Factor VIII (Human, Recombinant) Form

The following are factor VIII (FVIII) products requiring prior authorization: human – Hemofil M®, Koate-DVI®; recombinant – Advate®, Adynovate®, Afstyla®, Altuviiio™ , Eloctate®, Esperoct®, Helixate FS®, Jivi®, Kogenate FS®, Kovaltry®, Novoeight®, Nuwiq®, Obizur®, Recombinate®, Xyntha®, and Xyntha® Solofuse®. FDA Approved Indication(s) FVIII products are indicated for patients with hemophilia A for the following uses: • Control and prevention of bleeding episodes: o Children and adults: Advate, Adynovate, Afstyla, Altuviiio, Eloctate, Esperoct, Helixate FS, Hemofil M, Jivi (in previously treated patients ≥ 12 years of age only), Koate-DVI, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha • Perioperative management: o Children and adults: Advate, Adynovate, Afstyla, Altuviiio, Eloctate, Esperoct, Helixate FS, Hemofil M, Jivi (in previously treated patients ≥ 12 years of age only), Koate-DVI, Kogenate FS, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes: o Adults only: Kogenate FS o Children and adults: Advate, Adynovate, Afstyla, Altuviiio, Eloctate, Esperoct, Helixate FS, Jivi (in previously treated patients ≥ 12 years of age only), Kovaltry, Novoeight, Nuwiq, Xyntha • Routine 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: o Children: Helixate FS, Kogenate FS • On-demand treatment and control of bleeding episodes in acquired hemophilia A: o Adults: Obizur Limitation(s) of use: • FVIII products are not indicated for treatment of von Willebrand disease. • Safety and efficacy of Obizur have not been established in patients with a baseline anti-porcine FVIII inhibitor titer of > 20 Bethesda units (BU). • Jivi is not indicated for use in children < 12 years of age due to a greater risk for hypersensitivity reactions. • Jivi is not indicated for use in previously untreated patients. Page 1 of 14

CLINICAL POLICY Factor VIII (Human, Recombinant) Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that FVIII products are medically necessary when the following criteria are met: I. Initial Approval Criteria A. Hemophilia A (must meet all):

1. Diagnosis of one of the following (a or b): a. Congenital hemophilia A (FVIII deficiency) (all products except Obizur); b. Acquired hemophilia A (Obizur only);
2. Prescribed by or in consultation with a hematologist;
   3. Request is for one of the following uses (a, b, or c): a. Control and prevention of bleeding episodes; b. Perioperative management (all products except Obizur); c. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes;
3. For routine prophylaxis requests: Request is for Advate, Adynovate, Afstyla, Altuviiio, Eloctate, Esperoct, Helixate FS, Jivi, Kogenate FS, Kovaltry, Novoeight, Nuwiq, or Xyntha, and member meets one of the following (a, b, or c): a. Member has previously used FVIII for routine prophylaxis; b. Member has severe hemophilia (defined as FVIII level of < 1%); c. Member has experienced at least one serious spontaneous bleed (see Appendix D);
4. For all products except Obizur: If FVIII coagulant activity levels are > 5%, failure of desmopressin acetate, unless contraindicated, clinically significant adverse effects are experienced, or an appropriate formulation of desmopressin acetate is unavailable;
5. For Jivi: Member meets both of the following (a and b): a. Age ≥ 12 years; b. Has previously been treated for hemophilia A;
   7. Documentation of member’s body weight (in kg);
   8. Dose does not exceed the FDA-approved maximum recommended dose for the relevant indication. Approval duration: 3 months for surgical/acute bleeding or 6 months for prophylaxis (12 months for prophylaxis for HIM Texas)
      B. Other diagnoses/indications (must meet 1 or 2):

6. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: Page 2 of 14

   CLINICAL POLICY Factor VIII (Human, Recombinant) CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

7. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Hemophilia A (must meet all):
8. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
   2. Member is responding positively to therapy;
   3. Documentation of member’s body weight (in kg);
   4. If request is for a dose increase, new dose does not exceed the FDA-approved maximum recommended dose for the relevant indication. Approval duration: 3 months for surgical/acute bleeding or 6 months for prophylaxis (12 months for prophylaxis for HIM Texas) B. Other diagnoses/indications (must meet 1 or 2):
9. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

10. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized: A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policy – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents; B. Von Willebrand disease. Page 3 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key
    BU: Bethesda units FDA: Food and Drug Administration FVIII: factor VIII Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent and may require prior authorization. Drug Name Dosing Regimen desmopressin acetate (Stimate nasal spray; generic injection solution) When FVIII coagulant activity levels are > 5% Injection: 0.3 mcg/kg IV every 48 hours Nasal spray: < 50 kg: 1 spray intranasally in one nostril only; may repeat based on laboratory response and clinical condition ≥ 50 kg: 1 spray intranasally in each nostril; may repeat based on laboratory response and clinical condition Dose Limit/ Maximum Dose Injection: 0.3 mcg/kg IV every 48 hours Nasal spray: 1 spray intranasally in each nostril Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
    o Life-threatening hypersensitivity reactions, including anaphylaxis, to the product and its constituentsIncluding bovine, mouse, or hamster protein for Advate, Adynovate, Afstyla, Altuviiio, Esperoct, Helixate FS, Hemofil M, Jivi, Kogenate FS, Kovaltry, Novoeight, Obizur, Recombinate, and Xyntha o Obizur: congenital hemophilia A with inhibitors • Boxed warning(s): none reported Appendix D: General Information • Serious bleeding episodes include bleeds in the following sites: intracranial; neck/throat; gastrointestinal; joints (hemarthrosis); muscles (especially deep compartments such as the iliopsoas, calf, forearm); or mucous membranes of the mouth, nose and genitourinary tract. • Spontaneous bleed is defined as a bleeding episode that occurs without apparent cause and is not the result of trauma. Page 4 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) V. Dosage and Administration Indication Control and prevention of bleeding episodes Drug Name Antihemophilic factor – recombinant (Advate, Adynovate, Afstyla, Kovaltry, Novoeight, Nuwiq, Recombinate, ReFacto, Xyntha) Antihemophilic factor – recombinant,
    Fc-VWF-XTEN (Altuviiio) Control and prevention of bleeding episodes Antihemophilic factor – recombinant, Fc fusion protein (Eloctate) Control and prevention of bleeding episodes Maximum Dose 50 IU/kg every 6 hours until the bleeding episode is resolved 50 IU/kg/dose 50 IU/kg every 8 hours until the bleeding episode is resolved Dosing Regimen Minor episodes: 10-20 IU/kg IV every 12-24 hours (Advate: 8-24 hours for age < 6 years) Moderate episodes: 15-30 IU/kg IV every 12-24 hours (Advate: 8-24 hours for age < 6 years) Major episodes: 30-50 IU/kg IV every 8- 24 hours (Advate: 6- 12 hours for age < 6 years) Minor and moderate episodes: 50 IU/kg IV as a single dose; for episdoes occurring within 2-3 days after a prophylactic dose, a lower dose of 30 IU/kg may be used; additional doses of 30 or 50 IU/kg every 2-3 days may be considered Major episodes: 50 IU/kg IV as a single dose; additional doses of 30 or 50 IU/kg every 2-3 days may be considered Minor and moderate episodes: 20-30 IU/kg every 24-48 hours (12-24 hours for age < 6 years) Major episodes: 40- 50 IU/kg every 12- 24 hours (8 to 24 hours for age < 6 years) Page 5 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) Drug Name Antihemophilic factor – recombinant (Helixate FS, Kogenate FS) Indication Control and prevention of bleeding episodes Dosing Regimen Minor episodes: 10- 20 IU/kg IV; repeat dose if there is evidence of further bleeding Maximum Dose 50 IU/kg single dose or 30 IU/kg/repeated dose Antihemophilic factor – recombinant, glycopegylated (Esperoct) Control and prevention of bleeding episodes Antihemophilic factor – recombinant (Advate, Adynovate) Perioperative management Moderate episodes: 15-30 IU/kg IV every 12-24 hours Major episodes: initial 40-50 IU/kg IV, followed by 20-25 IU/kg every 8-24 hours (Kogenate FS: every 8- 12 hours) Minor to moderate episodes: 40-65 IU/kg IV; one dose should be sufficient for minor episodes; additional dose may be administered after 24 hours for moderate episodes. Major episodes: 50-65 IU/kg IV; additional doses may be administered approximately every 24 hours. Minor surgery: 30-50 IU/kg IV as a single dose within 1 hour of the operation and every 12- 24 hours (Adynovate: 24 hours) thereafter as needed to control bleeding Major surgery: 40-60 IU/kg IV as a single dose preoperatively to achieve 100% activity and every 8- 24 hours thereafter to keep FVIII At least 12 years old: 40 IU/kg < 12 years old: 65 IU/kg
    Minor surgery: 50 IU/kg/dose Major surgery: 60 IU/kg/dose Page 6 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) Drug Name Indication Antihemophilic factor – recombinant,
    Fc-VWF-XTEN (Altuviiio) Perioperative management Antihemophilic factor – recombinant, Fc fusion protein (Eloctate) Perioperative management Antihemophilic factor – recombinant, glycopegylated (Esperoct) Perioperative management Maximum Dose 50 IU/kg/dose Minor surgery: 40 IU/kg/dose Major surgery: 60 IU/kg/dose At least 12 years old: 50 IU/kg < 12 years old: 65 IU/kg Dosing Regimen activity in desired range (Advate: every 6-24 hours for age < 6 years; Adynovate: every 6-24 hours if age < 12 years) Minor surgery: 50 IU/kg IV as a single dose; additional dose of 30 or 50 IU/kg after 2-3 days may be considered Major surgery: 50 IU/kg IV as a single dose; additional doses of 30 or 50 IU/kg every 2-3 days may be administered as clinically needed Minor surgery: 25- 40 IU/kg every 24 hours (12-24 hours age < 6 years) Major surgery: pre- operative dose of 40- 60 IU/kg followed by a repeat dose of 40-50 IU/kg after 8-24 hours (6-24 hours for age < 6 years) and then every 24 hours to maintain FVIII activity within the target range Minor and major surgery: 50-65 IU/kg IV; additional doses can be administered after 24 hours if necessary for minor surgeries; additional doses can be administered approximately every 24 hours for the first week and then approximately every 48 hours until wound healing has Page 7 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) Drug Name Indication Antihemophilic factor – recombinant (Helixate FS, Kogenate FS) Perioperative management Perioperative management Antihemophilic factor – recombinant (Afstyla, Kovaltry, Novoeight, Nuwiq, Recombinate, Xyntha) Antihemophilic factor – recombinant (Xyntha) Routine prophylaxis Antihemophilic factor – recombinant (Advate) Routine prophylaxis Antihemophilic factor – recombinant (Adynovate) Routine prophylaxis Dosing Regimen occurred for major surgeries
    Minor surgery: 15- 30 IU/kg IV every 12-24 hours Major surgery: pre- operative dose of 50 IU/kg IV followed by a repeat dose every 6- 12 hours to maintain FVIII activity within the target range Minor surgery: 15-30 IU/kg IV every 24 hours (Xyntha: every 12- 24 hours) (Recombinate: 30- 40 IU/kg as a single infusion) Major surgery: 40- 50 IU/kg IV every 8-24 hours (Xyntha: 30-50 IU/kg) 30 IU/kg IV 3 times weekly < 12 years of age: 25 IU/kg every other day
    20-40 IU/kg IV every other day (3 to 4 times weekly) OR Use every third day dosing regimen targeted to maintain FVIII trough levels ≥ 1% ≥ 12 years of age: 40-50 IU/kg IV 2 times per week Maximum Dose Minor surgery: 30 IU/kg/dose Major surgery: 50 IU/kg/dose Minor surgery: 30 IU/kg/dose (Recombinate: 40 IU/kg/dose) Major surgery: 50 IU/kg every 8 hours 30 IU/kg/dose 40 IU/kg every other day 70 IU/kg/dose Page 8 of 14

    Routine prophylaxis 50 IU/kg IV every 4 days 65 IU/kg/dose CLINICAL POLICY Factor VIII (Human, Recombinant) Drug Name Indication Antihemophilic factor – recombinant (Afstyla) Routine prophylaxis Routine prophylaxis Antihemophilic factor – recombinant,
    Fc-VWF-XTEN (Altuviiio) Antihemophilic factor – recombinant, Fc fusion protein (Eloctate) Antihemophilic factor – recombinant, glycopegylated (Esperoct) Antihemophilic factor – recombinant (Helixate FS, Kogenate FS) Routine prophylaxis Routine prophylaxis Antihemophilic factor – recombinant (Novoeight) Routine prophylaxis Antihemophilic factor – recombinant (Nuwiq) Routine prophylaxis Maximum Dose Dosing Regimen < 12 years of age: 55 IU/kg IV 2 times per week ≥ 12 years of age: 20-50 IU/kg IV 2-3 times per week < 12 years of age: 30- 50 IU/kg IV 2-3 times per week 50 IU/kg IV once weekly 50 IU/kg/dose 50 IU/kg/dose For children < 6 years of age: 50 IU/kg IV twice weekly At least 12 years old: 50 IU/kg IV every 4 days < 12 years old: 65 IU/kg IV twice weekly Adults: 25 IU/kg IV three times per week Children: 25 IU/kg every other day ≥ 12 years of age: 20-50 IU/kg IV 3 times per week OR 20-40 IU/kg IV every other day < 12 years of age: 25-60 IU/kg IV 3 times per week OR 25- 50 IU every other day ≥ 12 years of age: 30-40 IU/kg IV every other day < 12 years of age: 30-50 IU/kg IV At least 12 years old: 50 IU/kg < 12 years old: 65 IU/kg 25 IU/kg/dose 60 IU/kg/dose 50 IU/kg/dose Page 9 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) Drug Name Indication Antihemophilic factor – recombinant (Kovaltry) Routine prophylaxis Antihemophilic factor – recombinant, porcine sequence (Obizur) Antihemophilic factor – human (Hemofil M) Treatment of bleeding episodes in acquired hemophilia A Control and prevention of bleeding episodes Antihemophilic factor – human (Koate-DVI) Control and prevention of bleeding episodes Dosing Regimen every other day or 3 times/week

    12 years of age: 20- 40 IU/kg IV 2-3 times per week ≤ 12 years of age: 25-50 IU/kg twice or three times weekly or every other day according to individual requirements 200 IU/kg every 4- 12 hours Maximum Dose 50 IU/kg every other day 200 IU every 4 hours Minor episodes: 10- 20 IU/kg IV every 12-24 hours 100 IU/kg every 8 hours 25 IU/kg every 8 hours until the bleeding episode is resolved Moderate episodes: 15-30 IU/kg IV every 12-24 hours Major episodes: 30- 50 IU/kg IV every 8-24 hours Minor episodes: 10 IU/kg IV as a single dose; repeat only if there is evidence of further bleeding Moderate episodes: 15- 25 IU/kg IV as a single dose followed by 10-15 IU/kg every 8-12 hours if needed Major episodes: 40- 50 IU/kg IV as a single dose followed by 20-25 IU/kg IV every 8-12 hours Page 10 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) Drug Name Antihemophilic factor – human (Hemofil M) Indication Perioperative management Antihemophilic factor – human (Koate-DVI) Perioperative management Antihemophilic factor – recombinant, PEGylated-aucl (Jivi) Control and prevention of bleeding episodes Perioperative management Routine prophylaxis Dosing Regimen Minor surgery: 30- 40 IU/kg as a single infusion Major surgery: 40- 50 IU/kg every 8- 24 hours Major surgery: 50 IU/kg pre-operative dose followed by 50 IU/kg every 6-12 hours as needed Minor surgery: less intensive schedules may be adequate Minor episodes: 10- 20 IU/kg every 24- 48 hours Moderate episodes: 15-30 IU/kg every 24-48 hours Major episodes: 30- 50 IU/kg every 8-24 hours Minor surgery: 15- 30 IU/kg every 24 hours Major surgery: 40- 50 IU/kg every 12- 24 hours 30-40 IU/kg twice weekly; may be adjusted to 45-60 IU/kg every 5 days with further individual adjustment to less or more frequent dosing Maximum Dose Minor surgery: 80 IU/kg/dose Major surgery: 100 IU/kg every 8 hours Major surgery: 50 IU/kg every 6 hours 50 IU/kg every 8 hours Minor surgery: 30 IU/kg/dose Major surgery: 50 IU/kg/dose 60 IU/kg/dose; frequency varies based on bleeding episodes Page 11 of 14

    CLINICAL POLICY Factor VIII (Human, Recombinant) VI. Product Availability Drug Name Antihemophilic factor – recombinant (Advate) Antihemophilic factor – recombinant (Adynovate) Antihemophilic factor – recombinant (Afstyla) Antihemophilic factor – recombinant (Altuviiio) Antihemophilic factor – recombinant (Eloctate) Antihemophilic factor – recombinant, glycopegylated- exei (Esperoct) Antihemophilic factor – recombinant (Helixate FS, Kogenate FS, Kovaltry) Antihemophilic factor – recombinant (Novoeight) Antihemophilic factor – recombinant (Nuwiq) Antihemophilic factor – recombinant (Recombinate) Antihemophilic factor – recombinant (ReFacto, Xyntha) Antihemophilic factor – recombinant (Xyntha Solofuse) Antihemophilic factor – recombinant (Obizur) Antihemophilic factor – human (Hemofil M) Antihemophilic factor – human (Koate-DVI) Antihemophilic factor – recombinant, PEGylated- aucl (Jivi) Availability Vial: 250, 500, 1,000, 1,500, 2,000, 3,000, 4,000 IU Vial: 250, 500, 750, 1,000, 1,500, 2,000, 3,000 IU Vial: 250, 500, 1,000, 1,500, 2,000, 2,500, 3,000 IU Vial: 250, 500, 750, 1,000, 2,000, 3,000, 4,000 IU Vial: 250, 500, 750, 1,000, 1,500, 2,000, 3,000 4,000, 5,000, 6,000 IU Vial: 500, 1,000, 1,500, 2,000, 3,000 IU Vial: 250, 500, 1,000, 2,000, 3,000 IU Vial: 250, 500, 1,000, 1,500, 2,000, 3,000 IU Vial: 250, 500, 1,000, 1,500, 2,000, 2,500, 3,000, 4,000 IU Vial: 220-400, 401-800, 801-1240, 1241-1800, 1801-2400 IU Vial: 250, 500, 1,000, 2,000 IU Prefilled syringe: 250, 500, 1,000, 2,000, 3,000 IU Vial: 500 IU Vial: 250, 500, 1,000, 1,700 IU Vial: 250, 500, 1,000 IU Vial: 500, 1,000, 2,000, 3,000 IU VII.