Kcentra (human prothrombin complex concentrate 4-factor)

The dose of prothrombin complex concentrate (human) (Kcentra(R)) is expressed in international units (IU, units) and is based on units of factor IX activity. The actual amount of factor IX contained in each vial of Kcentra(R) labeled with 500 units ranges from 400 to 620 units, and the actual amount of factor IX contained in each vial labeled with 1000 units ranges from 800 to 1240 units. The actual potency of each vial is indicated on the carton and vial label.

Prothrombin complex concentrate (human) (Kcentra(R)) is administered by IV infusion. The drug is given as a single dose for the urgent reversal of warfarin anticoagulation; repeat dosing of the drug currently is not recommended due to the lack of supporting clinical data.

Kcentra(R) is commercially available as a kit that contains a single-use vial of lyophilized drug (with nominal potency of 500 or 1000 units), a 20- or 40-mL vial of sterile water for injection diluent, and a filter transfer set. Prior to use, the lyophilized powder for injection should be stored at 2-25degreesC in the original container and protected from light and freezing. When stored under recommended conditions, unopened vials of Kcentra(R) are stable for 36 months from the date of manufacture up to the expiration date.

Kcentra(R) should be reconstituted as directed by the manufacturer. Prior to reconstitution, the lyophilized powder for injection and sterile water for injection diluent provided by the manufacturer should be warmed to room temperature. Each vial of Kcentra(R) should be reconstituted with 20 mL (for the vial labeled with nominal potency of 500 units) or 40 mL (for the vial labeled with nominal potency of 1000 units) of sterile water for injection using the filter transfer set provided by the manufacturer; the resultant solution will contain 20-31 units of factor IX per mL depending on the actual amount of factor IX contained in the vial, which is listed on the carton and vial label. Following addition of diluent, the vial should be gently swirled (not shaken) until the powder is completely dissolved. The reconstituted solution should be colorless and clear to slightly opalescent, and free from visible particles. If more than one vial is required for a dose, the reconstituted contents of multiple vials may be pooled; however, a separate transfer filter set should be used to reconstitute each vial.

Kcentra(R) must be administered within 4 hours after reconstitution. If not used immediately, the solution may be stored at 2-25degreesC but should not be frozen; if stored under refrigeration, the solution should be warmed to room temperature (20-25degreesC) prior to administration. Vials of Kcentra(R) contain no preservatives and are for single use only; partially used vials should be discarded.

Kcentra(R) should not be mixed with other drugs and should be administered through a separate infusion line. During administration, care should be taken to prevent blood from entering the syringe to minimize the risk of fibrin clot formation.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Factor Ix; Anti-Inhibitor Coagulant Conc/Antifibrinolytics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use may result in additive or synergistic effects on the coagulation pathways.(1-3)

CLINICAL EFFECTS: Concurrent use may result in thrombosis.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of aminocaproic acid states that aminocaproic acid should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates.(1) The US manufacturer of tranexamic acid states that concomitant use with Factor IX Complex concentrates or with Anti-inhibitor Coagulant concentrates should be avoided.(2,3) The Japanese manufacturer of tranexamic acid recommends caution when coadministered with drugs such as coagulation factor agents as coagulation may be further activated at sites with enhanced local fibrinolysis.(4) Concurrent use may be warranted in select patients with hemophilia A or hemophilia B or in select major trauma scenarios. Monitor patients closely for signs of thrombosis, disseminated intravascular coagulation, and hypercoagulability if concurrent use is deemed necessary.(5-13)

DISCUSSION: There is very limited data on the risk of thrombosis with combination therapy. In a study, eight hemophilia B patients undergoing dental extraction procedures received combination therapy with aminocaproic acid or tranexamic acid and monoclonal antibody purified factor IX for bleeding prophylaxis. All patients achieved hemostasis without clinical evidence of thrombosis as well as no changes were seen in hemoglobin, hematocrit, or in markers of hemostatic system activation.(5) In a study, seven hemophilia A patients with inhibitors and one with acquired hemophilia patient received activated prothrombin complex concentrate (APCC) and tranexamic acid for management of bleeding episodes and prevention of hemorrhage during surgery. Hemostatic outcomes were rated excellent or good in 10 out of 11 (91%) treatment episodes. No episodes of thrombosis or disseminated intravascular coagulation occurred during treatment.(6) A study in six hemophilia A patients and five healthy volunteers evaluated the use of tranexamic acid as an adjunct to APCC to control bleeding. Patients who received tranexamic acid had a significant increase in maximum clot firmness compared to healthy controls. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed.(7) In a retrospective cohort of 76 patients who received PCC for bleeding not caused by anticoagulation, some patients received additional hemostatic agents (protamine (59%), desmopressin (43%), and tranexamic acid (42%). Eight patients (11%) suffered thromboembolic complications but this was not stratified by the hemostatic agent.(8) In a prospective case crossover study, five healthy volunteers and six hemophilia patients with inhibitors received tranexamic acid with single-dose activated PCC or with recombinant activated factor VII. There were no thromboembolic events during the study.(9) In a double-blind, randomized, placebo-controlled superiority trial to investigate the efficacy and safety of 4-factor prothrombin complex concentrate (4F-PCC) administration in trauma patients at risk of massive transfusion, a significantly higher risk of thromboembolic events occurred in the 4F-PCC group compared to the placebo group (35% vs 24%; relative risk 1.48 [95% CI, 1.04-2.10]). This was observed despite more frequent use of tranexamic acid in the placebo group (86% vs 76%).(10) Case reports reviewed the use of recombinant factor VIIa and FEIBA in 4 patients with severe hemophilia with inhibitors who underwent major surgery. The patients were also treated with tranexamic acid. Non-surgical bleeding was encountered in 4 of 8 surgical procedures. The overall outcome was good for all procedures.(11) In a retrospective cohort of 112 ambulatory tooth extractions in 23 hemophilia patients using a coagulation factor replacement therapy in combination with tranexamic acid, only one episode of mild postoperative bleeding occurred after seven days in a patient who did not have good treatment compliance.(12) In a prospective study evaluating the use of initial hemoglobin levels as a guideline for the initial treatment of clotting disorders in multiple trauma patients, 25 patients received a combination of hemostatic agents (fibrinogen (100%), PCC (96%), desmopressin (56%), tranexamic acid (52%), and factor VIIa (44%). Of the 25 patients treated, 16 (64%) survived. Two patients (8%) suffered thromboembolic complications but this was not stratified by the hemostatic agent. One patient survived after developing a grade II pulmonary embolism caused by deep leg vein trombosis and one patient died from multi-organ failure after developing multiple small vessel thrombosis.(13)

There are no moderate interactions for this drug.

*Known anaphylactic or severe systemic reactions to any component in the formulation (i.e., factors II, VII, IX, or X; proteins C or S; heparin; antithrombin III; human albumin)

*Disseminated intravascular coagulation (DIC)

*Known heparin-induced thrombocytopenia (HIT).

• Disseminated intravascular coagulation
• Heparin-induced thrombocytopenia

• Thromboembolic disorder

There are no moderate contraindications for this drug.

The most common adverse reactions (frequency >=2.8%) reported with prothrombin complex concentrate (human) in clinical trials include headache, nausea, vomiting, anemia, and hypotension. The most serious adverse effects observed in these trials were thromboembolic events, including stroke, pulmonary embolism, and deep-vein thrombosis.

Less Frequent

• Deep venous thrombosis
• Hypervolemia
• Thromboembolic disorder

Rare or Very Rare

• Angioedema
• Bronchospastic pulmonary disease
• Cerebrovascular accident
• Disseminated intravascular coagulation
• Peripheral venous insufficiency
• Pulmonary edema

More Frequent

• Headache disorder

Less Frequent

• Arthralgia
• Hypertension
• Hypotension
• Injection site sequelae
• Nausea and vomiting
• Tachycardia

Rare or Very Rare

• Dyspnea
• Flushing
• Symptoms of anxiety
• Urticaria
• Wheezing

No enhanced messaging available.

Safety and efficacy of prothrombin complex concentrate (human) (Kcentra(R)) have not been established in pediatric patients.

There are no data on the use of prothrombin complex concentrate (human) (Kcentra(R)) during pregnancy. Animal reproduction studies have not been conducted. It is not known whether prothrombin complex concentrate (human) can cause fetal harm when administered to pregnant women or affect reproduction capacity. Prothrombin complex concentrate (human) should be used during pregnancy only when clearly needed.

It is not known whether prothrombin complex concentrate (human) is distributed into human milk. Because many drugs are distributed into milk, the manufacturer states that prothrombin complex concentrate (human) should be used in breast-feeding women only if clearly needed.

Among 431 patients in clinical studies who received prothrombin complex concentrate (human) (Kcentra(R)) for reversal of warfarin anticoagulation, 66% were 65 years of age or older and 39% were 75 years of age or older. No clinically important age-related differences in safety were observed.