ModifiedCentenePolicy CP.PHAR.393

Leucovorin Injection

Policy governing medical necessity and prior authorization criteria for leucovorin injection for commercial and Medicaid lines of business within Centene-affiliated health plans.

Policy Summary

PayerCentene

PolicyLeucovorin Injection

Policy CodePolicy CP.PHAR.393

Change TypeRevised approval durationscontinuation pathway added

Effective Date12.01.18

Next Review Date

Key ActionSubmit prior authorization with supporting documentation (chart notes, labs) demonstrating indication and relevant MTX levels or guideline support.

SourceLink

POLICY UPDATE CHANGES

Revised initial approval durations for high-dose MTX therapy rescue and combination chemotherapy with 5-FU to 12 months for Medicaid line of business; added continuation of care pathway for high-dose MTX rescue as part of chemotherapy or combination chemotherapy with 5-FU.

Updated Appendix D per NCCN Compendium and reviewed/updated references.

HIM line of business removed.

Commercial, MedicaidLines of business

12m / 6mApproval durations (Medicaid/Commercial)

≤1 mg/dayDose cap (megaloblastic anemia)

J0640HCPCS

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Policy Header & Overview

Leucovorin — definition & primary uses

DefinitionLeucovorin: a reduced folate used to diminish toxicity or counteract impaired methotrexate (MTX) elimination/overdose and as an adjunct with 5‑fluorouracil (5‑FU).

Primary clinical usesRescue after high‑dose MTX, antidote for impaired MTX elimination or inadvertent folic‑acid‑antagonist overdose, treatment of megaloblastic anemia when oral therapy not feasible, and adjunct with 5‑FU for advanced colorectal cancer.

Routes of administrationOral (PO), intravenous (IV), or intramuscular (IM) depending on indication and regimen.

Leucovorin injection — strengths / formulation / QL summary

Available single‑dose vial strengths50 mg, 100 mg, 200 mg, 350 mg, 500 mg.

FormulationSingle‑dose vial for injection (leucovorin calcium).

Billing/HCPCS groupingHCPCS code J0640 corresponds to injection, leucovorin calcium, per 50 mg (see coding).

Abbreviations

MTXMethotrexate (abbreviation MTX).

5‑FU5‑Fluorouracil (abbreviation 5‑FU).

Coverage Criteria

Initial Therapy - MTX/Folic Acid Antagonist Toxicity

Covered when ALL of the following are met for Methotrexate/Folic Acid Antagonist Toxicity Prophylaxis

A. Methotrexate/Folic Acid Antagonist Toxicity Prophylaxis: 1. Prescribed for one of the following uses: a) Rescue after MTX therapy for osteosarcoma or an NCCN‑recommended cancer (see Appendix D); b) Antidote for impaired MTX elimination; c) Antidote for accidental overdose of folic acid antagonists (including MTX). 2. Request meets one of the following: a) Dose is appropriate and will be adjusted as necessary per section V; b) Dose is supported by practice guidelines or peer‑reviewed literature for the relevant use (prescriber must submit supporting evidence). 3. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Approval duration: Impaired elimination/accidental overdose: 1 month. High‑dose MTX therapy rescue: Medicaid 12 months; Commercial 6 months or to the member's renewal date, whichever is longer.

Initial Therapy - Megaloblastic Anemia

Covered when ALL of the following are met for Megaloblastic Anemia

B. Megaloblastic Anemia: 1. Diagnosis of megaloblastic anemia due to folic acid deficiency; 2. Member is not a candidate for oral folic acid therapy; 3. Dose does not exceed 1 mg per day.

Initial Authorization Criteria

Prior Authorization

Prior Authorization Required

Prior Authorization is required for leucovorin (see policy header). Approvals are granted only when all applicable clinical criteria are met and required documentation is provided. Failure to submit required documentation or requests for non‑covered indications may result in denial.

PA requests must include supporting clinical documentation (see list below).
Approvals issued for specified indications and durations only.
Requests for indications not listed under Initial or Continued Therapy are not covered.

Documentation Required

Required clinical documentation

Use this box to confirm the clinical information submitted with the prior authorization request. Lack of required documentation may delay or result in denial of the request.

Diagnosis and indication for leucovorin (e.g., rescue after high‑dose methotrexate, impaired MTX elimination, inadvertent MTX overdose, megaloblastic anemia due to folic acid deficiency, or use with 5‑FU combination chemotherapy).

Continuation / Renewal Criteria

Continuation Therapy - Megaloblastic Anemia

Continuation therapy for Megaloblastic Anemia - Covered when ALL are met

Continuation - Megaloblastic Anemia: 1. Member meets one of the following: a) Currently receiving medication via Centene benefit or previously met initial approval criteria; b) Member is currently receiving medication and is enrolled in a state/product with continuity of care regulations; 2. Member is not a candidate for oral folic acid therapy; 3. Member is responding positively to therapy; 4. If request is for a dose increase, new dose does not exceed 1 mg per day.<=1 mg/day

Approval duration: Medicaid 12 months; Commercial 6 months or to the member's renewal date, whichever is longer.

Continuation Therapy - Other Indications

Continuation therapy for other indications in Section I - Covered when ALL are met

Continuation - Other Indications: 1. Member meets one of the following: a) Currently receiving medication via Centene benefit or previously met initial approval criteria; b) Member is currently receiving medication and is enrolled in a state/product with continuity of care regulations; c) Documentation supports member has received the requested drug for high‑dose MTX rescue as part of chemotherapy or combination chemotherapy with 5‑FU for at least 30 days; 2. Member is responding positively to therapy; 3. If request is for a dose increase, new dose either does not exceed regimen in section V or is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence). Prescribed regimen must be FDA‑approved or recommended by NCCN.

Provider Actions, Documentation & Alerts

Documentation Required

Submit chart notes, labs, or other clinical information

Providers must submit supporting clinical documentation—such as office chart notes, laboratory results, or other clinical information—demonstrating that the member meets all approval criteria.

Include documentation of indication, dosing, and response to therapy as applicable.

Documentation Required

Document serum MTX levels/timing and serum creatinine changes

Clinical documentation should include serum methotrexate levels with timing (e.g., 24, 48, 72, 96 hours) and any changes in serum creatinine to guide dosing and duration of rescue therapy.

Record MTX levels and timing to demonstrate when rescue can be stopped (e.g., continue until MTX <0.05 μM) and to justify extended or intensified rescue for delayed elimination or renal injury.

Coding & Billing

HCPCS CodesHCPCS

J0640

Injection, leucovorin calcium, per 50 mg

Serum methotrexate levels — clinical thresholds

Normal elimination benchmarksSerum MTX ~10 μM at 24 hours; ~1 μM at 48 hours; <0.2 μM at 72 hours.

Rescue stop thresholdContinue leucovorin until serum MTX < 5 x 10^-8 M (0.05 μM).

Delayed/severe thresholdsDelayed elimination: >0.2 μM at 72 h and >0.05 μM at 96 h. Severe: ≥50 μM at 24 h or ≥5 μM at 48 h (or 100% increase in serum creatinine at 24 h).

Background

Leucovorin is a reduced folate (folinic acid) used clinically to diminish toxicity from folic acid antagonists. It functions as a rescue agent after high‑dose methotrexate (MTX) therapy, as an antidote in cases of impaired MTX elimination or accidental overdosage of folic acid antagonists, and as an adjunct to enhance the cytotoxicity of fluorouracil (5‑FU) in certain chemotherapy regimens.

Typical uses described in the policy include: rescue following high‑dose MTX (to reduce marrow and mucosal toxicity until serum MTX concentrations fall to target thresholds), treatment of megaloblastic anemia when oral folic acid is not feasible, and administration in combination with 5‑FU for colorectal and other NCCN‑recommended cancer regimens. Clinical guidance and dosing regimens are drawn from recognized practice guidelines and the policy’s referenced literature and appendices.

Rescue therapy — definition & operational note

Rescue therapy — definitionAdministration of leucovorin after high‑dose methotrexate to reduce toxicity and continue until serum MTX falls below specified thresholds (e.g., <0.05 μM).

Operational note — timingStandard rescue begins 24 hours after start of MTX infusion; dosing repeated every 6 hours as specified until MTX targets met.

AdjustmentsExtend or intensify rescue for delayed elimination or renal injury per specified higher‑dose regimens (see dosing guidance).

Quantity Limits & Formulations

Leucovorin injection — strengths and HCPCS per‑50 mg code

Single‑dose vial strengths (recap)50 mg, 100 mg, 200 mg, 350 mg, 500 mg available as single‑dose injection vials.

HCPCS per‑50 mg codeJ0640 — Injection, leucovorin calcium, per 50 mg (use for billing per 50 mg increments).

Implication for quantityBilling and quantity calculations reference 50 mg units (J0640); select vial strengths to match ordered mg and billing increments.

Revision History & Policy Changes

2018-12-01Effective date

Policy effective date set to 12.01.18.

2021-07-01Annual review

4Q 2021 annual review — no significant clinical changes; administrative reference code updated and references reviewed.

2022-08-25Annual review

4Q 2022 annual review — Appendix D updated per NCCN Compendium; template changes applied to continued therapy section; references reviewed.

Policy Summary

PayerCentene

PolicyLeucovorin Injection

Policy CodePolicy CP.PHAR.393

Change TypeRevised approval durationscontinuation pathway added

Effective Date12.01.18

Next Review Date

Key ActionSubmit prior authorization with supporting documentation (chart notes, labs) demonstrating indication and relevant MTX levels or guideline support.

SourceLink

On This Page

Approval duration: Medicaid 12 months; Commercial 6 months or to the member's renewal date, whichever is longer.

Initial Therapy - Combination with 5‑FU

Covered when ALL of the following are met for use in combination with 5‑FU

C. Combination Chemotherapy with 5‑FU: 1. Prescribed for use in a fluorouracil‑based chemotherapy regimen for colorectal cancer or an NCCN‑recommended cancer (see Appendix D); 2. Prescribed by or in consultation with an oncologist; 3. Prescribed in combination with 5‑FU; 4. Request meets one of the following: a) For colorectal cancer, dose does not exceed the regimen in section V; b) Dose is supported by practice guidelines or peer‑reviewed literature for the relevant use (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN. Approval duration: (per policy) Medicaid 12 months; Commercial 6 months or to the member's renewal date, whichever is longer.

Initial therapy — general initial authorization criteria by indication

Covered when ALL of the following initial authorization criteria by indication are met

Initial Therapy: See Initial Approval Criteria sections for MTX/Folic Acid Antagonist Toxicity, Megaloblastic Anemia, and Combination Chemotherapy with 5‑FU. Prescribed regimens must be FDA‑approved or recommended by NCCN; prescriber must submit supporting evidence when dosing deviates from section V or for nonstandard regimens.

Approval durations vary by indication and line of business (see individual sections).

Covered Indications

Covered when ALL of the following are met for specified indications

High‑dose MTX rescue: Leucovorin administered as rescue after high‑dose methotrexate per dosing regimens: 15 mg (approximately 10 mg/m2) PO, IV, or IM every 6 hours for 10 doses starting 24 hours after beginning of MTX infusion; continue until MTX level is below 5 x 10^-8 M (0.05 μM). Adjust or extend rescue based on clinical situation and laboratory findings; alternative regimens described for delayed elimination and renal injury.MTX level targets described in section V

Adjust or extend rescue based on clinical situation and lab findings.

Inadvertent MTX overdosage: Administer as soon as possible and within 24 hours of MTX administration: 10 mg/m2 PO, IV, or IM every 6 hours until serum MTX < 10^-8 M; increase to 100 mg/m2 IV q3h if 24‑hour creatinine increased 50% over baseline or if 24‑hour MTX > 5 x 10^-6 M or 48‑hour MTX > 9 x 10^-7 M.Serum MTX and creatinine criteria per dosing guidance

Give promptly.

Combination with 5‑FU (advanced colorectal cancer): Leucovorin administered with 5‑fluorouracil per recommended regimens: either 200 mg/m2 IV over ≥3 minutes followed by 5‑FU 370 mg/m2 IV, or 20 mg/m2 IV leucovorin followed by 5‑FU 425 mg/m2 IV; repeated daily x5 days and may be repeated at 28‑day intervals as tolerated.Treatment intervals and recovery from prior toxicity as described

Used to enhance 5‑FU cytotoxicity.

Megaloblastic anemia: Leucovorin up to 1 mg IV or IM once daily for treatment of megaloblastic anemia due to folic acid deficiency when oral therapy is not feasible.1 mg/day max

Requests for use of leucovorin for indications that are not FDA‑approved and are not specifically addressed in this policy will not be authorized unless the provider submits sufficient documentation of efficacy and safety in accordance with the applicable off‑label use policies: CP.CPA.09 (commercial) or CP.PMN.53 (Medicaid). Supporting materials may include peer‑reviewed literature, recognized practice guidelines, or other evidence of coverage documents demonstrating the requested off‑label use is medically appropriate.

Coding listed in this clinical policy is provided for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage; providers should consult current professional coding guidance prior to submitting claims for reimbursement.

Within the excerpt of this document there are no explicit entries described as “not medically necessary”. Absence of such a list in this excerpt does not preclude application of medical necessity determinations based on clinical review and policy criteria.

Prescriber specialty or documentation of oncology consultation when required (e.g., combination chemotherapy with 5‑FU).

Planned dosing regimen, route of administration and duration.

Laboratory data supporting need when applicable (serum methotrexate levels and serum creatinine values, with dates/times), and any evidence of delayed MTX elimination.

If dose/regimen differs from guideline-listed regimens, submit peer‑reviewed literature or guideline support.

For accidental overdose or impaired elimination, documentation of timing of MTX administration and clinical course.

Denial Risk

Non‑covered Indications Risk

Leucovorin is not covered for uses other than those specified in the Initial or Continued Therapy criteria (for example, general vitamin supplementation or indications without supporting evidence/guideline recommendation). Requests for non‑covered indications will be denied.

Any use not listed under Initial Approval Criteria or Continuation Requirements is considered not covered.
Doses exceeding the maximums specified in the Dosage and Administration section without supporting evidence are at high risk of denial.
Use outside of FDA‑approved or NCCN‑recommended regimens without adequate literature support may be denied.

Dosing and Initial Approval Durations

Initial therapy dosing regimens and approval durations

dosing_initial

Approval duration: Impaired elimination/accidental overdose: 1 month; All other indications: Medicaid 12 months; Commercial 6 months or to the member's renewal date, whichever is longer. Continuation of care pathway added for high‑dose MTX rescue as part of chemotherapy or combination with 5‑FU.

Continuation therapy — general rules for continuation of covered indications

Continuation eligibility: Member currently receiving medication via Centene benefit or has previously met initial approval criteria; OR member is currently receiving medication and is enrolled in a state/product with continuity of care regulations; OR documentation supports at least 30 days of therapy for high‑dose MTX rescue when applicable.

Member must be responding positively to therapy; dose increases require that new dose not exceed section V regimens or be supported by practice guidelines/peer‑reviewed literature (prescriber must submit evidence). Continuation of care pathway added for high‑dose MTX rescue as part of chemotherapy or combination chemotherapy with 5‑FU; initial approval durations for Medicaid set to 12 months for specified indications.

Step Therapy

Continuation/renewal eligibility and documentation required

Continuation/renewal requests require that the member is currently receiving the medication via a Centene benefit or previously met initial approval criteria, or is eligible under continuity‑of‑care rules; the member must be responding positively to therapy and documentation must support ongoing use.

For other indications, documentation that the member has received the drug for high‑dose MTX rescue as part of chemotherapy or with 5‑FU for at least 30 days satisfies continuation eligibility.

Note

Continuation pathway added for high‑dose MTX rescue

A specific continuation‑of‑care pathway was added for high‑dose MTX rescue when given as part of chemotherapy or in combination with 5‑FU to support continuation of therapy.

Continuation pathway / step	Requirement summary
Continuation of care pathway for high‑dose methotrexate (MTX) rescue as part of chemotherapy or combination chemotherapy with 5‑fluorouracil (5‑FU)
Member currently receiving medication via the Centene benefit, previously met initial approval criteria, or is eligible under continuity‑of‑care regulations; documentation of at least 30 days of therapy for high‑dose MTX rescue may be accepted for continuation
Member is responding positively to therapy (clinical documentation required: office notes, lab results including serum MTX levels and timing, and creatinine changes)
Continuation approvals follow revised initial approval duration policy (initial approval for applicable Medicaid indications revised to 12 months); renewal duration aligns with applicable line of business and member renewal date

Denial Risk

Off‑label requests risk denial without sufficient evidence

Requests for indications that are non‑FDA approved and not addressed in this policy will be denied unless sufficient documentation of efficacy and safety is provided in accordance with the off‑label use policies (CP.CPA.09 for commercial; CP.PMN.53 for Medicaid).

Billing Rule

Coding inclusion/exclusion does not guarantee coverage

Coding listed in the policy is for informational purposes only; inclusion or exclusion of codes does not guarantee coverage—providers should verify current coding guidance before submitting claims.

Reference up‑to‑date professional coding resources prior to claim submission.

Prior Authorization

Prior authorization duration revised to 12 months for Medicaid (certain indications)

Initial approval durations for high‑dose MTX rescue and combination chemotherapy with 5‑FU have been revised to 12 months for the Medicaid line of business; prior authorization requirements and durations have been updated accordingly.

Medicaid initial approval duration for high‑dose MTX rescue: 12 months (updated).

Step Therapy

Continuation pathway added for high‑dose MTX rescue (operational)

A specific continuation‑of‑care pathway was added to permit continuation for high‑dose MTX rescue given as part of chemotherapy or in combination with 5‑FU, enabling continuation requests when documentation shows the member has received the medication for the required period.

Continuation eligibility includes documentation of at least 30 days of therapy for high‑dose MTX rescue when applicable.

NCCN‑recommended indications (Appendix D)

NCCN Appendix D referenceAppendix D lists NCCN‑recommended cancer indications for leucovorin use in combination with MTX (2A) and with fluorouracil (2A) for multiple tumor types.

ScopeIncludes pediatric and adult hematologic and solid tumor indications (see Appendix D for full list).

Policy requirementPrescribed regimens must be FDA‑approved or recommended by NCCN per policy criteria when applicable.

2023-08-09Annual review

4Q 2023 annual review — Appendix D updated per NCCN Compendium; references reviewed and updated.

2024-07-15Annual review

4Q 2024 annual review — HIM line of business removed; Appendix D updated per NCCN Compendium; references reviewed and updated.

2025-07-09Material changeLatest

4Q 2025 annual review — revised initial approval durations for high-dose methotrexate rescue and combination chemotherapy with 5‑FU to 12 months for Medicaid line of business and added a continuation-of-care pathway for high‑dose MTX rescue as part of chemotherapy or combination chemotherapy with 5‑FU; references reviewed and updated.

Material changes in the most recent review were applied to the Medicaid line of business and were approved by Pharmacy & Therapeutics (P&T). Specifically, initial approval durations for high‑dose MTX rescue and for leucovorin used in combination chemotherapy with 5‑FU were revised to an initial authorization period of 12 months for Medicaid. In addition, a continuation of care pathway was added to support ongoing authorization for high‑dose MTX rescue when provided as part of chemotherapy or combination chemotherapy with 5‑FU; references and Appendix D were updated per the NCCN Compendium.