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.

For intravenous use after reconstitution only.

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.

1.

Allow the vial of FEIBA and Sterile Water for Injection (diluent) to reach room temperature.

2.

Remove the plastic caps from the concentrate and diluent vials.

3.

Wipe the rubber stoppers of both vials with a sterile alcohol swab and allow it to dry prior to use.

4.

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.

5.

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).

6.

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.

7.

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.

8.

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.

9.

Administer FEIBA within 3 hours after reconstitution. Do not refrigerate after reconstitution. Discard unused portion.

2.3 Administration

For intravenous injection or intravenous infusion after reconstitution only.

•

Accidental needle stick with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single- dose use.

•

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.

1.

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).

2.

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).

3.

Ensure that the tight connection between the BAXJECT II Hi-Flow device and the syringe is maintained.

4.

Disconnect the syringe.

5.

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).

FEIBA is available as a lyophilized powder in single-dose glass vials containing nominally 500, 1000, or 2500 units per vial.

•

Known anaphylactic or severe hypersensitivity reactions to FEIBA or any if its components, including factors of the kinin generating system.

•

Disseminated intravascular coagulation (DIC).

•

Acute thrombosis or embolism (including myocardial infarction).

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.

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)]

FEIBA (Anti-Inhibitor Coagulant Complex) is a freeze-dried sterile human plasma fraction with factor VIII inhibitor bypassing activity to be reconstituted for intravenous administration. Factor VIII inhibitor bypassing activity is expressed in arbitrary units. One unit of activity is defined as that amount of FEIBA that shortens the aPTT of high titer factor VIII inhibitor reference plasma to 50% of the blank value.

FEIBA contains mainly non-activated factors II, IX, and X and mainly activated factor VII. It contains approximately equal unitages of factor VIII inhibitor bypassing activity and prothrombin complex factors. In addition, the preparation contains 1-6 units of factor VIII coagulant antigen (FVIII C:Ag) per mL. The product contains traces of factors of the kinin generating system. It contains no heparin. Reconstituted FEIBA contains 4 mg of trisodium citrate and 8 mg of sodium chloride per mL.

FEIBA is manufactured from large 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 is collected 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) Mini-pools of the plasma are tested and found negative for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT).

To reduce the risk of viral transmission, the manufacturing process of FEIBA includes two dedicated and independent virus removal/inactivation steps namely 35 nm nanofiltration and a vapor heat treatment process. In addition, the DEAE-Sephadex adsorption contributes to the virus safety profile of FEIBA.

In vitro spiking studies have been used to validate the capability of the manufacturing process to remove and inactivate viruses. Table 3 summarizes the results of the viral clearance studies for FEIBA.

Control and Prevention of Bleeding Episodes

The efficacy of FEIBA in the treatment of bleeding episodes has been demonstrated by two prospective clinical trials1,2.

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 total of 150 bleeding episodes including 117 joint, 20 musculoskeletal and 4 mucocutaneous bleeds, were treated. 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. 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 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 Bethesda Units 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.

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.

1.

Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP, van Geijlswijk JL, van Houwelingen H, van Asten P, Sixma JJ. The effect of Activated Prothrombin-Complex Concentrate (FEIBA) on joint and muscle bleeding in patients with Hemophilia A and antibodies to Factor VIII. N Engl J Med. 1981;305(13): 717-721.

2.

Hilgartner MW, Knatterud GL. The use of Factor-Eight-Inhibitor-By-Passing-Activity (FEIBA IMMUNO) product for treatment of bleeding episodes in Hemophiliacs with inhibitors. Blood. 1983;61(1): 36-40.

3.

Antunes SV, Tangada S, Stasyshyn O, Mamonov V, Phillips J, Guzman-Becerra N, Grigorian A, Ewenstein B, Wong WY. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2013; DOI 10.1111/hae.12246.

4.

Turecek PL, Varadi K, Gritsch H, Auer W, Pichler L, Eder G, Schwarz HP. Factor Xa and prothrombin: mechanism of action of FEIBA. Vox Sanguinis 1999;77 Suppl 1:72-79.

5.

Turecek PL, Varadi K, Gritch H, Schwarz HP. FEIBA: Mode of action Haemophilia 2004;10: Suppl. 2:3-9

6.

Oldenburg et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017:377:809-818.

How Supplied

FEIBA is available in single-dose vials in the following nominal dosage strengths:

The number of units of factor VIII inhibitor bypassing activity is stated on the label of each vial.

FEIBA is packaged with a suitable volume (10 mL, 20 mL or 50 mL) of Sterile Water for Injection, U.S.P., one BAXJECT II Hi-Flow Needleless Transfer Device, and one Package Insert.

Storage and Handling

•

Store at room temperature, not to exceed 25°C (77°F).

•

Store in the original package in order to protect from light.

•

Do not freeze.

1. Inform patients:
   • of the signs and symptoms of thrombosis, such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling and/or pain. Advise patients to seek immediate medical attention if any of these symptoms occur.
   • of the signs and symptoms of hypersensitivity reactions, such as urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment.
   • that because FEIBA is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
   • if they are on emicizumab prophylaxis therapy and need FEIBA to treat a breakthrough bleeding episode then they must be monitored by their hemophilia treating physician, preferably at the hemophilia 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.

BAXALTA® and FEIBA® are trademarks of Baxalta Incorporated, a wholly-owned, indirect subsidiary of Shire plc.

SHIRE and the Shire Logo are trademarks or registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates.

Baxalta US Inc.
Lexington, MA 02421 USA
U.S. License No. 2020

20 mL size, dried
NDC 64193-424-02
Anti-Inhibitor Coagulant Complex
FEIBA
Nanofiltered & Vapor Heated

Shire

For Intravenous Use After Reconstitution
Contains no preservative

Dosage and Administration: See accompanying package insert.

Storage: Room temperature not to exceed 25°C (77°F). Store in the original package in order to protect from
light.

Reconstitution: Use 20 mL sWFI, U.S.P.; Keep at room temperature not to exceed 25°C (77°F);
Use within 3 hours of reconstitution.

Do Not Freeze

Rx Only

Includes
BAXJECT II Hi-Flow
Needleless Transfer Device

20 mL size, dried
NDC 64193-324-01

Anti-Inhibitor Coagulant Complex
FEIBA
Nanofiltered & Vapor Heated

Shire

For Intravenous Use After Reconstitution
Contains no preservative
Dosage & Administration: See accompanying package insert.
Storage: Room temperature not to exceed 25°C (77°F).
Reconstitution: Use 20 mL sWFI, U.S.P.; Keep at room temperature not to
exceed 25°C (77°F); Use within 3 hours of reconstitution.

0742873
Rx only

20 mL
NDC 52919-006-05
Shire

Sterile Water for Injection, USP
for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been
added. Do not use for intravascular injection without making approximately
isotonic by addition of suitable solute. Discard unused portion.
Rx only

Single dose container
Nonpyrogenic

Single-dose vial
NDC 64193-425-02

Anti-Inhibitor Coagulant Complex
FEIBA
Nanofiltered & Vapor Heated

Shire

For Intravenous Use After Reconstitution
Contains no preservative

Dosage and Administration: See accompanying package insert.

Storage: Room temperature not to exceed 25°C (77°F).
Store in the original package in order to protect from light.

Reconstitution: Use 50 mL sWFI, U.S.P.; Keep at room temperature not to exceed 25°C (77°F);
Use within 3 hours of reconstitution.

Do Not Freeze

Rx Only

Includes
BAXJECT II Hi-Flow
Needleless Transfer Device

50 mL size, dried
NDC 64193-325-01

Anti-Inhibitor Coagulant Complex
FEIBA
Nanofiltered & Vapor Heated

Shire

For Intravenous Use After Reconstitution
Contains no preservative
Dosage & Administration: See accompanying package insert.
Storage: Room temperature not to exceed 25°C (77°F).
Reconstitution: Use 50 mL sWFI, U.S.P.; Keep at room temperature not to
exceed 25°C (77°F); Use within 3 hours of reconstitution.

0742877
Rx only

50 mL
NDC 52919-011-04
Shire

Sterile Water for Injection, USP
for reconstitution of accompanying product
Do not use unless clear. No antimicrobial agent or other substance has been added.
Do not use for intravascular injection without making approximately isotonic by
addition of suitable solute. Discard unused portion.
Rx Only

Single-Dose Container
Nonpyrogenic

Single-dose vial
NDC 64193-426-02
Anti-Inhibitor
Coagulant Complex
FEIBA
Nanofiltered & Vapor Heated

Shire

For Intravenous Use After Reconstitution
Contains no preservative

Dosage and Administration: See accompanying package insert.

Storage: Room temperature not to exceed 25°C (77°F). Store in the original package in
order to protect from light.

Reconstitution: Use 10 mL sWFI, U.S.P.; Keep at room temperature not to exceed 25°C
(77°F); Use within 3 hours of reconstitution.

Do Not Freeze

Rx Only

Includes
BAXJECT II Hi-Flow
Needleless Transfer Device

Single-dose vial
NDC 64193-326-01

Anti-Inhibitor Coagulant Complex
FEIBA
Nanofiltered & Vapor Heated

Shire

For Intravenous Use After Reconstitution
No preservative
Dosage & Administration: See accompanying package insert.
Storage: Room temperature not to exceed 25°C (77°F).
Reconstitution: Use 10 mL sWFI, U.S.P.; Keep at room temperature not
to exceed 25°C (77°F); Use within 3 hours of reconstitution.

0742880
Rx only

10 mL
NDC 52919-005-05
Shire

Sterile Water for Injection, USP
for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been
added. Do not use for intravascular injection without making approximately
isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single-Dose Container
Nonpyrogenic
0742615