Kcentra:

A 4-Factor Prothrombin Concentrate

Sylvia Doyle, Pharm.D.

Elva Angelique Van Devender, Ph.D., Pharm.D., BCPS

Legacy Good Samaritan Emergency Department

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.

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!

The Clotting Cascade

5/3/2015 4

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

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.

5/3/2015 6

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

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

5/3/2015 8

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

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

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

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

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

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

Monitoring

blood pressure

heart rate

respiratory rate

baseline INR (for warfarin)

aPTT (for dabigatran)

5/3/2015 15

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

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.

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

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

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

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

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

Thank you!