(prothrombin, coagulation factor vii human, coagulation factor ix human, coagulation factor x human, protein c, protein s human, and water)
[CSL Behring GmbH]
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use KCENTRA safely and effectively. See full prescribing information for KCENTRA.
KCENTRA (Prothrombin Complex Concentrate (Human))
For Intravenous Use, Lyophilized Powder for Reconstitution
Initial U.S. Approval: 2013
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, 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.
INDICATIONS AND USAGE
Kcentra, Prothrombin Complex Concentrate (Human), is 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.
Kcentra is not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding. (1)
DOSAGE AND ADMINISTRATION
For intravenous use only.
DOSAGE FORMS AND STRENGTHS
Kcentra is contraindicated in patients with:
WARNINGS AND PRECAUTIONS
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. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION
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. (5.2)
- 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. (5.2)
Kcentra, (Prothrombin Complex Concentrate (Human)), is 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.
Kcentra is not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding.
For intravenous use only.
- The actual potency per vial of Factors II, VII, IX and X, Proteins C and S is stated on the carton.
- Individualize Kcentra dosing based on the patient's current pre-dose International Normalized Ratio (INR) value, and body weight.
- 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.
- Repeat dosing with Kcentra is not supported by clinical data and is not recommended.
- Dose ranging other than what is recommended has not been studied in randomized clinical trials of Kcentra.
Dosage Required for Reversal of VKA Anticoagulation in Patients with Acute Major Bleeding
Reconstitute Kcentra with 20 mL of diluent (Sterile Water for Injection, USP) provided with the kit [see Dosage and Administration (2.2)]. When reconstituted, the final concentration of drug product in Factor IX units will be in a range from 20-31 units/mL, depending on the actual potency, which is listed on the carton.
Coagulation factor levels may be unstable in patients with acute major bleeding who are receiving Vitamin K. Measure INR prior to treatment close to the time of dosing, then individualize dosage based on the INR value and the subject's body weight (kg) as shown in Table 1 below.
|Pre-treatment INR||2 – < 4||4 – 6||> 6|
|Dose* of Kcentra (units† of Factor IX) / kg body weight||25||35||50|
(units of Factor IX)
|Not to exceed 2500||Not to exceed 3500||Not to exceed 5000|
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*|
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 [see Clinical Studies (14)].
- Reconstitute using aseptic technique with 20 mL of diluent provided with the kit.
- Do not use Kcentra beyond the expiration date on the vial label and carton.
- 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:
- 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.
- Record the lot number of the product in the patient's medical record when Kcentra is administered to the patient.
- 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. When reconstituted using 20 mL of diluent, 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.
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 [see Description (11)].
Hypersensitivity reactions including flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, and bronchospasm have been observed with Kcentra [see Adverse Reactions (6.2)].
If severe allergic reaction or anaphylactic type reactions occur, immediately discontinue administration, and institute appropriate treatment.
Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance [see Adverse Reactions (6.1), (6.2), and Clinical Studies (14)]. Patients being treated with VKA therapy have underlying disease states that predispose them to thromboembolic events. Reversing VKA therapy exposes patients to the thromboembolic risk of their underlying disease. Resumption of anticoagulation should be carefully considered following administration of Kcentra and Vitamin K once the risk of thromboembolic events outweighs the risk of acute bleeding.
Thromboembolic events occurred more frequently following Kcentra compared to plasma in a randomized, plasma controlled trial in subjects requiring urgent reversal of VKA anticoagulation due to acute major bleeding, and the excess in thromboembolic events was more pronounced among subjects who had a history of prior thromboembolic event, although these differences were not statistically significant [see Adverse Reactions (6.1), Clinical Studies (14)]. Potential benefits of treatment with Kcentra should be weighed against the potential risks of thromboembolic events [see Adverse Reactions (6, 6.1, 6.2)]. Patients with a history of thrombotic events, myocardial infarction, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, severe peripheral vascular disease, or disseminated intravascular coagulation, within the previous 3 months were excluded from participating in the plasma-controlled RCT. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. Because of the risk of thromboembolism associated with reversal of VKA, closely monitor patients for signs and symptoms of thromboembolism during and after administration of Kcentra. [see 17 Patient Counseling Information]
Because Kcentra is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease agent. There is also the possibility that unknown infectious agents may be present in such products. Despite the use of two dedicated virus reduction steps in manufacturing to reduce risks, such products may still potentially transmit disease.
Reports of suspected virus transmission of hepatitis A, B, C, and HIV were generally confounded by concomitant administration of blood/blood components and/or other plasma-derived products. No causal relationship to Kcentra administration was established for any of these reports since introduction of a virus filtration step in 1996.
All infections thought by a physician to have been possibly transmitted by Kcentra should be reported by the physician or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The most common adverse reactions (ARs) (frequency ≥2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension.
The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis.
The following serious adverse reactions are described below and/or elsewhere in the labeling:
- Hypersensitivity reactions [see Warnings and Precautions (5.1)]
- Arterial and venous thromboembolic complications [see Boxed Warning and Warnings and Precautions (5.2)]
- Possible transmission of infectious agents [see Warnings and Precautions (5.3)]
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Randomized, Plasma-Controlled Trial in Acute Major Bleeding
In a prospective, randomized, open-label, active-controlled multicenter non-inferiority trial, 212 subjects who required urgent reversal of VKA therapy due to acute major bleeding were enrolled and randomized to treatment; 103 were treated with Kcentra and 109 with plasma. Subjects with a history of a thrombotic event, myocardial infarction, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, severe peripheral vascular disease, or disseminated intravascular coagulation, within the previous 3 months were excluded from participating. Subjects ranged in age from 26 years to 96 years.
Randomized, Plasma-Controlled Trial in Urgent Surgery/Invasive Procedures
In a prospective, randomized, open-label, active-controlled, multicenter non-inferiority trial, 176 subjects who required urgent reversal of VKA therapy due to the need for an urgent surgical or urgent invasive procedure were enrolled; 88 were treated with Kcentra and 88 with plasma. Subjects ranged in age from 27 years to 94 years.
Adverse reactions are summarized for Kcentra and plasma in the Acute Major Bleeding RCT (see Table 3).
Adverse Reactions are defined as adverse events that began during or within 72 hours of test product infusion plus adverse events considered possibly/probably related or related to study treatment according to the investigator, sponsor, or the blinded safety adjudication board (SAB), and with at least a 1.3‐fold difference between treatments.
|No. (%) of subjects|
(N = 103)
(N = 109)
|General disorders and administration site conditions|
|Chest pain||1 (1.0%)||3 (2.8%)|
|Nervous system disorders|
|Headache||8 (7.8%)||2 (1.8%)|
|Hemorrhage intracranial||3 (2.9%)||0|
|Respiratory, thoracic, and mediastinal disorders|
|Respiratory distress/dyspnea/hypoxia||2 (1.9%)||4 (3.7%)|
|Breath sounds abnormal/rates||1 (1.0%)||3 (2.8%)|
|Pulmonary edema||0||4 (3.7%)|
|Nausea/vomiting||4 (3.9%)||1 (0.9%)|
|Constipation||2 (1.9%)||6 (5.5%)|
|Tachycardia||3 (2.9%)||1 (0.9%)|
|International normalized ratio increased*||3 (2.9%)||0|
|Metabolism and nutrition disorders|
|Hypokalemia||2 (1.9%)||5 (4.6%)|
|Fluid overload†||1 (1.0%)||6 (5.5%)|
|Mental status changes||3 (2.9%)||0|
|Insomnia||1 (1.0%)||3 (2.8%)|
|Musculoskeletal and connective tissue disorders|
|Hypotension‡||5 (4.9%)||3 (2.8%)|
|Blood pressure increased/hypertension||3 (2.9%)||0|
|Injury, poisoning, and procedural complications|
|Skin laceration/contusion/subcutaneous hematoma||3 (2.9%)||1 (0.9%)|
|Transfusion reaction§||0||4 (3.7%)|
|Blood and lymphatic disorders|
Serious adverse reactions in subjects receiving Kcentra in both RCTs included ischemic cerebrovascular accident (stroke), DVT, thrombosis, and venous insufficiency. Serious adverse reactions in both RCTs for plasma included myocardial ischemia, myocardial infarction, fluid overload, embolic cerebral infarction, pulmonary edema, respiratory failure, and DVT.
There were a total of 10 subjects (9.7%) who died in the Kcentra group (1 additional death occurred on day 46 just after completion of the study reporting period) and 5 (4.6%) who died in the plasma group in the plasma-controlled RCT in acute major bleeding. The 95% confidence interval for the Kcentra minus Plasma between-group difference in deaths ranged from -2.7% to 13.5%. In a preliminary analysis of data from the plasma-controlled RCT in urgent surgery/invasive procedures, there were a total of 3 subjects (3.4%) who died in the Kcentra group and 8 (9.1%) who died in the Plasma group. The 95% confidence interval for the Kcentra minus Plasma between-group difference in deaths in this trial ranged from -14.6% to 2.7%. One death in the Kcentra group in the RCT in Acute Major Bleeding and one death in the Plasma group in the RCT in urgent surgery/invasive procedures were considered possibly related to study treatment according to an assessment of masked data by an independent safety adjudication board. No factors common to all deaths were identified, except for the frequent findings of a high comorbidity burden, advanced age, and death after being placed on comfort care. Although, a greater proportion of subjects in the RCT in acute major bleeding than in the RCT in surgery/invasive procedure received the highest two recommended doses of Kcentra because more subjects in the trial in acute major bleeding had a baseline INR in the ranges of 4-6 and > 6.0, an analysis of deaths and factor levels in subjects with major bleeding revealed that subjects who died had similar median factor levels to subjects that did not die. Additionally, outliers with supraphysiologic factor levels did not have a mortality rate out of proportion to the overall population.
There were 6 subjects (5.8%, all non-related by investigator assessment) in the Kcentra group who experienced fluid overload in the plasma-controlled RCT in acute major bleeding and 14 (12.8%, 7 events related by investigator assessment) who had fluid overload in the plasma group. The 95% confidence interval for the Kcentra minus Plasma between-group difference in fluid overload event incidence ranged from -15.8% to 1.8%.
Post-hoc subgroup analyses of the RCT in acute major bleeding were conducted according to whether subjects had a prior history of congestive heart failure (Table 4). The incidence of fluid overload events was 8.7% in the Kcentra group and 25% in the plasma group in the subgroup of subjects with a history of prior congestive heart failure. The 95% confidence interval (CI) for the Kcentra minus Plasma between-group difference in fluid overload in subjects with a prior history of congestive heart failure ranged from -33.0% to 0.9%. In subjects without a history of congestive heart failure, the Kcentra minus Plasma between-group difference in fluid overload was – 1.1% (95% CI -10.7 to 9.1%).
|Subgroup||Major Bleeding Study|
|All subjects||103||6 (5.8)||109||14 (12.8)|
|With history of CHF||46||4 (8.7)||44||11 (25.0)|
|Without history of CHF||57||2 (3.5)||65||3 (4.6)|
There were 9 subjects (8.7%) in the Kcentra group who experienced possible thromboembolic events (TEEs) in the plasma-controlled RCT in acute major bleeding and 6 (5.5%) who had TEEs in the plasma group. The 95% confidence interval for the Kcentra minus Plasma between-group difference in possible TEE incidence ranged from -4.7% to 11.5%. The incidence of thromboembolic (TE) adverse reactions assessed as at least possibly related to study treatment by the Investigator or, in the case of serious thromboembolic events, the blinded safety adjudication board (SAB)] was 5 (4.9%) in the Kcentra group and 3 (2.8%) in the plasma group. When also considering the events which began during or within 72 hours of test product infusion, the incidence was 5 (4.9%) in the Kcentra group and 4 (3.7%) in the plasma group (95% confidence interval) for the Kcentra minus plasma difference ranged from -5.6% to 8.3%. TE events observed in the major bleeding study are shown in Table 5.
|System Organ Class||No. (%) of subjects|
(N = 103)
(N = 109)
|Any possible TEE*||9 (8.7%)||6 (5.5%)|
|TEE Adverse reactions||6 (5.5%)†||4 (3.7%)|
|Myocardial infarction‡||0||1 (0.9%)|
|Myocardial ischemia||0||2 (1.8%)|
|Nervous system disorders|
|Ischemic cerebrovascular accident (stroke)†||2 (1.9%)||0|
|Cerebrovascular disorder§||0||1 (0.9%)|
|Venous thrombosis calf||1 (1.0%)||0|
|Deep vein thrombosis (DVT)¶||1 (1.0%)||0|
|Fistula Clot||1 (1.0%)||0|
|Unknown Cause of Death (not confirmed TEE)|
|Sudden death||1 (1.0%)||0|
Post-hoc subgroup analyses of the RCT in acute major bleeding were conducted according to whether subjects had a prior history of a thromboembolic event. Among subjects who received Kcentra, the incidence of TE events was 11.6% (95% confidence interval 6.0 –21.2%) in the subgroup of subjects with a history of prior TE event compared to 2.9% (95% confidence interval 0.5 – 14.9%) in the subgroup without such history. The incidence of TE events in the plasma group was 3.8% (95% confidence interval 1.3 – 10.6%) in the subgroup of subjects with a history of prior TE event compared to 10.0% (95% confidence interval 3.5 – 25.6%) in the subgroup without such history.
Table 6 shows treatment-emergent TE events by randomized treatment subgroup according to whether subjects had a prior history of TE event.
|Acute Major Bleeding Study|
|All subjects||103||9 (8.7)||109||6 (5.5)|
|With history of TE event†||69||8 (11.6)||79||3 (3.8)|
|Without history of TE event||34||1 (2.9)||30||3 (10.0)|
In a prospective, open label, single-arm, multicenter safety and efficacy trial, 17 subjects who required urgent reversal of VKA due to acute bleeding were enrolled and 26 subjects who required urgent reversal of Vitamin K antagonist due to the need for an urgent surgical/invasive procedure were enrolled, all were treated with Kcentra. Subjects ranged in age from 22 years to 85 years. Serious adverse events considered possibly related to Kcentra included a suspected pulmonary embolism which occurred in one subject following a second dose of Kcentra. A single non-fatal TE event occurred in another Kcentra-treated subject in that trial.
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified and reported during postmarketing use of Kcentra outside the US since 1996.
- Hypersensitivity or Allergic reactions: flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, and bronchospasm.
- Thromboembolic complications: arterial thromboembolic events (including acute myocardial infarction and arterial thrombosis), venous thromboembolic events (including pulmonary embolism and venous thrombosis), and disseminated intravascular coagulation.
Kcentra has not been studied for use during labor and delivery. Safety and effectiveness in labor and delivery have not been established.
It is not known whether Kcentra is excreted in human milk. Because many drugs are excreted in human milk, use Kcentra only if clearly needed when treating a nursing woman.
The safety and efficacy of Kcentra in the pediatric population has not been studied.
Of the total number of subjects (229) with acute major bleeding treated to reverse VKA anticoagulation in two clinical studies, 71% were 65 years old or greater and 43% were 75 years old or greater. There were no clinically significant differences between the safety profile of Kcentra and plasma in any age group.
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.
|Ingredient||Kcentra 500 units|
|Total protein||120 – 280 mg|
|Factor II||380 – 800 units|
|Factor VII||200 – 500 units|
|Factor IX||400 – 620 units|
|Factor X||500 – 1020 units|
|Protein C||420 – 820 units|
|Protein S||240 – 680 units|
|Heparin||8 – 40 units|
|Antithrombin III||4 – 30 units|
|Human albumin||40 – 80 mg|
|Sodium chloride||60 – 120 mg|
|Sodium citrate||40 – 80 mg|
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.
|Virus Studied||Manufacturing Steps||Overall Virus Reduction
|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|
|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|
|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|
Kcentra has not been studied in patients with congenital factor deficiencies.
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. If the patient has an acquired coagulation factor deficiency where one or more of the Vitamin K-dependent coagulation factors are deficient, bleeding may occur.
The coagulation cascade is a series of pro-coagulant and antithrombotic reactions involving the activation of zymogens. The vascular endothelium provides a protective barrier separating blood cells and plasma factors from subendothelial vessel wall reactive adhesive proteins and tissue factor (TF). The latter proteins trigger blood coagulation. Thrombin converts fibrinogen to fibrin for clot formation.
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, 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.
International Normalized Ratio (INR)
In the plasma-controlled RCT in acute major bleeding, the INR was determined at varying time points after the start or end of infusion, depending upon study design. The median INR was above 3.0 prior to the infusion and dropped to a median value of 1.20 by the 30 minute time point after start of Kcentra infusion. By contrast, the median value for plasma was 2.4 at 30 minutes after the start of infusion. The INR differences between Kcentra and plasma were statistically significant in randomized plasma-controlled trial in bleeding up to 12 hours after start of infusion [see Table 9].
The relationship between these or other INR values and clinical hemostasis in patients has not been established [see Clinical Studies (14)].
|Study||Treatment||Baseline||30 min||1 hr||2-3 hr||6-8 hr||12 hr||24 hr|
|INR = international normalized ratio.|
|Acute Major Bleeding Study||Kcentra|
(N = 98)
(N = 104)
Pharmacokinetic (PK) parameters were obtained in healthy subjects. PK parameters obtained from data derived from the study of healthy subjects may not be directly applicable to those with acute major bleeding and INR elevation due to VKA anticoagulation therapy.
Fifteen healthy subjects received 50 units/kg of Kcentra. No subjects were receiving VKA therapy or were experiencing acute bleeding. A single intravenous Kcentra infusion produced a rapid and sustained increase in plasma concentration of Factors II, VII, IX and X. Concentrations of Proteins C and S also increased rapidly and substantially. The PK analysis [see Table 10 and Table 11] shows that factor II had the longest half-life (59.7 hours) and factor VII the shortest (4.2 hours) in healthy subjects. The mean residence time (MRT) was longest for factor II (81.7 hours) and shortest for factor VII (6.1 hours).
|Parameter||Factor IX||Factor II||Factor VII||Factor X|
|Terminal half-life (h)||16.7 (14.2-67.7)||59.7 (45.5-65.9)||4.2 (3.9-6.6)||30.7 ( 23.7-41.4)|
|IVR (%/units/kg bw)†||1.57 (1.38-1.90)||2.11 ( 1.95-2.45)||2.43 (2.33-2.77)||2.08 (1.94-2.39)|
|AUC (IU/dL × h)||1490 (1153-2376)||6577 (5870-7912)||424 (331-742)||6707 (5234-8577)|
|Clearance (mL/ kg × h)||3.63 (2.27- 4.68)||0.97 (0.81-1.09)||7.06 (4.04-9.05)||1.25 (0.98-1.60)|
|MRT (h)‡||21.6 (17.1-83.8)||81.7 (62.0-87.6)||6.1 (5.6-9.5)||44.3 (34.2-59.8)|
|Vdss (mL/kg)§||92.4 (76.2-182.2)||71.0 (61.2-78.9)||41.8 (39.3-52.5)||56.1 (52.9-60.1)|
|Parameter||Protein C||Protein S|
|Terminal half-life (h)||47.2 (9.3-121.7)||49.1 (33.1-83.3)|
|IVR (%/units/kg bw)*||2.76 (2.16–3.31)||2.02(1.46–2.70)|
|AUC (IU/dL × h)||5,276 (1,772–10,444)||3,667 (2,218–3,667)|
|Clearance (mL/ kg × h)||1.1 (0.6-3.3)||1.1 (0.7-1.8)|
|MRT (h)†||57.0-13.4-161.4)||69.2 (45.3-113.5)|
|Vdss (mL/kg)‡||62.9 (43.9-109.3)||76.6 (61.9-105.0)|
Plasma levels of Coagulation Factors II, VII, IX, X, and antithrombotic Proteins C and S were measured after the infusion of Kcentra or plasma in studies of subjects requiring urgent reversal due to acquired deficiency of Vitamin K-dependent coagulation factors. In randomized, plasma-controlled study in acute major bleeding, the mean duration of Kcentra infusion was 24 minutes (+/- 32 minutes) and the mean duration of infusion for plasma was 169 minutes (+/-143 minutes). The mean infusion volume of Kcentra was 105 mL +/-37 mL and the mean infusion volume of plasma was 865 mL +/- 269 mL.
The increase in mean factor levels over time following Kcentra and plasma administration in the plasma-controlled RCT in acute major bleeding is shown in Figure 9 below. Levels of some factors continued to increase at later time points, consistent with the effect of concomitant Vitamin K treatment. Formal pharmacokinetic parameters were not derived because of the effect of Vitamin K on factor levels at time points required for pharmacokinetic profiling.
|Time axis is scheduled measuring time: hours after start of infusion (BL=pre-infusion)|
|Figure 9: Mean Factor Levels (Factors II, VII, IX, X, Proteins C & S) over 24 hours|
The mean in vivo recovery (IVR) of infused factors was calculated in subjects who received Kcentra. The IVR is the increase in measurable factor levels in plasma (units/dL) that may be expected following an infusion of factors (units/kg) administered as a dose of Kcentra. The in vivo recovery ranged from 1.29 (Factor IX) to 2.4 (Protein S) [see Table 12 and Table 13].
|Analyte||Incremental (units/dL per units/kg b.w.)|
|Mean (SD)||95% CI†|
|Factor IX||1.37 (0.50)||(1.21–1.53)|
|Factor II||1.91 (0.52)||(1.75–2.08)|
|Factor VII||1.60 (0.54)||(1.43–1.77)|
|Factor X||1.93 (0.47)||(1.78–2.07)|
|Protein C||2.07 (0.44)||(1.94–2.21)|
|Protein S||2.44 (0.82)||(2.18–2.69)|
|Parameter||Incremental (units/dL per units/kg b.w.)|
|Mean (SD)||95% CI†|
|Factor IX||1.29 (0.71)||(1.14-1.43)|
|Factor II||2.00 (0.88)||(1.82-2.18)|
|Factor VII||2.15 (2.96)||(1.55-2.75)|
|Factor X||1.96 (0.87)||(1.79-2.14)|
|Protein C||2.04 (0.96)||(1.85-2.23)|
|Protein S||2.17 (1.66)||(1.83-2.50)|
Long-term studies in animals to evaluate the carcinogenic potential of Kcentra, or studies to determine the effects of Kcentra on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of Kcentra was completed and suggests minimal carcinogenic risk from product use.
The efficacy of Kcentra has been evaluated in a prospective, open-label, (blinded assessor), active-controlled, non-inferiority, multicenter RCT in subjects who had been treated with VKA therapy and who required urgent replacement of their Vitamin K-dependent clotting factors to treat acute major bleeding. A total of 216 subjects with acquired coagulation factor deficiency due to oral Vitamin K antagonist therapy were randomized to a single dose of Kcentra or plasma. Two hundred twelve (212) subjects received Kcentra or plasma for acute major bleeding in the setting of a baseline INR ≥ 2.0 and recent use of a VKA anticoagulant. The doses of Kcentra (25 units/kg, 35 units/kg, or 50 units/kg) based on nominal Factor IX content and plasma (10 mL/kg, 12 mL/kg, or 15 mL/kg) were calculated according to the subject's baseline INR (2-<4, 4-6, >6, respectively). The observation period lasted for 90 days after the infusion of Kcentra or plasma. The modified efficacy (ITT-E) population for Kcentra included 98 subjects and for plasma included 104 subjects. Additionally, intravenous Vitamin K was administered.
The efficacy endpoint was hemostatic efficacy for the time period from the start of infusion of Kcentra or plasma until 24 hours. Efficacy was adjudicated as "effective" or "not effective" by a blinded, independent Endpoint Adjudication Board for all subjects who received study product. Criteria for effective hemostasis were based upon standard clinical assessments including vital signs, hemoglobin measurements, and CT assessments at pre-defined time points, as relevant to the type of bleeding (i.e., gastrointestinal, intracranial hemorrhage, visible, musculoskeletal, etc.). The proportion of subjects with effective hemostasis was 72.4% in the Kcentra group and 65.4% in the plasma group. The lower limit of the 95% confidence interval (CI) for the difference in proportions of Kcentra minus plasma was -5.8%, which exceeded -10% and thereby demonstrated the non-inferiority of Kcentra versus plasma (the study's primary objective) [see Table 14]. Because the lower limit of the CI was not greater than zero, the prospectively defined criterion for superiority of Kcentra for hemostatic efficacy (a secondary objective) was not met.
|Rating||No. (%) of subjects [95% CI]||Difference Kcentra – plasma (%) [95% CI]*|
(N = 98)
(N = 104)
|CI = confidence interval; N = number of subjects|
|"Effective" hemostasis||71 (72.4%)|
Results of a post-hoc analysis of hemostatic efficacy stratified by actual dose of Kcentra or plasma administered are presented in Table 15.
|Low Dose||Mid Dose||High Dose|
|N = 49 (K)||N = 22 (K)||N = 26|
|N = 55 (P)||N = 18 (P)||N = 31|
|Kcentra||36 (74.5%)||16 (72.7%)||18 (69.2%)|
|Plasma||38 (69.1%)||11 (61.1%)||19 (61.3%)|
|95% CI K– P||-13.2 – 21.9||-17.4 – 40.6||-17.0 – 32.9|
An additional endpoint was the reduction of INR to ≤ 1.3 at 30 minutes after the end of infusion of Kcentra or plasma for all subjects that received study product. The proportion of subjects with this decrease in INR was 62.2% in the Kcentra group and 9.6% in the plasma group. The 95% confidence interval for the difference in proportions of Kcentra minus plasma was 39.4% to 65.9%. The lower limit of the 95% CI of 39.4% demonstrated superiority of Kcentra versus plasma for this endpoint [see Table 16].
|Rating||No. (%) of subjects [95% CI]||Difference Kcentra – plasma (%) [95% CI]*|
(N = 98)
(N = 104)
|CI = confidence interval; INR = international normalized ratio; N = total subjects|
|Decrease of INR to ≤1.3 at 30 min||61 (62.2%)|
The Bleeding and Surgical Study – European Study was an open-label, single-arm, multicenter study.1 Forty-three (43) subjects who were receiving VKA were treated with Kcentra, because they either (1) required a surgical or an invasive diagnostic intervention (26 subjects), or (2) experienced an acute bleeding event (17 subjects). The dose of Kcentra (25 units/kg, 35 units/kg, or 50 units/kg) based on nominal Factor IX content was calculated according to the subject's baseline INR value (2-<4, 4-6, >6). The endpoint was the decrease of the INR to ≤ 1.3 within 30 minutes after end of Kcentra infusion in subjects who received any portion of study product.
Of the 17 evaluable subjects receiving Kcentra for acute bleeding, 16 subjects (94%) experienced a decrease in INR to ≤ 1.3 within 30 minutes after the end of the Kcentra infusion.
- Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Kcentra) for emergency anticoagulation reversal: a prospective multinational clinical trial. Journal of Thrombosis and Haemostasis 2008; 6: 622-631.
- Kcentra is supplied in a single-use vial.
- The actual units of potency of all coagulation factors (Factors II, VII, IX and X), Proteins C and S in units are stated on each Kcentra carton.
- The Kcentra packaging components are not made with natural rubber latex.
Each kit consists of the following:
16.2.1 Prior to Reconstitution
- Kcentra is for single use only. Contains no preservatives.
- Store Kcentra between 2 - 25°C (36 - 77°F), this includes room temperature, not to exceed 25°C (77°F). Do not freeze.
- Kcentra is stable for 36 months from the date of manufacture, up to the expiration date on the carton and vial labels.
- Do not use beyond the expiration date on the carton and the vial label.
- Store the vial in the original carton to protect it from light.
- Inform patients of the signs and symptoms of allergic hypersensitivity reactions, such as urticaria, rash, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of Kcentra [see Warnings and Precautions (5.1)].
- Inform patients of signs and symptoms of thrombosis, such as limb or abdomen swelling and/or pain, chest pain or pressure, shortness of breath, loss of sensation or motor power, altered consciousness, vision, or speech [see Warnings and Precautions (5.2)].
- Inform patients that, because Kcentra is made from human blood, it 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 [see Warnings and Precautions (5.3) and Description (11)].
CSL Behring GmbH
35041 Marburg Germany
US License No. 1765
CSL Behring LLC
Kankakee, IL 60901 USA
PRINCIPAL DISPLAY PANEL - 500 U Vial Label
Prothrombin Complex Concentrate (Human)
For Intravenous Administration Only
Each Kcentra™ single-use vial contains 400-620 units of
lyophilized Factor IX concentrate for reconstitution with 20 mL
Sterile Water for Injection, USP. Also contains Factors II, VII, X
and proteins C and S. When stored at temperatures of 2-25°C
(36-77°F), Kcentra™ is stable for 36 months, up to the expiration
date on the carton and vial label. Do not use if the reconstituted
solution is cloudy or contains particulates.
Do not freeze. Protect from light. Contains no preservatives.
PRINCIPAL DISPLAY PANEL - Kit Carton
One single-use vial containing 400 – 620 units
of lyophilized Factor IX concentrate for reconstitution.
Also contains Factors II, VII, X and proteins C and S.
For Intravenous Administration Only
prothrombin, coagulation factor vii human, coagulation factor ix human, coagulation factor x human, protein c, protein s human, and water kit
|Labeler - CSL Behring GmbH (326530474)|
|Registrant - CSL Behring LLC (058268293)|
|CSL Behring GmbH||326530474||MANUFACTURE|