HAEMONINE 500 POWDER AND SOLVENT FOR SOLUTION FOR INJECTION

PACKAGE LEAFLET: INFORMATION FOR THE USER Powder and solvent for solution for injection Human coagulation factor IX Read all of this leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, please ask your doctor or your pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Haemonine 500 / Haemonine 1000 is and what it is used for 2. Before you use Haemonine 500 / Haemonine 1000 3. How to use Haemonine 500 / Haemonine 1000 4. Possible side effects 5. How to store Haemonine 500 / Haemonine 1000 6. Further information
1. WHAT HAEMONINE 500 / HAEMONINE 1000 IS AND WHAT IT IS USED FOR Haemonine 500 / Haemonine 1000 is presented as a powder and a solvent for solution for injection. Each vial of Haemonine 500 contains 500 IU (international units) of human coagulation factor IX. In a separate vial, 5 ml water for injections are provided. Each vial of Haemonine 1000 contains 1000 IU (international units) of human coagulation factor IX. In a separate vial, 10 ml water for injections are provided. After reconstitution of the dry substance in the water for injections the product contains 100 IU human coagulation factor IX per ml. The specific activity of Haemonine 500 / Haemonine 1000 is 70 IU/mg protein.

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Haemonine 500 / Haemonine 1000 is being prescribed to stop or prevent bleeding because of a lack of factor IX (Haemophilia B) in your blood. Thus, Haemonine 500 / Haemonine 1000 as a coagulation factor IX preparation belongs to the pharmacotherapeutic group of antihaemorrhagics. Factor IX is a protein that is part of the bodys natural way of forming clots to stop bleeding. If it is absent or low in your blood, you will suffer from blood coagulation problems which may lead to bleeding in joints, muscles or internal organs. You may have this condition from birth or acquire it later in life. The administration of Haemonine 500 / Haemonine 1000 can compensate for this deficiency.
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2. BEFORE YOU USE HAEMONINE 500 / HAEMONINE 1000 Do not use Haemonine 500 / Haemonine 1000: if you are allergic (hypersensitive) or have had any reactions to coagulation factor IX, to any of the other ingredients of Haemonine 500 / Haemonine 1000 (these are listed in section 6 of this leaflet) or to heparin. Usually, if you are allergic (hypersensitive) to Haemonine 500 / Haemonine 1000 it will show up within the first applications. The early signs of hypersensitivity reactions include reddening of the skin, nettle rash, itching over the entire body, swelling of lips and tongue, breathing difficulties, tightness of the chest, wheezing, drop in blood pressure, loss of consciousness, which can progress to severe allergic reactions. If you detect one or more of the symptoms listed above in yourself, call your doctor instantly. Take special care with Haemonine 500 / Haemonine 1000: Before you use Haemonine 500 / Haemonine 1000 you should tell your doctor if you know that you have a risk of thrombosis or you have had thromboembolic complications in the past, if you suffer from liver disease or if a surgery is planned. These are conditions that increase your risk of developing internal blood clots, even if you have not been injured. If you are unsure, you should discuss this with your doctor. When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of virus/infections. Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot totally be excluded. This also applies to any unknown or emerging viruses or other types of infections. The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, and for the non-enveloped hepatitis A virus. 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 whose immune system is depressed or who have some types of anaemia (e.g. sickle cell disease or haemolytic anaemia). Your doctor may recommend that you consider vaccination against hepatitis A and B if you regularly/repeatedly receive human plasma-derived factor IX products. It is strongly recommended that every time you receive a dose of Haemonine 500 / Haemonine 1000 the name and batch number of the product are recorded in order to maintain a record of the batches used.

Taking other medicines Please tell your doctor if you are taking, or have recently taken, any other medicines including medicines obtained without a prescription. No interactions of Haemonine 500 / Haemonine 1000 with other medicinal products are known. Children There are insufficient data to recommend the use of Haemonine 500 / Haemonine 1000 in children less then 6 years of age. Pregnancy and breast-feeding Haemophilia B in women is rare. Therefore there is no experience regarding the use of Haemonine 500 / Haemonine 1000 during pregnancy and breast-feeding. If you are pregnant, planning a family, or breast-feeding ask your doctor or pharmacist for advice before taking any medicine. If you have already told your doctor then follow any instructions that may have been given to you. Driving and using machines No effects on the ability to drive or use machines have been observed. Important information about some of the ingredients of Haemonine 500 / Haemonine 1000 This medicinal product contains a maximum of 4.9 mmol (113 mg) sodium per standard dose of 2,000 IU. To be taken into consideration by patients on a controlled sodium diet. 3. HOW TO USE HAEMONINE 500 / HAEMONINE 1000 Always use Haemonine 500 / Haemonine 1000 exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Haemonine 500 / Haemonine 1000 treatment should be started by a doctor who has experience in the treatment of haemophilia. Dosage and Frequency of Administration The amount of Haemonine 500 / Haemonine 1000 you need to use depends on your weight, the severity of your haemophilia, the site and severity of your bleed, and the need to prevent bleeding, for example before dentistry or an operation. Your doctor will calculate the dose of Haemonine 500 / Haemonine 1000 and how often you need to inject it to obtain the correct levels in your blood. Factor IX products rarely require to be administered more than once daily. 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 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 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: Degree of haemorrhage/ Factor IX level Type of surgical procedure required (%) (IU/dl) Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding More extensive haemarthrosis, muscle bleeding or haematoma Life threatening haemorrhages 20 - 40 Frequency of doses (hours)/ Duration of therapy (days)

Repeat every 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved. Repeat infusion every 24 hours for 3 - 4 days or more until pain and acute disability are resolved. Repeat infusion every 8 to 24 hours until threat is resolved. Every 24 hours, at least 1 day, until healing is achieved. Repeat infusion every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor IX activity of 30 to 60% (IU/dl).

30 - 60

60 - 100

Surgery Minor 30 - 60 including tooth extraction Major 80 - 100 (pre- and postoperative)

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. It is recommended to not exceed a maximal infusion rate of 5 ml/min.

If you have the impression that the effect of Haemonine 500 / Haemonine 1000 is too weak, talk to your doctor. You may have developed antibodies to factor IX (see Possible Side Effects). If you use more Haemonine 500 / Haemonine 1000 than you should No symptoms of overdose with human coagulation factor IX have been reported. Instructions for use Haemonine 500 / Haemonine 1000 is given by injection into a vein. If you have been prescribed Haemonine 500 / Haemonine 1000 to use at home, your doctor or haemophilia centre nurse will have to make sure that you know how to use it. If you are in any doubt about injecting Haemonine 500 / Haemonine 1000, go back to your doctor or Haemophilia Centre for more advice and training before attempting to give yourself any treatment. Follow the directions given to you by your doctor or haemophilia nurse. During the preparation and injection of Haemonine 500 / Haemonine 1000, it is important to use sterile conditions. Haemonine 500 / Haemonine 1000 must not be mixed with other medicinal products. Only the provided injection set should be used, otherwise treatment may not be efficient due to factor IX adsorption to the internal surfaces of some other injection equipment.

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Any unused product or waste material should be disposed of in accordance with local requirements. If you have any further questions on the use of the product, ask your doctor or pharmacist.

Fig. 7

Dissolution of the concentrate: Warm the solvent (water for injections) and powder to room temperature (max. 35C) in the unopened vials and maintain this temperature. If a water bath is used for warming, make Fig. 1 sure that the water does not come into contact with the caps or stoppers of the vials. Remove the caps from both vials to expose the central portions of the rubber stoppers (Fig. 1). Clean the stoppers with a disinfectant. Pull off the closure of the packaging of the transfer system pack (Fig. 2). With the water bottle standing upright, place Fig. 3 the open side of the pack (blue part of the transfer system) onto the water bottle (Fig. 3). 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 powder standing upright, push the transparent part of the transfer system into the dry powder vial (Fig. 4). The vacuum present in the dry powder vial causes the water to run into this vial (Fig. 5). Unscrew the Fig. 5 blue part of the transfer system together with the water vial (Fig. 6). Gently rocking the vial helps to dissolve the powder. Do not shake; there should be no foam. 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 powder, screw the enclosed syringe with its Luer-Lock connector onto the substrate vial with the transparent part of the transfer system (Fig. 7). This will allow you to draw the dissolved preparation into the syringe. Carefully unscrew the bottle with the transparent part of the transfer system and inject the injection preparation slowly into a vein using the enclosed butterfly needle. You should inject slowly (2 - 3 ml/minute). After the butterfly needle has been used, it can be made safe with the protective cap.

4. POSSIBLE SIDE EFFECTS Like all medicines, Haemonine 500 / Haemonine 1000 can cause side effects, although not everybody gets them. The following side effects have been reported: Nephrotic syndrome (a disorder where the kidneys are damaged) has been reported in haemophilia B patients with a history of allergic reaction. Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. This may mean that your bleeding cannot be adequately controlled by application of Haemonine 500 / Haemonine 1000. If this happens contact your haemophilia centre. In addition, you may also have an increased risk of allergic reactions if you have antibodies to factor IX. There is a small risk of thromboembolic episodes (blood clots). All medicines can cause allergic reactions or non-specific hypersensitivity reactions although serious reactions are very rare (less than 1 user in 10,000). Any sudden wheeziness, difficulty in breathing, tightness of the chest, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body), chills, flushing, fever, headache, hives, hypotension, tiredness, nausea, restlessness, rapid heartbeat, tingling or vomiting should be reported to a doctor immediately. Haemonine 500 / Haemonine 1000 may contain traces of heparin 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: Very common: Common: Uncommon: Rare: Very rare: affects more than 1 user in 10 affects 1 to 10 users in 100 affects 1 to 10 users in 1,000 affects 1 to 10 users in 10,000 affects less than 1 user in 10,000

The following adverse reactions have been reported from patients in clinical studies (1,493 exposure days): MedDRA Standard System Organ Class General disorders and administration site conditions Respiratory, thoracic and mediastinal disorders Adverse reactions Feeling cold Dyspnoe (breathing difficulty) Frequency rare rare

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE HAEMONINE 500 / HAEMONINE 1000 Keep out of the reach and sight of children. Keep the vials in the outer carton in order to protect them from light. Haemonine 500 / Haemonine 1000 should not be stored above 25C. Do not freeze. The product, once opened or dissolved, should be used immediately. Do not use Haemonine 500 / Haemonine 1000 after the expiry date which is stated on the label and the outer carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Haemonine 500 / Haemonine 1000 contains: Powder: The active substance is human coagulation factor IX. Each vial of Haemonine 500 contains 500 IU of human coagulation factor IX. Each vial of Haemonine 1000 contains 1000 IU of human coagulation factor IX. The other ingredients are arginine, lysine, sodium chloride, and sodium citrate. Solvent: Water for injections What Haemonine 500 / Haemonine 1000 looks like and contents of the pack Powder and solvent for solution for injection. After dissolving the powder in the provided water for injections, the Haemonine 500 / Haemonine 1000 solution must be clear or slightly opalescent without any visible particles. 1 package Haemonine 500 contains: 1 glass vial with powder 1 glass vial with 5 ml water for injections 1 disposable syringe (5 ml) 1 double filter transfer system 1 butterfly cannula 1 package Haemonine 1000 contains: 1 glass vial with powder 1 glass vial with 10 ml water for injections 1 disposable syringe (10 ml) 1 double filter transfer system 1 butterfly cannula

Marketing Authorisation Holder and Manufacturer: Biotest Pharma GmbH Landsteinerstrasse 5 63303 Dreieich Germany Phone: +49 6103 801-0 Fax: +49 6103 801-150 info@biotest.de Local representative in the UK: Biotest (UK) Ltd. 28 Monkspath Business Park Highland Road Shirley Solihull West Midlands B90 4NZ Phone: 0121 733 3393 Fax: 0121 733 3066 biotestuk@biotestuk.com This medicinal product is authorised in the Member States of the EEA under the following names: Austria: Haemonine 100 I.E./ml Germany: Haemonine 500 and 1000 Greece: Haemonine 500 and 1000 Italy: HaemoBionine 100 UI/ml UK: Haemonine 500 and 1000 This leaflet was last approved in 12/2008.