4.1. Therapeutic indications

Spinraza is indicated for the treatment of 5q Spinal Muscular Atrophy.

4.2. Posology and method of administration

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

The recommended dosage is 12 mg (5 ml) per administration.

Spinraza treatment should be initiated as early as possible after diagnosis with 4 loading doses on Days 0, 14, 28 and 63. A maintenance dose should be administered once every 4 months thereafter.

Duration of treatment

Information on long term efficacy of this medicinal product is not available. 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 dose or a maintenance dose is delayed or missed Spinraza should be administered according to the schedule in Table 1 below.

Table 1: Recommendations for delayed or missed dose

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.

e.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.

Maintenance dose

Timing of Dosing Administration

> 4 to < 8 months from last dose

• Administer the delayed maintenance dose as soon as possible; then

• The next maintenance dose per the original scheduled date, as long as these two doses are administered at least 14 days apart*;

≥ 8 to < 16 months from last dose

• Administer the missed dose as soon as possible and then the next dose 14 days later*;

≥ 16 to < 40 months from last dose

• Administer the missed dose as soon as possible and then the next dose 14 days later, followed by a third dose 14 days later*;

≥ 40 months from last dose

• Administer the entire loading regimen on the prescribed intervals (Days 0, 14, 28 and 63)*;

*then subsequently to the above recommendations, a maintenance dose 4 months after the last dose should be administered and repeated every 4 months.

Special populations

Renal impairment

Nusinersen has not been studied in patients with renal impairment. The safety and efficacy in patients with renal impairment has not been established and they should be closely observed.

Hepatic impairment

Nusinersen has not been studied in patients with hepatic impairment. Nusinersen is not metabolised via the cytochrome P450 enzyme system in the liver, therefore dose adjustment is unlikely to be required in patients with hepatic impairment (see sections 4.5 and 5.2).

Method of administration

Spinraza is for intrathecal use by lumbar puncture.

Treatment should be administered by health care professionals experienced in performing lumbar punctures.

Spinraza is administered as an intrathecal bolus injection over 1 to 3 minutes, using a spinal anaesthesia needle. The injection must not be administered in areas of the skin where there are signs of infection or inflammation. It is recommended that the volume of cerebral spinal fluid (CSF), equivalent to the volume of Spinraza to be injected, is removed prior to administration of Spinraza.

Sedation may be required to administer Spinraza, as indicated by the clinical condition of the patient.

Ultrasound (or other imaging techniques) may be considered to guide intrathecal administration of Spinraza, particularly in younger patients and in patients with scoliosis; see instructions for use in section 6.6.

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. arachnoiditis, headache, back pain, vomiting; see section 4.8). 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 extension 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 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'.

Potassium

This medicinal product contains potassium, less than 1 mmol (39 mg) per 5 ml vial, i.e. essentially 'potassium-free'.

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

No interaction studies have been performed. In vitro studies indicated that nusinersen is not an inducer or inhibitor of CYP450 mediated metabolism. In vitro studies indicate that the likelihood for interactions with nusinersen due to competition for plasma protein binding, or competition with or inhibition of transporters is low.

4.6. Fertility, pregnancy and lactation

Pregnancy

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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of nusinersen during pregnancy.

Breast-feeding

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 (see section 5.3). There are no data available on the potential effects on fertility in humans.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

The most common adverse reactions (ADRs) associated with the administration of Spinraza 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 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. 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).

Tabulated list of adverse reactions

The safety assessment of Spinraza is based on data from patients from clinical trials and from post-marketing surveillance. The ADRs associated with Spinraza administration are summarised in Table 2.

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)

Table 2: Adverse reactions related Spinraza administration

MedDRA System Organ Class

Adverse reaction

Frequency category

Infections and infestations

Meningitis

Not known

Immune system disorders

Hypersensitivity*

Not known

Nervous system disorders

Headache**

Aseptic meningitis

Arachnoiditis

Very common

Not known

Not known

Gastrointestinal disorders

Vomiting**

Very common

Musculoskeletal and connective tissue disorders

Back pain**

Very common

General Disorders and Administration Site Conditions

Pyrexia

Very common

*e.g. angioedema, 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.

Events of communicating hydrocephalus have been observed in the post-marketing setting (see section 4.4).

Description of selected adverse reactions

Adverse reactions associated with the administration of Spinraza 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 Spinraza.

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

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 adverse reactions 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.