, septicemia, or concomitant treatment with recombinant factor viia have an increased risk of developing thrombotic events due to circulating tissue factor or predisposing coagulopathy. potential benefit of treatment with feiba should be weighed against the potential risk of these thromboembolic events. monitor patients receiving more than 100 units per kg of body weight of feiba for the development of dic, acute coronary ischemia and signs and symptoms of other thromboembolic events. if clinical signs or symptoms occur, such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling and/or pain, discontinue the infusion and initiate appropriate diagnostic and therapeutic measures. the safety and efficacy of feiba for breakthrough bleeding in patients receiving emicizumab has not been established. cases of thrombotic microangiopathy (tma) were reported in a clinical trial where subjects received feiba as part of a treatment regimen for breakthrough bleeding following treatment with emicizumab. 6 consider the benefits and risks with feiba if considered required for patients receiving emicizumab prophylaxis. if treatment with feiba is required for patients receiving emicizumab, the hemophilia treating physician should closely monitor for signs and symptoms of tma. in feiba clinical studies thrombotic microangiopathy (tma) has not been reported. 5.2 hypersensitivity reactions hypersensitivity and allergic reactions, including severe anaphylactoid reactions, can occur following the infusion of feiba. the symptoms include urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension. these reactions can be severe and systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). other infusion reactions, such as chills, pyrexia, and hypertension have also been reported. if signs and symptoms of severe allergic reactions occur, immediately discontinue administration of feiba and provide appropriate supportive care. 5.3 transmission of infectious agents because feiba is made from human plasma it may carry a risk of transmitting infectious agents, e.g., viruses, and the variant creutzfeldt-jakob disease (vcjd) agent, and theoretically, the creutzfeldt-jakob disease (cjd) agent. the risk has been minimized by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections and by inactivating and removing certain viruses during the manufacturing process [see description (11) ]. despite these measures, the product may still potentially transmit human pathogenic agents. there is also the possibility that unknown infectious agents may still be present. all infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare providers to baxalta us inc., at 1-800-423-2090 (in the u.s.) and /or to fda med watch (1-800-fda-1088 or www.fda.gov/medwatch ). 5.4 presence of isohemagglutinins and interference with laboratory tests feiba contains blood group isohemagglutinins (anti-a and anti-b). passive transmission of antibodies to erythrocyte antigens, e.g., a, b, d, may interfere with some serological tests for red cell antibodies, such as antiglobulin test (coombs test).

til 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 and 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. administer feiba within 3 hours after 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 (do not draw air into the syringe) by turning the syringe in clockwise direction until stop position. use of a luer lock syringe is highly recommended to ensure a tight connection between the syringe and the baxject ii hi-flow device (fig. e). invert the system so that the dissolved feiba product is on top. draw the dissolved product carefully into the syringe by pulling the plunger back slowly to avoid foaming (fig. f). ensure that the tight connection between the baxject ii hi-flow device and the syringe is maintained. disconnect the syringe. attach a suitable needle and inject or infuse intravenously at a rate that does not exceed 2 units per kg of body weight per minute. a syringe pump may be used to control the rate of administration. for a patient with a body weight of 75 kg, this corresponds to an infusion rate of 2.5-7.5 ml per minute depending on the number of units per vial (see actual potency presented on the vial label) . figure e figure f figure e figure f

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 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of feiba. because post-marketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. blood and lymphatic system disorders : disseminated intravascular coagulation cardiac disorders : tachycardia, flushing respiratory, thoracic, and mediastinal disorders : bronchospasm, wheezing gastrointestinal disorders : abdominal discomfort skin and subcutaneous tissue disorders : pruritus general disorders and administration site conditions : malaise, feeling hot, injection site pain

ed child from feiba or from the underlying condition. 8.4 pediatric use safety and efficacy of feiba have been evaluated in nine pediatric subjects treated in the routine prophylaxis trial including 4 subjects ≥7 to <12 years of age and 5 subjects ≥12 to <16 years of age. the dosing for all pediatric subjects was based on body weight. a total of 576 infusions were given for the treatment of 223 bleeding episodes (504 infusions for joint bleeding episodes, 72 infusions for muscle and soft tissue bleeding episodes). in 223 (100%) of the episodes, hemostasis was achieved with one or more infusions. hemostatic efficacy was rated as excellent or good in a majority (96.9%) of the bleeding episodes in both regimens at 24 hours post infusion. the median annualized bleeding episode rate (abr) for children ≥7 to <12 years of age was 7.7 bleeds per patient per year, as compared to 39 for subjects treated with on-demand therapy. [see clinical studies (14) ] the safety and efficacy of feiba has not been evaluated in neonates. 8.5 geriatric use the safety and efficacy of feiba has not been evaluated in subjects ≥ 65 years of age.

n formally studied in humans.

partially effective, not effective or not sure. the criteria for evaluation of the effectiveness were severity of pain, subjective improvement, circumference of muscle or joint, restriction of joint mobility, cessation of open bleeding, start of rebleeding and quantity and nature of analgesics. feiba was effective in 41% and partly effective in 25% of episodes (i.e. combined effectiveness of 66%), while prothrombin complex concentrate was rated effective in 25% and partly effective in 21% of episodes (i.e., combined effectiveness of 46%). the second trial with feiba was a multicenter randomized, prospective trial. this trial was conducted in 44 hemophilia a subjects with inhibitors, 3 hemophilia b subjects with inhibitors and 2 acquired factor viii inhibitor subjects. it was designed to evaluate 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. the inclusion criteria used were age >4 years, history of inhibitor titer ≥4 bethesda units (bu) and without chronic liver disease. subjects were excluded if they had a history of thromboembolic events or allergic reactions to feiba. forty-nine (49) subjects with inhibitor titers of greater than 5 bu were enrolled from nine co-operating hemophilia centers. subjects were treated with 50 units per kg of body weight, repeated at 12-hour intervals (6-hour intervals in mucous membrane bleedings), if necessary. a total of 489 infusions were given for the treatment of 165 bleeding episodes (102 joint, 33 muscle and soft tissue, 20 mucous membrane, and 10 emergency bleeds, including 3 central nervous system bleeds and 4 surgical procedures). 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. 14.2 routine prophylaxis in a multicenter, open-label, prospective, randomized clinical trial comparing subjects receiving feiba for prophylaxis with subjects receiving feiba for on-demand treatment, 36 hemophilia a and b subjects with inhibitors to factor viii or ix were analyzed in the intent-to-treat analysis. study population included 29 (80.6%) caucasian, 3 (8.3%) asian, 2 (5.6%) black/african american, and 2 (5.6%) other. inclusion criteria were subjects with a history of high titer inhibitors or low titer refractory to increased factor viii or ix dosing, age range between 4 and 65, and subjects receiving bypassing agents with ≥12 bleeds in the 12 months prior to trial entry. subjects with a history of thromboembolic events, symptomatic liver disease, or a platelet count <100,000 per ml, and those receiving immune tolerance induction or routine prophylaxis were excluded. subjects were randomized to receive 12 months of prophylactic or on-demand treatment with feiba. seventeen subjects randomized to the prophylaxis arm received 85 units per kg of feiba every other day. nineteen subjects randomized to the on-demand arm received feiba for the treatment of acute bleeding episodes per the dose and dosing regimen recommended. target joints were defined as ≥4 bleeding episodes within 6 months. in this trial, ankles, knees, elbows and hips were target joint locations. preexisting target joints were not considered as new target joints. hemostatic efficacy for treatment of acute bleeds was evaluated at 6 and 24 hours according to a pre-specified four-point scale of excellent, good, fair, or none. an evaluation of "none" was considered a treatment failure. the criteria for evaluation of the effectiveness were relief of pain, cessation of bleeding, and number of infusions required to treat a bleed. a total of 825 bleeding episodes were reported including 196 that occurred during prophylaxis and 629 that occurred during on-demand therapy. a majority (78%) of the 794 bleeding episodes that were rated for efficacy were treated with 1 or 2 infusions. hemostatic efficacy was rated as excellent or good for 74% of bleeding episodes rated at 6 hours post infusion and for 87% of the bleeding episodes at 24 hour post infusion. a total of 19 (2.4%) bleeds were rated as "none" at 6 hours post infusion; 1 bleed (0.1%) was rated "none" at 24 hours. hemostatic efficacy for routine prophylaxis was evaluated against subjects who received on-demand therapy. the overall median annual bleed rate (abr) for the on-demand arm was 28.7 compared to 7.9 for the prophylaxis arm, which represents a 72% reduction in median abr with prophylaxis. when analyzed by site (e.g. joint, non-joint) and cause of bleed (e.g. spontaneous, traumatic), prophylactic treatment with feiba resulted in a greater than 50% reduction in abr. there were fewer subjects in the prophylaxis arm who developed new target joints (7 new target joints in 5 subjects treated with prophylaxis compared to 23 new target joints in 11 subjects in the on-demand arm). target joints developed in two subjects in the on-demand arm and three in the prophylaxis arm who did not have reported target joints at trial enrollment. a total of 3 of 17(18%) subjects had no bleeding episodes on prophylaxis. in the on-demand arm, all subjects experienced a bleeding episode. abr by age category between on-demand and prophylaxis regimens is provided in table 4. one adolescent subject on prophylaxis had a higher rate of bleeding possibly due to increased physical activity after study enrollment. table 4: abr by age category age category on-demand prophylaxis number of subjects abr median number of subjects abr median children (≥7 to <12 years old) 2 39.3 2 7.7 adolescent (≥12 to <16 years old) 2 30.9 3 27.5 adult (≥16 years old) 15 23.9 12 6.9

efrigerated.

lia treatment center (htc) to report any adverse reactions or problems following feiba administration to their hemophilia treating physician. to enroll in the confidential, industry-wide patient notification system, call 1-888-873-2838. feiba ® is a registered trademark of baxalta incorporated, a takeda company. shire and the shire logo are trademarks or registered trademarks of members of the shire group of companies, now part of takeda.