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Anti-inhibitor Coagulant Complex (Human)

Medically reviewed by Drugs.com. Last updated on Sep 9, 2020.

Pronunciation

(an TEE in HI bi tor coe AG yoo lant KOM pleks HYU man)

Index Terms

  • Activated PCC
  • AICC
  • aPCC
  • Coagulant Complex Inhibitor
  • Factor Eight Inhibitor Bypassing Activity
  • Factor VIII Inhibitor Bypassing Activity
  • FEIBA NF
  • FEIBA VH

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

FEIBA: 500 units (1 ea); 1000 units (1 ea); 2500 units (1 ea)

Brand Names: U.S.

  • FEIBA

Pharmacologic Category

  • Activated Prothrombin Complex Concentrate (aPCC)
  • Antihemophilic Agent
  • Blood Product Derivative

Pharmacology

Multiple interactions of the components in anti-inhibitor coagulant complex restore the impaired thrombin generation of hemophilia patients with inhibitors. In vitro, anti-inhibitor coagulant complex shortens the activated partial thromboplastin time of plasma containing factor VIII inhibitor.

Onset of Action

Peak thrombin generation: Within 15 to 30 minutes (Varadi 2003)

Duration of Action

8 to 12 hours (based on thrombin generation) (Varadi 2003)

Half-Life Elimination

4 to 7 hours (based on thrombin generation) (Varadi 2003)

Use: Labeled Indications

Hemorrhage in patients with hemophilia: Control and prevention of bleeding episodes in patients with hemophilia A and B with inhibitors.

Perioperative bleeding management in patients with hemophilia: Perioperative bleeding management in patients with hemophilia A and B with inhibitors.

Routine prophylaxis of bleeding events in patients with hemophilia: Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A and B with inhibitors.

Off Label Uses

Acquired hemophilia with factor VIII or factor IX inhibitor titers >5 Bethesda units

Data from a retrospective evaluation in patients treated with anti-inhibitor coagulant complex (human) who had autoantibodies to factor VIII suggests that anti-inhibitor coagulant complex (human) may be beneficial for the treatment of this condition [Sallah 2004]. Additional data may be necessary to further define the role of anti-inhibitor coagulant complex (human) in this condition.

Based on international recommendations on the diagnosis and treatment of patients with acquired hemophilia A, the use of anti-inhibitor coagulant complex (human) is effective and recommended for the treatment of severe bleeding in patients with this condition [Huth-Kuhne 2009].

Intracranial hemorrhage, pentasaccharide-mediated (eg, fondaparinux) (full-therapeutic dose)

Based on the Neurocritical Care Society and Society of Critical Care Medicine guidelines for reversal of antithrombotics in intracranial hemorrhage, use of anti-inhibitor coagulant complex (human) or 4-factor prothrombin complex concentrate (human) is suggested for patients with intracranial hemorrhage associated with full-therapeutic dose pentasaccharides (eg, fondaparinux) [Cuker 2019].

Life-threatening bleeding associated with non-vitamin K antagonists

Data from a limited number of patients (multiple case reports) suggest that anti-inhibitor coagulant complex (human) may be beneficial in the treatment of life-threatening bleeding associated with dabigatran [Dager 2013], [Faust 2014], [Kiraly 2013], [Neyens 2014], [Schulman 2014] or rivaroxaban [Kiraly 2013], [Maurice-Szamburski 2014]. In addition, in vitro and ex vivo data evaluating the effect of anti-inhibitor coagulant complex (human) on various coagulation parameters affected by apixaban, edoxaban, or rivaroxaban suggests that anti-inhibitor coagulant complex (human) may be effective in the reversal of these agents [Escolar 2013], [Fukuda 2012], [Halim 2014], [Marlu 2012], [Perzborn 2014].

Based on the Anticoagulation Forum guidance document on the reversal of direct oral anticoagulants, use of anti-inhibitor coagulant complex (human) (ie, activated prothrombin complex concentrate) may be considered for the treatment of life-threatening bleeding associated with dabigatran if idarucizumab is unavailable [Cuker 2019]. The American College of Cardiology Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants gives similar recommendations regarding dabigatran reversal and also suggests that anti-inhibitor coagulant complex (human) may be considered as a second line therapy for reversal of oral direct factor Xa inhibitors (apixaban, edoxaban, or rivaroxaban) [ACC [Tomaselli 2020]].

Reversal of dabigatran in patients who require urgent procedure (if idarucizumab unavailable)

Clinical experience suggests the utility of anti-inhibitor coagulant complex (human) (if idarucizumab is not available) for the reversal of dabigatran in patients who require urgent surgical procedures when the procedure cannot safely be performed while the patient is anticoagulated or cannot be delayed [Baugh 2019].

Based on the Reversal of Direct Oral Anticoagulants: Guidance from the Anticoagulation Forum, anti-inhibitor coagulant complex (human) may be effective for the reversal of dabigatran (if idarucizumab is not available) in patients who require urgent surgical procedures when the procedure cannot safely be performed while the patient is anticoagulated or cannot be delayed [Cucker 2019].

Contraindications

Known anaphylactic or severe hypersensitivity to anti-inhibitor coagulant complex or any component of the formulation, including factors of the kinin generating system; disseminated intravascular coagulation (DIC); acute thrombosis or embolism (including myocardial infarction)

Dosing: Adult

Note: Anti-inhibitor coagulant complex (Human) contains mainly non-activated therapeutic levels of factors II, IX, and X and mainly activated factor VII

Control and prevention of bleeding episodes in patients with hemophilia: IV: Note: Considered a first-line treatment when factor VIII inhibitor titer is >5 Bethesda units (BU) (antihemophilic factor may be preferred when titer <5 BU).

General dosing guidelines: 50 to 100 units/kg/dose. Dosage and duration of treatment depend on the location and extent of bleeding and clinical condition of the patient.

Joint hemorrhage: 50 to 100 units/kg every 12 hours until pain and acute disabilities are improved (maximum: 100 units/kg/dose; 200 units/kg/day).

Mucous membrane bleeding: 50 to 100 units/kg every 6 hours for at least 1 day or until bleeding is resolved (maximum: 100 units/kg/dose; 200 units/kg/day).

Soft tissue hemorrhage (eg, retroperitoneal bleed): 100 units/kg every 12 hours until resolution of bleed (maximum: 100 units/kg/dose; 200 units/kg/day).

Other severe hemorrhage (eg, intracranial hemorrhage): 100 units/kg every 6 to 12 hours; continue until resolution of bleed (maximum: 100 units/kg/dose; 200 units/kg/day).

Perioperative management:

Preoperative: 50 to 100 units/kg (single dose) administered immediately prior to surgery.

Postoperative: 50 to 100 units/kg every 6 to 12 hours until resolution of bleed and healing is achieved (maximum: 100 units/kg/dose; 200 units/kg/day).

Routine prophylaxis: 85 units/kg every other day.

Hemorrhage (moderate to severe) due to acquired hemophilia (off-label use): IV: Optimal dosing has not been established: 50 to 100 units/kg every 8 to 12 hours until bleeding controlled has been suggested; may continue for 24 to 72 hours based on site, type, and severity of bleeding (maximum: 200 units/kg/day) (Huth-Kuhne 2009; Sallah 2004).

Intracranial hemorrhage, pentasaccharide-mediated (eg, fondaparinux) (full-therapeutic dose) (off-label use): IV:

20 units/kg. Note: In patients receiving fondaparinux for venous thromboembolism prophylaxis (ie, not a full therapeutic dose), the Neurocritical Care Society and Society of Critical Care Medicine guidelines suggest against reversal unless there is evidence of bioaccumulation or impaired clearance (NCS/SCCM [Frontera 2016]).

Life-threatening bleeding associated with non-vitamin K antagonists (off-label use): Note: Generally used for life-threatening bleeding or bleeding into a critical organ that is not controlled with maximal supportive measures (Baugh 2019; Cuker 2019). The use of anti-inhibitor coagulant complex may be associated with a higher risk of thrombosis compared to nonactivated prothrombin complex concentrate, especially with higher doses; monitor closely for arterial and venous thrombosis.

Oral direct factor Xa inhibitor-mediated (apixaban, betrixaban, edoxaban, rivaroxaban [if andexanet alfa unavailable]): IV: 50 units/kg once, in addition to other supportive measures as clinically indicated (eg, activated charcoal [if ingestion is within 2 to 4 hours], antifibrinolytic agent) (ACC [Tomaselli 2020]; Baugh 2019; NCS/SCCM [Frontera 2016]).

Direct thrombin inhibitor-mediated (argatroban, dabigatran, bivalirudin, desirudin [if idarucizumab unavailable]): IV: 50 units/kg once, in addition to other supportive measures as clinically indicated (eg, activated charcoal [if ingestion is within 2 to 4 hours], hemodialysis, antifibrinolytic agent) (ACC [Tomaselli 2020]; Cuker 2019; NCS/SCCM [Frontera 2016]).

Reversal of dabigatran in patients who require urgent procedure (if idarucizumab unavailable) (off-label use): Note: Reversal agent should be administered only if the procedure cannot safely be performed while the patient is anticoagulated or cannot be delayed (Cuker 2019).

IV: 50 units/kg once (Cuker 2019).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Anti-inhibitor coagulant complex (Human) contains mainly nonactivated therapeutic levels of factors II, IX, and X and mainly activated factor VII. Dosage is expressed in units of factor VIII inhibitor bypassing activity and is dependent upon the severity and location of bleeding. Maximum dose should only be exceeded if bleeding severity warrants; monitor closely for disseminated intravascular coagulation, coronary ischemia and/or signs and symptoms of other thromboembolic events.

Control and prevention of bleeding episodes: Infants, Children, and Adolescents: Note: Dosage will vary with the bleeding site and severity.

Joint hemorrhage: IV: 50 to 100 units/kg/dose every 12 hours until pain and acute disabilities are improved; maximum daily dose: 200 units/kg/day.

Mucous membrane bleeding: IV: 50 to 100 units/kg/dose every 6 hours for at least one day or until bleeding is resolved; maximum daily dose: 200 units/kg/day.

Soft tissue hemorrhage (eg, retroperitoneal bleeding): IV: 100 units/kg/dose every 12 hours until resolution of bleed; maximum daily dose: 200 units/kg/day.

Other severe hemorrhages (eg, CNS bleeds): IV: 100 units/kg/dose every 6 to 12 hours until resolution of bleed; maximum daily dose: 200 units/kg/day.

Perioperative management: Infants, Children, and Adolescents:

Preoperative: IV: 50 to 100 units/kg (single dose) administered immediately prior to surgery.

Postoperative: IV: 50 to 100 units/kg/dose every 6 to 12 hours until resolution of bleed and healing is achieved; maximum daily dose: 200 units/kg/day.

Routine prophylaxis: Infants, Children, and Adolescents: IV: 85 units/kg/dose every other day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Reconstitution

If refrigerated, allow the vials of anti-inhibitor coagulant complex (concentrate) and SWFI (diluent) to reach room temperature. Reconstitute with provided SWFI. Swirl to gently dissolve powder; do not shake.

Administration

IV: For IV injection or infusion only; maximum infusion rate: 2 units/kg/minute. A syringe pump may be used to control the rate of administration. Use plastic luer lock syringes (anti-inhibitor coagulant complex may stick to the surface of all-glass syringes); do not administer in the same tubing or container with other medications. Following reconstitution, complete infusion within 3 hours.

Dietary Considerations

Some products may contain sodium.

Storage

Store intact vials at 2°C to 25°C (36°F to 77°F); store in the original package to protect from light. Do not freeze. Following reconstitution, do not refrigerate and administer within 3 hours.

Drug Interactions

Antifibrinolytic Agents: May enhance the thrombogenic effect of Anti-inhibitor Coagulant Complex (Human). Avoid combination

Emicizumab: May enhance the thrombogenic effect of Anti-inhibitor Coagulant Complex (Human). Monitor therapy

Factor VIIa (Recombinant): Anti-inhibitor Coagulant Complex (Human) may enhance the thrombogenic effect of Factor VIIa (Recombinant). Management: Consider avoiding concomitant use of factor VIIa (recombinant) and activated prothrombin concentrates, such as anti-inhibitor coagulant complex (human), due to an increased risk of developing thrombotic events. Consider therapy modification

Test Interactions

Contains blood group isohemagglutinins; passive transmission of antibodies to erythrocyte antigens may interfere with serological tests for red cell antibodies (eg, Coombs test).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.

Cardiovascular: Cerebrovascular accident (embolic/thrombotic stroke), chest discomfort, chest pain, decreased blood pressure, flushing, hypertension, hypotension, myocardial infarction, pulmonary embolism, tachycardia, thromboembolism, thrombosis (arterial thrombosis, venous thrombosis)

Central nervous system: Chills, dizziness, drowsiness, headache, hypoesthesia (including facial), malaise, paresthesia

Dermatologic: Pruritus, skin rash, urticaria

Gastrointestinal: Abdominal distress, diarrhea, dysgeusia, nausea, vomiting

Hematologic & oncologic: Disseminated intravascular coagulation

Hypersensitivity: Angioedema, hypersensitivity reaction (including anaphylaxis)

Immunologic: Antibody development (anamnestic response)

Local: Pain at injection site

Respiratory: Bronchospasm, cough, dyspnea, wheezing

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Thromboembolic events:

Thromboembolic events have been reported during postmarketing surveillance following infusion of anti-inhibitor coagulant complex, particularly following the administration of high doses and/or in patients with thrombotic risk factors. Monitor patients receiving anti-inhibitor coagulant complex for signs and symptoms of thromboembolic events.

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Hypersensitivity and allergic reactions (including severe and systemic reactions [eg, anaphylaxis with urticaria and angioedema, bronchospasm, circulatory shock]) have been observed following administration. Discontinue immediately with signs/symptoms of severe hypersensitivity reactions and provide appropriate supportive care.

• Infusion reactions: Infusion reactions (eg, chills, pyrexia, hypertension) have been reported.

• Thromboembolic events: [US Boxed Warning]: Thromboembolic events (including venous thrombosis, pulmonary embolism, MI, and stroke) have been reported following administration of anti-inhibitor coagulant complex, particularly with administration of high doses and/or in patients with thrombotic risk factors. Monitor patients receiving anti-inhibitor coagulant complex for signs and symptoms of thromboembolic events, especially if more than 200 units/kg/day is administered. Use with caution in patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with factor VIIa. Weigh the potential benefit of treatment against the potential risk of these thromboembolic events. Monitor patients receiving >100 units/kg for the development of DIC, acute coronary ischemia, and signs/symptoms of other thromboembolic events. If clinical signs/symptoms occur, discontinue use. In an emicizumab clinical trial where patients were also administered anti-inhibitor coagulant complex for breakthrough bleeding, there were reported cases of thrombotic microangiopathy (TMA). TMA has not been reported in clinical studies of anti-inhibitor coagulant complex. Use with caution and monitor closely if anti-inhibitor coagulant complex is used in patients receiving emicizumab.

Dosage form specific issues:

• Factor VIII: Product contains minute amounts of factor VIII which may cause an anamnestic response; anamnestic rises were not associated with reduced efficacy.

• Human plasma: Product of human plasma; may potentially contain infectious agents that could transmit disease. During the manufacturing process, screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer and/or to FDA MedWatch. Patients with signs/symptoms of infection (eg, fever, chills, drowsiness) should be encouraged to consult health care provider.

Other warnings/precautions:

• Appropriate use: Not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to factor VIII or factor IX. Use of antifibrinolytics within ~6 to 12 hours after the administration of anti-inhibitor coagulant complex is not recommended.

Monitoring Parameters

Monitor for control of bleeding; signs/symptoms of disseminated intravascular coagulation (DIC), acute coronary ischemia, and thromboembolic events, especially if >100 units/kg is administered; hemoglobin and hematocrit; hypotension; signs/symptoms of hypersensitivity reactions. Note: Tests used to monitor hemostatic efficacy, such as aPTT and TEG, are not useful for monitoring responses with anti-inhibitor coagulant complex (Hoffman 2012). Dosing to normalize these values may result in DIC.

Pregnancy Considerations

Limited outcome information is available from a pregnancy registry following use of anti-inhibitor coagulant complex (human) in pregnant women with acquired hemophilia A (Tengborn 2012). Other products are preferred for the routine prophylaxis of bleeding events in pregnant patients with known hemophilia (NHF 2017; WFH [Srivastava 2013]; RCOG [Pavord 2017]). However, the use of anti-inhibitor coagulant complex (human) may be considered in select patients with bleeding associated with postpartum acquired hemophilia A (a recombinant product may be preferred) (Huth-Kuhne 2009; Kruse-Jarres 2017; Windyga 2019).

Patient Education

What is this drug used for?

• It is used to treat hemophilia.

• It is used to treat or prevent bleeding.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Fatigue

• Diarrhea

• Nausea

• Vomiting

• Change in taste

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.

• Parvovirus B19 or Hepatitis A infection like chills, severe fatigue, runny nose, rash, joint pain, lack of appetite, nausea, vomiting, abdominal pain, or yellow skin.

• Severe dizziness

• Passing out

• Severe loss of strength and energy

• Severe headache

• Vision changes

• Chills

• Joint pain

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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