Nanofiltered and Vapor Heated

Lyophilized powder for solution

Intravenous

DESCRIPTION

FEIBA NF (Anti-Inhibitor Coagulant Complex), nanofiltered and vapor heated, is a freeze-dried sterile human plasma fraction with Factor VIII inhibitor bypassing activity. In vitro, FEIBA NF shortens the activated partial thromboplastin time (APTT) of plasma containing Factor VIII inhibitor. Factor VIII inhibitor bypassing activity is expressed in arbitrary units. One unit of activity is defined as that amount of FEIBA NF that shortens the APTT of a high titer Factor VIII inhibitor reference plasma to 50% of the blank value.

FEIBA NF contains Factors II, IX, and X, mainly non-activated, and Factor VII mainly in the activated form. The product contains approximately equal unitages of Factor VIII inhibitor bypassing activity and Prothrombin Complex Factors. In addition, 1–6 units of Factor VIII coagulant antigen (FVIII C:Ag) per mL are present. The preparation contains only traces of factors of the kinin generating system. It contains no heparin.

Reconstituted FEIBA NF contains 4 mg of trisodium citrate and 8 mg of sodium chloride per mL.

FEIBA NF is manufactured from large plasma pools of human plasma. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of FEIBA NF is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. Regulatory Requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative. In addition, two dedicated and independent virus removal/inactivation steps have been integrated into the manufacturing process, namely 35 nm nanofiltration and a vapor heat treatment process. In addition, the DEAE-Sephadex adsorption contributes to the virus safety profile of FEIBA NF. Despite these measures, such products can still potentially transmit disease (see WARNINGS).

In vitro spiking studies have been used to validate the capability of the manufacturing process to remove and inactivate viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed under extreme conditions (e.g. at minimum incubation times and temperatures below specifications for vapor-heat treatment). Virus clearance studies for FEIBA NF performed in accordance with good laboratory practices have demonstrated, that the manufacturing process of FEIBA NF ensures a high margin of safety with respect to adventitious viruses (Table 1).

CLINICAL STUDIES

FEIBA NF is identical in formulation to FEIBA VH. Biochemical and preclinical studies have confirmed the comparability of FEIBA NF and FEIBA VH.

The safety and efficacy of FEIBA has been demonstrated by two prospective clinical trials.1,2 The first, conducted by Sixma and collaborators, was a randomized double-blind study comparing the effect of FEIBA and PROTHROMPLEX IMMUNO (a non-activated prothrombin complex concentrate) in 15 patients with hemophilia A and inhibitors to Factor VIII. A total of 150 bleeding episodes (primarily joint and musculoskeletal plus a few mucocutaneous) were treated. A single dose of 88 Units per kg of body weight was used uniformly for treatments with FEIBA . The study showed that, based on subjective patient eva luation, FEIBA was fully effective in 41.0% and partly effective in 24.6% of episodes (i.e. combined effectiveness of 65.6%), while PROTHROMPLEX was rated fully effective in 25.0% and partly effective in 21.4% of episodes (i.e. combined effectiveness of 46.4%).

The second study with FEIBA was a multicenter study conducted by Hilgartner et al. It was designed to eva luate the efficacy of FEIBA in the treatment of joint, mucous membrane, musculocutaneous and emergency bleeding episodes such as central nervous system hemorrhages and surgical bleedings. In 49 patients with inhibitor titers of greater than 5 Bethesda Units (from nine co-operating hemophilia centers), 489 single doses were given for the treatment of 165 bleeding episodes. The usual dosage was 50 Units per kg of body weight, repeated at 12-hour intervals (6-hour intervals in mucous membrane bleedings), if necessary. Bleeding was controlled in 153 episodes (93%). In 130 (78%) of the episodes, hemostasis was achieved with one or more infusions within 36 hours. Of these, 36% were controlled with one infusion within 12 hours. An additional 14% of episodes responded after more than 36 hours.

Of the 489 single doses, only 18 (3.7%) caused minor transient reactions in recipients. Out of 49 patients, 10 (20%) showed a rise in their inhibitor titers. In 5 of these patients (10%), the rise was tenfold or more. However, of these 10 patients, 3 had received Factor VIII or Factor IX concentrates within 2 weeks prior to treatment with FEIBA. These anamnestic rises have not been observed to interfere with the efficacy of FEIBA.

INDICATIONS AND USAGE

FEIBA NF (Anti-Inhibitor Coagulant Complex) is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors.

In addition, the use of FEIBA has been described in a few non-hemophiliacs with acquired inhibitors to multiple coagulation factors3,4. One case has been reported where FEIBA was effective in a patient with von Willebrand’s disease with an inhibitor.

Clinical experience suggests that patients with a Factor VIII inhibitor titer of less than 5 B.U. may be successfully treated with Antihemophilic Factor. Patients with titers ranging between 5 and 10 B.U. may either be treated with Antihemophilic Factor or FEIBA NF. Cases with Factor VIII inhibitor titers greater than 10 B.U. have generally been refractory to treatment with Antihemophilic Factor.

Inadequate response to treatment may result from an abnormal platelet count or impaired platelet function5-7 that were present before treatment with FEIBA nanofiltered and vapor-heated.

CONTRAINDICATIONS

The use of FEIBA NF is contraindicated in patients who are known to have a normal coagulation mechanism.

WARNINGS

FEIBA NF (Anti-Inhibitor Coagulant Complex), nanofiltered and vapor heated, is made from human plasma. Products made from plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by effective donor screening, testing for the presence of certain current virus infections, by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly non-A, non- B hepatitis. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other health care provider to Baxter Healthcare Corporation, at 1-800-423-2862 (in the U.S.). The physician should discuss the risks and benefits of this product with the patient.

As with all human plasma products, allergic reactions, ranging from mild, short-term urticarial rashes to severe anaphylactoid reactions, have been seen. Administration of FEIBA NF should be discontinued immediately if such signs appear. Allergic reactions should be treated with antihistamines and glucocorticoids. Shock should be treated in the usual way.

Thromboembolic events may occur in the course of treatment with preparations containing the prothrombin complex. Thromboembolic events are a rare (4.05 to 8.24 events per 100,000 infusions8,9) but well recognized potential complication of FEIBA infusion, particularly following the administration of high doses and/or in patients with thrombotic risk factors.

In individual instances, myocardial infarction was found to occur after high doses and/or prolonged administration and/or in the presence of risk factors predisposing to myocardial infarction.

FEIBA NF must be used only in patients with circulating inhibitors to one or more coagulation factors and should not be used for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors. It should not be given to patients with significant signs of disseminated intravascular coagulation (DIC) or fibrinolysis.

Infusion of FEIBA NF should not exceed single dosage of 100 units per kg of body weight and daily doses of 200 units per kg of body weight. Patients receiving more than 100 units per kg of body weight of FEIBA NF must be monitored for the development of DIC and/or symptoms of acute coronary ischemia.

High doses of FEIBA NF should be given only as long as absolutely necessary to stop bleeding.

Anamnestic responses with rise in Factor VIII inhibitor titer have been observed in 20% of the cases (see CLINICAL STUDIES).

PRECAUTIONS

General

If clinical signs of intravascular coagulation occur, which include changes in blood pressure, changes in pulse rate, respiratory distress, chest pain and/or cough, the infusion should be stopped promptly and appropriate diagnostic and therapeutic measures are to be initiated.

Laboratory indications of DIC are decreased fibrinogen, decreased platelet count, and/or presence of fibrin-fibrinogen degradation products (FDP). Other indications of DIC include significantly prolonged thrombin time, prothrombin time, or partial thromboplastin time.

It has been reported that FEIBA NF and antifibrinolytics have been given simultaneously without complications. It is recommended not to use antifibrinolytics until 12 hours after the administration of FEIBA NF.

Information for Patients

Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time. Parvovirus B19