2.1 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 (see 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 it is not recommended.
• Dose ranging within pre-treatment INR groups has not been studied in randomized clinical trials of KCENTRA.

2.2 Preparation and Reconstitution

• Reconstitute KCENTRA using aseptic technique with 20 mL (nominal potency 500 U kit) or 40 mL (nominal potency 1000 U kit) of Sterile Water for Injection (diluent) provided in the kit.
• Do not use KCENTRA beyond the expiration date on the vial label and carton.
• KCENTRA is for single-dose only. Contains no preservatives. Discard partially used vials.

2.3 Administration

• Do not mix KCENTRA with other medicinal products; administer through a separate infusion line.
• Visually inspect the reconstituted solution 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 if the solution is cloudy, discolored, or contains particulates.
• 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.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions including flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, and bronchospasm have been observed with KCENTRA.

If severe allergic reaction or anaphylactic type reactions occur, immediately discontinue administration, and institute appropriate treatment.

5.2 Thromboembolic Risk/Complications

Both fatal and non-fatal arterial thromboembolic events (including acute myocardial infarction and arterial thrombosis), and venous thromboembolic events (including pulmonary embolism and venous thrombosis) and disseminated intravascular coagulation have been reported with KCENTRA in clinical trials and post marketing surveillance [see Adverse Reactions (6) 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 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) and Clinical Studies (14)].

In a postmarketing observational study, there was no significant difference in the risk of post-treatment thromboembolic events after receiving KCENTRA compared with plasma therapy for VKA-associated acute major bleeding [see Adverse Reactions (6.2)].

Potential benefits of treatment with KCENTRA should be weighed against the potential risks of thromboembolic events [see Adverse Reactions (6)]. 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].

5.3 Transmissible Infectious Agents

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. 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.

6.1 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.

6.2 Postmarketing Experience

In a postmarketing observational study, the risk of TEEs was assessed using Kaiser Permanente's databases in a matched, real-world cohort of hospitalized adults receiving either KCENTRA or plasma for VKA-associated major bleeding. For the primary analysis, 1119 KCENTRA patients and 1119 historical plasma patients with no recent history of TEEs were grouped in 1:1 individually matched cohort based on propensity scores. During the 45-day follow-up after acute VKA reversal, there was no statistically significant difference in the adjusted risk of TEEs between KCENTRA-treated patients and plasma-treated patients. . In a secondary analysis, 101 KCENTRA patients and 101 historical plasma patients with a recent history of TEEs diagnosed ≤90 days before study entry were also grouped in 1:1 individually matched cohort based on propensity scores. During the 45-day follow-up after acute VKA reversal, there was no statistically significant difference in the adjusted risk of TEEs between KCENTRA-treated patients and plasma-treated patients.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and efficacy of KCENTRA in the pediatric population has not been studied.

8.5 Geriatric Use

Of the total number of subjects (431) with acute major bleeding or with the need for an urgent surgery/invasive procedure treated to reverse VKA anticoagulation in three clinical studies, 66% were 65 years old or greater and 39% were 75 years old or greater. There were no clinically significant differences between the safety profile of KCENTRA and plasma in any age group.

8.6 Congenital Factor Deficiencies

KCENTRA has not been studied in patients with congenital factor deficiencies.

12.1 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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 as well as Proteins C and S. The PK analysis [see Table 9] shows that factor II had the longest half-life (59.7 hours) and factor VII the shortest (4.2 hours) in healthy subjects. PK parameters obtained from data derived from the study of healthy subjects may not be directly applicable to patients with INR elevation due to VKA anticoagulation therapy.

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 1.15 (Factor IX) to 2.81 (Protein S) [see Table 10].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Acute Major Bleeding RCT

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 11]. 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.

Results of a post-hoc analysis of hemostatic efficacy stratified by actual dose of KCENTRA or plasma administered in the acute major bleeding RCT are presented in Table 12.

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 13].

Urgent Surgery/Invasive Procedure RCT

The efficacy of KCENTRA has been evaluated in a prospective, open-label, 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 because of their need for an urgent surgery/invasive procedure. A total of 181 subjects with acquired coagulation factor deficiency due to oral Vitamin K antagonist therapy were randomized to a single dose of KCENTRA or plasma. One hundred seventy-six (176) subjects received KCENTRA or plasma because of their need for an urgent surgery/invasive procedure 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 87 subjects and for plasma included 81 subjects. Additionally, oral or 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 the end of the urgent surgery/invasive procedure. Criteria for effective hemostasis were based upon the difference between predicted and actual blood losses, subjective hemostasis rating, and the need for additional blood products containing coagulation factors. The proportion of subjects with effective hemostasis was 89.7% in the KCENTRA group and 75.3% in the plasma group. The lower limit of the 95% confidence interval (CI) for the difference in proportions of KCENTRA minus plasma was 2.8%, 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 greater than 0, the prospectively defined criterion for superiority of KCENTRA for hemostatic efficacy (a secondary objective) was also met.

Results of a post-hoc analysis of hemostatic efficacy stratified by actual dose of KCENTRA or plasma administered in the urgent surgery/invasive procedure RCT are presented in Table 15.

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 55.2% in the KCENTRA group and 9.9% in the plasma group. The 95% confidence interval for the difference in proportions of KCENTRA minus plasma was 31.9% to 56.4%. The lower limit of the 95% CI of 31.9% demonstrated superiority of KCENTRA versus plasma for this endpoint [see Table 16]. The relationship between a decrease in INR to less than or equal to 1.3 and clinical hemostatic efficacy has not been established.

The European Bleeding and Surgical 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.

In RCTs, levels of Coagulation Factors II, VII, IX, X, and Antithrombotic Proteins C and S were measured after the infusion of KCENTRA or plasma and the results were similar for subjects with acute major bleeding or subjects requiring an urgent surgery or invasive procedure. In the plasma-controlled RCT 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. In the plasma-controlled RCT for patients needing urgent surgery/invasive procedures, the mean duration of KCENTRA infusion was 21 minutes (± 14 minutes) and the mean duration of infusion for plasma was 141 minutes (± 113 minutes). The mean infusion volume of KCENTRA was 90 mL ± 32 mL and the mean infusion volume of plasma was 819 mL ± 231 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 (the mean factor levels over time following KCENTRA and plasma administration in the plasma-controlled RCT for patients needing urgent surgery/invasive procedures are not shown, but showed similar profiles). 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 in Acute Major Bleeding RCT

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

Storage and Handling