Last Review Date: 08/01/2024

Date of Origin: 10/17/2008

Dates Reviewed: 06/2009, 12/2009, 06/2010, 07/2010, 09/2010, 12/2010, 03/2011, 6/2011, 09/2011, 12/2011, 03/2012, 06/2012, 09/2012, 12/2012, 03/2013, 06/2013, 09/2013, 12/2013, 03/2014, 06/2014, 09/2014, 12/2014, 03/2015, 04/2015, 08/2015, 11/2015, 02/2016, 05/2016, 08/2016, 11/2016, 02/2017, 05/2017, 08/2017, 11/2017, 02/2018, 05/2018, 04/2019, 04/2020, 04/2021, 04/2022, 07/2022, 04/2023, 04/2024, 08/2024

1. Length of Authorization

Coverage will be provided for 6 months and may be renewed.

2. Dosing Limits

1. Quantity Limit (max daily dose) [NDC Unit]:

2. Max Units (per dose and over time) [HCPCS Unit]:

Severe Chronic Neutropenia (Congenital Neutropenia):

• 1560 billable units per day

 BMT or PBPC or H-ARS:

• 1200 billable units per day

All other indications:

• 600 billable units per day

3. Initial Approval Criteria

Coverage is provided in the following conditions:

Bone Marrow Transplant (BMT) † ‡ Ф ^1-4,6,7

Peripheral Blood Progenitor Cell (PBPC) mobilization and transplant † ‡ Ф ^{1-3,6,7,20,31,34,36-38}

Prophylactic use in patients with solid tumors or non-myeloid malignancy † ‡ ^{1-8,10,11,13,14,16,18,28-30}

• Patient is undergoing myelosuppressive chemotherapy with an expected incidence of febrile neutropeniav of > 20% §; OR
• Patient is undergoing myelosuppressive chemotherapy with an expected incidence of febrile neutropeniav of 10% to 20% § AND one or more of the patient-related risk factors ¥; OR
• Patient is undergoing myelosuppressive chemotherapy with an expected incidence of febrile neutropeniav of < 10% § AND two or more of the patient-related risk factors ¥ **

**Use in this setting is based on clinical judgment

Note: Dose-dense therapy, in general, requires growth factor support to maintain dose intensity and schedule. In the palliative setting, consideration should be given to dose reduction or change in regimen.

Treatment of chemotherapy-induced febrile neutropenia ‡ ^{7,8,10,11,13,14,16,18,28-30}

• Patient has been on prophylactic therapy with filgrastim or tbo-filgrastim (Note: therapy should not be used concomitantly with pegfilgrastim); OR
• Patient has not received prophylactic therapy with a granulocyte colony stimulating factor; AND
  • • • Patient has one or more of the following risk factors for developing infection-related complications:
  • Sepsis Syndrome
  • Age greater than 65 years
  • Absolute neutrophil count [ANC] less than 100/mcL
  • Duration of neutropenia expected to be greater than 10 days
  • Pneumonia or other clinically documented infections
  • Invasive fungal infection
  • Hospitalization at the time of fever
  • Prior episode of febrile neutropenia

Patient who experienced a neutropenic complication from a prior cycle of the same chemotherapy ‡ ^{7,8,10,11,13,14,16,18,28-30}

Note: Dose-dense therapy, in general, requires growth factor support to maintain dose intensity and schedule. In the palliative setting, consideration should be given to dose reduction or change in regimen.

Acute Myeloid Leukemia (AML) † ‡ Ф ^{1-4,6,9,15,36}

• Used in patients receiving induction/consolidation or re-induction chemotherapy; OR
• Used for relapsed or refractory disease

Bone Marrow Transplantation (BMT) failure or Engraftment Delay ‡ ^{26,27,31,34,36-38}

Severe Chronic Neutropenia † ‡ Ф ^1-4,6,12

• Patient must have an absolute neutrophil count (ANC) < 500/mm³; AND
• Patient must have a diagnosis of one of the following:
  • Congenital neutropenia; OR
  • Cyclic neutropenia; OR
  • Idiopathic neutropenia

Myelodysplastic Syndromes (MDS) ‡ ^7,39

• Patient has symptomatic anemia with no del(5q) mutation; AND
• Patient has lower risk disease (i.e., defined as IPSS-R [Very Low, Low, Intermediate]); AND
• Patient has a serum erythropoietin level of ≤500 mUnits/mL; AND
• Used in combination with an erythropoiesis stimulating agent (ESA); AND
  • Patient has ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation); AND
    • Used following no response* to luspatercept; OR
  • Patient has ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation); AND
    • Used following no response* to ESAs alone (despite adequate iron stores); OR
    • Used following no response* to luspatercept

* Note: No response defined as a lack of ≥1.5 gm/dL rise in hemoglobin OR lack of a decrease in RBC transfusion requirement (within 3-6 months if treated with luspatercept or 6-8 weeks if treated with ESAs)

Patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome [H-ARS]) † ‡ Ф ^1-4,6-8,19

Management of CAR T-cell related Toxicity ‡ ⁷

• Patient has been receiving therapy with CAR T-cell therapy (e.g., axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, tisagenlecleucel, etc.); AND
• Patient is experiencing neutropenia related to their therapy

Wilms Tumor (Nephroblastoma) ‡ ⁷

• Patient has favorable histology disease; AND
• Used in combination with a cyclophosphamide-based chemotherapy regimen (i.e., Regimen M or I only)

† FDA Approved Indication(s); ‡ Compendia Recommended Indication(s); Ф Orphan Drug

4. Renewal Criteria ^1-6

Coverage may be renewed based upon the following criteria:

• Patient continues to meet indication-specific relevant criteria such as concomitant therapy requirements (not including prerequisite therapy), performance status, etc. identified in section III; AND
• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: 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, MDS/AML (when used for congenital neutropenia or used in conjunction with chemotherapy and/or radiation for breast or lung cancer), etc.

5. Dosage/Administration ^1-6

6. Billing Code/Availability Information

HCPCS Code(s):

• J1442 – Injection, filgrastim (g-csf), excludes biosimilars, 1 mcg: 1 billable unit = 1 mcg
• Q5110 – Injection, filgrastim-aafi, biosimilar, (Nivestym), 1 mcg: 1 billable unit = 1 mcg
• Q5101 – Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 mcg: 1 billable unit = 1 mcg
• J1447 – Injection, tbo-filgrastim (Granix), 1 mcg: 1 billable unit = 1 mcg
• Q5125 – Injection, filgrastim-ayow, biosimilar, (Releuko), 1 mcg; 1 billable unit = 1 mcg
• J3590 – Unclassified biologics (Nypozi ONLY)

NDC(s):

7. References

1. Neupogen [package insert]. Thousand Oaks, CA; Amgen Inc; April 2023. Accessed March 2024.
2. Nivestym [package insert]. Lake Forest, IL; Hospira Inc; February 2024. Accessed March 2024.
3. Zarxio [package insert]. Princeton, NJ; Sandoz Inc; January 2024. Accessed March 2024.

4. Releuko [package insert]. Piscataway, NJ; Kashiv Biosciences, Inc; September 2023. Accessed March 2024.
5. Granix [package insert]. North Wales, PA; Teva Pharmaceuticals USA, Inc.; November 2023. Accessed March 2024.
6. Nypozi [package insert]. San Diego, CA; Tanvex BioPharma USA, Inc,; June 2024. Accessed July 2024.
7. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) filgrastim. National Comprehensive Cancer Network, 2024.  The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org.  Accessed March 2024.
8. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Hematopoietic Growth Factors. Version 3.2023.  National Comprehensive Cancer Network, 2024. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org.  Accessed March 2024.
9. Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood. 1997;90:4710-4718.
10. Rusthoven J, Bramwell V, Stephenson B. Use of granulocyte colony-stimulating factor (G-CSF) in patients receiving myelosuppressive chemotherapy for the treatment of cancer. Provincial Systemic Treatment Disease Site Group. Cancer Prev Control. 1998;2(4):179-190.
11. Berghmans T, Paesmans M, Lafitte JJ, et al. Therapeutic use of granulocyte and granulocyte-macrophage colony-stimulating factors in febrile neutropenic cancer patients. A systematic review of the literature with meta-analysis. Support Care Cancer. 2002;10(3):181-188.
12. Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood. 1993;81(10):2496-2502.
13. Timmer-Bonte JN, de Boo TM, Smit HJ, et al. Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: A Dutch randomized Phase III study. J Clin Oncol. 2005;23:7974–84. doi: 10.1200/JCO.2004.00.7955.
14. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991;325:164–70.
15. Lilienfeld-Toal M, Hahn-Ast C, Kirchner H, et al. A randomized comparison of immediate versus delayed application of G-CSF in induction therapy for patients with acute myeloid leukemia unfit for intensive chemotherapy. Haematologica. 2007;92:1719–1720.
16. García-Carbonero R, Mayordomo JI, Tornamira MV, et al. Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: A multicenter randomized trial. J Natl Cancer Inst. 2001;93(1):31-38.
17. Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood. 1997;90(12):4710-4718.
18. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015 Oct 1;33(28):3199-212. doi: 10.1200/JCO.2015.62.3488.
19. Farese AM, MacVittie TJ. Filgrastim for the treatment of hematopoietic acute radiation syndrome. Drugs Today (Barc) 2015;51:537-48.
20. Schmitt M, Publicover A, Orchard KH, et al. Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Theranostics. 2014;4(3):280-289.
21. Abraham I, Tharmarajah S, MacDonald K. Clinical safety of biosimilar recombinant human granulocyte colony-stimulating factors. Expert Opin Drug Saf. 2013;12(2):235-246.
22. Yao HM, Ottery FD, Borema T, et al. PF-06881893 (Nivestym™), a Filgrastim Biosimilar, Versus US-Licensed Filgrastim Reference Product (US-Neupogen®): Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Safety of Single or Multiple Subcutaneous Doses in Healthy Volunteers. BioDrugs. 2019 Apr;33(2):207-220.
23. Lubenau H, Sveikata A, Gumbrevicius G, et al. Bioequivalence of two recombinant granulocyte colony-stimulating factor products after subcutaneous injection in healthy volunteers. Int J Clin Pharmacol Ther. 2009;47(4):275-282.
24. Gascon P, Fuhr U, Sörgel F, et al. Development of a new G-CSF product based on biosimilarity assessment. Ann Oncol. 2010 Jul;21(7):1419-29.
25. Kelaidi C, Beyne-Rauzy O, Braun T, et al. High Response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM. Ann Hematol 2013; 92:621-631.
26. Elayan MM, Horowitz JG, Magraner JM, et al. Tbo-Filgrastim versus Filgrastim during Mobilization and Neutrophil Engraftment for Autologous Stem Cell Transplantation. Biol Blood Marrow Transplant. 2015 Nov; 21(11):1921-5. doi: 10.1016/j.bbmt.2015.05.024.
27. Trifilio S, Zhou Z, Galvin J, et al. Filgrastim versus TBO-filgrastim to reduce the duration of neutropenia after autologous hematopoietic stem cell transplantation: TBO, or not TBO, that is the question. Clin Transplant. 2015 Oct 22. doi: 10.1111/ctr.12637.
28. del Giglio A, Eniu A, Ganea-Motan D, et al. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer. 2008;8:332.
29. Gatzemeier U, Ciuleanu T, Dediu M, et al. XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol. 2009;4(6):736-40.
30. Engert A, Griskevicius L, Zyuzgin Y, et al. XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with non-Hodgkin lymphoma receiving chemotherapy. Leuk Lymphoma. 2009;50(3):374-79.
31. Bhamidipati PK, Fiala MA, Grossman BJ, et al. Results of a prospective randomized, open-label, noninferiority study of tbo-filgrastim (Granix) versus filgrastim (Neupogen) in combination with Plerixafor for autologous stem cell mobilization in patients with multiple myeloma and non-Hodgkin lymphoma. Biol Blood Marrow Transplant. August 7, 2017
32. Engert A, del Giglio A, Bias P, et al. Incidence of febrile neutropenia and myelotoxicity of chemotherapy: A meta-analysis of biosimilar G-CSF studies in breast cancer, lung cancer, and non-Hodgkin's lymphoma. Onkologie. 2009;32(10):599-604.
33. Lubenau H, Bias P, Maly AK, et al. Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed filgrastim Neupogen: Single-blind, randomized, crossover trial. BioDrugs. 2009;23(1):43-51.
34. Andreola G, Babic A, Rabascio C, et al. Plerixafor and Filgrastim XM02 (Tevagastrim) as a first line peripheral blood stem cell mobilisation strategy in patients with multiple myeloma and lymphoma candidated to autologous bone marrow transplantation. Eur J Haematol. 2012;88(2):154-158.
35. Bagalagel A, Mohammed A, MacDonald K, Abraham I. Clinical efficacy and safety of Tevagrastim® (XM02), a biosimilar recombinant human granulocyte colony-stimulating factor. Biosimilars. 2013;2013(3):55-62.
36. Danylesko I, Sareli R, Bloom-Varda N, et al. The use of Tevagrastim (biosimilar filgrastim XMO2) for hematopoietic stem cell mobilization In HLA matched sibling donors for allogeneic stem cell transplantation to AML/MDS patients. Blood. 2013;122(21):3275.
37. Schmitt M, Xu X, Hilgendorf I, et al. Mobilization of PBSC for allogeneic transplantation by the use of the G-CSF biosimilar XM02 in healthy donors. Bone Marrow Transplant. 2013;48(7):922-925
38. Schmitt M, Hoffmann JM, Lorenz K, et al. Mobilization of autologous and allogeneic peripheral blood stem cells for transplantation in haematological malignancies using biosimilar G-CSF. Vox Sang. 2016;111(2):178-186.
39. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium®) Myelodysplastic Syndromes. Version 1.2024.  National Comprehensive Cancer Network, 2024. The NCCN Compendium® is a derivative work of the NCCN Guidelines®. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org.  Accessed March 2024.
40. Palmetto GBA. Local Coverage Determination: White Cell Colony Stimulating Factors (A56748). Centers for Medicare & Medicaid Services, Inc. Updated on 08/10/2023 with effective date 10/01/2023. Accessed March 2024.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

The preceding information is intended for non-Medicare coverage determinations. Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA):