Sunflower Health Plan LEUCOVORIN CALCIUM, Leucovorin Calcium Form

Leucovorin is a reduced folate. FDA Approved Indication(s) Leucovorin injection is indicated: • After high-dose methotrexate (MTX) therapy in osteosarcoma. • To diminish the toxicity and counteract the effects of impaired MTX elimination and of inadvertent overdosages of folic acid antagonists. • For the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. • For use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer 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 leucovorin injection is 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. Request meets one of the following (a or b):* a. Dose is appropriate and will be adjusted as necessary per section V; b. 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 Page 1 of 8 CLINICAL POLICY Leucovorin B. Megaloblastic Anemia (must meet all): 1. Diagnosis of megaloblastic anemia due to folic acid deficiency; 2. Member is not a candidate for oral folic acid therapy; 3. Dose does not exceed 1 mg per day. Approval duration: Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer C. Combination Chemotherapy with 5-FU (must meet all): 1. Prescribed for use in a fluorouracil-based chemotherapy treatment regimen for colorectal cancer or an NCCN-recommended cancer (see Appendix D); 2. Prescribed by or in consultation with an oncologist; 3. Prescribed in combination with 5-FU; 4. Request meets one of the following (a or b):* a. Colorectal cancer: dose does not exceed regimen in section V; b. 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 D. Other diagnoses/indications (must meet 1 or 2): 1. 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. or 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 2. 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. Megaloblastic 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; Page 2 of 8 CLINICAL POLICY Leucovorin 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 not a candidate for oral folic acid therapy; 3. Member is responding positively to therapy; 4. If request is for a dose increase, new dose does not exceed 1 mg per day. Approval duration: Medicaid – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. All Other Indications in Section I (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); 2. Member is responding positively to therapy; 3. If request is for a dose increase, request meets any of the following (a or b):* a. New dose does not exceed regimen in section V; b. 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 C. Other diagnoses/indications (must meet 1 or 2): 1. 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 2. 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. Page 3 of 8 CLINICAL POLICY Leucovorin 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 5-FU: 5-fluorouracil FDA: Food and Drug Administration MTX: methotrexate Appendix B: Therapeutic Alternatives Not applicable NCCN: National Comprehensive Cancer Network Appendix C: Contraindications/Boxed Warnings • Contraindication(s): improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurologic manifestations continue to progress. • Boxed warning(s): none reported Appendix D: General Information • The NCCN guidelines recommend the combination use of leucovorin with MTX as a rescue for the following cancers (2A recommendation): 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, primary mediastinal large B-cell lymphoma, post-transplant lymphoproliferative disorders) 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 leucovorin with fluorouracil- based regimens for the following cancers (2A recommendation): o Thymomas and thymic carcinomas o Occult primary adenocarcinoma, squamous cell carcinoma, or carcinoma not otherwise specified o Mucinous carcinoma of the ovary Page 4 of 8 CLINICAL POLICY Leucovorin o Colon cancer (including appendiceal adenocarcinoma) 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 Biliary tract cancers (gallbladder cancer, intrahepatic or extrahepatic cholangiocarcinoma) • The NCCN guidelines recommend the combination use of leucovorin with MTX for the management of symptomatic Bing-Neel syndrome (2A recommendation) in Waldenström macroglobulinemia / lymphoplasmacytic lymphoma. V. Dosage and Administration Indication Dosing Regimen Rescue after high-dose MTX therapy Administer 15 mg (approximately 10 mg/m2) PO, IV, or IM every 6 hours for 10 doses starting 24 hours after beginning of MTX infusion. Continue leucovorin administration until the MTX level is below 5 x 10-8 M (or 0.05 μM). Maximum Dose See regimen Adjust or extend rescue based on clinical situation and laboratory findings: Normal MTX elimination (serum MTX 10 μM at 24 hours, 1 μM at 48 hours, and < 0.2 μM at 72 hours after administration): 15 mg PO, IV, or IM 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): 15 mg PO, IV, or IM 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): 150 mg IV every 3 hours until MTX < 1 μM; then 15 mg IV every 3 hours until MTX < 0.05 μM Page 5 of 8 CLINICAL POLICY Leucovorin Indication Dosing Regimen Inadvertent MTX overdosage Administer as soon as possible after overdose and within 24 hours of MTX administration if there is delayed excretion: 10 mg/m2 PO, IV, or IM every 6 hours until serum MTX is < 10-8 M. Megaloblastic anemia Advanced colorectal cancer Increase to 100 mg/m2 IV every 3 hours if 24 hour serum creatinine has increased 50% over baseline or if the 24 hour MTX level is > 5 x 10-6 M or the 48 hour level is > 9 x 10-7 M until the MTX level is less than 10-8 M Up to 1 mg, IV or IM, once a day Either of the following two regimens is recommended: • Leucovorin is administered at 200 mg/m2 by slow IV injection over a minimum of 3 minutes, followed by 5- fluorouracil at 370 mg/m2 by IV injection. • Leucovorin is administered at 20 mg/m2 by IV injection followed by 5-fluorouracil at 4252 mg/m by IV injection. Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course. Maximum Dose See regimen 1 mg/day See regimen VI. Product Availability Single-dose vial for injection: 50 mg, 100 mg, 200 mg, 350 mg, 500 mg VII.