Consumer medicine information

Zilbrysq

Zilucoplan

BRAND INFORMATION

Brand name

Zilbrysq

Active ingredient

Zilucoplan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zilbrysq.

SUMMARY CMI

Zilbrysq®

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Zilbrysq?

Zilbrysq contains the active ingredient zilucoplan tetrasodium. Zilbrysq is used to treat generalised myasthenia gravis by blocking the body's inflammatory response. Myasthenia gravis can lead to intense muscle weakness, extreme fatigue, difficulty breathing, difficulty with moving and activities of daily living.

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

2. What should I know before I use Zilbrysq?

Do not use if you have ever had an allergic reaction to Zilbrysq or any of the ingredients listed at the end of the CMI and if you have not been vaccinated against meningococcal infection and/or have a meningococcal infection.

Talk to your doctor if you 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 Zilbrysq? in the full CMI.

3. What if I am taking other medicines?

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

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Zilbrysq?

  • Your healthcare professional should show you how to prepare and inject Zilbrysq using the pre-filled syringe. Do not inject yourself or someone else until you have been shown how to inject Zilbrysq the right way.
  • You and your caregiver should read 4. How do I use Zilbrysq? before each use of Zilbrysq
  • 1 pre-filled syringe is injected under the skin daily.

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

5. What should I know while using Zilbrysq?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Zilbrysq.
  • Use the product once in one patient only and discard any residue after use.
  • Be vaccinated against meningococcal infection at least 2 weeks before receiving your first dose of Zilbrysq.
Things you should not do
  • Do not inject yourself with this medicine unless you have been trained by a healthcare professional.
  • Do not use this medicine after the expiry date which is stated on the label and carton after EXP.
Looking after your medicine
  • Keep this medicine out of the sight and reach of children.
  • Store in a refrigerator between 2°C – 8°C. Do not freeze. Keep in the original carton to protect from light.
  • Zilbrysq may be stored at room temperature (up to 30°C) for a single period of a maximum of 3 months with protection from light. Once removed from the refrigerator and stored under these conditions, discard after 3 months or by the expiry date, whichever occurs first. A field for the date is provided on the carton to record the date removed from the refrigerator.

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

6. Are there any side effects?

  • Common side effects include: Bruising and pain at site of injection, upper respiratory tract infections (sore throat, blocked nose and headache), diarrhoea and morphoea (condition that causes localised discoloured and hardened areas of the skin).

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.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

As Zilbrysq inhibits the body's natural defences against infection, its use may increase your risk of infections caused by Neisseria meningitidis, such as meningococcal infection (severe infection of the linings of the brain and spinal cord and/or an infection of the blood) and also of other infections caused by Neisseria bacteria, such as gonorrhea.

These infections require urgent and appropriate care as they may become rapidly serious or fatal, or lead to major disabilities. It is important to understand the precautions to take to reduce the risk of these infections and what to do if you are worried you may have an infection (see “What I should know before I use Zilbrysq” below or refer to your Patient Alert Card).
• You must be vaccinated against meningococcal infection before starting Zilbrysq.
• If you initiate Zilbrysq treatment less than 2 weeks after receiving a meningococcal vaccine you must take antibiotics until 2 weeks after you have been vaccinated to reduce the risk of meningococcal infection.
• You need to be aware of the signs and symptoms of meningococcal infection (see “What I should know before I use Zilbrysq” below or refer to your Patient Alert Card) and notify your doctor immediately if any of the symptoms occur. If you cannot reach your doctor, go to the Emergency Department at your nearest hospital. Show your Patient Alert Card to any doctor or nurse who treats you.



FULL CMI

Zilbrysq®

Active ingredient(s): zilucoplan tetrasodium

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Zilbrysq

Zilbrysq contains the active ingredient zilucoplan tetrasodium. Zilbrysq is a selective immunosuppressant. Zilucoplan binds to and inhibits a specific protein in the body that causes inflammation, preventing your body's systems from attacking and destroying connections between nerves and muscles.

Zilbrysq is used to treat generalised myasthenia gravis by blocking the body's inflammatory response. Myasthenia gravis can lead to intense muscle weakness, extreme fatigue, difficulty breathing, difficulty with moving and activities of daily living.

2. What should I know before I use Zilbrysq?

Warnings

Do not use Zilbrysq if:

  • you are allergic to zilucoplan, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine
  • you have not been vaccinated against meningococcal infection
  • you have a meningococcal infection.

Check with your doctor if you:

  • have any other medical conditions, such as at risk of having gonorrhoea, have an infection, suspicion of infection or a fever
  • take any medicines for any other condition
  • have not been vaccinated against meningococcal infection
  • have been vaccinated against meningococcal infection less than 2 weeks before receiving the first dose of Zilbrysq

Meningococcal and other Neisseria infections:

Zilbrysq treatment may reduce your natural resistance to infections with Neisseria bacteria, which can cause a meningococcal infection (an infection of the linings of the brain and spinal cord (meningitis) and/or an infection of the blood (septicemia)) and other infections such as gonorrhea.

Consult with your doctor before you use this medicine to be sure that you receive vaccination against Neisseria meningitidis, an organism that causes meningococcal infection, at least 2 weeks before beginning therapy, or that you take antibiotics to reduce the risk of infection until 2 weeks after you have received your first vaccine dose. Ensure that your meningococcal vaccinations are up to date.

If you are at risk of gonorrhoea, ask your doctor or pharmacist for advice before using this medicine.

Meningococcal infection symptoms:

Meningococcal infections may become life-threatening or fatal if not recognised and treated early. Due to the importance of rapidly identifying and treating meningococcal infections in patients who receive Zilbrysq, if you experience any of the following symptoms, you should immediately inform your doctor:

  • Headache with additional symptoms such as nausea, vomiting, fever and stiff neck or back
  • Fever with or without a rash
  • Eyes sensitive to light
  • Confusion / drowsiness
  • Muscle pain with flu-like symptoms.

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

Check with your doctor if you are pregnant or intend to become pregnant. Zilbrysq is not recommended during pregnancy and in women of childbearing potential not using contraception.

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

Children and adolescents

Zilbrysq is not recommended for children and young people under 18 years of age.

3. What if I am taking other medicines?

Tell your doctor 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.

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

4. How do I use Zilbrysq?

How much to take / use

1 pre-filled syringe is injected under the skin daily. Your doctor will prescribe you the recommended dose of Zilbrysq based on your body weight. The following table indicates the total daily dose of Zilbrysq according to body weight:

Body WeightDoseNumber of pre-filled syringes and colour
from 43 to below 56 kg16.6 mg1 rubine red
from 56 to below 77 kg23 mg1 orange
from 77 to below 150 kg32.4 mg1 dark blue
  • There is limited experience with patients below 43 kg and above 150 kg. You should therefore receive the lowest and the highest dose, respectively.
  • Follow the instructions provided and use Zilbrysq until your doctor tells you to stop.

When to take / use Zilbrysq

Zilbrysq should be used daily approximately at the same time each day.

How to Inject Zilbrysq pre-filled syringe

  • Your doctor should show you how to prepare and inject Zilbrysq pre-filled syringe properly before you use it for the first time.
  • You and your caregiver should read this Instruction For Use before initiating treatment with Zilbrysq.
  • Call your doctor if you or your caregiver have any questions about how to inject Zilbrysq correctly.

Zilbrysq pre-filled syringe (see figure A):

Before Use

After Use

Figure A

Step 1: Setting up for your injection:

a: If the prefilled syringes are stored in the refrigerator:
Take 1 Zilbrysq pre-filled syringe out of refrigerator and let it sit on a clean, flat surface at room temperature for 30 to 45 minutes before injecting. Do not warm in any other way (for example in a microwave, in hot water or in direct sunlight). Place the rest of the carton in refrigerator and proceed with step b below.

If the pre-filled syringes are stored at room temperature:
Take 1 Zilbrysq pre-filled syringe out of the carton. Any remaining syringes from the carton should not be placed in the refrigerator once stored at room temperature.

The pre-filled syringe must always be lifted straight up out of the tray (see figure A.1 and A.2)

b: Place the following items on a clean flat, well-lit work surface, like a table:

  • 1 Zilbrysq pre-filled syringe

You will also need (not included in the carton):

  • 1 alcohol wipe
  • 1 clean cotton ball
  • 1 adhesive bandage
  • 1 sharps disposal container

Figure A.1

Figure A.2

Do not remove the needle cap from the pre-filled syringe until you are ready to inject.

c: Inspect the pre-filled syringe:

  • Check the pre-filled syringe for damage (see Figure B):
    - Do not use if any part of the pre-filled syringe appears to be cracked, leaking, or broken.
    - Do not use if the needle cap is cracked or broken, missing or not securely attached to the pre-filled syringe.
  • Check if the name Zilbrysq and the expiration date appear on the pre-filled syringe label.
  • Check the medicine inside the pre-filled syringe (Figure B). The medicine should be clear to slightly opalescent and colourless. It is normal to see air bubbles in the syringe. Do not use if the medicine is cloudy, discoloured, or contains floating particles.
  • Check the dose on the label (Figure B). Do not use if the dose does not correspond to your prescription.

Figure B

Step 2: Choose injection site and prepare your injection

a: Choose your injection site

Choose an injection site from the following areas (Figure C):

  • The stomach (abdomen), except for the 5cm area around the belly button (navel)
  • The front of the thighs
  • The back of your arm may also be used if a caregiver is giving you the injection

Figure C

  • Do not inject Zilbrysq into an area that is tender, red, bruised, hard or that has scars or stretch marks.
  • Choose a different site for each injection. If you want to use the same injection site, make sure it is at least 2.5 cm from a spot you used the last time.

b: Wash your hands well with soap and water and dry with a clean towel.

c: Prepare your skin

  • Clean the injection site with an alcohol wipe (Figure D).
  • Let the skin dry for 10 seconds before injecting.
  • Do not touch the cleaned area again before injecting.

Figure D

Step 3: Inject Zilbrysq

a: Remove the needle cap
Hold the body of the pre-filled syringe with one hand and pull the needle cap straight off with your other hand (Figure E).

Throw away the needle cap into your household trash or a sharps container (see Step 4).

  • Do not touch the needle or let it touch anything.
  • Do not recap the needle at any time to avoid injury.
  • Do not try to remove any air bubbles from the syringe. Air bubbles will not affect your dose and will not harm you. This is normal. You can continue to take your injection.

Figure E

b: Pinch your injection site
Use your other hand to pinch the area of cleaned skin and hold it firmly (Figure F).

Figure F

c: Insert the needle
Insert the entire needle into the pinched skin at a 45° to 90° angle. When the needle is fully inserted, hold the pre-filled syringe in place (Figure G).

  • Do not pull back on the plunger at any time because this could break the syringe.
  • Do not touch the needle guard activation clips.

Figure G

d: Release the pinched skin
When the needle is fully inserted, hold the pre-filled syringe in place and release the pinched skin (Figure H).

  • Do not reinsert the needle into the skin if the needle is pulled out when releasing the skin because this may bend or break the needle, causing trauma to the tissue. If this happens, safely throw away the syringe in a sharps container, and get a new syringe to give the injection.

Figure H

e: Inject the medicine
Push the plunger all the way down while holding onto the finger grip to inject all the medicine (Figure I). All the medicine is injected when you cannot push the plunger head any further

Figure I

f: Release the plunger
Slowly release the plunger by lifting your thumb. After a complete injection, the needle guard will cover the needle and you may hear a click (Figure J).

Figure J

g: Examine the injection site
Press a cotton ball or gauze pad over the injection site and hold it for 10 seconds (Figure K). Do not rub the injection site. You may have slight bleeding, this is normal. Apply an adhesive bandage if needed (Figure L).

Figure K

Figure L

Step 4: Throw away (dispose of) the used Zilbrysq syringe

Throw away the used syringe into a sharps container (Figure M) right away.

Do not throw away the syringe in your household trash.

Always keep the sharps disposal container out of the reach of children.

Figure M

If you forget to use Zilbrysq

If you miss your dose, administer the dose as soon as possible on the same day and then resume dosing at the scheduled time on the following day.

Do not administer more than one dose per day.

Do not take a double dose to make up for the dose you missed.

If you use too much Zilbrysq

If you think that you have used too much Zilbrysq, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), 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 Zilbrysq?

Remind any doctor, dentist or pharmacist you visit that you are using Zilbrysq.

Call your doctor straight away if you:

Experience any of the following meningococcal infection symptoms:

  • Headache with additional symptoms such as nausea, vomiting, fever and stiff neck or back
  • Fever with or without a rash
  • Eyes sensitive to light
  • Confusion / drowsiness
  • Muscle pain with flu-like symptoms.

Things you should not do

Do not use:

  • if the expiration date on the packaging has passed
  • if the carton seals have been broken
  • if the pre-filled syringe has been dropped or looks damaged
  • if the liquid has ever been frozen (even if thawed)
  • if the medicine is cloudy, discolored, or contains floating particles
  • if the needle cap is cracked or broken, missing or not securely attached to the syringe
  • if the needle is bent, broken, or missing
  • if the dose on the label does not correspond to your prescription.

Driving or using machines

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

Zilbrysq is not likely to affect your driving and use of machines.

Looking after your medicine

  • Store in a refrigerator between 2°C – 8°C.
  • Do not freeze.
  • Keep the pre-filled syringe in the outer carton in order to protect from light.
  • The Zilbrysq pre-filled syringe may be stored at room temperature (up to 30°C) for a single period of a maximum 3 months with protection from light. Once removed from the refrigerator and stored under these conditions, discard after 3 months or by the expiry date, whichever occurs first. A field for the date is provided on the carton to record the date removed from the refrigerator.

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

Keep it where young children cannot reach it.

When to discard your medicine (as relevant)

Discard after the expiry date, or 3 months after being removed from the refrigerator.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

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 or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Injection site reactions:
  • Such as bruising, pain or rash
Infection:
  • Upper respiratory tract infections such as sore throat, blocked nose and headache.
Gastrointestinal disorders:
  • Diarrhoea
Skin disorders:
  • Morphoea (condition that causes localised discoloured and hardened areas of the skin).
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction:
  • Difficulty breathing or swallowing
  • Low blood pressure, which can make you dizzy or light-headed
  • Swelling of the face, lips, tongue or throat
  • Severe itching of the skin, with a red rash or raised bumps.
Meningococcal Infection:
  • Headache with additional symptoms such as nausea, vomiting, fever and stiff neck or back
  • Fever with or without a rash
  • Eyes sensitive to light
  • Confusion / drowsiness
  • Muscle pain with flu-like symptoms.
Serious Infection:
  • Fever, fast heart rate, fast breathing, confusion, and body pain
Pancreatitis
  • Sudden severe abdominal pain, nausea, vomiting, fevers, sweating, rapid pulse.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you 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 Zilbrysq contains

Active ingredient
(main ingredient)		Zilucoplan tetrasodium
Other ingredients
(inactive ingredients)		Monobasic sodium phosphate monohydrate, dibasic sodium phosphate, sodium chloride and water for injections

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

Pre-filled syringe components are not made with natural rubber latex.

What Zilbrysq looks like

Zilbrysq is clear to slightly opalescent and colorless, free of visible particles. It comes in a single use disposable pre-filled syringe.

Zilbrysq is available in unit packs containing 7 pre-filled syringes or multipacks containing 28 (4 packs of 7) pre-filled syringes in the following strengths:

  • A pre-filled syringe of 0.416 mL containing 16.6 mg of zilucoplan (as zilucoplan tetrasodium) (AUST R 410994)
  • A pre-filled syringe of 0.574 mL containing 23.0 mg of zilucoplan (as zilucoplan tetrasodium) (AUST R 414648)
  • A pre-filled syringe of 0.810 mL containing 32.4 mg of zilucoplan (as zilucoplan tetrasodium) (AUST R 414649)

Who distributes Zilbrysq

UCB Pharma
A division of UCB Australia Pty Ltd
Level 1, 1155 Malvern Road
Malvern VIC 3144, Australia

This leaflet was prepared in August 2024

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Zilbrysq

Active ingredient

Zilucoplan

Schedule

S4

 

1 Name of Medicine

Zilucoplan tetrasodium.

2 Qualitative and Quantitative Composition

Zilucoplan is a 15 amino acid, synthetic macrocyclic peptide.
Three pre-filled syringe presentations are available:
a pre-filled syringe of 0.416 mL contains zilucoplan tetrasodium, equivalent to 16.6 mg of zilucoplan;
a pre-filled syringe of 0.574 mL contains zilucoplan tetrasodium, equivalent to 23.0 mg of zilucoplan;
a pre-filled syringe of 0.810 mL contains zilucoplan tetrasodium, equivalent to 32.4 mg of zilucoplan.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
The solution is sterile, clear to slightly opalescent and colourless, free of visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Zilbrysq is indicated as an add-on to standard therapy for the treatment of generalised myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive.

4.2 Dose and Method of Administration

Before starting therapy with Zilbrysq, patients must be vaccinated against Neisseria meningitidis. If treatment with Zilbrysq needs to start less than 2 weeks after vaccination against meningococcal infection, the patient must receive appropriate prophylactic antibiotic treatment until 2 weeks after the first vaccination dose (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
The recommended dose corresponds to approximately 0.3 mg/kg, given as a once daily subcutaneous injection.
Zilbrysq is for single use in one patient only. Discard any residue.
Table 1 indicates the total daily dose of Zilbrysq per body weight range (see Section 5.2 Pharmacokinetic Properties).
There is limited experience with patients below 43 kg and above 150 kg. These patients should receive the lowest and the highest dose, respectively.
The daily dose should be administered approximately at the same time every day.

Missed dose.

If the Zilbrysq dose is missed, administer the dose as soon as possible on the same day and then resume dosing at the scheduled time on the following day. Do not administer more than one dose per day.

Special populations.

No dose adjustment is required based on age, gender, race or ethnicity, or in patients with renal impairment and/or mild to moderate hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Method of administration.

Zilbrysq is administered by subcutaneous injection.
Suitable injection sites include front of the thighs, the abdomen and the back of the upper arms.
Injection sites should be rotated and injections should not be given in areas where the skin is tender, erythematous, bruised, indurated or where the skin has scars or stretch marks.
Administration should be performed by an individual who has been trained in the correct injection techniques for Zilbrysq and following the detailed instructions for use within the pack.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).
Patients who are not currently vaccinated against Neisseria meningitidis, unless they receive appropriate prophylactic antibiotic treatment until 2 weeks after the first vaccination dose (see Section 4.4 Special Warnings and Precautions for Use).
Patients with unresolved Neisseria meningitidis infection.

4.4 Special Warnings and Precautions for Use

Neisseria infections.

Meningococcal infection.

Due to its mechanism of action, the use of Zilbrysq may increase the patient's susceptibility to infections with Neisseria meningitidis. As a precautionary measure, all patients must be vaccinated against meningococcal infections, at least 2 weeks prior to the start of treatment with Zilbrysq.
If urgent treatment with Zilbrysq needs to start less than 2 weeks after vaccination against meningococcal infections, the patient must receive appropriate prophylactic antibiotic treatment until 2 weeks after the first vaccination dose. As meningococcal vaccines reduce but do not completely eliminate the risk of meningococcal infections, consideration should be given to official guidance on the appropriate use of antibiotics. Prescribers and patients should discuss the potential role of ongoing prophylactic antibiotic use.
Vaccines against serogroups A, C, Y, W, and where available, serogroup B, are recommended for preventing the commonly pathogenic meningococcal serogroups. Vaccination, revaccination (boosters) and prophylactic antibiotic treatment should occur according to current relevant guidelines.
During treatment with Zilbrysq, patients should be monitored for signs and symptoms of meningococcal infection and evaluated immediately if infection is suspected. In case of suspected meningococcal infection, appropriate measures such as treatment with antibiotics and discontinuation of treatment with Zilbrysq, should be taken until meningococcal infection can be ruled out. Patients should be instructed to seek immediate medical advice if signs or symptoms of meningococcal infections occur.
No cases of meningococcal infections were reported in the Phase 2 and Phase 3 placebo-controlled studies with Zilbrysq in gMG.
Prescribers should be familiar with the educational materials for the management of meningococcal infections and provide a patient alert card and patient/carer guide to patients treated with zilucoplan.

Other Neisseria infections.

In addition to Neisseria meningitidis, patients treated with Zilbrysq may also be susceptible to infections with other Neisseria species, such as gonococcal infections. Patients should be informed on the importance of gonorrhoea prevention and treatment.

Other infections.

Zilbrysq blocks terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria. During treatment with Zilbrysq, patients should be monitored for signs and symptoms of infections and evaluated if infection is suspected.

Pancreatic enzymes increased.

Elevations of lipase and/or amylase were observed, of which some were marked (CTCAE grade 3 and 4). These were transient and rarely led to treatment discontinuation. Although a causal relationship with pancreatitis or other pancreas pathologies (cysts, masses) has not been identified, cases of both were reported amongst patients treated with zilucoplan. In the evaluation of abdominal pain with suspicion of pancreatitis, appropriate investigations, including measurement of amylase and lipase should be undertaken.

Use in hepatic impairment.

No dose adjustment is required for patients with mild and moderate hepatic impairment. There are no data on patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

No dose adjustment is required for patients with renal impairment. There are no data on patients requiring dialysis (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

No dose adjustment is required in elderly patients.

Paediatric use.

The safety and efficacy of Zilbrysq in children below the age of 18 years have not been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical interaction studies have been performed. Based on results from in vitro testing, clinically relevant interactions are not expected between zilucoplan and an inhibitor or inducer of major CYP enzymes or transporters.
Zilucoplan is not a substrate of major CYP enzymes or transporters (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4, or P-gp, BCRP, OATP1B1 or OATP1B3).
The potential of zilucoplan to inhibit CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A and 4F2) and UGTs (1A1, 1A3, 1A4, 1A6, 1A9, 2B7, and 2B15) or transporters (P-gp, BCRP, BSEP, MRP2, MRP3, MATE1, MATE2-k, NTCP, OCT1, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3) was evaluated in vitro. In addition, the potential of CYP induction of CYP1A2, 2B6 and CYP3A4 by zilucoplan was evaluated. Based on the results, zilucoplan will not inhibit or induce these major drug metabolising enzymes (CYPs and UGTs) and transporters in a clinically relevant manner. Some inhibition of MRP3 was observed, the relevance of which is unknown.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Zilbrysq on human fertility has not been evaluated.
In a monkey male fertility study, minimal to slight testicular germ cell degeneration/depletion was observed at all subcutaneous doses (greater than or equal to 1 mg/kg/day, resulting in exposures based on AUC greater than or equal to 2 times the clinical AUC at the maximum human recommended dose) at the end of the 13-week dosing period and after the 8-week recovery period, but severity did not increase with dose. The findings in non-human primates are of uncertain clinical relevance as the underlying mechanism is unknown.
Zilucoplan-induced effects on female fertility was not investigated in animals.
(Category D)
There are no data from the use of Zilbrysq in pregnant women. Zilbrysq is not recommended during pregnancy and in women of childbearing potential not using contraception.
Subcutaneous administration of zilucoplan (0, 1, 2, or 4 mg/kg/day) to pregnant monkeys throughout gestation resulted in an increase in embryofetal death at all doses, in the absence of maternal toxicity. A no effect dose for adverse developmental effects in monkeys was not identified. The lowest dose tested was associated with maternal exposures (AUC) similar to that in humans at the maximum recommended human dose.
Data collected from an ex vivo human placental transfer model suggests a low transfer rate of zilucoplan (0.5-1.0%) in the fetal compartment. The clinical relevance of these data in human pregnancies is unknown.
 There are no data on the presence of Zilbrysq in human milk, the effects on the breastfed infant, or the effects on milk production.
A decision must be made whether to discontinue breastfeeding or to discontinue Zilbrysq therapy taking into account the benefit of breastfeeding for the child, as well as any potential adverse effects, and the benefit of therapy for the woman based on their underlying condition.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

A total of 115 patients have been treated with zilucoplan in placebo-controlled clinical studies in gMG, representing 26.4 patient-years of exposure.
Table 2 presents the treatment emergent adverse events reported in at least 5% of Zilbrysq-treated patients and more frequently than the placebo in the 12-week controlled period of the Phase 3 clinical trial in gMG.
Very common adverse reactions were injection site reactions and upper respiratory tract infections reported in ≥ 10% of patients. Common adverse reactions were diarrhoea, amylase increased, lipase increased, and morphoea (localised scleroderma) reported in > 5% of patients. Uncommon adverse reactions were blood eosinophils increased reported in < 1% of patients.

Description of selected adverse reactions.

Injection site reactions.

Most common terms were injection site bruising, pain, nodule, pruritus and haematoma. All cases were non-serious, mild or moderate in severity, and less than 3% of events led to treatment discontinuation. In pooled placebo-controlled studies, injection site reactions were reported in 25.2% of patients treated with zilucoplan and in 15.5% of patients treated with placebo.

Upper respiratory tract infections.

Most common terms were nasopharyngitis, upper respiratory tract infection and sinusitis. More than 95% of the cases were non-serious, mild or moderate in severity and did not lead to treatment discontinuation. In pooled placebo-controlled studies, upper respiratory tract infections were reported in 13.0% of patients treated with zilucoplan and in 7.8% of patients treated with placebo.

Blood eosinophils increased.

Elevations of blood eosinophils were observed in some subjects, of which some were marked. The majority peaked approximately 2 months after starting zilucoplan. These were transient, not leading to treatment discontinuation and not associated with clinically relevant organ dysfunction.

Morphoea.

Cases of morphoea (common, 1-10%) were observed after long-term treatment during the open-label extension study; the longest exposure to Zilbrysq in this study (RAISE-XT) was more than 4 years. The majority of the cases had a time to onset longer than one year after start of treatment, were mild or moderate in severity and did not lead to treatment discontinuation. The incidence of morphoea observed with zilucoplan appears to be higher than the expected background incidence in the MG population.

Immunogenicity.

As with all therapeutic peptides, there is a potential for immunogenicity with zilucoplan. The detection of anti-drug antibody (ADA) formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of ADA positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to zilucoplan with the incidence of antibodies to other products may be misleading.
In the Phase 3 clinical trial (MG0010), the patients were tested for ADA positivity and anti-PEG (polyethylene glycol) antibody positivity. A total of 2 patients (2.3%) each in the zilucoplan 0.3 mg/kg and placebo group were ADA positive. A total of 8 patients (9.3%) in the zilucoplan 0.3 mg/kg group and 6 patients (6.8%) in the placebo group were anti-PEG positive, respectively. Antibody titres were low and there was no evidence of an association between positive ADA status or positive anti-PEG status and the incidence of adverse events.

Patients with other diseases.

Supportive safety data were obtained from 7 completed clinical studies that enrolled 225 patients exposed to zilucoplan in disease populations other than gMG (Immune-mediated necrotizing myopathy, COVID-19 associated respiratory syndrome and paroxysmal nocturnal hemoglobinuria). No additional ADR were identified in patients with these diseases compared to patients with gMG.

Reporting suspected adverse effects.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Limited experience with doses higher than the recommended dose of zilucoplan is available from clinical trials in humans.
In a healthy volunteer study where 32 participants were exposed to supratherapeutic doses of 0.6 mg/kg, administered subcutaneously for up to 7 days, safety data were consistent with the safety profile of the recommended dose.
In cases of overdosage, it is recommended that patients are monitored closely for any adverse effects, and appropriate supportive measures should be instituted immediately.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In gMG patients, binding of anti-AChR auto-antibodies (mainly IgG1 and IgG3) to AChR results in uncontrolled and inappropriate activation of the classical complement pathway. The immune complex formed by the autoantibody-antigen complex activates the C1 component of the classical complement pathway. This leads to a series of enzymatic cleavage steps, culminating in the cleavage of C5 into C5a and C5b and deposition of the cytolytic membrane attack complex (C5b-9, MAC) on the post-synaptic membrane of the neuromuscular junction and subsequent injury to the neuromuscular endplate, leading to failure of neuromuscular transmission.
Zilucoplan inhibits the effects of C5 through a dual mechanism of action. It specifically binds to complement protein C5, thereby inhibiting its cleavage by the C5 convertase to C5a and C5b, which results in a downregulation of the assembly and cytolytic activity of the MAC. Additionally, by binding to the C5b moiety of C5, zilucoplan sterically hinders binding of C5b to C6, which prevents the subsequent assembly and activity of the MAC, should any C5b be formed.

Pharmacodynamic effects.

The pharmacodynamic effect of zilucoplan was analysed through the ability of inhibiting ex vivo, complement-induced sheep red blood cell (sRBC) lysis.
In the Phase 2 study in gMG (MG0009), patients received zilucoplan 0.3 mg/kg, zilucoplan 0.1 mg/kg or placebo daily for 12 weeks. There was rapid complement inhibition within 1-3 hours and at Week 12, complement inhibition was 95.7% in patients receiving zilucoplan 0.3 mg/kg, compared with 81.8% in patients receiving zilucoplan 0.1 mg/kg.
In the Phase 3 study in gMG (MG0010), patients received zilucoplan 0.3 mg/kg or placebo daily for 12 weeks. Similarly, complete complement inhibition of 97.5% could be seen from Week 1 through Week 12 with zilucoplan.
This effect was maintained in the Phase 3 open-label extension study MG0011 where complement inhibition at Week 12 was 97.3% in patients who were treated with zilucoplan in MG0009 or MG0010 and 95.9% in patients who had been treated with placebo in MG0009 or MG0010 and switched to zilucoplan in the open-label extension.
Data from the Phase 2 and Phase 3 studies demonstrate rapid, complete and sustained complement inhibition with zilucoplan 0.3 mg/kg.

Clinical trials.

The safety and efficacy of zilucoplan were evaluated in a 12-week multicentre, randomised, double-blind placebo-controlled study MG0010 (RAISE) and the open-label extension study MG0011 (RAISE-XT).

Study MG0010 (RAISE).

A total of 174 patients were enrolled, who were at least 18 years of age, had anti-AChR antibody positive gMG, MGFA Class II-IV (mild to severe), a Myasthenia Gravis­-Activities of Daily Living (MG-­ADL) Score of ≥ 6 and a Quantitative Myasthenia Gravis (QMG Score) of ≥ 12 (see Table 3).
Patients were treated with zilucoplan 0.3 mg/kg once daily or placebo. The 0.3 mg/kg dose was given according to the same weight categories as the proposed clinical use. Stable standard of care (SOC) therapy was allowed.
The primary endpoint was the change from baseline (CFB) to Week 12 in MG­-ADL total score. MG-ADL is an 8-item patient reported outcome measure assessing impact of gMG on daily function of signs and symptoms. The total score is the sum of the 8 individual scores and ranges from 0 to 24, with higher scores indicating more severe impact of gMG on daily function.
Key secondary endpoints were the CFB to Week 12 in QMG total score, in Myasthenia Gravis Composite (MGC) total score and in MG Quality of Life (MG-QoL15r) total score.
QMG is a 13-item clinician reported outcome measure assessing muscle weakness. The total score is the sum of the 13 individual scores and ranges from 0 to 39, with higher scores indicating more severe weakness.
MGC is a 10-item gMG composite (reported by clinician and patient) outcome measure to evaluate gMG clinical status. The range of total scores is 0 to 50, with higher scores indicating more severe impairment due to gMG.
MG-QoL15r is a 15-item patient reported outcome measure assessing the impact of gMG on patient's quality of life. The total score ranges from 0 to 30, with higher scores indicating greater impairment of QoL.
All 4 outcome measures are validated in gMG.
The majority of study participants received treatment for gMG at baseline which included parasympathomimetics (84.5%), systemic corticosteroids (63.2%) and immunosuppressants (51.1%). The immunosuppressants used were mainly azathioprine and mycophenolate. 13.2% of patients were on intravenous immunoglobulin (IVIG) at baseline.
The mean weight of participants was 89.1 kg and mean BMI was 31 kg/m2 and these were balanced between the groups.
The treatment effect in the zilucoplan group for all 4 endpoints started rapidly at Week 1, further increased to Week 4 and was sustained through Week 12.
At Week 12, a clinically meaningful and highly statistically significant improvement in the primary endpoint, MG-ADL total score (Figure 1) was observed for zilucoplan versus placebo.
For the key secondary endpoints, at Week 12, a clinically meaningful and highly statistically significant improvement in QMG total score (Figure 2) was observed for zilucoplan versus placebo. At Week 12, a clinically meaningful and statistically significant improvement in MGC total score (Figure 3) and a statistically significant improvement in MG-QoL15r total score (Figure 4) was observed for zilucoplan versus placebo.
For the secondary endpoints, all p-values were based on the pre-defined hierarchy. At Week 12, 73.1% of the patients in the zilucoplan group were MG-ADL clinical responders (defined as having at least a 3-point decrease in MG-ADL score) without rescue therapy, vs. 46.1% in the placebo group (statistically significant, p < 0.001). 58.0% of the patients in the zilucoplan group were QMG clinical responders (defined as having at least a 5-point decrease in QMG score) without rescue therapy, vs. 33.0% in the placebo group (statistically significant, p=0.0012). The proportion of clinical responders at higher response thresholds was consistently greater for zilucoplan compared with placebo. 14.0% of the patients in the zilucoplan group achieved Minimal Symptom Expression (MG-ADL score of 0 or 1; MSE) without rescue therapy, vs. 5.8% in the placebo group (p=0.0885).
Table 4 presents the CFB at week 12 in the total scores for MG-ADL, QMG, MGC and MG-QoL15r.
At Week 12, the cumulative portion of patients that needed rescue therapy was lower in the zilucoplan group (5%) compared with the placebo group (12%). Separation of zilucoplan from placebo was first observed by Week 2 (Day 15); this separation was sustained through Week 12 (Day 84). This only shows a trend and is non-significant.
Treatment with zilucoplan resulted in consistently greater decreases from baseline in the respective subgroups (refractory status, age, gender, ethnicity, disease duration or severity, baseline MG-ADL and QMG scores and prior treatment with steroids, plasma exchange (PLEX), IVIG, subcutaneous immunoglobulin (SCIG) or immunosuppressants) compared with placebo for the primary and key secondary endpoints.

Study MG0011 (RAISE-XT).

Two hundred patients who completed the placebo-controlled Phase 2 (MG0009) or Phase 3 (MG0010) studies entered the open-label extension study MG0011 and were treated with zilucoplan 0.3 mg/kg daily. MG0011 was primarily a safety and tolerability study which was not randomized or placebo-controlled, therefore efficacy is inferred. Efficacy endpoints were the CFB in MG-ADL, QMG, MGC and MG-QoL15r score at Week 12 of the open-label extension period. The results of MG0011 demonstrated sustained efficacy through to Week 60.
Figure 5 shows the mean changes from double-blind study baseline to Week 48 of the open-label extension for total MG-ADL score. See Table 5.

5.2 Pharmacokinetic Properties

The pharmacokinetic (PK) properties of zilucoplan and the major circulating metabolites (RA102758 and RA103488) have been evaluated in healthy adult subjects and in patients with gMG.
A population PK analysis showed that zilucoplan PK was not time and dose dependent. At the therapeutic dose of 0.3 mg/kg, the PK of zilucoplan is in the linear dose range.

Absorption.

Following single and multiple daily subcutaneous administration of zilucoplan 0.3 mg/kg in healthy subjects, zilucoplan reached peak plasma concentrations generally between 3 to 6 hours post-dose.
In study MG0010 in patients with gMG, after daily repeated subcutaneous administration of zilucoplan 0.3 mg/kg, plasma concentrations of zilucoplan were consistent, with steady state trough concentrations being reached by Week 4 of zilucoplan treatment and maintained through Week 12. The ADA and anti-PEG antibody status of patients treated with zilucoplan did not affect zilucoplan concentrations.
Exposures after subcutaneous administration of single zilucoplan (0.3 mg/kg) doses in the abdomen, thigh, or upper arm were comparable.

Distribution.

Zilucoplan and its 2 major metabolites are highly bound to plasma proteins (> 99%). The mean volume of distribution for zilucoplan (Vc/F) using a population PK analysis is 3.51 L.

Metabolism.

In plasma, 2 major metabolites, RA103488 and RA102758 were detected. The formation of RA103488 is mainly due to cytochrome CYP450 4F2. RA103488 has pharmacological activity similar to zilucoplan but is present at a much lower concentration compared with zilucoplan. The contribution of RA103488 to pharmacological activity is low. RA102758 is pharmacologically inactive. Further, as a peptide, zilucoplan is expected to be degraded into small peptides and amino acids via catabolic pathways.

Excretion.

The mean plasma terminal elimination half-life was approximately 172 hours (7-8 days). The excretion of zilucoplan and its metabolites was measured in both urine and faeces and was negligible or < 1%.

Special populations.

Elderly.

Based on population PK analysis, age did not influence the PK of zilucoplan. No dose adjustment is required.

Renal impairment.

The effect of renal impairment on the PK of zilucoplan and its metabolites was studied in an open-label Phase 1 study, where a single dose of zilucoplan 0.3 mg/kg was administered to healthy subjects and subjects with severe renal impairment (creatinine clearance between 15 and < 30 mL/min).
Systemic exposure to zilucoplan and the major inactive metabolite RA102758 was not different in subjects with severe renal impairment compared to subjects with normal renal function. The exposure to the active metabolite RA103488 was approximately 1.5-fold higher in subjects with severe renal impairment compared to subjects with normal renal function.
Based on the PK results, no dose adjustment is required in patients with renal impairment.

Hepatic impairment.

The effects of moderate hepatic impairment (as defined by a Child-Pugh score between 7 and 9) on the PK of zilucoplan and its metabolites were studied in an open-label Phase 1 study, where a single dose of 0.3 mg/kg zilucoplan was administered to healthy subjects and subjects with moderate hepatic impairment.
Systemic exposure to zilucoplan, based on AUC0-last and AUC(0-inf), was 24% lower in subjects with moderate impaired liver function compared with healthy subjects, which was in line with a higher systemic and peak exposures of both metabolites in subjects with hepatic impairment compared with healthy subjects. Zilucoplan peak exposure as well as terminal half-life were comparable between both groups. Further pharmacodynamic analysis did not identify meaningful differences in complement levels or inhibition of complement activity between both groups. Based on these results, no dose adjustment is required in patients with mild and moderate hepatic impairment.

Racial and ethnic groups.

In a Phase 1 clinical study in healthy Caucasian and Japanese subjects, the PK profile of zilucoplan and its 2 major metabolites was compared following a single dose of 0.3 mg/kg and after multiple dosing of 0.3 mg/kg for 14 days. Results were generally similar between both groups. The population PK analysis demonstrated that there are no differences between the different race categories (Black/African American, Asian/Japanese, and Caucasians). No dose adjustment is required.

Gender.

In the population PK analysis, no difference in PK between genders was observed. No dose adjustment is required.

Weight.

Population PK analysis on data collected across studies in gMG showed that body weight significantly influences the PK of zilucoplan. Zilucoplan dosing is based on body weight categories (see Section 4.2 Dose and Method of Administration), no further dose adjustment is needed.

5.3 Preclinical Safety Data

Genotoxicity.

Zilucoplan was not genotoxic when tested in the in vitro mutagenicity test (Ames), the in vitro chromosomal aberration assay and in the in vivo micronucleus test in rat bone marrow cells.

Carcinogenicity.

No carcinogenicity studies were conducted with zilucoplan.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients are monobasic sodium phosphate monohydrate, dibasic sodium phosphate, sodium chloride and water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the pre-filled syringe in the original carton to protect from light.
Patients may store the Zilbrysq pre-filled syringe(s) at room temperature in the original carton (with protection from light) at up to 30°C for a single maximum period of 3 months. Once Zilbrysq has been stored at room temperature, it should not be placed back into the refrigerator and should be discarded if not used within the 3 month period or by the expiry date, whichever occurs first.

6.5 Nature and Contents of Container

Each pre-filled syringe is type I glass with a 29 G ½" thin wall needle closed with a grey fluoropolymer-laminated bromobutyl rubber plunger stopper. The needle is protected with a rigid needle shield consisting of a thermoplastic elastomer needle shield and a polypropylene rigid shield. The pre-filled syringe components are not made with natural rubber latex.
Each pre-filled syringe is pre-assembled with a needle safety device, a finger grip and a coloured plunger.
The pre-filled syringes are available as 3 different presentations, with different volumes to allow patients to receive the appropriate dose based on a weight range:
0.416 mL pre-filled syringe with rubine red plunger;
0.574 mL pre-filled syringe with orange plunger;
0.810 mL pre-filled syringe with dark blue plunger.
Pack size: 7 pre-filled syringes.
Multipack containing 28 (4 packs of 7) pre-filled syringes.

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 name: zilucoplan tetrasodium.
Molecular formula and mass: the molecular formula of zilucoplan (free acid form) is C172H278N24O55 and its molecular weight is 3562.23 Da.

Chemical structure.


The four sodium ions in the structure are shown associated with designated carboxylates, but they may be associated with any of the acidic groups in the molecule.

CAS number.

1841136-73-9 (free acid).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes