Nusinersen

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

There have been reports of communicating hydrocephalus not related to meningitis or bleeding in patients treated with nusinersen in the post-marketing setting. Some patients were implanted with a ventriculo-peritoneal shunt. In patients with decreased consciousness, an evaluation for hydrocephalus should be considered. The benefits-and risks of nusinersen treatment in patients with a ventriculo-peritoneal shunt are unknown at present and the maintenance of treatment needs to be carefully considered.

There are no or limited amount of data from the use of nusinersen in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of nusinersen during pregnancy.

It is unknown whether nusinersen/metabolites are excreted in human milk. A risk to the newborn/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from nusinersen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

In toxicity studies in animals no effects on male or female fertility were observed. There are no data available on the potential effects on fertility in humans.

Nusinersen has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

The safety assessment of nusinersen was based on two Phase 3 clinical studies in infants (CS3B) and children (CS4) with SMA, together with one Phase 2 study in infants and children with SMA (CS7) and open-label studies including pre-symptomatic infants (CS5) genetically diagnosed with SMA and infants and children with SMA. Study CS11 enrolled infantile and later-onset patients including those who had completed studies CS3B, CS4 and CS12. Of the 346 patients who received nusinersen up to a maximum of 5 years, 258 patients received treatment for at least 1 year.

List of adverse reactions

The assessment of undesirable effects is based on the following frequency data: Very common (≥1/10), Not known (cannot be estimated from the available data).

Adverse reactions related to lumbar puncture procedure reported in CS4 (later onset SMA) with an incidence at least 5% higher in patients treated with nusinersen than sham-control:

Nervous system disorders

Very common: Headache*

Gastrointestinal disorders

Very common: Vomiting*

Musculoskeletal and connective tissue disorders

Very common: Back pain*

* Adverse events considered related to the lumbar puncture procedure. These events can be considered manifestations of post-lumbar puncture syndrome.

Post-marketing experience

Adverse reactions have been identified during post-approval use of nusinersen. Among patients treated with nusinersen by lumbar puncture, serious infection, such as meningitis, has been observed. Communicating hydrocephalus, aseptic meningitis and hypersensitivity (e.g. angioedema, urticaria and rash) have also been reported. The frequency of these reactions is not known as they have been reported from the post marketing setting.

Description of selected adverse reactions

Adverse reactions associated with the administration of nusinersen by lumbar puncture have been observed. The majority of these are reported within 72 hours of the procedure. The incidence and severity of these events were consistent with events expected to occur with lumbar puncture. No serious complications of lumbar puncture, such as serious infections, have been observed in the clinical trials of nusinersen.

Some adverse events commonly associated with lumbar puncture (e.g. headache and back pain) could not be assessed in the infant population exposed to nusinersen due to the limited communication appropriate for that age group.

Immunogenicity

The immunogenic response to nusinersen was determined in 346 patients with baseline and post-baseline plasma samples evaluated for anti-drug antibodies (ADA). Overall, the incidence of ADAs was low, with 15 (4%) patients classified as ADA positive overall, of which 4 had a transient response, 5 had a persistent response, and 6 patients had responses which could not be classified as transient or persistent at the time of data cut off. The impact of immunogenicity on safety was not formally analysed as the number of patients with ADAs was low. However, individual safety data for the treatment-emergent ADA-positive cases were reviewed, and no AEs of interest were identified.