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

2. 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

3. 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

4. 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 40
1 - 2
Factor VII
1:500,000 (Severe)
4 - 6
5 - 10 25
Factor IX
1:30,000 only males (Severe)
Factor X
1:700,000 (Moderate - severe)

5. 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 h
Elevated INR
Vitamin K 2 mg orally
[Cruickshank J et al; Emergency Medicine 2001; 13:91-97
* Where PCC unavailable, FFP 15 ml/kg BW

6. 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

7. 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

8. 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

9. 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

10. 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)

11. 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 (pmol/IU FIX)
Lutze G, Heim M. Haemostasiologie 2004; 24: 27

12. 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

13. 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

14. 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

15. 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

16. 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