4.1. Therapeutic indications

Qalsody is indicated for the treatment of adults with amyotrophic lateral sclerosis (ALS), associated with a mutation in the superoxide dismutase 1 (SOD1) gene.

4.2. Posology and method of administration

Treatment with tofersen should only be initiated by a physician with experience in the management of ALS.

Qalsody should be administered by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.

Posology

The recommended dose is 100 mg of tofersen per treatment.

Tofersen treatment should be initiated with 3 loading doses administered at 14-day intervals.

A maintenance dose should be administered once every 28 days thereafter.

Missed or delayed doses

If the second loading dose is delayed or missed, tofersen should be administered as soon as possible, and the third loading dose should be administered 14 days later.

If the third loading dose is delayed or missed, tofersen should be administered as soon as possible, and the first maintenance dose should be administered 28 days later.

If a maintenance dose is delayed or missed, tofersen should be administered as soon as possible. Subsequent maintenance doses should be administered every 28 days from the last dose.

Duration of treatment

The need for continuation of therapy should be reviewed regularly and considered on an individual basis depending on the patient's clinical presentation and response to the therapy.

Special populations

Elderly

Experience with the use of tofersen in the elderly is limited. However, from the clinical data available, the efficacy and safety of tofersen are expected to be similar to that of other age groups studied.

There is no evidence for special dose considerations based on age when tofersen is administered.

Renal impairment

Tofersen has not been studied in patients with renal impairment.

Hepatic impairment

Tofersen has not been studied in patients with hepatic impairment.

Paediatric population

The safety and efficacy of Qalsody in paediatric patients below the age of 18 years has not been established. No data are available.

Method of administration

Qalsody is for intrathecal use by lumbar puncture.

• It is recommended to ensure intrathecal access prior to removing the plastic cap from the vial and drawing up the tofersen dose.

• Just prior to administration, the plastic cap should be removed from the vial and a nonspinal anesthesia needle attached to the syringe for the purpose of withdrawing tofersen from the vial. The syringe needle is inserted into the vial through the center of the overseal to withdraw the required dose of 15 ml (equivalent to 100 mg) from the vial.

– Qalsody must not be diluted.

– External filters, including bacterial or particulate filters, are not required.

• It is recommended that approximately 10 ml of cerebrospinal spinal fluid (CSF) is removed using a lumbar puncture needle prior to administration of tofersen.

• Tofersen is administered as an intrathecal bolus injection using a lumbar puncture needle over 1 to 3 minutes.

Procedural preparation instruction:

• If indicated by the clinical condition of the patient, sedation can be considered.

• If indicated by the clinical condition of the patient, imaging to guide intrathecal administration of tofersen can be considered.

• Prior to removing the vial's cap on the aluminium overseal, readiness of the patient should be confirmed. An unopened vial can be returned to the refrigerator; for total time permitted, see section 6.3.

• Patients should be evaluated prior to and after intrathecal injection for the presence of potential conditions related to lumbar puncture to avoid serious procedural complications.

Following injection, standard post-lumbar-puncture care is recommended.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Lumbar puncture procedure

There is a risk of adverse reactions occurring as part of the lumbar puncture procedure (e.g. headache, back pain, post lumbar puncture syndrome, infection).

Myelitis and/or radiculitis

Serious cases of myelitis and radiculitis have been reported in patients treated with tofersen. If symptoms consistent with these adverse reactions develop, diagnostic evaluation and treatment should be initiated according to the standard of care.

Increased intracranial pressure and/or papilloedema

Serious cases of increased intracranial pressure and/or papilloedema have been reported in patients treated with tofersen. If symptoms consistent with these adverse reactions develop, diagnostic evaluation and treatment should be initiated according to the standard of care.

Thrombocytopenia and coagulation abnormalities

Thrombocytopenia and coagulation abnormalities, including acute severe thrombocytopenia, have been observed after administration of subcutaneously or intravenously administered antisense oligonucleotides. If clinically indicated, platelet and coagulation laboratory testing is recommended prior to administration of tofersen.

Renal toxicity

Renal toxicity has been observed after administration of subcutaneously and intravenously administered antisense oligonucleotides. If clinically indicated, urine protein testing (preferably using a first morning urine specimen) is recommended. For persistent elevated urinary protein, further evaluation should be considered.

Excipients

Sodium

This medicinal product contains 52 mg sodium in each 15 ml, equivalent to 3% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult.

Potassium

This medicinal product contains potassium, less than 1 mmol (39 mg) per 15 ml dose, i.e., essentially 'potassium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

The co-administration of other intrathecal medicinal products with tofersen has not been evaluated and the safety of these combinations is not known.

Tofersen is not an inducer or inhibitor of CYP450-mediated oxidative metabolism; therefore, it should not interfere with other medicinal products that interact with these metabolic pathways.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of tofersen in pregnant women. Studies in animals in which tofersen is not pharmacologically active do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Tofersen is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

There are no data on the use of tofersen during breast-feeding in humans. Available pharmacodynamic data in animals have shown excretion of tofersen in milk (see section 5.3). A risk to the newborn/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tofersen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data available on the potential effects on fertility in humans. Toxicity studies in animals have indicated that tofersen would not appear to have harmful effects on male or female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Tofersen has minor influence on the ability to drive and use machines. Patients who develop visual disturbance under tofersen should be cautioned to avoid driving or operating machinery.

4.8. Undesirable effects

Summary of safety profile

The serious adverse reactions in tofersen-treated participants were myelitis (2.7%), increase intracranial pressure and/or papilloedema (2.7%), radiculitis (1.4%) and aseptic meningitis (1.4%). The most common adverse reactions reported in tofersen-treated participants were pain (66%), arthralgia (34%), fatigue (28.6%), CSF white blood cell increased (26.5%), CSF protein increased (26.5%), myalgia (19%) and pyrexia (18.4%).

Tabulated list of adverse reactions

The adverse reactions are listed by system organ class and frequency using the following convention: Very Common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1 000 to <1/100); Rare (≥1/10 000 to <1/1 000); Very Rare (<1/10 000); not known (cannot be estimated from the available data).

Table 1: Adverse reactions with Qalsody-treated participants in Study 101 and Study 102

System Organ Class (SOC)

Adverse reaction

Frequency

Nervous system disorders

CSF white blood cell increased*

Very common

CSF protein increased

Very common

Papilloedema‡

Common

Neuralgia

Common

Aseptic meningitis††

Common

Radiculitis†

Common

Myelitis§

Common

Musculoskeletal and connective tissue disorders

Arthralgia

Very common

Myalgia

Very common

Musculoskeletal stiffness

Common

General disorders and administration site conditions

Pain‡‡

Very common

Fatigue

Very common

Pyrexia

Very common

* CSF white blood cell increased includes preferred terms of CSF white blood cell increased and pleocytosis.

† Radiculitis includes preferred terms of radiculopathy and lumbar radiculopathy.

‡ Papilloedema includes preferred terms of papilloedema and intracranial pressure increased. See discussion in Description of selected adverse reactions (ARs).

§ Myelitis includes preferred terms of myelitis, myelitis transverse, and neurosarcoidosis. See discussion in Description of selected adverse reactions.

†† Aseptic meningitis includes preferred terms of meningitis chemical and meningitis aseptic. See discussion in Description of selected adverse reactions.

‡‡ Pain includes preferred terms of pain, back pain, and pain in extremity.

Description of selected adverse reactions

Lumbar puncture procedure

Adverse reactions associated with the administration of tofersen by lumbar puncture have been observed. The adverse reactions commonly associated with lumbar puncture are headache, back pain, post lumbar puncture syndrome, infection. The incidence and severity of these events were consistent with events expected to occur with lumbar puncture.

Myelitis and/or radiculitis

In the clinical studies, 4 participants receiving tofersen 100 mg reported serious reactions of myelitis (2.7%). The number of tofersen doses received before the onset of myelitis ranged from 5 to 15 doses. Two participants were symptomatic and 2 participants were asymptomatic. All 4 participants had abnormal magnetic resonance imaging (MRI) findings related to the event. Two participants discontinued treatment, and the event resolved. In the remaining 2 participants, the event did not lead to discontinuation of treatment (see section 4.4).

Two participants receiving tofersen 100 mg reported serious reactions of radiculitis (1.4%). The number of tofersen doses received before the onset of radiculitis ranged from 1 to 24 doses. Both reactions were symptomatic. One participant had abnormal MRI findings related to the event and one participant had a normal MRI. No participants discontinued treatment, and the reactions resolved with sequelae in one and without sequalae in the second participant (see section 4.4).

Increased intracranial pressure and/or papilloedema

Four participants receiving tofersen 100 mg reported serious reactions of increased intracranial pressure and/or papilloedema (2.7%). The number of tofersen doses received before the onset of increased intracranial pressure and/or papilloedema ranged from 7 to 18 doses. All 4 reactions of increased intracranial pressure and/or papilloedema were symptomatic. Four participants had an MRI with no findings pertinent to the event. One reaction finally led to permanent discontinuation of tofersen, one reaction led to interruption of tofersen treatment. All reactions were manageable with standard of care (see section 4.4).

Aseptic or chemical meningitis

Two participants receiving tofersen 100 mg reported serious reactions of aseptic or chemical meningitis (1.4%). The number of tofersen doses received before the onset of aseptic or chemical meningitis ranged from 5 to 7 doses. Both reactions of aseptic or chemical meningitis were symptomatic. One participant had an MRI with no findings pertinent to the event. One participant discontinued tofersen, and the other participant did not.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No cases of overdose associated with tofersen were reported in clinical studies.

In the event of an overdose, supportive medical care should be provided including consulting with a healthcare professional and close observation of the clinical status of the patient.