Last Review Date: 05/02/2024

Date of Origin: 10/17/2008

Dates Reviewed: 11/2008, 06/2009, 12/2009, 09/2010, 12/2010, 02/2011, 03/2011, 06/2011, 08/2011, 09/2011, 12/2011, 03/2012, 06/2012, 09/2012, 10/2012, 12/2012, 03/2013, 05/2013, 06/2013, 09/2013, 12/2013, 03/2014, 06/2014, 09/2014, 12/2014, 03/2015, 05/2015, 08/2015, 11/2015, 02/2016, 05/2016, 08/2016, 11/2016, 02/2017, 04/2017, 8/2017, 11/2017, 12/2017, 05/2018, 06/2018, 04/2019, 04/2020, 05/2021, 05/2022, 05/2023, 05/2024

1. Length of Authorization

Coverage will be provided for 45 days and may be renewed unless otherwise specified.

• Coverage for Reduction of Allogeneic Blood Transfusions in Elective, Non-Cardiac, Non-Vascular Surgery may not be renewed.

2. Dosing Limits

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

• 2,000 U/mL single-dose vial: 3 vials per week
• 3,000 U/mL single-dose vial: 3 vials per week
• 4,000 U/ml single-dose vial: 3 vials per week
• 10,000 U/mL single-dose vial: 3 vials per week
• 10,000 U/mL 2 mL multi-dose vial: 3 vials per week
• 20,000 U/mL 1 mL multi-dose vial: 3 vials per week
• 40,000 U/mL single-dose vial: 1 vial per week

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

• MDS: 120 billable units every 7 days
• Surgery patients: 600 billable units every 15 days
• All other indications: 60 billable units every 7 days

3. Initial Approval Criteria ^1-3,6,7

Coverage is provided in the following condition(s):

• Patient is at least 18 years of age (unless otherwise specified); AND
• Initiation of therapy Hemoglobin (Hb) < 10 g/dL and/or Hematocrit (Hct) < 30% (unless otherwise specified); AND

Universal Criteria ^1-3,5,8,29

• Lab values are obtained within 30 days of the date of administration (unless otherwise indicated); AND
• Patient has adequate iron stores as demonstrated by serum ferritin ≥ 100 ng/mL (mcg/L) and transferrin saturation (TSAT) ≥ 20% (measured within the previous 3 months for renewal)*; AND
• Other causes of anemia (e.g. hemolysis, bleeding, vitamin deficiency, etc.) have been ruled out; AND
• Patient does not have uncontrolled hypertension; AND

Anemia Due to Myelodysplastic Syndromes (MDS) ‡ ^4,6,27

• Patient has symptomatic anemia; AND
• Patient has serum erythropoietin ≤ 500 mU/mL; AND
  • Patient has lower risk disease (defined as IPSS [Low/Intermediate-1]); AND
    • Used as a single agent for del(5q) mutation (excluding use in patients with cytogenetic abnormality involving chromosome 7); OR
  • Patient has lower risk disease (defined as IPSS-R [Very Low, Low, Intermediate]); AND
    • Patient does not have del(5q) mutation; AND
      • Patient has ring sideroblasts < 15% (or <5% with an SF3B1 mutation); AND
        • Used as a single agent; OR
        • Used in combination with either lenalidomide or a granulocyte-colony stimulating factor (G-CSF); AND
          5. Patient had no response** (despite adequate iron stores) to an erythropoiesis-stimulating agent (ESA) alone; OR
          5. Patient had no response** to luspatercept; OR
      • Patient has ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation); AND
        • Patient had no response** to luspatercept; AND
          5. Used as a single agent; OR
          5. Used in combination with a G-CSF

** 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 6-8 weeks when treated with ESAs or within 3-6 months when treated with luspatercept).

Anemia Due to Myeloproliferative Neoplasms (MPN) - Myelofibrosis ‡ ^4,7,27

• Patient has myelofibrosis-associated anemia with serum erythropoietin level of < 500 mU/mL; AND
  • Patient has symptomatic splenomegaly and/or constitutional symptoms currently controlled on a JAK inhibitor; AND
    • Used in combination with ruxolitinib; OR
  • Patient has no symptomatic splenomegaly and/or constitutional symptoms; AND
    • Used as a single agent

Anemia Due to Chemotherapy Treatment † ‡ ^1-5,27

• Patient is at least 5 years of age; AND
• Patient has anemia due to concomitant myelosuppressive chemotherapy for a non-myeloid malignancy; AND
• Patient is receiving chemotherapy that is not intended to cure their disease (i.e., palliative treatment) ±; AND
• There are a minimum of two additional months of planned chemotherapy

± Note: Patients who are not undergoing palliative treatment and refuse blood transfusions may be reviewed on a case-by-case basis

Anemia Due to Chronic Kidney Disease (Non-Dialysis Patients) † Ф ^1-3,8,29

• Patient is at least 1 month of age

Anemia Due to Zidovudine in Patients with HIV-Infection † (Ф – applicable to Procrit/Epogen only) ^1-3

• Patient is at least 8 months of age; AND
• Endogenous serum erythropoietin level of ≤ 500 mUnits/mL; AND
• Patient is receiving zidovudine administered at ≤ 4200 mg/week

Reduction of Allogeneic Blood Transfusions in Elective, Non-Cardiac, NonVascular Surgery † ^1-3

• Hemoglobin (Hb) >10 g/dL and ≤ 13 g/dL and/or Hematocrit (Hct) > 30% and ≤ 39%; AND
• Patient is at high-risk of blood-loss from surgery that is elective, non-cardiac and non-vascular; AND
• Patient is unwilling or unable to participate in an autologous blood donation program prior to surgery

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

4. Renewal Criteria ^1-3,6,7,30

Coverage can be renewed based upon the following criteria:

• Patient continues to meet universal and other indication-specific relevant criteria identified in section III; AND
• Previous dose was administered within the past 60 days; AND
• Disease response with treatment as defined by improvement in anemia compared to pretreatment baseline; AND
• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: severe cardiovascular events (stroke, myocardial infarction, congestive heart failure, thromboembolism, etc.), uncontrolled hypertension, increased risk of tumor progression/ recurrence in patients with cancer, seizures, pure red cell aplasia, serious allergic reactions (anaphylaxis, angioedema, bronchospasm, etc.), severe cutaneous reactions (erythema multiforme, Stevens-Johnson Syndrome [SJS]/Toxic Epidermal Necrolysis [TEN], etc.), “gasping syndrome” (central nervous system depression, metabolic acidosis, gasping respirations) due to benzyl alcohol preservative, etc.; AND

Anemia Due to Myelodysplastic Syndrome (MDS)

• Hemoglobin (Hb) <12 g/dL and/or Hematocrit (Hct) <36%

Anemia Due to Myeloproliferative Neoplasms (MPN) – Myelofibrosis

• Hemoglobin (Hb) <10 g/dL and/or Hematocrit (Hct) <30%

Anemia Due to Chemotherapy Treatment

• Refer to Section III for criteria (age was met initially)

Anemia Due to Chronic Kidney Disease (Non-Dialysis Patients)

• Pediatric patients: Hemoglobin (Hb) < 12 g/dL and/or Hematocrit (Hct) < 36%
• Adult patients: Hemoglobin (Hb) < 11 g/dL and/or Hematocrit (Hct) < 33%

Anemia Due to Zidovudine in Patients with HIV-Infection

• Hemoglobin (Hb) < 12 g/dL and/or Hematocrit (Hct) < 36%; AND
• Patient is receiving zidovudine administered at ≤ 4200 mg/week

Reduction of Allogeneic Blood Transfusions in Elective, Non-Cardiac, NonVascular Surgery

• Coverage may not be renewed.

5. Dosage/Administration ^1-3,6,24,28

6. Billing Code/Availability Information

HCPCS code(s):

• J0885 – Injection, epoetin alfa, (for non-ESRD use), 1000 units; 1 billable unit = 1,000 units
• Q5106 – Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for non-ESRD use), 1000 units; 1 billable unit = 1,000 units

NDC(s):

7. References

1. Procrit [package insert]. Horsham, PA; Janssen, LP; April 2023. Accessed April 2024. 
2. Epogen [package insert]. Thousand Oaks, CA; Amgen, Inc.; July 2018. Accessed April 2024.
3. Retacrit [package insert]. Lake Forest, IL; Hospira, Inc.; April 2023. Accessed April 2024.
4. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) epoetin alfa. 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 April 2024.
5. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Hematopoietic Growth Factors Version 3.2024. 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 April 2024.
6. 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 April 2024.
7. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) Myeloproliferative Neoplasms 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 April 2024.
8. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012;2(suppl):279-335. https://kdigo.org/guidelines/anemia-in-ckd/. Published August 2012.
9. Piccoli A, Malagoli A, Komninos G, Pastori G. Subcutaneous epoetin-alpha every one, two, and three weeks in renal anemia. J Nephrol. 2002;15(5):565-574.
10. Provenzano R, Bhaduri S, Singh AK; PROMPT Study Group. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clin Nephrol. 2005;64(2):113-123.
11. Provenzano R, Garcia-Mayol L, Suchinda P,et al; POWER Study Group. Once-weekly epoetin alfa for treating the anemia of chronic kidney disease. Clin Nephrol. 2004;61(6):392-405.
12. Singh AJ, Szczech L, Tang Kl, et al, “Correction of Anemia With Epoetin Alfa in Chronic Kidney Disease,” N Engl J Med, 2006, 355(20):2085-98.
13. Fishbane S, Spinowitz BS, Wisemandle WA, et al. Randomized Controlled Trial of Subcutaneous Epoetin Alfa-epbx Versus Epoetin Alfa in End-Stage Kidney Disease. Kidney Int Rep. 2019 May 22;4(9):1235-1247.
14. Thadhani R, Guilatco R, Hymes J, et al. Switching from Epoetin Alfa (Epogen®) to Epoetin Alfa-Epbx (RetacritTM) Using a Specified Dosing Algorithm: A Randomized, Non-Inferiority Study in Adults on Hemodialysis. Am J Nephrol. 2018;48(3):214-224.
15. Fishbane S, Singh B, Kumbhat S, et al. Intravenous Epoetin Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End-Stage Kidney Disease. Clin J Am Soc Nephrol. 2018 Aug 7;13(8):1204-1214.
16. US Food and Drug Administration. FDA briefing document. Oncologic Drugs Advisory Committee Meeting. BLA 125545: Epoetin Hospira, a proposed biosimilar to Epogen/Procrit (epoetin alfa). Hospira Inc., a Pfizer Company. May 25, 2017.
17. Fenaux P, Santini V, Spiriti MAA, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018;32(12):2648-2658. doi: 10.1038/s41375-018-0118-9.
18. Park S, Greenberg P, Yucel A, et al. Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review. Br J Haematol. 2019;184(2):134-160. doi: 10.1111/bjh.15707
19. Greenberg PL, Sun Z, Miller KB, et al. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood. 2009;114(12):2393-2400.
20. Peeters, HR, Jongen-Lavrencic, M, Vreugdenhil, G, Swaak, AJ. Effect of recombinant human erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: a randomized placebo controlled double blind 52 weeks clinical trial. Ann Rheum Dis 1996; 55:739.
21. Pincus T, Olsen NJ, Russell IJ, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990; 89:161-8.
22. Saag, MS, Bowers, P, Leitz, GJ, Levine, AM. Once-weekly epoetin alfa improves quality of life and increases hemoglobin in anemic HIV+ patients. AIDS Res Hum Retroviruses 2004; 20:1037.
23. Grossman, HA, Goon, B, Bowers, P, Leitz, G. Once-weekly epoetin alfa dosing is as effective as three times-weekly dosing in increasing hemoglobin levels and is associated with improved quality of life in anemic HIV-infected patients. J Acquir Immune Defic Syndr 2003; 34:368.
24. Cervantes F, Alvarez-Laran A, Hernandez-Boluda JC, et al. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. British Journal of Haematology, 127: 399–403. doi:10.1111/j.1365-2141.2004.05229.x.
25. Shaffer CL, Ransom JL. Current and theoretical considerations of erythropoietin use in anemia of bronchopulmonary dysplasia. J of Pediatric Pharmacy Practice 1996; 1:23-29.
26. Reiter PD, Rosenberg AA, Valuck RJ. Factors associated with successful epoetin alfa therapy in premature infants. Ann Pharmacother 2000; 34:433-439.
27. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) epoetin alfa-epbx. 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 April 2024.
28. Tsiara SN, Chaidos A, Bourantas LK, et al. Recombinant human erythropoietin for the treatment of anaemia in patients with chronic idiopathic myelofibrosis. Acta Haematol. 2007;117(3):156-61. doi: 10.1159/000097463.
29. Mikhail A, Brown C, Williams JA, et al. Renal association clinical practice guideline on Anaemia of Chronic Kidney Disease. BMC Nephrol. 2017 Nov 30;18(1):345. doi: 10.1186/s12882-017-0688-1.
30. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013 Aug 22;122(8):1395-8. doi: 10.1182/blood-2013-03-488098.

31. National Coverage Determination (NCD) for Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (110.21). Centers for Medicare & Medicare Services, Inc. Updated 01/14/2021 with an effective date 07/30/2007. Accessed April 2024.
32. Wisconsin Physicians Service Insurance Corporation. Local Coverage Article: Billing and Coding: Erythropoiesis Stimulating Agents (ESAs) (A56795). Centers for Medicare & Medicaid Services, Inc. Updated on 05/23/2023 with effective date 06/01/2023. Accessed April 2024.
33. CGS Administrators, LLC. Local Coverage Article: Billing and Coding: Erythropoiesis Stimulating Agents (ESA) (A56462). Centers for Medicare & Medicaid Services, Inc. Updated on 02/29/2024 with effective date 03/07/2024. Accessed April 2024.
34. Palmetto GBA. Local Coverage Article: Billing and Coding: Erythropoiesis Stimulating Agents (A58982). Centers for Medicare & Medicaid Services, Inc. Updated on 02/16/2024 with effective date 03/01/2024. Accessed April 2024.

Appendix 1 – Covered Diagnosis Codes

Dual coding requirements:

• Preoperative use: must bill D63.8 or D64.9 AND Z41.8
• Anemia due to CKD (not on dialysis): must bill D63.1 AND I12.9, I13.0, I13.10, N18.30, N18.31, N18.32, N18.4 or N18.5

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.