Coverage Policy Manual
Policy #: 2021007
Category: Pharmacy
Initiated: May 2021
Last Review: March 2024
  Levoleucovorin Agents (e.g., Fusilev) and (e.g., Khapzory)
Description:
Levoleucovorin calcium and Levoleucovorin are folate analogues primarily used to diminish the toxicity and counteract the effects of impaired folic acid antagonists (such as methotrexate) and to enhance the therapeutic effects of fluoropyrimidines (such as 5-fluorouracil) in the treatment of various types of cancer. Levoleucovorin (l-LV) is the l-isomer, or biologically active moiety of leucovorin and is dosed at one-half that of the racemic mixture d,l-leucovorin (d-LV).
 
The FDA approved indications for levoleucovorin calcium and levoleucovorin include rescue following high-dose methotrexate in osteosarcoma, to diminish the toxicity and counteract the effects of impaired methotrexate elimination or inadvertent overdosage of folic acid antagonists, and in combination chemotherapy with 5-fluorouracil for advanced metastatic colorectal cancer.
 
The FDA also established limitations for use of both formulations.  Neither one is indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B12 because of the risk of progression of neurology manifestations despite hematologic remission.  
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Effective March 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of levoleucovorin meets primary coverage criteria for the treatment of the indications [FDA 2011] listed below only when there is documentation [FDA Drug Shortages Index] leucovorin is unavailable.
 
Levoleucovorin calcium and Levoleucovorin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for adults and pediatric individuals (>6 yrs) (Goorin, 1995: O’Connell, 1989) for the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
1. Rescue after high-dose methotrexate therapy with osteosarcoma (Fusilev, 2011; Khapzory, 2018); OR
2. Diminishing the toxicity of impaired methotrexate elimination (Fusilev, 2011; Khapzory, 2018); OR
3. Diminishing the toxicity of inadvertent over-dosage of folic acid (Fusilev, 2011; Khapzory, 2018); OR
4. In combination chemotherapy with fluorouracil-based regimens to treat metastatic colorectal adenocarcinoma (Fusilev, 2011; Khapzory, 2018).
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
CONTINUED APPROVAL for up to 12 months:
 
1. Individual continues to meet initial approval criteria; AND
2. Absence of unacceptable toxicity from the drug, e.g., hypersensitivity reactions, seizures, and severe gastrointestinal disorders such as stomatitis, severe diarrhea, severe nausea and vomiting; AND
3. Must be dosed in accordance with the FDA label.
 
Dosage and Administration
Dosing per FDA Guidelines
 
Rescue after high-dose Methotrexate therapy:
Adults and children >6 yrs:
7.5 mg (approximately 5 mg/m2) IV every 6 hrs for 10 doses starting 24 hours after the beginning of the methotrexate infusion.  
 
The levoleucovorin dosage may need to be increased or therapy may need to be extended based on methotrexate levels.  If significant clinical toxicity is observed, extend the levoleucovorin rescue for an additional 24 hours.  Administer levoleucovorin therapy, hydration and urinary alkalinization until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar)
 
Minimize toxic effects after an inadvertent folic acid antagonist overdose OR in those with impaired methotrexate elimination:
Adults and children > 6 yrs
7.5 mg (approximately 5 mg/m2) IV every 6 hours until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar); begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion.
 
If 24-hour serum creatinine concentration increases 50% or more from baseline or the serum methotrexate concentration is higher than 5 x 10-6 Molar at 24 hours or higher than 9 x 10-7 Molar at 48 hours, increase the levoleucovorin dosage to 50 mg/m2 IV every 3 hours until the serum methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar). Administer hydration (3 L/day) and urinary alkalinization with sodium bicarbonate; adjust the bicarbonate dose to maintain a urine pH 7 or higher.
 
For the palliative treatment of advanced metastatic colorectal cancer, in combination with 5-fluorouracil:
    • Levoleucovorin 100 mg/m2 by slow IV injection over at least 3 minutes followed by *5-fluorouracil 370 mg/m2 by IV injection once daily for 5 consecutive days; and
    • Levoleucovorin 10 mg/m2 by IV injection followed by *5-fluorouracil 425 mg/m2 by IV injection once daily for 5 consecutive days.
 
*Administer levoleucovorin and 5-fluorouracil separately to avoid precipitation:
Either regimen is given daily for 5 days repeated every 4 weeks (28-day) intervals for 2 cycles; subsequent cycles may be given at 4 to 5-week  (28 to 35 day) intervals once the patient has recovered from the toxic effects of the previous cycle.
 
Levoleucovorin doses are not adjusted for toxicity. Reduce the 5-fluorouracil daily dose by 20% in patients who experience moderate hematologic or gastrointestinal toxicity in the prior treatment course; reduce 5-fluorouracil daily dose by 30% in patients who have severe toxicity. The 5-fluorouracil dosage may be increased by 10% in patients who do not have toxicity in the prior cycle of therapy.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Levoleucovorin calcium and Levoleucovorin, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Levoleucovorin calcium and Levoleucovorin, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective September 2021 to February 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of levoleucovorin meets primary coverage criteria for the treatment of the indications [FDA 2011] listed below only when there is documentation [FDA Drug Shortages Index] leucovorin is unavailable.
 
Levoleucovorin calcium and Levoleucovorin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for adults and pediatric patients (>6 yrs) (Goorin, 1995: O’Connell, 1989) for the following indications:
 
Initial Treatment (approved for 1 yr)
1.  Rescue after high-dose methotrexate therapy with osteosarcoma (Fusilev, 2011; Khapzory, 2018); ; OR
2.  Diminishing the toxicity of impaired methotrexate elimination (Fusilev, 2011; Khapzory, 2018);  OR
3.  Diminishing the toxicity of inadvertent over-dosage of folic acid (Fusilev, 2011; Khapzory, 2018); ; OR
4.  In combination chemotherapy with fluorouracil-based regimens to treat metastatic colorectal adenocarcinoma (Fusilev, 2011; Khapzory, 2018).
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Continued treatment (12-month approval)
Continuation of therapy with Levoleucovorin calcium (Fusilev) and Levoleucovorin (Khapzory) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for continued therapy if all the following is met:
  1. Individual continues to meet initial approval criteria.  
  2. Absence of unacceptable toxicity from the drug, e.g., hypersensitivity reactions, seizures, and severe gastrointestinal disorders such as stomatitis, severe diarrhea, severe nausea and vomiting.
 
Dosage and Administration
 
Rescue after high-dose Methotrexate therapy:
Adults and children >6 yrs:
7.5 mg (approximately 5 mg/m2) IV every 6 hrs for 10 doses starting 24 hours after the beginning of the methotrexate infusion.  
 
The levoleucovorin dosage may need to be increased or therapy may need to be extended based on methotrexate levels.  If significant clinical toxicity is observed, extend the levoleucovorin rescue for an additional 24 hours.  Administer levoleucovorin therapy, hydration and urinary alkalinization until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar)
 
Minimize toxic effects after an inadvertent folic acid antagonist overdose OR in those with impaired methotrexate elimination:
Adults and children > 6 yrs
7.5 mg (approximately 5 mg/m2) IV every 6 hours until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar); begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion.
 
If 24-hour serum creatinine concentration increases 50% or more from baseline or the serum methotrexate concentration is higher than 5 x 10-6 Molar at 24 hours or higher than 9 x 10-7 Molar at 48 hours, increase the levoleucovorin dosage to 50 mg/m2 IV every 3 hours until the serum methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar). Administer hydration (3 L/day) and urinary alkalinization with sodium bicarbonate; adjust the bicarbonate dose to maintain a urine pH 7 or higher.
 
For the palliative treatment of advanced metastatic colorectal cancer, in combination with 5-fluorouracil:
  • Levoleucovorin 100 mg/m2 by slow IV injection over at least 3 minutes followed by *5-fluorouracil 370 mg/m2 by IV injection once daily for 5 consecutive days; and
  • Levoleucovorin 10 mg/m2 by IV injection followed by *5-fluorouracil 425 mg/m2 by IV injection once daily for 5 consecutive days.
 
*Administer levoleucovorin and 5-fluorouracil separately to avoid precipitation:
Either regimen is given daily for 5 days repeated every 4 weeks (28-day) intervals for 2 cycles; subsequent cycles may be given at 4 to 5-week  (28 to 35 day) intervals once the patient has recovered from the toxic effects of the previous cycle.
 
Levoleucovorin doses are not adjusted for toxicity. Reduce the 5-fluorouracil daily dose by 20% in patients who experience moderate hematologic or gastrointestinal toxicity in the prior treatment course; reduce 5-fluorouracil daily dose by 30% in patients who have severe toxicity. The 5-fluorouracil dosage may be increased by 10% in patients who do not have toxicity in the prior cycle of therapy.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Levoleucovorin calcium and Levoleucovorin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for all other indications.
 
For members with contracts without primary coverage criteria, the use of Levoleucovorin calcium and Levoleucovorin for the use of any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to September 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Levoleucovorin calcium (Fusilev) and Levoleucovorin (Khapzory) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for adults and pediatric patients (>6 yrs) for the following indications:
 
Initial Treatment (approved for 1 yr)
1.  Rescue after high-dose methotrexate therapy with osteosarcoma; OR
2.  Diminishing the toxicity of impaired methotrexate elimination; OR
3.  Diminishing the toxicity of inadvertent over-dosage of folic acid antagonists; OR
4.  In combination chemotherapy with fluorouracil-based regimens to treat metastatic colorectal adenocarcinoma.
5. Unavailability of racemic d,l-leucovorin in treatment regimen (and levoleucovorin used in place),  confirmed shortage by the FDA Drug Shortage website: http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting of specified criteria
Continued treatment (12-month approval)
Continuation of therapy with Levoleucovorin calcium (Fusilev) and Levoleucovorin (Khapzory) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for continued therapy if all the following is met:
    1. Individual continues to meet initial approval criteria.  
    2. Unavailability of racemic d,l-leucovorin in treatment regimen (and levoleucovorin used in place),  confirmed shortage by the FDA Drug Shortage website: http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm.
    3.  Absence of unacceptable toxicity from the drug, e.g., hypersensitivity reactions, seizures, and severe gastrointestinal disorders such as stomatitis, severe diarrhea, severe nausea and vomiting.
 
Dosage and Administration
 
Rescue after high-dose Methotrexate therapy.
Adults and children >6 yrs
7.5 mg (approximately 5 mg/m2) IV every 6 hrs for 10 doses starting 24 hours after the beginning of the methotrexate infusion.  
 
 The levoleucovorin dosage may need to be increased or therapy may need to be extended based on methotrexate levels.  If significant clinical toxicity is observed, extend the levoleucovorin rescue for an additional 24 hours.  Administer levoleucovorin therapy, hydration and urinary alkalinization until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar)
 
Minimize toxic effects after an inadvertent folic acid antagonist overdose OR in those with impaired methotrexate elimination.
Adults and children > 6 yrs
7.5 mg (approximately 5 mg/m2) IV every 6 hours until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar); begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion.
 
If 24-hour serum creatinine concentration increases 50% or more from baseline or the serum methotrexate concentration is higher than 5 x 10-6 Molar at 24 hours or higher than 9 x 10-7 Molar at 48 hours, increase the levoleucovorin dosage to 50 mg/m2 IV every 3 hours until the serum methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar). Administer hydration (3 L/day) and urinary alkalinization with sodium bicarbonate; adjust the bicarbonate dose to maintain a urine pH 7 or higher.
 
For the palliative treatment of advanced metastatic colorectal cancer, in combination with 5-fluorouracil
1) levoleucovorin 100 mg/m2 by slow IV injection over at least 3 minutes followed by *5-fluorouracil 370 mg/m2 by IV injection; and
 
2) levoleucovorin 10 mg/m2 by IV injection followed by *5-fluorouracil 425 mg/m2 by IV injection.
*Administer levoleucovorin and 5-fluorouracil separately to avoid precipitation.
 
Either regimen is given daily for 5 days repeated every 4 weeks (28-day) interval s for 2 cycles; subsequent cycles may be given at 4 to 5-week  (28 to 35 day) intervals once the patient has recovered from the toxic effects of the previous cycle.
 
Levoleucovorin doses are not adjusted for toxicity. Reduce the 5-fluorouracil daily dose by 20% in patients who experience moderate hematologic or gastrointestinal toxicity in the prior treatment course; reduce 5-fluorouracil daily dose by 30% in patients who have severe toxicity. The 5-fluorouracil dosage may be increased by 10% in patients who do not have toxicity in the prior cycle of therapy.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Levoleucovorin calcium (Fusilev) and Levoleucovorin (Khapzory) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for all other indications.
For members with contracts without primary coverage criteria, the use of Levoleucovorin calcium (Fusilev) and Levoleucovorin (Khapzory) for the use of any other indication is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Rescue after High-Dose Methotrexate Therapy in Patients with Osteosarcoma
The efficacy of levoleucovorin rescue following high-dose methotrexate were evaluated in 16 patients, ages 6-21 years, who received 58 courses of chemotherapy 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 adverse reaction profile.
 
Metastatic Colorectal Cancer
In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with metastatic colorectal cancer comparing d,l-leucovorin (LV) 200 mg/m2 and fluorouracil 370 mg/m2 versus LV 20 mg/m2 and fluorouracil 425 mg/m2 versus fluorouracil 500 mg/m2 , with all drugs administered by intravenous infusion daily for 5 days every 28 to 35 days, response rates were 26% (p=0.04 versus fluorouracil alone), 43% (p=0.001 versus fluorouracil alone), and 10%, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose LV regimen was associated with a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen was associated with a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms, but these were not statistically significant. In a second Mayo/NCCTG randomized clinical study the fluorouracil alone arm was replaced by sequentially administered methotrexate (MTX), fluorouracil, and LV. Response rates with LV 200 mg/m2 and fluorouracil 370 mg/m2 versus LV 20 mg/m2 and fluorouracil 425 mg/m2 versus sequential MTX and fluorouracil and LV were 31% (p≤0.01), 42% (p≤0.01), and 14%, respectively. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months. There was no statistically significant difference in weight gain of more than 5% or in improvement in performance status between the treatment arms. A randomized controlled trial conducted by the NCCTG in patients with metastatic colorectal cancer failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l-leucovorin in overall survival. Patients were randomized to fluorouracil 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, then every 5 weeks until disease progression or unacceptable toxicity.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2024. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
J0641Injection, levoleucovorin, not otherwise specified, 0.5 mg
J0642Injection, levoleucovorin (khapzory), 0.5 mg
References: Fusilev® (d,l Levoleucovorin; Levoleucovorin) [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020140s002lbl.pdf; last accessed 02/12/2021

Goorin A, Strother D, Poplack D, et al.(1995) Safety and Efficacy of l-Leucovorin Rescue Following High-Dose Methotrexate for Osteosarcoma. Med Pediatr Oncol. 1995 Jun;24(6):362-7. doi: 10.1002/mpo.2950240605

Khapzory™ (d,l Levoleucovorin; Levoleucovorin) [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211226s000lbl.pdf; last accessed 02/12/2021

NCCN Compendium®. Levoleucovorin. https://www.nccn.org/professionals/drug_compendium/content/

O’Connell MJ.(1989) A Phase Ill Trial of 5-Fluorouracil and Leucovorin in the Treatment of Advanced Colorectal Cancer A Mayo Clinic/North Central Cancer Treatment Group Study. Cancer 1989 Mar 15;63(6 Suppl):1026-30. doi: 10.1002/1097-0142(19890315)63:6+<1026::aid-cncr2820631307>3.0.co;2-r.

U.S. Food and Drug Administration, FDA Drug Shortages. http://www.fda.gov/Drugs/drugsafety/DrugShortages/default.htm. Last accessed February 05, 2021
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.