OTREXUP, Methotrexate (Antirheumatic) XATMEP, Methotrexate RASUVO, Methotrexate (Antirheumatic) Form

Methotrexate injection (Otrexup™, Rasuvo®, Reditrex®) and oral solution (Xatmep®, Jylamvo®) are folate analog metabolic inhibitors. FDA Approved Indication(s) Otrexup, Rasuvo, and Reditrex are indicated for: • Management of selected adults with severe, active rheumatoid arthritis (RA), or children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs). In adults for the symptomatic control of severe, recalcitrant, disabling psoriasis (PsO) that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. • Limitation(s) of use: Otrexup, Rasuvo, and Reditrex are not indicated for the treatment of neoplastic diseases. Xatmep is indicated for: • Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi- phase, combination chemotherapy maintenance regimen. • Management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose NSAIDs. Jylamvo is indicated for: • Treatment of adults with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen • Treatment of adults with mycosis fungoides (MF) • Treatment of adults with relapsed or refractory non-Hodgkin lymphoma (NHL) as part of a metronomic combination regimen • Treatment of adults with rheumatoid arthritis • Treatment of adults with severe psoriasis
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.
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CLINICAL POLICY
Methotrexate
It is the policy of health plans affiliated with Centene Corporation® that Otrexup, Rasuvo, Xatmep, Reditrex, and Jylamvo are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Polyarticular Juvenile Idiopathic Arthritis (must meet all):

1. Diagnosis of PJIA;
   2. Request is for Otrexup, Rasuvo, Reditrex, or Xatmep;
   3. Prescribed by or in consultation with a rheumatologist;
   4. Member meets one of the following (a or b): a. For Otrexup, Rasuvo, or Reditrex: Age ≥ 2 years; b. For Xatmep: Age ≤ 18 years;
2. For Otrexup, Rasuvo, or Reditrex: Failure of generic methotrexate injection, unless contraindicated or clinically significant adverse effects are experienced;
3. For Xatmep: Documentation supports inability to swallow pills;
   7. Dose does not exceed the following (a or b): a. Otrexup, Ravuso, or Reditrex: 20 mg per week; b. Xatmep: 30 mg/m2 per week.
      Approval duration: Medicaid/HIM – 6 months Commercial – Otrexup, Rasuvo, and Reditrex: 6 months or to the member’s renewal date, whichever is longer; Xatmep: 12 months or duration of request, whichever is less
      B. Rheumatoid Arthritis or Psoriasis (must meet all):
4. Diagnosis of RA or PsO;
   2. Request is for Otrexup, Rasuvo, Reditrex, or Jylamvo;
   3. Prescribed by or in consultation with one of the following specialists (a or b): a. RA: Rheumatologist; b. PsO: Rheumatologist or a dermatologist;
   4. Member meets one of the following (a or b): a. For Otrexup, Rasuvo, or Reditrex: Age ≥ 2 years; b. For Jylamvo: Age ≥ 18 years;
5. For Oxtrexup, Rasuvo, and Reditrex: Failure of generic methotrexate injection, unless contraindicated or clinically significant adverse effects are experienced;
6. For Jylamvo: Documentation supports inability to swallow pills;
   7. Dose does not exceed 30 mg per week.
      Approval duration: Medicaid/HIM – 6 months Commercial – Oxtrexup, Rasuvo, and Reditrex: 6 months or to the member’s renewal date, whichever is longer; Jylamvo: 12 months or duration of request, whichever is less C. Acute Lymphoblastic Leukemia (must meet all):

7. Diagnosis of ALL;

   2. Request is for Xatmep or Jylamvo;
   3. Prescribed by or in consultation with an oncologist or hematologist; Page 2 of 10

   CLINICAL POLICY
   Methotrexate

8. Member meets on of the following (a or b): a. Xatmep: Age < 18 years; b. Jylamvo: Age ≥ 18 years;
9. Documentation supports inability to swallow pills;
   6. Request meets one of the following (a or b): a. Dose does not exceed 20 mg/m2 per week; 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
      Approval duration:
      Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less D. Mycosis Fungoides (must meet all):

10. Diagnosis of MF;

    2. Request is for Jylamvo;
    3. Prescribed by or in consultation with an oncologist or hematologist;
    4. Age ≥ 18 years;
    5. Documentation supports inability to swallow pills;
    6. Request meets one of the following (a, b, or c): a. Dose does not exceed 75 mg per week when administered as a single agent; b. Dose does not exceed 10 mg/m2 twice weekly as part of a combination chemotherapy regimen;
       c. 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 Approval duration: Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less E. Non-Hodgkin Lymphoma (must meet all):
    7. Diagnosis of relapsed or refractory NHL;
    8. Request is for Jylamvo;
    9. Prescribed by or in consultation with an oncologist or hematologist;
    10. Age ≥ 18 years;
    11. Documentation supports inability to swallow pills;
    12. Request meets one of the following (a or b): a. Dose does not exceed 10 mg per week; 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 Approval duration: Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less
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    CLINICAL POLICY
    Methotrexate
    F. Other diagnoses/indications (must meet 1 or 2):

11. 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
12. 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):
13. Member meets one of the following (a, b, or c): 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); c. Documentation supports that member is currently receiving Xatmep for ALL and has received this medication for at least 30 days.

14. Member is responding positively to therapy;

    3. If request is for a dose increase, new dose does not exceed the following (a, b, or c): a. Otrexup, Ravuso, or Reditrex (i or ii): i. pJIA: 20 mg per week; ii. RA, psoriasis: 30 mg per week; b. Xatmep (i or ii):
       i. pJIA: 30 mg/m2 per week; ii. ALL: Request meets one of the following (1 or 2): 1) Dose does not exceed 20 mg/m2 per week; 2) 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 c. Jylamvo (i, ii, iii, or iv): RA, psoriasis: 30 mg per week; i. ii. ALL: Request meets one of the following (1 or 2): 1) Dose does not exceed 20 mg/m2 per week; 2) 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 4 of 10

    CLINICAL POLICY
    Methotrexate
    iii. MF: Request meets one of the following (1, 2, or 3): 1) Dose does not exceed 75 mg per week when administered as a single agent; 2) Dose does not exceed 10 mg/m2 twice weekly as part of a combination chemotherapy regimen;
    3) 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 iv. NHL: Request meets one of the following (1 or 2): 1) Dose does not exceed 10 mg per week; 2) 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 Approval duration:
    Medicaid/HIM – 12 months Commercial – Otrexup, Rasuvo, and Reditrex: 6 months or to the member’s renewal date, whichever is longer; Xatmep and Jylamvo: 12 months or duration of request, whichever is less
    B. 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.
    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 Key ALL: acute lymphoblastic leukemia FDA: Food and Drug Administration MF: mycosis fungoides NHL: non-Hodgkin lymphoma Page 5 of 10

    CLINICAL POLICY
    Methotrexate
    NSAID: non-steroidal anti-inflammatory drug PJIA: polyarticular juvenile idiopathic arthritis PsO: psoriasis RA: rheumatoid arthritis Appendix B: Therapeutic Alternatives Dosing Regimen Drug Name methotrexate injection RA 7.5 mg SC once weekly PJIA 10 mg/m2 SC once weekly PsO 10-25 mg SC once weekly ALL, PJIA 10 – 30 mg/m2 PO once weekly methotrexate tablets MF 25 mg – 75 mg PO once weekly or 10 mg/m2 PO twice weekly NHL 2.5 mg PO two to four times weekly Dose Limit/ Maximum Dose pJIA: 20 mg/week; RA, PsO: 30 mg/week ALL: 20 mg/m2/week; MF: 75 mg/ week or 20 mg/m2 /week; NHL: 10 mg/ week; pJIA: 30 mg/m2/week 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 Otrexup, Rasuvo, Reditrex: pregnancy; alcoholism or liver disease; immunodeficiency syndromes; pre-existing blood dyscrasias; hypersensitivity o Xatmep: pregnancy in patients with PJIA; severe hypersensitivity to methotrexate o Jylamvo: pregnant patients with non-neoplastic diseases; severe hypersensitivity to methotrexate
    • Boxed warning(s): severe toxic reactions, including embryo-fetal toxicity and death Appendix D: General Information • Otrexup, Rasuvo, and Reditrex are not indicated for the treatment of neoplastic diseases. • Jylamvo is not approved for use in pediatric patients.
    V. Dosage and Administration Drug Name Methotrexate injection (Otrexup, Rasuvo, Reditrex) Indication Dosing Regimen RA PJIA PsO 7.5 mg SC once weekly 10 mg/m2 SC once weekly 10-25 mg SC once weekly Maximum Dose 30 mg/week 20 mg/week 30 mg/week Page 6 of 10

    CLINICAL POLICY
    Methotrexate
    Drug Name Methotrexate oral solution (Xatmep) Methotrexate oral solution (Jylamvo) Indication Dosing Regimen ALL PJIA 20 mg/m2 PO once weekly 10 mg/m2 PO once weekly RA PsO ALL NHL MF 7.5 – 20 mg PO once weekly 10 – 25 mg PO once weekly
    20 mg/m2 PO once weekly 2.5 mg PO two to four times weekly 25 – 75 mg PO once weekly or 10 mg/m2 PO twice weekly Maximum Dose 20 mg/m2/week 30 mg/m2/week 30 mg/ week 30 mg/ week 20 mg/m2/week 10 mg/week 75 mg/ week or 20 mg/m2/week VI. Product Availability Drug Methotrexate injection (Otrexup) Methotrexate injection
    (Rasuvo) Methotrexate injection (Reditrex) Methotrexate oral solution
    (Xatmep) Methotrexate oral solution (Jylamvo) Availability
    Auto-injector: 10 mg/0.4 mL, 12.5 mg/0.4 mL, 15 mg/0.4 mL, 17.5 mg/0.4 mL, 20 mg/0.4 mL, 22.5 mg/0.4 mL, 25 mg/0.4 mL Auto-injector: 7.5 mg/0.15 mL, 10 mg/0.2 mL, 12.5 mg/0.25 mL, 15 mg/0.3 mL, 17.5 mg/0.35 mL, 20 mg/0.4 mL, 22.5 mg/0.45 mL, 25 mg/0.5 mL, 27.5 mg/0.55 mL, 30 mg/0.6 mL Single-dose pre-filled injection: 15 mg/0.6 mL, 20 mg/0.8 mL, 25 mg/mL 2.5 mg/mL in a 60 mL or 120 mL bottle 2 mg/mLin a 60 mL bottle VII.