nusinersen: prescribing information – dosing, contraindications, interactions, side effects

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

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.

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.

Table 2: Recommendations for delayed or missed dose for 50/28 mg dosing regimen
Delayed or Missed Dose
Timing of Dosing Administration
Second loading dose
- If time since last dose is less than 4.5 months, administer the missed 50 mg loading dose as soon as possible; administer the 28 mg maintenance dose per the original scheduled date, as long as these two doses are administered at least 14 days apart; then administer 28 mg every 4 months thereafter.
- If time since last dose is 4.5 months to less than 8.5 months, administer the missed 50 mg loading dose as soon as possible; followed by the 28 mg maintenance dose 14 days later, then administer the next 28 mg maintenance dose 4 months thereafter.
- If time since last dose exceeds 8.5 months, restart regimen.
Maintenance dose
<8 months from last dose
- Administer the missed dose as soon as possible; then
- Administer the next maintenance dose per the original scheduled date, as long as these two doses are administered at least 14 days apart; then
- Administer next maintenance doses every 4 months thereafter.
8 months to <12 months from last dose
- Administer the delayed dose as soon as possible; then
- Administer one additional maintenance dose 14 days later;
then
- Administer next maintenance doses every 4 months thereafter
≥12 months from last dose
- Restart regimen

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 from the patient 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.

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

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.
A total of 128 SMA patients were treated with Spinraza 50 mg or 28 mg and total time on study ranged from 13 to 1521 days (>4 years) (median 740.5 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.

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 3: Adverse reactions related to 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. 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.

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 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 reactions 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.

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 national reporting system listed in Appendix V.

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 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’.

Potassium

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

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.

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.

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

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code:
M09AX07

Mechanism of action

Nusinersen is an antisense oligonucleotide (ASO) which increases the proportion of exon 7 inclusion in survival motor neuron 2 (SMN2) messenger ribonucleic acid (mRNA) transcripts by binding to an intronic splice silencing site (ISS-N1) found in intron 7 of the SMN2 pre-messenger ribonucleic acid (pre-mRNA). By binding, the ASO displaces splicing factors, which normally suppress splicing.
Displacement of these factors leads to retention of exon 7 in the SMN2 mRNA and hence when SMN2 mRNA is produced, it can be translated into the functional full length SMN protein.

SMA is a progressive neuromuscular disease resulting from mutations in chromosome 5q in the SMN1 gene. A second gene SMN2, located near SMN1, is responsible for a small amount of SMN protein production. SMA is a clinical spectrum of disease with disease severity linked to fewer numbers of SMN2 gene copies and younger age of symptom onset.

Plasma neurofilament light chain (Nf-L)

Levels of plasma neurofilament light chain (Nf-L), a blood-based marker of axonal injury were measured at baseline and at several timepoints in study SM203 assessing the 50/28 mg dosing regimen in patients with infantile-onset and later-onset SMA.

Levels of plasma Nf-L were reduced more rapidly in the 50/28 mg group compared to the 12 mg group with an 88% reduction from baseline to Day 64 in the 50/28 mg group, compared to a 77% reduction in the 12 mg group (difference in geometric mean ratios for 50/28 mg group to 12 mg group:
49%; (p = 0.0035) (Figure 1).

Similarly, treatment naïve patients with later-onset SMA experienced reductions of 62% in plasma Nf- L levels in the 50/28 mg group from baseline to Day 64, as compared to a 34% reduction in the 12 mg group (difference in geometric mean ratios for 50/28 mg group to 12 mg group: 42%; (p = 0.0047).

Figure 1: Study SM203 Part B Infantile-Onset SMA Plasma NfL LS mean ratio to baseline (95% CI) by visit from ANCOVA analysis using MI: ITT, Matched Sham Set

Day 64 is the secondary endpoint for comparison of 12 mg versus 50/28 mg
Day 183 is the secondary endpoint for comparison of matched sham versus 50/28 mg

Immunogenicity

The presence of ADAs appeared to decrease Spinraza plasma clearance. No discernible effects of ADAs on plasma Nf-L or measures of clinical function have been observed in Spinraza 12 mg and 50/28 mg dosing regimens. ADAs had no effect on safety as measured by incidence of adverse events (AEs) including hypersensitivity, anaphylactic reaction, and angio-oedema.

Clinical efficacy and safety

Symptomatic patients treated with Spinraza 50/28 mg regimen

Single- and multiple-dose pharmacokinetics (PK) of nusinersen, administered via intrathecal injection, were determined in paediatric and adult patients diagnosed with SMA.

Absorption

Intrathecal injection of nusinersen into the CSF allows nusinersen to be fully available for distribution from the CSF to the target central nervous system (CNS) tissues.
Cumulative CSF PK data evaluated in the long-term exposure study CS11 in the 12 mg dosing regimen indicated that in infantile and later onset SMA patients, CSF concentrations continued to accumulate over approximately 9 years.

A similar trend in accumulation of CSF concentration was also observed for the 50/28 mg dosing regimen in Study SM203 and Study SM302 from CSF PK collected over the entire duration of data.

Following intrathecal administration trough plasma concentrations of nusinersen were relatively low compared to the trough CSF concentration. Median plasma Tmax values ranged from 1.7 to 6.0 hours.
Mean plasma Cmax and AUC values increased approximately dose proportionally over the evaluated dose range. There was no accumulation in plasma exposure measures (Cmax and AUC) after multiple doses.

Distribution

Autopsy data from patients (n=3) show that nusinersen administered intrathecally is broadly distributed within the CNS achieving therapeutic levels in the target spinal cord tissues. Presence of

nusinersen was also demonstrated in neurons and other cell types in the spinal cord and brain, and peripheral tissues such as skeletal muscle, liver, and kidney.

Biotransformation

Nusinersen is metabolized slowly and predominantly via exonuclease (3’- and 5’) -mediated hydrolysis and is not a substrate for, or inhibitor or inducer of CYP450 enzymes.

Elimination

The mean terminal elimination half-life in CSF is estimated at approximately 20 months. The primary route of elimination is expected via urinary excretion of nusinersen and its metabolites.

Interactions