Risdiplam: Pediatric drug information

Copyright 1978-2021 Lexicomp, Inc. All rights reserved.

(For additional information see "Risdiplam: Drug information" and see "Risdiplam: Patient drug
information")

For abbreviations and symbols that may be used in Lexicomp (show table)

Brand Names: US
Evrysdi

Brand Names: Canada

Evrysdi

Therapeutic Category
Survival of Motor Neuron 2 (SMN2)-Directed RNA Splicing Modifier

Dosing: Pediatric
Spinal muscular atrophy (SMA):

Infants ≥2 months to Children <2 years: Oral: 0.2 mg/kg/dose once daily.

Children ≥2 years and Adolescents: Oral:

<20 kg: 0.25 mg/kg/dose once daily.

≥20 kg: 5 mg once daily.

Dosing: Renal Impairment: Pediatric

Infants ≥2 months, Children, and Adolescents: There are no dosage adjustments
provided in the manufacturer's labeling; however, renal impairment is not expected
to alter exposure to risdiplam.
Dosing: Hepatic Impairment: Pediatric
Infants ≥2 months, Children, and Adolescents: Oral:

Mild to moderate impairment (Child-Pugh class A or B): No dosage

adjustment needed based on data in patients ≥20 kg.

Severe impairment (Child-Pugh class C): There are no dosage adjustments

provided in the manufacturer's labeling (has not been studied).

Dosing: Adult
(For additional information see "Risdiplam: Drug information")

Spinal muscular atrophy

: Oral: 5 mg once daily.

Missed dose:

≤6 hours since usual administration: Administer as soon as possible and

resume usual dosing schedule the next day.

>6 hours since usual administration: Skip missed dose and administer next
dose at usual administration time the next day.

Dosage adjustment for concomitant therapy: Significant drug interactions

exist, requiring dose/frequency adjustment or avoidance. Consult drug
interactions database for more information.

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling;
however, renal impairment is not expected to alter exposure to risdiplam.

Dosing: Hepatic Impairment: Adult

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment
needed.
 Severe impairment (Child-Pugh class C): There are no dosage adjustments
provided in the manufacturer's labeling (has not been studied).

Dosage Forms: US
Excipient information presented when available (limited, particularly for generics);
consult specific product labeling.

Solution Reconstituted, Oral:

Evrysdi: 0.75 mg/mL (80 mL) [contains edetate (edta) disodium dihydrate,
polyethylene glycol, sodium benzoate]

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics);
consult specific product labeling.

Solution Reconstituted, Oral:

Evrysdi: 0.75 mg/mL (80 mL) [contains edetate (edta) disodium dihydrate,
polyethylene glycol, sodium benzoate]

Administration: Pediatric
Oral: Prepare dose only using the provided reusable oral syringe; do not use
household tablespoon or other measuring device. Administer immediately after
drawing up into oral syringe. If dose is not administered within 5 minutes, discard
from the oral syringe and prepare a new dose. Wash syringe after each use.

Administer at the same time each day after a meal or feeding. Do not mix with
milk or formula. Drink water after administration to ensure dose is completely
swallowed. If unable to swallow, dose may be administered through an NG or
gastrostomy tube. Flush tube with water following administration. If dose is
 not fully swallowed or vomiting occurs after administration, do not administer
another dose; resume regular schedule the following day.

Missed dose:

If a dose is missed ≤6 hours from the usual time it is taken, take the dose
as soon as possible.

If >6 hours have passed since the missed dose, do NOT take the missed
dose; resume regular schedule the following day.

Administration: Adult
Oral: Administer after a meal at approximately the same time each day. In infants
who are breastfed, administer after breastfeeding. Do not mix with formula or
milk. Instruct patients to drink water after taking dose to ensure it has been
completely swallowed. If patient is unable to swallow, dose may be administered
through a nasogastric or gastrostomy tube. Flush tube with water following
administration. Prepare dose using the reusable oral syringe provided. Administer
immediately after drawing up into oral syringe. If dose is not administered within 5
minutes, discard from the oral syringe and prepare a new dose. If vomiting occurs
following dose or dose is not fully swallowed, another dose should not be
administered; next dose should be administered at next regularly scheduled time.

Storage/Stability
Prior to reconstitution, store the dry powder at 20°C to 25°C (68°F to 77°F);
excursions permitted between 15°C to 30°C (59°F to 86°F). Keep in the original
carton. Store reconstituted solution refrigerated at 2°C to 8°C (36°F to 46°F) and
use within 64 days. Keep the reconstituted oral solution in the original amber
bottle to protect from light.

Use
Treatment of spinal muscular atrophy (SMA) (FDA approved in ages ≥2 months
and adults).
Medication Safety Issues
High alert medication:

This medication is in a class the Institute for Safe Medication Practices

(ISMP) includes among its list of drug classes that have a heightened risk
of causing significant patient harm when used in error.

Adverse Reactions
The following adverse drug reactions and incidences are derived from product
labeling unless otherwise specified.

>10%:

Dermatologic: Skin rash (17%; including allergic dermatitis, erythema of

skin, erythematous rash, folliculitis, maculopapular rash, papular rash)

Gastrointestinal: Constipation (infants: ≥10%), diarrhea (17%), vomiting

(infants: ≥10%)

Respiratory: Pneumonia (infants: ≥10%), upper respiratory tract infection

(infants: ≥10%; including nasopharyngitis, rhinitis)

Miscellaneous: Fever (22%; including hyperpyrexia)

1% to 10%:

Gastrointestinal: Aphthous stomatitis (≤7%), oral mucosa ulcer (≤7%)

Genitourinary: Urinary tract infection (5%)

Neuromuscular & skeletal: Arthralgia (5%)

Contraindications
There are no contraindications listed in the US manufacturer's labeling.
 Canadian labeling: Hypersensitivity to risdiplam or any component of the
formulation.

Warnings/Precautions
Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium
benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl
alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been
associated with a potentially fatal toxicity (“gasping syndrome”) in
neonates; the “gasping syndrome” consists of metabolic acidosis,
respiratory distress, gasping respirations, CNS dysfunction (including
convulsions, intracranial hemorrhage), hypotension, and cardiovascular
collapse (AAP 1997; CDC 1982); some data suggest that benzoate
displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use
dosage forms containing benzyl alcohol derivative with caution in
neonates. See manufacturer's labeling.

Metabolism/Transport Effects
None known.

Drug Interactions
(For additional information: Launch drug interactions program)

MATE1/2-K Substrates (High Risk with Inhibitors): Risdiplam may increase the
serum concentration of MATE1/2-K Substrates (High Risk with Inhibitors).
Management: Avoid use of risdiplam with MATE substrates if possible. If the
combination cannot be avoided, monitor closely for adverse effects. Consider
a reduced dose of the MATE substrate according to that substrate's labeling if
appropriate. Risk D: Consider therapy modification

Reproductive Considerations
Evaluate pregnancy status prior to use in females of reproductive potential.

Females of reproductive potential should use effective contraception during

therapy and for at least 1 month after the last risdiplam dose.

Adverse effects to male reproductive function and fertility were observed in animal
toxicology studies; males of reproductive potential may want to consider sperm
preservation prior to risdiplam therapy.

Pregnancy Considerations
Based on data from animal reproduction studies, in utero exposure to risdiplam
may cause fetal harm.

Monitoring Parameters
Pregnancy test (in females of reproductive age) prior to initiation.

Mechanism of Action
Treats spinal muscular atrophy caused by mutations in chromosome 5q that lead
to survival motor neuron (SMN) protein deficiency; exerts effect by increasing
exon 7 inclusion in SMN2 messenger ribonucleic acid transcripts and production
of full-length SMN protein.

Pharmacodynamics and Pharmacokinetics (Adult data unless

noted)
Distribution: Vdss: 6.3 L/kg.

Protein binding: ~89%, primarily to albumin.

Metabolism: Primarily hepatic via flavin monooxygenase 1 and 3 (FMO1 and

FMO3); also metabolized by CYP1A1, 2J2, 3A4, and 3A7; forms inactive
metabolite M1.

Half-life elimination: ~50 hours.

 Time to peak: 1 to 4 hours.

Excretion: Feces: ~53% (14% as unchanged drug); urine: 28% (8% as

unchanged drug).

Pharmacodynamics and Pharmacokinetics: Additional

Considerations
Pediatric: Patients <2 months of age are expected to have reduced activity of
flavin monooxygenase 3 (FMO3), which may lead to increased exposure to
risdiplam.

Pricing: US
Solution (reconstituted) (Evrysdi Oral)

0.75 mg/mL (per mL): $167.56

Disclaimer: A representative AWP (Average Wholesale Price) price or price range

is provided as reference price only. A range is provided when more than one
manufacturer's AWP price is available and uses the low and high price reported by
the manufacturers to determine the range. The pricing data should be used for
benchmarking purposes only, and as such should not be used alone to set or
adjudicate any prices for reimbursement or purchasing functions or considered to
be an exact price for a single product and/or manufacturer. Medi-Span expressly
disclaims all warranties of any kind or nature, whether express or implied, and
assumes no liability with respect to accuracy of price or price range data
published in its solutions. In no event shall Medi-Span be liable for special, indirect,
incidental, or consequential damages arising from use of price or price range data.
Pricing data is updated monthly.
REFERENCES

1. Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr.

2001;139(2):317-319. doi:10.1067/mpd.2001.116281
2. Centers for Disease Control (CDC). Neonatal deaths associated with use of
benzyl alcohol--United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-
291. [PubMed 6810084]
3. Evrysdi (risdiplam) [prescribing information]. South San Francisco, CA:
Genentech Inc; April 2021.
4. Evrysdi (risdiplam) [product monograph]. Mississauga, Ontario, Canada:
Hoffmann-La Roche Limited; April 2021.
5. "Inactive" ingredients in pharmaceutical products: update (subject review).
American Academy of Pediatrics Committee on Drugs. Pediatrics.
1997;99(2):268-278. doi:10.1542/peds.99.2.268 [PubMed 9024461]

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