Consumer medicine information

Spinraza

Nusinersen

BRAND INFORMATION

Brand name

Spinraza

Active ingredient

Nusinersen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Spinraza.

SUMMARY CMI

SPINRAZA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried for you or your child about using this medicine, speak to your doctor, nurse or pharmacist.

1. Why am I using SPINRAZA?

SPINRAZA has nusinersen (as heptadecasodium) as active ingredient. SPINRAZA is used to treat the genetic disease called Spinal Muscular Atrophy (SMA).

For more information, see Section 1. Why am I using SPINRAZA? in the full CMI.

2. What should I know before I use SPINRAZA?

Do not use if you have ever had an allergic reaction to SPINRAZA or any of the ingredients listed at the end of the CMI.

Talk to your doctor or nurse if you or your child have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SPINRAZA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SPINRAZA and affect how it works.

Additional information is found in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SPINRAZA?

  • The usual dose of SPINRAZA is 12 mg administered by an experienced doctor, and given as a continuous injection (over 1 to 3 minutes) into the lower back by lumbar puncture.
  • Your doctor may give you or your child a medicine to make you or your child relax or sleep (sedation) before giving SPINRAZA.

More instructions can be found in Section 4. How do I use SPINRAZA? in the full CMI.

5. What should I know while using SPINRAZA?

Things you should do
  • Keep all of your or your child's hospital, doctor and physiotherapy appointments so that you or your child's progress can be checked.
  • Remind any doctor, dentist, nurse or pharmacist you or your child visit that you are receiving SPINRAZA.
Things you should not do
  • Do not stop receiving this medicine without consulting your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how SPINRAZA affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • SPINRAZA is usually stored in the hospital pharmacy until it is time for it to be given to you or your child.

For more information, see Section 5. What should I know while using SPINRAZA? in the full CMI.

6. Are there any side effects?

Side effect may include infections, allergic reactions, gut, skin or breathing related effects. You or your child might experience side effects caused by the lumbar puncture procedure.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

SPINRAZA®

Active ingredient(s): nusinersen (as heptadecasodium) 12mg/5mL solution for injection


Consumer Medicine Information (CMI)

This leaflet provides important information about using SPINRAZA. You should also speak to your doctor, nurse or pharmacist if you would like further information or if you have any concerns or questions about using SPINRAZA.

Where to find information in this leaflet:

1. Why am I using SPINRAZA?
2. What should I know before I use SPINRAZA?
3. What if I am taking other medicines?
4. How do I use SPINRAZA?
5. What should I know while using SPINRAZA?
6. Are there any side effects?
7. Product details

1. Why am I using SPINRAZA?

SPINRAZA contains the active ingredient nusinersen (as heptadecasodium). SPINRAZA is a type of medicine called an anti-sense oligonucleotide (ASO).

SPINRAZA is used to treat the genetic disease called Spinal Muscular Atrophy (SMA).

Spinal Muscular Atrophy (SMA) is a genetic disease caused by a shortage of a protein called survival motor neuron (SMN). This results in the loss of nerve cells in the spine, leading to weakness of the muscles in the shoulders, hips, thighs and upper back. It may also weaken the muscles used for breathing and swallowing.

SPINRAZA works by causing the body to produce more SMN protein.

SPINRAZA has only been proven to work in a type of SMA known as 5q SMA.

Ask your doctor if you have any questions about why this medicine has been prescribed for you or your child.

Your doctor may have prescribed it for another reason.

There is no information on the use of this medicine in adults above 18 years of age.

This medicine is not addictive.

It is available only with a doctor's prescription.

This medicine is given to you or your child by a doctor.

2. What should I know before I use SPINRAZA?

Warnings

Do not use SPINRAZA if:

  • you or your child have an allergy to:
  • Nusinersen, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath.
  • wheezing or difficulty breathing.
  • swelling of the face, lips, tongue or other parts of the body.
  • rash, itching or hives on the skin.

If any of these signs occur, stop using SPINRAZA and notify your doctor, nurse or pharmacist immediately.

  • Do not receive this medicine after the expiry date printed on the vial or if the packaging is torn or shows signs of tampering.
    If you receive it after the expiry date has passed, it may not work as intended.
  • Do not receive SPINRAZA if the medicine is cloudy, contains particles or is discoloured.
    It should be clear and colourless.
  • If you are not sure whether you or your child should start receiving this medicine, talk to your doctor.

Check with your doctor if you or your child:

  • have bleeding problems, problems with blood clotting, or low platelet counts.
  • Tell your doctor if you or your child have kidney problems.
  • Tell your doctor if you or your child have allergies to any other medicines, foods, preservatives or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or intend to become pregnant.

There is no information on the use of SPINRAZA during pregnancy. Your doctor will discuss the risks and benefits of receiving it if you are pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether SPINRAZA passes into breast milk. Your doctor will discuss the risks and benefits of receiving it if you are breast-feeding.

3. What if I am taking other medicines?

Tell your doctor, nurse or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Your doctor and nurse have more information on medicines to be careful with or avoid while taking this medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SPINRAZA.

4. How do I use SPINRAZA?

How much to use

  • The usual dose of SPINRAZA is 12 mg, given as a continuous injection into the lower back (over 1 to 3 minutes) by lumbar puncture.

When to use SPINRAZA

  • You or your child will usually be given SPINRAZA on the first day of treatment then again approximately 14, 28 and 63 days later. After this, SPINRAZA is given once every 4 months.
  • Continue receiving your medicine for as long as your doctor tells you.
    Your doctor will tell you how long you or your child needs to keep having SPINRAZA.

How to give SPINRAZA

  • SPINRAZA is given by injection into the lower back. This injection, called a lumbar puncture, is done by inserting a needle in the space around the spinal cord (intrathecal space). This will be done by a doctor experienced in doing lumbar punctures. Your doctor may give you or your child a medicine to make you or your child relax or sleep (sedation) before giving SPINRAZA.

If you or your child forget to use SPINRAZA

SPINRAZA should be used regularly. If you or your child miss your dose at the usual time, talk to your doctor or nurse as soon as possible.

If you or your child are unable to receive SPINRAZA as planned, speak with your doctor to ensure that SPINRAZA can be given as soon as possible.

If you use too much SPINRAZA

There have been no reported overdoses of SPINRAZA.

Your doctor is trained to calculate the correct dose and administer your medicine.

If you think that you or your child have been given too much SPINRAZA, you may need urgent medical attention.

You should immediately:

  • phone the Australian Poisons Information Centre (by calling 13 11 26), or the New Zealand National Poisons Information Centre (by calling 0800 POISON or 0800 764 766), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SPINRAZA?

Things you should do

Keep all of your or your child's hospital, doctor and physiotherapy appointments so that you or your child's progress can be checked.

Remind any doctor, nurse, dentist or pharmacist you visit that you or your child are using SPINRAZA.

Things you should not do

  • Do not stop using this medicine without consulting your doctor.
  • Do not give your or your child's medicine to anyone else, even if they appear to have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SPINRAZA affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

SPINRAZA is usually stored in the hospital pharmacy until it is time for it to be given to you or your child.

However, if you need to store SPINRAZA:

Follow the instructions in the carton on how to take care of your medicine properly.

  • Keep SPINRAZA in the original carton until it is time for it to be given.
  • Keep it in the refrigerator, between 2°C and 8°C. Do not freeze. Protect from light.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

Each vial of SPINRAZA should be used once only. The doctor, nurse or pharmacist will discard any unused portion.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor, nurse or pharmacist if you have any further questions about side effects.

In studies with SPINRAZA the side effects are consistent with the signs and symptoms of SMA or are side effects which can occur when medications are given by lumbar puncture.

There is a risk of side effects occurring after SPINRAZA is given by a lumbar puncture procedure.

This can include headaches, vomiting, back pain and infection. There may also be difficulties with giving a medicine by this method in very young patients and those with scoliosis (twisted and curved spine).

You or your child may be at risk of bleeding complications whilst receiving treatment with SPINRAZA. Before you or your child are given SPINRAZA your doctor may decide to do a blood test to check that your or your child's blood can clot properly.

Your doctor may decide to repeat this test from time to time whilst you or your child are given SPINRAZA.

SPINRAZA may affect the kidneys. Before you or your child are given SPINRAZA your doctor may decide to do a urine test to check that your or your child's kidneys are working normally. This may not be required every time you or your child are given SPINRAZA.

You or your child should be aware that symptoms and signs of SMA may still occur when being treated with SPINRAZA, e.g. breathing problems, muscle weakness, joint and bone problems, or digestive problems.

Less serious side effects

Less serious side effectsWhat to do
  • infections of the airways due to viruses such as the cold virus including symptoms such as a blocked, stuffy or runny nose, sneezing and coughing, a sore or scratchy throat and watery or itchy eyes
  • infections in the ears leading to painful ears or loss of balance (Otitis media)
  • heart-burn (Gastro-esophageal reflux disease)
  • diarrhoea
  • stiffness of muscles or joints, curving of the back or spine, pain

There may be side effects which are due to the lumbar puncture and which some people experience during or shortly after SPINRAZA is given. These can include:

  • back-pain
  • headache
  • feeling or being sick (nausea or vomiting)
  • swelling or pain at the injection site
Speak to your doctor, nurse or pharmacist if you or your child have any of these less serious side effects and they worry you.
These are less common side effects.

Serious side effects

Serious side effectsWhat to do
  • increase in heart rate
  • bluish-tinge of the skin, fingertips or lips
  • infections of the lungs such as pneumonia
  • infections of the nose, sinuses, throat, airways or lungs such as respiratory tract infections, bronchitis
  • constipation
  • feeling or being sick (nausea or vomiting)
  • difficulty or being unable to swallow
  • rash
  • fever
  • cough
  • nose bleed
Tell your doctor, nurse or pharmacist immediately if you notice any of the following happening to you or your child and they worry you.
If any of these persist or worsen, talk to your doctor.
These are very common side effects.
  • swelling of the face, lips, tongue or other parts of the body, rash, itching or hives which may be an allergic or allergic-like reaction
  • shortness of breath, wheezing, difficulty breathing including rapid or shallow breathing, chest pain or discomfort
  • confusion or loss of consciousness
  • fever, vomiting, headache, stiff neck (which may be symptoms of a serious infection and/or aseptic meningitis)
  • in babies and children, an increase in head size which may appear to worsen over a short period of time
Go straight to the Emergency Department at your nearest hospital if you or your child notice any of these serious side effects. Notify your doctor.
These are very serious side effects.
You or your child may need urgent medical attention or hospitalisation.
These side effects are very rare.

Tell your doctor, nurse or pharmacist if you notice anything else that may be making you or your child feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What SPINRAZA contains

Active ingredient
(main ingredient)
nusinersen (as heptadecasodium)
Other ingredients
(inactive ingredients)
sodium chloride
potassium chloride
calcium chloride dihydrate
magnesium chloride hexahydrate
dibasic sodium phosphate
sodium phosphate monobasic dihydrate
sodium hydroxide
hydrochloric acid
water for injection
Potential allergensNone

Do not take this medicine if you are allergic to any of these ingredients.

What SPINRAZA looks like

SPINRAZA comes as a clear and colourless solution in a glass vial. Each pack of SPINRAZA contains 12mg nusinersen (as heptadecasodium) in 5mL of solution in a single 5mL vial.

SPINRAZA is only available in one pack size.

SPINRAZA is usually drawn up into a syringe ready for your or your child's dose to be given by a doctor.

SPINRAZA - AUST R 282522.

Further information

You can obtain more information from your doctor, pharmacist or nurse or by telephoning 1800 852 289 in Australia or 0800 852 289 in New Zealand.

Who distributes SPINRAZA

SPINRAZA is supplied in Australia by:

Biogen Australia Pty Ltd
Level 4, 2 Banfield Road
Macquarie Park, NSW 2113
Australia

SPINRAZA is supplied in New Zealand by:

Biogen NZ Biopharma Limited
188 Quay Street
Auckland
New Zealand

This leaflet was prepared in July 2023.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Spinraza

Active ingredient

Nusinersen

Schedule

S4

 

1 Name of Medicine

Nusinersen.

2 Qualitative and Quantitative Composition

Each single use vial contains 12.6 mg of nusinersen heptadecasodium equivalent to 12 mg of nusinersen as the free acid (or 2.4 mg/mL) in artificial cerebrospinal fluid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Spinraza is a sterile, preservative-free clear to colourless isotonic solution for injection in a single use vial, practically free from visible particles. The pH is approximately 7.2.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Treatment should be initiated and supervised by specialist medical practitioners experienced in the diagnosis and management of SMA.

Dosage.

The recommended dosage is 12 mg (5 mL) per administration. Initiate Spinraza treatment 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. (See Special dosage instructions for intrathecal administration).

Dose delay.

If a loading or a maintenance dose is delayed or missed Spinraza should be administered according to schedule in Table 1.

Method of administration.

Treatment should be administered by health care professionals experienced in performing lumbar punctures.
Spinraza is for intrathecal use by lumbar puncture.

Special populations.

Adults.

There are limited clinical data in patients over the age of 18 years. There is real world evidence data from post-marketing experience in adult SMA patients (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties).

Paediatric.

Spinraza has been studied in patients ranging from newborn to 17 years (see Section 5.1, Clinical trials).

Use in the elderly.

There are no data in patients over the age of 65.

Use in patients with renal impairment.

Spinraza has not been studied in patients with renal impairment.

Use in patients with hepatic impairment.

Spinraza has not been studied in patients with hepatic impairment. Spinraza is not metabolized via the cytochrome P450 enzyme system in the liver; therefore, dosage adjustment is unlikely to be required in patients with hepatic impairment. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).

Instructions for preparation of the injection.

1. The Spinraza vial should be inspected for particles prior to preparation. If particles are observed and/or the liquid in the vial is not clear and colourless, the vial must not be used.
2. Aseptic technique should be used when preparing Spinraza solution for intrathecal administration.
3. The vial should be taken out of the refrigerator and allowed to warm to room temperature (25°C) without using external heat sources, prior to administration.
4. If the vial remains unopened and the solution is not used, it should be returned back to the refrigerator (2-8°C).
5. Just prior to administration, insert the syringe needle into the vial through the center of the over-seal to remove the appropriate volume (see dosing regimen and dose adjustments). Spinraza must not be diluted.
6. Once drawn in to the syringe, if the solution is not used within 6 hours, it must be discarded.
7. Any unused product or waste material must be disposed of in accordance with local requirements.

Special dosage instructions for intrathecal administration.

1. The solution must be visually inspected prior to administration. Only clear and colourless solutions, free from particles, should be administered. The use of external filters is not required.
2. Aseptic technique must be used when administering Spinraza.
3. Sedation may be required to administer Spinraza, as indicated by the clinical condition of the patient.
4. Ultrasound (or other imaging techniques) may be considered to guide intrathecal administration of Spinraza, particularly in younger patients.
5. It is recommended that the volume of cerebrospinal fluid equivalent to the volume of Spinraza to be injected is removed prior to administration of Spinraza.
6. 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.
7. Any unused contents of the vial should be discarded.
Spinraza is for single use in one patient only. Discard any residue.

4.3 Contraindications

Spinraza is contraindicated in patients who have a history of hypersensitivity reactions, to the active ingredient or its excipients.

4.4 Special Warnings and Precautions for Use

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.
In a combined analysis of the sham-controlled studies for patients with infantile-onset and later-onset SMA, 71 of 123 (58%) of Spinraza-treated patients had elevated urine protein, compared to 22 of 65 (34%) sham-controlled patients.
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-market 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.

Type 0 or IV SMA.

Patients most likely to develop type 0 or IV SMA have not been included in the clinical development program for Spinraza. The decision to treat should be based on individualized expert evaluation of the expected benefits of treatment for that individual, balanced against the potential risk of treatment with nusinersen. The full benefits and risks are unknown among patients diagnosed with type 0 or IV SMA.

Use in the elderly.

There are no data in patients over the age of 65.

Paediatric use.

Spinraza has been studied in patients ranging from newborn to 17 years (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

There are no data available on whether Spinraza interferes with laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical studies of interactions with other medicines have been performed.
Nusinersen is metabolized via nucleases and not by the cytochrome P450 (CYP450) system.
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

Effects on fertility.

Data from nonclinical studies do not suggest that nusinersen would be associated with effects on male or female fertility. Administration of nusinersen via subcutaneous injection to male and female mice at doses of up to 25 mg/kg every other day (87.5 mg/kg/week) had no effects on fertility.
There are no data on the effects of nusinersen on human fertility.
(Category B1)
Data from nonclinical studies do not suggest that nusinersen would be associated with effects on embryo-fetal development. Administration of nusinersen via subcutaneous injection to mice and rabbits at doses up to 25 mg/kg every other day (87.5 mg/kg/week) did not produce any adverse effects on embryo-fetal development. Using liver concentration as a measure of systemic exposure, the estimated nusinersen concentration in the liver at 25 mg/kg every other day (87.5 mg/kg/week) provides an approximately ≥ 8.4-fold margin over the liver nusinersen concentration in humans at the maximum recommended clinical dose of 12 mg.
The effects of nusinersen on labour and delivery in humans are unknown.
There are no data on the presence of nusinersen in human milk, the effects on the breastfed infant or the effects of the drug on milk production.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive or use machines during treatment with Spinraza have been performed.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse events.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.
In Australia, healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
In New Zealand, healthcare professionals are asked to report any suspected adverse reactions at https://nzphvc.otago.ac.nz/reporting/.

Clinical trials.

The safety of Spinraza in infants and children with SMA was assessed in 3 randomised, double-blind, sham-controlled studies two of which were phase 3 (Study CS3B and Study CS4) and one phase 2 (Study SM202), in an open-label phase 2 study in symptomatic infants (Study CS3A), an open-label study in pre-symptomatic infants genetically diagnosed with SMA (Study CS5) and in patients aged 2 to 15 years (at first dose) in an integrated analysis of 4 open-label studies (Studies CS2, CS12, CS1 and CS10). Study CS11 enrolled infantile- and later-onset subjects including those who complete studies CS3B, CS4 and CS12. A total of 346 SMA patients were treated with Spinraza and total time on study ranged from 6 to 2028 days (median 627 days).
In Study CS3B, 121 patients were dosed, of whom 80 patients received Spinraza (median exposure 280 days) and 41 patients received sham-control (median exposure 187 days).
In Study CS4, 126 patients were dosed, of whom 84 patients received Spinraza (median exposure 451 days) and 42 patients received sham-control (median exposure 450 days).
Adverse events reported at an incidence at least 5% higher in patients treated with Spinraza compared to sham-control in Studies CS3B and CS4 are summarized in Tables 2 and 3, respectively. Events reported across open-label studies CS3A, CS2, CS12, CS5, CS1, CS10, CS11 and the double-blind study SM202 were consistent with those observed in Studies CS3B and CS4. No serious adverse events were considered related to study drug. The majority of adverse events reported in clinical trials were considered related to SMA disease or related to intrathecal administration procedure. See Table 4.
The adverse events are presented as MedDRA preferred terms and are listed by system organ class and frequency using the following convention: Very Common (≥ 1/10); Common (≥ 1/100 - < 1/10); Uncommon (≥ 1/1,000 - < 1/100); Rare (≥ 1/10,000 - < 1/1,000); Very Rare (< 1/10,000).
Within each frequency grouping, adverse events are presented in order of decreasing seriousness.
Use in adults from post-marketing setting. Safety data in the adult population from use in the post-marketing setting are consistent with the known safety profile of nusinersen and with co-morbidities associated with the underlying disease of SMA. No controlled data are available. (See Section 5.1 Pharmacodynamic Properties).
Description of selected adverse events.

Lumbar-puncture-related events.

Adverse events associated with the administration of Spinraza by lumbar puncture, such as headache, back pain, vomiting and post lumbar puncture syndrome, have been observed. 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 clinical studies.

Immunogenicity.

Treatment-emergent antidrug antibody (ADA) status was assessed in 346 subjects treated with Spinraza in ongoing and completed clinical studies. Overall, the incidence of ADAs was 15 (4%) patients and were classified as ADA positive overall, of which 4 had a transient response, 5 subjects had a persistent response, and 6 subjects had responses that could not be classified as transient or persistent yet at the time of data cutoff. The impact of immunogenicity on safety was not formally analysed because the number of subjects with ADAs was low. However, individual safety data for the treatment-emergent ADA-positive cases were reviewed, and no AEs of interest were identified.

Post-marketing experience.

Adverse events associated with the administration of Spinraza by lumbar puncture have been observed in the post-marketing setting. Serious infections associated with lumbar puncture, such as meningitis, have been observed. Communicating hydrocephalus, aseptic meningitis and hypersensitivity (e.g. angioedema, urticaria, rash) have also been reported.

4.9 Overdose

No cases of overdose associated with adverse reactions were reported in clinical studies. In case of overdose with Spinraza the patient should be advised to seek medical attention if they experience any signs or symptoms of adverse reactions.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 in Australia or the National Poisons Centre on 0800 POISON (0800 764766) in New Zealand.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Spinraza is an antisense oligonucleotide (ASO) specifically designed to treat Spinal Muscular Atrophy (SMA), an autosomal recessive progressive neuromuscular disease, due to mutations in the chromosome 5q. These mutations lead to loss of function of the survival motor neuron 1 (SMN1) gene, resulting in deficiency of SMN protein. The SMN2 gene also produces SMN protein but at low levels.
SMA is a clinical spectrum of disease, with age of onset and disease severity associated to the number of SMN2 gene copies present; fewer SMN2 gene copies are associated with earlier age of onset and increased severity of symptoms.

Mechanism of action.

Nusinersen (contained in Spinraza) increases the proportion of exon 7 inclusion in 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. Once SMN2 mRNA is produced, it can be translated into the functional full length SMN protein.

Pharmacodynamics.

The pharmacodynamic effects are consistent with the biological effects of nusinersen.
Autopsy samples from treated infants had higher levels of SMN2 messenger ribonucleic acid (mRNA) containing exon 7 in the thoracic spinal cord compared to untreated SMA infants.

Clinical trials.

The efficacy of Spinraza was demonstrated in 7 clinical trials in symptomatic patients (Studies CS3B, CS3A, CS4, CS2, CS12, SM202 and CS11), who ranged in age from 30 days to 15 years at the time of first dose, and one clinical trial in pre-symptomatic patients (Study CS5), who ranged in age from 3 days to 42 days at the time of first dose. Efficacy results from these studies of up to 1429 days of treatment demonstrate that treatment with Spinraza provides benefit across disease phenotypes and support the initiation of treatment as soon as possible following diagnosis (Figures 6, 7, 8 and 9). Spinraza has only been studied in patients with 5q SMA.

Motor function measures used in clinical studies.

Hammersmith infant neurological examination (HINE) section 2.

A measure of the achievement of motor milestones comprised of 8 milestone categories (head control, sitting, grasping, ability to kick in supine position, rolling, crawling, standing and walking) with 3 to 5 progressively more difficult items for each milestone category.

WHO motor milestones.

A set of 6 major motor milestones (sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone, walking alone) that are expected to be attained by 24 months of age in healthy children.

Children's hospital of Philadelphia infant test for neuromuscular disease (CHOP INTEND).

A 64-point motor assessment that captures neck, trunk, proximal, and distal limb strength in 14 elicited and 2 observational items, designed to evaluate muscle strength and function in infants with SMA.

Hammersmith functional motor scale - expanded (HFMSE).

A measure to assess motor function in children with limited ambulation, comprising of 33 scored activities that give objective information on motor ability and clinical progression.

Upper limb module (ULM).

Designed to assess upper limb function in non-ambulatory patients, consisting of 9 upper limb performance items reflective of activities of daily living. Higher scores indicate greater functional abilities.

Revised upper limb module (RULM).

Designed to assess upper limb function in patients with SMA, consisting of 20 items for a maximum total score of 37.

Six-minute walk test (6 MWT).

An evaluation of the distance a person can walk quickly in 6 minutes.

Compound muscle action potential (CMAP).

An electrophysiological measure of motor neuron health for tracking disease progression in neuromuscular disorders, such as SMA.

Symptomatic patients.

Patients with infantile-onset SMA.

Study CS3B (ENDEAR).

Study CS3B was a phase 3, randomised, double-blind, sham-procedure controlled study conducted in 121 symptomatic infants ≤ 7 months of age, diagnosed with SMA (symptom onset before 6 months of age). Patients were randomised 2:1 to either Spinraza or sham-control, with a length of treatment ranging from 6 to 442 days (median 258). Spinraza-treated patients received a 12 mg scaled equivalent dose based on CSF volume scaling on study days 1, 15, 29, 64, 183 and 302. The median age of onset of clinical signs and symptoms of SMA was 6.5 weeks (range 2-18) and 8 weeks (range 1-20) for Spinraza-treated versus sham-control patients respectively, with 99% of patients having 2 copies of the SMN2 gene. Patients in this study were deemed most likely to develop Type I SMA. At baseline, the mean total motor milestone score was 1.37 (range 0-6), the median CHOP INTEND score was 28 (range 8-50.5), and the median CMAP amplitudes were 0.20 (range 0.00-0.87) and 0.30 (range 0.00-1.50) for the ulnar nerve and peroneal nerves, respectively. The median age when patients received their first dose was 164.5 days (range 52-242) for treated patients, and 205 days (range 30-262) for sham-control.
Baseline disease characteristics were largely similar in the Spinraza treated patients and sham-control patients except that Spinraza treated patients at baseline had a higher percentage compared to sham-control patients of paradoxical breathing (89% vs 66%), pneumonia or respiratory symptoms (35% vs 22%), swallowing or feeding difficulties (51% vs 29%) and requirement for respiratory support (26% vs 15%).
A planned interim analysis was conducted based on patients with the opportunity to reach a 6 month evaluation. The primary endpoint assessed at the interim analysis was the proportion of responders: patients achieving a pre-defined level of improvement in motor milestones (HINE section 2).
At the final analysis, time to death or permanent ventilation (≥ 16 hours ventilation/day continuously for > 21 days in the absence of an acute reversible event or tracheostomy) was assessed as the primary endpoint. Statistically significant effects on event-free survival, overall survival, the proportion of patients achieving the definition of a motor milestone responder, and the percentage of patients with at least a 4-point improvement from baseline in CHOP-INTEND score were observed in patients in the Spinraza group compared to those in the sham-control group (Table 5, Figures 1 and 2).
In the efficacy set, 18 (25%) patients in the Spinraza group and 12 (32%) patients in the sham-control group required permanent ventilation. Of these patients, 6 (33%) in the Spinraza group and 0 (0%) in the sham-control group met the protocol-defined criteria for a motor-milestone responder.
Upon completion of study CS3B, 89 patients (65 [Spinraza] and 24 [sham]) enrolled in the ongoing open-label extension study (study CS11) where all patients received Spinraza for 65 to 592 days (median 289 days) at the time of the interim analysis (cut-off date 30 June 2017). Improvements in motor function were observed among patients continuing Spinraza from study CS3B as well as patients who initiated Spinraza in study CS11 (Figures 8 and 9), with the greatest benefit observed in those with earlier treatment initiation. Among subjects without permanent ventilation at the baseline of study CS11, a majority were alive and without permanent ventilation at the interim analysis.
In subjects randomized to Spinraza in study CS3B and including the experience in study CS11, the median time to death or permanent ventilation was 73 weeks. At the time of the study CS11 interim analysis, 61/65 (94%) subjects were alive. Of the 45/65 subjects who had not met the definition of permanent ventilation in study CS3B, 38/45 (84%) were alive without permanent ventilation in study CS11 at the interim analysis. Further improvement in mean total motor milestone (2.1; SD 4.36; n = 22) and CHOP INTEND (4.68; SD 3.993, n = 22) scores were observed from baseline to study day 304 in study CS11.
Patients who initiated treatment with Spinraza in CS11 (n = 24; assigned to sham in study CS3B) were of a median age of 17.8 months (range 10 - 23 months) and had a mean CHOP INTEND score of 17.25 (range 2.0-46.0) at baseline in study CS11. As of the interim analysis 22/24 (92%) subjects were alive. Of the 12/24 subjects (50%) who had not met the definition of permanent ventilation in study CS3B, 7/12 (58%) were alive without permanent ventilation in study CS11 at the interim analysis. The median time to death or permanent ventilation was 50.9 weeks after initiation of Spinraza in study CS11. Improvement in mean total motor milestone (1.2; SD 1.8; n = 12) and CHOP INTEND (3.58; SD 7.051, n = 12) scores were observed from baseline to study day 304 in study CS11.

Study CS3A.

Study CS3A was an open-label phase 2 study in symptomatic patients diagnosed with SMA. Median age of onset of clinical signs and symptoms was 56 days (range 21 to 154 days) and patients had either 2 SMN2 gene copies (n=17) or 3 SMN2 gene copies (n=2) (SMN2 gene copy number unknown for 1 patient). Patients in this study were deemed most likely to develop Type I SMA. Patients were randomised to receive either a 6 mg or 12 mg scaled equivalent dose of Spinraza based on CSF volume during the loading dose phase on days 1, 15 and 85. During the maintenance phase all patients received a 12 mg scaled dose on days 253, 379, 505, 631, 757, 883, 1009, 1135 and 1261. Median age at first dose was 162 days (range 37-223). At screening, the median number of motor milestones (HINE section 2) achieved was 2 (range 1 to 12), median CHOP-INTEND total score was 27 (range 17 to 64), median baseline ulnar CMAP amplitude was 0.235 mV (range 0.00 to 3.20 mV) and baseline peroneal CMAP amplitude was 0.345 mV (range 0.00 to 2.70 mV). The patients in the study had a median time on study of 1101 days (range 62 - 1429 days).
As of the study closure date, 15 of 20 patients (75%) were alive and 5 patients had died [aged 5.13 to 36.28 months]. 11 (55%) were alive and free of permanent ventilation (4 patients were on permanent ventilation aged 6.28 to 39.97 months) (see Figure 4). Of the 15 patients alive all were at least 14 months of age (median 43.5 months, range 14.1 to 54 months), with 6 at > 45 months and 2 at > 50 months of age.
The primary endpoint was the proportion of patients who improved in one or more categories in motor milestones (HINE section 2) (according to HINE section 2: ≥ 2 point increase [or maximal score] in ability to kick or voluntary grasp OR ≥ 1 point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking). Twelve out of 20 patients (60%) had met the primary endpoint, with a sustained improvement in mean motor milestone achievement over time (see Figures 8 and 9). In contrast to the natural history of SMA where there is a failure to achieve motor milestones after symptom onset, 8 of 20 patients (40%) developed the ability to sit independently, 4 of 20 patients (20%) gained the ability to stand with support or independently, 2 of 20 patients (10%) gained the ability to walk with support or independently.
A sustained improvement in mean CHOP-INTEND score was observed from baseline to day 1072 (mean change 21.30). Overall, 11 out of 20 patients (55%) met the endpoint of an increase in total CHOP INTEND score of ≥ 4 points as of their last study visit prior to data cut-off.
Patients with later-onset SMA.

Study CS4 (CHERISH).

Study CS4 was a phase 3, randomised, double-blind, sham-procedure controlled study in 126 symptomatic children with later-onset SMA (symptom onset after 6 months of age). Patients were randomised 2:1 to either Spinraza or sham-control, with a length of treatment ranging from 324 to 482 days (median 450). Spinraza-treated patients received a 12 mg (5 mL) dose on study days 1, 29, 85 and 274.
The median age at screening was 3 years (range 2-9), and the median age of onset of clinical signs and symptoms of SMA was 11 months (range 6-20). The majority of patients (88%) have 3 copies of the SMN2 gene (8% have 2 copies, 2% have 4 copies, and 2% have an unknown copy number). At baseline, patients had a mean HFMSE score of 21.6, a mean RULM of 19.1, all had achieved independent sitting, and no patients had achieved independent walking. Patients in this study were deemed most likely to develop Type II or III SMA. Baseline disease characteristics were generally similar except for an imbalance in the proportion of patients who had ever achieved the ability to stand without support (13% of patients in the Spinraza group and 29% in sham-control) or walk with support (24% of patients in the Spinraza group and 33% in sham-control).
At the final analysis, a statistically significant improvement in HFMSE score from baseline to Month 15 was seen in the Spinraza group compared to the sham-control group (Table 3, Figure 3). The analysis was conducted in the ITT population (Spinraza: n=84; sham-control: n=42), and post-baseline HFMSE data for patients without a Month 15 visit were imputed using the multiple imputation method. An analysis of the subset of patients in the ITT population who had observed values at Month 15 demonstrated consistent, statistically significant results. Of those with observed values at Month 15, a higher proportion of Spinraza treated subjects had improvement (73% vs 41%, respectively) and a lower proportion had worsening (23% vs 44%, respectively) in total HFMSE score compared to sham-control (Figure 4). All secondary endpoints including functional measures and WHO motor milestone achievement were formally statistically tested and are described in Table 6 and illustrated in Figure 5. Initiation of treatment sooner after symptom onset resulted in earlier and greater improvement in motor function than those with delayed treatment initiation; however, both groups experienced benefit compared to sham-control.
Upon completion of Study CS4, 125 patients enrolled in an ongoing open-label extension study (Study CS11) where they have received Spinraza for 74 to 474 days (median 250 days) at the time of the interim analysis. A majority of subjects treated with Spinraza experienced stabilization or improvement in motor function with the greatest benefit observed in those who initiated treatment with Spinraza in Study CS4.
Of the patients who initiated treatment with Spinraza in Study CS4 (n = 39), stabilisation or additional improvements in mean HFMSE (0.2; SD 3.06) and RULM (0.7; SD 2.69) scores were observed from baseline to Study Day 265 in Study CS11.
Patients who initiated treatment with Spinraza in Study CS11 (n = 20) had a median age of 4.0 years (range 3, 8 years). Of these patients, stabilization or improvement in mean HFMSE (1.4; SD 4.02) and RULM (2.1; SD 2.56) scores were observed from baseline to Study Day 265 in Study CS11.

Study CS2 and study CS12.

The efficacy of Spinraza in Type II and Type III SMA patients has also been demonstrated in a longitudinal analysis across 2 open-label studies (Study CS2 and Study CS12). The analysis included 28 patients who received their first dose in Study CS2, and then transferred to the extension phase, Study CS12. In Study CS2, patients received 9 mg doses of Spinraza on days 1 and 85, or 3, 6, or 12 mg doses on days 1, 29, and 85. In Study CS12, patients received 12 mg doses of Spinraza on Days 1, 169, 351, and 533. The studies enrolled patients who were between 2 to 15 years of age at first dose. Of the 28 patients, 3 were at least 18 years of age at their last study visit. 1 out of 28 patients had 2 SMN2 gene copies, 21 had 3 copies, and 6 had 4 copies. Outcome measures included HFMSE in all patients, and either the ULM test in non-ambulatory patients, or the 6 MWT performed in ambulatory patients.
Patients were assessed over a 3-year treatment period. A sustained improvement was seen in patients with Type II SMA who experienced a mean improvement from baseline HFMSE score of 5.1 (SD 4.05, n=11) at Day 253, and 9.1 (SD 6.61, n=9) at Day 1050. The mean total score was 26.4 (SD 11.91) at Day 253 and 31.3 (SD 13.02) at Day 1050, no plateau was observed. This is in comparison to the decline typically observed in patients with later-onset SMA over time.
Patients with Type III SMA demonstrated a mean improvement from baseline HFSME score of 1.3 (SD 1.87, n=16) at Day 253 and 1.2 (SD 4.64, n=11) at Day 1050. The mean total score was 49.8 (SD 12.46) at Day 253 and 52.6 (SD 12.78) at 1050 days.
In patients with Type II SMA the ULM test was conducted, with mean improvement of 1.9 (SD 2.68, n=11) at Day 253 and 3.5 (SD 3.32, n=9) at Day 1050. The mean total score was 13.8 (SD 3.09) at Day 253 and 15.7 (SD 1.92) at Day 1050. The 6 MWT was conducted for ambulatory patients only. In these patients, a mean improvement of 28.6 meters (SD 47.22, n=12) at Day 253 and 86.5 meters (SD 40.58, n=8) at Day 1050. The mean 6 MWT distance was 278.5 meters (SD 206.46) at Day 253 and 333.6 meters (SD 176.47) at Day 1050. Two previously non-independent ambulatory patients (Type III) achieved independent walking, and one non-ambulatory patient (Type II) achieved independent walking. See Table 7.

Patients with infantile- or later-onset SMA.

Study SM202 (EMBRACE).

Study SM202 is a phase 2, two-part study of which Part 1 was randomised, double-blind, and sham procedure-controlled and Part 2 was an open label extension. The study enrolled symptomatic patients diagnosed with infantile-onset SMA (≤ 6 months) or later-onset SMA (> 6 months) and 2 or 3 copies of SMN2 who were not eligible for participation in Study CS3B or Study CS4 due to screening age or SMN2 copy number. Subjects were followed for a median of 302 days in Part 1 of the study.
All subjects treated with Spinraza were alive as of the early termination of Part 1, however, one subject in the control arm died at Study day 289. In addition, no subjects in the Spinraza group or sham-control group required the use of permanent ventilation. Of the 13 subjects with infantile-onset SMA, 7/9 (78%; 95%CI: 45, 94) of the Spinraza group and 0/4 (0%; 95%CI: 0, 60) of the sham group met the criteria for motor milestone response (HINE section 2). Of the 8 subjects with later-onset SMA, 4/5 (80%; 95% CI: 38, 96) of the Spinraza group and 2/3 (67%; 95%: 21, 94) of the sham-control group met this definition of response.

Adults.

No controlled clinical data are available.
Real world clinical findings support the effectiveness of nusinersen to stabilise or improve motor function (HFMSE, 6 MWT, RULM) in some SMA adult Type II and III patients who initiated nusinersen in adulthood and were followed up over 10 to 14 months. A decline in motor function over time has been reported in untreated SMA patients.
Limited clinical data from an interim analysis from 7 young adults with Type II or III SMA (aged 18.8 - 22.5 years) who initiated treatment during adolescence and who were followed for 5.3 - 6.8 years in the CS2/CS12/SHINE studies indicate a stabilisation or improvement in motor function in these patients as assessed by the 6 MWT and HFMSE.

Pre-symptomatic infants.

Study CS5 (NURTURE).

Study CS5, is an open-label study in pre-symptomatic infants genetically diagnosed with SMA who were enrolled at 6 weeks of age or younger. Patients in this study were deemed most likely to develop Type I or II SMA. Patients received a 12 mg scaled equivalent dose of Spinraza based on CSF volume scaling on study days 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778. Median age at first dose was 22 days (range 3-42 days). At baseline the median number of motor milestones achieved was 3 (range 0-7), the median CHOP-INTEND total score was 50.0 (range 25-60), and the median ulnar CMAP amplitude was 2.65 mV (1.0-6.7).
The latest interim analysis (cut-off date 15 May 2018) was conducted when subjects had been on study for a median of 27.1 months (15.1 - 35.5 months) and were of a median age at last visit of 26.0 months (14.0 - 34.3 months). At the time of the interim analysis, all 25 of the patients (2 SMN2 gene copies, n = 15; 3 SMN2 gene copies, n = 10) are alive without permanent ventilation. The primary endpoint time to death or respiratory intervention (defined as invasive or non-invasive ventilation for ≥ 6 hours/day continuously for ≥ 7 consecutive days or tracheostomy) could not be estimated as there were too few events. Four subjects (2 SMN2 copies) required respiratory intervention > 6 hours/day continuously for ≥ 7 days, all of whom initiated ventilatory support during an acute reversible illness (see Figure 5).
Patients achieved milestones unexpected in Type I or II SMA and more consistent with normal development. At the interim analysis, all 25 (100%) subjects had achieved the WHO motor milestone of sitting without support, 22 (88%) had achieved the ability to walk with assistance. Among patients older than the WHO defined window for expected age of achievement (95th percentile), 17 of 22 (77%) had achieved walking alone. The mean CHOP INTEND score at last assessment was 61.0 (46-64) amongst subjects with 2 SMN2 copies and 62.6 (58-64) amongst those with 3 SMN2 copies. All subjects had maintained the ability to suck and swallow, with 22/25 (88%) infants achieving a maximum score on the HINE section 1.
The proportion of patients developing clinically manifested SMA was assessed amongst patients who reached the Day 700 (n = 16) visit at the interim analysis. The protocol-defined criteria for clinically manifested SMA included age-adjusted weight below the fifth WHO percentile, a decrease of 2 or more major weight growth curve percentiles, the placement of a percutaneous gastric tube, and/or the inability to achieve expected age-appropriate WHO milestones (sitting without support, standing with assistance, hands-and-knees crawling, walking with assistance, standing alone and walking alone). At Day 700, 7/11 (64%) of subjects with 2 SMN2 copies and 0/5 subjects with 3 SMN2 copies met the protocol-defined criteria for clinically manifested SMA; however, these patients were gaining weight, and achieving WHO milestones, inconsistent with Type I SMA.
As illustrated in Figures 6, 7 and 8, the greatest benefit in overall survival and motor milestones occurred when Spinraza treatment was initiated prior to symptom onset.

5.2 Pharmacokinetic Properties

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

Absorption.

Intrathecal injection of nusinersen into the cerebrospinal fluid (CSF) allows nusinersen to be fully available for distribution from the CSF to the target central nervous system (CNS) tissues.
Mean CSF trough concentrations of nusinersen accumulated approximately 1.4- to 3-fold after multiple loading and maintenance doses, and reached a steady state within approximately 24 months. No further accumulation in CSF or CNS tissues would be expected with additional doses after steady state.
Following IT 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 is 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.

Metabolism/biotransformation.

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

Excretion.

The mean terminal elimination half-life in CSF is estimated at 135 to 177 days. The primary route of elimination is likely by urinary excretion of nusinersen and its metabolites.

Special populations.

Gender.

Population pharmacokinetic analysis shows that gender does not affect the pharmacokinetics of nusinersen.

Renal and hepatic impairment.

The pharmacokinetics of nusinersen in patients with renal impairment or hepatic impairment has not been studied.

5.3 Preclinical Safety Data

Genotoxicity.

Nusinersen demonstrated no evidence of genotoxicity in in vitro (Ames and chromosomal aberrations in CHO cells) and in vivo (mouse micronucleus) assays. However, no assays were performed to demonstrate nusinersen uptake into bacterial and mammalian cells.

Carcinogenicity.

In a carcinogenicity study in mice, subcutaneous administration of nusinersen for 2 years resulted in an increased incidence of benign uterine haemangioma in female mice at 50 mg/kg every 2 weeks. No significant effects were seen in males at this dose or females at the lower doses of 5 mg/kg and of 15 mg/kg every 2 weeks. The estimated systemic exposures at the no effect levels in both sexes far exceed the expected systemic exposures in patients.

Toxicology.

In repeat-dose toxicity studies (14-weeks and 53-weeks) of IT administration to juvenile cynomolgus monkeys, nusinersen was well tolerated. The exception was an acute, transient deficit in lower spinal reflexes which occurred at the highest dose levels in each study (3 or 4 mg per dose). These effects were observed within several hours post-dose and generally resolved within 48 hours.

6 Pharmaceutical Particulars

6.1 List of Excipients

The product contains the following excipients: sodium chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, dibasic sodium phosphate, sodium phosphate monobasic dihydrate, sodium hydroxide (q.s.), hydrochloric acid (q.s.), water for injections (q.s. to 5 mL).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store between 2°C to 8°C. Refrigerate. Do not freeze.
Spinraza should be protected from light and kept in the original carton until time of use.
Prior to administration, unopened vials of Spinraza can be removed from and returned to the refrigerator a total of 5 times, if necessary. If removed from the original carton, the total combined time out of refrigeration and secondary packaging (carton) should not exceed 30 hours, at a temperature that does not exceed 25°C.
Do not dilute. Once drawn in to the syringe, administer within 6 hours. Discard any unused product. For single use in one patient on one occasion only.
Dispose of all the materials, including any unused solution contained within the vial in accordance with local requirements.

6.5 Nature and Contents of Container

Each pack contains one 5 mL liquid in vial (type 1 glass) with a bromobutyl rubber stopper, an aluminium over-seal and a flip-off plastic cap. Each vial contains 5 mL of a clear and colourless solution, of 12.6 mg nusinersen heptadecasodium, equivalent to 12 mg of nusinersen for intrathecal injection.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Nusinersen is a fully modified 2'-O-2-methoxyethyl antisense oligonucleotide designed to bind to a specific sequence in the intron downstream of Exon 7 of the SMN2 transcript.
Australian approved name: nusinersen heptadecasodium.
C234H340N61O128P17S17 (nusinersen). MW 7127.1 g/mol.
C234H323N61O128P17S17Na17 (nusinersen heptadecasodium). MW 7501.0 g/mol.
Chemical name: all-P-ambo-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2- methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl- (3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)- 5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')- 2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2- methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl- (3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2- methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P- thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl) guanosine.
The pKa of the dinucleoside phosphate diester is approximately 2. The bases have acidic and basic pKas ranging from approximately 3.5 to 10 and the 5' and 3'-hydroxy groups have pKas of approximately 16 and 12, respectively. The API is a white to yellow amorphous, hygroscopic solid.

CAS number.

The CAS Registry Number (nusinersen) is 1258984-36-9.
Spinraza is a sterile, preservative-free clear to colourless isotonic solution for injection in a single use vial, practically free from visible particles. The pH is approximately 7.2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes