PROMACTA, Eltrombopag Olamine Form

Eltrombopag (Alvaiz™, Promacta®) is a thrombopoietin receptor agonist. FDA Approved Indication(s) Promacta is indicated for the treatment of: • Thrombocytopenia in adult and pediatric patients 1 year and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Promacta should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. • Thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Promacta should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon- based therapy or limits the ability to maintain interferon-based therapy. In combination with standard immunosuppressive therapy for the first-line treatment of adults and pediatric patients 2 years and older with severe aplastic anemia. • Patients with severe aplastic anemia who have had an insufficient response to • immunosuppressive therapy. Alvaiz is indicated for the treatment of: • Thrombocytopenia in adult and pediatric patients 6 years and older with persistent or chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Alvaiz should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. • Thrombocytopenia in adult patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. Alvaiz should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy. • Adult patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. Limitation(s) of use: • Promacta and Alvaiz are not indicated for the treatment of patients with myelodysplastic syndromes (MDS). • Safety and efficacy of Promacta and Alvaiz have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection. Page 1 of 12

CLINICAL POLICY Eltrombopag 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 Alvaiz and Promacta are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Persistent/Chronic Immune Thrombocytopenia (must meet all):

1. Diagnosis of persistent or chronic ITP (see Appendix D);
   2. Prescribed by or in consultation with a hematologist;
   3. Age is one of the following (a or b): a. For Promacta: ≥ 1 year;
      b. For Alvaiz: ≥ 6 years;
   4. One of the following (a or b): a. Current (within 30 days) platelet count is < 30,000/µL; b. Member has an active bleed;
2. Member meets one of the following (a or b): a. Failure of a systemic corticosteroid; b. Member has intolerance or contraindication to systemic corticosteroids, and failure of an immune globulin, unless contraindicated or clinically significant adverse effects are experienced (see Appendix B); *Prior authorization may be required for immune globulins
3. Promacta and Alvaiz are not prescribed concurrently with rituximab, another thrombopoietin receptor agonist (e.g., Doptelet®, Mulpleta®, Nplate®), or spleen tyrosine kinase inhibitor (e.g., Tavalisse™);
4. Dose does not exceed 1 tablet per day and one of the following (a or b): a. For Promacta: 75 mg per day; b. For Alvaiz: 54 mg per day. Approval duration: 6 months B. Chronic Hepatitis C-Associated Thrombocytopenia (must meet all):
   
   1. Diagnosis of chronic hepatitis C-associated thrombocytopenia;
   2. Prescribed by or in consultation with a hematologist, hepatologist, gastroenterologist or infectious disease specialist;
5. Age ≥ 18 years;
   4. Promacta or Alvaiz will be used concomitantly with interferon-based therapy;
   5. The degree of thrombocytopenia has prevented the initiation of interferon-based therapy or limited the ability to maintain interferon-based therapy;
6. Current (within 30 days) platelet count is < 75,000/µL;
   7. Promacta and Alvaiz are not prescribed concurrently with another thrombopoietin receptor agonist (e.g., Doptelet, Mulpleta, Nplate) or spleen tyrosine kinase inhibitor (e.g., Tavalisse);

7. Dose does not exceed 2 tablets per day and one of the following (a or b): a. For Promacta:100 mg per day; b. For Alvaiz: 72 mg per day. Page 2 of 12

   CLINICAL POLICY Eltrombopag Approval duration: 6 months C. Severe Aplastic Anemia (must meet all):

   1. Diagnosis of severe aplastic anemia;
   2. Prescribed by or in consultation with a hematologist;
   3. Age is one of the following (a or b): a. For Promacta: ≥ 2 years;
      b. For Alvaiz: ≥ 18 years
8. Prescribed for one of the following (a or b): a. For Promacta only: As first-line therapy in combination with immunosuppressive therapy (e.g., Atgam®, cyclosporine, cyclophosphamide); b. Refractory or second-line treatment as a single agent following insufficient response to immunosuppressive therapy (e.g., Atgam, cyclosporine, cyclophosphamide); *Prior authorization may be required for Atgam and cyclosphosphamide
9. Current (within 30 days) platelet count is < 50,000/µL;
   6. Promacta and Alvaiz are not prescribed concurrently with another thrombopoietin receptor agonist (e.g., Doptelet, Mulpleta, Nplate) or spleen tyrosine kinase inhibitor (e.g., Tavalisse);
10. Dose does not exceed 2 tablets per day and one of the following (a or b): a. For Promacta: 150 mg per day; b. For Alvaiz: 108 mg per day. Approval duration: 6 months D. NCCN Compendium Indications (off-label) (must meet all):
11. Prescribed for one of one of the following (a or b): a. MDS, and request is for Promacta; b. Post-hematopoietic cell transplant with prolonged thrombocytopenia;

12. Prescribed by or in consultation with an oncologist or hematologist;

    3. For MDS: Member has lower-risk MDS (IPSS-R [Very Low, Low, Intermediate]);
    4. For MDS: One of the following (a, b, c, or d): a. Member has severe thrombocytopenia; b. Member has refractory thrombocytopenia following disease progression or no response to hypomethylating agents (e.g., azacitadine, decitabine), immunosuppressive therapy (e.g., Atgam, cyclosporine), or clinical trial; c. Member has thrombocytopenia or neutropenia and one of the following (i, ii, iii, or iv): i. Age ≤ 60 years with ≤ 5% marrow blasts; ii. Hypocellular marrows; iii. Paroxysmal nocturnal hemoglobinuria (PNH) clone positivity; iv. STAT-3 mutant cytotoxic T-cell clones; d. Member has symptomatic anemia with all the following (i, ii, and iii): i. No del(5q);
       ii. Serum erythropoietin > 500 mU/mL;
       iii. Good probability to respond to immunosuppressive therapy; Page 3 of 12

    CLINICAL POLICY Eltrombopag

13. Promacta and Alvaiz are not prescribed concurrently with another thrombopoietin receptor agonist (e.g., Doptelet, Mulpleta, Nplate);
14. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN
    Approval duration: 6 months E. Other diagnoses/indications (must meet 1 or 2):
15. 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
16. 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. Persistent/Chronic Immune Thrombocytopenia, Chronic Hepatitis C-Associated Thrombocytopenia and Severe Aplastic Anemia (must meet all):
    
    1. 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);
17. Member is responding positively to therapy (see Appendix D);
    
    3. Current (within the last 90 days) platelet count is < 400,000/µL;
    4. For chronic hepatitis C-associated thrombocytopenia, member continues to receive interferon-based therapy;
18. Promacta and Alvaiz are not prescribed concurrently with another thrombopoietin receptor agonist (e.g., Doptelet, Mulpleta, Nplate) or spleen tyrosine kinase inhibitor (e.g., Tavalisse);
19. For persistent or chronic ITP: Promacta and Alvaiz are not prescribed concurrently with rituximab;

20. If request is for a dose increase, new dose does not exceed the following:
    a. For persistent or chronic ITP: 1 tablet per day and either (i or ii):
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    CLINICAL POLICY Eltrombopag i. For Promacta: 75 mg per day; ii. For Alvaiz: 54 mg per day; b. For chronic hepatitis C-associated thrombocytopenia: 2 tablets per day and either (i or ii):
    i. For Promacta: 100 mg per day; ii. For Alvaiz: 72 mg per day; c. For severe aplastic anemia: 2 tablets per day and either (i or ii):
    i. For Promacta: 150 mg per day; ii. For Alvaiz: 108 mg per day.
    Approval duration:
    Hepatitis C-associated thrombocytopenia – 6 months;
    All other indications – 12 months
    B. NCCN Compendium Indications (off-label) (must meet all):

21. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Promacta or Alvaiz for a covered indication and has received this medication for at least 30 days;
    2. Member is responding positively to therapy;
    3. Promacta and Alvaiz are not prescribed concurrently with another thrombopoietin receptor agonist (e.g., Doptelet, Mulpleta, Nplate);
22. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN
    Approval duration: 12 months C. Other diagnoses/indications (must meet 1 or 2):
23. 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

24. 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.
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    CLINICAL POLICY Eltrombopag 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 policies – 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 ANC: absolute neutrophil count FDA: Food and Drug Administration
    IPSS-R: Revised International Prognostic Scoring System
    ITP: chronic immune thrombocytopenia MDS: myelodysplastic syndromes PNH: paroxysmal nocturnal hemoglobinuria STAT-3: signal transducer and activator of transcription
    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 for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Corticosteroids* dexamethasone
    ITP Oral dosage:
    Adults: Initially, 0.75 to 9 mg/day PO, given in 2 to 4 divided doses. Adjust according to patient response.
    Children and adolescents: 0.02 to 0.3 mg/kg/day PO or 0.6 to 9 mg/m2/day PO, given in 3 to 4 divided doses Intramuscular or intravenous dosage:
    Adults: Initially, 0.5 to 9 mg/day IV or IM, given in 2 to 4 divided doses. Adjust according to patient response. Children: 0.02 to 0.3 mg/kg/day or 0.6 to 9 mg/m2/day IV or IM given in 3-4 divided doses. Adjust according to patient response. methylprednisolone ITP Oral dosage:
    Adults: 4 to 48 mg/day PO in 4 divided doses. Adjust according to patient response. Children: 0.5 to 1.7 mg/kg/day PO in divided doses every 6 to 12 hrs Intravenous dosage: Page 6 of 12 Dosage must be individualized and is highly variable depending on the nature and severity of the disease, route of treatment, and on patient response. Dosage must be individualized and is highly variable depending on the nature and severity of the disease, route of treatment, and on patient response.

    CLINICAL POLICY Eltrombopag Drug Name Dosing Regimen prednisone Adults: 10 to 40 mg IV every 4 to 6 hours for up to 72 hours Children: 0.11 to 1.6 mg/kg/day IV in 3 or 4 divided doses. ITP Adults: Initially, 1 mg/kg PO once daily; however, lower doses of 5 mg/day to 10 mg/day PO are preferable for long-term treatment. ITP Refer to prescribing information Immune globulins immune globulins (e.g., Carimune® NF, Flebogamma® DIF 10%, Gammagard® S/D, Gammaked™, Gamunex®-C, Gammaplex®, Octagam® 10%, Privigen®) Immunosuppressive agents Atgam® (antithymocyte globulin)
    Aplastic anemia 10 to 20 mg/kg/day IV infusion for 8 to 14 days, continuing with every-other-day dosing up to a total of 21 doses, if needed
    Off-label dosing: 40 mg/kg IV daily for four consecutive days in combination with cyclosporine
    Aplastic anemia 12 mg/kg PO daily cyclosporine† (Sandimmune®) cyclophosphamide† Aplastic anemia 45 to 50 mg/kg IV divided over 4 days Dose Limit/ Maximum Dose Dosage must be individualized and is highly variable depending on the nature and severity of the disease, route of treatment, and on patient response. Refer to prescribing information Varies Varies Varies 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. Examples of corticosteroids/immunosuppressive agents provided are not all inclusive
    †Off-label indication
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    CLINICAL POLICY Eltrombopag Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported • Boxed warning(s): risk for hepatic decompensation in patients with chronic hepatitis C and risk of hepatotoxicity Appendix D: General Information • Definition of persistent vs chronic ITP per the 2019 American Society of Hematology Guideline o Persistent ITP: ITP duration of 3-12 months o Chronic ITP: ITP duration of > 12 months • Examples of positive response to therapy may include:
    o For ITP or hepatitis C-associated thrombocytopenia:
    Increase in platelet count from baseline levels;   Platelet count ≥ 50,000/µL;
     Reduction in clinically important bleeding events; o For aplastic anemia: any of the following hematologic responses:
     Platelet count ≥ 50,000/µL  Platelet count increases to 20,000/µL above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks;
     Hemoglobin increase > 1.5 g/dL, or a reduction of ≥ 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; o Absolute neutrophil count (ANC) increase of 100% or an ANC increase greater than 500/µL. • MDS prognostic scoring system online calculator for IPSS-R: https://qxmd.com/calculate/calculator_109/mds-revised-international-prognostic-scoring- system-ipss-r
    V. Dosage and Administration
    Drug Name Indication Dosing Regimen Eltrombopag (Promacta) Persistent or chronic ITP Chronic hepatitis C-associated thrombocytopenia Severe aplastic anemia Adults and pediatrics age ≥ 6 years: 50 mg PO QD
    Pediatrics age 1 to 5 years: 25 mg PO QD Adjust to maintain platelet count ≥ 50,000/µL. 25 mg PO QD Adjust to achieve target platelet count required to initiate antiviral therapy. After an insufficient response to immunosuppressive therapy:
    50 mg PO QD
    Page 8 of 12 Maximum Dose 75 mg/day 100 mg/day 150 mg/day

    CLINICAL POLICY Eltrombopag Drug Name Indication Dosing Regimen Maximum Dose Adjust to maintain platelet count > 50,000/µL. For first-line treatment in combination with immunosuppressive therapy:
    Patients ≥ 12 years: 150 mg PO QD Patients 6 to 11 years: 75 mg PO QD Patients 2 to 5 years: 2.5 mg/kg PO QD Adjust to maintain platelet count greater than 50,000/µL. Total duration of treatment is 6 months. Adults and pediatrics age ≥ 6 years: 36 mg PO QD Adjust to maintain platelet count ≥ 50,000/µL. 18 mg PO QD Adjust to achieve target platelet count required to initiate antiviral therapy. After an insufficient response to immunosuppressive therapy: 36 mg PO QD
    Adjust to maintain platelet count > 50,000/µL. 54 mg/day 72 mg/day 108 mg/day Eltrombopag (Alvaiz) Persistent or chronic ITP Chronic hepatitis C-associated thrombocytopenia Severe aplastic anemia VI. Product Availability
    Drug Name Eltrombopag (Promacta) Eltrombopag (Alvaiz) Availability Oral tablets: 12.5 mg, 25 mg, 50 mg, 75 mg Oral suspension: 12.5 mg, 25 mg Oral tablets: 9 mg, 18 mg, 36 mg, 54 mg VII.