Introduction

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

Uses for Prothrombin Complex Concentrate

Reversal of Warfarin Anticoagulation

Used for urgent reversal of vitamin K antagonist (VKA; e.g., warfarin) anticoagulation in adults with acute major bleeding or need for urgent surgery/invasive procedure; designated an orphan drug by FDA for this use.

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

Prothrombin complex concentrate (human) is a 4-factor PCC that rapidly restores vitamin K-dependent coagulation factors depleted by warfarin.

Experts generally consider 4-factor PCC preferable to fresh frozen plasma for urgent reversal of anticoagulation in patients with warfarin-induced major bleeding. Compared with fresh frozen plasma, 4-factor PCC is associated with more rapid INR reduction, reduced drug preparation time, reduced risk of anaphylaxis and transmission of infectious pathogens, and lower risk of volume overload.

Although fresh frozen plasma has traditionally been used for rapid reversal of VKAs in the perioperative and periprocedural settings, 4-factor PCC is recommended in current clinical practice guidelines.

When considering use of prothrombin complex concentrate (human) for reversal of VKA anticoagulation, weigh potential benefits against risk of thromboembolic complications.

Reversal of Direct Oral Anticoagulants

Has been used for reversal of direct oral anticoagulants (DOACs)^{† [off-label]} in both the setting of major bleeding and the perioperative/periprocedural setting.

Specific reversal agents (e.g., idarucizumab, coagulation factor Xa [recombinant] inactivated-zhzo [also known as andexanet alfa]) are generally recommended when DOAC reversal is needed; 4-factor PCC is suggested as an alternative when specific reversal agents not available.

Management of bleeding complications in patients receiving DOACs should be individualized according to severity and location of hemorrhage.

Most bleeding events related to DOACs can be managed with supportive measures and by withholding the anticoagulant alone. Reversal agents should generally be reserved for patients with severe and life-threatening bleeding.

Experts state that reversal agents should only be considered in patients undergoing invasive procedures or surgery if the procedure cannot be safely performed while the patient is anticoagulated and cannot be delayed.

Prothrombin Complex Concentrate Dosage and Administration

General

• Administer concurrently with vitamin K (phytonadione).

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

Administration

IV Administration

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

Reconstitution

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

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

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.

Administer within 4 hours after reconstitution. 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. Vials of Kcentra contain no preservatives and are for single use only; discard partially used vials.

Do not mix with other drugs; administer through a separate infusion line. During administration, ensure that blood does not enter the syringe to prevent fibrin clot formation.

Rate of Administration

Infuse at a rate of 0.12 mL/kg per minute (maximum of 8.4 mL/minute). Mean duration of infusion in principal clinical studies was 24 ± 32 minutes for acute major bleeding and 21 ± 14 minutes for urgent surgery/invasive procedures.

Dosage

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

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

Adults

Urgent Reversal of Warfarin Anticoagulation

IV

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

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

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

A low, fixed-dose^{† [off-label]}, non-INR-based strategy also has been used. Fixed doses reported in the literature range from 1000–2000 units with doses at the higher end of the range for patients with higher initial INRs or body weight. The American College of Cardiology recommends a fixed dose of 1000 units for nonintracranial major bleeding and a dose of 1500 units for intracranial hemorrhage; there is some evidence indicating that higher doses (e.g., 2000 units) may be required in patients with intracranial hemorrhage or high baseline INR.

Reversal of Direct Oral Anticoagulants† [off-label]

IV

50 units/kg or a fixed dose of 2000 units has been used for reversal of DOAC anticoagulation in patients with major bleeding or undergoing an urgent procedure.

Prescribing Limits

Adults

Urgent Reversal of Warfarin Anticoagulation

IV

Maximum rate of infusion is 8.4 mL/minute.

Maximum dose 2500 units in patients with baseline INR 2 to <4.

Maximum dose 3500 units in patients with baseline INR 4–6.

Maximum dose 5000 units in patients with baseline INR >6.

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).

• DIC.

• Known heparin-induced thrombocytopenia (HIT).

Warnings/Precautions

Warnings

Thromboembolic Complications

Serious, and sometimes fatal, thromboembolic events reported in clinical trials and during postmarketing surveillance. Such events included DVT, PE, MI, DIC, and stroke. (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. Risk appears to be higher in patients with a prior history of a thromboembolic event.

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 studies; therefore, prothrombin complex concentrate (human) may not be suitable in such patients.

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

Sensitivity Reactions

Hypersensitivity Reactions

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

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

Other Warnings and Precautions

Risk of Transmissible Agents in Plasma-derived Preparations

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).

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

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.

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.

Specific Populations

Pregnancy

Not known whether drug can cause fetal harm when administered to pregnant women or affect reproduction capacity. Use in pregnant women only when clearly needed.

Lactation

Not known whether distributed into human milk. Use in breast-feeding women only if clearly needed.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No clinically important age-related differences in safety observed.

Patients with Congenital Factor Deficiencies

Not studied in patients with congenital factor deficiencies (e.g., hemophilia, von Willebrand disease).

Common Adverse Effects

Headache, nausea, vomiting, anemia, hypotension.

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

General

• Administer concurrently with vitamin K (phytonadione).

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

Administration

IV Administration

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

Reconstitution

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

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

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.

Administer within 4 hours after reconstitution. 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. Vials of Kcentra contain no preservatives and are for single use only; discard partially used vials.

Do not mix with other drugs; administer through a separate infusion line. During administration, ensure that blood does not enter the syringe to prevent fibrin clot formation.

Rate of Administration

Infuse at a rate of 0.12 mL/kg per minute (maximum of 8.4 mL/minute). Mean duration of infusion in principal clinical studies was 24 ± 32 minutes for acute major bleeding and 21 ± 14 minutes for urgent surgery/invasive procedures.

Dosage

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

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

Adults

Urgent Reversal of Warfarin Anticoagulation

IV

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

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

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

A low, fixed-dose^{† [off-label]}, non-INR-based strategy also has been used. Fixed doses reported in the literature range from 1000–2000 units with doses at the higher end of the range for patients with higher initial INRs or body weight. The American College of Cardiology recommends a fixed dose of 1000 units for nonintracranial major bleeding and a dose of 1500 units for intracranial hemorrhage; there is some evidence indicating that higher doses (e.g., 2000 units) may be required in patients with intracranial hemorrhage or high baseline INR.

Reversal of Direct Oral Anticoagulants† [off-label]

IV

50 units/kg or a fixed dose of 2000 units has been used for reversal of DOAC anticoagulation in patients with major bleeding or undergoing an urgent procedure.

Prescribing Limits

Adults

Urgent Reversal of Warfarin Anticoagulation

IV

Maximum rate of infusion is 8.4 mL/minute.

Maximum dose 2500 units in patients with baseline INR 2 to <4.

Maximum dose 3500 units in patients with baseline INR 4–6.

Maximum dose 5000 units in patients with baseline INR >6.

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.