Cigna Drug and Biologic Coverage Policy

Transcription

1 Cigna Drug and Biologic Coverage Policy Subject Clotting Factors and Antithrombin Effective Date... 4/15/2018 Next Review Date... 3/15/2019 Coverage Policy Number Table of Contents Coverage Policy... 1 General Background... 4 Coding/Billing Information References Related Coverage Resources INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Coverage Policy The Clotting Factors and Antithrombin coverage policy includes the following products: Antithrombin III o Human plasma-derived: Thrombate III o Recombinant: ATryn Anti-Inhibitor Coagulant Complex: FEIBA Coagulation Factor X, (human): Coagadex Factor VIIa: NovoSeven RT Activating Antibody Antihemophilic Factor: Hemlibra Factor VIII - Antihemophilic factor o Human plasma-derived: Hemofil M, Koate, Monoclate-P o Recombinant: Advate, Helixate FS, Kogenate FS, Novoeight, Nuwiq, Recombinate, Xyntha o Recombinant, Fc fusion protein: Eloctate o Recombinant, human DNA sequence derived: Kovaltry o Recombinant, pegylated: Adynovate o Recombinant, porcine sequence: Obizur o Recombinant, single chain: Afstyla Factor VIII-Antihemophilic factor/von Willebrand factor complex (human): Alphanate, Humate-P Factor IX o Human plasma-derived: AlphaNine SD, Mononine o Complex (human plasma-derived): Bebulin, Profilnine o Recombinant: BeneFIX, Ixinity, Rixubis o Recombinant, albumin fusion protein: Idelvion o Recombinant, glycopegylated: Rebinyn Page 1 of 40

2 o Recombinant, Fc fusion protein: Alprolix Factor XIII o Concentrate (human plasma-derived): Corifact o Recombinant (Coagulation Factor XIII A-Subunit): Tretten Fibrinogen concentrate: RiaSTAP, Fibryga von Willebrand factor, recombinant: Vonvendi von Willebrand factor/coagulation factor VIII complex (human plasma-derived): Wilate NOTE: Each Clotting Factor product has unique indications and uses and are only approved for use as listed in the criteria below. Cigna covers each of the Clotting Factor products as medically necessary for the following criteria listed below: Product Advate (factor VIII, recombinant) Adynovate [factor VIII - antihemophilic factor (recombinant), pegylated] Afstyla (antihemophilic factor, recombinant, single chain) Alphanate (factor VIII - antihemophilic factor/von Willebrand factor complex) Alphanine SD (factor IX, human plasmaderived) Alprolix (factor IX, recombinant, Fc fusion protein) ATryn [antithrombin III (recombinant)] Bebulin [factor IX, complex (human plasma-derived)] BeneFIX (factor IX, recombinant) Coagadex [coagulation Factor X (human)] Corifact [factor XIII Concentrate (human plasma-derived)] Eloctate [antihemophilic factor Criteria for Use Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A Individual with congenital coagulation factor VIII deficiency (hemophilia A) for ANY of the following: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes Individual with congenital coagulation factor VIII deficiency (hemophilia A) for ANY of the following: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes EITHER of the following: Treatment and prevention of bleeding in hemophilia A Von Willebrand disease (VWD) when there is a failure, contraindication or intolerance to desmopressin, and the indication is for surgical and/or invasive procedures. NOT indicated for severe VWD (type 3) undergoing major surgery Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient individuals Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Individual 12 years of age and older with coagulation factor X deficiency with EITHER of the following: On-demand treatment and control of bleeding episodes Perioperative management of bleeding in individuals with mild hereditary factor X deficiency EITHER of the following: Routine prophylactic treatment of congenital factor XIII deficiency Peri-operative management of surgical bleeding in congenital factor XIII deficiency Prevention or treatment of bleeding in an individual with hemophilia A (congenital factor VIII deficiency) Page 2 of 40

3 Product (recombinant, Fc fusion protein)] Fibryga (fibrinogen concentrate) FEIBA (anti-inhibitor coagulant complex) Helixate FS (factor VIII, recombinant) Hemlibra (activating antibody antihemophilic factor) Hemofil M (factor VIII, human plasmaderived) Humate-P (factor VIII - antihemophilic factor/von Willebrand factor complex) Idelvion (factor IX, recombinant, albumin fusion protein) Ixinity (factor IX, recombinant) Koate (factor VIII, human plasma-derived) Kogenate FS (factor VIII, recombinant) Kovaltry (factor VIII, recombinant) Monoclate-P (factor VIII, human plasmaderived) Mononine (factor IX, human plasmaderived) Novoeight (factor VIII, recombinant) NovoSeven RT (factor VIIa) Criteria for Use Treatment of acute bleeding episodes in an individual 13 years of age and older with congenital fibrinogen deficiency (afibrinogenemia and hypofibrinogenemia) Treatment of spontaneous bleeding episodes or to cover surgical interventions in EITHER of the following: Individual with hemophilia A and B with inhibitors Non-hemophiliac individual with acquired inhibitors to Factors VIII, XI, and XII Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A BOTH of the following are met: Individual with hemophilia A (congenital factor VIII deficiency) with documented factor VIII inhibitors Use is for routine prophylaxis to prevent or reduce the frequency of bleeding episodes Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A EITHER of the following: Treatment and prevention of bleeding in hemophilia A in an adult Mild to moderate VWD when there is failure, contraindication or intolerance to desmopressin OR severe VWD for EITHER of the following indications: o Treatment of spontaneous and/or trauma-induced bleeding episodes o Prevention of excessive bleeding during and/or following surgery Individual with congenital coagulation factor IX deficiency (hemophilia B) for ANY of the following: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to prevent or reduce the frequency of bleeding episodes Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A Individual with congenital coagulation factor VIII deficiency (hemophilia A) for ANY of the following: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A (congenital factor VIII deficiency or classic hemophilia) EITHER of the following: Treatment of bleeding episodes and peri-operative management in an individual with ANY of the following: o Hemophilia A or B with inhibitors o Congenital Factor VII (FVII) deficiency o Glanzmann s thrombasthenia with refractoriness to platelet transfusions Treatment of bleeding episodes and peri-operative management in an adult with Page 3 of 40

4 Product Nuwiq (factor VIII, recombinant) Obizur [antihemophilic factor (recombinant, porcine sequence)] Profilnine [factor IX, complex (human plasma-derived)] Rebinyn (factor IX, recombinant, glycopegylated) Recombinate (factor VIII, recombinant) RiaSTAP (fibrinogen concentrate) Rixubis (factor IX, recombinant) Thrombate III [antithrombin III (human)] Tretten [factor XIII A-Subunit (recombinant)] Vonvendi (von Willebrand factor, recombinant) Wilate (von Willebrand factor/coagulation factor VIII complex) Xyntha (factor VIII, recombinant) Criteria for Use acquired hemophilia Individual with hemophilia A and ANY of the following: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes Treatment of bleeding episodes in an adult when BOTH of the following are met: Diagnosis of acquired hemophilia A that is confirmed by documentation of autoimmune inhibitory antibodies to human factor VIII Individual does NOT have congenital hemophilia A or von Willebrand disease Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Individual with hemophilia B for EITHER of the following: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A Treatment of acute bleeding episodes in congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia Prevention or treatment of bleeding in an individual with Factor IX deficiency due to hemophilia B Treatment of an individual with hereditary antithrombin III deficiency for EITHER of the following: Treatment and prevention of thromboembolism Prevention of peri-operative and peri-partum thromboembolism BOTH of the following: Diagnosis of congenital factor XIII A-subunit deficiency Use is for routine prophylaxis of bleeding On-demand treatment and control of bleeding episodes in an individual 18 years of age or older diagnosed with von Willebrand disease On-demand treatment and control of bleeding episodes or perioperative management of bleeding in an individual with severe von Willebrand disease (VWD) or an individual with mild or moderate VWD when there is documented failure/inadequate response, contraindication per FDA label, or intolerance to desmopressin Prevention or treatment of bleeding in an individual with Factor VIII deficiency due to hemophilia A or acquired hemophilia A Cigna does not cover the use of Clotting Factors or Antithrombin for any other indication because it is considered experimental, investigational or unproven. When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to Clotting Factors or Antithrombin. Note: Receipt of sample product does not satisfy any criteria requirements for coverage. General Background Hemophilia A Hemophilia A or classic hemophilia is a deficiency of factor VIII. Factor VIII, or antihemophilic factor, is an endogenous glycoprotein necessary for blood clotting and hemostasis. It is a cofactor necessary for factor IX to activate factor X in the intrinsic pathway. Per the National Hemophilia Foundation (NHF), hemophilia occurs in 1 in 5,000 live births in the United States and hemophilia A is 4 times more common than hemophilia B (NHF, Page 4 of 40

5 2016). The average normal plasma activity of factor VIII is designated as 100%, and a factor VIII concentration of 25% of normal is required for hemostasis. Patients with severe hemophilia have a factor VIII concentration of less than 1% of normal and frequently experience bleeding even in the absence of trauma. Patients with a factor VIII concentration between 1% and 5% (moderate hemophilia) experience less bleeding, and patients with a factor VIII concentration greater than 5% (mild hemophilia) usually experience bleeding only after obvious trauma. The administration of factor VIII temporarily replaces the missing clotting factor to correct or prevent bleeding episodes. Factor VIII is obtained from pooled human plasma or produced by recombinant deoxyribonucleic acid (DNA) technology. Three products contain factor VIII and von Willebrand factor (Alphanate, Humate-P, and Koate), but only Alphanate and Humate-P have the indication for the treatment of von Willebrand disease. FDA Approved Products for Hemophilia A Brand Name Approved Indication(s) Advate Advate [Antihemophilic Factor (Recombinant)] is a recombinant antihemophilic factor (antihemophilic indicated for use in children and adults with hemophilia A (congenital factor VIII factor, deficiency) for: recombinant) Control and prevention of bleeding episodes. Perioperative management. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Adynovate (antihemophilic factor [recombinant], pegylated) Afstyla (antihemophilic factor [recombinant], single chain) Alphanate (antihemophilic factor/von Willebrand factor complex [human]) Eloctate (antihemophilic factor [recombinant, Fc fusion protein]) Helixate FS Advate is not indicated for the treatment of von Willebrand disease. Adynovate, Antihemophilic Factor (Recombinant), PEGylated, is a human antihemophilic factor indicated in children and adults with hemophilia A (congenital factor VIII deficiency) for: On-demand treatment and control of bleeding episodes Perioperative management Routine prophylaxis to reduce the frequency of bleeding episodes Limitation of Use Adynovate is not indicated for the treatment of von Willebrand disease. Afstyla, Antihemophilic Factor (Recombinant), Single Chain is a recombinant, antihemophilic factor indicated in adults and children with hemophilia A (congenital Factor VIII deficiency) for: On-demand treatment and control of bleeding episodes, Routine prophylaxis to reduce the frequency of bleeding episodes, Perioperative management of bleeding. Limitations of Use Afstyla is not indicated for the treatment of von Willebrand disease. Alphanate, (antihemophilic factor/von Willebrand factor complex [human]), is indicated for: Control and prevention of bleeding episodes and perioperative management in adult and pediatric patients with Factor VIII (FVIII) deficiency due to hemophilia A. Surgical and/or invasive procedures in adult and pediatric patients with von Willebrand Disease (VWD) in whom desmopressin (DDAVP) is either ineffective or contraindicated. It is not indicated for patients with severe VWD (Type 3) undergoing major surgery. 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: On-demand treatment and control of bleeding episodes, Perioperative management of bleeding, Routine prophylaxis to reduce the frequency of bleeding episodes. Limitation of Use Eloctate is not indicated for the treatment of von Willebrand disease. Helixate FS is a recombinant antihemophilic factor indicated for: Page 5 of 40

6 Brand Name (antihemophilic factor [recombinant]) Hemofil M (antihemophilic factor [human]) Humate-P (antihemophilic factor/von Willebrand factor complex [human]) Koate (antihemophilic factor [human]) Kogenate FS (antihemophilic factor [recombinant]) Kovaltry (antihemophilic factor [recombinant]) Monoclate-P (antihemophilic Approved Indication(s) On-demand treatment and control of bleeding episodes in adults and children with hemophilia A. Perioperative management of bleeding in adults and children with hemophilia A. Routine prophylaxis to reduce the frequency of bleeding episodes in children with hemophilia A and to reduce the risk of joint damage in children without pre-existing joint damage. Routine prophylaxis to reduce the frequency of bleeding episodes in adults with hemophilia A. Helixate FS is not indicated for the treatment of von Willebrand disease. Hemofil M is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes. Hemofil M is not indicated in von Willebrand's disease. Hemophilia A Humate-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia). Von Willebrand Disease (VWD) Humate-P is also indicated in adult and pediatric patients with von Willebrand disease (VWD) for: Treatment of spontaneous and trauma-induced bleeding episodes, and Prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin (DDAVP) is known or suspected to be inadequate. Controlled clinical trials to evaluate the safety and efficacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects. Koate is a human plasma-derived antihemophilic factor indicated for the control and prevention of bleeding episodes or in order to perform emergency and elective surgery in patients with hemophilia A (hereditary Factor VIII deficiency). Limitation of Use Koate is not indicated for the treatment of von Willebrand disease. Kogenate FS is a recombinant antihemophilic factor indicated for: On-demand treatment and control of bleeding episodes in adults and children with hemophilia A. Perioperative management of bleeding in adults and children with hemophilia A. Routine prophylaxis to reduce the frequency of bleeding episodes in children with hemophilia A and to reduce the risk of joint damage in children without pre-existing joint damage. Routine prophylaxis to reduce the frequency of bleeding episodes in adults with hemophilia A. Kogenate FS is not indicated for the treatment of von Willebrand disease. Kovaltry, Antihemophilic Factor (Recombinant), is a recombinant, human DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes Kovaltry is not indicated for the treatment of von Willebrand disease. Monoclate-P is indicated for treatment of classical hemophilia (Hemophilia A). Affected individuals frequently require therapy following minor accidents. Surgery, when required in Page 6 of 40

7 Brand Name factor [human]) Novoeight (antihemophilic factor [recombinant]) Nuwiq (antihemophilic factor [recombinant]) Obizur (antihemophilic factor [recombinant, porcine sequence]) Recombinate (antihemophilic factor [recombinant]) Approved Indication(s) such individuals, must be preceded by temporary corrections of the clotting abnormality. Surgical prophylaxis in severe AHF deficiency can be accomplished with an appropriatelydosed pre-surgical IV bolus of Monoclate-P followed by intermittent maintenance doses. Monoclate-P is not effective in controlling the bleeding of patients with von Willebrand's disease. Novoeight, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency or classic hemophilia) for: Control and prevention of bleeding episodes Perioperative management Routine prophylaxis to prevent or reduce the frequency of bleeding episodes Novoeight is not indicated for the treatment of von Willebrand disease. Nuwiq is a recombinant antihemophilic factor [blood coagulation factor VIII (Factor VIII)] indicated in adults and children with Hemophilia A for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes Nuwiq is not indicated for the treatment of von Willebrand Disease. Obizur, Antihemophilic Factor (Recombinant), Porcine Sequence, is a recombinant DNA derived, antihemophilic factor indicated for the treatment of bleeding episodes in adults with acquired hemophilia A. Limitations of Use: Safety and efficacy of Obizur has not been established in patients with baseline antiporcine factor VIII inhibitor titer greater than 20 BU. Obizur is not indicated for the treatment of congenital hemophilia A or von Willebrand disease. The use of Recombinate [Antihemophilic Factor (Recombinant)] is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes. Recombinate is also indicated in the perioperative management of patients with hemophilia A (classical hemophilia). Recombinate can be of therapeutic value in patients with acquired Factor VIII inhibitors not exceeding 10 Bethesda Units per ml. In clinical studies with Recombinate, patients with inhibitors who were entered into the previously treated patient trial and those previously untreated children who have developed inhibitor activity on study, showed clinical hemostatic response when the titer of inhibitor was less than 10 Bethesda Units per ml. However, in such uses, the dosage of Recombinate should be controlled by frequent laboratory determinations of circulating Factor VIII levels as well as the clinical status of the patient. Xyntha, (antihemophilic factor [recombinant]) Recombinate is not indicated in von Willebrand s disease. Xyntha, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for: Control and prevention of bleeding episodes Perioperative management Xyntha does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand's disease. Hemophilia B Hemophilia B or Christmas disease is a deficiency of factor IX. Factor IX is activated by factor VIIa or factor XIa. Activated factor IX, along with factor VIII, will activate factor X. As with hemophilia A, hemophilia B is classified Page 7 of 40

8 as mild, moderate, or severe depending on the percentage of normal plasma factor level obtained rather than the severity of bleeding. Per the National Hemophilia Foundation (NHF), hemophilia occurs in 1 in 5,000 live births in the United States and hemophilia A is 4 times more common than hemophilia B (NHF, 2016). Factor IX (human) is a highly purified concentrate of factor IX and contains only non-therapeutic concentrations of factors II, VII and X. Therefore, factor IX (human) should not be used for replacement treatment of factor II, VII, or X deficiencies or for the treatment or reversal of coumarin anticoagulant-induced hemorrhage or hemorrhagic states caused by hepatitis-induced lack of production of liver dependent coagulation factors. Recombinant factor IX is produced using genetically engineered Chinese hamster ovary cell lines. FDA Approved Products for Hemophilia B Brand Name AlphaNine SD (factor IX [human]) Alprolix (factor IX [recombinant, Fc fusion protein]) Approved Indication(s) AlphaNine SD is indicated for the prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B. AlphaNine SD contains low, non-therapeutic levels of Factors II, VII, and X, and, therefore, is not indicated for the treatment of Factor II, VII or X deficiencies. This product is also not indicated for the reversal of coumarin anticoagulant-induced hemorrhage, nor in the treatment of hemophilia A patients with inhibitors to Factor VIII. Alprolix, Coagulation Factor IX (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, coagulation Factor IX concentrate indicated in adults and children with hemophilia B (congenital Factor IX deficiency) for: On demand treatment and control of bleeding episodes Perioperative management of bleeding, Routine prophylaxis to reduce the frequency of bleeding episodes. Bebulin (factor IX complex [human]) BeneFIX (factor IX [recombinant]) Idelvion (Coagulation Factor IX [recombinant], Albumin Fusion Protein) Ixinity (factor IX Limitation of Use: Alprolix is not indicated for induction of immune tolerance in patients with hemophilia B. Bebulin is indicated for the prevention and control of bleeding episodes in adult patients with hemophilia B (congenital Factor IX deficiency or Christmas disease). Bebulin is not indicated for use in the treatment of Factor VII deficiency. No clinical studies have been conducted to show benefit from this product for treating deficiencies other than Factor IX deficiency. BeneFIX, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease) for: control and prevention of bleeding episodes peri-operative management Limitations of Use: BeneFIX is NOT indicated for: Treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X) Treatment of hemophilia A patients with inhibitors to factor VIII Reversal of coumarin-induced anticoagulation Treatment of bleeding due to low levels of liver-dependent coagulation factors Idelvion, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rix-fp), a recombinant DNA-derived coagulation Factor IX concentrate, is indicated in children and adults with Hemophilia B (congenital Factor IX deficiency) for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Routine prophylaxis to reduce the frequency of bleeding episodes Limitations of Use: Idelvion is not indicated for immune tolerance induction in patients with Hemophilia B. Ixinity, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adults and children 12 years of age with hemophilia B for: Page 8 of 40

9 Brand Name Approved Indication(s) [recombinant]) Control and prevention of bleeding episodes Perioperative management Mononine (factor IX [human]) Ixinity is not indicated for induction of immune tolerance in patients with hemophilia B. Mononine is indicated for the prevention and control of bleeding in Factor IX deficiency, also known as Hemophilia B or Christmas disease. Limitations of Use: Mononine is not indicated in the treatment or prophylaxis of Hemophilia A patients with inhibitors to Factor VIII. Mononine contains non-detectable levels of Factors II, VII and X (< IU per Factor IX unit using standard coagulation assays) and is, therefore, not indicated for replacement therapy of these clotting factors. Profilnine (factor IX complex [human]) Rebinyn (factor IX, recombinant, glycopegylated) Rixubis (factor IX [recombinant]) Mononine is also not indicated in the treatment or reversal of coumarin-induced anticoagulation or in a hemorrhagic state caused by hepatitis-induced lack of production of liver dependent coagulation factors. Profilnine, Factor IX Complex, is indicated for the prevention and control of bleeding in patients with factor IX deficiency (hemophilia B). Profilnine contains non-therapeutic levels of factor VII, and is not indicated for use in the treatment of factor VII deficiency. Rebinyn, Coagulation Factor IX (Recombinant), GlycoPEGylated, is a recombinant DNAderived coagulation Factor IX concentrate indicated for use in adults and children with hemophilia B for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding 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. Rixubis (Coagulation Factor IX [Recombinant]) is an antihemophilic factor indicated in adults and children with hemophilia B for: Control and prevention of bleeding episodes, perioperative management, and routine prophylaxis. Rixubis is not indicated for induction of immune tolerance in patients with hemophilia B. Guidelines for Management of Hemophilia A and B In January 2013 the World Federation of Hemophilia (WFH) published guidelines addressing the management of hemophilia. While the WFH does recommend use of clotting factor concentrates (viral-inactivated plasmaderived or recombinant) over fresh frozen plasma or cryoprecipitate, it does not place a preference on recombinant over plasma-derived. For hemophilia B, there is a recommendation to use factor IX-only containing products over prothrombin complex concentrates that include other clotting factors, such as factors II, VII, and X, in addition to factor IX. For hemophilia A, WFH notes that administration of desmopressin (DDAVP) can raise factor VIII levels to control bleeding in patients with mild, and possibly, moderate hemophilia A (Srivastava, 2013). Similar to the WFH guidelines, the Medical and Scientific Advisory Council (MASAC) for the National Hemophilia Foundation (NHF) advise against use of cryoprecipitate for hemophilia A. However the MASAC-NHF does place a preference on use of recombinant products for hemophilia A and B over the plasma-derived products due to the possibility of transmission of human viruses with the plasma-derived products (NHF, 2017). Hemophilia A or B with Inhibitors Page 9 of 40

10 Approximately 15-20% of people with hemophilia will develop inhibitors (antibodies) to the product that they use for prevention and treatment of bleeding (CDC, 2016). Two products are FDA approved for hemophilia A and B patients with inhibitors. FDA Approved Products for Hemophilia A and B with Inhibitors Brand Name Approved Indication(s) FEIBA FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B patients with inhibitors for: Control and prevention of bleeding episodes Perioperative management Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Hemlibra (activating antibody antihemophilic factor) NovoSeven RT (coagulation factor VIIa [recombinant]) FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX. Hemlibra is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. NovoSeven RT (Coagulation Factor VIIa [Recombinant]) is a coagulation factor indicated for: Treatment of bleeding episodes and peri-operative management in adults and children with hemophilia A or B with inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmann s thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets Treatment of bleeding episodes and peri-operative management in adults with acquired hemophilia FEIBA, Anti-Inhibitor Coagulant Complex is a freeze-dried sterile human plasma fraction with Factor VIII inhibitor bypassing activity. FEIBA contains Factors II, IX, and X, mainly non-activated, and Factor VII mainly in the activated form. The product contains approximately equal unitages of Factor VIII inhibitor bypassing activity and Prothrombin Complex Factors. The use of FEIBA Immuno (AICC) has been described in non-hemophiliacs with acquired inhibitors to Factors VIII, XI, and XII and is listed as a use in the American Hospital Formulary Service (AHFS) (McEvoy, 2015). One case has been reported where FEIBA Immuno (AICC) was effective in a patient with von Willebrand s disease with an inhibitor. Clinical experience suggests that patients with a Factor VIII inhibitor titer of less than 5 B.U. may be successfully treated with Antihemophilic Factor. Patients with titers ranging between 5 and 10 B.U. may either be treated with Antihemophilic Factor or FEIBA (AICC). Cases with Factor VIII inhibitor titers greater than 10 B.U. have generally been refractory to treatment with Antihemophilic Factor. Hemlibra is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure binding factor IXa and factor X. It bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis. Recombinant factor VIIa is another therapeutic option that can be used for the prevention and control of bleeding in hemophilia patients with inhibitors. The treatment of choice depends on several factors including the severity and location of the bleed, level and type of inhibitors, and whether the patient has a history of an anamnestic increase in inhibitor levels following use of preparations containing Factor VIII or Factor IX. Guidelines for Management of Hemophilia A and B with Inhibitors The World Hemophilia Federation (WHF) 2013 Guidelines for the Management of Hemophilia state that product choice for patients with inhibitors is based on many factors (e.g., titer and type of inhibitor, previous response, site and nature of the bleed). The WHF makes the following statements regarding the management of bleeding in patients with inhibitors: Page 10 of 40

11 Patients with a low-responding inhibitor may be treated with a specific factor replacement at a much higher dose, if possible, to neutralize the inhibitor with excess factor activity and stop bleeding. Patients with a history of a high responding inhibitor but with low titers may be treated similarly in an emergency until an anamnestic response occurs, usually in 3-5 days, precluding further treatment with concentrates that only contain the missing factor. The efficacy of two doses of recombinant factor VIIa and one dose of activated prothrombin complex for management of joint bleeding has shown to be essentially equivalent. Notably, however, some patients respond better to one agent than the other, highlighting the need to individualize therapy. (Srivastava, 2013) In addition the WHF provides recommendations regarding immune tolerance induction (ITI) noting that eradication of inhibitors is possible using ITI in individuals with severe hemophilia A. WHF also states that the optimal regimen for ITI is not defined and that experience in those with hemophilia B inhibitors is limited (Srivastava, 2013). The Medical and Scientific Advisory Council of the National Hemophilia Foundation (MASAC-NHF) also note that the choice product is dependent on several factors and that the available licensed products are not interchangeable (NHF, 2015). von Willebrand Disease Von Willebrand factor (VWF) promotes platelet aggregation and platelet adhesion on damaged vascular endothelium and serves as a stabilizing carrier protein for the pro-coagulant protein, Factor VIII. Von Willebrand disease, a deficiency of VWF or having abnormal VWF, is a genetic disorder that affects up to 1% of the population (NHF, 2016). Treatment options depend on the severity of disease. Von Willebrand disease is generally classified as one of 3 types: Type 1 is the most common and mildest form. Type 2 is when VWF is abnormal and is further subdivided into four subtypes: 2A, 2B, 2M, or 2N. Type 3 is a complete absence of VWF and is the most severe. FDA Approved Products for von Willebrand Disease Brand Name Approved Indication(s) Alphanate Alphanate, (antihemophilic factor/von Willebrand factor complex [human]), is (antihemophilic indicated for: factor/von Willebrand Control and prevention of bleeding episodes and perioperative management in factor complex [human]) adult and pediatric patients with Factor VIII (FVIII) deficiency due to hemophilia A. Surgical and/or invasive procedures in adult and pediatric patients with von Willebrand Disease (VWD) in whom desmopressin (DDAVP) is either ineffective or contraindicated. It is not indicated for patients with severe VWD (Type 3) Humate-P (antihemophilic factor/von Willebrand factor complex [human]) undergoing major surgery. Hemophilia A Humate-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia). Vonvendi (von Willebrand factor Von Willebrand Disease (VWD) Humate-P is also indicated in adult and pediatric patients with von Willebrand disease (VWD) for: 1) Treatment of spontaneous and trauma-induced bleeding episodes, and 2) Prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin (DDAVP) is known or suspected to be inadequate. Controlled clinical trials to evaluate the safety and efficacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects. Vonvendi [von Willebrand factor (Recombinant)] is a recombinant von Willebrand factor indicated for on-demand treatment and control of bleeding episodes in adults Page 11 of 40

12 Brand Name [recombinant]) Wilate (von Willebrand factor/coagulation factor VIII complex [human]) Approved Indication(s) (age 18 and older) diagnosed with von Willebrand disease Wilate is indicated in children and adults with von Willebrand disease for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding Limitations of Use: WILATE is not indicated for the treatment of hemophilia A. Guidelines for Management of von Willebrand Disease In 2012 the American Society of Hematology (ASH) published a summary guide to the National Heart, Lung, and Blood Institute 2007 recommendations for managing von Willebrand disease. Desmopressin (DDAVP) and von Willebrand factor replacement products (Humate-P, Wilate, Koate, and Alphanate) are listed as therapies to elevate VWF. Some of the key management recommendations from the guide regarding treatment of minor and major bleeding and prophylaxis for minor and major surgery include: Minor bleeding should be treated with intravenous or nasal DDAVP, if supported by results of a DDAVP trial. If response to DDAVP is inadequate, VWF concentrate should be used, with dosing primarily based on VWF:RCo units and secondarily on FVIII units. For minor surgery, prophylaxis should achieve VWF:RCo and FVIII activity levels >/= 30 IU/dL, and preferably > 50 IU/dL, for 1-5 days. For severe bleeding (e.g. intracranial, retroperitoneal) or prophylaxis of major surgery, initial target VWF:RCo and Factor VIII activity levels should be > 100 IU/dL, and levels > 50 IU/dL should be maintained for at least 7-10 days (ASH, 2012). The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) includes recommendations for management of VWD. Desmopressin (DDAVP) is recommended for the majority of type 1 patients and for clinically responsive type 2A patients. VWF-containing Factor VIII concentrates are recommended for type 1 and 2A patients who become transiently unresponsive to DDAVP and in surgical situations and for type 2B and 3 VWD that do not respond to DDAVP. While not FDA-approved for VWD, Koateis listed as possibly effective for some patients (NHF, 2015). Factor VII Deficiency Recombinant coagulation Factor VIIa (NovoSeven RT) is a vitamin K-dependent glycoprotein that is structurally similar to human plasma-derived Factor VIIa. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. When complexed with tissue factor, it can activate coagulation Factor X to Factor Xa, and Factor IX to Factor IXa. Activated Factor X (Factor Xa), complexed with other factors converts prothrombin to thrombin and fibrinogen to fibrin to form a hemostatic plug, inducing local hemostasis. The incidence of factor VII deficiency is estimated as 1 per 300, ,000 (NHF, 2016). FDA Approved Product for Factor VII Deficiency Brand Name Approved Indication(s) NovoSeven RT NovoSeven RT (Coagulation Factor VIIa [Recombinant]) is a coagulation factor (coagulation factor VIIa indicated for: [recombinant]) Treatment of bleeding episodes and peri-operative management in adults and children with hemophilia A or B with inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmann s thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets Treatment of bleeding episodes and peri-operative management in adults with acquired hemophilia Factor XIII Deficiency Factor XIII is a plasma glycoprotein responsible for normal clot formation. Activated Factor XIII catalyzes fibrin cross-linking, the final step in the coagulation cascade. At steady state, Factor XIII concentrate has a half-life of approximately 6 days. Congenital factor XIII deficiency is very rare with an incidence of one person every 5 million births (NHF, 2016). Page 12 of 40

13 FDA Approved Product for Factor XIII Deficiency Brand Name Corifact (factor XIII concentrate [human]) FXIII deficiency. Tretten (coagulation factor XIII A-subunit [recombinant]) Approved Indication(s) Corifact is a Factor XIII Concentrate indicated for routine prophylactic treatment and perioperative management of surgical bleeding in adult and pediatric patients with congenital Tretten, Coagulation Factor XIII A-Subunit (Recombinant), is indicated for routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency. Tretten is not for use in patients with congenital factor XIII B-subunit deficiency Factor X Deficiency Factor X needed for effective hemostasis. Factor X is an inactive zymogen, which can be activated by Factor IXa (via the intrinsic pathway) or by Factor VIIa (via the extrinsic pathway). Factor X is converted from its inactive form to the active form (Factor Xa) by the cleavage of a 52-residue peptide from the heavy chain. Factor Xa associates with Factor Va on a phospholipid surface to form the prothrombinase complex, which activates prothrombin to thrombin in the presence of calcium ions. Thrombin then acts upon soluble fibrinogen and Factor XIII to generate a cross-linked fibrin clot. The National Hemophilia Foundation estimates the incidence at 1 in 500,000 to 1 in a million (NHF, 2016). FDA Approved Product for Factor X Deficiency Brand Name Approved Indication(s) Coagadex Coagadex, Coagulation Factor X (Human), is a plasma-derived human blood coagulation (coagulation factor X Factor indicated in adults and children (aged 12 years and above) with hereditary Factor [human]) X deficiency for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding in patients with mild hereditary Factor X deficiency. Limitation of Use Perioperative management of bleeding in major surgery in patients with moderate and severe hereditary Factor X deficiency has not been studied. Fibrinogen Deficiency Fibrinogen deficiency, or factor I deficiency, affects men and women and is further classified as either a quantitative or qualitative disorder. Afibrinogenemia (no production of fibrinogen) and hypofibrinogenemia (insufficient production of normal structure fibrinogen to allow for hemostasis) are quantitative disorders. Dysfibrinogenemia is a qualitative disorder, meaning there is adequate production of fibrinogen that does not function or clot properly (NHF, 2016). FDA Approved Products for Fibrinogen Deficiency Brand Name Approved Indication(s) Fibryga Fibryga is a human fibrinogen concentrate indicated for the treatment of acute bleeding (fibrinogen episodes in adults and adolescents with congenital fibrinogen deficiency, including concentrate [human]) afibrinogenemia and hypofibrinogenemia. RiaSTAP (fibrinogen concentrate [human]) Fibryga is not indicated for dysfibrinogenemia. RiaSTAP, Fibrinogen Concentrate (Human) is a human blood coagulation factor indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. Antithrombin Deficiency Antithrombin (AT) is a natural anticoagulant that inhibits thrombin, factor Xa, and other enzymes. AT deficiency can be either inherited or acquired. Congenital AT deficiency is an autosomal dominant trait with an incidence of 1:2,000 to 1:5,000. Type 1 AT deficiency is a quantitative reduction in AT and Type II is a qualitative impairment. Normal plasma AT activity is % and 40-50% activity is considered a clinically important deficiency (Pal, 2010). Page 13 of 40

14 Exogenous AT-III (human) is derived from pooled human plasma and must be administered intravenously. Antithrombin III clotting factor complexes are rapidly removed from the circulation by binding to a specific receptor present on hepatocytes. The elimination half-life of AT-III (human) is approximately two to three days. However, the half-life may be decreased following surgery, hemorrhage or acute thrombosis, and during concurrent use of heparin. Recombinant antithrombin is produced through genetically engineered goat milk. Recombinant antithrombin has a shorter half-life and is cleared more rapidly compared to human plasmaderived antithrombin. FDA Approved Products for Antithrombin Deficiency Brand Name Approved Indication(s) ATryn Prevention of peri-operative and peri-partum thromboembolic events in hereditary (antithrombin antithrombin deficient patients. Not indicated for the treatment of thromboembolic [recombinant]) events in hereditary antithrombin deficient patients. Thrombate III (antithrombin III [human]) It is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients. Thrombate III is a human antithrombin (AT) indicated in patients with hereditary antithrombin III deficiency for: Treatment and prevention of thromboembolism Prevention of peri-operative and peri-partum thromboembolism FDA Recommended Dosing (products listed by trade name alphabetically) Advate (antihemophilic factor [recombinant]) For intravenous injection after reconstitution only. Each vial of Advate contains the labeled amount of recombinant Factor VIII in International Units (IU). Control and prevention of bleeding episodes and perioperative management: o Dose (IU) = body weight (kg) desired factor VIII rise (IU/dL or % of normal) 0.5 (IU/kg per IU/dL). o Determine treatment frequency based on type of bleeding episode. Routine Prophylaxis o 20 to 40 IU per kg every other day (3 to 4 times weekly). o Alternatively, use every third day dosing regimen targeted to maintain FVIII trough levels 1%. Adynovate (antihemophilic factor [recombinant]) For intravenous use after reconstitution only. One unit per kilogram body weight will raise the factor VIII level by 2% international units per deciliter (IU per dl). Each vial of ADYNOVATE is labeled with the actual amount of recombinant factor VIII present in IU. On-demand treatment and control of bleeding episodes and perioperative management: o Estimated Increment of factor VIII (IU/dL or % of normal) = [Total Dose (IU)/body weight (kg)] o x 2 (IU/dL per IU/kg) Dose (IU) = Body Weight (kg) x Desired factor VIII Rise (IU/dL or % of Normal) x 0.5 (IU/kg per IU/dL) Routine prophylaxis: Administer IU per kg body weight 2 times a week (Starting dose of 55 IU per kg body weight 2 times a week patients <12 years of age with a maximum of 70 IU per kg). Inject intravenously over a period of less than or equal to 5 minutes (maximum infusion rate of 10 ml per min). Afstyla (antihemophilic factor [recombinant], single chain) For intravenous use after reconstitution only. Page 14 of 40

15 Each vial of Afstyla is labeled with the amount of recombinant Factor VIII in international units (IU or unit). One unit per kilogram body weight will raise the Factor VIII level by 2 IU/dL. Plasma Factor VIII levels can be monitored using either a chromogenic assay or a one-stage clotting assay routinely used in US clinical laboratories. If the one-stage clotting assay is used, multiply the result by a conversion factor of 2 to determine the patient s Factor VIII activity level. Calculating Required Dose: Dose (IU) = Body Weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) Routine Prophylaxis: Adults and adolescents ( 12 years): The recommended starting regimen is 20 to 50 IU per kg of Afstyla administered 2 to 3 times weekly. Children (< 12 years): The recommended starting regimen is 30 to 50 IU per kg of Afstyla administered 2 to 3 times weekly. More frequent or higher doses may be required in children < 12 years of age to account for the higher clearance in this age group. The regimen may be adjusted based on patient response. Perioperative Management: Ensure the appropriate Factor VIII activity level is achieved and maintained. Alphanate (human antihemophilic factor/von Willebrand factor complex) For Intravenous injection after reconstitution only. Alphanate contains the labeled amount of Factor VIII expressed in International Units (IU) FVIII/vial and von Willebrand Factor:Ristocetin Cofactor activity in IU VWF:RCo/vial. Dose: Treatment and Prevention of Bleeding Episodes and Excess Bleeding During and After Surgery in Patients with Hemophilia A o Dose (units) = body weight (kg) x desired FVIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL). o Dosing frequency determined by the type of bleeding episode and the recommendation of the treating physician. Treatment and Prevention of Excess Bleeding During and After Surgery or Other Invasive Procedures in Patients with von Willebrand Disease o Adults: Pre-operative dose of 60 IU VWF:RCo/kg body weight; subsequent doses of IU VWF:RCo/kg body weight. o Pediatric: Pre-operative dose of 75 IU VWF:RCo/kg body weight; subsequent doses of IU VWF:RCo/kg body weight. AlphaNine SD (coagulation factor IX [human] For adult usage: o AlphaNine SD should be administered intravenously promptly following reconstitution. Administration of AlphaNine SD within three hours after reconstitution is recommended to avoid the potential ill effect of any inadvertent bacterial contamination occurring during reconstitution. Discard any unused contents into the appropriate safety container. o Each vial of AlphaNine SD is labeled with the total units expressed as International Units (IU) of Factor IX, which is referenced to the WHO International Standard. One unit approximates the activity in one ml of pooled normal human plasma. o The amount of AlphaNine SD required to establish hemostasis will vary with each patient and depend upon the circumstances. The following formula may be used as a guide in determining the number of units to be administered. Body weight (in kg) x Desired increase in Plasma Factor IX (Percent) x 1.0 IU/kg = Number of Factor IX IU required Example: 70 kg x 40 (% increase) x 1.0 IU/kg = 2,800 IU AlphaNine SD o In clinical practice there is variability between patients and their clinical response. Therefore, the Factor IX level of each patient should be monitored frequently during replacement therapy. For pediatric usage: See PRECAUTIONS (Clinical trials for safety and effectiveness in pediatric patients 16 years of age and younger have not been conducted. Across a well-controlled half-life and recovery Page 15 of 40