NOVANTRONE, Mitoxantrone HCl Form

Mitoxantrone is a synthetic antineoplastic anthracenedione. FDA Approved Indication(s) Mitoxantrone is indicated for: • Reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS) (i.e., patients whose neurologic status is significantly abnormal between relapses) • Treatment of patients with pain related to advanced hormone-refractory prostate cancer as • initial chemotherapy in combination with corticosteroids Initial therapy of acute nonlymphocytic leukemia (ANLL) (including myelogenous, promyelocytic, monocytic, and erythroid acute leukemias) in adults in combination with other approved drug(s) Limitation(s) of use: Mitoxantrone is not indicated in the treatment of patients with primary progressive MS. 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 mitoxantrone is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Multiple Sclerosis (must meet all):

1. Diagnosis of one of the following (a or b): a. Relapsing-remitting MS, and failure of all of the following at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated (i, ii, iii, and iv): i. Dimethyl fumarate (generic Tecfidera®);
   ii. Teriflunomide (generic Aubagio®);
   iii. Fingolimod (Gilenya®); iv. An interferon-beta agent (Avonex®, Betaseron®/Extavia®†, Rebif®, or Plegridy®) or glatiramer (Copaxone®, Glatopa®); Prior authorization may be required for all disease modifying therapies for MS Page 1 of 10

   CLINICAL POLICY Mitoxantrone †Betaseron is preferred for the Commercial and HIM lines of business; Extavia is preferred for the Medicaid line of business b. Secondary progressive MS;

2. Prescribed by or in consultation with a neurologist;
   3. Age ≥ 18 years;
   4. Mitoxantrone is not prescribed concurrently with other disease modifying therapies for MS (see Appendix D);
3. Documentation of both baseline number of relapses per year and expanded disability status scale (EDSS) score;
4. Dose does not exceed the following (a and b): a. 12 mg/m2 every 3 months; b. Total cumulative lifetime dose of 140 mg/m2. Approval duration:
   Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Prostate Cancer (must meet all):
5. Diagnosis of advanced or metastatic prostate cancer;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Disease is hormone-refractory (i.e., castration-resistant);
   5. Mitoxantrone is prescribed concurrently with a corticosteroid (e.g., prednisone);
   6. Request meets one of the following (a or b): a. Dose does not exceed 14 mg/m2 every 21 days; b. Dose 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.
6. Total cumulative lifetime dose does not exceed 140 mg/m2. Approval duration:
   Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer C. Acute Nonlymphocytic Leukemia (must meet all):
7. Diagnosis of ANLL (including myelogenous [i.e., acute myelogenous leukemia], promyelocytic, monocytic, and erythroid acute leukemias);
8. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Mitoxantrone is prescribed in combination with other therapies for the diagnosis;
   5. Request meets one of the following (a or b): a. Dose does not exceed 12 mg/m2 per infusion; b. Dose 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.

9. Total cumulative lifetime dose does not exceed 140 mg/m2. Approval duration:
   Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer Page 2 of 10

   CLINICAL POLICY Mitoxantrone D. Lymphoma (off-label) (must meet all):

10. Diagnosis of one of the following (a, b, or c): a. Classical Hodgkin lymphoma, and both (i and ii): i. Refractory to at least 3 prior lines of therapy; ii. Prescribed as a component of MINE (mesna, ifosfamide, mitoxantrone, and etoposide); b. One of the following B-cell lymphomas: follicular lymphoma, diffuse large B-cell lymphoma, high grade B-cell lymphoma, HIV-related B-cell lymphoma, or post- transplant lymphoproliferative disorder; and both (i and ii): i. Prescribed as second line and subsequent therapy; ii. Prescribed as a component of MINE (mesna, ifosfamide, mitoxantrone, and etoposide); c. Symptomatic T-cell prolymphocytic leukemia as a component of FMC (fludarabine, mitoxantrone, and cyclophosphamide);
11. Prescribed by or in consultation with an oncologist or hematologist;
    3. Age ≥ 18 years;
    4. Dose 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.
12. Total cumulative lifetime dose does not exceed 140 mg/m2. Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer E. Acute Lymphoblastic Leukemia (off-label) (must meet all):

13. Diagnosis of acute lymphoblastic leukemia (ALL);

    2. Prescribed by or in consultation with an oncologist or hematologist;
    3. Member meets one of the following (a or b): a. Age ≥ 18 years, and both of the following (i and ii): i. One of the following (1 or 2): 1) Disease is Philadelphia chromosome (Ph)-negative T-ALL or B-ALL, and relapsed or refractory; 2) Disease is Ph-positive B-ALL, and refractory to tyrosine kinase inhibitor therapy (e.g., dasatinib, imatinib, ponatinib, nilotinib, bosutinib); ii. Mitoxantrone is prescribed as a component of an alkylator combination regimen (e.g., etoposide, ifosfamide, and mitoxantrone) or FLAM (fludarabine, cytarabine, and mitoxantrone); b. Age < 18 years, and one of the following (i, ii, or iii): i. Relapsed/refractory Ph-negative B-ALL;
       ii. Relapsed/refractory Ph-positive B-ALL in combination with dasatinib or imatinib; iii. Relapsed/refractory T-ALL as a component of UKALL R3 Block 1 (dexamethasone, mitoxantrone, pegaspargase, and vincristine);
    4. Dose 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. Page 3 of 10

    CLINICAL POLICY Mitoxantrone

14. Total cumulative lifetime dose does not exceed 140 mg/m2. Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer F. 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. Multiple Sclerosis (must meet all):
17. 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 meets one of the following (a or b): a. If member has received < 1 year of total treatment: Member is responding positively to therapy; b. If member has received ≥ 1 year of total treatment: Member meets one of the following (i, ii, iii, or iv): i. Member has not had an increase in the number of relapses per year compared to baseline; ii. Member has not had ≥ 2 new MRI-detected lesions; iii. Member has not had an increase in EDSS score from baseline; iv. Medical justification supports that member is responding positively to therapy;

18. Mitoxantrone is not prescribed concurrently with other disease modifying therapies for MS (see Appendix D); Page 4 of 10

    CLINICAL POLICY Mitoxantrone

19. If request is for a dose increase, new dose does not exceed the following (a and b): a. 12 mg/m2 every 3 months; b. Total cumulative lifetime dose of 140 mg/m2. Approval duration:
    Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. All Other Indications in Section I (must meet all):
20. Currently receiving medication via Centene benefit or documentation supports that member is currently receiving mitoxantrone for an oncology indication listed in Section I;
21. Member is responding positively to therapy;
    3. If request is for a dose increase, request meets one of the following (a, b, or c): a. Prostate cancer: New dose does not exceed 14 mg/m2 every 21 days; b. ANLL: New dose does not exceed 12 mg/m2 per infusion; c. Any indication: New dose 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.
22. Total cumulative lifetime dose does not exceed 140 mg/m2. Approval duration:
    Medicaid/HIM – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer 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.
    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 – Page 5 of 10

    CLINICAL POLICY Mitoxantrone CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents; B. Primary progressive MS. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALL: acute lymphoblastic leukemia ANLL: acute nonlymphocytic leukemia EDSS: expanded disability status scale FDA: Food and Drug Administration MS: multiple sclerosis NCCN: National Comprehensive Cancer Network Ph: Philadelphia chromosome 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 14 mg/day Avonex: 30 mcg/week Rebif: 44 mcg TIW 125 mcg/2 weeks 7 mg or 14 mg PO QD Avonex: 30 mcg IM Q week Rebif: 22 mcg or 44 mcg SC TIW 125 mcg SC Q2 weeks teriflunomide (Aubagio®) Avonex®, Rebif® (interferon beta-1a) Plegridy® (peginterferon beta-1a) Betaseron®, Extavia® (interferon beta-1b) glatiramer acetate (Copaxone®, Glatopa®) fingolimod (Gilenya®) 0.5 mg PO QD 120 mg PO BID for 7 days, dimethyl fumarate (Tecfidera®) followed by 240 mg PO BID 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. 20 mg/day or 40 mg TIW 0.5 mg/day 480 mg/day 20 mg SC QD or 40 mg SC TIW 250 mcg SC QOD 250 mg QOD Appendix C: Contraindications/Boxed Warnings • Contraindication(s): prior hypersensitivity to mitoxantrone • Boxed warning(s): cardiotoxicity, secondary leukemia Appendix D: General Information • Disease-modifying therapies for MS are: glatiramer acetate (Copaxone®, Glatopa®), interferon beta-1a (Avonex®, Rebif®), interferon beta-1b (Betaseron®, Extavia®), peginterferon beta-1a (Plegridy®), dimethyl fumarate (Tecfidera®), diroximel fumarate (Vumerity®), monomethyl fumarate (Bafiertam™), fingolimod (Gilenya®, Tascenso ODT™), teriflunomide (Aubagio®), alemtuzumab (Lemtrada®), mitoxantrone (Novantrone®), natalizumab (Tysabri®), ocrelizumab (Ocrevus®), cladribine (Mavenclad®), siponimod (Mayzent®), ozanimod (Zeposia®), ponesimod (Ponvory™), ublituximab-xiiy (Briumvi™), and ofatumumab (Kesimpta®). Page 6 of 10

    CLINICAL POLICY Mitoxantrone • Mitoxantrone has Drugdex IIa recommendations for use in anthracycline-resistant breast cancer, liver cancer, and ovarian cancer; however, these indications are not supported by the National Comprehensive Cancer Network (NCCN). Of note, use of mitoxantrone in invasive breast cancer is actually listed as a use no longer recommended by the NCCN. • Per the NCCN, prostate cancer that stops responding to traditional androgen deprivation therapy (i.e., hormone therapy) is categorized as castration-recurrent (also known as castration-resistant). V. Dosage and Administration
    Indication Relapsing MS Hormone- refractory prostate cancer ANLL Dosing Regimen 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months 12 to 14 mg/m2 given as a short intravenous infusion every 21 days Maximum Dose Cumulative lifetime dose of ≥ 140 mg/m2 Cumulative lifetime dose of ≥ 140 mg/m2 Induction: 12 mg/m2 of mitoxantrone injection (concentrate) daily on Days 1 to 3 given as an intravenous infusion. A second induction course (2 days) may be given if there is an incomplete antileukemic response Consolidation: 12 mg/m2 given by intravenous infusion daily on Days 1 and 2
    Cumulative lifetime dose of ≥ 140 mg/m2 VI. Product Availability
    Multidose vial: 20 mg/10 mL, 25 mg/12.5 mL, 30 mg/15 mL VII.