ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 4

2 1. NAME OF THE MEDICINAL PRODUCT BeneFIX 2. QUALITATIVE AND QUANTITATIVE COMPOSITION BeneFIX, recombinant coagulation factor IX, is prepared in lyophilised powder for solution for injection containing nominally 250 IU per vial. The product reconstituted with 5 ml water for injection contains approximately 50 IU/ml. The potency (IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International standard. The specific activity of BeneFIX, recombinant coagulation factor IX, is not less than 200 IU/mg protein. BeneFIX contains recombinant coagulation factor IX, (INN = nonacog alfa). Recombinant coagulation factor IX is a purified protein that has 415 amino acids in a single chain. It has a primary amino acid sequence that is identical to the Ala 148 allelic form of plasma-derived factor IX, and the post-translational modifications of the recombinant molecule appear to be almost identical to those of the plasma-derived molecule. Recombinant coagulation factor IX is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications BeneFIX, recombinant coagulation factor IX, is indicated for the control and prevention of hemorrhagic episodes and for routine and surgical prophylaxis in previously treated patients with hemophilia B (congenital factor IX deficiency or Christmas disease). Treatment with BeneFIX can be pursued in the presence of a factor IX inhibitor (neutralizing antibody) less than 5 Bethesda Units, if the patient continues to respond clinically with an increase in circulating factor IX. 4.2 Posology and Method of Administration Posology Dosage and duration of treatment is dependent on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and recovery of factor IX. Doses administered should be adjusted to the patient's clinical response and, when clinically indicated, factor IX activity recovery levels. Estimation of the required dose of BeneFIX, recombinant coagulation factor IX, can be based on the empirical finding that one unit of factor IX activity per kg body weight is expected to increase the circulating level of factor IX, on average by 0.8 IU/dL. The method of dose estimation is illustrated in the following example: number of factor IX body weight desired factor IX 1.2 I.U./kg I.U. required = (in kg) X increase (%) X 5

3 To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised, in particular, for surgical interventions. The following chart can be used to guide dosing in bleeding episodes and surgery: Type of Hemorrhage Circulating Factor IX Activity Required (%) Frequency of Doses (h) Duration of Therapy (d) Minor Uncomplicated hemarthroses, superficial muscle, or soft tissue Moderate Intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria Treat until bleeding stops and healing begins; about 2 to 7 days Major Pharynx, retropharynx, retroperitoneum, CNS, surgery Source: Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am 1993;7(6): The amount of BeneFIX to be infused, as well as the frequency of infusion, will vary with each patient and clinical situation. BeneFIX may also be administered at approximate doses of IU/kg on a regular schedule (2-3 times per week) for prophylaxis of bleeding. Even in the absence of factor IX inhibitor, the doses in the clinical efficacy studies have been increased in several patients. Therefore, close monitoring of factor IX plasma activity should be performed in order to adjust doses as appropriate. Patients using BeneFIX should be monitored for the development of factor IX inhibitors. If expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, biological testing should be performed in order to determine if a factor IX inhibitor is present. Patients with inhibitors Factor IX treatment remains efficacious in patients who developed factor IX inhibitors (neutralizing antibodies) less than 5 Bethesda Units (B.U.). Factor IX levels and inhibitor titres 6

4 must be assessed to ensure adequate replacement therapy. The control of bleeding episodes in patients with high titre inhibitors, typically above 5 B.U., may require an extensive factor IX infusion therapy, but might be impractical because of the very large dose needed to maintain adequate factor IX levels. If hemostasis can not be achieved with factor IX in the presence of high titre inhibitors, the use of (activated) prothrombin complex concentrate (PCC) or activated factor VII preparation must be considered. These therapies should be directed by physicians with experience in the care of patients with hemophilia B Method of Administration Treatment with BeneFIX, recombinant coagulation factor IX, should be initiated under the supervision of a physician experienced in the treatment of hemophilia B. BeneFIX is administered by IV infusion after reconstitution of the lyophilized powder for injection with Sterile Water for Injections, Ph. Eur. The reconstituted solution should be used immediately, ie., within three hours. Because the use of BeneFIX by continuous infusion has not been evaluated, BeneFIX should not be mixed with infusion solutions or be given in a drip. BeneFIX should be administered at a slow infusion rate. In most of the cases, an infusion rate of up to 4 ml per minute was well tolerated. 4.3 Contraindications BeneFIX, recombinant coagulation factor IX, may be contraindicated in patients with a known history of hypersensitivity to hamster proteins and other constituents of the preparation. 4.4 Special Warnings and Special Precautions for Use Activity-neutralizing antibodies (inhibitors) is a very rare event in PTPs receiving factor IXcontaining products. Since during clinical studies one PTP treated with BeneFIX developed a clinically relevant low responding inhibitor and experience on antigenicity with recombinant factor IX is still limited, patients treated with BeneFIX should be carefully monitored for the development of factor IX inhibitors that should be titrated in Bethesda Units using appropriate biological testing. Up to now, results have not been obtained from ongoing clinical studies on the treatment of previously untreated patients (PUPs), with BeneFIX. 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, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. It has been reported that patients developing inhibitors to factor IX may be at an increased risk of anaphylaxis with subsequent challenge with factor IX. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur. If any reaction takes place that is thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. Although BeneFIX contains only factor IX, the risk of thrombosis and disseminated intravascular coagulation (DIC) should be recognized. Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to neonates, or to patients at 7

5 risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIX should be weighed against the risk of these complications. 4.5 Interaction with Other Medicaments and Other Forms of Interaction No formal drug interaction studies have been conducted with BeneFIX, recombinant coagulation factor IX. 4.6 Pregnancy and Lactation No animal reproduction and lactation studies have been conducted with BeneFIX, recombinant coagulation factor IX. It is not known whether BeneFIX can affect reproductive capacity or cause fetal harm when given to pregnant women. BeneFIX should only be administered to pregnant and lactating women if clearly indicated. 4.7 Effects on Ability to Drive and Use Machines There are no indications that BeneFIX may impair the ability to drive or operate machines. 4.8 Undesirable Effects As with the administration of any protein product intravenously, 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. During clinical studies with BeneFIX, recombinant coagulation factor IX, conducted in previously treated patients the following reactions were reported as being directly or possibly-related to therapy: nausea, discomfort at the IV site, altered taste, burning sensation in jaw and skull, allergic rhinitis, lightheadedness, headache, dizziness, chest tightness, fever, phlebitis/cellulitis at IV site, drowsiness, dry cough/sneeze, rash, and a single hive. Twelve days after a dose of BeneFIX for a bleeding episode, one patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX is uncertain. The patient continued to be treated with BeneFIX. A clinically relevant, low responding inhibitor was detected in 1 out of 39 BeneFIX patients who had previously received plasma derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise in inhibitor or anaphylaxis. Patients treated with BeneFIX should be monitored for inhibitor development. 4.9 Overdose In case of accidental overdosage, the development of thrombotic complications or DIC is enhanced in patients at risk for these complications. Therefore, surveillance should be carried out to detect the first signs of thrombosis and consumptive coagulopathy complications. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic Properties Pharmacotherapeutic Group: Antihemorrhagic Blood Coagulation Factor IX; ATC Code: B02BD04 BeneFIX contains recombinant coagulation factor IX, (nonacog alfa). Recombinant coagulation factor IX is a single chain glycoprotein with an approximate molecular mass of 55,000 Daltons that is a member of the serine protease family of vitamin K-dependent coagulation factors. Recombinant coagulation factor IX is a recombinant DNA-based protein therapeutic which has structural and functional characteristics comparable to endogenous factor IX. Factor IX is activated by factor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, 8

6 activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Factor IX activity is absent or greatly reduced in patients with haemophilia B and substitution therapy may be required. Laboratory tests Temporary correction of partial thromboplastin time (PTT) was observed. No effect on normal prothrombin time was seen. 5.2 Pharmacokinetic Properties After single IV doses of 50 IU/kg of BeneFIX, recombinant coagulation factor IX, in 36 patients given as a 10-minute infusion, the maximum activities ranged from 20 to 64 IU/dl (mean of 37.9 ± 11 IU/dl) and the biologic half-life ranged from 11 to 36 hours (mean of 19.4 ± 5.4 hours). The in vivo recovery ranged from 18 to 62 % (mean 35.1 ±10.6 %). The in vivo recovery using BeneFIX was statistically significantly less (28% lower) than the recovery using a highly purified plasma-derived factor IX product. One International Unit of BeneFIX per kilogram of body weight administered showed a mean 0.8 IU/dl (0.4 to 1.3 IU/dl) increase in the circulating level of factor IX. 5.3 Preclinical Safety Data In preclinical studies BeneFIX, recombinant coagulation factor IX, was used to safely and effectively restore hemostasis. All pharmacological effects of BeneFIX observed in the preclinical studies are consistent with the safe administration of the product to patients. BeneFIX shows no genotoxic properties. No investigations on carcinogenicity, fertility impairment and foetal development have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of Excipients Sucrose Glycine L-Histidine Polysorbate 80 Ph. Eur. Ph. Eur. Ph. Eur. Ph. Eur. 6.2 Incompatibilities None known. 6.3 Shelf Life - the product as packaged for sale: When stored at a refrigerated temperature of 2 C to 8 C, BeneFIX, recombinant coagulation factor IX, is stable for 2 years. - the reconstituted solution should be used immediately, i.e., within three hours. 9

7 6.4 Special Precautions for Storage Do not use BeneFIX recombinant coagulation factor IX, after the expiry date on the label. Freezing should be avoided to prevent damage to the solvent vial. BeneFIX must be stored continuously by the wholesaler/pharmacist in a refrigerator at a temperature of 2 C to 8 C. The patient must also store the product continuously in a refrigerator at a temperature between 2 C to 8 C. For the purpose of ambulatory use the product may be removed from such storage for one single period of maximum 1 month at room temperature (up to 25 C). At the end of this period, the product should not be put back in the refrigerator. 6.5 Nature and Contents of Container The container closure system for the 250 IU dosage forms of BeneFIX consists of a 10-ml USP Type I glass vial, a 20-mm-OD rubber closure, and a 20-mm-diameter flip-off crimp seal. Each vial of BeneFIX is provided with one vial of sterile water for injections (Ph. Eur.), and accessories required for reconstitution and administration (see User Package Insert). 6.6 Instructions for Use/Handling Do not use after the expiry date given on the label. Detailed instructions for preparation and administration are contained in the User Package Insert provided with BeneFIX, recombinant coagulation factor IX. Reconstitute lyophilised BeneFIX powder for injection, with the supplied solvent (Sterile Water for Injections, Ph. Eur.) using the sterile double-ended transfer needle. Gently rotate the vial until all powder is dissolved. After reconstitution, the solution is drawn through the sterile filter spike (supplied) into a sterile disposable syringe. The solution should be discarded if visible particulate matter or discoloration is observed. After reconstitution, the drug product should be used within 3 hours. All unused solution, empty vials and used needles and syringes must be discarded appropriately. Store all medicinal products properly. Keep out of the reach of children. 7. MARKETING AUTHORIZATION HOLDER Genetics Institute of Europe, B.V. 8, rue de la Michodière Paris France 8. NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 9. DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION 10. DATE OF REVISION OF TEXT 10

8 1. NAME OF THE MEDICINAL PRODUCT BeneFIX 2. QUALITATIVE AND QUANTITATIVE COMPOSITION BeneFIX, recombinant coagulation factor IX, is prepared in lyophilised powder for solution for injection containing nominally 500 IU per vial. The product reconstituted with 5 ml water for injection contains approximately 100 IU/ml. The potency (IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International standard. The specific activity of BeneFIX, recombinant coagulation factor IX, is not less than 200 IU/mg protein. BeneFIX contains recombinant coagulation factor IX, (INN = nonacog alfa). Recombinant coagulation factor IX is a purified protein that has 415 amino acids in a single chain. It has a primary amino acid sequence that is identical to the Ala 148 allelic form of plasma-derived factor IX, and the post-translational modifications of the recombinant molecule appear to be almost identical to those of the plasma-derived molecule. Recombinant coagulation factor IX is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications BeneFIX, recombinant coagulation factor IX, is indicated for the control and prevention of hemorrhagic episodes and for routine and surgical prophylaxis in previously treated patients with hemophilia B (congenital factor IX deficiency or Christmas disease). Treatment with BeneFIX can be pursued in the presence of a factor IX inhibitor (neutralizing antibody) less than 5 Bethesda Units, if the patient continues to respond clinically with an increase in circulating factor IX. 4.2 Posology and Method of Administration Posology Dosage and duration of treatment is dependent on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and recovery of factor IX. Doses administered should be adjusted to the patient's clinical response and, when clinically indicated, factor IX activity recovery levels. Estimation of the required dose of BeneFIX, recombinant coagulation factor IX, can be based on the empirical finding that one unit of factor IX activity per kg body weight is expected to increase the circulating level of factor IX, on average by 0.8 IU/dL. The method of dose estimation is illustrated in the following example: number of factor IX body weight desired factor IX 1.2 I.U./kg I.U. required = (in kg) X increase (%) X 11

9 To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised, in particular, for surgical interventions. The following chart can be used to guide dosing in bleeding episodes and surgery: Type of Hemorrhage Circulating Factor IX Activity Required (%) Frequency of Doses (h) Duration of Therapy (d) Minor Uncomplicated hemarthroses, superficial muscle, or soft tissue Moderate Intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria Treat until bleeding stops and healing begins; about 2 to 7 days Major Pharynx, retropharynx, retroperitoneum, CNS, surgery Source: Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am 1993;7(6): The amount of BeneFIX to be infused, as well as the frequency of infusion, will vary with each patient and clinical situation. BeneFIX may also be administered at approximate doses of IU/kg on a regular schedule (2-3 times per week) for prophylaxis of bleeding. Even in the absence of factor IX inhibitor, the doses in the clinical efficacy studies have been increased in several patients. Therefore, close monitoring of factor IX plasma activity should be performed in order to adjust doses as appropriate. Patients using BeneFIX should be monitored for the development of factor IX inhibitors. If expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, biological testing should be performed in order to determine if a factor IX inhibitor is present. Patients with inhibitors Factor IX treatment remains efficacious in patients who developed factor IX inhibitors (neutralizing antibodies) less than 5 Bethesda Units (B.U.). Factor IX levels and inhibitor titres 12

10 must be assessed to ensure adequate replacement therapy. The control of bleeding episodes in patients with high titre inhibitors, typically above 5 B.U., may require an extensive factor IX infusion therapy, but might be impractical because of the very large dose needed to maintain adequate factor IX levels. If hemostasis can not be achieved with factor IX in the presence of high titre inhibitors, the use of (activated) prothrombin complex concentrate (PCC) or activated factor VII preparation must be considered. These therapies should be directed by physicians with experience in the care of patients with hemophilia B Method of Administration Treatment with BeneFIX, recombinant coagulation factor IX, should be initiated under the supervision of a physician experienced in the treatment of hemophilia B. BeneFIX is administered by IV infusion after reconstitution of the lyophilized powder for injection with Sterile Water for Injections, Ph. Eur. The reconstituted solution should be used immediately, ie., within three hours. Because the use of BeneFIX by continuous infusion has not been evaluated, BeneFIX should not be mixed with infusion solutions or be given in a drip. BeneFIX should be administered at a slow infusion rate. In most of the cases, an infusion rate of up to 4 ml per minute was well tolerated. 4.3 Contraindications BeneFIX, recombinant coagulation factor IX, may be contraindicated in patients with a known history of hypersensitivity to hamster proteins and other constituents of the preparation. 4.4 Special Warnings and Special Precautions for Use Activity-neutralizing antibodies (inhibitors) is a very rare event in PTPs receiving factor IXcontaining products. Since during clinical studies one PTP treated with BeneFIX developed a clinically relevant low responding inhibitor and experience on antigenicity with recombinant factor IX is still limited, patients treated with BeneFIX should be carefully monitored for the development of factor IX inhibitors that should be titrated in Bethesda Units using appropriate biological testing. Up to now, results have not been obtained from ongoing clinical studies on the treatment of previously untreated patients (PUPs), with BeneFIX. 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, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. It has been reported that patients developing inhibitors to factor IX may be at an increased risk of anaphylaxis with subsequent challenge with factor IX. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur. If any reaction takes place that is thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. Although BeneFIX contains only factor IX, the risk of thrombosis and disseminated intravascular coagulation (DIC) should be recognized. Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the use of factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to neonates, or to patients at 13

11 risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIX should be weighed against the risk of these complications. 4.5 Interaction with Other Medicaments and Other Forms of Interaction No formal drug interaction studies have been conducted with BeneFIX, recombinant coagulation factor IX. 4.6 Pregnancy and Lactation No animal reproduction and lactation studies have been conducted with BeneFIX, recombinant coagulation factor IX. It is not known whether BeneFIX can affect reproductive capacity or cause fetal harm when given to pregnant women. BeneFIX should only be administered to pregnant and lactating women if clearly indicated. 4.7 Effects on Ability to Drive and Use Machines There are no indications that BeneFIX may impair the ability to drive or operate machines. 4.8 Undesirable Effects As with the administration of any protein product intravenously, 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. During clinical studies with BeneFIX, recombinant coagulation factor IX, conducted in previously treated patients the following reactions were reported as being directly or possibly-related to therapy: nausea, discomfort at the IV site, altered taste, burning sensation in jaw and skull, allergic rhinitis, lightheadedness, headache, dizziness, chest tightness, fever, phlebitis/cellulitis at IV site, drowsiness, dry cough/sneeze, rash, and a single hive. Twelve days after a dose of BeneFIX for a bleeding episode, one patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX is uncertain. The patient continued to be treated with BeneFIX. A clinically relevant, low responding inhibitor was detected in 1 out of 39 BeneFIX patients who had previously received plasma derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise in inhibitor or anaphylaxis. Patients treated with BeneFIX should be monitored for inhibitor development. 4.9 Overdose In case of accidental overdosage, the development of thrombotic complications or DIC is enhanced in patients at risk for these complications. Therefore, surveillance should be carried out to detect the first signs of thrombosis and consumptive coagulopathy complications. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic Properties Pharmacotherapeutic Group: Antihemorrhagic Blood Coagulation Factor IX; ATC Code: B02BD04 BeneFIX contains recombinant coagulation factor IX, (nonacog alfa). Recombinant coagulation factor IX is a single chain glycoprotein with an approximate molecular mass of 55,000 Daltons that is a member of the serine protease family of vitamin K-dependent coagulation factors recombinant coagulation factor IX is a recombinant DNA-based protein therapeutic which has structural and functional characteristics comparable to endogenous factor IX. Factor IX is activated by factor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, 14

12 activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Factor IX activity is absent or greatly reduced in patients with haemophilia B and substitution therapy may be required. Laboratory tests Temporary correction of partial thromboplastin time (PTT) was observed. No effect on normal prothrombin time was seen. 5.2 Pharmacokinetic Properties After single IV doses of 50 IU/kg of BeneFIX, recombinant coagulation factor IX, in 36 patients given as a 10-minute infusion, the maximum activities ranged from 20 to 64 IU/dl (mean of 37.9 ± 11 IU/dl) and the biologic half-life ranged from 11 to 36 hours (mean of 19.4 ± 5.4 hours). The in vivo recovery ranged from 18 to 62 % (mean 35.1 ±10.6 %). The in vivo recovery using BeneFIX was statistically significantly less (28% lower) than the recovery using a highly purified plasma-derived factor IX product. One International Unit of BeneFIX per kilogram of body weight administered showed a mean 0.8 IU/dl (0.4 to 1.3 IU/dl) increase in the circulating level of factor IX. 5.3 Preclinical Safety Data In preclinical studies BeneFIX, recombinant coagulation factor IX, was used to safely and effectively restore hemostasis. All pharmacological effects of BeneFIX observed in the preclinical studies are consistent with the safe administration of the product to patients. BeneFIX shows no genotoxic properties. No investigations on carcinogenicity, fertility impairment and foetal development have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of Excipients Sucrose Glycine L-Histidine Polysorbate 80 Ph. Eur. Ph. Eur. Ph. Eur. Ph. Eur. 6.2 Incompatibilities None known. 6.3 Shelf Life - the product as packaged for sale: When stored at a refrigerated temperature of 2 C to 8 C, BeneFIX, recombinant coagulation factor IX, is stable for 2 years. - the reconstituted solution should be used immediately, i.e., within three hours. 15

13 6.4 Special Precautions for Storage Do not use BeneFIX recombinant coagulation factor IX, after the expiry date on the label. Freezing should be avoided to prevent damage to the solvent vial. BeneFIX must be stored continuously by the wholesaler/pharmacist in a refrigerator at a temperature of 2 C to 8 C. The patient must also store the product continuously in a refrigerator at a temperature between 2 C to 8 C. For the purpose of ambulatory use the product may be removed from such storage for one single period of maximum 1 month at room temperature (up to 25 C). At the end of this period, the product should not be put back in the refrigerator. 6.5 Nature and Contents of Container The container closure system for the 500 IU dosage forms of BeneFIX consists of a 10-ml USP Type I glass vial, a 20-mm-OD rubber closure, and a 20-mm-diameter flip-off crimp seal. Each vial of BeneFIX is provided with one vial of sterile water for injections (Ph. Eur.), and accessories required for reconstitution and administration (see User Package Insert). 6.6 Instructions for Use/Handling Do not use after the expiry date given on the label. Detailed instructions for preparation and administration are contained in the User Package Insert provided with BeneFIX, recombinant coagulation factor IX. Reconstitute lyophilised BeneFIX powder for injection, with the supplied solvent (Sterile Water for Injections, Ph. Eur.) using the sterile double-ended transfer needle. Gently rotate the vial until all powder is dissolved. After reconstitution, the solution is drawn through the sterile filter spike (supplied) into a sterile disposable syringe. The solution should be discarded if visible particulate matter or discoloration is observed. After reconstitution, the drug product should be used within 3 hours. All unused solution, empty vials and used needles and syringes must be discarded appropriately. Store all medicinal products properly. Keep out of the reach of children. 7. MARKETING AUTHORIZATION HOLDER Genetics Institute of Europe, B.V. 8, rue de la Michodière Paris France 8. NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 9. DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION 10. DATE OF REVISION OF TEXT 16

14 17

15 1. NAME OF THE MEDICINAL PRODUCT BeneFIX 2. QUALITATIVE AND QUANTITATIVE COMPOSITION BeneFIX, recombinant coagulation factor IX, is prepared in lyophilised powder for solution for injection containing nominally 1000 IU per vial. The product reconstituted with 10 ml water for injection contains approximately 100 IU/ml. The potency (IU) is determined using an in vitro one-stage clotting assay against the World Health Organization (WHO) International standard. The specific activity of BeneFIX, recombinant coagulation factor IX, is not less than 200 IU/mg protein. BeneFIX contains recombinant coagulation factor IX, (INN = nonacog alfa). Recombinant coagulation factor IX is a purified protein that has 415 amino acids in a single chain. It has a primary amino acid sequence that is identical to the Ala 148 allelic form of plasma-derived factor IX, and the post-translational modifications of the recombinant molecule appear to be almost identical to those of the plasma-derived molecule. Recombinant coagulation factor IX is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection. 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications BeneFIX, recombinant coagulation factor IX, is indicated for the control and prevention of hemorrhagic episodes and for routine and surgical prophylaxis in previously treated patients with hemophilia B (congenital factor IX deficiency or Christmas disease). Treatment with BeneFIX can be pursued in the presence of a factor IX inhibitor (neutralizing antibody) less than 5 Bethesda Units, if the patient continues to respond clinically with an increase in circulating factor IX. 4.2 Posology and Method of Administration Posology Dosage and duration of treatment is dependent on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age and recovery of factor IX. Doses administered should be adjusted to the patient's clinical response and, when clinically indicated, factor IX activity recovery levels. Estimation of the required dose of BeneFIX, recombinant coagulation factor IX, can be based on the empirical finding that one unit of factor IX activity per kg body weight is expected to increase the circulating level of factor IX, on average by 0.8 IU/dL. The method of dose estimation is illustrated in the following example: number of factor IX body weight desired factor IX 1.2 I.U./kg I.U. required = (in kg) X increase (%) X 18

16 To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised, in particular, for surgical interventions. The following chart can be used to guide dosing in bleeding episodes and surgery: Type of Hemorrhage Circulating Factor IX Activity Required (%) Frequency of Doses (h) Duration of Therapy (d) Minor Uncomplicated hemarthroses, superficial muscle, or soft tissue Moderate Intramuscle or soft tissue with dissection, mucous membranes, dental extractions, or hematuria Treat until bleeding stops and healing begins; about 2 to 7 days Major Pharynx, retropharynx, retroperitoneum, CNS, surgery Source: Roberts HR, Eberst ME. Current management of hemophilia B. Hematol Oncol Clin North Am 1993;7(6):1269B1280. The amount of BeneFIX to be infused, as well as the frequency of infusion, will vary with each patient and clinical situation. BeneFIX may also be administered at approximate doses of IU/kg on a regular schedule (2-3 times per week) for prophylaxis of bleeding. Even in the absence of factor IX inhibitor, the doses in the clinical efficacy studies have been increased in several patients. Therefore, close monitoring of factor IX plasma activity should be performed in order to adjust doses as appropriate. Patients using BeneFIX should be monitored for the development of factor IX inhibitors. If expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, biological testing should be performed in order to determine if a factor IX inhibitor is present. Patients with inhibitors 19

17 Factor IX treatment remains efficacious in patients who developed factor IX inhibitors (neutralizing antibodies) less than 5 Bethesda Units (B.U.). Factor IX levels and inhibitor titres must be assessed to ensure adequate replacement therapy. The control of bleeding episodes in patients with high titre inhibitors, typically above 5 B.U., may require an extensive factor IX infusion therapy, but might be impractical because of the very large dose needed to maintain adequate factor IX levels. If hemostasis can not be achieved with factor IX in the presence of high titre inhibitors, the use of (activated) prothrombin complex concentrate (PCC) or activated factor VII preparation must be considered. These therapies should be directed by physicians with experience in the care of patients with hemophilia B Method of Administration Treatment with BeneFIX, recombinant coagulation factor IX, should be initiated under the supervision of a physician experienced in the treatment of hemophilia B. BeneFIX is administered by IV infusion after reconstitution of the lyophilized powder for injection with Sterile Water for Injections, Ph. Eur. The reconstituted solution should be used immediately, ie., within three hours. Because the use of BeneFIX by continous infusion has not been evaluated, BeneFIX should not be mixed with infusion solutions or be given in a drip. BeneFIX should be administered at a slow infusion rate. In most of the cases, an infusion rate of up to 4 ml per minute was well tolerated. 4.3 Contraindications BeneFIX, recombinant coagulation factor IX, may be contraindicated in patients with a known history of hypersensitivity to hamster proteins and other constituents of the preparation. 4.4 Special Warnings and Special Precautions for Use Activity-neutralizing antibodies (inhibitors) is a very rare event in PTPs receiving factor IXcontaining products. Since during clinical studies one PTP treated with BeneFIX developed a clinically relevant low responding inhibitor and experience on antigenicity with recombinant factor IX is still limited, patients treated with BeneFIX should be carefully monitored for the development of factor IX inhibitors that should be titrated in Bethesda Units using appropriate biological testing. Up to now, results have not been obtained from ongoing clinical studies on the treatment of previously untreated patients (PUPs), with BeneFIX. 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, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. It has been reported that patients developing inhibitors to factor IX may be at an increased risk of anaphylaxis with subsequent challenge with factor IX. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur. If any reaction takes place that is thought to be related to the administration of BeneFIX, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient. Although BeneFIX contains only factor IX, the risk of thrombosis and disseminated intravascular coagulation (DIC) should be recognized. Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the use of 20

18 factor IX-containing products may be potentially hazardous in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC). Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit of treatment with BeneFIX should be weighed against the risk of these complications. 4.5 Interaction with Other Medicaments and Other Forms of Interaction No formal drug interaction studies have been conducted with BeneFIX, recombinant coagulation factor IX. 4.6 Pregnancy and Lactation No animal reproduction and lactation studies have been conducted with BeneFIX, recombinant coagulation factor IX. It is not known whether BeneFIX can affect reproductive capacity or cause fetal harm when given to pregnant women. BeneFIX should only be administered to pregnant and lactating women if clearly indicated. 4.7 Effects on Ability to Drive and Use Machines There are no indications that BeneFIX may impair the ability to drive or operate machines. 4.8 Undesirable Effects As with the administration of any protein product intravenously, 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. During clinical studies with BeneFIX, recombinant coagulation factor IX, conducted in previously treated patients the following reactions were reported as being directly or possibly-related to therapy: nausea, discomfort at the IV site, altered taste, burning sensation in jaw and skull, allergic rhinitis, lightheadedness, headache, dizziness, chest tightness, fever, phlebitis/cellulitis at IV site, drowsiness, dry cough/sneeze, rash, and a single hive. Twelve days after a dose of BeneFIX for a bleeding episode, one patient developed a renal infarct. The relationship of the infarct to prior administration of BeneFIX is uncertain. The patient continued to be treated with BeneFIX. A clinically relevant, low responding inhibitor was detected in 1 out of 39 BeneFIX treated patients who had previously received plasma derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise in inhibitor or anaphylaxis. Patients treated with BeneFIX should be monitored for inhibitor development. 4.9 Overdose In case of accidental overdosage, the development of thrombotic complications or DIC is enhanced in patients at risk for these complications. Therefore, surveillance should be carried out to detect the first signs of thrombosis and consumptive coagulopathy complications. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic Properties Pharmacotherapeutic Group: Antihemorrhagic Blood Coagulation Factor IX; ATC Code: B02BD04 21

19 BeneFIX contains recombinant coagulation factor IX, (nonacog alfa). Recombinant coagulation factor IX is a single chain glycoprotein with an approximate molecular mass of 55,000 Daltons that is a member of the serine protease family of vitamin K-dependent coagulation factors. Recombinant coagulation factor IX, is a recombinant DNA-based protein therapeutic which has structural and functional characteristics comparable to endogenous factor IX. Factor IX is activated by factor VII/tissue factor complex in the extrinsic pathway as well as factor XIa in the intrinsic coagulation pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Factor IX activity is absent or greatly reduced in patients with haemophilia B and substitution therapy may be required. Laboratory tests Temporary correction of partial thromboplastin time (PTT) was observed. No effect on normal prothrombin time was seen. 5.2 Pharmacokinetic Properties After single IV doses of 50 IU/kg of BeneFIX, recombinant coagulation factor IX, in 36 patients given as a 10-minute infusion, the maximum activities ranged from 20 to 64 IU/dl (mean of 37.9 ± 11 IU/dl) and the biologic half-life ranged from 11 to 36 hours (mean of 19.4 ± 5.4 hours). The in vivo recovery ranged from 18 to 62 % (mean 35.1 ±10.6 %). The in vivo recovery using BeneFIX was statistically significantly less (28% lower) than the recovery using a highly purified plasma-derived factor IX product. One International Unit of BeneFIX per kilogram of body weight administered showed a mean 0.8 IU/dl (0.4 to 1.3 IU/dl) increase in the circulating level of factor IX. 5.3 Preclinical Safety Data In preclinical studies BeneFIX, recombinant coagulation factor IX, was used to safely and effectively restore hemostasis. All pharmacological effects of BeneFIX observed in the preclinical studies are consistent with the safe administration of the product to patients. BeneFIX shows no genotoxic properties. No investigations on carcinogenicity, fertility impairment and foetal development have been conducted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of Excipients Sucrose Glycine L-Histidine Polysorbate 80 Ph. Eur. Ph. Eur. Ph. Eur. Ph. Eur. 6.2 Incompatibilities None known. 6.3 Shelf Life - the product as packaged for sale: When stored at a refrigerated temperature of 2 C to 8 C, BeneFIX, recombinant coagulation factor IX, is stable for 2 years. 22

20 - the reconstituted solution should be used immediately, i.e., within three hours. 6.4 Special Precautions for Storage Do not use BeneFIX, recombinant coagulation factor IX, after the expiry date on the label. Freezing should be avoided to prevent damage to the solvent vial. BeneFIX must be stored continuously by the wholesaler/pharmacist in a refrigerator at a temperature of 2 C to 8 C. The patient must also store the product continuously in a refrigerator at a temperature between 2 C to 8 C. For the purpose of ambulatory use the product may be removed from such storage for one single period of maximum 1 month at room temperature (up to 25 C). At the end of this period, the product should not be put back in the refrigerator. 6.5 Nature and Contents of Container The container closure system for the 1000 IU dosage forms of BeneFIX consists of a 20-ml USP Type I glass vial, a 20-mm-OD rubber closure, and a 20-mm-diameter flip-off crimp seal. Each vial of BeneFIX is provided with one vial of sterile water for injections (Ph. Eur.), and accessories required for reconstitution and administration (see User Package Insert). 6.6 Instructions for Use/Handling Do not use after the expiry date given on the label. Detailed instructions for preparation and administration are contained in the User Package Insert provided with BeneFIX, recombinant coagulation factor IX. Reconstitute lyophilised BeneFIX powder for injection, with the supplied solvent (Sterile Water for Injections, Ph. Eur.) using the sterile double-ended transfer needle. Gently rotate the vial until all powder is dissolved. After reconstitution, the solution is drawn through the sterile filter spike (supplied) into a sterile disposable syringe. The solution should be discarded if visible particulate matter or discoloration is observed. After reconstitution, the drug product should be used within 3 hours. All unused solution, empty vials and used needles and syringes must be discarded appropriately. Store all medicinal products properly. Keep out of the reach of children. 7. MARKETING AUTHORIZATION HOLDER Genetics Institute of Europe, B.V. 8, rue de la Michodière Paris France 8. NUMBER IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 9. DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION 23

21 10. DATE OF REVISION OF TEXT 24

22 ANNEX II THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR IMPORT AND BATCH RELEASE, CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE, AND SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER 25

23 A. MANUFACTURING AUTHORISATION HOLDER Manufacturer responsible for import and batch release in the European Economic Area Baxter S.A. Boulevard René Branquart Lessines - Belgium Manufacturing authorization issued on 13 December 1994 by Ministère de la Santé Publique et de l Environnement, Inspection Générale de la Pharmacie, Quartier Vésale, 1010 Bruxelles, Belgium. B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted non renewable medical prescription. C. SPECIFIC OBLIGATIONS The Marketing Authorisation Holder shall complete the following programme of studies within the specified time frame, the results of which shall form the basis of the annual re-assessment of the benefit/risk profile. Clinical aspects 1. The Company will complete the current ongoing PTPs studies (C and C ) in which each of the 54 enrolled patients will remain on study for two years: the relevant final data will be submitted on 31 July Patients enrolled in the Surgery study (C ) will be followed for any adverse events for 12 months. The relevant information will be submitted on 31 July The need for an increased dosage of BeneFIX is not fully explained. During the clinical studies the dosing of BeneFIX increased in several patients for the treatment of bleeding episodes or prophylaxis. Genetics Institute will provide precise statistics on the relation between the dosage and the clinical response in all patients enrolled in the studies on 31 July The company is asked to carefully monitor for any evidence of thrombogenicity in the BeneFIX treated patients and to submit regularly the relevant data in the Periodic Safety Update Reports. Data on the intravascular coagulation markers (Prothrombin fragments 1 and 2, TAT and D-dimer) in at least 12 patients will be submitted in the first periodic safety update on 31 January The company is asked to carefully monitor PTPs treated with BeneFIX for any evidence of inhibitor occurrence and will submit the relevant data in accordance with the current EU legislation. Full report of the gathered experience will be also submitted by 31 July

24 ANNEX III LABELLING AND PACKAGE LEAFLET 27

25 A. LABELLING 28

26 Information to be Included on Folding Box (Outer Packaging) BeneFIX 250 IU Nonacog alfa (recombinant coagulation factor IX) Powder and solvent for solution for injection Contents: One vial with powder for injection contains nonacog alfa 250 IU and Excipients One vial of 5 ml Water for Injection, Ph. Eur. One double-ended needle One filter spike One mini-infusion set One 10 ml sterile disposable syringe for administration Two alcohol swabs Two plasters Package Insert with instructions for use Store at 2-8 C. BeneFIX, recombinant coagulation factor IX, can be stored at room temperature (15-25 C) for up to 1 month. Medicinal product subject to medical prescription. Keep out of the reach of children. The reconstituted product nominally contains 50 IU/ml nonacog alfa (recombinant coagulation factor IX), sucrose, glycine, L-histidine and polysorbate 80 after reconstitution with 5 ml of Water for Injection, Ph.Eur. For intravenous use, single dose administration only. See Package Insert for instructions for use. Number in The Community Register of Medicinal Products Genetics Institute of Europe, B.V Paris, France Logo LOT EXPIRY Potency xxx IU 29