Nusinersen is an intrathecally administered survival motor neuron-2 (SMN2)-directed antisense oligonucleotide. Nusinersen is the first drug to be approved to treat pediatric and adult patients with spinal muscular atrophy (SMA). SMA is a rare and often fatal hereditary genetic disease affecting muscle strength and movement. It causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. The age of onset, symptoms, and rate of progression vary widely between patients. A clinical trial in 121 patients with infantile-onset SMA (diagnosed before 6 months of age; less than 7 months old when receiving the first nusinersen dose) assessed the percentage of patients with improvement in motor milestones (i.e. head control, rolling, sitting, crawling, standing, or walking). In a planned interim efficacy analysis including 82 patients, 40% of patients treated with nusinersen achieved improvement in motor milestones, whereas none of the control did. Additional open-label uncontrolled clinical studies conducted in symptomatic patients (age 30 days to 15 years at the time of the first dose) and in presymptomatic patients (age 8 days to 42 days at the time of the first dose) appear to support the clinical efficacy demonstrated in the controlled clinical trial in infants. Because thrombocytopenia, coagulation abnormalities, and renal toxicity can occur during nusinersen therapy, platelet count, coagulation laboratory testing (prothrombin time; activated partial thromboplastin time), and quantitative spot urine protein testing are recommended at baseline and prior to each dose. Nusinersen was approved by the FDA in December 2016.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-For intrathecal use only.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-If a loading dose is delayed or missed, administer nusinersen as soon as possible, and adjust the date for subsequent doses to maintain recommended dosing intervals. Administer a missed maintenance dose as soon as possible. For a missed maintenance dose that is less than 8 months from the last dose, administer the dose and follow with the next maintenance dose on the regularly scheduled date, ensuring that the 2 doses are given at least 14 days apart. For a missed maintenance dose that is at least 8 months but less than 16 months from the last dose, administer the dose, followed by 1 additional dose 14 days later, and then administer the next maintenance dose 4 months thereafter. For a missed maintenance dose that is at least 16 months but less than 40 months from the last dose, administer the dose, followed by 2 additional doses 14 days apart, and then administer the next maintenance dose 4 months thereafter. Restart with initial loading dose schedule if a missed maintenance dose is 40 months or more from the last dose.
Intrathecal Administration
Preparation
-Remove the nusinersen vial from the refrigerator.
-Allow the vial to warm to room temperature (25 degrees C or 77 degrees F) prior to administration. Do not use external heat sources to warm the medication.
-Do not administer if visible particulates are observed or if the liquid in the vial is discolored. Nusinersen is a clear and colorless solution. The use of external filters is not required.
-Use aseptic technique. Each vial is for single-use only.
-Withdraw 12 mg (5 mL) of nusinersen from the vial into a syringe; discard unused vial contents.
-Administer nusinersen within 4 hours of removal from the vial.
Intrathecal Administration
-Administered by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.
-Consider sedation as indicated by the clinical condition of the patient.
-Consider ultrasound or other imagining techniques to guide intrathecal administration of nusinersen, particularly in younger patients.
-Prior to administration, remove 5 mL of cerebrospinal fluid (CSF).
-Administer nusinersen as an intrathecal bolus injection over 1 to 3 minutes using a spinal anesthesia needle. Do not administer in areas of the skin where there are signs of infection or inflammation.
Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. In a clinical study, 16% of nusinersen-treated patients with normal, above normal, or unknown platelet counts at baseline developed a platelet count below the lower limit of normal, compared to 14% of patients receiving a sham-control. Two nusinersen-treated patients developed platelet counts less than 50,000 cells/microliter in this study, with a lowest count of 10,000 cells/microliter recorded on study day 28. Epistaxis (7% vs. 0% sham-control patients) was reported in pediatric patients with later spinal muscular atrophy (SMA) onset receiving nusinersen. Monitor platelet counts and coagulation parameters prior to each dose; monitor the patient clinically for potential signs or symptoms of bleeding. Instruct patients and caregivers to seek medical attention if unexpected bleeding occurs.
Nephrotoxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Nusinersen is present in and excreted by the kidney. In sham-controlled studies for patients with infantile-onset and later-onset spinal muscular atrophy (SMA), 71 of 123 (58%) nusinersen-treated patients had elevated urine protein, compared to 22 of 65 (34%) sham-control patients. Quantitative spot urine protein testing is required at baseline and prior to each dose; for a urinary protein concentration more than 0.2 grams/L, consider repeat testing and further evaluation.
In a controlled study, constipation (35% vs. 22% sham-control patients) and flatulence (5% vs. 2% sham-control patients) were reported. Vomiting (29% vs. 12% sham-control patients) was reported in pediatric patients with later spinal muscular atrophy (SMA) onset receiving nusinersen.
Headache (29%) and back pain (25%) were commonly reported adverse reactions in an open-label study in pediatric patients with later spinal muscular atrophy (SMA) onset receiving nusinersen. Post lumbar puncture syndrome has also been reported. The nusinersen lumbar puncture-related adverse reaction frequency is similar to that previously reported in children receiving other types of lumbar puncture procedures.
Respiratory adverse reactions that have been reported in infants receiving nusinersen for spinal muscular atrophy (SMA) include lower respiratory infection (55% vs. 37% sham-control patients), respiratory tract congestion (e.g., nasal congestion) (5% to 8% vs. 2% sham-control patients), and ear infection (6% vs. 2% sham-control patients). Seasonal allergy (5% vs. 2% sham-control patients) was reported in infants receiving nusinersen for SMA. Serious adverse reactions of atelectasis were more frequent in nusinersen-treated patients (18%) than in control patients (10%). In the controlled study, baseline disease characteristics were largely similar in the nusinersen-treated patients and sham-control patients except nusinersen-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%). Urinary tract infection (9% vs. 0% sham-control patients) was reported in infants receiving nusinersen for SMA. Serious infections, including meningitis, have occurred during postmarketing experience as a complication of lumbar puncture in patients treated with nusinersen. Hydrocephalus, aseptic meningitis, and arachnoiditis have also been reported during postmarketing experience with nusinersen.
Cases of rash were reported in patients treated with nusinersen. Eight months after starting nusinersen, 1 patient 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 at 10 months after the start of nusinersen treatment, which resolved over 3 months. Both cases continued to receive nusinersen and had spontaneous resolution of the rash. Hypersensitivity reactions (e.g., angioedema, urticaria, rash) have occurred during postmarketing experience with nusinersen.
Teething (18% vs. 7% sham-control patients) was reported in infants receiving nusinersen for spinal muscular atrophy (SMA). In an open-label study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with nusinersen; salt supplementation was required for 14 months.
Nusinersen may cause growth inhibition and weight loss. Growth inhibition (as measured by height) was observed in the controlled study in infants and it is unknown if it is reversible with cessation of treatment. Weight loss (5% vs. 2% sham-control patients) was reported in infants receiving nusinersen for spinal muscular atrophy (SMA).
As with all therapeutic proteins, there is a potential for immunogenicity (antibody formation) with nusinersen use. In clinical trials, 17 out of 294 (6%) patients developed treatment-emergent anti-drug antibodies (ADAs) during nusinersen treatment, of which 5 were transient, and 12 were considered to be persistent. There are insufficient data to evaluate an effect of ADAs on clinical response, adverse reactions, or the pharmacokinetic profile of nusinersen.
During a clinical trial of 247 patients with spinal muscular atrophy who received either nusinersen or a sham-control, a QTcF more than 500 msec and an increase from baseline of more than 60 msec were observed in 2.4% (4 out of 164) of patients receiving nusinersen and no patients receiving placebo. Compared to the sham-control, there was no increase in the incidence of cardiac adverse reactions associated with delayed ventricular repolarization or QT prolongation in patients treated with nusinersen.
Fever (43% vs. 36% sham-control patients) and fall (5% vs. 0% sham-control patients) were reported in pediatric patients with later spinal muscular atrophy (SMA) onset receiving nusinersen.
At the time of FDA approval, the product labeling reported no contraindications for the use of nusinersen in patients with spinal muscular atrophy (SMA).
Nusinersen therapy requires an experienced clinician who is trained in performing lumbar punctures and intrathecal drug therapy. Administration of nusinersen requires a specialized care setting such as a hospital or treatment facility. Treatment may require sedation and ultrasound or other imaging techniques to guide intrathecal administration of nusinersen.
Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. In a clinical study, 16% of nusinersen-treated patients with normal, above normal, or unknown platelet counts at baseline developed a platelet count below the lower limit of normal, compared to 14% of patients receiving a sham-control. Two nusinersen-treated patients developed platelet counts less than 50,000 cells/microliter in this study, with a lowest count of 10,000 cells/microliter recorded on study day 28. Because of the risk of thrombocytopenia and coagulation abnormalities, patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline, prior to each administration, and as clinically needed.
Nephrotoxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Nusinersen is present in and excreted by the kidney. In sham-controlled studies for patients with infantile-onset and later-onset spinal muscular atrophy (SMA), 71 of 123 (58%) nusinersen-treated patients had elevated urine protein, compared to 22 of 65 (34%) sham-control patients. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of nusinersen. If the urinary protein concentration is more than 0.2 grams/L, consider repeat testing and further evaluation.
There are no available data regarding nusinersen use during human pregnancy to inform a drug-associated risk. Animal data in mice found that developmental toxicity (long-term neurobehavioral impairment) was observed at all doses tested. When nusinersen 1.4, 5.8, or 17.2 mg/kg was administered subcutaneously to pregnant female mice every other day throughout organogenesis and continuing once every 6 days throughout the lactation period, adverse neurobehavioral effects (alterations in locomotor activity, learning and memory deficits) were observed. A no-effect level for neurobehavioral impairment was not established.
There are no data on the presence of nusinersen in human milk, the effects on breast-feeding infants, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of spinal muscular atrophy (SMA):
NOTE: The FDA has designated nusinersen as an orphan drug for this indication.
Intrathecal dosage:
Adults: 12 mg intrathecally every 14 days for the first 3 loading doses. Administer the fourth loading dose 30 days after the third. Then, administer a maintenance dose once every 4 months thereafter. If a loading dose is delayed or missed, administer nusinersen as soon as possible, and adjust the date for subsequent doses to maintain recommended dosing intervals. Administer a missed maintenance dose as soon as possible. For a missed maintenance dose that is less than 8 months from the last dose, administer the dose and follow with the next maintenance dose on the regularly scheduled date, ensuring that the 2 doses are given at least 14 days apart. For a missed maintenance dose that is at least 8 months but less than 16 months from the last dose, administer the dose, followed by 1 additional dose 14 days later, and then administer the next maintenance dose 4 months thereafter. For a missed maintenance dose that is at least 16 months but less than 40 months from the last dose, administer the dose, followed by 2 additional doses 14 days apart, and then administer the next maintenance dose 4 months thereafter. Restart with initial loading dose schedule if a missed maintenance dose is 40 months or more from the last dose.
Infants, Children, and Adolescents: 12 mg intrathecally every 14 days for the first three loading doses. Administer the fourth loading dose 30 days after the third. Administer a maintenance dose once every 4 months thereafter. If a loading dose is delayed or missed, administer nusinersen as soon as possible, and adjust the date for subsequent doses to maintain recommended dosing intervals. Administer a missed maintenance dose as soon as possible. For a missed maintenance dose that is less than 8 months from the last dose, administer the dose and follow with the next maintenance dose on the regularly scheduled date, ensuring that the 2 doses are given at least 14 days apart. For a missed maintenance dose that is at least 8 months but less than 16 months from the last dose, administer the dose, followed by 1 additional dose 14 days later, and then administer the next maintenance dose 4 months thereafter. For a missed maintenance dose that is at least 16 months but less than 40 months from the last dose, administer the dose, followed by 2 additional doses 14 days apart, and then administer the next maintenance dose 4 months thereafter. Restart with initial loading dose schedule if a missed maintenance dose is 40 months or more from the last dose.
Neonates: 12 mg intrathecally every 14 days for the first 3 loading doses. Administer the fourth loading dose 30 days after the third. Administer a maintenance dose once every 4 months thereafter. If a loading dose is delayed or missed, administer nusinersen as soon as possible, and adjust the date for subsequent doses to maintain recommended dosing intervals. Administer a missed maintenance dose as soon as possible. For a missed maintenance dose that is less than 8 months from the last dose, administer the dose and follow with the next maintenance dose on the regularly scheduled date, ensuring that the 2 doses are given at least 14 days apart. For a missed maintenance dose that is at least 8 months but less than 16 months from the last dose, administer the dose, followed by 1 additional dose 14 days later, and then administer the next maintenance dose 4 months thereafter. For a missed maintenance dose that is at least 16 months but less than 40 months from the last dose, administer the dose, followed by 2 additional doses 14 days apart, and then administer the next maintenance dose 4 months thereafter. Restart with initial loading dose schedule if a missed maintenance dose is 40 months or more from the last dose.
Therapeutic Drug Monitoring:
In addition to platelet count and coagulation laboratory testing (prothrombin time; activated partial thromboplastin time), conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of nusinersen. For urinary protein concentration greater than 0.2 gram/L, consider repeat testing and further evaluation.
Maximum Dosage Limits:
-Adults
12 mg/dose intrathecally.
-Geriatric
12 mg/dose intrathecally.
-Adolescents
12 mg/dose intrathecally.
-Children
12 mg/dose intrathecally.
-Infants
12 mg/dose intrathecally.
-Neonates
12 mg/dose intrathecally.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Nusinersen products.
Nusinersen is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide (ASO) designed to treat spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. Nusinersen increases exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein.
Autopsy samples from patients (n=3) had higher levels of SMN2 messenger ribonucleic acid (mRNA) containing exon 7 in the thoracic spinal cord compared to untreated SMA infants. Analysis of autopsy tissue from patients exposed to nusinersen during a clinical trial showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord.
Cardiac electrophysiology has been studied with nusinersen. In a clinical trial, QTcF values more than 500 ms, and change from baseline values more than 60 ms, were observed in 5% of 121 patients with spinal muscular atrophy receiving nusinersen. There was no increase in the incidence of cardiac adverse reactions associated with delayed ventricular repolarization in patients treated with nusinersen compared to the sham-control.
Nusinersen is administered intrathecally. Nusinersen distributes into the CNS and peripheral tissues, such as skeletal muscle, liver, and kidney. In a clinical study, analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions. Nusinersen is metabolized via exonuclease (3'- and 5')-mediated hydrolysis and is not a substrate for, or inhibitor or inducer of CYP450 enzymes. The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma following intrathecal injection. The primary route of elimination of nusinersen and its chain-shortened metabolites is likely by urinary excretion. At 24 hours, only 0.5% of the administered dose was recovered in the urine.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Other Route(s)
Intrathecal Route
Injection into the cerebrospinal fluid (CSF) allows nusinersen to be distributed from the CSF to the target central nervous system (CNS) tissues. After intrathecal injection of nusinersen, trough plasma concentrations were relatively low compared to the trough CSF concentration. Median time to maximal concentration (Tmax) plasma values were 1.7 to 6 hours. Mean plasma maximal concentration (Cmax) and AUC values increased approximately dose-proportionally up to an intrathecal dose of 12 mg.