Haemoctin^® 250

Haemoctin^® 500

Powder and solvent for solution for injection

Human plasma derived coagulation factor VIII

One vial of Haemoctin^® 250 / Haemoctin^® 500 contains 250 IU / 500 IU human plasma derived coagulation factor VIII. When reconstituted with either 5 ml or 10 ml of water for injections, Haemoctin^® 250 / Haemoctin^® 500 contains approximately 50 IU/ml human coagulation factor VIII.

The potency (IU) is determined using the European Pharmacopoeia chromogenic factor VIII coagulation assay. The specific activity of Haemoctin^® 250 / Haemoctin^® 500 is approximately 100 IU/mg protein.

For a complete list of excipients, see 6.1.

Powder and solvent for solution for injection.

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

This preparation does not contain von Willebrand factor in pharmacologically effective quantities and is therefore not indicated in von Willebrand´s disease.

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.

Posology

The dosage and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient´s clinical condition.

The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1 % to 2 % of normal activity.

The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (%) x 0.5

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

There are insufficient data to recommend the use of Haemoctin^® 250 / Haemoctin^® 500 in children less then 6 years of age.

Patients should be monitored for the development of factor VIII inhibitors. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. In patients with high levels of inhibitor factor VIII therapy may not be effective, and other therapeutic options should be considered.

Management of such patients should only be directed by physicians with experience in the care of patients with haemophilia.

See also 4.4.

Method of administration

Dissolve the preparation as described at 6.6. The product should be administered via the intravenous route. It is recommended not to administer more than 2 3 ml/min of Haemoctin^® 250 / Haemoctin^® 500.

Hypersensitivity to the active substance or to any of the excipients.

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product contains traces of human proteins other than factor VIII. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, they should be advised to discontinue use of the product immediately and contact their physician.

In case of shock, the current medical standards for shock-treatment should be observed.

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 and HCV, and for the non-enveloped virus HAV. The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19.

Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

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

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days. Patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory test. See also 4.8. Undesirable effects.

It is strongly recommended that every time that Haemoctin^® 250 / Haemoctin^® 500 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.

This medicinal product contains a maximum of 3.3 mmol sodium per standard dose of 2000 IU. To be taken into consideration by patients on a controlled sodium diet.

No interactions of human coagulation factor VIII products with other medicinal products are known.

Animal reproduction studies have not been conducted with Haemoctin^® 250 / Haemoctin^® 500. Based on the rare occurrence of haemophilia A in women, experience regarding the use of Haemoctin^® 250 / Haemoctin^® 500 during pregnancy and breast-feeding is not available. Therefore, Haemoctin^® 250 / Haemoctin^® 500 should be used during pregnancy and lactation only if clearly indicated.

No effects on ability to drive and use machines have been observed.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently, and may in some cases progress to severe anaphylaxis (including shock). On rare occasions, fever has been observed.

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

From introduction in the market until January 2006 a total of about 500 000 standard dosages of Haemoctin^® 250, 500 and 1000 were applied. In total 12 cases of suspected development of inhibitors were received from clinical trials, spontaneous reporting and non interventional studies. This corresponds to a reporting frequency of 1 case on 40 864 applications.

• 6 of these cases concern transient inhibitors.

• In 9 cases the titres of inhibitors were below 10 BU and in 3 cases higher than 10 BU.

• 5 cases concern inhibitor development in previously treated patients (PTPs), 3 cases concern inhibitor development in previously untreated patients (PUPs), 1 case concerned a minimally pretreated patient (16 ED) and in 3 cases exposure days were not reported.

• 4 cases concern children under 6 years of age, in three of these cases the inhibitors were transient.

For the evaluation of undesirable effects the following frequencies were used:

From clinical trials, non interventional studies, spontaneous reporting and regular literature screening the following adverse reactions were reported on Haemoctin^® 250, 500 and 1000:

No cases of transmission of infective agents have been confirmed so far.

For information on safety with respect to transmissible agents, see 4.4.

No case of overdose has been reported.

Pharmacotherapeutic Group: antihemorrhagics: blood coagulation factor VIII.

ATC code: B02BD02.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions.

When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in patient´s circulation.

Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X (factor Xa). Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

In addition to its role as a factor VIII protecting protein, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.

In patients with high levels of inhibitor factor VIII therapy may not be effective, and other therapeutic options should be considered. Following such treatment options Haemoctin^® has been shown to be effective in 11 patients with inhibitors undergoing immune tolerance therapy.

Plasma factor VIII activity decreases by a two-phase exponential decay after intravenous use. In the initial phase, distribution between intravascular and other compartments (body fluids) occurs with a half-life of elimination from the plasma of 1 to 8 hours. In the subsequent phase the half-life varies between 5 - 18 hours, with an average of about 12 hours. This appears to correspond to the true biological half-life.

The incremental recovery of Haemoctin^® 250, 500 or 1000 is approximately 0.020 ± 0.003 IU/ml/IU/kg b.w. The level of factor VIII activity after intravenous use of 1 IU factor VIII per kg b.w. is about 2 %.

Other pharmacokinetic parameters of Haemoctin^® 250, 500 or 1000 are:

• Area under the curve (AUC): about 17 IU x h / ml

• Mean residence time (MRT): about 15 h

• Clearance: about 155 ml/h.

Human plasma coagulation factor VIII (from the concentrate) is a normal constituent of the human plasma and acts like the endogenous factor VIII. Single dose toxicity testing is of no relevance since higher doses result in overloading. Repeated dose toxicity testing in animals is impracticable due to the interference with developing antibodies to heterologous protein.

Even doses of several times the recommended human dosage per kilogram body weight show no toxic effects on laboratory animals.

Since clinical experience provides no hint for tumorigenic and mutagenic effects of human plasma coagulation factor VIII, experimental studies, particularly in heterologous species, are not considered imperative.

Powder: glycine, sodium chloride, sodium citrate, calcium chloride

Solvent: water for injections

Haemoctin^® 250 / Haemoctin^® 500 must not be mixed with other medicinal products.

Only the provided infusion sets should be used because treatment failure can occur as a consequence of human coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.

2 years

Do not store above 25°C.

Do not freeze.

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

1 package Haemoctin ^® 250 contains:

1 vial with powder (20 ml) out of glass type I acc. to Ph.Eur. (current edition). Freeze-drying stoppers out of halobutyl-caoutchouc, type I acc. to Ph.Eur. (current edition).

1 vial with solvent (5 ml), glass type I acc. to Ph.Eur. (current edition). Injection stoppers out of halobutyl-caoutchouc, type I acc. to Ph.Eur. (current edition).

The pack also contains:

1 disposable syringe (5 ml), 1 transfer system with integral filter, 1 butterfly cannula.

1 package Haemoctin ^® 500 contains:

1 vial with powder (20 ml) out of glass type I acc. to Ph.Eur. (current edition). Freeze-drying stoppers out of halobutyl-caoutchouc, type I acc. to Ph.Eur. (current edition).

1 vial with solvent (10 ml), glass type I acc. to Ph.Eur. (current edition). Injection stoppers out of halobutyl-caoutchouc, type I acc. to Ph.Eur. (current edition).

The pack also contains:

1 disposable syringe (10 ml), 1 transfer system with integral filter, 1 butterfly cannula.

Further pack sizes:

1 package Haemoctin ^® 1000 contains:

1 vial with powder (20 ml) out of glass type I acc. to Ph.Eur. (current edition). Freeze-drying stoppers out of halobutyl-caoutchouc, type I acc. to Ph.Eur. (current edition).

1 vial with solvent (10 ml), glass type I acc. to Ph.Eur. (current edition). Injection stoppers out of halobutyl-caoutchouc, type I acc. to Ph.Eur. (current edition).

The pack also contains:

1 disposable syringe (10 ml), 1 transfer system with integral filter, 1 butterfly cannula.

Absolute sterility is to be ensured in all steps of the procedure!

Dissolution of the concentrate:

• Warm the solvent (water for injections) and powder to room temperature in the unopened vials; this temperature (max. 35°C) is to be maintained during the dissolution process (about 10 minutes). If a water bath is used for warming, it must be scrupulously ensured that the water does not come into contact with the caps or stoppers of the vials. Otherwise the medicinal product could be contaminated.

• Remove the caps from both vials in order to expose the central portions of the rubber stoppers.

• Clean the stopper with a disinfectant.

• Pull off the closure of the packaging of the transfer system pack. With the water bottle standing upright, place the open side of the pack (blue part of the transfer system) onto the water bottle.

• Remove the packaging. This exposes the transparent part of the transfer system.

• Turn the combination of transfer system and water vial upside down and, with the vial of dry substance standing upright, push the transparent part of the transfer system into the dry substance vial. The vacuum present in the dry substance vial causes the water to run into the vial of product. Unscrew the blue part of the transfer system together with the water vial. Gently rocking the vial with product helps to dissolve the dry substance. Do not shake vigorously, all foaming is to be avoided! The solution is clear or slightly opalescent.

• The solution ready for use should be used immediately after dissolving. Do not use solutions that are cloudy or contain visible particles.

Injection:

• Once you have dissolved the dry substance as described above, screw the enclosed syringe with its Luer-Lock connector onto the substrate vial with the transparent part of the transfer system. This will allow you to draw the dissolved preparation easily into the syringe. A separate filter is unnecessary because the transfer system has its own integral filter.

• Carefully unscrew the bottle with the transparent part of the transfer system and inject the injection preparation slowly intravenously using the enclosed butterfly needle. Injection rate: 2 - 3 ml/minute.

• After the butterfly needle has been used, it can be made safe with the protective cap.

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

Biotest Pharma GmbH

Landsteinerstrasse 5

63303 Dreieich

Germany

Phone: +49 6103 801-0

Fax: +49 6103 801-150

PL 04500/0009

06/08/2008

March 2008