Feiba Drug Information
Generic name: ANTI-INHIBITOR COAGULANT COMPLEX
Uses of Feiba
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. Perioperative management.
Dosage & Administration of Feiba
Dose
A guide for dosing FEIBA is provided in Table 1. Table 1: Dosing Guidelines 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.
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
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. 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 10 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 up to 15 mL per minute.
Figure E Figure F Figure E Figure F
| 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 |
| 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 | ||
| Figure A | Figure B |
| Figure C | Figure D |
| Figure E | Figure F |
Side Effects of Feiba
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. 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 subjects received a total of 4,513 infusions (3,131 for prophylaxis and 1,382 for on-demand). Table 3: Adverse Reactions (ARs) and Infusion Related Adverse Events in >5% of Subjects, in Patients 18 Years and Older
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of FEIBA. Because postmarketing 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 Investigations: Fibrin D-dimer increased
| 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 |
| 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 |
Warnings & Cautions for Feiba
Embolic and Thrombotic Events
Thromboembolic events (including venous thrombosis, pulmonary embolism, myocardial infarction, and stroke) can occur with FEIBA, particularly following the administration of high doses (above 200 units per kg per day) and/or in patients with thrombotic risk factors. Patients with DIC, advanced atherosclerotic disease, crush injury, 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.
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.
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. 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 Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) (in the U.S.) and /or to FDA Med Watch (1-800-FDA-1088 or www.fda.gov/medwatch ).
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).
Drug Interactions with Feiba
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.
Pregnancy Safety for Feiba
Pregnancy Risk Summary There are no data with FEIBA use in pregnant women to inform a drug-associated risk. There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have not been conducted with FEIBA.
It is also not known whether FEIBA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. In the U.S. general population, the estimated background risk for major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. There is no information available on the effect of FEIBA on labor and delivery.
Pediatric Use of Feiba
The dosing for all pediatric subjects was based on body weight. 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 safety and efficacy of FEIBA has not been evaluated in neonates.
Contraindications for Feiba
Known anaphylactic or severe hypersensitivity reactions to FEIBA or any of its components, including factors of the kinin generating system. Disseminated intravascular coagulation (DIC). Acute thrombosis or embolism (including myocardial infarction).
Disseminated intravascular coagulation (DIC).
Clinical Studies of Feiba
Control and Prevention of Bleeding Episodes The efficacy of FEIBA in the treatment of bleeding episodes has been demonstrated by two prospective clinical trials. 1,2 The first trial was a multicenter, randomized, double-blind trial comparing the effect of FEIBA and a non-activated prothrombin complex concentrate in 15 subjects with hemophilia A and inhibitors to factor VIII. The inclusion criteria were history of high titer inhibitors, high responder status, more than 1 bleeding episode per month in the prior year and no signs of liver failure. A single dose of 88 units per kg of body weight was used uniformly for treatments with FEIBA.
A second treatment was allowed for muscle bleeds after 12 hours and 6 hours after mucocutaneous bleeds, if necessary. Subjects and investigators were asked to rate hemostatic efficacy based on a scale of effective, 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.
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 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.
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. 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. 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. 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 5. One adolescent subject on prophylaxis had a higher rate of bleeding possibly due to increased physical activity after study enrollment. Table 5: ABR by
| Age Category | On-Demand: Number of Subjects | On-Demand: ABR Median | Prophylaxis: Number of Subjects | Prophylaxis: 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 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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