Risdiplam

Introduction Overview

Generic Name

risdiplam

Brand Name

Evrysdi

Dosage Form

oral powder for reconstitution (0.75 mg/mL), oral tablet (5 mg)

Drug Class

Miscellaneous uncategorized agents

Pharmacokinetics

Absorption:
Risdiplam is administered orally in either tablet or oral solution form. It exhibits good oral bioavailability, allowing systemic absorption with or without food intake. Clinical pharmacokinetic studies demonstrate that risdiplam achieves therapeutic plasma concentrations following once-daily dosing, with a median time to peak plasma concentration (Tmax) occurring approximately 2 to 4 hours post-dose. The absorption process is consistent across both pediatric and adult populations with spinal muscular atrophy (SMA), and is not significantly influenced by food, permitting flexible administration.

Distribution:
After absorption, risdiplam distributes widely throughout the body, including penetration into the central nervous system (CNS), which is essential for its pharmacological effect in SMA. It binds moderately to plasma proteins, primarily albumin, with the unbound fraction available for therapeutic action. Preclinical and clinical data indicate risdiplam crosses the blood-brain barrier effectively, ensuring adequate spinal cord exposure. The volume of distribution suggests a moderate extensive tissue distribution, supporting its action on motor neurons.

Metabolism:
Risdiplam is metabolized primarily in the liver via multiple pathways, including oxidative metabolism predominantly mediated by cytochrome P450 enzymes, notably CYP3A4, as well as by flavin-containing monooxygenases (FMO). Phase I and Phase II metabolic pathways contribute to its biotransformation, generating inactive metabolites excreted renally and biliary. The drug exhibits a relatively low potential for metabolic drug-drug interactions due to its involvement of multiple enzymes and pathways, which reduces dependency on a single metabolic route.

Elimination:
The elimination half-life of risdiplam is approximately 50 to 60 hours, supporting once-daily dosing. It is primarily cleared via renal excretion of metabolites, with minor fecal elimination. Less than 10% of the parent drug is excreted unchanged. The elimination process is consistent among pediatric and adult patients with SMA, with no significant accumulation observed at steady state. Renal or hepatic impairment may modestly alter elimination; however, dosage adjustments are typically not required based on current data.

Dosage Forms

Available Dosage Forms:
- Oral tablet: 5 mg strength
- Oral powder for reconstitution: 0.75 mg/mL solution

Dosages for Adults and Adolescents:
- Adults and children aged 2 years and older weighing 20 kg or more: 5 mg orally once daily

Specific Patient Populations:
- Infants and children less than 2 years:
* Less than 2 months of age: 0.15 mg/kg orally once daily
* 2 months to less than 2 years: 0.2 mg/kg orally once daily
* Children aged 2 years and older but weighing less than 20 kg: 0.25 mg/kg orally once daily
- For patients unable to swallow tablets, risdiplam oral solution provides precise weight-based dosing.
- The oral powder requires reconstitution with water to prepare the 0.75 mg/mL dosing solution; administration should follow specific instructions to ensure accurate dosing.
- Risdiplam oral solution can be administered via feeding tube when necessary, offering flexibility in debilitated or pediatric patients.
- Dosage adjustments based on weight and age ensure therapeutic levels while minimizing toxicity.
- Administration guidelines recommend taking risdiplam at the same time daily, with or without food, to maintain consistent plasma concentrations.
- The tablet should be swallowed whole and not crushed or chewed to preserve stability and absorption characteristics.
- Oral solution dosing should be measured with the supplied device for accuracy, and patients are advised to drink a glass of water after administration to ensure complete dosing.
- Stability and storage instructions include keeping tablets in original packaging at room temperature away from moisture and heat; the powder should be stored as per pharmacy guidance until reconstitution.

Mechanism Of Action

Risdiplam functions as an oral small-molecule splicing modifier designed to treat spinal muscular atrophy (SMA), a genetic disorder characterized by reduced levels of the survival motor neuron (SMN) protein due to mutation or deletion of the SMN1 gene. Its primary molecular mechanism involves modulating the alternative splicing of the SMN2 gene pre-mRNA, promoting inclusion of exon 7 during mRNA processing. This action increases the production of full-length, functional SMN protein from the SMN2 gene, partially compensating for the deficient SMN1 gene product.

At the cellular level, risdiplam binds selectively to two regions within the SMN2 pre-mRNA, stabilizing the RNA structure and facilitating the recruitment of splicing enhancers. This modulation enhances exon 7 inclusion, resulting in a higher yield of full-length SMN protein, which is critical for motor neuron survival and function. By increasing the availability of SMN protein, risdiplam helps to improve neuromuscular junction integrity, motor neuron viability, and muscle function.

Biochemically, risdiplam interacts with the splicing machinery without affecting other RNA splicing processes, demonstrating a targeted mechanism that limits off-target effects. Its oral bioavailability and CNS penetration enable widespread distribution, allowing it to exert therapeutic effects in the spinal cord and peripheral tissues affected in SMA.

Clinically, risdiplam's mechanism provides a disease-modifying therapy by addressing the underlying protein deficiency rather than only symptomatic relief. Compared to other SMA treatments like nusinersen, an intrathecal antisense oligonucleotide, risdiplam offers non-invasive administration and systemic SMN protein increase, potentially benefiting peripheral tissues as well. Emerging clinical trials have demonstrated improvements in motor milestones, survival, and quality of life for treated patients, confirming the efficacy of risdiplam’s splicing modulation mechanism.

Pharmacological Actions

Selective modulation of SMN2 pre-mRNA splicing to increase full-length SMN protein production
Oral small-molecule splicing modifier facilitating CNS and peripheral tissue distribution
Enhancement of motor neuron survival and function via increased SMN protein levels
Disease-modifying agent targeting the genetic root cause of spinal muscular atrophy
Improvement of neuromuscular junction integrity and muscle strength
Once-daily oral dosing providing convenient systemic therapy
Minimal off-target RNA splicing effects due to targeted molecular interaction
Pharmacokinetic profile supporting steady-state CNS penetration
Potential to stabilize or improve motor function in pediatric and adult SMA patients
Non-invasive alternative to intrathecal SMA treatments

Therapeutic Or Clinical Uses

Treatment of spinal muscular atrophy (SMA) in pediatric patients including infants
Management of SMA in adult patients to improve motor function
Used to increase survival motor neuron protein levels in genetically confirmed SMA
Treatment option for patients unable or unwilling to undergo intrathecal therapy
Adjunct therapy in SMA to slow progression of muscle weakness
Used in both symptomatic and pre-symptomatic SMA patients to modify disease course
Therapy for all types of SMA irrespective of disease severity or age
Potential use in combination with other SMA therapies under clinical evaluation
Oral administration providing outpatient treatment feasibility
Approved for continuous long-term use with regular monitoring
May improve patient quality of life by enhancing respiratory and motor functions
Therapeutic alternative when gene therapy or antisense oligonucleotide treatments are contraindicated or inaccessible
Applicable for treatment of infants at risk of rapid disease progression
Treatment aimed at genetic normalization rather than symptom suppression

Side Or Adverse Effects

Fever, commonly reported in pediatric SMA patients
Upper respiratory tract infections including cough and cold symptoms
Gastrointestinal disturbances such as vomiting, diarrhea, and constipation
Rash or skin reactions occasionally observed
Sore throat and nasal congestion
Allergic reactions including hives and swelling (rare but serious)
Potential for respiratory infections requiring medical attention
Transient mild to moderate gastrointestinal upset during dose initiation
Possible injection site reactions if administered via feeding tube
Fatigue and general malaise documented in clinical trials
Potential impact on fertility; advice for pregnancy planning is necessary
No significant hepatotoxicity or nephrotoxicity reported
Rare reports of hypersensitivity necessitating drug discontinuation
Monitor for signs of allergic reaction, especially during initial therapy phase

Precautions

Use only under medical supervision and according to prescribed dosing
Pregnancy: potential for fetal harm; effective contraception required during treatment and for at least 1 month after last dose
Breastfeeding: unknown safety; consult healthcare provider
Avoid exposure to eyes and skin; rinse immediately if contact occurs
Not recommended to change dose or discontinue without physician approval
Patients should inform healthcare providers about all concomitant medications including supplements
Monitor for signs of infection due to frequent respiratory side effects
Use caution in patients with known hypersensitivity to risdiplam or components of the formulation
Regular evaluation recommended to monitor treatment response and adverse effects
Ensure accurate dosing especially in pediatric patients via weight-based guidance
Handle and store medication as per instructions to maintain stability
Avoid mixing oral solution with infant formula or milk
Patients with feeding tubes should follow administration instructions carefully
Report any unusual symptoms or side effects promptly to healthcare provider
Consider fertility counseling for patients planning conception

Warnings

Risk of serious allergic reactions; immediate medical attention needed if symptoms develop
Pregnancy risk: may harm unborn baby; pregnancy testing and strict birth control measures required
Potential decrease in male fertility; discuss reproductive plans with physician
Avoid accidental exposure to eyes and skin; rinse thoroughly if this occurs
Do not take extra doses or double dose if a dose is missed beyond 6 hours
Use caution when administering to infants and young children due to variable pharmacokinetics
Patients should be instructed not to alter dose or discontinue therapy without medical advice
Monitor for respiratory infections as they can be serious especially in SMA patients
Proper storage required to prevent degradation which may affect efficacy
Not intended for use beyond approved indications without physician supervision
Inform all healthcare providers about use of risdiplam to avoid interactions
Use only reconstituted oral solution prepared by pharmacist or as directed
Adherence to dosing schedule important to maintain therapeutic drug levels
Avoid use of expired medication to prevent reduced effectiveness or adverse events

Contraindication

Known hypersensitivity to risdiplam or any ingredient in the formulation
Patients with severe allergic reactions to previous doses of risdiplam
Do not use oral powder without proper reconstitution
Contraindicated to mix oral solution with milk or infant formula
Not recommended for patients with uncorrected swallowing disorders without feeding tube support
Use in treatment of conditions other than spinal muscular atrophy has not been established
Contraindicated in patients unwilling to comply with strict dosing and monitoring regimen
Avoid use in pregnant women unless clearly needed and benefits outweigh risks
No established safety in breastfeeding; avoid if possible
Contraindicated in patients with unstable respiratory infections without medical clearance
Avoid concurrent use with unknown or interacting agents without professional guidance
Contraindicated if oral tablets cannot be swallowed whole and no alternative formulation given
Use with caution in patients with significant hepatic or renal impairment until further data available

Drug Interactions

Potential interactions with strong CYP3A4 inhibitors or inducers may alter risdiplam metabolism
Concurrent use with other central nervous system active agents requires monitoring
Interaction with vitamin and herbal supplements possible; disclose all medications to provider
No significant interactions reported with common over-the-counter medications based on current data
Interaction with drugs affecting RNA splicing has not been fully studied, caution advised
Co-administration with anticoagulants or antiplatelet drugs requires careful monitoring
Avoid concomitant use with medications known to prolong QT interval without ECG monitoring
Other investigational drugs for SMA may interact; use under clinical supervision
Drug interactions with neonatal medications require special consideration
No significant food interactions; risdiplam absorption not affected by meals
Avoid grapefruit or grapefruit juice due to CYP3A modulation potential
Interactions with immunosuppressants have not been documented but warrant observation
Herbal supplements like St. John's Wort may reduce risdiplam efficacy via CYP induction
Adjust dosage if co-administered with strong enzyme modulators to maintain therapeutic levels
Clinical monitoring recommended during initiation or discontinuation of interacting drugs

Preparations Of The Drug

Evrysdi oral tablet: available as 5 mg tablets for once-daily dosing
Oral powder for reconstitution provided as a powder to prepare 0.75 mg/mL solution
Risdiplam oral solution intended for pediatric and adult patients requiring precise weight-based dosing
The powder requires mixing with water according to pharmacy instructions prior to administration
Supplied with specific measuring devices to ensure accurate oral dosing
Reusable oral syringes provided for patients requiring administration via feeding tube
Storage conditions: tablets stored at room temperature, protected from moisture and heat
Liquid preparation should be stored as per pharmacist’s instructions, usually refrigerated after reconstitution
Do not use liquid medicine in powder form; always ensure proper preparation before dosing
Package insert includes detailed Instructions for Use to maximize safety and efficacy
Preparation and administration instructions provided for caregivers assisting infants and pediatric patients
Multi-dose bottles and single-dose vials may be available depending on market
Product labeling emphasizes patient adherence and proper handling to maintain drug stability
Powder packets designed for single use to prevent contamination
Pharmacy mixing service recommended to ensure uniform solution concentration