Nusinersen

FDA Drug Information • Also known as: Spinraza

Brand Names: Spinraza
Dosage Form: INJECTION, SOLUTION
Product Type: DRUG FOR FURTHER PROCESSING

Description

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. Each 1 mL solution 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. 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

What Is Nusinersen Used For?

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 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION SPINRAZA is administered intrathecally ( 2.1 ) Dosing Information ( 2.1 ) The recommended dosage is 12 mg (5 mL) per administration Initiate SPINRAZA treatment with 4 loading doses: the first three loading doses should be administered at 14-day intervals; the 4 th loading dose should be administered 30 days after the 3 rd dose. A maintenance dose should be administered once every 4 months thereafter. Important Preparation and Administration Instructions ( 2.2 ) 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 ( 2.3 ) At baseline and prior to each dose, obtain a platelet count, coagulation laboratory testing, and quantitative spot urine protein testing 2.1 Dosing Information SPINRAZA is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. Recommended Dosage The recommended dosage is 12 mg (5 mL) per administration. Initiate SPINRAZA treatment with 4 loading doses. The first three loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter. Missed Dose Missed Loading Dose If a 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 dose Administer the missed 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 dose Administer the missed 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 dose Administer the missed 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 dosing as described in Recommended Dosage. 2.2 Important Preparation and Administration Instructions SPINRAZA is for intrathecal use only. Prepare and use SPINRAZA according to the following steps using aseptic technique. Each vial is intended for single dose only. Preparation Store SPINRAZA in the carton in a refrigerator until time of use. Allow the SPINRAZA vial to warm to room temperature (25 o C/77 o F) prior to administration. Do not use external heat sources. Inspect the SPINRAZA vial for particulate matter and discoloration prior to administration....

Side Effects (Adverse Reactions)

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 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 ) 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. In clinical studies, 346 patients (47% male, 76% Caucasian) were treated with SPINRAZA, including 314 exposed for at least 6 months, 258 exposed for at least 1 year, and 138 exposed for at least 2 years. The safety of SPINRAZA was studied in presymptomatic infants with SMA; pediatric patients (approximately 3 days to 16 years of age at first dose) with symptomatic SMA; in a sham-controlled trial in infants with symptomatic SMA (Study 1; n=80 for SPINRAZA, n=41 for control); in a sham-controlled trial in children with symptomatic SMA (Study 2; n=84 for SPINRAZA, n=42 for control); in an open-label study in presymptomatic infants (Study 3, n=25) and other studies in symptomatic infants (n=54) and later-onset patients (n=103). In Study 1, 58 patients were exposed for at least 6 months and 28 patients were exposed for at least 12 months. In Study 2, 84 patients were exposed for at least 6 months and 82 patients were exposed for at least 12 months. 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 1. 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 Loading doses followed by 12 mg (5 mL) once every 4 months 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,...

Contraindications

4 CONTRAINDICATIONS None. None.

Pregnancy and Breastfeeding

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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SPINRAZA injection is a sterile, clear and colorless solution supplied as a 12 mg/5 mL (2.4 mg/mL) solution in a single-dose glass vial free of preservatives. The NDC is 64406-058-01. 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 solution supplied as a 12 mg/5 mL (2.4 mg/mL) solution in a single-dose glass vial free of preservatives. The NDC is 64406-058-01.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.