Risdiplam

Approved Indications:

• Spinal Muscular Atrophy (SMA):
  Risdiplam is indicated for the treatment of 5q-associated Spinal Muscular Atrophy (SMA) in patients 2 months of age and older, with a bi-allelic mutation in the SMN1 gene, including:
• Type 1 SMA (infantile-onset)
• Type 2 SMA (intermediate severity)
• Type 3 SMA (juvenile-onset)
  It is approved irrespective of the number of SMN2 gene copies and may be used in patients with or without respiratory support.

Clinically Accepted Off-Label Use:

• No well-established off-label uses currently exist. Risdiplam’s application is disease-specific, and investigational use is ongoing for adult-onset SMA and SMA type 0 in clinical settings.

Route of Administration: Oral solution (administered orally or via feeding tube)

Administration Instructions:

• Administer once daily after a meal at the same time each day.
• Do not mix with food or liquids.
• The solution should be swallowed directly or given via a nasogastric or gastrostomy tube.
• Do not shake the bottle.
• Use the provided oral syringe for accurate dosing.

Dosage by Body Weight:

Pediatric Patients (≥2 months):

• Dose according to weight as outlined above.
• Not established for use in infants under 2 months.

Adolescents and Adults (≥20 kg):

• 5 mg once daily

Elderly:

• No dosage adjustment based on age alone; limited data in patients ≥65 years.

Renal Impairment:

• No adjustment required in mild or moderate impairment.
• Use with caution in severe renal impairment (insufficient data available).

Hepatic Impairment:

• No adjustment needed in mild to moderate hepatic dysfunction.
• Avoid in severe hepatic impairment unless clearly necessary.

Risdiplam is a small-molecule SMN2 pre-mRNA splicing modifier. It acts by binding to specific sites on the SMN2 pre-mRNA and promotes the inclusion of exon 7 during the mRNA splicing process. This leads to increased production of full-length, functional SMN (Survival of Motor Neuron) protein, which is essential for the survival and proper function of motor neurons. By enhancing SMN protein levels both in the central nervous system and peripheral tissues, Risdiplam helps slow or prevent degeneration of motor neurons, thereby improving or maintaining motor function in patients with SMA.

• Absorption: Rapid oral absorption with peak plasma concentration (Tmax) reached within 1 to 4 hours.
• Bioavailability: Approximately 88% following oral administration.
• Distribution: Volume of distribution ~190 L. Plasma protein binding ranges from 11% to 29%.
• Metabolism: Primarily metabolized by FMO1, and to a lesser extent by CYP3A4. No significant active metabolites.
• Elimination: Excreted mainly as unchanged drug — ~53% via feces and ~28% via urine.
• Half-life: Approximately 50 hours (terminal elimination half-life).
• Steady-State: Achieved within 7–14 days of once-daily dosing.

• Pregnancy:
• Not assigned a formal FDA category.
• Animal studies show potential teratogenic effects including fetal death, skeletal abnormalities, and postnatal growth delay at exposures similar to those in humans.
• Use only if the potential benefit outweighs the fetal risk.
• Lactation:
• Unknown whether Risdiplam is excreted in human milk.
• Due to potential risks, breastfeeding is not recommended during treatment and for at least 1 week after the final dose.
• Precaution: Effective contraception is recommended for women of reproductive potential during treatment and for 1 month after stopping therapy.

• Primary Class: SMN2 Splicing Modifier
• Subclass: Disease-Modifying Agent for 5q-Associated Spinal Muscular Atrophy

• Hypersensitivity to Risdiplam or any of its components
• Pregnancy (relative contraindication due to potential embryofetal toxicity)
• Severe hepatic impairment (due to lack of data)
• Concomitant use with strong inhibitors of FMO1 and CYP3A4 without clinical justification

• Embryo-Fetal Toxicity: Avoid in pregnancy; teratogenic effects observed in animals.
• Male Reproductive Toxicity: Decreased sperm counts and testicular degeneration were observed in preclinical studies; clinical relevance unknown.
• Hematological Effects: Periodic monitoring of platelet count, hemoglobin, and neutrophil levels is recommended.
• Liver Function Abnormalities: Caution in patients with hepatic impairment; monitor liver enzymes if needed.
• Vision Effects: Retinal toxicity seen in animal studies; monitor for visual symptoms though human relevance is unclear.
• Growth Monitoring: Long-term use may require assessment of pediatric growth parameters.

Common Side Effects (≥5%):

• Gastrointestinal: Diarrhea, nausea, constipation, vomiting
• General: Fever, headache, fatigue
• Respiratory: Upper respiratory tract infection, cough
• Dermatologic: Rash
• Oropharyngeal: Mouth ulcers, sore throat

Serious or Rare Side Effects:

• Thrombocytopenia
• Anemia
• Elevated liver enzymes
• Severe hypersensitivity reactions
• Male fertility issues (seen in animals)

Severity & Onset:

• Most side effects are mild to moderate and occur early in the treatment course.
• Hematologic and hepatic events may develop with continued use and require monitoring.

• Strong CYP3A4 and FMO1 Inhibitors (e.g., fluvoxamine, cimetidine):
• May increase Risdiplam plasma concentration; avoid or monitor closely.
• Moderate/Strong CYP Inducers (e.g., rifampin, carbamazepine):
• May reduce efficacy; avoid unless necessary.
• Food Interactions:
• Should be taken after a meal; food does not significantly affect absorption.
• Alcohol:
• No known direct interaction; use caution in patients with liver disease.

Enzyme Involvement:

• Metabolized primarily by FMO1, with minor CYP3A4 contribution. Not a major substrate or inhibitor of CYP450 enzymes.

• FDA Approval (2020): Risdiplam became the first oral treatment approved for SMA in patients ≥2 months of age.
• Clinical Trial Outcomes (SUNFISH & FIREFISH):
• Demonstrated sustained improvement in motor function over 24+ months.
• Showed benefit across SMA types 1, 2, and 3.
• Guidelines (Cure SMA, AAN):
• Recognized as a first-line treatment, particularly for patients who are not candidates for gene therapy or intrathecal injections.
• Fertility & Pregnancy Warning Reinforcement:
• Updated product labeling emphasizes reproductive toxicity.

• Temperature: Store in a refrigerator at 2°C to 8°C.
• Room Temperature Stability: After dispensing, may be stored at room temperature (≤30°C) for up to 60 days.
• Light Protection: Keep in the original carton to protect from light.
• Humidity: Keep tightly closed; avoid exposure to moisture.
• Reconstitution: Not required; the oral solution is provided ready-to-use.
• Discard Policy: Discard any unused solution 60 days after opening, even if the bottle is not empty.