Pegfilgrastim agents (Neulasta, Neulasta Onpro, Fulphila, Nyvepria, Udenyca, Ziextenzo, Fylnetra, Rolvedon, Stimfend)

Neulasta* (pegfilgrastim), Neulasta Onpro (pegfilgrastim), Fulphila (pegfilgrastim-jmdb), Nyvepria (pegfilgrastim-apgf), Udenyca (pegfilgrastim-cbqv), Ziextenzo* (pegfilgrastim-bmez), Fylnetra (pegfilgrastim-pbbk), Rolvedon (eflapegrastim-xnst), Stimufend (pegfilgrastim-fpgk)

Office-Administration or Self-Administration

* preferred pegfilgrastim agent for pharmacy benefit only.

Diagnosis considered for coverage:

• Febrile Neutropenia (FN), Prophylaxis Indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Limitations of Use: Pegfilgrastim is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
• Hematopoietic Subsyndrome of Acute Radiation Syndrome To increase survival in patients acutely exposed to myelosuppressive doses of radiation. (Off-label use for Fulphila, Nyvepria, Udenyca, Ziextenzo, Fylnetra, Rolvedon, Stimufend) 
• Limitation of Use: Pegfilgrastim agents are not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Coverage Criteria:

For prophylaxis of febrile neutropenia (FN) caused by myelosuppressive chemotherapy and request for Neulasta, Neulasta Onpro (medical benefit only), Nyvepria, Udenyca, Ziextenzo, Fylnetra, Rolvedon (medical benefit only), or Stimufend:

• Dose does not exceed 6 mg/0.6 mL injection per chemotherapy cycle; AND
• Prescribed by or in consultation with a hematologist or oncologist; AND
• Medical records document ONE of the following:
  • Patient is receiving chemotherapy regimen(s) associated with greater than 20% incidence of FN (see Table 1).
  • Both of the following:
    • Diagnosis of acute febrile neutropenia (FN).
    • Patient is at high risk for infection-associated complications (see Table 4).
  • Both of the following:
    • Patient is receiving chemotherapy regimen(s) associated with 10-20% incidence of FN (see Table 2).
    • Patient has one or more risk factors associated with chemotherapy induced infection, FN, or neutropenia.
  • Both of the following:
    • Patient is receiving myelosuppressive anticancer drugs associated with neutropenia (see Table 3).
    • Patient has a history of FN or dose-limiting event during a previous course of chemotherapy (i.e., secondary prophylaxis); AND
• Requested G-CSF agent will not be used in combination with other G-CSF/GM-CSF agents; AND
• One of the following:
  • For requests prescribed through the medical benefit: a medically appropriate reason is provided why the patient cannot use the medical group's preferred pegfilgrastim agent.
  • For requests prescribed through the pharmacy benefit:
    • For Fulphila, Nyvepria, Udenyca, Fylnetra, or Stimufend: Tried and failed, contraindicated, or intolerant to BOTH of the following:
      • Neulasta, Neulasta Onpro (Neulasta Onpro available through medical benefit only)
      • Ziextenzo

For prevention or treatment of acute radiation syndrome (ARS) neutropenia and request for Neulasta, Neulasta Onpro (medical benefit only), Fulphila*, Nyvepria*, Udenyca*, Ziextenzo*, Fylnetra*, Rolvedon* (medical benefit only), or Stimufend*: 

• Dose does not exceed one 6 mg/0.6 mL injection followed by an additional 6 mg/0.6 mL injection one week later; AND
• Prescribed by or in consultation with a radiologist, hematologist, or oncologist; AND
• Medical records document the patient was, or will be, acutely exposed to myelosuppressive doses of radiation; AND
• Requested G-CSF agent will not be used in combination with other G-CSF/GM-CSF agents; AND
• One of the following:
  • For requests prescribed through the medical benefit: a medically appropriate reason is provided why the patient cannot use the medical group's preferred pegfilgrastim agent.
  • For requests prescribed through the pharmacy benefit:
    • For Fulphila, Nyvepria, Udenyca Fylnetra, or Stimufend: Tried and failed, contraindicated, or intolerant to BOTH of the following:
      • Neulasta, Neulasta Onpro (Neulasta Onpro available through medical benefit only)
      • Ziextenzo

*Off-label

Reauthorization Criteria:

For prophylaxis of febrile neutropenia (FN) caused by myelosuppressive chemotherapy and request for Neulasta/Neulasta Onpro, Nyvepria, Udenyca, Ziextenzo, Fylnetra, Rolvedon (medical benefit only), or Stimufend:
 

• Dose does not exceed 6 mg/0.6 mL injection every 2 weeks; AND
• Medical records document the patient continues to receive myelosuppressive chemotherapy; AND
• Requested G-CSF agent will not be used in combination with other G-CSF/GM-CSF agents.

Coverage Duration:

• FN prophylaxis:
  • Initial: 3 months
  • Reauthorization: duration of chemotherapy
• ARS: 1 month (2 doses)

Authorization is not covered for the following:

• The use of this drug for indications not listed in this policy does not meet the coverage criteria established by the Western Health Advantage (WHA) Pharmacy and Therapeutics (P&T) Committee.

Additional Information:

• Do not administer pegfilgrastim products between 14 days before and 24 hours after administration of cytotoxic chemotherapy.
• The FDA defines biosimilar as a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product. The American Society of Clinical Oncology states that pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars as they become available) can be used for the prevention of treatment-related febrile neutropenia. The choice of agent depends on convenience, cost, and clinical situation. NCCN lists FDA-approved biosimilars as appropriate substitutes for filgrastim and pegfilgrastim. Limited data suggest that patients can alternate between the biosimilar and the originator biologic without any clinically meaningful differences regarding efficacy or safety.
• Dose dense chemotherapy is a treatment plan in which drugs are given with less time between treatments than in a standard chemotherapy treatment plan.
• FN is described by clinical practice guidelines as neutropenia with a single oral or tympanic temperature greater than or equal to 101°F (38.3°C) or greater than or equal to 100.4°F (38°C) for at least one hour.
• The Infectious Diseases Society of America (IDSA) guidelines recommend against the use of pegfilgrastim products for all patients with established fever and neutropenia, whereas the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines state that their use can be "considered" for patients at high risk for infection-associated complications or who have prognostic factors that are predictive of a poor clinical outcome.
• Non-myeloid malignancies are cancers that are not classified as: (1) myelodysplastic syndromes (MDSs); (2) myeloproliferative neoplasms (MPNs); (3) myelodysplastic/myeloproliferative neoplasms (MDS/MPN); or (4) myeloid malignancies associated with eosinophilia and abnormalities of growth factor receptors derived from platelets or fibroblasts.
• Bone marrow transplants are most commonly used in the following diseases: leukemias, lymphomas, multiple myeloma, immune deficiency disorders, severe aplastic anemia, and some solid-tumor cancers (in rare circumstances).
• Hematopoietic progenitor cells (HPCs) or hematopoietic stem cells (HSCs) are cells present in blood and bone marrow. HPCs are capable of forming mature blood cells, such as red blood cells (the cells that carry oxygen), platelets (the cells that help stop bleeding) and white blood cells (the cells that fight infections). Hematopoietic stem cell transplantation is the IV infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with a variety of acquired and inherited malignant and nonmalignant disorders.
  • Allogeneic stem cell transplantation involves transferring the stem cells from a healthy person (the donor) to the patient’s body after high-intensity chemotherapy or radiation. The donated stem cells can come from either a related or an unrelated donor.
  • An autologous stem cell transplant uses healthy blood stem cells from your own body to replace your diseased or damaged bone marrow. An autologous stem cell transplant is also called an autologous bone marrow transplant.
• One cubic millimeter (mm^3) = One microliter (µL).

Review History:

• 02/15/2022 – New policy approved by P&T.
• 06/01/2023 - Addition of Fylentra, Rolvedon, and Stimufend to Pegfilgrastim medication policy (P&T 5/16/23). 

References:

1. Bellon A, Wang J, Skerjanec A, et al. A large multi-center, randomized, double-blind, cross-over study in healthy volunteers to compare pharmacokinetics, pharmacodynamics and safety of a pegfilgrastim biosimilar with its US- and EU-reference biologics. Br J Clin Pharmacol. 2020;86(6):1139-1149. doi: 10.1111/bcp.14226.
2. Blackwell K, Donskih R, Jones CM, et al. A comparison of proposed biosimilar LA-EP2006 and reference pegfilgrastim for the prevention of neutropenia in patients with early-stage breast cancer receiving myelosuppressive adjuvant or neoadjuvant chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a phase III, randomized, double-blind trial. Oncologist. 2016;21(7):789-794. doi: 10.1634/theoncologist.2016-0011.
3. Botteri E, Krendyukov A, Curigliano G. Comparing granulocyte colony-stimulating factor filgrastim and pegfilgrastim to its biosimilars in terms of efficacy and safety: a meta analysis of randomized clinical trials in breast cancer patients. Eur J Cancer.2018;89:49-55
4. Castagna L, Bramanti S, Levis A, et al. Pegfilgrastim vs filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell support. Ann Oncol. 2010 Jul;21(7):1482-1485.
5. Cesaro S, Nesi F, Tridello G, et al. A randomized, non-inferiority study comparing efficacy and safety of a single dose of pegfilgrastim versus daily filgrastim in pediatric patients after autologous peripheral blood stem cell transplant. PLoS ONE. 2013;8(1): e53252. doi: 10.1371/journal.pone.0053252.
6. Finck B, Tang H, Civoli F, Hodge J, O'Kelly H, Vexler V. Pharmacokinetic and pharmacodynamic equivalence of pegfilgrastim-cbqv and pegfilgrastim in healthy subjects. Adv Ther. 2020;37(10):4291-4307. doi:10.1007/s12325-020-01459-y
7. Fulphila [package insert]. Mylan Institutional LLC. Rockford, IL; March 2021.
8. Gerds A, Fox-Geiman M, Dawravoo K, et al. Randomized phase III trial of pegfilgrastim versus filgrastim after autologous peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2010;16:678-685.
9. Green MD, Koelbl H, Baselga J, et al. VA randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim vs daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003 Jan;14(1):29-35.
10. Harbeck N, Lipatov O, Frolova M, et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol. 2016 Jun;12(11):1359-1367. doi: 10.2217/fon-2016-0016.
11. Hecht JR, Pillai M, Gollard R, et al. A randomized, placebo-controlled phase II study evaluating the reduction of neutropenia and febrile neutropenia in patients with colorectal cancer receiving pegfilgrastim with every-2-week chemotherapy. Clinical Colorectal Cancer. 2010;9:95-101.
12. Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle vs daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002;20(3):727-731.
13. Kuan JW, Su AT, Leong CF. Pegylated granulocyte-colony stimulating factor versus non-pegylated granulocyte-colony stimulating factor for peripheral blood stem cell mobilization: a systematic review and meta-analysis. J Clin Apher. 2017;32(6):517-542.
14. Li X, Zheng H, Yu MC, et al. Is PEGylated G-CSF superior to G-CSF in patients with breast cancer receiving chemotherapy?  A systematic review and meta-analysis. Support Care Cancer. 2020;28(11):5085-5097. doi: 10.1007/s00520-020-05603-w
15. Lucas AJ, Olin JL, Coleman MD. Management and preventive measures for febrile neutropenia. Pharmacy and Therapeutics. 2018 Apr;43(4):228.
16. Martino M, Praticò G, Messina G, et al. Pegfilgrastim compared to filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients. Eur J Haematol. 2006 Nov;77(5):410-415.
17. Nakov R, Gattu S, Wang J, Velinova M, Schaffar G, Skerjanec A. Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects. Br J Clin Pharmacol. 2018 Dec;84(12):2790-2801.
18. Neulasta [package insert], Amgen Inc. Thousand Oaks, CA; March 2021.
19. Nyvepria [package insert]. Hospira Inc. Lake Forest, IL; April 2021Rifkin R, Spitzer G, Orloff G, et al. Pegfilgrastim appears equivalent to daily dosing of filgrastim to treat neutropenia after autologous peripheral blood stem cell transplantation in patients with Non-Hodgkin Lymphoma. Clin Lymphoma Myeloma Leuk. 2010;10:186-191.
20. Russell N, Mesters R, Schubert J, et al. A phase 2 pilot study of pegfilgrastim and filgrastim for mobilizing peripheral blood progenitor cells in patients with non-Hodgkin’s lymphoma receiving chemotherapy. Haematologica. 2008;93(3):405-412.
21. Sebban C, Lefranc A, Perrier L, et al. A randomized phase II study of the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after autologous stem cell transplant for lymphoma and myeloma (PALM study). Eur J Cancer. 2012 Mar;48(5):713-720.
22. Shi YK, Chen Q, Yun-Zhong Z, et al. Pegylated filgrastim is comparable with filgrastim as support for commonly used chemotherapy regimens: a multicenter, randomized, crossover phase 3 study. Anti-Cancer Drugs. 2013;24:641-647.
23. Udenyca [package insert]. Coherus BioSciences Inc. Redwood City, CA; June 2021.
24. Ziextenzo [package insert]. Sandoz Inc. Princeton, NJ; March 2021.
25. Fylentra [package insert]. Amneal Pharmaceuticals LLC. Bridgewater, NJ; May 2022.