Levoleucovorin (Fusilev, Khapzory) Form

Levoleucovorin (Fusilev®, Khapzory™) is a folate analog. FDA Approved Indication(s) Fusilev and Khapzory are indicated for: • Rescue after high-dose methotrexate (MTX) therapy in adult and pediatric patients with osteosarcoma • Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired MTX elimination in adult and pediatric patients • The treatment of adults with metastatic colorectal cancer in combination with fluorouracil
Limitation(s) of use: Fusilev and Khapzory are not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B12 because of the risk of progression of neurologic manifestations despite hematologic remission. 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 Fusilev and Khapzory are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Methotrexate/Folic Acid Antagonist Toxicity Prophylaxis (must meet all):

1. Prescribed for one of the following uses (a, b, or c): a. Rescue after MTX therapy for osteosarcoma or an NCCN-recommended cancer (see Appendix D); b. Antidote for impaired MTX elimination; c. Antidote for accidental overdose of folic acid antagonists (including MTX);

2. Age ≥ 6 years;

   3. Member meets one of the following (a or b): a. Documentation supports contraindication or clinically significant adverse effects to leucovorin; b. Leucovorin is not available for use due to a national drug shortage documented on the FDA’s Drug Shortages Index (see Appendix D); Page 1 of 9

   CLINICAL POLICY Levoleucovorin

3. Request meets one of the following (a or b): a. For Fusilev or Khapzory: Dose is appropriate and will be adjusted as necessary per section V; b. For Fusilev or Khapzory: Dose is supported by practice guidelines or peer- reviewed literature for the relevant use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
   Impaired elimination/accidental overdose: 1 month High-dose MTX therapy rescue:
   Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Combination Chemotherapy with 5-FU (must meet all):
4. Prescribed for use in a fluorouracil-based chemotherapy treatment regimen for colorectal cancer or an NCCN-recommended cancer (see Appendix D);
5. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 6 years;
   4. Prescribed in combination with 5-FU;
   5. Member meets one of the following (a or b): a. Documentation supports contraindication or clinically significant adverse effects to leucovorin;
      b. Leucovorin is not available for use due to a national drug shortage documented on the FDA's Drug Shortages Index (see Appendix D);
6. Request meets one of the following (a or b): a. For Fusilev or Khapzory: Colorectal cancer: dose does not exceed regimen in section V; b. For Fusilev or Khapzory: Dose is supported by practice guidelines or peer- reviewed literature for the relevant use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration: Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer C. Other diagnoses/indications (must meet 1 or 2):

7. 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 Page 2 of 9

   CLINICAL POLICY Levoleucovorin

8. 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):
9. 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 the requested drug for high-dose MTX rescue as part of chemotherapy or combination chemotherapy with 5-FU and has received this medication for at least 30 days;
10. Member is responding positively to therapy;
    3. Documentation supports contraindication or clinically significant adverse effects to leucovorin, or leucovorin continues to be unavailable due to a national drug shortage;
11. If request is for a dose increase, request meets one of the following (a or b): a. For Fusilev or Khapzory: New dose does not exceed regimen in section V; b. For Fusilev or Khapzory: New dose is supported by practice guidelines or peer- reviewed literature for the relevant use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
    Impaired elimination/accidental overdose: 1 month All other indications:
    Medicaid/HIM – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Other diagnoses/indications (must meet 1 or 2):
12. 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

13. 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 Page 3 of 9

    CLINICAL POLICY Levoleucovorin 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 policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents; B. Pernicious or megaloblastic anemia. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key 5-FU: 5-fluorouracil
    FDA: Food and Drug Administration MTX: methotrexate NCCN: National Comprehensive Cancer Network 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 Varies leucovorin MTX rescue 15 mg (~10 mg/m2) PO, IM, or IV given 24 hrs after MTX infusion, then every 6 hrs for 10 doses until MTX level is < 0.05 μM (dose may be adjusted based on elimination rates) Folic acid antagonist overdose 5 to 15 mg PO QD Colorectal cancer (or other combination chemotherapy with 5-FU) 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. Off-label Appendix C: Contraindications/Boxed Warnings • Contraindication(s): previous allergic reactions attributed to leucovorin products, folic acid, or folinic acid • Boxed warning(s): none reported Page 4 of 9

    CLINICAL POLICY Levoleucovorin Appendix D: General Information • The FDA’s Drug Shortages Index can be found at: www.accessdata.fda.gov/scripts/drugshortages/default.cfm. • Per NCCN, 400 mg/m2 of leucovorin is equivalent to 200 mg/m2 of levoleucovorin.
    • The NCCN guidelines recommend the combination use of levoleucovorin with MTX as a rescue for the following cancers (2A recommendation) when leucovorin is not available: o (Pediatric) acute lymphoblastic leukemia o T-cell lymphomas (including peripheral T-cell lymphomas, adult T-cell leukemia/lymphoma, extranodal NK/T-cell lymphoma, hepatosplenic T-Cell lymphoma)
    o Bone cancer (including osteosarcoma, dedifferentiated chondrosarcoma, high-grade undifferentiated pleomorphic sarcoma) o CNS cancer (including primary CNS lymphoma, brain metastases, leptomeningeal metastases) o B-cell lymphomas (including mantle cell lymphoma, HIV-related B-cell lymphoma, Burkitt lymphoma, high grade B-cell lymphomas, diffuse large B-cell lymphoma, post-transplant lymphoproliferative disorders, primary mediastinal large B-cell lymphoma) o Gestational trophoblastic neoplasia o Chronic lymphocytic leukemia and small lymphocytic lymphoma o Blastic plasmacytoid dendritic cell neoplasm • The NCCN guidelines recommend the combination use of levoleucovorin with fluorouracil-based regimens for the following cancers (2A recommendation) when leucovorin is not available: o Occult primary adenocarcinoma, squamous cell carcinoma, or carcinoma not otherwise specified o Mucinous carcinoma of the ovary o Colon cancer
    o Gastric cancer o Esophageal and esophagogastric junction cancers o Anal carcinoma o Extrapulmonary poorly differentiated neuroendocrine carcinoma/large or small cell carcinoma, mixed neuroendocrine-non-neuroendocrine neoplasm o Neuroendocrine tumors of the pancreas (well-differentiated Grade 1/2) o Well-differentiated Grade 3 neuroendocrine tumors o Cervical cancer o Rectal cancer o Pancreatic adenocarcinoma o Bladder cancer (non-urothelial and urothelial with variant histology) o Small bowel adenocarcinoma o Ampullary adenocarcinoma o Appendiceal adenocarcinoma o Biliary tract cancers (gallbladder cancer, intrahepatic or extrahepatic cholangiocarcinoma) o Thymomas and thymic carcinomas Page 5 of 9

    CLINICAL POLICY Levoleucovorin • The NCCN guidelines recommend the combination use of levoleucovorin with MTX for the management of symptomatic Bing-Neel syndrome in Waldenström macroglobulinemia /lymphoplasmacytic lymphoma when leucovorin is not available (2A recommendation). V. Dosage and Administration
    Indication Dosing Regimen Rescue after high-dose MTX therapy in osteosarcoma 7.5 mg (approximately 5 mg/m2) IV every 6 hours for 10 doses starting 24 hours after beginning of MTX infusion; adjust or extend rescue based on the following clinical situation and laboratory findings: Maximum Dose See regimen Normal MTX elimination (serum MTX 10 μM at 24 hours, 1 μM at 48 hours, and < 0.2 μM at 72 hours after administration): 7.5 mg IV every 6 hours for 60 hours (10 doses starting 24 hours after start of MTX infusion) Delayed late MTX elimination (serum MTX > 0.2 μM at 72 hours and > 0.05 μM at 96 hours after administration): 7.5 mg IV every 6 hours until MTX < 0.05 μM
    Delayed early MTX elimination and/or evidence of acute renal injury (serum MTX ≥ 50 μM at 24 hours, ≥ 5 μM at 48 hours, or ≥ 100% increase in serum creatinine at 24 hours after MTX administration): 75 mg IV every 3 hours until MTX < 1 μM; then 7.5 mg IV every 3 hours until MTX < 0.05 μM If significant clinical toxicity is observed, Fusilev or Khapzory therapy should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent course of therapy. Administer as soon as possible after overdose and within 24 hours of MTX administration if there is delayed excretion: 7.5 mg (approximately 5 mg/m2) IV every 6 hours until serum MTX is < 5 x 10-8 M. Increase to 50 mg/m2 IV every 3 hours if one of the following: • 24 hour serum creatinine has increased 50% over baseline See regimen Inadvertent MTX overdose • 24 hour MTX level is > 5 x 10-6 M
    • 48 hour level is > 9 x 10-7 M Regimens used historically include: • 100 mg/m2 IV followed by 5-FU 370 mg/m2 IV; or Colorectal cancer
    See regimen Page 6 of 9

    CLINICAL POLICY Levoleucovorin Indication Dosing Regimen Maximum Dose • 10 mg/m2 IV followed by 5-FU 425 mg/m2 IV Administer Fusilev or Khapzory, and 5-FU separately. Repeat Fusilev or Khapzory daily for 5 day course. Courses may be repeated at 4 week intervals for 2 courses, then repeated at 4 to 5 week intervals. VI. Product Availability
    Drug Name Fusilev (levoleucovorin) Khapzory (levoleucovorin) Availability • Single-use vial with powder for reconstitution: 50 mg • Single-use vial with solution: 175 mg/17.5 mL, 250 mg/25 mL Single-use vial with powder for reconstitution: 175 mg and 300 mg VII.