Tofersen (Monograph)

Brand name: Qalsody
Drug class: Amyotrophic Lateral Sclerosis (ALS) Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Antisense oligonucleotide.

Uses for Tofersen

Amyotrophic Lateral Sclerosis

Treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease, Charcot's sclerosis); designated an orphan drug by FDA for treatment of ALS.

The current indication is approved under the accelerated approval pathway based on reduction in plasma neurofilament light chain observed in patients treated with tofersen; continue approval may be contingent upon verification of clinical benefit in confirmatory trial(s).

There is no cure for ALS; limited treatment options available have shown only modest benefits in delaying disease progression and death.

The American Academy of Neurology published an evidence-based review of treatments for ALS in 2009; however, the only disease-modifying drug available at that time was riluzole. Additional agents (e.g., edaravone, tofersen) are currently available; however, these drugs have not been shown to provide much, if any, improvement in survival. Referral to a specialized multidisciplinary clinic should be considered for patients with ALS.

Tofersen Dosage and Administration

General

Patient Monitoring

Monitor patients for symptoms of myelitis, radiculitis, papilledema, elevated intracranial pressure, and aseptic meningitis.

Premedication and Prophylaxis

If indicated, consider administering sedative medications.

Dispensing and Administration Precautions

Administer at a treatment center under the care of healthcare professionals experienced in performing lumbar punctures.
Evaluate patients prior to and after intrathecal injection for potential complications related to the procedure.

Administration

Intrathecal Administration

Administer using a lumbar puncture needle as an intrathecal bolus injection over 1 to 3 minutes.

Prior to administration, allow vial to warm to room temperature (25^oC) without using external heat sources.

Inspect solution; do not use if it is not clear and colorless to slightly yellow, or contains particulates.

Do not shake vial.

Prior to administration, remove approximately 10 mL of CSF using a lumbar puncture needle.

Withdraw the required dose of 15 mL (equivalent to 100 mg) from the vial; do not dilute.

The solution does not contain any preservatives; once drawn into the syringe, administer immediately (within 4 hours of removal from vial) at room temperature; otherwise, discard solution. Discard any unused contents of single-dose vials.

See manufacturer's prescribing information for additional details on preparation and administration of tofersen.

Dosage

Adults

ALS

Intrathecal

100 mg (15 mL) given intrathecally as 3 loading doses administered 14 days apart, followed by a maintenance dose of 100 mg once every 28 days.

If second loading dose is missed, administer as soon as possible, and administer third loading dose 14 days after. If third loading dose or maintenance dose is missed, administer as soon as possible, and administer next dose 28 days later.

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.

Renal Impairment

Manufacturer makes no specific dosage recommendations.

Geriatric Patients

Dosage adjustments not needed; some older individuals may exhibit greater sensitivity.

Cautions for Tofersen

Contraindications

None.

Warnings/Precautions

Myelitis and/or Radiculitis

Myelitis and radiculitis reported.

If symptoms develop, initiate diagnostic workup and treatment according to standard of care; management may require interruption or discontinuation of tofersen.

Papilledema and Elevated Intracranial Pressure

Papilledema and elevated intracranial pressure reported.

If symptoms develop, initiate diagnostic workup and treatment according to standard of care.

Aseptic Meningitis

Serious adverse reactions of aseptic meningitis reported. Nonserious increases in CSF white blood cells and CSF protein also reported.

If symptoms develop, initiate diagnostic workup and treatment according to standard of care.

Immunogenicity

Anti-drug antibodies detected in controlled studies. Antibody development did not appear to affect efficacy or safety of the drug.

Specific Populations

Pregnancy

No adequate data on use of tofersen in pregnant women. In animal studies, no adverse effects on embryofetal development and pre- or postnatal development.

Lactation

Not known whether tofersen is distributed into human milk or if the drug has any effects on the breast-fed infant or milk production. Distributed into milk in mice.

Females and Males of Reproductive Potential

Female and male reproductive effects not known. Adverse effects on reproductive organs in male mice; no functional adverse effects.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy or safety compared with younger adults. However, increased sensitivity cannot be ruled out.

Hepatic Impairment

Safety and efficacy not studied in hepatic impairment.

Renal Impairment

Safety and efficacy not studied in renal impairment.

Common Adverse Effects

Most common adverse reactions (≥10%): Pain, fatigue, arthralgia, increased CSF white blood cells, and myalgia.

Drug Interactions

No clinical drug interaction studies performed. Tofersen is not a substrate or inhibitor/inducer of major CYP enzymes, or a substrate or inhibitor of major transporters.

Tofersen Pharmacokinetics

Absorption

Following intrathecal administration, peak CSF concentrations occur after the third dose.

Median time to maximum plasma concentration 2-6 hours.

Distribution

Distributed within CSF.

Elimination

Half-life

4 weeks.

Stability

Storage

Intrathecal

Injection Solution

Store vials at 2-8°C in original container; protect from light and do not freeze. If refrigeration not possible, may store in original carton (≤30°C) for up to 14 days. Protect from light.

Unopened vials can be removed from and returned to refrigerator if necessary, for not more than 6 hours a day at temperatures ≤30°C for a maximum of 6 days (36 hours).

Actions

Antisense oligonucleotide; binds to SOD1 mRNA, causing degradation of mRNA and reduction in SOD1 protein synthesis.
Approximately 2% of all ALS cases and 15% of familial ALS cases are associated with mutations in SOD1, an antioxidant enzyme that protects cell from reactive oxide species toxicity.
Neuronal degeneration in ALS is thought to be caused by toxic gain of function of the mutant SOD1 protein.
Tofersen treatment has been shown to reduce total CSF SOD1 proteins by 35% at 28 weeks.

Advice to Patients

Inform patients and caregivers that tofersen could cause myelitis and radiculitis. Instruct patients and caregivers to contact their healthcare provider if symptoms consistent with these adverse reactions develop.
Inform patients and caregivers that tofersen could cause papilledema and elevated intracranial pressure. Instruct patients and caregivers to contact their healthcare provider if symptoms consistent with these adverse reactions develop.
Inform patients and caregivers that tofersen could cause aseptic meningitis. Instruct patients and caregivers to contact their healthcare provider if symptoms consistent with meningitis develop.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.