MHN levoleucovorin (Khapzory) Coverage Update

Coverage Criteria

Initial Therapy - MTX/Folic Acid Antagonist Toxicity

Covered when ALL of the following are met:

Initial MTX/Folic Acid Antagonist Toxicity: 1) Prescribed for one of the following: rescue after MTX therapy for osteosarcoma or an NCCN‑recommended cancer; antidote for impaired MTX elimination; or antidote for accidental overdose of folic acid antagonists (including MTX). 2) Age ≥ 6 years. 3) One of the following: (a) documentation supports contraindication or clinically significant adverse effects to leucovorin; or (b) leucovorin is not available due to a documented national drug shortage on the FDA Drug Shortages Index. 4) Request meets one of the following: (a) dose is appropriate and will be adjusted as necessary per section V; or (b) dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN.

Initial Therapy - Combination with 5-FU

Covered when ALL of the following are met:

Combination with 5-FU: 1) Prescribed for use in a fluorouracil‑based chemotherapy regimen for colorectal cancer or an NCCN‑recommended cancer. 2) Prescribed by or in consultation with an oncologist. 3) Age ≥ 6 years. 4) Prescribed in combination with 5‑FU. 5) One of the following: (a) documentation supports contraindication or clinically significant adverse effects to leucovorin; or (b) leucovorin is not available due to a documented national drug shortage on the FDA Drug Shortages Index. 6) Request meets one of the following: (a) for colorectal cancer, dose does not exceed regimen in section V; or (b) dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN.

Continuation Therapy

Continued coverage requires ALL of the following:

Continuation Criteria: 1) Member meets one of the following: (a) currently receiving medication via Centene benefit or previously met initial approval criteria; (b) currently receiving medication and enrolled in a state/product with continuity of care regulations; or (c) documentation shows member has received Khapzory 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) Documentation supports contraindication or clinically significant adverse effects to leucovorin, or leucovorin remains unavailable due to a national drug shortage. 4) If request is for a dose increase: (a) new dose does not exceed the regimen in section V; or (b) new dose is supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).

Prescribed regimen must be FDA‑approved or recommended by NCCN; approval durations vary by line of business.

Initial and rescue dosing

Covered when dosing and monitoring criteria for methotrexate rescue or overdose are met

High-dose MTX rescue: If delayed early MTX elimination and/or evidence of acute renal injury (serum MTX ≥ 50 μM at 24 hours, ≥ 5 μM at 48 hours, or ≥100% increase in serum creatinine at 24 hours after MTX administration): administer 75 mg IV every 3 hours until MTX < 1 μM; then 7.5 mg IV every 3 hours until MTX < 0.05 μM. If significant clinical toxicity is observed, extend Khapzory therapy an additional 24 hours.see text

Maximum dose references 'See regimen' in source.

Inadvertent MTX overdose: Administer as soon as possible after overdose and within 24 hours of MTX administration if there is delayed excretion: 7.5 mg (≈5 mg/m2) IV every 6 hours until serum MTX < 5 x 10^-8 M. Increase to 50 mg/m2 IV every 3 hours if any of the following: 24‑hour serum creatinine has increased 50% over baseline; 24‑hour MTX level is > 5 x 10^-6 M; or 48‑hour MTX level is > 9 x 10^-7 M.see text

Maximum dose references 'See regimen' in source.

Non–FDA approved indications that are not specifically addressed in this policy are excluded from coverage unless the provider submits sufficient documentation of efficacy and safety consistent with the applicable off‑label use policies (CP.CPA.09 for Commercial, HIM.PA.154 for Health Insurance Marketplace, and CP.PMN.53 for Medicaid).

Per the 4Q 2025 annual review, Fusilev has been removed from the policy because it is no longer available. This administrative change was approved by P&T on 11.25 and is reflected in the policy coding and agent availability language.

Use of levoleucovorin for pernicious anemia or megaloblastic anemia secondary to vitamin B12 deficiency is not authorized. The policy excludes these diagnoses because hematologic improvement in B12‑related anemia does not address the risk of progression of neurologic manifestations associated with B12 deficiency.

Any lists of procedure or HCPCS codes included in this policy are provided for informational purposes only. Inclusion or exclusion of codes does not guarantee coverage; lack of documentation that the member meets the clinical criteria in this policy may result in the service not being covered. Providers should verify current professional coding guidance before claim submission.

Initial Therapy Criteria

Initial Therapy

Initial approval criteria per indication

Initial MTX rescue: See Initial Approval Criteria: indication (rescue after high‑dose MTX for osteosarcoma/NCCN cancers; antidote for impaired elimination; antidote for accidental overdose), age ≥ 6 years, and documentation of leucovorin contraindication/adverse effects or documented national leucovorin shortage. Dose must be appropriate per section V or supported by guidelines/peer‑reviewed literature (prescriber must submit evidence).

Approval durations differ by indication and line of business (see sections V and approval duration notes).

Initial dosing

Initial dosing regimens by indication

High-dose MTX rescue initial: Delayed early MTX elimination and/or acute renal injury (serum MTX ≥ 50 μM at 24 hours, ≥ 5 μM at 48 hours, or ≥100% increase in serum creatinine at 24 hours): 75 mg IV every 3 hours until MTX < 1 μM; then 7.5 mg IV every 3 hours until MTX < 0.05 μM. Extend an additional 24 hours if significant clinical toxicity is observed.serum MTX levels as specified

Continuation Criteria

Continuation Therapy

Continuation requirements for previously authorized therapy

Continuation: Member must be currently receiving medication or have previously met initial approval criteria; must be responding positively to therapy; documentation must support contraindication/adverse effects to leucovorin or ongoing national shortage; dose increases must not exceed regimens in section V or must be supported by practice guidelines/peer‑reviewed literature (prescriber must submit evidence).

Approval durations vary by line of business (see approval duration notes).

Duration updates

Initial approval durations updated for certain lines of business

Continuation: Initial approval durations for high‑dose MTX rescue and combination chemotherapy with 5‑FU revised to 12 months for Medicaid and HIM lines of business (from 4Q 2025 annual review).12 months

Coding

HCPCS CodesHCPCS

J0641	Injection, levoleucovorin, not otherwise specified, 0.5 mg
J0642	Injection, levoleucovorin (Khapzory), 0.5 mg

Serum methotrexate levels guiding dosing

Normal eliminationSerum MTX ≈ 10 μM at 24 hours; 1 μM at 48 hours; <0.2 μM at 72 hours

Delayed late eliminationSerum MTX > 0.2 μM at 72 hours and >0.05 μM at 96 hours — continue 7.5 mg IV every 6 hours until MTX < 0.05 μM

Severe/delayed early eliminationSerum MTX ≥ 50 μM at 24 hours or ≥5 μM at 48 hours (see severe thresholds in next block)

MTX and creatinine rescue thresholds

24-hour MTX thresholdSerum MTX ≥ 50 μM at 24 hours

48-hour MTX thresholdSerum MTX ≥ 5 μM at 48 hours

Provider Actions & Requirements

Prior Authorization

Prior Authorization Required

Prior authorization required — initial approval criteria must be met (age, indication, contraindication/shortage conditions). Providers must request PA before dispensing Khapzory.

Initial approval durations: Medicaid/HIM — 12 months; Commercial — 6 months or to member renewal date, whichever is longer (see Initial Approval Criteria).

Documentation Required

Documentation Required to Support Medical Necessity

Provider must submit supporting clinical documentation (office chart notes, laboratory results, or other clinical information). Failure to submit requested documentation may result in denial or delay of the request.

Examples of acceptable documentation: office progress notes, chemotherapy regimen documentation, and relevant consult notes.
If documentation is not received, the request may be pended or denied per plan policy.

Step Therapy / Therapeutic Alternatives

Step	Required prior therapy / therapeutic alternative	Notes
1	Leucovorin (therapeutic alternative)	Levoleucovorin (Khapzory) is allowed when leucovorin is contraindicated, not tolerated, or unavailable due to a documented national shortage; leucovorin is listed as the preferred therapeutic alternative in Appendix B.

Step	Required prior therapy / therapeutic alternative	Notes
1	No alternate leucovorin agent required	Fusilev has been removed from the policy as it is no longer available; no step-therapy requirement between Fusilev and Khapzory remains (Khapzory is the covered levoleucovorin product).

Site of Care / Administration

Note

Administer IV regimens per institutional infusion protocols

IV administration regimens and rescue/overdose dosing are provided in the Dosage and Administration section; administer per the institution’s/site’s infusion protocols in the infusion center setting.

Follow the dosing regimens for rescue, delayed elimination, or overdose as specified in section V.
Administer per institutional/site infusion protocols.

Note

Product supplied as single‑use vials — follow usual infusion practices

Product is supplied as single‑use vials (powder for reconstitution); follow usual infusion center reconstitution and administration practices for single‑use vials.

Available single‑use vial sizes: 175 mg and 300 mg.
Prepare and administer per standard single‑use vial reconstitution procedures.

Background

Levoleucovorin (Khapzory) is a folate analog (a form of folinic acid) used primarily as rescue therapy after high‑dose methotrexate (MTX), as an antidote for impaired MTX elimination or accidental MTX overdose, and historically in combination with fluorouracil (5‑FU) for metastatic colorectal cancer. For high‑dose MTX rescue, dosing is guided by serum MTX and renal function; in the setting of delayed MTX elimination (for example, serum MTX ≥ 50 μM at 24 hours or ≥ 5 μM at 48 hours), levoleucovorin rescue regimens are used to reduce toxicity. The product is supplied as single‑use vials for reconstitution and is administered intravenously per institutional infusion protocols.

Definitions

Khapzory (levoleucovorin) — description, indications

Drug class/descriptionLevoleucovorin (Khapzory) is a folate analog (folinic acid derivative) used as a rescue agent for methotrexate and as a modulator in combination with 5-FU.

FDA‑approved indicationsRescue after high‑dose methotrexate therapy; diminishing toxicity from overdosage of folic acid antagonists or impaired MTX elimination; in combination with 5‑FU for metastatic colorectal cancer.

Formulation/availabilitySingle‑use vials with powder for reconstitution (175 mg and 300 mg).

Typical use scenariosHigh‑dose MTX rescue, inadvertent MTX overdose antidote, and historical combination regimens with 5‑FU for colorectal cancer.

Delayed early MTX elimination definition

Definition (delayed early MTX elimination)

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Levoleucovorin (Khapzory) Coverage and Prior Authorization Criteria