nusinersen (Rx)

Data are from controlled study in infants

>10%

Headache (50%)

Lower respiratory infection (43%)

Back pain (41%)

Postlumbar puncture syndrome (41%)

Upper respiratory infection (39%)

Elevated urine protein (33%)

Constipation (30%)

Atelectasis (14%)

Thrombocytopenia (11%)

1-10%

Upper respiratory tract congestion (6%)

Aspiration (5%)

Ear infection (5%)

Emergent treatment antidrug antibodies (4%)

Postmarketing Reports

Hydrocephalus

Aseptic meningitis

Hypersensitivity reactions (e.g. angioedema, urticaria, rash)

Contraindications

None

Cautions

Coagulation

• Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides
• Because of risk of thrombocytopenia and coagulation abnormalities, patients may be at increased risk of bleeding complications
• Obtain platelet count and coagulation laboratory testing at baseline and prior to each administration and as clinically needed

Renal toxicity

• Nusinersen is present in and excreted by the kidney
• Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides
• Conduct quantitative spot urine protein testing (preferably using a first-morning urine specimen) at baseline and prior to each dose
• For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation

Pregnancy

There are no adequate data on the developmental risk associated with use in pregnant women

No adverse effects on embryofetal development were observed in animal studies in which nusinersen was administered by subcutaneous injection to mice and rabbits during pregnancy

Lactation

Unknown if distributed in human breast milk; detected in milk of lactating mice when administered by subcutaneous injection

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

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, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein

Absorption

Trough plasma levels relatively low, compared to trough CSF concentration

Peak plasma time: 1.7-6 hr

Distribution

CSF and peripheral tissues (eg, skeletal muscle, liver, kidney)

Metabolism

Metabolized via exonuclease (3’- and 5’)-mediated hydrolysis

Not a substrate for, or inhibitor, or inducer of CYP450 enzymes

Elimination

Half-life: 135-177 days (CSF); 63-87 days (plasma)

Excretion: primary route of elimination is likely by urinary excretion; at 24 hr, only 0.5% of the administered dose was recovered in the urine

Intrathecal Preparation

Obtain laboratory testing before each dose (see Dosing)

Use aseptic technique

Each vial is intended for single dose only

Store drug in the carton in a refrigerator until time of use

Allow the vial to warm to room temperature (25°C/77°F) prior to administration; do not use external heat sources

Inspect vial content for particulate matter and discoloration prior to administration; do not administer if visible particulates are observed or if the liquid in the vial is discolored (should be clear and colorless)

Use of external filters not required

Withdraw 12 mg (5 mL) from the single-dose vial into a syringe and discard unused contents (ie, overfill) of the vial

Administer within 4 hr of removal from vial

Intrathecal Administration

For intrathecal use only

Consider sedation as indicated by the clinical condition of the patient

Consider ultrasound or other imaging techniques to guide intrathecal administration of, particularly in younger patients

Prior to administration, remove 5 mL of cerebrospinal fluid

Administer as an intrathecal bolus injection over 1-3 minutes using a spinal anesthesia needle

Do not administer in areas of the skin where there are signs of infection or inflammation

Missed dose

• If a loading dose is delayed or missed, administer as soon as possible, with at least 14-days between doses and continue dosing as prescribed
• If a maintenance dose is delayed or missed, administer as soon as possible and continue dosing every 4 month

Storage

Store in a refrigerator between 2-8°C (36-46°F) in the original carton to protect from light

Do not freeze

Should be protected from light and kept in the original carton until time of use

If no refrigeration is available, may be stored in its original carton, protected from light at ≤30°C (86°F) for up to 14 days

Prior to administration, unopened vials 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°C (77°F)