Berinert^®

500 IU

Powder and solvent for solution for injection / infusion.

Active substance: C1-esterase inhibitor, human

Berinert contains 500 IU C1-esterase inhibitor per injection vial.

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.

The product contains 50 IU/ml C1-esterase inhibitor after reconstitution with 10 ml water for injections.

The total protein content of the reconstituted solution is 6.5 mg/ml.

Excipients recognized to have a known effect:

Sodium up to 486 mg (approximately 21 mmol) per 100 ml solution.

For a full list of excipients, see section 6.1.

Powder (white lyophilisate) and solvent for solution for injection / infusion.

Hereditary angioedema type I and II (HAE)

Treatment of acute episodes

Treatment should be initiated under the supervision of a physician experienced in the treatment of C1-esterase inhibitor deficiency.

Posology

20 IU per kilogram body weight (20 U/kg b.w.)

Dosage for neonates, infants and children

The dose for children is 20 IU per kilogram body weight (20 IU/kg b.w.).

Method of administration

Berinert is to be reconstituted according to section 6.6. The reconstituted solution is to be administered by slow i.v. injection or infusion (4 ml/minute).

Known hypersensitivity to any of the components of the product.

In patients with known tendency towards allergies, antihistamines and corticosteroids should be administered prophylactically.

If allergic or anaphylactic-type reactions occur, the administration of Berinert has to be stopped immediately (e.g. discontinue injection/infusion) and an appropriate treatment has to be 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 with emergency treatment in stand-by.

Unlicenced use or treatment of Capillary Leak Syndrome (CLS) with Berinert (see also section "4.8 Undesirable effects") is not advised.

Berinert contains up to 486 mg sodium (approximately 21 mmol) per 100 ml solution. To be taken into consideration by 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 reviewed at intervals.

Virus safety

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV, HCV and for the non-enveloped viruses HAV and parvovirus B19.

Appropriate vaccination (hepatitis A and B) should be generally considered for patients in regular/repeated receipt of human plasma-derived products.

It is strongly recommended that every time Berinert is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

No interaction studies have been performed.

Pregnancy

There are limited amount of data that indicate no increased risk from the use of Berinert in pregnant women. Berinert is a physiological component of human plasma. Therefore, no studies on reproduction and developmental toxicity have been performed in animals and no adverse effects on fertility, pre- and postnatal development are expected in humans.

Therefore, Berinert should be given to a pregnant woman only if clearly needed.

Lactation

It is unknown whether Berinert is excreted in human milk, but due to its high molecular weight, the transfer of Berinert into breast milk seems unlikely. However, breastfeeding is questionable in women suffering from hereditary angioedema. A decision must be made whether to discontinue breastfeeding or to discontinue the Berinert therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

No studies on the effects on the ability to drive and use machines have been performed.

The following adverse reactions are based on post marketing experience as well as scientific literature. The following standard categories of frequency are used:

Undesired reactions with Berinert are rare.

* In treatment attempts with high doses of Berinert for prophylaxis or therapy of Capillary Leak Syndrome (CLS) before, during or after cardiac surgery under extracorporal circulation (unlicensed indication and dose), in single cases with fatal outcome.

For safety with respect to transmissible agents, see section 4.4.

No case of overdose has been reported.

Pharmacotherapeutic group: C1-inhibitor

ATC code: B02A B03

C1-esterase inhibitor is a plasma glycoprotein with a molecular weight of 105 kD and a carbohydrate moiety of 40 %. Its concentration in human plasma ranges around 240 mg/l. Besides its occurrence in human plasma, also the placenta, the liver cells, monocytes and platelets contain C1-esterase inhibitor.

C1-esterase inhibitor belongs to the serine-protease-inhibitor-(serpin)-system of human plasma as do also other proteins like antithrombin III, alpha-2-antiplasmin, alpha-1-antitrypsin and others.

Under physiological conditions C1-esterase inhibitor blocks the classical pathway of the complement system by inactivating the enzymatic active components C1s and C1r. The active enzyme forms a complex with the inhibitor in a stoichiometry of 1:1.

Furthermore, C1-esterase inhibitor represents the most important inhibitor of the contact activation of coagulation by inhibiting factor XIIa and its fragments. In addition, it serves, besides alpha-2-macroglobulin, as the main inhibitor of plasma kallikrein.

The therapeutic effect of Berinert in hereditary angioedema is induced by the substitution of the deficient C1-esterase inhibitor activity.

The product is to be administered intravenously and is immediately available in the plasma with a plasma concentration corresponding to the administered dose.

Pharmacokinetic properties have been investigated in 40 patients (6 patients < 18 years) with hereditary angioedema. These included 15 patients under prophylactic treatment (with frequent/severe attacks), as well as 25 patients with less frequent/mild attacks and "on demand" treatment. The data were generated in an attack-free interval.

The median in-vivo recovery (IVR) was 86.7 % (range: 54.0 - 254.1 %). The IVR for children was slightly higher (98.2 %, range: 69.2 - 106.8 %)) than for adults (82.5 %, range: 54.0 - 254.1 %). Patients with severe attacks had a higher IVR (101.4 %) compared to patients with mild attacks (75.8 %, range: 57.2 - 195.9 %).

The median increase in activity was 2.3%/IU/kg b.w. (range: 1.4 - 6.9 %/IU/kg b.w.). 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, range: 1.4 - 6.9 vs. 2.1, range: 1.5 - 5.1 %/IU/kg b.w.).

The maximum concentration of C1-esterase inhibitor activity in plasma was reached within 0.8 hours after administration of Berinert 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).

Berinert contains as active ingredient C1-esterase inhibitor. It is derived from human plasma and acts like an endogenous constituent of plasma. Single-dose application of Berinert in rats and mice and repeated-dose applications in rats did not show any evidence of toxicity.

Preclinical studies with repeated-dose application to investigate carcinogenicity and reproductive toxicity have not been conducted because they cannot be reasonably performed in conventional animal models due to the development of antibodies following the application of heterologous human proteins.

The in-vitro Ouchterlony test and the in-vivo PCA model in guinea pigs did not show any evidence of newly arising antigenic determinants in Berinert following pasteurisation.

Powder:

Glycine

Sodium chloride

Sodium citrate

Solvent:

Water for injections

Berinert should not be mixed with other medicinal products and diluents in the syringe/infusion set.

30 months

After reconstitution, from a microbiological point of view and as Berinert contains no preservative, the reconstituted product should be used immediately. The physico-chemical stability has been demonstrated for 48 hours at room temperature (max. 25°C). However, if it is not administered immediately, storage shall not exceed 8 hours at room temperature.

Do not store above 25 °C.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

Powder: Injection vial of colourless glass Type II, sealed with bromobutyl rubber infusion stopper Type I, aluminium seal and plastic flip-off cap.

Solvent: 10 ml water for injections in an injection vial of colourless glass Type I, sealed with chlorobutyl rubber infusion stopper Type I, aluminium seal and plastic flip-off cap.

Administration set: 1 filter transfer device 20/20, 1 disposable 10 ml syringe, 1 venipuncture set, 2 alcohol swabs, 1 plaster

Any unused product or waste material should be disposed of in accordance with local requirements.

Method of administration

General instructions

- The solution should be colourless and clear. After filtering/withdrawal (see below) reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.

- Do not use solutions that are cloudy or have deposits.

- Reconstitution and withdrawal must be carried out under aseptic conditions.

Reconstitution

Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an aseptic solution and allowed to dry prior to opening the Mix2Vial package.

Withdrawal and application

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

PL 15036/0030

29 January 2009

05 April 2012