Clotting Factors

Number: 0131

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses clotting factors for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of clotting factors is required of all Aetna participating providers and members in applicable plan designs. For precertification of clotting factors, call Aetna's Special Case Precert Unit at (855) 888-9046.

Factor VIII Products: Advate, Adynovate, Afstyla, Alphanate, Altuviiio, Eloctate, Esperoct, Hemofil M, Humate-P, Jivi, Koate, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate or Xyntha

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval
1. Hemophilia A
  
  Aetna considers Advate, Adynovate, Afstyla, Alphanate, Altuviiio, Eloctate, Esperoct, Hemofil M, Humate-P, Koate, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate or Xyntha medically necessary for treatment of hemophilia A when either of the following criteria is met:
  1. Member has mild disease (see Appendix A) and has had an insufficient response to desmopressin or a documented clinical reason for not using desmopressin (see Appendix B); or
  2. Member has moderate or severe disease (see Appendix A).
  Aetna considers Jivi medically necessary for treatment of hemophilia A when both of the following criteria are met:
  1. Member has previously received treatment for hemophilia A with a factor VIII product; and
  2. Member is 12 years of age or older.
2. Von Willebrand Disease (VWD)
  
  Aetna considers Alphanate, Humate-P or Koate medically necessary for treatment of VWD when any of the following criteria is met:
  1. Member has type 1, 2A, 2M, or 2N VWD and has had an insufficient response to desmopressin or a documented clinical reason for not using desmopressin (see Appendix B); or
  2. Member has type 2B or type 3 VWD.
3. Acquired Hemophilia A
  
  Aetna considers Advate, Alphanate, Hemofil M, Humate-P, Koate, Kogenate FS, Novoeight, Recombinate or Xyntha medically necessary for treatment of acquired hemophilia A.
4. Acquired von Willebrand Syndrome
  
  Aetna considers Alphanate or Humate-P medically necessary for treatment of acquired von Willebrand syndrome.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section II when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Anti-inhibitor Coagulant Complex [Human] (FEIBA)

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval

Aetna considers anti-inhibitor coagulant complex [human] (FEIBA) medically necessary for the treatment of the following indications:
1. Hemophilia A with inhibitors (see Appendix C) when the inhibitor titer is greater than or equal to 5 Bethesda units per milliliter (BU/mL) or if the member has a history of an inhibitor titer greater than or equal to 5 BU; or
2. Hemophilia B with inhibitors (see Appendix C) when the inhibitor titer is greater than or equal to 5 Bethesda units per milliliter (BU/mL) or if the member has a history of an inhibitor titer greater than or equal to 5 BU; or
3. Acquired Hemophilia A.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section II when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Antihemophilic Factor [Recombinant], Porcine Sequence (Obizur)

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval

Acquired hemophilia A

Aetna considers antihemophilic factor [recombinant], porcine sequence (Obizur), medically necessary for treatment of acquired hemophilia A.

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continued treatment medically necessary for all members (including new members) requesting reauthorization for an indication listed in Section II who meet all initial authorization criteria.

Factor IX Products: coagulation factor IX [recombinant], glycoPEGylated (Rebinyn); coagulation factor IX [recombinant], albumin fusion protein (Idelvion); coagulation factor IX [recombinan], Fc fusion protein (Alprolix); coagulation factor IX [recombinant] Benefix, Ixinity, Rixubis; and coagulation factor IX [human] (Alphanine SD)

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval

Aetna considers these Factor IX and rFIXFc products medically necessary for treatment of hemophilia B.

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section II when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Factor IX Complex [Human] (Profilnine)

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval

Aetna considers human factor IX complex (Profilnine) medically necessary for treatment of the following indications:
1. Hemophilia B;
2. Bleeding due to low levels of liver-dependent coagulation factors;
3. Factor II deficiency.
Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section II when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Emicizumab-kxwh (Hemlibra)

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval

Hemophilia A (congenital factor VIII deficiency)

Aetna considers emicizumab-kxwh (Hemlibra) medically necessary for treatment of hemophilia A (congenital factor VIII deficiency), when all of the following criteria are met:
1. Member must be using the requested medication for routine prophylaxis to prevent or reduce the frequency of bleeding episodes; and
2. Member meets one of the following criteria:
  1. Member has mild disease (see Appendix A) and has had an insufficient response to desmopressin or a documented clinical reason for not using desmopressin (see Appendix B); or
  2. Member has moderate or severe disease (see Appendix A).
3. Prophylactic use of factor VIII products (e.g., Advate, Adynovate, Eloctate) will be discontinued after the first week of starting therapy with the requested medication.
Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section II when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds) and member is not using the requested medication in combination with factor VIII products (e.g., Advate, Adynovate, Eloctate, etc.) for prophylactic use.

Recombinant von Willebrand Factor (Vonvendi)

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval

Von Willebrand Disease

Aetna considers recombinant von Willebrand factor (Vonvendi) medically necessary for von Willebrand disease (VWD) when any of the following criteria is met:
1. Member has type 1, 2A, 2M, or 2N VWD and has had an insufficient response to desmopressin or a documented clinical reason for not using desmopressin (see Appendix); or
2. Member has type 2B or type 3 VWD.
Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continued treatment medically necessary in all members (including new members) requesting reauthorization for an indication lised in Section II when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

von Willebrand Factor/Coagulation Factor VIII Complex (human) (Wilate)

Prescriber Specialties

Must be prescribed by or in consultation with a hematologist.
Criteria for Initial Approval
1. Aetna considers von Willebrand factor/coagulation factor VIII complex (human) (Wilate) medically necessary for Von Willebrand Disease (VWD) when either of the following criteria is met:
  1. Member has type 1, 2A, 2M, or 2N VWD and has had an insufficient response to desmopressin or a documented clinical reason for not using desmopressin (see Appendix); or
  2. Member has type 2B or type 3 VWD.
2. Aetna considers von Willebrand factor/coagulation factor VIII complex (human) (Wilate) medically necessary for acquired von Willebrand Syndrome.
3. Aetna considers von Willebrand factor/coagulation factor VIII complex (human) (Wilate) medically necessary for Hemophilia A when the requested medication will be used for either of the following:
  1. Member has mild disease (Appendix A) and has had an insufficient response to desmopressin or a documented clinical reason for not using desmopressin (see Appendix B); or
  2. Member has moderate or severe disease (see Appendix A).
Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continued treatment medically necessary in all members (including new members) requesting reauthorization for an indication listed in Section II when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Coagulation Factor VIIa [Recombinant] (rFVIIa), (NovoSeven RT), Coagulation Factor VIIa [Recombinantt]-jncw, (rFVIIa) (Sevenfact)

NovoSeven RT (coagulation factor VIIa [recombinant])
1. Prescriber Specialties
  
  Must be prescribed by or in consultation with a hematologist.
2. Criteria for Initial Approval
  
  Aetna considers coagulation factor VIIa [recombinant], (NovoSeven RT) medically necessary for the treatment of the following indications:
  1. Acquired hemophilia; or
  2. Acquired von Willebrand syndrome when other therapies failed to control the member’s condition (e.g., desmopressin or factor VIII/von Willebrand factor); or
  3. Congenital factor VII deficiency; or
  4. Glanzmann’s thrombasthenia; or
  5. Hemophilia A with inhibitors (see Appendix C) when the inhibitor titer is greater than or equal to 5 Bethesda units per milliliter (BU/mL) or the member has a history of an inhibitor titer greater than or equal to 5 BU; or
  6. Hemophilia B with inhibitors (see Appendix C) when the inhibitor titer is greater than or equal to 5 Bethesda units per milliliter (BU/mL) or the member has a history of an inhibitor titer greater than or equal to 5 BU; or
  7. Inhibitors to factor XI
  Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
3. Continuation of Therapy
  
  Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section IB when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).
Sevenfact (coagulation factor VIIa [recombinant]-jncw)
1. Exclusions
  
  Aetna considers coverage will not be provided for members less than 12 years of age.
2. Criteria for Initial Approval
  
  Aetna considers coagulation factor VIIa [recombinant]-jncw, (Sevenfact) medically necessary for the treatment of the following indications:
  1. Hemophilia A with inhibitors (see Appendix C) when the inhibitor titer is greater than or equal to 5 Bethesda units per milliliter (BU/mL) or the member has a history of an inhibitor titer greater than or equal to 5 BU; or
  2. Hemophilia B with inhibitors (see Appendix C) when the inhibitor titer is greater than or equal to 5 Bethesda units per milliliter (BU/mL) or the member has a history of an inhibitor titer greater than or equal to 5 BU.
  Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
3. Continuation of Therapy
  
  Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section IIB when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Factor X (Coagadex)

Criteria for Initial Approval

Aetna considers Factor X (Coagadex) medically necessary for Hereditary Factor X Deficiency for:
1. Prophylaxis to reduce the frequency of bleeding episodes; or
2. On-demand treatment and control of bleeding episodes; or
3. Perioperative management of bleeding in members with mild or moderate hereditary Factor X deficiency (i.e., baseline Factor X assay level greater than or equal to 1 %).
Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continued treatment medically necessary for the following indications:
1. Perioperative management of bleeding for all members (including new members) requesting authorization for continuation of therapy must meet all initial authorization criteria;
2. All other indications for members requesting reauthorization for an indication listed in Section I when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Factor XIII Concentrate [Human] (Corifact)

Criteria for Initial Approval

Aetna considers Factor XIII concentrate [human] (Corifact) medically necessary for treatment of factor XIII deficiency.

Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section I when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Prothrombin Complex Concentrate (Human) (Kcentra)

Criteria for Initial Approval

Acquired Coagulation Factor Deficiency

Aetna considers prothrombin complex concentrate (human) (Kcentra) medically necessary for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA, e.g., Warfarin) therapy when the member has acute major bleeding or is undergoing an urgent surgery or invasive procedure.

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continued treatment medically necessary in all members (including new members) requesting reauthorization for a medically necessary indication who meet all initial selection criteria.

Recombinant Coagulation Factor XIII A-Subunit (Tretten)

Criteria for Initial Approval

Congenital Factor XIII A-Subunit Deficiency

Aetna considers recombinant coagulation Factor XIII A-subunit (Tretten) medically necessary for prophylaxis of bleeding in members with congenital factor XIII A-subunit deficiency.

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continued treatment medically necessary in members requesting reauthorization for an indication listed in Section I when the member is experiencing benefit from therapy (e.g., reduced frequency or severity of bleeds).

Antithrombin [Recombinant] (ATryn) and Antithrombin III [Human] (Thrombate III)

Criteria for Initial Approval
1. Hereditary antithrombin deficiency in connection with obstetrical procedures, or surgical procedures
  
  Aetna considers antithrombin [recombinant] (ATryn) or antithrombin III [human] (Thrombate III) medically necessary for hereditary antithrombin deficiency for either of the following indications:
  1. Prevention of peri-operative (i.e., surgical procedures) thromboembolism; or
  2. Prevention of peri-partum (i.e., obstetrical procedures) thromboembolism.
2. Hereditary antithrombin deficiency in connection with thromboembolism
  
  Aetna considers antithrombin III [human] (Thrombate III) medically necessary for treatment and prevention of thromboembolism in members with hereditary antithrombin deficiency.
3. Acquired antithrombin deficiency
  
  Aetna considers antithrombin III [human] (Thrombate III) medically necessary for acquired antithrombin deficiency when both of the following criteria are met:
  1. Member has a condition associated with low levels of antithrombin III (e.g., disseminated intravascular coagulation (DIC) associated with sepsis or trauma, liver failure, asparaginase-induced antithrombin deficiency); and
  2. Antithrombin III [human] (Thrombate III) will be used for the treatment or prophylaxis of thromboembolism.
4. Heparin resistance
  
  Aetna considers antithrombin [recombinant] (ATryn) or antithrombin III [human] (Thrombate III) medically necessary for treatment of heparin resistance prior to and during cardiopulmonary bypass (CPB).
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy

Aetna considers continuation of therapy with antithrombin [recombinant] (ATryn) or antithrombin III (human) (Thrombate III) therapy medically necessary for all members (including new members) for an indication listed in Section I who meet all initial selection criteria.

Factor Xa [(recombinant), inactivated-zhzo] (Andexxa)

Criteria for Initial Approval

Reversal of direct-acting oral anticoagulation due to life-threatening or uncontrolled bleeding

Aetna considers coagulation factor Xa [(recombinant), inactivated-zhzo] (Andexxa) medically necessary for members treated with rivaroxaban, apixaban, edoxaban, or betrixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continuation with coagulation Factor Xa [(recombinant), inactivated-zhzo] (Andexxa) therapy medically necessary for all members (including new members) for an indication listed in Section I who meet all initial selection criteria.

Idarucizumab (Praxbind)

Criteria for Initial Approval

Reversal of the anticoagulation effects of dabigatran

Aetna considers idarucizumab (Praxbind) medically necessary for members treated with dabigatran, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding or for emergency surgery or urgent procedures

Aetna considers all other indications as experimental and investigational.
Continuation of Therapy

Aetna considers continuation of therapy with idarucizumab (Praxbind) therapy medically necessary for all members (including new members) for an indication listed in Section I who meet all initial selection criteria.

Note: This policy applies only to clotting factor products available through pharmaceutical suppliers. Cryoprecipitated clotting factors are available only through blood banks and have slightly different indications.

Diagnostic Testing for von Willebrand Disease (VWD)

von Willebrand Factor-Collagen Binding (VWF:CB)/VWF:Ag (the ratio of VWF collagen binding to antigen) Assay

Aetna considers VWF:CB/VWF:Ag assay medically necessary to diagnose type 2 VWD for a member suspected of type 2A, 2B, or 2M in need of additonal testing.
von Willebrand Factor-Factor VIII (VWF:FVIII) Binding Assay

Aetna considers VWF:FVIII binding assay medically necessary to diagnose type 2N VWD for a member suspected of type 2N VWD.
Platelet-Binding Activity of von Willebrand Factor (VWF) Assay

Aetna considers platelet-binding activity of VWF (e.g., [VWF:GPIbM], [VWF:GPIbR]) assay medically necessary for the diagnosis of VWD in a member suspected of VWD.

Note: For genetic testing related to von Willebrand disease (VWD), see CPB 0140 - Genetic Testing

Dosage and Administration

Recombinant Factor VIII Concentrates

Advate

Advate is available as a lyophilized powder in single-use vials containing nominally 250, 500, 1000, 1500, 2000, 3000 or 4000 IU.

For intravenous injection after reconstitution only.

Each vial of Advate contains the labeled amount of recombinant factor VIII in International Units (IU).

Control and prevention of bleeding episodes and perioperative management:
- Dose (IU) = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL).
- Determine treatment frequency based on type of bleeding episode.
Routine Prophylaxis:
- 20 to 40 IU per kg every other day (3 to 4 times weekly).
- Alternatively, use every third day dosing regimen targeted to maintain FVIII trough levels ≥ 1%.

Source: Baxalta, 2018

Afstyla

Afstyla is available as a white or slightly yellow lyophilized powder supplied in singledose vials containing nominally 250, 500, 1000, 1500, 2000, 2500, or 3000 International Units (IU).

For intravenous use after reconstitution only.

Each vial of Afstyla is labeled with the amount of recombinant Factor VIII in international units (IU or unit). One unit per kilogram body weight will raise the Factor VIII level by 2 IU/dL.

Routine Prophylaxis
- Adults and adolescents (≥12 years): The recommended starting regimen is 20 to 50 IU per kg of Afstyla administered 2 to 3 times weekly.
- Children (<12 years): The recommended starting regimen is 30 to 50 IU per kg of Afstyla administered 2 to 3 times weekly. More frequent or higher doses may be required in children <12 years of age to account for the higher clearance in this age group.
- The regimen may be adjusted based on individual's response.
Perioperative Management
- Ensure the appropriate Factor VIII activity level is achieved and maintained.

Source:CSL Behring, 2021

Kogenate FS

Kogenage FS is available as lyophilized powder in single use vials containing nominally 250, 500, 1000, 2000, and 3000 IU. Kogenate FS is provided with a sterile vial adapter with 15-micrometer filter and a prefilled diluent syringe, which together serve as an alternative needleless reconstitution system.

For intravenous use only.

Each vial of Kogenate FS contains the labeled amount of recombinant factor VIII in international units (IU, unit).

Control of bleeding episodes and perioperative management:
- Dose (units) = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL).
- Titrate doses to patient’s clinical response.
- Determine treatment frequency based on type of bleeding episode.
For routine prophylaxis in adults: 25 units per kg three times a week.
For routine prophylaxis in children: 25 units per kg every other day.

Source: Bayer HealthCare, 2019

Kovaltry

Kovaltry is available as lyophilized powder in single-dose vials containing nominally 250, 500, 1000, 2000, or 3000 IU. Each vial of KOVALTRY contains the labeled amount of recombinant Factor VIII in IU.

For intravenous use after reconstitution only.

Control of bleeding episodes and perioperative management:
- Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL) x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg).
- Estimated Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg).
Routine prophylaxis:
- Adults and adolescents: 20-40 IU/kg 2 or 3 times per week.
- Children ≤12 years old: 25-50 IU/kg 2 times per week, 3 times per week or every other day.

Source: Bayer HealthCare, 2022

Novoeight

Novoeight is is available as a lyophilized powder in single-dose vials of 250, 500, 1000, 1500, 2000 and 3000 international units.

For intravenous injection after reconstitution only.

Each vial of Novoeight contains the labeled amount of recombinant Factor VIII in international units (IU).

Dosage and duration of treatment depend on the severity of the factor VIII deficiency, 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. Refer to the full prescribing information for Novoeight with regard to dosing for the following

On-demand Treatment and Control of Bleeding Episodes
Perioperative Management
Routine Prophylaxis

Source: Novo Nordisk, 2020

Nuwiq

Nuwiq is available as a white sterile, non-pyrogenic, lyophilized powder for reconstitution in single-use vials containing nominally 250, 500, 1000, 1500, 2000, 2500, 3000 or 4000 IU Factor VIII potency.

For intravenous use after reconstitution.

Each vial of Nuwiq is labeled with the actual amount of Factor VIII potency in international units (IU).

Dose and duration of therapy depend on the severity of the Factor VIII defciency, the location and extent of the bleeding, FVIII level, and the patient’s clinical condition. Refer to the full prescribing information for Nuwiq with regard to the following:

On-demand Treatment and Control of Bleeding Episodes
Perioperative Management
Routine Prophylaxis

Source: Octapharma USA, 2021

Recombinate

Recombinate is available in single-dose vials, which contain nominally 250, 500, 1000, 1500, and 2000 International Units per vial.

Recombinate is administered by intravenous (IV) injection after reconstitution.

Each vial of Recombinate is labeled with the Factor VIII activity expressed in IU per vial.

Refer to the full prescribing information for Recombinate with regard to the following:

Hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes
Perioperative management of individuals with hemophilia A (classical hemophilia)

Source: Baxalta US, 2018

Xyntha and Xyntha Solufuse

Xyntha is available as lyophilized powder in single-use vials containingnominally 250, 500, 1000, or 2000 IU. Xyntha Solufuse is available as lyophilized powder in single-useprefilled dual-chamber syringes containing nominally 250, 500, 1000, 2000,or 3000 IU.

For intravenous use after reconstitution only

Refer to the full prescribing information for Xyntha for the following:

On-demand treatment and Control of Bleeding Episodes
Perioperative Management
Rouine Prophylaxis:
- Adults and adolescents (≥12 years): The recommended starting regimen is 30 IU/kg of Xyntha administered 3 times weekly.
- Children (<12 years): The recommended starting regimen is 25 IU/kg of Xyntha administered every other day. More frequent or higher doses may be required in children <12 years of age to account for the higher clearance in this age group.
- Adjust the dosing regimen (dose or frequency) based on the patient's clinical response.

Source: Wyeth Pharamceuticals, 2022

Extended Half-life Recombinant Factor VIII Concentrates

Adynovate

Adynovate is available as a lyophilized powder in single-use vials containing nominally (approximately) 250, 500, 750, 1000, 1500, 2000, or 3000 international units.

For intravenous use after reconstitution only.

One unit per kilogram body weight will raise the factor VIII level by 2% international units per deciliter (IU per dL). Each vial of Adynovate is labeled with the actual amount of recombinant factor VIII present in IU.

On-demand treatment and control of bleeding episodes and perioperative management:
- Estimated Increment of factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg)
- Dose (IU) = Body Weight (kg) x Desired factor VIII Rise (IU/dL or % of Normal) x 0.5 (IU/kg per IU/dL)
Routine prophylaxis:
- Administer 40-50 IU/kg body weight twice weekly in adults and adolescents (12 years and older).
- Administer 55 IU/kg twice weekly in children (<12 years) with a maximum of 70 IU/kg.
- Adjust the dose and dosing intervals based on the patient’s clinical response.
- Inject intravenously over a period of less than or equal to 5 minutes (maximum infusion rate 10 mL per min).

Source: Baxalta US, 2021

Altuviiio

Altuviiio is available for injection as nominally 250, 500, 750, 1000, 2000, 3000, or 4000 IU, lyophilized powder in single-dose vials for reconstitution.

For intravenous use after reconstitution only.

Each Altuviiio vial label states Factor VIII activity in international units (IU or unit).

For routine prophylaxis: 50 IU/kg once weekly
For on-demand treatment and control of bleeding episodes and perioperative management: 50 IU/kg

Source: Bioverativ Therapeutics, 2023

Esperoct

Each vial label for Esperoct states the actual Factor VIII activity in international units (IU).

On-Demand Treatment/Control of Bleeding Episodes:
- Adolescents / adults: 40 IU/kg body weight for minor/moderate bleeds and 50 IU/kg body weight for major bleeds;
- Children (<12 years), 65 IU/kg body weight for minor/moderate/major bleeds.
Perioperative Management for Minor/Major Surgery:
- Adolescents / adults: pre-operative dose of 50 IU/kg body weight;
- Children (<12 years), pre-operative dose of 65 IU/kg body weight.

Frequency of administration is determined by the treating physician.

Routine Prophylaxis:
- Adolescents/adults, 50 IU/kg every 4 days;
- Children (<12 years), 65 IU/kg twice weekly.

A regimen may be individually adjusted to less or more frequent dosing based on bleeding episodes.

Esperoct also may be dosed to achieve a specific target Factor VIII activity level, depending on the severity of hemophilia, for on-demand treatment/control of bleeding episodes or perioperative management. To achieve a specific target

Factor VIII activity level, use the following formula: Dosage (IU) = Body Weight (kg) × Desired Factor VIII Increase (IU/dL or % normal) × 0.5 (IU/kg per IU/dL).

Source: Novo Nordisk, 2019

Jivi

For intravenous use after reconstitution only.

Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the person's clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.

On-Demand Control of Bleeding Episodes and Perioperative Management:
- Calculation of the required dose is based on the empirical finding that one international unit per kilogram body weight of Jivi will increase the plasma Factor VIII level by 2 international units per deciliter (IU/dL).
- Estimate the required dose for on-demand treatment and control of bleeding and perioperative management using the following formula: Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL) x reciprocal of expected recovery (or observed recovery, if available).
- Estimate the in vivo peak increase using the following formula: Increment of Factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg).
- The total recommended maximum dose per infusion is approximately 6000 IU (rounded to vial size).
Dosing for Control of Bleeding Episodes:
- Minor bleeding (e.g., early hemarthrosis, minor muscle bleeding, oral bleeds): 10–20 IU/kg, repeat every 24–48 hours until bleeding is resolved. Factor VIII Level Required (IU/dL or % of normal): 20–40.
- Moderate bleeding (e.g., more extensive hemarthrosis, muscle bleeding, or hematoma): 15–30 IU/kg, repeat every 24–48 hours until bleeding is resolved. Factor VIII Level Required (IU/dL or % of normal): 30-60.
- Major bleeding (e.g., intracranial, intra-abdominal or intrathoracic hemorrhages, gastrointestinal bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, life- or limb- threatening hemorrhage): 30-50 IU/kg, repeat every 8–24 hours until bleeding is resolved. Factor VIII Level Required (IU/dL or % of normal): 60-100.
Dosing for Perioperative Management:
- Minor surgery (e.g., tooth extraction): 15–30 IU/kg, repeat every 24 hours for at least 1 day until healing is achieved. Factor VIII Level Required (IU/dL or % of normal): 30–60 (pre- and post-operative).
- Major surgery (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement surgery): 40–50 IU/kg, repeat every 12–24 hours until adequate wound healing is complete, then continue therapy for at least another 7 days to maintain Factor VIII activity of 30–60% (IU/dL). Factor VIII Level Required (IU/dL or % of normal) 80–100 (pre- and post-operative).
Dosing for Routine Prophylaxis:
- The recommended initial regimen is 30–40 IU/kg twice weekly.
- Based on the bleeding episodes:, the regimen may be adjusted to 45–60 IU/kg every 5 days. A regimen may be further individually adjusted to less or more frequent dosing.

Source: Bayer Healthcare, 2018

Human Plasma-Derived Factor VIII Concentrates That Contain Von Willebrand Factor

Alphanate

Alphanate is available as a lyophilized powder for intravenous injection after reconstitution in single dose vials containing 250, 500, 1000, 1500 IU and 2000 IU FVIII,

For intravenous injection after reconstitution only.

Treatment and Prevention of Bleeding Episodes and Excess Bleeding During and After Surgery in Patients with Hemophilia A:
- Dose (units) = body weight (kg) x desired FVIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL).
- Dosing frequency determined by the type of bleeding episode and the recommendation of the treating physician.
Treatment and Prevention of Excess Bleeding During and After Surgery or Other Invasive Procedures in Patients with von Willebrand Disease:
- Adults: Pre-operative dose of 60 IU VWF:RCo/kg body weight; subsequent doses of 40-60 IU VWF:RCo/kg body weight.
- Pediatric: Pre-operative dose of 75 IU VWF:RCo/kg body weight; subsequent doses of 50-75 IU VWF:RCo/kg body weight.

Source: Grifols Biologicals, 2021

Rebinyn

For intravenous use after reconstitution only.

On-Demand Treatment

Recommended dose for on-demand treatment and control of bleeding episodes: 40 IU/kg body weight for minor and moderate bleeds, and 80 IU/kg body weight for major bleeds. Additional doses of 40 IU/kg can be given.

Perioperative Management

Recommended dose: Pre-operative dose of 40 IU/kg body weight for minor surgery, and 80 IU/kg body weight for major surgery. As clinically needed for the perioperative management of bleeding, repeated doses of 40 IU/kg (in 1-3 day intervals) within the first week after major surgery may be administered. Frequency may be extended to once weekly after the first week until bleeding stops and healing is achieved.

Source: Novo Nordisk, 2020

Andexxa

Andexxa dosing is based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the person's last dose of FXa inhibitor. It is administered as an intravenous (IV) bolus, with a target rate of 30 mg/min, followed by continuous infusion for up to 120 minutes. For the low dose regimen, the initial bolus is 400 mg at a target rate of 30 mg/min and the follow-on IV infusion is 4 mg/min for up to 120 minutes. For the high dose regimen, the initial bolus is 800 mg at a target rate of 30 mg/min and the follow-on IV infusion is 8 mg/min for up to 120 minutes.

Source: Portola Pharmaceuticals, 2018

Praxbind

The recommended dose of Praxbind is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab. There is limited data to support administration of an additional 5 g of Praxbind.

Source: Boehringer Ingelheim, 2018

Hemlibra

Note: For initial and continuation requests, dosing does not exceed the following:

Induction: 3mg/kg subcutaneously once weekly for the first 4 weeks;
Maintenance: 1.5 mg/kg once weekly, or 3mg/kg once every 2 weeks, or 6mg/kg once every 4 weeks.

Per the prescribing information, the recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose of: 1.5 mg/kg once every week, or 3 mg/kg once every two weeks, or 6 mg/kg once every four weeks.

Source: Genentech, 2018

Coagadex

The Coagadex prescribing information states that the dosage and duration of treatment depend on the severity of the Factor X deficiency, on the location and extent of the bleeding and on the person's clinical condition.

For Prophylaxis of Bleeding Episodes

In children less than 12 years of age, use 40 IU per kg body weight twice weekly. In adults and adolescents 12 years of age and older, use 25 IU per kg body weight twice weekly. In all age groups, monitor trough blood levels of Factor X targeting ≥5 IU/dL and adjust dosage to clinical response and trough levels. Do not exceed a peak level of 120 IU/dL.

For Treatment of Bleeding Episodes

In children less than 12 years of age, use 30 IU per kg body weight. In adults and adolescents 12 years of age and older, use 25 IU per kg body weight. In all age groups, repeat dosing repeated at intervals of 24 hours until the bleed stops.

For Perioperative Management

In children less than 12 years of age, use a factor 0f 0.6 to calculate the required dose. In adults and adolescents 12 years of age and older, use a factor of 0.5 to calculate the required dose. In all age groups, pre-surgery, raise plasma Factor X levels to 70-90 IU/dL. Post-surgery, maintain plasma Factor X levels at a minimum of 50 IU/dL until the person is no longer at risk of bleeding due to surgery.

See full prescribing information for additional dosage and administration details.

Source: Bio Products Laboratory USA, 2018

Sevenfact

Mild-to-moderate bleeding episodes in congenital hemophilia A or B with inhibitors: 75 mcg/kg repeated every 3 hours until bleeds: hemostasis is achieved; or initial dose of 225 mcg/kg. If hemostasis is not achieved within 9 hours, additional 75 mcg/kg doses may be administered every 3 hours as needed to achieve hemostasis.

Source: HEMA Biologics, 2020

NovoSeven RT

Bleeding Episodes

Congenital Hemophilia A or B with Inhibitors: 90 mcg/kg every 2 hours, adjustable based on severity of bleeding until hemostasis is achieved; or 90 mcg/kg every 3-6 hours after hemostasis is achieved for severe bleeds;
Acquired Hemophilia: 70-90 mcg/kg every 2-3 hours until hemostasis is achieved;
Congenital Factor VII Deficiency: 15-30 mcg/kg every 4-6 hours until hemostasis is achieved;
Glanzmann’s Thrombasthenia: 90 mcg/kg every 2-6 hours until hemostasis is achieved.

Peri-operative Management

Congenital Hemophilia A or B with Inhibitors, Minor: 90 mcg/kg immediately before surgery, repeat every 2 hours during surgery; or 90 mcg/kg every 2 hours after surgery for 48 hours, then every 2-6 hours until healing has occurred;
Congenital Hemophilia A or B with Inhibitor, Major: 90 mcg/kg immediately before surgery, repeat every 2 hours during surgery; or 90 mcg/kg every 2 hours after surgery for 5 days, then every 4 hours or by continuous infusion at 50 mcg/kg/hr until healing has occurred;
Acquired Hemophilia: 0-90 mcg/kg immediately before surgery and every 2-3 hours for the duration of surgery and until hemostasis is achieved;
Congenital Factor VII Deficiency: 15-30 mcg/kg immediately before surgery and every 4-6 hours for the duration of surgery and until hemostasis is achieved;
Glanzmann’s Thrombasthenia: 90 mcg/kg immediately before surgery and repeat every 2 hours for the duration of the procedure; 90 mcg/kg every 2-6 hours to prevent post-operative bleeding.

Source: Novo Nordisk, 2020

Thrombate III

Thrombate III: Individualize dose to achieve AT level of 80% to 120% of normal human plasma. See prescribing information for full dosing guidelines.

Source: Grifols, 2019

ATryn

ATryn: Individualize dosage based on the pretreatment functional AT activity level (expressed in percent of normal) and body weight (expressed in kilograms) and using therapeutic drug monitoring. The goal of treatment is to restore and maintain functional antithrombin (AT) activity levels between 80% - 120% of normal (0.8 - 1.2 IU/mL). See prescribing information for full dosing guidelines. See full prescribing information for additional dosage and administration details.

For other products, see prescribing information for dosage and administration.

Source: GTC Biotherapeutics, 2012

Experimental and Investigational

Aetna considers Jivi experimental and investigational for all other indications (e.g., use in children younger than 12 years of age due to a greater risk for hypersensitivity reactions, use in previously untreated persons, treatment of von Willebrand disease) because its effectiveness for indications other than the ones listed above has not been established.
Aetna considers detection of elevated factor VIII and von Willebrand factor levels experimental and investigational for assessment of acute ischemic stroke risk because the effectiveness of this approach has not been established.
Aetna considers Ixinity and rFIXFc experimental and investigational for induction of immune tolerance in persons with hemophilia B.
Aetna considers Obizur experimental and investigational for the treatment of congenital hemophilia A or von Willebrand disease.
Aetna considers FEIBA experimental and investigational for all other indications (e.g., reversal of anticoagulant-associated coagulopathy, rescue treatment of coagulopathy after cardiac surgery; prevention and treatment of bleeding in non-hemophilic persons with acquired inhibitors, not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established.
Aetna considers rFVIIa experimental and investigational for all other indications including prevention of bleeding unrelated to hemophilia or factor deficiency (e.g., in persons undergoing cardiac surgery such as aortic dissection, liver transplantation, vascular surgery, or prostatectomy); or treatment of bleeding unrelated to hemophilia or factor deficiency (e.g., acute coronary syndromes, acute spontaneous intracerebral hemorrhage, acute variceal bleeding, diffuse alveolar hemorrhage, gastro-intestinal bleeding after hematopoietic stem cell transplantation, gastro-intestinal bleeding secondary to Crohn's disease, hemoptysis due to invasive pulmonary aspergillosis, and intracranial bleeding from traumatic brain injury or stroke, trauma, not an all-inclusive list).
Aetna considers rFVIIa-jncw (Sevenfact) experimental and investigational for members younger than 12 years of age.
Aetna considers prothrombin complex concentrate (human) (Kcentra) experimental and investigational for reversal of VKA anti-coagulation in persons without acute major bleeding or is not undergoing an urgent surgery or invasive procedure; and trauma-induced hemorrhage because its effectiveness for these indications has not been established.
Recombinant coagulation factor XIII A-subunit (Tretten) is considered experimental and investigational for persons with congenital factor XIII B-subunit deficiency and for all other indications.
Aetna considers human anti-thrombin III experimental and investigational for recurrent early miscarriage.
Aetna considers von Willebrand Factor propeptide antigen (VWFpp)/VWF:Ag (the ratio of VWF propeptide to antigen) assay experimental and investigational for a member with VWD suspected of type 1C based on low certainty in the evidence from diagnostic accuracy studies.
Aetna considers recombinant coagulation Factor VIIa (rFVIIa) (NovoSeven, Sevenfact) experimental and investigational for treatment of qualitative platelet defects.

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
Other CPT codes related to the CPB:
85002	Bleeding time
85335	Factor inhibitor test
85610 - 85611	Prothrombin time, and substitution, plasma fractions, each
85730 - 85732	Thromboplastin time, partial (PTT); plasma or whole blood, and substitution, plasma fractions, each
96365 - 96379	Therapeutic, prophylactic, and diagnostic injections and infusions
99601	Home infusion/specialty drug administration, per visit (up to 2 hours)
+ 99602	each additional hour (List separately in addition to code for primary procedure)
Other HCPCS codes related to the CPB:
S9345	Home infusion therapy, antihemophilic agent infusion therapy (e.g., factor VIII); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
*Factor VIII Products, including Advate, Adynovate, Afstyla, Alphanate, Altuviiio, Eloctate, Hemofil M, Humate-P, Jivi, Koate, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate or Xyntha*:
Other CPT codes related to the CPB:
85240	Clotting: factor VIII (AHG), 1 - stage
85244	factor VIII related antigen
85245	factor VIII, VW factor, ristocetin cofactor
85246	factor VIII, VW factor antigen
85247	factor VIII, von Willebrand factor, multimetric analysis
HCPCS codes covered if selection criteria are met:
J7182	Injection, factor VIII, (antihemophilic factor, remcombinant), (NovoEight)
J7185	Injection, factor viii (antihemophilic factor, recombinant) (Xyntha), per IU
J7186	Injection, antihemophilic factor VIII / von Willebrand factor complex (human), per factor VIII i.u.
J7187	Injection, von Willebrand factor complex (Humate-P), per IU vWF-RCO
J7190 - J7191	Factor VIII (antihemophilic factor, human or porcine) per IU
J7192	Factor VIII (antihemophilic factor, recombinant) per IU, not otherwise specified
J7204	Injection, Factor VIII, antihemophilic factor (recombinant), (Esperoct), glycopegylated-exei, per IU
J7205	Injection, factor viii fc fusion (recombinant), per IU
J7207	Injection, factor viii, (antihemophilic factor, recombinant), pegylated, 1 IU
J7208	Injection, Factor VIII, (antihemophilic factor, recombinant), PEGylated-aucl, (Jivi), 1 IU
J7209	Injection, factor viii, (antihemophilic factor, recombinant), (nuwiq), 1 IU
J7210	Injection, factor viii, (antihemophilic factor, recombinant), (afstyla), 1 IU
J7211	Injection, factor viii, (antihemophilic factor, recombinant), (kovaltry), 1 IU
J7214	Injection, factor viii/von willebrand factor complex, recombinant (altuviiio), per factor viii i.u
ICD-10 codes covered if selection criteria are met:
D66	Hereditary factor VIII deficiency [Hemophilia A]
D67	Hereditary factor IX deficiency [Hemophilia B]
D68.01	Von Willebrand disease, type 1
D68.020	Von Willebrand disease, type 2A
D68.021	Von Willebrand disease, type 2B
D68.022	Von Willebrand disease, type 2M
D68.023	Von Willebrand disease, type 2N
D68.03	Von Willebrand disease, type 3
D68.04	Acquired von Willebrand disease
D68.311	Acquired hemophilia [acquired hemophilia A]
Factor VIII inhibitor bypassing activity (FEIBA) anti-inhibitor coagulant complex:
Other HCPCS codes related to the CPB:
J7198	Antiinhibitor, per IU
ICD-10 codes covered if selection criteria are met:
D66	Hereditary factor VIII deficiency [Hemophilia A]
D67	Hereditary factor IX deficiency [Hemophilia B]
D68.1	Hereditary factor XI deficiency
D68.2	Hereditary deficiency of other clotting factors [acquired inhibitors to Factors VIII, XII]
I97.110 - I97.191	Postprocedural cardiac complications [rescue treatment of coagulopathy after cardiac surgery]
T45.511A – T45.514S	Poisoning by anticoagulants
ICD-10 codes not covered for indications listed in the CPB:
D68.311	Acquired hemophilia
Anti-hemophilic factor (recombinant), porcine sequence (Obizur):
HCPCS codes covered if selection criteria are met:
J7188	Injection, factor viii (antihemophilic factor, recombinant), (obizur), per i.u.
ICD-10 codes covered if selection criteria are met:
D68.311	Acquired hemophilia
ICD-10 codes not covered for indications listed in the CPB:
D66	Hereditary factor VIII deficiency
D68.00 – D68.09	Von Willebrand disease
Factor IX Products:
Factor IX Products: Rebinyn (coagulation factor IX [recombinant], glycoPEGylated); Idelvion (coagulation factor IX [recombinant], albumin fusion protein); Alprolix (coagulation factor IX [recombinant], Fc fusion protein); Benefix, Ixinity, Rixubis (coagulation factor IX [recombinant]) and Alphanine SD
Other CPT codes related to the CPB:
85250	Factor IX (PTC or Christmas)
HCPCS codes covered if selection criteria are met:
J7193	Factor IX (antihemophilic factor, purified, nonremcombinant) per IU
J7195	Injection, factor IX (antihemophilic factor, recombinant) per IU, not otherwise specified
J7200	Injection, factor ix, (antihemophilic factor, recombinant), rixubis, per iu
J7201	Injection, factor IX, fc fusion protein (recombinant), per IU
J7202	Injection, factor ix, albumin fusion protein, (recombinant), idelvion, 1 IU
J7203	Injection factor ix, (antihemophilic factor, recombinant), glycopegylated, (rebinyn), 1 IU
J7213	Injection, coagulation factor ix (recombinant), ixinity, 1 i.u
ICD-10 codes covered if selection criteria are met:
D67	Hereditary factor IX deficiency
Human factor IX complex (Profilnine):
HCPCS codes covered if selection criteria are met:
J7194	Factor IX complex, per IU
ICD-10 codes covered if selection criteria are met:
D67	Hereditary factor IX deficiency [Hemophilia B]
D68.2	Hereditary deficiency of other clotting factors [Factor II, X deficiency]
Hemlibra:
HCPCS codes covered if selection criteria are met:
J7170	Injection, emicizumab-kxwh, 0.5 mg
Other HCPCS codes related to the CPB:
J2597	Injection, desmopressin acetate, per 1 mcg
ICD-10 codes covered if selection criteria are met:
D66	Hereditary factor VIII deficiency
Recombinant Von Willebrand factor (Vonvendi):
HCPCS codes covered if selection criteria are met:
J7179	Injection, Von willebrand factor (recombinant), (vonvendi), 1 i.u. vwf:rco
ICD-10 codes covered if selection criteria are met:
D68.01	Von Willebrand disease, type 1
D68.020	Von Willebrand disease, type 2A
D68.021	Von Willebrand disease, type 2B
D68.022	Von Willebrand disease, type 2M
D68.023	Von Willebrand disease, type 2N
D68.03	Von Willebrand disease, type 3
ICD-10 codes not covered for indications listed in the CPB:
D66	Hereditary factor VIII deficiency [Hemophilia A]
Von Willebrand factor/coagulation factor VIII complex (Wilate®) :
HCPCS codes covered if selection criteria are met:
J7183	Injection, Von Willebrand factor complex (human), wilate, 1 I.U. VWF:RCO
ICD-10 codes covered if criteria are met:
D66	Hereditary factor VIII deficiency
D68.01	Von Willebrand disease, type 1
D68.020	Von Willebrand disease, type 2A
D68.021	Von Willebrand disease, type 2B
D68.022	Von Willebrand disease, type 2M
D68.023	Von Willebrand disease, type 2N
D68.03	Von Willebrand disease, type 3
D68.04	Acquired von Willebrand disease
ICD-10 codes not covered for indications listed in the CPB:
D78.01 - D78.02, D78.21 - D78.22, E36.01 - E36.02, G97.31 - G97.32, G97.51 - G97.52, H59.111 - H59.129, H59.311 - H59.329, H95.21 - H95.22, H95.41 - H95.42, I97.410 - I97.418, I97.42, I97.610 - I97.648, J95.61 -J95.62, J95.830 - J95.831, K91.61 - K91.62, K91.840 - K91.841, L76.01 - L76.02, L76.21 - L76.22, M96.810 - M96.811, M96.830 - M96.831, M96.840 - M96.841, N99.61 - N99.62, N99.820 - N99.821, T88.8XXA - T88.8XXS	Hemorrhage complicating a procedure [prevention of excessive bleeding during and after surgery in individuals with VWD]
Q90.2	Hematoma of obstetric wound [prevention of excessive bleeding during and after surgery in individuals with VWD]
*Recombinant factor VIIa (rFVIIa, NovoSeven, Sevenfact)*:
Other CPT codes related to the CPB:
85230	Clotting: factor VII (proconvertin, stable factor)
HCPCS codes covered if selection criteria are met:
J7189	Factor VIIa (antihemophilic factor, recombinant) per 1 mcg
J7212	Factor viia (antihemophilic factor, recombinant)-jncw (sevenfact), 1 microgram
ICD-10 codes covered if selection criteria are met:
D66	Hereditary factor VIII deficiency [Hemophilia A]
D67	Hereditary factor IX deficiency [Hemophilia B]
D68.1	Hereditary factor XI deficiency
D68.2	Hereditary deficiency of other clotting factors
D68.311	Acquired hemophilia
ICD-10 codes not covered for indications listed in the CPB:
B44.0	Invasive pulmonary aspergillosis [with hemoptysis]
D69.1	Qualitative platelet defects [Glanzmann's thrombasthenia with antibodies to glycoprotein IIb-, IIIa and/or human leukocyte antigen (HLA), refractory to platelet infusions]
D78.01 - D78.02, E36.01 - E36.02 G97.31 - G97.32, H59.111 - H59.129 H95.21 - H95.22, I97.410 - I97.42 J95.61 - J95.62, K91.61 - K91.62 L76.01 - L76.02, M96.810 - M96.811 N99.61 - N99.62	Intraoperative hemorrhage and hematoma complicating a procedure
I20.0	Unstable angina
I24.0	Acute coronary thrombosis not resulting in myocardial infarction
I60.00 - I69.998	Cerebrovascular disease [including treatment of acute spontaneous intracerebral hemorrhage unrelated to hemophilia]
I85.00 - I85.11	Esophageal varices [with acute bleeding]
K50.00 - K50.919	Crohn's disease [regional enteritis]
K91.841	Postprocedural hemorrhage of a digestive organ or structure following other procedure [hematopoietic stem cell transplantation]
R04.2	Hemoptysis [due to invasive pulmonary aspergillosis]
R04.81 - R04.89	Hemorrhage from other sites in respiratory passages
R04.9	Hemorrhage from respiratory passages, unspecified
S02.0XXA – S02.92XS	Fracture of skull and facial bones [with intracranial bleeding]
S06.0X0A – S06.9X9S	Intracranial injury, excluding those with skull fracture [with intracranial bleeding]
T86.5	Complications of stem cell transplant [gastro-intestinal bleeding]
Factor X (Coagadex):
HCPCS codes covered if selection criteria are met:
J7175	Injection, factor x, (human), 1 IU
ICD-10 codes covered if selection criteria are met:
D68.2	Hereditary deficiency of other clotting factors [Factor X deficiency]
Factor XIII Concentrate [Human] (Corifact):
Other CPT codes related to the CPB:
85290	Factor XIII (fibrin stabilizing)
85291	Factor XIII (fibrin stabilizing), screen solubility
HCPCS codes covered if selection criteria are met:
J7180	Injection, Factor XIII (antihemophilic factor, human), 1 IU
Other HCPCS codes related to the CPB:
J7198	Antiinhibitor, per IU
J7199	Hemophilia clotting factor, not otherwise classified
ICD-10 codes covered if selection criteria are met:
D68.2	Hereditary deficiency of other clotting factors [factor XIII]
Prothrombin complex concentrate (human) (Kcentra):
HCPCS codes covered if selection criteria are met:
J7168	Prothrombin complex concentrate (human), kcentra, per i.u. of factor ix activity
ICD-10 codes covered if selection criteria are met:
D68.4	Acquired coagulation factor deficiency
T45.515A – T45.515S	Adverse effect of anticoagulants
Recombinant coagulation factor XIII A-subunit (Tretten):
HCPCS codes covered if selection criteria are met:
J7181	Injection, factor XIII A-subunit, (recombinant), per IU [Tretten]
ICD-10 codes covered if selection criteria are met:
D68.2	Hereditary deficiency of other clotting factors [congenital factor XIII A-subunit deficiency]
*Human anti-thrombin III (Thrombate III), recombinant human anti-thrombin III (ATryn)*:
Other CPT codes related to the CPB:
85300	Clotting inhibitors or anticoagulants; anti-thrombin III, activity
85301	anti-thrombin III, antigen assay
HCPCS codes covered if selection criteria are met:
J7196	Injection, antithrombin recombinant, 50 i.u. [recombinant human anti-thrombin III (ATryn)]
J7197	Anti-thrombin III (human) [Thrombate III]
ICD-10 codes covered if selection criteria are met:
D68.59	Other primary thrombophilia [anti-thrombin III deficiency] [covered in connection with thrombo-embolism, obstetrical procedures, or surgical procedures only] [asparaginase-induced antithrombin deficiency][heparin resistance prior to and during cardiopulmonary bypass] [acquired antithrombin deficiency]
ICD-10 codes not covered for indications listed in the CPB:
N96	Recurrent pregnancy loss
O03.0 - O03.9	Spontaneous abortion
O09.291 - O09.299	Supervision of pregnancy with other poor reproductive or obstetrical history
O26.20 - O26.23	Pregnancy care for patient with recurrent pregnancy loss
*Andexxa*:
HCPCS codes covered if selection criteria are met:
J7169	Injection, coagulation factor xa (recombinant), inactivated-zhzo (andexxa), 10 mg
Other HCPCS codes related to the CPB:
Rivaroxaban, Apixaban, Edoxaban, Betrixaban - no specific code
ICD-10 codes covered if selection criteria are met:
D68.32	Hemorrhagic disorder due to extrinsic circulating anticoagulants
T45.515A - T45.515S	Adverse effect of anticoagulants
T45.525A – T45.525S	Adverse effect of antithrombotic drugs
*Praxbind*:
HCPCS codes covered if selection criteria are met:
Idarucizumab (Praxbind), dabigatran - no specific code
Diagnostic Testing for Von Willebrand Disease:
CPT codes covered if selection criteria are met:
0279U	Hematology (von Willebrand disease [VWD]), von Willebrand factor (VWF) and collagen III binding by enzyme-linked immunosorbent assays (ELISA), plasma, report of collagen III binding
0280U	Hematology (von Willebrand disease [VWD]), von Willebrand factor (VWF) and collagen IV binding by enzyme-linked immunosorbent assays (ELISA), plasma, report of collagen IV binding
0283U	Von Willebrand factor (VWF), type 2B, platelet-binding evaluation, radioimmunoassay, plasma
0284U	Von Willebrand factor (VWF), type 2N, factor VIII and VWF binding evaluation, enzyme-linked immunosorbent assays (ELISA), plasma
CPT codes not covered for indications listed in the CPB:
0281U	Hematology (von Willebrand disease [VWD]), von Willebrand propeptide, enzyme-linked immunosorbent assays (ELISA), plasma, diagnostic report of von Willebrand factor (VWF) propeptide antigen level
ICD-10 codes covered if selection criteria are met:
D68.00	Von Willebrand disease, unspecified
D68.020	Von Willebrand disease, type 2A
D68.021	Von Willebrand disease, type 2B
D68.022	Von Willebrand disease, type 2M
D68.023	Von Willebrand disease, type 2N
D68.029	Von Willebrand disease, type 2, unspecified
D68.09	Other von Willebrand disease

Background

Hemophilia and von Willebrand's disease are the most common congenital bleeding disorders. Hemophilia refers to X-linked bleeding disorders in which there is a deficiency (activity level of 35 % or less) of either factor VIII (hemophilia A, classic hemophilia) or factor IX (hemophilia B, Christmas disease). In general, administration of anti-hemophilic factor is indicated for hemophilia when a bleeding episode arises (demand treatment) or when bleeding is anticipated or likely (prophylactic treatment).

Primary prophylactic therapy may be indicated for patients with severe hemophilia A or hemophilia B who have less than 1 % of normal factor (less than 0.01 IU/ml; National Hemophilia Foundation, 2001). Primary prophylactic therapy should be instituted early, prior to the onset of frequent bleeding, with the aim of keeping the trough factor or VIII or factor IX level above 1 % between doses (National Hemophilia Foundation, 2001). In some cases, continuous prophylactic therapy may be indicated in persons with hemophilia A or hemophilia B that is not severe (i.e., hemophiliacs with more than 1 % of normal factor levels) who have repeated episodes of spontaneous bleeding.

Short-term prophylactic treatment is given to patients before they undergo surgical procedures or engage in activities that carry a high risk of provoking a bleed. It may also be given to break the cycle of frequent bleeding into specific joints (target joints). Potential harm, including the risk of hepatitis B, hepatitis C and HIV infection, has now been minimized through viral inactivation of plasma-derived coagulation-factor concentrates and through the use of recombinant clotting factor concentrates and other non-plasma-derived hemostatic agents. Currently, cryoprecipitate does not undergo viral inactivation procedures.

Immune tolerance induction is designed to overcome the effects of anti-hemophilic factor or factor IX inhibitors in certain hemophiliac patients, thus restoring effectiveness of antihemophilic factor or factor IX therapy to resolve active bleeding in these patients. It consists of administration of very high doses of anti-hemophilic factor or factor IX over an extended period of time.

A number of different immune tolerance therapy regimens have been developed using replacement factor VIII or factor IX to produce long-term inhibitor suppression or eradication. These protocols utilize various doses of replacement factor VIII or factor IX with or without additional therapies.

There are a number of established protocols for immune tolerance induction; these regimens differ in dose and duration of therapy (Stachnik, 2003). The North American Immune Tolerance Registry was established in 1993 to assess the various protocols used for immune tolerance therapy in the United States and Canada (Stachnik, 2003; Kroner, 1999; DiMichele and Kroner, 1999). Based on a survey of 168 centers that provide medical care to hemophilia patients, many clinicians in North America (about 50 %) use 100 to 200 U/kg of replacement factor VIII daily for immune tolerance therapy. In general, the duration of treatment is shorter when using higher doses of factor VIII. For doses of factor VIII over 50 U/kg daily, the mean treatment time was between 6 and 7 months; however, with lower doses of factor VIII (less than 50 U/kg daily), the mean duration of treatment was nearly 19 months. Highest success rates were found among patients who had a history of low maximum inhibitor titers (less than 50 Bethesda Units).

Immune tolerance induction is not successful in all patients – approximately 20 % to 30 % fail to respond (Stachnik, 2003). Although the duration of treatment varies among the immune tolerance protocols, most clinicians would agree that a patient who has not responded as expected after 12 to 24 months of treatment is unlikely to respond with further treatment. Re-induction tolerance, although occasionally successful, generally is not effective (Stachnik, 2003). For these patients, bleeding episodes can usually be controlled using bypassing agents, including factor IX complex (prothrombin complex concentrates or PCCs), recombinant factor VIIa (rFVIIa, NovoSeven RT), or activated anti-inhibitor coagulant complexes (AICCs or aPCCs).

In view of the increasing safety of clotting-factor concentrates, long-term prophylactic therapy in the form of factor VIII infusion at least 3 times a week or factor IX infusion at least twice a week to prevent hemarthrosis in severely affected patients is gaining acceptance, especially in the treatment of infants and children. It has been shown that increasing in-vivo clotting-factor levels to more than 1 % activity (usually accomplished by giving 25 to 40 U/kg of factor VIII 3 times a week or 25 to 40 U/kg of factor IX twice a week) is sufficient to prevent most spontaneous joint bleeds and preserve joint function.

von Willebrand's disease is typically mild and it generally exhibits an autosomal dominant pattern of inheritance. Anti-hemophilic factor/von Willebrand factor complex (Humate-P) is indicated for use in adult patients for treatment and prevention of bleeding in hemophilia A and in adult and pediatric patients for treatment of spontaneous and trauma-induced bleeding episodes in severe von Willebrand disease and in mild and moderate von Willebrand disease where use of desmopressin is known or suspected to be inadequate.

Factor VIII

Graham and Jaworski (2014) noted that standard dosing for individuals with hemophilia A is based on body weight such that 50 IU/kg is defined as a 100 % dose, or one attaining 1.00 IU/ml FVIII clotting activity. No guidelines exist, however, for individuals with hemophilia who are obese, body mass index (BMI) greater than or equal to 30, who may actually be "over-treated" based on higher in-vivo recovery based on higher weight. Alternative treatment guidelines are needed for such patients. To determine FVIII pharmacokinetics, these researchers retrospectively collected data during ideal-body-weight dosing from 6 obese (BMI greater than or equal to 30) hemophilia A patients cared for at the Hemophilia Center of Western PA for prophylaxis or surgery. The pharmacokinetic data from 6 subjects undergoing ideal-body-weight dosing with recombinant FVIII indicated peak levels and half-life comparable to standard 50 IU/ dosing. The mean peak FVIII:C was 1.00 IU/dL and the mean FVIII:C half-life was 10.14 hours. IBW-dosing resulted in an average 48.9 % reduction in factor use per patient over a 3-month period, for an annualized savings of $133,000 per patient. Ideal-body-weight dosing of recombinant FVIII in obese patients with hemophilia A resulted in comparable pharmacokinetics, including peak and half-life, with comparable hemostatic efficacy for prophylaxis and surgical treatment, at a significant reduction in factor use and cost. The authors stated that future studies are needed to confirm these findings in individuals with other congenital bleeding disorders and in children.

CSL Behring announced that Helixate FS will no longer be manufactured after December 2017. Supply will continue to be available though 2019 (CSL, 2017).

CSL Behring announced that Monoclate-P, antihemophilic factor (human), factor VIII, will be discontinued with supply being available through December 2018 (CSL, 2018).

Factor VIII Products

U.S. Food and Drug Administration (FDA)-Approved Indications and Compendial Uses

Table: U.S. Food and Drug Administration (FDA)-Approved Indications and Compendial Uses
Brand	Generic	FDA-Approved Indication	Compendial Use
Recombinant Factor VIII Concentrates
Advate	antihemophilic factor [recombinant]	Hemophilia A	Acquired Hemophilia A
Afstyla	antihemophilic factor [recombinant], single chain	Hemophilia A
Kogenate FS	antihemophilic factor [recombinant]	Hemophilia A	Acquired Hemophilia A
Kovaltry	antihemophilic factor [recombinant]	Hemophilia A
Novoeight	antihemophilic factor [recombinant]	Hemophilia A	Acquired Hemophilia A
Nuwiq	antihemophilic factor [recombinant]	Hemophilia A
Recombinate	antihemophilic factor [recombinant]	Hemophilia A	Acquired Hemophilia A
Xyntha	antihemophilic factor [recombinant]	Hemophilia A	Acquired Hemophilia A
Extended Half-life Recombinant Factor VIII Concentrates
Adynovate	antihemophilic factor [recombinant], PEGylated	Hemophilia A
Altuviiio	antihemophilic factor [recombinant], Fc-VWF-XTEN fusion protein-ehtl	Hemophilia A
Eloctate	antihemophilic factor [recombinant], Fc fusion protein	Hemophilia A
Jivi	antihemophilic factor [recombinant], PEGylated-aucl	Hemophilia A
Esperoct	antihemophilic factor [recombinant], Glycopegylated-exei	Hemophilia A
Human Plasma-Derived Factor VIII Concentrate
Hemofil M		Hemophilia A	Acquired Hemophilia A
Human Plasma-Derived Factor VIII Concentrates That Contain Von Willebrand Factor
Alphanate Humate-P	antihemophilic factor/von Willebrand factor complex [human]	Hemophilia A, von Willebrand Disease	Acquired Hemophilia A, Acquired von Willebrand Syndrome
Koate	antihemophilic factor [human]	Hemophilia A	Acquired Hemophilia A, von Willebrand Disease

Afstyla

Afstyla is a long-acting recombinant factor VIII single-chain therapy for adults and children with hemophilia A, designed for greater molecular stability and longer duration of action. Once activated, Afstyla is identical to natural factor VIII. It was approved by the FDA for use in adults and children with hemophilia A for routine prophylaxis to reduce the frequency of bleeding episodes; on-demand treatment and control of bleeding episodes; and the perioperative management of bleeding. Afstyla is not indicated for the treatment of von Willebrand disease.

The data from the AFFINITY clinical development program showed a median annualized spontaneous bleeding rate (AsBR) of 0.00 in both the adult and adolescent study as well as the pediatric study. The median annualized bleeding rate (ABR) was 1.14 in adult and adolescent patients and 3.69 in children less than 12 years of age using Afstyla prophylactically. Of 1,195 bleeds treated in the pivotal study (848 in adults and adolescents; 347 in children), 94 percent of bleeds in adult and adolescent patients and 96 percent of bleeding events in pediatric patients were effectively controlled with no more than two infusions of Afstyla weekly; 81 percent of bleeds in adult and adolescent patients and 86 percent of bleeding events in pediatric patients were effectively controlled by only one infusion. The majority of bleeding events treated with Afstyla (94 percent in adults and adolescents; 96 percent in children) were rated as excellent or good.

Side effects included dizziness and anaphylaxis. No inhibitor development noted in study patients.

Perioperative management studies: Of the 13 adult or adolescent patients in the study who underwent surgical procedures (16 total surgeries), hemostatic efficacy of Afstyla was rated as excellent (15 times) or good (once). The most common adverse reactions reported in clinical trials were dizziness and hypersensitivity.

Afstyla is available as a white or slightly yellow lyophilized powder supplied in single use vials containing nominally 250, 500, 1000, 2000, or 3000 International Units (IU) and is intravenously administered..

Dosing for routine prophylaxis: Adults and adolescents aged 12 years and older: The recommended starting regimen is 20 to 50 IU per kg of Afstyla administered 2 to 3 times weekly.

Children (less than 12 years): The recommended starting regimen is 30 to 50 IU per kg of Afstyla administered 2 to 3 times weekly. More frequent or higher doses may be required in children less than 12 years of age to account for the higher clearance in this age group.

The regimen may be adjusted based on patient response.

Dosing for perioperative management: Ensure the appropriate Factor VIII activity level is achieved and maintained.

Adynovate

The FDA has approved Adynovate, a pegylated recombinant human antihemophilic factor, for adolescent and adult patients with hemophilia A (congenital factor VIII deficiency) for:

On-demand treatment and control of bleeding episodes
Routine prophylaxis to reduce the frequency of bleeding episodes.

The labeling states that Adynovate is not indicated for the treatment of von Willebrand disease.

Adynovate is contraindicated in patients who have had prior anaphylactic reaction to Adynovate, to the parent molecule (Advate), to mouse or hamster protein, or to excipients of Adynovate (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).

The prescribing information warns that hypersensitivity reactions are possible with Adynovate. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, Advate. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. The prescribing information recommends immediate discontinuation of administration and initiation of appropriate treatment if hypersensitivity reactions occur.

Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of Adynovate. Patients should be monitored regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. The prescribing information recommends performance of an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.

Common adverse reactions (=1% of subjects) reported in the clinical studies of Adynovate were headache and nausea.

Adynovate prescribing information states that each vial is labeled with the actual amount of recombinant factor VIII present in international units (IU). One unit per kilogram body weight will raise the factor VIII level by 2% international units per deciliter (IU per dL).

The labeling indicates use of the following formulas for calculating the dose of Adynovate for on-demand treatment and control of bleeding episodes:

Estimated Increment of factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg)
Dose (IU) = Body Weight (kg) x Desired factor VIII Rise (IU/dL or % of Normal) x 0.5 (IU/kg per IU/dL)

The recommended dose of Adynovate for routine prophylaxis is 40-50 IU per kg body weight 2 times a week.

Altuviiio

Antihemophilic factor [recombinant], Fc-VWF-XTEN fusion protein-ehtl is available as Altuviiio (Bioverativ Therapeutics Inc.) which temporarily replaces the missing coagulation factor VIII needed for effective hemostasis. Altuviiio is a recombinant FVIII analog fusion protein that is independent of endogenous VWF in order to overcome the half-life limit imposed by FVIII-VWF interactions. It contains 2 XTEN polypeptides which further increase the half-life of the molecule. Altuviiio has demonstrated 3- to 4-fold prolonged half-life relative to other standard and extended half-life FVIII products (Bioverativ Therapeutics, 2023).

According to the prescribing information, Altuviiio carries the following warnings and precautions:

Hypersensitivity reactions, including anaphylaxis, may occur. Should symptoms occur, immediately discontinue Altuviiio and initiate appropriate treatment.
Neutralizing antibodies (inhibitors) to Factor VIII have been reported. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor VIII inhibitor concentration.

Per the prescribing information for Altuviiio, the most common adverse reactions (incidence > 10%) are headache and arthralgia.

On February 23, 2023, the U.S. Food and Drug Administration approved Altuviiio [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl], previously denoted by efanesoctocog alfa. Altuviiio is a first-in-class, high-sustained factor VIII replacement therapy. Altuviiio is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for routine prophylaxis and on-demand treatment to control bleeding episodes, as well as perioperative management. The FDA approval was based on supporting data from two multicenter, prospective, open-label, non-randomized, phase 3, interventional studies, XTEND-1 study in adults and adolescents ≥ 12 years of age, and XTEND-Kids in children < 12 years of age (Sanofi, 2023).

von Drygalsk and colleagues (2023) conducted the pivotal XTEND-1 phase 3 study enrolled a total of 159 previously treated patients (158 male and 1 female) 12 years of age or older with severe hemophilia A. Patients in group A (133 patients) received once-weekly prophylaxis with Altuviiio (50 IU per kilogram of body weight) for 52 weeks and patients in group B (26 patients) received on-demand treatment with Altuviiio for 26 weeks, followed by once-weekly prophylaxis with Altuviiio for 26 weeks. The primary end point was the mean annualized bleeding rate in group A. The key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII. Other endpoints included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. Once-weekly Altuviiio prophylaxis meth the primary end point for patients in group A, where the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). Altuviiio also met the key secondary end point for patients in group A, where the mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (p<0.001). Nearly all bleeding episodes (97%) resolved with one injection of Altuviiio in the overall population. Weekly Altuviiio prophylaxis provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with Altuviiio for 52 weeks (group A) improved physical health (p<0.001), pain intensity (p = 0.03), and joint health (p = 0.01). Altuviiio had an acceptable side-effect profile, and the development of inhibitors to factor VIII was undetectable. The investigators concluded that once-weekly Altuviiio administration in patients with severe hemophilia A provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health.

In the ongoing XTEND-Kids study, the efficacy of weekly 50 IU/kg Altuviiio as routine prophylaxis in children < 12 years of age was evaluated as estimated by the mean annualized bleed rate (ABR). A total of 67 previously treated children (31 children <6 years of age and 36 children 6 to <12 years of age) were enrolled and received Altuviiio 50 IU/kg once weekly for 52 weeks for routine prophylaxis. An interim data analysis showed that subjects with at least 26 weeks of exposure (N=23), routine prophylaxis resulted in a mean ABR (95% CI) of 0.5 (0.2, 1.3) and a median (Q1, Q3) ABR of 0 (0, 1.3) for treated bleeds. For all bleeds (treated and non-treated), the mean ABR (95% CI) was 3.6 (1.6, 8.4) and the median (Q1, Q3) ABR was 0 (0, 4.5). The safety results were consistent with data from the XTEND-1 trial (Bioverativ Therapeutics, 2023; Sanofi, 2023).

Eloctate

The U.S. Food and Drug Administration (FDA) has approved Eloctate [Antihemophilic Factor (Recombinant), Fc Fusion Protein] for the control and prevention of bleeding episodes, perioperative (surgical) management and routine prophylaxis in adults and children with hemophilia A (Biogen Idec, 2014). Eloctate reduces the frequency of bleeding episodes with prophylactic infusions every three to five days, offering people with hemophilia A the potential to extend the interval between prophylactic infusions. Eloctate was developed by fusing B-domain deleted factor VIII to the Fc portion of immunoglobulin G subclass 1 (IgG1) which enables Eloctate to prolong the time the therapy remains in the body.

The recommended starting prophylactic regimen for Eloctate is 50 IU/kg every four days. Based on clinical response, the regimen may be adjusted in the range of 25 to 65 IU/kg and every three to five days (Biogen Idec., 2014).

In clinical trials, Eloctate was effective for both routine prophylaxis and to treat acute bleeding episodes with a favorable safety and tolerability profile (Biogen Idec, 2014). The approval of Eloctate is based on results from the global, Phase 3 A-LONG clinical study, as well as interim pharmacokinetic and safety data from the Phase 3 Kids A-LONG study.

The A-LONG study was an open-label, multi-center study that examined the efficacy, safety and pharmacokinetics of Eloctate in 165 previously treated males 12 years of age and older with severe hemophilia A (Biogen Idec, 2014). Results showed that adults and adolescents with severe hemophilia A achieved a statistically significant reduction of bleeding episodes in both of the study’s prophylaxis arms, relative to the on-demand treatment arm. In addition, 98 percent of bleeding episodes were controlled with one or two Elocttate infusions.

The study evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes, and on-demand dosing to treat bleeding episodes (Biogen Idec, 2014). In the individualized arm, each study participant started on a twice-weekly dosing regimen. Participants’ pharmacokinetic parameters were used to guide adjustments to dosing interval (every three to five days), and dose (25 to 65 IU/kg) to target a minimum factor VIII level of 1 to 3 IU/dL or higher as needed to maintain control of breakthrough bleeding episodes. In the study, the dose in the weekly prophylaxis arm was 65 IU/ kg/week. The overall median annualized bleeding rates (ABR), or projected number of bleeding episodes per year, reported in the study were 1.6 for the individualized prophylaxis arm, 3.6 for the weekly prophylaxis arm and 33.6 for the on-demand arm.

No participants in the A-LONG study developed inhibitors to Eloctate (Biogen Idec, 2014). One participant had a transient, positive neutralizing antibody test result, which was not confirmed upon repeat testing. There were no reports of serious vascular clots or serious allergic reactions. Across the routine prophylaxis and on-demand therapy arms, adverse reactions were reported in 5.5 percent of participants. Adverse reactions included arthralgia, malaise, upper abdominal pain, lower abdominal pain, angiopathy, bradycardia, chest pain, cough, dizziness, dysgeusia, cold and heat intolerance, headache, hypertension, joint swelling, myalgia, procedural hypotension and rash. Each event occurred in two or fewer study participants. Two participants were withdrawn from the study due to adverse reactions: one participant due to rash and one due to arthralgia.

The pediatric indication for Eloctate is supported by interim safety and pharmacokinetic results in 38 boys ages two to 11 years old from the Phase 3 Kids A-LONG study (Biogen Idec, 2014). These data showed that Eloctate was generally well-tolerated and no inhibitors were detected. The relative increase in half-life seen with Eloctate was consistent with findings in adults and adolescents. In comparison with adolescents and adults, children two to five years old have a shorter half-life and higher clearance of hemophilic factors (adjusted for body weight); therefore, a higher dose or more frequent dosing may be needed in this age group. In April 2014, Biogen Idec and Swedish Orphan Biovitrum (Sobi) reported positive top-line results from the completed Kids A-LONG study, which confirmed and expanded upon the interim data. Common adverse reactions (incidence of greater than or equal to 1 percent) reported in the A-LONG study were arthralgia and malaise.

Esperoct

On February 19, 2019, the FDA approved Esperoct (antihemophilic factor [recombinant], glycopegylated-exei], a coagulation Factor VIII concentrate for use in adults and children with hemophilia A for on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes. Esperoct is not indicated for the treatment of von Willebrand disease. Esperoct is a glycopegylated form of recombinant anti-hemophilic factor that temporarily replaces the missing coagulation Factor VIII needed for effective hemostasis in congenital hemophilia A patients. The Factor VIII in Esperoct is conjugated to a 40-kDa polyethylene glycol molecule which increases the half-life and decreases the clearance compared to the non-pegylated molecule. The administration of Esperoct increases plasma levels of Factor VIII and can temporarily correct the coagulation defect in hemophilia A patients, as reflected by a decrease in activated partial thromboplastin time (aPTT).

The FDA’s decision to approve Esperoct was based on clinical data collected from five Phase 3 multinational, open-label trials in children and adults, with severe hemophilia A (<1% endogenous Factor VIII activity) (NCT01731600, NCT01480180, NCT01489111, NCT03528551, and NCT02137850). One trial was subsequently partially randomized to evaluate two different prophylaxis regimens. All subjects were previously treated, which was defined as having received other Factor VIII products for ≥150 exposure days for adolescents and adults, and ≥50 exposure days for pediatric subjects. The key exclusion criteria across trials included known or suspected hypersensitivity to trial or related products and known history of Factor VIII inhibitors or current inhibitor ≥0.6 Bethesda units (BU).

The efficacy evaluation included 254 subjects, who received at least one dose of Esperoct, in the following trials:

Adolescent/adult trial: This trial included 186 subjects, 161 adults (18 to 65 years old) and 25 adolescents (12 to <18 years old); it consisted of a Main Phase and optional Extension Phase. During the Main Phase, 175 subjects received the prophylaxis regimen which consisted of 50 IU/kg every 4 days (Q4D), while 12 adults chose to be treated on-demand. (One subject changed from on-demand to prophylaxis and is counted in both groups.) Thirteen (7%) of 175 adults in the prophylaxis arm modified their dosing regimen to Q3-4D dosing for ease of use. All subjects received at least one dose of Esperoct and are evaluable for safety and efficacy. A total of 165 subjects (91%) completed the Main Phase of this trial. This extension compared two dose regimens: 75 IU/kg every 7 days (Q7D) and 50 IU/kg Q4D. The randomization was open to subjects who experienced 2 or fewer bleeds during the last 6 months in the Main Phase.
Pediatric trial: This trial included 68 subjects who were evenly divided with 34 in each age group, 0–<6 and 6–<12 years of age. All subjects received the same prophylaxis regimen of approximately 65 IU/kg (50–75 IU/kg) twice weekly. A total of 63 subjects (93%) completed the Main Phase.
Surgery trial: In the surgery trial, 33 previously treated adolescents/adults underwent 45 major surgeries. The dose level of Esperoct was chosen so that FVIII activity at least as recommended by World Federation of Hemophilia (WFH) guidelines was targeted. All subjects returned to the adolescent/adult trial after the surgery trial assessments were completed.

On-demand Treatment and Control of Bleeding Episodes: There were 1506 bleeds reported in 171 of 254 subjects across the completed clinical trials, and the most common bleed types were joint (65.2%), muscle (14.5%), and subcutaneous (8.9%). Doses used for treatment of bleeding episodes depended on age, treatment regimen and the severity of the bleed. Of the 1407 mild and moderate bleeding episodes in all subjects in the adolescent/adult study, the median dose used was 42 IU/kg. For subjects who were on the on-demand arm the median initial dose was 28 IU/kg and 88.4% of the bleeds were treated successfully with a single dose. In subjects receiving routine prophylaxis, the median initial dose was 52 IU/kg, and 76.4% of the bleeds were successfully treated with a single dose. Of the 15 severe bleeds, 12 (80%) required more than one dose with a total median dose of 111 IU/kg. In the pediatric study, 70 mild/moderate bleeds in children < 12 years old receiving routine prophylaxis were treated with a median initial dose of 64 IU/kg per injection, with 63% treated with a single injection. When needed, additional median doses of 62 IU/kg were used at approximately 24 hour intervals. The median total dose was 70 IU/kg per bleed.

Routine Prophylaxis in Adolescents/Adults: The efficacy of Esperoct in routine prophylaxis with Q4D dosing was demonstrated for the adult/adolescent population. In the extension part of the study, treatment success of the Q7D arm was not established. During the Main Phase of the adolescent/adult trial, 186 subjects had a total of 159 exposure years. The median annualized bleeding rate (ABR) for treated bleeds in adults and adolescents treated every 4 days was 1.2 (IQR: 0.0:4.3), and mean ABR was 3.0 (SD: 4.7). When including all bleeds (treated and non-treated), the median ABR was 1.2 (IQR: 0.0; 4.7) and the mean ABR was 3.3 (SD: 4.9).

Routine Prophylaxis in Children <12 Years of Age: Overall, 68 children below 12 years received prophylactic treatment with Esperoct at an average dose of approximately 65 IU/kg twice weekly. The prophylactic effect of Esperoct was demonstrated with a median ABR rate of 2.0 (IQR: 0.0; 2.8) and 2.0 (IQR: 0.0; 4.2) for treated bleeds and all bleeds respectively. The mean ABR (SD) for treated bleeds and all bleeds were 3.1 (7.1) and 4.4 (8.7), respectively. Of the 68 children, 22 (32%) did not experience any bleeding episodes and 29 (43%) did not experience any bleeding episodes that required treatment during the Main Phase of the trial. Of the 13 subjects with 17 documented target joints at baseline, 10 subjects (77%) and 14 target joints (82%) did not have any bleeds during the Main Phase of the trial.

Perioperative Management: The efficacy analysis of Esperoct in perioperative management included 45 major surgical procedures performed in 33 adolescent and adult subjects. The procedures included 15 joint replacements, 9 arthroscopic orthopedic interventions, 17 other orthopedic interventions, and 4 non-orthopedic surgeries. The clinical evaluation of hemostatic response during major surgery was assessed using a 4-point scale of excellent, good, moderate, or none. The hemostatic effect of Esperoct was rated as "excellent" or "good" in 43 of 45 surgeries (95.6%), while the effect was rated as "moderate" in 2 surgeries (4.4%). No surgery had an outcome rated as "none" or "missing."

The median pre-operative dose for adults and adolescents undergoing major surgeries was 52 IU/kg, and the median total dose was 702 IU/kg. During post-operative days 1-6, the median dose was 32 IU/kg at approximately 24 hour intervals. During post-operative days 7-14, the median dose was 36 IU/kg at approximately 28 hour intervals. The number of doses and duration of treatment varied by procedure.

The FDA clinical review of submitted data concluded that due to the PEG moiety, Esperoct has demonstrated a half-life 1.6 times longer than non-modified FVIII products. The efficacy of Esperoct was demonstrated for treatment of and prevention of spontaneous or traumatic bleeding in patients with Hemophilia A. Esperoct was effective in the perioperative setting for reduction of bleeding during surgery.Treatment, given as a single injection of a fixed Esperoct dose of every four days in adults and teenagers, and every 3–4 days in children, was shown to be an effective routine prophylactic to prevent bleeds. Adult and adolescent patients were able sustain a median annualized bleeding rate of 1.18 by using Esperoct 50 IU/kg every four days; and given the number of subjects who required rescue treatment and change to a more frequent dosing and the potential for selection bias for subjects who were selected for randomization, the every 7 day prophylaxis regimen is not recommended. In infants and children up to 12 years old, treatment was found to significantly improve their quality of life and satisfaction. Esperoct was also found to be an effective in controlling bleeding episodes and in managing bleedings prior to surgery. In all clinical trials and across all age groups, Esperoct was well-tolerated, and in general, its safety profile was described as similar to that of other long-acting factor VIII replacement therapies.

The most frequently reported adverse reactions (incidence greater than or equal to 1%) in clinical trials were rash, redness, itching (pruritus), and injection site reactions. The formation of neutralizing antibodies (inhibitors) to Factor VIII has occurred following administration of Esperoct. Patients should be monitored for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests (e.g., a chromogenic or one-stage clotting assay appropriate for use with Esperoct). If bleeding is not controlled with the recommended dose of Esperoct, or if the expected Factor VIII activity levels in plasma are not attained, then a Bethesda assay should be performed to determine if Factor VIII inhibitors are present. Esperoct is contraindicated in patients who have known hypersensitivity to Esperoct or its components (including hamster proteins).

Jivi

On August 30, 2018, the FDA approved antihemophilic factor (recombinant) PEGylated-aucl (Jivi) for the treatment of hemophilia A in adolescents and adults 12 years of age and over. This treatment has been approved for prophylactic, on-demand control, and perioperative management of bleeding in this population. The approval of Jivi was based on the Phase 2/3 PROTECT VIII trial (NCT01580293). This was a 36-week, multi-national, open label, partially randomized trial in 126 previously treated adolescent and adult patients (12 to 65 years of age). The trial consisted of three parts: Part A (Weeks 0 – 36) evaluated the efficacy and safety for on-demand and prophylactic treatment; an optional extension phase for subjects who completed Part A to accumulate at least 100 exposure days; and Part B evaluated the efficacy and safety during major surgery (i.e., perioperative management).

Jivi was engineered to have an extended half-life (17.9 hours) by using PEG-technology. Shah et al (2018) stated recombinant factor VIII (rFVIII) products with extended half-lives, such as Jivi, can potentially maintain higher FVIII levels for longer periods of time, thus providing improved bleeding protection vs standard-acting FVIII products. The aim of this study was to characterize the pharmacokinetic (PK) profile of Jivi from phase 1, phase 2/3 (PROTECT VIII) and phase 3 (PROTECT VIII Kids) clinical trials in adults, adolescents and children with severe haemophilia A. Patients with severe haemophilia A (FVIII <1%) with >50 FVIII exposure days (EDs) and no history of inhibitors were included in the phase 1 (18-65 years, ≥150 EDs), PROTECT VIII (12-65 years, ≥150 EDs) and PROTECT VIII Kids (<12 years, >50 EDs) trials. PK parameters were assessed following a 25-IU/kg or 60-IU/kg Jivi dose in the phase 1 study after the first and repeated infusion, in PROTECT VIII after the first and repeated 60-IU/kg infusion and in PROTECT VIII Kids after a single 60-IU/kg infusion. The chromogenic assay was used to assess FVIII activity. Compared with sucrose-formulated rFVIII, Jivi had reduced clearance that resulted in a ~1.4-fold increase in half-life and dose-normalized area under the curve (AUC). The Jivi PK profile was comparable after single- and repeated-dose administrations. Dose-proportional increases were observed between 25- and 60-IU/kg administrations. Jivi PK characteristics were age dependent, consistent with other FVIII products. The authors concluded that Jivi shows an extended half-life and increased AUC vs standard-acting FVIII products. These PK characteristics will result in higher FVIII levels for longer duration.

On-Demand Treatment and Control of Bleeding Episodes

The results from Part A were reported by Reding et al (2017), who stated Jivi (BAY 94-9027) is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. The objective of this study was to assess the efficacy and safety of Jivi for prophylaxis and on-demand treatment of bleeds in patients with severe hemophilia A. In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received Jivi for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg-1 body weight two times per week. A total of 388 bleeding episodes were treated with Jivi in the on-demand group; 317 bleeding episodes were treated in the prophylaxis groups. During the extension phase, 14 subjects receiving on-demand treatment and 107 subjects on routine prophylaxis had 514 and 428 total bleeds, respectively at the cut-off date for the interim analysis. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg-1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg-1 ) or every-7-days (60 IU kg-1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were successfully treated with 1 or 2 infusions in both the on-demand and prophylaxis groups. No patient developed a FVIII inhibitor. The authors concluded Jivi prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds.

Perioperative Management

A total of 17 subjects successfully completed 20 major surgeries in Part B of Study 1 (14 subjects with 17 surgeries) or the extension study (3 subjects with 3 surgeries), using Jivi for hemostasis. There were 6 non-orthopedic surgeries and 14 orthopedic surgeries (3 arthroplasties, 6 joint replacements, 3 synovectomies, and 2 other joint procedures). Treatment with Jivi provided ‘good’ or ‘excellent’ hemostatic control during all 20 major surgeries. The initial Jivi pre-surgery doses administered ranged between 2500 and 5000 IU. The median total dose per surgery was 219 IU/kg with a median of 35 IU/kg/infusion and a median of 7 infusions per surgery (up to 3 weeks). The median number of infusions on day of surgery was 2 (range 1 – 3).

An additional 17 minor surgeries were performed in 10 subjects during Part A of Study 1. The adequacy of hemostasis during minor surgeries was assessed as either ‘good’ or ‘excellent’ in all reported cases.

Kovaltry

The U.S. Food and Drug Administration approved Kovaltry antihemophilic factor VIII (recombinant) (Bayer) for the treatment of hemophilia A in children and adults. Kovaltry is an unmodified, full-length recombinant factor VIII product. The approval is based on results from the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials, which demonstrated that Kovaltry controls bleeds, and reduces frequency of bleeding episodes with routine prophylaxis in children and adults with hemophilia A when used two or three times per week.

The LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) Clinical Development Program consists of three multinational clinical trials designed to evaluate the pharmacokinetics, efficacy and safety of Kovaltry in subjects with severe hemophilia A (<1% FVIII:C). The combined trials evaluated Kovaltry in more than 200 children and adults with severe hemophilia A from 60 sites in 25 countries worldwide.

Kovatry, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for:

On-demand treatment and control of bleeding episodes
Perioperative management of bleeding
Routine prophylaxis to reduce the frequency of bleeding episodes.

Kovaltry is not indicated for the treatment of von Willebrand disease.

The clinical trial program was designed to evaluate KOVALTRY pharmacokinetics, safety, efficacy of prophylaxis, treatment of bleeds and perioperative management in adults, adolescents, and children with severe hemophilia A. LEOPOLD 1 was a multi-center, open-label, cross-over, uncontrolled study in adolescent and adult (age >12 years to <65 years) previously treated patients (PTPs) evaluating the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding with Kovaltry. The annualized bleeding rate (ABR) was the primary efficacy variable.

LEOPOLD 2 was a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult (age ≥12 years to <65 years) PTPs evaluating the superiority of prophylaxis over on-demand treatment with KOVALTRY over a one-year treatment period. ABR was the primary efficacy variable.

LEOPOLD Kids Part A was a multi-center, open-label, uncontrolled study in pediatric (<12 years of age) PTPs evaluating the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative management of bleeding with KOVALTRY. The primary efficacy variable was annualized number of total bleeds during routine prophylaxis that occurred within 48 hours of previous prophylaxis infusion.

Kovaltry is contraindicated in patients who have history of hypersensitivity reactions to the active substance, mouse or hamster protein, or other constituents of the product.

The most frequently reported adverse reactions in the clinical trials (>= 3%) were headache, pyrexia (fever), and pruritus (itchy rash).

Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, discontinue treatment with Kovaltry and administer appropriate treatment.

Development of Factor VIII neutralizing antibodies can occur. Perform an assay that measures Factor VIII inhibitor concentration if expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled as expected with administered dose

Kovaltry is available as lyophilized powder in single-use vials containing nominally 250, 500, 1000, 2000, or 3000 IU. Each vial of Kovaltry contains the labeled amount of recombinant Factor VIII in IU.

Recommended Dosing for Kovaltry: Individualize the patient's dose based on clinical response.

Adults and adolescents: 20 to 40 IU of Kovaltry per kg of body weight two or three times per week.

Children <12 years old: 25 to 50 IU of Kovaltry per kg body weight twice weekly, three times weekly, or every other day according to individual requirements.

Novoeight Antihemophilic Factor (Recombinant)

Novoeight is an antihemophilic factor (recombinant) that has been FDA approved for use in adults and chldren wiith hemophilia A for control and prevention of bleeding, perioperative management, or routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The FDA has also stated that Novoeight is not indicated for the treatment of von Willebrand disease. Dosage of Novoeight can be determined using the following formula: Dosage (IU) = Body Weight (kg) multiplied by Desired Factor VIII Increase (IU/dL or % normal) multiplies by 0.5 Novoeight is contraindicated in patients who have had life-threatening hypersensitivity reactions, including anaphylaxis, to Novoeight or its components, including hamster proteins (NovoNordisk, 2013)

Jimenez-Yuste et al (2015) evaluated the pharmacokinetics (PK) of turoctocog alfa in all age groups across clinical trials. They utilized data from previously treated patients with severe hemophilia A (Factor VIII activity level ≤1%) with no history of Factor VIII inhibitors, in a non-bleeding state. The PK was assessed following a wash-out period and a subsequent single intravenous (i.v.) 50 IU/kg dose of turoctocog alfa and blood was sampled during a 48-hour period post-dose. Standard PK parameters were estimated based on plasma FVIII activity versus time (PK profiles) using non-compartmental methods and a population PK analysis was conducted. The authors reported that from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after first dose of turoctocog alfa were comparable with the results obtained after first dose while similar PK characteristics were shown for different lots and strengths of the drug product. The authors reported that AUC and t½ tended to increase with increasing age, with lower AUC and shorter t½ seen in children compared with adolescents and adults. The authors concluded that PK characteristics of turoctocog alfa have been shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products.

Santagostino et al (2015) stated that recombinant factor VIII products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A and they conducted an investigation from the multinational, open-label guardian(^™) clinical trials. They evaluated the hemostatic response of turoctocog alfa (NovoEight(^®) in patients with severe haemophilia A undergoing surgery. All patients had a minimum of 50 exposure days to any Factor VIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4-59 years., of which, 15 procedures were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as 'excellent' or 'good' haemostatic outcome) and turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg(-1) . The authors stated that the mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, they did not identify any safety issues and no thrombotic events were observed and none of the patients developed Factor VIII inhibitors. The authors concluded that the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery.

Nuwiq

The U.S. Food and Drug Administration (FDA) has approved Nuwiq, Antihemophilic Factor (Recombinant), an intravenous therapy for adults and children living with Hemophilia A (Octapharma, 2015). Nuwiq is a B-domain deleted recombinant Factor VIII (FVIII) derived from a human cell-line designed for the treatment of patients with Hemophilia A, congenital FVIII deficiency. The product was approved for on-demand treatment and control of bleeding episodes; routine prophylaxis to reduce the frequency of bleeding episodes; and perioperative management of bleeding.

The initial global clinical study program for Nuwiq commenced with a pharmacokinetic (PK) evaluation in an open-label, multi-center clinical trial of 22 (20 adults, 2 adolescents) previously treated patients (Octapharma, 2015). In this study, Nuwiq demonstrated a mean half-life of 17.1 hours using a one-stage clotting assay in adults. Nuwiq was also evaluated in children using a one-stage clotting assay with a mean half-life of 11.9 hours for ages 2 to 5; and a mean half-life of 13.1 hours for ages 6 to 12. These PK results for mean half-life were longer than earlier generations of recombinant FVIII products currently available in the U.S.

The second set of global clinical studies for Nuwiq also evaluated overall efficacy and tolerability in three prospective, open-label clinical studies in previously treated patients with severe hemophilia A (Octapharma, 2015). Across all clinical studies, a total of 135 patients with Hemophilia A were treated with Nuwiq, including 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11. These 135 patients were treated with a total of 16,134 infusions over 15,950 exposure days using Nuwiq.

In a study of 32 adults, overall prophylactic efficacy of Nuwiq for spontaneous bleeds was rated as excellent or good in 92% of patients (Octapharma, 2015). In a study of 59 children, prophylactic efficacy for spontaneous bleeds was rated as excellent or good in 97% of patients. The mean annualized bleeding rates (ABR) for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults. For hemophilia A patients receiving Nuwiq prophylaxis compared to on-demand treatment, the ABR was reduced 96% for adults and 93% for children. Treatment of breakthrough bleeds during Nuwiq prophylaxis was rated as excellent or good in 30 of 30 (100%) bleeds in adults and for 89 of 108 (82%) bleeds in children. For on-demand treatment with Nuwiq in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was excellent or good in 931 of 986 (94%) bleeds. Overall efficacy in surgical prophylaxis was rated excellent or good in 32 of 33 (97%) procedures using Nuwiq.

In all clinical studies, Nuwiq had a total of 7 reported adverse events (Octapharma, 2015). Each of these adverse events occurred one time with a rate of 0.7% across all 135 patients. These events were parathesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

Nuwiq is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis to the product or its components (Octapharma, 2015). Hypersensitivity reactions, including anaphylaxis, are possible. The labeling recommends, should symptoms occur, discontinue Nuwiq and administer appropriate treatment. Development of Factor VIII neutralizing antibodies (inhibitors) may occur. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor VIII inhibitor concentration. The labeling recommends monitoring all patients for Factor VIII activity and development of Factor VIII inhibitor antibodies.

Recombinant Antihemophilic Factor

Recombinant antihemophilic factor – plasma/albumin free method (rAHF-PFM) (Advate, Baxter Healthcare, Westlake Village, CA) is produced using a protein-free manufacturing process. Based on clinical studies submitted to the FDA comparing rAHF-PFM to a standard recombinant antihemophilic factor (rAHF) (Recombinate, Baxter Healthcare), the FDA has concluded that rAHF-PFM is therapeutically equivalent to rAHF. Human or animal plasma proteins or albumin are used in the cell-culture process of rAHF, with the theoretical risk of transmission viruses, prions or other pathogens (Schesinger and Ragni, 2002; Adis, 2003). The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation has recommended that "all efforts should be made to remove human albumin from recombinant factor VIII products" and that "increased efforts should be made to eliminate human and bovine proteins from the manufacturing process of recombinant products." However, there are no documented episodes of transmission of HIV, West Nile Virus, Creutzfeld-Jacob Disease or other such viral pathogens from rAHF products currently on the market.

Factor VIII Inhibitory Antibodies and Anti-inhibitor Coagulant Complex [Human] FEIBA

U.S. Food and Drug Administration (FDA)-Approved Indications for FEIBA

Hemophilia A and hemophilia B with inhibitors

Compendial Use for FEIBA

Acquired hemophilia A

The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. Two hemostatic agents with different bypassing mechanisms have been used in the treatment of patients with inhibitors:

rFVIIa and
activated prothrombin complex concentrate (APCC).

Berntorp (2009) noted that the bypassing agents FEIBA anti-inhibitor coagulant complex and rFVIIa have been established as safe and effective therapies for treating bleeding episodes in hemophilia patients with inhibitors. However, the efficacy of each bypassing agent can vary, and neither agent is universally effective. The reasons for such variability have yet to be confirmed, but may involve patient-specific factors and the mechanisms of action and pharmacokinetic profiles of these 2 agents. Gomperts et al (2008) noted that FEIBA VH and rFVIIa are currently available to circumvent the need for factor FVIII in hemophilia A patients with inhibitors, yet their hemostatic efficacy can be unpredictable. As the results of the FEIBA NovoSeven study illustrated, patients may respond better to one bypassing agent than the other. Furthermore, guidelines from an expert panel reflect that responsiveness to bypassing therapy may change from one bleed to the next in the same patient and even from hour to hour during the course of a single bleeding event. These findings underscored the need to have both bypassing products available to treat bleeding episodes in inhibitor patients, to frequently evaluate the efficacy of hemostasis during the course of a bleeding event, and to switch products early if the response to treatment is unsatisfactory.

A cost-effectiveness analysis found that a rFVIIa regimen appears to be a less expensive treatment option in inhibitor patients with minor-to-moderate bleeds. Joshi et al (2006) compared the cost-effectiveness of 3 treatment regimens using rFVIIa, and APCC (FEIBA vapor heated), for home treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors. The regimens consisting of 1st-, 2nd-, and 3rd-line treatments were: rFVIIa-rFVIIa-rFVIIa; APCC-rFVIIa-rFVIIa; and APCC-APCC-rFVIIa. Patients not responding to 1st-line treatment were administered 2nd-line treatment, and those failing 2nd-line received 3rd-line treatment. Using literature and expert opinion, the model structure and base-case inputs were adapted to the U.S. from a previously published analysis. The percentage of evaluable bleeds controlled with rFVIIa and APCC were obtained from published literature. Drug costs (2005 US$) based on average wholesale price were included in the base-case model. Uni-variate and probabilistic sensitivity analyses (2nd-order Monte Carlo simulation) were conducted by varying the efficacy, re-bleeding rates, patient weight, and dosing to ascertain robustness of the model. In the base-case analysis, the average cost per resolved bleed using rFVIIa as 1st-, 2nd-, and 3rd-line treatment was $28,076. Using APCC as 1st-line and rFVIIa as 2nd- and 3rd-line treatment resulted in an average cost per resolved bleed of $30,883, whereas the regimen using APCC as 1st- and 2nd-line, and rFVIIa as 3rd-line treatment was the most expensive, with an average cost per resolved bleed of $32,150. Cost offsets occurred for the rFVIIa-only regimen through avoidance of 2nd and 3rd lines of treatment. In probabilistic sensitivity analyses, the rFVIIa-only strategy was the least expensive strategy more than 68 % of the time. The authors concluded that the management of minor-to-moderate bleeds extends beyond the initial line of treatment, and should include the economic impact of re-bleeding and failures over multiple lines of treatment. In the majority of cases, the rFVIIa-only regimen appears to be a less expensive treatment option in inhibitor patients with minor-to-moderate bleeds over 3 lines of treatment.

Steen Carlsson et al (2008) compare cost and outcome of APCC and rFVIIa in the treatment of joint bleeds. The analyses were based on the FENOC (FEIBA NovoSeven Comparative Study) cross-over study where 48 patients used APCC and rFVIIa to treat 2 joint bleeds. Incremental cost-effectiveness ratios were calculated for 3 outcome measures and the variation in cost was analyzed using 2 alternative regression methods. Results were subjected to sensitivity analyses. Key determinants of cost were prescribed dose, body weight and treatment in addition to protocol. The cost of APCC was on average lower than rFVIIa. At all but one time-point, patients rated slightly higher (but not statistically significantly) percentages of treatment efficacy and stopping of the bleed by APCC. The reported reduction in pain from start of treatment up to 48 hours varied considerably among individuals. The different relative prices in the U.S., Turkey and Sweden mattered, but did not reverse the main results. The authors concluded that the cost per episode was significantly lower for APCC. The large individual-level variation in reduction of pain supports decisions that consider the individual patient's experience and that accept trade-offs between cost and reduction in pain rather than focusing on cost only.

In an unified Bayesian meta-regression model, Treur et al (2009) analyzed the published efficacy of rFVIIa and/or APCC as on-demand treatments for joint bleeds in hemophilia patients with inhibitors. A systematic search was carried out to identify studies reporting on dosage and efficacy of rFVIIa and APCC in the treatment of joint bleeds in the target patient population. Data were abstracted and included in the model and adjusted for potential sources of heterogeneity. Pooled efficacy levels for typical rFVIIa and APCC regimens were estimated. A total fo 17 studies, collectively reporting on more than 2,000 joint bleeds, were included. Medication type combined with dosage was the only significant explanatory parameter. The model predicts that a typical regimen of 90 microg kg(-1) rFVII repeated every 3 hours if needed results in cumulative joint bleed resolution of 66 %, 88 % and 95 % after 12, 24 and 36 hours, respectively. In comparison, a typical regimen of 75 IU kg(-1) APCC repeated every 12 hours if needed results in cumulative joint bleed resolution of 39 %, 62 % and 76 %, respectively. These differences were statistically significant and were also robust in sensitivity analyses. This analysis suggested that a typical rFVIIa regimen will resolve joint bleeds more effectively than a typical APCC regimen after 12, 24 and 36 hours.

Anti-inhibitor coagulant complex, factor eight inhibitor bypassing activity-vapor heated (FEIBA VH), is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors. In addition, the use of FEIBA VH has been described in a few non-hemophiliacs with acquired inhibitors to factors VIII, XI, and XII.

Awad and Cocchio (2013) stated that PCC products are emerging as alternative strategies for reversing anticoagulant pharmacotherapy. Factor eight inhibitor bypassing activity (FEIBA, or anti-inhibitor coagulant complex) is an activated PCC (aPCC). Although FEIBA is approved by the FDA to control spontaneous bleeding episodes and to prevent bleeding with surgical interventions in hemophilia A and hemophilia B patients with inhibitors to factor VIII, recent data have suggested that the product may be used off-label as an anticoagulant-reversal agent. These researchers evaluated the safety and effectiveness of aPCC products in reversing anticoagulant pharmacotherapy. They searched online databases for English-language publications that discussed this topic. The EMBASE, MEDLINE, and International Pharmaceutical Abstracts databases were used. These researchers evaluated all articles published in the English language identified from the data sources. They included studies conducted in human subjects and in in-vitro and in-vivo models in this review. Current published evidence suggested that the use of an aPCC, compared with fresh-frozen plasma, is associated with a significantly faster correction of supra-therapeutic INRs secondary to warfarin therapy. Conflicting evidence exists regarding the ability of aPCCs to reverse the prolonged bleeding times caused by the anticoagulant agents including dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and fondaparinux (Arixtra). The authors concluded that the theoretical risks of thrombosis associated with PCC products must be carefully considered before they are administered to patients who require coagulation therapy. The use of aPCCs to reverse the anticoagulant effects of warfarin, dabigatran, or rivaroxaban should be limited because of the lack of safety and effectiveness data in humans. Moreover, the safety of aPCCs in off-label indications has not been adequately assessed.

Stewart and Pettit (2013) summarized their experiences with FEIBA for the reversal of warfarin-related bleeding in a community hospital. A protocol was put in place in March of 2011, which outlined the use of FEIBA for the emergent reversal of warfarin-related coagulopathy. A fixed low-dose was given based on INR. For an INR less than 5.0, 500 U of FEIBA was administered’ for an INR greater than or equal to 5.0, 1,000 U of FEIBA was given. Intravenous vitamin K was given concurrently regardless of INR. A total of 16 patients were treated with FEIBA per the protocol. Average patient age was 73 years. Intracranial hemorrhage was the most common indication for reversal. Mean pre-treatment INR was 3.56 (1.3 to 6.8); mean post-treatment INR was 1.16 (1.01 to 1.32). Two of the patients required a second 500-U dose, per the protocol, for an INR that had not yet normalized. Bleeding appeared clinically controlled in 93 % of cases; 87 % of patients survived to discharge. There were no signs or symptoms of thrombosis in any of the cases. The authors concluded that emergent reversal of warfarin utilizing a fixed low-dose of FEIBA appears to be effective, consistent, and safe. Moreover, they stated that further comparator studies with other reversal agents are needed.

Antihemophilic Factor [Recombinant], Porcine Sequence (Obizur)

U.S. Food and Drug Administration (FDA)-Approved Indications

Obizur is indicated for the on-demand treatment and control of bleeding episodes in adults with acquired hemophilia A.
Limitations of Use:
- Safety and efficacy of Obizur has not been established in patients with a baseline anti-porcine factor VIII inhibitor titer of greater than 20 BU.
- Obizur is not indicated for the treatment of congenital hemophilia A or von Willebrand disease.

On October 24, 2014, the FDA approved Obizur [anti-hemophilic factor (recombinant), porcine sequence] for the treatment of bleeding episodes in adults with acquired hemophilia A (acquired Factor VIII [FVIII] deficiency). Obizur contains a recombinant analog of porcine FVIII. Porcine FVIII is used because it is similar to human FVIII to be effective in blood clotting, but is less likely to be affected by the antibodies against human FVIII that are present in individuals with acquired hemophilia A. The safety and effectiveness of Obizur was evaluated in a clinical trial of 29 adults with acquired hemophilia A and who received Obizur to treat a serious bleeding episode. The trial demonstrated the effectiveness of Obizur in the treatment of bleeding episodes. No safety concerns were identified in the trial.

According to the Prescribing Information, the safety and efficacy of Obizur has not been established in patients with a baseline anti-porcine factor VIII inhibitor titer of greater than 20 BU. Furthermore, Obizur is not indicated for the treatment of congenital hemophilia A or von Willebrand disease.

Factor IX Products

U.S. Food and Drug Administration (FDA)-Approved Indications

Table: U.S. Food and Drug Administration (FDA)-Approved Indications
Alphanine SD	coagulation factor IX [human]	Hemophilia B
Alprolix	coagulation factor IX [recombinant], Fc fusion protein	Hemophilia B
Benefix, Ixinity, Rixubis	coagulation factor IX [recombinant]	Hemophilia B
Idelvion	coagulation factor IX [recombinant], albumin fusion protein	Hemophilia B
Rebinyn	coagulation factor IX [recombinant], glycoPEGylated	Hemophilia B

Note: Coagulation factor IX [human] (Mononine) has been discontinued by CSL Behring, LLC as of September 2020.

Alprolix

The U.S. Food and Drug Administration approved Alprolix (Biogen Idec, Cambridge, MA), Coagulation Factor IX (Recombinant), Fc Fusion Protein, for use in adults and children who have hemophilia B to help control and prevent bleeding episodes, manage bleeding during surgical procedures, and prevent or reduce the frequency of bleeding episodes (prophylaxis). Alprolix is designed to require less frequent injections when used to prevent or reduce the frequency of bleeding. Alprolix consists of the Factor IX molecule linked to a protein fragment, Fc, to make the product last longer in circulation. Alprolix received orphan-drug designation for this use by the FDA because it is intended for treatment of a rare disease or condition.

The safety and efficacy of Alprolix were evaluated in a multi-center clinical trial that compared each of two prophylactic treatment regimens to on-demand treatment. Powell, et al. (2013) conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of Alprolix for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter, or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of Alprolix per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and Alprolix. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. As compared with recombinant factor IX, Alprolix exhibited a prolonged terminal half-life (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving Alprolix; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. The authors concluded that prophylactic Alprolix, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B.

One IU of Alprilox per kg body weight increases the circulating level of Factor IX by 1%. The recommended dose for routine prophylaxis is 50 IU/kg once weekly or 100 IU/kg once every 10 days, with dosing regimen adjusted based upon individual response. For control of minor and moderate bleeding episodes (for example, uncomplicated hemarthoses, superficial muscle bleeding (except iliopsoas) without neurovascular compromise, superficial soft tissue bleeding, bleeding of mucous membranes) requires a circulating factor IX level of 30 to 60 IU/dL or 30 to 60 percent of normal). For control of major bleeding (for example, iliopsoas and deep muscle bleeding with neurovascular injury, or substantial blood loss; pharyngea, retropharyngeal, retroperitoneal or CNS bleeding) requires a circulating factor IX level of 80 to 100 IU/dL or 80 to 100 percent of normal. For minor surgery (including uncomplicated dental extraction), the required circulating Factor IX level is 50 to 80 IU/dL or 50 to 80% normal. For major surgery, the required circulating Factor IX level is 60 to 100 IU/dL or 60 to 100 percent of normal.

Idelvion

U.S. Food and Drug Administration (FDA) has approved Idelvion [Coagulation Factor IX (Recombinant), Albumin Fusion Protein], a long-acting albumin fusion protein linking recombinant coagulation factor IX with recombinant albumin, for the treatment of hemophilia B. Idelvion is a long-acting factor IX therapy that delivers high-level protection with up to 14-day dosing in appropriate patients. This dosing interval has been achieved while maintaining high levels of factor activity, above 5 percent over 14 days at 75 IU/kg. This reduces the monthly number of units needed for prophylaxis therapy.

Idelvion was engineered to extend the half-life of recombinant factor IX through fusion with recombinant albumin. Recombinant albumin was used as a fusion partner for the coagulation factor proteins due to its long physiological half-life.

Idelvion is indicated in children and adults with hemophilia B (congenital factor IX deficiency) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes; on-demand control and prevention of bleeding episodes; and the perioperative management of bleeding (around the time of surgery). Idelvion is not indicated for induction of immune tolerance in patients with hemophilia B.

The data from PROLONG-9FP showed median annualized spontaneous bleeding rates (AsBR) of zero and factor IX activity levels above 5 percent in patients using Idelvion prophylactically (Santagostino, et al., 2016). According to the World Federation of Hemophilia, patients with factor IX activity levels above 5 percent (and below 50 percent) are considered to have mild hemophilia. This result was achieved for both 14-day dosing and 7-day dosing. The data for on-demand therapy showed that 94 percent of bleeds were controlled with one infusion, while 99 percent were controlled with one or two infusions. The most common adverse reaction in clinical trials (incidence > 1%) was headache.

Idelvion is contraindicated in patients who have had life-threatening hypersensitivity to the product or its components, including hamster proteins.

Hypersensitivity reactions, including anaphylaxis, are possible. Advise patients who self-administer to immediately report symptoms of hypersensitivity, including angioedema, chest tightness, hypotension, generalized urticaria, wheezing, and dyspnea. If symptoms occur, discontinue Idelvion and administer appropriate treatment.

Development of neutralizing antibodies (inhibitors) to Idelvion may occur. If expected factor IX activity plasma levels are not attained or bleeding is not controlled with appropriate dose, perform an assay to measure factor IX inhibitor concentration. Factor IX activity assay results may vary with the type of activated partial thromboplastin time reagent used.

Thromboembolism (e.g., pulmonary embolism, venous thrombosis, and arterial thrombosis) can occur when using factor IX-containing products. In addition, nephrotic syndrome has been reported following immune tolerance induction in hemophilia B patients with factor IX inhibitors and allergic reactions to factor IX.

Ixinity

Coagulation factor IX (recombinant) (IXINITY) is a purified protein containing 415 amino acids, and is formulated as a sterile powder to be reconstituted with sterile water for injection for intravenous administration. Initial dosage of IXINITY is calculated based on the empirical finding that one international unit (IU) of IXINITY per kg of body weight increases the circulating level of factor IX by 0.98 international units/dL of plasma in adults and children greater than or equal to 12 years of age. For incremental recovery in previously treated patients, the dose is titrated based on the patient’s clinical response and individual pharmacokinetics, especially incremental recovery and half-life (Cangene Corporation, 2015).

A prospective, open-label, uncontrolled study of 77 subjects evaluated IXINITY for treatment of hemophilia B or for perioperative management (76 male, 1 female carrier). Previously treated patients were defined as patients with a minimum of 150 exposures to another factor IX preparation. For control and prevention of bleeding episodes analysis, a total of 508 bleeding episodes were treated with IXINITY, of which 360 bleeding episodes (70.9%) resolved after a single infusion of IXINITY and in 66 episodes (13%) after 2 infusions. The analysis of data further illustrated that for 24 bleeding episodes (4.7%), 5 or more infusions were required and that these episodes were predominantly related to muscle bleeds, target joints, or trauma (Cangene Corporation, 2015).

For perioperative management, IXINITY was used in 19 major surgeries in 16 male, previously treated patients between 12 and 56 years of age. Efficacy of IXINITY was defined as an estimation of blood loss at the time of surgery and at 12 and 24 hours post-operatively. INIXITY, which was administered during major surgical procedures as bolus (n=13) or continuous infusion (n=6), was rated by the surgeon as adequate or better in controlling hemostasis post-surgery, and blood loss at surgery was reported as expected or less than expected in all instances (Cangene Corporation, 2015).

Rebinyn

On May 31, 2017, Novo Nordisk announced the U.S. FDA approval for the Biologics License Application (BLA) for Rebinyn, a glycoPEGylated recombinant human coagulation factor IX concentrate. Rebinyn, brand name for nonacog beta pegol (N9-GP), is indicated for on-demand treatment and control of bleeding episodes, and the perioperative management of bleeding in adults and children with hemophilia B. BLA approval was based on the efficacy and safety from four paradigm™ clinical trials, and review by the Blood Products Advisory Committee. Novo Nordisk expects to launch Rebinyn in the U.S. in the first half of 2018.

Collins et al. (2014) conducted a multinational, randomized (prophylaxis group only), single-blind, phase 3 trial (Paradigm™ 2) which investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 patients (males aged 13 to 70 yrs) previously treated for hemophilia B (FIX activity ≤2 IU/dL). Patients were randomized to two routine treatment arms, either for prophylaxis 10 IU/kg or 40 IU/kg once-weekly for 52 weeks, or to on-demand treatment of 28 weeks. Of the 345 bleeding episodes treated, there was an estimated 92.2% success rate. The median annualized bleeding rates were 1.04 in the 40 IU/kg prophylaxis group, 2.93 in the 10 IU/kg prophylaxis group, and 15.58 in the on-demand treatment group. In the 40 IU/kg group, 10 (66.7%) of 15 patients experienced no bleeding episodes into target joints compared with 1 (7.7%) of 13 patients in the 10 IU/kg group. The authors concluded that their prospective trial demonstrated that nonacog beta pegol was effective for the treatment of bleeding episodes in both prophylaxis and on-demand patients. They note that once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL. Although data suggests that once-weekly prophylaxis may provide a safe alternative for the prevention and treatment of bleeding episodes, the authors state that further evaluations in subsequent extension trials will hopefully confirm their findings. (Clinicaltrials.gov NCT01333111)

Escobar et al. (2017) conducted an open-label, multicenter, non-randomized, non-controlled, phase 3 surgery trial (Paradigm™ 3) aimed as assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 patients (age 13 to 70 yrs of age) previously treated for hemophilia B (FIX activity below or equal to 2%). All patients received preoperative bolus of Rebinyn 80 IU/kg on the day of surgery, and post-operatively received infusions of 40 IU/kg at the investigator’s discretion, for up to 3 weeks after surgery. Intraoperative hemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. No unexpected intra- or postoperative complications were observed. The authors concluded that their results indicate that nonacog beta pegol (Rebinyn) was safe and effective for patients with hemophilia B in the perioperative setting. (Clinicaltrials.gov NCT01386528)

Young et al (2016) conducted an international extension trial (Paradigm™4) which investigated the safety and efficacy of nonacog beta pegol in 71 hemophilia B patients (FIX activity ≤2%; aged 13-70years) who had previously participated in the phase 3 pivotal Paradigm™2 or surgery (paradigm™3) trials. Patients chose to continue treatment with either one of two once-weekly prophylaxis arms (10 IU/kg or 40 IU/kg), or an on-demand arm (40 IU/kg for mild/moderate bleeds; 80 IU/kg for severe bleeds). The primary objective was to evaluate immunogenicity, and key secondary objectives included assessing safety and hemostatic efficacy in the treatment and prevention of bleeds. No patient developed an inhibitor and no safety concerns were identified. The success rate for the treatment of reported bleeds was 94.6%; most (87.9%) resolved with one injection. The mean FIX activity trough achieved for 10 and 40 IU once weekly was 9.8% and 21.3%, respectively. The authors concluded that nonacog beta pegol (Rebinyn) showed good prophylactic protection and control of bleeding, without safety issues identified, in previously treated hemophilia B patients. (Clinicaltrials.gov NCT01395810)

Pediatric trial: Carcao et al (2016) conducted an open label, phase 3 trial (Paradigm™5) which evaluated the safety and efficacy of nonacog beta pegol (Rebinyn) in 25 pediatric previously treated hemophilia B patients (males aged 1-12 yrs old, FIX ≤ 2%). Patients received routine treatment with Rebinyn 40 IU/kg once-weekly for 52 weeks. Forty-two bleeds in 15 patients were reported to have been treated with the overall success rate of 92.9%. Most bleeds (85.7%) resolved after one dose. The median annualized bleeding rates (ABR) were 1.0 in the total population, 0.0 in the 0-6-year group, and 2.0 in the 7-12-year group; the estimated mean ABRs were 1.44 in the total population, 0.87 in the 0-6-year group, and 1.88 in the 7-12-year group. For 22 patients who had previously been receiving prophylaxis, the estimated mean ABR was 1.38 versus a historical ABR of 2.51. Estimated mean steady-state FIX trough levels were 0.153 IU mL(-1) (0-6 years) and 0.190 IU mL(-1) (7-12 years). The authors concluded that the results show that Reinyn was well tolerated and that 40 IU/kg dose provided effective once-weekly prophylaxis and hemostasis when bleeds were treated. (Clinicaltrials.gov NCT01467427).

Rixubis

On June 27, 2013, the FDA approved Rixubis [Coagulation Factor IX (Recombinant)] for use in people with hemophilia B who are 16 years of age and older. Rixubis is indicated for the control and prevention of bleeding episodes, peri-operative (period extending from the time of hospitalization for surgery to the time of discharge) management, and routine use to prevent or reduce the frequency of bleeding episodes (prophylaxis). Rixubis is a purified protein produced by recombinant DNA technology. It does not contain human or animal proteins. It is supplied in single-use vials of freeze-dried powder and is administered by intravenous injection after reconstitution with sterile water for injection. When used for the routine prevention of bleeding episodes, it is administered twice-weekly. The effectiveness of Rixubis was evaluated in a multi-center study in which a total of 73 male patients between 12 and 65 years of age received Rixubis for routine prophylaxis or as needed in response to symptoms of bleeding (on-demand). Overall, patients in the prophylaxis study had a 75 % lower annual bleeding rate when compared to patients who have historically received on-demand treatment. An additional study in a pediatric population is currently ongoing. Although serious side effects including anaphylaxis can occur, the most common side effects observed in patients in clinical studies were dysgeusia, pain in an extremity, and atypical blood test results.

An UpToDate review on "Treatment of hemophilia" (Hoots, 2013) states that "Recombinant human factor IX has been genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line. It has been proven to be safe and effective in the treatment of patients with previously treated and previously untreated hemophilia B, with a half-life of 16 to 17 hours. The product has no added albumin, giving it a theoretical advantage over plasma-derived concentrates. The volume of distribution of recombinant factor IX is larger than that for plasma-derived factor IX, with a more pronounced increase in infants and children. Available products include BeneFIX and Rixubis, which was licensed by the US Food and Drug Administration in 2013".

Recombinant Factor IX

Franchini et al (2013) summarized the current knowledge on treatment strategies for hemophilia B, focusing on recombinant FIX (rFIX) products either clinically used or in development. There is only 1 rFIX product that is licensed to treat hemophilia B patients. From the analysis of the literature data presented in this review, the authors concluded that this rFIX product has demonstrated an excellent safety profile and excellent clinical effectiveness for halting and preventing bleeds in hemophilia B patients. While prophylaxis has emerged as the best therapeutic strategy for such patients because of its ability to prevent hemophilic arthropathy, and to improve patients' quality of life, the pharmacokinetically tailored dosing of rFIX is another key point when planning hemophilia B treatment, as it allows optimization of the factor concentrate usage.

Windyga et al (2014) stated that BAX326 is a rFIX manufactured without the addition of any materials of human or animal origin, and with 2 viral inactivation steps (solvent/detergent treatment and 15 nm nano-filtration). The aim of this prospective trial was to investigate the pharmacokinetics, hemostatic efficacy and safety of BAX326 in previously treated patients aged 12 to 65 years with severe or moderately severe hemophilia B. BAX326 was safe and well-tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7 % incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC0-72 h per dose. Twice-weekly prophylaxis [mean duration 6.2 (+/- 0.7) months; 1.8 (+/- 0.1) infusions per week, 49.5 (+/- 4.8) IU kg-1 per infusion] was effective in preventing bleeding episodes, with a significantly lower (79 %, p < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43 %) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7 %) were controlled with 1 to 2 infusions of BAX326. Hemostatic efficacy at resolution of bleed was rated excellent or good in 96.0 % of all treated bleeding episodes. The authors concluded that these findings indicated that BAX326 is safe and effectives in treating bleeds and routine prophylaxis in patients aged 12 years and older with hemophilia B.

Factor IX Complex [Human] (Profilnine)

U.S. Food and Drug Administration (FDA)-Approved Indications for Profilnine

Hemophilia B

Compendial Uses for Profilnine

Bleeding due to low levels of liver-dependent coagulation factors
Factor II deficiency

Hemblibra (emicizumab-kxwh)

U.S. Food and Drug Administration (FDA)-Approved Indications

Hemlibra is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older with hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors.

On November 16, 2017, Genentech announced the FDA approval of Hemlibra (emicizumab-kxwh), a bispecific factor IXa- and factor X-directed antibody, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients with hemophilia A with factor VIII inhibitors. On October 4. 2018, the FDA also approved emicizumab in patients with hemophilia A, but without factor VIII inhibitors. The efficacy of Hemlibra for routine prophylaxis in patients with hemophilia A with factor VIII inhibitors was evaluated in three clinical trials in adults and adolescents (HAVEN 1 AND HAVEN 4) and a pediatric study (HAVEN 2). The efficacy of Hemlibra for routine prophylaxis in patients with hemophilia A without FVIII inhibitor was evaluated in adults and adolescents (HAVEN 3 and HAVEN 4).

Oldenburg et al. (2017) conducted a mulitcenter, open-label, randomized, phase 3 trial (HAVEN 1; NCT02622321) to evaluate the efficacy and safety of once-weekly subcutaneous emicizumab prophylaxis in persons (n = 109; 12 years of age or older) with hemophilia A with factor VIII inhibitors. Male participants who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. The results reflected that those who received emizizumab prophylaxis had a statistically significant reduction in treated bleeds of 87 percent (95 percent CI: 72.3; 94.3, p<0.0001) compared to those who received no prophylaxis. Furthermore, emicizumab prophylaxis resulted in a statistically significant reduction in treated bleeds of 79 percent (95 percent CI: 51.4; 91.1, p=0.0003) compared to previous treatment with bypassing agent prophylaxis collected in a non-interventional study prior to enrollment. Thus, emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors.

The HAVEN 2 study (NCT02795767) is a single-arm, multicenter, open-label, phase 3 trial that is evaluating the efficacy and safety of once-weekly subcutaneous emicizumab prophylaxis in children younger than 12 years of age who have hemophilia A with inhibitors to factor VIII. Interim results showed that 87 percent (95 percent CI: 66.4; 97.2) of children (n=23) who received emicizumab prophylaxis experienced zero treated bleeds. In an intra-patient analysis of 13 children who had participated in the non-interventional study, emicizumab prophylaxis resulted in a 99 percent reduction in treated bleeds compared to previous treatment with a bypassing agent prophylaxis either as prophylaxis (n=12) or on-demand (n=1). The most common adverse events (AEs) occurring in 10 percent or more of people treated with emicizumab in pooled studies were injection site reactions, headache and arthralgia (Genentech, 2017).

Mahlangu et al (2018) conducted a phase 3, multicenter trial (HAVEN 3; NCT02847637) to investigate the use of emicizumab use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors. Patients were randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study. A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors. The authors concluded that emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis

The HAVEN 4 study (NCT03020160) was a single-arm, multicenter, open-label, clinical trial in 41 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A with or without FVIII inhibitors who previously received either episodic (on demand) or prophylactic treatment with FVIII or bypassing agents. Patients received emicizumab prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 6 mg/kg once every four weeks thereafter. Efficacy was evaluated in a subgroup of 5 patients with hemophilia A with FVIII inhibitors and 36 patients with hemophilia A without FVIII inhibitors, based on the bleed rate for bleeds requiring treatment with coagulation factors. The median observation time was 25.6 weeks. Emicizumab prophylaxis resulted in an ABR (95% CI) for treated bleeds of 2.4 (1.4, 4.3) based on negative binomial regression. On emicizumab prophylaxis, 56.1% of patients had zero treated bleeds.

Black box warning includes thrombotic microangiopathy and thromboembolism risk. Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving Hemlibra prophylaxis (Genentech, 2017).

Precautions include laboratory coagulation test interference. Hemlibra interferes with activated clotting time (ACT), activated partial thromboplastin time (aPTT), and coagulation laboratory tests based on aPTT, including onestage aPTT-based single-factor assays, aPTT-based Activated Protein C Resistance (APC-R), and Bethesda assays (clotting-based) for factor VIII (FVIII) inhibitor titers. Intrinsic pathway clotting-based laboratory tests should not be used (Genentech, 2017).

Hemlibra is intended for use under the guidance of a healthcare provider. After proper training in subcutaneous injection technique, a patient (older than 7 years old) may self-inject, or the patient’s caregiver may administer if a healthcare provider determines that it is appropriate (Genentech, 2017).

Per prescribing information (2017), recommended dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly.

Recombinant von Willebrand Factor (Vonvendi)

U.S. Food and Drug Administration (FDA)-Approved Indications

Vonvendi is indicated for use in adults (age 18 and older) diagnosed with von Willebrand disease (VWD) for:

On-demand treatment and control of bleeding episodes
Perioperative management of bleeding
Routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 VWD receiving on-demand therapy.

The U.S. Food and Drug Administration (FDA) approved Vonvendi, a recombinant von Willebrand factor indicated for on-demand treatment and control of bleeding episodes in adults (age 18 and older) diagnosed with von Willebrand disease.

The FDA approval was based on positive results from a Phase III multicenter, open-label clinical trial that assessed the safety, efficacy and pharmacokinetics of recombinant von Willebrand factor with and without recombinant FVIII (Gill, et al., 2015). In the pivotal study, all participants (100 percent) reported successful treatment of bleeding episodes, with 96.9 percent of treated bleeds (N=192 bleeds in 22 patients) achieving an "excellent" efficacy rating and 3.1 percent achieving a "good" efficacy rating. Most bleeds (81.8 percent) were resolved with a single infusion, and the treatment showed a mean half-life of 21.9 hours (± 8.36).

No thrombotic events or severe product-related adverse events were observed during the clinical trial, nor were there treatment-related binding or neutralizing antibodies against VWF or neutralizing antibodies against FVIII. The most common adverse reaction observed in approximately 2% of subjects in clinical trials (n=66) was generalized pruritus.

Vonvendi is contraindicated in patients who have had life-threatening hypersensitivity reactions to Vonvendi or constituents of the product (tri-sodium citrate-dihydrate, glycine, mannitol, trehalose-dihydrate, polysorbate 80, and hamster or mouse proteins).

The labeling warns that thromboembolic reactions, including disseminated intravascular coagulation (DIC), venous thrombosis, pulmonary embolism, myocardial infarction, and stroke, can occur, particularly in patients with known risk factors for thrombosis. The product labeling recommends monitoring for early signs and symptoms of thrombosis such as pain, swelling, discoloration, dyspnea, cough, hemoptysis, and syncope.

In patients requiring frequent doses of Vonvendi with recombinant factor VIII, the labeling recommends monitoring plasma levels for FVIII:C activity because an excessive rise in factor VIII levels can increase the risk of thromboembolic complications.

Hypersensitivity reactions, including anaphylaxis, may occur. Symptoms can include anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock, lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, wheezing and/or acute respiratory distress. The labeling states that, if signs and symptoms of severe allergic reactions occur, immediately discontinue administration of Vonvendi and provide appropriate supportive care.

Neutralizing antibodies (inhibitors) to von Willebrand factor and/or factor VIII can occur. If the expected plasma levels of VWF activity (VWF:RCo) are not attained, an appropriate assay should be performed to determine if anti-VWF or anti-FVIII inhibitors are present. Other therapeutic options should be considered and the patient directed to a physician with experience in the care of either von Willebrand disease or hemophilia A. In patients with high levels of inhibitors to VWF or factor VIII, Vonvendi therapy may not be effective and infusion of this protein may lead to severe hypersensitivity reactions. Since inhibitor antibodies can occur concomitantly with anaphylactic reactions, patients experiencing an anaphylactic reaction should be evaluated for the presence of inhibitors.

For each bleeding episode, the first dose of Vonvendi is administered with factor VIII if factor VIII baseline levels are below 40% or are unknown. The prescribing information recommends an initial dose of 40 to 80 international units (IU) per kg body weight, with dosage adjusted based upon the extent and location of bleeding. For minor hemorrhage, the prescribing information recommends 40 to 50 IU/kg, with subsequent doses of 40 to 50 IU/kg every 8 to 24 hours (as clinically required). For major hemorrhage, the prescribing information recommends 50 to 80 IU/kg, with subsequent doses of 40 to 60 IU/kg every 8 to 24 hours for approximately 2 to 3 days (as clinically required).

On April 17, 2018, the FDA approved Vonvendi [von Willebrand factor (recombinant)], for perioperative management of bleeding in adults (age 18 and older) with von Willebrand disease (VWD). People with VWD lack proper quantities of VWF or functioning VWF, and they may or may not have a secondary factor VIII (FVIII) deficiency. Since not every person with VWD or every bleed requires FVIII replacement and an excessive rise in factor VIII levels may increase the risk of thromboembolic complications, Vonvendi allows healthcare providers to dose recombinant VWF independent of recombinant FVIII based on clinical judgement for each patient, taking into account severity, site of bleeding, the patient’s medical history and monitoring of appropriate clinical and laboratory measures.

The approval of Vonvendi in surgical settings was based on results from a Phase 3 prospective, open-label, multicenter trial to evaluate the efficacy and safety of Vonvendi with or without recombinant FVIII treatment (Advate) in elective surgical procedures in adults (age 18 years and older) diagnosed with severe VWD who were followed for 14 days after surgery. A total of 15 VWD subjects completed the trial and 93% of the subjects were less than 65 years old (range 20 to 70 years), of whom 53.3% were females and 53% (8/15) were Type 3 VWD patients. Out of 15 subjects, 10 subjects underwent major surgeries and 5 subjects underwent minor surgeries. Major surgeries included orthopedic surgeries: total hip replacement, total knee replacement, knee endoprosthesis, ankle prosthesis, anterior cruciate ligament surgery and meniscectomy. Other major surgeries included laparoscopic cholecystectomy, laparoscopic cystectomy and complex dental extractions. Minor surgeries/procedures included nasopharyngoscopy, dental extractions, colonoscopy and radioisotope synovectomy. All subjects were administered a 12 to 24 hour preoperative dose of 40 to 60 IU/kg of Vonvendi to increase the factor VIII levels to target levels. Within 3 hours prior to surgery, the subjects’ FVIII:C levels were assessed to ensure that target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries was achieved. Within 1 hour prior to surgery, subjects received a dose of Vonvendi. Advate (recombinant Factor VIII) was administered based on FVIII:C levels performed 3 hours prior to surgery. VWF and factor VIII Incremental recovery were used to guide the initial and subsequent doses. Six of the 10 subjects undergoing major surgery received protocol-specified loading dose. It should be noted that the protocol-specified loading dose was based on VWF:RCo levels assessed prior to the 12 to 24 hour preoperative dose. Four of 10 subjects undergoing major surgery and 4 out of 5 subjects undergoing minor surgery received a loading dose of Vonvendi based on VWF:RCo assessed prior to loading dose and after administration of the 12 to 24 hour preoperative dose. Unlike the protocol-specified loading dose based on the levels assessed prior to the preoperative dose between 12 to 24 hours of the surgery, the loading doses in these eight subjects were calculated based on VWF:RCo levels after a preoperative dose, and were therefore lower doses than protocol-specified loading dose. No differences in safety or efficacy were noted between the two groups.

The primary outcome measure was the overall hemostatic efficacy assessed 24 hours after the last perioperative Vonvendi infusion or at completion of study visit whichever occurred earlier using a 4-point ordinal efficacy scale ("excellent", "good", "moderate" and "none") based on estimated expected versus actual blood loss, transfusion requirements and postoperative bleeding and oozing. A rating of excellent or good was required to declare the outcome a success. Overall hemostatic efficacy for major and minor surgeries was 100% (15/15) with a 90% confidence interval of 81.9% to 100%. It was excellent for 60% of surgeries and good for 40% of surgeries. Intraoperative hemostatic efficacy was a secondary endpoint. For major and minor surgeries, it was 100% with a 90% confidence interval of 81.9% to 100%. It was excellent for 73.3% of surgeries and good for 26.7% of surgeries. Dosing was individualized based on incremental recovery results performed before surgery. Mean total 12 to 24 preoperative dose was 50.9 IU/kg (median 55.0 IU/kg; range 36.1 to 59.9 IU/kg). Mean total loading dose (1 hour preoperative dose) per infusion was 38.6 IU/kg (median 35.8 IU/kg; range 8.0 to 82.7 IU/kg). Major surgeries required a mean loading dose of 42.8 IU/kg (median 37.6 IU/kg; range 15.7 to 82.7 IU/kg) in comparison with a mean loading dose of 30.2 IU/kg (median 34.2 IU/kg; range 8.0 to 46.4 IU/kg) for minor surgeries. For subjects treated with Vonvendi (with or without Advate), the median total postoperative dose within the first 7 days after surgery was 114.2 IU/kg with a range of 23.8 to 318.9 IU/kg (n=13) and 76.2 IU/kg with a range of 23.8 to 214.4 IU/kg for the next 7 postoperative days (n=8).

The authors concluded that the results from the study showed Vonvendi met its primary endpoint. The overall median dosing frequency of once-daily was demonstrated to normalize hemostasis in appropriate patients. One study participant developed deep vein thrombosis three days after undergoing hip replacement surgery while receiving Vonvendi.

von Willebrand Factor/Coagulation Factor VIII Complex (Wilate)

U.S. Food and Drug Administration (FDA)-Approved Indications

Wilate is indicated in children and adults with von Willebrand Disease (VWD) for:

On-demand treatment and control of bleeding episodes
Perioperative management of bleeding.

Wilate is indicated in adolescents and adults with hemophilia A for:

Routine prophylaxis to reduce the frequency of bleeding episodes
On-demand treatment and control of bleeding episodes.

Compendial Uses

Acquired von Willebrand Syndrome

Wilate is a human plasma-derived, sterile, purified, double virus inactivated von Willebrand factor/coagulation factor VIII Complex (human). It is indicated for the treatment of spontaneous and/or trauma-induced bleeding episodes in individuals with severe von Willebrand disease (VWD) or individuals with mild or moderate VWD when there is failure, contraindication or intolerance to desmopressin. It is also indicated for prevention of excessive bleeding during and after minor and major surgery in adult and pediatric VWD patients.

In September 2019, the FDA approved to add an indication for Wilate in adults and adolescents with hemophilia A for routine prophylaxis to reduce the frequency of bleeding episodes and on demand treatment and control of bleeding episodes. The efficacy of Wilate in routine prophylaxis was evaluated in a prospective, open-label, multicenter clinical study in which adult subjects and pediatric subjects aged 12-15 years were treated during 6 months of prophylaxis with 20-40 IU/kg Wilate, mean dose 32 IU/kg (NCT02954575). Within the group of 55 subjects, of which 50 adults and 5 pediatric subjects, there were 30 (54.6%) subjects with 0 bleeding episodes, 12 (21.8%) subjects with 1 bleeding episode, 4 (7.3%) subjects with 2 bleeding episodes, 4 (7.3%) subjects with 3 bleeding episodes, and 5 (9%) subjects with 5 or more bleeding episodes. The primary outcome measure was the reduction of total annualized bleeding rate. A key secondary endpoint was the spontaneous annualized bleeding rate (SABR). The annualized bleeding rate (per subject) for all types of bleeds was 2.39 ± 3.77 (median 0, range 0-15.69) in the adult subjects, and 0.4 ± 0.89 (median 0, range 0-2) in the pediatric subjects. The annualized bleeding rates (per subject) for spontaneous bleeds was 1.67 ± 3.11 (median 0, range 0-11.76) in the adult subjects, and 0 (median 0, range 0-0) in the pediatric subjects.

The study also provided data on the efficacy of Wilate in the on demand treatment of bleeding episodes. The break-through bleeds were treated with Wilate doses adjusted to the severity of the bleed. Treatment efficacy was assessed by the patient (together with the investigator in case of on-site treatment) using the predefined criteria using an ordinal scale of excellent (abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection), good (definite pain relief and/or improvement in signs of bleeding within approximately 8–12 hours after an injection, requiring up to two injections for complete resolution), moderate (probable or slight beneficial effect within approximately 12 hours after the first injection, requiring more than two injections for complete resolution), or none (no improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution). In the per protocol population (n=52), 57 bleeding episodes were treated with Wilate, of which 15 (26.3%) bleeding episodes were minor (e.g. early onset muscle and joint bleeds with no visible symptoms, such as little or no change in the range of motion of affected joint, mild restriction of mobility and activity, scrapes, superficial cuts, bruises, superficial mouth bleeds, and most nose bleeds), 32 (56.1%) were moderate (e.g. advanced soft tissue and muscle bleeds into the limbs, bleeding into the joint space, such as the elbow, knee, ankle, wrist, shoulder, hip, foot, or finger), 10 (17.5%) were major (e.g. complicated joint bleeds, bleeds of the pelvic muscles, eyes), and 0 (0%) were life-threatening (e.g. bleedings in the abdomen, digestive system or chest, central nervous system bleeds, bleedings in the area of the neck or throat or pharynx, or other major trauma). Forty-one bleeds (71.9%) were spontaneous and 16 (28.1%) were traumatic. Thirty-six bleeding episodes (63.2%) were managed with one Wilate injection, 12 (21.1%) were managed with two injections, 7 (12.3%) were managed with 3 injections, and 2 (3.6%) required more than 3 injections. The mean dose of Wilate per injection was 34 IU/kg. Treatment efficacy was judged as excellent for 16 (28.1%) bleeding episodes, good for 32 (56.1%) bleeding episodes and moderate for 9 (15.8%) bleeding episodes. Therefore, 84.2% of all bleeding episodes were treated successfully. The one bleeding episode in one subject younger than 16 years (bleeding in finger) was treated with a single injection of 62.81 IU/kg of Wilate with excellent efficacy (successful treatment). Further efficacy data in the treatment of bleeding episodes is available from a pooled analysis of 37 subjects with hemophilia A included in 3 additional clinical studies. These subjects had at least 150 exposure days at the time of enrollment into the study and had been treated for at least 50 exposure days and 6 months in the study. The analysis encompassed 986 bleeding episodes, of which 936 (94.9%) were treated successfully

Klukowska et al (2011) stated the new-generation coagulation factor VIII (FVIII)/von Willebrand factor (VWF) concentrate, Wilate, is effective in the therapy of von Willebrand disease for which it was originally developed. The ratio of haemostatic components (FVIII to VWF) of this high-purity plasma-derived concentrate is 1:1, with VWF naturally stabilizing FVIII. Bleeding episode control in patients with haemophilia A (HA) is generally managed by replacement therapy with recombinant or plasma-derived FVIII. When complexed with VWF as in the physiological situation, the product may also show a lower incidence of inhibitor development in patients with HA. The clinical efficacy, safety and tolerability of Wilate were therefore evaluated in 81 previously treated individual patients with severe HA. Data from 5 good clinical practice (GCP) prospective clinical studies were pooled and assessed with regards to the prevention and treatment of bleeding and during surgical procedures. Haemostatic efficacy was excellent or good in 96.7% of 1495 rated treatments of bleeding episodes. The average dose per treatment was approximately 30 IU FVIII/kg. In surgical settings, the global haemostatic efficacy of Wilate was generally rated excellent or good for use during and after operations with a mean total dose of FVIII of 848.6 IU/kg±578.5 IU/kg administered peri-operatively. Overall, tolerability of Wilate was rated very good or good by patients and physicians. Rarely occurring adverse events were mild in intensity and no anti-FVIII inhibitors were detected. Wilate also displayed a good viral safety profile with no seroconversions occurring in response to treatment. These data show that Wilate is an efficacious treatment option in the management of patients with severe HA.

The most common adverse reactions to treatment with Wilate in patients with VWD have been urticaria and dizziness. The most serious adverse reactions to treatment with Wilate in patients with VWD have been hypersensitivity reactions.

Samai et al (2014) stated that despite clear roles of factor VIII (FVIII) and von Willebrand factor (vWF) in thrombosis, few studies have examined the relationship of these factors with acute ischemic stroke (AIS). These investigators examined if concurrent elevation in FVIII and vWF was associated with adverse events and outcomes. From the authors’ prospective stroke registry, patients consecutively admitted with AIS between July 2008 and October 2013 were included if both FVIII and vWF were measured during admission. The primary outcome was the modified Rankin Scale score on discharge. Among 1,453 cases in the authors’ stroke registry, 148 patients with AIS met inclusion criteria; 62 patients (41.9 %) had FVIII-/vWF-, 16 patients (10.8 %) had FVIII+/vWF-, and 51 patients (34.5 %) had FVIII+/vWF+. In the fully adjusted model, patients with FVIII+/vWF+ had increased odds of inpatient complications (odds ratio [OR], 8.6; 95 % CI: 1.58 to 46.85; p = 0.013) and neuro-worsening (OR, 3.2; 95 % CI: 1.18 to 8.73; p = 0.022) than patients with FVIII-/vWF-. Adjusted for age, baseline stroke severity, and glucose, patients with FVIII+/vWF+ had increased odds of poor functional outcome (modified Rankin Scale greater than 2; OR, 2.87; 95 % CI: 1.16 to 7.06; p = 0.021) than patients with FVIII-/vWF-. The authors concluded that concurrent FVIII/vWF elevation predicted higher odds of inpatient complications, neuro-worsening, and worse functional outcomes for patients with AIS compared with patients with normal levels. They stated that these findings suggested that FVIII and vWF levels may serve as clinically useful stroke biomarkers by providing risk profiles for patients with AIS.

Furthermore, an UpToDate review on "Stroke prognosis in adults" (Edwardson and Dromerick, 2014) does not mention the use of factor VIII or von Willebrand factor as biomarkers for stroke.

Coagulation Factor VIIa [Recombinant] (NovoSeven RT), Coagulation Factor VIIa [Recombinant]-jncw (Sevenfact)

U.S. Food and Drug Administration (FDA)-Approved Indications for NovoSeven RT

Hemophilia A or hemophilia B with inhibitors
Congenital factor VII deficiency
Glanzmann’s thrombasthenia
Acquired hemophilia

Compendial Uses for NovoSeven RT

Acquired von Willebrand syndrome
Inhibitors to factor XI

U.S. Food and Drug Administration (FDA)-Approved Indications for Sevenfact

Sevenfact is indicated for the treatment and control of bleeding episodes occurring in adults and adolescents (12 years of age and older) with hemophilia A or B with inhibitors.
Limitation of Use: Sevenfact is not indicated for the treatment of patients with congenital Factor VII deficiency.

NovoSeven RT is a recombinant activated human factor VII (recombinant FVIIa) produced by transfection of the human factor VII gene into cultured hamster cells. NovoSeven was first approved by the FDA in March 1999 for the treatment of bleeding episodes in hemophilia A or B patients who have inhibitors to factor VIII or factor IX, congenital Factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets. The products were further approved in October 2006 for the treatment of acute bleeding episodes and the prevention of surgical bleeding in adults with acquired hemophilia. In 2008, the FDA approved NovoSeven RT (Coagulation Factor VIIa [Recombinant] Room Temperature Stable), the first room temperature stable recombinant product available for the treatment of bleeding episodes in patients with hemophilia with inhibitors.

On April 1, 2020, the U.S. Food and Drug Administration approved Sevenfact [coagulation factor VIIa (recombinant)-jncw] for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors (neutralizing antibodies). Sevenfact contains an active ingredient expressed in genetically engineered rabbits. The safety and efficacy of Sevenfact were determined using data from a clinical study that evaluated 27 patients with hemophilia A or B with inhibitors, which included treatment of 465 mild or moderate, and three severe bleeding episodes. The study assessed the efficacy of treatment 12 hours after the initial dose was given. The proportion of mild or moderate bleeding episodes treated successfully both with the lower dose of 75mcg/kg and higher dose of 225 mcg/kg (requiring no further treatment for the bleeding episode, no administration of blood products and no increase in pain beyond 12 hours from initial dose) was approximately 86%. The study also included three severe bleeding episodes that were treated successfully with the higher dose. Another study evaluated the safety and pharmacokinetics of three escalating doses of Sevenfact in 15 patients with severe hemophilia A or B with or without inhibitors. Results from this study were used to select the two doses, 75mcg/kg and 225 mcg/kg, that were evaluated in the study described above. The most common side effects of Sevenfact were headache, dizziness, infusion site discomfort, infusion related reaction, infusion site hematoma and fever. Sevenfact is contraindicated in patients with known allergy or hypersensitivity to rabbits or rabbit proteins. Patients with hemophilia A or B with inhibitors who have other risk factors for blood clots (thrombosis) may be at increased risk of serious arterial and venous thrombotic events. Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms of a thrombotic event or hypersensitivity reaction occur, patients should discontinue Sevenfact and seek appropriate medical intervention.

Case reports have been published on the successful use of rFVIIa in patients with Glanzmann's thrombasthenia, which is an inherited hemorrhagic disorder characterized by a severe reduction in, or absence of, platelet aggregation in response to multiple physiologic agonists due to qualitative or quantitative abnormalities of platelet glycoprotein IIb-IIIa. The European Medicine’s Agency (EMEA) has approved rFVIIa for use in persons with Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb-IIIa and/or human leukocyte antigen (HLA), and with past or present refractoriness to platelet transfusions. A scientific discussion prepared by the EMEA (2005) states that the clinical experience with the treatment of patients with Glanzmann’s thrombasthenia with rFVIIa is based on data from a clinical trial (n = 4), an International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders (n = 59), and 10 published case reports. Most of the reported clinical experience with the use of rFVIIa in persons with Glanzmann’s thrombasthenia is in patients without anti-glycoprotein antibodies and platelet refractoriness. The EMEA analyzed the efficacy data for persons with anti-glycoprotein IIb/IIIa and/or anti-HLA antibodies and platelet refractoriness. Seventeen patients with from the International Registry and 2 patients from independently published case reports were identified, with a total of 40 evaluable bleeding episodes. The EMEA scientific discussion reports that rFVIIa was effective for bleeding prophylaxis in 18 (95 %) of 19 evaluable (minor plus major) surgical procedures. The EMEA states that rFVIIa was effective in stopping 28/40 (70 %) of the evaluable bleeding episodes, which is similar as the efficacy of rFVIIa in bleeding episodes reported in Glanzmann’s thrombasthenia patients generally. The EMEA scientific discussion states that 3 recurrent bleedings (3/40, 8 %) could be successfully treated with additional doses of rFVIIa (but in 1 case a concomitant platelet transfusion was given).

There is a lack of reliable evidence of the effectiveness of rFVIIa for non-hemophilic indications. Levi and colleagues (2005) performed a systematic review on the safety and effectiveness of rFVIIa in patients with or without coagulation disorders. They concluded that more randomized controlled clinical trials are needed to evaluate the safety and effectiveness of rFVIIa for patients without a pre-existent coagulation disorder and with severe bleeding. In the meantime, off-labeled use of rFVIIa may be considered in patients with life-threatening bleeding. This is in agreement with the observations of Lam et al (2005) who stated that until further prospective controlled data are available, it is recommended that conventional intervention for prevention and control of hemorrhage in non-hemophiliac patients should remain the standard of care. More recently, O’Connell and colleagues (2006) reported that the use of rFVIIa is associated with severe adcerse events (AEs) especially when it is used for off-labeled indications. They analyzed 431 incidents of AEs reported to the FDA during the first 5 years after the approval of NovoSeven. They noted that most reported thromboembolic AEs followed the use of the drug for off-labeled indications (n = 151) and occurred in the arterial and venous systems, often resulting in serious morbidity and mortality. The majority of complications occurred within 24 hours of taking the drug. These investigators concluded that randomized controlled studies are needed to ascertain the safety and effectiveness of rFVIIa in patients without hemophilia.

A number of studies have found that hemostatic therapy with rFVIIa may reduce growth of hematoma but does not improve survival or functional outcome after intra-cerebral hemorrhage. In a prospective, randomized, placebo-controlled, dose-escalation study, Narayan and colleagues (2008) evaluated the safety and preliminary effectiveness of rFVIIa to limit traumatic intra-cerebral hemorrhage (tICH) progression. Patients were enrolled if they had tICH lesions of at least 2 ml on a baseline computed tomographic scan obtained within 6 hours of injury. Recombinant factor VIIa or placebo was administered within 2.5 hours of the baseline computed tomographic scan but no later than 7 hours after injury. Computed tomographic scans were repeated at 24 and 72 hours. Five escalating dose tiers were evaluated (40, 80, 120, 160, and 200 microg/kg rFVIIa). Clinical evaluations and AEs were recorded until day 15. No significant differences were detected in mortality rate or number and type of AEs among treatment groups. Asymptomatic deep vein thrombosis, detected on routinely performed ultrasound at day 3, was observed more frequently in the combined rFVIIa treatment group (placebo, 3 %; rFVIIa, 8 %; not significant). A non-significant trend for rFVIIa dose-response to limit tICH volume increase was observed (placebo, 21.0 ml; rFVIIa, 10.1 ml). The authors concluded that in this first prospective study of rFVIIa in tICH, there appeared to be a trend toward less hematoma progression in rFVIIa-treated patients (80 to 200 microg/kg) compared with that seen in placebo-treated patients. The authors stated that the potential significance of this biological effect on clinical outcomes and the significance of the somewhat higher incidence of ultrasound-detected deep vein thromboses in the rFVIIa-treated group need to be examined in a larger prospective randomized clinical trial.

Mayer et al (2008) carried out a phase 3 trial to evaluate whether rFVIIa reduces growth of hematoma and improves survival and functional outcomes in patients with ICH. A total of 841 patients were randomly assigned to receive placebo (n = 268), 20 microg of rFVIIa per kilogram of body weight (n = 276), or 80 microg of rFVIIa per kilogram (n = 297) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the ICH at 24 hours was 26 % in the placebo group, as compared with 18 % in the group receiving 20 microg of rFVIIa per kilogram (p = 0.09) and 11 % in the group receiving 80 microg (p < 0.001). The growth in volume of ICH was reduced by 2.6 ml (95 % confidence interval [CI]: -0.3 to 5.5; p = 0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95 % CI: 0.9 to 6.7; p = 0.009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the 3 groups in the proportion of patients with poor clinical outcome (24 % in the placebo group, 26 % in the group receiving 20 microg of rFVIIa per kilogram, and 29 % in the group receiving 80 microg). The overall frequency of thromboembolic serious AEs was similar in the 3 groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9 % versus 4 %, p = 0.04). The authors concluded that hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after ICH. Whether this hemostatic effect can translate to clinical benefit in a subgroup of patients at high risk for active bleeding, either by treatment within an earlier time window or by demonstration of intra-hematomal contrast extravasation after CT angiography deserves further study.

A randomized controlled study found no effect of rFVIIa on a primary composite endpoint of failure to control 24-hr variceal bleeding, failure to control rebleeding or death in patients with advanced cirrhosis. In a randomized controlled study, Bosch and associates (2008) evaluated the safety and effectiveness of rFVIIa in patients with advanced cirrhosis and active variceal bleeding. At 31 hospitals in an emergency setting, 256 patients (Child-Pugh greater than 8; Child-Pugh B = 26 %, C = 74 %) were randomized equally to: placebo; 600 microg/kg rFVIIa (200 + 4x 100 microg/kg); or 300 microg/kg rFVIIa (200 + 100 microg/kg). Dosing was intravenous at 0, 2, 8, 14, and 20 hrs after endoscopy, in addition to standard vasoactive, prophylactic antibiotic, and endoscopic treatment. The primary composite endpoint consisted of failure to control 24-hr bleeding, or failure to prevent re-bleeding or death at day 5. Secondary endpoints included AEs and 42-day mortality. Baseline characteristics were comparable between groups. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo (p = 0.37). There was no significant difference in 5-day mortality between groups; however, 42-day mortality was significantly lower with 600 microg/kg rFVIIa compared with placebo (odds ratio 0.31, 95 % CI: 0.13 to 0.74), and bleeding-related deaths were reduced from 12 % (placebo) to 2 % (600 microg/kg). A marked heterogeneity in the failure rate in all treatment groups was observed across participating centers. Adverse events, including overall thromboembolic events, were comparable between groups. The authors concluded that treatment with rFVIIa had no significant effect on the primary composite endpoint compared with placebo. Thus, decision on the use of rFVIIa in acute variceal bleeding should be carefully considered, because results of this study do not support the routine use of rFVIIa in this setting.

A Cochrane systematic evidence review (Marti-Carvajal et al, 2007) concluded that they found no evidence that rFVIIa reduces the risk of death in patients with liver disease and upper gastrointestinal bleeding. "More randomised clinical trials having low risk of bias are necessary in order to determine the role of human recombinant factor VIIa in clinical practice."

An assessment by the Canadian Coordinating Office for Health Technology Assessment (Selin and Tejani, 2006) reported that rFVIIa is increasingly used to control bleeding in non-hemophilic patients during surgery, or during treatment for severe trauma or ICH. The assessment noted that there is potential for non-hemophilic use of rFVIIa, particularly if clinical and cost-effectiveness are established. The assessment concluded that adequately powered randomized controlled trials are needed to clarify the efficacy and safety of rFVIIa for non-bleeding disorder indications. The assessment noted that phase III trials in ICH and trauma are underway.

A randomized controlled clinical study found that propylactic use of rFVIIa did not decrease perioperative blood loss in patients with normal hemostasis undergoing surgical repair of traumatic pelvic-acetabular fracture. In a double-blind, randomized, placebo-controlled trial, Raobaikady and associates (2005) examined the clinical value of rFVIIa in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum (n = 48). Patients were randomized to receive an intravenous bolus injection of rFVIIa 90 microg/kg or placebo as add-on therapy at the time of the first skin incision. All patients also received intra-operative salvaged red blood cells (RBC). There was no significant difference in the total volume of peri-operative blood loss, the primary outcome variable, between the rFVIIa and placebo groups. In addition, there were no differences between the 2 groups in the total volume of blood components, including salvaged RBC transfused, number of patients requiring allogeneic blood components, total volume of fluids infused, total operating time, time taken after entry to the intensive care unit to reach normal body temperature and acid-base status, and time spent in hospital. No adverse events, in particular thromboembolic events, were reported in either group. The authors concluded that in patients with normal hemostasis undergoing repair surgery of traumatic pelvic-acetabular fracture, the prophylactic use of rFVIIa does not decrease the volume of peri-operative blood loss.

A review found that the evidence does not support the use of rFVIIa to prevent or control excessive bleeding after cardiac surgery. Hardy and co-workers (2009) noted that excessive bleeding is a common and morbid problem after cardiac surgery. There is no doubt a need for an effective and safe hemostatic agent in order to minimize transfusions and avoid surgical re-intervention for hemostasis. Recombinant activated factor VII is being used (off-label) increasingly after cardiac surgery to prevent or to control hemorrhage, but its efficacy and safety remain unclear. Several case reports, case series and registries would tend to support the use of rFVIIa to control excessive bleeding after cardiac operations. On the contrary, 2 randomized controlled trials have produced negative results whereas a 3rd has not been published yet. Adverse thrombotic events have been reported with increasing frequency. The authors concluded that at present, the generalized use of rFVIIa to prevent or to control excessive bleeding after cardiac surgery cannot be recommended.

Analaysis of a large cohort of persons in placebo-controlled trials of rFVIIa found that treatment with high doses of rFVIIa on an off-label basis significantly increased the risk of arterial thromboembolic events. Levi and colleagues (2010) evaluated the rate of thromboembolic events in all published randomized, placebo-controlled trials of rFVIIa used on an off-label basis (i.e., non-hemophilia). These investigators analyzed data from 35 randomized clinical trials (26 studies involving patients and 9 studies involving healthy volunteers) to determine the frequency of thromboembolic events. The data were pooled with the use of random-effects models to calculate the odds ratios and 95 % CI. Among 4,468 subjects (4,119 patients and 349 healthy volunteers), 498 had thromboembolic events (11.1 %). Rates of arterial thromboembolic events among all 4,468 subjects were higher among those who received rFVIIa than among those who received placebo (5.5 % versus 3.2 %, p = 0.003). Rates of venous thromboembolic events were similar among subjects who received rFVIIa and those who received placebo (5.3 % versus 5.7 %). Among subjects who received rFVIIa, 2.9 % had coronary arterial thromboembolic events, as compared with 1.1 % of those who received placebo (p = 0.002). Rates of arterial thromboembolic events were higher among subjects who received rFVIIa than among subjects who received placebo, particularly among those who were 65 years of age or older (9.0 % versus 3.8 %, p = 0.003); the rates were especially high among subjects 75 years of age or older (10.8 % versus 4.1 %, p = 0.02). The authors concluded that in a large and comprehensive cohort of persons in placebo-controlled trials of rFVIIa, treatment with high doses of rFVIIa on an off-label basis significantly increased the risk of arterial but not venous thromboembolic events, especially among the elderly.

In an editorial that accompanied the aforementioned study, Aledort (2010) stated that "[t]his article uniquely presents data on the off-label use of rFVIIa in a variety of clinical conditions, and it specifically addresses the incidence of thromboembolic events. In patients with bleeding disorders, the challenge is to establish hemostasis without incurring thromboembolic events. Clinical trials are put in place to evaluate the safety and efficacy of new agents. Data and safety monitoring boards, as independent entities, are charged with the responsibility of determining the safety of drugs in a given clinical trial. If the board determines that the data demonstrate that the risk outweighs the benefit, the trial may be halted, but the reasons for stopping the trial may not be widely promulgated. Even if trials are not discontinued, regulators, such as the Food and Drug Administration or the European Medicines Agency, when reviewing a portfolio of information about a drug, may not approve a label indication because of adverse events; however, the data on the adverse events often do not reach the public record. Therefore, patients and health care professionals may have no way to learn about adverse events associated with off-label use".

Furthermore, the editorialist stated that "[t]he authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombotic sequelae reported here are not inconsequential. The risk is particularly notable among older patients. This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions".

The Canadian Agency for Drugs and Technologies in Health's technology assessment on rFVIIa for the prevention of bleeding unrelated to hemophilia (Murphy et al, 2010) concluded that "no consistent benefit of rFVIIa therapy was detected among studies evaluating the prevention of bleeding in patients undergoing prostatectomy, liver transplantation, or cardiac surgery. The risk of adverse events after the prophylactic use of rFVIIa in surgical patients is unknown. No conclusions can be drawn on the effectiveness or safety of using rFVIIa in the prevention of bleeding in patients who have received supra-therapeutic doses of anticoagulant agents. When used for prevention of bleeding, no specific method is available to monitor the effectiveness of rFVIIa".

Mannucci et al (2010) stated that the main cause of the hemostasis defects and related bleeding complications in patients with acute coronary syndromes (ACS) are the intake of multiple anti-thrombotic drugs, alone or concomitantly with invasive procedures such as coronary angiography and percutaneous coronary intervention (PCI). Anti-thrombotic drugs that impair several phases of hemostasis (platelet function, coagulation, and fibrinolysis) are causing bleeding particularly in elderly patients, in those who are under-weight and with co-morbidities such as renal insufficiency, diabetes, hypertension and malignancy. Identification of patients at high risk of bleeding is the most important preventive strategy, because the choice and dosages of drugs may to some extent be tailored to the degree of risk. Transfusions of blood products, which may become necessary in patients with major bleeding, should be used with caution, because they are associated with adverse cardiovascular events. To reduce the need of transfusion, the hemostatic drugs that decrease blood loss and transfusion requirements in cardiac surgery (anti-fibrinolytic amino acids, desmopressin, and rFVIIa) might be considered. However, the efficacy of these drugs in the control of bleeding complications is not unequivocally established in ACS and there is concern for an increased risk of thrombosis. The authors concluded that evidence-based recommendations for the management of bleeding in patients with ACS are currently lacking, so that prevention through accurate assessment of the individual risk is the most valid strategy.

A Cochrane review found no reliable evidence from randomized controlled clincial trials to support the effectiveness of hemostatic drugs in reducing mortality or disability in patients with traumatic brain injury. Perel et al (2010) evaluated the effects of hemostatic drugs on mortality, disability and thrombotic complications in patients with traumatic brain injury (TBI). These investigators included published and unpublished randomized controlled trials comparing hemostatic drugs (anti-fibrinolytics: aprotinin, tranexamic acid (TXA), aminocaproic acid or rFVIIa) with placebo, no treatment, or other treatment in patients with acute TBI. Two review authors independently examined all electronic records, and extracted the data. They judged that there was clinical heterogeneity between trials so they did not attempt to pool the results of the included trials. The results are reported separately. Two trials were included; one was a post-hoc analysis of 30 TBI patients from a randomized controlled trial of rFVIIa in blunt trauma patients. The risk ratio for mortality at 30 days was 0.64 (95 % CI: 0.25 to 1.63) for rFVIIa compared to placebo. This result should be considered with caution as the subgroup analysis was not pre-specified for the trial. The other trial evaluated the effect of rFVIIa in 97 TBI patients with evidence of intra-cerebral bleeding in a computed tomography (CT) scan. The corresponding risk ratio for mortality at the last follow-up was 1.08 (95 % CI: 0.44 to 2.68). The quality of the reporting of both trials was poor so it was difficult to assess the risk of bias. The authors concluded that there is no reliable evidence from randomized controlled trials to support the effectiveness of hemostatic drugs in reducing mortality or disability in patients with TBI. New randomized controlled trials assessing the effects of hemostatic drugs in TBI patients should be conducted. These trials should be large enough to detect clinically plausible treatment effects.

Logan et al (2011) stated that rFVIIa is increasingly used for off-label indications. In a retrospective database analysis, these investigators estimated patterns of off-label rFVIIa use in U.S. hospitals. Data were extracted from the Premier Perspectives database (Premier, Charlotte, NC), which contains discharge records from a sample of academic and non-academic U.S. hospitals. A total of 12,644 hospitalizations for patients who received rFVIIa during a hospital stay were analyzed. Hospital diagnoses and patient dispositions from 1 January 2000 to 31 December 2008 were reviewed. Statistical weights for each hospital were used to provide national estimates of rFVIIa use. From 2000 to 2008, off-label use of rFVIIa in hospitals increased more than 140-fold, such that in 2008, 97 % (95 % CI: 96 % to 98 %) of 18,311 in-hospital uses were off-label. In contrast, in-hospital use for hemophilia increased less than 4-fold and accounted for 2.7 % (CI: 1.9 % to 3.5 %) of use in 2008. Adult and pediatric cardiovascular surgery (29 % CI: 21 % to 33 %), body and brain trauma (29 % CI: 19 % to 38 %), and intracranial hemorrhage (11 % CI: 7.7 % to 14 %) were the most common indications for rFVIIa use. Across all indications, in-hospital mortality was 27 % (CI: 19 % to 34 %) and 43 % (CI: 26 % to 59 %) of patients were discharged to home. The authors concluded that off-label use of rFVIIa in the hospital setting far exceeds use for approved indications. These patterns raise concern about the application of rFVIIa to conditions for which strong supporting evidence is lacking.

Yank et al (2011) evaluated the benefits and harms of rFVIIa use for 5 off-label, in-hospital indications:

cardiac surgery,
ICH,
liver transplantation,
prostatectomy, and
trauma.

A total of 10 databases (including PubMed, EMBASE, and the Cochrane Library) queried from inception through December 2010. Articles published in English were analyzed. Two reviewers independently screened titles and abstracts to identify clinical use of rFVIIa for the selected indications and identified all randomized, controlled trials (RCTs) and observational studies for full-text review. Two reviewers independently assessed study characteristics and rated study quality and indication-wide strength of evidence. A total of 16 RCTs, 26 comparative observational studies, and 22 non-comparative observational studies met inclusion criteria. Identified comparators were limited to placebo (RCTs) or usual care (observational studies). For ICH, mortality was not improved with rFVIIa use across a range of doses. Arterial thrombo-embolism was increased with medium-dose rFVIIa use (risk difference [RD], 0.03 [95 % CI: 0.01 to 0.06]) and high-dose rFVIIa use (RD, 0.06 [CI: 0.01 to 0.11]). For adult cardiac surgery, there was no mortality difference, but there was an increased risk for thrombo-embolism (RD, 0.05 [CI: 0.01 to 0.10]) with rFVIIa. For body trauma, there were no differences in mortality or thrombo-embolism, but there was a reduced risk for the acute respiratory distress syndrome (RD, -0.05 [CI: -0.02 to -0.08]). Mortality was higher in observational studies than in RCTs. The authors concluded that limited available evidence for 5 off-label indications suggested no mortality reduction with rFVIIa use. For some indications, it increases thrombo-embolism.

In an editorial that accompanied the aforementioned studies, Avorn and Kesselheim (2011) stated that overall, Yank and co-workers found no evidence that rFVIIa reduced mortality for any off-label use; however, it did increase the risk for thrombo-embolism. Their findings are compatible with other recent studies. The editorialists noted that "[a]llowing physician autonomy to choose medications is appealing, but not when it results in unhelpful, dangerous, and costly decisions. With such compelling data in place about the runaway use, uselessness, and risk for this expensive treatment, what can be done to reduce it? First, if evidence should emerge that the manufacturer played a role in building a market for the unauthorized and increasingly implausible prescribing of its product, both civil and criminal responses will probably be brought to bear, as has occurred for many other instances of corporate-sponsored drug misuse. Second, rFVIIa is used in hospitals, which should be providing organizational oversight to protect patients, as well as the institutions’ own pharmacy budgets. In hospitals where such use continues, existing quality assurance, patient safety, and risk-management groups will surely want to look hard at these practices. Although off-label prescribing by physicians is not illegal, physicians who persist in such use in the face of clear evidence of inutility and harm could be subject to civil action by the affected patients or their heirs".

Koncar et al (2011) examined the influence of rFVIIa on the treatment of intractable peri-operative bleeding in vascular surgery when conventional hemostatic measures are inadequate. There were 2 groups of patients: the NovoSeven group (group N), 10 patients with ruptured abdominal aortic aneurysms (RAAAs) and 14 patients operated on due to thoraco-abdominal aortic aneurysms (TAAAs); the control group (group C), 14 patients with RAAAs and 17 patients with TAAAs. All patients suffered intractable hemorrhage refractory to conventional hemostatic measures, while patients from group N were additionally treated with rFVIIa. Post-operative blood loss was significantly lower in group N treated with rFVII (p < 0.0001). Post-operative administration of packed red blood cells, fresh frozen plasma, and platelets was lower in patients from group N, (p < 0.0001). Successful hemorrhage arrest was reported in 21 patients (87.5 %) treated with rFVIIa, and in 9 patients (29.03 %) in group C (p < 0.001). Thirty-day mortality in these 2 groups significantly differed. The mortality rate was 12.5 % (3 patients) in group N and 80.65 % (25 patients) in group C (p < 0.0001). The authors concluded that these findings suggested that rFVIIa may play a role in controlling the intractable peri-operative and post-operative bleeding in surgical patients undergoing a repair of RAAAs and TAAAs. They stated that prospective randomized trials are necessary to further confirm the efficacy and cost-effectiveness of rFVIIa in these patients.

Witmer et al (2011) described the off-label use of rFVIIa in tertiary care pediatric hospitals across the United States and to assess thrombotic events. A retrospective multi-center cohort study using the Pediatric Health Information System administrative database was performed. Children 18 years of age or younger who received rFVIIa between 2000 and 2007 were included. A label admission was defined as an admission with an International Classification of Diseases diagnostic code for hemophilia or factor VII deficiency; admissions without these codes were classified as off-label. There were 4,942 rFVIIa admissions, representing 3,764 individual subjects; 74 % (3,655) of the admissions were off-label. There was a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007 (from 2 to 20.8 per 10,000 hospital admissions, p < 0.001). The mortality rate in the off-label group was 34 % (1,258/3,655). Thrombotic events occurred in 10.9 % (399/3,655) of the off-label admissions. The authors concluded that off-label use of rFVIIa in hospitalized children is increasing rapidly despite the absence of adequate clinical trials demonstrating safety and efficacy. Thrombotic events are common and mortality is high among patients receiving off-label rFVIIa. They stated that further studies are warranted to determine whether these adverse events are attributable to rFVIIa.

In a Cochrane review, Lin et al (2011) evaluated the effectiveness of rFVIIa when used therapeutically to control active bleeding, or prophylactically to prevent (excessive) bleeding in patients without hemophilia. These investigators searched the Cochrane Injuries Group Specialized Register, CENTRAL, MEDLINE, EMBASE and other specialized databases up to 25 February 2009. Randomized controlled trials comparing rFVIIa with placebo, or one dose of rFVIIa with another, in any patient population (except hemophilia) were included in this study. Outcomes were mortality, blood loss or control of bleeding, red cell transfusion requirements, number of patients transfused and thrombo-embolic adverse events. Two authors independently assessed potentially relevant studies for inclusion, extracted data and examined risk of bias. They considered prophylactic and therapeutic rFVIIa studies separately. A total of 25 RCTs were included: 24 were placebo-controlled double-blind RCTs and 1 compared different doses of rFVIIa. Fourteen trials involving 1,137 participants examined the prophylactic use of rFVIIa; 713 received rFVIIa. There was no evidence of mortality benefit (RR 1.06; 95 % CI: 0.50 to 2.24). There was decreased blood loss (WMD -272 ml; 95 % CI: -399 to -146) and decreased red cell transfusion requirements (WMD -243 ml; 95 % CI: -393 to -92) with rFVIIa treatment; however these values were likely over-estimated due to the inability to incorporate data from trials showing no difference of rFVIIa treatment compared to placebo. There was a trend in favor of rFVIIa in the number of participants transfused (RR 0.91; 95 % CI: 0.82 to 1.02). But there was a trend against rFVIIa with respect to thrombo-embolic adverse events (RR 1.32; 95 % CI: 0.84 to 2.06). Eleven trials involving 2,366 participants examined the therapeutic use of rFVIIa; 1,507 received rFVIIa. There were no outcomes where any observed advantage, or disadvantage, of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favor of rFVIIa for reducing mortality (RR 0.89; 95 % CI: 0.77 to 1.03). However, there was a trend against rFVIIa for increased thrombo-embolic adverse events (RR 1.21; 9 5% CI: 0.93 to 1.58). The authors concluded that the effectiveness of rFVIIa as a more general hemostatic drug, either prophylactically or therapeutically, remains unproven. They stated that the use of rFVIIa outside its current licensed indications should be restricted to clinical trials.

Dewhirst (2013) performed a short-cut review to establish whether rFVIIa improves survival and functional outcome in acute spontaneous intracranial hemorrhage. A total of 92 papers were found using the reported searches, of which 2 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers were tabulated. The authors concluded that current evidence does not support the use of rFVIIa in acute spontaneous intracranial hemorrhage.

Individuals with severe factor XI deficiency who have developed a factor XI inhibitor may not have an increase in factor XI with factor XI replacement products and may require treatment with a bypassing agent such as recombinant activated factor VII (recombinant factor VIIa; rFVIIa). In their review, Roberts et al (2004) state recombinant VIIa has also been used to treat patients with factor XI deficiency either with or without inhibitors to factor XI. Doses of 90 to 120 μg/kg every 2 to 3 hours until bleeding ceases have been found to be effective in this condition, but the optimal dose has not been clearly defined. Some investigators now consider rfVIIa to be the treatment of choice in factor XI deficiency and for inhibitors to factor XI (Roberts 2004).

NovoSeven (Recombinant Factor VIIa) for Hemostasis During Repair of Aortic Dissection

Karkouti et al (2005) stated that cardiac surgery is occasionally complicated by massive blood loss that is refractory to standard hemostatic interventions; rF-VIIa is being increasingly used as rescue therapy in such cases, but little information is available on its safety and efficacy for this indication. The outcomes of the first 51 cardiac surgery patients who received rF-VIIa for intractable blood loss (from November 2002 to February 2004) at a single institution according to a standardized clinical guideline were compared to 51 matched control patients, with the control patients identified from a large database and matched based on the propensity for massive blood loss. Blood loss and blood product usage were significantly decreased after 2.4 to 4.8 mg of rF-VIIa. In those treated after sternal closure (n = 32), there was a significant reduction in blood loss from the hour before to the hour after treatment: 100 (70, 285) ml (median [25th, 75th percentiles]; p < 0.0001). Except for a slower post-operative recovery and higher incidence of acute renal dysfunction, the adverse event (AE) rates were similar between the rF-VIIa-treated patients and their matched controls. The authors concluded that these results suggested that rF-VIIa may be an effective rescue therapy for patients with intractable hemorrhage after cardiac surgery. A clinically important risk of stroke or other major thrombotic complications could not be ruled out by this study. Moreover, they stated that controlled clinical trials with adequate power to detect the impact of rF-VIIa therapy on morbidity and mortality therefore are necessary before one can recommend its routine use in patients undergoing cardiac surgery who have excessive bleeding.

Diprose and colleagues (2005) noted that receiving an allogeneic transfusion may be an independent predictor of mortality for patients undergoing cardiac surgery. Furthermore, these patients utilize 15 % of all donated blood in the United Kingdom. In the authors’ unit, 80 % of patients undergoing complex non-coronary cardiac surgery requiring cardio-pulmonary bypass (CPB) receive an allogeneic transfusion. In a randomized, double-blind, placebo-controlled, pilot study, these researchers examined if activated rFVIIa may be effective in reducing this need for transfusion. A total of 20 patients undergoing complex cardiac surgery were randomized to receive rFVIIa or placebo after CPB and reversal of heparin. Two patients in the rFVIIa group received 13 units of allogeneic red cells and coagulation products compared with 8 patients receiving 105 units of allogeneic red cells and coagulation products in the placebo group (relative risk [RR] of any transfusion 0.26; confidence interval [CI]: 0.07 to 0.9; p = 0.037). The groups did not differ for AEs. The authors concluded that despite major limitations (under-powered study and prone to type I error), the author showed that rFVIIa significantly reduced the need for allogeneic transfusion in complex non-coronary cardiac surgery without causing AEs. Moreover, they stated that its true efficacy and safety profile will not be known until further appropriately powered randomized trials are performed.

Ferraris et al (2011) noted that practice guidelines reflect published literature. Because of the ever changing literature base, it is necessary to update and revise guideline recommendations from time to time. The Society of Thoracic Surgeons recommended review and possible update of previously published guidelines at least every 3 years. This summary was an update of the blood conservation guideline published in 2007. The search methods used in the current version differed in comparison to the previously published guideline. Literature searches were conducted using standardized MeSH terms from the National Library of Medicine PubMed database list of search terms. The following terms comprised the standard baseline search terms for all topics and were connected with the logical "OR" connector – Extracorporeal circulation (MeSH number E04.292), cardiovascular surgical procedures (MeSH number E04.100), and vascular diseases (MeSH number C14.907). Use of these broad search terms allowed specific topics to be added to the search with the logical 'AND' connector. In this 2011 guideline update, areas of major revision include: management of dual anti-platelet therapy before operation, use of drugs that augment red blood cell volume or limit blood loss, use of blood derivatives including fresh frozen plasma, Factor XIII, leuko-reduced red blood cells, platelet plasmapheresis, recombinant Factor VII, anti-thrombin III, and Factor IX concentrates, changes in management of blood salvage, use of minimally invasive procedures to limit peri-operative bleeding and blood transfusion, recommendations for blood conservation related to extracorporeal membrane oxygenation (ECMO) and cardiopulmonary perfusion, use of topical hemostatic agents, and new insights into the value of team interventions in blood management. The authors concluded that much has changed since the previously published 2007 STS blood management guidelines and this document contained new and revised recommendations.

The updated guideline stated that the use of recombinant factor VIIa concentrate may be considered for the management of intractable non-surgical bleeding that is unresponsive to routine hemostatic therapy after cardiac procedures using cardiopulmonary bypass (CPB). (Class of Recommendation: IIb; Level of evidence: B)

Thiele and Raphael (2014) stated that coagulopathy after cardiac surgery with CPB is a serious complication that may result in massive bleeding requiring transfusion of significant amounts of blood products, plasma, and platelets. In addition to increased patient morbidity and mortality, it is associated with longer hospital stay and increased resource utilization. The current review discussed aspects in CPB-induced coagulopathy with emphasis on point-of-care (POC) testing and individualized "goal-directed" therapy in patients who developed excessive bleeding after cardiac surgery. The authors noted that "at least 7 prospective, randomized trials and 1 large, retrospective analysis have examined the use of POC-based transfusion algorithms in cardiac surgery patients, with all but 1 demonstrating decreased transfusion requirements and/or fewer surgical re-explorations. In addition, a reduction in hospital costs and a significant decrease in the off-label use of rFVIIa as a rescue therapy has also been reported … rFVIIa is a potent hemostatic agent and as reported, its use is associated with increased risk of thrombotic/thromboembolic adverse events. Therefore, its use should be reserved to situations in which the benefit clearly out-weighs potential risks, especially as rescue therapy for massive ongoing bleeding due to refractory coagulopathy".

Yan et al (2014) noted that refractory blood loss is a common problem in surgeries for acute type A aortic dissections. Significant evidence has supported the benefit of using rFVIIa to control of intractable bleeding in patients after cardiac surgery. In this prospective, clinical study, these researchers presented a novel method to achieve intra-operative hemostasis by using a combination of platelets and rFVIIa during operations for acute type A aortic dissections. Between May 2009 and August 2012, a total of 71 patients with acute type A dissections who underwent emergency surgery were prospectively included and allocated to one of the following 2 intervention groups for hemostasis: 3 units platelets combined with 2.4 mg rFVIIa (n = 25), and conventional methods (n = 46). The patients who received the combination of platelets and rFVIIa required fewer transfusions of red blood cells (6.2 ± 3.1 units versus 9.8 ± 2.8 units; p < 0.05), fresh frozen plasma (736.9 ± 178.3 ml versus 1,264.3 ± 245.2 ml, p < 0.05), platelet concentrates (3 units versus 5.0 ± 1.8 units, p < 0.001), and cryoprecipitate (2.8 ± 0.9 units versus 8.2 ± 2.3 units, p < 0.05). These patients also required less time for sternal closure (76.9 ± 17.2 mins versus 102.3 ± 10.7 mins, p < 0.05) compared with the conventional therapy patients. There was no statistically significant difference in the incidence of serious AEs between these 2 groups. The authors concluded that using a combination of platelets and rFVIIa was an effective strategy for achieving hemostasis during acute type A dissection surgery. This hemostatic strategy did not appear to be associated with an increase in post-operative AEs.

The major drawback of this study were the small sample size (n = 25), the lack of mechanistic research to determine the dosages of platelets and rFVIIa selected, and the combined use of platelets and rFVIIa. This new hemostatic strategy was designed by using clinical experience, and it lacked laboratory study support. In addition, these researchers did not include the data regarding the incidence of heparin induced thrombocytopenia and thrombosis (HITT) in their analyses; therefore, the incidences of HITT in both groups were unavailable. Moreover, these researchers could not confirm the causes of the 2 cases of ischemic stroke (1 in each group). Judged from the clinical manifestation of the 2 patients and based on their experiences, HITT may be a possible reason for the stroke, and the impacts of cerebral hypo-perfusion and congenital cerebral malformation could also not be ignored. Despite of these limitations, this study was the 1st report of hemostatic strategy with confirmed transfusion guidelines, uniform practice, and administration of a low-dose of rFVIIa.

Zatta et al (2015) noted that rFVIIa has been widely used as an off-licence pan-hemostatic agent in patients with critical bleeding. However, outside the trauma setting, there is relatively little high quality evidence on the risks and benefits of this agent. The Hemostasis Registry was established to investigate the extent of use, dosing, safety and outcomes of patients after off-licence rFVIIa treatment of critical bleeding. The Registry recruited non-hemophiliac patients treated with rFVIIa from 2000 to 2009 (inclusive) in Australia and New Zealand. Detailed information was gathered on patients' demographics, context of bleeding, rFVIIa administration, laboratory results, blood component and other therapies, and outcomes. Outcome measures included subjectively assessed effect of rFVIIa on bleeding (response), AEs (thromboembolic and other) and 28-day mortality. The registry included 3,446 cases in 3,322 patients (median [IQR] age of 56 [33 to 70] years, 65 % (n = 2,147) male). Clinical indications included cardiac surgery (45 %), other surgery (18 %), trauma (13 %), medical bleeding (6 %), liver disease (6 %), and obstetric hemorrhage (5 %). The median [IQR] dose was 91 [72 to 103] μg/kg and 77 % received a single dose. Reduction or cessation of bleeding was reported in 74 % and 28-day survival was 71 % but outcomes varied depending on clinical context. pH strongly correlated with outcome measures; 81 % of patients with pH less than 7.1 died. Approximately 11 % of patients had thrombo-embolic AEs. In multi-variate analysis, pH prior to administration and bleeding context were independently associated with reported response to rFVIIa and 28-day mortality. The authors concluded that the Hemostasis Registry is the largest dataset of its kind and provided observational data on the off-licence use of rFVIIa over a 10-year period. It has been an invaluable resource for rigorously tracking adverse events and helping to inform clinical practice. These researchers stated that these data did not provide any causal link between rFVIIa use and survival but showed that patients with a reported decrease in bleeding following rFVIIa use are more likely to survive. The clinical context of bleeding and pH are the most important predictors of outcome, with the utility of therapy substantially reduced in certain clinical situations and at very low pH (<7.1).

Rosenfeldt et al (2016) stated that donation after circulatory death (DCD) represents a potential new source of hearts to increase the donor pool. These investigators showed previously that DCD hearts in Greyhound dogs could be resuscitated and preserved by continuous cold crystalloid perfusion, but not by cold static storage and could demonstrate excellent contractile and metabolic function on an in-vitro system. In the current study, these researchers demonstrated that resuscitated DCD hearts are transplantable. Donor Greyhound dogs (n = 12) were divided into perfusion (n = 8) and cold static storage (n = 4) groups. General anesthesia was induced and ventilation ceased for 30 minutes to achieve circulatory death. Donor cardiectomy was performed, and for 4 hours the heart was preserved by controlled reperfusion, followed by continuous cold perfusion with an oxygenated crystalloid perfusate or by static cold storage, after which orthotopic heart transplantation was performed. Recovery was assessed over 4 hours by hemodynamic monitoring. During cold perfusion, hearts showed continuous oxygen consumption and low lactate levels, indicating aerobic metabolism. The 8 dogs in the perfusion group were weaned off bypass, and 4 hours after bypass produced cardiac output of 4.73 ± 0.51 liters/min, left ventricular power of 7.63 ± 1.32 J/s, right ventricular power of 1.40 ± 0.43 J/s, and left ventricular fractional area shortening of 39.1 % ± 5.2 %, all comparable to pre-transplant values. In the cold storage group, 3 of 4 animals could not be weaned from cardiopulmonary bypass, and the 4th exhibited low-level function. The authors concluded that cold crystalloid perfusion, but not cold static storage, can resuscitate and preserve the DCD donor heart in a canine model of heart transplantation, thus rendering it transplantable. Moreover, they stated that controlled reperfusion and cold crystalloid perfusion have potential for clinical application in DCD transplantation.

The editorial comments on "TAVR-Is there a path to an all-surgical-risk indication?" by Arora and Vavalle (2018) did not mention the use of recombinant factor VIIa.

Recombinant Factor VIIa and Diffuse Alveolar Hemorrhage

Park and Kim (2015) stated that diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or autoimmune disorders, and it has a high mortality rate. The current therapeutic options of corticosteroids, transfusions, and immuno-suppressants have been limited and largely unsuccessful, and they can be accompanied by multiple complications. Intra-pulmonary administration of rFVIIa has been reported in adults, but there are scarce data on its use in children. These investigators reviewed their institutional experience with intra-pulmonary rFVIIa for the treatment of DAH in children. The study included 6 pediatric patients with acute, bronchoscopically confirmed DAH treated between 2011 and 2013. The median age was 11 years, and patient diagnoses were as follows: acute myeloid leukemia (2 patients), myelodysplastic syndrome (1 patient), hemophagocytic lymphohistiocytosis (1 patient), T-cell lymphoblastic lymphoma (1 patient), and idiopathic pulmonary hemosiderosis (1 patient). These patients were treated with intra-pulmonary rFVIIa concurrent with methylprednisolone, fresh-frozen plasma, and maintenance of the platelet count greater than 50,000/mm(3). Complete and sustained hemostasis after rFVIIa treatment and an absence of AEs were observed in all patients. The PaO2/fraction of inspired oxygen ratio increased significantly, and rapid clinical improvements were observed; 2 patients who received hematopoietic stem cell transplantation (HSCT) died of subsequent respiratory syncytial virus and Acinetobacter baumannii infections, but the other 4 patients exhibited rapid improvement, were successfully weaned from ventilators, and experienced long-term survival. The authors concluded that these findings indicated that intra-pulmonary administration of rFVIIa is a safe and effective therapeutic option for children with DAH; however, further clinical studies are needed.

Pathak and colleagues (2015) noted that DAH is associated with many drugs and diseases including chemotherapy, HSCT, and autoimmune disorders. In a retrospective study, these investigators reported their experience with 23 patients who had DAH and received intravenous rFVIIa. They performed a retrospective chart review of patients who received intravenous rFVIIa for DAH at a tertiary care university hospital between January 1, 2003 and May 31, 2013. They reported demographics, etiology of DAH, frequency and total dose of intravenous rFVIIa, effect of rFVIIa on DAH, and morbidity and mortality. Mean age was 47 ± 19 years. There were 13 men and 10 women; 9 patients had anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, 2 had systemic lupus erythematosus (SLE), 3 had Good pasture's syndrome, 7 were post-bone marrow transplant, 1 had idiopathic thrombocytopenic purpura, and 1 had cryoglobulinemia. Treatment in the ICU was needed for 22 patients of whom 18 were intubated and on mechanical ventilation; 1 patient was treated on general medical service. All patients received 35 to 120 mcg/kg rFVIIa every 2 hours until hemostasis was achieved or treatment was judged to be inadequate. In 22/23 patients, bleeding resolved with rFVIIa therapy. The mean dose to control bleeding was 5 ± 3 mg; 8 patients died (36 %) of their underlying condition; 6 of them had received bone marrow transplant, while 2 had ANCA vasculitis. Deaths were due to multi-organ failure, sepsis, and progressive underlying disease. No overt, clinically obvious adverse thrombotic events were observed with the use of rFVIIa. The authors concluded that activated Factor VII can achieve hemostasis in patients with DAH.

In a pilot study, Bafaqih and associates (2015) examined the feasibility and effectiveness of nebulized tranexamic acid TXA (n-TXA) and nebulized rFVIIa (n-rFVIIa) when used in a 2-step therapy protocol in children with intractable DAH in a pediatric intensive care unit (ICU). In this prospective trial, n-TXA (250 mg/dose for children less than 25 kg and 500 mg/dose for children greater than 25 kg) was administered to 18 children (median age [interquartile range] of 24.0 months [11.3 to 58.5]) with intractable DAH; n-rFVIIa (35 ug/kg/dose for children less than 25 kg, and 50 ug/kg/dose for children greater than 25 kg) was added if no or minimal response was seen after 3 to 4 doses (18 to 24 hours) of n-TXA. Diffuse alveolar hemorrhage was stopped in 10 (55.6 %) children with n-TXA alone within 24 hours of therapy. Documented concomitant respiratory infection showed a significant negative association with response to n-TXA in a step-wise regression analysis (OR = 0.06; 95 % CI: 0.01 to 0.74). In the other 8 (44.4 %) children, n-rFVIIa was added due to n-TXA failure; 6 (75.0 %) showed complete cessation of DAH, while 2 children failed to respond with the addition of n-rFVIIa (25.0 %). None of the children who responded to therapy showed recurrence of DAH after therapy termination. No complications related to therapy were recorded. The authors concluded that n-TXA and n-rFVIIa were safe and effective when used in a 2-step-therapy protocol to control intractable DAH in pediatric patients in ICU settings. They stated that this therapy modality warrants further exploration through larger multi-center clinical trials.

Park (2016) stated that the current therapeutic options for DAH (e.g., corticosteroids, transfusions, extra-corporeal membrane oxygenation (ECMO), and immuno-suppressants) have been limited and largely unsuccessful. Recombinant activated factor VII has been successfully administered, either systemically or bronchoscopically, to adults for the treatment of DAH, but there are few data on its use in pediatric patients. The author reviewed the current literature in the PubMed database to evaluate the effectiveness and risk of rFVIIa treatment for DAH in pediatric patients. This review discussed the diagnosis and treatment of DAH, as well as a new treatment paradigm that includes rFVIIa. The author also discussed the risks and benefits of off-label use of rFVIIa in pediatric patients.

Baker and colleagues (2016) presented a case series of 6 patients treated with intra-pulmonary rFVIIa for the treatment of refractory DAH. Subjects were treated with intra-pulmonary instillation of rFVIIa. Doses were divided equally between the right and the left lungs. Doses were 30, 50, or 60 mcg/kg and frequencies varied from a single administration to repeated doses on subsequent days on the basis of the clinical response. All patients received high-dose steroids, and 4 also received an aminocaproic acid infusion. Intra-pulmonary rFVIIa treated DAH effectively in 5 of 6 patients. Doses used were smaller and less frequent than those described previously. The authors concluded that intra-pulmonary factor VII is an effective adjunctive treatment for DAH. It achieved treatment success with both smaller and less frequent doses than those described previously. The authors noted that this may be a good therapeutic option for DAH, especially when standard therapies have failed or bleeding is immediately life-threatening. They stated that it is possible that intra-pulmonary rFVIIa could save costs, while improving the intensive care unit length of stay; however, further prospective studies are needed to evaluate the optimal dose and frequency for adequate therapeutic efficacy.

An UpToDate review on "The diffuse alveolar hemorrhage syndromes" (Danoff and Hallowell, 2022) does not mention rFVIIa as a therapeutic option. Furthermore, an UpToDate review on "Therapeutic uses of recombinant coagulation factor VIIa in non-hemophiliacs" (Hoffman, 2016) states that "There are anecdotal reports of the successful use of rFVIIa in patients with pulmonary hemorrhage (e.g., diffuse alveolar hemorrhage or massive hemoptysis) following a variety of insults, including pneumonia, hematopoietic cell transplant, metastatic choriocarcinoma, and microscopic polyangiitis".

Recombinant Factor VIIa and Gastro-Intestinal Bleeding After Hematopoietic Stem Cell Transplantation

Tang and colleagues (2015) noted that rVIIa has an off-label use to control life-threatening bleeding that is refractory to other measures and was shown to decrease transfusion requirements. Gastro-intestinal (GI) bleeding is a severe complication following hematopoietic stem cell transplantation (HSCT) in patients with thrombocytopenia, while hemostatic measures based on anti-fibrinolytic or transfusion therapy may not always be successful. These researchers investigated the treatment with rFVIIa in severe GI bleeding among thrombocytopenia patients undergoing HSCT; rFVIIa was given as a single dose of 60 μg/kg in patients with GI bleeding following HSCT. Among all patients enrolled, 12 (75 %) of 16 patients obtained a response, of which 5 achieved a complete response (CR) and 7 achieved a partial response (PR). The 4 remaining patients (25 %) had no response; 9 patients (56.3 %) died in a follow-up of 90 days. No thromboembolic events were associated with the drug administration occurred. The authors concluded that the findings of this study showed that rFVIIa may represent an additional therapeutic option in such cases. These preliminary findings need to be validated by well-designed studies.

Recombinant Factor VIIa and Hemoptysis Due to Invasive Pulmonary Aspergillosis

Gurlek Gokcebay et al (2015) noted that invasive fungal infections have turned out to be a significant cause of morbidity and mortality in pediatric patients with malignant disorders. Massive hemoptysis, a rare complication of invasive pulmonary aspergillosis, may threaten the lives of patients, usually during the resolution of neutropenia. These investigators described a patient with massive hemoptysis due to invasive pulmonary aspergillosis whose bleeding was controlled successfully with off-label use of rFVIIa and subsequent coil embolization of the right pulmonary artery. The role of rFVIIa in the treatment of massive hemoptysis as a consequence of invasive pulmonary aspergillosis needs to be further investigated.

Furthermore, an UpToDate review on "Treatment and prevention of invasive aspergillosis" (Patterson, 2022) does not mention recombinant factor VIIa as a therapeutic option.

Recombinant Factor VIIa and Qualitative Platelet Defects

Balci et al (2011) noted that Glanzmann thrombasthenia (GT) is a rare inherited qualitative platelet disorder due to the deficiency or defect of platelet membrane glycoprotein (GP) IIb/IIIa complex. Symptoms include purpura, petechiae, bruising, gingival bleeding, epistaxis, and menorrhagia. Platelet transfusion is considered the standard therapy for securing hemostasis in patients with GT when local measures and anti-fibrinolytic agents are inadequate. However, repeated platelet transfusions may result in GP IIb/IIIa and/or human leukocyte antigen (HLA) immunization and development of platelet refractoriness. Recombinant factor VIIa (rFVIIa) has been introduced as therapeutic alternative and has been suggested to be effective. Recombinant factor VIIa is indicated in Europe for the treatment of GT refractory of platelet transfusion. In previous studies, rFVIIa has been used in the prophylactic treatment of bleeding in patients with GT undergoing pelvic surgery, Cesarean section, and vaginal delivery. These investigators presented a case of intensive menstrual bleeding refractory to previous anti-fibrinolytic agents and platelet transfusions; but which responded well to treatment with rFVIIa. To the authors’ knowledge, there was no study or reported case in the literature reporting successful use of rFVIIa in a patient with excessive menstrual bleeding due to GT. The authors stated that this was the 1st case treated successfully with rFVIIa; however, it was a unique experience. They stated that although it may shed light for further studies, larger case-series studies and confrontation with other therapeutic modalities are needed to settle a specific treatment protocol for the management of menorrhagia in GT.

Furthermore, an UpToDate review on “Congenital and acquired disorders of platelet function” (Leung, 2022) states that “Antibodies to integrin αIIbβ3 and/or HLA antigens may occur in subjects with Glanzmann thrombasthenia who have received multiple platelet transfusions, resulting in refractoriness to such transfusions. The use of recombinant factor VIIa and other hemostatic agents in such settings has been helpful in controlling bleeding, although controlled efficacy studies are lacking … Recombinant factor VIIa (rFVIIa) has had some success for the treatment of bleeding in patients with congenital platelet disorders … Patients who cannot receive platelet transfusions because of alloimmunization or antibody formation to the absent platelet glycoprotein (e.g., Glanzmann thrombasthenia and Bernard-Soulier syndrome) may benefit from rFVIIa. This use was evaluated in a review of observational studies and case reports that included 165 bleeding episodes and 56 surgical procedures in patients with Glanzmann thrombasthenia. Approximately half had a history of or concern for platelet isoimmunization. Patients treated with rFVIIa typically received one or more bolus infusions of approximately 90 to 100 mcg/kg. Most patients had resolution of or prevention of excessive bleeding; it was difficult to determine if efficacy was solely due to rFVIIa as many patients received other therapies as well … The rFVIIa product is approved in Europe for use in patients with Glanzmann thrombasthenia refractory to platelet transfusions. Benefits of rFVIIa must be balanced against the risk of thrombosis”.

Recurrent Early Miscarriage

Wang and colleagues (2015) examined the association between thrombophilia and recurrent early miscarriage (REM) by the change of thrombophilia markers and evaluated their contribution in diagnosis and treatment of REM. A total of 199 women with REM history were divided into 2 groups within the study group:

151 pregnant (REM-P) and
48 non-pregnant (REM-NP).

In addition, 121 healthy age-matched women without REM history were divided into 2 groups of the control group:

75 pregnant (Control-P) and
46 non-pregnant (Control-NP).

Lupus anticoagulant (LA), anti-cardiolipin antibodies (ACA), and anti-β2-glycoprotein-I antibodies (anti-β2GPI-ab) and coagulation-related factors such as protein S (PS), protein C (PC), anti-thrombin III (AT-III), and D-dimer were analyzed. The prevalence of anti-phospholipid antibodies (aPL) and the coagulation-related factors between groups were compared. The overall prevalence of aPL positivity in REM-P (14.57 %) showed a difference compared with REM-NP (2.66 %) but not for aCL, anti-β2GPI-ab or LA alone. There were significant differences in the mean levels of protein S, protein C, and AT-III in REM-P. The mean values of protein C (90.3 ± 28.42 %) and protein S (71.80 ± 24.68 %) in the aPL-positive study group were similar with that of the aPL-negative study group (p = 0.406, p = 0.880). Comparing with the aPL-negative study group, the mean value of AT-III (87.71 ± 21.84 %) was significantly lower (p = 0.018), while the mean value of D-dimer (0.98 ± 1.1 mg/L FEU) was significantly higher (p = 0.013). The authors addressed the role of the prevalence of aPL and the related coagulation factors for predicting a pre-thrombotic state in patients with REM. They stated that these findings of the use of anti-coagulants for treating REM are encouraging.

Factor X (Coagadex)

U.S. Food and Drug Administration (FDA)-Approved Indications

Coagadex is indicated in adults and children with hereditary Factor X deficiency for:
- Routine prophylaxis to reduce the frequency of bleeding episodes
- On-demand treatment and control of bleeding episodes
- Perioperative management of bleeding in patients with mild and moderate hereditary Factor X deficiency.
- Limitation of Use: Perioperative management of bleeding in major surgery in patients with severe hereditary Factor X deficiency has not been studied.

The FDA approved coagulation Factor X (human) (Coagadex), for hereditary Factor X deficiency. Hereditary factor X deficiency is a rare bleeding disorder that affects approximately 300-600 patients in the U.S. Factor X deficient patients are at increased risk of bleeding and need to be managed similarly to hemophilia patients. Patients with the disorder were usually treated with fresh-frozen plasma or plasma-derived prothrombin complex concentrates to stop or prevent bleeding.

Coagadex, which is derived from human plasma, is indicated for individuals with hereditary Factor X deficiency for routine prophylaxis, on-demand treatment and control of bleeding episodes, and for perioperative (period extending from the time of hospitalization for surgery to the time of discharge) management of bleeding in patients with mild hereditary Factor X deficiency. Perioperative management of bleeding in major surgery in patients with moderate and severe hereditary Factor X deficiency has not been studied. The FDA granted Coagadex orphan product designation for these uses.

On-Demand Treatment and Control of Bleeding Episodes

The safety and efficacy of Coagadex was evaluated in a multi-center, non-randomized study involving 16 participants (208 bleeding episodes) for treatment of spontaneous, traumatic and heavy menstrual (menorrhagic) bleeding episodes. Coagadex was demonstrated to be effective in controlling bleeding episodes in participants with moderate to severe hereditary Factor X deficiency. The study enrolled patients with moderate to severe hereditary factor X deficiency who were treated on-demand for spontaneous or traumatic bleeding episodes. The primary efficacy endpoints were pharmacokinetic measures including recovery rate and half-life, and secondary endpoints included overall assessment of efficacy and the number of infusions needed to treat a bleed. The criteria for treatment success were satisfied in the study, and the pharmacokinetic parameters were consistent with previously published data. The overall mean in-vivo recovery rate was 2.0 IU/dL per IU/kg and the half-life was approximately 30 hours. There were 187 assessable bleeds in the study with patients rating the treatment as "excellent" in 170 (91%) cases, "good" in 14 (7.5%) cases, and "poor" in 2 (1.1%) cases. In addition, most bleeding episodes (155/187 [82.9%]) were effectively treated with only one infusion of Coagadex. Two patients in the study reported six adverse events considered possibly related to the medication: two events of fatigue in one patient, two events of infusion site erythema in one patient, and one of infusion site pain and back pain in each patient. There were no other drug-related adverse events, no serious drug-related adverse events, and no patients discontinued from the study due to adverse events.

Perioperative Management of Bleeding

Coagadex was also evaluated in five participants with mild to severe Factor X deficiency who were undergoing surgery. The five individuals received Coagadex for perioperative management of seven surgical procedures. Coagadex was demonstrated to be effective in controlling blood loss during and after surgery in participants with mild deficiency.related adverse events, and no patients discontinued from the study due to adverse events.This study collected data on two surgical patients receiving Coagadex perioperatively. Surgical data from three patients in the first study was added and resulted in five patients undergoing seven surgical procedures. For all surgical procedures, Coagadex was assessed by the investigator as excellent in controlling blood loss during and after surgery. All patients undergoing major procedures were diagnosed with mild factor X deficiency (i.e., factor X level >5 IU/dL and < 20 IU/dL). One patient with moderate deficiency and two with severe deficiency underwent minor procedures. No patients with moderate or severe disease underwent a major procedure. There were no treatment-related adverse events reported in surgical patients in this study No individuals with moderate or severe Factor X deficiency received Coagadex for perioperative management of major surgery.

Prophylaxis of Bleeding Episodes

In a multicenter, open-label, non-randomized clinical trial, the use of Coagadex in routine prophylaxis of bleeding episodes was evaluated in nine children aged less than 12 years of age. The mean age was 7.3 (range 2.6 to 11.9) years. Eight subjects had severe FX deficiency and the other had moderate deficiency. Four subjects were between 0 and 5 years of age and five were between 6 and 11 years of age inclusive. The majority of subjects were Asian (7; 77.8%) and the remainder were Caucasian/White (2; 22.2%). After the first dose of Coagadex 50 IU/kg, given at a rate not exceeding 3 mL/minute, all subjects underwent a 30-minute post-dose incremental recovery assessment. Routine prophylaxis was started on Day 2 or 3 with unit doses of 40-50 IU/kg and during the first 6 weeks trough levels of Factor X were measured to adjust the dosage regimen to maintain a trough level of at least 5 IU/dL. At the end of the study (at least 6 months and at least 50 exposure days) a repeat 30-minute incremental recovery was performed. A total of 537 (mean 59.7 per subject) prophylactic infusions were administered. The median prophylactic dose per infusion per subject was 39.60 IU/kg (mean 38.76 IU/kg), and ranged from 18.0 to 47.3 IU/kg. Median and mean doses per infusion in the four children less than 6 years of age were both 40.1 IU/kg (95% CI 30.70, 49.57) and in the five children 6 to 11 years of age inclusive, median dose was 39.6 IU/kg and mean dose was 37.7 IU/kg (95% CI: 23.42, 51.91). The median dosing interval for all of the nine children was 3 days (range 2 to 8 days). Investigators’ assessment following 6 months of routine prophylaxis was rated excellent in all 9 subjects; excellent was defined as ‘no minor or major bleeds occurred during the study period’ or ‘lower frequency of bleeds than expected, given subject’s medical/treatment history’. In addition, 22 infusions were given to treat a bleed, equivalent to 2.1 bleeds per subject per year. One subject had three episodes of epistaxis and the other bleeds were due to trauma or menorrhagia. All bleeds were treated with a single infusion; the median and mean doses per subject were both 31.7 IU/kg (range 24.6 to 38.8 IU/kg) and all recorded efficacy ratings were categorized as ‘excellent’ i.e. Overt bleed: bleeding stopped within 12 hours with a single dose; Menorrhagic bleed: no additional doses required; Covert bleeds: there were none in this study.

Coagadex is contraindicated in patients with known hypersensitivity to any of the components of the product.

The product labeling states that allergic type hypersensitivity reactions, including anaphylaxis, are possible with Coagadex. If symptoms occur, patients should discontinue use of the product immediately and contact their physician.

The labeling states that formation of neutralizing antibodies (inhibitors) to factor X is a possible complication in the management of individuals with factor X deficiency. The labeling recommends carefully monitoring patients taking Coagadex for the development of inhibitors by appropriate clinical observations and laboratory tests.

Coagadex is made from human plasma and may contain infectious agents, e.g. viruses and, theoretically, the Creutzfeldt-Jakob disease agent. No cases of transmission of viral diseases, vCJD or CJD, have been associated with the use of Coagadex.

In clinical studies, the most common adverse events (frequency ≥5% of subjects) with Coagadex were infusion site erythema, infusion site pain, fatigue and back pain. No safety concerns were identified in either study.

Factor XIII Concentrate [Human] (Corifact)

U.S. Food and Drug Administration (FDA)-Approved Indications

Corifact is indicated in adults and pediatric patients with congenital factor XIII deficiency for routine prophylactic treatment and peri-operative management of surgical bleeding.

Compendial Use

Acquired factor XIII deficiency

Congenital factor XIII deficiency is rare and affects 1 out of every 3 to 5 million people in the United States. It is associated with a tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intra-cranial hemorrhage. The clinical severity of this deficiency requires regular prophylaxis from the time of diagnosis. Accordingly, replacement material can be infused at intervals as long as every 20 to 30 days. Three types of factor XIII-containing product are available: fresh-frozen plasma (FFP; preferably virus-inactivated), cryoprecipitate, and a pasteurized plasma concentrate (Fibrogammin-P, Dade-Behring). The pasteurized concentrate and virus-inactivated FFP, when available, are preferred to cryoprecipitate (Lovejoy et al, 2006; Mannucci et al, 2010).

On February 17, 2011, the FDA approved Corifact (factor XIII concentrate [Human]), derived from the pooled plasma of healthy donors, via orphan-drug designation for the prevention of bleeding in people with congenital factor XIII deficiency. The FDA approved Corifact based on results of a clinical study of 14 people, including children, with congenital factor XIII deficiency. The most common side effects observed were hypersensitivity reactions (allergy, rash, pruritus, and erythema), chills, fever, arthralgia, headache, elevated thrombin-antithrombin levels, and an increase in hepatic enzymes. It potentially can cause adverse events from abnormal clotting if doses higher than the labeled dose are given to patients.

Factor XIII (human) also has been used to treat acquired factor XIII deficiency, a condition associated with various diseases and other conditions (e.g., inflammatory bowel/autoimmune diseases, Henoch-Schonlein purpura, leukemia, adverse effects of certain drugs [e.g., isoniazid, penicillin, phenytoin, valproic acid], autoantibody against the A or B subunit of factor XIII). In addition to therapy with factor XIII (human), patients with acquired factor XIII deficiency associated with autoantibodies against factor XIII have received adjunctive therapy with immunosuppressant drugs (e.g., cyclosporine, cyclophosphamide) to eradicate these antibodies (AHFS-Lexicomp).

Hayashi et al (2012) stated acquired factor XIII (FXIII) deficiency due to an autoantibody against FXIII is a very rare, yet potentially life-threatening bleeding disorder. As the standard coagulation tests (prothrombin time and activated partial thromboplastin time) are normal, the specialized tests are required to make an accurate diagnosis. Here, we report a case of acquired FXIII deficiency with severe bleeding symptoms. A 75-year-old man was referred to our hospital because of severe bleeding tendency after a tooth extraction. Laboratory findings showed that routine coagulation studies were normal, but factor XIII (FXIII) activity was low (3%). The presence of FXIII inhibitor was detected with dot blotting studies. Although the bleeding tendency was very severe, it was successfully controlled by infusion of FXIII concentrates combined with immunosuppressive treatment (oral prednisolone). Fibrin cross-linking study showed the significant delay of the γ-chain dimer and α-chain polymer formation. Western blotting revealed the marked decrease in FXIII-A level. The mixing study of FXIII activity measured using amine-incorporation assay showed the incomplete inhibition pattern. There seems to be little agreement as to the treatment strategy of acquired FXIII deficiency. In this patient, the use of FXIII concentrates was very useful in the initial treatment of bleeding symptom. The use of steroids was also effective in increasing FXIII activity without any serious complications.

In their review, Naderi et al (2013) stated factor XIII or "fibrin-stabilizing factor," is a transglutaminase circulates in the blood circulation as a hetero tetramer with two catalytic A subunits and two carrier B subunits. This important coagulation factor has a crucial role in clotting cascade and produces strong covalent bonds between soluble formed fibrin monomers during coagulation. This stable cross-linked fibrin strands are resistant to degradation by the fibrinolytic system that enables the body to stop potential bleeding episodes. In the absence or severe decrease of factor XIII, although the clot is formed, but is rapidly degraded by the fibrinolytic system, and delayed bleeding occurs. Factor XIII deficiency is an extremely rare bleeding disorder with estimated incidence of 1/2-3000,000 in the general population. Presumptive diagnosis of factor XIII deficiency was by clot solubility test in 5M urea or 1% monochloroacetic acid environments. In patients with abnormal screening clot solubility test, the disease can be confirmed by more specific tests such as quantitative factor XIII activity assay and FXIII Ag assay. After diagnosis of disease all patients with severe factor XIII deficiency (<1 U/dl) should receive prophylactic substitution therapy with fresh frozen plasma (FFP) and cryoprecipitate as traditional choices or purified concentrate of blood coagulation factor XIII (Fibrogammin P) in order to control severe and life-threatening clinical complications of factor XIII deficiency. The authors note that the treatment of bleeding episode on this deficiency is based on half-life of FXIII (11-14 days) therefore replacement material should be used at large interval (20-30 days). Replacement therapy in this deficiency can be administered through fresh frozen plasma ( preferably virus-inactivated) in doses of 10 mL kg−1in 4–6 weeks interval, cryoprecipitate (cryo) administered in doses of 1 bag per 10–20 kg every 3–4 weeks and pasteurized FXIII concentrates(about 240 units/vial). Among these items, the virus inactivated FFP and particularly pasteurized concentrates are preferred. The first FXIII from human source that used in replacement therapy was produced from placenta (Fibrogammin HS®) but later this product replaced by plasma extracted FXIII concentrates [Fibrogammin P® (CSL Behring, Marburg, Germany) and FXIII-BLP® (Bio-Product Laboratory, Elstree, United Kingdom)]. Factor XIII purified from human plasma is known as Fibrogammin and Fibrogammin-P in Europe, South America, and Asia; Corifact in the United States.

Prothrombin Complex Concentrate [Human] (Kcentra)

U.S. Food and Drug Administration (FDA)-Approved Indications

Kcentra is indicated in adult patients for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy with acute major bleeding or need for an urgent surgery/invasive procedure.

Ferreira and DeLosSantos (2013) stated that PCC is an inactivated concentrate of factors II, IX, and X, with variable amounts of factor VII. Guidelines recommend the use of PCC in the setting of life-threatening bleeds, but little is known on the most effective dosing strategies and how the presenting international normalized ratio affects response to therapy. These investigators high-lighted available data on monitoring techniques, address shortcomings of currently available data, the reversal of life-threatening and critical bleeds with PCC, and how this product compares to other therapeutic options used in critically ill patients. Prothrombin complex concentrate has been identified as a potential therapy for critically bleeding patients, but patient-specific factors, product availability, and current data should weigh the decision to use it. Most data exist regarding patients experiencing VKA-induced bleeding, more specifically, those with intra-cranial hemorrhage. Prothrombin complex concentrate has also been studied in trauma-induced hemorrhage; however, it remains controversial, as its potential benefits have the abilities to become flaws in this setting. The authors concluded that health care professionals must remain aware of the differences in products and interpret how 3- versus 4-factor products may affect patients, and interpret literature accordingly. The clinician must be cognizant of how to progress when treating a bleeding patient, propose a supported dosing scheme, and address the need for appropriate factor VII supplementation. At this point, PCC cannot be recommended for first-line therapy in patients with traumatic hemorrhage, and should be reserved for refractory bleeding until more data are available.Cabral and colleagues (2013) evaluated the safety and effectiveness of a PCC-based protocol in patients with warfarin-associated ICH, sub-dural hematoma (SDH), or sub-arachnoid hemorrhage (SAH). This was a retrospective case-series review of patients treated with an institution-approved warfarin reversal protocol. Patients with ICH and known warfarin use with an INR greater than 1.4 received FFP, vitamin K (phytonadione), and weight-based, 3-factor PCC (Profilnine(^®) SD) dose based on the initial INR. Demographic and clinical information, the degree of and time to INR normalization, and adverse events were recorded. The 30 study patients included 19 with primary ICH, 7 with SDH, and 4 with SAH. The mean age was 72.8 (± 11) years, including 11 (37 %) patients greater than or equal to 80 years old. The median presenting INR was 2.3 (IQR 2 to 3.3) and post-treatment INR was 1.4 (IQR 1.3 to 1.5, Z score 6.4, p < 0.001). Median time from PCC administration to the first follow-up INR was 95 (IQR 50 to 140) mins. No patient's INR increased by more than 0.3 over 72 hrs. Nine patients (30 %) underwent neurosurgical procedures after PCC administration and no procedure-related bleeding complication was noted. Adverse events included 3 instances of early hematoma expansion, 1 ischemic stroke in a patient with endocarditis on post-PCC day 1, 1 pulmonary embolism 5 weeks after PCC treatment, and 1 coronary in-stent thrombosis 60 days after PCC treatment. Six patients died prior to hospital discharge of anticipated complications of their initial event, and none from identifiable thrombotic complications of PCC. The authors concluded that a 3-factor PCC preparation (Profilnine(^®) SD), administered with FFP and vitamin K to patients with acute warfarin-associated intracranial bleeding is a reasonable approach to urgent warfarin reversal. Moreover, they stated that randomized, prospective trials are needed to verify the safety and clinical effectiveness of PCC administration in this population.

Song et al (2014) reported their initial experience with the PCC FEIBA for the rescue treatment of coagulopathy and life-threatening bleeding after cardiac surgery. A total of 25 patients who underwent cardiac surgery with coagulopathy and life-threatening bleeding refractory to conventional treatment received FEIBA as rescue therapy at the authors’ institution. This cohort represented approximately 2 % of patients undergoing cardiac surgery in the authors’ university-based practice during the study. The patients were at high risk for post-operative coagulopathy with nearly all patients having at least 2 risk factors for this. Aortic root replacement (Bentall or valve-sparing procedure) and heart transplant with or without left ventricular assist device explant were the most common procedures. The mean FEIBA dose was 2,154 units. The need for fresh frozen plasma and platelet transfusion decreased significantly after FEIBA administration (p = 0.0001 and p < 0.0001). The mean INR decreased from 1.58 to 1.13 (p < 0.0001). Clinical outcomes were excellent. No patient returned to the operating room for re-exploration. There was no hospital mortality and all patients were discharged home. One patient who had a central line and trans-venous pacemaker developed an upper extremity DVT. The authors concluded that their initial experience with FEIBA administration for the rescue treatment of post-operative coagulopathy and life-threatening bleeding has been favorable. Moreover, they stated that further studies are indicated to confirm its safety and effectiveness; and determine specific clinical indications for its use in patients undergoing cardiac surgery.

Patients receiving chronic anti-coagulation therapy with warfarin and other vitamin K antagonist (VKA) anti-coagulants to prevent blood clotting in conditions such as atrial fibrillation or the presence of an artificial heart valve sometimes develop acute bleeding. Hickey et al (2013) determined adverse event frequency after urgent reversal with frozen plasma versus the prothrombin complex concentrate (PCC) – Octaplex. This natural before-after retrospective cohort study in 2 tertiary care emergency departments compared anti-coagulation reversal with frozen plasma (September 2006 to August 2008) and with Octaplex (September 2008 to August 2010), without other system changes. These researchers included adult patients on warfarin with an international normalized ratio (INR) of greater than or equal to 1.5 who received frozen plasma or Octaplex. The primary outcome was serious adverse events (death, ischemic stroke, myocardial infarction, heart failure, venous thromboembolism, or peripheral arterial thromboembolism) within 7 days. Secondary outcomes included time to INR reversal, hospital length of stay, and red blood cells transfused within 48 hours. They included 149 patients receiving frozen plasma and 165 receiving Octaplex. The incidence of serious adverse events for the frozen plasma group was 19.5 % compared with 9.7 % for the Octaplex group (p = 0.014; relative risk, 2.0; 95 % CI: 1.1 to 3.5). This remained significant after adjustment for baseline history and reason for treatment (p = 0.038; adjusted relative risk, 1.85; 95 % CI: 1.03 to 3.3) in multi-variable regression analysis. Median INR reversal was 11.8 hours with frozen plasma and 5.7 hours with Octaplex (p < 0.0001). Mean red cell transfusion was 3.2 with frozen plasma and 1.4 with Octaplex (p < 0.0001). The authors concluded that Octaplex for urgent reversal of warfarin resulted in faster reversal and lower red cell transfusion requirement with fewer adverse events than frozen plasma.

Hanke et al (2013) noted that the rapid reversal of the effects of VKA is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intra-cranial hemorrhage. Increasingly, 4-factor PCCs (4F-PCC) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anti-coagulation reversal. Both the safety and effectiveness of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either peri-operatively or in cases of acute trauma. After 15 years of clinical use, findings of a pharmaco-vigilance report (February 1996 to March 2012) relating to the 4F-PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analyzed and were presented here. Furthermore, a review of the literature with regard to the safety and effectiveness of 4F-PCCs was performed. Since receiving marketing authorization (February 21, 1996), approximately 647,250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (1 in approximately 31,000) is in line with the incidence observed with other 4F-PCCs. The authors concluded that in general, 4F-PCCs have proven to be well-tolerated and highly effective in the rapid reversal of VKA.

Sarode et al (2013) performed a prospective clinical trial to compare non-activated 4F-PCC with plasma for urgent VKA reversal. In this phase IIIb, multi-center, open-label, non-inferiority trial, non-surgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was non-inferior to plasma for the co-primary end-points of 24-hour hemostatic efficacy from start of infusion and INR correction (less than or equal to 1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n = 98; plasma, n = 104). Median (range) baseline INR was 3.90 (1.8 to 20.0) for the 4F-PCC group and 3.60 (1.9 to 38.9) for the plasma group. Effective hemostasis was achieved in 72.4 % of patients receiving 4F-PCC versus 65.4 % receiving plasma, demonstrating non-inferiority (difference, 7.1 % [95 % CI: -5.8 to 19.9]). Rapid INR reduction was achieved in 62.2 % of patients receiving 4F-PCC versus 9.6 % receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6 % [95 % CI: 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (p < 0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced greater than or equal to 1 adverse event. The authors concluded that 4F-PCC is an effective alternative to plasma for urgent reversal of VKA therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of INR and factor levels.

The National Institute for Health and Clinical Excellence’s clinical guideline on "Acute upper gastrointestinal bleeding: Management" (NICE, 2012) recommended PCC to patients who are taking warfarin and actively bleeding.

UpToDate chapter on rare inherited coagulation disorder states severe factor II (prothrombin) deficiency is characterized by excessive bleeding after invasive procedures, and umbilical cord, joint, muscle, and mucosal bleeding. Life-threatening bleeding may also occur. No recombinant or plasma-derived factor II concentrates are available to treat bleeding. However, factor II is present in 3 factor and 4 factor Prothrombin Complex Concentrates (PCCs) (Kcentra, Profilnine SD, and Feiba NF). PCCs are dosed at 20 to 30 units/kg, with a target factor II level >30 percent. The plasma half-life of factor II is three to four days; thus, dosing interval may be less frequent than for some other rare (or recessively) inherited coagulation disorders (RICDs), guided by clinical bleeding and factor activity levels. Laboratory monitoring of other factors is advisable when prolonged administration of PCCs is used, in order to avoid levels of the non-deficient factors in excess of 150 percent (factors IX and X for 3 factor PCC; factors VII, IX, X for 4 factor PCC). FFP (solvent/detergent treated if available) is dosed at 15 to 20 mL/kg.

Prothrombin Complex Concentrate (Human) Kcentra

On April 29, 2013, the FDA approved Kcentra (prothrombin complex concentrate, human) for the urgent reversal of acquired coagulation factor deficiency induced by VKA (e.g., warfarin) therapy in adult patients with acute major bleeding. Kcentra is not indicated for urgent reversal of VKA anti-coagulation in patients without acute major bleeding. The FDA approval of Kcentra was based on a study of 216 patients who had been receiving VKA anti-coagulation and who had acute major bleeding along with a clotting test value indicative of anti-coagulant use. Kcentra was demonstrated to be similar to plasma in terms of the ability to stop acute major bleeding. Kcentra is made from the pooled plasma of healthy donors. It is processed in a way to minimize the risk of transmitting viral and other diseases.

Recombinant Coagulation Factor XIII A-Subunit (Tretten)

U.S. Food and Drug Administration (FDA)-Approved Indication

Tretten is indicated for routine prophylaxis of bleeding in patients with congenital factor XIII A-subunit deficiency.

Tretten is not for use in patients with congenital factor XIII B-subunit deficiency.

The U.S. Food and Drug Administration approved recombinant coagulation factor XIII A-subunit (Tretten, Novo Nordisk) for use in the routine prevention of bleeding in adults and children who have a congenital Factor XIII A-subunit deficiency. Tretten received orphan-drug designation for this use by the FDA because it is intended for treatment of a rare disease or condition. Congenital Factor XIII deficiency is a rare genetic disorder. Factor XIII is composed of two subunits, A and B. Factor XIII deficiency is usually caused by a deficiency of the A-subunit.

Tretten is a recombinant analogue of the human Factor XIII A-subunit that is produced in yeast cells and then further purified. It is a sterile freeze-dried-powder to be reconstituted with diluent and injected intravenously. Tretten can be administered by a physician or be self-administered. The effectiveness of coagulation factor XIII A-subunit was studied in 77 patients with congenital Factor XIII A-subunit deficiency. The study found that coagulation factor XIII A-subunit was effective in preventing bleeding in 90 percent of the patients when given monthly. Among the side effects reported in this study were headache, pain in the extremities and pain at injection site. No individual in the trial developed abnormal clots.

The FDA-approved labeling for Tretten states that the dose for routine prophylaxis for bleeding in patients with congenital factor XIII (FXIII) A-subunit deficiency is 35 international units (IU) per kilogram body weight once monthly to achieve a target trough level of FXIII activity at or above 10% using a validated assay. The labeling states that dose adjustment should be considered if adequate coverage is not achieved with the recommended 35 IU/kg dose.

Anti-Thrombin III (Thrombate III and ATryn)

U.S. Food and Drug Administration (FDA)-Approved Indications

Thrombate III (antithrombin III; human) is indicated in patients with hereditary antithrombin deficiency for:
- Treatment and prevention of thromboembolism; and
- Prevention of peri-operative and peri-partum thromboembolism
ATryn (antithrombin; recombinant) is indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. It is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients.

It is not indicated for the treatment of thromboembolic events in hereditary antithrombin deficient patients.

Compendial Uses

ATryn and Thrombate III: heparin resistance prior to or during cardiopulmonary bypass (CPB)
Thrombate III:
- Acquired antithrombin deficiency
- Treatment of asparaginase-induced antithrombin deficiency

Antithrombin, or Antithrombin III (AT III), is also called heparin cofactor I, a factor in plasma necessary for heparin to exert its anticoagulant activity. AT III is a natural anticoagulant synthesized in the liver and regulates hemostasis by inhibiting thrombin; factors IXa, Xa, XIa, and XIIa; kallikrein; and plasmin. AT III deficiency predisposes patients to venous thromboembolic events by impairing the clearance of activated coagulation factors. Thrombate III is AT III concentrate produced from pooled human plasma and indicated in patients with hereditary antithrombin III deficiency for treatment and prevention of thromboembolism, including thromboembolism in connection surgical or obstetrical procedures.

Another antithrombin product, ATryn, is the first biological agent produced by genetically engineered animals (goats) and the first recombinant human antithrombin. ATryn is produced utilizing recombinant DNA technology in which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland-specific DNA sequence that directs the expression of antithrombin into the milk of goats. ATryn is indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.

Rogers (2009) stated that anti-thrombin (AT) functions as a potent natural anticoagulant and serine protease inhibitor that inactivates many enzymes in the coagulation cascade. Antithrombin also possesses anti-inflammatory properties, many of which are mediated by its actions as an anti-coagulant. Hereditary AT deficiency is a rare, under-recognised medical condition that is associated with inadequate endogenous anti-coagulation thought to result from impaired inhibition of serine protease coagulation factors. Inherited as an autosomal dominant trait, congenital AT deficiency typically reduces functional AT levels to 40 to 60 % of normal. As a result, individuals with hereditary AT deficiency have a greater than or equal to 50 % lifetime risk of venous thromboembolism (VTE). Specifically, AT deficiency is associated with a 3- to 7-fold higher risk of VTE compared with other thrombophilias. Thus, maintaining adequate levels of AT during high-risk periods is an important treatment goal. Long-term anti-coagulant thrombo-prophylaxis is not recommended in asymptomatic patients with AT deficiency because of the increased risk of hemorrhage. However, treatment guidelines recommend short-term thromboprophylaxis in high-risk clinical settings, including surgery, trauma, and management of pregnancy, labor, and delivery. The goal of treatment for patients with hereditary AT deficiency is an initial increase in AT activity to greater than or equal to 120 % of normal levels followed by maintenance of AT activity at greater than or equal to 80 % of normal levels. Plasma-derived AT, heparin, fresh frozen plasma, and human recombinant AT are treatment options for individuals with hereditary AT deficiency.

Tiede et al (2008) stated that during surgery and childbirth, patients with hereditary AT deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently effective. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT has been developed. In a phase III multi-center study, these investigators assessed the safety and effectiveness of prophylactic intravenous administration of AT alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Anti-thrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100 % of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on AEs and laboratory evaluations. Five surgical and 9 obstetrical hereditary AT deficiency patients received AT alfa for a mean period of 7 days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in 2 out of 13 evaluable patients. No AT alfa-related AEs were reported. No patient developed anti-AT alfa antibodies. The authors concluded that these findings suggested that AT alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.

A Cochrane review concluded that AT III cannot be recommended for critically ill patients based on the available evidence. Afshari et al (2008) noted that AT III is an anti-coagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ill patients are unknown. These researchers evaluated the benefits and harms of AT III in critically ill patients. They searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to November 2006); and contacted authors and manufacturers in the field. They included all randomized clinical trials, irrespective of blinding or language, that compared AT III with no intervention or placebo in critically ill patients. The primary outcome measure was mortality. These investigators each independently abstracted data and resolved any disagreements by discussion. They presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (RR) with 95 % CI; performed subgroup analyses to assess risk of bias, the effect of AT III in different populations (sepsis, trauma, obstetric, and pediatric patients), and the effect of AT III in patients with or without the use of concomitant heparin. They assessed the adequacy of the available number of participants and performed a trial sequential analysis to establish the implications for further research. These researchers included 20 randomized trials with a total of 3,458 participants; 13 of these trials had high risk of bias. When they combined all trials, AT III did not statistically significantly reduce overall mortality compared with the control group (RR 0.96, 95 % CI: 0.89 to 1.03; no heterogeneity between trials). A total of 32 subgroup and sensitivity analyses were carried out. Analyses based on risk of bias, different populations, and the role of adjuvant heparin gave insignificant differences. Anti-thrombin III reduced the multi-organ failure score among survivors in an analysis involving very few patients. It increased bleeding events (RR 1.52, 95 % CI: 1.30 to 1.78). The authors concluded that AT III cannot be recommended for critically ill patients based on the available evidence. The authors stated that a randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion criteria and good bias protection is needed.

Zwicker et al (2020) presented the guidance on hemostasis and malignancy from the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH). The authors state venous thromboembolism is a common complication of asparaginase-based chemotherapy regimens for the treatment of acute lymphoblastic leukemia. Thrombosis associated with asparaginase administration poses a number of specific and often clinically challenging management decisions. This review provides guidance on the prevention and treatment of thrombosis associated with asparaginase in adults including discussions on antithrombin repletion, pharmacologic thromboprophylaxis, cerebral venous thrombosis, and therapeutic anticoagulation.

Stock et al (2011) state the rapidly increasing use of pegasparaginase (pegASNase) in adults, after a half century of use of asparaginase (ASNase) in children, has prompted a need for guidelines in the management and prevention of toxicities of asparagine depletion in adults. Accordingly, an initial set of recommendations are provided herein. Major advantages of pegASNase are its 2-3-week duration of action, in contrast to less than 3 days with native ASNase, and the flexibility of intravenous or intramuscular administration of pegASNase and associated patient and physician convenience. The most frequent toxicities of both types of ASNase are hepatic and pancreatic, with pancreatitis being the most serious. Other toxicities are hypersensitivity reactions, thrombosis, nausea/vomiting, and fatigue. Whether or not the replacement of one dose of pegASNase for 6-9 doses of native ASNase can be achieved in adults with similar efficacy and acceptable toxicities to those achieved in children remains to be established.

Hunault-Berger et al (2008) state the effects of L-asparaginase on hemostasis during induction chemotherapy are less defined in adults than in children. The authors studied the effects of L-asparaginase in this retrospective analysis of 214 adult patients treated with L-asparaginase (7500 IU/m(2) x 6) for acute lymphoblastic leukemia or lymphoblastic lymphoma. Between day 1 of the induction course and discharge, clinical events, and biological and therapeutic modifications were reviewed. Antithrombin and fibrinogen levels were lower than 60% and 1 g/L in 71% and 73% of patients, respectively. Twenty thromboses occurred in 9.3% of the patients; these patients had a median antithrombin level of 53% (range, 21-111) at the time of the event. Forty-two episodes of bleeding occurred in 31 patients with a median fibrinogen level of 1.3 g/L. Infusions of L-asparaginase were reduced or delayed in 64% of patients due to low fibrinogen and/or antithrombin levels. Fresh-frozen plasma, antithrombin and fibrinogen were infused in 31%, 41% and 52% of patients, respectively. The mean antithrombin and fibrinogen levels increased from 61% to 88% and from 1 to 1.4 g/L after infusion of antithrombin or fibrinogen respectively, while both levels remained unchanged after the infusion of fresh-frozen plasma. In patients who received antithrombin concentrates L-asparaginase injections were less frequently omitted or delayed (53% vs. 72%, p=0.005), the rate of thrombosis was lower (4.8% vs. 12.2%, p=0.04) and the disease-free survival was also reduced (p=0.05). The authors concluded that this retrospective study suggests that antithrombin concentrates may have a beneficial effect on the outcome of adults treated for acute lymphoblastic leukemia with L-asparaginase; prospective studies are essential to confirm this hypothesis.

Mitchell et al (2003) stated that an association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by

incidence of thrombosis
incidence of bleeding, and
plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis.

The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP. Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. The authors concluded that, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.

Factor Xa [(recombinant), inactivated-zhzo] (Andexxa)

U.S. Food and Drug Administration (FDA)-Approved Indications

Andexxa is indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

Limitations of Use:

Andexxa has not been shown to be effective for, and is not indicated for, treatment of bleeding related to any FXa inhibitors other than apixaban or rivaroxaban.

Compendial Uses

Reversal of edoxaban or betrixaban anticoagulation due to life-threatening or uncontrolled bleeding

On May 3, 2018, the FDA approved Andexxa as the first and only antidote approved for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is necessary due to fatal or uncontrolled bleeding. It was previously granted both U.S. Orphan Drug and FDA Breakthrough Therapy designations, and was approved under the FDA’s Accelerated Approval pathway based on changes from baseline in anti-Factor Xa activity in healthy volunteers. Continued approval for this indication may be contingent upon post-marketing study results to exhibit an improvement in hemostasis in patients. Andexxa dosing is based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient’s last dose of FXa inhibitor. It is administered as an intravenous (IV) bolus, with a target rate of 30 mg/min, followed by continuous infusion for up to 120 minutes. For the low dose regimen, the initial bolus is 400 mg at a target rate of 30 mg/min and the follow-on IV infusion is 4 mg/min for up to 120 minutes. For the high dose regimen, the initial bolus is 800 mg at a target rate of 30 mg/min and the follow-on IV infusion is 8 mg/min for up to 120 minutes.

The approval was based on data from a two Phase 3 prospective, randomized, placebo-controlled studies (ANNEXA-R and ANNEXA-A) which assessed the safety and efficacy of the therapy in overturning the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban in healthy volunteers. Both studies examined the percent change in anti-FXa activity, from baseline to nadir, for the low-dose and high-dose regimens of bolus followed by continuous infusion. Baseline is the last assessment obtained prior to the first dose of Andexxa or placebo. Nadir is defined as the smallest value measured within 5 minutes after the end of the continuous infusion.

In Study 1 (apixaban reversal), healthy subjects (median age: 57 years; range: 50 to 73 years) received apixaban 5 mg twice daily for 3.5 days to achieve steady-state. At 3 hours after the last apixaban dose (~ Cmax), Andexxa or placebo was administered. Eight subjects received placebo and 24 received ANDEXXA, administered as a 400 mg intravenous (IV) bolus followed by a 4 mg per minute continuous infusion for 120 minutes (total 480 mg). In Study 2 (rivaroxaban reversal), healthy subjects (median age: 57 years, range: 50 to 68 years) received rivaroxaban 20 mg once per day for 4 days to achieve steady-state. At 4 hours after the last rivaroxaban dose (~ Cmax), Andexxa or placebo was administered. Thirteen subjects received placebo and 26 received Andexxa, administered as an 800 mg IV bolus followed by an 8 mg per minute continuous infusion for 120 minutes (total 960 mg).

Study results revealed that the percent change from baseline in anti-FXa activity at its nadir was statistically significant (p < 0.0001) in favor of the Andexxa groups compared to placebo in both Studies 1 and 2. The mean percent change in anti-FXa activity, from baseline to nadir was -92.3% for apixaban compared with -32.7% for placebo (95% CI: -59.5; -64.1, -55.2) and -96.7% for rivaroxaban compared with -44.6% for placebo (95% CI: -51.9; -58.0, -47.0).

The FDA also assessed interim data from the ongoing ANNEXA-4 single-arm, open-label study in patients with major bleeding as part of its review and approval. Data from 185 evaluable patients demonstrated that the median decrease from baseline was 90% for rivaroxaban and 93% for apixaban. Andexxa has not been shown to be effective for bleeding related to any FXa inhibitors other than apixaban and rivaroxaban. The post-marketing requirement is a clinical trial that randomizes patients to be administered either Andexxa or the typical standard of care. This study is scheduled to be initiated in 2019 and be reported in 2023.

Idarucizumab (Praxbind)

U.S. Food and Drug Administration (FDA)-Approved Indications

Praxbind is indicated in patients treated with Pradaxa when reversal of the anticoagulant effects of dabigatran is needed:

For emergency surgery/urgent procedures
In life-threatening or uncontrolled bleeding.

Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect.

The safety and effectiveness of Idarucizumab was investigated in three randomized placebo-controlled healthy volunteer trials, Trials 1321.1, 1321.2 and 1321.5 (NCT01688830, NCT01955720, NCT02028780), and in RE-VERSE AD (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial (NCT02104947), a single cohort case series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedure. Trials 1321.1, 1321.2 and 1321.5 assessed the safety, dose-response, and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and 30 subjects aged 65 years or older (overall mean age 36 years). Fourteen subjects received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as one 5 g intravenous infusion over five minutes.

Glund et al (2015) stated idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. The authors investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here the authors present the results of the proof-of-concept part of the study. In this randomized, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analyzed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4.

Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site hematoma), and four during dabigatran etexilate pretreatment (three hematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. The authors concluded that these phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. This trial is registered with ClinicalTrials.gov, number NCT01688830.

Glund et al (2017) stated idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses ≥2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. The authors concluded that impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. This trial is registered with ClinicalTrials.gov, number NCT01955720.

Pollack et al (2017) performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. The authors concluded that in emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. RE-VERSE AD trial is registered with ClinicalTrials.gov, number NCT02104947.

Measurement / Monitoring of Factor VIII and Factor IX Replacement

Van den Bossche and colleagues (2018) noted that several recombinant factor VIII and factor IX concentrates with extended half-life (EHL) have recently been validated by clinical studies. The availability of these novel concentrates is expected to significantly facilitate the treatment of patients with hemophilia A and B. However, the modification applied to these molecules has introduced variations in their activity measurement in routine coagulation assays. Depending on the assays, under-estimations of up to 10-fold or over-estimations of up to approximately 30-fold in the measurements of the recovery have been reported in some factor concentrates. Such biases in monitoring may lead to major under- or over-treatment, as well as unnecessary searching for inhibitor antibodies. These investigators discussed the guidelines and recommendations that allowed the selection of optimal strategies to monitor patients treated with these novel factor concentrates. Based on the specificities of the assays and on local regulations, different chromogenic substrate assays in addition to 1-stage clotting assays may be validated to allow the accurate measurement of all novel products. An efficient communication between the clinical laboratory and the clinicians is essential to ensure that the appropriate assays are performed in laboratories and that the clinicians correctly evaluate the data. The authors concluded that further laboratory and clinical studies are needed for the optimization of the laboratory assays that can be used in the measurement of novel factor VIII and factor IX concentrates with EHL.

Platelet-Binding Activity of von Willebrand Factor Assay

The von Willebrand Factor ristocetin cofactor activity assay (VWF:RCo) has been a mainstay in the assessment of VWF binding to platelets. Ristocetin which is an antibiotic is used to cause a conformational change and esuing VWF A1 domain exposure to allow platelet GPIbα binding. Notably, the high coefficient of variation and poor sensitivity of VWF:RCo poses difficulty in the assessment of patients with very low VWF levels. The recent development of VWF platelet-binding activity assays (e.g., [VWF:GPIbR] and [VWF:GPIbM]), which do not require the use of ristocetin, have shown less variability, more sensitivity, and excellent correlation with VWF:RCo (Sharma and Haberichter, 2019). In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest newer assays that measure the platelet-binding activity of VWF (e.g., [VWF:GPIbM], [VWF:GPIbR]) over the VWF:RCo assay for the diagnosis of VWD.

von Willebrand Factor-Collagen Binding (VWF:CB)/VWF:Ag (the ratio of VWF collagen binding to antigen) Assay

A functionality of von Willebrand factor (VWF) lies in its binding capability to exposed collagen a site of vascular trauma. Specifically, VWF can bind to many different types of collagen (e.g., type 1, 3, 4, and 6). The purpose of the von Willebrand factor-collagen binding (VWF:CB) assay is to study the VWF-collagen interaction. The significance of this interaction is that patients with defective VWF multimers (type 2A or type 2B) have diminished VWF:CB (Sharma and Haberichter, 2019). Although, most clinical laboratories perform the type 1 and/or type 3 collagen assay, Versiti offers the VWF Collagen III Binding (VWF:CB3) and VWF Collagen IV Binding (VWF:CB4) assays. In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest either VWF multimer analysis or VWF:CB/VWF:Ag (ratio of VWF collagen binding to antigen) to diagnose type 2 VWD for patients suspected of type 2A, 2B, or 2M in need of additonal testing.

von Willebrand Factor-Factor VIII (VWF:FVIII) Binding Assay

In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest using either von Willebrand Factor-Factor VIII (VWF:FVIII) binding assay or targeted genetic testing (when available) for patients with suspected type 2N VWD in need of additional testing.

von Willebrand Factor Propeptide Antigen (VWFpp)/VWF:Ag (the ratio of VWF propeptide to antigen) Assay

Sharma and Haberichter (2019) noted that von Willebrand Factor propeptide (VWFpp) has most utility in identifying the subset of type 1 VWD patients with very low VWF:Ag owing to increase clearance of plasma and is commonly known as type 1C. In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, James and colleagues (2021) suggest against using the VWFpp/VWF:Ag (ratio of VWF propeptide to antigen) and instead administer a desmopressin trial with 1- and 4-hour postinfusion blood work to confirm increased VWF clearance for patients with VWD suspected of type 1 C should be used.

FEIBA for Refractory Bleeding in Cardiac Surgery

Sera et al (2021) stated that uncontrolled bleeding following cardiac surgery can be life-threatening; and FEIBA is a prothrombin complex concentrate empirically used as rescue therapy for correction of refractory bleeding diathesis post-cardiopulmonary bypass (CPB). FEIBA used as rescue therapy for bleeding diathesis following CPB has been associated with a low incidence of complications and a reduction in transfusion requirement and re-exploration. In a small, randomized, double-blinded, placebo-controlled, pilot study, these researchers examined the feasibility and effectiveness of early administration of FEIBA following the termination of CPB. This pilot trial was designed to evaluate the feasibility of a larger pivotal trial to determine the effectiveness of FEIBA in reducing the total volume of blood products transfused perioperatively, and its safety profile. Study participants were adult patients undergoing elective major aortic cardiovascular surgery at a tertiary referral hospital, who were equally randomized to receive a single dose of either FEIBA or matched placebo intra-operatively at the end of CPB. A total of 20 patients were screened and 12 were randomized and included in the analysis. Protocol adherence was high, and all patients received the study drug per intention-to-treat (ITT) except 1 patient. There were no protocol deviations or events of unblinding, and AEs were not different between groups. Patients in the FEIBA group were older and more likely to be female and had higher BMI, lower hematocrit (Hct), and longer hypothermic circulatory arrest . There were no differences in post-randomization blood product transfusions (difference FEIBA versus placebo -899 ml; 95 % CI -5,206 to 3,409) or in the administration of open-label FEIBA. The authors concluded that the findings of this pilot trial confirmed the adequacy of the trial design that involved the early, blinded administration of FEIBA, by demonstrating excellent protocol adherence. These researchers stated that a larger trial establishing the effectiveness of early prothrombin complex concentrate administration to reduce the use of blood products in the setting of high-risk cardiac surgery is feasible.

Khoury et al (2022) noted that significant blood loss during cardiac surgery is associated with a dramatic increase in morbidity and mortality. FEIBA, a hemostatic bypassing agent mainly used in hemophiliac patients, has also been used for intractable bleeding during cardiac surgical procedures in non-hemophiliac patients. However, concerns exist that its use may be linked to increased incidence of peri-operative adverse effects including thrombotic complications. These investigators carried out a systematic literature search on Medline, Embase, and the Cochrane Central Register of Controlled Trials databases for all studies that examined the administration of FEIBA for treatment of bleeding during adult cardiac surgery in non-hemophiliac patients. After selecting the title and abstracts, 2 authors evaluated the methodological quality of the full-text articles before final inclusion in the manuscript. The safety profile of FEIBA was ascertained via an aggregate count of AEs. Major complications included renal failure, re-operation for unresolved bleeding, post-operative mortality, and thromboembolic events. The authors concluded that there is insufficient robust evidence to make a definitive conclusion regarding the safety or effectiveness of using of FEIBA as a hemostatic agent in the setting of cardiac surgery.

Kcentra for Reversal of VKA Anti-Coagulation

Nagalla et al (2016) hypothesized that the 4‐factor prothrombin complex concentrate (4F‐PCC) Kcentra 25 unit/kg would reverse impairment of thrombin generation in healthy volunteers dosed with apixaban to steady state. In this randomized, 2‐period cross-over, assessor‐blinded trial, a total of 12 healthy subjects received 5-mg apixaban every 12 hours. Three hours after the 5th dose, 4F‐PCC 25 unit/kg or saline were infused. Serial blood samples were examined for thrombin generation using PPP‐reagent and PPP‐reagent low, anti‐Xa, PT, and PTT assays. Geometric mean ratio was calculated at 30 mins post-infusion, and at 24, 48, and 72 hours. Peak thrombin generation was 76 % higher at 30 mins post-infusion with 4F‐PCC (p = 0.025). The difference declined to 24 % at 24 hours and resolved by 48 hours. Other thrombin generation parameters were also partially normalized. There was no difference between 4F‐PCC and saline in anti‐Xa assessment at 30 mins or later time-points. This was a small (n = 12) study with healthy volunteers; the proof-of-concept finding provided evidence of improvement in hemostatic potential in patients with apixaban use and bleeding. (Note: This trial was supported by a grant from Bristol Myers Squibb; and Kcentra was supplied by CSL Behring).

Replacement Therapies with Clotting Factors in Patients with Hemophilia

Olasupo et al (2021) stated that the hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies. In a Cochrane review, these investigators examined the effectiveness of clotting factor concentrate (CFC) prophylaxis in managing previously treated individuals with hemophilia A or B. They searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and hand-searching of journals and conference abstract books. Furthermore, these investigators searched Medline and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: February 24, 2021. RCTs and quasi-RCTs examining individuals with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia were selected for analysis. Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to evaluate the certainty of the evidence. A total of 10 studies (including 608 participants) were eligible for inclusion; 8 of the trials (477 participants) had arms comparing 2 or more prophylactic regimens to one another and 4 of the trials (n = 258) compared prophylaxis to on-demand treatment (2 trials had multiple arms and were included in both comparisons). Comparison of 2 or more prophylactic regimens: For trials comparing 1 prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, 3 trials reported the primary outcome of joint bleeding, and none showed a difference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely resulted in reduced total bleeds compared to a once-weekly regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (1 trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in 1 of the trials. Blood-transmitted infections were not identified. Other AEs reported include hypersensitivity, edema, and weight gain; however, these were rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens: 4 of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95 % CI: -46.95 to -13.73) (2 trials, 164 participants, low-certainty evidence); 1 of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, QOL, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In 1 trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improved joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95 % CI: 0.23 to 1.65) and improved total pain scores, MD -17.20 (95 % CI: -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely resulted in a slight increase in AEs, RR of 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect. The authors concluded that there was evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously treated individuals with hemophilia. Prophylaxis may also improve joint function, pain and QOL, even though this did not translate into a detectable improvement of articular damage when assessed by MRI. When comparing 2 different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved effectiveness. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons. These researchers stated that well-designed RCTs and prospective observational controlled studies with standardized definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.

Delgado-Flores et al (2022) noted that different prophylactic and episodic clotting factor treatments are used in the management of hemophilia; a summary of the evidence is needed to inform decision-making. In a systematic review and meta-analysis, these investigators compared the effects of clotting factor replacement therapies in patients with hemophilia. They carried out a systematic search in PubMed, Central Cochrane Library, and Scopus; and included RCTs published up to December 2020, which compared different clotting factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were carried out whenever possible. The certainty of the evidence was assessed using the GRADE methodology. A total of 9 RCTs were included in this review, of which 6 compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95 % CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95 % CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95 % CI: 0.04 to 0.13) with significant difference between these subgroups (p = 0.003, I2 = 82.9 %). Furthermore, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95 % CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95 % CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95 % CI: 0.04 to 0.16) without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. The authors concluded that these findings suggested that prophylactic treatment (at either low, intermediate, or high doses) was superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate appeared to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results exhibited a very low certainty of the evidence; thus, future, high-quality studies that compare low, intermediate, and high prophylaxis doses are still needed to confirm these findings and inform the decision-making process regarding clotting factor replacement therapies.

The authors stated that this study had several drawbacks. First, studies had a heterogeneous follow-up period (between 8 months and 82.5 months), and used different types of replacement therapies, which rendered the comparability of these findings difficult. Second, all of the studies that compared high- or low-dose of prophylaxis with episodic treatment were carried out in children, and all studies were conducted in patients with hemophilia A; therefore, extrapolation to adults and patients with hemophilia B should be made with caution. Third, ABR and annualized joint bleeding rate (AJBR) rate outcomes were measured as self-report, which may have under-estimated or over-estimated the real figures. Fourth, assessment of joint health was performed using different clinical tools across studies; thus, it was not possible to carry out meta-analyses. Fifth, almost all the studies in the meta-analyses were at high risk or unclear risk of bias in several domains, mainly in the blinding of subjects and personnel, and blinding outcome assessment. Sixth, the main outcomes had a very low certainty of the evidence, mainly due to the risk of bias, inconsistency, and small sample size.

Appendix

Appendix A: Classification of Hemophilia by Clotting Factor Level (% Activity) and Bleeding Episodes

Table: Classification of Hemophilia by Clotting Factor Level (% Activity) and Bleeding Episodes
Severity	Clotting Factor Level % activityFootnotes*	Bleeding Episodes
Severe	<1%	Spontaneous bleeding episodes, predominantly into joints and muscles Severe bleeding with trauma, injury or surgery
Moderate	1% to 5%	Occasional spontaneous bleeding episodes Severe bleeding with trauma, injury or surgery
Mild	6% to 40%	Severe bleeding with serious injury, trauma or surgery

Footnotes*Factor assay levels are required to determine the diagnosis and are of value in monitoring treatment response.

Source: National Hemophilia Foundation, 2020a; Srivastava et al, 2020

Appendix B: Clinical Reasons For Not Utilizing Desmopressin in Patients with Hemophilia A and Type 1, 2A, 2M and 2N VWD

Age < 2 years
Pregnancy
Fluid/electrolyte imbalance
High risk for cardiovascular or cerebrovascular disease (especially the elderly)
Predisposition to thrombus formation
Trauma requiring surgery
Life-threatening bleed
Contraindication or intolerance to desmopressin
Severe type 1 von Willebrand disease
Stimate Nasal Spray is unavailable due to backorder/shortage issues (where applicable)

Source: AHFS DI, 2021; Leissinger et al., 2014; National Hemophilia Foundation, 2020b

Appendix C: Inhibitors - Bethesda Units (BU)

The presence of inhibitors is confirmed by a specific blood test called the Bethesda inhibitor assay.

High-titer inhibitors:
- > 5 BU/mL
- Inhibitors act strongly and quickly neutralize factor

Low-titer inhibitors:
- < 5 BU/mL
- Inhibitors act weakly and slowly neutralize factor.

Source: Kruse-Jarres et al., 2017; Srivastava et al., 2020

References

The above policy is based on the following references:

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U.S. Food and Drug Administration (FDA). FDA approves first long-acting recombinant coagulation Factor IX concentrate for patients with Hemophilia B. FDA News Release. Silver Spring, MD: FDA; March 28, 2013.
U.S. Food and Drug Administration (FDA). FDA approves first recombinant coagulation factor IX that is specifically indicated for routine use in preventing bleeding episodes (prophylaxis). FDA News. Silver Spring, MD: FDA; June 27, 2013..
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Last Review 11/09/2023

Effective: 06/13/1996

Next Review: 12/14/2023
Review History
Definitions

Clotting Factors

Table Of Contents

Policy

Scope of Policy

Factor VIII Products: Advate, Adynovate, Afstyla, Alphanate, Altuviiio, Eloctate, Esperoct, Hemofil M, Humate-P, Jivi, Koate, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate or Xyntha

Prescriber Specialties

Criteria for Initial Approval

Hemophilia A

Von Willebrand Disease (VWD)

Acquired Hemophilia A

Acquired von Willebrand Syndrome

Continuation of Therapy

Anti-inhibitor Coagulant Complex [Human] (FEIBA)

Prescriber Specialties

Criteria for Initial Approval

Continuation of Therapy

Antihemophilic Factor [Recombinant], Porcine Sequence (Obizur)

Prescriber Specialties

Criteria for Initial Approval

Continuation of Therapy

Prescriber Specialties

Criteria for Initial Approval

Continuation of Therapy

Factor IX Complex [Human] (Profilnine)

Prescriber Specialties

Criteria for Initial Approval

Continuation of Therapy

Emicizumab-kxwh (Hemlibra)

Prescriber Specialties

Criteria for Initial Approval

Hemophilia A (congenital factor VIII deficiency)

Continuation of Therapy

Recombinant von Willebrand Factor (Vonvendi)

Prescriber Specialties

Criteria for Initial Approval

Von Willebrand Disease

Continuation of Therapy

von Willebrand Factor/Coagulation Factor VIII Complex (human) (Wilate)

Prescriber Specialties

Criteria for Initial Approval

Continuation of Therapy

Coagulation Factor VIIa [Recombinant] (rFVIIa), (NovoSeven RT), Coagulation Factor VIIa [Recombinantt]-jncw, (rFVIIa) (Sevenfact)

NovoSeven RT (coagulation factor VIIa [recombinant])

Prescriber Specialties

Criteria for Initial Approval

Continuation of Therapy

Sevenfact (coagulation factor VIIa [recombinant]-jncw)

Exclusions

Criteria for Initial Approval

Continuation of Therapy

Factor X (Coagadex)

Criteria for Initial Approval

Continuation of Therapy

Factor XIII Concentrate [Human] (Corifact)

Criteria for Initial Approval

Continuation of Therapy

Prothrombin Complex Concentrate (Human) (Kcentra)

Criteria for Initial Approval

Acquired Coagulation Factor Deficiency

Continuation of Therapy

Recombinant Coagulation Factor XIII A-Subunit (Tretten)

Criteria for Initial Approval

Congenital Factor XIII A-Subunit Deficiency

Continuation of Therapy

Antithrombin [Recombinant] (ATryn) and Antithrombin III [Human] (Thrombate III)

Criteria for Initial Approval

Hereditary antithrombin deficiency in connection with obstetrical procedures, or surgical procedures

Hereditary antithrombin deficiency in connection with thromboembolism

Acquired antithrombin deficiency

Heparin resistance

Continuation of Therapy

Factor Xa [(recombinant), inactivated-zhzo] (Andexxa)

Criteria for Initial Approval

Reversal of direct-acting oral anticoagulation due to life-threatening or uncontrolled bleeding

Continuation of Therapy

Idarucizumab (Praxbind)

Criteria for Initial Approval

Reversal of the anticoagulation effects of dabigatran

Continuation of Therapy

Diagnostic Testing for von Willebrand Disease (VWD)