Factor VIII/von Willebrand Factor Complex (Human – Alphanate, Humate-P, Wilate); von Willebrand Factor (Recombinant – Vonvendi) Form

The following are factor VIII (FVIII)/von Willebrand factor complexes (human) or recombinant von Willebrand factor requiring prior authorization: Alphanate®, Humate®-P, Vonvendi®, and Wilate®. FDA Approved Indication(s) FVIII/von Willebrand factor complexes are indicated for: • Hemophilia A o Alphanate: Control and prevention of bleeding episodes and perioperative management in adult and pediatric patients with FVIII deficiency due to hemophilia A o Humate-P: Treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia) o Wilate: Adolescents and adults for  On-demand treatment and control of bleeding episodes  Routine prophylaxis to reduce the frequency of bleeding episodes • Von Willebrand disease (VWD) in children and adults:
o Alphanate: Surgical and/or invasive procedures in patients in whom desmopressin (DDAVP) is either ineffective or contraindicated
o Humate-P:
 Treatment of spontaneous and trauma-induced bleeding episodes  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 DDAVP is known or suspected to be inadequate o Wilate:
 On-demand treatment and control of bleeding episodes  Perioperative management of bleeding  Routine prophylaxis to reduce the frequency of bleeding episodes in children 6 years of age and older and adults
Vonvendi is indicated in adults with VWD for:
• On-demand treatment and control of bleeding episodes • Perioperative management of bleeding • Routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe Type 3 von Willebrand disease receiving on-demand therapy Page 1 of 12

CLINICAL POLICY Factor VIII/von Willebrand Factor Complex; von Willebrand Factor Limitation(s) of use: Alphanate is not indicated for patients with severe VWD (type 3) undergoing major surgery. 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 Alphanate, Humate-P, Vonvendi, and Wilate are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Congenital Hemophilia A (must meet all):

1. Diagnosis of congenital hemophilia A (FVIII deficiency);
   2. Request is for Alphanate, Humate-P, or Wilate;
   3. Prescribed by or in consultation with a hematologist;
   4. Request is for one of the following uses (a, b, or c): a. Control or prevention of bleeding episodes; b. Perioperative management (Alphanate only); c. Routine prophylaxis to reduce the frequency of bleeding episodes (Wilate only);
   5. For routine prophylaxis requests (Wilate only), for members who have not previously used Wilate for routine prophylaxis, member meets one of the following (a or b): a. Member has severe hemophilia (defined as FVIII level of < 1%); b. Member has experienced at least one serious spontaneous bleed (see Appendix D);
2. 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;
3. Documentation of member’s current body weight (in kg);
   8. Dose does not exceed the FDA approved maximum recommended dose for the relevant indication.
      Approval duration: 3 months (12 months for prophylaxis for HIM Texas) B. Von Willebrand Disease (must meet all):
4. Diagnosis of one of the following (a or b): a. VWD type 1 or 2 (except type 2B), and member has had a failure of desmopressin acetate, unless contraindicated, clinically significant adverse effects are experienced, or an appropriate formulation of desmopressin acetate is unavailable; b. VWD type 2B or 3;

5. Prescribed by or in consultation with a hematologist;

   3. For Vonvendi only: age ≥ 18 years;
   4. Request is for one of the following uses (a, b, or c): a. Treatment of bleeding episodes (Humate-P, Vonvendi, and Wilate only); b. Perioperative management; c. Routine prophylaxis to reduce the frequency of bleeding episodes and one of the following (i or ii):
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   CLINICAL POLICY Factor VIII/von Willebrand Factor Complex; von Willebrand Factor i. Request is for Vonvendi, and member is diagnosed with severe VWD type 3 receiving on-demand therapy; ii. Request is for Wilate, and age ≥ 6 years;

   5. Documentation of member’s current body weight (in kg);
   6. Dose does not exceed the FDA approved maximum recommended dose for the relevant indication.
      Approval duration: 3 months (12 months for prophylaxis for HIM Texas) C. 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: 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. All Indications in Section I (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 current 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 (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): Page 3 of 12

   CLINICAL POLICY Factor VIII/von Willebrand Factor Complex; von Willebrand Factor 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.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key DDAVP: desmopressin acetate FDA: Food and Drug Administration FVIII: factor VIII VWD: von Willebrand disease vWF: von Willebrand factor 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 Dose Limit/ Maximum Dose Injection: 0.3 mcg/kg IV every 48 hours Nasal spray: 1 spray intranasally in each nostril desmopressin acetate (Stimate nasal spray; generic injection solution) When FVIII coagulant activity levels are > 5% and for VWD type 1 or 2 (except 2B): 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
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    CLINICAL POLICY Factor VIII/von Willebrand Factor Complex; von Willebrand Factor 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): FVIII/vWF complex: patients with known hypersensitivity reactions, including anaphylactic or severe systemic reaction, to human plasma-derived products, any ingredient in the formulation, or components of the container; Vonvendi: history of life-threatening hypersensitivity reactions to Vonvendi or its components • 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. Maximum Dose 100 IU/kg/day 75 IU/kg/day V. Dosage and Administration
    Drug Name Indication Dosing Regimen FVIII/von Willebrand factor complex (Alphanate) Hemophilia A

    • control and prevention of bleeding episodes FVIII/von Willebrand factor complex (Humate-P) Hemophilia A
    • control and prevention of bleeding episodes Minor episodes: 15 IU/kg IV every 12 hours Moderate episodes: 25 IU/kg IV every 12 hours Major episodes: 40-50 IU/kg IV initially followed by 25 IU/kg IV every 12 hours Minor episodes: 15 IU/kg IV loading dose to achieve a FVIII:C plasma level of approximately 30% of normal; one infusion may be sufficient. If needed, half of the loading dose may be given once or twice daily Moderate episodes: 25 IU/kg IV loading dose to achieve a FVIII:C plasma level of approximately 50% of normal, followed by 15 IU/kg IV every 8-12 hours for the first 1- 2 days to maintain the FVIII:C plasma level at 30% of normal. Continue the same dose once or twice daily for up to 7 days or until adequate wound healing is achieved. Page 5 of 12

    CLINICAL POLICY Factor VIII/von Willebrand Factor Complex; von Willebrand Factor Drug Name Indication Dosing Regimen FVIII/von Willebrand factor complex (Alphanate) FVIII/von Willebrand factor complex (Humate-P) Hemophilia A – perioperative management VWD – control and prevention of bleeding episodes FVIII/von Willebrand factor complex (Wilate) Hemophilia A

    • control and prevention of bleeding episodes Major episodes: 40-50 IU/kg IV initially followed by 20-25 IU/kg IV every 8 hours to maintain the FVIII:C plasma level at 80- 100% of normal for 7 days. Continue the same dose once or twice daily for another 7 days to maintain the FVIII:C level at 30-50% of normal. Pre-operative: 40-50 IU/kg IV once as a single dose Post-operative: 30-50 IU/kg IV every 12 hours Type 1 VWD, mild disease Minor or major episodes: 40-60 IU/kg IV loading dose followed by 40-50 IU/kg IV every 8-12 hours for 3 days to keep the trough level of VWF:RCo > 50%. Then 40- 50 IU/kg daily for up to 7 days. Type 1 VWD, moderate or severe disease Minor episodes: 40-50 IU/kg IV as one or two doses Major episodes: 50-75 IU/kg loading dose followed by 40-60 IU/kg every 8-12 hours for 3 days to keep the trough level of VWF:RCo > 50%. Then 40-60 IU/kg daily for up to 7 days. Type 2 or 3 VWD
      Minor episodes: 40-50 IU/kg IV as one or two doses Major episodes: 60-80 IU/kg IV loading dose followed by 40-60 IU/kg every 8-12 hours for 3 days to keep the trough level of VWF:RCo > 50%. Then 40-60 IU/kg daily for up to 7 days. Minor or moderate episodes: 30-40 IU/kg IV every 12-24 hours Major episodes: 35-50 IU/kg IV every 12-24 hours Page 6 of 12 Maximum Dose 100 IU/kg/day 240 IU/kg/day 150 IU/kg/day

    CLINICAL POLICY Factor VIII/von Willebrand Factor Complex; von Willebrand Factor Drug Name Indication Dosing Regimen FVIII/von Willebrand factor complex (Wilate) FVIII/von Willebrand factor complex (Wilate) FVIII/von Willebrand factor complex (Wilate) FVIII/von Willebrand factor complex (Wilate) von Willebrand factor (Vonvendi) Hemophilia A – routine prophylaxis VWD – control and prevention of bleeding episodes VWD – perioperative management VWD – Routine prophylaxis to reduce the frequency of bleeding episodes VWD – treatment and control of bleeding episodes Life-threatening episodes: 35-50 IU/kg IV every 8-24 hours 20-40 IU/kg IV every 2 to 3 days Maximum Dose 40 IU/kg/day Minor episodes: 20-40 IU/kg IV loading dose followed by 20-30 IU/kg every 12-24 hours
    60 IU/kg/day Major episodes: 40-60 IU/kg IV loading dose followed by 20-40 IU/kg every 12-24 hours Minor surgeries (including tooth extraction): 30-60 IU/kg IV loading dose followed by 15-30 IU/kg every 12-24 hours 60 IU/kg/day Major surgeries: 40-60 IU/kg IV loading dose followed by 20-40 IU/kg every 12-24 hours 20 – 40 IU/kg two to three times weekly Minor episodes: 40-50 IU/kg IV loading dose followed by 40-50 IU/kg every 8-24 hours
    Major episodes: 50-80 IU/kg IV loading dose followed by 40-60 IU/kg every 8-24 hours for approximately 2 to 3 days 40 IU/kg three times weekly Minor episodes: 150 IU/kg/day Major episodes: 180 IU/kg/day Page 7 of 12

    CLINICAL POLICY Factor VIII/von Willebrand Factor Complex; von Willebrand Factor Drug Name Indication Dosing Regimen von Willebrand factor (Vonvendi) VWD – perioperative management Minor surgeries: 25-30 IU/kg IV every 12- 48 hours Major surgeries: 40-60 IU/kg IV every 12-48 hours Initiation of prophylactic treatment: 40-60 IU/kg IV twice weekly von Willebrand factor (Vonvendi) VWD- Routine prophylaxis to reduce the frequency of bleeding episodes in patients with severe type 3 VWD receiving on- demand therapy VI. Product Availability
    Maximum Dose Minor surgeries: 60 IU/kg/day Major surgeries: 120 IU/kg/day 60 IU/kg twice weekly Drug Name FVIII/von Willebrand factor complex (Alphanate) FVIII/von Willebrand factor complex (Humate-P) von Willebrand factor (Vonvendi) FVIII/von Willebrand factor complex (Wilate) Availability Vials: 250, 500, 1,000, 1,500 IU and 2,000 IU FVIII Vials: 250/600, 500/1,200, 1,000/2,400 IU FVIII/VWF:RCo Vials: 450-850 IU (5 mL), 900-1,700 IU (10 mL) VWF:RCo Vials: 500/500, 1,000/1,000 IU FVIII/VWF:RCo VII.