1

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT ReFacto 250 IU powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ReFacto is prepared as a lyophilised powder for solution for injection containing nominally 250 IU moroctocog alfa (recombinant coagulation factor VIII) per vial. The product reconstituted with 4 ml of 0.9% w/v sodium chloride solution for injection contains approximately 62.5 IU/ml moroctocog alfa. The potency (IU) is determined using the European Pharmacopoeia chromogenic assay against the World Health Organization (WHO) international standard. The specific activity of ReFacto is approximately 13000 IU/mg protein. ReFacto contains recombinant coagulation factor VIII (INN=moroctocog alfa). Moroctocog alfa is a purified protein that has 1438 amino acids. It has an amino acid sequence that is comparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted), and post-translational modifications that are similar to those of the plasma-derived molecule. Recombinant coagulation factor VIII is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line. ReFacto is not purified from human blood and contains no preservatives or added animal or human components in the final formulation. For excipients, see 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications ReFacto is indicated for the control and prevention of haemorrhagic episodes and for routine and surgical prophylaxis in patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia). ReFacto does not contain von Willebrand factor and hence is not indicated in von Willebrand’s disease. 4.2 Posology and method of administration Posology ReFacto is appropriate for use in adults and children of all ages, including new-borns. Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required. Dosage adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.

3

One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl per IU/kg administered. The required dosage is determined using the following formula:

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

The following table can be used to guide dosing in bleeding episodes and surgery:

Type of Haemorrhage

Factor VIII Level Required (%)

Frequency of Doses (h)/ Duration of Therapy (d)

Minor Early haemarthrosis, superficial muscle or soft tissue and oral bleeds

20-40

Repeat every 12 to 24 hours as necessary until resolved. At least 1 day, depending upon the severity of the haemorrhage.

Moderate Haemorrhages into muscles. Mild trauma capitis. Minor operations including tooth extraction. Haemorrhages into the oral cavity.

30-60

Repeat infusion every 12-24 hours for 3-4 days or until adequate wound healing. For tooth extraction a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient.

Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic haemorrhages. Fractures. Major operations.

60-100

Repeat infusion every 8-24 hours until threat is resolved or until adequate wound healing in the case of surgery, then therapy for at least another 7 days.

Precise monitoring of the replacement therapy by means of coagulation analysis (plasma factor VIII activity) is recommended, particularly for surgical intervention. Product is labelled on the basis of the chromogenic assay and, if clinically indicated, factor VIII blood levels should be determined using the chromogenic assay. The one-stage clotting assay may be used if the chromogenic assay is not available, however it must be noted that the one-stage clotting assay yields results which are lower than the values obtained with the chromogenic assay. For routine prophylaxis to prevent spontaneous musculoskeletal haemorrhage in patients with haemophilia A, doses of 10 to 50 IU of factor VIII per kg body weight should be given at least twice a week. In infants and children, shorter dosage intervals or higher doses may be necessary. Patients using ReFacto should be monitored for the development of factor VIII inhibitors. If 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. If the inhibitor is present at levels less than 10 Bethesda Units (B.U.) per ml, administration of additional antihaemophilic factor may neutralise the inhibitor. Inhibitor titers above 10 Bethesda Units per ml may make haemostasis control with antiheamophilic factor impractical because of the very large dose required. Appropriate specific anti-inhibitor treatment should be given. Method of Administration Treatment with ReFacto should be initiated under the supervision of a physician experienced in the treatment of haemophilia A.

4

ReFacto is administered by intravenous (IV) injection after reconstitution of the lyophilised powder for injection with 0.9% w/v sodium chloride solution for injection (provided). The reconstituted solution should be used within 3 hours. ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level. 4.3 Contraindications Known severe hypersensitivity to the active substance or to mouse, hamster or bovine proteins or 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. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic or anaphylactic reactions occur, administration of ReFacto should be stopped immediately, and appropriate medical management should be given, which may include treatment for shock. Activity-neutralising antibodies (inhibitors) have been detected in patients receiving coagulation factor VIII-containing products. If plasma AHF levels fail to reach expected levels or if bleeding is not controlled after adequate dosage, appropriate laboratory tests to detect the presence of inhibitor should be performed. As with all coagulation factor VIII products, previously untreated patients should be monitored for the development of inhibitors that should be titrated in Bethesda Units using appropriate biological testing. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been conducted with ReFacto. 4.6 Use during pregnancy and lactation No animal reproduction and lactation studies have been conducted with ReFacto. It is not known whether ReFacto can affect reproductive capacity or cause foetal harm when given to pregnant women. ReFacto should be administered to pregnant and lactating women only if the benefit outweighs the risk. 4.7 Effects on ability to drive and use machines No studies on the ability to drive and use machines have been performed. 4.8 Undesirable effects As with the intravenous administration of any protein product, the following undesirable effects may be observed after administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, or manifestations of allergic reactions. During clinical studies with ReFacto, 72 adverse events probably or possibly related to therapy were reported for 32013 infusions (0.2%). These were nausea, dyspnea, venous access catheter complications, headache, paresthesia, transaminase elevation, altered taste, fever, dizziness, chills, injection site reaction, somnolence, fatigue, perspiration, pain, anaphylaxis, acne, pruritus, rash, blurred vision, anorexia, gastritis, gastroenteritis, tachycardia, coughing, trauma, moniliasis, increased bilirubin, slight creatine phosphokinase muscle brain isotype (CK MB) elevation and muscle weakness. The occurrence of neutralising antibodies (inhibitors) is well known in the treatment of patients with

5

haemophilia A. Twenty-nine out of 101 (29%) previously untreated patients (PUPs) developed inhibitors: 10 out of 101 (10%) with a high titer (> 10 B.U.) and 19 out of 101 (19%) with a low titer (< 10 B.U.). One of 112 (0.8%) previously treated patients (PTPs) developed an inhibitor after 93 exposure days with ReFacto. If any reaction takes place that is thought to be related to the administration of ReFacto, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. 4.9 Overdose No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Antihaemorrhagic Blood Coagulation Factor VIII; ATC Code: B02BD02 ReFacto, recombinant coagulation factor VIII is a glycoprotein with an approximate molecular mass of 170,000 Da consisting of 1438 amino acids. ReFacto is a recombinant DNA-based substance which has functional characteristics comparable to those of endogenous factor VIII. Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Factor VIII activity is greatly reduced in patients with haemophilia A and therefore replacement therapy is necessary. 5.2 Pharmacokinetic properties In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay, the circulating mean half-life for ReFacto was 14.1 ± 4.5 hours (ranged from 8.3-26.3), which was not statistically significantly different from plasma-derived Antihaemophilic Factor (Human), Hemofil®M which had a circulating mean half-life of 13.1 ± 3.5 hours (ranged from 8.3-22.3). Mean in vivo recovery of ReFacto in plasma was 2.9 ± 0.5 IU/dl per IU/kg (ranged from 2.2-3.9). This was comparable to the mean recovery observed in plasma for pdAHF which was 2.7 ± 0.4 IU/dl per IU/kg (ranged from 2.0-3.5). Results obtained from this well-controlled, pharmacokinetic study, using a central laboratory for the analysis of plasma samples, showed that the one-stage assay gave results which were approximately 50% of the values obtained with the chromogenic assay. In additional clinical studies, pharmacokinetic parameters measured using the chromogenic assay were determined for previously treated patients (PTPs) and previously untreated patients (PUPs). In PTPs (n=87), ReFacto had a recovery of 2.7 ± 0.4 IU/dl per IU/kg (ranged from 1.2 to 3.9). In PUPs (n=46), ReFacto had a mean recovery of 1.9 ± 0.5 IU/dl per IU/kg (ranged from 0.3 to 3.2). Mean modified elimination half-life of ReFacto in PTPs (n=70) is 10.5 ± 2.6 hours. Mean modified elimination half-life of ReFacto in PUPs (n=11) is 7.6 ± 2.7 hours. Recovery and half-life did not change over time (12 months) for PTPs or PUPs. 5.3 Preclinical safety data In preclinical studies ReFacto was used to safely and effectively restore haemostasis. ReFacto and plasma derived factor VIII demonstrated similar toxicological profiles when tested in repeated dose toxicology studies in animals.

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ReFacto shows no genotoxic properties in the mouse micronucleus assay. No other mutagenicity studies and no investigations on carcinogenesis, impairment of fertility or foetal development have been conducted.

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6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Sucrose Calcium chloride L-histidine Polysorbate 80 Sodium chloride Solvent Sodium chloride 6.2 Incompatibilities ReFacto should not be mixed with other medicinal products. Only the provided injection accessories should be used. ReFacto should not be mixed with other infusion solutions. 6.3 Shelf-life 2 years. The reconstituted solution should be used immediately or within 3 hours. 6.4 Special precautions for storage Store at 2°C - 8°C. Do not freeze. For the purpose of ambulatory use, the product may be removed from the refrigerator for one single period of maximum 3 months at room temperature (do not store above 25°C). The product may not be returned to refrigerated storage after storage at room temperature. During storage, avoid prolonged exposure of ReFacto vial to light. 6.5 Nature and contents of container The container-closure system for ReFacto consists of an injection vial, 10 ml, glass type I, stoppered with a bromobutyl rubber stopper and sealed with a flip off seal. Each vial of ReFacto is provided with one 8 ml vial containing 4 ml of 0.9% w/v sodium chloride solution for injection, and accessories required for reconstitution and administration (double-ended needle, alcohol swabs, filter needle, infusion set, and disposable syringe). 6.6 Instructions for use and handling, and disposal Do not use after the expiry date given on the label. Reconstitute lyophilised ReFacto powder for injection with the supplied 0.9% w/v sodium chloride solution for injection using the sterile double-ended needle. Gently rotate the vial until all powder is dissolved. After reconstitution, the solution is drawn through the sterile filter needle (supplied) into a sterile disposable syringe. The solution should be discarded if visible particulate matter or discolouration is observed. After reconstitution, the medicinal product should be used immediately or within 3 hours.

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Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER

Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany

8. MARKETING AUTHORISATION NUMBER 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF TEXT

9

1. NAME OF THE MEDICINAL PRODUCT ReFacto 500 IU powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ReFacto is prepared as a lyophilised powder for solution for injection containing nominally 500 IU moroctocog alfa (recombinant coagulation factor VIII) per vial. The product reconstituted with 4 ml of 0.9% w/v sodium chloride solution for injection contains approximately 125 IU/ml moroctocog alfa. The potency (IU) is determined using the European Pharmacopoeia chromogenic assay against the World Health Organization (WHO) international standard. The specific activity of ReFacto is approximately 13000 IU/mg protein. ReFacto contains recombinant coagulation factor VIII (INN=moroctocog alfa). Moroctocog alfa is a purified protein that has 1438 amino acids. It has an amino acid sequence that is comparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted), and post-translational modifications that are similar to those of the plasma-derived molecule. Recombinant coagulation factor VIII is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line. ReFacto is not purified from human blood and contains no preservatives or added animal or human components in the final formulation. For excipients, see 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications ReFacto is indicated for the control and prevention of haemorrhagic episodes and for routine and surgical prophylaxis in patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia). ReFacto does not contain von Willebrand factor and hence is not indicated in von Willebrand’s disease. 4.2 Posology and method of administration Posology ReFacto is appropriate for use in adults and children of all ages, including new-borns. Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required. Dosage adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.

10

One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl per IU/kg administered. The required dosage is determined using the following formula:

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

The following table can be used to guide dosing in bleeding episodes and surgery:

Type of Haemorrhage

Factor VIII Level Required (%)

Frequency of Doses (h)/ Duration of Therapy (d)

Minor Early haemarthrosis, superficial muscle or soft tissue and oral bleeds

20-40

Repeat every 12 to 24 hours as necessary until resolved. At least 1 day, depending upon the severity of the haemorrhage.

Moderate Haemorrhages into muscles. Mild trauma capitis. Minor operations including tooth extraction. Haemorrhages into the oral cavity.

30-60

Repeat infusion every 12-24 hours for 3-4 days or until adequate wound healing. For tooth extraction a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient.

Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic haemorrhages. Fractures. Major operations.

60-100

Repeat infusion every 8-24 hours until threat is resolved or until adequate wound healing in the case of surgery, then therapy for at least another 7 days.

Precise monitoring of the replacement therapy by means of coagulation analysis (plasma factor VIII activity) is recommended, particularly for surgical intervention. Product is labelled on the basis of the chromogenic assay and, if clinically indicated, factor VIII blood levels should be determined using the chromogenic assay. The one-stage clotting assay may be used if the chromogenic assay is not available, however it must be noted that the one-stage clotting assay yields results which are lower than the values obtained with the chromogenic assay. For routine prophylaxis to prevent spontaneous musculoskeletal haemorrhage in patients with haemophilia A, doses of 10 to 50 IU of factor VIII per kg body weight should be given at least twice a week. In infants and children, shorter dosage intervals or higher doses may be necessary. Patients using ReFacto should be monitored for the development of factor VIII inhibitors. If 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. If the inhibitor is present at levels less than 10 Bethesda Units (B.U.) per ml, administration of additional antihaemophilic factor may neutralise the inhibitor. Inhibitor titers above 10 Bethesda Units per ml may make haemostasis control with antiheamophilic factor impractical because of the very large dose required. Appropriate specific anti-inhibitor treatment should be given.

11

Method of Administration Treatment with ReFacto should be initiated under the supervision of a physician experienced in the treatment of haemophilia A. ReFacto is administered by intravenous (IV) injection after reconstitution of the lyophilised powder for injection with 0.9% w/v sodium chloride solution for injection (provided). The reconstituted solution should be used within 3 hours. ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level. 4.3 Contraindications Known severe hypersensitivity to the active substance or to mouse, hamster or bovine proteins or 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. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic or anaphylactic reactions occur, administration of ReFacto should be stopped immediately, and appropriate medical management should be given, which may include treatment for shock. Activity-neutralising antibodies (inhibitors) have been detected in patients receiving coagulation factor VIII-containing products. If plasma AHF levels fail to reach expected levels or if bleeding is not controlled after adequate dosage, appropriate laboratory tests to detect the presence of inhibitor should be performed. As with all coagulation factor VIII products, previously untreated patients should be monitored for the development of inhibitors that should be titrated in Bethesda Units using appropriate biological testing. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been conducted with ReFacto. 4.6 Use during pregnancy and lactation No animal reproduction and lactation studies have been conducted with ReFacto. It is not known whether ReFacto can affect reproductive capacity or cause foetal harm when given to pregnant women. ReFacto should be administered to pregnant and lactating women only if the benefit outweighs the risk. 4.7 Effects on ability to drive and use machines No studies on the ability to drive and use machines have been performed. 4.8 Undesirable effects As with the intravenous administration of any protein product, the following undesirable effects may be observed after administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, or manifestations of allergic reactions. During clinical studies with ReFacto, 72 adverse events probably or possibly related to therapy were reported for 32013 infusions (0.2%). These were nausea, dyspnea, venous access catheter complications, headache, paresthesia, transaminase elevation, altered taste, fever, dizziness, chills, injection site reaction, somnolence, fatigue, perspiration, pain, anaphylaxis, acne, pruritus, rash, blurred vision, anorexia, gastritis, gastroenteritis, tachycardia, coughing, trauma,

12

moniliasis, increased bilirubin, slight creatine phosphokinase muscle brain isotype (CK MB) elevation and muscle weakness. The occurrence of neutralising antibodies (inhibitors) is well known in the treatment of patients with haemophilia A. Twenty-nine out of 101 (29%) previously untreated patients (PUPs) developed inhibitors: 10 out of 101 (10%) with a high titer (> 10 B.U.) and 19 out of 101 (19%) with a low titer (< 10 B.U.). One of 112 (0.8%) previously treated patients (PTPs) developed an inhibitor after 93 exposure days with ReFacto. If any reaction takes place that is thought to be related to the administration of ReFacto, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. 4.9 Overdose No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Antihaemorrhagic Blood Coagulation Factor VIII; ATC Code: B02BD02 ReFacto, recombinant coagulation factor VIII is a glycoprotein with an approximate molecular mass of 170,000 Da consisting of 1438 amino acids. ReFacto is a recombinant DNA-based substance which has functional characteristics comparable to those of endogenous factor VIII. Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Factor VIII activity is greatly reduced in patients with haemophilia A and therefore replacement therapy is necessary. 5.2 Pharmacokinetic properties In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay, the circulating mean half-life for ReFacto was 14.1 ± 4.5 hours (ranged from 8.3-26.3), which was not statistically significantly different from plasma-derived Antihaemophilic Factor (Human), Hemofil®M which had a circulating mean half-life of 13.1 ± 3.5 hours (ranged from 8.3-22.3). Mean in vivo recovery of ReFacto in plasma was 2.9 ± 0.5 IU/dl per IU/kg (ranged from 2.2-3.9). This was comparable to the mean recovery observed in plasma for pdAHF which was 2.7 ± 0.4 IU/dl per IU/kg (ranged from 2.0-3.5). Results obtained from this well-controlled, pharmacokinetic study, using a central laboratory for the analysis of plasma samples, showed that the one-stage assay gave results which were approximately 50% of the values obtained with the chromogenic assay. In additional clinical studies, pharmacokinetic parameters measured using the chromogenic assay were determined for previously treated patients (PTPs) and previously untreated patients (PUPs). In PTPs (n=87), ReFacto had a recovery of 2.7 ± 0.4 IU/dl per IU/kg (ranged from 1.2 to 3.9). In PUPs (n=46), ReFacto had a mean recovery of 1.9 ± 0.5 IU/dl per IU/kg (ranged from 0.3 to 3.2). Mean modified elimination half-life of ReFacto in PTPs (n=70) is 10.5 ± 2.6 hours. Mean modified elimination half-life of ReFacto in PUPs (n=11) is 7.6 ± 2.7 hours. Recovery and half-life did not change over time (12 months) for PTPs or PUPs. 5.3 Preclinical safety data

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In preclinical studies ReFacto was used to safely and effectively restore haemostasis. ReFacto and plasma derived factor VIII demonstrated similar toxicological profiles when tested in repeated dose toxicology studies in animals. ReFacto shows no genotoxic properties in the mouse micronucleus assay. No other mutagenicity studies and no investigations on carcinogenesis, impairment of fertility or foetal development have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Sucrose Calcium chloride L-histidine Polysorbate 80 Sodium chloride Solvent Sodium chloride 6.2 Incompatibilities ReFacto should not be mixed with other medicinal products. Only the provided injection accessories should be used. ReFacto should not be mixed with other infusion solutions. 6.3 Shelf-life 2 years. The reconstituted solution should be used immediately or within 3 hours. 6.4 Special precautions for storage Store at 2°C - 8°C. Do not freeze. For the purpose of ambulatory use, the product may be removed from the refrigerator for one single period of maximum 3 months at room temperature (do not store above 25°C). The product may not be returned to refrigerated storage after storage at room temperature. During storage, avoid prolonged exposure of ReFacto vial to light. 6.5 Nature and contents of container The container-closure system for ReFacto consists of an injection vial, 10 ml, glass type I, stoppered with a bromobutyl rubber stopper and sealed with a flip off seal. Each vial of ReFacto is provided with one 8 ml vial containing 4 ml of 0.9% w/v sodium chloride solution for injection, and accessories required for reconstitution and administration (double-ended needle, alcohol swabs, filter needle, infusion set, and disposable syringe). 6.6 Instructions for use and handling, and disposal Do not use after the expiry date given on the label.

14

Reconstitute lyophilised ReFacto powder for injection with the supplied 0.9% w/v sodium chloride solution for injection using the sterile double-ended needle. Gently rotate the vial until all powder is dissolved. After reconstitution, the solution is drawn through the sterile filter needle (supplied) into a sterile disposable syringe. The solution should be discarded if visible particulate matter or discolouration is observed. After reconstitution, the medicinal product should be used immediately or within 3 hours. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER

Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany

8. MARKETING AUTHORISATION NUMBER 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF TEXT

15

1. NAME OF THE MEDICINAL PRODUCT ReFacto 1000 IU powder and solvent for solution for injection 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ReFacto is prepared as a lyophilised powder for solution for injection containing nominally 1000 IU moroctocog alfa (recombinant coagulation factor VIII) per vial. The product reconstituted with 4 ml of 0.9% w/v sodium chloride solution for injection contains approximately 250 IU/ml moroctocog alfa. The potency (IU) is determined using the European Pharmacopoeia chromogenic assay against the World Health Organization (WHO) international standard. The specific activity of ReFacto is approximately 13000 IU/mg protein. ReFacto contains recombinant coagulation factor VIII (INN=moroctocog alfa). Moroctocog alfa is a purified protein that has 1438 amino acids. It has an amino acid sequence that is comparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted), and post-translational modifications that are similar to those of the plasma-derived molecule. Recombinant coagulation factor VIII is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line. ReFacto is not purified from human blood and contains no preservatives or added animal or human components in the final formulation. For excipients, see 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications ReFacto is indicated for the control and prevention of haemorrhagic episodes and for routine and surgical prophylaxis in patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia). ReFacto does not contain von Willebrand factor and hence is not indicated in von Willebrand’s disease. 4.2 Posology and method of administration Posology ReFacto is appropriate for use in adults and children of all ages, including new-borns. Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required. Dosage adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.

16

One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl per IU/kg administered. The required dosage is determined using the following formula:

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

The following table can be used to guide dosing in bleeding episodes and surgery:

Type of Haemorrhage

Factor VIII Level Required (%)

Frequency of Doses (h)/ Duration of Therapy (d)

Minor Early haemarthrosis, superficial muscle or soft tissue and oral bleeds

20-40

Repeat every 12 to 24 hours as necessary until resolved. At least 1 day, depending upon the severity of the haemorrhage.

Moderate Haemorrhages into muscles. Mild trauma capitis. Minor operations including tooth extraction. Haemorrhages into the oral cavity.

30-60

Repeat infusion every 12-24 hours for 3-4 days or until adequate wound healing. For tooth extraction a single infusion plus oral antifibrinolytic therapy within 1 hour may be sufficient.

Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic haemorrhages. Fractures. Major operations.

60-100

Repeat infusion every 8-24 hours until threat is resolved or until adequate wound healing in the case of surgery, then therapy for at least another 7 days.

Precise monitoring of the replacement therapy by means of coagulation analysis (plasma factor VIII activity) is recommended, particularly for surgical intervention. Product is labelled on the basis of the chromogenic assay and, if clinically indicated, factor VIII blood levels should be determined using the chromogenic assay. The one-stage clotting assay may be used if the chromogenic assay is not available, however it must be noted that the one-stage clotting assay yields results which are lower than the values obtained with the chromogenic assay. For routine prophylaxis to prevent spontaneous musculoskeletal haemorrhage in patients with haemophilia A, doses of 10 to 50 IU of factor VIII per kg body weight should be given at least twice a week. In infants and children, shorter dosage intervals or higher doses may be necessary. Patients using ReFacto should be monitored for the development of factor VIII inhibitors. If 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. If the inhibitor is present at levels less than 10 Bethesda Units (B.U.) per ml, administration of additional antihaemophilic factor may neutralise the inhibitor. Inhibitor titers above 10 Bethesda Units per ml may make haemostasis control with antiheamophilic factor impractical because of the very large dose required. Appropriate specific anti-inhibitor treatment should be given.

17

Method of Administration Treatment with ReFacto should be initiated under the supervision of a physician experienced in the treatment of haemophilia A. ReFacto is administered by intravenous (IV) injection after reconstitution of the lyophilised powder for injection with 0.9% w/v sodium chloride solution for injection (provided). The reconstituted solution should be used within 3 hours. ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level. 4.3 Contraindications Known severe hypersensitivity to the active substance or to mouse, hamster or bovine proteins or 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. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic or anaphylactic reactions occur, administration of ReFacto should be stopped immediately, and appropriate medical management should be given, which may include treatment for shock. Activity-neutralising antibodies (inhibitors) have been detected in patients receiving coagulation factor VIII-containing products. If plasma AHF levels fail to reach expected levels or if bleeding is not controlled after adequate dosage, appropriate laboratory tests to detect the presence of inhibitor should be performed. As with all coagulation factor VIII products, previously untreated patients should be monitored for the development of inhibitors that should be titrated in Bethesda Units using appropriate biological testing. 4.5 Interaction with other medicinal products and other forms of interaction No formal drug interaction studies have been conducted with ReFacto. 4.6 Use during pregnancy and lactation No animal reproduction and lactation studies have been conducted with ReFacto. It is not known whether ReFacto can affect reproductive capacity or cause foetal harm when given to pregnant women. ReFacto should be administered to pregnant and lactating women only if the benefit outweighs the risk. 4.7 Effects on ability to drive and use machines No studies on the ability to drive and use machines have been performed. 4.8 Undesirable effects As with the intravenous administration of any protein product, the following undesirable effects may be observed after administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, or manifestations of allergic reactions. During clinical studies with ReFacto, 72 adverse events probably or possibly related to therapy were reported for 32013 infusions (0.2%). These were nausea, dyspnea, venous access catheter complications, headache, paresthesia, transaminase elevation, altered taste, fever, dizziness, chills, injection site reaction, somnolence, fatigue, perspiration, pain, anaphylaxis, acne, pruritus, rash, blurred vision, anorexia, gastritis, gastroenteritis, tachycardia, coughing, trauma,

18

moniliasis, increased bilirubin, slight creatine phosphokinase muscle brain isotype (CK MB) elevation and muscle weakness. The occurrence of neutralising antibodies (inhibitors) is well known in the treatment of patients with haemophilia A. Twenty-nine out of 101 (29%) previously untreated patients (PUPs) developed inhibitors: 10 out of 101 (10%) with a high titer (> 10 B.U.) and 19 out of 101 (19%) with a low titer (< 10 B.U.). One of 112 (0.8%) previously treated patients (PTPs) developed an inhibitor after 93 exposure days with ReFacto. If any reaction takes place that is thought to be related to the administration of ReFacto, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. 4.9 Overdose No case of overdose has been reported. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Antihaemorrhagic Blood Coagulation Factor VIII; ATC Code: B02BD02 ReFacto, recombinant coagulation factor VIII is a glycoprotein with an approximate molecular mass of 170,000 Da consisting of 1438 amino acids. ReFacto is a recombinant DNA-based substance which has functional characteristics comparable to those of endogenous factor VIII. Activated factor VIII acts as a cofactor for activated factor IX accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Factor VIII activity is greatly reduced in patients with haemophilia A and therefore replacement therapy is necessary. 5.2 Pharmacokinetic properties In a crossover pharmacokinetic study of eighteen (18) previously treated patients using the chromogenic assay, the circulating mean half-life for ReFacto was 14.1 ± 4.5 hours (ranged from 8.3-26.3), which was not statistically significantly different from plasma-derived Antihaemophilic Factor (Human), Hemofil®M which had a circulating mean half-life of 13.1 ± 3.5 hours (ranged from 8.3-22.3). Mean in vivo recovery of ReFacto in plasma was 2.9 ± 0.5 IU/dl per IU/kg (ranged from 2.2-3.9). This was comparable to the mean recovery observed in plasma for pdAHF which was 2.7 ± 0.4 IU/dl per IU/kg (ranged from 2.0-3.5). Results obtained from this well-controlled, pharmacokinetic study, using a central laboratory for the analysis of plasma samples, showed that the one-stage assay gave results which were approximately 50% of the values obtained with the chromogenic assay. In additional clinical studies, pharmacokinetic parameters measured using the chromogenic assay were determined for previously treated patients (PTPs) and previously untreated patients (PUPs). In PTPs (n=87), ReFacto had a recovery of 2.7 ± 0.4 IU/dl per IU/kg (ranged from 1.2 to 3.9). In PUPs (n=46), ReFacto had a mean recovery of 1.9 ± 0.5 IU/dl per IU/kg (ranged from 0.3 to 3.2). Mean modified elimination half-life of ReFacto in PTPs (n=70) is 10.5 ± 2.6 hours. Mean modified elimination half-life of ReFacto in PUPs (n=11) is 7.6 ± 2.7 hours. Recovery and half-life did not change over time (12 months) for PTPs or PUPs. 5.3 Preclinical safety data

19

In preclinical studies ReFacto was used to safely and effectively restore haemostasis. ReFacto and plasma derived factor VIII demonstrated similar toxicological profiles when tested in repeated dose toxicology studies in animals. ReFacto shows no genotoxic properties in the mouse micronucleus assay. No other mutagenicity studies and no investigations on carcinogenesis, impairment of fertility or foetal development have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder Sucrose Calcium chloride L-histidine Polysorbate 80 Sodium chloride Solvent Sodium chloride 6.2 Incompatibilities ReFacto should not be mixed with other medicinal products. Only the provided injection accessories should be used. ReFacto should not be mixed with other infusion solutions. 6.3 Shelf-life 2 years. The reconstituted solution should be used immediately or within 3 hours. 6.4 Special precautions for storage Store at 2°C - 8°C. Do not freeze. For the purpose of ambulatory use, the product may be removed from the refrigerator for one single period of maximum 3 months at room temperature (do not store above 25°C). The product may not be returned to refrigerated storage after storage at room temperature. During storage, avoid prolonged exposure of ReFacto vial to light. 6.5 Nature and contents of container The container-closure system for ReFacto consists of an injection vial, 10 ml, glass type I, stoppered with a bromobutyl rubber stopper and sealed with a flip off seal. Each vial of ReFacto is provided with one 8 ml vial containing 4 ml of 0.9% w/v sodium chloride solution for injection, and accessories required for reconstitution and administration (double-ended needle, alcohol swabs, filter needle, infusion set, and disposable syringe). 6.6 Instructions for use and handling, and disposal Do not use after the expiry date given on the label.

20

Reconstitute lyophilised ReFacto powder for injection with the supplied 0.9% w/v sodium chloride solution for injection using the sterile double-ended needle. Gently rotate the vial until all powder is dissolved. After reconstitution, the solution is drawn through the sterile filter needle (supplied) into a sterile disposable syringe. The solution should be discarded if visible particulate matter or discolouration is observed. After reconstitution, the medicinal product should be used immediately or within 3 hours. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER

Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany

8. MARKETING AUTHORISATION NUMBER 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF TEXT

21

ANNEX II A. MANUFACTURING AUTHORISATION HOLDER

RESPONSIBLE FOR BATCH RELEASE AND MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE

B. CONDITIONS OF THE MARKETING AUTHORISATION

22

A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE AND MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE

Name and address of the manufacturer of the biological active substance Pharmacia Upjohn AB Lindhagensgatan 133 SE-11287 Stockholm Sweden Manufacturing Authorisation, issued on 05 December 1997 by Läkemedelsverket, Medical Products Agency, Husargatan 8, Box 26, SE-751 03 Uppsala, Sweden. Name and address of the manufacturer responsible for batch release Pharmacia Upjohn AB Lindhagensgatan 133 SE-11287 Stockholm Sweden Manufacturing Authorisation issued on 05 December 1997 by Läkemedelsverket, Medical Products Agency, Husargatan 8, Box 26, SE-751 03 Uppsala, Sweden. B. CONDITIONS OF THE MARKETING AUTHORISATION • CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON

THE MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, 4.2).

23

ANNEX III LABELLING AND PACKAGE LEAFLET

24

A. LABELLING

25

PARTICULARS TO APPEAR ON REFACTO OUTER PACKAGING PRODUCT PACKAGING ReFacto 250 IU powder and solvent for solution for injection Moroctocog alfa (Recombinant coagulation factor VIII) Contents: One vial with powder for solution for injection nominally contains moroctocog alfa 250 IU and sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride. One vial containing 4 ml of 0.9% w/v sodium chloride solution for injection. One double-ended needle. One filter needle. One infusion set. One 10-ml sterile disposable syringe for administration. Two alcohol swabs. Package Leaflet with instructions for use. Store at 2°C - 8°C. Do not freeze. During storage, avoid prolonged exposure of ReFacto vial to light. ReFacto can be stored at room temperature (do not store above 25°C) for a single period up to 3 months. The product may not be returned to refrigerated storage after storage at room temperature. Date removed from refrigerator: __________ Reconstitute powder before use. See Package Leaflet with instructions for use. Discard any remaining reconstituted solution. Do not use after expiry date. Medicinal product subject to medical prescription. Keep out of the reach and sight of children. The reconstituted product nominally contains 62.5 IU/ml moroctocog alfa, sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride after reconstitution with 4 ml of 0.9% w/v sodium chloride solution for injection. Use immediately or within 3 hours after reconstitution. For intravenous single use administration only. EU/1/99/103/001 Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany Lot XXXXXXXX Expiry mm/yyyy Potency xxxx IU

26

PARTICULARS TO APPEAR ON THE REFACTO VIAL LABEL (IMMEDIATE PACKAGING) ReFacto 250 IU powder for solution for injection. Moroctocog alfa (Recombinant coagulation factor VIII) Each vial of powder for solution for injection nominally contains 62.5 IU/ml moroctocog alfa after reconstitution. For intravenous single use injection. Store at 2°C - 8°C. Protect from light. Genetics Institute of Europe B.V. Lot, Expiry (Exp.), Potency (Pot.): See front label.

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PARTICULARS TO APPEAR ON SOLVENT VIAL 0.9% w/v Sodium Chloride solution for injection 4 ml single use vial. Use the entire content. Do not use unless clear. Do not freeze. Do not store above 25°C. Sterile, nonpyrogenic. For reconstitution of the accompanying ReFacto powder for solution for injection as directed by physician. Genetics Institute of Europe B.V. Lot, Expiry (Exp.): See front label.

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PARTICULARS TO APPEAR ON REFACTO OUTER PACKAGING PRODUCT PACKAGING ReFacto 500 IU powder and solvent for solution for injection Moroctocog alfa (Recombinant coagulation factor VIII) Contents: One vial with powder for solution for injection nominally contains moroctocog alfa 500 IU and sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride. One vial containing 4 ml of 0.9% w/v sodium chloride solution for injection. One double-ended needle. One filter needle. One infusion set. One 10-ml sterile disposable syringe for administration. Two alcohol swabs. Package Leaflet with instructions for use. Store at 2°C - 8°C. Do not freeze. During storage, avoid prolonged exposure of ReFacto vial to light. ReFacto can be stored at room temperature (do not store above 25°C) for a single period up to 3 months. The product may not be returned to refrigerated storage after storage at room temperature. Date removed from refrigerator: __________ Reconstitute powder before use. See Package Leaflet with instructions for use. Discard any remaining reconstituted solution. Do not use after expiry date. Medicinal product subject to medical prescription. Keep out of the reach and sight of children. The reconstituted product nominally contains 125 IU/ml moroctocog alfa, sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride after reconstitution with 4 ml of 0.9% w/v sodium chloride solution for injection. Use immediately or within 3 hours after reconstitution. For intravenous single use administration only. EU/1/99/103/002 Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany Lot XXXXXXXX Expiry mm/yyyy Potency xxxx IU

29

PARTICULARS TO APPEAR ON THE REFACTO VIAL LABEL (IMMEDIATE PACKAGING) ReFacto 500 IU powder for solution for injection. Moroctocog alfa (Recombinant coagulation factor VIII) Each vial of powder for solution for injection nominally contains 125 IU/ml moroctocog alfa after reconstitution. For intravenous single use injection. Store at 2°C - 8°C. Protect from light. Genetics Institute of Europe B.V. Lot, Expiry (Exp.), Potency (Pot.): See front label.

30

PARTICULARS TO APPEAR ON SOLVENT VIAL 0.9% w/v Sodium Chloride solution for injection 4 ml single use vial. Use the entire content. Do not use unless clear. Do not freeze. Do not store above 25°C. Sterile, nonpyrogenic. For reconstitution of the accompanying ReFacto powder for injection as directed by physician. Genetics Institute of Europe B.V. Lot, Expiry (Exp.): See front label.

31

PARTICULARS TO APPEAR ON REFACTO OUTER PACKAGING PRODUCT PACKAGING ReFacto 1000 IU powder and solvent for solution for injection Moroctocog alfa (Recombinant coagulation factor VIII) Contents: One vial with powder for solution for injection nominally contains moroctocog alfa 1000 IU and sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride. One vial containing 4 ml of 0.9% w/v sodium chloride solution for injection. One double-ended needle. One filter needle. One infusion set. One 10-ml sterile disposable syringe for administration. Two alcohol swabs. Package Leaflet with instructions for use. Store at 2°C - 8°C. Do not freeze. During storage, avoid prolonged exposure of ReFacto vial to light. ReFacto can be stored at room temperature (do not store above 25°C) for a single period up to 3 months. The product may not be returned to refrigerated storage after storage at room temperature. Date removed from refrigerator: __________ Reconstitute powder before use. See Package Leaflet with instructions for use. Discard any remaining reconstituted solution. Do not use after expiry date. Medicinal product subject to medical prescription. Keep out of the reach and sight of children. The reconstituted product nominally contains 250 IU/ml moroctocog alfa, sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride after reconstitution with 4 ml of 0.9% w/v sodium chloride solution for injection. Use immediately or within 3 hours after reconstitution. For intravenous single use administration only. EU/1/99/103/003 Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany Lot XXXXXXXX Expiry mm/yyyy Potency xxxx IU

32

PARTICULARS TO APPEAR ON THE REFACTO VIAL LABEL (IMMEDIATE PACKAGING) ReFacto 1000 IU powder for solution for injection. Moroctocog alfa (Recombinant coagulation factor VIII) Each vial of powder for solution for injection nominally contains 250 IU/ml moroctocog alfa after reconstitution. For intravenous single use injection. Store at 2°C - 8°C. Protect from light. Genetics Institute of Europe B.V. Lot, Expiry (Exp.), Potency (Pot.): See front label.

33

PARTICULARS TO APPEAR ON SOLVENT VIAL 0.9% w/v Sodium Chloride solution for injection 4 ml single use vial. Use the entire content. Do not use unless clear. Do not freeze. Do not store above 25°C. Sterile, nonpyrogenic. For reconstitution of the accompanying ReFacto powder for injection as directed by physician. Genetics Institute of Europe B.V. Lot, Expiry (Exp.): See front label.

34

B. PACKAGE LEAFLET

35

PACKAGE LEAFLET ReFacto 250 IU powder and solvent for solution for injection Moroctocog alfa (Recombinant coagulation factor VIII) Important information about the product your doctor has prescribed for you. Please read carefully. What is in your medicine? ReFacto contains the following substances: Active substance: Moroctocog alfa (recombinant coagulation factor VIII) Other ingredients: Sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride Solvent: 0.9% w/v sodium chloride solution for injection Each ReFacto vial contains 250 IU of moroctocog alfa. After reconstitution with the supplied solvent, 1 ml of the prepared solution for injection contains 62.5 IU of moroctocog alfa. This product has been prescribed for you personally. Who is responsible for ReFacto? Marketing Authorisation Holder Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany Manufacturer Pharmacia & Upjohn AB Lindhagensgatan 133 SE-11287 Stockholm Sweden How is ReFacto packaged? The ReFacto package contains: One vial with white powder for solution for injection One vial of accompanying 0.9% w/v sodium chloride solution for injection for reconstitution One double-ended needle One filter needle One infusion set One 10 ml sterile disposable syringe for administration Two alcohol swabs How does ReFacto work? ReFacto is a highly purified, man-made form of human coagulation factor VIII.

36

Patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia) are deficient in coagulation factor VIII. ReFacto works by replacing factor VIII in haemophilia A patients to enable their blood to clot.

37

Who should use ReFacto? ReFacto is indicated in patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia) for the control and treatment of bleeding and for routine and surgical prophylaxis (prevention of bleeding). ReFacto is appropriate for use in adults and children of all ages, including new-borns. ReFacto does not contain von Willebrand factor and hence is not indicated in von Willebrand’s disease. When should ReFacto not be used? ReFacto should not be used by patients with a known history of severe hypersensitivity to the active substance contained in ReFacto, mouse, hamster or bovine proteins and other constituents of the preparation. What precautions should be observed during the use of ReFacto? See your doctor immediately if your bleeding does not stop as expected. If bleeding is not controlled with the usual dose, you should be monitored in order to determine if a factor VIII inhibitor is present. If you experience allergic reactions such as chest tightness, wheezing, dizziness or hives, itching, hypotension, anaphylaxis, stop the infusion immediately and contact your doctor. May ReFacto be used during pregnancy or while breast-feeding? If you are pregnant or breast-feeding you should only take ReFacto upon specific instructions from your physician. It is not known whether ReFacto can affect reproductive capacity or cause foetal harm when given to pregnant women. Your doctor may advise you to stop treatment with ReFacto if you are breast-feeding or become pregnant. Effects on ability to drive and use machines No studies on the effect of ReFacto on the ability to drive and use machines have been performed. What to be aware of if you are taking any other medicine You should consult with your doctor before taking other medicines with ReFacto. Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed. How is ReFacto used? Dosage Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required. Dosage adjustment for patients with kidney or liver impairment has not been studied in clinical trials.

38

One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl per IU/kg administered. The required dosage is determined using the following formula:

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

For routine prophylaxis to prevent spontaneous muscle and joint bleeding in patients with haemophilia A, doses of 10 to 50 IU of factor VIII per kg body weight should be given a least twice a week. In infants and children, shorter dosage intervals or higher doses may be necessary. Your doctor will decide the dose of ReFacto you will receive. This dose and duration will depend upon your individual needs for replacement factor VIII therapy. Your doctor may decide to change the dose of ReFacto you receive during your treatment. Reconstitution and Administration ReFacto is administered by intravenous (IV) injection after reconstitution of the lyophilised powder for injection with the supplied 0.9% w/v sodium chloride solution for injection (solvent). ReFacto should not be mixed with other infusion solutions.

Always wash your hands before performing the following reconstitution and administration procedures. Aseptic technique (meaning clean and germ free) should be used during the reconstitution procedure. Reconstitution 1. Allow the vials of lyophilised ReFacto and solvent to reach room temperature. 2. Remove the caps from the ReFacto vial and solvent vial, to expose the central portion of the

rubber stoppers. 3. Wipe the tops of both vials with the alcohol swab provided, or use another antiseptic solution and

allow to dry. 4. Remove the protective cover from one end of the sterile double-ended needle, and insert that end

of the needle into the solvent vial at the centre of the stopper. 5. Remove the protective cover from the other end of the sterile double-ended needle and insert this

end of the needle into the ReFacto vial at the centre of the stopper. 6. Fully invert the solvent vial to the vertical position and allow the solvent to run completely into

the ReFacto vial. 7. Once the transfer is complete, remove the double-ended needle from the ReFacto vial, recap and

properly discard the needle with the solvent vial. Note: If the solvent does not completely transfer into the ReFacto vial, DO NOT USE the contents of the vial. Note that it is acceptable for a small amount of fluid to remain in the solvent vial after transfer.

8. Gently rotate the vial to dissolve the powder. 9. The final solution should be inspected visually for particulate matter before administration. The

solution should appear clear and colourless.

39

ReFacto should be used immediately or within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration. Administration (Intravenous Injection) ReFacto should be administered using a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the sterile filter needle. 1. Using aseptic technique, attach the sterile filter needle to the sterile disposable syringe. Pull back

the syringe plunger to the 5 ml mark. 2. Insert the filter needle end into the stopper of the ReFacto vial. Push plunger forward to inject air

into the vial. 3. Invert the vial and withdraw the reconstituted solution into the syringe.

4. Remove and discard the filter needle. Note: If you use more than one vial of ReFacto the contents of multiple vials may be drawn into the same syringe through a separate, unused filter needle.

5. Attach the syringe to the Luer end of the infusion set and perform venipuncture as instructed by

your physician. After reconstitution, ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level. Please dispose of all unused solution, empty vials and used needles and syringes that might hurt others if not handled properly, in an appropriate container for dangerous waste. What effect could an overdose of ReFacto have? No information on symptoms of overdose is available. Are there any side effects associated with the use of ReFacto? As with the intravenous administration of any protein product, the following reactions may be observed following administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, discomfort at the injection site, or other manifestations of allergic reactions. Adverse reactions observed in clinical trials which were probably or possibly related to therapy were: nausea, shortness of breath, venous access catheter complications, headache, numbness, increased liver enzymes, altered taste, fever, dizziness, chills, injection site reaction, sleepiness, tiredness, sweating, pain, severe allergic reaction, acne, itching, rash, blurred vision, loss of appetite, stomach pain, gastroenteritis, rapid heart beat, coughing, trauma, yeast infection, slight increase in heart enzymes, increased bilirubin, and muscle weakness. Should you find it necessary to increase your usage of ReFacto in order to control a bleed, please contact your doctor immediately: your blood should be checked for inhibitors to factor VIII activity. If you experience any severe side effects or side effects which are not included here, please notify your doctor or pharmacist. How should ReFacto be stored? Keep all medicines and needles out of the reach and sight of children.

40

Store at 2°C - 8°C in a refrigerator. The product may be removed from such storage for one single period of maximum 3 months at room temperature (do not store above 25°C). The product may not be returned to refrigerated storage after storage at room temperature. During storage, avoid prolonged exposure of ReFacto vial to light. Use the reconstituted solution immediately or within 3 hours.

Use only the accessories provided in the box for reconstitution and administration. To prevent damage to the solvent vial, DO NOT freeze. Only use solutions which are clear and colourless. The expiry date is given on the outer box and vial labels. Do not use the product after this date. Last Revision

41

For additional information on this product, please contact any of the following representatives of the marketing authorisation holder:

Belgique/België/Belgien Italia AHP Pharma S.A. Wyeth Lederle S.p.A. 15, rue du Bosquet Via Nettunense, 90 B-1348 Louvain-la-Neuve I-04011 Aprilia (Latina) Tel. : +32-(0)10-494711 Tel. : +39-06-927151 Danmark Nederland Wyeth Lederle Danmark AHP Pharma B.V. Produktionsvej 24 Postbus 255 DK-2600 Glostrup NL-2130 AG Hoofddorp Tel. : +45-(0)44–888805 Tel. : +31-(0)23-5672567 Deutschland Österreich Wyeth Pharma GmbH Wyeth Lederle GmbH Schleebrüggenkamp 15 Storchengasse 1 D-48159 Münster A-1150 Wien Tel. : +49-(0)251-2040 Tel. : +43-(0)1-891140 Ελλάδα Portugal Wyeth Hellas S.A. Wyeth Lederle Portugal (Farma) Lda Wyeth Ελλάς AEBE Rua Dr. Antonio Loureiro Borges, 2 Λåùöüñï Κýðñïõ 126êáé 25çò Μαñôßïõ Arquiparque - Miraflores T.K. 164 52 Αργυρούπολη P-1495 Alges Αθήνα Tel. : +351-(0)1-4128200 Τηλ : +30-(0)1-9981600 Suomi España Wyeth Lederle Finland Wyeth Orfi SA Rajatorpantie 41C Ctra de Burgos, km. 23 FIN-01640 Vantaa San Sebastian de los Reyes Tel. : +358-(0)9-85202180 S-28700 Madrid Tel. : +34-91-3346565 Sverige Wyeth Lederle Nordiska AB France Råsundavägen 1-3 Wyeth Lederle, Le Wilson 2 S-16967 Solna 80, Avenue du Général de Gaulle Tel. : +46-(0)8-4703200 F-92031 Paris La Défense Cedex Tel. : +33-(0)1-41027000 United Kingdom Wyeth Laboratories Ireland Huntercombe Lane South Wyeth Laboratories Berkshire SL6 0PH - UK 765 South Circular Road Tel. : +44-(0)1628-604377 Islandbridge IRL – Dublin 8 Tel. :+353-(0)1-6709200 Luxembourg/Luxemburg AHP Pharma S.A. 15, rue du Bosquet B-1348 Louvain-la-Neuve Belgique Tel. : +32-(0)10- 494711

42

PACKAGE LEAFLET ReFacto 500 IU powder and solvent for solution for injection Moroctocog alfa (Recombinant coagulation factor VIII) Important information about the product your doctor has prescribed for you. Please read carefully. What is in your medicine? ReFacto contains the following substances: Active substance: Moroctocog alfa (recombinant coagulation factor VIII) Other ingredients: Sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride Solvent: 0.9% w/v sodium chloride solution for injection Each ReFacto vial contains 500 IU of moroctocog alfa. After reconstitution with the supplied solvent, 1 ml of the prepared solution for injection contains 125 IU of moroctocog alfa. This product has been prescribed for you personally. Who is responsible for ReFacto? Marketing Authorisation Holder Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany Manufacturer Pharmacia & Upjohn AB Lindhagensgatan 133 SE-11287 Stockholm Sweden How is ReFacto packaged? The ReFacto package contains: One vial with white powder for solution for injection One vial of accompanying 0.9% w/v sodium chloride solution for injection for reconstitution One double-ended needle One filter needle One infusion set One 10 ml sterile disposable syringe for administration Two alcohol swabs How does ReFacto work? ReFacto is a highly purified, man-made form of human coagulation factor VIII.

43

Patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia) are deficient in coagulation factor VIII. ReFacto works by replacing factor VIII in haemophilia A patients to enable their blood to clot.

44

Who should use ReFacto? ReFacto is indicated in patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia) for the control and treatment of bleeding and for routine and surgical prophylaxis (prevention of bleeding). ReFacto is appropriate for use in adults and children of all ages, including new-borns. ReFacto does not contain von Willebrand factor and hence is not indicated in von Willebrand’s disease. When should ReFacto not be used? ReFacto should not be used by patients with a known history of severe hypersensitivity to the active substance contained in ReFacto, mouse, hamster or bovine proteins and other constituents of the preparation. What precautions should be observed during the use of ReFacto? See your doctor immediately if your bleeding does not stop as expected. If bleeding is not controlled with the usual dose, you should be monitored in order to determine if a factor VIII inhibitor is present. If you experience allergic reactions such as chest tightness, wheezing, dizziness or hives, itching, hypotension, anaphylaxis, stop the infusion immediately and contact your doctor. May ReFacto be used during pregnancy or while breast-feeding? If you are pregnant or breast-feeding you should only take ReFacto upon specific instructions from your physician. It is not known whether ReFacto can affect reproductive capacity or cause foetal harm when given to pregnant women. Your doctor may advise you to stop treatment with ReFacto if you are breast-feeding or become pregnant. Effects on ability to drive and use machines No studies on the effect of ReFacto on the ability to drive and use machines have been performed. What to be aware of if you are taking any other medicine You should consult with your doctor before taking other medicines with ReFacto. Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed. How is ReFacto used? Dosage Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required. Dosage adjustment for patients with kidney or liver impairment has not been studied in clinical trials.

45

One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl per IU/kg administered. The required dosage is determined using the following formula:

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

For routine prophylaxis to prevent spontaneous muscle and joint bleeding in patients with haemophilia A, doses of 10 to 50 IU of factor VIII per kg body weight should be given a least twice a week. In infants and children, shorter dosage intervals or higher doses may be necessary. Your doctor will decide the dose of ReFacto you will receive. This dose and duration will depend upon your individual needs for replacement factor VIII therapy. Your doctor may decide to change the dose of ReFacto you receive during your treatment. Reconstitution and Administration ReFacto is administered by intravenous (IV) injection after reconstitution of the lyophilised powder for injection with the supplied 0.9% w/v sodium chloride solution for injection (solvent). ReFacto should not be mixed with other infusion solutions.

Always wash your hands before performing the following reconstitution and administration procedures. Aseptic technique (meaning clean and germ free) should be used during the reconstitution procedure. Reconstitution 1. Allow the vials of lyophilised ReFacto and solvent to reach room temperature. 2. Remove the caps from the ReFacto vial and solvent vial, to expose the central portion of the

rubber stoppers. 3. Wipe the tops of both vials with the alcohol swab provided, or use another antiseptic solution and

allow to dry. 4. Remove the protective cover from one end of the sterile double-ended needle, and insert that end

of the needle into the solvent vial at the centre of the stopper. 5. Remove the protective cover from the other end of the sterile double-ended needle and insert this

end of the needle into the ReFacto vial at the centre of the stopper. 6. Fully invert the solvent vial to the vertical position and allow the solvent to run completely into

the ReFacto vial. 7. Once the transfer is complete, remove the double-ended needle from the ReFacto vial, recap and

properly discard the needle with the solvent vial. Note: If the solvent does not completely transfer into the ReFacto vial, DO NOT USE the contents of the vial. Note that it is acceptable for a small amount of fluid to remain in the solvent vial after transfer.

8. Gently rotate the vial to dissolve the powder. 9. The final solution should be inspected visually for particulate matter before administration. The

solution should appear clear and colourless.

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ReFacto should be used immediately or within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration. Administration (Intravenous Injection) ReFacto should be administered using a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the sterile filter needle. 1. Using aseptic technique, attach the sterile filter needle to the sterile disposable syringe. Pull back

the syringe plunger to the 5 ml mark. 2. Insert the filter needle end into the stopper of the ReFacto vial. Push plunger forward to inject air

into the vial. 3. Invert the vial and withdraw the reconstituted solution into the syringe.

4. Remove and discard the filter needle. Note: If you use more than one vial of ReFacto the contents of multiple vials may be drawn into the same syringe through a separate, unused filter needle.

5. Attach the syringe to the Luer end of the infusion set and perform venipuncture as instructed by

your physician. After reconstitution, ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level. Please dispose of all unused solution, empty vials and used needles and syringes that might hurt others if not handled properly, in an appropriate container for dangerous waste. What effect could an overdose of ReFacto have? No information on symptoms of overdose is available. Are there any side effects associated with the use of ReFacto? As with the intravenous administration of any protein product, the following reactions may be observed following administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, discomfort at the injection site, or other manifestations of allergic reactions. Adverse reactions observed in clinical trials which were probably or possibly related to therapy were: nausea, shortness of breath, venous access catheter complications, headache, numbness, increased liver enzymes, altered taste, fever, dizziness, chills, injection site reaction, sleepiness, tiredness, sweating, pain, severe allergic reaction, acne, itching, rash, blurred vision, loss of appetite, stomach pain, gastroenteritis, rapid heart beat, coughing, trauma, yeast infection, slight increase in heart enzymes, increased bilirubin, and muscle weakness. Should you find it necessary to increase your usage of ReFacto in order to control a bleed, please contact your doctor immediately: your blood should be checked for inhibitors to factor VIII activity. If you experience any severe side effects or side effects which are not included here, please notify your doctor or pharmacist.

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How should ReFacto be stored? Keep all medicines and needles out of the reach and sight of children. Store at 2°C - 8°C in a refrigerator. The product may be removed from such storage for one single period of maximum 3 months at room temperature (do not store above 25°C). The product may not be returned to refrigerated storage after storage at room temperature. During storage, avoid prolonged exposure of ReFacto vial to light. Use the reconstituted solution immediately or within 3 hours.

Use only the accessories provided in the box for reconstitution and administration. To prevent damage to the solvent vial, DO NOT freeze. Only use solutions which are clear and colourless. The expiry date is given on the outer box and vial labels. Do not use the product after this date. Last Revision

48

For additional information on this product, please contact any of the following representatives of the marketing authorisation holder:

Belgique/België/Belgien Italia AHP Pharma S.A. Wyeth Lederle S.p.A. 15, rue du Bosquet Via Nettunense, 90 B-1348 Louvain-la-Neuve I-04011 Aprilia (Latina) Tel. : +32-(0)10-494711 Tel. : +39-06-927151 Danmark Nederland Wyeth Lederle Danmark AHP Pharma B.V. Produktionsvej 24 Postbus 255 DK-2600 Glostrup NL-2130 AG Hoofddorp Tel. : +45-(0)44–888805 Tel. : +31-(0)23-5672567 Deutschland Österreich Wyeth Pharma GmbH Wyeth Lederle GmbH Schleebrüggenkamp 15 Storchengasse 1 D-48159 Münster A-1150 Wien Tel. : +49-(0)251-2040 Tel. : +43-(0)1-891140 Ελλάδα Portugal Wyeth Hellas S.A. Wyeth Lederle Portugal (Farma) Lda Wyeth Ελλάς AEBE Rua Dr. Antonio Loureiro Borges, 2 Λåùöüñï Κýðñïõ 126êáé 25çò Μαñôßïõ Arquiparque - Miraflores T.K. 164 52 Αργυρούπολη P-1495 Alges Αθήνα Tel. : +351-(0)1-4128200 Τηλ : +30-(0)1-9981600 Suomi España Wyeth Lederle Finland Wyeth Orfi SA Rajatorpantie 41C Ctra de Burgos, km. 23 FIN-01640 Vantaa San Sebastian de los Reyes Tel. : +358-(0)9-85202180 S-28700 Madrid Tel. : +34-91-3346565 Sverige Wyeth Lederle Nordiska AB France Råsundavägen 1-3 Wyeth Lederle, Le Wilson 2 S-16967 Solna 80, Avenue du Général de Gaulle Tel. : +46-(0)8-4703200 F-92031 Paris La Défense Cedex Tel. : +33-(0)1-41027000 United Kingdom Wyeth Laboratories Ireland Huntercombe Lane South Wyeth Laboratories Berkshire SL6 0PH - UK 765 South Circular Road Tel. : +44-(0)1628-604377 Islandbridge IRL – Dublin 8 Tel. :+353-(0)1-6709200 Luxembourg/Luxemburg AHP Pharma S.A. 15, rue du Bosquet B-1348 Louvain-la-Neuve Belgique Tel. : +32-(0)10- 494711

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PACKAGE LEAFLET ReFacto 1000 IU powder and solvent for solution for injection Moroctocog alfa (Recombinant coagulation factor VIII) Important information about the product your doctor has prescribed for you. Please read carefully. What is in your medicine? ReFacto contains the following substances: Active substance: Moroctocog alfa (recombinant coagulation factor VIII) Other ingredients: Sucrose, calcium chloride, L-histidine, polysorbate 80 and sodium chloride Solvent: 0.9% w/v sodium chloride solution for injection Each ReFacto vial contains 1000 IU of moroctocog alfa. After reconstitution with the supplied solvent, 1 ml of the prepared solution for injection contains 250 IU of moroctocog alfa. This product has been prescribed for you personally. Who is responsible for ReFacto? Marketing Authorisation Holder Genetics Institute of Europe B.V. Lochhamerstrasse 11 D-82152 Martinsried Germany Manufacturer Pharmacia & Upjohn AB Lindhagensgatan 133 SE-11287 Stockholm Sweden How is ReFacto packaged? The ReFacto package contains: One vial with white powder for solution for injection One vial of accompanying 0.9% w/v sodium chloride solution for injection for reconstitution One double-ended needle One filter needle One infusion set One 10 ml sterile disposable syringe for administration Two alcohol swabs

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How does ReFacto work? ReFacto is a highly purified, man-made form of human coagulation factor VIII. Patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia) are deficient in coagulation factor VIII. ReFacto works by replacing factor VIII in haemophilia A patients to enable their blood to clot. Who should use ReFacto? ReFacto is indicated in patients with haemophilia A (congenital factor VIII deficiency or classic haemophilia) for the control and treatment of bleeding and for routine and surgical prophylaxis (prevention of bleeding). ReFacto is appropriate for use in adults and children of all ages, including new-borns. ReFacto does not contain von Willebrand factor and hence is not indicated in von Willebrand’s disease. When should ReFacto not be used? ReFacto should not be used by patients with a known history of severe hypersensitivity to the active substance contained in ReFacto, mouse, hamster or bovine proteins and other constituents of the preparation. What precautions should be observed during the use of ReFacto? See your doctor immediately if your bleeding does not stop as expected. If bleeding is not controlled with the usual dose, you should be monitored in order to determine if a factor VIII inhibitor is present. If you experience allergic reactions such as chest tightness, wheezing, dizziness or hives, itching, hypotension, anaphylaxis, stop the infusion immediately and contact your doctor. May ReFacto be used during pregnancy or while breast-feeding? If you are pregnant or breast-feeding you should only take ReFacto upon specific instructions from your physician. It is not known whether ReFacto can affect reproductive capacity or cause foetal harm when given to pregnant women. Your doctor may advise you to stop treatment with ReFacto if you are breast-feeding or become pregnant. Effects on ability to drive and use machines No studies on the effect of ReFacto on the ability to drive and use machines have been performed. What to be aware of if you are taking any other medicine You should consult with your doctor before taking other medicines with ReFacto. Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.

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How is ReFacto used? Dosage Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required. Dosage adjustment for patients with kidney or liver impairment has not been studied in clinical trials. One International Unit (IU) of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl per IU/kg administered. The required dosage is determined using the following formula:

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

For routine prophylaxis to prevent spontaneous muscle and joint bleeding in patients with haemophilia A, doses of 10 to 50 IU of factor VIII per kg body weight should be given a least twice a week. In infants and children, shorter dosage intervals or higher doses may be necessary. Your doctor will decide the dose of ReFacto you will receive. This dose and duration will depend upon your individual needs for replacement factor VIII therapy. Your doctor may decide to change the dose of ReFacto you receive during your treatment. Reconstitution and Administration ReFacto is administered by intravenous (IV) injection after reconstitution of the lyophilised powder for injection with the supplied 0.9% w/v sodium chloride solution for injection (solvent). ReFacto should not be mixed with other infusion solutions.

Always wash your hands before performing the following reconstitution and administration procedures. Aseptic technique (meaning clean and germ free) should be used during the reconstitution procedure. Reconstitution 1. Allow the vials of lyophilised ReFacto and solvent to reach room temperature. 2. Remove the caps from the ReFacto vial and solvent vial, to expose the central portion of the

rubber stoppers. 3. Wipe the tops of both vials with the alcohol swab provided, or use another antiseptic solution and

allow to dry. 4. Remove the protective cover from one end of the sterile double-ended needle, and insert that end

of the needle into the solvent vial at the centre of the stopper. 5. Remove the protective cover from the other end of the sterile double-ended needle and insert this

end of the needle into the ReFacto vial at the centre of the stopper. 6. Fully invert the solvent vial to the vertical position and allow the solvent to run completely into

the ReFacto vial. 7. Once the transfer is complete, remove the double-ended needle from the ReFacto vial, recap and

properly discard the needle with the solvent vial.

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Note: If the solvent does not completely transfer into the ReFacto vial, DO NOT USE the contents of the vial. Note that it is acceptable for a small amount of fluid to remain in the solvent vial after transfer.

8. Gently rotate the vial to dissolve the powder. 9. The final solution should be inspected visually for particulate matter before administration. The

solution should appear clear and colourless. ReFacto should be used immediately or within 3 hours after reconstitution. The reconstituted solution may be stored at room temperature prior to administration. Administration (Intravenous Injection) ReFacto should be administered using a single sterile disposable plastic syringe. In addition, the solution should be withdrawn from the vial using the sterile filter needle. 1. Using aseptic technique, attach the sterile filter needle to the sterile disposable syringe. Pull back

the syringe plunger to the 5 ml mark. 2. Insert the filter needle end into the stopper of the ReFacto vial. Push plunger forward to inject air

into the vial. 3. Invert the vial and withdraw the reconstituted solution into the syringe.

4. Remove and discard the filter needle. Note: If you use more than one vial of ReFacto the contents of multiple vials may be drawn into the same syringe through a separate, unused filter needle.

5. Attach the syringe to the Luer end of the infusion set and perform venipuncture as instructed by

your physician. After reconstitution, ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient’s comfort level. Please dispose of all unused solution, empty vials and used needles and syringes that might hurt others if not handled properly, in an appropriate container for dangerous waste. What effect could an overdose of ReFacto have? No information on symptoms of overdose is available. Are there any side effects associated with the use of ReFacto? As with the intravenous administration of any protein product, the following reactions may be observed following administration: headache, fever, chills, flushing, nausea, vomiting, lethargy, discomfort at the injection site, or other manifestations of allergic reactions. Adverse reactions observed in clinical trials which were probably or possibly related to therapy were: nausea, shortness of breath, venous access catheter complications, headache, numbness, increased liver enzymes, altered taste, fever, dizziness, chills, injection site reaction, sleepiness, tiredness, sweating, pain, severe allergic reaction, acne, itching, rash, blurred vision, loss of appetite, stomach pain, gastroenteritis, rapid heart beat, coughing, trauma, yeast infection, slight increase in heart enzymes, increased bilirubin, and muscle weakness.

53

Should you find it necessary to increase your usage of ReFacto in order to control a bleed, please contact your doctor immediately: your blood should be checked for inhibitors to factor VIII activity. If you experience any severe side effects or side effects which are not included here, please notify your doctor or pharmacist. How should ReFacto be stored? Keep all medicines and needles out of the reach and sight of children. Store at 2°C - 8°C in a refrigerator. The product may be removed from such storage for one single period of maximum 3 months at room temperature (do not store above 25°C). The product may not be returned to refrigerated storage after storage at room temperature. During storage, avoid prolonged exposure of ReFacto vial to light. Use the reconstituted solution immediately or within 3 hours.

Use only the accessories provided in the box for reconstitution and administration. To prevent damage to the solvent vial, DO NOT freeze. Only use solutions which are clear and colourless. The expiry date is given on the outer box and vial labels. Do not use the product after this date. Last Revision

54

For additional information on this product, please contact any of the following representatives of the marketing authorisation holder:

Belgique/België/Belgien Italia AHP Pharma S.A. Wyeth Lederle S.p.A. 15, rue du Bosquet Via Nettunense, 90 B-1348 Louvain-la-Neuve I-04011 Aprilia (Latina) Tel. : +32-(0)10-494711 Tel. : +39-06-927151 Danmark Nederland Wyeth Lederle Danmark AHP Pharma B.V. Produktionsvej 24 Postbus 255 DK-2600 Glostrup NL-2130 AG Hoofddorp Tel. : +45-(0)44–888805 Tel. : +31-(0)23-5672567 Deutschland Österreich Wyeth Pharma GmbH Wyeth Lederle GmbH Schleebrüggenkamp 15 Storchengasse 1 D-48159 Münster A-1150 Wien Tel. : +49-(0)251-2040 Tel. : +43-(0)1-891140 Ελλάδα Portugal Wyeth Hellas S.A. Wyeth Lederle Portugal (Farma) Lda Wyeth Ελλάς AEBE Rua Dr. Antonio Loureiro Borges, 2 Λåùöüñï Κýðñïõ 126êáé 25çò Μαñôßïõ Arquiparque - Miraflores T.K. 164 52 Αργυρούπολη P-1495 Alges Αθήνα Tel. : +351-(0)1-4128200 Τηλ : +30-(0)1-9981600 Suomi España Wyeth Lederle Finland Wyeth Orfi SA Rajatorpantie 41C Ctra de Burgos, km. 23 FIN-01640 Vantaa San Sebastian de los Reyes Tel. : +358-(0)9-85202180 S-28700 Madrid Tel. : +34-91-3346565 Sverige Wyeth Lederle Nordiska AB France Råsundavägen 1-3 Wyeth Lederle, Le Wilson 2 S-16967 Solna 80, Avenue du Général de Gaulle Tel. : +46-(0)8-4703200 F-92031 Paris La Défense Cedex Tel. : +33-(0)1-41027000 United Kingdom Wyeth Laboratories Ireland Huntercombe Lane South Wyeth Laboratories Berkshire SL6 0PH - UK 765 South Circular Road Tel. : +44-(0)1628-604377 Islandbridge IRL – Dublin 8 Tel. :+353-(0)1-6709200 Luxembourg/Luxemburg AHP Pharma S.A. 15, rue du Bosquet B-1348 Louvain-la-Neuve Belgique Tel. : +32-(0)10- 494711

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