EVRYSDI

Risdiplam is an

Oral bioavailable mRNA splicing modifier used for the treatment of spinal muscular atrophy (SMA).

It increases systemic

SMN protein concentrations by improving the efficiency of SMN2 gene transcription.

This mechanism of action is similar to its predecessor nusinersen, the biggest difference being their route of administration: nusinersen requires intrathecal administration, as does the one-time gene therapy onasemnogene abeparvovec, whereas risdiplam offers the ease of oral bioavailability. 9, 4 Risdiplam was approved by the FDA in August for the treatment of spinal muscular atrophy (SMA). 6, 7 Set to be substantially cheaper than other available SMA therapies, 9 risdiplam appears to provide a novel and relatively accessible treatment option for patients with SMA regardless of severity or type.

Risdiplam is indicated for the treatment of spinal muscular atrophy (SMA).

Risdiplam helps to alleviate symptoms of spinal muscular atrophy by stimulating the production of a critical protein in which these patients are deficient.

Early trials with risdiplam demonstrated up to a 2-fold increase in SMN protein concentration in SMA patients after 12 weeks of therapy.

Spinal muscular atrophy (SMA) is a severe and progressive congenital neuromuscular disease resulting from mutations in the survival of motor neuron 1 ( SMN1 ) gene responsible for making SMN proteins.

Clinical features of

SMA include degeneration of motor neurons in the spinal cord which ultimately leads to muscular atrophy and, in some cases, loss of physical strength.

SMN proteins are expressed ubiquitously throughout the body and are thought to hold diverse intracellular roles in DNA repair, cell signaling, endocytosis, and autophagy.

A secondary

SMN gene ( SMN2 ) can also produce SMN proteins, but a small nucleotide substitution in its sequence results in the exclusion of exon 7 during splicing in approximately 85% of the transcripts.

• this means that only ~15% of the SMN proteins produced by SMN2 are functional, 1 which is insufficient to compensate for the deficits caused by SMN1 mutations.

Emerging evidence suggests that many cells and tissues are selectively vulnerable to reduced SMN concentrations, making this protein a desirable target in the treatment of SMA.

Risdiplam is an mRNA splicing modifier for SMN2 that increases the inclusion of exon 7 during splicing, which ultimately increases the amount of functional SMN protein produced by SMN2.

It does so by binding to two sites in SMN2 pre-mRNA: the 5' splice site (5'ss) of intron and the exonic splicing enhancer 2 (ESE2) of exon 7.

T max following oral administration is approximately 1-4 hours. 3, 7 Following once-daily administration with a morning meal (or after breastfeeding), risdiplam reaches steady-state in approximately 7-14 days.

The pharmacokinetics of risdiplam were found to be approximately linear between all studied dosages in patients with SMA.

Following oral administration, risdiplam distributes well into the central nervous system and peripheral tissues.

The apparent volume of distribution at steady-state is 6.3 L/kg.

The metabolism of risdiplam is mediated primarily by flavin monooxygenases and 3 (FMO1 and FMO3), with some involvement of CYP1A1, CYP2J2, CYP3A4, and CYP3A7.

Parent drug comprises approximately 83% of circulating drug material.

A pharmacologically-inactive metabolite, M1, has been identified as the major circulating metabolite.

• this M1 metabolite has been observed in vitro to inhibit MATE1 and MATE2-K transporters, similar to the parent drug.

Hover over products below to view reaction partners Risdiplam Risdiplam M1 metabolite.

Following the oral administration of 18 mg risdiplam, approximately 53% of the dose was excreted in the feces and 28% was excreted in the urine.

Unchanged parent drug comprised 14% of the dose excreted in feces and 8% of the dose excreted in urine.

The terminal elimination half-life of risdiplam is approximately 50 hours in healthy adults.

For a 14.9 kg patient, the apparent clearance of risdiplam is 6.3 L/kg.

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Data regarding overdose of risdiplam are unavailable.

Symptoms of overdose are likely to be consistent with risdiplam's adverse effect profile, and may therefore involve significant fever, diarrhea, and skin reactions.

Administer once daily with or without food per the table below: Age and Body Weight Recommended Daily Dosage Dosage Form Less than 2 months of age 0.15 mg/kg EVRYSDI for Oral Solution 2 months to less than 2 years of age 0.2 mg/kg 2 years of age and older weighing less than 20 kg 0.25 mg/kg 2 years of age and older weighing 20 kg or more 5 mg EVRYSDI for Oral Solution or EVRYSDI Tablet Swallow EVRYSDI tablet whole with water or dispersed in non-chlorinated drinking water (e.g., filtered water).

EVRYSDI for oral solution with the provided oral syringe.

EVRYSDI for oral solution must be constituted by a healthcare provider prior to dispensing.

Information for important preparation and administration instructions. 2.1 Dosing Information EVRYSDI is administered orally once daily with or without food at approximately the same time each day. The recommended dosage is determined by age and body weight.

EVRYSDI tablets are available for patients prescribed the 5 mg dose.

Table 1 Adult and Pediatric Dosing Regimen by Age and Body Weight Age and Body Weight Recommended Daily Dosage Dosage Form Less than 2 months of age 0.15 mg/kg EVRYSDI for Oral Solution 2 months to less than 2 years of age 0.2 mg/kg 2 years of age and older weighing less than 20 kg 0.25 mg/kg 2 years of age and older weighing 20 kg or more 5 mg EVRYSDI for Oral Solution or EVRYSDI Tablet 2.2 Important Administration Instructions It is recommended that a healthcare provider discuss with the patient or caregiver how to prepare the prescribed daily dose prior to administration of the first dose.

In infants who are breastfed, EVRYSDI for oral solution can be administered before or after breastfeeding.

EVRYSDI cannot be mixed with formula or milk.

Instruct patients or caregivers to administer the dose using the reusable oral syringe provided.

EVRYSDI for oral solution must be taken immediately after it is drawn up into the oral syringe.

If EVRYSDI is not taken within 5 minutes, EVRYSDI should be discarded from the oral syringe, and a new dose should be prepared.

Instruct patients to drink water after taking EVRYSDI for oral solution to ensure the drug has been completely swallowed.

EVRYSDI for oral solution can be administered via a nasogastric or gastrostomy tube.

The tube should be flushed with water after delivering EVRYSDI for oral solution.

EVRYSDI tablets whole with water.

Do not chew, cut, or crush the tablets.

Alternatively, the EVRYSDI tablet can also be dispersed in one teaspoon (5 mL) of room temperature non-chlorinated drinking water (e.g., filtered water).

EVRYSDI tablets must not be dispersed in any liquid other than non-chlorinated drinking water.

Do not expose the prepared dispersion to sunlight.

Swirl the small cup gently for up to 3 minutes until fully mixed (though some particles will remain).

Administer the dispersed tablet immediately.

To ensure no particles are left in the small cup, refill it with at least one tablespoon (15 mL) of non-chlorinated drinking water, swirl, and administer immediately again.

EVRYSDI must be taken immediately after it is dispersed in non-chlorinated drinking water.

Discard the prepared dispersion if it is not used within 10 minutes of adding non-chlorinated drinking water.

The dispersed

EVRYSDI tablet can be administered via a nasogastric or gastrostomy tube that is 8 French or higher.

Flush the tube with the non-chlorinated drinking water [at least one tablespoon (15 mL)] used to rinse the dispersion cup. 2.3 Missed Dose If a dose of EVRYSDI is missed, EVRYSDI should be administered as soon as possible if still within 6 hours of the missed dose, and the usual dosing schedule can be resumed on the next day. Otherwise, the missed dose should be skipped, and the next dose should be taken at the regularly scheduled time on the next day. If a dose is not fully swallowed or vomiting occurs after taking a dose of EVRYSDI, another dose should not be administered to make up for the lost dose.

The patient should wait until the next day to take the next dose at the regularly scheduled time. 2.4 Preparation of Powder for Oral Solution by Healthcare Provider EVRYSDI powder must be constituted to the oral solution by a pharmacist or other healthcare provider prior to dispensing to the patient.

Solution 0.75 mg/mL The EVRYSDI " Instructions for Constitution " booklet contains more detailed instructions on the preparation of the oral solution.

Caution should be exercised when handling

EVRYSDI powder for oral solution.

Avoid inhalation and direct contact with skin or mucous membranes with the dry powder and the constituted solution.

If such contact occurs, wash thoroughly with soap and water; rinse eyes with water.

Wear disposable gloves during the preparation and cleanup procedure.

Gently tap the bottom of the closed glass bottle to loosen the powder.

Remove the cap.

Do not throw away the cap.

Carefully pour 79 mL of purified water into the EVRYSDI bottle to yield the 0.75 mg/mL oral solution.

Do not mix

EVRYSDI 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 tightly and shake well for 15 seconds.

Wait for 10 minutes.

You should have obtained a clear solution.

If not, shake well again for another 15 seconds or until you have obtained a clear solution.

Write the date of expiration of the constituted oral solution (calculated as 64 days after constitution) and the lot number on the bottle label.

Peel off the part of the bottle label that has the expiration date of the powder.

Put the bottle back in its original carton.

Select the appropriate oral syringes (1 mL, 6 mL, or 12 mL) based on the patient's dosage and remove the 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.

Storage Keep the constituted oral solution of EVRYSDI in the original amber bottle to protect from light.

Store in a refrigerator at 2°C to 8°C (36°F to 46°F).

Do not freeze.

Discard any unused portion 64 days after constitution.

Keep the bottle in an upright position with the cap tightly closed.

If refrigeration is not available, EVRYSDI can be kept at room temperature up to 40°C (up to 104°F) for a combined total of 5 days.

EVRYSDI can be removed from, and returned to, a refrigerator.

The total combined time out of refrigeration should not exceed 5 days.

for Oral Solution How Supplied Each amber glass bottle of EVRYSDI for oral solution is packaged with a bottle adapter, two 1 mL reusable oral syringes, two 6 mL reusable oral syringes, and one 12 mL reusable oral syringe.

EVRYSDI for oral solution is a light yellow, pale yellow, yellow, greyish yellow, greenish yellow, or light green powder.

Each bottle contains 60 mg of risdiplam (NDC 50242-175-07).

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.

Keep the constituted oral solution of

EVRYSDI in the original amber bottle to protect from light.

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) . 16.2 EVRYSDI Tablets How Supplied Pale yellow film-coated tablet, round and curved, with EVR debossed on one side; available in HDPE bottles of 30 tablets with a child-resistant cap (NDC 50242-202-01).

Store 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 bottle.

Keep the bottle tightly closed in order to protect from moisture.

Store 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 bottle.

Keep the bottle tightly closed in order to protect from moisture.

There is a 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 Risk Summary There are no adequate data on the developmental risk associated with the use of EVRYSDI 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% to 4% and 15% to 20%, respectively.

Based on animal data, advise pregnant women of the potential risk to the fetus.

Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg/day) 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/day) 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 pre.

• 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.

The safety and effectiveness of

EVRYSDI in pediatric patients (neonates and older) have been established.

Use of EVRYSDI for

SMA is supported by evidence from adequate and well-controlled studies of EVRYSDI in patients 2 months of age and older with SMA.

SMA in patients 2 months of age and younger is supported by pharmacokinetic and safety data from pediatric patients 16 days and older, and pharmacokinetic modeling and simulation to identify the dosing regimen.

Oral administration of risdiplam (0, 0.75, 1.5, 2.5 mg/kg/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/kg/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

EVRYSDI did not include patients aged 65 years and older to determine whether they respond differently from younger adult patients.