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Prothrombin Complex Concentrate

Class: Hemostatics
VA Class: BL500
Brands: Kcentra

Warning(s)

  • Risk of Thromboembolism
  • Risk of serious, and potentially fatal arterial and venous thromboembolic events (e.g., DVT, PE, MI, disseminated intravascular coagulation [DIC]).1 2 6 12 13 14 18 (See Thromboembolic Complications under Cautions.)

  • Carefully weigh benefits of treatment against risk of thromboembolism, particularly in those with a history of a thromboembolic event.1 5 15 16

  • Closely monitor for manifestations of thromboembolism during and after treatment.1 (See Advice to Patients.)

  • Carefully consider resumption of oral anticoagulant therapy as soon as risk of thromboembolism outweighs risk of bleeding.1

Introduction

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

Uses for Prothrombin Complex Concentrate

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

Prothrombin Complex Concentrate Dosage and Administration

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

Reconstitution

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

Rate of Administration

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

Urgent Reversal of Warfarin Anticoagulation
IV

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

Urgent Reversal of Warfarin Anticoagulation
IV

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

Cautions for Prothrombin Complex Concentrate

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

Thromboembolic Complications

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

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

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).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

Pregnancy

Category C.1

Lactation

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

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

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

Interactions for Prothrombin Complex Concentrate

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

Prothrombin Complex Concentrate Pharmacokinetics

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

Stability

Storage

Parenteral

Powder for Injection

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.)

Actions

  • Lyophilized concentrate of nonactivated blood coagulation factors II, VII, IX, and X derived from pooled human plasma.1 2 12 13 17 Also contains the antithrombotic proteins C and S, human antithrombin III, and heparin.1 13

  • Undergoes viral reduction/inactivation processes (e.g., cryoprecipitation, ion exchange chromatography, pasteurization, solvent/detergent treatment, nanofiltration) to reduce risk of viral transmission.1 13

  • Coagulation factors II, VII, IX, and X play key roles in the coagulation cascade and are essential for the ultimate conversion of factor II (prothrombin) to thrombin and formation of a fibrin clot; thus, deficiencies in one or more of these coagulation factors can cause bleeding.1 13 Administration of prothrombin complex concentrate (human) temporarily corrects the acquired coagulation deficiency induced by vitamin K antagonists.1 13

Advice to Patients

  • Importance of informing patients of the signs and symptoms of allergic hypersensitivity reactions (e.g., urticaria, rash, chest tightness, wheezing, hypotension, anaphylaxis) that may occur during or after injection of prothrombin complex concentrate (human) (Kcentra).1

  • Importance of informing patients of signs and symptoms of thrombosis (e.g., swelling and/or pain of limb or abdomen; chest pain or pressure; shortness of breath; loss of sensation or motor power; alteration in consciousness, vision, or speech).1

  • Importance of informing patients that because Kcentra is made from human blood, it may carry a risk of transmitting infectious agents.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Prothrombin Complex Concentrate (Human)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

number of units indicated on label

Kcentra (with sterile water for injection diluent; available with filter transfer set)

CSL Behring

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. CSL Behring LLC. Kcentra Prothrombin complex concentration (human) prescribing information. Kankakee, IL; 2013 April.

2. Pabinger I, Brenner B, Kalina U et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008; 6:622-31. [PubMed 18208533]

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [June 6, 2013]. From FDA web site .

4. Holbrook A, Schulman S, Witt DM et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e152S-84S. [PubMed 22315259]

5. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health Syst Pharm. 2013; 70(10 Suppl 1):S12-21.

6. Patanwala AE, Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother. 2011; 45:990-9. [PubMed 21730276]

7. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology. 2008; 109:918-26. [PubMed 18946305]

8. Morgenstern LB, Hemphill JC, Anderson C et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010; 41:2108-29. [PubMed 20651276]

9. Ageno W, Gallus AS, Wittkowsky A et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e44S-88S. [PubMed 22315269]

10. Grifols. Profilnine SD (Factor IX complex) prescribing information. Los Angeles, CA; 2011 Aug.

11. Baxter. Bebulin (Factor IX complex), nanofiltered and vapor heated prescribing information. Westlake Village, CA; 2012 July.

12. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 203585Orig1s000Orig1s000: Medical Review. From FDA website.

13. Scott LJ. Prothrombin complex concentrate (Beriplex P/N). Drugs. 2009; 69:1977-84. [PubMed 19747012]

14. Preston FE, Laidlaw ST, Sampson B et al. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol. 2002; 116:619-24. [PubMed 11849221]

15. Dager WE. Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects. Ann Pharmacother. 2011; 45:1016-20. [PubMed 21775688]

16. Dentali F, Marchesi C, Pierfranceschi MG et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011; 106:429-38. [PubMed 21800002]

17. Ostermann H, Haertel S, Knaub S et al. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost. 2007; 98:790-7. [PubMed 17938803]

18. Pabinger I, Tiede A, Kalina U et al. Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate: a prospective clinical trial of emergency anticoagulation reversal. Ann Hematol. 2010; 89:309-16. [PubMed 19787352]

19. Goodnough LT, Shander A. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood. 2011; 117:6091-9. [PubMed 21411756]

20. CSL Behring. Beriplex P/N Company core package insert; 2013 Jan.

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