risdiplam (Rx)

>10%

Fever (22%)

Diarrhea (17%)

Rash (17%)

Additional adverse effects in infantile-onset SMA

• Upper respiratory tract infection
• Pneumonia
• Constipation
• Vomiting

1-10%

Mouth and aphthous ulcers (7%)

Arthralgia (5%)

Urinary tract infection (5%)

Contraindications

None

Cautions

Drug interaction overview

• MATE substrates

  • Avoid coadministration; if unable to avoid, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug (based on the labeling of that drug) if needed
  • Based on in vitro data, risdiplam may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K (eg, metformin)

Pregnancy

There is pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to EVRYSDI during pregnancy; physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833- 760-1098 or visiting https://www.evrysdipregnancyregistry.com

Data are unavailable on developmental risk associated with the use in pregnant females

May cause embryofetal harm when administered to pregnant females

Pregnancy testing recommended for females of reproductive potential before initiating

Animal studies

• In animal studies, risdiplam administration 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 exposure

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for at least 1 month after last dose

Infertility

• Male fertility may be compromised by treatment
• Counsel male patients of reproductive potential about potential reproductive effects
• Male patients may consider sperm preservation before treatment

Lactation

Data are not available on presence in human milk, effects on breastfed infants, or effects on milk production

Orally administered risdiplam was excreted in milk of lactating rats

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Survival of motor neuron 2 (SMN2) mRNA splicing modifier designed treat mutations in chromosome 5q that lead to SMN protein deficiency

Absorption

Peak plasma time: 1-4 hr

Steady-state reached: 7-14 days

Distribution

Protein bound: Predominantly bound to serum albumin, without any binding to alpha-1 acid glycoprotein, with a free fraction of 11%

Vd: 6.3 L/kg

Metabolism

Primarily metabolized by flavin monooxygenase 1 and 3 (FMO1 and FMO3) and also by CYPs 1A1, 2J2, 3A4, and 3A7

Parent drug was the major component found in plasma, accounting for 83% of drug-related material in circulation

Elimination

Half-life: ~50 hr

Clearance: 2.1 L/h (14.9 kg patient)

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

Oral Preparation

Must be reconstituted to oral solution by a pharmacist or other healthcare provider before dispensing to patient

Preparation of oral solution 0.75 mg/mL

• Exercise caution handling powder for oral solution; avoid inhalation and direct contact with skin or mucous membranes with dry powder and reconstituted solution
• If such contact occurs, wash thoroughly with soap and water; rinse eyes with water
• Wear disposable gloves during preparation and cleanup procedure

• Reconstitution

  • Gently tap bottom of closed glass bottle to loosen powder
  • Remove cap, but do not throw away
  • Carefully pour 79 mL of purified water into bottle to yield 0.75 mg/mL oral solution; do not mix with formula or milk
  • Insert press-in bottle adapter into bottle opening by pushing it down against bottle lip; ensure it is completely pressed against bottle lip
  • Recap bottle tightly and shake well for 15 seconds; wait for 10 minutes; solution should appear clear; if not, shake well again for another 15 seconds
  • Write expiration date (calculated as 64 days after constitution) and lot number on bottle label; peel off the part of the bottle label listing the powder expiration date
  • Put bottle back in its original carton
  • Select appropriate oral syringes (1 mL, 6 mL, or 12 mL) based on dose and remove other oral syringes from the carton
  • Dispense with the “Instructions for Use” and FDA-approved patient labeling; alert patients to read the important handling information described in the Instructions for Use

Oral Administration

Take once daily after a meal at approximately the same time each day

Drink water after administration to ensure drug is completely swallowed

Breastfed infants: Administer after breastfeeding

Can be administered via nasogastric or gastrostomy tube; flush tube with water after administering

Missed dose

• Within 6 hr of missed dose: Take as soon as possible, and then resume usual dosing on following day
• >6 hr after missed dose: Skip missed dose and take next dose at regularly scheduled time on the following day
• Dose is not fully swallowed or vomited: Do not take another dose to make up for the lost dose; wait until the next day to take at regularly scheduled time

Storage

Dry powder

• Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
• Keep in the original carton

Reconstituted oral solution

• Refrigerate at 2-8ºC (36-46ºF)
• Do not freeze
• Keep oral solution in original amber bottle to protect from light
• Keep bottle in an upright position with the cap tightly closed
• Discard any unused portion 64 days after constitution