Levoleucovorin (Fusilev and Khapzory)

Number: 0889

Least Cost Medically Necessary Brands

In the event of a leucovorin shortage, Fusilev and its generic equivalent (levoleucovorin) are less costly to Aetna commercial plans and are at least as likely to produce equivalent therapeutic results as Khapzory.  Consequently, Khapzory will be considered medically necessary only if the member has a contraindication, intolerance or ineffective response to Fusilev or its generic equivalent.

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of levoleucovorin (Fusilev and Khapzory) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of levoleucovorin, call (866) 752-7021, or fax (866) 267-3277.

Aetna considers levoleucovorin (Fusilev or Khapzory) medically necessary for the following indications, when leucovorin is not appropriate/available option at this time Footnotes^*:

• Rescue treatment after high-dose methotrexate therapy; or
• Treatment of a folate antagonist overdose; or
• Combination therapy with fluorouracil based chemotherapy regimens.

Continued use of levoleucovorin is considered medically necessary for persons who meet initiation criteria.

Aetna considers levoleucovorin experimental and investigational for all other indications. 

Footnotes^* Note: The leucovorin shortage must be documented on the U.S. Food and Drug Administration's Drug Shortages Index.

Dosing Recommendations

Levoleucovorin in Combination with 5-Fluorouracil (5-FU) for the Treatment of Colorectal Cancer

• Levoleucovorin (Fusilev and Khapzory) is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5‐FU at 370 mg/m2 by intravenous injection.
• Levoleucovorin (Fusilev and Khapzory) is administered at 10 mg/m2 by intravenous injectionfollowed by 5-FU at 425 mg/m2 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.
• Fusilev and 5-FU should be administered separately to avoid the formation of a precipitate.
• Do not adjust Fusilev or Khapzory dosage for toxicity.

Source: Prescribing Information.

Background

Fusilev (levoleucovorin) is the levo isomeric form of racemicd, l-leucovorin, present as the calcium salt. Fusilev 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 methotrexate.

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.  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 methotrexate.

Fusilev (levoleucovorin) is approved by the U.S. Food and Drug Administration (FDA) for rescue after high‐dose methotrexate therapy in osteosarcoma, diminishing the toxicity and counteracting the effects of impaired methotrexate elimination 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 neurologicmanifestations continue to progress.

Fusilev was approved by the FDA in 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.  The safety and efficacy of levoleucovorin rescue following high-dose methotrexate was evaluated in 16 patients aged 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.

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.

On October 19, 2018, the U.S. FDA approved levoleucovorin (Khapzory) injection, a folate analog and the pharmacologically active levo isomer of racemic d,l-leucovorin, for three indications: rescue after high-dose methotrexate therapy in patients with osteosarcoma; diminishing the toxicity associated with overdosing on folic acid antagonists or impaired methotrexate elimination; and the treatment of patients with metastatic colorectal cancer in combination with fluorouracil. Khapzory is not indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to lack of vitamin B12 because of the risk of progression of neurologic manifestations despite hematologic remission.

The NCCN Drug and Biologics Compendium (NCCN, 2018) recommends the use of levoleucovorin in combination with fluorouracil-based regimens for the following recommendations, when leucovorin is not available: anal adenocarcinoma, appendiceal carcinoma, cervical adenocarcinoma or squamous cell carcinoma, colorectal adenocarcinoma, esophageal and esophagogastric junction (i.e. squamous cell carcinoma, adenocarcinoma), gastric adenocarcinoma, hepatocellular adenocarcinoma, neuroendocrine and adrenal tumors (i.e., poorly differentiated (high grade); large or small cell), occult primary (cancer of unknown primary [CUP]) adenocarcinoma, carcinoma not otherwise specified, or squamous cell carcinoma, ovarian mucinous carcinoma, pancreatic adenocarcinoma, pure adenocarcinoma of the urinary bladder including urachal, small bowel adenocarcinoma, and thymic carcinoma or thymoma.

NCCN Drug and Biologics Compendium (NCCN, 2018) also recommend use of levoleucovorinin combination with high-dose methotrexate when leucovorin is not available for the following indications: acute lymphoblastic leukemia, B-cell lymphomas, brain metastases, dedifferentiated chondrosarcoma, gestational trophoblastic neoplasia, high-grade undifferentiated pleomorphic sarcoma (UPS), leptomeningeal metastases, osteosarcoma, primary central nervous system lymphoma, and T-cell lymphomas.

The following allergic reactions were reported in patients receiving Fusilev: vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving Fusilev as rescue after high-dose methotrexate therapy. The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving Fusilev in combination with 5-FU were diarrhea, nausea and stomatitis.

The following allergic reactions were reported in patients receiving Khapzory: The most common adverse reactions (≥20%) in patients receiving highdose
methotrexate therapy with levoleucovorin rescue were stomatitis and vomiting.The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer were stomatitis, diarrhea, and nausea.

Levoleucovorin should not be utilized in the following:

• Do not administer intrathecally.
• 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 neurologicmanifestations continue to progress
• Levoleucovorin may enhance the toxicity of fluorouracil
• Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole forPneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo‐controlled study
• The Fusilev brand may counteract the antiepileptic effect of phenobarbital,phenytoin and primidone, and increase the frequency of seizures in susceptible members.
• Due to Ca++ content in the Fusilev brand, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute

Pancreatic Adenocarcinoma

National Comprehensive Cancer Network’s clinical practice guideline on "Pancreatic adenocarcinoma" (Version 1.2016) 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 2.2015) does not mention levoleucovorin as a therapeutic option.

Appendix

Fusilev 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.

Khapzory is supplied as: 175 mg vial and 300 mg single-dose vial, for intravenous use only.

Do not administer Fusilev or Khapzory intrathecally.

Fusilev (levoleucovorin) is dosed at one‐half the usual dose of the racemic form (leucovorin calcium).

Levoleucovorin for Rescue After High-Dose Methotrexate Therapy

Fusilev (levoleucovorin) rescue recommendations are based on a methotrexate dose of 12 grams/m² administered by intravenous infusion over four hours. Fusilev rescue is initiated 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 methotrexate infusion. Continue until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The Fusilev (levoleucovorin) dose and/or frequency may need to be adjusted.

Khapzory (levoleucovorin) rescue recommendations are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over four hours. Khaphzory rescue is initiated at a dose of 7.5 mg (approximately 5 mg/m² every six hours, 24 hours after the beginning of the methotrexate infusion. Continue until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). Adjust the Khapzory dose if necessary based on methotrexate elimination.

Dose Adjustments

Table: Dose Adjustments

Clinical Situation	Laboratory Findings	Fusilev and Khapzory Dosage and Duration
Normal methotrexate elimination	Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours	7.5 mg IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion)
Delayed late methotrexate elimination	Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration	Continue 7.5 mg IV q 6 hours, until methotrexate level is less than 0.05 micromolar
Delayed early methotrexate elimination and/or evidence of acute renal injury	Serum methotrexate 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 methotrexate administration (e.g., an increase 0.5 mg/dL to a level of 1 mg/dL or more)	75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Levoleucovorin (Fusilev and Khapzory):
Other CPT codes related to the CPB:
96365 - 96368	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
J0642	Injection, levoleucovorin (Khapzory), 0.5 mg
Other HCPCS codes related to the CPB:
J0640	Injection, leucovorin calcium, per 50 mg
J8610	Methotrexate, oral, 2.5 mg
J9190	Injection, fluorouracil, 500 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
ICD-10 codes covered if selection criteria are met:
C16.0 - C16.9	Malignant neoplasm of stomach
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]
C22.0	Liver cell carcinoma
C25.0 - C25.9	Malignant neoplasm of pancreas [pancreatic adenocarcinoma]
C37	Malignant neoplasm of thymus
C41.0 - C41.9	Malignant neoplasm of bone and articular cartilage
C49.0 - C49.9	Malignant neoplasm of connective and soft tissue [chondrosarcoma]
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C56.1 - C56.9	Malignant neoplasm of ovary [ovarian mucinous carcinoma]
C58	Malignant neoplasm of placenta [gestational trophoblastic neoplasia]
C67.0 - C67.9	Malignant neoplasm of bladder
C74.00 - C74.92	Malignant neoplasm of adrenal gland
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
C7A.00 - C7A.8	Malignant neuroendocrine tumors
C7B.00 - C7B.8	Secondary neuroendocrine tumors
C80.1	Malignant (primary) neoplasm, unspecified
C83.00 - C83.39	Non-follicular lymphoma [B-cell lymphoma]
C84.40 - C84.49	Peripheral T-cell lymphoma, not classified
C84.90 - C84.99	Mature T/NK-cell lymphomas, unspecified
C84.A0 - C84.A9	Cutaneous T-cell lymphoma, unspecified
C84.Z0 - C84.Z9	Other mature T/NK-cell lymphomas
C85.10 - C85.29	Other specified and unspecified types of non-Hodgkin lymphoma [B-cell lymphoma]
C91.00 - C91.02	Acute lymphoblastic leukemia [ALL]
T45.1X1+	Poisoning by antineoplastic and immunosuppressive drugs, accidental (unintentional), [methotrexate]
T45.1X5+	Adverse effect of antineoplastic and immunosuppressive drugs
T45.8X1+	Poisoning by other primarily systemic and hematological agents, accidental (unintentional) [methotrexate]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C44.520	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: