Kcentra is a 4-factor prothrombin complex concentrate approved for reversing vitamin K antagonist-related major bleeding. It contains factors II, VII, IX, X as well as proteins C and S. Kcentra is more effective than fresh frozen plasma for rapidly reversing warfarin-associated coagulopathies and bleeding within 30 minutes of administration. While there is no antidote for newer oral anticoagulants like dabigatran and rivaroxaban, Kcentra may help manage life-threatening bleeding by generating thrombin. Kcentra administration requires monitoring of coagulation parameters and concomitant vitamin K to prevent rebound coagulopathy.

1. Kcentra:
A 4-Factor Prothrombin Concentrate
Sylvia Doyle, Pharm.D.
Elva Angelique Van Devender, Ph.D., Pharm.D., BCPS
Legacy Good Samaritan Emergency Department

2. May 3, 2015 2
Background
 Kcentra is the first four-factor prothrombin complex
concentrate approved for the urgent reversal of
vitamin K antagonist-related major bleeding.
 Approved on April 29, 2013 and expected to be
available by third quarter 2013.
 Kcentra contains the vitamin K-dependent
coagulation factors II, VII, IX, and X and the
antithrombotic proteins C and S.
 Legacy currently uses three factor PCC (generic
names Prothrombin Complex Concentrate or Factor
IX Complex, brand name Profilnine) as its preferred
product.

3. Comparing Profilnine and Kcentra
Characteristics Prothrombin Complex Concentrates
Brand name Profilnine 3-factor PCC Kcentra 4-factor PCC
Source material Pooled human plasma Pooled human plasma
Microbial
reduction
Solvent detergent (no preservative) Chromatographic, heat-treated (no
preservative)
Formulation Single-dose vials (multiple sizes) Single-dose 500 unit vials
Factor
composition
Factor IX
500 units 400-620 units
Factor II NMT 750 units 380-800 units
Factor VII NMT 175 units 200-500 units
Factor X NMT 500 units 500-1020 units
May 3, 2015 3
NOTE: Profilnine does NOT contain heparin, but Kcentra does!

4. The Clotting Cascade
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5. FFP vs. PCC
 Fresh frozen plasma (FFP), in combination with vitamin
K, has long been the most widely used blood product for
urgent reversal of coagulopathies in warfarin patients.
 A number of concerns exist with the use of FFP in these
situations:
> Potential for transfusion reactions
> Time required for cross-matching and thawing
> Potential for fluid overload (200-250 mL/unit FFP)
> 10-20 mL/kg of FFP results in a 20-30% increase in clotting
factors (800-1600 mL for an 80 kg patient)
 The 9th edition of the American College of Chest
Physicians Practice Guidelines recommends rapid
reversal of vitamin K antagonists (VKA) with 4-factor
PCC, rather than plasma, in patients with major bleeding
due to warfarin therapy (grade 2C).
May 3, 2015 5

6. Pharmacology
 The administration of PCC temporarily increases
plasma levels of factor II, VII, IX and X, that are
depleted with warfarin use
> reverses the antithrombotic effects of vitamin K
antagonism.
 Because of the long half-life of warfarin, vitamin K is
required to reverse its anticoagulant effect
> allows the synthesis of vitamin-K dependent clotting
factors necessary to avoid a rebound increase in the
INR following PCC administration.
 Clinical data consistently shows a rapid reversal of
the INR (within 10-30 minutes) in warfarin patients
following administration of PCC.
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7. The Challenge of the Newer Target-
Specific Oral Anticoagulants
 New anticoagulants directly inhibit both free and clot-
bound coagulation factors.
 Unlike warfarin, (which can be reversed with vitamin K),
there is no antidote for these new agents
> Dabigatran (direct thrombin inhibitor)
Consider oral charcoal if last dose < 2 hours ago
HD will remove 60% of drug over 2-3 hours
> Apixaban and rivaroxaban (direct factor Xa inhibitors)
5/3/2015 7

8. The Challenge of the Newer Target-
Specific Oral Anticoagulants cont.
 How to reverse them?
> Withhold the agent in patients with mild-moderate bleeding
> Use PCC, FEIBA, or rFVIIa in patients with life-threatening
bleeding (lack of evidence!!!)
 PCC does NOT directly reverse the anticoagulant effect of the
newer anticoagulation agents, but may overwhelm inhibitory
effects on factor IIa or Xa
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9. Efficacy: Use of Kcentra for warfarin
reversal in acute bleeding
 Study design: Non-inferiority, open label, randomized
controlled trial of 212 warfarin patients followed for 90
days post PCC administration.
 Study population/intervention:
> Age 26-96, on warfarin with acute major bleed; baseline
INR of ≥2.0
> All patients were given intravenous vitamin K
 Exclusion criteria: h/o of thrombotic event, myocardial
infarction, cerebral vascular accident, transient
ischemic attack, unstable angina, severe peripheral
vascular disease, or disseminated intravascular
coagulation w/in the previous three months.
 Kcentra dose was 25, 35, or 50 units (factor IX) per
kilogram (kg) body weight
5/3/2015 9

10. Results
Outcome
PCC
(n=98)
FFP
(n=104)
95% CI
“Effective” hemostasis
72.4%
(71)
65.4%
(68)
-5.8, 19.9
INR reduction to ≤ 1.3 at 30 minutes
after end of infusion
62.2%
(61)
9.6%
(10)
39.4, 65.9
5/3/2015 10
Adverse
events
PCC (n=98) FFP (n=104) 95% CI
Deaths 9.7% (10) 4.6% (5) -2.7, 13.5
Fluid
overload
5.8% (6) unrelated to
study drug
12.8% (14) 7 related to
study drug
15.8, 1.8
Thrombo-
embolic
events
8.7% (9) 5 possibly
related to study drug
5.5% (6) 3 possibly
related to study drug
-4.7, 11.5
“Effective” hemostasis was defined as a rating of excellent or good by a
blinded adjudication board

11. Efficacy: Use of 4-factor PCC for mgmt of
dabigatran-associated bleeding:
Authors Study type N Manageme
nt
Results
Zhou et al.
2011
Murine model
induced ICH
and tail-vein
bleeding time
4F-PCC 25-
100U/kg vs.
FFP vs.
rFVIIa
8mg/kg
· PCC > FFP in preventing hematoma expansion, higher doses PCC
more effective
· rFVIIa ineffective in reducing hematoma expansion
· Mortality lowest in PCC group
Eerenberg
et al 2011
RCT healthy
adult males
(in vivo)
12 4F-PCC
50U/kg vs.
placebo
· PCC had no effect on aPTT, Thrombin Time, or Ecarin Clotting time.
VanRyn et
al 2011
Rat model
tail-vein
bleeding time
(RTBT) vs.
TT, aPTT,
ECT, PT
4F-PCC 35-
40 U/kg vs.
FEIBA
100U/kg vs.
rFVIIa
0.5mcg/kg
· Complete normalization of rat tail bleeding time w/ all coagulation factor
concentrates
· TT, aPTT, ECT not normalized, despite reversal of RTBT
· PT reversed regardless of RTBT reversal
Marlu et al.
2012
Cross-over
healthy adult
males (ex
vivo)
10 4F-PCC
25units/kg
vs. FEIBA
80units/kg
vs. rFVIIa
120mcg/kg
· PCC increased endogenous thrombin potential area under the curve
(ETP-AUC) and increased peak thrombin generation
· FEIBA increased peak thrombin generation and corrected thrombin
generation lag time
· rFVIIa corrected thrombin generation lag time
5/3/2015 11

12. Efficacy: Use of 4-factor PCC for mgmt
of rivaroxaban-associated bleeding
Authors Study
type
N Management Results
Eerenberg
et al.
2011
RCT
healthy
adult
males (in
vivo)
12 4F-PCC
50U/kg vs.
placebo
· PCC immediately and completely normalized the PT and
endogenous thrombin potential tests
Godier et
al. 2012
Rabbit
model
Using
high dose
rivaroxab
an
4F-PCC 40
units/kg vs.
rFVIIa
150mcg/kg
· Both PCC and rFVIIa corrected aPTT, and only partially
improved PT, ROTEM and thrombin generation parameters
· Neither PCC nor rFVIIa were effective in stopping bleeding
Marlu et
al. 2012
Cross-
over
healthy
adult
males (ex
vivo)
10 4F-PCC
25units/kg vs.
FEIBA
80units/kg vs.
rFVIIa
120mcg/kg
· PCC strongly corrected ETP-AUC, and partially corrected
peak thrombin generation
· FEIBA corrected peak thrombin generation
· rFVIIa partial correction of peak thrombin generation
5/3/2015 12

13. Safety/Adverse Reactions:
 Black box warning: Arterial and venous
thromboembolic complications
 Kcentra was not studied in patients with a history of
TE, MI, DIC, CVA, TIA, UA, or severe PVD within the
prior 3 months.
 The most common adverse reactions
> headache (7.8%)
> hypotension (4.9%)
> nausea and vomiting (3.9%)
> arthralgia (3.9%).
 Kcentra is derived from pooled human plasma and
there may be risk for transmission of infectious
agents.
5/3/2015 13

14. Contraindications
 Absolute
> Patients with known anaphylactic or severe systemic
reactions to Kcentra or its components
> Patients with DIC
> Patients with known heparin-induced
thrombocytopenia (HIT)
 Relative
> Venous or arterial TE in the past three months
> Underlying conditions that increase the risk of
thrombosis (e.g. crush injury, sepsis, recent major
surgery)
> Liver disease
> Intracranial hemorrhage not felt to be survivable
5/3/2015 14

15. Monitoring
 blood pressure
 heart rate
 respiratory rate
 baseline INR (for warfarin)
 aPTT (for dabigatran)
5/3/2015 15

16. Target Patient Population
 Legacy guidelines recommend the use of PCC for
antithrombotic-related bleeding in adult patients for
the following P&T approved indications:
> Patients on warfarin therapy with an elevated INR
greater than 2.0, or
> Patients on fondaparinux, rivaroxaban, dabigatran
AND
Patients with life-threatening bleeding (traumatic bleeding,
bleeding into a critical organ, hemoglobin drop > 5g/dL,
requiring reversal in 2 hours) related to anticoagulation
Patients requiring emergent surgery in a critical organ
5/3/2015 16

17. Administration and Dosing of Kcentra
 For warfarin reversal in patients with an INR greater
than 2 AND life-threatening bleeding related to
anticoagulation
> The recommended dosage of Kcentra is 25–50
units/kg of body weight (up to 100 kg), depending on
the patient’s pretreatment INR value. Do not exceed
maximum dose for patients weighing more than 100 kg.
> (Unlike Profilnine, we do NOT use adjusted body weight
in obese patients!)
5/3/2015 17
Baseline INR ≥2.0 to <4.0 ≥4.0 to ≤6.0 >6.0
Dose* of Kcentra (units of factor IX)
per kg total body weight
25 units/kg 35 units/kg 50 units/kg
Maximum dose (units of factor IX) Not to exceed 2500
units
Not to exceed
3500 units
Not to exceed
5000 units
*Dose based on actual potency stated on carton for factor IX units. Pharmacy to round dose to
nearest vial.

18. Administration and Dosing of Kcentra
 Only ONE course of treatment should be given to
stop the bleeding episode
> unlike Profilnine, where we can give multiple doses!
 As with Profilnine, we STILL must administer with
Vitamin K 10mg IV to avoid a rebound increase in the
INR.
> But FFP is NOT needed since more Factor VII
included!
 Infuse reconstituted Kcentra intravenously at a rate of
0.12 mL/kg/min (~3 units/kg/min) up to a maximum
rate of 8.4 mL/min (~210 units/min).
 Recheck INR 30 minutes after PCC administration.
5/3/2015 18

19. Administration and Dosing of Kcentra
 For management of life-threatening bleeding in
patients on dabigatran
> There is no antidote for dabigatran!
> Check baseline aPTT, if greater than 1.5 x control (50
seconds in Legacy) administer Kcentra
> Kcentra 50 units (factor IX)/kg [total body weight] IV
x 1, no maximum dose, round to nearest whole vial
 For management of life-threatening bleeding in
patients on apixaban or rivaroxaban
> There is no antidote for apixaban or rivaroxaban!
> No qualitative lab test available
> Kcentra 50 units (factor IX)/kg [total body weight] IV
x 1, no maximum dose, round to nearest whole vial

5/3/2015 19

20. Cost
 Kcentra is $635 per 500 unit vial purchased on
consignment ($3,810 for an 80 kg patient with INR >
4 to < 6))
 Profilnine is $0.87 per unit purchased on
consignment ($3,480 for an 80 kg pt with INR > 4)
 FFP = $93 per unit, plus $93 for blood typing ($465
for an 80 kg pt – approximately 4 units FFP)
 NovoSeven (r FVIIa) $1430 (1000 mcg vial), $2860
(2000mcg vial), $7153 (5000 mcg vial) purchased on
consignment ($10,013 for an 80 kg patient)
5/3/2015 20

21. Key Tips to Remember About Kcentra
Monitor When Why Comment
INR on
admit
and 30
minutes
after
kcentra
admin
To assess INR
reversal prior to
surgery/proced
ure
Only one course of treatment should be given to stop the
bleeding episode .
Vitamin
K dose
(10 mg
IV)
With
PCC
order
To avoid
rebound in INR
after PCC
wears off (6
hours)
Must be given IV to ensure more rapid correction; IM
administration is contraindicated due to risk of hematomas
Dose
(MDs
and
RPHs)
Order
Entry or
Verifica
tion
To ensure
efficacy and
safety
INR 2-4: 25 u/kg (NTE 2500 Units)
INR 4-6: 35 u/kg (NTE 3500 Units)
INR >6: 50 u/kg (NTE 5000 Units)
Use TBW for patients up to 100 kg. Do not exceed the
maximum recommended dose for patients >100 kg.
5/3/2015 21

22. References
1. Profilnine SD [package insert] Grifols Biologicals Inc., Los Angeles, CA; August 2010
2. Kcentra [package insert] CSL Behring, Marburg, Germany; April 2013.
3. Holbrook A, et al. Evidence-Based Management of Anticoagulant Therapy, 9th edition: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST
2012;141(suppl):e152s-e1842s.
4. Sarode R, et al. Randomized phase IIIb study comparing safety and efficacy of 4-factor prothrombin
complex concentrate with plasma in subjects receiving vitamin K antagonists with major bleeding
[abstract]. Presented at Thrombosis and Hemostasis Summit of North America; Chicago, IL; May 3-5,
2012.
5. Eerenberg ES, et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate.
A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Circulation 2011; 124:1573-
1579.
6. Van Ryn J, et al. The Successful Reversal of Dabigatran-Induced Bleeding by Coagulation Factor
Concentrates in a Rat Tail Bleeding Model Do Not Correlate with Ex Vivo Markers of Anticoagulation.
Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 2316
7. Marlu R, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and
rivaroxaban: A randomized crossover ex vivo study in healthy volunteers. Thrombosis and
Haemostasis. 2012;108(2):217-224.
8. Godier A, et al. Evaluation of Prothrombin Complex Concentrate and Recombinant Activated Factor
VII to Reverse Rivaroxaban in a Rabbit Model. Anesthesiology 2012;116:94-102.
9. Levi M, et al. Safety of Recombinant Activated FVII in Randomized Clinical Trials. NEJM
2010;363:1791-1800.
10. Crowther MA, et al. Managing bleeding in anticoagulated patients with a focus on novel therapeutic
agents. J Thromb Haemost 2009;7:197-110.
11. Siegal DM, et al. Reversal of novel oral anticoagulants in patients with major bleeding. J Thrombosis
and Thrombolysis 2013;35(3):391-398.
5/3/2015 22

23. Thank you!