SPINRAZA

Treatment with Spinraza should only be initiated by a physician with experience in the management of spinal muscular atrophy (SMA). The decision to treat should be based on an individualised expert evaluation of the expected benefits of treatment for that individual, balanced against the potential risk of treatment with Spinraza.

Patients with profound hypotonia and respiratory failure at birth, where Spinraza has not been studied, may not experience a clinically meaningful benefit due to severe survival motor neuron (SMN) protein deficiency. Posology Two dosing regimens are available.

A low dose regimen of 12 mg, and a high dose regimen of 50/28 mg. Spinraza treatment should be initiated as early as possible after diagnosis. Low dose regimen This regimen is administered with a loading dose of 12 mg on Day 0, 14, 28 and 63, and a maintenance dose of 12 mg once every 4 months thereafter.

High dose regimen A 50 mg loading dose should be administered on Day 0 and on Day 14. A maintenance dose of 28 mg should be administered once every 4 months thereafter. Switching low dose regimen to the high dose regimen Patients currently treated with Spinraza 12 mg may be transitioned to the 50/28 mg dosing regimen with one loading dose of 50 mg administered at least 4 months (+/- 14 days) after the last dose of 12 mg.

The maintenance dose of 28 mg should be administered once every 4 months thereafter. 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.

Missed or delayed doses If a loading or a maintenance dose is delayed or missed, Spinraza should be administered according to the schedule in Table 1 and Table 2 below for the 12 mg and 50/28 mg dosing regimens, respectively.

Table 1:

Recommendations for delayed or missed dose for 12 mg dosing regimen Delayed or Missed dose Timing of Dosing Administration Loading dose • Administer the delayed or missed loading dose as soon as possible with at least 14 days between doses; continue with subsequent doses on the prescribed intervals from the last dose.

g. if the third loading dose is administered 30 days late at Day 58 (instead of the original schedule at Day 28), then the fourth loading dose should be administered 35 days later at Day 93 (instead of the original schedule at Day 63) with a maintenance dose 4 months thereafter.

Summary of safety profile The most common adverse reactions (ADRs) associated with the administration of nusinersen by lumbar puncture were headache, vomiting, and back pain. Experience from administering 12 mg dosing regimen The safety of Spinraza 12 mg was assessed in clinical trials 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 presymptomatic 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. A total of 385 SMA patients were treated with Spinraza 12 mg or lower and total time on study ranged from 1 to 3940 days (>10 years) (median 2388 days).

Experience from administering 50/28 mg dosing regimen The safety of Spinraza at 50/28 mg in infants, children and adults with SMA was assessed in study SM203 and study SM302 in symptomatic SMA patients who ranged in age from 14 days to 65 years at the time of first study dose.

5 days). Tabulated list of adverse reactions The safety assessment of nusinersen is based on data from patients from clinical trials and from post-marketing surveillance. The ADRs associated with nusinersen administration are summarised in Table 3.

g. angiodema, urticaria and rash. **Adverse reactions considered related to the lumbar puncture procedure. These reactions can be considered manifestations of post-lumbar puncture syndrome. These adverse reactions were reported in CS4 (later onset SMA) with an incidence at least 5% higher in patients treated with Spinraza 12 mg (n=84) compared to Sham control.

4). 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.

g. 8). Potential difficulties with this route of administration may be seen in very young patients and those with scoliosis. The use of ultrasound or other imaging techniques to assist with intrathecal administration of Spinraza, can be considered at the physician’s discretion.

Should arachnoiditis be suspected, an MRI should be performed to confirm arachnoiditis and the extent of the inflammation. Identification of arachnoiditis precludes the use of the injection site until local inflammation has been ruled out.

Thrombocytopenia and coagulation abnormalities 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 Spinraza. Renal toxicity Renal toxicity has been observed after administration of other 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. Hydrocephalus There have been reports of communicating hydrocephalus not related to meningitis or bleeding in patients treated with nusinersen 12 mg 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.

Excipients Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per 5 ml vial, that is to say essentially ‘sodium-free’. e. essentially ‘potassium-free’.

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