Nusinersen (Monograph)

Brand name: Spinraza
Drug class: Antisense Oligonucleotides
Chemical name: [2′-O-(2-Methoxyethyl)](P-thio)(m5U-m5C-A-m5C-m5U-m5U-m5U-m5C-A-m5U-A-A-m5U-G-m5C-m5U-G-G) RNA
Molecular formula: C₂₃₄H₃₂₃N₆₁O₁₂₈P₁₇S₁₇Na₁₇
CAS number: 1258984-36-9

Medically reviewed by Drugs.com on Jan 20, 2025. Written by ASHP.

Introduction

Antisense oligonucleotide that binds to the pre-mRNA of survival motor neuron 2 (SMN2).

Uses for Nusinersen

Spinal Muscular Atrophy

Management of spinal muscular atrophy (designated an orphan drug by FDA for use in this condition).

Associated with substantial improvement in motor milestones (e.g., ability to sit unassisted, stand, walk).

May be used across full range of patients with spinal muscular atrophy (e.g., infantile-onset to later-onset disease). Available evidence to date supports early initiation of therapy.

Nusinersen Dosage and Administration

General

Monitor platelet counts, prothrombin time (PT), activated partial thromboplastin time (aPTT), and urine protein levels at baseline, prior to each dose, and as clinically indicated. (See Cautions.)
Consider use of sedation during administration as indicated by patient's clinical condition.
Consider use of ultrasound or other imaging techniques to guide intrathecal administration, especially in younger patients.

Administration

Intrathecal Administration

Administer by intrathecal injection only. Administer by, or under the direction of, a clinician experienced in performing lumbar punctures. For specific procedures and techniques of administration, consult manufacturer's full prescribing information.

Prior to administration, allow vials to warm to room temperature; do not use external heat sources for warming. Solution should be clear and colorless; do not use if visible particulates or discoloration observed.

Prior to administration, remove 5 mL of CSF. To prepare dose for intrathecal injection, withdraw 5 mL (12 mg) of nusinersen injection solution into a syringe using proper aseptic technique; administer by direct (“bolus”) intrathecal injection over 1–3 minutes using a spinal anesthesia needle. Do not inject into areas of skin showing signs of infection or inflammation.

Administer drug within 4 hours after removal from vial. Vials contain no preservatives and are intended for single use only; discard unused contents.

If a loading dose is delayed or missed, administer delayed or missed dose as soon as possible with at least 14 days between doses; resume regular dosing schedule thereafter. If a maintenance dose is delayed or missed, administer delayed or missed dose as soon as possible and resume regular dosing schedule.

Dosage

Dosage of nusinersen sodium expressed in terms of nusinersen.

Pediatric Patients

Spinal Muscular Atrophy

Intrathecal

Initiate therapy with a series of 4 loading doses of 12 mg (5 mL) each as follows: administer first 3 doses every 14 days and the fourth dose 30 days after the third dose.

Thereafter, continue with a maintenance dosage of 12 mg once every 4 months.

Adults

Spinal Muscular Atrophy

Intrathecal

Initiate therapy with a series of 4 loading doses of 12 mg (5 mL) each as follows: administer first 3 doses every 14 days and the fourth dose 30 days after the third dose.

Thereafter, continue with a maintenance dosage of 12 mg once every 4 months.

Special Populations

No special population dosage recommendations at this time.

Cautions for Nusinersen

Contraindications

None.

Warnings/Precautions

Thrombocytopenia and Coagulation Abnormalities

Thrombocytopenia (sometimes severe and acute) and coagulation abnormalities observed following administration of some antisense oligonucleotides.

Possible increased risk of bleeding complications. Monitor platelet count, PT, and aPTT at baseline, prior to each dose of the drug, and as clinically indicated.

Renal Toxicity

Renal toxicity, including potentially fatal glomerulonephritis, observed following administration of some antisense oligonucleotides.

Nusinersen accumulates in the kidneys; proteinuria has been reported.

Perform quantitative spot urine protein testing (preferably using first morning urine specimen) at baseline, prior to each dose of the drug, and as clinically indicated. For urine protein concentrations >0.2 g/L, consider repeat testing and further evaluation.

Immunogenicity

Development of treatment-emergent antibodies to nusinersen reported. Data insufficient to determine whether these antibodies affect clinical response to or adverse effects or pharmacokinetic profile of the drug.

Specific Populations

Pregnancy

No adequate data on use in pregnant women.

Lactation

Not known whether nusinersen is distributed into human milk, affects milk production, or affects the breast-fed infant.

Consider known benefits of breast-feeding along with woman's clinical need for nusinersen and any potential adverse effects of the drug or disease on the infant.

Pediatric Use

Safety and efficacy established in pediatric patients of all ages.

Geriatric Use

No experience in geriatric patients; spinal muscular atrophy is generally a disease of children and young adults.

Hepatic Impairment

Not expected to affect nusinersen exposure because of intrathecal route of administration.

Renal Impairment

Not expected to affect nusinersen exposure because of intrathecal route of administration.

Common Adverse Effects

Lower and upper respiratory infections, constipation, teething, upper respiratory tract congestion, aspiration, ear infection, scoliosis.

Drug Interactions

Drug interaction studies not conducted. In vitro findings indicate nusinersen is not a substrate for, nor an inhibitor or inducer of, CYP isoenzymes or the various transporters.

Nusinersen Pharmacokinetics

Absorption

Bioavailability

Following intrathecal administration, trough plasma concentrations relatively low compared with trough CSF concentrations.

Following intrathecal administration, mean peak plasma concentrations and AUC increased approximately dose proportionally up to dose of 12 mg.

Peak plasma concentrations achieved in a median of 1.7–6 hours.

Special Populations

No apparent correlations between age or total body weight and CSF concentrations.

Distribution

Extent

Intrathecally-administered nusinersen appears to rapidly distribute from CSF into systemic circulation, consistent with normal CSF turnover. Intrathecal injection into CSF allows distribution into target CNS tissues (e.g., motor neurons). Also distributed within peripheral tissues (e.g., skeletal muscle, liver, kidney).

Does not cross intact blood-brain barrier when administered systemically.

Not known whether distributed into human milk.

Elimination

Metabolism

Exonuclease-mediated hydrolysis.

Elimination Route

Principally excreted in urine.

At 24 hours post-dose, only 0.5% of administered dose recovered in urine.

Half-life

In CSF: 135–177 days.

In plasma: 63–87 days.

Stability

Storage

Parenteral

Injection for Intrathecal Administration

2–8°C. Store unopened vials in original carton to protect from light. Do not freeze.

If refrigeration not possible, may store at ≤30°C in the original carton for ≤14 days.

Unopened vials may be moved to and from refrigerated storage if necessary; if removed from original carton, total combined time out of refrigeration should not exceed 30 hours at a temperature that does not exceed 25°C.

Actions

Phosphorothioate-modified antisense oligonucleotide that modulates splicing of SMN2 mRNA and enhances production of the deficient survival motor neuron (SMN) protein in patients with spinal muscular atrophy.
Spinal muscular atrophy is caused by mutations in the survival motor neuron 1 (SMN1) gene, resulting in SMN protein deficiency. Absence of SMN1 leads to reliance on the nearly identical SMN2 gene; however, 80–90% of SMN2 mRNA transcripts exclude exon 7, encoding a truncated form of SMN protein that is rapidly degraded.
Nusinersen binds to a specific sequence in the intron downstream of exon 7 on the SMN2 transcript, thus promoting inclusion of exon 7 and subsequent production of full-length, fully functional SMN protein.

Advice to Patients

Risk of bleeding; importance of routine blood laboratory testing. Importance of instructing patients to seek medical attention if unexpected bleeding occurs.
Risk of renal toxicity; importance of routine urine testing.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.