Product Monograph. Key Scientific Information

Transcription

1 Product Monograph Key Scientific Information

2 Ko ate -DVI (Double Viral Inactivation) Infusion of more than 2 billion IUs worldwide with no confirmed cases of viral transmission.* Talecris is a leader in pathogen safety, specializing in plasma-derived therapies. Koāte -DVI effective treatment, commitment to supply. *Ko ate -DVI and Ko ate -HP As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Because this product is made from human blood it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. Hepatitis B vaccination is essential for patients with hemophilia A; vaccination is recommended at birth or at the time of diagnosis. Hepatitis A vaccination is also recommended for hemophilia patients who are hepatitis A seronegative. Please see accompanying Koāte -DVI Full Prescribing Information.

3 TABLE OF CONTENTS HISTORY OF HEMOPHILIA CARE Page ii 1. STRUCTURE AND FUNCTION OF FACTOR VIII (FVIII) Page 1 2. MANUFACTURE OF KOATE -DVI, ANTIHEMOPHILIC FACTOR (HUMAN) Page 3 3. PATHOGEN SAFETY Page 5 Plasma Donor Screening and Selection Plasma Donation Testing Plasma Inventory Hold and Look Back Plasma Manufacturing Pool Testing Pathogen Removal and Inactivation During Koāte -DVI Manufacturing Post-market Surveillance 4. PRODUCT CHARACTERISTICS Page 13 Composition and Clotting Activity Specific Activity Protein Composition Storage 5. CLINICAL STUDIES Page 15 Pharmacokinetics Treatment of Bleeding Episodes Neoantigenicity 6. DOSING AND ADMINISTRATION Page 17 General Approach to Treatment and Assessment of Treatment Efficacy Calculation of Dosage 7. PRESCRIBING INFORMATION Back Cover Package Insert i

4 HISTORY OF HEMOPHILIA CARE Koāte -DVI (Double Viral Inactivation) Trusted by patients worldwide, more than 2 billion IUs have been infused with no confirmed cases of viral transmission. Koāte -DVI is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII. Factor VIII in the Management of Hemophilia A Hemophilia A, a blood coagulation disorder, is an inherited genetic disease linked to the X chromosome. The disease is characterized by a defect or deficiency of the blood coagulation factor VIII (FVIII), which leads to spontaneous, as well as traumatically induced, bleeding episodes in affected patients. The original therapy for hemophilia A provided FVIII replacement with whole plasma or cryoprecipitate. This approach was only partially effective, because of the large volume of plasma and the large amounts of protein that were needed to achieve only partial and transient hemostasis. An additional drawback of replacement therapy with plasma was the required hospitalization of the patient. As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. High-purity FVIII products are concentrated up to one thousand-fold in comparison to plasma. The resulting injection volume is small, allowing convenient home treatment of bleeding episodes. These advances in treatment have dramatically improved the quality of life for hemophilia patients. Now patients can undergo surgery when needed, treat most bleeding episodes at home, and live a more normal lifestyle with fewer days lost from work or school. The following chapters of this monograph describe the production, safety and efficacy of Koāte -DVI, Antihemophilic Factor (Human). The Strength of Talecris Talecris Biotherapeutics is a new company with a long history of innovation. Talecris carries on a tradition of developing life-saving therapies derived from human plasma that began in the 1940s through our affiliation with Cutter Laboratories and Bayer Biological Products (Miles in the U.S.). Koāte -DVI is manufactured with U.S.-sourced plasma at the Clayton, North Carolina, USA, facility. Talecris specializes in a variety of plasma-derived therapies. ii

5 1. STRUCTURE AND FUNCTION OF FACTOR VIII (FVIII) In the cell, the FVIII molecule (antihemophilic factor, AHF) is initially synthesized as a 2,351 amino acid, single-chain precursor protein. A 19-amino acid peptide is cleaved from the amino-terminal portion during passage through the cytoplasm. Therefore, the secreted protein consists of 2,332 amino acids with a calculated molecular weight of approximately 265,000 daltons. Carbohydrates are bound to the protein backbone at approximately 25 sites, bringing the effective molecular weight closer to 300,000 daltons. FVIII PRECURSOR A1 FVIII IN PLASMA heavy chain 200 kd 90 kd 50 kd 43 kd A2 B A3 C1 C2 Secretion A1 A2 B A3 C1 C2 Thrombin Activation Inactivation light chain 80 kd A1 A2 B A3 C1 C2 80 kd A1 A2 A3 C1 C2 73 kd THE INTACT PRECURSOR MOLECULE The intact precursor molecule comprises three types of domains and two smaller linker regions, as shown in Figure 1: A domains: three A segments (A1, A2, A3), each approximately 330 amino acids B domain: a unique middle segment (B) consisting of 980 amino acids, to which most of the carbohydrates are bound C domains: two C segments 45 kd 25 kd 73 kd (C1, C2) of 150 amino acids each Figure 1 In plasma, the FVIII molecule is cleaved to produce two peptides, an amino-terminal heavy chain (domains A1, A2, B) and a carboxy-terminal light chain (A3, C1, C2). The protein circulates as a dimer, with calcium ions binding the chains together by linking the A and C domains. When activated by thrombin, the heavy chain is cleaved, expelling the carbohydraterich B domain, which is not required for coagulant activity. Several additional cleavage steps generate 50, 43 and 73 kd peptides, producing maximal coagulant activity. Further cleavage inactivates the coagulant activity of the FVIII protein. By itself, FVIII is a highly reactive unstable molecule. It is stabilized in plasma by binding to von Willebrand factor (vwf). 1

6 Manufacturing Process of Koāte -DVI Flow Diagram Plasma Pooling 1. Cryo-Separation Cryoprecipitate 2. Adsorption and PEG Precipitation AHF Filtrate 3. Glycine/NaCl Precipitation AHF Precipitate 4. Solvent/Detergent Treatment Viral Inactivation Step 5. Gel Chromatography As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. Factor VIIIC von Willebrand Concentrate 6. Formulation Final Product Viral Inactivation Step 7. Sterile Filtration 8. Filling 9. Freeze Drying 10. Dry Heat Treatment 80 C 72 hrs Figure 2 2

7 2. MANUFACTURE OF KOATE -DVI, ANTIHEMOPHILIC FACTOR (HUMAN) Manufacturing Process of Koāte -DVI Koāte -DVI is manufactured at Talecris biological products production facility in Clayton, North Carolina, USA. The manufacturing process is outlined in the flow diagram in Figure 2 and described below. 1. Cryo-Separation. Frozen plasma is thawed and centrifuged to collect the cryoprecipitate. 2. Adsorption and PEG Precipitation. The cryoprecipitate is solubilized in water. Aluminum hydroxide and polyethylene glycol (PEG) are added to precipitate the non-ahf proteins. The precipitate is removed by centrifugation or filtration and the AHF filtrate is collected. This step removes non-product-related plasma proteins while retaining AHF, bound and stabilized by von Willebrand Factor. 3. Glycine/Sodium Chloride Precipitation. AHF is precipitated by the addition of glycine/sodium chloride and the precipitate is collected by centrifugation. 4. Solvent/Detergent Treatment. A solvent/detergent solution consisting of TNBP (tri-n-butyl phosphate) and polysorbate 80 (Tween-80) is added to the AHF and the suspension is incubated for six hours. This step is included in the manufacturing process specifically to inactivate enveloped viruses by disrupting their lipid-soluble envelopes. 5. Gel Chromatography. The AHF solution is passed through a gel chromatography column that removes low molecular weight compounds. This step serves a dual purpose: 1) removal of the TNBP and polysorbate 80; and 2) further purification of the AHF, the larger FVIII molecules associated with their protective von Willebrand Factor proteins and impurities. The resulting FVIII solution is 300 to 1,000 times purified over whole plasma. MANUFACTURE OF KOATE -DVI, ANTIHEMOPHILIC FACTOR (HUMAN) Koāte -DVI is a FVIII concentrate for the treatment of hemophilia A. The product is prepared from human plasma from healthy donors collected at FDA-licensed commercial plasma centers that meet Talecris specifications. Individual units of plasma are tested, frozen rapidly, and quarantined for 60 days before use (60-day Plasma Inventory Hold and Lookback) as described in Section 3 (Pathogen Safety). 6. Formulation. The purified AHF solution is collected and diluted, as needed, for filtration and filling. Pasteurized Albumin (Human), USP, which is often used to stabilize plasma-derived and recombinant proteins in pharmaceutical preparations, is added to preserve AHF activity. 7. Sterile Filtration. The solution is passed through a sterilizing filter to remove any bacterial contaminants. 8. Filling. The solution is dispensed aseptically into the final vial. 9. Freeze Drying. Vials containing the final AHF formulation are freeze-dried and stoppered. 10. Dry Heat Treatment. The final freeze-dried product is then heated at 80 C for 72 hours. The second viral inactivation step, the combined freeze dry/ dry heat treatment (steps 9 and 10), inactivates many enveloped and non-enveloped viruses. 3

8 Two Independent Viral Inactivation Steps: Solvent/Detergent Step 1, 2 Disrupts the viral lipid coat and inactivates enveloped viruses such as HIV and hepatitis B and C viruses. Freeze Dry/Dry Heat Treatment Step 1,2 Freeze drying followed by 80 C 72-hour heating under controlled moisture conditions denatures virus proteins and inactivates enveloped and non-enveloped viruses such as parvovirus B19 and hepatitis A virus. InventoryHold and Lookback Adsorption and Precipitation Koate -DVI Figure 3 As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. 1. Horowitz et al. Viral safety of solvent/detergent-treated blood products. Blood Coagulation and Fibrinolysis. 1994; 5 (suppl 3): Horowitz et al. Inactivation of lipid-enveloped viruses by tri (n-butyl) phosphate detergent combination. Transfusion. 1985; 25:

9 3. PATHOGEN SAFETY The use of plasma products is not without risk. Human plasma may contain pathogenic agents capable of transmitting Acquired Immunodeficiency Disease Syndrome (AIDS), CJD, hepatitis and other diseases. In order to ensure the safety of Koāte -DVI and minimize the risk from pathogen contamination, Talecris has implemented a multi-layered system of overlapping safety measures that include Plasma Donor Screening and Selection, Plasma Donation Testing, Plasma Inventory Hold and Lookback, Plasma Manufacturing Pool Testing, and Validated Viral Reduction Steps within the Manufacturing Process. PLASMA DONOR SCREENING AND SELECTION The viral safety of Koāte -DVI begins with high-quality source material: carefully screened and tested human plasma collected exclusively from approved plasma suppliers in the USA. All plasma suppliers must be US FDA-licensed collection centers with Clinical Laboratory Improvement Amendments (CLIA) certification, Plasma Protein Therapeutics Association (PPTA) certification, and International Quality Plasma Program (IQPP) certification. The centers must be regularly inspected and deemed acceptable by the US FDA, US Department of Health and Human Services Health Care Finance Administration (HCFA), and other federal, state and local authorities as required. In addition, all facilities, procedures and records at each center must be inspected regularly by Talecris Quality Operations (QO). Talecris enforces careful plasma donor qualification and screening standards at every point in the plasma procurement process that includes identification and residency checks, a detailed medical history, and a physical examination. During the screening interview, very specific and direct questions are asked about risk factors and donors who are unsuitable to donate plasma are excluded at this step. In accordance with current US FDA regulatory requirements 3 to reduce the theoretical risk of transmission of transmissible spongiform encephalopathies (TSE), such as Creutzfeldt-Jakob disease (CJD), the following prospective donors are excluded from donating plasma: donors who have been diagnosed with variant CJD or any other form of CJD, donors at increased risk for CJD (e.g., family history), donors at potential risk for CJD (e.g., residence in the UK for no less than three months during 1980 to 1996), donors who received blood transfusions in the UK and donors who have injected bovine insulin since PLASMA TESTING Plasma testing must be performed by a testing facility that meets all regulatory and licensing requirements and has been pre-approved by Talecris. In addition, plasma intended for use by Talecris must meet the following virus safety criteria: Test Type Test Requirement HBsAg Non-reactive Anti-HIV-1/2 Non-reactive Anti-HCV Non-reactive HCV NAT Negative HIV-1 NAT Negative HBV NAT Negative Parvovirus B19 NAT Non-elevated 3. Guidance for Industry, Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vcjd) by Blood and Blood Products, January

10 PLASMA DONATION TESTING Only plasma units from qualified repeat donors are used. To become qualified, all applicant donors must have two consecutive acceptable sets of viral marker test results and screening interviews within a period of six months. If an applicant donor does not return within six months, his or her unit of plasma is destroyed, regardless of test results, and any qualified donor who has donated at a different center or has allowed more than six months to elapse before donating must be re-qualified. Each plasma donation must undergo serological testing and must be found nonreactive or negative for antibodies against human immunodeficiency virus types 1 or 2 (anti-hiv-1/2) and hepatitis C virus (anti-hcv) and non-reactive for hepatitis B virus surface antigen (HBsAg). Because it takes time for a body to develop antibodies in response to a viral infection and time for virus particles to reach concentrations that are high enough to be detected by conventional serological methods, testing by nucleic acid technologies (NAT) is also performed. NAT tests have significantly improved the safety of plasma-derived products by enabling reliable, early, direct detection of minute concentrations of pathogens in plasma and are performed to detect HBV, HCV and HIV and elevated levels of parvovirus B19. During the tests, selected regions of viral genetic material are amplified and, because NAT is so sensitive, testing can be performed in a mini-pool format rather than on each individual unit of plasma. As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. Plasma donors testing positive/reactive for HBsAg, anti-hiv-1/2, anti-hcv, HBV by NAT, HCV by NAT or HIV-1 by NAT are notified, permanently deferred from donating plasma, and entered into the National Donor Deferral Registry (NDDR). The NDDR is a centralized database, maintained by the American Blood Resources Association, which lists all plasma donors in North America who have been permanently rejected due to viral testing. All potential donors must be checked against the registry to prevent the use of units from deferred donors. Because of the nature of parvovirus B19 infections, the notification and deferral of plasma donors with elevated B19 NAT test results would provide little or no public health benefit and, therefore, are not performed. 6

11 PLASMA INVENTORY HOLD AND LOOKBACK Each plasma unit is assigned a unique identification number and all documentation that accompanies the unit (e.g., viral marker and NAT test results) must contain this unique identifier. As a result, there is complete traceability of every single plasma unit. Each unit of plasma is held in inventory for at least 60 days to ensure they have been tested and donation records have been verified. This also allows time to see if donors develop any infections since they donated the plasma. If new information on a donor s health status becomes available or if any potential problems are identified, a lookback procedure is initiated to trace and destroy previous donations from that individual. PLASMA MANUFACTURING POOL TESTING All acceptable units are pooled at the manufacturing facility and then a second round of viral marker and NAT testing is performed on the plasma manufacturing pool. The only pools that are further processed are those that test negative/non-reactive for HBsAg, anti-hiv-1/2, anti-hcv, HBV by NAT, HCV by NAT, HIV-1 by NAT and are nonelevated for parvovirus B19 by NAT. Thus, only the highest-quality plasma is used in producing Koāte -DVI. PATHOGEN REMOVAL AND INACTIVATION DURING KOATE -DVI MANUFACTURING The safety of Koāte -DVI is further enhanced by the incorporation of virus inactivation/ removal steps into the manufacturing process. Studies to evaluate various steps of the manufacturing process for their capacity to clear pathogens have been conducted in accordance with regulatory guidelines 4, 5. The steps investigated in the Koāte -DVI production process were: 1. Removal of cryoprecipitate from thawed pooled plasma ( cryo removal ) 2. Aluminum hydroxide adsorption and polyethylene glycol precipitation of solubilized cryoprecipitate ( adsorption + precipitation ) 3. Treatment of soluble AHF with TNBP/polysorbate 80 ( solvent/detergent ) 4. Freeze drying, followed by 72 hours 80 C dry heat treatment of AHF 4. CPMP Note for Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses. CPMP/BWP/268/95 (1996). 5. CPMP Note for Guidance on Plasma-derived Medicinal Products. CPMP/BWP/269/95 rev. 3 (2001). 7

12 CJD clearance, using an experimental model agent of TSE, was investigated. These studies provide reasonable assurance that low levels of CJD/variant CJD infectivity, if present in plasma, would be reduced during the Koāte -DVI manufacturing process 6. The Koāte -DVI viral validation studies were performed using relevant or model viruses. HIV-1 and hepatitis A virus (HAV) were chosen as relevant blood-borne pathogens, while bovine viral diarrhea (BVDV) and porcine parvovirus (PPV) were chosen to model HCV and human parvovirus B19, respectively. Pseudorabies virus (PRV) was used as a surrogate for HBV and the human herpes viruses. Vesicular stomatitis virus (VSV) was utilized as an additional model enveloped virus and Reovirus type 3 (Reo) was included as another model non-enveloped virus. As shown in Table 1 on page 11, the viruses used in the studies were very different in their structure and composition and represented a wide range of physico-chemical challenges to the manufacturing process. As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. Table 2 on page 12 shows the viral reduction of each test virus across the individual manufacturing steps 7. The greatest reduction in virus load was achieved by the two very different inactivation steps, steps 3 and 4, with approximately 4 log 10 or more reduction obtained per step for each virus. Having multiple steps with independent mechanisms of viral reduction improves safety because viruses that survive one step would be less likely to survive a subsequent step and a single step with a large effect (e.g., 4 log 10 virus reduction) should provide more safety than several less effective steps. The overall reduction in virus infectivity was used as a measure of the virus reduction capacity of the manufacturing process and was calculated by adding all individual reduction factors that were greater than 1 log 10 and that employed different mechanisms of viral reduction 8. The data shows that the Koāte -DVI manufacturing process is capable of reducing a variety of viral challenges from both enveloped and non-enveloped viruses and provides a high margin of safety against the risk of viral transmission. 8

13 POST-MARKET SURVEILLANCE Although the safety of plasma-derived products is achieved using a controlled, step-by-step process, the ultimate proof of product safety comes from a consistent record of safe use. In 1989, Koāte -HP, Antihemophilic Factor (Human), a plasma-derived AHF product which incorporated a solvent/detergent treatment step in its manufacturing process, was introduced. A second viral inactivation step (freeze dry/80 C dry heat treatment) was added to the manufacturing process for Koāte -HP to develop Koāte -DVI (double viral inactivation) and to provide an even greater margin of safety. History has shown that the removal by adsorption and precipitation and the double viral inactivation by solvent/detergent and by freeze dry/80 C dry heat are capable of removing a variety of challenges. Over 2 billion IUs of Koāte -DVI and Koāte -HP have been used throughout the world without any confirmed transmission of HBV, HCV, HIV or TSE 6, 9. As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Because this product is made from human blood it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. Hepatitis B vaccination is essential for patients with hemophilia A; vaccination is recommended at birth or at the time of diagnosis. Hepatitis A vaccination is also recommended for hemophilia patients who are hepatitis A seronegative. Please see accompanying Koāte -DVI Full Prescribing Information. 6. Data on File, Antihemophilic Factor (Human), Assessment of SE Safety. T , valid from 11/21/ Data on file, Antihemophilic Factor (Human), Clearance Potential of the Purification for Viruses. T , valid from 05/03/ Joint Announcement of the Federal Health Agency and the Paul Ehrlich Institute Federal Office for Sera and Vaccines: Requirements for Validation Studies to Demonstrate the Virus Safety of Drugs Derived from Human Blood or Plasma. Federal Gazette 84: Tabor E. The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1. Transfusion 1999; 39:

14 Solvent/Detergent Treatment Step Destroys Viral Infectivity Viral DNA or RNA Lipid envelope Receptor binding proteins Enveloped Virus Solvent Detergent step disrupts the viral lipid coat and inactivates enveloped viruses Chemical process that disrupts the lipid envelope structure and removes the receptor proteins that are critical for virus attachment to the host cell Enveloped viruses such as HIV, HBV and HCV are rendered non-infectious Freeze Dry/Dry Heat Treatment Step Inactivates Viruses Protein spikes Viral DNA or RNA Enveloped and non-enveloped viruses Heat Treatment inactivates enveloped and non-enveloped viruses As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. Freeze dry/80 C dry heat treatment for 72 hours with moisture control denatures critical viral proteins Enveloped viruses (e.g., HIV, HBV, HCV) and non-enveloped viruses (e.g., parvovirus B19, HAV) are inactivated 10

15 Characteristics of Viruses used in Viral Validation Studies VIRUS* Model for: Genome Enveloped Size/Diameter, nm Resistance to physicochemical treatment HIV-1 HIV-1, HIV-2 BVDV HCV PRV HBV, CMV, Epstein-Barr virus, HHV-1, 2, 6, 7 RNA yes low RNA yes low HIV: Human Immunodeficiency Virus BVDV: Bovine Viral Diarrhea Virus PRV: Pseudorabies Virus VSV: Vesicular Stomatitis Virus Reo: Reovirus Type 3 HAV: Hepatitis A Virus PPV: Porcine Parvovirus DNA yes medium HCV: Hepatitis C Virus HBV: Hepatitis B Virus CMV: Cytomegalovirus HSV: Herpes Virus *Viruses recommended by the European Agency for the Evaluation of Medicinal Products (CPMP/BWP/268/95) Table 1 VSV Enveloped viruses RNA yes medium Reo HAV Nonenveloped HAV viruses RNA no high RNA no high PPV Parvo B19 DNA no very high Table 1 shows that the viruses used in viral validation studies vary greatly in their structure and composition. Demonstrating effective removal/inactivation of such a diverse panel of viruses provides assurance that the manufacturing process is capable of clearing any unknown or emerging pathogen that could potentially contaminate the plasma pools. 11

16 Viral Reduction Factors (log 10 ) for Koāte -DVI Production Process PURIFICATION STEP Cryo removal Adsorption + Precipitation Solvent/Detergent Freeze Dry/80 C Dry Heat Global Reduction Factor* N/S Not Studied N/A Not Applicable HIV-1 N/S N/S BVDV Table 2 PRV VSV N/S N/S Reo N/A HAV N/S N/S N/A PPV N/S N/S N/A *Only steps that employ different mechanisms of viral reduction may be added. Steps that provide less than 1 log 10 reduction are not included in calculating the global reduction factor. Table 2 shows that the manufacturing process is capable of reducing a variety of viral challenges by both enveloped and non-enveloped viruses. Therefore, the Koāte -DVI manufacturing process provides a reasonable margin of safety against the risk of viral transmission. It is relevant to emphasize again that viral reduction and inactivation steps have been incorporated into the manufacturing process as added safety procedures. Virus safety begins with careful donor screening, plasma testing and plasma hold measures to minimize the risk of infectious agents from entering the plasma pool prior to fractionation and product manufacture. As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. 12

17 4. PRODUCT CHARACTERISTICS COMPOSITION AND CLOTTING ACTIVITY When reconstituted as directed, Koāte -DVI, Antihemophilic Factor (Human), contains approximately times as much factor VIII as an equal volume of fresh plasma. Each bottle of Koāte -DVI contains the labeled amount of antihemophilic factor activity in International Units (IU). One IU, as defined by the World Health Organization Standard for Blood Coagulation Factor VIII, Human, is approximately equal to the level of AHF found in 1.0 ml of fresh-pooled human plasma. Each lot of Koāte -DVI is tested for AHF activity using the aptt coagulation assay. This test measures the ability of Koāte -DVI to correct clotting time in factor VIII-deficient human plasma. The final product also contains inert additives to facilitate solubility, freeze-drying and stabilization. When reconstituted as directed, each vial contains NMT (not more than) 1,500 ppm polyethylene glycol (PEG), NMT 0.05 M glycine, NMT 25 ppm polysorbate 80, NMT 5 ppm tri-n-butyl phosphate (TNBP), NMT 3mM calcium chloride, NMT 1mg/mL aluminum, NMT 0.06 M histidine and NMT 10 mg/ml Albumin (Human). SPECIFIC ACTIVITY Specific activity refers to the quantity of the desired protein as a fraction of total protein in a mixture. In the case of factor VIII products, specific activity is referred to as purity and is measured as the amount of clotting activity per mg of total protein in the product. The Koāte -DVI production process includes multiple steps that remove extraneous non-ahf proteins, including acid precipitation, adsorption with Al(OH) 3, and polyethylene glycol (PEG) precipitation. In addition, the AHF is gel-filtered to achieve an approximate one hundred-fold purification of FVIII from the starting cryoprecipitate. Since AHF is a reactive protein, prone to protease degradation, Albumin (Human) USP is added back to the formulation before freeze-drying. Albumin has been used routinely as a stabilizer for both native and recombinant proteins in pharmaceutical preparations. PURITY AND SAFETY Purity, in the context of coagulation concentrates, refers to specific activity or the percentage of the desired protein relative to other proteins present. A solution containing only FVIII is termed high purity, while natural, whole human blood with appropriate concentrations of plasma proteins would be considered very low purity. Therefore purity is a measure of protein concentration and not a measure of safety. The purity of FVIII concentrate is related to its production process. The specific activity of Koāte -DVI was studied at various stages throughout the production process. Average values for the starting material, the purified concentrate before albumin addition, and the final heat-treated vial are shown in Table 3. The average specific activity of Koāte -DVI prior to albumin addition is close to 50 IU/mg protein. Specific Activity Through the Koāte -DVI Production Process Process Step Cryo suspension (n=31) Concentrate before albumin addition (n=4) Final product (n=6) Potency IU/mL / / / Table 3 Specific Activity IU/mg Protein / / /

18 PROTEIN COMPOSITION Of greater importance than the specific activity or the total concentration of protein in Koāte -DVI is the nature of the non-ahf proteins. Data on the protein composition of the cryo suspension starting material and the Koāte -DVI final product, assayed by immunonephelometry, are shown in Table 4. This study demonstrates the very substantial removal of non-ahf plasma proteins during the production process. Non-AHF proteins in Koāte -DVI are primarily Albumin (Human) and a trace of fibronectin. Other plasma proteins are below detection limits. Protein Composition (IU/mg) Through the Koāte -DVI Production Process As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. Protein A-1 Apolipoprotein Albumin Alpha1-acid glycoprotein Alpha1-antitrypsin ATIII Ceruloplasmin Fibrinogen Fibronectin Haptoglobin IgA IgE (IU/ml) IgG IgM Transferrin STORAGE Cryo Suspension *ND = not detected Table 4 Final Product ND* 5.27 ND* ND* ND* ND* ND* 0.05 ND* ND* ND* ND* ND* ND* Detection Limit Koāte -DVI should be stored under refrigeration (2-8 C/36-46 F). Storage of lyophilized powder at room temperature (up to 25 C or 77 F) for six months, such as in-home treatment situations, may be done without loss of factor VIII activity. Freezing should be avoided. Reconstituted concentrate should not be refrigerated and should be infused within three hours after reconstitution. 14

19 5. CLINICAL STUDIES PHARMACOKINETICS Nineteen hemophilia subjects, of which eighteen had severe hemophilia A (<2% plasma FVIII), were randomly assigned to receive either Koāte -DVI or Koāte -HP. After a wash-out period of 4-7 days, the subjects received an infusion of the other product. FVIII levels and the corresponding activated Partial Thromboplastin Time (aptt) levels were obtained at prescribed intervals over a 48-hour period after each infusion. Dosages ranged between 44.8 and 55.1 IU/kg. Mean biologic half-life of Koāte -DVI was hours. In a second study after the first pharmacokinetics study, Koāte -DVI was administered to 17 HIV-negative patients with severe hemophilia A (<2% FVIII) as prophylaxis for bleeding episodes over a six-month period. Fifteen of the 17 patients had fewer than 10 bleeding episodes. In a total of 158 bleeding episodes, 137 (86.7%) required no more than one or two treatments. Of the 69 adverse events observed in the course of 972 infusions administered, only one was deemed to be related (remotely) to Koāte -DVI. None of the adverse events were considered severe or life-threatening. There was no evidence of inhibitor formation throughout the 26 weeks of therapy (mean exposure days / ), as evidenced by the absence of any detectable inhibitors on Bethesda assay and by the stability of the in vivo recoveries over time. TREATMENT OF BLEEDING EPISODES Nineteen previously treated subjects with severe hemophilia A, 18 of whom had participated in the pharmacokinetic study described above plus one other subject, were provided with Koāte -DVI as their sole AHF source of home therapy for a period of six months. Infusions at a minimum dose level of IU/kg had to be administered at least twice weekly. Following this schedule, each subject experienced approximately 50 exposure days during the six-month study period. Throughout the study, subjects maintained home diaries to document AHF usage. At weeks 8, 17 and 26, subjects returned to the clinic for an interim history, physical examination, laboratory studies, including a 10-minute FVIII recovery study, hematologic tests, and serum chemistry test, and a Bethesda assay for inhibitor detection. At the end of the study, a 48-hour pharmacokinetic study with Koāte -DVI was repeated, along with clinical and lab studies. CLINICAL STUDIES There was no evidence of inhibitor formation throughout the 26 weeks of therapy (mean exposure days / ), as evidenced by the absence of any detectable inhibitors on Bethesda assay and by the stability of the in vivo recoveries over time. 15

20 Over the study period, the 19 subjects experienced 152 bleeding episodes (Figure 4). A single treatment was effective in over 90% of bleeding episodes, and two treatments were sufficient in another 6.6% of cases. Koāte -DVI was well tolerated, with 29 adverse events (2.75%) observed in the course of 1,053 infusions. Only 10 of the adverse reactions, related to seven infusions, were considered to be related to Koāte -DVI, and all were mild. Koāte -DVI, therefore, provides an effective and safe treatment for bleeding episodes. Treatment of Bleeding Episodes with Koāte -DVI % Mild Moderate Severe Number of Episodes % 0.7% 1.3% Number of Treatments Required 1.3% 4+ As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. NEOANTIGENICITY Figure 4 No evidence of inhibitor formation was observed in 19 previously treated patients after approximately 50 treatment days in the study described above. This is supported by the absence of detectable inhibitors on repeat Bethesda assays, the stability of in vivo recovery of FVIII and the reproducibility of the pharmacokinetic parameters before and after the 26-week study. Therefore, the terminal heat treatment step in the manufacture of Koāte -DVI is not shown to alter the molecule in any way that would increase the incidence of FVIII inhibitor formation. von Willebrand factor may play a 10, 11 role in reducing the risk of inhibitor formation. 10. Goudemand et al. Influence of the type factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with Hemophilia A. Blood. 2006; 107: Gringeri et al. Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate. Haemophilia. 2006; 12:

21 6. DOSING AND ADMINISTRATION Each bottle of Koāte -DVI has the AHF(H) content in international units per bottle stated on the label of the bottle. The reconstituted product must be administered intravenously by either direct syringe injection or drip infusion. The product must be administered within three hours after reconstitution. GENERAL APPROACH TO TREATMENT AND ASSESSMENT OF TREATMENT EFFICACY The dosages described below are presented as general guidance. It should be emphasized that the dosage of Koāte -DVI required for hemostasis must be individualized according to the needs of the patient, the severity of the deficiency, the severity of the hemorrhage, the presence of inhibitors and the factor VIII level desired. It is often critical to follow the course of therapy with factor VIII level assays. The clinical effect of Koāte -DVI is the most important element in evaluating the effectiveness of treatment. It may be necessary to administer more Koāte -DVI than would be estimated to attain satisfactory clinical results. If the calculated dose fails to attain the expected factor VIII levels, or if bleeding is not controlled after administration of the calculated dosage, the presence of a circulating inhibitor in the patient should be suspected. Its presence should be substantiated and the inhibitor level quantitated by appropriate laboratory tests. DOSING AND ADMINISTRATION Each bottle of Koāte -DVI has the AHF(H) content in international units per bottle stated on the label of the bottle. The reconstituted product must be administered intravenously by either direct syringe injection or drip infusion. The product must be administered within three hours after reconstitution. When an inhibitor is present, the dosage requirement for AHF(H) is extremely variable and the dosage can be determined only by the clinical response. Some patients with low titer inhibitors, (10 Bethesda Units) can be successfully treated with factor VIII without a resultant anamnestic rise in inhibitor titer. Factor VIII levels and clinical response to treatment must be assessed to insure adequate response. Use of alternative treatment products, such as Factor IX Complex concentrates, Antihemophilic Factor (Porcine) or Anti-Inhibitor Coagulant Complex, may be necessary for patients with high titer inhibitors. Immune tolerance therapy using repeated doses of FVIII concentrate administered frequently on a predetermined schedule may result in eradication of the FVIII inhibitor. Consultation with a hemophilia expert experienced with the management of immune tolerance regimens is also advisable. 17

22 Administration is Convenient Approximate Factor VIII NDC Number Activity 250 IU 500 IU 1000 IU Diluent 5 ml 5 ml 10 ml Available in single-dose bottles Administer intravenously within three hours after reconstitution Administration in 5-10 minutes is generally well-tolerated Rate of administration should be adapted to the individual CALCULATION OF DOSAGE The in vivo percent elevation in factor VIII level can be estimated by multiplying the dose of AHF(H) per kilogram of body weight (IU/kg) by 2%. This method of calculation is based on clinical findings by Abildgaard et al. 12, and is illustrated in the following examples: Expected % factor VIII increase = # units administered x 2%/IU/kg body weight (kg) Example for a 70 kg adult: or Dosage required (IU) 1400 IU x 2%/IU/kg 70 kg = = 40% body weight (kg) x desired % factor VIII increase 2%/IU/kg As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. Example for a 15 kg child: 15 kg x 100% 2%/IU/kg 750 IU required Dosage for hemostasis must be individualized According to the needs of the patient, the severity of the deficiency and hemorrhage, the presence of inhibitors and the factor VIII level desired Dosage Based on Severity of Bleeding Mild Hemorrhage Moderate Hemorrage Severe Hemorrage Dosage 10 IU/kg IU/kg IU/kg = Rise in Factor 20% 30-50% % Maintenance Single Dose IU/kg every 8-12 hours IU/kg every 8-12 hours Dosage varies based on severity of the deficiency and severity of the hemorrhage 12. Abildgaard et al. Treatment of hemophilia with glycine-precipitated factor VIII. N Engl J Med 275(9):471 5,

23 Talecris Biotherapeutics, Inc. Post Office Box Research Commons 79 T.W. Alexander Drive Research Triangle Park, NC Visit our website at for more information about Talecris and how Koate -DVI can help you. Contact our representatives to find out how we can serve your needs and earn your trust. For customer service, call: For clinical and technical information, call: or

24 For customer service, call: For clinical and technical information, call: or Talecris is a leader in pathogen safety, specializing in plasma-derived therapies. Koāte -DVI (Double Viral Inactivation) Trusted by patients worldwide, more than 2 billion IUs have been infused with no confirmed cases of viral transmission.* Koāte -DVI effective treatment, commitment to supply. As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Please see accompanying Koāte -DVI Full Prescribing Information. *Koāte -DVI and Koāte -HP A new approach to a proud history of patient care Talecris Biotherapeutics, Inc. All rights reserved. Printed in USA June 2006 KD