FDA approves 4PCC for acute major bleeding

Human-derived 4-factor prothrombin complex concentrate (4PCC) (Kcentra, CSL Behring) was approved on April 30, 2013, as the first nonactivated agent for urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adult patients with acute major bleeding.

Three-factor PCC products typically contain clotting factors II, IX, and X, but seldom factor VII, which is also included in 4PCC. A purified, heat-treated, nanofiltered, lyophilized, and preservative-free powder for reconstitution, 4PCC also contains heparin and antithrombotic proteins C and S. Although 4PCC has been available in Europe and Canada for many years, it is currently the only 4-factor PCC available in the United States.

4PCC has not been studied in patients with congenital factor deficiencies.

Efficacy

Warfarin-associated bleeding can be severely detrimental, but reversal agents are available, if not always timely. Vitamin K can take up to 24 hours to fully restore coagulation factors, and fresh-frozen plasma (FFP) must be blood-typed and crossed, thawed, and administered with large volumes of fluid. The fluids involved with FFP can also be a burden to a delicate heart-failure patient or one who is elderly.

4PCC can lower INR rapidly and with superior effectiveness when compared to FFP and three-factor PCCs, respectively. In its 2012 evidence-based guidelines for management of anticoagulant therapy, the American College of Chest Physicians now recommends the administration of 5 to 10 mg of IV vitamin K plus 4PCC. 4PCC is not currently approved for the reversal of the direct thrombin inhibitors or direct factor Xa inhibitors.

A prospective, open-label, active-control, noninferiority, multicenter, randomized, controlled trial assessed the efficacy of 4PCC in patients treated with vitamin K antagonists (VKA) who required urgent replacement of their vitamin K-dependent clotting factors to treat acute major bleeding. Doses of 4PCC were calculated in accordance with each subject’s baseline INR. Patients were observed for 90 days after the infusion. Patients also received intravenous vitamin K. Patients were defined as having hemostatic efficacy by a blinded board. The proportion of subjects with effective hemostasis was 72.4% in the 4PCC group vs. 65.4% in the FFP (control) group. They showed noninferiority, but did not meet the criterion for superiority (a secondary objective in the study).

The Pabinger et al. study was an open-label, single-arm, multicenter study with 43 subjects receiving VKA and required 4PCC for acute bleeding. The doses were calculated in accordance with the each subject’s baseline INR, and the end point was the decrease of the INR to <1.3 within 30 minutes after completion of 4PCC administration. Sixteen (94%) of the 17 patients who could be evaluated showed a decrease in INR to <1.3 within 30 minutes after completion of 4PCC infusion.

Safety

A black-box warning for both fatal and nonfatal arterial and venous thromboembolic complications exists for 4PCC. Thromboembolic events occurred more frequently following 4PCC administration than with FFP. Patients should be monitored for signs and symptoms of thromboembolic events. Further, 4PCC was not studied in patients who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the previous three months; therefore 4PCC may not be advisable for use in these patients.

Because it contains heparin, 4PCC is contraindicated in patients with known heparin-induced thrombocytopenia (HIT). Further, it is contraindicated in patients with known anaphylactic or severe systemic reactions to any components, including heparin; factors II, VII, IX, X; proteins C and S; antithrombin III; and human albumin. Patients with disseminated intravascular coagulation (DIC) should not receive 4PCC.

Occurring in > 2.8% of patients, headache, nausea/vomiting, arthralgias, and hypotension were the most commonly reported adverse reactions observed in patients during trials. The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism, and deep vein thrombosis. Hypersensitivity reactions have also been observed with 4PCC. In addition, because 4PCC is made from human blood, the risk of transmitting infectious diseases exists, despite the rigorous steps toward virus reduction taken during manufacture and filtration to reduce and prevent such transmission.

Dosing

The potency (units) of 4PCC, which is available as a single-use, preservative-free vial for intravenous administration, is defined by Factor IX content. After reconstitution of 4PCC for injection with 20 mL of sterile water as the diluent, the final concentration of drug product in Factor IX units will range from 20-31 units/mL, depending upon the actual potency, which is listed on the carton. The range of Factor IX units per vial is 400 to 620 units.

The pretreatment INR will determine the dose of 4PCC per kg of body weight for each patient. For example, if the pretreatment INR is between 2 and 4, the dose of 4PCC is 25 units of Factor IX per kg of body weight, not to exceed 2500 units of Factor IX. If the pretreatment INR is between 4 and 6, the dose of 4PCC is 35 units of Factor IX per kg of body weight, not to exceed 3,500 units of Factor IX. If the pretreatment INR is >6, the dose of 4PCC is 50 units of Factor IX per kg of body weight, not to exceed 5,000 units of Factor IX. Repeat dosing with 4PCC is not supported by clinical data and is not recommended.

The rate of infusion for all doses should be 0.12 mL/kg/min (~3 units/kg/min), up to a maximum rate of 8.4 mL/min (~210 units/min). 4PCC should be administered through a separate infusion line and not mixed with other medicinal products. Vitamin K should be coadministered with 4PCC to maintain factor levels once the effects of 4PCC have been diminished.

INR should be monitored during and after administration, with the INR decreasing to <1.3 within 30 minutes in most subjects.

No age-related differences were seen in the safety profile of 4PCC in clinical trials. It has not been studied in pediatric patients. 4PCC is labeled pregnancy category C and should be prescribed for a pregnant woman only if clearly needed.

4PCC may be stored at room temperature, not to exceed 25°C (77°F). It cannot be frozen. 4PCC is stable for 36 months from the date of manufacture, up to the expiration date on the carton and vial labels. The product vial should be stored in the original carton to protect it from light.

References:

Kcentra (prothrombin complex concentrate [human]) product information. Kankakee, IL: CSL Behring LLC; 2013. Accessed September 3, 2013.

Kalus JS, et al. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health Syst Pharm 2013;70[10 Suppl 1]:S12.

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.

Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy. Antithrombotic therapy and prevention of thrombosis, 9th ed. CHEST 2012;141(Suppl 2):e152S-e184S.

Kevin W. Chamberlin, PharmD, is assistant clinical professor and assistant department head, pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.