Risdiplam is a survival motor neuron 2 (SMN2)-directed RNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA) in adult and pediatric patients, including neonates. SMA is a rare and often fatal hereditary genetic disease affecting muscle strength and movement. It causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. Risdiplam is associated with an increased risk of teratogenicity; therefore, adolescent and adult women should use birth control while on treatment and for at least 1 month after stopping treatment. Male infertility may occur during treatment; male patients may consider sperm preservation prior to treatment. The most common adverse reactions of risdiplam are fever, diarrhea, and rash. A clinical trial in pediatric patients with infantile-onset SMA (median age of onset of clinical signs and symptoms was 1.5 months; median age at enrollment was 5.6 months) assessed the percentage of patients able to sit without support for at least 5 seconds and survival without permanent ventilation. After 12 months, 32.8% of patients were able to sit independently for at least 5 seconds, and 87.1% were alive without permanent ventilation. At 24 months of treatment, 60.3% of patients were able to sit independently for at least 5 seconds, and 83.8% were alive without permanent ventilation. A clinical trial in pediatric and adult patients with later-onset SMA (n = 180; aged 2 to 25 years) assessed the change in baseline Motor Function Measure-32 (MFM32), a test of motor function, at 12 months. Patients in the risdiplam group saw an average 1.36 increase in their score at the 1 year mark, compared to a 0.19 decrease in patients receiving placebo.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Risdiplam must be constituted by a pharmacist prior to dispensing to the patient.
-The "Instructions for Constitution" booklet contains more detailed instructions on the preparation of the oral solution.
-Use caution when handling risdiplam powder for oral solution. Wear disposable gloves during the preparation and cleanup procedure. Avoid inhalation and direct contact of the dry powder or constituted solution with the skin or mucous membranes. If contact occurs, wash thoroughly with soap and water and rinse eyes with water.
-Discuss with the patient or caregiver how to prepare the prescribed daily dose prior to administration of the first dose.
Oral Liquid Formulations
Reconstitution
-Loosen the powder by gently tapping the bottom of the closed glass bottle.
-Remove the cap, but do not throw it away.
-Pour 79 mL of Purified Water into the risdiplam bottle to yield the 0.75 mg/mL oral solution. Do NOT mix with formula or milk.
-Insert the Press-In bottle adapter into the bottle opening by pushing it down against the bottle lip. Ensure it is completely pressed against the bottle lip.
-Re-cap the bottle and shake well for 15 seconds. Wait 10 minutes to see if the solution is clear. If not, shake well again for another 15 seconds.
-Write the expiration date (calculated as 64 days after constitution) and the lot number on the bottle label of the constituted oral solution. Remove the part of the bottle label that has the expiration date of the powder.
-Return the bottle into the original container and select the appropriate syringe (1 mL, 6 mL, or 12 mL). Discard other syringes
-Storage: Store the constituted oral solution in the original amber bottle (to protect from light) in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze. The solution may be kept at room temperature up to 40 degrees C (104 degrees F) for a combined total of 5 days. It can be removed from and returned to a refrigerator. Keep the bottle in an upright position. Discard any unused portion after a combined total of 5 days at room temperature or after 64 days since reconstitution.
Administration
-Instruct patient or caregiver to prepare the dose using the provided reusable oral syringe.
-Administer dose immediately after it is drawn up into the oral syringe; if more than 5 minutes pass, discard the dose, and prepare a new dose.
-Administer once daily after a meal at approximately the same time every day. Follow dose with water to ensure the drug has been completely swallowed.
-In breast-feeding infants, administer dose after breastfeeding; risdiplam cannot be mixed with milk or formula.
-If the patient is unable to swallow and has a nasogastric or gastrostomy tube, administer risdiplam via the tube. Flush with water after the dose is delivered.
-If a dose is missed, administer risdiplam as soon as possible if still within 6 hours of the missed dose, and resume the usual dosing schedule on the next day. Otherwise, skip the missed dose and take the next dose at the regularly scheduled time on the next day. If a dose is not fully swallowed or vomiting occurs after taking the dose, do not administer another dose to make up for the lost dose.
Fever, which includes pyrexia and hyperpyrexia, occurred in 22% of patients receiving risdiplam for later-onset spinal muscular atrophy (SMA) compared to 17% of patients receiving placebo. Urinary tract infection, including cystitis, occurred in 5% of patients receiving risdiplam compared to 0% of patients receiving placebo. Cough, upper respiratory tract infection (including naso-pharyngitis and rhinitis), and lower respiratory tract infection (including pneumonia and bronchitis) were reported in 10% or more of patients receiving risdiplam for infantile-onset SMA.
Rash, which includes erythema, maculopapular rash, erythematous rash, papular rash, allergic dermatitis, and folliculitis, occurred in 17% of patients receiving risdiplam for later-onset spinal muscular atrophy (SMA) compared to 2% of patients receiving placebo.
Diarrhea occurred in 17% of patients receiving risdiplam for later-onset spinal muscular atrophy (SMA) compared to 8% of patients receiving placebo. Constipation and vomiting were reported in 10% or more of patients receiving risdiplam for infantile-onset SMA.
Oral ulceration, which includes mouth and aphthous ulcers, occurred in 7% of patients receiving risdiplam for later-onset spinal muscular atrophy (SMA) compared to 0% of patients receiving placebo. Arthralgia occurred in 5% of patients receiving risdiplam compared to 0% of patients receiving placebo.
Risdiplam may cause embryofetal harm when administered during pregnancy. There are no available data regarding risdiplam use during human pregnancy to inform a drug-associated risk; however, embryofetal harm has been documented in animals. Animal data in rats found that oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg) resulted in decreased fetal body weight and increased incidences of fetal structural variations at the highest dose tested, which was not associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development (3 mg/kg/day) was associated with a maternal plasma exposure (AUC) approximately 2 times that in humans at the maximum recommended human dose (MRHD) of 5 mg. Oral administration of risdiplam (0, 1, 4, or 12 mg/kg) to pregnant rabbits during organogenesis resulted in embryofetal mortality, fetal malformations (hydrocephaly), and structural variations at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development (4 mg/kg/day) was associated with a maternal plasma exposure (AUC) approximately 4 times that in humans at the MRHD. When risdiplam (0, 0.75, 1.5, or 3 mg/kg) was orally administered to rats throughout pregnancy and lactation, gestation was prolonged in dams, and delayed sexual maturation (vaginal opening) and impaired reproductive function (decreased numbers of corpora lutea, implantation sites, and live embryos) were observed in female offspring at the highest dose. The no-effect dose for adverse effects on embryofetal development (1.5 mg/kg/day) was associated with a maternal plasma exposure (AUC) similar to that in humans at the MRHD. There is a pregnancy exposure registry that monitors outcomes in patients exposed to risdiplam during pregnancy. Health care providers are encouraged to register pregnant patients, or pregnant patients may enroll themselves in the registry by calling 1-833-760-1098 or visiting www.evrysdipregnancyregistry.com.
Counsel patients about risdiplam associated reproductive risk and contraception requirements. Females of reproductive age are advised to use effective contraception prior to the initial dose, during treatment, and for at least 1 month after the last dose. Pregnancy testing is recommended for females of reproductive age prior to treatment initiation with risdiplam. In addition, based on animal data, risdiplam may cause impaired male fertility or infertility. Specifically, risdiplam affected male reproductive systems, including germ cells, in juvenile and adult rats and monkeys when administered at clinically-relevant plasma exposures. Counsel male patients about the potential effects on fertility; patients may consider sperm preservation prior to treatment.
There are no data on the presence of risdiplam in human milk, the effects on the breastfed infant, or the effects on milk production. Risdiplam was excreted in the milk of lactating rats receiving oral risdiplam. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of spinal muscular atrophy (SMA):
Oral dosage:
Adults: 5 mg PO once daily after a meal at the same time each day.
Children and Adolescents 2 to 17 years weighing 20 kg or more: 5 mg PO once daily after a meal at the same time each day.
Children 2 to 12 years weighing less than 20 kg: 0.25 mg/kg/dose PO once daily after a meal at the same time each day.
Infants and Children 2 months to younger than 2 years of age: 0.2 mg/kg/dose PO once daily after a meal at the same time each day.
Infants younger than 2 months of age: 0.15 mg/kg/dose PO once daily after a meal at the same time each day.
Neonates: 0.15 mg/kg/dose PO once daily after a meal at the same time each day.
Maximum Dosage Limits:
-Adults
5 mg/day PO.
-Geriatric
5 mg/day PO.
-Adolescents
5 mg/day PO.
-Children
2 to 12 years weighing 20 kg or more: 5 mg/day PO.
2 to 12 years weighing less than 20 kg: 0.25 mg/kg/day PO.
1 year: 0.2 mg/kg/day PO.
-Infants
2 to 11 months: 0.2 mg/kg/day PO.
younger than 2 months: 0.15 mg/kg/day PO.
-Neonates
0.15 mg/kg/day PO.
Patients with Hepatic Impairment Dosing
The pharmacokinetic changes of risdiplam in patients with mild or moderate hepatic impairment (as defined by Child-Pugh class A and B, respectively) are not considered to be clinically meaningful. The pharmacokinetics of risdiplam in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Alogliptin; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Canagliflozin; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Dapagliflozin; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Empagliflozin; Linagliptin; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Empagliflozin; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Ertugliflozin; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Glipizide; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Glyburide; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Linagliptin; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Metformin; Repaglinide: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Metformin; Saxagliptin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Metformin; Sitagliptin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Pioglitazone; Metformin: (Moderate) Concomitant administration of metformin and risdiplam may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion 1 (MATE1) substrate and risdiplam is a an MATE1/2-K inhibitor. MATE inhibitors may decrease metformin elimination by blocking renal tubular secretion.
Risdiplam is a survival of motor neuron 2 (SMN2)-directed ribonucleic acid (RNA) splicing modifier designed to treat patients with spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. Risdiplam was shown to increase exon 7 inclusion in SMN2 messenger RNA transcripts and production of full-length SMN protein in the brain when using in vitro assays and studies in transgenic animal models of SMA. Based on in vitro and in vivo data, risdilam may cause alternative splicing of additional genes, including FOXM1 and MADD. FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse reactions seen in animals.
Risdiplam is administered orally. Risdiplam pharmacokinetics were approximately linear between 0.6 and 18 mg in a single-ascending-dose study in healthy adult patients, and between 0.02 and 0.25 mg/kg once daily in a multiple-ascending-dose study in patients with spinal muscular atrophy. Risdiplam is predominately bound to serum albumin, without any binding to alpha-1 acid glycoprotein, with a free fraction of 11%. The Vd at steady-state is 190.4 L for a 31.3 kg patient. The apparent clearance of risdiplam was 2.45 L/hour in a 31.3 kg patient and the terminal elimination half-life was approximately 50 hours in healthy adults. Parent drug was the major component found in plasma, accounting for 83% of drug-related material in circulation. M1, the pharmacologically-inactive metabolite, was the major circulating metabolite. After administration of an 18 mg dose, approximately 53% of the dose (14% unchanged risdiplam) was excreted in the feces and 28% in the urine (8% unchanged risdiplam).
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A1, CYP2J2, CYP3A4, CYP3A7, FMO1, FMO3, MATE1, and MATE2-K
Risdiplam is primarily metabolized by CYPs 1A1, 2J2, 3A4, and 3A7 and also by flavin monooxygenase 1 and 3 (FMO1 and FMO3). In vitro, risdiplam and its metabolite are inhibitors of the multidrug and toxin extrusion (MATE) 1 and MATE2-K transporters.
-Route-Specific Pharmacokinetics
Oral Route
An approximately 3-fold accumulation of peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC0-24h) was observed after once-daily oral risdiplam administration in healthy patients. Risdiplam reaches steady-state 7 to 14 days after once-daily administration. After oral administration, the time to reach maximum plasma concentration (Tmax) is between 1 and 4 hours. During clinical efficacy studies, risdiplam was administered with a morning meal or after breastfeeding.
-Special Populations
Hepatic Impairment
After administration of risdiplam 5 mg, the AUC and Cmax were approximately 20% and 5% lower, respectively, in patients with mild hepatic impairment (Child-Pugh class A, n = 8) and were approximately 8% and 20% higher, respectively, in patients with moderate hepatic impairment (Child-Pugh class B, n = 8), versus matched healthy controls (n = 10). The pharmacokinetics of risdiplam in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Renal Impairment
The pharmacokinetics of risdiplam do not appear to be altered in patients with renal impairment.
Pediatrics
Body weight and age were found to have a significant effect on the pharmacokinetics of risdiplam. The estimated exposure (mean AUC0-24h) in pre-symptomatic infants (age 1 to 2 months at enrollment) was 1,920 ng*hour/mL at a dose of 0.15 mg/kg once daily. The estimated exposure (mean AUC0-24h) for infantile-onset spinal muscular atrophy (SMA) patients (age 2 to 7 months at enrollment) was 1,930 ng*hour/mL at a dose of 0.2 mg/kg once daily. The estimated exposure for later-onset SMA patients (age 2 to 25 years at enrollment) was 2,070 ng*hour/mL at doses of 0.25 mg/kg once daily for patients with a body weight less than 20 kg and 5 mg once daily for patients with a body weight 20 kg or more.
Gender Differences
There are no clinically significant differences in the pharmacokinetics of risdiplam based on gender.
Ethnic Differences
There are no clinically significant differences in the pharmacokinetics of risdiplam based on race.