Evrysdi
(risdiplam)Dosage & Administration
EVRYSDI must be constituted by a healthcare provider prior to dispensing.
Administer orally once daily after a meal using the provided oral syringe.
| Age and Body Weight | Recommended Daily Dosage |
|---|---|
| Less than 2 months of age | 0.15 mg/kg |
| 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 |
See Full Prescribing Information for important preparation and administration instructions.
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Evrysdi Prescribing Information
EVRYSDI is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.
Important Administration Instructions
Dose Preparation
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 [see Instructions for Use].
Instruct patients or caregivers to prepare the dose using the reusable oral syringe provided.
EVRYSDI 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.
Dose Administration
EVRYSDI is taken orally once daily after a meal at approximately the same time each day.
In infants who are breastfed, EVRYSDI should be administered after breastfeeding. EVRYSDI cannot be mixed with formula or milk.
Instruct patients to drink water after taking EVRYSDI to ensure the drug has been completely swallowed.
If the patient is unable to swallow and has a nasogastric or gastrostomy tube, EVRYSDI can be administered via the tube. The tube should be flushed with water after delivering EVRYSDI [see Instructions for Use].
Dosing Information
EVRYSDI is administered orally once daily. The recommended dosage is determined by age and body weight (see Table 1).
| Age and Body Weight | Recommended Daily Dosage |
|---|---|
| Less than 2 months of age | 0.15 mg/kg |
| 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 |
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.
Preparation of 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.
Preparation of the EVRYSDI Oral Solution 0.75 mg/mL
The EVRYSDI " Instructions for Constitution" booklet contains more detailed instructions on the preparation of the oral solution [see Instructions for Constitution].
Caution should be exercised in the handling of 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.
- 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.
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.
EVRYSDI for oral solution: 60 mg as a light yellow, pale yellow, yellow, greyish yellow, greenish yellow, or light green powder for constitution. Following constitution, the volume of the greenish yellow to yellow solution is 80 mL, providing 60 mg/80 mL (0.75 mg/mL) risdiplam.
Pregnancy
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 https://www.evrysdipregnancyregistry.com.
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 [see Data].
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.
Data
Animal Data
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.
Lactation
Risk Summary
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 EVRYSDI and any potential adverse effects on the breastfed infant from EVRYSDI 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 [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.1)].
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiating EVRYSDI [see Use in Specific Populations (8.1)].
Contraception
EVRYSDI may cause embryofetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Female Patients
Advise female patients of reproductive potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after her last dose.
Infertility
Male Patients
Male fertility may be compromised by treatment with EVRYSDI [see Nonclinical Toxicology (13.1)].
Counsel male patients of reproductive potential receiving EVRYSDI about the potential effects on fertility. Male patients may consider sperm preservation prior to treatment.
Pediatric Use
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. Use of EVRYSDI for 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
Juvenile Animal Toxicity Data
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.
Geriatric Use
Clinical studies of EVRYSDI did not include patients aged 65 years and older to determine whether they respond differently from younger adult patients.
None.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
In clinical trials including patients with infantile-onset SMA, later-onset SMA, and pre-symptomatic SMA, a total of 491 patients (51% female, 74% Caucasian) were exposed to EVRYSDI for up to a median duration of 48.1 months (range: 0.6 to 63.4 months), with 231 patients receiving treatment for more than 24 months. At the time of first EVRYSDI dose, 90 (18%) patients were 18 years and older, 119 (24%) were 12 years to less than 18 years, 189 (39%) were 2 years to less than 12 years, 67 (14%) 2 months to less than 2 years, and 26 (5%) were less than 2 months.
Clinical Trial in Later-Onset SMA
The safety of EVRYSDI for later-onset SMA is based on data from a randomized, double-blinded, placebo-controlled study (Study 2 Part 2) in patients with SMA Type 2 or 3 (n = 180) [see Clinical Studies (14.2)]. The patient population in Study 2 Part 2 ranged in age from 2 to 25 years at the time of the first dose.
The most common adverse reactions (reported in at least 10% of patients treated with EVRYSDI and at an incidence greater than on placebo) in Study 2 Part 2 were fever, diarrhea, and rash. Table 2 lists the adverse reactions that occurred in at least 5% of patients treated with EVRYSDI and at an incidence ≥ 5% greater than on placebo in Study 2 Part 2.
| Adverse Reaction | EVRYSDI (N = 120) % | Placebo (N = 60) % |
|---|---|---|
| ||
| Fever * | 22 | 17 |
| Diarrhea | 17 | 8 |
| Rash † | 17 | 2 |
| Mouth and aphthous ulcers | 7 | 0 |
| Arthralgia | 5 | 0 |
| Urinary tract infection ‡ | 5 | 0 |
Clinical Trial in Infantile-Onset SMA
The safety of EVRYSDI therapy for infantile-onset SMA is based on data from an open-label study in 62 patients (Study 1) [see Clinical Studies (14.1)]. The patient population ranged in age from 2 to 7 months at the time of the first EVRYSDI dose (weight range 4.1 to 10.6 kg).
The most frequent adverse reactions reported in infantile-onset SMA patients treated with EVRYSDI in Study 1 were similar to those observed in later-onset SMA patients in Study 2. Additionally, the following adverse reactions reported in ≥ 10% of patients were: upper respiratory tract infection (including nasopharyngitis, rhinitis), lower respiratory tract infection (including pneumonia, bronchitis), constipation, vomiting, and cough.
Clinical Trial in Pre-Symptomatic SMA
The safety of EVRYSDI therapy for pre-symptomatic SMA is based on data from an open-label, single-arm study in 26 patients (Study 3) [see Clinical Studies (14.3)]. The patient population ranged in age from 16 to 41 days at the time of the first dose (weight range 3.1 to 5.7 kg). The safety profile of EVRYSDI in pre-symptomatic patients in Study 3 is consistent with the safety profile for symptomatic SMA patients treated with EVRYSDI in clinical trials.