Levoleucovorin (Khapzory)
Number: 0889
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Brand Selection for Medically Necessary Indications for Commercial Medical Plans
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: 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: its generic equivalents.
Policy
Scope of Policy
This Clinical Policy Bulletin addresses levoleucovorin (Khapzory) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.
Note: Requires Precertification:
Precertification of levoleucovorin (Khapzory) is required of all Aetna participating providers and members in applicable plan designs. For precertification of levoleucovorin (Khapzory), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.
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Criteria for Initial Approval
Aetna considers levoleucovorin (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*:
- Rescue treatment after high-dose methotrexate therapy; or
- Treatment of a folate antagonist overdose or impaired methotrexate elimination; or
- Combination therapy with fluorouracil-based chemotherapy regimens.
Aetna considers all other indications as experimental, investigational, or unproven.
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Continuation of Therapy
Aetna considers continuation of therapy with levoleucovorin (Khapzory or generic formulation) medically necessary in all members (including new members) requesting reauthorization who meet all initial medical necessity selection criteria.
Footnotes* Note: The leucovorin shortage must be documented on the U.S. Food and Drug Administration's Drug Shortages Index.
Dosage and Administration
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 generic formulation is available for intravenous administration only as the following:
For injection: 175 mg/17.5 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 (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 (Khapzory) intrathecally.
Levoleucovorin in Combination with Fluorouracil for the Treatment of Colorectal Cancer
- Levoleucovorin (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 (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, 2024; Meitheal Pharmaceuticals, 2020
Note: The branded product, Fusilev, has been discontinued by the manufacturer.
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
- Levoleucovorin/Khapzory is indicated for rescue after high-dose methotrexate therapy in adults and pediatric patients with osteosarcoma.
- Levoleucovorin/Khapzory is indicated for diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients.
- Levoleucovorin/Khapzory is indicated for the treatment of adults with metastatic colorectal cancer in combination with fluorouracil.
Compendial Uses
- Rescue treatment after high-dose methotrexate therapy
- Combination with fluorouracil-based chemotherapy regimens
Levoleucovorin is available as generic and as the brand 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 and Khapzory carry the following warnings and precautions:
- Increased gastrointestinal toxicities with fluorouracil
- Drug interaction with trimethoprim-sulfamethoxazole.
Generic levoleucovorin carries the additional warning and precaution (Meitheal Pharmaceuticals, 2020):
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 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.
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.
References
The above policy is based on the following references:
- Acrotech Biopharma, LLC. Khapzory (levoleucovorin) for injection, for intravenous use. Prescribing Information. East Windsor, NJ: Acrotech Biopharma; revised December 2024.
- Deshpande H. Levoleucovorin inhibits LOXL2 (lysyl oxidase like-2) to control breast cancer proliferation: A repurposing approach. J Biomol Struct Dyn. 2023 Jun 20 [Online ahead of print].
- 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):1236-1242.
- Meitheal Pharmaceuticals Inc. Levoleucovorin for injection, for intravenous use. Prescribing Information. Chicago, IL: Meitheal Pharmaceuticals; revised December 2020.
- National Comprehensive Cancer Network (NCCN). Levoleucovorin. NCCN Drugs and Biologics Compendium. Plymouth Meeting, PA: NCCN; July 2025.
- Yuuki S, Komatsu Y, Fuse N, et al. Modified-irinotecan/fluorouracil/levoleucovorin therapy as ambulatory treatment for metastatic colorectal cancer: Results of phase I and II studies. Clin Drug Investig. 2010;30(4):243-249.
