Nusinersen

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 )

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 )

None. None.

Thrombocytopenia and Coagulation Abnormalities: Increased risk for bleeding complications; testing required at baseline and before each dose and as clinically needed ( 5.1 , 2.3 ) Renal Toxicity: Quantitative spot urine protein testing required at baseline and prior to each dose ( 5.2 , 2.3 )

5.1 Thrombocytopenia and Coagulation Abnormalities Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. In the sham-controlled studies for patients with infantile-onset (Study 1) and later-onset (Study 2) SMA who received Low Dose Regimen [see Clinical Studies ( 14.1 , 14.2 )] , 24 of 146 (16%) SPINRAZA-treated patients with high, normal, or unknown platelet count at baseline developed a platelet level below the lower limit of normal, compared to 10 of 72 (14%) sham-controlled patients. In Study 2, two SPINRAZA-treated patients developed platelet counts less than 50,000 cells per microliter, with a lowest level of 10,000 cells per microliter recorded on study day 28. In patients who received High Dose Regimen, decreases in platelet counts were also observed. Because of the risk of thrombocytopenia and coagulation abnormalities from SPINRAZA, patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed.

5.2 Renal Toxicity Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. SPINRAZA is present in and excreted by the kidney [see Clinical Pharmacology ( 12.3 )] . In Study 1 and Study 2, 71 of 123 (58%) of SPINRAZA-treated patients had elevated urine protein, compared to 22 of 65 (34%) sham-controlled patients. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration greater than 0.2 g/L, consider repeat testing and further evaluation.

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 forearm, leg, and foot over an 8-week period. The lesions ulcerated and scabbed over within 4 weeks, and resolved over several months. A second patient developed red macular skin lesions on the cheek and hand ten months after the start of SPINRAZA treatment, which resolved over 3 months. Both cases continued to receive SPINRAZA and had spontaneous resolution of the rash. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment. Clinical Trial in Later-Onset SMA (Study 2) In Study 2, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except for the proportion of SPINRAZA-treated patients who had ever achieved the ability to stand without support (13% vs 29%) or walk with support (24% vs 33%). 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 pyrexia, headache, vomiting, and back pain. Table 3. 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 Later-Onset SMA (Study 2) 1 Low Dose Regimen [see Dosage and Administration ( 2.1 )] Adverse Reactions SPINRAZA 12 mg 1 N=84 % Sham – Procedure Control N=42 % Pyrexia 43 36 Headache 29 7 Vomiting 29 12 Back pain 25 0 Epistaxis 7 0 Fall 5 0 Respiratory tract congestion 5 2 Seasonal allergy 5 2 Post-lumbar puncture syndrome has also been observed after administration of SPINRAZA. SPINRAZA High Dose Regimen (50 mg loading doses/28 mg maintenance doses) The safety of SPINRAZA High Dose Regimen was studied in 2 clinical trials in symptomatic patients with SMA (approximately 14 days to 65 years of age at first dose). In clinical studies, 128 patients (50% male, 63% Caucasian, and 22% Asian) were treated with SPINRAZA High Dose Regimen [see Dosage and Administration ( 2.1 )], including 113 exposed for at least 6 months, 95 exposed for at least 1 year, and 67 exposed for at least 2 years. Clinical Trial in Infantile-Onset SMA (Study 4) The most common adverse reactions that occurred in at least 10% of SPINRAZA treated patients and occurred at least 5% more frequently than in historic-matched sham-control patients from Study 1 were pneumonia, COVID-19, pneumonia aspiration, and malnutrition in patients with infantile-onset SMA. COVID-19 was not discovered at the time of Study 1. Table 4: Adverse Reactions that Occurred in at least 5% of SPINRAZA High Dose Regimen Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than Matched Sham Control in Patients with Infantile Onset SMA (Study 4) SPINRAZA High Dose Regimen (Study 4) (N=50) % Matched Sham Control (Study 1) (N=20) % Pneumonia 20 5 COVID-19 16 0 Pneumonia aspiration 14 5 Malnutrition 10 0 Procedural pain 6 0 Myocardial necrosis marker increased 6 0 Anemia 6 0

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SPINRAZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious infections associated with lumbar puncture, such as meningitis, have been reported. Hydrocephalus, aseptic meningitis, hypersensitivity reactions (e.g. angioedema, urticaria, rash), and arachnoiditis have also been reported.

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.

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.