Octaplex – The Modern PCC Biochemical Quality plus High Virus Safety The PCC for Treatment and Prophylaxis in Prothrombin Complex Deficiency

Octaplex – An Ideal PCC? Octapharma has specially developed Octaplex to provide a PCC for clinical use with high virus safety, efficacy and tolerability Optimised characteristics: Double virus inactivation/removal Haemostatically balanced factors Therapeutic levels of protein C (PC) and protein S (PS) Minimised activation of coagulation factors

Octaplex – Used When? To substitute factors II, VII, IX and X in treatment, prophylaxis of bleeding and peri-operatively in hereditary factor deficiency For rapid correction of bleeding in acquired factor deficiency, e.g. surgery under oral anticoagulants and oral anticoagulant over-dosage For rapid correction of bleeding due to vitamin K deficiency and vitamin K re-adsorption disorders (biliary tract or pancreatic disorders, persistent diarrhoea, massive antibiotic therapy) Coagulopathy resulting in severe factor depletion, e.g. DIC

Congenital Factor II, VII, IX and X Deficiencies Coagulation factor Prevalence congenital deficiency (Severity) Factor half-life in vivo (h) Target levels (%) 1 IU PCC/kg BW raises plasma activity (%) Minor bleeding, surgery Major bleeding, surgery Factor II Very rare (Moderate) ~ 72 15 - 40 40 1 - 2 Factor VII 1:500,000 (Severe) 4 - 6 5 - 10 25 0.5 - 1 Factor IX 1:30,000 only males (Severe) 18 - 30 20 - 50 80 - 100 Factor X 1:700,000 (Moderate - severe) 24 - 48 10 - 20

PCC in Acquired FII, FVII, FIX and FX Deficiency Warfarin induced bleeding Step 1 2 3 Major bleeding Resuscitation Control bleeding Cease oral anticoagulant Vitamin K 5-10 mg, IV PCC 50 IU/kg BW* Minor bleeding Cease oral anticoagulant 1-2 days Re-assess dose and contributing factors Elevated INR > 10 Vitamin K 2-5 mg orally No PCC Control INR in 6 -12 h Elevated INR 6 - 10 Vitamin K 2 mg orally [Cruickshank J et al; Emergency Medicine 2001; 13:91-97 * Where PCC unavailable, FFP 15 ml/kg BW

Octaplex Manufacturing Process Cryoprecipitate supernatant plasma Diafiltration Heparin and pH adjustment Ultrafiltration Ion Exchange Chromatography Heparin and pH adjustment S/D Virus inactivation Sterile filtration, filling Ion exchange chromatography Lyophilisation Virus removal: Nanofiltration OCTAPLEX

Octaplex Manufacturing Process Cryoprecipitate supernatant plasma is heparinised to prevent activation The prothrombin complex factors, II, VII, IX and X, as well as protein C and S, are captured by ion exchange chromatography The first virus inactivation step is solvent/detergent (S/D) The S/D reagents are removed and the prothrombin factors are purified in a second ion exchange chromatography step The second step of virus removal is nanofiltration Octaplex is purified and concentrated by diafiltration and ultrafiltration Albumin is not added to the final formulation Heparin is added to the final product before sterile filling and freeze drying to prevent activation of the prothrombin complex factors when reconstituted

Octaplex - Viral Safety: Conclusion Solvent/detergent treatment ensures rapid inactivation of enveloped viruses, such as HIV, HBV and HCV Octaplex is a PCC derived from human plasma with very high viral safety against both enveloped and non enveloped viruses due to the combination of two very efficient virus elimination steps with different modes of action Other process steps, such as chromatography, provide additional safety

Octaplex Virus Validation Studies Enveloped Viruses Non Enveloped Viruses Virus Genome HIV-1 Human Immuno- deficiency RNA SBV Sindbis PRV Pseudo- rabies DNA HAV Hepatitis A REO Reovirus-3 Step Virus Reduction (log10) SD Treatment > 5.5 > 6.3 > 7.2 Nanofiltration > 6.5 > 7.3 > 6.6 5.3 8.5 Chromato-graphy 2.6 3.1 Total Reduction > 12.0 > 13.6 > 13.8 7.9 11.6

Octaplex – Minimised Activation A further important characteristic for clinical safety is a low level of activated factors and A low level of proteolytic activity, when reconstituted Critical markers of activation and proteolytic activity include prothrombin fragments F1+2, and F VIIa (activated factor VII)

Octaplex – Minimised Activation Minimised Content of Factor VIIa Minimised Content of Compared to Factor VII Prothrombin Fragments 1 + 2 Factor VIIa / Factor VII (%) Prothrombin F 1 + 2 (pmol/IU FIX) Lutze G, Heim M. Haemostasiologie 2004; 24: 27

Octaplex Biochemical and Viral Safety Features Octaplex is a modern, S/D-treated and nanofiltered prothrombin complex concentrate from human plasma In vitro characterisation and virus validation studies reveal Octaplex is an efficacious and safe PCC In Octaplex, the factors, II, VII, IX and X correspond to a haemostatically balanced ratio of ~ 1:1:1:1 Octaplex contains therapeutic levels of Protein C and Protein S In Octaplex, activation of coagulation factors is minimised

Octaplex – The Physiological PCC Excellent batch consistency 1:1:1:1 Ratio Proteins C and S No added albumin Protein Units per IU of F IX* Factor II 1.19 Factor VII 0.76 Factor IX 1.00 Factor X 0.98 Protein C Protein S 0.95 *Batch Analysis of 39 Batches. Octapharma: Data on File

Octaplex Clinical Features The clinical efficacy and safety of Octaplex were shown in congenital and acquired coagulation factor deficiencies Efficacy: The recovery and half-life of coagulation factors and inhibitors showed that Octaplex has good clinical efficacy Efficacy: The mean doses used in the clinical trials for achieving efficacy were in the lower range of those normally required for such treatment Efficacy: The number of treatment days necessary were in the lower range of those normally required Safety: Thrombotic events reported with the use of PCC in the literature were not observed during clinical trials with Octaplex

Octaplex Routine Clinical Use Octaplex has been used since 1998 in Norway and since June 2003 in Germany Octaplex was registered mid-2004 in 7 further European countries There have been no reported thromboembolic events in routine clinical use Octaplex is convenient to use

Octaplex Convenience Octaplex is available as a 500 IU presentation, standardised on factor IX, for reconstitution in 20 ml of Water for Injections Octaplex can be stored for 2 years at + 2 °C to + 8 °C Octaplex dissolves quickly at room temperature Octaplex can be injected at a rate of up to 3 ml per minute