Dosing & Uses
Dosage Forms & Strengths
injection, solution
- 100mg/15mL (6.7mg/mL) single-dose vial
Amyotrophic Lateral Sclerosis
Indicated for amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene
100 mg per administration intrathecally using a lumbar puncture by, or under the direction of, healthcare professionals experienced in performing lumbar punctures
Loading doses: 1 dose every 14 days x 3 doses
Maintenance doses: Administer every 28 days
Dosage Modifications
Renal or hepatic impairment
- No clinical studies conducted to evaluate pharmacokinetics of tofersen in patients with renal or hepatic impairment
- Tofersen is not expected to undergo metabolism by hepatic enzymes
Safety and efficacy not established
Adverse Effects
>10%
Pain (42%)
Fatigue (17%)
Arthralgia (14%)
Cerebrospinal fluid (CSF) WBCs increased (14%)
Myalgia (14%)
1-10%
CSF protein increased (8%)
Musculoskeletal stiffness (6%)
Neuralgia (6%)
Frequency Not Defined
Myelitis
Radiculitis
Papilledema
Elevated intracranial pressure (ICP)
Aseptic meningitis
Pyrexia
Warnings
Contraindications
None
Cautions
Myelitis and radiculitis reported; initiate workup and treatment according to standard of care if symptoms consistent with myelitis or radiculitis occur; management may require dosage interruption or discontinuation
Papilledema and elevated intracranial pressure reported; if symptoms develop, initiate diagnostic workup and treatment according to standard of care
Aseptic meningitis (ie, chemical meningitis, drug-induced aseptic meningitis) reported; additionally, nonserious adverse drug reactions of increased CSF white blood cells and CSF protein have also been reported; if symptoms consistent with aseptic meningitis develop, initiate diagnostic workup and treatment according to standard of care
Pregnancy & Lactation
Pregnancy
There are no adequate data on developmental risks associated with use in pregnant females to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes
Animal studies
- SC administration (0, 3, 10, 30 mg/kg) every other day to pregnant mice during organogenesis resulted in no adverse effects on embryofetal development; plasma exposure at highest dose tested (30 mg/kg) was ~4 times that in humans at the recommended human dose (RHD) of 100 mg
- Similarly, SC administration to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development; plasma exposure at the highest dose tested (30 mg/kg) was ~20 times that in humans at the RHD
Lactation
Data are not available on presence of tofersen or its metabolites in human milk, effects on breastfed infants, or effects on milk production
Detected in milk of lactating mice following SC administration
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.Pharmacology
Mechanism of Action
Antisense oligonucleotide that causes degradation of superoxide dismutase 1 (SOD1), which is the second most common and best understood genetic cause of amyotrophic lateral sclerosis (ALS)
Tofersen binds to SOD1 mRNA, allowing for its degradation by RNase-H in an effort to reduce synthesis of SOD1 protein production
Absorption
Maximum CSF trough concentration occurred at 3rd (last) loading dose
Little to no accumulation for CSF tofersen with monthly dosing after loading phase
Tofersen is transferred from CSF into the systemic circulation, with median time to maximum concentration plasma values ranging from 2-6 hr
No accumulation in plasma tofersen exposure following monthly maintenance dosing
Distribution
Intrathecal administration allows for distribution within CNS tissues
Metabolism
Expected to be metabolized through exonuclease (3'- and 5')-mediated hydrolysis
Not a substrate for, or inhibitor or inducer of CYP450 enzymes
Elimination
CSF half-life (estimated): 4 weeks
Primary route of elimination has not been characterized
Administration
Intrathecal Preparation
Vial preparation
- Allow refrigerated vial to warm to room temperature (25ºC/77ºF) before administration without using external heat sources
- Inspect solution before administering; discard if particles observed or solution is not clear and colorless to slightly yellow
- Do NOT shake vial
- Do NOT dilute solution
- No external filters are required for administration
- Use aseptic technique when preparing
- Before administration, remove ~10 mL of cerebrospinal spinal fluid (CSF) using lumbar puncture needle
- Remove plastic cap and attach needle to syringe, for purpose of withdrawing tofersen from vial
- Insert needle into vial through center of overseal and withdraw required dose of 15 mL (100 mg) from vial
Procedural preparation instructions
- Consider sedation if indicated by patient’s clinical condition
- Consider imaging to guide intrathecal administration if indicated by patient’s clinical condition
- Before removing vial’s cap on aluminum overseal, confirm readiness of patient
- An unopened vial can be returned to refrigerator
- Evaluate patient before and after intrathecal injection for presence of potential conditions related to lumbar puncture, to avoid serious procedural complications
Intrathecal Administration
Administer intrathecally using a lumbar puncture by, or under the direction of, healthcare professionals experienced in performing lumbar punctures
Administer using lumbar puncture needle as an intrathecal bolus injection over 1-3 minutes
Contains no preservatives; once drawn into syringe, use immediately (within 4 hr of removal from vial) at room temperature; otherwise, discard
Discard any unused contents
Missed dose
- If 2nd loading dose missed, administer as soon as possible, and administer 3rd loading dose 14 days later
- If third loading dose or maintenance dose missed, administer as soon as possible, and administer next dose 28 days later
Storage
Upopened vials
- Refrigerate between 2-8ºC (36-46ºF) in original carton to protect from light
- Do not freeze
- If no refrigeration is available, may store in its original carton to protect from light at or below 30ºC (86ºF) for up to 14 days
- If removed from original carton, unopened vials can be returned to refrigerator, if necessary, for not more than 6 hr/day ≤30ºC (86ºF) for maximum of 6 days (36 hr)
Prepared syringes
- Once drawn into syringe, use immediately (within 4 hr of removal from vial) at room temperature
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Formulary
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