Human Prothrombin Complex (PCC) (Beriplex® P/N) in the ...

Human Prothrombin Complex (PCC)
(Beriplex ® P/N) in the emergency
reversal of anticoagulation
BCSLS Congress 2012
Kamloops, BC
Ayman Kafal
Medical Affairs, Leader
CSL Behring Canada
1

Prothrombin Complex
Concentrate in
anticoagulant reversal

Contents
• Anticoagulant reversal
• Epidemiology
• Mode of action
• Guidelines
• Prothrombin complex concentrates
• Beriplex ® P/N
• History and differentiation
• Indications and clinical use
• Clinical studies in anticoagulant reversal
• Challenges of the new Oral Anticoagulants
• What do we know?
3

Epidemiology

Epidemiology of oral anticoagulation
therapy
France Netherlands USA Canada
Population 60 million 16.3 million 280 million 34 million
Oral
anticoagulation
600,000
(1.0%)
325,072
(2.0%)
2,500,000
(0.9%)
306,000
(0.9%)
Leading drug Phenindione Acenocoumarol Warfarin Warfarin
5
Pengo et al. J Thromb Thrombolysis 2006; 21: 73–7

Primary indications for warfarin in clinical
practice in the USA
Primary indication
Percentage of use
Atrial fibrillation 39%
DVT or pulmonary embolism 27%
Valve replacement 13%
Cardiomyopathy 10%
Stroke 6%
Other venous thrombosis 1%
Left ventricular thrombus 1%
Peripheral vascular disease 1%
Other arterial thrombosis 1%
N=1020 patients taking warfarin; DVT, deep vein thrombosis
6
Wittkowsky and Devine. Pharmacotherapy 2004; 24: 1311–16

Bleeding risk in oral anticoagulant therapy
• Major haemorrhage
• 1.2–7.0 episodes per 100 patient-years (population cohort studies)
• 0.5–4.2% (clinical trials)
• Minor haemorrhage
• 2–24 episodes per 100 patient-years
US:
26,000–210,000 major bleeds/year estimated
• Intracranial bleeding associated with oral anticoagulation
• Approximately 13,000 cases per year in US
• ~70% intracerebral bleeds
• ~30% subdural haematomas
• Mortality from intracranial bleeds ~60%
• Progression of bleeding in ~50% of patients within 24 hours
7
Flaherty et al. Neurology 2007; 68:116–21; Libby and Garcia. Arch Intern Med 2002; 162: 1893–6;
McMahan et al. J Gen Intern Med 1998; 13: 311–16; Schulman. N Engl J Med 2003; 349: 675–83

Mode of action of
anticoagulant reversal

Mode of action of vitamin K antagonists
Vitamin K
Reductase
Targets
Factors II, VII, IX, X
Proteins C and S
Reductase
Vitamin K H 2
Glutamic acid
Vitamin K oxide
-Carboxyglutamic
acid
Oral anticoagulation agents (warfarin, phenprocoumon, fluindione
and acenocoumarol) block both reduction steps
9
Adapted from Hirsh J, et al. Chest 1995; 108: 231–246

10
Options available for reversal of
oral anticoagulation
• Coagulation factor
concentrates (e.g. Beriplex P/N)
• Contain all clotting factors required
in a concentrated form
• Fast application possible
• Low volume (20ml)
• Predictable and measurable effect
• A demonstrated rapid decrease in
INR to ≤1.3 within 30 min after
administration of Beriplex® P/N*
*PM Beriplex® P/N (human prothrombin complex),Nov 5, 2010.
• Vitamin K
• Available orally or intravenous
• Readily available and inexpensive
• Response slow and unpredictable
• Not appropriate for emergencies
• Human plasma
(e.g. FFP, 24-hour plasma)
• Contains factors that are required
and some that are not required
• Risk of fluid overload and viral
transmission
• Longer time required to thaw and
transfuse the product
• Duration of infusion requires patient
monitoring
• May fail to completely reverse
anticoagulation
FFP, Fresh Frozen Plasma; FVIIa, activated Factor VII
Source: The Pharmacology and Management of Vitamin K Antagonists, CHEST, September 2004

Prothrombin complex concentrates
in anticoagulant reversal

Emergency reversal of oral anticoagulation
Human plasma
PCC
Volume High Low
Availability Widespread Widespread
Speed of administration Slow Rapid
Preparation time Slow Rapid
Virus inactivation procedure
Pooled
SD plasma: yes
single donor plasma: no
SD plasma: yes
single donor plasma: no
Yes
Yes
Blood group Group specific Not group specific
12
Balanced factor content
Thrombogenicity
SD, solvent-detergent inactivated
Every factor present, high
inter-individual variation
SD plasma: yes
Methylene blue: yes
Concentrated factors and
thromboinhibitors
Variable between PCCs
PCC, prothrombin complex concentrate
Hanley. J Clin Pathol 2004; 57: 1132–9; Stanworth, et al. Br J Haematol 2004; 126: 139–52;
Makris et al. Br J Haematol 2001; 114: 271–80; Kohler. Thromb Res 1999; 95: S13–7

Median clotting factor values (IU/dL)
Median clotting factor values (IU/dL)
Emergency reversal of oral anticoagulation:
fresh frozen plasma vs PCCs
Pre-treatment
Post-treatment
FFP (800 mL)
PCC (25–50 IU FIX/kg)
80
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
II VII IX X
0
II VII IX X
Factor
Factor
13
51 patients were enrolled in the study. The objectify was to compare the efficacy of infusion
of fresh frozen plasma (FFP) and clotting factor concentrates on correction of the coagulation
FFP, fresh frozen plasma; PCC, prothrombin complex concentrate
Makris et al. Thromb Haemost 1997; 77: 477–80

What is the ideal prothrombin complex
concentrate?
Rapid
response
time
Balance of
coagulation factors
and
thromboinhibitors
Normalisation
of INR
Ideal PCC
Virus
inactivated
14
Fast
coagulation
correction
Easy and fast
to administer
INR, International Normalised Ratio; PCC, prothrombin complex concentrate
Spahn DR, Cerny V, Coats TJ, et al. Management of bleeding following major trauma:
a European guideline. Crit Care 2007; 11: R17 doi:10.1186/cc5686
Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res 1999; 95: S13–17

PCC : Coagulation factors
One 20mL vial contains:
Component octaplex Beriplex in vivo T1/2
Factor II 220-760 IU 380-800 IU ~60h
Factor VII 180-480 IU 200-500 IU ~4h
Factor IX 400-620 IU 400-620 IU ~17h
Factor X 360-600 IU 500-1020 IU ~31h
Protein C 140-620 IU 420-820 IU ~47h
Protein S 140-640 IU 240-680 IU ~49h
Heparin 80-310 IU 8-40 IU
Sodium citrate 17-27 mM 3 mM
Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789
Beriplex Product Monograph, November 2010
15

Beriplex P/N(Human prothrombin complex)-
history and differentiation

Product features of Beriplex P/N
• Beriplex ® P/N (Human Prothrombin Complex) is a balanced PCC, which contains
all the components necessary to rapidly restore haemostasis in a bleeding
emergency caused by vitamin K antagonists.
• Beriplex ® P/N contains all essential coagulation factors: Factor II, Factor VII, Factor IX
and Factor X
• Beriplex ® P/N contains the thromboinhibitors: Protein C and Protein S
• Beriplex ® P/N comes in a 500 IU vial and 20 ml diluent vial
• Factors in Beriplex P/N are immediately bioavailable after administration
• Beriplex P/N is tested by PCR, nanofiltered and pasteurised with proven risk
reduction for transmissable infectious agents
• Storage at room temperature (up to +25°C)
• The shelf life of Beriplex ® P/N is 36 months.
• Beriplex ® P/N comes with the Mix2Vial* application set
• Maximum infusion speed 8mL/min
17
* Mix2Vial is a registered trademark of West or one of its subsidiaries PCR, polymerase chain reaction
Beriplex® P/N Product Monograph, November 5, 2010

Indications for Beriplex P/N
• Beriplex® P/N (Human prothrombin complex) is indicated in adults (≥
18 years of age) for the treatment of bleeding and perioperative
prophylaxis of bleeding in acquired deficiency of the prothrombin
complex coagulation factors, such as deficiency caused by treatment
with vitamin K antagonists, or in case of overdose of vitamin K
antagonists, when rapid correction of the deficiency is required.
• No adequate study in subjects with congenital deficiency is available.
Beriplex® P/N can be used for the treatment of bleeding and
perioperative prophylaxis of bleeding in congenital deficiency of any of
the vitamin K dependent coagulation factors only if purified specific
coagulation factor product is not available.
18
Beriplex® P/N Product Monograph, November 5, 2010

Composition of Beriplex P/N
Medical Ingredients
Factor II
Factor VII
Factor IX
Factor X
Protein C
Protein S
Beriplex ® P/N 500
IU content per vial
380-800 IU
200-500 IU
400-620 IU
500-1020 IU
420-820 IU
240-680 IU
Beriplex® P/N also contains heparin and human antithrombin III.
19
Beriplex® P/N Product Monograph, November 5, 2010

Contraindications
• Known hypersensitivity to any of the components of
the product
• Risk of thrombosis, angina pectoris, recent myocardial
infarction (exception: lifethreatening haemorrhages
following overdosage of oral anticoagulants, and
before induction of a fibrinolytic therapy).
• In the case of disseminated intravascular coagulation,
prothrombin complex-preparations may only be
applied after termination of the consumptive state.
• Known history of heparin-induced thrombocytopenia
20

Beriplex ® P/N: dosing recommendations
• Guide for dosage: 1 IU FIX, FVII, FII, FX per kg body weight can be
expected to raise FIX by 1.3%, FVII by 1.6%, FII, FX by 1.8%
• Required dosage:
The dose will depend on the International Normalised Ratio (INR) before
treatment and the targeted INR. In the following table approximate doses (ml/kg
b.w.) of the reconstituted product and IU of Factor IX/kg b.w. required for
normalisation of INR (e.g. ≤ 1.3) at different initial INR levels are given.
Initial INR 2.0 - 3.9 4.0 - 6.0 > 6.0
Approximate dose ml/kg b.w. 1 1.4 2
Approximate dose IU (Factor IX)/kg b.w. 25 35 50
• Administered by i.v. injection
• Administration speed should not exceed 210 IU/min (~8 mL/min)
• Important for Beriplex ® P/N substitution:
• Determination of antithrombin activity in cases with suspected coagulation activation
21
i.v., intravenous
Beriplex® P/N Product Monograph, November 5, 2010

Key Features Summary
Beriplex ® P/N Octaplex ®
Infusion Speed
8.4ml/min
Start: 1 ml/min
Thereafter: 2-3 ml/min
Maximum dose 5000 IU 3000 IU
Double Virus
Inactivation
Safety Profile
Nanofiltration and
Pasteurisation
Nanofiltration and
Solvent/detergent
Over 16 years UK Licence 2006
Ease and
Convenience
Room Temp.
Storage
Mix2Vial with tighter
grip
3 years
Mix2Vial
2 years
22

Beriplex P/N – clinical trials
in anticoagulant reversal

Beriplex ® P/N in healthy volunteers:
Phase I pharmacokinetic (PK) study
• First study to evaluate the PK of coagulation factors and anticoagulant
proteins after PCC administration
• 15 healthy volunteers (mean age 41 ± 13 years)
• Single 50 IU/kg dose of Beriplex ® P/N infused i.v. at a maximum rate
of 210 IU/min
• Actual rate achieved = 7.9 mL/min
• Blood taken at 5, 10, 15 and 30 minutes then at frequent intervals up
to 144 hours post-infusion
• Assess plasma levels of coagulation factors and thrombogenicity
markers
24
i.v., intravenous; PCC, prothrombin complex concentrate
Ostermann et al. Thromb Haemost 2007; 98: 790–7

FX (%)
Beriplex P/N Phase I PK Study: Demonstrated
rapid and sustained increases in coagulation
factors
FVII (%) FII (%) FIX (%)
200
150
100
50
250
200
150
100
200
150
100
50
300
Mean PCC infusion 200IU/min; Mean PPC dose 150 mL (3750IU)
200
100
Pre
5
10
15
30
60
2
6
12
18
24
48
72
96
144
i.v.
PCC
Minutes: Post-Infusion
Time
Hours: Post-Infusion
25
i.v., intravenous; PCC, prothrombin complex concentrate
Ostermann et al. Thromb Haemost 2007; 98: 790–7

Protein S (%)
Protein C (%)
i.v. PCC
Beriplex P/N Phase I PK Study: Demonstrated rapid
and sustained increases in thromboinhibitors
300
200
100
200
150
100
Pre
5
10
30
60
2
6
12
18 24
48
7296
144
Minutes
Hours
Time
26
i.v., intravenous; PCC, prothrombin complex concentrate
Ostermann et al. Thromb Haemost 2007; 98: 790–7

Beriplex ® P/N in anticoagulant reversal:
prospective Phase III study
• Prospective, open, uncontrolled, multinational, Phase III study
• 43 patients from 25 centres in eight countries
• To determine the efficacy of prothrombin complex concentrates
(Beriplex ® P/N) in the emergency reversal of oral anticoagulation
• when urgent surgical intervention is required
• in patients experiencing an acute bleed
• To document the safety and tolerability of Beriplex ® P/N
• Beriplex ® P/N dosing based on baseline INR:
Baseline INR Dose of Beriplex ® P/N
2.0–3.9 25 IU/kg
4.0–6.0 35 IU/kg
>6.0 50 IU/kg
• Rapid infusion: up to a maximum of 210 IU/min
• most patients simultaneously received i.v. vitamin K
27
INR, International Normalised Ratio; i.v., intravenous
Pabinger et al. J Thromb Hemost, Volume 6, Number 4, April 2008

IU/mL
Beriplex ® P/N Phase III study: coagulation
factor and thromboinhibitor levels
Patients receiving OAT were eligible for this prospective multinational study if their INR
exceeded 2 and they required either emergency surgical or urgent invasive diagnostic
intervention or INR normalization due to acute bleeding. Study endpoints included INR
normalization (

Mean INR ± SD
Beriplex ® P/N Phase III study: INR response
10
9
8
7
6
5
4
3
2
25 IU/kg (INR = 2.0–3.9)
35 IU/kg (INR = 4.0–6.0)
50 IU/kg (INR >6.0)
1
0
Pre-
Inf
3
6
9
12 15 18 21 24 27 30 33 36 39
Time after end of infusion (hours)
42
45
48
29
INR, International Normalised Ratio
Pabinger et al. J Thromb Hemost, Volume 6, Number 4, April 2008

Thank you
Ayman Kafal
CSL Behring Canada
Medical Affairs, Leader
Phone: 514.332.7248
Cell: 514.219.7560
Email: Ayman.kafal@cslbehring.com
30