Kcentra by CSL Behring

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Specialty Pharmacy Times, March/April 2014, Volume 5, Issue 2

Kcentra is the first nonactivated 4-factor prothrombin complex concentrate for the urgent reversal of acquired coagulation deficiency induced by vitamin K antagonist therapy.

Kcentra is the first nonactivated 4-factor prothrombin complex concentrate for the urgent reversal of acquired coagulation deficiency induced by vitamin K antagonist therapy.

Kcentra (human prothrombin complex concentrate) is the first nonactivated 4-factor prothrombin complex concentrate for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA) therapy (eg, warfarin) in adult patients with acute major bleeding. Each year, approximately 3 to 4 million people in the United States are treated with the oral anticoagulant warfarin to prevent blood clots from forming; however, because of the inhibition in blood clotting factors, patients may experience severe bleeding. It has been estimated that emergency departments in the United States see approximately 29,000 cases of warfarin-associated bleeding annually.1

Mechanism of Action/Pharmacology2-4

Kcentra contains the vitamin K—dependent coagulation factors II, VII, IX, and X—together known as the prothrombin complex—and the antithrombotic proteins C and S. The coagulation cascade is a series of procoagulant and antithrombotic reactions involving the activation of zymogens. The vascular endothelium provides a protective barrier separating blood cells and plasma factors from subendothelial vessel wall–reactive adhesive proteins and tissue factor. The latter proteins trigger blood coagulation. Thrombin converts fibrinogen to fibrin for clot formation. 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.

Clinical Trials2-4

The efficacy of Kcentra has been evaluated in a prospective, open-label, active-controlled, noninferiority, randomized, controlled phase-IIIb study. A total of 212 subjects were randomized to receive Kcentra or plasma for acute major bleeding in the setting of an international normalized ratio (INR) ≥2.0 and recent use of a VKA anticoagulant. The doses of Kcentra (25, 35, or 50 IU/kg) were calculated according to the subjects’ baseline INR (2 to <4, 4 to 6, or >6, respectively), and the observation period lasted 90 days after infusion of Kcentra or plasma. Kcentra achieved the end points of hemostatic efficacy with respect to the adequate stopping of a major bleed assessed at 24 hours from the start of infusion (72.4% of patients receiving Kcentra vs 65.4% receiving plasma) and INR reduction (≤1.3) at 30 minutes after treatment (62.2% of patients receiving Kcentra vs 9.6% receiving plasma).

In regards to secondary end points, a single Kcentra infusion produced a rapid and sustained increase in plasma levels of clotting factors II, VII, IX, and X within 30 minutes after treatment (P <.0001), with 87% less volume than plasma.

Dosing2-4

The dosing of Kcentra is shown in the Table.

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Kcentra has a rapid onset of action in which a significant INR reduction is seen (INR reduced to <1.3 in more than 60% of patients); the duration of effect is approximately 6 to 8 hours. Kcentra is given by intravenous administration only. It should be reconstituted at room temperature before infusion should not be mixed with other medicinal productions, and must be administered through a separate infusion line.

Contraindications, Warnings, and Precautions2-4

Common (≥2.8%) adverse reactions to Kcentra include headache, nausea/vomiting, arthralgia, and hypotension. The most serious adverse reactions have been thromboembolic events, including stroke, deep venous thrombosis, and pulmonary embolism. Use of Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any components of Kcentra, including heparin; factors II, VII, IX, and X; proteins C and S; antithrombin III; and human albumin. Its use is also contraindicated in patients with disseminated intravascular coagulation and patients with known heparin-induced thrombocytopenia. No specific dosage adjustments are necessary for renal or hepatic impairment, although caution should be used in pregnant women, as Kcentra is rated Pregnancy Category C. SPT

References

  • Zareh M, Davis A, Henderson S. Reversal of warfarin-induced hemorrhage in the emergency department. West J Emerg Med. 2011;12(4):386-392.
  • Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Kcentra) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6:622-631.
  • Bleeding from acquired coagulation defects and antithrombotic therapy. In: Raife TJ, Rose JS, Lentz SR, eds. Rossi’s Principles of Transfusion Medicine. 4th ed. Hoboken, NJ: Wiley-Blackwell; 2009.
  • Wysowski D, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167(13):1414-1419.

About the Authors

Dr. Agbahiwe is a clinical pharmacist specialist at Harris Health System, Settegast Health Center, in Houston, Texas, as well as adjunct faculty, Department of Pharmacy Practice, at Texas Southern University College of Pharmacy & Health Sciences. Mrs. Obi is a PharmD candidate at Texas Southern University College of Pharmacy & Health Sciences.