Public Assessment Report

Transcription

1 Public Assessment Report Haemoctin SDH 250/500/1000 Human Coagulation Factor VIII DE/H/0478/ /MR Applicant: Biotest Pharma GmbH This module reflects the scientific discussion for the approval of Haemoctin. The procedure has been finalised at For information on changes after this date please refer to the module Update. Haemoctin DE/H/0478/ /MR EPAR 1/40

2 TABLE OF CONTENTS I.1 General comments on the submitted dossier 4 I.2 General comments on compliance with GMP, GLP, GCP and agreed ethical principles 4 II. Scientific Overview 4 III. Overall conclusion, benefit/risk assessment and recommendation 6 IV. Product Information 7 Haemoctin DE/H/0478/ /MR EPAR 2/40

3 1. INFORMATION OF THE INITIAL PROCEDURE 1. Type of application Full application according article 8.3 (i) Directive 2001/83/EC 2. Active substance Human Coagulation Factor VIII 3. Form Powder and solvent for solution for injection 4. Strength 250 IU/vial 500 IU/vial 1000 IU/vial 5. Marketing Authorisation Holder Biotest Pharma GmbH Landsteiner Straße Dreieich Germany 6. Reference Member State Paul-Ehrlich-Institut Germany 7. Concerned Member States BE, ES, IT, NL, SI, UK 8. Procedure-number DE/H/0478/ /MR 9. Timetable submission of application: start of procedure: termination of procedure: Haemoctin DE/H/0478/ /MR EPAR 3/40

4 I.1 General comments on the submitted dossier Haemoctin SDH 250/500/1000 is a stand alone application according Art. 8(3) of Directive 2001/83 EC. I.2 General comments on compliance with GMP, GLP, GCP and agreed ethical principles The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for the manufacture and assembly of Haemoctin SDH 250/500/1000. II. SCIENTIFIC OVERVIEW Quality Haemoctin SDH is a purified human coagulation factor VIII preparation, which is marketed as a freeze-dried powder in presentations of 250 IU, 500 IU and 1000 IU of FVIII per vial. The final product comprises two vials (one for the powder and one for the solvent swfi), a disposable syringe (5 ml or 10 ml), a transfer set with integral filter and a butterfly needle. Haemoctin SDH is produced from human plasma which complies with the Ph.Eur. monograph no on human plasma for fractionation and with the Ph.Eur. monograph no on human coagulation factor VIII. After reconstitution with swfi Haemoctin SDH 250 and Haemoctin SDH 500 contain approximately 50 IU/ml human coagulation FVIII, whereas Haemoctin SDH 1000 contains approximately 100 IU/ml human coagulation FVIII. The specific activity of Haemoctin SDH 250, 500 and 1000 is about 100 IU FVIII/mg protein. In addition, Haemoctin SDH contains glycine, sodium chloride, sodium citrate, calcium chloride dihydrate as excipients. All excipients comply with the respective Ph.Eur. monographs. Haemoctin is manufactured from solvent/detergent-treated cryoprecipitate which is purified by aluminium hydroxide adsorption and after solvent/detergent-treatment by anion-exchange chromatography and subsequent concentration by ultrafiltration to achieve the required volume activity. The resulting bulk solution is sterile filtered and directly filled into the final sales units. After lyophilisation, the product is subjected to heat treatment, which is performed as a second virus inactivation step. Afterwards, labelling, quality control and batch release of the final product is performed. Haemoctin is stable for 24 months at a temperature of up to 25 C when protected from light. Haemoctin represents a medium to highly purified FVIII product. The manufacture includes well known purification steps leading to a consistent finished product, which complies with Ph.Eur.- monograph. The finished product is controlled by appropriately selected methods and specifications. Adventitious Agents The overall viral safety strategy includes selection of qualified donors and testing of plasma donations. Plasma is collected in Austria, Belgium, Germany, the Netherlands, Switzerland and the USA, and single donations are screened by an adequate testing program for viral infections (HIV-1 and HIV-2 antibodies, HBs antigen and HCV antibodies). In addition, all plasma used for the manufacture of Haemoctin is tested for absence of HBV, HIV-1 and HCV genomes by minipool NAT screening. Manufacturing pools are tested for HIV-1 and HIV-2 antibodies, HBs antigen and HCV antibodies Haemoctin DE/H/0478/ /MR EPAR 4/40

5 Further testing of the manufacturing pools is performed by NAT on HIV-1 group M RNA, HIV-1 group O and HIV-2 RNA, HBV DNA, HCV RNA, and Parvovirus B19 DNA. The donor selection and plasma donation testing strategy for viral markers is considered adequate. Haemoctin SDH is purified by cryoprecipitation, aluminium hydroxide Al(OH) 3 adsorption, S/D treatment, and chromatography. No animal-derived TSE risk material is used during production. Effective reduction of TSE agents at the Al(OH) 3 adsorption has been demonstrated. In addition, several steps for virus inactivation/removal have been introduced into the manufacturing process: Al(OH) 3 adsorption, S/D treatment (1% Tween 80 and 0.3% TnBP, 8-14 hours, 25.0±1 C), and the final dry heat treatment (100±1.5 C, 32.5±2.5 minutes). Effective inactivation/removal of enveloped viruses has been demonstrated for two out of three validated production steps (S/D and dry heat treatment). The final dry heat treatment at 100±1.5 C, 32.5±2.5 minutes was introduced into production in order to inactivate small non-enveloped viruses. Adequate inactivation of HAV has been shown. The combination of three production steps with complementary mechanisms for virus inactivation or virus removal (Al(OH) 3 adsorption, S/D treatment, dry heat treatment) results in a high overall reduction capacity for enveloped viruses and an effective reduction of non-enveloped viruses such as HAV. In summary, virus safety of the product has been demonstrated. Non-clinical aspects The non-clinical testing strategy was based on the following considerations: the active substance of Haemoctin SDH are physiologically active serum proteins of human origin, therefore the standard non-clinical testing program usual for chemical entities is not applicable. In particular, those nonclinical tests which are used to examine long term effects following repeated doses are not meaningful to perform with heterologuous proteins. Since the mode of action of human factor VIII concentrate is broadly understood pharmacodynamic and pharmacokinetic investigations in animals have not been performed with Haemoctin. The MAH focussed the non-clinical testing strategy for Haemoctin SDH on the investigation of its potential immunogenic properties. The induction (formation) of neoantigens involving a heattreatment step in the Haemoctin SDH manufacturing procedure has been evaluated and in a second series of experiments, immunogenicity endpoints of several commercially available FVIII products (rfviii and pdfviii) were compared with regard to the immunomodulatory influence of VWF in a FVIII knockout mouse model. Although the non-clinical data available for Haemoctin SDH are not fully state of the art, it can be concluded that there is no evidence for concern related to the pharmacological-toxicological profile of Haemoctin SDH. Clinical aspects Three Clinical trials have been presented: Pharmacokinetic properties and long-term-efficacy are demonstrated in study 933 (2001) in 12 patients. 39 mitt (modified Intention-to-Treat) patients have been evaluated for long-term clinical efficacy in study 939 (2001). Efficacy of FVIII substitution has been demonstrated in 10 surgical cases (8 patients) in study 934 (1999). The studies included safety issues. Two Post-marketing surveillance studies ( and from 1998 ongoing) have been started to document routine use of Haemoctin SDH. One retrospective surgical study ( ) has been provided, in addition. Haemoctin DE/H/0478/ /MR EPAR 5/40

6 Concerning immune tolerance treatment the MAH provided 11 case reports of successfully treated inhibitor patients. Efficacy and safety of Haemoctin SDH have been demonstrated in three clinical trials and supplemented by post-marketing experience and Periodic Safety Update Reports. It is acknowledged that the presented data partially reflect the scientific and clinical knowledge of more than 10 years ago. Consequently, some deviations - when compared to today requirements - of the investigational approaches have been identified. However, wide clinical use of Haemoctin SDH for nearly 15 years did not show evidence for safety hazards or any suspicion of general efficacy issues. III. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Efficacy and safety of Haemoctin SDH have been demonstrated in clinical studies and supplemented by long-term post-marketing experience and Periodic Safety Update Reports. The wide clinical use of the medicinal product did not reveal any evidence for safety hazards or any suspicion of general efficacy issues. In conclusion, based on data on quality, non-clinical and clinical aspects it has been considered that Haemoctin SDH demonstrates adequate evidence of efficacy and safety for the approved indication as well as a favourable risk/benefit profile. Haemoctin DE/H/0478/ /MR EPAR 6/40

7 IV. PRODUCT INFORMATION SUMMARY OF PRODUCT CHARACTERISTICS 1. TRADE NAME OF THE MEDICINAL PRODUCT Haemoctin 250 Haemoctin 500 Haemoctin 1000 Powder and solvent for solution for injection Human plasma derived coagulation factor VIII 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One vial contains 250, 500 or 1000 IU human plasma derived coagulation factor VIII. Haemoctin 250 or Haemoctin 500 contains approximately 50 IU/ml human coagulation factor VIII when reconstituted with 5 or 10 ml of water for injections. Haemoctin 1000 contains approximately 100 IU/ml human coagulation factor VIII when reconstituted with 10 ml of water for injections. The potency (IU) is determined using the European Pharmacopoeia chromogenic factor VIII coagulation assay. The specific activity of Haemoctin 250, 500 or 1000 is approximately 100 IU/mg protein. For a complete list of excipients, see PHARMACEUTICAL FORM Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications 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. 4.2 Posology and method of administration 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 Haemoctin DE/H/0478/ /MR EPAR 7/40

8 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: Degree of haemorrhage/ Type of surgical procedure Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding More extensive haemarthrosis, muscle bleeding or haematoma Life threatening haemorrhages Factor VIII level required (%) Frequency of doses (hours)/duration of therapy (days) Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved Repeat infusion every 12 to 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. Surgery Minor including tooth extraction Major (pre- and postoperative) 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 VIII activity of 30-60%. 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, 500 or 1000 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. Haemoctin DE/H/0478/ /MR EPAR 8/40

9 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 Haemoctin 250, 500 or 1000/min. 4.3 Contra-indications Hypersensitivity to the active substance or to any of the excipients. 4.4 Special warnings and special precautions for use 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 nonenveloped 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, 500 or 1000 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. 4.5 Interaction with other medicinal products and other forms of interaction No interactions of human coagulation factor VIII products with other medicinal products are known. Haemoctin DE/H/0478/ /MR EPAR 9/40

10 4.6 Pregnancy and lactation Animal reproduction studies have not been conducted with Haemoctin 250, 500 or Based on the rare occurrence of haemophilia A in women, experience regarding the use of Haemoctin 250, 500 or 1000 during pregnancy and breast-feeding is not available. Therefore, Haemoctin 250, 500 or 1000 should be used during pregnancy and lactation only if clearly indicated. 4.7 Effects on ability to drive and use machines No effects on ability to drive and use machines have been observed. 4.8 Undesirable effects 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 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 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: Very common: 1/10 Common: 1/100 to <1/10 Uncommon: 1/1,000 to <1/100 Rare: 1/10,000 to <1/1,000 Very rare: <1/10,000, including isolated reports From clinical trials, non interventional studies, spontaneous reporting and regular literature screening the following adverse reactions were reported on Haemoctin 250, 500 and 1000: MedDRA Standard System Organ Class Adverse reactions Frequency Nervous system disorder Haemorrhage brain very rare Blood and lymphatic system disorders Anaemia very rare Skin and subcutaneous tissue disorder Exanthema, urticaria, erythema very rare Investigations Anti factor VIII antibody positive very rare No cases of transmission of infective agents have been confirmed so far. For information on safety with respect to transmissible agents, see 4.4. Haemoctin DE/H/0478/ /MR EPAR 10/40

11 4.9 Overdose No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties 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. 5.2 Pharmacokinetic properties 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 halflife 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 ± 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. 5.3 Preclinical safety data 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. Haemoctin DE/H/0478/ /MR EPAR 11/40

12 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. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder: glycine, sodium chloride, sodium citrate, calcium chloride Solvent: water for injections 6.2 Incompatibilities Haemoctin 250, 500 or 1000 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. 6.3 Shelf-life 2 years 6.4 Special precautions for storage Do not store above 25 C. Do not freeze. Keep the vials in the outer carton in order to protect from light. 6.5 Nature and contents of container 1 package Haemoctin 250, 500 or 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 (5 ml, 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 (5 ml, 10 ml), 1 transfer system with integral filter, 1 butterfly cannula. 6.6 Instructions for use and handling, and disposal 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. (1) Clean the stopper with a disinfectant. Pull off the closure of the packaging of the transfer system pack. (2) With the water bottle standing upright, place the open side of the pack (blue part of the transfer system) onto the water bottle. (3) Haemoctin DE/H/0478/ /MR EPAR 12/40

13 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. (4) The vacuum present in the dry substance vial causes the water to run into the vial of product. (5) Unscrew the blue part of the transfer system together with the water vial. (6) 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. (7) 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. 7. MARKETING AUTHORISATION HOLDER Biotest Pharma GmbH Landsteinerstrasse Dreieich Germany Phone: Fax: MARKETING AUTHORISATION NUMBER(S) - 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION DATE OF REVISION OF THE TEXT March 2008 Haemoctin DE/H/0478/ /MR EPAR 13/40

14 PACKAGE LEAFLET: INFORMATION OF THE USER Haemoctin 250 Powder and solvent for solution for injection Human plasma derived coagulation factor VIII Please 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, ask your doctor or 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 listed gets serious, or if you notice any side-effects not listed in this leaflet, please tell your doctor or pharmacist. This package insert contains: 1. What is Haemoctin 250 and what it is used for? 2. Before you use Haemoctin How to use Haemoctin Possible side-effects 5. How to store Haemoctin Further information 1. WHAT IS HAEMOCTIN 250 AND WHAT IT IS USED FOR? Haemoctin 250 is a medicine derived from human plasma. It contains the coagulation factor VIII, which is necessary for a normal course of blood coagulation. Haemoctin 250 is used for the haemostasis and thus belongs to the group of so-called antihaemorrhagics. After reconstitution of the dry substance in 5 ml water for injections the product contains 50 IU (international units) coagulation factor VIII per ml of liquid. One vial contains 250 IU blood coagulation factor VIII. For determination of the potency (quantity of IU) the chromogenic factor VIII coagulation assay according to European Pharmacopoeia is applied. Here, a chemical colour reaction is used to evaluate the coagulation activity of the preparation. The specific activity of Haemoctin 250 is approximately 100 IU/mg protein. Administration of Haemoctin 250: Haemoctin 250 is suitable for treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). Haemoctin 250 does not contain von Willebrand factor in pharmacologically effective quantities, and is therefore not suitable for the treatment of von Willebrand's disease. 2. BEFORE YOU USE HAEMOCTIN 250 Do not use Haemoctin 250, if you are allergic (hypersensitive) to coagulation factor VIII or to any of the other ingredients. Haemoctin DE/H/0478/ /MR EPAR 14/40

15 Take special care with the use of Haemoctin 250, after multiple use with factor VIII concentrates. In this case it is possible that your immune system develops antibodies (inhibitors) to factor VIII. These inhibitors may impact the effect of Haemoctin 250. Your doctor should check you regularly using a biological test (the Bethesda test) for the formation of inhibitors. The appearance of such factor VIII inhibitors manifests itself as a lack of therapeutic success. The amount of inhibitors in the body is expressed in Bethesda units (BU) per ml of blood plasma. The risk of developing inhibitors depends on the administration of factor VIII, and is greatest during the first 20 days of administration. Inhibitors rarely form after more than 100 days of administration. to keep risk of infection as low as possible. When medicinal products 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. A plasma pool is made from the donated blood plasma of several donors. 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 be totally 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 (HBV) and hepatitis C virus (HCV), and for the non-enveloped hepatitis A virus (HAV). The virus elimination/inactivation may be of limited value against other nonenveloped viruses such as parvovirus B19. The parvovirus B19 is the causative agent of infectious erythema. The parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals whose immune system is depressed or who have an increased production of red blood cells (e.g. haemolytic anaemia). It is strongly recommended that every time you receive a dose of Haemoctin 250 the name and batch number of the product are recorded in order to maintain a record of the batches used. Your doctor may recommend that you consider vaccination against hepatitis A and B if you regularly/repeatedly receive human plasma derived factor VIII products. Using Haemoctin 250 with other medicines Interactions between Haemoctin 250 and other medicinal products are unknown. Haemoctin 250 should not be mixed with other medicinal products. Only the supplied infusion set should be used because treatment failure can occur as a consequence of factor VIII adsorption to the internal surfaces of some infusion equipment. Please inform your doctor or pharmacist if you are taking or have recently taken other medicines, including medicines obtained without a prescription. Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. Because of the rare occurrence of haemophilia A in women, there is no experience available on the use of Haemoctin 250 during pregnancy or while breast-feeding. No animal experiments have been performed during pregnancy and nursing. If you are pregnant or if you are breast-feeding please Haemoctin DE/H/0478/ /MR EPAR 15/40

16 discuss with your doctor whether Haemoctin 250 could be of benefit to you and whether the benefit outweighs the risks. What needs to be taken into consideration for children? There is only limited experience of treatment of children under 6 years of age. The same applies to previously untreated patients. Driving and using machines The ability to drive and operate machines is not impaired by the use of Haemoctin 250. Important information about some of the ingredients of Haemoctin 250 This medicine contains only known and physiologically safe constituents. This means that the normal body functions are not impaired by the use of Haemoctin 250. This medicinal product contains a maximum of 3.3 mmol sodium (excipient) per standard dose of 2000 IU, which should be taken into consideration by patients on a controlled sodium diet. 3. HOW TO USE HAEMOCTIN 250 Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia A. Always use Haemoctin 250 exactly as your doctor told you. You should check with your doctor if you are not sure. The dosage and duration of treatment depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on your clinical condition. Your doctor will determine the dose which is suitable for you. Ensure sterile working in all steps of the procedure. Pictures Reconstitution of the powder: 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 contamination of the medicine may occur. Remove the caps from both vials in order to expose the central portions of the rubber stoppers. (1) Clean the stopper with a disinfectant. Pull off the closure of the packaging of the transfer system pack. (2) With the water bottle standing upright, place the open side of the pack (blue part of the transfer system) onto the water bottle. (3) Remove the packaging. This exposes the transparent part of the transfer system. Haemoctin DE/H/0478/ /MR EPAR 16/40

17 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. (4) The vacuum present in the dry substance vial causes the water to run into the vial of product. (5) Immediately unscrew the blue part of the transfer system together with the water vial. (6) 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. (7) 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. If you forget to use Haemoctin 250 In this case your doctor will decide whether a further treatment is necessary. If you stop using Haemoctin 250 In this case your doctor will decide whether a further treatment is necessary. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Haemoctin 250 can cause side effects, although not everybody gets them. 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. Hypersensitivity or allergic reactions (which may include mild reddening of the skin, burning and stinging at the infusion site, chills, flushing, local or whole-body urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently. In some cases, allergic reactions have led to an allergic shock (so called anaphylaxis). 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. Haemoctin DE/H/0478/ /MR EPAR 17/40

18 For the evaluation of undesirable effects the following frequencies were used: Very common: 1/10 Common: 1/100 to <1/10 Uncommon: 1/1,000 to <1/100 Rare: 1/10,000 to <1/1,000 Very rare: <1/10,000, including isolated reports From clinical trials, non interventional studies, spontaneous reporting and regular literature screening the following adverse reactions were reported on Haemoctin 250, 500 and 1000: MedDRA Standard System Organ Class Adverse reactions Frequency Nervous system disorder Bleeding in the brain very rare Blood and lymphatic system disorders Anaemia very rare Skin and subcutaneous tissue disorder Exanthema, nettle rash, reddening of very rare the skin Investigations Anti factor VIII antibody positive very rare No cases of transmission of infective agents have been confirmed so far. 5. HOW TO STORE HAEMOCTIN 250 Do not store above 25 C. Do not freeze. Keep the vials in the outer carton in order to protect from light. Do not use Haemoctin 250 after the expiry date which is stated on the label of the vial and the carton. The expiry date refers to the last day of that month. Unused solution should be disposed of in accordance with the valid requirements. The medicine may 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. Keep medicinal products out of the reach of children. Do not use Haemoctin 250, if you notice the following: Turbidity of the solution Visible particles in the solution The solution should be clear to slightly opalescent. 6. FURTHER INFORMATION What Haemoctin 250 contains - The active substance is: Human coagulation factor VIII - The other ingredients are: Powder: Glycine, sodium chloride, sodium citrate, calcium chloride Solvent: Water for injections Haemoctin DE/H/0478/ /MR EPAR 18/40

19 What Haemoctin 250 looks like and contents of the pack Powder and solvent for solution for injection Each pack contains: one vial with powder (250 IU) one vial with 5 ml water for injections one disposable syringe one transfer system with integral filter one butterfly cannula Further pack sizes: Haemoctin 500 Powder and solvent for solution for injection Each pack contains: one vial with powder (500 IU) one vial with 10 ml water for injections one disposable syringe one transfer system with integral filter one butterfly cannula Haemoctin 1000 Powder and solvent for solution for injection Each pack contains: one vial with powder (1000 IU) one vial with 10 ml water for injections one disposable syringe one transfer system with integral filter one butterfly cannula Marketing Authorization Holder and Manufacturer Biotest Pharma GmbH Landsteinerstrasse Dreieich Germany Phone: Fax: info@biotest.de This medicine is registered in the countries of the EU under the following trade names: Germany, Estonia, Greece, Lithuania, Malta, Portugal, Czech Republic, Hungary, Romania: Haemoctin SDH 250 Italy, Spain, Belgium, Netherlands, United Kingdom: Haemoctin 250 Slovenia: Haemoctin 250 i.e. Austria: Haemoctin SDH 50 I.E./ml Date of information: March 2008 Haemoctin DE/H/0478/ /MR EPAR 19/40

20 THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL OR HEALTHCARE PROFESSIONALS ONLY: 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: Degree of haemorrhage/ Type of surgical procedure Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding More extensive haemarthrosis, muscle bleeding or haematoma Factor VIII level required (%) Frequency of doses (hours)/duration of therapy (days) Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved Repeat infusion every 12 to 24 hours for 3-4 days or more until pain and acute disability are resolved. Life threatening haemorrhages Repeat infusion every 8 to 24 hours until threat is resolved. Surgery Minor including tooth extraction Major (pre- and postoperative) 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 VIII activity of 30-60%. 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 Haemoctin DE/H/0478/ /MR EPAR 20/40

21 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, 500 or 1000 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 doctors with experience in the care of patients with haemophilia. See also 3. HOW TO USE HAEMOCTIN 250. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties 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. Pharmacokinetic properties 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 ± 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. Haemoctin DE/H/0478/ /MR EPAR 21/40

22 Preclinical safety data 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. Haemoctin DE/H/0478/ /MR EPAR 22/40

23 Haemoctin 500 Powder and solvent for solution for injection Human plasma derived coagulation factor VIII Please 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, ask your doctor or 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 listed gets serious, or if you notice any side-effects not listed in this leaflet, please tell your doctor or pharmacist. This package insert contains: 1. What is Haemoctin 500 and what it is used for? 2. Before you use Haemoctin How to use Haemoctin Possible side-effects 5. How to store Haemoctin Further information 1. WHAT IS HAEMOCTIN 500 AND WHAT IT IS USED FOR? Haemoctin 500 is a medicine derived from human plasma. It contains the coagulation factor VIII, which is necessary for a normal course of blood coagulation. Haemoctin 500 is used for the haemostasis and thus belongs to the group of so-called antihaemorrhagics. After reconstitution of the dry substance in 10 ml water for injections the product contains 50 IU (international units) coagulation factor VIII per ml of liquid. One vial contains 500 IU blood coagulation factor VIII. For determination of the potency (quantity of IU) the chromogenic factor VIII coagulation assay according to European Pharmacopoeia is applied. Here, a chemical colour reaction is used to evaluate the coagulation activity of the preparation. The specific activity of Haemoctin 500 is approximately 100 IU/mg protein. Administration of Haemoctin 500: Haemoctin 500 is suitable for treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). Haemoctin 500 does not contain von Willebrand factor in pharmacologically effective quantities, and is therefore not suitable for the treatment of von Willebrand's disease. 2. BEFORE YOU USE HAEMOCTIN 500 Do not use Haemoctin 500, if you are allergic (hypersensitive) to coagulation factor VIII or to any of the other ingredients. Haemoctin DE/H/0478/ /MR EPAR 23/40