risdiplam

Action and Spectrum

Actions and Spectrum: 

risdiplam is an oral medication approved for treating spinal muscular atrophy (SMA). It is a disease-modifying therapy that increases the production of the survival motor neuron protein. 

The action of risdiplam: 

• SMN2 gene splicing modification: SMA is caused by the mutations in the survival motor neuron 1 gene, leading to a deficiency of the SMN protein. However, humans also have a backup gene called SMN2, which produces some functional SMN proteins. Unfortunately, the SMN2 gene typically produces a truncated and unstable version of the protein, resulting in lower levels of functional SMN protein. risdiplam is designed to modify the splicing of SMN2 pre-mRNA (the intermediary step in protein production), increasing the production of full-length, functional SMN protein from the SMN2 gene. 
• Restoration of motor neuron function: By increasing the production of functional SMN protein, risdiplam helps restore critical SMN protein levels in motor neurons, which transmit signals from the brain to muscles, thus improving motor neuron function and slowing down the progression of muscle weakness. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Constipation 

Rash  

Upper respiratory tract infection 

Diarrhea  

Fever 

Vomiting 

Pneumonia 

1-10% 

Arthralgia (5%) 

Mouth and aphthous ulcers (7%) 

Urinary tract infection (5%) 

Black Box Warning

Black Box Warning: 

None 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: risdiplam should not be used in individuals with known hypersensitivity/allergy to the active substance (risdiplam) or any other ingredients present in the formulation. 
• Concomitant Use with Strong CYP3A4 Inducers: risdiplam is metabolized by CYP3A4, a liver enzyme involved in drug metabolism. Concomitant use of strong CYP3A4 inducers (medications that increase the activity of CYP3A4) may reduce the effectiveness of risdiplam and should generally be avoided. 
• Severe Hepatic Impairment: risdiplam has not been studied in individuals with severe hepatic impairment, and its safety and efficacy in such patients are not established. Therefore, its use in individuals with severe liver problems may be contraindicated. 

Caution 

• Hepatotoxicity: risdiplam may cause liver-related adverse effects. Liver function tests should be performed before starting treatment, every two weeks for the first three months, and periodically afterward. If signs of liver problems (e.g., elevated liver enzymes) are observed, further evaluation and possible dose adjustment may be necessary. 
• Interactions with CYP3A4 Inducers: risdiplam is metabolized by the liver enzyme CYP3A4. Co-administration of strong CYP3A4 inducers may reduce the effectiveness of risdiplam. Therefore, caution should be exercised when using risdiplam in combination with strong CYP3A4 inducers, and alternative treatment options may need to be considered. 
• Risk of Bleeding: risdiplam may increase the risk of bleeding, particularly in individuals taking medications that affect blood clotting. Caution is advised when using risdiplam in patients with a history of bleeding disorders or those taking anticoagulant medications. 
• Respiratory Complications: Patients with SMA may have respiratory muscle weakness, which could lead to respiratory complications. Caution should be exercised when initiating risdiplam treatment in patients with compromised respiratory function. 
• Interaction with Vaccines: There may be a potential risk of reduced vaccine efficacy when administered with risdiplam. The timing of vaccinations should be discussed with healthcare providers. 
• Pregnancy and Breastfeeding: The safety of risdiplam in pregnant and breastfeeding women has not been fully established.  
• Pediatric Use: risdiplam has been approved for use in pediatric patients with SMA. However, specific dosing and monitoring considerations for this age group should be discussed with healthcare providers. 

Pregnancy / Lactation

Pregnancy consideration:  

AU TGA pregnancy category: D 

US FDA pregnancy category: Not assigned. 

Lactation:   

Excreted into human milk: Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

risdiplam is an orally administered minor molecule medication used to treat spinal muscular atrophy (SMA). As a survival motor neuron 2 (SMN2) mRNA splicing modifier, it targets the root cause of SMA by enhancing the production of functional SMN protein from the SMN2 gene. By modifying the splicing of SMN2 pre-mRNA, risdiplam promotes the synthesis of full-length SMN protein, which is important for the survival and function of motor neurons.

This disease-modifying therapy helps slow the progression of muscle weakness, improves motor function, and has been approved for use in various age groups, including infants, children, and adults with SMA. Regular monitoring and appropriate dose adjustments are crucial to ensure its safety and effectiveness in SMA patients. 

Pharmacodynamics: 

Mechanism of action: The action of risdiplam is centered around increasing the production of functional survival motor neuron protein, which is essential for the survival and function of motor neurons.  

• Splicing Modification of SMN2 Gene: SMA is caused by mutations in the SMN1 gene, leading to a deficiency of the SMN protein. However, humans also have a backup gene called SMN2, which can produce some functional SMN proteins. Unfortunately, the SMN2 gene usually generates a shorter and less stable form of the SMN protein, resulting in lower levels of functional SMN protein than SMN1. 
• SMN2 Gene Pre-mRNA Splicing: In the process of producing the SMN protein, the SMN2 gene undergoes pre-mRNA splicing, which involves removing certain non-coding regions (introns) and joining the coding regions (exons) to form the mature mRNA. This splicing process results in the generation of both full-length and truncated SMN proteins. 
• Modifying SMN2 Splicing with risdiplam: risdiplam is a small molecule drug known as an SMN2 mRNA splicing modifier. It specifically targets the splicing of the SMN2 gene pre-mRNA to promote the production of full-length, functional SMN protein. By acting on the splicing machinery, risdiplam enhances the inclusion of exon seven during splicing, leading to increased production of the full-length SMN protein. 
• Increased Functional SMN Protein Levels: With risdiplam treatment, the levels of functional SMN protein are augmented in motor neurons. This helps compensate for the SMN protein deficiency caused by the mutations in the SMN1 gene, thus improving motor neuron survival and function. 
• Disease Modification in SMA: By increasing functional SMN protein levels, risdiplam aims to modify the disease course of SMA. It can slow down the progression of muscle weakness and atrophy, improving motor function and quality of life in individuals with SMA. 

Pharmacokinetics: 

Absorption 

risdiplam is administered orally in the form of a liquid solution. After ingestion, it is expected to be absorbed from the gastrointestinal tract into the bloodstream. Factors such as food intake and individual patient characteristics may influence the absorption rate. 

Distribution 

Once absorbed into the bloodstream, risdiplam will likely distribute throughout the body. It is expected to reach various tissues, including the central nervous system, where it can exert its therapeutic effects on the survival motor neuron (SMN) protein. 

Metabolism 

risdiplam is metabolized primarily in the liver. The publicly available information should have extensively discussed the specific metabolic pathways and metabolites generated during its metabolism. The metabolism of risdiplam is likely to involve liver enzymes, particularly the cytochrome P450 (CYP) enzyme system. 

Elimination and Excretion 

The elimination of risdiplam and its metabolites from the body primarily occurs through feces and urine. The available information did not specify the exact excretion pathways and the proportion of the drug excreted unchanged or as metabolites. 

Adminstartion

Administration: 

Oral administration 

• Dosage: The appropriate dosage of risdiplam is determined by the patient’s age, weight, and medical condition. It is essential to follow the healthcare provider’s dosing instructions or as mentioned on the prescription label. 
• Oral Administration: risdiplam is taken orally, which means it is swallowed. It is essential to use the provided dosing syringe or measuring device to ensure accurate dosing. 
• Timing: The dosing schedule for risdiplam may vary based on the patient’s age and treatment plan. Generally, taking risdiplam at the same time each day is recommended to maintain consistent levels in the bloodstream. 
• Food: risdiplam can be taken with or without food. Patients can take it at a time that fits best with their meal schedule. 
• Storage: risdiplam should be stored according to the manufacturer’s instructions. Typically, it is kept at room temperature, away from direct sunlight and moisture. It is essential to keep it out of the reach of children. 
• Missed Dose: If a dose of risdiplam is missed, the patient should take it as soon as they remember. However, if it is close to the time of the next scheduled dose, it is better to skip the missed dose and continue with the regular dosing schedule.  
• Overdose: In case of accidental overdose, immediate medical attention should be sought. Overdose symptoms may include nausea, vomiting, diarrhea, or other adverse effects. 
• Duration of Treatment: risdiplam treatment will depend on the patient’s medical condition and also response to the medication. To achieve the best possible outcome, it is essential to continue the treatment as prescribed by the healthcare provider, even if the patient feels better. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: risdiplam 

Why do we use risdiplam? 

risdiplam is specifically designed to address the underlying cause of SMA, a deficiency of the survival motor neuron (SMN) protein. It helps increase the production of functional SMN protein, which is important for the survival and function of motor neurons. By increasing SMN protein levels, risdiplam aims to slow the progression of muscle weakness and improve motor function in patients with SMA. 

Treatment of Spinal Muscular Atrophy (SMA): risdiplam is approved for the treatment of SMA in various age groups, including: 

• Infants with SMA who are under two months of age. 
• Pediatric patients with SMA aged two months and older. 
• Adult patients with SMA 

Disease-Modifying Therapy: risdiplam is classified as a disease-modifying therapy because it targets the root cause of SMA by enhancing the production of functional SMN protein. This approach differs from symptomatic treatments, which aim to manage the symptoms of the disease rather than addressing its underlying cause.