King of Prussia, PA — CSL Behring announced today that the U.S. Food and Drug Administration (FDA) approved Kcentra™ (Prothrombin Complex Concentrate [Human]), the first non-activated 4-factor prothrombin complex concentrate (PCC) for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) therapy in adult patients with acute major bleeding. The pivotal clinical trial showed that Kcentra met all efficacy and safety endpoints, including the endpoints of 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,” said Ravi Sarode, M.D., Professor of Pathology and Director of Transfusion Medicine and Hemostasis Reference Laboratory at the University of Texas Southwestern Medical Center, and coordinating investigator for the Kcentra trial.
Each year, approximately three to four million people in the U.S. are treated with the oral anticoagulant warfarin to prevent blood clots from forming following a stroke, heart attack, heart valve surgery, deep vein thrombosis/pulmonary embolism, or certain types of irregular heartbeat, such as atrial fibrillation. However, because of the deficiency in blood clotting factors induced by warfarin treatment, patients may experience severe bleeding. It is estimated that emergency departments in the U.S. see approximately 29,000 cases annually for warfarin-associated bleeding.
“FDA approval of Kcentra is an important advancement in warfarin reversal, as it provides medical professionals with a new tool that can efficiently stop major bleeding in patients for whom plasma may not be optimal,” said Lynne Powell, Senior Vice President, North America Commercial Operations, CSL Behring. “Kcentra is CSL Behring’s fifth FDA product approval since 2009. This record of success further underscores our commitment to innovation and bringing therapies to market that effectively treat and manage serious medical conditions.”
About the Pivotal Clinical Trial
The randomized, controlled Phase IIIb study used as the basis for the FDA approval of Kcentra enrolled 212 evaluable patients and was the first prospective analysis to compare a 4-factor PCC and vitamin K with plasma and vitamin K for urgent warfarin reversal in patients with acute major bleeding. Kcentra achieved the endpoints of hemostatic efficacy with respect to the adequacy of stopping a major bleed assessed at 24 hours from the start of infusion (72.4 percent of patients receiving Kcentra versus 65.4 percent receiving plasma) and INR reduction (≤1.3) at 30 minutes post treatment (62.2 percent of patients receiving Kcentra versus 9.6 percent 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 post-treatment (p values<0.0001) with 87 percent less volume (105 mL +/-37 mL versus 865 mL +/- 269 mL) than plasma. Additionally, infusion time with Kcentra was seven times faster than with plasma (24 minutes versus nearly 3 hours for plasma).
The most common adverse reactions (frequency ≥2.8%) observed in subjects 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.
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. In more than 25 countries, CSL Behring markets Kcentra as Beriplex® or Confidex®.
CSL Behring’s Integrated Safety System helps ensure Kcentra meets high quality and safety standards for virus inactivation and reduction. The processes involved in the manufacture of CSL plasma-derived products meet the highest regulatory standards for purity, safety and quality. CSL applies effective and robust pathogen inactivation and removal processes, including heat treatment and virus filtration, to the manufacture of products, resulting in final products with a high margin of safety.
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. The FDA’s Orphan Drug Designation program provides orphan status to unique drugs and biologics defined as those intended for the safe and effective treatment or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Orphan designation qualifies the sponsor of the product for important tax credits, elimination of FDA license application fees and certain marketing incentives.
Important Safety Information
Kcentra™, Prothrombin Complex Concentrate (Human) is indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—e.g., warfarin) therapy in adult patients with acute major bleeding. Kcentra is not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding. Kcentra is for intravenous use only.
Warning: Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events. Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding. Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra, and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior three months. Kcentra might not be suitable in patients with thromboembolic events in the prior three months.
Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with DIC. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT).
Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment. In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects 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.
Kcentra is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.
The safety and efficacy of Kcentra in pediatric use have not been studied, and Kcentra should be used in women who are pregnant or nursing only if clearly needed.
About CSL Behring
CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide.
CSL Behring therapies are used around the world to treat coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease, and neurological disorders in certain markets. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in the newborn. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX:CSL), a biopharmaceutical company headquartered in Melbourne, Australia. For more information, visit www.cslbehring.com.