Granulocyte Colony Stimulating Factors Form

PART B DRUG MEDICAL/PHARMACY

Effective Date: 01/06/2026
Policy # Colony Stimulating Factors Short-Acting Granulocyte Colony Stimulating Factors (G-CSFs) Neupogen (filgrastim) and Biosimilars Nivestym (filgrastim-aafi); Zarxio (filgrastim-sndz); Releuko (filgrastim-ayow); Nypozi (filgrastim-txid)

Granix (Tbo-filgrastim) Last Review Date Applicable to: 11/17/2025 Medicare Advantage Elevance Health HMO Blue Shield Trio Approver’s Name & Title QI & UM Drug Subcommittee

Aspire Health Plan (AHP) applies medical drug clinical criteria as a reference for medical policy information only. Federal and state laws or requirements, contract language, and Plan benefit may take precedence over the application of these clinical criteria. Please consult the applicable certificate or contract for benefit details. This policy is subject to revision at the discretion of the Plan and is therefore subject to change. Refer to the disclaimer section below for more information.

POLICY

This policy addresses the use of short-acting granulocyte colony stimulating factor (G‐CSF) products, which include filgrastim and biosimilars. Several filgrastim products are available (e.g., filgrastim [Neupogen], filgrastim-aafi [Nivestym], filgrastim-sndz [Zarxio], filgrastim-txid (Nypozi), tbo-filgrastim [Granix], filgrastim-ayow, [Releuko]) and there is no reliable evidence of the superiority of any one product of filgrastim compared to other products.

APPLICABLE HCPCS

• J1442: Injection, filgrastim (g-csf), excludes biosimilars, 1 mcg: 1 billable unit = 1 mcg Biosimilar of Neupogen: Nivestym, Releuko, Zarxio, and Nypozi • Q5101: Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 mcg: 1 billable unit = 1 mcg • Q5110: Injection, filgrastim-aafi, biosimilar, (Nivestym), 1 mcg: 1 billable unit = 1 mcg • Q5125: Injection, filgrastim-ayow, biosimilar, (Releuko), 1 mcg; 1 billable unit = 1 mcg • C9399, J3590: Nypozi (filgrastim-txid) --FDA approved June 2024; anticipated availability currently unknown. Nypozi is approved as a biosimilar to Neupogen. • J1447: Injection, tbo-filgrastim (Granix), 1 mcg: 1 billable unit = 1 mcg Available as: Filgrastim (Neupogen) and related biosimilars and tbo-pegfilgrastim (Granix) are available as a single-dose prefilled syringe for manual use only and a single-dose vial.

CLINICAL CRITERIA

The requested G-CSF product may be authorized when ALL of the following have been met with relevant documentation. I. INITIAL CRITERIA

A. Prescribed by, or in consultation with, a board-certified hematologist, oncologist, nephrologist, infectious disease (HIV or Hep C treatment related neutropenia), or transplant specialist, or other specialist with expertise in the treatment of member’s condition. If prescribed in consultation, consultation notes must be submitted with initial request and reauthorization requests.

AND B. Documented diagnosis meets ONE of the following:

1. FDA approved product labeling, CMS-approved compendia, or

2. National Comprehensive Cancer Network (NCCN) as a Category 1 or 2A recommendation, or

3. Peer-reviewed literature that meets the requirements of the CMS Medicare Benefit Policy Manual Chapter 15 (Refer to CMS Medicare Benefit Policy Manual link HERE for complete details; a summary is provided in the “Appendix’ of this policy)

   AND C. Clinical documentation, including but not limited to, progress notes documenting previous treatments, diagnostic testing, laboratory test results, genetic testing/biomarker results, imaging and other objective or subjective measures of benefit which support continued use of the requested product AND D. EXCLUSIONS: All other uses for filgrastim (Neupogen) and related biosimilars (e.g., filgrastim-aafi [Nivestym], filgrastim-sndz [Zarxio], filgrastim-txid (Nypozi), filgrastim-ayow, [Releuko]) and tbo-filgrastim [Granix]) will be evaluated based on Aspire Health Plan’s clinical policy for “Off-Label Use of Drugs and Biologic Agents.”

   II. REAUTHORIZATION / CONTINUATION OF THERAPY CRITERIA Applicable to AHP members who have previously received authorization of treatment for the requested drug product OR newly enrolled members established on the requested product within the previous year.

   Requested G-CSF may be authorized for continuation of therapy when initial criteria have been met AND the following with documentation:

   A. Prescriber attests to regular lab monitoring (i.e., CBC) as clinically appropriate; AND

   B. Clinical benefits to support continuation of treatment including positive response to therapy (i.e., reduction in the interruption of chemotherapy cycles; reduced incidence of febrile neutropenia episodes); AND

   C. If reauthorization request is also for a dose increase, ONE of the following (a or b) must be met:

4. New dose does not exceed the FDA-approved maximum recommended dose for the relevant indication (see Appendix F for dose rounding guidelines); or
5. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

AND D. Prescriber attests to, or clinical reviewer has found, no evidence of intolerable adverse effects or unacceptable toxicity from G-CSF therapy (e.g. splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions/anaphylaxis, sickle cell crisis, glomerulonephritis, leukocytosis, capillary leak syndrome, potential for tumor growth stimulation of malignant cells, aortitis, alveolar hemorrhage and hemoptysis, thrombocytopenia, cutaneous vasculitis, etc.)

STEP THERAPY

Step therapy criteria do not apply for members who are currently being treated with the requested medications. Step therapy is only applied for members that are new to therapy (have not received the requested drug in the last 365 days. A. PREFERRED PRODUCT: Filgrastim-sndz (Zarxio)

There is no reliable evidence of the superiority of any one product of filgrastim compared to other products. The FDA defines “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”

B. NONPREFERRED PRODUCTS Neupogen (filgrastim); Nivestym (filgrastim-aafi); Releuko (filgrastim-ayow); Nypozi (filgrastim-txid); Granix (Tbo-filgrastim)

Authorization for a non-preferred filgrastim product is considered medically necessary and, therefore, may be authorized when the clinical criteria above are met AND the member meets the following criteria for a non-preferred drug is met:

1. Inadequate response to a trial of the preferred agent; or

2. History of contraindication or adverse event(s) to the preferred agent; or

3. Member has been on the requested agent within the past 365 days, or

4. Documented diagnosis is for a medically necessary indication not indicated in the preferred product.

   DOSAGE AND AUTHORIZATION TIMEFRAMES

5. Recommended Dosage: Dose and frequency should be consistent with FDA labeling, NCCN, or CMS recognized compendia. Dosage is based on body weight and varies dependent upon response, product selected, and indication. Refer to product-specific labeling for complete dosing information.

6. Quantity Limit: Based on FDA labeling or *CMS recognized compendia for individual product.

7. Authorization Period: Authorizations may be provided up to six (6) months

8. Reauthorization: Reassess every 6 months to confirm that current criteria are met, and there is a beneficial response (e.g., demonstrated by a decrease in the interruption of chemotherapy cycles and reduced incidence of febrile neutropenia)

9. Authorization is limited to the submitted request that was reviewed. Any modifications to the diagnosis or prescribed indication necessitates a new prior authorization request.

DRUG INFORMATION

PHARMACOLOGIC CATEGORY: Colony Stimulating Factor; Hematopoietic Agent

Filgrastim is a granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology. G-CSFs stimulate the production, maturation, and activation of neutrophils to increase both their migration and cytotoxicity.

PRODUCTS: Granix; Neupogen; Nivestym; Nypozi; Releuko; Zarxio; Nypozi • Neupogen (filgrastim) and biosimilar of Neupogen: Filgrastim-aafi (Nivestym); Filgrastim-sndz (Zarxio); Filgrastim-ayow (Releuko); filgrastim-txid (Nypozi) • Tbo-Filgrastim (Granix)

ROUTE OF ADMINISTRATION: Intravenous, Subcutaneous

FDA-APPROVED INDICATIONS • Chemotherapy-induced myelosuppression in nonmyeloid malignancies (ALL PRODUCTS: GRANIX / NEUPOGEN / NIVESTYM / NYPOZI / RELEUKO / ZARXIO / NYPOZI) To decrease the incidence of infection (neutropenic fever) in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a significant incidence of severe neutropenia with fever. • Acute myeloid leukemia following induction or consolidation chemotherapy (NEUPOGEN / ZARXIO / NIVESTYM / RELEUKO / NYPOZI): To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in adults with acute myeloid leukemia. • Bone marrow transplantation (NEUPOGEN / ZARXIO / NIVESTYM / RELEUKO / NYPOZI): To reduce the duration of neutropenia and neutropenia-related events (e.g., neutropenic fever) in patients with nonmyeloid malignancies receiving myeloablative chemotherapy followed by marrow transplantation. • Hematopoietic Syndrome of Acute Radiation Syndrome (NEUPOGEN/NYPOZI): To increase survival in patients acutely exposed to myelosuppressive doses of radiation. • Peripheral blood progenitor cell collection and therapy (NEUPOGEN / ZARXIO / NIVESTYM / NYPOZI): Mobilization of autologous hematopoietic progenitor cells into the peripheral blood for apheresis collection. • Severe chronic neutropenia (NEUPOGEN / ZARXIO / NIVESTYM / RELEUKO / NYPOZI): Long-term administration to reduce the incidence and duration of neutropenic complications (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital, cyclic, or idiopathic neutropenia.

COMPENDIAL APPROVED (OFF-LABELED) USES: Refer to CMS-approved compendia for the relevant off-label use.

CONTRAINDICATIONS: History of serious allergic reactions to human granulocyte colony-stimulating factors, such as filgrastim or pegfilgrastim, or any component of the formulation.

MONITORING PARAMETERS: • Chemotherapy-induced neutropenia: CBC with differential and platelets prior to chemotherapy and twice weekly during growth factor treatment. • Bone marrow transplantation: CBC with differential and platelets frequently. • Hematopoietic radiation injury syndrome (acute): CBC at baseline (do not delay filgrastim for baseline CBC) and approximately every 3 days until ANC remains >1,000/mm3 for 3 consecutive CBCs. Estimate absorbed radiation dose (radiation exposure) based on information from public health authorities, biodosimetry (if available), or clinical findings (e.g., onset of vomiting or lymphocyte depletion kinetics). • Peripheral progenitor cell collection: Neutrophil counts after 4 days of filgrastim treatment.

• Severe chronic neutropenia: CBC with differential and platelets twice weekly during the first month of therapy and for 2 weeks following dose adjustments; once clinically stable, monthly for 1 year and quarterly thereafter. Monitor bone marrow and karyotype prior to treatment; and monitor marrow and cytogenetics annually throughout treatment. • Monitor for signs/symptoms of acute respiratory distress syndrome (evaluate patients who develop fever/lung infiltrates or respiratory distress), allergic reactions, aortitis, capillary leak syndrome, cutaneous vasculitis, myelodysplastic syndrome and acute myeloid leukemia, and splenic rupture (e.g., upper abdominal pain, left upper quadrant pain, or shoulder tip pain). Refer to product-specific labeling for complete monitoring parameters.

CLINICAL SUMMARY / APPENDIX

Centers for Medicare and Medicaid Services (CMS) Compendia CMS has established five drug compendia as authoritative sources (listed in the CMS Internet Only Manual (IOM) Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.4.5) as follows in no particular order: • American Hospital Formulary Service - Drug Information (AHFS-DI) • Elsevier Gold Standard Clinical Pharmacology Compendium (Clinical Pharmacology) • National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN) • Truven Health Analytics Micromedex® DrugDex® Compendium • Wolters Kluwer Lexi-Drugs

Peer-reviewed literature generally considered acceptable for supporting medical necessity in the CMS Medicare Benefit Policy Manual, Chapter 15 to support the use of certain drugs and treatments, especially when prescribed for off-label use. The following is a brief outline of some key criteria; please refer to CMS Internet Only Manual (IOM) Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 50.4.5) Publication in Recognized Journals: • The literature must be published in one of the peer-reviewed journals recognized by CMS. While the list is not exhaustive, it includes prominent journals like the New England Journal of Medicine, JAMA, The Lancet, and others. • Note: CMS may update this list periodically, so it's essential to refer to the latest version of Chapter 15 for the current list of recognized journals. Study Design and Methodology: • Strong evidence: Randomized controlled trials (RCTs) are generally considered the gold standard for evidence. • Non-randomized trials: Well-designed non-randomized clinical trials with a significant number of subjects may also provide supportive evidence. • Case reports: Case reports are generally considered anecdotal and do not provide sufficient evidence to support medical necessity on their own. Relevance to the Indication: • The literature must be relevant to the specific indication for which the drug or treatment is being used. • It should clearly demonstrate the safety and effectiveness of the intervention for that particular condition. Publication Date: • CMS generally prefers recent publications to ensure the information is up-to-date. Older studies may be considered if they are still relevant and no newer, higher-quality evidence is available. Absence of Conflicts of Interest: • The literature should be free from conflicts of interest that could bias the results or conclusions. • Studies funded by parties with a vested interest in the outcome may be viewed with more scrutiny. Clarity and Completeness: • The literature should be clearly written and provide sufficient detail about the study methodology, results, and conclusions. • It should be readily accessible to the contractor for review. Documentation: Prescribers should submit copies of the relevant literature to Aspire Health Plan when requesting the drug product or upon request for additional information.

REFERENCES

Government Agency

1. Centers for Medicare and Medicaid Services (CMS). Medicare coverage database: National coverage determination (NCD) [search: no NCD identified; no applicable LCD for MAC identified; search terms: white blood cell colony stimulating factors (CSFs)]. Available from CMS.

2. Medicare Benefit Policy Manual Chapter 15 Covered Medical and Other Health Services: https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/bp102c15.pdf

   Prescribing Information

3. Granix (tbo-filgrastim) injection, for subcutaneous use [prescribing information]. Sunnyvale, CA; Pharmacyclics, Inc.; November 2023
4. Neupogen (filgrastim) injection, for subcutaneous or intravenous use [prescribing information].Thousand Oaks, CA; Amgen Inc; April 2023.
5. Nivestym (filgrastim-aafi) injection, for subcutaneous or intravenous use [prescribing information]. Lake Forest, IL; Pfizer; February 2024
6. Nypozi (filgrastim-txid) injection, for subcutaneous or intravenous use [prescribing information]. San Diego, CA: Tanvex BioPharma USA, Inc,; June 2024.
7. Releuko (filgrastim-ayow) injection, for subcutaneous or intravenous use [prescribing information]. Piscataway, NJ; Kashiv Biosciences, Inc.; September 2023.
8. Zarxio (filgrastim-sndz) injection, for subcutaneous or intravenous use [prescribing information]. Princeton, NJ: Sandoz, Inc.; January 2024.

IMPORTANT REMINDER

This Medicare Part B Step Therapy Medical Necessity Guideline is provided for informational purposes only and neither constitutes nor replaces professional medical advice. Physicians, hospitals, and other providers are expected to administer or use drugs/biologicals in the most effective and clinically appropriate manner. Treating physicians and other health care providers is solely responsible for all medical care decisions. In accordance with the member's Evidence of Coverage (EOC), every benefit plan has its own coverage provisions, limitations, and exclusions. In the event of a conflict between this policy and the member's EOC, the member's EOC provisions will take precedence. Aspire Health Plan (AHP) adheres to Medicare guidelines, including National Coverage Determination (NCD), Local Coverage Determinations (LCDs), Local Coverage Articles (LCAs), and other relevant Medicare manuals established by CMS. Compliance with these guidelines is required when applicable. Refer to the CMS website at http://www.cms.hhs.gov. For the most up-to-date Medicare policies and coverage, please search the Medicare Coverage Database. All LCDS are the same for each state within a Jurisdiction. Medicare Part B Administrative Contractor (MAC) for CA LCDs - JE Part B – Noridian (noridianmedicare.com). In the event of a discrepancy between this policy and the Medicare NCD or LCD, the Medicare NCD/LCD will govern.

This policy is utilized by AHP to determine coverage in the absence of applicable CMS Medicare guidelines. Please refer to the links provided in the References section below to access the Medicare source materials that were used for developing this resource document. This document does not serve as a substitute for the official Medicare source materials that provide detailed information on Medicare coverage requirements. In the event of a conflict between this document and Medicare source materials, the Medicare source materials will take precedence.

The inclusion of a code in this policy does not imply that the health service it describes is covered or not covered. Benefit coverage for health services is determined by the member-specific plan document and applicable laws that may mandate coverage for a particular service. Inclusion of a code does not imply or guarantee reimbursement or payment of a claim. Other Policies and Standards may also apply. Providers are expected to retain or have access to the necessary documentation when requested to support coverage. The use of physician samples or manufacturer discounts does not guarantee later coverage under the provisions of the medical certificate and/or pharmacy benefit. All criteria must be met to obtain coverage of the listed drug product.

POLICY HISTORY

Committee Date Summary of Changes 11/19/2024 New Policy (effective 05/15/2025) 11/17/2025 Reviewed – No revisions