ModifiedCentenePolicy CP.PHAR.304

Irinotecan Liposome (Onivyde) - Clinical Policy

Defines medical necessity, dosing limits, and authorization requirements for Onivyde (irinotecan liposome) for adults with metastatic or recurrent pancreatic adenocarcinoma and selected off‑label use in ampullary adenocarcinoma for Centene-affiliated lines of business.

Policy Summary

PayerCentene

PolicyIrinotecan Liposome (Onivyde) - Clinical Policy

Policy CodePolicy CP.PHAR.304

Change TypeMaterial clinical updates and approval-duration extension

Effective DateFeb 1, 2017

Next Review Date

Key ActionSubmit prior authorization with documentation demonstrating diagnosis, prescriber specialty, age, regimen, and dosing within specified limits.

SourceLink

POLICY UPDATE CHANGES

Added ampullary adenocarcinoma off-label criteria as supported by NCCN compendium and guideline.

Updated FDA-approved indications section to align with prescriber information and updated continued therapy section from 'pancreatic adenocarcinoma' to 'all indications in Section I'.

Updated initial approval duration from 6 months to 12 months for initial approval criteria.

Clarified prior therapy language to require fluoropyrimidine-based therapy and no prior irinotecan; recognized NALIRIFOX regimen components.

50 mg/m2Dose limit (NALIRIFOX q2w)

70 mg/m2Dose limit (FU + leucovorin q2w)

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Coverage Criteria for Irinotecan Liposome (Onivyde)

Initial Therapy — Pancreatic Adenocarcinoma

Covered when ALL of the following are met:

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) as a component of NALIRIFOX (irinotecan liposome + oxaliplatin + fluorouracil + leucovorin) as first-line therapy, or (b) in combination with fluorouracil and leucovorin for disease progression following gemcitabine-based therapy, or following fluoropyrimidine-based therapy without prior irinotecan; 5) Requested dose does not exceed regimen-specific limits (50 mg/m2 every 2 weeks when used as a component of NALIRIFOX; 70 mg/m2 every 2 weeks when used with fluorouracil + leucovorin) or is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence); 6) Prescribed regimen must be FDA-approved or recommended by NCCN; 7) Approval duration: 12 months.

Initial Therapy — Ampullary Adenocarcinoma (off‑label)

Covered when ALL of the following are met:

Ampullary Adenocarcinoma initial: 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 one of: i) gemcitabine-based therapy, ii) fluoropyrimidine-based therapy without prior irinotecan, or iii) oxaliplatin-based therapy without prior irinotecan; or (b) for metastatic disease, prescribed as a component of NALIRIFOX (irinotecan liposome + oxaliplatin + fluorouracil + leucovorin) as first-line therapy per NCCN; 5) Dose is within FDA maximum limits for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence); 6) Prescribed regimen must be FDA-approved or recommended by NCCN; 7) Approval duration: 12 months.

Continuation of Therapy

Covered when ALL of the following are met:

Continuation: 1) Member is currently receiving Onivyde via the Centene benefit, or documentation supports at least 30 days of prior therapy for a covered indication; 2) Member is responding positively to therapy; 3) If request is for a dose increase, the new dose does not exceed regimen-specific limits (50 mg/m2 q2w for NALIRIFOX; 70 mg/m2 q2w with fluorouracil + leucovorin) or is supported by practice guidelines or peer-reviewed literature (prescriber must submit supporting evidence); 4) Prescribed regimen must be FDA-approved or recommended by NCCN; 5) Approval duration: 12 months.

Other Indications / Off‑label handling

Other diagnoses/uses: 1) If the drug has recently (within the last 6 months) undergone a label change not yet reflected in this policy, follow the applicable formulary/no-coverage or non-formulary policy for the line of business (HIM.PA.33, CP.PMN.255, HIM.PA.103, CP.PMN.16). 2) If the requested use (diagnosis, age, dosing regimen) is not specifically listed under 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; CP.PMN.53 for Medicaid).

Extracted criteria notes

Policy criteria notes and changes captured in annual reviews:

Prior therapy requirement (historical/revised): Disease must be locally advanced, metastatic, or recurrent and demonstrate progression following gemcitabine-based therapy or fluoropyrimidine-based therapy (and no prior irinotecan) where specified.as stated

Added/clarified across 4Q2022-4Q2023 reviews

Ampullary adenocarcinoma options: Ampullary adenocarcinoma was added as an NCCN-supported off-label indication; option added to prescribe as a component of NALIRIFOX as first-line therapy for metastatic disease per NCCN.per NCCN guidance

Added 4Q2024 and 4Q2025 reviews

Approval duration: Initial approval duration was extended from 6 months to 12 months for initial approval criteria.

This policy defines the clinical indications and scope for coverage of irinotecan liposome (Onivyde). Coverage is limited to the scenarios and regimens described in the Approval Criteria sections (Section I). Per the FDA prescribing information, Onivyde is indicated in combination regimens for adult patients with metastatic pancreatic adenocarcinoma — specifically: as a component of NALIRIFOX for first-line treatment and in combination with fluorouracil and leucovorin after progression on gemcitabine-based therapy. The drug is not indicated as monotherapy. Off‑label uses are considered only where explicitly addressed in this policy (for example, selected NCCN‑supported ampullary adenocarcinoma criteria) and when the documented regimen, prior therapies, dosing limits, and prescriber qualifications meet the policy requirements.

Inclusion of procedure or HCPCS codes in this clinical policy (for example, J9205 for irinotecan liposome) is for informational and billing guidance only. Inclusion or exclusion of codes does not guarantee coverage. Providers must follow plan‑level coverage documents, claims submission rules, and the most current professional coding guidance when submitting reimbursement requests.

Uses that are non‑FDA approved and are not addressed in this policy should be treated as not authorized unless sufficient documentation is provided demonstrating efficacy and safety in accordance with the Health Plan off‑label use requirements (see off‑label policies such as CP.PMN.53 / HIM.PA.154). Requests for off‑label indications may be denied if supporting clinical evidence and documentation are not submitted.

This clinical policy is intended to provide a framework for medical necessity determinations and to assist in coverage decision-making. It is not a guarantee of payment and does not alter plan contract terms. Coverage decisions remain subject to all applicable evidence of coverage documents, benefit limitations, exclusions, and legal/regulatory requirements; the Health Plan may change, amend, or withdraw the policy as needed.

Coding and Dose Limits

HCPCS CodesHCPCS

J9205

Injection, irinotecan liposome, 1 mg

Dose limits by regimen

Dose limit when used as component of NALIRIFOX50 mg/m2 IV every 2 weeks

Dose limit when used with fluorouracil + leucovorin (no oxaliplatin)70 mg/m2 IV every 2 weeks

UGT1A1*28 homozygous dosing noteStart 50 mg/m2 IV q2w if homozygous for UGT1A1*28; may increase to 70 mg/m2 as tolerated in subsequent cycles

Provider Actions and Authorization Requirements

Prior Authorization

Prior authorization required — demonstrate all approval criteria

Prior authorization is required. Provider must demonstrate that all approval criteria are met, including diagnosis (locally advanced, metastatic, or recurrent pancreatic adenocarcinoma or ampullary adenocarcinoma where applicable), prescriber specialty (prescribed by or in consultation with an oncologist), patient age (Age ≥ 18 years), prescribed regimen, and regimen‑specific dosing limits.

Diagnosis must be documented (see Section I criteria).
Prescriber must be or consult an oncologist.
Dose must not exceed regimen limits (50 mg/m2 q2w for NALIRIFOX; 70 mg/m2 q2w for fluorouracil+leucovorin).

Prior Authorization

Prior authorization and approval duration — 12‑month initial approval

Prior authorization is required for requests using HCPCS code J9205. Initial approval duration for initial authorization has been extended to 12 months; ampullary adenocarcinoma off‑label criteria and first‑line NALIRIFOX combination options were added per recent reviews.

Definitions and Regimen Components

Definition: NALIRIFOX

Regimen componentsFluorouracil, leucovorin, liposomal irinotecan (nal-irinotecan), and oxaliplatin

Regimen nameNALIRIFOX

Use contextIdentified as a multi-agent regimen in Appendix D

NALIRIFOX regimen (nal-irinotecan-based)

Regimen descriptionNALIRIFOX: nal-irinotecan (liposomal irinotecan) combined with oxaliplatin, fluorouracil, and leucovorin

Component dosing guidanceWhen nal-irinotecan is used as part of NALIRIFOX, nal-irinotecan dosing is 50 mg/m2 IV every 2 weeks

Line of Therapy Designations

first-line | second-line

Line of therapy: First-line: NALIRIFOX (liposomal irinotecan + oxaliplatin + fluorouracil + leucovorin) for metastatic pancreatic adenocarcinoma; Second-line: irinotecan liposome in combination with fluorouracil + leucovorin after progression on gemcitabine-based therapy or following fluoropyrimidine-based therapy without prior irinotecan as specified in the policy.

first-line

First-line NALIRIFOX option: NALIRIFOX (liposomal irinotecan + oxaliplatin + fluorouracil + leucovorin) as first-line therapy for metastatic pancreatic adenocarcinoma; when used as a component of NALIRIFOX, liposomal irinotecan dose limit is 50 mg/m2 every 2 weeks.

second-line

Second-line or later therapy (pancreatic):

Covered Regimens and Dose Limits

Regimen	Indication	Dose limit / Notes	Coverage
NALIRIFOX (liposomal irinotecan + oxaliplatin + fluorouracil + leucovorin)	First-line metastatic pancreatic adenocarcinoma	Liposomal irinotecan 50 mg/m2 IV every 2 weeks when used as component of NALIRIFOX (Appendix D)	Covered with criteria

Regimen	Indication	Dose limit / Notes	Coverage
Irinotecan liposome in combination with fluorouracil and leucovorin	Treatment of metastatic pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy	Dose does not exceed 70 mg/m2 IV every 2 weeks when prescribed in combination with fluorouracil and leucovorin	Covered with criteria

Regimen	Indication	Dose limit / Notes	Coverage
Irinotecan liposome in combination with oxaliplatin, fluorouracil, and leucovorin (component of NALIRIFOX)	First-line metastatic ampullary adenocarcinoma per NCCN	When used as component of NALIRIFOX follow regimen dosing; liposomal irinotecan 50 mg/m2 IV every 2 weeks when used as component	Covered with criteria (NCCN-supported off-label)

Background

Irinotecan liposome (Onivyde) is a liposomal formulation of the topoisomerase I inhibitor irinotecan designed for intravenous administration as part of combination chemotherapy regimens. The FDA‑approved indications specify use in combination with oxaliplatin, fluorouracil, and leucovorin for first‑line metastatic pancreatic adenocarcinoma and in combination with fluorouracil and leucovorin after disease progression on gemcitabine‑based therapy. The product is not indicated as a single agent. The policy recognizes the NALIRIFOX regimen (liposomal irinotecan + oxaliplatin + fluorouracil + leucovorin) as a covered first‑line option where specified and applies regimen‑specific dosing limits when determining authorization.

Policy Summary

PayerCentene

PolicyIrinotecan Liposome (Onivyde) - Clinical Policy

Policy CodePolicy CP.PHAR.304

Change TypeMaterial clinical updates and approval-duration extension

Effective DateFeb 1, 2017

Next Review Date

Key ActionSubmit prior authorization with documentation demonstrating diagnosis, prescriber specialty, age, regimen, and dosing within specified limits.

SourceLink

On This Page

Step Therapy

Therapy sequence — use with fluorouracil + leucovorin after gemcitabine progression

For the FDA‑approved second‑line pancreatic adenocarcinoma indication, irinotecan liposome must be prescribed in combination with fluorouracil and leucovorin following disease progression on gemcitabine‑based therapy.

Use only in combination with fluorouracil + leucovorin for second‑line pancreatic disease.
Document prior progression on gemcitabine‑based therapy.

Step Therapy

Prior therapy requirements — document progression and prior‑therapy status

Prior therapy must be documented: disease progression following gemcitabine‑based therapy or fluoropyrimidine‑based therapy (and no prior irinotecan) where specified; policy also recognizes NALIRIFOX regimen components for first‑line use.

If claiming second‑line use, document progression after gemcitabine‑based or fluoropyrimidine‑based therapy.
Document that patient has not received prior irinotecan when required.

Documentation Required

Required documentation — submit office notes and clinical data

Provider 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 notes confirming diagnosis, prior therapies and progression status.
Include dosing rationale and any guideline/literature support for doses exceeding regimen limits.

Billing Rule

Coding guidance — verify current professional coding guidance before claims

Codes referenced in this clinical policy are for informational purposes only; providers should reference the most up-to-date professional coding guidance (and use HCPCS J9205 where appropriate) prior to claim submission.

Confirm coding with current coding manuals and payer-specific guidance before claim submission.
Use J9205 for irinotecan liposome (1 mg) as referenced in the policy.

Denial Risk

Off‑label requests may be denied without adequate supporting evidence

Requests for non‑FDA approved indications that are not addressed in this policy may be denied unless sufficient documentation of efficacy and safety is provided per off‑label use policies (CP.PMN.53 / HIM.PA.154).

If requesting off‑label use, include literature or compendium evidence supporting efficacy and safety.
Reference applicable off‑label policies (CP.PMN.53 for Medicaid, HIM.PA.154 for marketplace).

Denial Risk

Coding does not guarantee coverage — follow payer guidance to avoid denials

Inclusion or exclusion of codes in this policy does not guarantee coverage; failure to follow payer coding guidance and plan-level coverage documents may result in claim denial.

Follow plan-level coverage documents and state Medicaid provisions where applicable.
Coding in this policy is informational and does not assure payment.