ModifiedmhnPolicy CP.PHAR.304

Irinotecan Liposome (Onivyde) Coverage Criteria

Medical necessity and prior authorization criteria for Onivyde (liposomal irinotecan) for pancreatic and select off-label adenocarcinomas, including dosing limits, prescriber requirements, and duration of approval for affected members under Centene-affiliated health plans.

Policy Summary

Payermhn

PolicyIrinotecan Liposome (Onivyde) Coverage Criteria

Policy CodePolicy CP.PHAR.304

Change TypeMaterial clinical updates (FDA/NCCN alignment)

Effective DateFeb 1, 2017

Next Review Date

Key ActionSubmit prior authorization with documentation demonstrating diagnosis, prior therapies, regimen and dosing per criteria.

SourceLink

POLICY UPDATE CHANGES

Added newly FDA-approved use as first-line therapy when prescribed in combination with oxaliplatin, fluorouracil, and leucovorin for metastatic disease.

Specified that disease must be locally advanced, metastatic, or recurrent and required disease progression following gemcitabine-based therapy or fluoropyrimidine-based therapy without prior irinotecan for certain indications.

Updated language replacing 'FOLFIRINOX' with 'fluoropyrimidine-based therapy and no prior irinotecan' and added 'component of NALIRIFOX regimen'.

Added ampullary adenocarcinoma off-label criteria supported by NCCN compendium and guideline and option for combination with NALIRIFOX as first-line therapy for metastatic ampullary adenocarcinoma.

Extended initial approval duration from 6 months to 12 months.

12 monthsapproval duration

50 mg/m2NALIRIFOX dose

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Coverage Criteria

Initial Therapy — Covered when ALL of the following are met for the specified diagnosis group

Covered when ALL of the following are met for the specified diagnosis group

Pancreatic Adenocarcinoma Initial: 1. Diagnosis of locally advanced, metastatic, or recurrent pancreatic adenocarcinoma; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Prescribed in one of the following ways: (a) In combination with oxaliplatin, fluorouracil, and leucovorin (component of the NALIRIFOX regimen) as first-line therapy; OR (b) In combination with fluorouracil and leucovorin for disease progression following gemcitabine-based therapy, or fluoropyrimidine-based therapy without prior irinotecan; 5. Request meets one of the following dosing conditions: (a) Dose does not exceed 50 mg/m2 every 2 weeks when used as a component of NALIRIFOX; OR (b) Dose does not exceed 70 mg/m2 every 2 weeks when prescribed with fluorouracil and leucovorin only; OR (c) Dose is supported by practice guidelines or peer-reviewed literature with prescriber submission of supporting evidence.

Approval duration: 12 months

Ampullary Adenocarcinoma Initial (off-label): 1. Diagnosis of ampullary adenocarcinoma; 2. Prescribed by or in consultation with an oncologist; 3. Age ≥ 18 years; 4. Member meets one of the following: (a) Prescribed in combination with fluorouracil and leucovorin for disease progression after prior therapy with: (i) gemcitabine-based therapy; OR (ii) fluoropyrimidine-based therapy without prior irinotecan; OR (iii) oxaliplatin-based therapy without prior irinotecan; OR (b) For metastatic disease, prescribed in combination with oxaliplatin, fluorouracil, and leucovorin (component of NALIRIFOX) as first-line therapy; 5. Dose is within FDA maximum limits for any FDA-approved indication or is supported by practice guidelines/peer-reviewed literature (prescriber must submit supporting evidence).

Approval duration: 12 months

Other Diagnoses/Indications: 1. If the drug has undergone a label change within the last 6 months that is not yet reflected in this policy, follow the formulary/non-formulary or no-coverage criteria policies as applicable; OR 2. If the requested use is not listed in Section III and criterion 1 does not apply, refer to the off-label use policy for the relevant line of business (HIM.PA.154 for marketplace or CP.PMN.53 for Medicaid).

Prescribed regimen must be FDA-approved or recommended by NCCN

Continuation Therapy — Covered for continuation when ALL of the following are met

Covered for continuation when ALL of the following are met

Continuation Therapy: 1. Member is currently receiving Onivyde via the Centene benefit, or documentation supports that the member has received Onivyde for at least 30 days for a covered indication; 2. Member is responding positively to therapy; 3. If request is for a dose increase, the new dose must meet one of the following: (a) Does not exceed 50 mg/m2 every 2 weeks as a component of NALIRIFOX; (b) Does not exceed 70 mg/m2 every 2 weeks when used with fluorouracil and leucovorin only; (c) New dose is supported by practice guidelines or peer‑reviewed literature with prescriber submission of supporting evidence; 4. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Approval duration: 12 months

Coverage with criteria (narrative updates) — Covered when criteria align with FDA label and NCCN compendium guidance as updated

Covered when criteria align with FDA label and NCCN compendium guidance as updated

General coverage prerequisites: 1. Member has locally advanced, metastatic, or recurrent disease; 2. Indication aligns with FDA‑approved use or is supported by the NCCN compendium; 3. Documentation of prior progression on required prior therapies when specified (e.g., progression after gemcitabine‑based therapy or after fluoropyrimidine‑based therapy without prior irinotecan) when applicable; 4. Regimen details documented for combination uses (e.g., use with oxaliplatin/fluorouracil/leucovorin or as component of NALIRIFOX); 5. Prescribed regimen must be FDA‑approved or recommended by NCCN.

Updates in 4Q2022–4Q2025 clarified disease status, prior therapy requirements, added NALIRIFOX and ampullary adenocarcinoma options

Requests for uses that are non‑FDA approved and are not specifically addressed in this policy are not authorized unless the provider supplies sufficient documentation of efficacy and safety in accordance with the applicable off‑label use policies (CP.PMN.53 for Medicaid or HIM.PA.154 for the Health Insurance Marketplace) or other evidence of coverage documents.

This policy does not provide a separate, explicit exclusion list. Inclusion or exclusion of billing and procedure codes in the document is for informational purposes only and does not guarantee coverage. Providers must follow current professional coding guidance and applicable state Medicaid provisions, which may supersede this policy when determining coverage and reimbursement.

Uses for non‑FDA approved indications that lack sufficient supporting evidence per the applicable off‑label use policies are considered not authorized (not medically necessary) under this policy. Providers seeking coverage for off‑label uses must submit guideline- or literature‑based justification as described in the referenced off‑label policies.

The presence of a CPT/HCPCS code in this policy (for example, HCPCS J9205) does not by itself establish that a claim will be paid. Absent documentation of the medical indication, required prior therapies, regimen composition, or other policy criteria, the request may be denied even if an applicable code is submitted.

Coding and Billing

HCPCS CodesHCPCS

J9205

Injection, irinotecan liposome, 1 mg

Referenced HCPCS CodesHCPCS

J9205

Injection, irinotecan liposome, 1 mg

Dose limits — liposomal irinotecan

Dose limit (NALIRIFOX)50 mg/m2 IV every 2 weeks

Dose limit (with 5‑FU/leucovorin only)70 mg/m2 IV every 2 weeks

UGT1A1*28 homozygous guidanceIf homozygous for UGT1A1*28 allele start 50 mg/m2 IV every 2 weeks; may increase to 70 mg/m2 as tolerated in subsequent cycles

Initial approval duration

Initial approval duration12 months

Previous durationExtended from 6 months to 12 months per 4Q2025 review

Provider Actions and Requirements

Prior Authorization

Prior authorization required: demonstrate all criteria

Prior authorization is required. The provider must demonstrate that all approval criteria for the requested indication are met, including diagnosis (e.g., locally advanced, metastatic, or recurrent pancreatic adenocarcinoma), prescriber specialty, patient age, prescribed regimen, and dosing limits.

Examples of required criteria: diagnosis, prescriber specialty (oncologist involvement), age ≥ 18 years, regimen and dose within policy limits

Prior Authorization

Prior authorization for Onivyde (J9205) with indication and prior therapy

Prior authorization is required for irinotecan liposome (Onivyde; HCPCS J9205). Requests must include documentation of the indication and prior therapy progression when applicable, and regimen details when used in combination (e.g., oxaliplatin/fluorouracil/leucovorin or NALIRIFOX).

Relevant billing code: J9205 (Injection, irinotecan liposome, 1 mg)
Document indication, prior therapy progression (e.g., gemcitabine-based or fluoropyrimidine-based therapy without prior irinotecan), and combination regimen details

Covered Regimens and Dosing

Regimen	Indication	Liposomal irinotecan dose	Coverage status
NALIRIFOX (liposomal irinotecan + oxaliplatin + fluorouracil + leucovorin)
First-line metastatic pancreatic adenocarcinoma
50 mg/m2 IV every 2 weeks
Covered when criteria met

Regimen	Indication	Liposomal irinotecan dose	Coverage status
Liposomal irinotecan in combination with fluorouracil and leucovorin
Metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy
Up to 70 mg/m2 IV every 2 weeks (per dosing guidance)
Covered when criteria met

Regimen	Indication	Notes	Coverage status
Combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX)
First-line metastatic disease; component of NALIRIFOX for ampullary adenocarcinoma per NCCN
FDA-approved first-line combination for metastatic pancreatic adenocarcinoma; NCCN supports NALIRIFOX as option for metastatic ampullary adenocarcinoma
Covered when criteria met

Line of Therapy Definitions

first-line

First-line NALIRIFOX: Onivyde (irinotecan liposome) in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) as first-line therapy for metastatic pancreatic adenocarcinoma.Dose limit: 50 mg/m2 every 2 weeks

Must meet Initial Therapy criteria for pancreatic adenocarcinoma (see Initial Therapy block)

second-line

Second-line after gemcitabine: Onivyde in combination with fluorouracil and leucovorin for metastatic pancreatic adenocarcinoma after disease progression following gemcitabine‑based therapy (or fluoropyrimidine‑based therapy without prior irinotecan where specified).Dose limit: 70 mg/m2 every 2 weeks when used with fluorouracil and leucovorin only

Must meet Initial Therapy criteria for pancreatic adenocarcinoma (see Initial Therapy block)

Definitions

Definition — NALIRIFOX

NALIRIFOX componentsFluorouracil (5‑FU), leucovorin, liposomal irinotecan, and oxaliplatin

Regimen designationReferred to in policy Appendix D as 'NALIRIFOX'

Use contextUsed as a first‑line combination regimen for metastatic disease per FDA/NCCN updates

Definition — irinotecan liposome combination (NALIRIFOX)

Definition (regimen description)A chemotherapy regimen that includes irinotecan liposome as a component when combined with oxaliplatin, fluorouracil, and leucovorin — referred to as NALIRIFOX

Policy referencesAdded as a component/regimen in 4Q2023–4Q2024 reviews aligning with NCCN and FDA updates

Background

Irinotecan liposome (Onivyde) is a topoisomerase I inhibitor formulated as a liposomal injection and is used as a component of combination chemotherapy regimens for metastatic pancreatic adenocarcinoma and select off‑label adenocarcinomas. This policy aligns FDA‑approved indications and NCCN compendium recommendations to define covered combination regimens, dosing limits, prescriber requirements, and prior authorization criteria.

Step Therapy

Sequence requirement for second-line use: Onivyde + 5-FU/leucovorin

When used as second-line therapy for metastatic pancreatic adenocarcinoma, Onivyde must be prescribed in combination with fluorouracil and leucovorin after disease progression following gemcitabine-based therapy (or fluoropyrimidine-based therapy without prior irinotecan).

Second-line sequence: Onivyde + 5-FU/leucovorin following progression on gemcitabine-based therapy or fluoropyrimidine-based therapy without prior irinotecan

Step Therapy

Prior therapy requirement: document prior progression

Policy requires documentation of prior progression on specified prior therapies before use in certain indications — for example, progression following gemcitabine-based therapy or fluoropyrimidine-based therapy without prior irinotecan as specified in the coverage criteria.

Prior progression on gemcitabine-based therapy or on fluoropyrimidine-based therapy without prior irinotecan is required where stated in the criteria

Documentation Required

Required clinical documentation: submit office notes, labs, and evidence

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

Include documentation of diagnosis, disease status (locally advanced/metastatic/recurrent), prior therapies, and regimen/dose details
For doses or off‑label uses supported by guidelines/literature, prescriber must submit supporting evidence

Documentation Required

Required documentation: reference coding guidance and support indication

Providers should reference the most up-to-date professional coding guidance and supply documentation supporting FDA- or NCCN-based indications, disease status, prior therapies, and regimen components as applicable when submitting a request.

Confirm coding guidance prior to claim submission
Provide documentation linking the request to FDA label or NCCN recommendation (e.g., NALIRIFOX components)

Denial Risk

Non‑FDA indications require off‑label documentation or will be denied

Requests for non–FDA approved (off‑label) indications not addressed in this policy will be denied unless sufficient documentation of efficacy and safety is provided per the off-label use policies (CP.PMN.53 for Medicaid or HIM.PA.154 for marketplace).

If indication is off‑label and not in this policy, submit evidence per off‑label policies CP.PMN.53 or HIM.PA.154

Denial Risk

Coding-related denial risk: coding inconsistency may cause denial

Claims or authorization requests may be denied if coding is inconsistent with HCPCS guidance; inclusion or exclusion of codes in this policy does not guarantee coverage. Providers should reference current professional coding sources prior to claim submission.

Policy notes: inclusion/exclusion of codes does not guarantee coverage; verify HCPCS coding (J9205) against current guidance

first-line | subsequent

Line of therapy options: First‑line use when prescribed in combination with oxaliplatin, fluorouracil, and leucovorin (per recent FDA approval) OR use as component of NALIRIFOX for metastatic ampullary adenocarcinoma per NCCN; other uses require documented prior progression after gemcitabine‑based or fluoropyrimidine‑based therapy without prior irinotecan as specified in the policy.

Documented in 4Q2022–4Q2025 updates