Spinraza

Antisense Oligonucleotides for SMA

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.

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.

glomerulonephritis / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
hydrocephalus / Delayed / Incidence not known
angioedema / Rapid / Incidence not known

constipation / Delayed / 35.0-35.0
thrombocytopenia / Delayed / 16.0-16.0
antibody formation / Delayed / 6.0-6.0
QT prolongation / Rapid / 2.4-2.4
bleeding / Delayed / Incidence not known
meningitis / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
growth inhibition / Delayed / Incidence not known

infection / Delayed / 6.0-55.0
fever / Early / 43.0-43.0
vomiting / Early / 29.0-29.0
headache / Early / 29.0-29.0
back pain / Delayed / 25.0-25.0
nasal congestion / Early / 5.0-8.0
epistaxis / Delayed / 7.0-7.0
flatulence / Early / 5.0-5.0
weight loss / Delayed / 5.0-5.0
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known

Spinraza

Rx

Survival motor neuron-2 (SMN2)-directed antisense oligonucleotide
Used for adult and pediatric patients with spinal muscular atrophy (SMA); SMA is a rare and often fatal hereditary genetic disease affecting muscle strength and movement
Requires intrathecal dosing
Thrombocytopenia, coagulation abnormalities, and renal toxicity can occur; platelet count, coagulation laboratory testing, and quantitative spot urine protein testing recommended at baseline and prior to each dose

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.

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.

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.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

There are no drug interactions associated with Nusinersen products.

Spinraza Intrathecal Inj Sol: 1mL, 2.4mg

12 mg/dose intrathecally.

12 mg/dose intrathecally.

12 mg/dose intrathecally.

12 mg/dose intrathecally.

12 mg/dose intrathecally.

12 mg/dose intrathecally.

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

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.

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.[61627]

There are no data on the presence of nusinersen in human milk, the effects on breast-feeding infants, or the effects on milk production.[61627] 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.