BCBSNJ Medical Policy for - (Drugs) Policy Number

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Horizon BCBSNJ
Uniform Medical Policy Manual	Section:	Drugs
	Policy Number:	122
	Effective Date:	01/17/2020

	Original Policy Date:	10/28/2014
	Last Review Date:	12/10/2019
	Date Published to Web:	11/10/2014

Subject:
Levoleucovorin (Fusilev and Khapzory)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Fusilev was approved on March 7, 2008 for rescue after high-dose methotrexate therapy in osteosarcoma. It is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.

In December 2008, the National Comprehensive Cancer Network^® (NCCN) Drugs and Biologic Compendium™ listed Fusilev to be used in combination with high-dose methotrexate for the treatment of bone cancer (osteosarcoma and dedifferentiated chrondrosarcoma).

In April 2011, the FDA approved Fusilev for injection in combination with 5-FU containing regimens in advanced metastatic colorectal cancer. The NCCN Clinical Practice Guidelines in Oncology™ in Colon Cancer and Rectal Cancer were updated to state that Fusilev was available in the United States.

Fusilev is indicated to be administered as an intravenous infusion and is dosed at one-half the usual dose of the racemic form. It is not to be administered intrathecally.

In October 2018, the FDA approved Khapzory (levoleucovorin) injection for all indications that were previously approved in Fusilev, including: Rescue after high-dose methotrexate therapy in patients with osteosarcoma; Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination; and treatment of patients with metastatic colorectal cancer in combination with fluorouracil. The approval was based on the same clinical studies that were previously done in Fusilev.

Policy:
NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.

The requirements of the Horizon BCBSNJ Fusilev (Levoleucovorin for Intravenous Infusion) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).]

1. Fusilev and Khapzory are considered medically necessary for the FDA-approved indication of use as:

Patient is 6 years or older; AND
Patient is undergoing high dose MTX chemotherapy treatment for osteosarcoma; AND
Must be used as rescue therapy in combination with chemotherapy regimen containing high dose MTX; AND
Racemic (d,l) leucovorin calcium is not obtainable (in any dosage strength or with any generic manufacturer) as confirmed by FDA Drug shortage website located at: http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm

Patient is 6 years or older; AND
Patient is undergoing treatment with a folic acid antagonist such as MTX; AND
Patient has developed toxicity due to impaired elimination or inadvertent overdosage of the folic acid antagonist (i.e. MTX); AND
Racemic (d,l) leucovorin calcium is not obtainable (in any dosage strength or with any generic manufacturer) as confirmed by FDA Drug shortage website located at: http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm

Must be used as a component of palliative treatment with a chemotherapy regimen containing 5-fluorouracil (5-FU); AND
Racemic (d,l) leucovorin calcium is not obtainable (in any dosage strength or with any generic manufacturer) as confirmed by FDA Drug shortage website located at: http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm

[INFORMATIONAL NOTE: The safety and efficacy of Fusilev rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 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.

The mean number of Fusilev doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Fusilev rescue following high-dose methotrexate was based on the adverse reaction profile.]

2. When Fusilev and Khapzory are considered medically necessary, initial therapy will be approved for 6 months based on FDA-approved labeling:

a) Rescute after high-dose methotrexate (MTX) therapy in osteosarcoma

7.5 mg (approximately 5 mg/m2) IV every 6 hours for 10 doses starting 24 hours after beginning of methotrexate infusion. Dosing is based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Continue until methotrexate levels are less than 5 x 10^‐8 M (0.05 micromolar)

7.5 mg (approximately 5 mg/m²) IV every 6 hours until methotrexate levels are less than 10^‐8 M (0.01 micromolar)

100 mg/m² administered by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m² by intravenous injection.

10 mg/m² administered by intravenous injection followed by 5-FU at 425 mg/m²by intravenous injection.

[INFORMATIONAL NOTE: For palliative treatment in advanced metastatic colorectal cancer, treatment is repeated daily for 5 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.

The dosage of levoleucovorin should be one-half the usual dose of racemic d,l-leucovorin.

]

3. When medically necessary, Fusilev and Khapzory will be renewed for another 6 months based on the following criteria:

http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm

AND

b) Patient must be continuing combination therapy with high dose methotrexate for treatment of osteosarcoma; OR patient must be continuing palliative combination chemotherapy with 5 –fluorouracil (5-FU) for treatment of metastatic colorectal cancer; AND

c) Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include the following: hypersensitivity reactions, seizures, and severe gastrointestinal disorders such as stomatitis, severe diarrhea, and severe nausea and vomiting.

4. Fusilev and Khapzory are considered medically necessary for the following off-label uses:

http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm

Acute Lymphoblastic Leukemia (both Fusilev and Khapzory)
B cell Lymphomas (both Fusilev and Khapzory)
Bone Cancer(both Fusilev and Khapzory ~~only~~)
Central Nervous System Cancer(both Fusilev and Khapzory)
Gestational Trophoblastic Neoplasia (Fusilev only)
T-Cell Lymphomas (both Khapzory and Fusilev)
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (both Khapzory and Fusilev)
Soft Tissue Sarcoma - Rhabdomyosarcoma (both Khapzory and Fusilev)

http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm

Anal Carcinoma (both Fusilev and Khapzory)
Bladder Cancer (both Fusilev and Khapzory)
- Non-urothelial and urothelial with variant histology
Cervical Cancer (both Fusilev and Khapzory)
Esophageal and Esophagogastric Junction Cancers (both Fusilev and Khapzory)
Gastric Cancer (both Fusilev and Khapzory)
Neuroendocrine and Adrenal Tumors (both Fusilev and Khapzory)
- Poorly Differentiated (High Grade)/Large or Small Cell
Occult Primary (both Fusilev and Khapzory)
Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer – (both Fusilev and Khapzory)
- Mucinous Carcinoma
Pancreatic Adenocarcinoma (both Khapzory and Fusilev)
Thymomas and Thymic Carcinomas (both Fusilev and Khapzory ~~only~~)
Hepatobiliary cancers (both Khapzory and Fusilev)
Colon Cancer (both Fusilev and Khapzory)
Rectal Cancer (both Fusilev and Khapzory)
Small Bowel Adenocarcinoma (both Fusilev and Khapzory)

5. Other uses of Fusilev and Khapzory are considered investigational including, but not limited to, pernicious anemia and megaloblastic anemia.

Medicare Coverage

There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage will follow the Horizon Policy. See generally: Local Coverage Article: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available at: https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=53049&ver=44&name=314*1&UpdatePeriod=711&bc=AQAAEAAAAAAAAA%3d%3d&.

For step therapy criteria, Medicare Advantage product will follow the Horizon policy.

Medicaid Coverage

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Fusilev
Levoleucovorin

References:

1. Fusilev [package insert]. Irvine, CA; Spectrum Pharmaceuticals, Inc; April 2011. Accessed November 2019.

2. Spectrum Pharmaceuticals. FDA approves Fusilev for use in patients with colorectal cancer. April 2011. Available at: http://investor.spectrumpharm.com/releasedetail.cfm?ReleaseID=573364

3. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Colon Cancer; Version 1.2015. Accessed April 2016.

4. Goorin A, Strother D, Poplack D, et al. Safety and efficacy of l-leucovorin rescue following high-dose methotrexate for osteosarcoma. Med Pediatr Oncol. 1995 Jun;24(6):362-7.

5. National Comprehensive Cancer Network: Drugs and Biologics Compendium. Fusilev. 2019. Accessed November 2019. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=332

6. Khapzory [package insert]. Irvine, CA; Spectrum Pharmaceuticals, Inc; September 2019. Accessed November 2019.

7. National Comprehensive Cancer Network: Drugs and Biologics Compendium. Khapzory. 2019. Accessed November 2019. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=332

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

* CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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