Prothrombin Complex Concentrate

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

General

• Administer concurrently with phytonadione.1 6

• Obtain INR prior to treatment, as close as possible to the time of drug administration; individualize dose based on INR.1 Monitor INR and clinical response during and after treatment to assess degree of anticoagulant reversal.1 15

Administration

IV Administration

Administer by IV infusion as a single dose.1 Repeat dosing not recommended due to lack of supporting data.1

Prior to reconstitution, allow injection concentrate and sterile water for injection diluent to warm to room temperature.1

Reconstitute Kcentra with 20 mL of sterile water for injection provided by manufacturer; gently swirl (do not shake) until contents completely dissolve.1 Resultant solution will contain 20–31 units of factor IX per mL depending on actual amount of factor IX contained in vial.1

If more than one vial is required for a dose, may pool reconstituted contents of multiple vials; however, use separate transfer filter sets to reconstitute each vial.1

Administer within 4 hours after reconstitution.1 If not used immediately, may store at 2–25°C (do not freeze); if refrigerated, warm to room temperature (20–25°C) prior to administration.1 Vials of Kcentra contain no preservatives and are for single use only; discard partially used vials.1

Do not mix with other drugs; administer through a separate infusion line.1 During administration, ensure that blood does not enter the syringe to prevent fibrin clot formation.1 After administration, record lot number of drug in patient's medical record.1

Infuse at a rate of 0.12 mL/kg per minute (maximum of 8.4 mL/minute).1 Mean duration of infusion in principal clinical study was 24 ± 32 minutes.1

Dosage

Dose of prothrombin complex concentrate (human) (Kcentra) is expressed in international units (IU, units) and based on units of factor IX activity.1 7 The actual amount of factor IX in each vial of Kcentra ranges from 400–620 units and is indicated on carton and vial label.1

Determine dose based on patient's pretreatment INR and body weight (up to, but not exceeding 100 kg).1

Adults

Baseline INR 2 to <4: 25 units/kg (up to 2500 units) administered as a single dose.1

Baseline INR 4–6: 35 units/kg (up to 3500 units) administered as a single dose.1

Baseline INR >6: 50 units/kg (up to 5000 units) administered as a single dose.1

Prescribing Limits

Adults

Maximum rate of infusion is 8.4 mL/min.1

Maximum dose 2500 units in patients with baseline INR 2 to <4.1

Maximum dose 3500 units in patients with baseline INR 4–6.1

Maximum dose 5000 units in patients with baseline INR >6.1

Contraindications

• Known anaphylactic or severe systemic reactions to any component in the Kcentra formulation (i.e., factors II, VII, IX, or X; proteins C or S; heparin; antithrombin III; human albumin).1

• DIC.1

• Known heparin-induced thrombocytopenia (HIT).1

Warnings/Precautions

Warnings

Serious, and sometimes fatal, thromboembolic events reported in clinical trials and during postmarketing surveillance.1 2 6 12 13 14 16 18 Such events included DVT, PE, MI, DIC, and stroke.1 (See Boxed Warning.)

Patients receiving vitamin K antagonists (e.g., warfarin) usually have underlying conditions (e.g., atrial fibrillation) that predispose them to thromboembolism; thus, reversal of anticoagulation exposes them to this risk.1 2 19 Risk appears to be higher in patients with a prior history of a thromboembolic event.1

Patients with a recent (i.e., within the past 3 months) history of a thromboembolic event (i.e., MI, DIC, cerebrovascular accident, TIA, unstable angina, severe peripheral vascular disease) were excluded from principal efficacy study; therefore, prothrombin complex concentrate (human) may not be suitable in such patients.1

Closely monitor for manifestations of thromboembolism during and after treatment.1 (See Advice to Patients.) Following administration of the drug, carefully consider resuming oral anticoagulant therapy as soon as risk of thromboembolism outweighs risk of acute bleeding.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., flushing, urticaria, tachycardia, anxiety, angioedema, wheezing, nausea, vomiting, hypotension, tachypnea, dyspnea, pulmonary edema, bronchospasm) reported.1 (See Contraindications under Cautions.)

If a serious allergic or anaphylactic-type reaction occurs, discontinue immediately and initiate appropriate treatment.1

Other Warnings and Precautions

Potential risk of transmission of viruses (e.g., hepatitis A [HAV], B [HBV] or C virus [HCV]; HIV) and other infectious agents such as the causative agent for variant Creutzfeldt-Jakob disease (vCJD) and, theoretically, the causative agent of Creutzfeldt-Jakob disease (CJD).1

Despite use of 2 dedicated virus eliminating/reducing steps (i.e., pasteurization, nanofiltration) during the manufacturing process, a possibility for disease transmission still exists.1 12 13

Reports of suspected transmission of HAV, HBV, HCV, and HIV with prothrombin complex concentrate (human) generally have been confounded by concomitant administration of blood or blood components and/or other plasma-derived products; manufacturer states no causal relationship to Kcentra has been established since introduction of a virus filtration step in 1996.1 13

Report any infections thought to be associated with Kcentra to the manufacturer at 866-915-6958 or to the FDA at 800-FDA-1088 or www.fda.gov/medwatch.1

Specific Populations

Category C.1

Not known whether distributed into human milk.1 Use in nursing women only if clearly needed.1

Safety and efficacy not established in pediatric patients.1

No clinically important age-related differences in safety observed.1

Common Adverse Effects

Headache, nausea, vomiting, arthralgia, hypotension.1

Most common serious adverse effects include thromboembolic events (i.e., stroke, PE, DVT).1

Drugs Affecting Coagulation

Avoid concomitant use of other procoagulant agents (e.g., other coagulation factor preparations, fibrinolytic agents, protamine, desmopressin) because of increased risk of thromboembolism.6

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

Storage

Parenteral

2–25°C in the original container; protect from light and freezing.1

Use reconstituted solution within 4 hours.1 (See Reconstitution under Dosage and Administration.)