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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J2000-31

Original Effective Date: 04/01/15

Reviewed: 03/08/17

Revised: 04/15/17

Subject: Levoleucovorin (Fusilev®) IV

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           

Dosage/ Administration

Position Statement

Billing/Coding

Reimbursement

Program Exceptions

Definitions

           

Related Guidelines

Other

References

Updates

 

Previous Version

           

DESCRIPTION:

Levoleucovorin (Fusilev®) is the pharmacologically active levoisomer of racemic leucovorin (also called folinic acid), a synthetic folate analogue. Folates are a group of vitamins that allow cells to reproduce by fueling the synthesis of purinic and pyrimidinic bases for DNA production. Levoleucovorin was approved by the US Food and Drug Administration (FDA) in March 2008 for use after high-dose methotrexate therapy in osteosarcoma and to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. 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 or leucovorin, therefore, bypasses the metabolic block affected by methotrexate. In May 2011, the FDA granted the additional indication of use in combination chemotherapy with 5-fluorouracil (5-FU) in the palliative treatment of patients with advanced metastatic colorectal cancer. Levoleucovorin enhances the binding of 5-FU to thymidylate synthase and is frequently administered concurrently with 5-FU for therapeutic advantage. Levoleucovorin was given orphan designation status by the FDA in 1990 for use in combination chemotherapy with the approved agent 5-fluorouracil in the palliative treatment of metastatic adenocarcinoma of the colon and rectum, and in 1991 for use in conjunction with high-dose methotrexate in the treatment of osteosarcoma.

In a bioequivalence study, 40 healthy volunteers received a 2-hour infusion of a single-dose of either levoleucovorin 200 mg/m2 or racemic leucovorin 400 mg/m2, which yielded similar mean Cmax values of the active metabolite 5-methyltetrahydrofolate of 4,930 nanograms/mL and 4,658 nanograms/mL, respectively. The safety and efficacy of levoleucovorin rescue following high-dose methotrexate was evaluated in 16 patients age 6 to 21 years who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate 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 methotrexate. Three patients received methotrexate 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 methotrexate. 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 methotrexate was based on the adverse reaction profile. The NCCN guidelines for colon and rectal cancer recommend the use of levoleucovorin in combination with fluorouracil-based regimens for colorectal cancer when leucovorin is not available. NCCN guidelines also recommend use of levoleucovorin as a component of high-dose methotrexate regimens in osteosarcoma.

POSITION STATEMENT:

Levoleucovorin (both brand Fusilev and generic formulations) meets the definition of medical necessity when BOTH of the following criteria are met:

1. Leucovorin injection is NOT available for use due to a national drug shortage.*

2. Any ONE of the following indications:

a) Used in combination with a systemic fluorouracil (5-FU)-based chemotherapy regimen administered for the treatment of cancer.

b) Used in combination with a high-dose methotrexate regimen (to diminish toxicity) used for the treatment of cancer.

c) To diminish the toxicity and counteract the effects of an overdosage of a folic acid antagonist (e.g., methotrexate, pemetrexed, proguanil, pyrimethamine, trimethoprim)

*To verify non-availability, the status of leucovorin injection must be listed as “Currently in Shortage” on the FDA Drug Shortages webpage (http://www.accessdata.fda.gov/scripts/drugshortages/) AND all listed manufactures must have all strengths unavailable.

Approval duration: 6 months.

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved: Levoleucovorin is indicated for: (1) rescue after high-dose methotrexate therapy in osteosarcoma, (2) diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists, and (3) use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. It is NOT approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

For IV use only. Do NOT administer intrathecally. Levoleucovorin is dosed at one-half the usual dose of racemic leucovorin.

Rescue After High-Dose Methotrexate Therapy

Rescue recommendations are based on a methotrexate dose of 12 grams/m2 administered IV over 4 hours. Provide levoleucovorin rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starting 24 hours after the beginning of the methotrexate infusion. Determine serum creatinine and methotrexate levels at least once daily. Continue levoleucovorin administration, hydration, and urinary alkalinization (pH of 7or greater) until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The dosage may need to be adjusted based on methotrexate levels. Refer to the prescribing information for dosing recommendations.

Administration in Combination with 5-Fluorouracil (5-FU)

The following regimens have been used historically for the treatment of colorectal cancer:

• Levoleucovorin 100 mg/m2 by slow IV injection over a minimum of 3 minutes, followed by 5-FU 370 mg/m2 IV.

• Levoleucovorin 10 mg/m2 by IV injection followed by 5-FU 425 mg/m2 IV.

Both treatments are repeated daily for five days. The 5-day treatment course may be repeated at 4 week (28-day) intervals, for two courses and then repeated at 4 to 5 week (28 to 35 day) intervals if the member has completely recovered from the toxic effects of the prior treatment course. In subsequent treatment courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. 5-FU and levoleucovorin should be administered separately to avoid the formation of a precipitate.

Methotrexate Overdosage

Rescue should begin as soon as possible after overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between methotrexate and rescue increases, levoleucovorin’s effectiveness in counteracting toxicity may decrease. Levoleucovorin 7.5 mg (approximately 5 mg/m2) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M. Serum creatinine and methotrexate levels should be determined at 24 hour intervals. The dosage may need to be adjusted based on methotrexate levels. Refer to the prescribing information for dosing recommendations.

PRECAUTIONS:

CONTRAINDICATION:

• Patients who have had previous allergic reactions attributed to folic acid or folinic acid

WARNINGS:

Rate of Administration: Due to the calcium ion (Ca2+) content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected IV per minute.

Potential for Enhanced Toxicity with 5-Fluorouracil: Levoleucovorin enhances the toxicity of 5-FU and deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and 5-FU. When administered concurrently, the dosage of 5-FU is typically lower than if administered alone. Compared to 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination.

Potential for Interaction with Trimethoprim-Sulfamethoxazole: Concomitant use of leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study.

Pregnancy and Nursing: Animal reproduction studies have not been conducted and it is unknown whether levoleucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Only give to a pregnant woman if clearly needed. It is not known whether this drug is excreted in human milk.

Drug Availability:

Fusilev brand: supplied in three different strengths: (1) 50 mg of freeze-dried powder for reconstitution in a single-use vial, (2) 175 mg per 17.5 mL solution (10 mg/mL) in a single-use vial, and (3) 250 mg per 25 mL solution (10 mg/mL) in a single-use vial. The unreconstituted powder may be stored at room temperature; however, the solution must be stored under refrigeration.

Generics also available in all strengths.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J0641

Injection, Levoleucovorin Calcium, 0.5 mg

ICD-10 Diagnoses Codes That Support Medical Necessity

C15.3 – C15.5, C15.8, C15.9

Malignant neoplasm of esophagus

C16.0 – C16.9

Malignant neoplasm of stomach

C17.0 – C17.3, C17.8, C17.9

Malignant neoplasm of small intestine

C18.0 – C18.9

Malignant neoplasm of colon

C19

Malignant neoplasm of rectosigmoid junction

C20

Malignant neoplasm of rectum

C21.8

Malignant neoplasm of overlapping sites of rectum, anus and anal canal

C25.0 - C25.4, C25.7 – C25.9

Malignant neoplasm of pancreas

C37

Malignant neoplasm of thymus

C40.00 – C40.02

Malignant neoplasm of scapula and long bones of upper limb

C40.10 – C40.12

Malignant neoplasm of short bones of upper limb

C40.20 – C40.22

Malignant neoplasm of long bones of lower limb

C40.30 – C40.32

Malignant neoplasm of short bones of lower limb

C40.80 – C40.82

Malignant neoplasm of overlapping sites of bone and articular cartilage of limb

C40.90 – C40.92

Malignant neoplasm of unspecified bones and articular cartilage of limb

C41.0 – C41.4, C41.9

Malignant neoplasm of bone and articular cartilage of other and unspecified sites

C56.1 – C56.9

Malignant neoplasm of ovary

C57.00 – C57.9

Malignant neoplasm of other and unspecified female genital organs

C67.0 – C67.9

Malignant neoplasm of bladder

C78.00 – C78.02

Secondary malignant neoplasm of lung

C78.1

Secondary malignant neoplasm of mediastinum

C78.2

Secondary malignant neoplasm of pleura

C78.30, C78.39

Secondary malignant neoplasm of other and unspecified respiratory organs

C78.4

Secondary malignant neoplasm of small intestine

C78.5

Secondary malignant neoplasm of large intestine and rectum

C78.6

Secondary malignant neoplasm of retroperitoneum and peritoneum

C78.7

Secondary malignant neoplasm of liver and intrahepatic bile duct

C78.80, C78.89

Secondary malignant neoplasm of other and unspecified digestive organs

C79.31, C79.32

Secondary malignant neoplasm of brain and cerebral meninges

C79.40, C79.49

Secondary malignant neoplasm of other and unspecified parts of nervous system

C80.0

Disseminated malignant neoplasm, unspecified

C80.1

Malignant (primary) neoplasm, unspecified

C83.00 – C83.09

Small cell b-cell lymphoma

C83.10 – C83.19

Mantle cell lymphoma

C83.30 – C83.39

Diffuse large b-cell lymphoma

C83.50 – C83.59

Lymphoblastic (diffuse) lymphoma

C83.70 – C83.79

Burkitt lymphoma

C83.80 – C83.89

Other non-follicular lymphoma

C83.90 – C83.99

Non-follicular (diffuse) lymphoma, unspecified

C84.40 – C84.49

Mature T/NK-cell lymphomas

C84.60 – C84.69

Anaplastic large cell lymphoma, alk-positive

C84.70 – C84.79

Anaplastic large cell lymphoma, alk-negative

C85.80 – C85.89

Other specified types of non-hodgkin lymphoma

C86.0 - C86.6

Other specified types of T/NK-cell lymphoma

C91.00 – C91.02

Acute lymphoblastic leukemia [all]

C91.50 – C91.52

Adult T-cell lymphoma/leukemia

C91.Z0

Other lymphoid leukemia not having achieved remission

C91.Z2

Other lymphoid leukemia, in relapse

D15.0

Benign neoplasm of thymus

D37.1 – D37.9

Neoplasm of uncertain behavior of oral cavity and digestive organs

T36.8X1A, T36.8X1D, T36.8X1S

Poisoning by other systemic antibiotics, accidental (unintentional)

T36.8X2A, T36.8X2D, T36.8X2S

Poisoning by other systemic antibiotics, intentional self-harm

T36.8X3A, T36.8X3D, T36.8X3S

Poisoning by other systemic antibiotics, assault

T36.8X4A, T36.8X4D, T36.8X4S

Poisoning by other systemic antibiotics, undetermined

T37.0X1A, T37.0X1D, T37.0X1S

Poisoning by sulfonamides, accidental (unintentional)

T37.0X2A, T37.0X2D, T37.0X2S

Poisoning by sulfonamides, intentional self-harm

T37.0X3A, T37.0X3D, T37.0X3S

Poisoning by sulfonamides, assault

T37.0X4A, T37.0X4D, T37.0X4S

Poisoning by sulfonamides, undetermined

T37.2X1A, T37.2X1D, T37.2X1S

Poisoning by antimalarials and drugs acting on other blood protozoa, accidental (unintentional)

T37.2X2A, T37.2X2D, T37.2X2S

Poisoning by antimalarials and drugs acting on other blood protozoa, intentional self-harm

T37.2X3A, T37.2X3D, T37.2X3S

Poisoning by antimalarials and drugs acting on other blood protozoa, assault

T37.2X4A, T37.2X4D, T37.2X4S

Poisoning by antimalarials and drugs acting on other blood protozoa, undetermined

T39.4X1A, T39.4X1D, T39.4X1S

Poisoning by antirheumatics, not elsewhere classified, accidental (unintentional)

T39.4X2A, T39.4X2D, T39.4X2S

Poisoning by antirheumatics, not elsewhere classified, intentional self-harm

T39.4X3A, T39.4X3D, T39.4X3S

Poisoning by antirheumatics, not elsewhere classified, assault

T39.4X4A, T39.4X4D, T39.4X4S

Poisoning by antirheumatics, not elsewhere classified, undetermined

T45.1X1A, T45.1X1D, T45.1X1S

Poisoning by antineoplastic and immunosuppressive drugs, accidental (unintentional)

T45.1X2A, T45.1X2D, T45.1X2S

Poisoning by antineoplastic and immunosuppressive drugs, intentional self-harm

T45.1X3A, T45.1X3D, T45.1X3S

Poisoning by antineoplastic and immunosuppressive drugs, assault

T45.1X4A, T45.1X4D, T45.1X4S

Poisoning by antineoplastic and immunosuppressive drugs, undetermined

T45.1X5A, T45.1X5D, T45.1X5S

Adverse effect of antineoplastic and immunosuppressive drugs

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

DEFINITIONS:

None

RELATED GUIDELINES:

None

OTHER:

None

REFERENCES:

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. URL www.clinicalpharmacilogy-ip.com. Accessed 2/14/17
  2. Fusilev (levoleucovorin calcium) [prescribing information]. Spectrum Pharmaceuticals, Inc. Irvine (CA). April 2011.
  3. Leucovorin calcium injection [prescribing information]. Bedford Laboratories. Bedford (OH). September 2013.
  4. Leucovorin calcium tablets [prescribing information]. Teva Pharmaceuticals. Sellersville (PA). February 2014.
  5. Levoleucovorin calcium injection [prescribing information]. Mylan Institutional. Rockford (IL). June 2015.
  6. Levoleucovorin calcium injection [prescribing information]. Sandoz Inc. Princeton (NJ). March 2015.
  7. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 2/14/17
  8. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 2/16/17.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 2.2017. Bone Cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/bone.pdf. Accessed 2/21/17.
  10. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 1.2017. Colon Cancer. Available at http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 2/21/2017.
  11. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 2.2017. Rectal Cancer. Available at http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed 2/21/17.
  12. Scheithauer W, Kornek G, Marczell A, et al. Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol. 1997 Mar;15(3):908-14.
  13. Goldberg RM, Hatfield AK, Kahn M, et al. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997;15(11):3320-3329.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 03/08/17.

GUIDELINE UPDATE INFORMATION:

04/01/15

New Medical Coverage Guideline.

11/01/15

Revision: ICD-9 Codes deleted.

04/15/16

Review and revision to guideline consisting of updating the description section, how supplied, and references.

10/01/16

Update to ICD-10 codes.

04/15/17

Review and revision to guideline consisting of updating description, drug availability, coding and references.

Date Printed: December 18, 2017: 11:33 AM