Policy. ( Number: *Pleasesee amendment forpennsylvaniamedicaidatthe endofthis CPB.

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1 1 of 11 ( Number: 0889 Policy *Pleasesee amendment forpennsylvaniamedicaidatthe endofthis CPB. Aetna considers levoleucovorin (Fusilev) medically necessary for the following indications, when leucovorin is not available*: Last Review 01/05/2018 Effective: 10/14/2014 Next Review: 10/25/2018 Diminishing the toxicity and counteracting the effects of impaired elimination and of inadvertent overdosage of folic acid antagonists; or Use in combination with fluorouracil based regimens in pancreatic adenocarcinoma, colorectal adenocarcinoma, small bowel adenocarcinoma, appendiceal carcinoma, and anal adenocarcinoma; or Use as a component of high dose regimens in dedifferentiated chondrosarcoma, high grade undifferentiated pleomorphic sarcoma (UPS), and osteosarcoma. Review History Definitions Clinical Policy Bulletin Notes Aetna considers levoleucovorin not medically necessary for members with pernicious anemia or megaloblastic anemia secondary to the lack of vitamin B12

2 2 of 11 Aetna considers levoleucovorin experimental and investigational for all other indications (e.g., cholangiocarcinoma) *Note: The leucovorin shortage must be documented on the U.S. Food and Drug Administration's Drug Shortages Index, /drugshortages/default.cfm. Background Fusilev (levoleucovorin) is the levo isomeric form of racemicd, l leucovorin, present as the calcium salt. Levoleucovorin is a folate analog injection containing the active isomer of leucovorin ((6 S) leucovorin, also called folinic acid). Fusilev (levoleucovorin) for injection contains levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by. Folates are a group of vitamins that allow cells to reproduce by fueling the synthesis of purinic and pyrimidinic bases, the building blocks of DNA. Folate deficiency hinders DNA synthesis and cell division, most notably affecting rapidly proliferating tissues, such as normal bone marrow and cancer tissue. Levoleucovorin and leucovorin are folate analogs that protect against the toxic effects of. Methotrexate is a folic acid antagonist that prevents folates from being metabolized to their reduced active form by binding and inhibiting enzymes involved in the activation of folic acid to folinic acid, leading to cell death. The administration of levoleucovorin and leucovorin, therefore, bypass the metabolic block effected by. Fusilev (levoleucovorin) is approved by the U.S. Food and Drug Administration (FDA) for rescue after high dose therapy in osteosarcoma, diminishing the toxicity and counteracting the effects of impaired elimination

3 3 of 11 and of inadvertent overdosage of folic acid antagonists, and use in combination chemotherapy with 5 fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Limitations of use include the treatment of pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B 12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. Fusilev was approved by the FDA in 2008 for use after high dose therapy in osteosarcoma and to diminish the toxicity and counteract the effects of impaired elimination and of inadvertent overdosage of folic acid antagonists. The safety and efficacy of levoleucovorin rescue following high dose was evaluated in 16 patients aged 6 to 21 years who received 58 courses of therapy for osteogenic sarcoma. High dose was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m2 IV over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of. Three patients received 12.5 g/m2 IV over 6 hours, followed by levoleucovorin 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of. The mean number of levoleucovorin doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of levoleucovorin rescue following high dose was based on the adverse reaction profile. Fusilev was approved by the FDA in 2011 for use in combination with 5 fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. This expanded indication supplemented the original 2008 FDA approval of Fusilev. The NCCN Drug and Biologics Compendium (NCCN, 2016) recommends the use of levoleucovorin in combination with fluorouracil based regimens for colon and rectal cancer when leucovorin is not available. NCCN guidelines also

4 4 of 11 recommend use of levoleucovorin as a component of high dose regimens in osteosarcoma. National Comprehensive Cancer Network s Drugs & Biologics Compendium (2017) lists dedifferentiated chondrosarcoma, and high grade undifferentiated pleomorphic sarcoma (UPS) as recommended indications of levoleucovorin. Levoleucovorin is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. Due to calcium content, no more than 16 ml (160 mg) of levoleucovorin solution should be injected intravenously per minute. Levoleucovorin enhances the cytotoxicity of fluorouracil. Concomitant use of d,l leucovorin with trimethoprim sulfamethoxazole for pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo controlled study. Allergic reactions were reported in patients receiving levoleucovorin. Vomiting (38 %), stomatitis (38 %) and nausea (19 %) were reported in patients receiving levoleucovorin as rescue after high dose therapy. The most common adverse reactions (greater than 50 %) in patients with advanced colorectal cancer receiving levoleucovorin in combination with 5 fluorouracil were diarrhea, nausea and stomatitis. Levoleucovorin may counteract the anti epileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients. Other adverse effects include typhilitis and abnormal renal function. Fusilev (levoleucovorin) should not be utilized in the following: Hypersensitivity to folic acid, folinic acid/leucovorin, or mannitol. The safety and efficacy has not been established in pediatric patients less than six years old. Patients with pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress Due to Ca++ content, no more than 16 ml (160 mg) of

5 5 of 11 levoleucovorin solution should be injected intravenously per minute Fusilev (levoleucovorin) may enhance the toxicity of fluorouracil Concomitant use of d,l leucovorin with trimethoprimsulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo controlled study Fusilev (levoleucovorin) may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible members. Do not administer intrathecally. Pancreatic Adenocarcinoma: National Comprehensive Cancer Network s clinical practice guideline on Pancreatic adenocarcinoma (Version ) states that There is currently a shortage of leucovorin in the United states. There are no specific data to guide management under these circumstances, and all proposed strategies are empiric. The panel recommends several possible options to help alleviate the problems associated with this shortage. One is the use of levo leucovorin, which is commonly used in Europe. Cholangiocarcinoma: UpToDate reviews on Systemic therapy for advanced cholangiocarcinoma (Stuart, 2015), Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis (Anderson and Stuart, 2015a) and Treatment options for locally advanced cholangiocarcinoma (Anderson and Stuart, 2015b) do not mention levoleucovorin as a therapeutic option. Furthermore, National Comprehensive Cancer Network s clinical practice guideline on Hepatobiliary cancers (Version ) does not mention levoleucovorin as a therapeutic option.

6 6 of 11 Appendix Levoleucovorin is supplied as a solution in 175 mg and 250 mg vials, and as freeze dried powder in 50 mg vials, for intravenous use only. Fusilev (levoleucovorin) Rescue After High Dose Methotrexate Therapy: Fusilev (levoleucovorin) rescue recommendations are based on a dose of 12 grams/m²administered by intravenous infusion over four hours. Fusilev (levoleucovorin) rescue at a dose of 7.5 mg (approximately 5 mg/m² every six hours for ten doses starts 24 hours after the beginning of the infusion. The Fusilev (levoleucovorin) dose and/or frequency may need to be adjusted. Fusilev Administration in Combination with 5 Fluorouracil (5 FU): The following regimens have been used historically for the treatment of colorectal cancer: Fusilev (levoleucovorin) is administered at 100 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5 FU at 370 mg/m 2 by intravenous injection. Fusilev (levoleucovorin) is administered at 10 mg/m 2 by intravenous injection followed by 5 FU at 425 mg/m 2 by intravenous injection. Treatment is repeated daily for five days. This five day treatment course may be repeated at 4 weeks (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. 5 FU and Fusilev should be administered separately to avoid the formation of a precipitate. Alternative dosing: Levoleucovorin, when substituted in place of leucovorin calcium within a chemotherapy regimen, is dosed at one half the usual dose of leucovorin calcium Do not administer intrathecally. Fusilev (levoleucovorin) is dosed at one half the usual dose of

7 7 of 11 the racemic form (leucovorin calcium). Dose Adjustments: Clinical Situation Normal elimination Delayed late elimination Laboratory Findings Serum level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours Serum level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration Fusilev Dosage and Duration 7.5 mg IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of infusion) Continue 7.5 mg IV q 6 hours, until level is less than 0.05 micromolar Delayed early elimination and/or evidence of acute renal injury Serum level of 50 micromolar or more than 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after administration (e.g., an increase 0.5 mg/dl to a level of 1 mg/dl or more) 75 mg IV q hours until level is less than 1 micromolar; then 7.5 mg IV q 3 hours until level is less than 0.05 micromolar

8 8 of 11 CPT Codes / HCPCS Codes / ICD 10 Codes Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+": Code Code Description Other CPT codes related to the CPB: Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug) HCPCS codes covered if selection criteria are met: J0641 Injection, levoleucovorin calcium, 0.5 mg Other HCPCS codes related to the CPB: J8610 J9190 J9250 J9260 Methotrexate, oral, 2.5 mg Injection, fluorouracil, 500 mg Methotrexate sodium, 5 mg Methotrexate sodium, 50 mg ICD 10 codes covered if selection criteria are met: C17.0 C17.9 Malignant neoplasm of small intestine [small bowel adenocarcinoma] C18.0 C20 Malignant neoplasm of colon, rectosigmoid junction and rectum [colorectal adenocarcinoma] C25.0 C25.9 Malignant neoplasm of pancreas [pancreatic adenocarcinoma]

9 9 of 11 Code C41.0 C41.9 Code Description Malignant neoplasm of bone and articular cartilage T45.1X1+ T45.1X5+ T45.8X1+ Poisoning by antineoplastic and immunosuppressive drugs, accidental (unintentional), [] Adverse effect of antineoplastic and immunosuppressive drugs Poisoning by other primarily systemic and hematological agents, accidental (unintentional) [] ICD 10 codes not covered for indications listed in the CPB (not all inclusive): C Squamous cell carcinoma of anal skin D51.0 Vitamin B12 deficiency anemia due to intrinsic factor deficiency [pernicious anemia] D53.1 Other megaloblastic anemias, not elsewhere classified Megaloblastic anemia NOS The above policy is based on the following references: 1. Spectrum Pharmaceuticals, Inc. Fusilev (levoleucovorin) injection, solution for intravenous use. Prescribing Information. Reference ID: Irvine, CA: Spectrum Pharmaceuticals; revised April Spectrum Pharmaceuticals, Inc. FDA approves Fusilev for use in patients with colorectal cancer. Press Release. Irvine, CA: Spectrum Pharmaceuticals; April 29, Fusilev (Levoleucovorin). New FDA Drug Approval. Boston,

10 10 of 11 MA: CenterWatch; March National Comprehensive Cancer Network (NCCN). Levoleucovorin. NCCN Drugs & Biologics Compendium. Fort Washington, PA: NCCN; Labianca R, Sobrero A, Isa L, et al.; Italian Group for the Study of Gastrointestinal Cancer GISCAD. Intermittent versus continuous chemotherapy in advanced colorectal cancer: A randomised 'GISCAD' trial. Ann Oncol. 2011;22(5): Yuuki S, Komatsu Y, Fuse N, et al. Modifiedirinotecan/fluorouracil/levoleucovorin therapy as ambulatory treatment for metastatic colorectal cancer: Results of phase I and II studies. Clin Drug Investig. 2010;30(4): National Comprehensive Cancer Network (NCCN). Pancreatic adenocarcinoma. NCCN Clinical Practice Guidelines in Oncology, Version Fort Washington, PA: NCCN; National Comprehensive Cancer Network. Drugs & Biologics Compendium. Levoleucovorin NCCN: Fort Washington, PA.

11 11 of 11 Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

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13 AETNA BETTER HEALTH OF PENNSYLVANIA Amendment to Aetna Clinical Policy Bulletin Number: 0889 Levoleucovorin (Fusilev) For the Pennsylvania Medical Assistance plan: Levoleucovorin (Fusilev) may be used in combination with fluorouracil based regimens when leucovorin is not available for Bladder Cancer, Cervical Cancer, Esophageal and Esophagogastric Junction Cancers, Gastric Cancer, Occult Primary Cancer, Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer Mucinous Carcinoma, and Thymomas and Thymic Carcinomas. Levoleucovorin (Fusilev) may be used with high dose when leucovorin is not available for Acute Lymphoblastic Leukemia, AIDS Related B Cell Lymphomas, Burkitt Lymphoma, Mantle Cell Lymphoma, Primary CNS Lymphoma, CNS Cancers Brain Metastases, Leptomeningeal Metastases, Peripheral T Cell Lymphomas, Adult T Cell Leukemia/Lymphoma, and Extranodal NK/T Cell Lymphoma, nasal type. Levoleucovorin (Fusilev) may be considered medically necessary for the indications listed above, as well as any other use supported by the NCCN. revised 01/05/2018

Clinical Policy: Levoleucovorin (Fusilev) Reference Number: ERX.SPA.181 Effective Date:

Clinical Policy: Levoleucovorin (Fusilev) Reference Number: ERX.SPA.181 Effective Date: Clinical Policy: (Fusilev) Reference Number: ERX.SPA.181 Effective Date: 01.11.17 Last Review Date: 11.18 Revision Log See Important Reminder at the end of this policy for important regulatory and legal