Spinraza

Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.5 ) 03/2026 Warnings and Precautions ( 5.1 ) 03/2026

1 INDICATIONS AND USAGE SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. SPINRAZA is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients ( 1 )

2 DOSAGE AND ADMINISTRATION SPINRAZA is administered intrathecally ( 2.1 ) Recommended Dosage ( 2.1 ) The recommended dosage is one of two options: Low Dose Regimen: Administer one 12 mg loading dose every 14 days for three doses; then a fourth 12 mg loading dose 30 days after the third dose; then administer a 12 mg maintenance dose once every 4 months thereafter. High Dose Regimen: Administer one 50 mg loading dose followed by a second 50 mg loading dose 14 days later; then administer a 28 mg maintenance dose once every 4 months thereafter. Important Preparation and Administration Instructions ( 2.3 ) Allow to warm to room temperature prior to administration Administer within 4 hours of removal from vial Prior to administration, remove 5 mL of cerebrospinal fluid Administer as intrathecal bolus injection over 1 to 3 minutes Laboratory Testing and Monitoring to Assess Safety ( 2.4 ) At baseline and prior to each dose, obtain a platelet count, coagulation laboratory testing, and quantitative spot urine protein testing 2.1 Recommended Dosage SPINRAZA is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. Two dosing regimen options for SPINRAZA, which consist of loading followed by maintenance dosages, are presented in Table 1 . Table 1: Recommended Dosage for SPINRAZA Loading Dosages Maintenance Dosage Low Dose Regimen (Low dose with four loading doses) Administer a total of four loading doses as follows: one 12 mg dose every 14 days for three doses, then a fourth 12 mg dose 30 days after the third dose. Administer 12 mg once every 4 months starting 4 months after the last loading dose. High Dose Regimen (High dose with two loading doses) Administer a total of two loading doses as follows: one 50 mg dose followed by a second 50 mg dose 14 days later. Administer 28 mg once every 4 months starting 4 months after the last loading dose. 2.2 Missed Doses Missed Dose of Low Dose Regimen Missed Loading Dose If a 12 mg loading dose (any of the 4 loading doses) is missed, administer the missed loading dose as soon as possible; adjust the date for the subsequent doses to maintain the recommended interval between doses. Missed Maintenance Dose Less than 8 months from last maintenance dose Administer the missed 12 mg maintenance dose as soon as possible; then administer the next maintenance dose per the originally scheduled date, as long as these two doses are administered at least 14 days apart. At least 8 months but less than 16 months from last maintenance dose Administer the missed 12 mg maintenance dose as soon as possible, followed by one additional dose 14 days later, and then administer the next maintenance dose 4 months thereafter. At least 16 months but less than 40 months from last maintenance dose Administer the missed 12 mg maintenance dose as soon as possible, followed by two additional doses 14 days apart, and then administer the next maintenance dose 4 months thereafter. At least 40 months from last dose Restart Low Dose Regimen with 12 mg loading dosesas described in Recommended Dosage. Missed Dose of High Dose Regimen Missed Second 50 mg Loading Dose Administer the missed 50 mg loading dose as soon as possible; then administer 28 mg maintenance doses every 4 months thereafter. Missed 28 mg Maintenance Dose Less than 8 months from last maintenance dose Administer the missed 28 mg maintenance dose as soon as possible; administer the next 28 mg maintenance dose per the originally scheduled date, as long as these two doses are administered at least 14 days apart; then administer 28 mg every 4 months thereafter. At least 8 months to less than 40 months from last maintenance dose Administer a 50 mg loading dose as soon as possible; then administer 28 mg maintenance doses every 4 months thereafter. At least 40 months from last maintenance dose Restart High Dose Regimen with two 50 mg loading doses as described in Recommended Dosage. 2.3 Important Preparati …

3 DOSAGE FORMS AND STRENGTHS Injection: nusinersen is a clear and colorless solution supplied in single-dose vials in the following strengths: 12 mg/5 mL (2.4 mg/mL) 28 mg/5 mL (5.6 mg/mL) 50 mg/5 mL (10 mg/mL) Injection: 12 mg/5 mL (2.4 mg/mL) in a single-dose vial ( 3 ) Injection: 28 mg/5 mL (5.6 mg/mL) in a single-dose vial ( 3 ) Injection: 50 mg/5 mL (10 mg/mL) in a single-dose vial ( 3 )

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS The following serious adverse reactions are described in detail in other sections of the labeling: Thrombocytopenia and Coagulation Abnormalities [see Warnings and Precautions ( 5.1 )] Renal Toxicity [see Warnings and Precautions ( 5.2 )] The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients who received Low Dose Regimen and occurred at least 5% more frequently than in control patients were: lower respiratory infection and constipation in patients with infantile-onset SMA ( 6.1 ) pyrexia, headache, vomiting, and back pain in patients with later-onset SMA ( 6.1 ) The most common adverse reactions in at least 10% of SPINRAZA-treated patients who received High Dose Regimen and occurred at least 5% more frequently than in historic matched sham-control were: pneumonia, COVID-19, pneumonia aspiration, and malnutrition in patients with infantile-onset SMA ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-844-477-4672 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of SPINRAZA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. SPINRAZA Low Dose Regimen (12 mg loading doses/12 mg maintenance doses) In clinical studies, 385 patients (47% male, 68% Caucasian, and 12% Asian) were treated with SPINRAZA Low Dose Regimen [see Dosage and Administration ( 2.1 )] , including 353 exposed for at least 6 months, 314 exposed for at least 1 year, and 256 exposed for at least 5 years. Clinical Trial in Infantile-Onset SMA (Study 1) In Study 1, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except that SPINRAZA-treated patients at baseline had a higher percentage compared to sham-control patients of paradoxical breathing (89% vs 66%), pneumonia or respiratory symptoms (35% vs 22%), swallowing or feeding difficulties (51% vs 29%), and requirement for respiratory support (26% vs 15%). The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (18%) than in control patients (10%). Because patients in Study 1 were infants, adverse reactions that are verbally reported could not be assessed in this study. Table 2. Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients with Infantile-Onset SMA (Study 1) 1 Low Dose Regimen [see Dosage and Administration ( 2.1 )] 2 Includes adenovirus infection, bronchiolitis, bronchitis, bronchitis viral, corona virus infection, Influenza, lower respiratory tract infection, lower respiratory tract infection viral, lung infection, parainfluenzae virus infection, pneumonia, pneumonia bacterial, pneumonia influenzal, pneumonia moraxella, pneumonia parainfluenzae viral, pneumonia pneumococcal, pneumonia pseudomonal, pneumonia respiratory syncytial viral, pneumonia viral, and respiratory syncytial virus bronchiolitis. Adverse Reactions SPINRAZA 12 mg 1 N = 80 % Sham-Procedure Control N = 41 % Lower respiratory infection 2 55 37 Constipation 35 22 Teething 18 7 Urinary tract infection 9 0 Upper respiratory tract congestion 8 2 Ear infection 6 2 Flatulence 5 2 Decreased weight 5 2 In an open-label clinical study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with SPINRAZA requiring salt supplementation for 14 months. Cases of rash were reported in patients treated with SPINRAZA. One patient, 8 months after starting SPINRAZA treatment, developed painless red macular lesions on the f …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of SPINRAZA in pregnant women. When nusinersen was administered by subcutaneous injection to mice throughout pregnancy and lactation, developmental toxicity (long-term neurobehavioral impairment) was observed at all doses tested (see Data ) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When nusinersen (0, 3, 10, or 25 mg/kg) was administered subcutaneously to male and female mice every other day prior to and during mating and continuing in females throughout organogenesis, no adverse effects on embryofetal development were observed. Subcutaneous administration of nusinersen (0, 6, 12.6, or 25 mg/kg) to pregnant rabbits every other day throughout organogenesis produced no evidence of embryofetal developmental toxicity. When nusinersen (1.4, 5.8, or 17.2 mg/kg) was administered to pregnant female mice by subcutaneous injection every other day throughout organogenesis and continuing once every six days throughout the lactation period, adverse neurobehavioral effects (alterations in locomotor activity, learning and memory deficits) were observed when offspring were tested after weaning or as adults. A no-effect level for neurobehavioral impairment was not established. 8.2 Lactation Risk Summary There are no data on the presence of nusinersen in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Nusinersen was detected in the milk of lactating mice when administered by subcutaneous injection. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SPINRAZA and any potential adverse effects on the breastfed infant from SPINRAZA or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SPINRAZA in pediatric patients from newborn to 17 years have been established [see Clinical Studies ( 14.1 )]. Juvenile Animal Toxicity Data In intrathecal toxicity studies in juvenile monkeys, administration of nusinersen (0, 0.3, 1, or 3 mg/dose for 14 weeks and 0, 0.3, 1, or 4 mg/dose for 53 weeks) resulted in brain histopathology (neuronal vacuolation and necrosis/cellular debris in the hippocampus) at the mid and high doses and acute, transient deficits in lower spinal reflexes at the high dose in each study. In addition, possible neurobehavioral deficits were observed on a learning and memory test at the high dose in the 53-week monkey study. In a combined 6 and 13 week toxicity study in juvenile monkeys, intrathecal administration of nusinersen at higher doses (0, 5, 10, or 15 mg/dose) resulted in additional acute, transient effects, including limited use of limbs at the mid and high dose and uncoordinated movement at the high dose. The no-effect dose for neurohistopathology in monkeys (0.3 mg/dose) is approximately equivalent to and lower than the recommended clinical maintenance doses of 12 and 28 mg, respectively, when calculated on annual dose basis and corrected for species differences in CSF volume. 8.5 Geriatric Use Clinical studies of SPINRAZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action SPINRAZA is an antisense oligonucleotide (ASO) designed to treat 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, SPINRAZA was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein.

11 DESCRIPTION Nusinersen is a modified antisense oligonucleotide, where the 2'-hydroxy groups of the ribofuranosyl rings are replaced with 2'-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages. Nusinersen binds to a specific sequence in the intron downstream of exon 7 of the SMN2 transcript. The structural formula is: SPINRAZA is supplied as a sterile, preservative-free, colorless solution for intrathecal use in a single-dose glass vial in the following strengths: 12 mg/5 mL (2.4 mg/mL) 28 mg/5 mL (5.6 mg/mL) 50 mg/5 mL (10 mg/mL) Each 1 mL solution of the 12 mg/5 mL strength contains 2.4 mg of nusinersen (equivalent to 2.53 mg of nusinersen sodium salt). Each 1 mL also contains calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.77 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic dihydrate (0.05 mg) USP, and Water for Injection USP. Each 1 mL solution of the 28 mg/5 mL strength contains 5.6 mg of nusinersen (equivalent to 5.90 mg of nusinersen sodium salt). Each 1 mL also contains calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.39 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic dihydrate (0.05 mg) USP, and Water for Injection USP. Each 1 mL solution of the 50 mg/5 mL strength contains 10 mg of nusinersen (equivalent to 10.54 mg of nusinersen sodium salt). Each 1 mL also contains calcium chloride dihydrate (0.21 mg) USP, magnesium chloride hexahydrate (0.16 mg) USP, potassium chloride (0.22 mg) USP, sodium chloride (8.11 mg) USP, sodium phosphate dibasic anhydrous (0.10 mg) USP, sodium phosphate monobasic dihydrate (0.05 mg) USP, and Water for Injection USP. For all strengths the product may contain hydrochloric acid or sodium hydroxide to adjust pH. The pH is ~7.2. The molecular formula of SPINRAZA is C 234 H 323 N 61 O 128 P 17 S 17 Na 17 and the molecular weight is 7501.0 daltons. Structural Formula

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SPINRAZA injection is a sterile, clear and colorless, preservative-free solution in single-dose glass vials supplied as one vial per carton in the following strengths: 12 mg/5 mL (2.4 mg/mL) (NDC 64406-058-01) 28 mg/5 mL (5.6 mg/mL) (NDC 64406-036-01) 50 mg/5 mL (10 mg/mL) (NDC 64406-037-01) 16.2 Storage and Handling Store in a refrigerator between 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. SPINRAZA should be protected from light and kept in the original carton until time of use. If no refrigeration is available, SPINRAZA may be stored in its original carton, protected from light at or below 30 o C (86 o F) for up to 14 days. Prior to administration, unopened vials of SPINRAZA can be removed from and returned to the refrigerator, if necessary. If removed from the original carton, the total combined time out of refrigeration should not exceed 30 hours at a temperature that does not exceed 25 o C (77 o F).

16.1 How Supplied SPINRAZA injection is a sterile, clear and colorless, preservative-free solution in single-dose glass vials supplied as one vial per carton in the following strengths: 12 mg/5 mL (2.4 mg/mL) (NDC 64406-058-01) 28 mg/5 mL (5.6 mg/mL) (NDC 64406-036-01) 50 mg/5 mL (10 mg/mL) (NDC 64406-037-01)