Modifiedsierra health and lifePolicy 2025D0061AD

White Blood Cell Colony Stimulating Factors

Clinical coverage and medical necessity criteria for FDA‑approved granulocyte and granulocyte‑macrophage colony stimulating factor products (pegfilgrastim and filgrastim agents and sargramostim) for UnitedHealthcare Commercial members; includes preferred product guidance and diagnosis‑specific indications.

Policy Summary

Payersierra health and life

PolicyWhite Blood Cell Colony Stimulating Factors

Policy CodePolicy 2025D0061AD

Change TypeAddition of Ryzneutacontinuation/switching rules clarified

Effective DateOctober 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and physician attestation documenting prior trial or intolerance to preferred products before requesting non-preferred CSF coverage.

SourceLink

POLICY UPDATE CHANGES

Revised list of applicable white blood cell colony stimulating factors (CSFs); added Ryzneuta (efbemalenograstim alfa-vuxw).

Coverage for Ryzneuta will be provided contingent on the criteria in the Preferred Product Criteria section and the coverage criteria in the Diagnosis-Specific Criteria section; members already on Ryzneuta are required to change therapy to Neulasta or Udenyca unless they meet the Preferred Product Criteria.

Defined clinical situations in which Ryzneuta is medically necessary (hematopoietic syndrome of acute radiation syndrome; primary and secondary prophylaxis of chemotherapy-induced febrile neutropenia; treatment of febrile neutropenia) when policy criteria are met.

Added HCPCS code J9361 to the Applicable Codes list.

Updated Background, FDA, and References sections to reflect current information and archived previous policy version 2025D0061AC.

>20%High‑risk FN threshold

10-20%Intermediate FN risk

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

ANC <500Severe neutropenia threshold

6%First‑cycle FN incidence

>=1New CSF product added

1New HCPCS code added

Coverage Criteria and Indications

Preferred Product Criteria — Pegfilgrastim

Treatment with Fulphila, Fylnetra, Nyvepria, Rolvedon, Ryzneuta, Stimufend, Ziextenzo, or other pegfilgrastim biosimilar is medically necessary for the indications specified in the policy when one of the following is met:

ANY of the following

Both of the following:
- History of a trial of adequate dose and duration of Neulasta or Udenyca, resulting in minimal clinical response.
- Physician attests that, in their clinical opinion, the clinical response would be expected to be superior with Fulphila, Fylnetra, Nyvepria, Rolvedon, Ryzneuta, Stimufend, Ziextenzo, or other pegfilgrastim biosimilar product, than experienced with Neulasta or Udenyca.
Both of the following:
- History of intolerance, contraindication, or adverse event to Neulasta or Udenyca.
- Physician attests that, in their clinical opinion, the same intolerance, contraindication, or adverse event would not be expected to occur with Fulphila, Fylnetra, Nyvepria, Rolvedon, Ryzneuta, Stimufend, Ziextenzo, or other pegfilgrastim biosimilar product.

Preferred Product Criteria — Filgrastim

Treatment with Granix, Neupogen, Nypozi, Releuko, or other filgrastim biosimilar is medically necessary for the indications specified in the policy when one of the following is met:

ANY of the following

Both of the following:
- History of a trial of adequate dose and duration of Zarxio or Nivestym, resulting in minimal clinical response.
- Physician attests that, in their clinical opinion, the clinical response would be expected to be superior with Granix, Neupogen, Nypozi, Releuko, or other filgrastim biosimilar product, than experienced with Zarxio or Nivestym.
Both of the following:
- History of intolerance, contraindication, or adverse event to Zarxio or Nivestym.

Bone Marrow/Stem Cell Transplant

Leukine, Neupogen, Nivestym, Nypozi, Releuko, and Zarxio are medically necessary when the following criteria are met:

ANY of the following

Patient has non-myeloid malignancies and is undergoing myeloablative chemotherapy followed by autologous or allogeneic bone marrow transplant (BMT).
Used for mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
Patient has had a peripheral stem cell transplant (PSCT) and has received myeloablative chemotherapy.

Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy / Primary Prophylaxis

Leukine, Neupogen, Nivestym, Nypozi, Releuko, and Zarxio are medically necessary when the following criteria are met:

ALL of the following

Diagnosis of acute myeloid leukemia (AML).
One of the following:
- Patient achieved complete remission after induction therapy.
- Patient is receiving consolidation chemotherapy.
- Patient is receiving fludarabine, cytarabine with or without idarubicin for relapsed or refractory disease.

Secondary Prophylaxis of Febrile Neutropenia

White blood cell colony stimulating factors are medically necessary when the following criteria for secondary prophylaxis are met:

ANY of the following

Patient is receiving myelosuppressive anticancer drug(s) given with a curative intent (curative chemotherapy, chemotherapy in curative adjuvant/neoadjuvant setting).
Patient is receiving myelosuppressive anticancer drug(s) for definitive therapy (bridge to stem cell transplant, organ transplant, definitive surgery for oligometastatic disease).

ALL of the following

And one of the following:
- Patient has a documented history of a neutropenic event (febrile neutropenia or low neutrophil count leading to delay of subsequent cycle) during a previous cycle of the same chemotherapy regimen at full dose for which primary prophylaxis was not received.

Treatment of Febrile Neutropenia (Off‑Label)

Fulphila, Fylnetra, Leukine, Neulasta, Neupogen, Nivestym, Nypozi, Nyvepria, Releuko, Rolvedon, Ryzneuta, Stimufend, Udenyca, Zarxio, and Ziextenzo are medically necessary for treatment of febrile neutropenia when ALL of the following are met:

ALL of the following

Diagnosis of febrile neutropenia.
Patient has not received long-acting prophylactic pegfilgrastim in the last 14 days.
Patient has one or more risk factors for an infection-associated complication such as sepsis syndrome, age > 65 years, absolute neutrophil count (ANC) < 100/mcL, neutropenia expected to be > 10 days in duration, pneumonia, clinically documented infections including invasive fungal infection, hospitalization at the time of fever, or prior episode(s) of febrile neutropenia.

Severe Chronic Neutropenia (SCN)

Neupogen, Nivestym, Nypozi, Releuko, and Zarxio are medically necessary for Severe Chronic Neutropenia (SCN) when ALL of the following are met:

ALL of the following

Diagnosis of SCN (i.e., congenital, cyclic, and idiopathic neutropenias with chronic ANC ≤ 500 neutrophils/mcL).
Medication is dosed in accordance with the United States Food and Drug Administration approved labeling.
Prescribed by or in consultation with a hematologist or oncologist.

Hematopoietic Syndrome of Acute Radiation Syndrome

Fulphila, Fylnetra, Leukine, Neulasta, Neupogen, Nivestym, Nypozi, Nyvepria, Releuko, Rolvedon, Ryzneuta, Stimufend, Udenyca, Zarxio, and Ziextenzo are medically necessary for Hematopoietic Syndrome of Acute Radiation Syndrome when ALL of the following are met:

ALL of the following

Patient has been acutely exposed to myelosuppressive doses of radiation.
Medication is dosed in accordance with the United States Food and Drug Administration approved labeling.
Prescribed by or in consultation with a hematologist or oncologist.

Ryzneuta (efbemalenograstim alfa-vuxw) — Covered Indications with Criteria

Coverage for Ryzneuta (efbemalenograstim alfa-vuxw) is provided when criteria in both the Preferred Product Criteria and the Diagnosis-Specific Criteria sections are met. Members already on Ryzneuta are required to change to Neulasta or Udenyca unless they meet the Preferred Product Criteria.

ANY of the following

Both of the following:
- History of a trial of adequate dose and duration of Neulasta or Udenyca, resulting in minimal clinical response to those agents.
- Physician attests that, in their clinical opinion, the clinical response would be expected to be superior with Ryzneuta than experienced with Neulasta or Udenyca.
Both of the following:
- History of intolerance, contraindication, or adverse event to Neulasta or Udenyca.

Initial Therapy — When to Start CSF

inv-52: Initial therapy — primary prophylaxis

Primary prophylaxis indications for initiating CSF:

Initiation - high risk regimens: Initiate CSF when patient is receiving dose-dense MVAC for bladder cancer; dose-dense AC followed by dose-dense paclitaxel for breast cancer; or chemotherapy regimens associated with >20% incidence of febrile neutropenia.FN incidence > 20%

Start prophylaxis at first cycle when indicated

inv-53: Initial therapy timing

Initial administration guidance from NCCN/ASCO and trials:

Start timing for filgrastim after chemotherapy: Filgrastim (and biosimilars) is recommended to start on the day after completion of chemotherapy when used for prophylaxis or mobilization per NCCN guidance.

NCCN recommendation

Continuation and Switching Rules

inv-56: Continuation therapy exceptions

Continuation on non-preferred agents for members already receiving them requires meeting exception criteria:

Continuation exception: Member already on a non-preferred agent must change to the preferred product (Neulasta or Udenyca for pegfilgrastim; Zarxio or Nivestym for filgrastim) unless criteria for trial failure (adequate dose/duration with minimal response) or intolerance/contraindication and physician attestation are met.

Documentation of prior trial or intolerance plus physician attestation required

inv-57: Continuation after FN

Guidance on continuing CSF after FN or prophylaxis:

Continue same G-CSF after FN: Patients with febrile neutropenia who received prophylactic G-CSF should continue with the same G-CSF; for patients who have not received prophylactic MGFs, evaluate risk factors for infection-related complications before initiating therapy.

NCCN guidance

Applicable Codes and Definitions

Applicable HCPCS/J‑codes and Q‑codesHCPCS

J1442	Injection, filgrastim, (G-CSF), excludes biosimilars, 1 microgram.
J1447	Injection, tbo-filgrastim, 1 microgram.
J1449	Injection, eflapegrastim-xnst, 0.1 mg.
J2506	Injection, pegfilgrastim, 0.5 mg.
J2820	Injection, sargramostim (GM-CSF), 50 mcg.
J3490	Unclassified drugs.
J3590	Unclassified biologics.
J9361	Injection, efbemalenograstim alfa-vuxw, 0.5 mg.
J9999	Not otherwise classified, antineoplastic drug.
Q5101	Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 microgram.

1–10 of 19

1/2

Applicable HCPCS Codes (added)HCPCS

J9361

Added HCPCS code (policy did not provide full descriptor in this chunk)

ANC thresholds — key definitions

Severe neutropeniaANC < 500 neutrophils/mcL

NeutropeniaANC < 1500 neutrophils/mcL

Febrile neutropenia (FN) — definitionSingle temperature ≥ 38.3 °C orally or 38.0 °C over 1 hour AND neutropenia: ANC < 500 neutrophils/mcL OR ANC < 1,000 neutrophils/mcL with predicted decline to ≤ 500 neutrophils/mcL within 48 hours

EORTC FN risk threshold

EORTC FN risk thresholdRecommend prophylactic G-CSF when overall febrile neutropenia (FN) risk is ≥ 20% (P20%).

Regimens with 10–20% FN riskAssess additional patient-related risk factors to determine need for prophylaxis; individualized decision per EORTC guidance.

Provider Requirements and Authorization Notes

Prior Authorization

Prior Authorization Required

Prior authorization is required for colony stimulating factors per this policy. Preferred pegfilgrastim products (Neulasta, Udenyca) and preferred filgrastim products (Zarxio, Nivestym) are covered when Diagnosis‑Specific Criteria are met; coverage for non‑preferred pegfilgrastim/filgrastim agents (including Ryzneuta, Fulphila, Fylnetra, Nyvepria, Rolvedon, Stimufend, Ziextenzo, Granix, Neupogen, Nypozi, Releuko) is contingent on meeting the Preferred Product Criteria in this policy. Members already receiving non‑preferred products will generally be required to switch to the preferred product unless they meet the exception criteria.

Prior authorization required for non‑preferred CSF agents unless Preferred Product Criteria met
Preferred pegfilgrastim: Neulasta, Udenyca
Preferred filgrastim: Zarxio, Nivestym

Note

Prior Authorization Depends on Benefit Plan

Coverage for off‑label, experimental, or investigational uses and other exceptions depends on the member’s specific benefit plan and any applicable state mandates. Always consult the member’s Certificate of Coverage/benefit document to determine whether a given use is covered and whether prior authorization is required.

Step Therapy and Prior Trial Requirements

Requirement	Details
Prior trial of preferred agent	History of trial of adequate dose and duration of the preferred pegfilgrastim product (Neulasta or Udenyca) with minimal clinical response; physician attestation that clinical response would be expected to be superior with the non‑preferred agent.
Intolerance/contraindication to preferred agent	Documentation of intolerance, contraindication, or adverse event to Neulasta or Udenyca plus physician attestation that the same intolerance/AE would not be expected with the non‑preferred pegfilgrastim biosimilar.

Prophylaxis Type	Clinical Criteria / Recommendation
Primary prophylaxis	Recommend CSF starting with the first cycle and continuing through subsequent cycles for patients with an approximately 20% or higher risk for febrile neutropenia based on patient-, disease-, and treatment-related factors; also for dose‑dense chemotherapy when appropriate.
Secondary prophylaxis	Recommend CSF for patients who experienced a neutropenic complication from a prior cycle (febrile neutropenia or neutropenia causing delay) when dose reduction or delay may compromise outcomes.

Medicare Part B Note	Action for Medicare Advantage Members
Local coverage/step therapy dependency	Medicare does not have an NCD for CSF therapy; local LCDs/LCAs and Medicare Part B Step Therapy Programs may define preferred therapy criteria—refer to applicable LCD/LCA and Part B step therapy requirements for Medicare Advantage members.

Authorization Basis	Documentation Required
Prior trial with inadequate response	History of trial of adequate dose and duration of Neulasta or Udenyca resulting in minimal clinical response; documentation of the trial and clinical outcome plus physician attestation that Ryzneuta is expected to provide superior clinical response.
Intolerance/contraindication/adverse event to preferred agent	Documentation of intolerance, contraindication, or adverse event to Neulasta or Udenyca plus physician attestation that the same intolerance/AE would not be expected to occur with Ryzneuta.

Site of Care Considerations

Note

Site‑of‑care: inpatient and outpatient use depending on indication

Use of filgrastim or pegfilgrastim may occur in inpatient and outpatient settings depending on indication (e.g., post‑transplant mobilization, oncology outpatient prophylaxis); verify site‑of‑care billing and coverage rules per the benefit.

Bone marrow/stem cell transplant and mobilization uses are supported by clinical trial evidence and occur in both inpatient and outpatient settings.

Billing Rule

Medicare Part B 'incident to' rules may affect site‑of‑care coverage

Medicare Part B generally covers outpatient drugs furnished 'incident to' physician services when they are not usually self‑administered; site‑of‑care coverage may vary and should be verified for the member.

For Medicare Advantage members, Part B rules and MAO step therapy programs may affect site‑of‑care coverage.

Biosimilar and Preferred Product Guidance

Billing Rule

Require prior adequate trial of Neulasta or Udenyca for non‑preferred pegfilgrastim

Non‑preferred pegfilgrastim biosimilars require documentation of a prior adequate trial of Neulasta or Udenyca with minimal clinical response, or documented intolerance/contraindication plus physician attestation, to support coverage.

Acceptable documentation includes dates, dose/duration of prior Neulasta or Udenyca therapy and clinical rationale/attestation from the physician.

Billing Rule

Require prior adequate trial of Zarxio or Nivestym for non‑preferred filgrastim

Non‑preferred filgrastim products require documentation of a prior adequate trial of Zarxio or Nivestym with minimal clinical response, or documented intolerance/contraindication plus physician attestation, to support coverage.

Include dose/duration and clinical outcome of the prior Zarxio or Nivestym trial and the physician's attestation in authorization requests.

Billing Rule

Key Definitions

Febrile Neutropenia — diagnostic criteria

Fever criteriaSingle temperature ≥ 38.3 °C orally or 38.0 °C over 1 hour

Neutropenia criteria for FNANC < 500 neutrophils/mcL OR ANC < 1,000 neutrophils/mcL with predicted decline to ≤ 500 neutrophils/mcL over the next 48 hours

Combined requirementBoth fever (as above) AND qualifying neutropenia are required to define febrile neutropenia.

Neutropenia — ANC threshold

Absolute neutrophil count (ANC) thresholdANC < 1500 neutrophils/mcL

Context of useUsed as the general laboratory definition of neutropenia for clinical assessment and policy criteria.

Background and Clinical Context

Neutropenia is an abnormally low neutrophil count that increases infection risk and is a major toxicity of myelosuppressive chemotherapy. Colony‑stimulating factors (CSFs) reduce the duration and severity of neutropenia and lower the risk of febrile neutropenia, supporting the safe delivery of dose‑dense or more intensive chemotherapy regimens.

Policy Summary

Payersierra health and life

PolicyWhite Blood Cell Colony Stimulating Factors

Policy CodePolicy 2025D0061AD

Change TypeAddition of Ryzneutacontinuation/switching rules clarified

Effective DateOctober 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and physician attestation documenting prior trial or intolerance to preferred products before requesting non-preferred CSF coverage.

SourceLink

On This Page

Physician attests that, in their clinical opinion, the same intolerance, contraindication, or adverse event would not be expected to occur with Granix, Neupogen, Nypozi, Releuko, or other filgrastim biosimilar product.

Patient is receiving cladribine, cytarabine with or without mitoxantrone or idarubicin for relapsed or refractory disease.

Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN)

One of the following:
Patient is receiving dose dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) for bladder cancer.
Patient is receiving dose dense AC (doxorubicin, cyclophosphamide) followed by dose-dense paclitaxel for breast cancer.
Patient is receiving chemotherapy regimen(s) associated with > 20% incidence of febrile neutropenia.

Patient has a documented history of neutropenic event from a previous course of chemotherapy.

Or both of the following:

Patient is receiving myelosuppressive anticancer drug(s) given with non-curative intent.
ANY of the following
- Patient has documented history of febrile neutropenia.
- Patient has had a trial of dose reduction, followed by a dose-limiting neutropenic event that resulted in delay in therapy.
- Patient is receiving myelosuppressive anticancer drug(s) and use of secondary prophylaxis is in accordance with the FDA approved label.

Or patient is receiving myelosuppressive anticancer drug(s) where primary prophylaxis is indicated.

Physician attests that, in their clinical opinion, the same intolerance, contraindication, or adverse event would not be expected to occur with Ryzneuta.

Continue same G-CSF after FN: The NCCN Panel recommends that patients with febrile neutropenia who received prophylactic G-CSF should continue with the same G-CSF.

NCCN recommendation

inv-55: Initial therapy

Initial use of Ryzneuta is covered when policy criteria are met for the listed indications.

Initial Ryzneuta coverage: Ryzneuta may be used for approved indications when the Preferred Product Criteria and the Diagnosis-Specific Criteria in the policy are met.

See Diagnosis-Specific Criteria for indication-specific requirements

inv-58: Continuation / Step to Preferred Products

Continuation and switching rules for members already receiving Ryzneuta:

Continuation exceptions for Ryzneuta: To continue coverage of Ryzneuta, members must meet the Preferred Product Criteria (documentation of prior adequate trial of Neulasta or Udenyca with minimal response, or intolerance/contraindication plus physician attestation); otherwise they must switch to Neulasta or Udenyca.

Policy revision effective 10/01/2025

Assessment timingAssess FN risk individually at the beginning of each chemotherapy cycle (EORTC recommendation).

Member specific benefit plan governs coverage decisions
State mandates may supersede plan or policy language

Step Therapy

Check Local Coverage / Step Therapy

For Medicare and Medicare Advantage members, consult applicable Local Coverage Determinations (LCDs)/Local Coverage Articles (LCAs) for White Cell Colony Stimulating Factors and Medicare Part B Step Therapy Programs which may define preferred therapy criteria. There is no Medicare National Coverage Determination (NCD) for CSF therapy.

Refer to LCD/LCA for White Cell Colony Stimulating Factors
See Medicare Part B Step Therapy Programs for preferred therapy criteria for Medicare Advantage members

Prior Authorization

Ryzneuta (J9361) Prior Authorization Requirement

Ryzneuta (HCPCS J9361) is covered only when the Preferred Product Criteria and the Diagnosis‑Specific Criteria in this policy are met. Members currently on Ryzneuta will be required to change therapy to a preferred pegfilgrastim (Neulasta or Udenyca) unless they meet the Preferred Product Criteria exceptions.

HCPCS J9361 (Ryzneuta) — prior authorization required and contingent on Preferred Product and Diagnosis‑Specific Criteria
Members on Ryzneuta must switch to Neulasta or Udenyca unless Preferred Product Criteria are met

Denial Risk

Non‑Preferred Product Continuation Risk

Coverage for continuation of non‑preferred pegfilgrastim or filgrastim products may be denied if the member has not met the Preferred Product Criteria or required step‑therapy requirements. To avoid denials, include documentation of prior trial of preferred product at adequate dose/duration or documentation of intolerance/contraindication with physician attestation.

Continuation of non‑preferred agents requires meeting Preferred Product Criteria
Document prior trial of preferred product (dose/duration) or intolerance/contraindication with physician attestation

Note

Benefit Limitations / Plan Mandates

Benefit limitations and state mandates may restrict or expand coverage. Always review the member‑specific benefit plan and any applicable state mandates; where state mandates apply they supersede the benefit document or policy language.

Consult the member’s Certificate of Coverage
State mandates may supersede plan/policy

Note

Plan and State Mandate Consultation

Consult the member‑specific benefit plan document prior to rendering services. The policy provides guidance but the member’s benefit plan governs coverage determinations and may contain different terms.

Member specific benefit plan document governs in event of conflict with policy
Check benefits and any applicable federal/state mandates before authorization

Documentation Required

Use FDA Labels as Documentation

FDA product labeling and package inserts for Neulasta, Neupogen, Leukine, filgrastim and pegfilgrastim biosimilars may be used as supporting clinical documentation for authorization decisions. FDA approval alone is informational and not a sole basis for coverage.

Use FDA labels/package inserts as supporting documentation
FDA approval is informational; policy criteria still apply

Note

Member‑Specific Benefit Reference

When deciding coverage and prior authorization, reference the member‑specific benefit plan document; the terms of the member’s benefit plan take precedence over this policy if there is a conflict.

Member‑specific benefit plan governs
Policy assists interpretation but does not override plan terms

Step Therapy

Preferred Product Step Requirement

Step‑therapy is enforced: members should be treated with preferred products (Neulasta or Udenyca for pegfilgrastim; Zarxio or Nivestym for filgrastim) before non‑preferred agents except when Preferred Product Criteria exceptions are met. Required documentation includes history of trial (adequate dose/duration) and/or documented intolerance/contraindication with physician attestation.

Preferred product step: Neulasta or Udenyca (pegfilgrastim); Zarxio or Nivestym (filgrastim)
Exceptions require documented trial of preferred product or intolerance/contraindication with physician attestation

Note

Clinical Step / Sequence Considerations

Clinical guidance supports primary prophylaxis with a colony stimulating factor when the patient’s risk of febrile neutropenia is approximately 20% or higher, and secondary prophylaxis for patients with prior neutropenic complications. Use clinical criteria (patient, disease, treatment factors) to determine appropriate CSF use in line with ASCO guidance.

Primary prophylaxis recommended when FN risk ≈20% or higher
Secondary prophylaxis for prior neutropenic complications
CSFs not routinely used for afebrile neutropenia; consider ASCO recommendations

Biosimilars may be used for FN prevention; check contract/step therapy

Biosimilars such as filgrastim‑sndz and filgrastim‑aafi can be used for prevention of febrile neutropenia; choice of agent may depend on contract, cost, and step therapy requirements.

Verify formulary/contract preferences and step therapy rules when selecting a biosimilar agent for FN prevention.

Billing Rule

Neulasta reference product and listed biosimilars

Neulasta is the reference pegfilgrastim product with multiple biosimilars listed in the policy; use of non‑preferred pegfilgrastim biosimilars requires meeting the policy's Preferred Product Criteria.

Neulasta biosimilars include Fulphila, Fylnetra, Nyvepria, Stimufend, Udenyca, and Ziextenzo as listed by FDA.

Billing Rule

Neupogen reference product and listed biosimilars

Neupogen is the reference filgrastim product with biosimilars listed; non‑preferred filgrastim agents require meeting Preferred Product Criteria for coverage.

Neupogen biosimilars include Nivestym, Nypozi, Releuko, and Zarxio as listed by FDA.

ReferenceDefinition cited from policy Definitions section (ANC < 1500 per microliter).

Severe Neutropenia — ANC threshold

Severe neutropenia thresholdANC < 500 neutrophils/mcL

Clinical significanceMarks high risk for infection and is used to define severe neutropenia and criteria for some policy indications (e.g., SCN, FN risk factors).

Relation to FNANC < 500 alone meets neutropenia component of FN definition when fever is present.

G-CSFs — examples and purpose

G-CSFs — definitionGranulocyte colony-stimulating factors that stimulate neutrophil production (examples include filgrastim and pegfilgrastim and their biosimilars).

Common agentsExamples listed in policy: filgrastim (Neupogen), pegfilgrastim (Neulasta) and biosimilars such as filgrastim-sndz (Zarxio) and pegfilgrastim-jmdb (Fulphila).

Clinical roleUsed to reduce duration and severity of neutropenia and lower risk of febrile neutropenia in myelosuppressive chemotherapy.

GM-CSFs — examples and role

GM-CSF — definitionGranulocyte-macrophage colony-stimulating factor that stimulates production of neutrophils and macrophages (example: sargramostim/Leukine).

Example agentSargramostim (Leukine) is the policy-listed GM-CSF used for indications including AML recovery, mobilization, post-transplant support, and radiation syndrome.

Clinical distinctionGM-CSFs have broader myeloid stimulation (neutrophils + macrophages) compared with G-CSFs which primarily stimulate neutrophils.

P20% — FN risk threshold

P20% definitionP20% denotes the febrile neutropenia (FN) risk threshold at which prophylactic G-CSF is recommended (overall FN risk ≥ 20%).

Policy applicationPrimary prophylaxis is recommended for regimens with ≈20% or higher FN risk; for 10–20% risk, assess additional patient risk factors.

Guideline sourceThreshold referenced from EORTC and used in ASCO/NCCN–aligned policy guidance.

Biosimilar — definition and examples

Biosimilar — definitionA biologic product approved based on demonstrating it is highly similar to an FDA‑approved reference product with no clinically meaningful differences in safety or effectiveness.

Regulatory noteOnly minor differences in clinically inactive components are allowable for biosimilars per FDA guidance referenced in the policy.

Examples in policyPolicy lists Neulasta biosimilars (Fulphila, Fylnetra, Nyvepria, Stimufend, Udenyca, Ziextenzo) and Neupogen biosimilars (Nivestym, Nypozi, Releuko, Zarxio).

Guideline sources — febrile neutropenia and neutropenia

Guideline referencesFebrile neutropenia and neutropenia definitions and management guidance referenced from ASCO, IDSA, CDC, and EORTC guidelines as cited in the policy references.

Definitions sourcePolicy definitions for FN, neutropenia, and severe neutropenia align with ASCO/IDSA/EORTC guidance and are cited in the References section (e.g., Taplitz et al., Freifeld et al.).

Management contextPolicy incorporates society guidance on when to use prophylactic G-CSF, assessment of FN risk per cycle, and special situations for treating FN with CSFs.