FDA Approves CSL Behring's Kcentra for Urgent Warfarin Reversal in Patients With Acute Major Bleeding

April 30, 2013—CSL Behring (King of Prussia, PA) announced that the US Food and Drug Administration (FDA) approved the company's Kcentra, a nonactivated, 4-factor, human prothrombin complex concentrate (PCC) for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (eg, warfarin) therapy in adult patients with acute major bleeding. In December 2012, the FDA granted Orphan Drug Designation for Kcentra for the treatment of patients needing urgent reversal of vitamin K antagonist therapy due to major bleeding and/or surgical procedures.

According to the CSL Behring press release, Kcentra contains four vitamin K-dependent factors: factor II (prothrombin), factor VII, factor IX, and factor X, as well as antithrombotic proteins C and S. CSL Behring markets Kcentra as Beriplex or Confidex in more than 25 countries.

The company advised that the pivotal clinical trial, which was used as the basis for the FDA approval, showed that Kcentra met all efficacy and safety endpoints, including hemostatic efficacy and International Normalized Ratio (INR) reduction compared with plasma, the most widely used agent for warfarin reversal in the United States.

“Kcentra has been shown to restore the decreased vitamin K-dependent clotting factors significantly faster than plasma in patients on warfarin,” commented Ravi Sarode, MD, in the CSL Behring's announcement. Dr. Sarode served as the coordinating investigator for the Kcentra trial. He is also Professor of Pathology and Director of Transfusion Medicine and Hemostasis Reference Laboratory at the University of Texas Southwestern Medical Center.

The company advised that the pivotal trial was a randomized, controlled, phase IIIb study of Kcentra that enrolled 212 evaluable patients. The study was a prospective analysis comparing 4-factor PCC and vitamin K with plasma and vitamin K for urgent warfarin reversal in patients with acute major bleeding. The company reported that Kcentra achieved the endpoint of hemostatic efficacy with respect to the adequacy of stopping 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 posttreatment (62.2% of patients receiving Kcentra vs 9.6% receiving plasma).

The secondary endpoints included plasma levels of major clotting factors (factors II, VII, IX, X, proteins C and S), time to INR correction, and safety and tolerability (including all-cause mortality). 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 value < .0001) with 87% less volume (105 mL ± 37 mL vs 865 mL ± 269 mL) than plasma. Additionally, infusion time with Kcentra was seven times faster than with plasma (24 minutes vs approximately 3 hours for plasma).

The company reported that in the study, the most common adverse reactions (frequency ≥ 2.8%) observed in patients receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension. The most serious adverse reactions were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis.

CSL Behring noted that its Integrated Safety System helps ensure Kcentra meets high quality and safety standards for virus inactivation and reduction and that the processes involved in the manufacturing of the company's plasma-derived products meet the highest regulatory standards for purity, safety and quality. More patient safety information is available online in the company's press release and website. The FDA announcement is available on the agency's website.