initiating therapy. Advise females of childbearing potential to use effective contraception during therapy and for at least 1 month after the last dose. Encourage enrolment in the EVRYSDI Pregnancy Registry (1-833-760-1098) for any patient who becomes pregnant on therapy.
Patient Counselling
Purpose of Therapy
Explain to the patient or caregiver that risdiplam is a once-daily oral medicine that helps the body make more of the survival motor neuron (SMN) protein — the protein the patient cannot produce in sufficient quantity because of the SMA gene change. Set realistic expectations: the medicine works best when started early and taken consistently over years. In pivotal trials, infants with Type 1 SMA gained motor milestones such as the ability to sit independently, and patients aged 2–25 years with Type 2 or non-ambulant Type 3 SMA experienced improvements or stabilisation of motor function compared with placebo. The medicine does not reverse damage already present.
How to Take It
Risdiplam is taken once a day, at roughly the same time each day, by mouth (or via feeding tube, oral solution only). The oral solution must be drawn into the supplied oral syringe and given within five minutes; if longer than that elapses, discard and prepare a fresh dose. Tablets (5 mg) can be swallowed whole with water or dispersed in 5 mL of non-chlorinated bottled water (e.g., filtered water) and given within ten minutes of dispersion. Do not chew, cut, or crush the tablet. Do not mix the oral solution with formula or milk. Food has no relevant effect, so the dose can be taken with or without meals. The constituted oral solution is stored in the refrigerator (upright, in the original amber bottle) and discarded 64 days after pharmacist constitution; up to 5 cumulative days at room temperature (≤ 40 °C) is permitted. Tablets are stored at room temperature.
Sources
- EVRYSDI® (risdiplam) US Prescribing Information. Genentech, Inc. Revised February 2025. accessdata.fda.gov Current FDA-approved label, including the 5 mg tablet formulation; primary source for dosing, adverse-reaction tables, drug interactions, and warnings.
- European Medicines Agency. Evrysdi (risdiplam) Summary of Product Characteristics. ema.europa.eu EMA reference document for indications, posology, and pharmacovigilance commitments in Europe.
- Roche Media Release. FDA Approves EVRYSDI Tablet for Spinal Muscular Atrophy. 12 February 2025. roche.com/media/releases/med-cor-2025-02-12 Documents FDA approval of the 5 mg tablet for patients aged ≥ 2 years and weighing ≥ 20 kg.
- Darras BT, Masson R, Mazurkiewicz-Bełdzińska M, et al. Risdiplam-treated infants with Type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021;385:427-435. doi.org/10.1056/NEJMoa2102047 FIREFISH Part 2 12-month primary outcome data for infantile-onset SMA, supporting FDA approval.
- Masson R, Mazurkiewicz-Bełdzińska M, Rose K, et al. Safety and efficacy of risdiplam in patients with Type 1 spinal muscular atrophy (FIREFISH Part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022;21(12):1110-1119. pubmed.ncbi.nlm.nih.gov/36244364 Source for the 24-month motor function results and the 54% URTI / 39% pneumonia / 7% respiratory distress figures used in the side effects section.
- Mercuri E, Deconinck N, Mazzone ES, et al. Safety and efficacy of once-daily risdiplam in Type 2 and non-ambulant Type 3 spinal muscular atrophy (SUNFISH Part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022;21(1):42-52. pubmed.ncbi.nlm.nih.gov/34942136 Pivotal placebo-controlled trial in later-onset SMA; source for SUNFISH adverse-event rates corroborating the FDA PI Table 2 figures.
- Mercuri E, Baranello G, Boespflug-Tanguy O, et al. Risdiplam in Types 2 and 3 spinal muscular atrophy: a randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment. Eur J Neurol. 2023;30(7):1945-1956. pubmed.ncbi.nlm.nih.gov/35837793 SUNFISH Part 1 dose-finding and 24-month extension data informing long-term tolerability.
- RAINBOWFISH Study (NCT03779334). Risdiplam in pre-symptomatic infants with genetically diagnosed SMA. clinicaltrials.gov/study/NCT03779334 Open-label single-arm study in 26 pre-symptomatic infants, basis for the pre-symptomatic indication described in FDA PI Section 14.3.
- Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: Part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115. doi.org/10.1016/j.nmd.2017.11.005 International consensus standard of care for SMA diagnosis, rehabilitation, and nutritional management informing the monitoring section.
- Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: Part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. doi.org/10.1016/j.nmd.2017.11.004 Companion consensus document covering pulmonary care and pharmacology — the basis for respiratory monitoring frequency recommendations.
- Glascock J, Sampson J, Connolly AM, et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi.org/10.3233/JND-190468 Cure SMA newborn-screening treatment algorithm relevant to early-treatment decisions in pre-symptomatic infants.
- Singh RN, Ottesen EW, Singh NN. The first orally deliverable small molecule for the treatment of spinal muscular atrophy. Neurosci Insights. 2020;15:1-11. doi.org/10.1177/2633105520973985 Mechanistic review of risdiplam’s action on SMN2 pre-mRNA splicing and exon 7 inclusion.
- Poirier A, Weetall M, Heinig K, et al. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacol Res Perspect. 2018;6(6):e00447. doi.org/10.1002/prp2.447 Preclinical biodistribution data supporting CNS and peripheral SMN protein increases.
- Kletzl H, Marquet A, Günther A, et al. Effect of mild or moderate hepatic impairment on the pharmacokinetics of risdiplam. Br J Clin Pharmacol. 2022;88(8):3814-3822. doi.org/10.1111/bcp.15319 Source for the recommendation that no dose adjustment is required in Child–Pugh A or B impairment.
- Cleary Y, Gertz M, Grimsey P, et al. Estimation of FMO3 ontogeny by mechanistic population pharmacokinetic modelling of risdiplam and its impact on drug-drug interactions in children. Clin Pharmacokinet. 2023;62(8):1169-1183. doi.org/10.1007/s40262-023-01241-7 Establishes the FMO3 ontogeny curve underlying age- and weight-stratified paediatric dosing.
- Exploration of adverse events associated with risdiplam use: retrospective cases from the US FDA Adverse Event Reporting System (FAERS) database. PMC10906863. ncbi.nlm.nih.gov/pmc/articles/PMC10906863 Real-world post-marketing pharmacovigilance signal review supplementing trial-derived adverse-event estimates.