Clinical UM Guideline

 

Subject: Antihemophilic Factors and Clotting Factors
Guideline #: CG-DRUG-78 Publish Date:    06/06/2018
Status: Revised Last Review Date:    05/03/2018

Description

This document addresses select hemophilia and clotting factor replacement treatments created from blood products (human plasma-derived) and others that are manufactured (recombinant). This document does not address fibrin products, fibrin sealants and blood products provided by blood banks. Replacement therapy may be given on a routine, preventive basis which is also called prophylactic therapy. The infusion of factor replacements given to stop a bleeding episode is called demand therapy.

Products in this document include:

Clinical Indications

A.  Anti-inhibitor Coagulant Complex (FEIBA)

Medically Necessary:

  1. Anti-inhibitor coagulant complex is considered medically necessary to treat individuals with hemophilia A or B with inhibitors to Factor VIII or Factor IX when the following criteria are met:
    1. Treatment of bleeding episodes; or
    2. Peri-procedural operative management for surgical, invasive or interventional radiology procedures; or
    3. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Not Medically Necessary:

Anti-inhibitor coagulant complex is considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation Factor VIII or coagulation Factor IX.

B.  Factor VIIa Recombinant (NovoSeven RT)

Medically Necessary:

  1. Recombinant coagulation Factor VIIa is considered medically necessary for treatment of bleeding episodes when the following criteria are met:
    1. Individual has hemophilia A or B with inhibitors to Factor VIII or Factor IX; or
    2. Individual has acquired hemophilia; or
    3. Individual has congenital Factor VII deficiency.
  2. Recombinant coagulation Factor VIIa is considered medically necessary in the prevention of bleeding in surgical interventions or invasive procedures for the following:
    1. Individual has hemophilia A or B with inhibitors to Factor VIII or Factor IX; or
    2. Individual has acquired hemophilia; or
    3. Individual has congenital Factor VII deficiency.
  3. Recombinant coagulation Factor VIIa is considered medically necessary for the treatment of bleeding episodes and peri-operative management in individuals with Glanzmann’s thrombasthenia and a documented refractoriness to platelet transfusions with or without antibodies to platelets.

Not Medically Necessary:

Recombinant coagulation Factor VIIa is considered not medically necessary when the above criteria are not met and for all other indications.

C.  Antihemophilic factor (factor VIII) Human plasma-derived (Hemofil M, Koate-DVI, Monoclate-P)

Medically Necessary:

  1. Human plasma-derived antihemophilic Factor VIII (Hemofil M, Koate-DVI, Monoclate-P) is considered medically necessary for treatment of bleeding episodes in an individual with hemophilia A and factor VIII deficiency.
  2. Human plasma-derived antihemophilic Factor VIII (Koate-DVI, Monoclate-P) is considered medically necessary as peri-procedural management for surgical, invasive or interventional radiology procedures in an individual with hemophilia A and factor VIII deficiency.
  3. Human plasma-derived antihemophilic Factor VIII (Hemofil M, Koate-DVI, Monoclate-P) is considered medically necessary as routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the following criteria are met:
    1. Individual has severe hemophilia A (defined as less than 1 International Unit per deciliter [IU/dL] or 1% endogenous Factor VIII); or
    2. Individual has mild to moderate hemophilia A (defined as endogenous Factor VIII less than 40 IU/dL [less than 40%], but greater than or equal to 1 IU); and
    3. When the individual has documented history of one of the following:
      1. 1 or more episodes of spontaneous bleeding into joint; or
      2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
      3. 4 or more episodes of soft tissue bleeding in an 8 week period.

Not Medically Necessary:

Human plasma-derived antihemophilic Factor VIII is considered not medically necessary when the above criteria are not met including, but not limited to treatment of individuals with von Willebrand disease (VWD).

D.  Antihemophilic factor (factor VIII) Recombinant (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha)

Medically Necessary:

  1. Antihemophilic Factor VIII Recombinant (Advate, Afystyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha) is considered medically necessary for treatment of bleeding episodes in an individual with hemophilia A and factor VIII deficiency.
  2. Antihemophilic Factor VIII Recombinant (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha) is considered medically necessary for the treatment of bleeding episodes in an individual with von Willebrand disease (VWD) when the following criteria are met:
    1. Antihemophilic Factor VIII Recombinant is used in combination with recombinant von Willebrand factor (per statement “H” below); and
    2. Baseline factor VIII levels are less than 40 IU/dL [less than 40%] or are unknown.
  3. Antihemophilic Factor VIII Recombinant (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha) is considered medically necessary as peri-procedural management for surgical, invasive or interventional radiology procedures for an individual with hemophilia A and Factor VIII deficiency.
  4. Antihemophilic Factor VIII Recombinant (Advate, Afstyla, Helixate FS, Kovaltry, Novoeight, Nuwiq, Xyntha) is considered medically necessary as routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the following criteria are met:
    1. Individual has severe hemophilia A (defined as less than1 International Unit per deciliter [IU/dL] or 1% endogenous Factor VIII); or
    2. Individual has mild to moderate hemophilia A (defined as endogenous Factor VIII less than 40 IU/dL [less than 40%], but greater than or equal to 1 IU); and
    3. When the individual has documented history of one of the following:
      1. 1 or more episodes of spontaneous bleeding into joint; or
      2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
      3. 4 or more episodes of soft tissue bleeding in an 8 week period.
  5. Antihemophilic Factor VIII Recombinant (Helixate FS, Kogenate FS) is considered medically necessary as routine prophylaxis for children (age 0-16 years) with hemophilia A and factor VIII deficiency to reduce the risk of joint damage in those without pre-existing joint damage.
  6. Antihemophilic Factor VIII Recombinant (Recombinate) is considered medically necessary as treatment of individuals with acquired Factor VIII inhibitors not exceeding 10 Bethesda Unit (BU) per milliliter (mL).

Not Medically Necessary:

Antihemophilic Factor VIII Recombinant (Advate, Afstyla, Helixate FS, Kogenate, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha) is considered not medically necessary when the above criteria are not met and for all other indications.

E.  Antihemophilic factor (factor VIII) - Long-Acting Recombinant, pegylated (Adynovate); Recombinant Antihemophilic Factor Fc Fusion Protein (Eloctate)

Medically Necessary:

  1. Antihemophilic factor (factor VIII) - Long-Acting Recombinant, pegylated (Adynovate); Recombinant Antihemophilic Factor Fc Fusion Protein (Eloctate) are considered medically necessary for individuals with severe hemophilia A (congenital factor VIII deficiency) when all of the following criteria are met:
    1. Individual has less than 1 International Unit per deciliter (IU/dL) (less than 1%) endogenous factor VIII; and
    2. Use is planned for one of the following indications:
      1. Control and prevention of acute bleeding episodes; or
      2. Peri-procedural management for surgical, invasive or interventional radiology procedures; or
      3. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
  2. Antihemophilic factor (factor VIII) Recombinant, pegylated (Adynovate); Recombinant Antihemophilic Factor Fc Fusion Protein (Eloctate) are considered medically necessary for individuals with mild to moderate hemophilia A (congenital factor VIII deficiency) when all of the following criteria are met:
    1. Individual has endogenous factor VIII level less than 40 IU/dl (less than 40%) but greater than or equal to 1 IU/dl; and
    2. Use is planned for one of the following indications:
      1. Control of acute bleeding episodes; or
      2. Peri-procedural management for surgical, invasive or interventional radiology procedures; or
      3. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the member has documented history of one of the following:
        1. 1 or more episodes of spontaneous bleeding into joint; or
        2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
        3. 4 or more episodes of soft tissue bleeding in an 8 week period.

Not Medically Necessary:

Antihemophilic factor (factor VIII) (Recombinant), pegylated (Adynovate); Recombinant Antihemophilic Factor Fc Fusion Protein (Eloctate) are considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to treatment of individuals with von Willebrand Disease

F.  Antihemophilic bispecific factor (Factor IXa- and Factor X-), Emicizumab (Hemlibra)

Medically Necessary:

  1. Emicizumab (Hemlibra) is considered medically necessary for individuals with severe hemophilia A (congenital factor VIII deficiency) when all of the following criteria are met:
    1. Individual has less than 1 International Unit per deciliter (IU/dL) (less than 1%) endogenous factor VIII; and
    2. Individual has a documented history of a high-titer of factor VIII inhibitor (that is: greater than or equal to [>/=] 5 bethesda units [BU]) requiring treatment with episodic or prophylactic bypassing agents; and
    3. Use is planned for routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
  2. Emicizumab (Hemlibra) is considered medically necessary for individuals with mild to moderate hemophilia A (congenital factor VIII deficiency) when all of the following criteria are met:
    1. Individual has endogenous factor VIII level less than 40 IU/dl (less than 40%) but greater than or equal to 1 IU/dl; and
    2. Individual has a documented history of a high-titer of factor VIII inhibitor (that is: greater than or equal to [>/=] 5 bethesda units [BU]) requiring treatment with episodic or prophylactic bypassing agents; and
    3. Use is planned for routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the member has documented history of one of the following:
      1. 1 or more episodes of spontaneous bleeding into joint; or
      2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
      3. 4 or more episodes of soft tissue bleeding in an 8 week period.

Not Medically Necessary:

Emicizumab (Hemlibra) is considered not medically necessary when the above criteria are not met and for all other indications.

G.  Antihemophilic Factor (Recombinant), Porcine Sequence (Obizur)

Medically Necessary:

  1. Antihemophilic Factor (Recombinant), Porcine Sequence is considered medically necessary for treatment of bleeding episodes in adults with acquired hemophilia A.

Not Medically Necessary:

Antihemophilic Factor (Recombinant), Porcine Sequence is considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to:

  1. Treatment of individuals with congenital hemophilia A with Factor VIII deficiency;
  2. Treatment of individuals with von Willebrand disease;
  3. Treatment of individuals with acquired hemophilia A and baseline anti-porcine Factor VIII inhibitor titer greater than 20 BU/mL.

H.  Antihemophilic Factor VIII/von Willebrand Factor Complex (Alphanate, Humate-P, Wilate)

Medically Necessary:

  1. Antihemophilic Factor VIII/von Willebrand Factor Complex (Alphanate, Humate-P, Wilate) is considered medically necessary as a treatment for individuals with von Willebrand disease when the following criteria are met:
    1. VWD is severe; or
    2. VWD is mild to moderate and use of desmopressin is known or suspected to be inadequate; and
    3. Individual is being treated for either:
      1. Spontaneous or trauma-induced bleeding episodes; or
      2. Peri-procedural management for surgical, invasive or interventional radiology procedures.
  2. Antihemophilic Factor VIII/von Willebrand Factor Complex (Alphanate, Humate-P) is considered medically necessary for treatment of bleeding episodes in an individual with hemophilia A and Factor VIII deficiency.
  3. Antihemophilic Factor VIII/von Willebrand Factor Complex (Alphanate, Humate-P) is considered medically necessary as routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the following criteria are met:
    1. Individual has severe hemophilia A (defined as less than 1 International Unit per deciliter [IU/dL] or 1% endogenous Factor VIII); or
    2. Individual has mild to moderate hemophilia A (defined as endogenous Factor VIII less than 40 IU/dL [less than 40%], but greater than or equal to 1 IU); and
    3. When the individual has documented history of one of the following:
      1. 1 or more episodes of spontaneous bleeding into joint; or
      2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
      3. 4 or more episodes of soft tissue bleeding in an 8 week period.
  4. Antihemophilic Factor VIII/von Willebrand Factor Complex (Alphanate) is considered medically necessary for treatment of bleeding episodes in an individual with acquired Factor VIII deficiency.

Not Medically Necessary:

Antihemophilic Factor/von Willebrand Factor Complex (Alphanate, Humate-P, Wilate) is considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to prophylaxis therapy in individuals with VWD.

Antihemophilic Factor/von Willebrand Factor Complex (Alphanate) is considered not medically necessary for individuals with severe VWD (Type 3) undergoing major surgery.

Antihemophilic Factor/von Willebrand Factor Complex (Wilate) is considered not medically necessary for individuals with hemophilia A.

I.  von Willebrand factor (Recombinant) (Vonvendi)

Medically Necessary:

  1. von Willebrand factor (Recombinant) is considered medically necessary as a treatment for adults (18 years of age and older) with von Willebrand disease when the following criteria are met:
    1. VWD is severe; or
    2. VWD is mild to moderate and use of desmopressin is known or suspected to be inadequate; and
    3. Individual is being treated for spontaneous or trauma-induced bleeding episodes or peri-procedural management for surgical, invasive or interventional radiology procedures.

Not Medically Necessary:

von Willebrand factor (Recombinant) is considered not medically necessary for all other indications

J.  Coagulation Factor IX, Human plasma-derived (Alphanine SD, Mononine)

Medically Necessary:

  1. Human plasma-derived coagulation Factor IX (Alphanine SD, Mononine) is considered medically necessary for treatment of bleeding episodes in an individual with hemophilia B and Factor IX deficiency.
  2. Human plasma-derived coagulation Factor IX (Alphanine SD, Mononine) is considered medically necessary as routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the following criteria are met:
    1. Individual has severe hemophilia B (defined as less than 1 IU/dL or 1% endogenous Factor IX); or
    2. Individual has mild to moderate hemophilia B (defined as endogenous Factor IX less than 40 IU/dL [less than 40% ], but greater than or equal to1 IU/dL); and
    3. When the member has documented history of one of the following:
      1. 1 or more episodes of spontaneous bleeding into joint; or
      2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
      3. 4 or more episodes of soft tissue bleeding in an 8 week period.

Not Medically Necessary:

Human plasma-derived coagulation Factor IX (Alphanine SD, Mononine) is considered not medically necessary when the above criteria are not met, including but not limited to the following:

K.  Factor IX Complex, Human plasma-derived (Bebulin, Profilnine SD)

Medically Necessary:

  1. Human plasma-derived Factor IX complex (Bebulin, Profilnine SD) is considered medically necessary for treatment of bleeding episodes in an individual with hemophilia B (congenital factor IX deficiency or Christmas disease).
  2. Human plasma-derived coagulation Factor IX (Bebulin, Profilnine SD) is considered medically necessary as routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the following criteria are met:
    1. Individual has severe hemophilia B (defined as less than1 IU/dL or 1% endogenous Factor IX); or
    2. Individual has mild to moderate hemophilia B (defined as endogenous Factor IX less than 40 IU/dL [less than 40% ], but greater than or equal to 1 IU/dL); and
    3. When the member has documented history of one of the following:
      1. 1 or more episodes of spontaneous bleeding into joint; or
      2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
      3. 4 or more episodes of soft tissue bleeding in an 8 week period.

Not Medically Necessary:

Human plasma-derived Factor IX complex (Bebulin, Profilnine SD) is considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to use for treatment of individuals with Factor VII deficiency.

L.  Factor IX Recombinant (Benefix, Ixinity, Rixubis)

Medically Necessary:

  1. Recombinant coagulation Factor IX (Benefix, Rixubis) is considered medically necessary to treat individuals with hemophilia B (congenital factor IX deficiency or Christmas disease) when the following criteria are met:
    1. To treat bleeding episodes; or
    2. Peri-procedural management for surgical, invasive or interventional radiology procedures.
  2. Recombinant coagulation Factor IX (Benefix, Rixubis) is considered medically necessary as routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the following criteria are met:
    1. Individual has severe hemophilia B (defined as less than 1 IU/dL or 1% endogenous Factor IX); or
    2. Individual has mild to moderate hemophilia B (defined as endogenous Factor IX less than 40 IU/dL [less than 40% ], but greater than or equal to1 IU/dL); and
    3. When the member has documented history of one of the following:
      1. 1 or more episodes of spontaneous bleeding into joint; or
      2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
      3. 4 or more episodes of soft tissue bleeding in an 8 week period.
  3. Recombinant coagulation Factor IX (Ixinity) is considered medically necessary to treat individuals aged 12 years and older with hemophilia B (congenital factor IX deficiency or Christmas disease) when the following criteria are met:
    1. To treat bleeding episodes; or
    2. Peri-procedural management for surgical, invasive or interventional radiology procedures; or
    3. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the following criteria are met:
      1. Individual has severe hemophilia B (defined as less than 1 IU/dL or 1% endogenous Factor IX); or
      2. Individual has mild to moderate hemophilia B (defined as endogenous Factor IX less than 40 IU/dL [less than 40% ], but greater than or equal to 1 IU/dL); and
      3. When the member has documented history of one of the following:
        1. 1 or more episodes of spontaneous bleeding into joint; or
        2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
        3. 4 or more episodes of soft tissue bleeding in an 8 week period.

Not Medically Necessary:

Recombinant coagulation Factor IX (Benefix, Ixinity, Rixubis) is considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to the following:

Recombinant coagulation Factor IX (Ixinity, Rixubis) is considered not medically necessary for the induction of immune tolerance in individuals with hemophilia B.

M.  Coagulation Factor IX - Long-Acting Recombinant, Albumin Fusion Protein (Idelvion); Recombinant Coagulation Factor IX, Fc Fusion Protein (Alprolix); Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn®)

Medically Necessary:

  1. Coagulation Factor IX - Long-Acting Recombinant, Albumin Fusion Protein (Idelvion); Recombinant Coagulation Factor IX, Fc Fusion Protein (Alprolix); Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn) are considered medically necessary for individuals with severe hemophilia B (congenital Factor IX deficiency) when all of the following criteria are met:
    1. Individual has less than 1 International Unit per deciliter (IU/dl) (less than 1%) endogenous factor IX; and
    2. Use of rIX-FP is planned for one of the following indications:
      1. Treatment of bleeding episodes; or
      2. Peri-procedural management for surgical, invasive or interventional radiology procedures; or
      3. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes (excluding Recombinant Coagulation Factor IX, GlycoPEGylated [Rebinyn].
  2. Coagulation Factor IX – Long-Acting Recombinant, Albumin Fusion Protein (Idelvion); Recombinant Coagulation Factor IX, Fc Fusion Protein (Alprolix); Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn) are considered medically necessary for individuals with mild to moderate hemophilia B (congenital Factor IX deficiency) when all of the following criteria are met:
    1. Individual has endogenous factor IX level less than 40 International Units per deciliter (IU/dl) (less than 40%) but greater than or equal to 1 IU/dl; and
    2. Use of rIX-FP is planned for one of the following indications:
      1. Treatment of bleeding episodes; or
      2. Peri-procedural management for surgical, invasive or interventional radiology procedures; or
      3. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes when the member has documented history of one of the following (excluding Recombinant Coagulation Factor IX, GlycoPEGylated [Rebinyn]:
        1. 1 or more episodes of spontaneous bleeding into joint; or
        2. 1 or more episodes of spontaneous bleeding into the central nervous system; or
        3. 4 or more episodes of soft tissue bleeding in an 8 week period.

Not Medically Necessary:

Coagulation Factor IX – Long-Acting Recombinant, Albumin Fusion Protein (Idelvion); Recombinant Coagulation Factor IX, Fc Fusion Protein (Alprolix); Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn) are considered not medically necessary when the above criteria are not met and for all other indications, including but not limited to induction of immune tolerance in individuals with hemophilia B.

Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn) is considered not medically necessary for prophylactic use in the prevention or reduction of the frequency of bleeding episodes.

N.  Coagulation Factor X, Human plasma-derived (Coagadex)

Medically Necessary:

Human plasma derived coagulation Factor X (Coagadex) is considered medically necessary for individuals aged 12 years or older when the following criteria are met:

  1. Individual has severe or moderate hereditary Factor X deficiency (defined as less than 5 International Unit per deciliter (IU/dl) or 5% endogenous Factor X) and the factor is to be used for the treatment of bleeding episodes; or
  2. Individual has mild hereditary Factor X deficiency (defined as greater than or equal to 5 International Unit per deciliter (IU/dl) or 5% endogenous Factor X) and the factor is to be used for peri-procedural management for surgical, invasive or interventional radiology procedures.

Not Medically Necessary

Human plasma derived coagulation Factor X (Coagadex) is considered not medically necessary when the above criteria are not met and for all other indications, including but not limited to perioperative management of bleeding in major surgery in individuals with moderate and severe hereditary Factor X deficiency.

O.  Factor XIII (Corifact, Tretten)

Medically Necessary:

  1. Human plasma-derived concentrate Factor XIII (Corifact) is considered medically necessary for individuals with Factor XIII deficiency for the following indications:
    1. As routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes; or
    2. Peri-procedural management for surgical, invasive or interventional radiology procedures.
  2. Recombinant coagulation Factor XIII A-Subunit (Tretten) is considered medically necessary as routine prophylaxis for bleeding in individuals with congenital Factor XIII A-subunit deficiency.

Not Medically Necessary:

Coagulation Factor XIII (Corifact, Tretten) is considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to treatment of individuals with congenital Factor XIII B-subunit deficiency.

P.  Fibrinogen Concentrate, Human plasma-derived (RiaSTAP); Human fibrinogen (Fibryna)

Medically Necessary:

Human plasma-derived fibrinogen concentrate (RiaSTAP) and human fibrinogen (Fibryna) are considered medically necessary for the treatment of acute bleeding episodes in individuals with congenital fibrinogen deficiency (that is, afibrinogenemia or hypofibrinogenemia).

Not Medically Necessary:

Human plasma-derived fibrinogen concentrate (RiaSTAP) and human fibrinogen (Fibryna) are considered not medically necessary when the above criteria are not met and for all other indications including, but not limited to treatment of individuals with dysfibrinogenemia.

Clinically Equivalent Cost Effective Agents

Note: When a hemophilia and clotting factor replacement treatment is determined to be medically necessary based on the clinical criteria above, the benefit plan may have in addition a medically necessary criterion that the treatment be cost effective.

A benefit plan may select any one or more of the following agents within a designated product class (classes A through H listed below) as clinically equivalent cost effective hemophilia and clotting factor replacement treatment agents:

  1. Antihemophilic factor (factor VIII) Human plasma-derived (Hemofil M, Koate-DVI, Monoclate-P)
  2. Antihemophilic factor (factor VIII) Recombinant (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha)
  3. Antihemophilic factor (factor VIII) - Long-Acting Recombinant, pegylated (Adynovate); Recombinant Antihemophilic Factor Fc Fusion Protein (Eloctate)
  4. Antihemophilic Factor VIII/von Willebrand Factor Complex (Alphanate, Humate-P, Wilate)
  5. Coagulation Factor IX, Human plasma-derived (Alphanine SD, Mononine)
  6. Factor IX Complex, Human plasma-derived (Bebulin, Profilnine SD)
  7. Factor IX Recombinant (Benefix, Ixinity, Rixubis)
  8. Coagulation Factor IX - Long-Acting Recombinant, Albumin Fusion Protein (Idelvion); Recombinant Coagulation Factor IX, Fc Fusion Protein (Alprolix); Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn)

A list of one or more cost effective antihemophilic and clotting factors for each plan is available here.

In benefit plans where there is a requirement to use a cost effective hemophilia and clotting factor replacement treatment agent, requests for a hemophilia and clotting factor replacement treatment agent that is not cost effective may be approved when the following criteria are met (A, B, C, or D):

  1. The cost effective agent is not acceptable due to the following concomitant clinical situation(s):
    1. The individual is currently medically stable on another hemophilia and clotting factor replacement treatment agent; or
    2. The individual has inhibitors specific to the cost effective agent and the presence of these inhibitors is expected to contribute to a difficulty in controlling bleeding events; or
  2. The cost effective agent is not readily available in the individual’s geographic treatment area; or
  3. The individual has had a trial with a cost effective agent in the designated product class and has demonstrated one of the following:
    1. Shorter than expected half-life degradation of the agent based on trough level dosing that is considered to be clinically significant (that is: expected to contribute to a difficulty in controlling bleeding events); or
    2. Intolerance to the agent; or
  4. For the prescribed indication, the cost effective agent(s) is/are not FDA-approved or does not meet the off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use (see Table 1. below).

Table 1. FDA-approved Indications or Indications Meeting off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use

 

Antihemo-philic factor (factor VIII) Human plasma-derived (Hemofil M, Koate-DVI, Monoclate-P)

Antihemo-philic factor (factor VIII) Recombinant (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha)

Antihemo-philic factor (factor VIII) - Long-Acting Recombinant, pegylated (Adynovate); Recombinant Antihemophilic Factor Fc Fusion Protein (Eloctate)

Antihemo-philic Factor VIII/von Willebrand Factor Complex (Alphanate, Humate-P, Wilate)

Acquired Factor VIII inhibitors not exceeding 10 BU per mL

 

X (Recombinate)

 

 

Acquired hemophilia A (Factor VIII deficiency)

 

 

 

Y

Hemophilia A (Factor VIII deficiency)

X

X

X

X (Alphanate; Humate-P)

Von Willebrand disease

 

Y

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Coagulation Factor IX, Human plasma-derived (Alphanine SD, Mononine)

Factor IX Complex, Human plasma-derived (Bebulin, Profilnine SD)

Factor IX Recombi- nant (Benefix, Ixinity, Rixubis)

Coagulation Factor IX - Long-Acting Recombinant, Albumin Fusion Protein (Idelvion); Recombinant Coagulation Factor IX, Fc Fusion Protein (Alprolix); Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn)

Hemophilia B (congenital factor IX deficiency or Christmas disease)

X

X

X

X

X = FDA-approved Indications (excluding cosmetic indications)
Y = Indications Meeting off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

A.  Anti-inhibitor Coagulant Complex (FEIBA)

HCPCS

 

 

J7198

Anti-inhibitor; per IU [FEIBA]

 

 

 

 

ICD-10 Diagnosis

 

D66

Hereditary factor VIII deficiency [hemophilia A]

D67

Hereditary factor IX deficiency [hemophilia B]

D68.311

Acquired hemophilia

D68.318

Other hemorrhagic disorder due to intrinsic circulating anticoagulants, antibodies, or inhibitors

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

B.  Factor VIIa Recombinant (NovoSeven RT)

HCPCS

 

 

J7189

Factor VIIa (antihemophilic factor, recombinant), per 1 microgram [NovoSeven RT]

 

 

 

 

ICD-10 Diagnosis

 

D66

Hereditary factor VIII deficiency [hemophilia A]

D67

Hereditary factor IX deficiency [hemophilia B]

D68.2

Hereditary deficiency of other clotting factors

D68.311

Acquired hemophilia

D68.318

Hemorrhagic disorder due to intrinsic circulating anticoagulants

D68.4

Acquired coagulation factor deficiency

D69.1

Qualitative platelet defects [when specified as Glanzmann’s thrombasthenia]

Z79.899

Other long term (current) drug therapy

C.  Antihemophilic factor (factor VIII) Human plasma-derived (Hemofil M, Koate-DVI, Monoclate-P)

HCPCS

 

 

J7190

Factor VIII antihemophilic factor, human, per IU [Hemofil M, Koate DVI, Monoclate-P]

 

 

 

ICD-10 Diagnosis

 

D66

Hereditary factor VIII deficiency [hemophilia A]

D68.311

Acquired hemophilia

D68.318

Other hemorrhagic disorder due to intrinsic circulating anticoagulants, antibodies, or inhibitors

D68.4

Acquired coagulation factor deficiency

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

D.  Antihemophilic factor (factor VIII) Recombinant (Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha)

HCPCS

 

 

J7182

Injection, factor VIII, (antihemophilic factor, recombinant), (Novoeight), per IU

 

J7185

Injection, factor VIII (antihemophilic factor, recombinant) (Xyntha), per IU

 

J7192

Factor VIII (antihemophilic factor, recombinant) per IU, not otherwise specified [Advate, Helixate-FS, Kogenate-FS, Recombinate]

 

J7209

Injection, factor VIII, (antihemophilic factor, recombinant), (Nuwiq), 1 I.U.

J7210

Injection, factor VIII, (antihemophilic factor, recombinant), (Afstyla), 1 I.U.

J7211

Injection, factor VIII, (antihemophilic factor, recombinant), (Kovaltry), 1 I.U.

 

 

ICD-10 Diagnosis

 

 

D66

Hereditary factor VIII deficiency [hemophilia A]

 

D68.0

Von Willebrand’s disease

 

D68.311

Acquired hemophilia

 

D68.318

Other hemorrhagic disorder due to intrinsic circulating anticoagulants, antibodies, or inhibitors

 

D68.4

Acquired coagulation factor deficiency

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

E.  Antihemophilic factor (factor VIII) – Long Acting Recombinant, pegylated (Adynovate); Recombinant Antihemophilic Factor, Fc Fusion Protein (Eloctate)

HCPCS

 

 

J7205

Injection, factor VIII Fc fusion protein, (recombinant), per IU [Eloctate]

 

J7207

Injection, factor VIII, (antihemophilic factor, recombinant), pegylated, 1 I.U. [Adynovate]

 

 

 

 

ICD-10 Diagnosis

 

D66

Hereditary factor VIII deficiency

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

F.  Antihemophilic bispecific factor (Factor IXa- and Factor X-), Emicizumab (Hemlibra)

HCPCS

 

J3590

Unclassified biologics [when specified as emicizumab (Hemlibra)]

J7199

Hemophilia clotting factor, not otherwise specified [when specified as emicizumab (Hemlibra)]

Q9995

Injection, emicizumab-kxwh, 0.5 mg [Hemlibra] [Note: code effective 07/01/2018]

 

 

ICD-10 Diagnosis

 

 

D66

Hereditary factor VIII deficiency [hemophilia A]

 

Z29.8

Encounter for other specified prophylactic measure

 

Z79.899

Other long term (current) drug therapy [prophylactic]

 

G.  Antihemophilic Factor (Recombinant), Porcine Sequence (Obizur)

HCPCS

 

 

J7188

Injection, factor VIII (antihemophilic factor, recombinant), (Obizur), per I.U.

 

J7191

Factor VIII, antihemophilic factor (porcine), per IU  

 

 

 

ICD-10 Diagnosis

 

D68.311

Acquired hemophilia

D68.318

Other hemorrhagic disorder due to intrinsic circulating anticoagulants, antibodies, or inhibitors

D68.4

Acquired coagulation factor deficiency

H.  Antihemophilic Factor VIII/von Willebrand Factor Complex (Alphanate, Humate-P, Wilate)

HCPCS

 

 

J7183

Injection, von Willebrand factor complex (human), Wilate, 1 I.U. VWF:RCo

 

J7186

Injection, antihemophilic factor VIII/von Willebrand factor complex (human), per factor VIII IU [Alphanate]

 

J7187

Injection, von Willebrand factor complex (Humate-P), per IU VWF:RCO

 

 

 

ICD-10 Diagnosis

 

 

D66

Hereditary factor VIII deficiency [hemophilia A]

 

D68.0

Von Willebrand’s disease

D68.311

Acquired hemophilia

D68.318

Other hemorrhagic disorder due to intrinsic circulating anticoagulants, antibodies, or inhibitors

D68.4

Acquired coagulation factor deficiency

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

I.  von Willebrand factor (Recombinant) (Vonvendi)

HCPCS

 

 

J7179

Injection, von Willebrand factor (recombinant), (Vonvendi), 1 I.U. VWF:RCO

 

 

 

ICD-10 Diagnosis

 

 

D68.0

Von Willebrand’s disease

Z29.8

Encounter for other specified prophylactic measure

J.  Coagulation Factor IX, Human plasma-derived (Alphanine SD, Mononine)

HCPCS

 

 

J7193

Factor IX (antihemophilic factor, purified, non-recombinant) per IU [AlphaNine SD, Mononine]

 

 

 

 

ICD-10 Diagnosis

 

D67

Hereditary factor IX deficiency [hemophilia B]

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

K.  Factor IX Complex Human (Bebulin, Profilnine SD)

HCPCS

 

 

J7194

Factor IX complex, per IU [Bebulin VH, Profilnine SD]

 

 

 

 

ICD-10 Diagnosis

 

D67

Hereditary factor IX deficiency [hemophilia B]

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

L.  Factor IX Recombinant (Benefix, Ixinity, Rixubis)

HCPCS

 

 

J7195

Injection, factor IX (antihemophilic factor, recombinant) per IU, not otherwise specified [Benefix, Ixinity]

 

J7200

Injection, factor IX, (antihemophilic factor, recombinant), Rixubis, per IU

 

 

ICD-10 Diagnosis

 

 

D67

Hereditary factor IX deficiency [hemophilia B]

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

M.  Coagulation Factor IX – Long Acting Recombinant, Albumin Fusion Protein (Idelvion); Recombinant Coagulation Factor IX, Fc Fusion Protein (Alprolix); Recombinant Coagulation Factor IX, GlycoPEGylated (Rebinyn)

HCPCS

 

C9468

Injection, factor IX (antihemophilic factor, recombinant), glycopegylated, Rebinyn, 1 i.u.

J7195

Injection, Factor IX (anti-hemophilic factor; recombinant per IU, not otherwise specified [when specified as Rebinyn]

J7201

Injection, factor IX, Fc fusion protein (recombinant), Alprolix, 1 I.U.

J7202

Injection, factor IX, albumin fusion protein, (recombinant), Idelvion, 1 i.u.

 

 

ICD-10 Diagnosis

 

 

D67

Hereditary factor IX deficiency

 

Z29.8

Encounter for other specified prophylactic measure

 

Z79.899

Other long term (current) drug therapy [prophylactic]

 

N.  Factor X (Coagadex)

HCPCS

 

 

J7175

Injection, factor X, (human), 1 I.U. [Coagadex]

 

 

 

 

ICD-10 Diagnosis

 

D68.2

Hereditary deficiency of other clotting factors

Z79.899

Other long term (current) drug therapy

O.  Factor XIII (Corifact, Tretten)

HCPCS

 

 

J7180

Injection, factor XIII (antihemophilic factor, human), 1 I.U. [Cortifact]

 

J7181

Injection, factor XIII A-subunit, (recombinant), per IU [Tretten]

 

 

 

 

ICD-10 Diagnosis

 

D68.2

Hereditary deficiency of other clotting factors

Z29.8

Encounter for other specified prophylactic measure

Z79.899

Other long term (current) drug therapy [prophylactic]

P.  Fibrinogen Concentrate, Human plasma-derived (RiaSTAP); Human fibrinogen (Fibryna)

HCPCS

 

 

J7178

Injection, human fibrinogen concentrate, 1 mg [RiaSTAP, Fibryna]

 

 

 

 

ICD-10 Diagnosis

 

D68.2

Hereditary deficiency of other clotting factors

Discussion/General Information

Hemophilia is an inherited blood disorder caused by a lack of a protein necessary for proper clotting. The type and severity of hemophilia differs depending on which protein is missing and to what degree it is deficient. Hemophilia A is caused by a deficiency in Factor VIII and accounts for 80% of hemophilia cases. Hemophilia B, also called Christmas disease, is related to mutations in the gene coding for coagulation Factor IX. Severe hemophilia A (specifically, low to absent levels of circulating plasma factor VIII) is epitomized by limb or life threatening bleeding episodes in the short term, and in the long term, recurrent bleeding in joints and soft tissues that can lead to severe arthropathy, muscle contractures and the associated chronic pain and disability (Manco-Johnson 2007, Gringeri 2011). Hemophilia A is about four times as common as hemophilia B (CDC, 2014). Approximately 70% of people with hemophilia A have a severe form of the disorder.

The U.S. National Hemophilia Foundation (2014) and the World Federation of Hemophilia (Srivastava, 2013) both note there is a relationship of bleeding severity to the clotting factor level. Both entities list “severe” hemophilia as a clotting factor level < 1 IU/dl or < 1% of normal. A “mild” bleeding severity is identified as a clotting factor level of 5-40 IU/dl or 5 to < 40% of normal. A bleeding episode for individuals with mild risk includes severe bleeding with major trauma or surgery. Individuals with 1-5 IU/dl or 1-5% of normal are considered “moderate” risk for occasional spontaneous bleeding and prolonged bleeding with minor trauma or surgery (Srivastava, 2013).

World Hemophilia Federation 2012 Guidelines for treatment of hemophilia state that prophylaxis prevents bleeding and joint destruction and should be a goal of therapy. More studies are needed to determine if all individuals should remain on therapy as adults (that is, those with severe hemophilia vs. moderate or mild). Short-term prophylaxis (of 4 to 8 weeks) may interrupt the bleeding cycle and benefit individuals with repeated bleeding into target joints. Prophylaxis does not reverse existing joint damage, but reduces bleeding and may slow progression of joint damage. Prophylactic clotting factor administration is recommended prior to the individual engaging in activities with higher risk of injury. Mild to moderate hemophilia may be managed in the home. Randomized trials of prophylactic therapy of hemophilia have demonstrated a decreased incidence of arthropathy (Gringeri, 2011; Manco-Johnson, 2007). Key points from the home therapy guidelines include (Srivastava, 2013):

The National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) updated recommendations for the treatment of bleeding disorders and hemophilia (2014). Desmopressin (DDVAP) is recommended for individuals with mild hemophilia A and for individuals with type 1 von Willebrand disease (VWD). DDAVP is similar to a naturally occurring hormone that releases stored factor VIII from various tissues in the body (CDC, 2014). DDAVP also stimulates the release of VWF from endothelial cells to increase plasma concentrations of VWF (Nichols, 2008). For individuals with mild hemophilia or VWD, DDVAP can increase their own factor VIII and VWF levels so that they do not have to use clotting factor. Recombinant factor VIII products are the recommended treatment of choice for individuals with hemophilia as the products have a reduced risk of human viral contamination compared to the products derived from plasma.

Inhibitor development is the most common and severe complication of factor replacement treatment, developing in approximately 15-20% of people with hemophilia (CDC, 2014). Inhibitors are antibodies to replacement factors which reduce response to factor replacement therapy and may result in need for higher doses of factor products. In addition, the use of other agents such as bypassing agents does not replace the missing factor “but go around or (bypass) the factors that are blocked by the inhibitor to help the body form a normal clot” (CDC, 2014) to control bleeding episodes. Bypassing agents include NovoSeven RT (recombinant factor VIIa [rFVIIa]) and Feiba (anti-inhibitor coagulant complex). A Cochrane Review (Iorio, 2010) analyzed data from two additional randomized trials comparing rFVIIa to plasma derived concentrates (high-dose human or recombinant FVIII or FIX concentrate; prothrombin complex concentrates [PCCs]; and activated prothrombin complex concentrate [aPCC; Feiba-NF]) in the treatment of acute bleeding episodes in hemophiliacs with inhibitors. Despite the possibilities of subjective bias in reporting pain and mobility, similar efficacy and the risk of thromboembolic events were low in both studies. The authors concluded rFVIIa and aPCC were found to be similarly effective in the treatment of bleeding in hemophiliacs with inhibitors.

Another treatment option for individuals with inhibitors is immune tolerance induction (ITI) therapy. ITI involves administration of large amounts of clotting factor concentrates every day for weeks or months. The goal is to teach the body to accept the factor treatment and to stop the inhibitor reaction from occurring. (CDC, 2014).

Data are insufficient to determine if one immune tolerance induction regimen is preferred in treating individuals with hemophilia A or B with inhibitors. A Cochrane Review by Athale (2014) noted the low quality of evidence available to suggest immune tolerance induction with high doses of factor may induce tolerance more quickly and may be associated with fewer bleeding complications. The authors concluded each case and choice of regimen for immune tolerance induction should be considered individually. Additional research of high quality is necessary to provide additional evidence regarding the efficacy and dosing of specific immune tolerance induction regimens.

Treatment indications for hemophilia and coagulation factors are based on the U.S. Food and Drug Administration (FDA) approved indications and specialty recommendations and guidelines. Dosage and duration of treatment depend on a number of variables which include the severity of the factor deficiency (initial/starting circulating factor); the treatment intent (such as, acute bleeding episode, perioperative management, or routine prophylaxis); the location and severity of bleeding (if acute); and the clinical condition (for example, severity of the overall disease, the individual’s weight, age). Additional considerations include the number of infusions required for each bleed and the number of units of clotting factor needed per infusion. Doses administered should be titrated to the clinical and pharmacokinetic (e.g., half-life, in vivo recovery) response of the individual which varies between individuals. In the presence of an inhibitor, higher doses may be required (Product Information Labels). Recommended dosage and administration information on products contained in this document can be found in the Appendix: FDA Product Label Prescribing Information.

The importance of a maintaining an adequate trough factor activity level in reducing bleeding has been demonstrated in a study of children and adults with severe hemophilia A who were receiving routine prophylaxis (44 children aged 1-6 and 99 individuals aged 10-65 years). Pharmacokinetic measurements demonstrated that increased total bleeds and hemartroses correlated strongly with lower trough levels. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance (Collins, 2009).

Anti-inhibitor Coagulant Complex (FEIBA)
A meta-analysis of 6 studies including a total of 34 individuals with hemophilia and inhibitors was conducted to assess the use of FEIBA in prophylactic regimens (Valentino, 2010). There was an average 63.9% (p=0.0009) reduction in bleeding events in 33 individuals while on a prophylactic FEIBA regimen. Joint bleeding was reported as an average reduction of 78.0% (95% confidence interval [CI], 70.3%, 85.7%; p<0.0001) with FEIBA prophylaxis compared to pre-prophylaxis rates. Four individuals were undergoing simultaneous ITI with FEIBA treatment and these individuals had a reduction in bleeding episodes by 79.2% compared to pre-prophylaxis levels.

Factor VIIa Recombinant (NovoSeven RT)
NovoSeven, recombinant coagulation factor VIIa (rFVIIa) was approved by the FDA in 1999 as an orphan drug treatment of bleeding episodes in individuals with hemophilia A or B with inhibitors to factor VIII or factor IX. NovoSeven is vitamin K-dependent and is structurally similar to human plasma-derived Factor VIIa. Hemostasis is achieved through the activation of the extrinsic pathway of the coagulation cascade. The FDA approved additional orphan indications for marketing in 2005 and 2006 which included prevention of bleeding episodes in surgical interventions or invasive procedures in individuals with hemophilia A or B with inhibitors, acquired hemophilia, and those with congenital FVII deficiency. In 2008, NovoSeven RT was FDA approved as a room temperature stable formulation of the recombinant coagulation factor VIIa for the previously approved indications. Additionally in 2014, NovoSeven RT was FDA approved for the treatment of bleeding episodes and peri-operative management in adults and children with Glanzmann's thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets. Clinical data on 218 individuals with Glanzmann’s thromboasthenia was obtained from the Glanzmann’s Thrombasthenia Registry (GTR) and the Hemostasis and Thrombosis Research Society (HTRS) registry. Overall, treatment with NovoSeven RT adequately controlled bleeding in 94.4% of bleeding episodes and 99.4% of surgical procedures. Individuals with clinical refractoriness with or without platelet-specific antibodies achieved 94.9% response rate to bleeding episodes and 98.6% of surgical procedures with NovoSeven RT treatment. The NovoSeven RT product label (2015) has a black box warning of serious arterial and venous thrombotic events following administration. Of note, the most common and serious adverse reaction in clinical trials are thrombotic events.

There have been published articles regarding the use of rFVIIa for off-label indications, but most have of the studies involved small numbers of participants. To address this issue, the Agency for Healthcare Research and Quality (AHRQ; Yank, 2010) conducted a comparative effectiveness review of hospital-based rFVIIa therapy compared to usual care for selected indications: intracranial hemorrhage, massive bleeding secondary to trauma, selected surgical procedures of cardiac surgery, liver transplantation, and prostatectomy. A total of 74 studies met the inclusion criteria and included 24 RCTs, 31 comparative observational studies, and 19 noncomparative registry or cohort reports. The dosing and timing of rFVIIa infusion varied across the studies. In addition, the authors reported difficulty identifying specific subpopulations that were more likely to experience benefits compared to adverse events from rFVIIa. Yank and colleagues (2010) concluded:

Considering the evidence as a whole, off-label rFVIIa may provide some benefit for certain clinical indications, but this conclusion is largely based on indirect outcomes that have an uncertain relationship to patient survival or functional status. Of the indications we studied, the benefit-to-risk ratio may be more favorable for body trauma than for other indications, because its use may reduce the occurrence of acute respiratory distress syndrome (ARDS); however, the strength of evidence is low for this as well as most other outcomes, which precludes definitive conclusions. Available evidence does not indicate that use of off-label rFVIIa reduces mortality or improves other direct outcomes for the indications we studied. Thromboembolic events are increased by use of rFVIIa in intracranial hemorrhage and adult cardiac surgery. Despite this state of evidence, in-hospital, off-label cases of rFVIIa use have increased in the last decade, particularly for cardiac surgery, trauma, and intracranial hemorrhage.

Factor VIII
Hemofil M, Koate-DVI and Monoclate-P are purified plasma products that contain factor VIII and are indicated for the treatment of bleeding episodes in individuals with hemophilia A. Koate-DVI and Monoclate-P are also approved for the prevention of bleeding during surgical procedures. The FDA label for Koate-DVI notes there are some naturally occurring VWF that is purified during the manufacturing process. However, the effectiveness of Koate-DVI to treat VWD has not been evaluated and is therefore not approved for this indication. Product information labels for both Hemofil-M and Monoclate-P state the products are not indicated to treat VWD (Product Information Labels).

Recombinant factor VIII products with FDA approval to treat bleeding episodes in individuals with hemophilia A and factor VIII deficiency include Advate, Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, and Xyntha. These products are also FDA approved as peri-operative management of surgical bleeding in individuals with hemophilia A. These products are not indicated for the treatment of von Willebrand disease (VWD) (Product Information Labels 2010, 2012-2016). However, the current product information label for von Willebrand factor (Recombinant) (Vonvendi, 2018) indicates that an approved factor VIII recombinant (non von Willebrand containing) may be required with Vonvendi in those with factor VIII baseline levels below 40%.

Advate, Afstyla, Kovaltry, Novoeight, Nuwiq and Xyntha have FDA approval for use as routine prophylaxis to prevent or reduce the frequency of bleeding in individuals with hemophilia A (Product Information Labels 2014-2016).

Helixate, Kogenate and Xyntha are free from plasma and albumin. Helixate and Kogenate have additional FDA approval for children (0-16 years-old) with hemophilia A as prophylaxis to prevent or reduce the frequency of bleeding episodes and to reduce the risk of joint damage in children without pre-existing joint damage (Product Information Labels). In a randomized trial, (Manco-Johnson, 2007) boys younger than 30 months of age upon entry with hemophilia A were randomized to prophylaxis or enhanced episodic care. Magnetic resonance imaging (MRI) and plain film radiography were performed at age 6 years. Boys treated with prophylaxis Kogenate had significantly increased normal index-joint (for example, ankles, knees and elbows) structure on MRI in 93% of the cases versus 55% of the children in the episodic-therapy group (p=0.006). There were a total of 18 abnormal joints detected in 15 children (13 in the episodic group and 2 children in the prophylaxis treatment group). The authors concluded prophylaxis with recombinant factor VIII products was effective in preventing hemarthroses and structural joint damage.

Recombinate has demonstrated therapeutic effects in individuals with Factor VIII inhibitor titers not exceeding 10 BU/mL. Factor VIII inhibitor concentration assay should be performed if the expected plasma factor VIII activity levels are not achieved or bleeding episodes are not adequately controlled with appropriate dosing. The product information label (2010) notes if the inhibitors are less than 10 BU/mL, additional recombinate may neutralize the inhibitor, permitting appropriate hemostatic response. However, adequate hemostasis may not be achieved with inhibitor titers greater than 10 BU/mL and alternate therapies are needed.

Obizur received FDA fast track and manufacturing approval of an orphan drug in October 2014. Obizur is a recombinant antihemophilic factor VIII, porcine sequence used to treat bleeding episodes in adults with a rare condition called acquired hemophilia (AHA). Circulating inhibitors (antibodies) neutralize human factor VIII creating a deficiency that makes blood clotting difficult. Manufactured with a recombinant porcine sequence factor VIII, Obizur is thought to be less susceptible to the neutralizing effects of circulating human factor VIII antibodies. The pivotal phase II/III open-label, multi-center clinical trial enrolled 29 adults with AHA, and efficacy data from 28 participants were analyzed. Participants had a history of prior bleeding episodes that required hospitalization. Excluded from the study were individuals with anti-porcine antibody titer greater than 20 BU/mL or if the bleeding episode was expected to resolve without intervention. Participants were evaluated for treatment response based on clinical assessments and factor VIII activity levels. Positive responses were assessed 8 hours after dosing in 95% (19/20) participants and 100% (18/18) at 16 hours. At 24 hours after Obizur dosing, 28 subjects had a positive response to the initial bleeding episodes. Investigators determined overall treatment success 86% (24/28) adults based on the ability to discontinue and/or reduce use of Obizur. A common adverse event included development of porcine FVIII inhibitors which was observed in 5% of 29 participants. AHA is not inherited and may develop in both males and females. The product information notes Obizur is not indicated for the treatment of individuals with congenital hemophilia A or VWD. In addition, the safety and efficacy of Obizur has not been established in individuals with a baseline anti-porcine factor VIII inhibitor titer of greater than 20 BU/mL (Product Information Label, 2014).

Adynovate is a pegylated recombinant factor VIII formulation. Pegylation slows the elimination of the active component, allowing less frequent dosing. In contrast, its non-pegylated counterpart product Advate (Coagulation Factor VIII [Recombinant] requires more frequent intravenous weekly dosing (3-4 times) for prevention of bleeding episodes than Adynovate (2 times).

Adynovate was originally approved by the FDA on November 13, 2015 with the following indications and usage statement:

Adynovate, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital factor VIII deficiency) for:

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

The safety and efficacy of Adynovate were evaluated in a clinical trial of 137 adults and adolescents aged 12 years of age and older, which compared the recommended routine prophylactic (preventive) treatment regimen to on-demand therapy (Konkle, 2015). On average 1-2 infusions of Adynovate 25.5-36.4 IU/kg helped control acute bleeding episodes for 96% of all bleeds with a good or excellent response rate of 95.3%. As compared to the prevention treatment arm (40-50 IU/kg twice weekly), on-demand treatment was associated with a higher median annualized bleeding rate (per-protocol 41.9 vs 1.9; p<0.0001). The median annualized joint bleeding rate was zero for those on prophylaxis as compared to 38.1 for those receiving Adynovate on-demand. The trial demonstrated that Adynovate was effective in reducing the number of bleeding episodes during routine care. Additionally, Adynovate was effective in treating and controlling bleeding episodes. No safety concerns were identified during the study.

However, in December of 2016 the FDA expanded indications for Adynovate to include use in children under 12 years of age. This approval was based on a prospective, uncontrolled, open-label, multi-center phase III trial by Mullins and colleagues (2016) designed to assess the safety, efficacy and immunogenicity of Adynovate. In the study, Adynovate met its primary endpoint with no previously treated children having developed inhibitory antibodies. Additionally, there were no treatment-related serious adverse events reported. A total of 73% of children had zero joint bleeds (n=48/66) while on prophylactic treatment with Adynovate, and overall 38% experienced zero bleeds (n=25/66). The median overall annualized bleeding rate (ABR) of children treated with Adynovate was similar to the rates seen in the adult study.

Afstyla was approved by the FDA on May 25, 2016 with the following indications and usage statement:

Afstyla, Antihemophilic Factor (Recombinant), Single Chain, is a recombinant, antihemophilic factor indicated in adults and children with hemophilia A (congenital Factor VIII deficiency) for:

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

Afstyla is the only single-chain product for hemophilia A that is designed for long-lasting protection from bleeding. The FDA approval of Afstyla was based on results from a clinical development program that included two pivotal and one extension open-label multi-center studies evaluating safety and efficacy in children, adolescents and adults with hemophilia A. Two completed studies consisted of 258 previously treated subjects with severe hemophilia A (<1% endogenous Factor VIII activity) who received at least one dose of Afstyla for either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management. A median annualized spontaneous bleeding rate (AsBR) of 0 in adults, adolescents and children undergoing prophylaxis was observed. The overall median ABR was 1.14 in adult and adolescents, and 3.69 in children less than 12 years old who were treated with Afstyla prophylactically. A total of 1,195 bleeds were treated during the study, including 848 in adults and adolescents, and 347 in children. Of those, 94% of bleeds in adults and adolescents, and 96% of bleeds in children were controlled with two or less weekly infusions of Afstyla. Additionally, 81% of bleeds in adults and adolescents, and 86% of bleeding events in children were effectively controlled by one weekly infusion. A total of 13 adult and adolescents underwent 16 total surgeries during the study. Overall, the hemostatic efficacy of Afstyla in surgical settings was rated as “excellent” for 15 of 16 surgeries and “good” once. The most common adverse reactions reported in clinical trials were dizziness and hypersensitivity. (Afstyla PI, 2016)

Antihemophilic bispecific factor (Factor IXa- and Factor X-)
On November 16, 2017, emicizumab (Hemlibra) was granted FDA approval for use as a routine prophylaxis to prevent or reduce the frequency of bleeding episodes in individuals with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors (Hemlibra PI, 2017). Hemlibra is a first-in-class therapy that works by bridging other factors in the blood to restore blood clotting in individuals with hemophilia A and has been granted breakthrough therapy designation, priority review status and orphan drug designation by the FDA. Establishment of the safety and efficacy of Hemlibra was based on data from two clinical trials [an adult and adolescent study (HAVEN 1) and a pediatric study (HAVEN 2)].

The HAVEN 1 study was a phase III randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged 12 to 75 years) with hemophilia A with factor VIII inhibitors who previously received either episodic or prophylactic treatment with bypassing agents. Hemlibra prophylaxis was administered weekly in the interventional study arms and not administered in the control arm. In total, 53 of the 109 males were randomized in a 2:1 ratio to receive Hemlibra or serve as a control. The control arm had the option of switching to Hemlibra prophylaxis after completing at least 24 weeks without prophylaxis. An additional 56 males were enrolled for prophylaxis with Hemlibra following the randomization period. The primary outcome was ABR requiring treatment with coagulation factors (minimum of 24 weeks or date of discontinuation). Secondary outcomes included the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds, in addition to self-reported symptoms and physical functioning. The percent reduction in ABR was 87% (95% CI: 72.3%-94.3%; p<0.0001); 2.9 events in the intervention arm versus 23.3 events in the control arm. The percent reduction in all bleeds (80%), spontaneous bleeds (92%), joint bleeds (89%) and target bleeds (95%) were also statistically significant. In the intra-patient analysis, Hemlibra prophylaxis resulted in a statistically significant reduction in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis prior to enrollment (79% reduction; p=0.0003). The most commonly reported side effects of Hemlibra included injection site reactions, headache, and joint arthralgia (Oldenberg, 2017).

The HAVEN 2 study was a single-arm, multicenter, open-label, clinical study in pediatric males (age 17 or younger) with hemophilia A and factor VIII inhibitors. A total of 23 males were enrolled and available at interim analysis (median duration of 38.1 weeks) who had received prophylactic Hemlibra once weekly. Similar to HAVEN 1, the primary outcome was ABR requiring treatment with coagulation factors with secondary outcomes including the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds. Weekly Hemlibra prophylaxis resulted in a 99% reduction in ABR for treated bleeds compared to previous bypassing agent treatment (Hemlibra PI, 2017).

The labeling for Hemlibra contains a boxed warning related to thrombotic microangiopathy and thromboembolism that may occur when individuals receive rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra (Hemlibra PI, 2017).

Factor VIII Recombinant Antihemophilic Factor, Fc Fusion Protein
Factor replacement treatments are created from blood products (plasma-derived) and others are manufactured (recombinant). rFVIIIFc is the first recombinant hemophilia A treatment that requires fewer injections in the prevention or reduction of bleeding frequency. It is a longer lasting product that can be given less frequently than most currently available Factor VIII products. rFVIIIFc can be given every 4 days (range of 3-5 days) for routine prophylaxis. 

In June of 2014, rFVIIIFc (Eloctate) received FDA approval with the following Indications and Usage statement:

Eloctate, Antihemophilic Factor (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, antihemophilic factor indicated in adults and children with Hemophilia A (congenital Factor VIII deficiency) for:

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

The FDA approval was based on a prospective, phase III multicenter, open-label trial that evaluated the efficacy of 2 prophylactic treatment regimens compared to an on demand treatment regimen in 165 previously treated males with severe Hemophilia A. Individuals were eligible for the prophylactic study arm if endogenous FVIII activity was less than1 IU/dL (1%) endogenous FVIII activity or severe genotype. Males with a history of 12 or more bleeding events in the prior 12 months were eligible for episodic treatment. The target steady state trough was 1 to 3 IU/dL or higher to maintain good control of breakthrough bleeding. A total of 118 males were enrolled into arm 1, individualized prophylaxis twice-weekly dosing (25 IU/kg on day 1; 50 IU/kg on day 4) followed by 35-65 IU/kg every 3-5 days. Twenty-four individuals in arm 2 received weekly prophylaxis with 65 IU/kg. Episodic (on-demand) treatment with 10-50 IU/kg, depending on bleeding, was provided to 23 individuals in arm 3. The primary efficacy end points were ABR per person, in study arms 1 versus 3. The secondary efficacy end points included ABR in arms 2 and 3 along with the number of injections required to resolve acute bleeding episodes. The median ABRs were 1.6 (arm 1), 3.6 (arm 2) and 33.6 (arm 3). ABRs were significantly reduced with prophylactic treatment (92%) compared to episodic treatment (76%). Of those in arm 1, 45.3% of the participants had no bleeding episodes on study. The overall bleeding episodes resolved with 1 injection were 87.3% and ≤ 2 injections were required to control bleeding in 97.8%. The terminal half-life of rFVIIIFc was significantly longer, 19.0 vs. 12.4 hours (p<0.001) compared to rFVIII in 28 participants in the sequential pharmacokinetics subgroup. The study showed that Eloctate was effective in treating bleeding episodes, in preventing or reducing bleeding, and in the control of bleeding during and after surgical procedures.

Antihemophilic Factor VIII/von Willebrand Factor Complex
The most common inherited bleeding disorder is VWD. VWD affects both females and males and occurs in about 1 out of every 100 to 1000 people (National Institute of Health, 2008). VWD involves ineffective or low levels of VWF protein that helps the blood clot. Bleeding can damage organs and on rare occasions, may be life threatening.

According to the VWD management guidelines (Nichols, 2008):

Von Willebrand factor concentrate replacement therapy is indicated for severe bleeding events or major surgery in patients with types 2 and 3 VWD as well as in individuals with type 1 VWD and who are unresponsive to desmopressin or require protracted therapy, or where desmopressin is contraindicated.

FDA approved agents to treat individuals with VWD include antihemophilic factor VIII/von Willebrand factor complex (Alphanate, Humate-P, Wilate). Alphanate is an antihemophilic factor/human von Willebrand factor complex indicated for control and prevention of bleeding in adults and children with hemophilia A and for surgical and/or invasive procedures in individuals with VWD in whom desmopressin is either ineffective or contraindicated (Product Information Label, 2015). It is not indicated for individuals with severe VWD (Type 3) undergoing major surgery.

Humate-P is a pasteurized antihemophilic factor/human von Willebrand factor complex indicated for treatment and prevention of bleeding in adults with hemophilia A, and for treatment of spontaneous and trauma-induced bleeding episodes and prevention of excessive bleeding during and after surgery (Product Information Label, 2014). This applies to individuals with severe VWD as well as those with mild to moderate VWD where use of desmopressin is known or suspected to be inadequate.

Peyvandi and colleagues (2016) conducted a multi-center, randomized clinical trial, named “Survey of Inhibitors in Plasma-Product Exposed Toddlers” (SIPPET) to evaluate the incidence of factor VIII inhibitors in children treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. A total of 264 subjects were randomized and 251 (126 assigned to receive recombinant factor VIII and 125 assigned to receive plasma-derived factor VIII) were subsequently analyzed. Eligibility criteria included male sex, age below 6 years, severe hemophilia A, and no prior treatment with any factor VIII concentrate or only minimal blood component treatment. Inhibitors developed in 76 subjects and of these, 50 had high titer inhibitors. Inhibitors developed in 29 of the 125 children that received plasma-derived factor VIII treatment and in 47 of the 126 children treated with recombinant factor VIII. The authors concluded that early replacement therapy with plasma-derived factor VIII was associated with a lower incidence of inhibitor development than was therapy with recombinant factor VIII.

Wilate is a von Willebrand Factor/Coagulation Factor VIII Complex (Human) indicated for the treatment of spontaneous and trauma-induced bleeding episodes in individuals with severe von Willebrand disease (VWD). Wilate is also indicated for individuals with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated. In August 2015, the FDA expanded the labeled indication to include perioperative management of bleeding. Wilate is not indicated for the treatment of hemophilia A.

On December 8, 2015, the FDA approved Vonvendi, the first recombinant von Willebrand factor for the on-demand treatment and control of bleeding episodes in adults 18 years of age and older diagnosed with von Willebrand disease. The FDA reported that Vonvendi was evaluated in two clinical trials of 69 adults and was found to be safe and effective for on-demand treatment and control of bleeding episodes from a variety of different sites in the body. No safety concerns were identified and the most common adverse reaction was generalized pruritus. Of significance, the product information label indicates that for each bleeding episode, the first dose of Vonvendi should be administered with an approved recombinant (non-von Willebrand factor-containing) factor VIII if factor VIII baseline levels are below 40% or are unknown.

On April 17, 2018, the FDA approved the expansion of Vonvendi for the perioperative management of bleeding. The label expansion was based on a phase 3 prospective, open-label, multicenter trial that evaluated the safety and efficacy of Vonvendi with or without recombinant factor VIII (FVIII) (Advate) for the treatment of 15 individuals 18 years or older, diagnosed with severe von Willebrand disease who were undergoing elective surgical procedures; 10 underwent major surgeries and 5 subjects underwent minor surgeries. Subjects were followed for 14 days post-procedure during which time the primary endpoint was met; overall hemostatic efficacy assessed 24 hours after the last perioperative infusion, or at completion of study visit, whichever occurred earlier. Overall hemostatic efficacy for major and minor surgeries was 100% (15/15); it was ‘excellent’ for 60% of surgeries and ‘good’ for 40% of surgeries. No safety concerns were reported (Product Information Label, 2018).

Factor IX
Bebulin and Profilnine SD are factor IX complexes made from processed pooled human plasma that has been treated to reduce the risks of infection. These products are FDA approved for the treatment of individuals with hemophilia B (congenital factor IX deficiency). Bebulin and Profilnine SD are not indicated as a treatment of factor VII deficiency because the level of factor VII in these products are considered non-therapeutic (Product Information Labels, 2015, 2010).

AlphaNine SD and Mononine are sterile lyophilized concentrates of factor IX derived from pooled human plasma and are FDA approved to treat factor IX deficiency (hemophilia B). These agents are not indicated for the prophylaxis treatment of individuals with hemophilia A with inhibitors to factor VIII. AlphaNine SD and Mononine are not indicated for replacement therapy of other clotting factors which include factors II, VII and X as the products contain non-therapeutic levels of these additional factors. The labels also specify these products are not indicated to treat or reverse coumarin-induced anticoagulation or in a hemorrhagic state caused by hepatitis-induced lack of production of liver dependent coagulation factors (Product Information Labels, 2014, 2016).

Benefix, Ixinity and Rixubis are recombinant factor IX drugs that are produced in Chinese hamster ovary (CHO) cell lines using recombinant deoxyribonucleic acid, (DNA) technology (Product Information Labels 2015, 2016, 2016). These agents are FDA approved for treatment of bleeding episodes and perioperative management in individuals with hemophilia B. Rixubis is also indicated for the routine prophylaxis for individuals with hemophilia B. Ixinity and Rixubis are not indicated for induction immune tolerance in individuals with hemophilia B. The product information notes Benefix is not indicated for the treatment of other factor deficiencies.  Benefix is not FDA approved for the treatment of individuals with hemophilia A or for the reversal of coumarin-induced anticoagulation.

Recombinant Coagulation Factor IX, Fc Fusion Protein
Recombinant factor IX Fc fusion protein (rFIXFc) was specifically designed to increase the half-life of the Factor IX and thus decrease the frequency of injections required to maintain adequate plasma levels of Factor IX. rFIXFc is not derived from human blood and contains no preservatives. The protein is composed of a single molecule of recombinant Factor IX covalently fused to the dimeric Fc domain of IgG. Fc fusion protein prolongs the drug’s half-life by delaying lysosomal degradation, thus allowing recycling of the protein back into the circulation (Product Information Label, 2014).

In March of 2014, rFIXFc (Alprolix) received FDA approval with the following Indications and Usage statement:

Alprolix Coagulation Factor IX (Recombinant) Fc Fusion Protein, is a recombinant DNA derived, coagulation Factor IX concentrate is indicated in adults and children with hemophilia B for:

Alprolix is not indicated for induction of immune tolerance in patients with Hemophilia B.

The FDA approval was based on the results of the B-LONG trial, a phase 3, nonrandomized open-label study that was designed to compare the pharmacokinetics of rFIXFc with those of recombinant factor IX (rFIX) and to assess the safety and efficacy of repeated administration of rFIXFc (Powell, 2013). The trial enrolled a total of 123 male subjects with severe hemophilia without inhibitors, and a prior history of Factor IX prophylaxis or a history of at least 8 bleeding events in the prior year. As a reflection of the relative rarity of Hemophilia B, participants were enrolled at 50 investigational sites in 16 countries over a 2 year period. Participants were assigned to 1 of the 4 following groups based on each participating center’s standard of care:

The trial’s primary efficacy endpoint was the annualized bleeding rate. The primary safety endpoints were the development of inhibitors and adverse events. Subjects were treated and followed for up to 77 weeks. In a subgroup of 22 participants in Group 1, the investigators also compared the pharmacokinetics of rFIXFc with a standard rFIX. As expected, the half-life of rFIXFc was significantly longer than that of rFIX (geometric mean, 82.1 vs. 33.8 hours, p<0.001), consistent with preliminary phase 1 and 2 studies (Santagostino, 2012). Considering the group as a whole, 80% or more of participants treated prophylactically required injections at least 2 times per week. In contrast, during the study prophylaxis was effective with injections every 1 to 2 weeks. The primary efficacy endpoint was met with a reduced annualized rate of bleeding for the prophylactic regimens by 83% with weekly dosing, and 87% for interval adjusted dosing compared to the episodic treatment group (p<0.001). The annualized bleeding rates and annualized spontaneous bleeding rates were improved for individuals treated with fixed or individualized interval therapy with rFIXFc compared to on demand. There were 14 major surgeries performed on 12 individuals. Excellent hemostatic response was achieved in 13 and good hemostatic response was achieved in 1 case (Powell, 2014).

Regarding the safety profile, inhibitors were not detected in any participants. Among the 119 participants in Groups 1, 2 and 3, 73.9% (n=88) had at least one adverse event during the study period. The most common included influenza, arthralgia and other common illness that the investigators judged to be unlikely related to the rFIXFc. There were no reports of vascular thrombotic events, serious hypersensitivity or anaphylaxis. The authors concluded that the study demonstrated that rFIXFc is safe and effective for the treatment and prevention of bleeding events in previously treated adolescents and adults with hemophilia B. Fc fusion did not impair Factor IX activity or result in increased immunogenicity. The prolonged half-life of rFIXFc allowed for effective prophylaxis with injections every 1 to 2 weeks. 

The authors also noted the limitations of this study design. For ethical considerations the authors felt a placebo-controlled trial was inappropriate. This trial does suggest that the increased half-life of rFIXFc will reduce the frequency of injections related to the longer half-life of rFIXFc compared to rFIX.

Coagulation Factor IX, Recombinant, Albumin Fusion Protein
Coagulation Factor IX, Recombinant, Albumin Fusion Protein (rIX-FP) (Idelvion) is the first coagulation factor-albumin fusion protein product to be approved, and the second long acting Factor IX fusion protein product approved in the U.S. The active ingredient in Idelvion is a purified protein produced by the genetic fusion of recombinant albumin to recombinant coagulation Factor IX. The fusion to recombinant albumin extends the half-life with dosing every 7 to 14 days (for prophylaxis).

On March 4, 2016 Idelvion received FDA approval with the following indications and usage statement:

Idelvion, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), a recombinant human blood coagulation factor, is indicated in children and adults with hemophilia B (congenital Factor IX deficiency) for:

Idelvion is not indicated for immune tolerance induction in patients with Hemophilia B.

The safety and efficacy of Idelvion were evaluated by the PROLONG-9FP clinical development program. PROLONG-9FP included Phase I through Phase III open-label, multi-center studies of children and adults (ages 12 to 61 years) with hemophilia B (Martinowitz, 2013; Martinowitz, 2015; Santagostino, 2013; Santagostino, 2015). Idelvion was shown to be effective in controlling bleeding episodes and in managing perioperative bleeding. As a prophylaxis, Idelvion led to a significant reduction in the rate of spontaneous bleeding episodes despite the need for less frequent infusions. The most common side effect observed for Idelvion was headache, and no safety concerns were identified in the studies.

Coagulation Factor IX, Recombinant, GlycoPEGylated
On May 31, 2017 Rebinyn received FDA approval with the following indications and usage statement:

Rebinyn, Coagulation Factor IX (Recombinant), GlycoPEGylated, is a recombinant DNA-derived coagulation Factor IX concentrate indicated for use in adults and children with hemophilia B for:

Limitations of Use: Rebinyn is not indicated for routine prophylaxis in the treatment of patients with hemophilia B. Rebinyn is not indicated for immune tolerance induction in patients with hemophilia B.

Rebinyn was studied in 115 individuals from four multicenter, non-controlled paradigm trials. A total of 597 bleeding episodes were reported in previously treated cases. Minor or moderate bleeds were treated with Rebinyn 40 IU/kg and major bleeds were treated with 80 IU/kg. The overall success rate ("excellent" or "good") for the treatment of bleeding episodes was 93.2%. One injection was needed to treat a bleeding episode in 87% of cases and two injections were needed to treat 10% of cases. In the on-demand treatment arm, 143 bleeding episodes were reported for which the overall success rate was 95.1%.

Coagulation Factor X, Human plasma-derived
Coagulation factor X (human) (Coagadex) was designed to temporarily replace the missing factor X needed for effective hemostasis in individuals with hereditary Factor X deficiency.

On October 20, 2015, coagulation factor X (human) (Coagadex) received FDA approval with the following Indications and Usage statement:

Coagadex, Coagulation Factor X (Human), is a plasma-derived human blood coagulation factor indicated in adults and children (aged 12 years and above) with hereditary Factor X deficiency for:

Limitation of Use
Perioperative management of bleeding in major surgery in patients with moderate and severe hereditary Factor X deficiency has not been studied.

The safety and efficacy of Coagadex was evaluated in a multi-center, non-randomized clinical trial of 16 subjects (aged 12-58 years) with moderate to severe hereditary Factor X deficiency (FX: C<5 IU/dl). Coagadex was given for the treatment of spontaneous, traumatic and menorrhagic bleeding episodes. Of the 208 bleeding episodes treated with Coagadex, 15 subjects (187 bleeding episodes) were evaluated. Coagadex was considered to be good (7%) or excellent (91%) in treating 98% of the bleeding episodes (Product Information Label, 2015).

The safety and efficacy of Coagadex was also evaluated for perioperative management in 5 subjects with mild (n=2), moderate (n=1) and severe (n=2) Factor X deficiency, who underwent a total of 7 surgical procedures. For all surgeries, Coagadex was reported as excellent (no post-operative bleeding, no blood transfusions needed, and blood loss was no more than expected) for the control of blood loss during and following surgery. For major surgeries, a median of 13 infusions were used to maintain hemostasis and for minor surgeries, a median of 2.5 infusions were required to maintain hemostasis (Product Information Label, 2015). Study limitations included a small number of participants.

Factor XIII
Corifact, Factor XIII Concentrate (Human), is concentrate of coagulation factor XIII pooled from human plasma and is reconstituted for intravenous infusion. According to the product information label (2013), Corifact (FXIII) “promotes cross-linking of fibrin during coagulation and is essential to the physiological protection of the clot against fibrinolysis.” FXIII is an enzyme that promotes the stabilization of fibrin and makes the fibrin clot more “elastic and resistant to fibrinolysis.”

In 2013, the FDA approved Tretten, a recombinant coagulation factor XIII A-subunit, as routine prophylaxis of bleeding in individuals with congenital factor XIII A-subunit deficiency. Tretten is not for use in individuals with congenital factor XIII B-subunit deficiency. Factor XIII B-subunit is only a carrier molecule and does not provide any activity to correct B-subunit deficiency (Product Information Label, 2016). Factor XIII is a rare condition and the usual cause is a deficiency in the A-subunit that is important for normal clotting. Tretten was approved for manufacturing to treat this orphan indication. In the pivotal trial that included 77 individuals treated with monthly Tretten infusion, bleeding was prevented in 90% of the participants. Most common 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 product label lists a drug interaction, “Thrombosis may occur with concomitant administration with factor VIIa.” 

Fibrinogen Concentrate; Human Fibrinogen
In 2009, the FDA approved manufacturing of the orphan approved RiaSTAP as a treatment for a rare genetic defect that includes a deficit of fibrinogen and could result in life-threatening bleeding. Fibrinogen is normally manufactured in the liver and circulates in the body, helping to form blood clots and to prevent bleeding. RiaSTAP is concentrated fibrinogen made from human derived-plasma to prevent bleeding by replacing very low levels or no fibrinogen for individuals with afibrinogenemia and hypofibrinogenemia. The product information label (2011) states RiaSTAP is not indicated for treatment of dysfibrinogenemia. In an open-label pharmacokinetic study, the maximum clot firmness (MCF) was studied in individuals with afibrinogenemia who were treated with RiaSTAP. “Clot firmness is a functional parameter that depends on: activation of coagulation, fibrinogen content of the sample and polymerization/crosslinking of the fibrin network” (Product Information Label, 2016). The MCF was measured by thromboelastometry at baseline and after RiaSTAP infusion. MCF values increased significantly after RiaSTAP infusion with a mean change post-infusion of 8.9 mm (9.9 mm for children < 16 years of age and 8.5 mm for individuals ≥ 16 to < 65 years of age) (Product Information Label, 2016). Adverse events include thrombosis with or embolization may occur as a result of the underlying fibrinogen deficiency and may occur after RiaSTAP infusion.

In 2017, the FDA approved human fibrinogen (Fibryna) for the treatment of acute bleeding episodes in adults and adolescents with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. Approval was based on interim analysis of a prospective, open-label, uncontrolled, multicenter clinical study conducted in 13 individuals diagnosed with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia). Study participants’ ages ranged from 13 years to 53 years of age. During the study, a total of 22 minor bleeding events occurred (defined as mild joint bleeding or superficial muscle, soft tissue, and oral bleeding). Of the 22 mild bleeding events, 15 (68%) were spontaneous and 7 (32%) were traumatic. The median number of infusions needed to stop the bleeding events was one, and no event required more than two infusions. The treatments of the bleeding events were assessed for efficacy using a 4-point haemostatic efficacy scale based on criteria such as bleeding cessation, changes in hemoglobin, and use of any other hemostatic means. Of 22 evaluable bleeding events, 21 (95%) were assessed as having a successful outcome (rating of good or excellent efficacy) by both the investigator and by an independent adjudication committee (the outcome of the remaining event was unreported). Human fibrinogen is not indicated for the treatment of dysfibrinogenemia (Product Information Label, 2017).

Definitions

Hemophilia severity:

Induction of immune tolerance (ITI): A therapy involving large amounts of clotting factor concentrates given every day for many weeks or months with the goal of stopping the inhibitor reaction and to sensitive the body to accept treatment with clotting factor concentrates.

Inhibitor: An antibody that binds to the infused clotting factor which makes it difficult, if not impossible, for the clotting factor to clot the blood and control/stop the bleeding. An undesired immune response that can neutralize the effect of clotting factor treatments.

On-demand regimen: Use of Factor IX to stop the bleeding occurrence; as-needed basis.

Prophylaxis or preventive regimen: Replacement factor therapy given on a regular basis to prevent bleeding.

References

Peer Reviewed Publications:

  1. Antunes SV, Tangada S, Stasyshyn O, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2014; 10(1):65-72.
  2. Berntorp E, Windyga J.; The European Wilate Study Group. Treatment and prevention of acute bleedings in von Willebrand disease – efficacy and safety of Wilate, a new generation von Willebrand factor/factor VIII concentrate. Haemophilia. 2009, 15(1):122-130.
  3. Bitting RL, Bent S, Li Y, Kohlwes J. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul and Fibrinolysis. 2009; 20(7):517-523.
  4. Chowdary P, Kearney S, Regnault A, et al. Improvement in health-related quality of life in patients with haemophilia B treated with nonacog beta pegol, a new extended half-life recombinant FIX product. Haemophilia. 2016; 22(4):e267-274.
  5. Collins PW, Blanchette VS, Fischer K, et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost. 2009; 7(3):413-420.
  6. Collins PW, Young G, Knobe K, et al.; paradigm 2 Investigators. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014; 124(26):3880-3886.
  7. Franchini M, Coppola A, Rocino A, et al. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia A: a 2013 update. Semin Thromb Hemost. 2013: 39(7):752-766.
  8. Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015; 126(17):2038-2046.
  9. Gringeri A, Leissinger C, Cortesi PA, et al. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia. 2013; 19(5):736-743.
  10. Grigeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Throm Haemost. 2011; 9(4):700-710.
  11. Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia.  Hemophilia. 2001; 7(4):392-396.
  12. Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015; 126(9):1078-1085.
  13. Kulkarni R, Soucie JM, Lusher J, et al.; Haemophilia Treatment Center Network Investigators. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project. Haemophilia. 2009; 15(6):1281-1290.
  14. Mahlangu J, Powell JS, Ragni MV, et al.; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014; 123(3):317-325.
  15. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357(6):535-544.
  16. Mancuso ME, Mannucci PM. Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias. Drug Des Devel Ther. 2014; 8:365-371.
  17. Martinowitz U, Lissitchkov T, Lubetsky A, et al. Results of a phase I/II open-label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients. Haemophilia. 2015; 21(6):784-790.
  18. Martinowitz U, Lubetsky A. Phase I/II, open-label, multicenter, safety, efficacy and PK study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in subjects with hemophilia B. Thromb Res. 2013; 131 Suppl 2:S11-S14.
  19. Monahan PE, Liesner R, Sullivan ST, et al. Safety and efficacy of investigator-prescribed BeneFIX prophylaxis in children less than 6 years of age with severe haemophilia B. Haemophilia. 2010; 16(3):460-468.
  20. Mullins ES, Stasyshyn O, Alvarez-Román MT, et al. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia. 2017; 23(2):238-246.
  21. Negrier C, Young G, Abdul Karim F, et al; paradigm™ 2 and 4 Investigators. Recombinant long-acting glycoPEGylated factor IX (nonacog beta pegol) in haemophilia B: assessment of target joints in multinational phase 3 clinical trials. Haemophilia. 2016; 22(4):507-513.
  22. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017; 377(9):809-818.
  23. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016; 374(21):2054-2064.
  24. Powell JS, Pasi KJ, Ragni MV, et al.; B-LONG Investigators. Phase 3 study of recombinant Factor IX Fc fusion protein in hemophilia B. N Eng J Med. 2013; 369(24):2313-2323.
  25. Santagostino E. PROLONG-9FP clinical development program--phase I results of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP). Thromb Res. 2013; 131 Suppl 2:S7-10.
  26. Santagostino E, Martinowitz U, Lissitchkov T, et al. Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016; 127(14):1761-1769.
  27. Santagostino E, Negrier C, Klamroth R, et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood; 2012; 120(12):2405-2411.
  28. Shapiro AD, Ragni MV, Valentino LA, et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood. 2012; 119(3):666-672.
  29. Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med. 2016; 374(21):2044-2053.
  30. Valentino LA. Assessing the benefits of FEIBA prophylaxis in haemophilia patients with inhibitors. Haemophilia. 2010; 16(2):263-271.
  31. Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 2012; 10(3):359-367.
  32. Young G, Collins PW, Colberg T, et al. Nonacog beta pegol (N9-GP) in haemophilia B: a multinational phase III safety and efficacy extension trial (paradigm™4). Thromb Res. 2016; 141:69-76.
  33. Zollner S, Raquet E, Claar P, et al. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII. Thromb Res. 2014; 134(1):125-131.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Athale AH, Marcucci M, Iorio A. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B. Cochrane Database Syst Rev. 2014;(4):CD010561.
  2. Iorio A, Marchesini E, Marcucci M, et al. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev. 2011;(9):CD003429.
  3. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008; 14(2):171-232.
  4. Simpson E, Lin Y, Stanworth S, et al. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. 2012; (3):CD005011.
  5. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al.; Treatment Guidelines Working Group on Behalf of the World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013; 19(1):e1-e47.
  6. Yank V, Tuohy CV, Logan AC, et al. Comparative effectiveness of recombinant factor VIIa for off-label indications vs. usual care. Comparative effectiveness review No. 21. Rockville, MD: Agency for Healthcare Research and Quality. May 2010. Available at: https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0047460/pdf/PubMedHealth_PMH0047460.pdf. Accessed on March 22, 2018.
Websites for Additional Information
  1. Centers for Disease Control and Prevention. Hemophilia Facts. Updated March 2, 2017. Available at: http://www.cdc.gov/ncbddd/hemophilia/facts.html. Accessed on March 22, 2018.
  2. National Hemophilia Foundation. Available at: http://www.hemophilia.org/. Accessed on March 22, 2018.
  3. U.S. Department of Health & Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. What is Hemophilia? Updated July 13, 2013. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/. Accessed on March 22, 2018.
  4. U.S. Department of Health & Human Services. National Institutes of Health. National Center for Advancing Translational Sciences. Office of Rare Diseases Research. Factor XIII deficiency. Updated December 16, 2011. Available at: http://rarediseases.info.nih.gov/gard/10766/factor-xiii-deficiency/resources/1. Accessed on March 22, 2018.
Index

Coagulation factor
Fc Fusion protein
Fibrinogen concentrate
Recombinant coagulation factor

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

05/02/2018

Hematology/Oncology Subcommittee review. Added MN criteria for Vonvendi. Added new section addressing preferred agents. Updated Description, Discussion/General Information and Reference sections. Updated Coding section to include 07/01/2018 HCPCS changes, added Q9995.

 

03/29/2018

Updated Coding section with 04/01/2018 HPCS changes; added C9468.

Revised

01/25/2018

MPTAC review.

Revised

01/17/2018

Hematology/Oncology Subcommittee review. MN Criteria added for emicizumab. Updated Discussion/General Information and Reference sections. Coding section updated; added J3590, J7199 for emicizumab.

New

11/02/2017

MPTAC review. Initial document development.

New

11/01/2017

Hematology/Oncology Subcommittee review. Moved content of DRUG.00066 Antihemophilic Factors and Clotting Factors to new clinical utilization management guideline document CG-DRUG-78 Antihemophilic Factors and Clotting Factors. Criteria added for recombinant coagulation factor IX, GlycoPEGylated (Rebinyn®) and Human Fibrinogen (Fibryna).

 

APPENDIX – FDA Product Label Prescribing Information and Drug Compendium References:

FDA Product Label Prescribing Information:

Antihemophilic Bispecific Factor (Factor IXa- and Factor X-)

Hemlibra [Product Information], San Francisco, CA. Genentech, Inc. November 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761083s000lbl.pdf. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant), Pegylated

Adynovate [Product Information], Westlake Village, CA. Baxalta US Inc. December 2016. Available at: http://www.shirecontent.com/PI/PDFs/ADYNOVATE_USA_ENG.pdf. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant), Plasma/Albumin Free

Advate [Product Information], Westlake Village, CA. Baxalta US Inc. November 2016. Available at:  http://www.advate.com/assets/pdf/advate_iri_pi.pdf. Accessed on March 22, 2018.

Helixate FS [Product Information], Kankakee, IL. CSL Behring, LLC. May 2016. Available at: http://labeling.cslbehring.com/PI/US/HelixateFS/EN/HelixateFS-Prescribing-Information.pdf. Accessed on March 22, 2018.

Xyntha [Product Information], Philadelphia, PA. Wyeth Pharmaceuticals, Inc. October 2014. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM055498.pdf
. Accessed on March 22, 2018. 

Xyntha Solufuse [Product Information], Phildelphia, PA. Wyeth Pharmaceuticals, Inc. October 2014. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM419498.pdf
. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant), Porcine Sequence

Obizur [Product Information], Westlake Village, CA. Baxalta US Inc. October 2015. Available at: http://www.shirecontent.com/PI/PDFs/OBIZUR_USA_ENG.pdf. Accessed on March 22, 2018.

Antihemophilic Factor/von Willebrand Factor Complex

Humate-P [Product Information], Kankakee, IL. CSL Behring, LLC. September 2016. Available at: http://www.humate-p.com/Professional/Prescribing-Information.aspx. Accessed on March 22, 2018.

Alphanate [Product Information], Los Angeles, CA. Grifols Biologicals, Inc. January 2018. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5a7aea94-654c-4113-9014-c3137de0a931. Accessed on March 22, 2018.

Wilate [Product Information], Hoboken, NJ. Octapharma USA Inc. August 2015. Available at: http://www.wilateusa.com/images/PDF_Files/WILATE_FPI_US_additional_Perioperative_Indication_8_2015.pdf. Accessed on March 22, 2018.

Anti-Inhibitor Coagulant Complex

FEIBA (Anti-Inhibitor Coagulant Complex) [Product Information], Westlake Village, CA. Baxalta US Inc.  April 2017. Available at:http://www.shirecontent.com/PI/PDFs/FEIBA_USA_ENG.pdf. Accessed on March 22, 2018.

Factor VIIa

NovoSeven RT (Coagulation Factor VIIa [Recombinant]) [Product Information], Princeton, NJ. Novo Nordisk Inc., Princeton, NJ. October 2015. Available at: http://www.novo-pi.com/novosevenrt.pdf. Accessed on March 22, 2018.

Factor VIII (Human)

Hemofil M [Product Information], Westlake Village, CA. Baxalta US Inc. July 2017. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b8953ff7-3bba-4a0b-a486-f26fb81f05d9. Accessed on March 22, 2018.

Koate DVI [Product Information], Research Triangle Park, NC. Grifols Therapeutics Inc. February 2016. Available at: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=2f77d685-e382-b2e7-2414-0d3a3448688a&type=display. Accessed on March 22, 2018.

Monoclate-P [Product Information], Kankakee, IL. CSL Behring LLC. February 2014. Available at: http://labeling.cslbehring.com/PI/US/Monoclate-P/EN/Monoclate-P-Prescribing-Information.pdf. Accessed on March 22, 2018.

Factor VIII (Recombinant) Antihemophilic Factor

Afystyla [Product Information], Kankakee, IL. CSL Behring LLC. April 2017. Available at: http://labeling.cslbehring.com/PI/US/Afstyla/EN/Afstyla-Prescribing-Information.pdf. Accessed on March 22, 2018.

Kogenate FS [Product Information], Tarrytown, NY. Bayer Corp. May 2016. Available at: http://www.kogenatefs.com/home/prescribing-information. Accessed on March 22, 2018.

Kovaltry [Product Information], Whippany, NJ. Bayer HealthCare LLC. March 2016. Available at: http://labeling.bayerhealthcare.com/html/products/pi/Kovaltry_PI.pdf. Accessed on March 22, 2018.

Novoeight [Product Information], Plainsboro, NJ. Novo Nordisk Inc. November 2016. Available at: http://www.novo-pi.com/novoeight.pdf. Accessed on March 22, 2018.

Nuwiq [Product Information], Hoboken, NJ. Octapharma USA, Inc. September 2015. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM461328.pdf
. Accessed on March 22, 2018.

Recombinate [Product Information], Westlake Village, CA. Baxter Healthcare Corporation. March 2010.
Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM200909.pdf
. Accessed on March 22, 2018.

Recombinant Antihemophilic Factor, Fc Fusion Protein

Eloctate [Product Information], Cambridge, MA. Biogen Idec Inc. January 2017. Available at: https://www.eloctate.com/Pdfs/full-prescribing-information.pdf. Accessed on March 22, 2018.

Factor IX (Human Purified)

AlphaNine SD [Product Information], Los Angeles, CA. Grifols Biologicals Inc. January 2013. Available at: https://www.alphaninesd.com/documents/24721187/24931048/AlphaNine+SD+PI.pdf/0ab74d6e-42b0-4c00-a143-67b39c9a6b53. Accessed on March 22, 2018.

Mononine [Product Information], CSL Behring LLC, Kanakee, IL. April 2016. Available at: http://labeling.cslbehring.com/PI/US/Mononine/EN/Mononine-Prescribing-Information.pdf. Accessed on March 22, 2018.

Factor IX (Complex Human)

Bebulin VH [Product Information], Baxter Healthcare Corporation, Westlake Village, CA. September 2017. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b375a2fb-7bd4-486c-87f6-72237713d528. Accessed on March 22, 2018.

Profilnine SD [Product Information]. Grifols Biologicals, Inc., Los Angeles, CA. May 2014. Available at: http://www.grifolsusa.com/documents/10192/89476/ft-profilnine-us-en/03a3eed9-2e02-4e7f-ae7b-9bff623d8535. Accessed on March 22, 2018.

Factor IX (Recombinant)

BeneFIX (Coagulation Factor IX [Recombinant]) [Product Information], Philadelphia, PA. Wyeth Pharmaceuticals. August 2015. Available at: http://labeling.pfizer.com/showlabeling.aspx?id=492. Accessed on March 22, 2018.

Ixinity (Coagulation Factor IX [Recombinant]) [Product Information], Winnipeg, Manitoba, Canada. Cangene Corporation. August 2016. Available at: http://www.ixinity.com/sites/all/themes/visia/images/pdfs/IXINITY_PI_Aptevo.pdf. Accessed on March 22, 2018.

Rixubis (Coagulation Factor IX [Recombinant]) [Product Information], Westlake Village, CA. Baxalta US Inc. March 2016. Available at: http://www.shirecontent.com/PI/PDFs/RIXUBIS_USA_ENG.pdf. Accessed on March 22, 2018.

Recombinant Coagulation Factor IX, Albumin Fusion Protein

Idelvion [Product Information]. Kankakee, IL. CSL Behring. LLC. March 2016. Available at: http://www.fda.gov/downloads/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/
fractionatedplasmaproducts/ucm489301.pdf
. Accessed on March 22, 2018.

Recombinant Coagulation Factor IX, Fc Fusion Protein

Alprolix [Product Information]. Cambridge, MA. Biogen Idec Inc. March 2014. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM391049.pdf
. Accessed on March 22, 2018.

Recombinant Coagulation Factor IX, GlycoPEGylated

Rebinyn [Product Information], Plainsboro, NJ. Novo Nordisk Inc. May 2017. Available at: http://www.novo-pi.com/rebinyn.pdf. Accessed on March 22, 2018.

Coagulation Factor X, Human

Coagadex [Product Information], Durham, NC. Bio Products Laboratory USA, Inc. October 2015. Available at: http://www.coagadex.com/. Accessed on March 22, 2018.

Factor XIII (Human)

Corifact Factor XIII Concentrate (Human) [Product Information], Kankakee, IL. CSL Behring, LLC. March 2015. Available at: http://labeling.cslbehring.com/PI/US/Corifact/EN/Corifact-Prescribing-Information.pdf. Accessed on March 22, 2018.

Factor XIII (Recombinant)

Tretten (Coagulation Factor XIII A-Subunit [Recombinant]) [Product Information], Plainsboro, NJ. Novo Nordisk Inc. November 2016. Available at: http://www.novo-pi.com/tretten.pdf. Accessed on March 22, 2018, 2017.

Fibrinogen

Riastap [Product Information], Kankakee, IL. CSL Behring, LLC. May 2016. Available at http://labeling.cslbehring.com/PI/US/RiaSTAP/EN/RiaSTAP-Prescribing-Information.pdf. Accessed on March 22, 2018.

Von Willebrand factor (Recombinant)

Vonvendi [Product Information], Westlake Village, CA. Shire. April 2018. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM476176.pdf
.  Accessed on April 19, 2018.

Drug Compendium References:

Antihemophilic Bispecific Factor (Factor IXa- and Factor X-)

Emicizumab. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated December 04, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor VIII (Recombinant), Pegylated

Antihemophilic Factor VIII (Recombinant) Pegylated. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated July 25, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant), Plasma/Albumin Free

Antihemophilic Factor (Recombinant) Plasma/Albumin-Free. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated August 10, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2017. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant), Porcine Sequence

Antihemophilic Factor (Recombinant) Porcine Sequence. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated April 17, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant), Porcine Sequence. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 30, 2017. Accessed on March 22, 2018.

Antihemophilic Factor VIII/von Willebrand Factor Complex

Antihemophilic Factor VIII/von Willebrand Factor Complex. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated July 12, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor (Human). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 23, 2017. Accessed on March 22, 2018.

Anti-Inhibitor Coagulant Complex

Anti-Inhibitor Coagulant Complex. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated August 10, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Anti-Inhibitor Coagulant Complex. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 1, 2007. Accessed on March 22, 2018.

Factor VIIa

Coagulation Factor VIIa. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated August 15, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Factor VIIa (Recombinant). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 1, 2010. Accessed on March 22, 2018.

Factor VIII (Human)

Antihemophilic Factor VIII (Human). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated August 10, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor VIII (Human). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 24, 2017. Accessed on March 22, 2018.

Factor VIII (Recombinant) Antihemophilic Factor

Factor VIII (Recombinant) Antihemophilic Factor. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated April 18, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2017. Accessed on March 22, 2018.

Recombinant Antihemophilic Factor, Fc Fusion Protein

Recombinant Antihemophilic Factor VIII, Fc Fusion Protein. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated March 6, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Antihemophilic Factor (Recombinant), Fc fusion protein. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2017. Accessed on March 22, 2018.

Factor IX (Human, Purified)

Factor IX Human, Purified. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated November 11, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Factor IX Human, Purified. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 25, 2017. Accessed on March 22, 2018.

Factor IX (Complex Human)

Factor IX (Complex Human). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated November 11, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Factor IX (Complex Human). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 25, 2017. Accessed on March 22, 2018.

Factor IX (Recombinant)

Coagulation Factor IX (Recombinant). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated August 15, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Factor IX (Recombinant). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 26, 2017. Accessed on March 22, 2018.

Recombinant Coagulation Factor IX, Albumin Fusion Protein

Recombinant Coagulation Factor IX, Albumin Fusion Protein. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated June 27, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Coagulation Factor IX (Recombinant, Human), Albumin Fusion Protein (rIX-FP). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised September 13, 2016. Accessed on March 22, 2018.

Recombinant Coagulation Factor IX, , Fc Fusion Protein

Recombinant Coagulation Factor IX, Fc Fusion Protein. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated March 1, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Factor IX (Recombinant), Fc Fusion Protein. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 24, 2017. Accessed on March 22, 2018.

Recombinant Coagulation Factor IX, GlycoPEGylated

Recombinant Coagulation Factor IX, GlycoPEGylated. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated June 29, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Factor X (Human)

Factor X Human. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated September 23, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Coagulation Factor X Human. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised September 8, 2016. Accessed on March 22, 2018.

Factor XIII (Human)

Factor XIII Human. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated March 04, 2016. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Factor XIII Human. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 27, 2017. Accessed on March 22, 2018.

Factor XIII (Recombinant)

Factor XIII Recombinant. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated March 4, 2016. Available at: http://www.micromedexsolutions.com. Accessed on December 22, 2017.

Factor XIII A-Subunit (Recombinant) Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised February 24, 2017. Accessed on March 22, 2018.

Fibrinogen

Fibrinogen. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated Decmber 27, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Fibrinogen. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised November 1, 2009. Accessed on March 22, 2018.

Von Willebrand factor (Recombinant)

Von Willebrand Factor (Recombinant). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated June 21, 2017. Available at: http://www.micromedexsolutions.com. Accessed on March 22, 2018.

Von Willebrand Factor (Recombinant). Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised March 16, 2017. Accessed on March 22, 2018.