Haemonine^® 250

Powder and solvent for solution for injection

Human plasma derived coagulation factor IX;

Haemonine^® 250 is presented as a powder and solvent for solution for injection containing 250 IU human coagulation factor IX per vial.

When reconstituted with 5 ml water for injections, Haemonine^® 250 contains approximately 50 IU/ml human coagulation factor IX.

The potency (IU) is determined using the European Pharmacopoeia one stage clotting test. The specific activity of Haemonine^® 250 is 70 IU/mg protein.

Excipients: The reconstituted product contains 0.19 mmol (4.37 mg) sodium per ml. For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).

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 IX deficiency, on the location and extent of the bleeding and on the patient´s clinical condition. The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX 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 IX in plasma). One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.

The calculation of the required dosage of factor IX is based on the empirical finding that 1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 1-2 % of normal activity. The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor IX rise (%) (IU/dl) x 0.8

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case. Factor IX products rarely require to be administered more than once daily.

In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or in IU/dl) 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 IX 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 IX activity) is indispensable. Individual patients may vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.

For long term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 30 IU of factor IX per kilogram of body weight at intervals of 3 to 4 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 Haemonine^® 250 in children less then 6 years of age. Patients should be monitored for the development of factor IX inhibitors. If the expected factor IX 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 IX inhibitor is present. In patients with high levels of inhibitor, F IX therapy may not be effective and other therapeutic options should be considered. Management of such patients should 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 in Section 6.6. The product should be administered via the intravenous route. It is recommended to not exceed a maximal infusion rate of 5 ml/min.

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

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product contains traces of human proteins other than factor IX. 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 IX products.

After repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing.

There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.

Because of the risk of allergic reactions with factor IX concentrates, the initial administrations of factor IX should, according to the treating physician's judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.

Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the risk being higher in low purity preparations, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new-born infants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with Haemonine^® 250 should be weighed against the risk of these complications.

This medicinal product contains a maximum of 4.9 mmol (113 mg) sodium per standard dose of 2000 IU. To be taken into consideration by patients on a controlled sodium diet.

It is strongly recommended that every time that Haemonine^® 250 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 interactions of human coagulation factor IX products with other medicinal products are known.

Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available. Therefore, factor IX 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, fever, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently in patients treated with factor IX containing products. In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also 4.4).

• Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.

• On rare occasions fever has been observed.

• Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. 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.

There is no experience with previously untreated patients (PUPs) so far.

During clinical development no factor IX inhibitor induction was observed in previously treated patients (PTPs, n=36) during 1,493 exposure days.

• There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such side effects.

• Haemonine^® 250 may contain traces of heparin below the limit of quantitation (0.1 IU/ml) which may cause allergic reactions and reduced blood cell counts which may affect the blood clotting system. Patients with a history of heparin-induced allergic reactions should avoid the use of heparin-containing medicines.

For the evaluation of undesirable reactions of Haemonine^®, the following frequencies were used:

The following adverse reactions have been reported from patients in clinical studies (1,493 exposure days):

For safety with respect to transmissible agents see 4.4.

No symptoms of overdose with human coagulation factor IX have been reported.

Pharmacotherapeutic Group: antihemorrhagics: blood coagulation factor IX.

ATC code: B02BD04.

Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Dalton. It is a vitamin-K dependent coagulation factor and it is synthesised in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX 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 IX are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

There are insufficient data to recommend the use of Haemonine^® 250 in children less than 6 years of age.

A pharmacokinetic study with 13 patients yielded the following results:

Using a biphasic model the mean initial half-life was 2.2 ± 1.9 h at initial visit and 3.1 ± 2.9 h at month 3, respectively. The mean terminal half-life was calculated as 28.5 ± 12.1 h at initial visit and 30.1 ± 14.7 h at month 3. The incremental recovery of Haemonine^® was 69.8 ± 21.6 % and 72.2 ± 22.2 % at initial visit and at month 3, respectively. This corresponded to an incremental recovery of 0.015 ± 0.005 IU/ml/IU/kg body weight at initial visit and of 0.016 ± 0.005 IU/ml/IU/kg body weight at month 3. Other pharmacokinetic parameters of Haemonine^® are: Area under the curve (AUC): about 25 IU · h/ml; Mean residence time (MRT): about 33 h; Clearance: about 200 ml/h.

The preparation contains exclusively human plasma derived proteins, namely high purity coagulation factor IX, which is identical with the endogenous factor IX.

Preclinical studies in an Ames test showed no mutagenic potential of the preparation.

Haemonine^® was tested for abnormal toxicity and thrombogenic potential in different rabbit models. The results revealed no signs for toxicological or thrombogenic potential.

Powder:

arginine

lysine

sodium chloride

sodium citrate

Solvent:

water for injections.

This medicinal product must not be mixed with other medicinal products.

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

2 years

The product should be used immediately after reconstitution.

Do not store above 25°C.

Do not freeze.

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

1 package Haemonine ® 250 contains:

1 vial with powder, glass type I (Ph. Eur.), closed with chlorobutyl rubber stopper, type I (Ph. Eur.)

1 vial with solvent (5 ml), glass type I (Ph. Eur.), closed with bromobutyl rubber stopper, type I (Ph. Eur.)

The pack also contains:

1 disposable syringe (5 ml), 1 double-filter transfer system, 1 butterfly cannula.

Further package sizes:

1 package Haemonine ® 500 contains:

1 vial with powder, glass type I (Ph. Eur.), closed with chlorobutyl rubber stopper, type I (Ph. Eur.)

1 vial with solvent (5 ml), glass type I (Ph. Eur.), closed with bromobutyl rubber stopper, type I (Ph. Eur.)

The pack also contains:

1 disposable syringe (5 ml), 1 double-filter transfer system, 1 butterfly cannula.

1 package Haemonine ® 1000 contains:

1 vial with powder, glass type I (Ph. Eur.), closed with chlorobutyl rubber stopper, type I (Ph. Eur.)

1 vial with solvent (10 ml), glass type I (Ph. Eur.), closed with bromobutyl rubber stopper, type I (Ph. Eur.)

The pack also contains:

1 disposable syringe (10 ml), 1 double-filter transfer system, 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 strictly 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 stoppers 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 this vial.

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 should be clear or slightly opalescent.

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

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 04500/0007

19/12/2008

19/12/2008