Anti-inhibitor coagulant complex

12.1 Mechanism of Action The mechanism of action of FEIBA is still the subject of scientific discussion. FEIBA contains multiple components, mainly non-activated factors II, IX, X and mainly activated factor VII. These factors can interact with plasma coagulation factors and platelets to increase the impaired thrombin generation of hemophilia patients with inhibitors, leading to hemostasis.

1 INDICATIONS AND USAGE FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B patients with inhibitors for: Control and prevention of bleeding episodes Perioperative management Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX. FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B patients with inhibitors for: Control and prevention of bleeding episodes. Perioperative management. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to factor VIII or factor IX. ( 1 )

2 DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only. For intravenous use after reconstitution only ( 2 ) Each vial of FEIBA contains the labeled amount of factor VIII inhibitor bypassing activity in units. ( 2.1 ) Type of Bleeding Dose (unit/kg) Frequency/Duration Control and Prevention of Bleeding 50 - 100 Determined by the type of bleeding episode Perioperative Management 50 - 100 Determined by the type of surgical intervention Routine Prophylaxis 85 Every other day Maximum injection or infusion rate must not exceed 10 units per kg of body weight per minute. ( 2.3 ) 2.1 Dose A guide for dosing FEIBA is provided in Table 1. Table 1: Dosing Guidelines Dose (unit/kg) Frequency of Doses (hours) Duration of Therapy Control and Prevention of Bleeding Joint Hemorrhage 50 – 100 12 Until pain and acute disabilities are improved. Mucous Membrane Bleeding 50 – 100 6 At least 1 day or until bleeding is resolved. Soft Tissue Hemorrhage (e.g., retroperitoneal bleeding) 100 12 Until resolution of bleed. Other Severe Hemorrhage (e.g., CNS bleeds) 100 6 – 12 Until resolution of bleed. Perioperative Management Preoperative 50 – 100 One time dose Immediately prior to surgery. Postoperative 50 – 100 6 – 12 Until resolution of bleed and healing are achieved. Routine Prophylaxis 85 Every other day Dosage and duration of treatment depend on the location and extent of bleeding, and the patient's clinical condition. Careful monitoring of replacement therapy is necessary in cases of major surgery or life-threatening bleeding episodes. Each vial of FEIBA contains the labeled amount of factor VIII inhibitor bypassing activity in units. Base the dose and frequency of FEIBA on the individual clinical response. Clinical response to treatment with FEIBA may vary by patient and may not correlate with the patient's inhibitor titer. Record the name of the patient and batch number of the product in order to maintain a link between the patient and the batch of the product. Do not exceed a single dose of 100 units per kg body weight or a daily dose of 200 units per kg body weight [see Warnings and Precautions (5.1) ] . 2.2 Preparation and Reconstitution Use aseptic technique throughout the entire reconstitution process. If the patient uses more than one vial per injection, reconstitute each vial according to the following instructions. Allow the vials of FEIBA and Sterile Water for Injection (diluent) to reach room temperature, if refrigerated. Remove the plastic caps from the concentrate and diluent vials. Wipe the stoppers of both vials with a sterile alcohol swab and allow them to dry prior to use. Open the package of BAXJECT II Hi-Flow device by peeling away the lid completely without touching the inside (Fig. A). Do not remove the device from the package. Do not touch the clear spike. Place the diluent vial on a flat and solid surface. Turn the package over and insert the clear plastic spike through the diluent stopper by pressing straight down (Fig. B). Grip the BAXJECT II Hi-Flow device package at the edges and pull the package off the device (Fig. C). Do not remove the blue protective cap from the BAXJECT II Hi-Flow device. Do not touch the purple spike. Turn the system over, so that the diluent vial is on top. Quickly insert the purple spike of the BAXJECT II Hi-Flow device fully into the FEIBA vial. The vacuum will draw the diluent into the FEIBA vial (Fig. D). The connection of the two vials should be done expeditiously to close the open fluid pathway created by the first insertion of the spike to the diluent vial. Gently swirl (do not shake) the vial until FEIBA is completely dissolved. Make sure that FEIBA has been dissolved completely; otherwise, active material will not pass through the device filter. The reconstituted solution should be inspected visually for particulate matter before administration. The solution should be discarded if it is not clear or is discolored. After reconstitution of FEIBA is complete, the injection or infusion should begin immediately and must be completed within three hours following reconstitution. Do not refrigerate after reconstitution. Discard unused portion. Figure A Figure B Figure C Figure D Figure A Figure B Figure C Figure D 2.3 Administration For intravenous injection or intravenous infusion after reconstitution only. Inspect the reconstituted FEIBA solution visually for particulate matter and discoloration prior to administration. The appearance of the solution should be colorless to slightly yellowish. Do not use if particulate matter or discoloration is observed. Flush venous access lines with isotonic saline prior to and after infusion of FEIBA. Do not administer in the same tubing or container with other medicinal products. Use plastic Luer lock syringes because protein such as FEIBA tends to stick to the surface of all-glass syringes. Remove the blue protective cap from the BAXJECT II Hi-Flow device. Tightly connect the syringe to the BAXJECT II Hi-Flow device (

6 ADVERSE REACTIONS The most frequently reported adverse reactions observed in >5% of subjects in the prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody positive, nausea, and vomiting. The serious adverse reactions seen with FEIBA are hypersensitivity reactions and thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis. The most common adverse reactions observed in >5% of subjects were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody positive, nausea, and vomiting. ( 6.1 ) The serious adverse drug reactions are hypersensitivity and thromboembolic events, including stroke, pulmonary embolism, and deep vein thrombosis. ( 5.1 , 5.2 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety assessment of FEIBA is based on the review of the data from two prospective clinical trials in which FEIBA was used for the treatment of acute bleeding episodes and a prospective trial that compared the use of FEIBA prophylactically versus on-demand treatment. The adverse reactions reported from two prospective clinical trials in which FEIBA was used for the treatment of acute bleeding episodes were chills, chest pain, chest discomfort, dizziness, dysgeusia, dyspnea, hypoesthesia, increase of inhibitor titer (anamnestic response), nausea, pyrexia, and somnolence. Specifically, the first trial was a multicenter randomized, double-blind trial in 15 hemophilia A subjects with inhibitors to factors VIII. The second trial was a multicenter FEIBA study conducted in 44 hemophilia A subjects with inhibitors, 3 hemophilia B subjects with inhibitors and 2 acquired factor VIII inhibitor subjects. Of the 489 infusions used to treat acute bleeds during the second trial, 18 (3.7%) caused minor transient reactions of chills, fever, nausea, dizziness and dysgeusia. Out of 49 subjects, 10 (20%) had a rise in their inhibitor titers after treatment with FEIBA. Five of these subjects (50%) had increases that were tenfold or more, and 3 (30%) of these subjects received factor VIII or IX concentrates within 2 weeks prior to treatment with FEIBA. These anamnestic rises were not associated with decreased efficacy of FEIBA. Table 2 lists the adverse reactions in >5% of subjects reported in the randomized, prospective prophylaxis trial comparing FEIBA prophylaxis with on-demand treatment in 36 hemophilia A and B subjects with inhibitors to factors VIII or IX 3 . The trial population included 33 (92%) subjects with hemophilia A and 3 (8.3%) subjects with hemophilia B. Four (11%) subjects were ≥7 to <12 years of age, 5 (14%) were ≥12 to <16 years of age, and 27 (75%) were ≥16 years of age. A total of 29 (80.6%) subjects were Caucasian, 3 (8.3%) Asian, 2 (5.6%) Black/African American, and 2 (5.6%) other. The subjects received a total of 4,513 infusions (3,131 for prophylaxis and 1,382 for on-demand). Table 2: Prophylaxis Study Adverse Reactions (ARs) in >5% of Subjects MedDRA System Organ Class Adverse Reaction Number of ARs Number of Subjects Percent of Subjects (N=36) Blood And Lymphatic System Disorders Anemia 2 2 5.6 Gastrointestinal Disorders Diarrhea 2 2 5.6 Nausea 2 2 5.6 Vomiting 2 2 5.6 Investigations Hepatitis B Surface Antibody Positive 4 4 11.1 Musculoskeletal And Connective Tissue Disorders Hemarthrosis 5 3 8.3 Table 3 lists the adverse reactions and infusion related adverse events reported in >5% of subjects in any of the three groups (50% Reduced Volume, Increased Rate 4 U/kg/min; 50% Reduced Volume, Increased Rate 10 U/kg/min; Overall 50% Reduced Volume) of the randomized, prospective crossover trial evaluating the tolerability and safety of infusing reduced volume of FEIBA at the standard infusion rate of 2 U/kg/min, and at increased rates of 4 and 10 U/kg/min in a total of 33 treated subjects with congenital Hemophilia A with inhibitors. Table 3: Adverse Reactions (ARs) and Infusion Related Adverse Events in >5% of Subjects, in Patients 18 Years and Older MedDRA System Organ Class Adverse Reaction 50% Reduced Volume; Increased Rate 4 U/kg/min (N=30) n (%); m 50% Reduced Volume; Increased Rate 10 U/kg/min (N=28) n (%); m Overall 50% Reduced Volume Includes the following infusion rates: 2 U/kg/min; 4 U/kg/min and 10 U/kg/min (N=30) n (%); m n=Number of subjects, m=number of events Adverse reactions (ARs) Nervous system disorders Headache 0 0 2 (6.7%); 2 Infusion related AEs Nervous system disorders Headache 0 0 2 (6.7%); 2 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of FEIBA. Bec

7 DRUG INTERACTIONS Consider the possibility of thrombotic events when systemic antifibrinolytics such as tranexamic acid and aminocaproic acid are used. Use of antifibrinolytics within approximately 6 to 12 hours after the administration of FEIBA is not recommended. ( 7 ) 7.1 Concomitant Medications Consider the possibility of thrombotic events when systemic antifibrinolytics such as tranexamic acid and aminocaproic acid are used during treatment with FEIBA. No adequate and well-controlled studies of the combined or sequential use of FEIBA and recombinant factor VIIa antifibrinolytics, or emicizumab have been conducted. Use of antifibrinolytics within approximately 6 to 12 hours after the administration of FEIBA is not recommended. Clinical experience from an emicizumab clinical trial suggests that a potential drug interaction may exist with emicizumab when FEIBA was used as part of a treatment regimen for breakthrough bleeding 6 [see Warnings and Precautions (5.1) ] .