Kcentra

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.

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]
• Arterial and venous thromboembolic complications [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Possible Transmission of Infectious Agents [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

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.

Table 3: Adverse Reactions Reported in 3 or more Subjects ( ≥ 2.8%) Following Kcentra or Plasma Administration in Acute Major Bleeding RCT

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 plasmacontrolled 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%).

Table 4: Subjects with Fluid Overload Events by Prior History of Congestive Heart Failure in Plasma-Controlled Trial in Subjects with Acute Major Bleeding

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.

Table 5: Adverse Reactions (TEEs only) Following Kcentra or Plasma Administration in the Acute Major Bleeding RCT

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.

Table 6: Subjects with Thromboembolic Events by Prior History of TE Event in Plasma-Controlled RCT in Acute Major Bleeding Acute Major Bleeding

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.

Postmarketing Experience

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 in patients with congenital factor deficiencies.

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. 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 anti-thrombotic Proteins C and S.

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

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.

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.

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.

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.

Pharmacodynamics

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].

Table 9: Median INR after Start of Infusion

Pharmacokinetics

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).

Table 10: Vitamin K-Dependent Coagulation Factor Pharmacokinetics after a Single Kcentra Infusion in Healthy Subjects (n=15) Median (IQR)*

Table 11: Antithrombotic Proteins C and S Pharmacokinetics after a Single Kcentra Infusion in Healthy Subjects- PK Study in Healthy Subjects (n=15) Median (Min – Max)

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.

Figure 9: Mean Factor Levels (Factors II, VII, IX, X, Proteins C & S) over 24 Hours

Time axis is scheduled measuring time: hours after start of infusion (P=pre-infusion)

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].

Table 12: In vivo Recovery (Single-Arm European Study in Bleeding and Surgery, ITT*, N=43)

Table 13: In vivo Recovery (Plasma-Controlled RCT in Acute Major Bleeding,  Kcentra, N=98*)

Clinical Studies

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 predefined 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.

Table 14: Rating of Hemostatic Efficacy in Subjects with Acute Major Bleeding

Results of a post-hoc analysis of hemostatic efficacy stratified by actual dose of Kcentra or plasma administered are presented in Table 15.

Table 15: Primary Rating of Hemostatic Efficacy Stratified by Actual Dose of Kcentra or Plasma (Number and % of Subjects rated “Effective” in Acute Major Bleeding RCT

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].

Table 16: Decrease of INR (1.3 or Less at 30 Minutes after End of Infusion)

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.

REFERENCES

1. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. Journal of Thrombosis and Haemostasis 2008; 6: 622-631.

Hemostatic agent; preparation of nonactivated blood coagulation factors II, VII, IX, and X derived from pooled human plasma;1 2 12 13 17 a 4-factor prothrombin complex concentrate (PCC).12

Urgent Reversal of Warfarin Anticoagulation

Used for the urgent reversal of vitamin K antagonist (e.g., warfarin) anticoagulation in adults with acute major bleeding; designated an orphan drug by FDA for this use.1 2 3

Rapidly restores vitamin K-dependent coagulation factors that are depleted by warfarin therapy.4 7 8

Use in conjunction with vitamin K (phytonadione) to maintain adequate levels of coagulation factors once the effects of prothrombin complex concentrate (human) have diminished.1 6

Experts generally consider PCCs such as prothrombin complex concentrate (human) (Kcentra) to be a reasonable (and in some cases, preferred) alternative to fresh frozen plasma for the urgent reversal of anticoagulation in patients with warfarin-induced bleeding.4 6 7 8 13 20 May provide some advantages over plasma including more rapid INR reduction, reduced drug preparation time, reduced risk of anaphylaxis and transmission of infectious pathogens, and lower drug volumes (which may be beneficial in patients with fluid restrictions).6 7 8 9 12

Not indicated for the urgent reversal of vitamin K antagonist anticoagulation in patients without acute major bleeding.1

Absorption

Plasma Concentrations

Mean in vivo recovery of factors II, VII, IX, X, and proteins C and S following a single IV infusion of Kcentra in patients with acute major bleeding was 2, 2.15, 1.29, 1.96, 2.04, and 2.17% per unit/kg administered, respectively.1

In healthy individuals, administration of a single IV infusion of Kcentra 50 units/kg produced a rapid and sustained increase in plasma concentrations of factors II, VII, IX, and X within 5 minutes.1 17

Distribution

Extent

Not known whether distributed into milk.1

Elimination

Half-life

Median terminal half-life of coagulation factors II, VII, IX, and X following single dose of Kcentra in healthy individuals was 59.7, 4.2, 16.7, and 30.7 hours, respectively.1 17

Prothrombin complex concentrate human injection is used to reverse the effects of anticoagulants or blood thinners (eg, warfarin, Coumadin®, Jantoven®) in adult patients with acute major bleeding.

Prothrombin complex human contains coagulation factors II, VII, IX, and X, and proteins C and S. This medicine is used to stop bleeding by helping the blood to clot.

This medicine is to be given only by or under the supervision of your doctor.

• It is used to undo the effects of certain blood thinners like warfarin.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Kcentra, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Kcentra. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Kcentra (prothrombin complex conc (human) [(factors II, VII, IX, X), prot C, prot S]).

Review Date: October 4, 2017

Use only if clearly needed. Excreted into human milk: Unknown Excreted into animal milk: Unknown The effects in the nursing infant are unknown.