Class: Other Miscellaneous Therapeutic Agents
Chemical Name: 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one
Molecular Formula: C22H23N7O
CAS Number: 1825352-65-5
Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier.
Uses for Risdiplam
Risdiplam has the following uses:
Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.
Risdiplam Dosage and Administration
Risdiplam is available in the following dosage form(s) and strength(s):
For Oral Solution: 60 mg of risdiplam as a powder for constitution to provide a 0.75-mg/mL solution.
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Risdiplam must be constituted by a pharmacist prior to dispensing.
Administer orally once daily after a meal using the provided oral syringe.
Age and Body Weight
Recommended Daily Dosage
2 months to less than 2 years of age
2 years of age and older weighing less than 20 kg
2 years of age and older weighing 20 kg or more
See the manufacturer's labeling for important preparation and administration instructions.
Cautions for Risdiplam
Risk Summary: There are no adequate data on the developmental risk associated with the use of risdiplam in pregnant women. In animal studies, administration of risdiplam during pregnancy or throughout pregnancy and lactation resulted in adverse effects on development (embryofetal mortality, malformations, decreased fetal body weights, and reproductive impairment in offspring) at or above clinically relevant drug exposures.
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Based on animal data, advise pregnant women of the potential risk to the fetus.
Animal Data: Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg) to pregnant rats throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal structural variations at the highest dose tested, which was not associated with maternal toxicity. The no-effect level for adverse effects on embryofetal development (3 mg/kg/day) was associated with 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 throughout 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 maternal plasma exposure (AUC) approximately 4 times that in humans at the MRHD.
When risdiplam (0, 0.75, 1.5, or 3 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, gestation was prolonged in the 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 prenatal and postnatal development in rats (1.5 mg/kg/day) was associated with maternal plasma exposure (AUC) similar to that in humans at the MRHD.
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 orally administered risdiplam.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for risdiplam and any potential adverse effects on the breastfed infant from risdiplam or from the underlying maternal condition.
Females and Males of Reproductive Potential
Studies of risdiplam in juvenile and adult rats and in monkeys demonstrated adverse effects on the reproductive organs, including germ cells, in males at clinically relevant plasma exposures.
Pregnancy testing is recommended for females of reproductive potential prior to initiating risdiplam.
Risdiplam may cause embryofetal harm when administered to a pregnant woman.
Advise female patients of reproductive potential to use effective contraception during treatment with risdiplam and for at least 1 month after her last dose.
Male fertility may be compromised by treatment with risdiplam. Counsel male patients of reproductive potential receiving risdiplam about the potential effects on fertility. Male patients may consider sperm preservation prior to treatment.
The safety and effectiveness of risdiplam in pediatric patients 2 months of age and older have been established. Safety and effectiveness in pediatric patients below the age of 2 months have not been established.
Juvenile Animal Toxicity Data: Oral administration of risdiplam (0, 0.75, 1.5, 2.5 mg/day) to young rats from postnatal day (PND) 4 through PND 31 resulted in decreased growth (body weight, tibia length) and delayed sexual maturation in males at the mid and high dose. The skeletal and body weight deficits persisted after cessation of dosing. Ophthalmic changes consisting of vacuoles in the anterior vitreous were seen at the high dose. Decreases in absolute B lymphocyte counts were observed at all doses after cessation of dosing. Decreases in testis and epididymis weights, which correlated with degeneration of the seminiferous epithelium in the testis, occurred at the mid and high doses; the histopathology findings were reversible, but organ weight persisted after cessation of dosing. Impaired female reproductive performance (decreased mating index, fertility index, and conception rate) was observed at the high dose. A no-effect dose for adverse developmental effects on preweaning rats was not identified. The lowest dose tested (0.75 mg/kg/day) was associated with plasma exposures (AUC) lower than that in humans at the maximum recommended human dose (MRHD) of 5 mg/day.
Oral administration of risdiplam (0, 1, 3, or 7.5 mg/day) to young rats from PND 22 through PND 112 produced a marked increase in micronuclei in the bone marrow, male reproductive organ histopathology (degeneration/necrosis of the seminiferous tubule epithelium, oligo/aspermia in the epididymis, spermatic granulomas), and adverse effects on sperm parameters (decreased sperm concentration and motility, increased sperm morphology abnormalities) at the highest dose tested. Increases in T lymphocytes (total, helper, and cytotoxic) were observed at the mid and high doses. The reproductive and immune effects persisted after cessation of dosing. The no-effect dose (1 mg/kg/day) for adverse effects on postweaning juvenile rats was associated with plasma exposures (AUC) lower than that in humans at the MRHD.
Clinical studies of risdiplam did not include patients aged 65 years and over to determine whether they respond differently from younger patients.
The safety and efficacy of risdiplam in patients with hepatic impairment have not been studied. Because risdiplam is predominantly metabolized in the liver, hepatic impairment may potentially increase the exposures to risdiplam. Avoid use of risdiplam in patients with impaired hepatic function.
Common Adverse Effects
The most common adverse reactions in later-onset SMA (incidence at least 10% of patients treated with risdiplam and more frequent than control) were fever, diarrhea, and rash.
The most common adverse reactions in infantile-onset SMA were similar to those observed in later-onset SMA patients. Additionally, adverse reactions with an incidence of at least 10% were upper respiratory tract infection, pneumonia, constipation, and vomiting.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Avoid coadministration with drugs that are substrates of multidrug and toxin extrusion (MATE) transporters.
Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier designed to treat patients with spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, risdiplam was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein in the brain.
In vitro and in vivo data indicate that risdiplam 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 effects seen in animals.
Advice to Patients
Advise the patient to read the FDA-approved patient labeling (patient information and instructions for use).
Pregnancy and Fetal Risk
Inform pregnant women and women of reproductive potential that, based on animal studies, risdiplam may cause fetal harm.
Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.
Advise women of childbearing potential to use effective contraception during treatment with risdiplam and for at least 1 month after stopping risdiplam.
Advise a female patient to immediately inform the prescriber if she is pregnant or planning to become pregnant.
Potential Effects on Male Fertility
Advise male patients that their fertility may be compromised while on treatment with risdiplam.
Instructions for Preparation of Oral Solution
Advise patients to ensure that risdiplam is in liquid form when received from the pharmacy.
Instruct patients/caregivers to take risdiplam after a meal or after breastfeeding at approximately the same time each day. However, instruct caregivers to not mix risdiplam with formula or milk.
Instruct patients/caregivers that risdiplam should be taken immediately after it is drawn up into the reusable oral syringe.
AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Powder, For Oral Solution
AHFS Drug Information. © Copyright 2021, Selected Revisions September 7, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
More about risdiplam
- Side Effects
- During Pregnancy
- Dosage Information
- Drug Interactions
- En Español
- Drug class: miscellaneous uncategorized agents
- Other brands