Spinraza (Solution) Instructions for Use

Marketing Authorization Holder

Biogen Netherlands, B.V. (Netherlands)

Manufactured By

Patheon Italia, S.P.A. (Italy)

Or

Vetter Pharma-Fertigung, GmbH & Co. KG (Germany)

Primary Packaging

PATHEON ITALIA, S.P.A. (Italy)

Or

VETTER PHARMA-FERTIGUNG, GmbH & Co.KG (Germany)

Secondary Packaging

FUJIFILM Diosynth Biotechnologies Denmark, ApS (Denmark)

Quality Control Release

BIOGEN NETHERLANDS, B.V. (Netherlands)

ATC Code

M09AX07 (Nusinersen)

Active Substance

Nusinersen (Rec.INN registered by WHO)

Dosage Form

Spinraza

Solution for intrathecal injection 2.4 mg/1 ml: 5 ml vial 1 pc.

Dosage Form, Packaging, and Composition

Solution for intrathecal injection clear, colorless, free from readily detectable undissolved particles.

Excipients : sodium dihydrogen phosphate dihydrate, disodium phosphate, sodium chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment), water for injections.

5 ml – type I glass vials (1) – cardboard packs^×.

^× may additionally have a first-opening control in the form of a sticker.

Clinical-Pharmacological Group

Gene therapy drug used for spinal muscular atrophy

Pharmacotherapeutic Group

Other agents for the treatment of musculoskeletal system diseases

Pharmacological Action

Nusinersen is an antisense oligonucleotide (ASO) whose structure is specifically designed for the treatment of spinal muscular atrophy, a progressive neuromuscular disease with an autosomal recessive inheritance pattern caused by mutations in the long arm of chromosome 5 (5q). These mutations lead to the loss of function of the SMN1 gene (survival motor neuron 1 gene), resulting in a deficiency of the SMN protein. The SMN2 gene is also responsible for the production of the SMN protein; however, the amount of functional protein produced by SMN2 is low. Spinal muscular atrophy represents a spectrum of various clinical conditions, with the severity of the disease depending on the age of onset and the number of copies of the SMN2 gene.

Nusinersen increases the proportion of messenger RNA (mRNA) transcripts that include exon 7 of the SMN2 gene by binding to the intronic splice silencing site (ISS N1) located in intron 7 of the SMN2 gene pre-mRNA. By binding to it, the ASO displaces splicing factors that normally suppress it. The displacement of these factors leads to the retention of exon 7 in the SMN2 mRNA. After the synthesis of SMN2 mRNA, it can be translated into a full-length, functionally active SMN protein.

The pharmacodynamic effects correspond to the biological effects of nusinersen.

Pharmacokinetics

Intrathecal injections of nusinersen into the cerebrospinal fluid ensure complete distribution of nusinersen throughout the cerebrospinal fluid to the CNS tissues that are the targets of its therapeutic action.

Mean trough concentrations of nusinersen in the cerebrospinal fluid increased approximately 1.4 to 3-fold after multiple administrations, reaching steady state in approximately 24 months. No further accumulation in the cerebrospinal fluid or in CNS tissues is expected with additional administrations after steady state is achieved.

Following intrathecal administration of nusinersen, trough plasma concentrations were relatively low compared to trough concentrations in the cerebrospinal fluid. The median T_max values in plasma ranged from 1.7 to 6 hours. A dose-proportional increase in mean plasma C_max and AUC values was observed within the studied dose range. No signs of accumulation in systemic plasma exposure (C_max and AUC) were observed after multiple administrations.

Nusinersen is characterized by wide distribution, achieving therapeutic concentrations in the tissues of the spinal cord, which represent the therapeutic target. Furthermore, the presence of nusinersen has been demonstrated in neurons and other cell populations of the spinal cord and brain, as well as in peripheral tissues, particularly in skeletal muscles, liver, and kidneys.

Nusinersen is slowly metabolized by hydrolysis mediated by exonucleases (3′ and 5′); it is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes.

The mean estimated terminal T_1/2 from the cerebrospinal fluid is 135-177 days. The most likely primary route of elimination is the excretion of nusinersen and its metabolites in the urine.

Indications

Treatment of spinal muscular atrophy.

ICD codes

Dosage Regimen

Treatment should be administered by healthcare professionals experienced in performing lumbar punctures.

Nusinersen therapy should be initiated as early as possible after diagnosis.

It is intended for intrathecal administration via lumbar puncture.

The recommended dose is 12 mg.

Administration schedule: on the first day of treatment (day 0); on days 14, 28, and 63 of treatment.

Subsequently, the dose should be administered once every 4 months.

Nusinersen should be used continuously and long-term. The decision to continue therapy is determined by the treating physician based on the patient’s clinical condition.

The efficacy and safety of nusinersen have been studied in children aged 0 to 17 years.

Experience in patients over 18 years of age is limited.

There is no experience in elderly patients over 65 years of age.

Adverse Reactions

Nervous system disorders very common – headache.

Gastrointestinal disorders very common – vomiting.

Musculoskeletal and connective tissue disorders very common – back pain.

These adverse reactions may be considered manifestations of post-lumbar puncture syndrome.

Contraindications

Hypersensitivity to nusinersen.

Use in Pregnancy and Lactation

No data available.

Special Precautions

The lumbar puncture procedure carries the risk of adverse reactions such as headache, back pain, and vomiting. Potential difficulties may arise when administering the drug to patients in the early age group and patients with scoliosis. At the physician’s discretion, ultrasound or other imaging techniques may be used to facilitate intrathecal administration.

If clinically indicated, it is recommended to perform laboratory tests to determine platelet count and coagulation parameters before administering nusinersen.

If clinically indicated, it is recommended to perform quantitative determination of protein in urine (preferably in the first morning urine sample). In case of a stable increase in urine protein content, further investigation is recommended.

Hydrocephalus not associated with meningitis and bleeding has been reported in patients receiving Nusinersen. The development of hydrocephalus should be assessed in patients with decreased consciousness. The benefits and risks of nusinersen treatment in patients with a ventriculoperitoneal shunt are currently unknown, and the need for continued treatment should be carefully evaluated.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.