Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Biogen Netherlands B.V., Prins Mauritslaan 13, 1171 LP Badhoevedorp, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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).
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.
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, 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 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.
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.
This medicinal product contains potassium, less than 1 mmol (39 mg) per 15 ml dose, i.e., essentially ‘potassium-free’.
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.
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.
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.
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).
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.
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%).
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.
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.
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).
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).
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 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 national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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