Consumer medicine information

Enspryng

Satralizumab

BRAND INFORMATION

Brand name

Enspryng

Active ingredient

Satralizumab

Schedule

What is in this leaflet

This leaflet answers some common questions about Enspryng. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Enspryng against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Enspryng is used for

Enspryng contains the active ingredient satralizumab.

Satralizumab belongs to a group of medicines called monoclonal antibodies. Monoclonal antibodies are a type of protein which recognise and attach to a specific protein in the body.

Enspryng is used to treat neuromyelitis optica spectrum disorders (NMOSD) in adult patients, who test positive for an antibody called AQP4-IgG (aquaporin-4 immunoglobulin G), also known as NMO-IgG (neuromyelitis optica immunoglobulin G).

NMOSD is an autoimmune disease of the central nervous system. This is a condition where the immune system attacks the central nervous system. NMOSD mainly affects the optic nerves (nerves found in your eye) and spinal cord. The damage to the optic nerves causes inflammation - leading to pain and loss of sight. The damage to the spinal cord causes weakness or loss of movement in the legs or arms, loss of feeling, and problems with bladder and bowel function.

In a ‘relapse’, or an ‘attack’ of NMOSD, there is inflammation in the nervous system. This inflammation causes people to have new symptoms, or have symptoms that they have had before.

Enspryng works by blocking the action of a protein called ‘interleukin-6’ (IL-6). This protein isinvolved in inflammation in the body and the levels of this protein are high in NMOSD. Enspryng may reduce the risk of a relapse or attack of NMOSD.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

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

Before you use Enspryng

If you are not sure if you should start receiving Enspryng, talk to your doctor.

When you must not use it

Do not use Enspryng:

if you have an allergy to satralizumab or any of the other ingredients listed at the end of this leaflet
if you have had an allergic reaction to any other medicine which contains proteins that are of hamster origin

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

Do not use Enspryng if the expiry date (EXP) printed on the pack has passed. If you use this medicine after the expiry date has passed it may not work as well.

Do not use this medicine if you notice that it is cloudy, discoloured or contains visible particles. Enspryng is a colourless to slightly yellow liquid.

Do not use this medicine if the pack is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use Enspryng

Tell your doctor or nurse straight away if you think you have any signs of infection before, during or after Enspryng treatment such as:

fever or chills
cough that does not go away
sore throat
herpes (such as cold sore, shingles or genital sores)
skin redness, swelling, tenderness or pain
feeling or being sick, diarrhoea or belly pain.

You cannot use Enspryng while you have an infection.

Your doctor will wait until the infection has resolved before starting or resuming treatment with Enspryng.

Tell your doctor if you have recently been given any vaccines or might be given vaccines in the near future.

Your doctor will check if you need any vaccines before you start Enspryng.
Do not have ‘live’ or ‘live attenuated’ vaccines while you are being treated with Enspryng (for example BCG for tuberculosis or vaccines against yellow fever).

You cannot receive Enspryng if you are having some vaccines (‘live’ or ‘live attenuated’).

Tell your doctor or nurse straight away if you have any of the following signs of increased liver enzymes during or after Enspryng treatment:

yellowing of the skin and the whites of the eyes (jaundice)
dark coloured urine
feeling and being sick

Enspryng can affect your liver function and increase the amount of some liver enzymes in your blood. Your doctor will do blood tests to check these amounts and monitor how well your liver is working.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or are planning to have a baby. Enspryng is not recommended during pregnancy. Women of childbearing potential must use effective contraception during and up to three months after treatment with Enspryng. However, if there is a need to use Enspryng when you are pregnant, your doctor will discuss the risks and benefits to you and your unborn baby.

Tell your doctor if you are breastfeeding or plan to breastfeed. Your doctor may advise you to stop breastfeeding during treatment with Enspryng. It is not known if Enspryng passes into breast milk.

Enspryng is not recommended in children and adolescents under the age of 18 years. Safety and efficacy in children and adolescents younger than 18 years have not been established.

Enspryng is not recommended in elderly patients over 74 years of age. Safety and efficacy of Enspryng in elderly over 74 years of age have not been established.

If you have not told your doctor about any of the above, tell him/ her before you start using Enspryng.

Taking other medicines

Tell your doctor or pharmacist if you are using any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop. Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use Enspryng

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

Enspryng is given by injection under the skin (subcutaneously).

At the start, your doctor or nurse may inject Enspryng. However, your doctor may decide that you or your adult caregiver can inject Enspryng.

You or your caregiver will get training on how to inject Enspryng.

Talk to your doctor or nurse if you or your caregiver have any questions about giving injections.

How much to use

Each injection contains 120 mg of satralizumab. Inject the entire content of the syringe each time.

How to use it

The first injection will be given under the supervision of your doctor or nurse.

The first three injections are given once every two weeks. These are called ‘loading doses’.

After this, the injection is given every four weeks. This is called the ‘maintenance dose’. Keep using Enspryng once every four weeks for as long as your doctor tells you to.

After removing the cap, the injection must be started within 5 minutes to prevent the medicine from drying out and blocking the needle. If the pre-filled syringe is not used within 5 minutes of cap removal, you must dispose of it in a sharps container and use a new pre-filled syringe.

Directions for self-injection

You or your caregiver should read these directions from beginning to end before starting to inject so that you or your caregiver are familiar with each step of the procedure. These instructions must be carefully followed.

Consult with your doctor if you or your caregiver require further instructions. These instructions do not replace the instructions from your doctor.

Your doctor should show you how to prepare and inject properly before you or your caregiver inject for the first time.

Ask them any questions you or your caregiver may have.

Do not attempt to administer an injection until you or your caregiver understand how to self- inject Enspryng. It is important to remain under your doctor's care while using Enspryng. It is recommended you have someone else present when you self-inject Enspryng in case you experience any symptoms of a serious allergic reaction described under Before you use Enspryng, When you must not use it.

The syringe is for single use only and should be safely discarded after use.

How to inject using the syringe

The syringe components:

Before use

After use

The syringe has a needle-shield that automatically covers the needle when the injection is complete.

Do not shake the syringe.

Do not try to open the syringe or take it apart.

Do not re-use the same syringe.

Gather what you will need:

Included in the pack:

1 pre-filled syringe

Not included in the pack:

Alcohol pad
Sterile cotton ball or gauze
Sharps container for safe disposal of the needle cap and used syringe.

STEP 1: Preparing to use Enspryng

Take the carton containing the syringe out of the refrigerator and place it on a clean, flat work surface (like a table).

Check the expiry date on the back of the carton. Do not use if the carton has expired.

Check that the front of the carton is sealed. Do not use if the seal has been broken.

STEP 2: Removal of the pre-filled syringe from the carton

Open the sealed carton and carefully lift the syringe out of the carton by holding the barrel.

Do not turn the carton upside down to remove the syringe.

Do not touch the activation guards as this may damage the syringe.

Do not hold the plunger or needle cap.

STEP 3: Visual inspection of the pre-filled syringe

Check the expiration date on the syringe. Do not use the syringe if it has expired.

Check the syringe for any damage. Do not use if it is cracked or broken.

Check that the liquid through the viewing window is clear and colourless to slightly yellow.

Do not inject the medicine if the liquid is cloudy, discoloured, or has particles in it.

There may be some small air bubbles in the syringe. This is normal and you should not try to remove them.

STEP 4: Preparing to inject Enspryng

Let your syringe reach room temperature. Place it on a clean, flat work surface (like a table) for 30 minutes to allow it to reach room temperature.

It is important to let the syringe gently warm up as injecting cold medicine may feel uncomfortable and make it harder to push.

Wash your hands with soap and water.

Choose your injection site in either:

the lower part of your stomach (abdomen) or
the front and middle of your thighs.

Do not inject into the 5 cm area around your belly button.
Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or broken.
Choose a different injection site for each new injection - choose a different place to inject which is at least 2.5 cm away from the place where you last injected.

Clean the injection site by wiping it with an alcohol pad and let it air dry.

Do not fan or blow on the area which you have cleaned.
Do not touch the injection site again before you inject Enspryng.

STEP 4: Injecting Enspyng

Hold the barrel of the syringe between your thumb and index finger. With your other hand, pull the needle cap straight off.

You may see a drop of liquid at the end of the needle - this is normal and will not affect your dose.

Use the syringe within 5 minutes of removing the cap or the needle may clog.
Do not take the needle cap off until you are ready to inject Enspryng.
Do not put the needle cap back on once it has been removed as this may damage the needle.
Do not touch the needle or let it touch any surfaces after removing the needle cap.

Hold the barrel of the syringe using your thumb and index finger. With your other hand, pinch the area of skin you have cleaned.

Use a quick, dart-like motion to insert the needle at an angle between 45° to 90°

Do not insert the needle through clothing.
Do not change the angle of the injection.
Do not insert the needle again.

After the needle is inserted, let go of the pinched skin.

Slowly inject all of the medicine by gently pushing the plunger all the way down until it touches the activation guards.

Gently release the plunger and allow the needle to come out of the skin at the same angle it was inserted.

The needle will now be covered by the needle-shield. If the needle is not covered, carefully place the syringe into a sharps container to avoid injury.

STEP 5: Taking care of the injection site

There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site but do not rub it. If needed, you may also cover the area you injected with a small bandage. If the medicine gets into contact with your skin, wash the area with water.

STEP 6: Disposing of Enspryng

Do not try to re-cap your syringe.

Put your used syringe in a sharps container immediately after use.

Do not throw away (dispose of) the syringe in your household waste and do not recycle them.

Ask your doctor or pharmacist for information about where you can get a sharps container or what other types of puncture-resistant containers you can use to safely dispose of your used syringes and needle caps.

When to use it

It does not matter if you use Enspryng before or after food.

How long to use it

Continue using Enspryng for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep using your medicine even if you feel well.

Do not suddenly stop using Enspryng without asking your doctor first. If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

If you forget to use it

If you missed a dose of Enspryng, talk to your doctor on how to continue Enspryng treatment.

Do not inject a double dose on the same day to make up for a forgotten dose. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to use your medicine, ask your pharmacist for some hints.

If you use too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much Enspryng.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using Enspryng

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Enspryng.

Tell any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

If you are having surgery, tell the surgeon or anaesthetist that you are using this medicine. It may affect other medicines used during surgery.

If you are having any blood tests, tell your doctor that you are using this medicine. It may interfere with the results of some tests.

If you develop a serious infection while using Enspryng, tell your doctor immediately. You may need to stop using Enspryng until the infection is controlled.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not use Enspryng to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop using your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Enspryng affects you. This medicine is not expected to affect your ability to drive a car or operate machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Enspryng.

This medicine helps most people with NMOSD, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

During or after the injection

If any of the following happen during or after the injection, particularly in the first 24 hours after the injection, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

redness, itching, pain or swelling where the injection is given
rash, red or itchy skin or hives
feeling flushed
headache
throat irritation, swelling or pain
feeling short of breath
low blood pressure
fever or chills
feeling tired or dizzy
feeling or being sick or diarrhoea
fast heart rate, fluttering or pounding heart (heart palpitations).

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

headache
joint pain
stiffness
migraine
being unable to sleep (insomnia)
swelling in your lower legs, feet or hands
rash or itching
allergies or hay fever
low fibrinogen (a protein involved in blood clotting) levels in the blood shown in tests.

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Some side effects can only be found when your doctor does blood tests from time to time to check your progress (for example, decreased white blood cell counts and increased bilirubin levels).

After using Enspryng

Storage

Keep your Enspryng pre-filled syringe in the carton until it is time to use it.

Store your Enspryng pre-filled syringe at 2°C - 8°C (Refrigerate. Do not freeze). Protect from light and moisture.

Do not shake.

Do not use the syringe if it has been frozen.

If stored at room temperature, the total time out of refrigeration should not be longer than 8 days at a temperature that does not exceed 30°C.

Do not store Enspryng or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your doctor or pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Each pack of Enspryng contains 1 pre-filled syringe which contains a colourless to slightly yellow liquid.

Ingredients

Enspryng contains 120 mg of satralizumab as the active ingredient.

It also contains:

histidine
aspartic acid
arginine
poloxamer
water for injections

Satralizumab is made using Chinese hamster ovary cells.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Distributor

Enspryng is distributed in Australia by:

Roche Products Pty Ltd
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information (CMI).

Australian Registration Number:

AUST R 326047

This leaflet was prepared in December 2020.

Published by MIMS June 2021

BRAND INFORMATION

Brand name

Enspryng

Active ingredient

Satralizumab

Schedule

1 Name of Medicine

Satralizumab.

2 Qualitative and Quantitative Composition

Each pre-filled syringe (PFS) contains 120 mg of satralizumab in 1 mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Colourless to slightly yellow liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Enspryng is indicated as monotherapy or in combination with immunosuppressive therapy (IST) for the treatment of adults with neuromyelitis optica spectrum disorders (NMOSD) who have an anti-aquaporin 4 antibody (AQP4)-IgG (also termed NMO-IgG) positive status.

4.2 Dose and Method of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of NMOSD.
Enspryng is not intended for the acute treatment of an NMOSD relapse.
In order to prevent medication errors, it is important to check the PFS label to ensure that the drug being administered is Enspryng.

Dosage.

For subcutaneous use only.
Enspryng may be used as monotherapy or in combination with IST such as oral corticosteroids (OCs), azathioprine (AZA), or mycophenolate mofetil (MMF) (see Section 5.1).

Loading dose.

The recommended loading dose of Enspryng is 120 mg by subcutaneous injection (SC) every 2 weeks (first dose at week 0, second dose at week 2 and third dose at week 4) for the first three administrations.

Maintenance dose.

The recommended maintenance dose is 120 mg SC every 4 weeks.

Duration of treatment.

Enspryng is intended for long-term treatment.

Delayed or missed dose.

If a dose of Enspryng is missed, for any reason other than increases in liver enzymes, it should be administered as described in Table 1.

Dosage modifications.

Liver enzyme abnormalities.

If the alanine aminotransferase (ALT) or aspartate transaminase (AST) elevation is > 5x Upper Limit of Normal (ULN) and associated with any bilirubin elevation, treatment with Enspryng must be discontinued, and re-initiation is not recommended.
If the ALT or AST elevation is > 5x ULN and not associated with any bilirubin elevation, treatment with Enspryng should be discontinued. Treatment with Enspryng can be restarted at a dose of 120 mg SC injection every 4 weeks, when the ALT or AST level has returned to the normal range and following a benefit-risk assessment of the patient. If treatment is restarted, the liver parameters must be closely monitored, and if any subsequent increase in ALT/AST and/or bilirubin is observed, Enspryng must be discontinued, and re-initiation is not recommended. See Table 2.

Neutropenia.

If the neutrophil count is below 1.0 x 10⁹/L and confirmed by repeat testing, Enspryng should be interrupted until the neutrophil count is > 1.0 x 10⁹/L.

Special populations.

Paediatric populations.

The safety and efficacy of Enspryng in children and adolescents aged < 18 years of age have not been established.

Elderly.

No dose adjustment of Enspryng is required in patients ≥ 65 years of age (see Section 5.2).

Renal impairment.

The safety and efficacy of Enspryng have not been formally studied in patients with moderate to severe renal impairment. No dose adjustment is necessary in patients with mild renal impairment (see Section 5.2).

Hepatic impairment.

The safety and efficacy of Enspryng have not been studied in patients with hepatic impairment (see Section 5.2).

Method of administration.

Enspryng 120 mg is administered by SC injection using a single-dose PFS. Enspryng must be administered as a SC injection. The total content (1 mL) of the PFS should be administered.
The recommended injection sites are the abdomen and thigh. Injection sites should be rotated and injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Precautions to be taken before handling or administering the medicine.

The first injection must be performed under the supervision of a physician experienced in the treatment of NMOSD.
An adult patient/caregiver may administer all other doses of Enspryng at home if the treating physician determines that it is appropriate and the adult patient or caregiver can perform the injection technique.
Patients or caregivers should seek immediate medical attention if the patient develops symptoms of serious allergic reactions and should check with their Health Care Professional to confirm whether treatment with Enspryng can be continued or not.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Enspryng solution should be clear and colourless to slightly yellow. Do not use Enspryng if the solution is cloudy, discoloured or contains particles, or if any part of the prefilled syringe appears to be damaged.

4.3 Contraindications

Enspryng is contraindicated in patients with known hypersensitivity to satralizumab, Chinese hamster ovary cell proteins or any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

General.

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded.

Infections.

Delay Enspryng administration in patients with an active infection until the infection is controlled.
If a patient develops a serious infection, administration of Enspryng should be interrupted until the infection is controlled. Physicians should exercise caution when considering the use of Enspryng in patients with a history of recurring or chronic infection, or with underlying conditions (e.g. diverticulitis, diabetes) which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving immunosuppressive agents, such as Enspryng, as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reaction. The effects of satralizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients/caregivers should be instructed to contact a physician immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Vaccinations.

Live or live-attenuated vaccines should not be given concurrently with Enspryng as clinical safety has not been established. The interval between live vaccinations and initiation of Enspryng therapy should be in accordance with current vaccination guidelines regarding immunomodulatory/immunosuppressive agents.
No data are available on the effects of vaccination in patients receiving Enspryng. It is recommended that all patients are brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Enspryng therapy.

Neutrophil count.

Decreases in neutrophil counts have occurred following treatment with Enspryng (see Section 5.1, Clinical trials).
Neutrophil counts should be monitored 4 to 8 weeks after the start of therapy and thereafter as clinically indicated. For recommended dose interruption, see Section 4.2, Dosage modifications.

Injection site and hypersensitivity reaction.

In clinical trials, mild to moderate local and systemic injection-related reactions were more common in patients taking Enspryng. Advise patients to seek medical attention if they experience serious or severe allergic reactions to Enspryng. If an anaphylactic or serious hypersensitivity reaction occurs, Enspryng should be discontinued.

Use in the elderly.

The safety and efficacy of Enspryng in geriatric patients > 74 years of age have not been studied.

Paediatric use.

The safety and efficacy of Enspryng in children and adolescents aged < 18 years of age have not been established.

Effects on laboratory tests.

Elevated liver enzymes.

Mild and moderate elevations of liver transaminases have been observed with Enspryng treatment. Most elevations were below 5x ULN and not treatment-limiting and resolved while continuing treatment with Enspryng (see Section 4.8).
ALT and AST levels should be monitored every 4 weeks for the first 3 months of treatment, followed by every 3 months for one year, thereafter as clinically indicated.
For recommended dose modifications based on transaminases see Section 4.2.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug-drug interaction studies have been performed.
Population pharmacokinetic (PK) analyses did not detect any effect of AZA, OCs or MMF on the clearance of Enspryng.
The potential for treatment with Enspryng to reduce exposure to concomitant medications metabolised by CYP450 isozymes via blockade of IL-6 signalling has been explored using physiologically based pharmacokinetic (PBPK) modelling approaches.
This indicates that suppression of IL-6 signalling by treatment with Enspryng from the low baseline levels seen in the phase III studies will have only a minor impact on exposure of a range of probe CYP450 substrates (≤ 15% decrease in AUC for all substrates of CYPs 1A2, 3A4, 2D6, 2C19). This indicates that the risk of drug interaction is low, however caution should be exercised when Enspryng is administered or discontinued in patients also receiving CYP450 substrates with a narrow therapeutic index (e.g. warfarin, carbamazepine, phenytoin and theophylline). Dose adjustments may be required.

Vaccinations.

Avoid use of live or live attenuated vaccines during treatment with Enspryng (see Section 4.4).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No clinical data are available on the effect of Enspryng on human fertility. Studies in cynomolgus monkeys showed no effects on reproductive organs, sperm parameters or menstrual cycling at subcutaneous doses up to 50 mg/kg/week (AUC exposure at least 100-fold higher than in human patients receiving Enspryng 120 mg every 4 weeks).
Women of childbearing potential must use effective contraception during and up to 3 months after treatment with Enspryng.
(Category C)
There are no data from the use of Enspryng in pregnant women. Pre- and postnatal treatment with up to 50 mg/kg/week satralizumab subcutaneously to pregnant monkeys did not elicit any adverse effects on fetal development, pregnancy outcome or infant survival and development including learning ability. AUC exposures were almost 100-fold higher than in human patients receiving Enspryng 120 mg every 4 weeks. However, placental transfer of satralizumab is likely and a slight impairment of T-cell dependent antibody responses were seen in infant monkeys that had been exposed to satralizumab during the gestational period.
Enspryng is not recommended during pregnancy unless the potential benefit for the mother outweighs the potential risk to the fetus.
It is unknown whether Enspryng is excreted in human breast milk or absorbed systemically after ingestion. However, because IgGs are excreted in human milk. Breast-feeding is not recommended during treatment with Enspryng unless the potential benefit for the mother outweighs the potential risk to the child.
Transfer of satralizumab into the milk of lactating monkeys has been observed, though concentrations of satralizumab in breast milk were very low (< 0.9% of the corresponding maternal plasma levels).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Enspryng has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety of Enspryng as monotherapy or in combination with IST was evaluated based on data from two phase III randomised, multicenter, double-blind, placebo-controlled clinical trials (BN40898 and BN40900), which includes 63 patients exposed to Enspryng monotherapy and 41 patients exposed to Enspryng in combination with IST (see Section 5.1). In the double-blind controlled period, patient median exposure to satralizumab was approximately 2 years in both studies BN40900 and BN40898 each. The median exposure to placebo was approximately 1 year.
The most frequently reported adverse drug reactions (ADRs) were headache, arthralgia and injection-related reactions.

Tabulated summary of adverse drug reactions from clinical trials.

Table 3 summarises the ADRs that have been reported in association with the use of Enspryng as monotherapy or in combination with IST in clinical trials. Patients in the Enspryng groups in both clinical studies had longer treatment period than those in the placebo (or placebo in combination with IST) groups, ADRs were evaluated during 194 patient-years (PY) in the Enspryng groups and 100 PY in the placebo groups.
Adverse reactions from clinical trials (Tables 3 and 4) are listed by MedDRA system organ class. The corresponding frequency category for each adverse reaction is based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Description of selected adverse reactions.

Injection-related reactions. Injection-related reactions reported in patients treated with Enspryng as monotherapy or in combination with IST were predominantly mild to moderate, and most occurred within 24 hours after injections. The most commonly reported systemic symptoms were diarrhoea and headache. The most commonly reported local injection site reactions were flushing, erythema, pruritus, rash and pain. None of the injection related reactions required dose interruption or discontinuation.
Infections. In the Enspryng monotherapy study, the rate of infections was lower in patients treated with Enspryng (99.8 events/100 PY [95% CI: 82.4, 119.8]) compared with patients receiving placebo (162.6 events/100 PY [95% CI: 125.8, 206.9]). The rate of serious infections was 5.2 events/100 PY (95% CI: 1.9, 11.3) in patients treated with Enspryng compared with 9.9 events/100 PY (95% CI: 2.7, 25.2) in patients receiving placebo.
In patients treated with Enspryng in combination with IST, the rate of infections was 132.5 events/100 PY (95% CI: 108.2, 160.5) compared with 149.6 events/100 PY (95% CI: 120.1, 184.1) in patients receiving placebo in combination with IST; the rate of serious infections was 2.6 events/100 PY (95% CI: 0.3, 9.2) compared with 5.0 events/100 PY (95% CI: 1.0, 14.7) in patients receiving placebo in combination with IST.
Body weight increase. In the double-blinded treatment period, body weight increase ≥ 15% from baseline were observed in 3.8% of patients treated with Enspryng (monotherapy or in combination with IST) as compared with 2.7% of patients receiving placebo (or placebo plus IST).
Paediatrics. The safety of Enspryng has been studied in a limited number of paediatric patients' ≥ 12 years of age. Safety results were consistent with those in adults.
Laboratory abnormalities.

Neutrophils.

In the double-blinded treatment period, decreased neutrophils were observed in 31.7% of patients treated with Enspryng (monotherapy or in combination with IST) compared with 21.6% of patients receiving placebo (or placebo plus IST). The majority of neutrophil decreases were transient or intermittent.
Of the patients in the Enspryng group, 9.6% had neutrophils below 1 x 10⁹/L compared with 5.4% in placebo or placebo plus IST groups. These neutrophil levels were not temporally associated with any serious infections.

Platelets count.

In the double-blinded treatment period, decreases in platelet counts occurred in 24% of patients on Enspryng (monotherapy or in combination with IST) compared with 9.5% of patients receiving placebo or placebo plus IST. The decreased platelet counts were not associated with bleeding events.
The majority of the decreased platelets were transient and not below 75 x 10⁹/L. None of the patients had a decrease in platelet count to ≤ 50 x 10⁹/L.

Liver enzymes.

In the double-blinded treatment period, elevations in ALT or AST occurred in 27.9% and 18.3% of patients treated with Enspryng (monotherapy or in combination with IST) respectively, compared with 12.2% and 13.5% of patients receiving placebo or placebo plus IST. The majority of the elevations were below 3x ULN, were transient and resolved without interruption of Enspryng.
Elevations in ALT or AST > 3x ULN occurred in 2.9% and 1.9% of patients treated with Enspryng (monotherapy or in combination with IST) respectively, and were not associated with increases in total bilirubin.
Elevation of ALT above 5x ULN were observed 4 weeks after initiation of therapy in one patient receiving Enspryng in combination with IST; normalising after discontinuation of Enspryng (see Section 4.2; Section 4.4).

Lipid parameters.

In the double-blinded treatment period, 10.6% of patients receiving Enspryng (monotherapy or in combination with IST) experienced elevations in total cholesterol above 7.75 mmol/L as compared with 1.4% of patients receiving placebo (or placebo plus IST); 20.2% of patients receiving Enspryng experienced elevations in triglycerides above 3.42 mmol/L as compared with 10.8% of patients receiving placebo. The elevations in lipid parameters did not require dose interruption.

Fibrinogen.

Decreased fibrinogen is a known effect of Enspryng related to its mechanism of action. In the double-blinded treatment period of clinical trials, 71.2% of Enspryng-treated patients and 20.3% of patients receiving placebo had downward shifts from baseline fibrinogen levels. There were no bleeding events among patients with decreased fibrinogen levels.

Reporting of suspected adverse reactions.

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. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience with overdose in human clinical trials. A single dose of up to 240 mg Enspryng was administered subcutaneously to healthy adult volunteers in a Phase I study and no serious or severe adverse events were observed in the study.
In the event of an overdose, the patient should be closely supervised, treated symptomatically, and supportive measures instituted as required.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors; ATC code: L04AC19.

Mechanism of action.

Satralizumab is a humanised IgG2 monoclonal antibody (mAb) that binds to soluble and membrane-bound human IL-6 receptor (IL-6R) and thereby prevents IL-6 downstream signalling through these receptors.
IL-6 is a pleiotropic cytokine produced by a variety of cell types and is involved in diverse processes such as B-cell activation, differentiation of B-cells to plasma blasts and production of autoantibodies, Th17-cell activation and differentiation, T-regulatory cell inhibition, and changes in blood-brain barrier permeability. IL-6 levels are increased in cerebrospinal fluid and serum of patients with NMO and NMOSD during periods of disease activity. Some IL-6 functions have been implicated in the pathogenesis of NMO and NMOSD, including production of pathological autoantibodies against Aquaporin-4 (AQP4), a water channel protein mainly expressed by astrocytes in the central nervous system (CNS).

Pharmacodynamic effect.

In clinical studies with satralizumab in NMO and NMOSD, decreases in C-reactive protein (CRP), fibrinogen and complement (C3, C4 and CH50) were observed.

Clinical trials.

The efficacy and safety of Enspryng was evaluated in two pivotal phase III clinical trials (BN40898 and BN40900) in patients with a diagnosis of AQP4-IgG seropositive or seronegative NMO (Wingerchuck 2006 criteria), or with a diagnosis of AQP4-IgG seropositive NMOSD (Wingerchuk 2007 criteria). In retrospect, these patients also met the latest criteria proposed by the international panel for NMO diagnosis. The effect of Enspryng was studied in adult (studies BN40898 and BN40900) and adolescent (aged ≥ 12 to < 18 years) patients (study BN40898). The inclusion of AQP4-IgG seronegative adult NMO patients was limited to approximately 30% in both studies in order for the study population to reflect the real-world NMO patient population.
The primary efficacy measure in both studies was protocol-defined relapses (PDR), based on a prespecified worsening in the Expanded Disability Status Scale (EDSS) and Functional System Score (FSS) and confirmed by an independent Clinical Endpoint Committee (CEC). The primary endpoint analysis was time to first CEC-confirmed PDR with EDSS/FSS assessment performed within 7 days after symptoms were reported by the patient (adjudicated relapse).
Study BN40898 (also known as SA-307JG or SAkuraSky). Study BN40898 was a randomised, multicentre, double-blind, placebo-controlled clinical trial to evaluate the effect of Enspryng in combination with stable IST (OCs up to 15 mg/day [prednisolone equivalent], AZA up to 3 mg/kg/day or MMF up to 3000 mg/day; adolescents received a combination of AZA and OCs or MMF and OCs). The study included 83 AQP4-IgG seropositive and seronegative patients (including 7 adolescents). Patients received the first 3 single doses of Enspryng 120 mg or matching placebo by SC injection in the abdominal or femoral region every 2 weeks for the first 4 weeks and once every 4 weeks thereafter.
Study design and baseline characteristics of the study population are presented in Table 5.
The study was event-driven and the double-blind study period for efficacy evaluation ended when a total of 26 adjudicated relapses were observed. Patients who experienced a CEC-confirmed PDR or received rescue therapy for a relapse during the double-blind period or completed the double-blind period could enter the open-label extension period where all patients received open-label treatment with Enspryng.

Study BN40900 (also known as SA-309JG or SAkuraStar). Study BN40900 was a randomised, multicentre, double-blind, placebo-controlled clinical trial to evaluate the effect of Enspryng monotherapy compared to placebo. The study included 95 AQP4-IgG seropositive and seronegative adult patients. Patients received the first 3 single doses of Enspryng 120 mg or matching placebo by SC injection in the abdominal or femoral region every 2 weeks for the first 4 weeks and once every 4 weeks thereafter.
Study design and baseline characteristics of the study population are presented in Table 6.
The double-blind study period for efficacy evaluation ended 1.5 years after the date of randomisation of the last enrolled patient. Patients who experienced a CEC-confirmed PDR during the double-blind period or completed the double-blind period could enter the open-label extension period where all patients received open-label treatment with Enspryng.

Primary efficacy.

Double-blind period.

Treatment with Enspryng resulted in a statistically significant 62% reduction in the risk of experiencing an adjudicated relapse (Hazard ratio [HR] [95% CI]: 0.38 [0.16, 0.88]; p [log rank] = 0.0184) when administered in combination with stable IST (study BN40898) and 55% reduction in the risk of adjudicated relapse (HR [95% CI]: 0.45 [0.23, 0.89]; p [log rank] = 0.0184) when used as monotherapy (study BN40900), when compared to placebo.
At 48 weeks, 88.9% and 76.1% of Enspryng-treated patients (66.0% and 61.9% of placebo-treated patients) remained adjudicated relapse-free when used in combination with IST or as monotherapy, respectively. At 96 weeks 77.6% and 72.1% of Enspryng-treated patients (58.7% and 51.2% of placebo-treated patients) remained adjudicated relapse-free when used in combination with IST or as monotherapy, respectively. When data from the two studies were pooled, Enspryng treatment resulted in a 58% reduction in risk of adjudicated relapse compared to placebo (HR [95% CI]: 0.42 [0.25-0.71]; p [log rank] = 0.0008) (see Table 7, Figures 1 and 2).
The strongest subgroup effect was observed in AQP4-IgG seropositive patients. In AQP4-IgG seropositive patients the relative risk of experiencing an adjudicated relapse in Study BN40898 was reduced by 79% (HR [95% CI]: 0.21 [0.06-0.75]), in Study BN40900 by 74% (HR [95% CI]: 0.26 [0.11-0.63]). At 48 weeks, 91.5% and 82.9% of Enspryng-treated AQP4-IgG seropositive patients (59.9% and 54.4% of placebo-treated AQP4-IgG seropositive patients) remained adjudicated relapse-free when used in combination with IST or as monotherapy, respectively. At 96 weeks 91.5% and 76.5% of Enspryng-treated AQP4-IgG seropositive patients (53.3% and 41.1% of placebo-treated AQP4-IgG seropositive patients) remained adjudicated relapse-free when used in combination with IST or as monotherapy, respectively. When data across studies BN40898 and BN40900 were pooled, treatment with Enspryng with or without IST led to an overall risk reduction of 75% (HR [95% CI]; 0.25 (0.12-0.50]) in AQP4-IgG seropositive patients (see Table 7, Figures 3 and 4). No significant differences in the time to first adjudicated relapse in AQP4-IgG seronegative patients between those patients receiving Enspryng with or without IST and those receiving placebo with or without IST were observed (BN40898 and BN40900 pooled: HR [95% CI]: 0.97 [0.41-2.33]).

Treatment with Enspryng reduced the annualised rate of adjudicated relapses (ARR) by 74% in Study BN40898 and 73% in Study BN40900 compared to treatment with placebo (Table 8). The relative reduction in ARR in the AQP4-IgG seropositive subgroup was 88% and 90% in Studies BN40898 and BN40900 respectively.

As compared to placebo-treated patients, the need for rescue therapy (e.g. corticosteroids, intravenous immunoglobulin, and/or apheresis [including plasmapheresis or plasma exchange]) was reduced in Enspryng-treated patients by 51% in Study BN40898 and by 55% in Study BN40900 (ITT population). In the AQP4-IgG seropositive subgroup, Enspryng treatment reduced the need for rescue therapy by 61% and 74% in Studies BN40898 and BN40900, respectively (Table 9).

Treatment with Enspryng reduced the risk of experiencing a severe relapse defined as an EDSS increase ≥ 2 points from the previous EDSS assessment by 84% in study BN40898 and by 74% in study BN40900 compared to treatment with placebo (Table 10). The relative reduction in severe relapses in AQP4-IgG seropositive patients was 85% and 79% in studies BN40898 and BN40900, respectively.

Open-label extension (Note: Generally regarded as providing lower level of efficacy evidence).

Analyses of longer-term data including the OLE period (based on relapse treated with rescue therapy) showed that 57% and 71% of patients treated with Enspryng remained relapse-free after 120 weeks of treatment, when Enspryng was administered as add-on therapy or as monotherapy, respectively.
In the AQP4-IgG seropositive population, 58% and 73% of patients remained relapse free after 120 weeks of treatment with Enspryng administered as add-on therapy or as monotherapy, respectively. See Figures 5-8.

Immunogenicity.

In phase III studies BN40898 (combination with IST) and BN40900 (monotherapy), anti-drug-antibodies (ADAs) were observed in 41% and 71% of patients receiving Enspryng in the double-blind period, respectively. The ability of these ADAs to neutralise satralizumab binding is unknown.
Exposure was lower in ADA positive patients, however there was no impact of ADAs on safety and no clear impact on efficacy nor pharmacodynamic markers indicative of target engagement.
Treatment with satralizumab led to a similar reduction in the risk of experiencing an adjudicated relapse in patients in the Phase 3 studies despite different ADA rates between those studies.
Patients with higher bodyweight and lower exposure were more likely to develop ADAs (irrespective of background treatment with IST), however treatment effect was comparable in all bodyweight groups when used either in combination with IST or as monotherapy. The recommended dose is appropriate for individuals of all bodyweights, and neither dose interruption nor modification is warranted in those patients who develop ADAs.

Paediatric population.

In study BN40898, there were 7 adolescent patients enrolled. Their mean age was 15.4 years and the median body weight was 79.6 kg. The majority were female (n=6). Four patients were White, 2 were Black/African American, and 1 was Asian. Three (42.9%) adolescent patients were AQP4-IgG seropositive at screening (2 in the placebo group and 1 in the Enspryng group). During the double-blind period, 1 of 3 adolescents in the placebo group and 1 of 4 adolescents in the Enspryng group experienced an adjudicated relapse. Due to the small sample size, the hazard ratio for the primary endpoint of time to first adjudicated relapse in this subgroup was not calculated.

5.2 Pharmacokinetic Properties

The pharmacokinetics of Enspryng have been characterised both in Japanese and Caucasian healthy volunteers, and in NMO and NMOSD patients. The pharmacokinetics in NMO and NMOSD patients using the recommended dose were characterised using population PK analysis methods based on a database of 154 patients.
The concentration-time course of Enspryng in patients with NMO or NMOSD was accurately described by a two-compartment population PK model with parallel linear and target mediated (Michaelis-Menten) elimination and first-order SC absorption. Enspryng clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and 1 for clearance and volume parameters, respectively). Bodyweight was shown to be a significant covariate, with clearance and central volume of distribution (Vc) for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to a 60 kg patient. However, as treatment effect was comparable in all bodyweight groups, despite an apparent association between higher bodyweight and development of ADAs, no dose adjustment is required in heavier bodyweight patients (see Section 5.1, Immunogenicity).
Pseudo-steady state pharmacokinetics were achieved after the loading period (8 weeks) for C_min, C_max and AUC as follows (mean (±SD)): C_min: 19.7 (12.2) microgram/mL, C_max: 31.5 (14.9) microgram/mL and AUC: 737 (386) microgram.mL/day. Pharmacokinetics were not impacted by background immunotherapy (see Section 4.5).

Absorption.

The absorption rate constant of Enspryng was 0.251 one/day (95% CI: 0.216 - 0.285) equating to an absorption half-life of around 3 days at the recommended dose (see Section 4.2). The bioavailability was high (85.4%; 95% CI: 79.5 - 95.3).

Distribution.

Satralizumab undergoes biphasic distribution. The central volume of distribution was 3.46 L (95% CI: 3.05 - 3.87), the peripheral volume of distribution was 2.07 L (95% CI: 1.67 - 2.47). The inter-compartmental clearance was 0.336 L/day (95% CI: 0.253 - 0.419).

Metabolism.

The metabolism of satralizumab has not been directly studied, as monoclonal antibodies are principally cleared by catabolism.

Excretion.

The total clearance of satralizumab is concentration-dependent. Linear clearance (accounting for approximately half of the total clearance at steady state using the recommended dose in NMO and NMOSD patients) is estimated to be 0.0601 L/day (95% CI: 0.0513 - 0.0689). Using the recommended dosing regimen, the associated t_1/2 based on total clearance is approximately 30 days (ranging between 22-37 days throughout the dosing interval) based on data pooled from the phase 3 studies.