Tofersen (Monograph)

Brand name: Qalsody
Drug class: Central Nervous System Agents, Miscellaneous

Introduction

Tofersen is an antisense oligonucleotide.

Uses for Tofersen

Tofersen has the following uses:

Tofersen is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain observed in patients treated with tofersen. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

Tofersen Dosage and Administration

General

Tofersen is available in the following dosage form(s) and strength(s):

Injection: 100 mg/15 mL (6.7 mg/mL) solution in a single-dose vial for intrathecal use.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Tofersen is administered intrathecally using a lumbar puncture by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.
Recommended dose is 100 mg (15 mL) per administration.
Initiate tofersen treatment with 3 loading doses administered at 14-day intervals. A maintenance dose should be administered once every 28 days thereafter.
Allow vial to warm to room temperature prior to administration.
Withdraw the required dose of 15 mL (equivalent to 100 mg) from the vial; do not dilute.
Administer within 4 hours of removal from vial.
Prior to administration, remove approximately 10 mL of CSF.
Administer as an intrathecal bolus injection over 1 to 3 minutes.
Consult prescribing information for additional instructions on preparation and administration of tofersen.

Cautions for Tofersen

Contraindications

None.

Warnings/Precautions

Myelitis and Radiculitis

Serious adverse reactions of myelitis and radiculitis have been reported in patients treated with tofersen. Six patients treated with tofersen experienced myelitis or radiculitis in the clinical studies. Two patients discontinued treatment with tofersen and required symptomatic management with full resolution of symptoms. In the remaining 4 patients, symptoms resolved without discontinuation of the drug. If symptoms consistent with myelitis or radiculitis develop, diagnostic workup and treatment should be initiated according to the standard of care. Management may require interruption or discontinuation of tofersen.

Papilledema and Elevated Intracranial Pressure

Serious adverse reactions of papilledema and elevated intracranial pressure have been reported in patients treated with tofersen. Four patients developed elevated intracranial pressure and/or papilledema. All patients received treatment with standard of care with resolution of symptoms, and no events led to discontinuation of tofersen. If symptoms consistent with papilledema or elevated intracranial pressure develop, diagnostic workup and treatment should be initiated according to the standard of care.

Aseptic Meningitis

Serious adverse reactions of aseptic meningitis (also called chemical meningitis or drug-induced aseptic meningitis) have been reported in patients treated with tofersen. One patient experienced a serious adverse reaction of chemical meningitis, which led to discontinuation of tofersen. One patient experienced a serious adverse reaction of aseptic meningitis, which did not lead to discontinuation of the drug. In addition, nonserious increases in CSF white blood cell and CSF protein have also been reported with tofersen. If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care.

Specific Populations

Pregnancy

There are no adequate data on developmental risks associated with the use of tofersen in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Lactation

There are no data on the presence of tofersen or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Tofersen was detected in the milk of lactating mice following subcutaneous administration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tofersen and any potential adverse effects on the breastfed infant from tofersen or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

A total of 13.5% (22/162) patients were 65 years of age and older and 1.2% (2/162) patients were 75 years of age and older at initiation of treatment in clinical studies for ALS in patients who have a mutation in the superoxide dismutase 1 (SOD1) gene. No overall differences in safety or effectiveness were observed between these patients and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. There is no evidence for special dosage considerations based on age when tofersen is administered.

Common Adverse Effects

The most common adverse reactions (≥ 10% of patients treated with tofersen and greater than placebo) were pain, fatigue, arthralgia, increased CSF white blood cell, and myalgia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Tofersen is an antisense oligonucleotide that causes degradation of superoxide dismutase 1 (SOD1) mRNA through binding to SOD1 mRNA, which results in a reduction of SOD1 protein synthesis.

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.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.