Introduction
Risdiplam is an orally administered small molecule approved for the treatment of spinal muscular atrophy (SMA), a rare genetic neuromuscular disorder characterized by progressive muscle weakness and atrophy. As the first orally available survival of motor neuron 2 (SMN2) splicing modifier, risdiplam represents a significant advancement in SMA therapeutics, offering a convenient administration route compared to existing intrathecal and intravenous options.
Mechanism of Action
Risdiplam modulates splicing of the SMN2 gene, increasing production of functional survival motor neuron (SMN) protein. The drug binds to specific sites on SMN2 pre-mRNA, promoting inclusion of exon 7 and enhancing production of full-length SMN protein. This mechanism compensates for the deficient SMN1 gene function in SMA patients, addressing the underlying molecular defect of the disease.
Indications
Risdiplam is approved for:
- Treatment of spinal muscular atrophy in patients aged 2 months and older
- Both pediatric and adult patients with SMA types 1, 2, and 3
- Patients with 5q autosomal recessive SMA
Dosage and Administration
Standard dosing:- Patients ≥2 months to <2 years: 0.15 mg/kg once daily
- Patients ≥2 years: 0.25 mg/kg once daily
- Administered orally 1 hour after a meal
- Hepatic impairment: No dosage adjustment recommended for mild to moderate impairment; use with caution in severe impairment
- Renal impairment: No dosage adjustment recommended
- Geriatric patients: Limited data available
Pharmacokinetics
Absorption: Time to peak concentration (Tmax) approximately 1-4 hours post-dose Distribution: Volume of distribution approximately 1.9 L/kg; plasma protein binding ~70% Metabolism: Primarily via flavin-containing monooxygenase (FMO) 1 and 3 pathways and cytochrome P450 (CYP) enzymes Elimination: Half-life approximately 50 hours; excreted primarily in feces (74%) and urine (26%)Contraindications
- Hypersensitivity to risdiplam or any component of the formulation
- No other absolute contraindications identified
Warnings and Precautions
Reproductive effects: May affect fertility based on animal studies Hepatic effects: Monitor liver function tests regularly Drug-induced toxicity: Potential for retinal toxicity; regular ophthalmological examinations recommended Pregnancy: No human data available; use only if potential benefit justifies potential risk Lactation: Decision should be made whether to discontinue nursing or discontinue drugDrug Interactions
Strong CYP3A inducers: Rifampin, carbamazepine, phenytoin, St. John's wort - may decrease risdiplam exposure Strong CYP3A inhibitors: Ketoconazole, itraconazole, clarithromycin - may increase risdiplam exposure Acid-reducing agents: Proton pump inhibitors, H2 antagonists, antacids - may decrease risdiplam absorptionAdverse Effects
Most common adverse reactions (≥10%):- Fever
- Diarrhea
- Rash
- Upper respiratory tract infection
- Pneumonia
- Constipation
- Vomiting
- Liver enzyme elevations
- Retinal changes
- Pneumonia
- Urinary tract infections
Monitoring Parameters
Baseline and periodic monitoring:- Liver function tests (ALT, AST, bilirubin) every 2 months for first year, then as clinically indicated
- Ophthalmological examinations at baseline and every 6 months
- Growth parameters in pediatric patients
- Renal function
- Complete blood count
- Clinical assessment of motor function
Patient Education
Administration instructions:- Take exactly as prescribed, once daily
- Administer 1 hour after a meal
- Use provided oral syringe for accurate dosing
- Store at room temperature
- Do not miss doses; maintain consistent dosing schedule
- Report any fever, rash, or vision changes immediately
- Inform all healthcare providers about risdiplam use
- Keep all scheduled monitoring appointments
- Discuss pregnancy planning with healthcare provider
- Report any new medications, including over-the-counter products
References
1. FDA prescribing information: Risdiplam (Evrysdi). 2020 2. Baranello G, et al. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021;384(10):915-923 3. Mercuri E, et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy. Lancet Neurol. 2021;20(10):832-841 4. Ratni H, et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018;61(15):6501-6517 5. ClinicalTrials.gov: FIREFISH, SUNFISH, and JEWELFISH studies