Levoleucovorin (Fusilev and Khapzory)

Number: 0889

Brand Selection for Medically Necessary Indications

Levoleucovorin Products

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Khapzory is more costly to Aetna than other levoleucovorin products. There is a lack of reliable evidence that Khapzory is superior to the lower cost levoleucovorin product: Fusilev or its generic equivalents. Therefore, when leucovorin is not an available/appropriate option, Aetna considers Khapzory to be medically necessary only for members who have a contraindication, intolerance or ineffective response to the available equivalent alternative levoleucovorin product: Fusilev or its generic equivalents.

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 (Fusilev and Khapzory), call (866) 752-7021(Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

1. Criteria for Initial Approval

   Aetna considers levoleucovorin (Fusilev, Khapzory, or generic formulation) medically necessary for any of the settings listed below, when leucovorin is not an appropriate/available option at this time Footnotes*:

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

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   See Dosage and Administration information.

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

Dosage and Administration

Fusilev is available for intravenous administration only as the following:

• For injection: 50 mg of levoleucovorin as a lyophilized powder in a single-dose vial for reconstitution.
• Injection: 175 mg/17.5 mL (10 mg/mL) or 250 mg/25 mL (10 mg/mL) in a single dose vial.

Khapzory is available for intravenous administration only as the following:

• For injection: 175 mg and 300 mg of levoleucovorin lyophilized powder in a single-dose vial for reconstitution.

Levoleucovorin is available for intravenous administration only as the following:

• For injection: 175 mg/17.5 mL (10 mg/mL) or 250 mg/25 mL (10 mg/mL) in a single-dose vial.

Rescue after high-dose methotrexate therapy

• Rescue recommendations are based on methotrexate dose of 12 grams/m² administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m²) every 6 hours, 24 hours after the beginning of methotrexate infusion.
• Continue until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). Adjust dose if necessary based on methotrexate elimination.

Overdosage of folic acid antagonists or impaired methotrexate elimination

• Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination.
• Administer levoleucovorin (Fusilev and Khapzory) injection 7.5 mg (approximately 5 mg/m2) intravenously every 6 hours until methotrexate level is less than 5 x 10-8 M (0.05 micromolar).

Do not administer levoleucovorin (Fusilev and Khapzory) intrathecally.

Levoleucovorin in Combination with Fluorouracil 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 fluorouracil 370 mg/m² once daily for 5 consecutive days.
• Levoleucovorin (Fusilev and Khapzory) is administered at 10 mg/m² by intravenous injection followed by fluorouracil 425 mg/m² once daily for 5 consecutive days.
• The above five-day courses may be repeated at 4 weeks for 2 courses, then every 4 to 5 weeks, if the person has recovered from toxicity from the prior course.
• Levoleucovorin and fluorouracil should be administered separately to avoid the formation of a precipitate.
• Do not adjust levoleucovorin dosage for toxicity.

Source: Acrotech Biopharma, 2020a, 2020b; Sandoz, 2020

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Levoleucovorin/Fusilev/Khapzory is indicated for rescue after high-dose methotrexate therapy in osteosarcoma.
• Levoleucovorin/Fusilev/Khapzory is indicated for diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination.
• Levoleucovorin/Fusilev/Khapzory is indicated for use in combination chemotherapy with fluorouracil for treatment of metastatic colorectal cancer.

Levoleucovorin is available as generic and as the brand Fusilev and Khapzory (Acrotech Biopharma, LLC). Levoleucovorin is the levo-isomer form of racemic d, 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). Leucovorin 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 purine and pyrimidine 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.

Per prescribing information, generic levoleucovorin, Fusilev, and Khapzory carry the following warnings and precautions:

• Increased gastrointestinal toxicities with fluorouracil
• Drug interaction with trimethoprim-sulfamethoxazole.

Generic levoleucovorin and Fusilev carry the additional warning and precaution (Sandoz, 2020; Acrotech Biopharma 2020a):

• Hypercalcemia: Due to the calcium content, inject no more than 16 mL (160 mg) of levoleucovorin solution intravenously per minute.

Per prescribing information, generic levoleucovorin, Fusilev, and Khapzory carry the following adverse reactions:

• The most common adverse reactions (≥20%) in patients on high-dose methotrexate therapy with levoleucovorin injection rescue are stomatitis and vomiting.
• The most common adverse reactions (>50%) in patients on levoleucovorin injection in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea.

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 neurologic manifestations continue to progress.

Fusilev (leucovorin) 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 (leucovorin) 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 Khapzory (levoleucovorin) 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.

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: