Consumer medicine information

Berinert IV

C1 esterase inhibitor, human

BRAND INFORMATION

Brand name

Berinert IV

Active ingredient

C1 esterase inhibitor, human

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Berinert IV.

SUMMARY CMI

Berinert® IV

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.

1. Why am I using Berinert® IV?

Berinert® IV contains the active ingredient, human C1 esterase inhibitor. Berinert® IV is used for the treatment of attacks in people with hereditary angioedema (HAE) (oedema=swelling).

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

2. What should I know before I use Berinert® IV?

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

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

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

3. What if I am taking other medicines?

Some medicines may interfere with Berinert® IV and affect how it works.

For more information see Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Berinert® IV?

  • The recommended dosage is 20 IU per kilogram of body weight.
  • Your doctor will prescribe the dosage that should be administered, based on your body weight.
  • Training will be provided for preparation and administration of Berinert® IV prior to use.
  • If Berinert® IV 500 IU is not injected immediately, it must be stored at 2-8°C and used within 24 hours of reconstitution.
  • If Berinert® IV 1500 IU is not injected immediately, it must be stored at 2-8°C and used within 8 hours of reconstitution.

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

5. What should I know while using Berinert® IV?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Berinert® IV.
  • Notice any signs of serious side effect – this may indicate that the administration of Berinert® IV needs to be stopped immediately.
Things you should not do
  • Do not give or share your medicine with anyone else, even if they have the same condition as you.
  • Do not mix Berinert® IV with other medicinal products or diluents either before or during administration.
Driving or using machines
  • Make sure you are aware of how Berinert® IV affects you before driving or operating machinery.
  • Berinert® IV has no or negligible influence on ability to drive and use machines However, side effects listed in Section 6. Are there any side effects? may impact your ability to drive and use machines.
Looking after your medicine
  • Store Berinert® IV in the carton in a cool, dry place protected from light where the temperature stays below 25°C.
  • Do not freeze.

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

6. Are there any side effects?

Serious side effects may include irregular or faster heart beat, feeling faint or sick, difficulty in breathing or dizziness. Other common side effects include reactions at the site of the injection, itching, rash, headache, abdominal pain, nausea, muscle spasms, pain, diarrhoea, vomiting and fever.

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



FULL CMI

Berinert® IV

Active ingredient(s): Human C1 esterase inhibitor

Consumer Medicine Information (CMI)

This leaflet provides important information about using Berinert® IV. 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 Berinert® IV.

Where to find information in this leaflet:

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

1. Why am I using Berinert® IV?

Berinert® IV contains the human protein C1 esterase inhibitor as the active ingredient. Berinert® IV is a product made from human plasma (this is the liquid part of the blood) and is presented as a powder and diluent.

Berinert® IV for intravenous (into the vein) injection is used for the treatment of acute attacks in patients with hereditary angioedema (HAE) (oedema – swelling).

HAE is a congenital disease of the vascular system. It is a non-allergic disease. HAE is caused by the deficiency, absence or defective production of C1 esterase inhibitor and is characterised by the following symptoms:

  • swelling of the hands and feet that occurs suddenly
  • facial swelling with tension sensation that occurs suddenly
  • eyelid swelling, lip swelling, possible laryngeal (voice-box) swelling with difficulty in breathing
  • tongue swelling
  • colic pain in abdominal region.

Generally all parts of the body can be affected.

Berinert® IV treats the HAE attack by replacing the missing or malfunctioning C1 esterase inhibitor protein your body needs.

2. What should I know before I use Berinert® IV?

Warnings

Do not use Berinert® IV if:

  • you are allergic to C1 esterase inhibitor, or any of the ingredients listed at the end of this leaflet.

Check with your doctor if you:

  • have any other medical conditions (pre-existing blood clotting condition or blood related condition)
  • take any medicines for any other condition
  • have an allergy to any medicine or food
  • are on a sodium controlled diet
  • are pregnant, plan to become pregnant or are breastfeeding.

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, think you are pregnant, intend to become pregnant or are breastfeeding.

Berinert® IV should only be used if clearly needed during pregnancy or breastfeeding.

Allergies to any medicine or food

If you have allergies, you may be treated with antihistamines and corticosteroids as a preventative measure.

History of blood clotting

There is a potential risk of blood clots forming when higher than recommended doses of Berinert® IV are used to treat Capillary Leak Syndrome (outflow of fluid from the small blood vessels into the tissue), which is a non-approved indication.

Tell your doctor if you notice any other effects not listed in Section 6. Are there any side effects?.

Virus safety

This product is made from human blood. When products are made from human blood and injected into you, it is possible that viruses or other substances could be present in the product and cause an illness. These could be viruses such as hepatitis, human immunodeficiency virus (HIV), or parvovirus B19. There could also be other infectious agents some of which may not have been discovered.

To reduce the risk of this happening extra steps are taken when manufacturing this product. Strict controls are applied when selecting blood donors and donations. The product is specially treated to kill and remove viruses. These special treatments are considered effective against certain viruses known as enveloped viruses (such as HIV and hepatitis B and C) and also for non-enveloped viruses hepatitis A and parvovirus B19. Despite these measures, the risk of transmitting infection cannot be totally eliminated.

Vaccines are available against some of these viruses and your doctor will be able to help you decide whether it is worthwhile having any of those vaccines.

Discuss the risk and benefits of this medicine with your doctor.

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.

Some medicines may affect the way other medicines work.

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

4. How do I use Berinert® IV?

Berinert® IV is used for intravenous (into the vein) injection.

Treatment should be started and supervised by a doctor. If your doctor decides that you should self-administer Berinert® IV at home or in other appropriate settings, they will ensure you receive detailed instructions and training on how to use it.

Your doctor will also tell you what to do if you experience an HAE attack.

If you do not understand the instructions, ask your doctor.

How much to use

  • The recommended dosage is 20 IU per kilogram of body weight.
  • Your doctor will prescribe the dosage that you should administer, based on your body weight.
  • Follow the instructions provided and use Berinert® IV until your doctor tells you to stop.

When to use Berinert® IV

  • Your doctor will discuss with you when Berinert® IV should be used.

How to prepare Berinert® IV for administration

If your doctor considers that you should self-administer Berinert® IV, the instructions below should be followed carefully.

  1. Allow the vial of Berinert® IV powder and diluent (Water for Injections) to reach room temperature prior to use.
  2. Wash hands with soap and water and dry hands thoroughly with a clean towel.
  3. Find a clean, flat working surface such as a table, where you can prepare Berinert® IV undisturbed.
  4. Thoroughly clean the preparation area with disinfectant wipes.
  5. Open the carton and take out the Mix2Vial™ filter transfer set. The Mix2Vial™ filter transfer set is intended to filter the contents of a single vial of Berinert® IV only. If multiple vials of Berinert® IV are to be given, a separate Mix2Vial™ must be used for each vial.
  6. Remove protective caps from both the product and diluent vials.
  7. Wipe the rubber stoppers of both the product and diluent vials with one of the alcohol swabs provided in the administration pack and allow to dry for two minutes. Do not leave the alcohol swab resting on the stoppers. Do not touch the rubber stoppers with your fingers.
  1. Open the Mix2Vial™ package by peeling away the lid. Do not remove the Mix2Vial™ from the blister package.

  1. Place the diluent vial on a flat surface and hold the vial firmly. Take the Mix2Vial™ together with the package and push the blue end straight down through the diluent stopper.

  1. Carefully remove the package from the Mix2Vial™ set. Make sure that you only pull up the package and not the Mix2Vial™ itself.

  1. Place the product vial on an even and firm surface. Invert the diluent vial with the Mix2Vial™ set attached and push the transparent adapter straight down through the product vial stopper. The diluent will automatically flow into the product vial.

  1. With one hand, hold the product side of the Mix2Vial™ set, hold the diluent side with the other hand and unscrew the set counterclockwise into two pieces. Discard the diluent vial with the blue part attached.

  1. Gently swirl the product vial until the substance is fully dissolved. Do not shake as this could damage the product.
    The 500 IU solution should be clear and colourless.
    The 1500 IU solution should be clear and colourless to slightly opalescent. It might sparkle when held up to the light but must not contain any obvious particles.
    Do not use solutions that are cloudy or contain flakes or particles.
    This medicine does not contain an antimicrobial preservative.

If the 500 IU solution is not injected immediately it must be stored at 2-8°C and used within 24 hours of preparation.

If the 1500 IU solution is not injected immediately it must be stored at 2-8°C and used within 8 hours of preparation.

The reconstituted product should only be stored in the vial. Allow the solution to reach room temperature before use.

  1. Draw air into an empty, sterile, syringe. Use the syringe provided with the product. While the product vial is upright, connect the syringe to the Mix2Vial™'s Luer Lock fitting by screwing clockwise. Inject air into the product vial.

  1. While keeping the syringe plunger pressed, invert the product vial and draw the solution into the syringe by slowly pulling the plunger back.

  1. When the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe in one hand, and with the other hand disconnect the Mix2Vial™ set and product vial from the syringe by unscrewing counterclockwise.

If the same patient is to receive more than one vial, the contents of multiple vials may be pooled in a single administration device (e.g. syringe). A new unused Mix2Vial™ transfer set should be used for each Berinert® IV vial.

How to administer Berinert® IV

Your doctor or nurse will instruct you on how to administer Berinert® IV yourself if you need to treat yourself at home or in other appropriate settings.

It is important that Berinert® IV is injected directly into a visible vein. Do not inject into surrounding tissues or into an artery. Once you learn how to self-administer, follow the instructions provided below.

  1. Assemble supplies

Gather the syringe filled with Berinert® IV, the remaining items in the administration pack (an infusion set and an alcohol swab) and the following supplies (not provided with Berinert® IV):

  • tourniquet
  • sterile gauze and tape, or transparent dressing
  • gloves (if recommended by your healthcare provider)
  • disinfectant wipes
  • sharps or other container.

You may also need a treatment diary or log book as instructed by your doctor or nurse.

  1. Wash hands
  • Thoroughly wash and dry your hands
  • If you have been told to wear gloves when preparing your infusion, put the gloves on.
  1. Clean surface
  • Thoroughly clean a table or other flat surface using the disinfectant wipes.
  1. Prime the infusion set
As instructed by your healthcare provider, to prime (fill) the infusion tubing, connect the syringe filled with Berinert® IV to the infusion set tubing and gently push on the syringe plunger to fill the tubing with Berinert® IV.

  1. Prepare the infusion site
Apply a tourniquet above the site of the infusion.
Prepare the infusion site by wiping the skin well with an alcohol swab and allow it to dry.

  1. Infusion
As instructed by your healthcare provider, insert the butterfly needle of the infusion set tubing into your vein

If necessary, use sterile gauze and tape or transparent dressing to hold the needle in place.
To make sure that the needle is in a vein, gently pull back on the syringe plunger and check to see if blood is in the tubing.
If there is blood present, then the needle is in a vein.
If there is no blood present, remove the needle and repeat this step using a new needle, new administration tubing, and a different injection site.
Remove the tourniquet.

Inject the Berinert® IV 500 IU solution by slow intravenous injection at a rate of approximately 4 mL per minute.
Inject the Berinert® IV 1500 IU solution as a bolus intravenous injection.

  1. Clean Up
After infusing the entire amount of Berinert® IV, remove the infusion set and cover the infusion site with a bandage, holding pressure on the site for a few minutes.
Dispose of all unused solution, the empty vials, and the used needles and syringe in an appropriate container used for throwing away waste that might hurt others if not handled properly.

  1. Record treatment
  • It is recommended that treatment details and lot number from the Berinert® IV vial label are recorded every time you use Berinert® IV.

Do not mix Berinert® IV with other medicinal products or diluents either before or during administration.

If you forget to use Berinert® IV

Berinert® IV should be used as prescribed by your doctor. If you miss a dose, follow your doctor's instructions or contact your doctor or pharmacist.

If you use too much Berinert® IV

No symptoms of overdose with Berinert® IV are known. No cases of overdose have been reported. If you think that you have used too much Berinert® IV,

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor.

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

5. What should I know while using Berinert® IV?

Things you should do

Call your doctor straight away if you:

  • Notice signs of a side effect. A serious side effect may indicate that the use of Berinert® IV needs to be stopped immediately.

Remind any doctor, dentist or pharmacist you visit that you are using Berinert® IV.

Use this medicine in one patient on one occasion only.

Things you should not do

  • Do not give or share your medicine with anyone else, even if they have the same condition as you.
  • Do not mix Berinert® IV with other medicinal products or diluents either before or during administration.
  • Stop using this medicine suddenly unless instructed by your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Berinert® IV affects you.

Berinert® IV has no or negligible influence on ability to drive and use machines. However, side effects listed in Section 6. Are there any side effects? may impact your ability to drive and use machines.

Looking after your medicine

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

Store Berinert® IV in the outer carton in a cool, dry place protected from light where the temperature stays below 25°C.

Do not freeze.

Keep it out of the sight and reach of children.

Disposal of your medicine

Do not use Berinert® IV after the expiry date detailed on the carton packaging.

The reconstituted medicine should only be stored in the vial at 2-8°C if it is not administered immediately.

Dispose of Berinert® IV 500 IU if it is not administered within 24 hours of reconstitution.

Dispose of Berinert® IV 1500 IU if it is not administered within 8 hours of reconstitution.

If your doctor tells you to stop using Berinert® IV or the pack has expired, ask them what to do if you have a pack left over.

Getting rid of any unwanted medicine

Any unused portion remaining in the vial must be discarded appropriately.

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

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
  • nausea or vomiting
  • muscle spasms
  • abdominal pain
  • general pain
  • diarrhoea
  • headache
  • chills and fever
  • pain and redness where the injection was given
  • abnormal taste.
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
  • irregular or faster heart beat
  • feeling faint (fall in blood pressure)
  • reddening of the skin
  • rash
  • difficulty in breathing
  • dizziness
  • feeling sick
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 Berinert® IV contains

Active ingredient
(main ingredient)		Human C1 esterase inhibitor
Other ingredients
(inactive ingredients)		Glycine
Sodium chloride
Sodium citrate

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

What Berinert® IV looks like

Berinert® IV is a white powder contained in a glass vial.

The 500 IU vial of Berinert® IV comes in a pack containing:

  • a vial of diluent (10 mL of Water for Injections) used to dissolve the powder
  • a Mix2Vial™ filter transfer set
  • an administration pack with:
    - a disposable 10 mL syringe
    - an infusion set
    - 2 alcohol swabs.

The 1500 IU vial of Berinert® IV comes in a pack containing:

  • a vial of diluent (3 mL of Water for Injections) used to dissolve the powder
  • a Mix2Vial™ filter transfer set
  • an administration pack with:
    - a disposable 5 mL syringe
    - an infusion set
    - 2 alcohol swabs.

500 IU: AUST R 157279

1500 IU: AUST R 281469

Who distributes Berinert® IV

Berinert® IV is supplied in Australia by

CSL Behring (Australia) Pty Ltd
ABN 48 160 734 761
189-209 Camp Road
Broadmeadows VIC 3047
Australia

For Medical/Technical Enquiries

TOLL FREE: 1800 642 865

For Customer Service Enquiries

TOLL FREE: 1800 063 892

[email protected]
www.cslbehring.com.au

This leaflet was prepared in September 2024.

® Registered trademark of CSL Limited Group of Companies

™ Mix2Vial is a trademark of West Pharmaceutical Services, Inc. or a subsidiary thereof

Published by MIMS June 2025

BRAND INFORMATION

Brand name

Berinert IV

Active ingredient

C1 esterase inhibitor, human

Schedule

Unscheduled

 

1 Name of Medicine

Human C1 esterase inhibitor.

2 Qualitative and Quantitative Composition

Berinert IV is a highly purified, freeze-dried C1 esterase inhibitor concentrate derived from human plasma.
Berinert IV is available in two presentations with different concentrations (strengths) as detailed in Table 1. When reconstituted, the 500 IU presentation contains 500 IU of C1 esterase inhibitor per vial at 50 IU/mL and the 1500 IU presentation contains 1500 IU of C1 esterase inhibitor per vial at 500 IU/mL.
The potency of C1 esterase inhibitor is expressed in International Units (IU), which are related to the current WHO Standard for C1 esterase inhibitor products.
Berinert IV contains up to 486 mg sodium per 100 mL of solution. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Berinert IV is produced as a sterile, pyrogen-free, freeze-dried white powder for intravenous injection and supplied with water for injections (clear, colourless) for reconstitution.

4 Clinical Particulars

4.1 Therapeutic Indications

Berinert IV is indicated for the treatment of acute attacks in patients with hereditary angioedema (HAE).

4.2 Dose and Method of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of C1 esterase inhibitor deficiency.
It is recommended that prescribed doses of Berinert IV should be expressed as International Units written in full.
Berinert IV is administered intravenously by a doctor or nurse. If self administration and home treatment is considered appropriate, see Self administration and home treatment under Administration.

Dosage.

The recommended dose is 20 IU per kg body weight for adult and paediatric patients.

Reconstitution.

Reconstitution and withdrawal must be carried out under aseptic conditions. Use the syringe provided with the product or a silicone free syringe. Bring the diluent to room temperature. Ensure product and diluent vial flip caps are removed and the stoppers are treated with a disinfectant and allowed to dry prior to opening the Mix2Vial package.
Open the carton and remove the Mix2Vial filter transfer set. The Mix2Vial filter transfer set is intended to filter the contents of a single vial of Berinert IV only.
See manufacturer's Product Information for diagrams.
1. Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package.
2. Place the diluent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the diluent vial stopper.
3. Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set.
4. Place the product vial on an even and firm surface. Invert the diluent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The diluent will automatically flow into the product vial.
5. With one hand grasp the product side of the Mix2Vial set and with the other hand grasp the diluents side and unscrew the set carefully counterclockwise into two pieces. Discard the diluent vial with the blue Mix2Vial adapter attached.
6. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake.
7. Draw air into an empty, sterile syringe. Use the syringe provided with the product. While the product vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting by screwing clockwise. Inject air into the product vial.

Withdrawal and application.

8. While keeping the syringe plunger pressed, turn the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly.
9. Now that the concentrate has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe by unscrewing counterclockwise.

Note.

The Mix2Vial is intended to filter the contents of a single vial of Berinert IV only. If multiple vials of Berinert IV are to be administered, a separate Mix2Vial must be used for each vial.
The reconstituted Berinert IV 500 IU solution should be colourless and clear. The reconstituted Berinert IV 1500 IU solution should be colourless and clear to slightly opalescent. After filtering/ withdrawal the reconstituted product should be inspected visually for particulate matter and discoloration prior to administration. Do not use solutions that are cloudy or contain flakes or particles.

Administration.

Caution.

The product does not contain an antimicrobial preservative. The reconstituted product should only be stored in the vial (see Section 6.3 for shelf life of reconstituted product). Any unused solution must be discarded appropriately. Use in one patient on one occasion only.
Berinert IV should not be mixed with other medicinal products and diluents.
It is strongly recommended that every time Berinert IV is administered to a patient, the name and batch number of the product are recorded in the patient notes in order to maintain a link between the patient and the batch of the product.
Berinert IV 500 IU. It is recommended that Berinert IV 500 IU be administered by slow intravenous injection at a rate of 4 mL/minute.
If not administered immediately, it must be stored at 2-8°C and used within 24 hours of reconstitution. Allow solution to reach room temperature before administration.
Berinert IV 1500 IU. It is recommended that Berinert IV 1500 IU be administered as a bolus intravenous injection.
If not administered immediately, it must be stored at 2-8°C and used within 8 hours of reconstitution. Allow solution to reach room temperature before administration.

Self administration and home treatment.

If deemed appropriate by the treating physician, Berinert IV may be self administered by the patient (or carer) following adequate training. This includes its administration in the home or other appropriate setting.
If self administration/home treatment is deemed appropriate, ensure that the patient/ carer receives clear instructions, adequate training on intravenous administration and has demonstrated the ability to perform intravenous infusions.
Ensure the patients/carers understand the importance of not starting treatment if the attack (regardless of type) has progressed to a point that the patients/ carers would be unable to successfully prepare and administer Berinert IV.
Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to immediately call an ambulance or seek urgent hospital treatment in addition to treatment with Berinert IV.
To help exclude the possibility that another potentially serious medical cause may be responsible for their symptoms, advise patients to contact their physician after treating suspected abdominal HAE attacks.
Instruct patients that Berinert IV is made from human blood and therefore it may carry a risk of transmitting infectious agents, e.g. viruses such as HIV, hepatitis B and C (see Section 4.4 Special Warnings and Precautions for Use, Pathogen safety). Inform patients of the risks and benefits of Berinert IV before prescribing or administering it to the patient.
Advise female patients to notify their physician if they become pregnant or intend to become pregnant or if they are breastfeeding or plan to breastfeed during the treatment of HAE attacks with Berinert IV.
The Australian Product Information (PI) and Consumer Medicine Information (CMI) document for Berinert IV are provided as a package insert and contain useful instructions for patients/ carers who will be administering Berinert IV. These documents are also available through https://www.ebs.tga.gov.au/.

4.3 Contraindications

Berinert IV is contraindicated in individuals with a known hypersensitivity to any of the components of the product.

4.4 Special Warnings and Precautions for Use

Antihistamines and corticosteroids should be administered prophylactically in patients with a known tendency towards allergies.
If allergic or anaphylactic-type reactions occur, the administration of Berinert IV should stop immediately (e.g. discontinue injection/ infusion) and an appropriate treatment initiated. Therapeutic measures depend on the kind and severity of the undesirable effect. The current medical standards for shock treatment are to be observed.
Patients with laryngeal oedema require particularly careful monitoring.
Treatment of Capillary Leak Syndrome with Berinert IV is not advised (see Section 4.8 Adverse Effects (Undesirable Effects)).
Berinert IV contains up to 486 mg sodium per 100 mL of solution. This is to be taken into consideration for patients on a controlled sodium diet.

Home treatment and self-administration.

There are limited data on the use of this medicinal product in home treatment or self-administration. Potential risks associated with home treatment are related to the administration itself as well as the handling of adverse drug reactions, particularly hypersensitivity. The decision on the use of home treatment for an individual patient should be made by the treating physician, who should ensure that appropriate training is provided and the use is reviewed at intervals to ensure the continued appropriate administration.
Patients with laryngeal oedema require particularly careful monitoring. Given the potential for airway obstruction during acute laryngeal HAE attacks, patients self-administering Berinert IV should be advised to immediately seek medical attention.
See Section 4.2 Dose and Method of Administration for further precautions regarding administration of Berinert IV.

Pathogen safety.

This product is made from human plasma. Products made from human plasma may contain infectious agents such as viruses that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain infectious agents and by testing for the presence of certain viral markers.
In addition, the Berinert IV manufacturing process includes pasteurisation (at 60°C for 10 hours), hydrophobic interaction chromatography and virus filtration (also called nanofiltration) by two filters, 20 nanometer and 15 nanometer, in series, as dedicated virus inactivation and removal steps to reduce the potential for pathogen transmission.
The current procedures applied in the manufacture of this product are effective against enveloped viruses such as HIV (human immunodeficiency virus), hepatitis B and hepatitis C viruses and for the non-enveloped viruses hepatitis A and parvovirus B19.
Despite these measures, such products may still potentially transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such products.
Vaccination for patients in receipt of medicinal products from human plasma should be considered where appropriate.

Use in the elderly.

Safety and efficacy of Berinert IV in the elderly population has not been established.

Paediatric use.

The safety and efficacy of Berinert IV was not systematically evaluated in children. There were no apparent differences in the safety and efficacy profiles as compared to adult subjects.

Effects on laboratory tests.

C1 esterase inhibitor is an endogenous plasma protein so no specific effects on laboratory tests are anticipated.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The interaction of Berinert IV with other medicines has not been established in appropriate studies.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies examining the effect of Berinert IV on fertility have been conducted.
The safety of Berinert IV for use in human pregnancy has not been established in controlled clinical trials. Experiences on the treatment of women during pregnancy have shown good tolerance and no negative impact on the mother and child during the observation period until directly after birth. Berinert IV should be used during pregnancy only if clearly needed.
Animal reproductive toxicity studies have not been conducted with Berinert IV.
 The safety of Berinert IV for use during lactation has not been established in controlled clinical trials. Berinert IV should be used during lactation only if clearly indicated.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Undesired reactions with Berinert IV are rare (frequency of rare defined as ≥ 1/10,000 to < 1/1,000).

Clinical studies experience.

The following safety data were obtained from clinical trials conducted using the Berinert IV 500 IU presentation (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Berinert IV 500 IU and 1500 IU had favourable and comparable safety and tolerability profiles when administered intravenously in a phase I study in healthy volunteers.

Pivotal study.

The most common adverse events (AEs) reported in subjects up to 4 hours after receiving 20 IU/kg body weight Berinert IV in the pivotal phase III study were nausea, dysgeusia, abdominal pain and vomiting.

Open-label extension study.

The most common AEs reported in subjects within 24 hours after receiving 20 IU/kg body weight Berinert IV in the open-label extension study were headache and rash.
The incidence and type of adverse reactions with Berinert IV when administered for treatment of HAE attacks was consistent across studies.
The most common AEs reported in subjects up to 9 days after infusion with 20 IU/kg body weight Berinert IV in the clinical studies were headache, HAE, abdominal pain, nausea, muscle spasms, pain, diarrhoea and vomiting. Of these, an increase in the severity of pain associated with HAE was considered the most serious.
Table 2 provides a summary of AEs in > 1 subject overall by preferred term and system organ class.
Table 3 provides a summary of AEs in > 1 subject overall by preferred term and system organ class (after 4-hour safety populations).

Post-marketing surveillance.

Post-market reporting of adverse reactions is voluntary and from a population of uncertain size and consequently it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
Adverse reactions reported in patients receiving Berinert IV for treatment of HAE include allergic/anaphylactic reactions, injection site pain, injection site redness, chills and fever.
In treatment attempts with high doses (> 90 IU/kg body weight) of Berinert IV for prophylaxis or therapy of Capillary Leak Syndrome before, during or after cardiac surgery under extracorporeal circulation (unlicensed indication and dose) the development of thrombosis was reported, including cases with fatal outcome.

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

4.9 Overdose

No case of overdose has been reported in connection with treatment of HAE.
The development of thrombosis has been reported after high doses (greater than 90 IU/kg body weight) of Berinert IV in newborns and young children with congenital heart anomalies during or after cardiac surgery under extracorporeal circulation.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

C1 esterase inhibitor belongs to the group of serine protease inhibitors that includes antithrombin III, alpha1-protease inhibitor, alpha2-antiplasmin and heparin cofactor II. It is a major inhibitor of the activated serine proteinases C1r and C1s, kallikrein and coagulation factors XIIa and XIa.
C1 esterase inhibitor has an important inhibiting potential on several of the major cascade systems of the human body including the complement system, the contact system, the fibrinolytic system and the coagulation cascade. A major function of C1 esterase inhibitor is the inhibition of the complement system to prevent spontaneous activation.
Berinert has been shown to inhibit the classical complement activity in both human (IC50 = 1.05 IU/mL) and rat (IC50 = 1.01 IU/mL) plasma in vitro. In animal disease models, it has been shown to block oedema formation, capillary leakage, sepsis and stroke where the complement and kallikrein/ kinin systems are also implicated.
Administration of Berinert IV to patients with C1 esterase inhibitor deficiency replaces the missing or malfunctioning protein in patients to relieve symptoms of hereditary angioedema (HAE). The product is to be administered intravenously and is immediately available in the plasma with a plasma concentration corresponding to the administered dose.

Clinical trials.

The following clinical trial data were obtained from clinical trials conducted using the Berinert IV 500 IU presentation. Bioequivalence of the 500 IU and 1500 IU presentations has been established in a separate clinical trial in healthy volunteers (see Section 5.2 Pharmacokinetic Properties).
A pivotal Phase III prospective, multinational, randomised, parallel-group, placebo-controlled, dose-finding, three-arm, double-blind clinical study assessed the efficacy and safety of Berinert IV in 124 adult and paediatric subjects with C1 esterase inhibitor deficiency who were experiencing an acute moderate to severe attack of abdominal or facial HAE. Subjects ranged in age from 6 to 72 years of age.
The study objectives were to show that Berinert IV shortens the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo and to compare the efficacy of two different doses of Berinert IV.
Subjects were randomised to either receive a 10 IU/kg body weight dose of Berinert IV (39 subjects), a 20 IU/kg dose of Berinert IV (43 subjects), or a dose of placebo (42 subjects) by slow intravenous infusion (4 mL per minute) within 5 hours of an attack.
Subjects treated with a 20 IU/kg dose of Berinert IV experienced a highly significant reduction (p = 0.0025) in the median time to onset of relief from symptoms of an HAE attack (30 minutes) as compared to placebo (90 minutes).
The median time to complete resolution of HAE symptoms was significantly shorter (p = 0.0237) in the Berinert IV 20 IU/kg group (4.9 hours) than in the placebo group (7.8 hours).
The study demonstrated that a 20 IU/kg body weight dose of Berinert IV was significantly more efficacious than a 10 IU/kg body weight dose of Berinert IV or placebo. Additionally, the 10 IU/kg body weight dose of Berinert IV did not show a clinically significant difference compared to placebo.
Berinert IV was further evaluated in a prospective, open-label, uncontrolled, multicentre extension study conducted at 15 centres in the US and Canada in subjects who had participated in the pivotal phase III study for the treatment of acute abdominal or facial attacks in subjects with HAE.
The purpose of this extension study was to provide Berinert IV to subjects who had participated in the pivotal study and who experienced any type of subsequent HAE attack (i.e. abdominal, facial, peripheral, or laryngeal).
The safety analysis of the open-label extension study included a total of 57 subjects (19 males and 38 females, age range: 10 to 53 years) with 1085 HAE attacks treated with 20 IU/kg body weight dose of Berinert IV per attack, who were observed at the study site until onset of relief of HAE symptoms, and were followed up for adverse reactions for 7 to 9 days following treatment of each HAE attack.
During the extension study, 51 subjects experienced 747 abdominal attacks, 21 subjects experienced 51 facial attacks, 30 subjects experienced 235 peripheral attacks, and 16 subjects experienced 48 laryngeal attacks. Some study subjects may have experienced HAE attacks in more than one location.
An analysis of laryngeal HAE attacks showed that the median time to initial onset of symptom relief and median time to complete resolution in the per-attack analysis were 0.25 hours and 8.4 hours, respectively (see Table 4), which were the shortest times among the various attack locations.
There were no clinically relevant or consistent data suggesting that gender, age group, race/ethnic group, type of HAE, routine use of androgens, or presence of detectable anti-C1 esterase inhibitor antibodies had an effect on the time to initial or complete relief of symptoms following Berinert IV.
The prospective open-label extension study demonstrated that, in comparison to untreated historical control data retrospectively collected at a study centre in Germany over a 20 year period, the Berinert IV 20 IU/kg body weight dose appeared to be effective in ameliorating laryngeal HAE attacks by achieving complete resolution of HAE symptoms within 24 hours from attack onset in the majority of subjects. The treatment effects observed with Berinert IV in the extension study are consistent with the findings from the placebo-controlled efficacy trial.
Adverse reactions encountered during the clinical trials are outlined, see Section 4.8 Adverse Effects (Undesirable Effects).

5.2 Pharmacokinetic Properties

Pharmacokinetic properties of Berinert IV have been investigated in two studies.
In the first study, the pharmacokinetics (PK) of Berinert IV were evaluated in an open-label, uncontrolled, single-centre study in 40 subjects (6 patients < 18 years) with either mild or severe HAE. The 25 subjects with mild HAE were treated on demand for an acute attack; the 15 subjects with severe HAE were treated on a prophylactic basis. All subjects received a single intravenous injection of Berinert IV ranging from 500 IU to 1500 IU.
The median in vivo recovery (IVR) was 86.7%. The IVR for children was slightly higher (98.2%) than for adults (82.5%). Patients with severe attacks had a higher IVR (101.4%) compared to patients with mild attacks (75.8%).
The median increase in C1 esterase inhibitor activity was 2.3%/IU/kg body weight. No significant differences were seen between adults and children. Patients with severe attacks showed a slightly higher increase in activity than patients with mild attacks (2.9 vs. 2.1%/IU/kg body weight).
The maximum concentration of C1 esterase inhibitor activity in plasma was reached within 0.8 hours after administration of Berinert IV without significant differences between the patient groups.
The median half-life was 36.1 hours. It was slightly shorter in children than in adults (32.9 vs. 36.1 hours) and in patients with severe attacks than in patients with mild attacks (30.9 vs. 37.0).
The second study, a phase 1 study conducted in 15 healthy adult subjects, provided PK data that was used to assess the relative bioavailability of the Berinert IV 1500 IU presentation and 500 IU presentation. Comparable bioavailability of the two presentations of Berinert IV was demonstrated. For C1 esterase inhibitor antigen concentrations, the maximum observed plasma concentration (Cmax) and area under the curve to the last quantifiable concentration (AUC0-last) geometric mean ratios (90% confidence intervals (CIs)) were 1.02 (0.99, 1.04) and 1.02 (0.99, 1.05) respectively. Half-life was estimated in a subset of subjects using non-compartmental PK analyses. The mean half-life of the 1500 IU presentation and 500 IU presentation was 87.7 hours and 91.4 hours respectively.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with Berinert IV.

Carcinogenicity.

No carcinogenicity studies have been conducted with Berinert IV.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glycine, sodium citrate, sodium chloride.

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products and diluents in the syringe/infusion set.

6.3 Shelf Life

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

Reconstituted product.

Berinert IV contains no antimicrobial preservative.
If Berinert IV 500 IU is not administered immediately, it must be stored at 2-8°C and used within 24 hours of reconstitution.
If Berinert IV 1500 IU is not administered immediately, it must be stored at 2-8°C and used within 8 hours of reconstitution.
The reconstituted product should only be stored in the vial.

6.4 Special Precautions for Storage

Store below 25°C. Do not freeze. Protect from light. Do not use after the expiry date.

6.5 Nature and Contents of Container

Each presentation includes Berinert IV powder for injection and water for injections in glass vials with latex-free rubber stoppers closed with an aluminium seal and a plastic flip-off cap.
Berinert IV 500 IU and Berinert IV 1500 IU presentations are supplied as:
1 vial with powder;
1 vial with water for injections (500 IU: 10 mL, 1500 IU: 3 mL);
1 Mix2Vial filter transfer set 20/20;
one administration pack containing: 1 disposable syringe (500 IU: 10 mL, 1500 IU: 5 mL), 1 infusion set, 2 alcohol swabs.
Not all presentations may be supplied.

6.6 Special Precautions for Disposal

In Australia, any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

C1 esterase inhibitor is a soluble single-chain glycoprotein containing 478 amino acid residues organised into three beta-sheets and eight or nine alpha-helices. The heavily glycosylated molecule has an apparent molecular weight of 105 kD, of which the carbohydrate chains comprise 26%-35%.

CAS number.

80295-38-1.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes