Clinical UM Guideline


Subject: Levoleucovorin Calcium (Fusilev®)
Guideline #:  CG-DRUG-63 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017


This document addresses the clinical indications for the folate analogue levoleucovorin calcium (Fusilev, Spectrum Pharmaceuticals Inc., Irvine, CA). Levoleucovorin is the pharmacologically active optical isomer of leucovorin, it is purely comprised of the biologically active l-isomer.

Clinical Indications

Medically Necessary:

Use of levoleucovorin calcium is considered medically necessary for any of the following indications: 

Not Medically Necessary:

Use of levoleucovorin calcium is considered not medically necessary when the criteria above are not met and for all other indications.

Clinically Equivalent Cost Effective Agents

Note: When levoleucovorin is determined to be medically necessary based on the clinical criteria above, the benefit plan may have in addition a medical necessity criterion that the treatment be cost effective.  

A benefit plan may select any one or more of the following as clinically equivalent cost effective leucovorin agents: Fusilev (levoleucovorin) and leucovorin. A list of one or more cost effective leucovorin agents for each plan is available here.

In benefit plans where there is a requirement to use a cost effective leucovorin agent, requests for a leucovorin agent that is not cost effective may be approved when the following criteria are met:

  1. The individual has had a trial of and inadequate response or is intolerant to one cost effective agent ; and
  2. For the prescribed indication, the cost effective agent(s) is/are not FDA-approved or does not meet the off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use (see below).

FDA-approved Indications or Indications Meeting off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use



Levoleucovorin Calcium (Fusilev®)


Osteosarcoma; after high dose methotrexate therapy



Methotrexate; to diminish toxicity and counteract the effects of impaired elimination



Colorectal cancer, advanced- in combination with fluorouracil (5-FU) as palliative treatment



Metastatic colorectal cancer, as palliative therapy for advanced disease in combination with 5FU



Megaloblastic anemia due to folic acid deficiency



Folic acid antagonists; unintentional or inadvertent overdosage



Central nervous system (CNS) cancers, Leptomeningeal metastases, Metastatic central nervous system lesions, Primary CNS lymphoma



Colon Cancer, adenocarcinoma



Esophageal and esophagogastric junction cancer, squamous cell carcinoma; adenocarcinoma



Gastric Cancer



Non Hodgkin’s Lymphoma

  • Adult T-Cell Leukemia/Lymphoma
  • AIDS-Related B-Cell Lymphoma
  • Anaplastic Large Cell Lymphoma (ALCL); breast implant associated
  • Burkitt Lymphoma
  • Mantle Cell Lymphoma
  • Peripheral T-Cell Lymphoma



Leukemia, Acute Lymphoblastic Leukemia (ALL)



Occult Primary; squamous cell, adenocarcinoma or carcinoma not otherwise specified



Ovarian Cancer - Mucinous Carcinoma of the Ovary



Pancreatic adenocarcinoma



Rectal cancer, adenocarcinoma



Thymic carcinoma or thymoma



X = FDA-approved Indications
Y = Indications Meeting off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use


The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




Injection, levoleucovorin calcium, 0.5 mg



ICD-10 Diagnosis



All diagnoses

Discussion/General Information

Levoleucovorin calcium, the levorotatory l isomer of racemic d,l-leucovorin, is an active, chemically reduced derivative of folic acid. Leucovorin is composed of both the d and l isomers. Levoleucovorin is derived from the l isomer, which is the biologically active isomer of leucovorin. The d isomer has been reported as being devoid of pharmacologic activity. For this reason, information on the pharmacology, adverse effects and drug interactions associated with leucovorin was assumed to also reflect the properties of levoleucovorin (Chuang, 2012). Both drugs reduce the effects of folic acid antagonists such as methotrexate which act by inhibiting dihydrofolate reductase. Both drugs also enhance the therapeutic and toxic effects of fluoropyrimidines such as 5-fluorouracil. 

The U.S. Food and Drug Administration (FDA) approved levoleucovorin in 2008 for use with high-dose methotrexate in osteosarcoma and as a treatment to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent over-dosage of folic acid antagonists. In 2011, the approval was updated for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

In 2008, a leucovorin shortage was reported. While the original shortage was resolved in 2009, shortages were again were reported in 2010. The FDA continues to report ongoing, intermittent shortages for leucovorin at this time. Levoleucovorin was FDA approved during the initial leucovorin shortage (Hayes, 2014). Many institutions have used levoleucovorin as a substitute for leucovorin when leucovorin has not been available. Pharmacokinetic and clinical studies have supported a conclusion that levoleucovorin is equivalent to leucovorin in terms of efficacy and safety and the two drugs can be used interchangeably. However, there is no evidence that levoleucovorin provides any incremental health benefits over leucovorin.

Kovoor and colleagues (2009) performed a comprehensive literature review of the use of levoleucovorin versus leucovorin in in gastrointestinal malignancies. The authors identified three studies which directly compared leucovorin (LV) and levoleucovorin (l-LV), two randomized controlled trials which compared LV and 1-LV in as a modulator of 5-Fluorouracil in advanced colorectal cancer and one pharmacokinetic comparison.  The results of the clinical studies demonstrated equivalence in terms of response, toxicity and survival. Similarly, there was no pharmacokinetic advantage shown regarding the use of l-LV versus LV. In addition, the authors also evaluated 125 studies which included LV, l-LV or a combination of either of these drugs. While most of the studies dealt with colon or rectal cancer, other studies evaluated l-LV or LV treatment in gastric, pancreatic or neuroendocrine cancers. The authors note that LV and racemic LV have been used interchangeably and there appears to be no difference in efficacy or side effects regardless of whether they are used in combination with other chemotherapeutic or alone.

In 2012, Chuang and Suno evaluated the literature regarding the efficacy and safety of levoleucovorin for oncologic indications and assessed whether levoleucovorin is a reasonable alternative to racemic leucovorin. The authors included both clinical studies and pharmacokinetic studies. A total of six randomized phase III trials evaluated the use of levoleucovorin and two randomized phase III trials directly compared treatments with leucovorin versus levoleucovorin. The authors noted that there was no significant difference in in efficacy or adverse effects between the two drugs whether or not they were used in combination with other chemotherapeutic agents. The authors concluded:

This review shows that levoleucovorin has been used interchangeably with leucovorin for modulating fluorouracil in patients with malignancies. There appears to be no significant difference in efficacy or adverse effects between levoleucovorin and leucovorin, regardless of whether they are used in combination with other chemotherapeutic agents.

The National Comprehensive Cancer Network® (NCCN®) recommends with a category 2A level of evidence, the use of levoleucovorin in colorectal cancer when used in combination with fluorouracil-based regimens when leucovorin is not available. The NCCN colon cancer clinical practice guideline (CPG) (2017) notes there is a recent shortage of leucovorin in the United States, the panel recommends the use of levoleucovorin in place leucovorin as an option to alleviate the effects of the shortage.

Several NCCN CPGs reference the current shortage of leucovorin in the U.S. and propose substitution with levoleucovorin as one option to alleviate the effects of the shortage (Pancreatic Adenocarcinoma, Esophageal and Esophagogastric Junction Cancers and Gastric Cancer, 2017). NCCN also indicated that using lower doses of leucovorin for all doses in all individuals is an option. The NCCN panel noted that based upon the results of several studies lower doses are likely to be as efficacious as higher doses. Finally, the NCCN panel noted that if the other options are not available, treatment without leucovorin is reasonable.

Adverse Events and Warnings

Levoleucovorin dosage is one half the standard dosage of leucovorin. While these medications can be used interchangeably there is an increased potential for dosing errors.

Limitations of use and warnings from the FDA PI Label (2011) include the following:


Analogue: A drug or substance which is similar to, but not identical, to another drug or substance.

Antagonist: An agent which blocks the binding of an agonist (a substance that binds to a specific receptor and triggers a response in the cell) at a receptor site.

FDA Drug Shortage Index. Available at: Accessed on September 19, 2017.

Isomer: Drugs or substances that share the same chemical formula but have different molecular arrangements. l-LV and d-LV are stereoisomers that are non-superimposable mirror images of each other. Though some isomers show different chemical properties, l-LV and d-LV have been shown to have equivalent therapeutic effects.


Peer Reviewed Publications:

  1. Chuang VT, Suno M. Levoleucovorin as replacement for leucovorin in cancer treatment. Ann Pharmacother. 2012; 46(10):1349-1357.
  2. 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.
  3. Hayes MS, Ward MA, Slabaugh SL, Xu Y. Lessons from the leucovorin shortages between 2009 and 2012 in a medicare advantage population: where do we go from here? Am Health Drug Benefits. 2014; 7(5):264-270.
  4. Jaffe N, Jorgensen K, Robertson R, et al. Substitution of l-leucovorin for d,l-leucovorin in the rescue from high-dose methotrexate treatment in patients with osteosarcoma. Anticancer Drugs. 1993; 4(5):559-564.
  5. Kovoor PA, Karim SM, Marshall JL. Is levoleucovorin an alternative to racemic leucovorin? A literature review. Clin Colorectal Cancer. 2009; 8(4):200-206.
  6. 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; 15(3):908-914.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Fusilev [Product Information]. Spectrum Pharmaceuticals, Inc.; April 2011. Available at: Accessed on September 19, 2017.
  2. Levoleucovorin. In: DrugPoints System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated February 17, 2017. Available at: Accessed on September 19, 2017.
  3. Levoleucovorin Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 13, 2012. Accessed on September 19, 2017.
  4. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: Accessed on September 19, 2017.
  5. NCCN Clinical Practice Guidelines in Oncology®. 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: Accessed on September 19, 2017.
    • Colon Cancer (V.2.2017). Revised March 13, 2017.
    • Esophageal and Esophagogastric Junction Cancers (V.2.2017). Revised August 7, 2017.
    • Gastric Cancer (V.3.2017) Revised August 22, 2017.
    • Pancreatic Adenocarcinoma (V.3.2017). Revised September 11, 2017.
    • Rectal Cancer (V.3.2017). Revised March 13, 2017.
Websites for Additional Information
  1. National Cancer Institute (NCI). Leucovorin Calcium. Updated July 11, 2013. Available at: Accessed on September 18, 2017.
  2. National Institute of Health: MedlinePlus. Leucovorin Injection. Revised February 11, 2012. Available at: Accessed on September 18, 2017.
  3. National Institute of Health: MedlinePlus. Levoleucovorin Injection. Revised December 11, 2012. Available at: Accessed on September 18, 2017.

Citrovorum factor
Folinic acid

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.







Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Discussion, Clinically Equivalent Cost Effective Agents, and References sections.



MPTAC review. Changed title of the “Preferred Agents” section to “Clinically Equivalent Cost Effective Agents”.



MPTAC review.



Hematology/Oncology Subcommittee review. Initial document development.