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Anti-inhibitor Coagulant Complex

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Mar.08.2023

Anti-inhibitor Coagulant Complex

Indications/Dosage

Labeled

  • bleeding prophylaxis
  • hemarthrosis
  • hemophilia A
  • hemophilia B
  • hemorrhage
  • surgical bleeding

Off-Label

  • dabigatran reversal
  • factor VII deficiency
  • rivaroxaban reversal
  • von Willebrand's disease
† Off-label indication

For the control and prevention of bleeding episodes (i.e., hemorrhage, hemarthrosis), perioperative management (surgical bleeding), and routine bleeding prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or hemophilia B with inhibitors or patients with acquired inhibitors to other factors including patients with factor VII deficiency† or von Willebrand's disease†

NOTE: 1 unit of activity is defined as the amount of FEIBA that shortens the aPTT of high titer factor VIII inhibitor reference plasma to 50% of the blank value.[41546]

NOTE: 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.[41546]

for treatment of joint hemorrhage

Intravenous dosage

Adults 18 to 64 years

50 to 100 units/kg/dose IV every 12 hours until pain and acute disabilities are improved.[41546]

Infants, Children, and Adolescents

50 to 100 units/kg/dose IV every 12 hours until pain and acute disabilities are improved.[41546]

for treatment of mucous membrane bleeding

Intravenous dosage

Adults 18 to 64 years

50 to 100 units/kg/dose IV every 6 hours for at least 1 day or until bleeding is resolved.[41546]

Infants, Children, and Adolescents

50 to 100 units/kg/dose IV every 6 hours for at least 1 day or until bleeding is resolved.[41546]

for the treatment of soft tissue hemorrhage

Intravenous dosage

Adults 18 to 64 years

100 units/kg/dose IV every 12 hours until resolution of bleeding.[41546]

Infants, Children, and Adolescents

100 units/kg/dose IV every 12 hours until resolution of bleeding.[41546]

for the treatment of severe hemorrhage (CNS bleeding)

Intravenous dosage

Adults 18 to 64 years

100 units/kg/dose IV every 6 to 12 hours until resolution of bleeding.[41546]

Infants, Children, and Adolescents

100 units/kg/dose IV every 6 to 12 hours until resolution of bleeding.[41546]

for preoperative management of surgical bleeding

Intravenous dosage

Adults 18 to 64 years

50 to 100 units/kg/dose IV as a single dose immediately prior to surgery.[41546]

Infants, Children, and Adolescents

50 to 100 units/kg/dose IV as a single dose immediately prior to surgery.[41546]

for postoperative management of surgical bleeding

Intravenous dosage

Adults 18 to 64 years

50 to 100 units/kg IV every 6 to 12 hours until resolution of bleeding and healing are achieved.[41546]

Infants, Children, and Adolescents

50 to 100 units/kg/dose IV every 6 to 12 hours until resolution of bleeding and healing are achieved.[41546]

for routine prophylaxis

Intravenous dosage

Adults 18 to 64 years

85 units/kg/dose IV every other day.[41546]

Infants, Children, and Adolescents

85 units/kg/dose IV every other day.[41546]

For rivaroxaban reversal†

Intravenous dosage

Adults

30 units/kg IV over 15 minutes just prior to neurosurgery was reported in 1 geriatric patient receiving rivaroxaban 20 mg daily who developed a subdural hematoma with a midline shift after a fall.[59596]

For dabigatran reversal†

Intravenous dosage

Adults

25 units/kg (rounded to vial size, 27.5 units/kg), 26 units/kg, 42 units/kg, 50 units/kg, or 100 units/kg IV once doses are described in various case reports. Following an initial dose of 26 units/kg IV, a second dose of 16 units/kg IV was administered in a single case due to concerns for rebleeding.[59614] [59615] [59616]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • Adults

    100 units/kg/dose IV or 200 units/kg/day IV.

  • Geriatric

    Safety and efficacy have not been established.

  • Adolescents

    100 units/kg/dose IV or 200 units/kg/day IV.

  • Children

    100 units/kg/dose IV or 200 units/kg/day IV.

  • Infants

    100 units/kg/dose IV or 200 units/kg/day IV.

  • Neonates

    Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

No dosage adjustments are needed.

Patients with Renal Impairment Dosing

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

† Off-label indication
Revision Date: 03/08/2023, 11:42:16 AM

References

41546 - Feiba (anti-inhibitor coagulant complex) package insert. Lexington, MA: Takeda Pharmaceuticals USA, Inc.; 2023 Jun.59596 - Maurice Szamburski A, Graillon T, Bruder N. Favorable outcome after subdural hematoma treated with feiba in a 77-year-old patient treated by rivaroxaban. J Neurosurg Anesthesiol 2014;26:183.59614 - Dager WE, Gosselin RC, Roberts J. Reversing dabigatran in life threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41:e42-6.59615 - Schulman S, Ritchie B, Goy JK, et al. Activated prothrombin complex concentrate for dabigatran associated bleeding. Br J Haematol. 2014;164:308-310.59616 - Faust AC, Peterson EJ. Management of dabigatran-associated intracerebral and intraventricular hemorrhage: a case report. J Emerg Med. 2014;46:525-9.

How Supplied

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA 500units Powder for Injection (64193-0426) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA NF 1000units Powder for Injection (64193-0424) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA NF 2500units Powder for Injection (64193-0425) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA NF 500units Powder for Injection (64193-0423) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA NF Immuno 1000units Powder for Injection (64193-0224) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA NF Immuno 2500units Powder for Injection (64193-0225) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA NF Immuno 500units Powder for Injection (64193-0223) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA VH Immuno 1000units Powder for Injection (64193-0222) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA VH Immuno 2500units Powder for Injection (64193-0222) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

FEIBA VH Immuno 500units Powder for Injection (64193-0222) (Baxalta Inc, a Shire Company) null

Anti-Inhibitor Coagulant Complex Powder for solution for injection

Feiba VH Immuno Powder for Injection (64193-0222) (Baxalta Inc, a Shire Company) (off market)

Description/Classification

Description

Anti-inhibitor coagulant complex (AICC) is derived from human plasma. Anti-inhibitor coagulant complex is similar to prothrombin complex concentrates (PCCs or factor IX complexes), but AICC has undergone in vitro activation resulting in an increased amount of activated and precursor vitamin K-dependent clotting factors (factors II, VII, IX, and X). Anti-inhibitor coagulant complex is used as coagulation factor bypass therapy in patients with hemophilia with inhibitors or in patients with acquired inhibitors to other clotting factors. In patients with high inhibitor titers (more than 10 Bethesda Units) or who rapidly develop inhibitors following exposure to factor products (high responders), AICC provides activated clotting factors and controls bleeding in about 80% to 90% of patients with 1 or 2 doses. FEIBA products contain factors II, IX, and X, which are mainly inactivated, and factor VII, which is mainly activated. FEIBA contains only trace amounts of factors of the kinin generating system and no heparin. The activity of FEIBA is expressed in arbitrary units; 1 unit of activity is defined as the amount of FEIBA that shortens the aPTT of high titer factor VIII inhibitor reference plasma to 50% of the blank value. These products undergo processes that are designed to reduce the risk of infectious contamination.[41546]

Classifications

  • Blood and Blood Forming Organs
    • Antihemorrhagics
      • Hemostatics
        • Blood Coagulation Factors
Revision Date: 10/26/2017, 02:07:43 PM

References

41546 - Feiba (anti-inhibitor coagulant complex) package insert. Lexington, MA: Takeda Pharmaceuticals USA, Inc.; 2023 Jun.

Administration Information

General Administration Information

For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration

  • Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be colorless to slightly yellowish. Do not use if particulate matter or discoloration is observed.[41546]

 

Reconstitution

  • Use aseptic technique throughout the entire reconstitution process. Allow concentrate and diluent vials to reach room temperature.
  • Remove caps from both vials. Wipe the rubber stoppers with a sterile alcohol swab and allow it to dry.
  • Peel away lid of BAXJECT II Hi-Flow device taking care not to touch the inside. Do not remove the device from the package. Do not touch the clear spike.
  • Turn the package over and insert the clear plastic spike through diluent stopper by pressing straight down. Grip the device package at the edges and pull the package off the device. Do not remove the blue protective cap from the 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 device fully into the concentrate vial. The vacuum will draw the diluent into the vial. The connection of the 2 vials should be done quickly to close the open fluid pathway created by the first insertion of the spike to the diluent vial.
  • Gently swirl until completely dissolved. If not dissolved completely, active material will not pass through the device filter. Do not shake.
  • After reconstitution is complete, begin the injection or infusion immediately; administration must be completed within 3 hours after reconstitution.
  • Storage: Do not refrigerate after reconstitution. Discard unused portion.[41546]

Intravenous Administration

  • Flush venous access lines with isotonic saline prior to and after infusion. Do not administer in the same tubing or container with other medicinal products.
  • Use plastic luer-lock syringes. Protein such as anti-inhibitor coagulant complex 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 device by turning the syringe in clockwise direction until stop position.
  • Invert the system so that the dissolved concentrate product is on top and draw the dissolved product into the syringe by pulling the plunger back slowly to avoid foaming. Ensure the tight connection between the device and syringe is maintained.
  • Disconnect the syringe.
  • Attach a suitable needle and inject or infuse intravenously at a rate not to exceed 10 units/kg/minute.[41546]

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 06/13/2023, 07:43:32 PM

    References

    41546 - Feiba (anti-inhibitor coagulant complex) package insert. Lexington, MA: Takeda Pharmaceuticals USA, Inc.; 2023 Jun.

    Adverse Reactions

    Moderate

    • anemia
    • chest pain (unspecified)
    • dyspnea
    • hot flashes
    • hypertension
    • hypotension
    • infusion-related reactions
    • sinus tachycardia
    • wheezing

    Mild

    • chills
    • diarrhea
    • dizziness
    • drowsiness
    • dysgeusia
    • fever
    • flushing
    • headache
    • hypoesthesia
    • infection
    • injection site reaction
    • malaise
    • nausea
    • pruritus
    • urticaria
    • vomiting

    Severe

    • anaphylactoid reactions
    • angioedema
    • bronchospasm
    • disseminated intravascular coagulation (DIC)
    • myocardial infarction
    • pulmonary embolism
    • stroke
    • thromboembolism

    Hypersensitivity and allergic reactions, including severe anaphylactoid reactions, have been reported in patients receiving anti-inhibitor coagulant complex (AICC). 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). Pruritus and wheezing have also been reported during postmarketing use. Discontinue administration immediately and provide appropriate supportive care if signs and symptoms of a severe allergic reaction occurs.[41546]

    Injection site reaction (i.e., injection site pain) has been reported during postmarketing use of anti-inhibitor coagulant complex (AICC). Infusion-related reactions, such as chills, fever, and hypertension, have also been reported.[41546]

    Thromboembolism including venous thrombosis, pulmonary embolism, myocardial infarction, and stroke can occur with anti-inhibitor coagulant complex (AICC), especially after the administration of high doses (more than 200 units/kg/day) and/or in patients with thrombotic risk factors. Disseminated intravascular coagulation (DIC) has been reported with postmarketing use. Monitor patients receiving more than 100 units/kg for the development of DIC, acute coronary ischemia, and signs and symptoms of other thromboembolic events. Discontinue the infusion and initiate appropriate diagnostic and therapeutic measures if symptoms occur.[41546]

    Anti-inhibitor coagulant complex (AICC) products are derived from human plasma donors and carry the possibility of causing iatrogenic infection via blood borne pathogens. The risk with AICC is considered to be low due to the careful screening of plasma donors and manufacturing processes. However, new blood borne pathogens not controlled by present measures can theoretically emerge at any time.[41546]

    Hypoesthesia, dizziness, and drowsiness were reported in clinical trials of anti-inhibitor coagulation complex (AICC) for the treatment of acute bleeding episodes. Headache was reported in 6.7% of subjects receiving 50% reduced volume of AICC at increased infusion rates up to 10 units/kg/minute during postmarketing experience in a clinical trial evaluating the tolerability and safety of infusing reduced volume of AICC at increased rates. Malaise and feeling hot (hot flashes) have been reported with postmarketing use.[41546]

    In a clinical trial of anti-inhibitor coagulant complex (AICC) for prophylaxis, the most frequently reported gastrointestinal-related adverse reactions observed in more than 5% of subjects were diarrhea (5.6%), nausea (5.6%), and vomiting (5.6%). Dysgeusia and nausea were also reported in clinical trials of AICC for acute bleeding episodes. Abdominal discomfort has been reported during postmarketing use.[41546]

    Anemia (5.6%) and hemarthrosis (8.3%) were reported in a clinical trial of anti-inhibitor coagulant complex (AICC) for prophylaxis. Chest pain (unspecified), chest discomfort, and dyspnea were reported during acute bleeding clinical trials. Sinus tachycardia and flushing have been reported during postmarketing use.[41546]

    Revision Date: 06/15/2023, 10:56:59 PM

    References

    41546 - Feiba (anti-inhibitor coagulant complex) package insert. Lexington, MA: Takeda Pharmaceuticals USA, Inc.; 2023 Jun.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • disseminated intravascular coagulation (DIC)
    • myocardial infarction
    • breast-feeding
    • laboratory test interference
    • pregnancy
    • thromboembolism
    • viral infection

    Anti-inhibitor coagulant complex is contraindicated in patients with known anaphylactic or severe hypersensitivity reactions toanti-inhibitor coagulant complex or any of its components, including factors of the kinin generating system.[41546]

    Anti-inhibitor coagulant complex (AICC) is contraindicated in patients with disseminated intravascular coagulation (DIC) and patients with acute thrombosis or embolism, including myocardial infarction. Thromboembolism, including DIC, venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, have been reported following AICC administration. Many of these events occurred after high doses (more than 200 units/kg/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 thrombosis due to predisposing coagulopathy or circulating tissue factor. Potential benefit of treatment with AICC should be weighed against risk for thromboembolic event. Monitor patients receiving AICC more than 100 units/kg for signs and symptoms of DIC, acute coronary ischemia, and other thromboembolic events. If signs or symptoms such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling and/or pain occur, discontinue the AICC infusion and initiate appropriate diagnostic and therapeutic measures.[41546]

    Anti-inhibitor coagulant complex (AICC) is derived from human plasma and may therefore carry a risk of transmitting viral infection, and theoretically, the Creutzfeldt-Jakob disease agent. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents; however, none of the processes are completely effective. All infections thought to have been transmitted by AICC should be reported to the manufacturer and/or the FDA (1-800-FDA-1088 or www.fda.gov/medwatch).[41546]

    Anti-inhibitor coagulant complex (AICC) contains blood group isohemagglutinins (anti-A and anti-B). Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D, may cause laboratory test interference with some serological tests for red cell antibodies, such as antiglobulin test (Coombs test).[41546]

    It is not known whether anti-inhibitor coagulant complex (AICC) can cause fetal harm or affect reproduction capacity when administered during pregnancy. There are no data with AICC use in pregnant women to determine a drug-associated risk. There are no adequate and well-controlled studies with AICC in pregnant women and animal reproduction studies have not been conducted.[41546]

    There is no information regarding the presence of anti-inhibitor coagulant complex (AICC) in human milk, the effect on the breast-fed child, or the effects on milk production. Consider the benefits of breast-feeding along with the mother's clinical need for AICC and any potential adverse effects on the breast-fed child from AICC or the underlying maternal condition.[41546]

    Revision Date: 06/18/2023, 04:16:01 PM

    References

    41546 - Feiba (anti-inhibitor coagulant complex) package insert. Lexington, MA: Takeda Pharmaceuticals USA, Inc.; 2023 Jun.

    Mechanism of Action

    Anti-inhibitor coagulant complex (AICC) provides activated coagulation factors to restore hemostasis in patients with inhibitors to certain coagulation factors. The actual active component of AICC has not been identified and may include activated factor VII, activated factor X with or without phospholipid or a combination of factors. Anti-inhibitor coagulant complex may induce a hypercoagulable state leading thrombosis or disseminated intravascular coagulation due to the administration of activated factors, presence of circulating tissue factor and the underlying coagulopathy. Administration of AICC results in changes in coagulation parameters, most notably prothrombin time (PT); however, the degree of change may not reflect the actual clinical effect.

    Revision Date: 06/23/2015, 10:27:25 AM

    References

    Pharmacokinetics

    Anti-inhibitor coagulant complex (AICC) is administered intravenously. The onset of activity is dependent upon the amount of activated factor present, type of inhibitor present, and the half-lives of the factors. The half-lives of the factors present in AICC are as follows: factor II, more than 60 hours; factor VII, 4 to 6 hours; factor IX, 20 to 24 hours; and factor X, 48 to 72 hours.

    Revision Date: 10/26/2017, 02:15:24 PM

    Pregnancy/Breast-feeding

    pregnancy

    It is not known whether anti-inhibitor coagulant complex (AICC) can cause fetal harm or affect reproduction capacity when administered during pregnancy. There are no data with AICC use in pregnant women to determine a drug-associated risk. There are no adequate and well-controlled studies with AICC in pregnant women and animal reproduction studies have not been conducted.[41546]

    breast-feeding

    There is no information regarding the presence of anti-inhibitor coagulant complex (AICC) in human milk, the effect on the breast-fed child, or the effects on milk production. Consider the benefits of breast-feeding along with the mother's clinical need for AICC and any potential adverse effects on the breast-fed child from AICC or the underlying maternal condition.[41546]

    Revision Date: 06/13/2023, 07:15:21 PM

    References

    41546 - Feiba (anti-inhibitor coagulant complex) package insert. Lexington, MA: Takeda Pharmaceuticals USA, Inc.; 2023 Jun.

    Interactions

    Level 2 (Major)

    • Aminocaproic Acid
    • Factor VIIa, Recombinant
    • Tranexamic Acid

    Level 3 (Moderate)

    • Emicizumab
    Aminocaproic Acid: (Major) Use of aminocaproic acid within approximately 6 to 12 hours after the administration of anti-inhibitor coagulant complex (human) is not recommended, due to the increased risk of thrombosis. [28471] [41546] Emicizumab: (Moderate) Consider the benefits and risks if anti-inhibitor coagulant complex (human), also known as activated prothrombin complex concentrate (aPCC), must be used in a patient receiving emicizumab. If aPCC is used, monitor for thrombotic microangiopathy (TMA) and thrombosis. Discontinue aPCC and interrupt emicizumab if clinical symptoms or laboratory findings consistent with TMA or thrombosis occur and manage as clinically indicated. Consider the benefits and risks of resuming emicizumab after resolution of TMA or thrombosis on a case-by-case basis. TMA and thrombotic events have been reported when, on average, a cumulative amount of more than 100 units/kg/24 hours of aPCC was administered for 24 hours or more to patients receiving emicizumab. The potential for interaction may persist for up to 6 months after the last emicizumab dose. [62628] Factor VIIa, Recombinant: (Major) Avoid concomitant use of recombinant factor VIIa and activated prothrombin complex concentrates (aPCCs) due to the increased risk for thrombotic events. [30132] Tranexamic Acid: (Major) Use of tranexamic acid within approximately 6 to 12 hours after the administration of anti-inhibitor coagulant complex (human) is not recommended, due to the increased risk of thrombosis. [37613] [41546]
    Revision Date: 09/29/2023, 01:50:00 AM

    References

    28471 - Amicar (aminocaproic acid) oral solution and tablets package insert. Marietta, GA: Clover Pharmaceuticals Corp.; 2015 May.30132 - NovoSeven RT (coagulation factor VIIa, recombinant) package insert. Princeton, NJ: Novo Nordisk, Inc.; 2020 July.37613 - Lysteda (tranexamic acid) package insert. Parsippany, NJ: Ferring Pharmaceuticals Inc.; 2020 Dec.41546 - Feiba (anti-inhibitor coagulant complex) package insert. Lexington, MA: Takeda Pharmaceuticals USA, Inc.; 2023 Jun.62628 - Hemlibra (emicizumab) injection package insert. South San Francisco, CA: Genentech, Inc.; 2024 Jan.

    Monitoring Parameters

    • activated partial thromboplastin time (APTT)
    • clotting inhibitor titers

    US Drug Names

    • FEIBA
    • FEIBA NF
    • Feiba NF Immuno
    • FEIBA VH Immuno
    ;