Anti-inhibitor Coagulant Complex (Human)

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)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

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.

Use: Off Label

Acquired hemophilia with factor VIII or factor IX inhibitor titers >5 Bethesda units (BU)c

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 associated with non-vitamin K antagonist anticoagulantsyes

Based on the American Heart Association/American Stroke Association (AHA/ASA) Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, the use of anti-inhibitor coagulant complex (human) (ie, activated prothrombin complex concentrate [PCC]) may be considered for the treatment of intracranial hemorrhage associated with dabigatran (if idarucizumab is unavailable) or oral direct factor Xa inhibitors (apixaban, edoxaban, or rivaroxaban) if anti-inhibitor coagulant complex (human) is readily available in the hospital.

More recently, the Neurocritical Care Society and Society of Critical Care Medicine guidelines for reversal of antithrombotics in intracranial hemorrhage have suggested the use of anti-inhibitor coagulant complex (human) or 4-factor prothrombin complex concentrate (human) for patients with intracranial hemorrhage associated with dabigatran (if idarucizumab is unavailable) or oral direct factor Xa inhibitors (eg, apixaban, edoxaban, or rivaroxaban) if intracranial hemorrhage occurred within 3 to 5 terminal half-lives of drug exposure or if liver failure exists. Anti-inhibitor coagulant complex (human) may also be used in patients with intracranial hemorrhage to reverse the effects of full-therapeutic dose pentasaccharides (fondaparinux).

Life-threatening bleeding associated with non-vitamin K antagonist anticoagulantscyes

Data from a limited number of patients studied (multiple case reports) suggests 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 oral direct factor Xa inhibitor mediated anticoagulation Escolar 2013, Fukuda 2012, Halim 2014, Marlu 2012, Perzborn 2014. Additional data may be necessary to further define the role of anti-inhibitor coagulant complex (human) in this setting. Of note, idarucizumab is FDA approved for the reversal of the anticoagulant effects of dabigatran in the event of a life-threatening or uncontrolled bleeding episode.

Based on the Updated European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Anticoagulants in Patients with Non-Valvular Atrial Fibrillation and the American College of Cardiology 2017 Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants, the use of anti-inhibitor coagulant complex (human) may be considered for the treatment of life-threatening bleeding associated with dabigatran (if idarucizumab is not available) or oral direct factor Xa inhibitors (apixaban, edoxaban, or rivaroxaban) if anti-inhibitor coagulant complex (human) is readily available in the hospital.

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)

Dosage and Administration

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 associated with non-vitamin K antagonist anticoagulants (off-label use): IV: NCS/SCCM (Frontera 2016):

Oral direct factor Xa inhibitor-mediated (apixaban, edoxaban, rivaroxaban): 50 units/kg if ICH occurred within 3 to 5 terminal half-lives of drug exposure or when liver failure co-exists.

Direct thrombin inhibitor-mediated (argatroban, dabigatran [if idarucizumab unavailable], bivalirudin, desirudin): 50 units/kg if direct thrombin inhibitor was administered within a period of 3 to 5 half-lives prior and there is no evidence of renal failure or there is renal impairment leading to drug exposure beyond 3 to 5 half-lives.

Pentasaccharide-mediated (fondaparinux)(full therapeutic dose): 20 units/kg. Note: In patients receiving fondaparinux for venous thromboembolism prophylaxis (ie, not a full therapeutic dose), the NCS/SCCM guidelines suggest against reversal unless there is evidence of bioaccumulation or impaired clearance.

Life-threatening bleeding associated with non-vitamin K antagonist anticoagulation (off-label use): IV: Optimal dosing has not been established. Based on multiple case reports with various types of hemorrhage due to either dabigatran or rivaroxaban, a dosage range of 25 to 100 units/kg has been used (Dager 2013; Faust 2014; Kiraly 2013; Maurice-Szamburski 2014; Neyens 2014; Schulman 2014). In 1 case study, after administration of 26 units/kg, an additional dose of 16 units/kg was administered for a concern of rebleeding (Dager 2013). Note: The use of anti-inhibitor coagulant complex (FEIBA, activated 4-factor PCC) may be associated with a higher risk of thrombosis compared to nonactivated PCCs especially with higher doses; monitor closely for arterial and venous thrombosis.

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, type and level of inhibitors, and whether the patient has a history of an anamnestic increase in antihemophilic inhibitor levels following use of preparations containing antihemophilic factor. Maximum dose should only be exceeded if bleeding severity warrants; monitor closely for DIC, 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

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 ≤25°C (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

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

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

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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions for more detailed information.

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

Pregnancy Considerations

Animal reproduction studies have not been conducted.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience fatigue, diarrhea, nausea, vomiting, or change in taste. Have patient report immediately to prescriber signs of blood clots (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), signs of parvovirus B19 or hepatitis A infection (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, signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.