Consumer medicine information

Berinert SC

C1 esterase inhibitor, human

BRAND INFORMATION

Brand name

Berinert SC

Active ingredient

C1 esterase inhibitor, human

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about Berinert® SC.

It does not contain all the available information. If you require further information about this medicine or your treatment generally, or if you have any questions or are not sure about something in this leaflet, consult your doctor.

All medicines have benefits and risks. Your doctor has weighed the benefits that Berinert® SC will have for you against the risks.

If you have any concerns about taking this medicine, ask your doctor. Follow your doctor’s advice even if it is different from what this leaflet says.

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

The information in this leaflet is subject to change.

Please check with your doctor whether there is any new information about this medicine that you should know since you were last treated.

What Berinert® SC is used for

Berinert® SC is administered subcutaneously (under the skin).

When given subcutaneously on a regular basis, Berinert® SC should prevent or reduce the number of hereditary angioedema attacks in patients aged 8 years and older.

Hereditary angioedema (HAE) (oedema = swelling) is a congenital disease of the vascular system. It is a non-allergic disease. HAE is caused by deficiency, absence or defective production of C1 esterase inhibitor, an important protein. The illness 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, possibly laryngeal (voice-box) swelling with difficulty in breathing
  • tongue swelling
  • colic pain in abdominal region.

Generally all parts of the body can be affected.

If you should experience an HAE attack, follow the instructions your doctor has given you.

Ask your doctor if you have any questions about why Berinert® SC has been prescribed for you.

How Berinert® SC works

This product is made from human plasma (this is the liquid part of the blood). It contains the human protein C1 esterase inhibitor as the active ingredient. Berinert® SC prevents an HAE attack by replacing the missing or malfunctioning C1 esterase inhibitor protein your body needs.

Before you are given Berinert® SC

When you must not have it

Do not have Berinert® SC:

  • if you have experienced life-threatening allergic reactions to the protein C1 esterase inhibitor or any of the other ingredients of this medicine listed at the end of this leaflet.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you are pregnant or breast-feeding. This medicine should only be used if clearly needed during pregnancy or breast-feeding.

Tell your doctor if you are on a controlled sodium diet. This medicine contains sodium which should be taken into consideration.

Tell your doctor if you are allergic to any medicine or food. If you have allergies you may be treated with antihistamines and corticosteroids as a preventative measure.

Tell your doctor if you have a history of blood clotting problems. There is no established link with blood clots at the dose your doctor is recommended to prescribe. However, it is advisable to tell your doctor if you have a pre-existing blood clotting condition or have history of heart or blood related conditions as these may increase your risk of having a blood clot after using Berinert® SC. Also tell your doctor what drugs you are using, as some drugs may increase your risk of developing a blood clot.

If you have not told your doctor about any of the above, tell them before you are given Berinert® SC.

Your doctor can discuss with you the risks and benefits involved with using this medicine.

About blood products

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 yet 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.

Please discuss the risks and benefits of this medicine with your doctor.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may affect the way other medicines work.

How to use Berinert® SC

Berinert® SC is used for subcutaneous injection.

Treatment should be started and supervised by a doctor. Your doctor will ensure you receive detailed instructions and training on how to administer Berinert® SC at home or in other appropriate settings.

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 is given

The recommended dosage is 60 IU per kilogram of body weight subcutaneously twice weekly (every 3–4 days).

Your doctor will prescribe the dose that you should administer, which is based on your body weight.

When it is given

Your doctor will discuss with you when you should be given Berinert® SC.

How to prepare it

Once you have received training on how to prepare and administer Berinert® SC, the instructions below should be followed carefully.

  1. Allow the vial of Berinert® SC 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® SC undisturbed.
  4. Using a clean cloth or paper towel, clean the preparation area with methylated spirits.
  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® SC only. If multiple vials of Berinert® SC 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 alcohol swabs and allow to dry for two minutes. Do not leave alcohol swabs resting on the stoppers. Do not touch the rubber stoppers with your fingers.
  8. Open the Mix2Vial™ package by peeling away the lid.

  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.

Berinert® SC 2000 IU is reconstituted (mixed) with 4 mL of diluent.
Berinert® SC 3000 IU is reconstituted with 5.6 mL of diluent.
  1. With one hand hold the product side of the Mix2Vial™ set, hold the diluent side with the other hand and unscrew the set into two pieces. Discard the diluent vial with the blue part attached.

  1. Gently swirl the product vial until the substance is fully dissolved. (Generally within 5 minutes, but may take as long as 10 minutes). Do not shake as this could damage the product. The solution should be clear or 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 it is not injected immediately, it must be stored at room temperature (below 30°C) and used within 6 hours.
The reconstituted product should only be stored in the vial.
  1. Draw air into an empty, sterile, syringe. Use the syringe provided with the product or a silicone-free syringe. While the product vial is upright, connect the syringe to the Mix2Vial™’s Luer Lock fitting. 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.
Attach the syringe to a needle or suitable subcutaneous injection set.

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® SC vial.

How to inject Berinert® SC

Your doctor or nurse will instruct you on how to inject Berinert® SC. You should always follow the specific instructions given by your doctor or nurse, even if they are different to what is in this leaflet.

The steps listed below are provided as a guide on how to inject Berinert® SC. If you are unsure of the steps, please contact your doctor before using.

  1. Assemble supplies
Gather the Berinert® SC syringe, the following disposable supplies and other items (sharps or other container, treatment diary or log book):
  • Hypodermic needle or subcutaneous injection set
  • sterile syringe
  • gloves (if recommended by your healthcare provider)
  • alcohol wipes
  1. Wash hands
  • Thoroughly wash and dry your hands
  • If you have been told to wear gloves when preparing your injection, put the gloves on.
  1. Clean surface
  • Thoroughly clean a table or other flat surface using one or more of the alcohol wipes.
  1. Prepare injection site
  • Select an area on your abdominal region (stomach) for the injection (unless your doctor has told you to use another area).

  • Do not inject yourself in areas where the skin is itchy, swollen, painful, bruised or red.
  • Avoid injecting yourself in areas where you have scars or stretch marks.
  • Clean the skin at the injection site with an alcohol swab and let the skin dry.

  1. Injection in the abdominal area
  • As instructed by your doctor, attach a needle or subcutaneous injection set and prime the needle or tubing as required and instructed.
  • If using a needle: pinch the skin around the injection site. Insert the needle into the fold of skin and inject the entire amount of the Berinert® SC solution as instructed by your doctor.

  • If using a subcutaneous injection set: pinch the skin around the injection site. Insert the needle into the fold of skin and inject the entire amount of the Berinert® SC solution as instructed by your doctor.

  1. Clean up
  • After injecting the entire amount of Berinert® SC, remove the needle as instructed by your doctor.
  • 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® SC vial label are recorded every time you use Berinert® SC.

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

If too much is given (overdose)

No symptoms of overdose with Berinert® SC are known.

If you have any questions consult your doctor.

While you are having Berinert® SC

Things you must do

If you notice signs or symptoms of a serious allergy or anaphylaxis (see Side effects) while you are being given Berinert® SC, tell your doctor immediately as the administration of Berinert® SC should be stopped immediately.

Things you must not do

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

Use this medicine in one patient on one occasion only.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are being given Berinert® SC.

This medicine helps most people with HAE but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor immediately if you notice any of the following symptoms which may be signs of a serious allergy or anaphylaxis as the injection of Berinert® SC should be stopped:

  • irregular or faster heart beat
  • feeling faint (fall in blood pressure)
  • reddening of the skin
  • rash
  • difficulty in breathing
  • dizziness
  • feeling sick.

Tell your doctor about any side effect that bothers you or does not go away.

The list below includes the more common side effects of Berinert® SC.

  • injection site reactions (such as pain, redness, itching, bruising or swelling where the injection was given)
  • cold-like symptoms (such as runny or stuffy nose, watery eyes, sneezing)
  • itching, rash
  • dizziness.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Do not be alarmed by this list of possible side effects.

Storing Berinert® SC

Keep in a cool dry place where the temperature stays below 30°C. Do not freeze.

Keep the product in the carton in order to protect it from light.

Do not use after the expiry date.

Keep it out of the sight and reach of children.

Disposal

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

Product description

What it looks like

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

How it is supplied

The 2000 IU vial of Berinert® SC comes in a pack containing:

  • a vial of diluent (4 mL of Water for Injections) used to dissolve the powder
  • a Mix2vial™ filter transfer set
  • an administration pack with:
    - a disposable 5 mL syringe
    - a hypodermic needle
    - a subcutaneous injection set
    - 2 alcohol swabs
    - a plaster (adhesive bandage).

The 3000 IU vial of Berinert® SC comes in a pack containing:

  • a vial of diluent (5.6 mL of Water for Injections) used to dissolve the powder
  • a Mix2vial™ filter transfer set
  • an administration pack with:
    - a disposable 10 mL syringe
    - a hypodermic needle
    - a subcutaneous injection set
    - 2 alcohol swabs
    - a plaster (adhesive bandage).

Ingredients

Berinert® SC contains human C1 esterase inhibitor as the active ingredient.

It also contains:

  • glycine
  • sodium citrate
  • sodium chloride.

Distributor

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

Manufacturer

Berinert® SC is manufactured by CSL Behring GmbH, Germany

Date of revision

September 2021

Australian Register Numbers

2000 IU: AUST R 292319

3000 IU: AUST R 292322

® Registered trademark of CSL Limited Group of Companies

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

Published by MIMS October 2021

BRAND INFORMATION

Brand name

Berinert SC

Active ingredient

C1 esterase inhibitor, human

Schedule

Unscheduled

 

1 Name of Medicine

Human C1 esterase inhibitor.

2 Qualitative and Quantitative Composition

Berinert SC is a highly purified, freeze dried C1 esterase inhibitor concentrate derived from human plasma.
Berinert SC is available in two presentations which contain 500 IU/mL of C1 esterase inhibitor when reconstituted as directed (see Table 1).
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 SC 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 SC is produced as a sterile, pyrogen-free, freeze-dried white powder for subcutaneous injection and supplied with Water for Injections (clear, colourless) for reconstitution.

4 Clinical Particulars

4.1 Therapeutic Indications

Berinert SC for subcutaneous injection is indicated for prevention of recurrent Hereditary Angioedema (HAE) attacks in patients aged 8 years and older with C1 esterase inhibitor deficiency.

4.2 Dose and Method of Administration

It is recommended that prescribed doses of Berinert SC should be expressed as International Units written in full.
Berinert SC is intended for self-administration by subcutaneous injection. The patient or carer should be trained on how to administer Berinert SC. See Self administration and home treatment section under Administration.

Dosage.

The recommended dose is 60 IU per kg body weight twice weekly (every 3-4 days).

Reconstitution.

Reconstitution and withdrawal must be carried out under aseptic conditions. Reconstitution is achieved generally within 5 minutes, but may take as long as 10 minutes. Use the syringe provided with the product or a silicone-free syringe. Bring the product and diluent (Water for Injections (WFI)) vials 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 SC only.
1. Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package!
2. Place the diluent (WFI) 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 Berinert SC 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 diluent-side and unscrew the set carefully 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. (Generally within 5 minutes, but may take as long as 10 minutes). Do not shake.
7. Draw air into an empty, sterile syringe. Use the syringe provided with the product or a silicone-free syringe. While the product vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting. 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.

Note.

The Mix2Vial is intended to filter the contents of a single vial of Berinert SC only. If multiple vials of Berinert SC are to be administered, a separate Mix2Vial must be used for each vial.
The 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.

The reconstituted preparation should be administered by subcutaneous injection at a rate tolerated by the patient.
The suggested site for injection is the abdomen.
In clinical trials the injection was administered into a single site.
Berinert SC should not be mixed with other medicinal products and diluents.
It is strongly recommended that every time Berinert SC 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.

Caution.

The product does not contain an antimicrobial preservative. If it is not administered immediately, it must be stored at room temperature (below 30°C) and used within 6 hours of reconstitution. The reconstituted product should only be stored in the vial. Any unused solution must be discarded appropriately. Use in one patient on one occasion only.

Self administration and home treatment.

Berinert SC may be self-administered by the patient (or carer); this includes its administration in the home or other appropriate setting. Potential risks associated with home treatment are related to the administration itself as well as the handling of adverse drug reactions.
Ensure that the patient/ carer receives clear instructions, adequate administration training and has demonstrated the ability to perform subcutaneous injections. This should be reviewed at intervals to ensure the continued appropriate administration.
Patients/ carers should be counselled regarding the appropriate course of action in case of an acute HAE attack, as individualised treatment should be initiated. See Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

Individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations or to any of the excipients listed, see Section 6.1.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

If severe allergic or anaphylactic-type reactions occur, the administration of Berinert SC should stop immediately (e.g. discontinue injection) and an appropriate treatment initiated.
In the event of an acute HAE attack, individualised treatment should be initiated.

Thromboembolic events.

At the recommended subcutaneous dose, no causal relationship between thromboembolic events and the use of C1 esterase inhibitor concentrate has been established.
Thrombosis has occurred in treatment attempts with high doses of C1 esterase inhibitor intravenously for prophylaxis and during therapy of capillary leak syndrome before, during or after cardiac surgery under extracorporeal circulation (off-label indication and dose).

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 SC manufacturing process includes pasteurisation (at 60°C for 10 hours), hydrophobic interaction chromatography and virus filtration (also called nanofiltration) by two filters, 20 nanometre and 15 nanometre, 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.

Seven patients 65 to 72 years of age were included in a multicentre, randomised, double blind, placebo controlled, cross-over clinical trial (COMPACT study). Ten patients 65 to 72 years of age were included in the COMPACT extension study (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Results of subgroup analysis by age were consistent with overall study results.

Paediatric use.

Six paediatric patients (12 to < 17 years) were included in a multicentre, randomised, double blind, placebo controlled, cross-over clinical trial (COMPACT study). Ten paediatric patients (8 to < 17 years) were included in the COMPACT extension study, of which 3 patients were under 12 years of age (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Results of subgroup analysis by age were consistent with overall study results.

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 SC with other medicines has not been established in appropriate studies.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

C1 esterase inhibitor is a physiological component of human plasma. No studies on fertility have been performed with Berinert SC in animals.
Berinert SC should be used during pregnancy only if clearly indicated.
In the open-label COMPACT extension study, 4 pregnant women with type 1 HAE and ranging in age from 19 to 32 years received Berinert SC. Patients received 40-60 IU/kg per subcutaneous administration for 4-8 weeks (9-15 doses) during the first trimester. All four women delivered healthy babies.
In an observational registry (318 subjects) data were collected on 11 pregnancies in 10 subjects (16 to 40 years of age) receiving up to 3000 IU of Berinert intravenously to treat or prevent HAE attacks. No adverse events were associated with Berinert treatment.
In a retrospective case collection study, 22 pregnant women with type I HAE and ranging in age from 20 to 38 years received C1 esterase inhibitor doses of 500 or 1000 IU per intravenous administration for the treatment of acute attacks before, during, and/or after pregnancy (total of 35 pregnancies). No adverse events were associated with C1 esterase inhibitor treatment before, during, or after pregnancy.
Animal reproductive and development toxicity studies have not been conducted with Berinert SC.
 Berinert SC should be given to a nursing mother only if clearly needed. There is no information regarding the excretion of Berinert SC in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Berinert SC and any potential adverse effects on the breastfed infant from Berinert SC.
In a retrospective case collection study, breastfeeding was documented for neonates from 21 of 35 births with a median duration of 4.8 months (ranging from 1 to 34 months). Mothers were treated postpartum with C1 esterase inhibitor doses up to 1000 IU per intravenous administration for the treatment of acute HAE attacks. No adverse events to the mothers were associated with C1 esterase inhibitor treatment after pregnancy. No information regarding the effect on the breastfed infant was reported.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Clinical studies experience.

Of the 90 subjects randomised in the COMPACT study, 86 subjects received at least 1 dose of Berinert SC and 86 subjects received at least 1 dose of placebo (Table 2). A total of 5081 injections of Berinert SC and placebo were administered over a range of 3 to 19 weeks (median of 16.6 weeks for Berinert SC; median of 16.3 weeks for placebo).
Of the injection site reactions occurring after treatment with Berinert SC subcutaneously, 95.0% were of mild intensity and 82.5% resolved within 1 day of onset.
Table 3 presents the frequencies of adverse reactions on a per-patient basis for Berinert SC administered subcutaneously according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) or unknown (cannot be estimated from the available data).
Overall, safety data from the open-label COMPACT extension study, consisting of 64 rollover patients and 62 non-rollover patients, was consistent with the safety data from the randomised, double-blind, placebo-controlled, crossover routine prophylaxis trial (COMPACT study).

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. Doses up to 117 IU/kg have been administered subcutaneously twice weekly in a fixed-dose clinical study and were well tolerated.
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 is a plasma glycoprotein which belongs to the group of serine protease inhibitors that includes antithrombin III, alpha1 protease inhibitor, alpha2 antiplasmin and heparin cofactor II. Its concentration in human plasma is approximately 240 mg/L. 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 SC to patients with C1 esterase inhibitor deficiency (hereditary angioedema; HAE) replaces the missing or malfunctioning protein.

Pharmacodynamics.

In untreated patients, insufficient levels of functional C1 esterase inhibitor lead to increased activation of C1, which results in decreased levels of complement component 4 (C4). The administration of Berinert increases plasma levels of C1 esterase inhibitor in a dose-dependent manner and subsequently increases plasma concentrations of C4. The C4 plasma concentrations after subcutaneous administration of 60 IU/kg of Berinert SC were in the normal range (160 to 380 mg/L).

Clinical trials.

The efficacy, safety, pharmacokinetics and quality of life (QoL) of Berinert SC as a prophylaxis regime to prevent HAE attacks has been demonstrated in two phase III clinical trials.

COMPACT study.

The first trial was a multicentre, randomised, double blind, placebo controlled, crossover study (COMPACT study). The study assessed 90 adult and adolescent subjects with symptomatic HAE type I or II. The median (range) age of subjects was 40 (12 to 72) years; 60 subjects were female and 30 subjects were male. Subjects were randomised to receive either 60 IU/kg or 40 IU/kg Berinert SC in one 16 week treatment period and placebo in the other 16 week treatment period. Patients subcutaneously self-administered Berinert SC or placebo 2 times per week. Efficacy was evaluated for the last 14 weeks of each treatment period. Eligible patients were also able to participate in an open-label extension study for up to 140 weeks. Approximately half of the subjects enrolled in the extension study participated in the COMPACT study (64/126, 50.8%), which contributed to the similarities between study populations.
Twice per week subcutaneous doses of 60 IU/kg or 40 IU/kg resulted in a significant difference in the time-normalised number of HAE attacks (the rate of attacks) relative to placebo (Table 4). The time-normalised number of HAE attacks in subjects dosed with 60 IU/kg was 0.52 attacks per month compared with 4.03 attacks per month while receiving placebo (p < 0.001). The time-normalised number of HAE attacks in subjects dosed with 40 IU/kg was 1.19 attacks per month compared with 3.61 attacks per month while receiving placebo (p < 0.001).
The median (25th, 75th percentile) percentage reduction in the time-normalised number of HAE attacks relative to placebo was 95.1% (79.0, 100.0) on 60 IU/kg and 88.6% (69.6, 100.0) on 40 IU/kg among subjects with evaluable data in both treatment periods.
The percentage of responders (95% CI) with a ≥ 50%, ≥ 70% and ≥ 90% reduction in the time-normalised number of HAE attacks was higher on Berinert SC relative to placebo (see Table 5).
The proportion of subjects that had ≥ 1 HAE attack per 4 week period on placebo and < 1 HAE attack per 4 week period on Berinert SC was 71.1% on 60 IU/kg and 53.3% on 40 IU/kg.
A total of 40.0% of subjects on 60 IU/kg and 37.8% of subjects on 40 IU/kg were attack-free, and the median rate of HAE attacks per month was 0.29 on both doses. The maximum rate of HAE attacks per month was 3.1 on 60 IU/kg and 12.5 on 40 IU/kg.
Berinert SC resulted in a significant difference in the time-normalised number of uses of rescue medication (the rate of rescue medication use) relative to placebo. The 60 IU/kg dose resulted in a mean rate of rescue medication use of 0.32 uses per month compared with 3.89 uses per month with placebo. The 40 IU/kg dose resulted in a mean rate of rescue medication use of 1.13 uses per month compared with 5.55 uses per month with placebo.
Results of subgroup analysis by age (12 to < 17, 17 to < 65, and ≥ 65 years) were consistent with overall study results.
Post-hoc analysis of exploratory endpoints demonstrated QoL and treatment satisfaction improved with Berinert SC treatment compared with placebo treatment, with significant improvements from baseline observed for the treatment satisfaction questionnaire for medication (TSQM); domain - Effectiveness and Overall satisfaction and for the work productivity and activity impairment (WPAI) questionnaire; domain - Presenteeism, Productivity Loss and Impairment.
The results of subject reported outcome measures provide evidence that routine prophylaxis with subcutaneous Berinert SC was effective, enabled subjects with HAE to be more active and productive, and increased overall satisfaction with treatment. Thus, Berinert SC may importantly reduce the burden of HAE as identified in a published patient survey.

COMPACT extension study.

The second phase III clinical trial (COMPACT extension study) was a multicentre, randomised, open-label parallel study, which provides long-term efficacy and safety data (and allowed continued treatment to subjects who had completed the COMPACT study). The COMPACT extension study included subjects with age range 8-72 years and included 10 subjects < 18 years of age (3 were < 12 years) and 10 subjects ≥ 65 years. The study assessed 126 subjects with symptomatic HAE type I or II for efficacy, safety, PK and QoL. Seventy six subjects were female and 50 subjects were male; the median (range) age of subjects was 41.0 (8-72) years. Subjects were randomised to receive either 60 IU/kg or 40 IU/kg Berinert SC subcutaneously over a 24 week fixed dose treatment period, followed by individualised dose adjustment over a 28 week treatment period. Subjects who experienced frequent HAE attacks during the fixed dose period were eligible for dose increases.
Patients that were enrolled into the study had a mean monthly attack rate of 4.3 in the 3 months prior to entry and were treated for a mean of 1.5 years. A total of 44 subjects (34.9%) had more than 2 years of exposure. The mean steady-state C1 esterase inhibitor functional increased from 30.4% baseline to 52.0% for the 40 IU/kg treatment group and 28.3% baseline to 66.6% for the 60 IU/kg treatment group.
The incidence of adverse events was low and similar in both dose groups. Event rates of 11.3 and 8.5 adverse events per patient-year were reported during treatment with 40 IU/kg and 60 IU/kg Berinert SC respectively. The majority of adverse events reported were mild in severity and were resolved within 24 hours of appearance.
The median rate of HAE attacks was 1.3 and 1.0 attacks per year in the 40 IU/kg and 60 IU/kg treatment groups respectively. The median number of use of rescue medication was 0.2 and 0.0 times per year in the 40 IU/kg and 60 IU/kg treatment groups respectively.
The proportion of subjects that were HAE attack-free throughout the study duration with a maximum exposure of > 2.5 years was 34.9% and 44.4% in the 40 IU/kg and 60 IU/kg treatment groups respectively. In a post-hoc analysis of the 21 subjects receiving 40 IU/kg > 2 years, 16 (76.2%) were HAE attack-free during months 25 to 30 of treatment. Of the 23 subjects receiving 60 IU/kg > 2 years, 19 (82.6%) were HAE attack-free during months 25 to 30 of treatment.
Results of subgroup analysis by age (≤ 17 years and > 17 years; < 65 years and ≥ 65 years) were consistent with overall study results.
The COMPACT extension study confirms results of the placebo controlled COMPACT study and demonstrates the long term safety and efficacy of Berinert SC replacement therapy for routine prophylaxis to prevent HAE attacks, therefore reducing the need for rescue medication.
Adverse reactions encountered during the clinical trials are outlined, see Section 4.8 Adverse Effects (Undesirable Effects).

5.2 Pharmacokinetic Properties

The pharmacokinetic (PK) characteristics of Berinert SC when administered subcutaneously were derived using population PK methods on pooled data from three clinical studies (study 1001; phase I healthy subject PK and safety study; COMPACT phase I/II patient PK and safety study; and the COMPACT phase III study) in healthy subjects and HAE patients. After inclusion of the COMPACT extension study, the population PK parameters derived using the previously developed PK model remain unchanged and the C1 esterase inhibitor functional activity was similar across all studies following Berinert SC administration for both 40 IU/kg and 60 IU/kg dose.
Studies have not been conducted to evaluate the PK of C1 esterase inhibitor in specific patient populations stratified by gender, race, or the presence of renal or hepatic impairment. The population analysis, evaluating age (8 to 72 years), was found not to influence the PK of C1 esterase inhibitor.

Absorption.

Following twice weekly subcutaneous dosing, Berinert SC is slowly absorbed, with a median (95% confidence interval; CI) time to peak concentration of approximately 59 hours (23, 134). Based on a median (95% CI) apparent plasma half-life of 69 hours (24, 250), steady state for C1 esterase inhibitor is expected within 3 weeks of dosing. A mean (95% CI) steady state trough functional C1 esterase inhibitor of 48% (25.1, 102) is expected after twice weekly subcutaneous administration of 60 IU/kg Berinert SC. The mean (95% CI) relative bioavailability of Berinert SC after subcutaneous administration was estimated to be approximately 43% (35.2, 50.2).

Distribution.

The population mean (95% CI) apparent volume of distribution of Berinert SC was estimated to be approximately 4.33 L (3.51, 5.15).

Excretion.

The population mean (95% CI) clearance of Berinert SC was estimated to be 83 mL/hr (72.7, 94.2). C1 esterase inhibitor clearance was found to be positively correlated with total body weight. The steady state PK of Berinert SC was found to be independent of dose between 20-80 IU/kg in HAE subjects.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with Berinert SC.

Carcinogenicity.

No carcinogenicity studies have been conducted with Berinert SC.

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.

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 carton packaging.

Reconstituted product.

The product does not contain an antimicrobial preservative. If it is not administered immediately, it must be stored at room temperature (below 30°C) and used within 6 hours of reconstitution. The reconstituted product should only be stored in the vial.

6.4 Special Precautions for Storage

Store below 30°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 SC powder for injection and Water for Injections in glass vials with latex-free rubber closures closed with an aluminium seal and a plastic flip-top cap.
Berinert SC 2000 IU and 3000 IU presentations are supplied as:
1 vial with powder;
1 vial with Water for Injections (2000 IU: 4 mL, 3000 IU: 5.6 mL);
1 Mix2Vial filter transfer set 20/20;
One administration pack containing: 1 disposable syringe (2000 IU: 5 mL, 3000 IU: 10 mL), 1 hypodermic needle, 1 subcutaneous injection set, 2 alcohol swabs, 1 non-sterile plaster (adhesive bandage).

6.6 Special Precautions for Disposal

In Australia, any unused medicine 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 26-30%.

CAS number.

80295-38-1.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes