KCENTRA™ (Prothrombin Complex Concentrate (Human)) prescribing information, dosing, indications

KCENTRA™ (Prothrombin Complex Concentrate (Human))

DESCRIPTION	CLINICAL PHARMACOLOGY	INDICATIONS AND USAGE
CONTRAINDICATIONS	PRECAUTIONS	ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION	HOW SUPPLIED	WARNINGS
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Drug Update: KCENTRA (Prothrombin Complex Concentrate (Human))
For Intravenous Use, Lyophilized Powder for Reconstitution
[Drug information / PDF]
Dosing: Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval: 2013

Mechanism of Action: Kcentra contains the Vitamin K-dependent coagulation Factors II (FII), VII (FVII), IX (FIX), and X (FX), together known as the Prothrombin Complex, and the antithrombotic Protein C and Protein S.

A dose-dependent acquired deficiency of the Vitamin K-dependent coagulation factors occurs during Vitamin K antagonist treatment. Vitamin K antagonists exert anticoagulant effects by blocking carboxylation of glutamic acid residues of the Vitamin K-dependent coagulation factors during hepatic synthesis, lowering both factor synthesis and function. The administration of Kcentra rapidly increases plasma levels of the Vitamin K-dependent coagulation Factors II, VII, IX, and X as well as the antithrombotic Proteins C and S.

Coagulation Factor II
Factor II (prothrombin) is converted to thrombin by activated FX (FXa) in the presence of Ca2+, FV, and phospholipids.

Coagulation Factor VII
Factor VII (proconvertin) is converted to the activated form (FVIIa) by splitting of an internal peptide link. The FVIIa-TF complex activates Factor IX and initiates the primary coagulation pathway by activating FX in the presence of phospholipids and calcium ions.

Coagulation Factor IX
Factor IX (antihemophilic globulin B, or Christmas factor) is activated by the FVIIa-TF complex and by FXIa. Factor IXa in the presence of FVIIIa activates FX to FXa.

Coagulation Factor X
Factor X (Stuart-Prower factor) activation involves the cleavage of a peptide bond by the FVIIIa-Factor IXa complex or the TF-FVIIa complex. Factor Xa forms a complex with activated FV (FVa) that converts prothrombin to thrombin in the presence of phospholipids and calcium ions.

Protein C
Protein C, when activated by thrombin, exerts an antithrombotic effect by inhibiting FVa and FVIIIa leading to a decrease in thrombin formation, and has indirect profibrinolytic activity by inhibiting plasminogen activator inhibitor-1.

Protein S
Protein S exists in a free form (40%) and in a complex with C4b-binding protein (60%). Protein S (free form) functions as a cofactor for activated Protein C in the inactivation of FVa and FVIIIa, leading to antithrombotic activity.

WARNINGS

See warnings and precautions below.

WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS

Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the potential risks of thromboembolic events (TE), especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding

Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events.
Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months.

DESCRIPTION

Description:

Initial U.S. Approval: 2013
Kcentra is a purified, heat-treated, nanofiltered and lyophilized non-activated four-factor Prothrombin Complex Concentrate (Human) prepared from human U.S. Source Plasma (21 CFR 640.60). It contains the Vitamin K dependent Coagulation Factors II, VII, IX and X, and the antithrombotic Proteins C and S. Factor IX is the lead factor for the potency of the preparation as stated on the vial label. The excipients are human antithrombin III, heparin, human albumin, sodium chloride, and sodium citrate. Kcentra is sterile, pyrogen-free, and does not contain preservatives.

The product contents are shown in Table 7 and listed as ranges for the blood coagulation factors.
Table 7: Composition per Vial of Kcentra *

Ingredient	Kcentra 500 units	Kcentra 1000 units
Total protein	120-280 mg	240-560 mg
Factor II	380-800 units	760-1600 units
Factor VII	200-500 units	400-1000 units
Factor IX	400-620 units	800-1240 units
Factor X	500-1020 units	1000-2040 units
Protein C	420-820 units	840-1640 units
Protein S	240-680 units	480-1360 units
Heparin	8-40 units	16-80 units
Antithrombin III	4-30 units	8-60 units
Human albumin	40-80 mg	80-160 mg
Sodium chloride	60-120 mg	120-240 mg
Sodium citrate	40-80 mg	80-160 mg
HCl	Small amounts	Small amounts
NaOH	Small amounts	Small amounts

*Exact potency of coagulant and antithrombotic proteins are listed on the carton

All plasma used in the manufacture of Kcentra is obtained from US donors and is tested using serological assays for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. The plasma is tested with Nucleic Acid Testing (NAT) for HCV, HIV-1, HAV, and HBV, and found to be non-reactive (negative), and the plasma is also tested by NAT for human parvovirus B19 (B19V) in order to exclude donations with high titers. The limit for B19V in the fractionation pool is set not to exceed 104 units of B19V DNA per mL. Only plasma that passed virus screening is used for production.

The Kcentra manufacturing process includes various steps, which contribute towards the reduction/ inactivation of viruses. Kcentra is manufactured from cryo-depleted plasma that is adsorbed via ion exchange chromatography, heat treated in aqueous solution for 10 hours at 60°C, precipitated, adsorbed to calcium phosphate, virus filtered, and lyophilized.

These manufacturing steps were independently validated in a series of in-vitro experiments for their virus inactivation / reduction capacity for both enveloped and non-enveloped viruses. Table 8 shows the virus clearance during the manufacturing process for Kcentra, expressed as the mean log10 reduction factor.
Table 8: Virus Reduction Factors [log10] of Kcentra

Virus Studied	Manufacturing Steps						Overall Virus Reduction [log10]
Virus Studied	Cryo- precipi-tation	DEAE-Adsorption (Ion Exchange Chroma-tography)	Heat treatment ("Pasteuri-zation")	Ammonium sulphate precipitation followed by Ca Phosphate adsorption	75/35 nm Filtration	Lyophili-zation	Overall Virus Reduction [log10]
Enveloped Viruses
HIV	n.d.	n.d	6.9	5.9	7.3	n.d.	20.1
BVDV	n.d.	n.d	8.5	2.2	4.2	n.d.	14.9
PRV	n.d.	n.d	4.1	7.2	6.8	n.d.	18.1
WNV	n.d.	n.d.	7.4	n.d.	n.d.	n.d.	7.4
Non-Enveloped Viruses
HAV	n.d	n.d	4.0	1.8	n.d.	2.2	8.0
CPV	1.3		[0.5]*	1.5	n.d.	n.d.	2.8
HIV Human immunodeficiency virus, a model for HIV-1 and HIV-2 BVDV Bovine viral diarrhea virus, model for HCV PRV Pseudorabies virus, a model for large enveloped DNA viruses WNV West Nile virus HAV Hepatitis A virus CPV Canine parvovirus, model for B19V n.d. not determined *Reduction factor below 1 log10 was not considered in calculating the overall virus reduction. Studies using human parvovirus B19, which are considered experimental in nature, have demonstrated a virus reduction factor of 3.5 log10 by heat treatment.

CLINICAL PHARMACOLOGY:

Mechanism of Action:
Kcentra contains the Vitamin K-dependent coagulation Factors II (FII), VII (FVII), IX (FIX), and X (FX), together known as the Prothrombin Complex, and the antithrombotic Protein C and Protein S.

A dose-dependent acquired deficiency of the Vitamin K-dependent coagulation factors occurs during Vitamin K antagonist treatment. Vitamin K antagonists exert anticoagulant effects by blocking carboxylation of glutamic acid residues of the Vitamin K-dependent coagulation factors during hepatic synthesis, lowering both factor synthesis and function. The administration of Kcentra rapidly increases plasma levels of the Vitamin K-dependent coagulation Factors II, VII, IX, and X as well as the antithrombotic Proteins C and S.

Coagulation Factor II:
Factor II (prothrombin) is converted to thrombin by activated FX (FXa) in the presence of Ca2+, FV, and phospholipids.

Coagulation Factor VII:
Factor VII (proconvertin) is converted to the activated form (FVIIa) by splitting of an internal peptide link. The FVIIa-TF complex activates Factor IX and initiates the primary coagulation pathway by activating FX in the presence of phospholipids and calcium ions.

Coagulation Factor IX:
Factor IX (antihemophilic globulin B, or Christmas factor) is activated by the FVIIa-TF complex and by FXIa. Factor IXa in the presence of FVIIIa activates FX to FXa.

Coagulation Factor X:
Factor X (Stuart-Prower factor) activation involves the cleavage of a peptide bond by the FVIIIa-Factor IXa complex or the TF-FVIIa complex. Factor Xa forms a complex with activated FV (FVa) that converts prothrombin to thrombin in the presence of phospholipids and calcium ions.

Protein C:
Protein C, when activated by thrombin, exerts an antithrombotic effect by inhibiting FVa and FVIIIa leading to a decrease in thrombin formation, and has indirect profibrinolytic activity by inhibiting plasminogen activator inhibitor-1.

Protein S:
Protein S exists in a free form (40%) and in a complex with C4b-binding protein (60%). Protein S (free form) functions as a cofactor for activated Protein C in the inactivation of FVa and FVIIIa, leading to antithrombotic activity.

INDICATIONS AND USAGE

INDICATIONS AND USAGE:
Kcentra, (Prothrombin Complex Concentrate (Human)), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with:

acute major bleeding or
need for an urgent surgery/invasive procedure.

CONTRAINDICATIONS

Contraindications:
Kcentra is contraindicated in:

Patients with known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin.
Patients with disseminated intravascular coagulation (DIC).
Patients with known heparin-induced thrombocytopenia (HIT). Kcentra contains heparin

PRECAUTIONS

WARNINGS AND PRECAUTIONS: [see package insert for more detailed comments]

Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment.
Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months.
Kcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

ADVERSE REACTIONS

ADVERSE REACTIONS:

The most common adverse reactions (ARs) (frequency

2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia.
The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis.

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS
Pregnancy: No human or animal data. Use only if clearly needed.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

DOSAGE AND ADMINISTRATION

DOSAGE AND ADMINISTRATION:
For intravenous use only.

Dosage:

Measurement of INR prior to treatment and close to the time of dosing is important because coagulation factors may be unstable in patients with acute major bleeding or an urgent need for surgery and other invasive procedures.
Individualize Kcentra dosing based on the patient's current pre-dose International Normalized Ratio (INR) value, and body weight> Table 1).
The actual potency per vial of Factors II, VII, IX and X, Proteins C and S is stated on the carton.
Administer Vitamin K concurrently to patients receiving Kcentra. Vitamin K is administered to maintain Vitamin K-dependent clotting factor levels once the effects of Kcentra have diminished.
The safety and effectiveness of repeat dosing have not been established and is not recommended.
Dose ranging within pre-treatment INR groups has not been studied in randomized clinical trials of Kcentra.

Table 1: Dosage Required for Reversal of VKA Anticoagulation in Patients with acute major bleeding or need for an urgent surgery/invasive procedure

Pre-treatment INR	2-< 4	4-6	> 6
Dose* of Kcentra (units† of Factor IX) / kg body weight	25	35	50
Maximum dose‡ (units of Factor IX)	Not to exceed 2500	Not to exceed 3500	Not to exceed 5000
*Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary from 20-31 Factor IX units/mL after reconstitution. Nominal potency is 500 or 1000 units per vial, approximately 25 units per mL after reconstitution. † Units refer to International Units. ‡Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

Example dosing calculation for 80 kg patient
For example, an 80 kg patient with a baseline of INR of 5.0, the dose would be 2,800 Factor IX units of Kcentra, calculated as follows based on INR range of 4-6, see Table 1:

35 units of Factor IX/kg × 80 kg = 2,800 units of Factor IX required*

*For a vial with an actual potency of 30 units/mL Factor IX, 93 mL would be given (2,800 U/30 U per mL = 93 mL).
Monitor INR and clinical response during and after treatment. In clinical trials, Kcentra decreased the INR to

1.3 within 30 minutes in most subjects. The relationship between this or other INR values and clinical hemostasis in patients has not been established

Preparation and Reconstitution:

Reconstitute using aseptic technique with 20 mL (500 U kit) or 40 mL (1000 U kit) of diluent provided with the kit.
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. Reconstituted Kcentra solution should be colorless, clear to slightly opalescent, and free from visible particles. Do not use solutions that are cloudy or have deposits.
Kcentra is for single use only. Contains no preservatives. Discard partially used vials.

The procedures provided in Table 2 are general guidelines for the preparation and reconstitution of Kcentra.

Reconstitute at room temperature as follows:
Table 2: Kcentra Reconstitution Instructions:

1. Ensure that the Kcentra vial and diluent vial are at room temperature. Prepare and administer using aseptic technique.
2. Place the Kcentra vial, diluent vial, and Mix2Vial® transfer set on a flat surface.
3. Remove Kcentra and diluent vial flip caps. Wipe the stoppers with the alcohol swab provided and allow to dry prior to opening the Mix2Vial transfer set package.
4. Open the Mix2Vial transfer set package by peeling away the lid. [Fig. 1] Leave the Mix2Vial transfer set in the clear package.	Fig. 1
5. Place the diluent vial on a flat surface and hold the vial tightly. Grip the Mix2Vial transfer set together with the clear package and push the plastic spike at the blue end of the Mix2Vial transfer set firmly through the center of the stopper of the diluent vial. [Fig. 2]	Fig. 2
6. Carefully remove the clear package from the Mix2Vial transfer set. Make sure that you pull up only the clear package, not the Mix2Vial transfer set. [Fig. 3]	Fig. 3
7. With the Kcentra vial placed firmly on a flat surface, invert the diluent vial with the Mix2Vial transfer set attached and push the plastic spike of the transparent adapter firmly through the center of the stopper of the Kcentra vial. [Fig. 4] The diluent will automatically transfer into the Kcentra vial.	Fig. 4
8. With the diluent and Kcentra vial still attached to the Mix2Vial transfer set, gently swirl the Kcentra vial to ensure that the Kcentra is fully dissolved. [Fig. 5] Do not shake the vial.	Fig. 5
9. With one hand, grasp the Kcentra side of the Mix2Vial transfer set and with the other hand grasp the blue diluent-side of the Mix2Vial transfer set, and unscrew the set into two pieces. [Fig. 6]	Fig. 6
10. Draw air into an empty, sterile syringe. While the Kcentra vial is upright, screw the syringe to the Mix2Vial transfer set. Inject air into the Kcentra vial. While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly. [Fig. 7]	Fig. 7
11. Now that the concentrate has been transferred into the syringe, firmly grasp the barrel of the syringe (keeping the plunger facing down) and unscrew the syringe from the Mix2Vial transfer set. [Fig. 8] Attach the syringe to a suitable intravenous administration set.	Fig. 8
12. After reconstitution, administration should begin promptly or within 4 hours.
13. If the same patient is to receive more than one vial, you may pool the contents of multiple vials. Use a separate unused Mix2Vial transfer set for each product vial.

Administration:

Do not mix Kcentra with other medicinal products; administer through a separate infusion line.
Use aseptic technique when administering Kcentra.
Administer at room temperature.
Administer by intravenous infusion 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).
No blood should enter the syringe, as there is a possibility of fibrin clot formation.

HOW SUPPLIED

DOSAGE FORMS AND STRENGTHS:

Kcentra is available as a single use vial containing coagulation Factors II, VII, IX and X, antithrombotic Proteins C and S as a lyophilized concentrate.
Kcentra potency (units) is defined by Factor IX content. The range of Factor IX units per vial is 400-620 units for the 500 U kit and 800-1240 units for the 1000 U kit. When reconstituted, the final concentration of drug product in Factor IX units will be in a range from 20-31 units/mL.
The actual content of Factor IX as measured in units of potency is stated on the vial.
The actual units of potency for each coagulation factor (Factors II, VII, IX and X), and Proteins C and S are stated on the carton.

REFERENCE

Reference(s):
Package insert data: [Accessed: June 2014]
Manufactured by:
CSL Behring GmbH
35041 Marburg Germany
US License No. 1765

Distributed by:
CSL Behring LLC
Kankakee, IL 60901 USA

PRINCIPAL DISPLAY PANEL - 500 U Vial Label

500 U

Prothrombin Complex Concentrate (Human)
Kcentra™
For Intravenous Administration Only