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Erythropoiesis-Stimulating Agents (ESAs)
08.00.75r

Policy

MEDICALLY NECESSARY CRITERIA FOR ANEMIA ASSOCIATED WITH​ CANCER AND RELATED ONCOLOGIC CONDITIONS

EPOETIN ALFA (EPOGEN®, PROCRIT®), DARBEPOETIN ALFA (ARANESP®) AND RELATED BIOSIMILARS (e.g., EPOETIN ALFA-EPBX [RETACRIT™]) 
Erythropoiesis-stimulating agents such as epoetin alfa (Epogen®, Procrit®), darbepoetin alfa (Aranesp®), or related biosimilars (e.g., epoetin alfa-epbx [Retacrit™]) are considered medically necessary and, therefore, covered for any indications listed below when the following criteria are met:​

 Initiation Criteria for Erythropoiesis-Stimulating Agent (ESA) Therapy for Cancer and Related Oncologic Conditions

  • The individual has anemia secondary to a regimen of myelosuppressive anticancer chemotherapy for nonmyeloid malignancies and has no other identifiable cause of anemia, and upon initiation, there is a minimum of 2 additional months of planned chemotherapy and both of the following:
    • The hemoglobin (Hb) level immediately prior to the first administration of ESA is less than 10 g/dL (or hematocrit [HCT] is <30%). ​
    • The individual​ is undergoing palliative treatment.
Treatment of Chemotherapy-Induced Anemia

  • As treatment of symptomatic chemotherapy-induced anemia in individuals with cancer with any of the following:
    • Have moderate to severe chronic kidney disease
    • Are undergoing palliative treatment
    • Are receiving myelosuppressive chemotherapy and have no other identifiable cause of anemia
    • Refuse blood transfusions in select cases​
​​National Comprehensive Cancer Network (​NCCN) note: Erythropoiesis-stimulating agents are not recommended when myelosuppressive chemotherapy is given with curative intent (except for individuals who refuse blood transfusions), for individuals with cancer who are not receiving therapy, or for individuals​ receiving nonmyelosuppressive therapy.

Myelodysplastic Syndrome

For individuals with symptomatic anemia related to myelodysplastic syndrome, as treatment of lower risk† disease, when all of the following criteria are met:
  • Individuals with one of the following:
    • Treatment of lower risk* disease associated with symptomatic anemia, with del(5q), with or without one other cytogenetic abnormality (except those involving chromosome 7) and serum erythropoietin ≤500 mU/mL​

    • Treatment of lower risk* disease associated with symptomatic anemia, with no del(5q), with or without other cytogenetic abnormalities with ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL

      • As a single agent
      • In combination with either lenalidomide or a granulocyte-colony stimulating factor (G-CSF) following no response to (despite adequate iron stores) or relapse after either an erythropoiesis-stimulating agent (ESA) alone or luspatercept-aamt​

    • Treatment of lower risk* disease associated with symptomatic anemia, with no del(5q), with or without other cytogenetic abnormalities with ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation) if serum erythropoietin <200 mU/mL

    • Treatment of lower risk* disease associated with symptomatic anemia, with no del(5q), with or without other cytogenetic abnormalities with ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after luspatercept-aamt

      • As a single agent
      • In combination with a granulocyte-colony stimulating factor (G-CSF)​
      ​
  • Hb is <10 g/dL (or HCT is <30%) at the initiation of therapy. 
  • The intent of therapy is to maintain a Hb/HCT level no greater than 10–12 g/dL (Hb) or 30%–36% (HCT).
  • Individuals have ≥1.5 gm/dL rise in hemoglobin or a decrease in RBC transfusion requirement by 6 to 8 weeks of treatment​
†Lower risk defined as International Prognostic Scoring System-Revised (IPSS-R; Very Low, Low, Intermediate), IPSS (Low/Intermediate-1), WHO Prognostic Scoring System (WPSS; Very Low, Low, Intermediate).

There are three main prognostic scoring systems. See Guidelines for more details.

Myelofibrosis

For individuals with anemia related to myelofibrosis when all of the following criteria are met:
  • Endogenous serum erythropoietin level less than 500 mU/mL
  • Hb is less than 10 g/dL (or HCT is <30%) at the initiation of therapy and one of the following:
    • With presence of splenomegaly and constitutional symptoms well controlled on current JAK inhibitor, to be given in combination with a JAK inhibitor
    • With no splenomegaly or constitutional symptoms​​​
Continuation of ESA Therapy for Cancer and Related Oncologic Conditions

Professional providers should use the lowest dose of ESA required to avoid RBC transfusions. 

ESA treatment is considered medically necessary and, therefore, covered for 8 weeks after the final dose of a myelosuppressive chemotherapy regimen.​

NOT MEDICALLY NECESSARY CRITERIA FOR EPOETIN ALFA (EPOGEN®, PROCRIT®), RELATED BIOSIMILARS (e.g., EPOETIN ALFA-EPBX [RETACRIT™]), AND DARBEPOETIN ALFA (ARANESP®)
An ESA such as epoetin alfa (Epogen®, Procrit®), related biosimilars (e.g., epoetin alfa-epbx [Retacrit™]), or darbepoetin alfa (Aranesp®) is considered not medically necessary and, therefore, not covered for any of the following indications because the available published peer-reviewed literature does not support its use:
  • Anemia of cancer not related to cancer treatment
  • Prophylactic use to prevent chemotherapy-induced anemia
  • Prophylactic use to reduce tumor hypoxia
  • Individuals with erythropoietin-type resistance due to neutralizing antibodies
  • Anemia in individuals who have cancer or are undergoing cancer treatment, when anemia is due to folate deficiency, vitamin B12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis
  • Anemia associated with the treatment of acute or chronic myelogenous leukemia (AML, CML) or erythroid cancers
  • Any anemia associated only with radiotherapy
  • For individuals receiving nonmyelosuppressive therapy
  • For individuals with pure red cell aplasia that begins following treatment with epoetin alfa or other erythropoietin protein drugs
  • For anemia due to cancer treatment if individuals have uncontrolled hypertension​
MEDICALLY NECESSARY CRITERIA FOR ANEMIA ASSOCIATED WITH NON-ONCOLOGIC CONDITIONS

EPOETIN ALFA (EPOGEN®, PROCRIT®), RELATED BIOSIMILARS (e.g., EPOETIN ALFA-EPBX [RETACRIT™]), AND DARBEPOETIN ALFA (ARANESP®)
Epoetin alfa (Epogen®, Procrit®), related biosimilars (e.g., epoetin alfa-epbx [Retacrit™]), or darbepoetin alfa (Aranesp®) are considered medically necessary and, therefore, covered for the treatment of anemia associated with the following indications when the following criteria for each indication are met:

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)

For individuals who have HIV/AIDS and have zidovudine (AZT)-related anemia when all of the following criteria are met:
  • Endogenous serum erythropoietin level of 500 mU/mL or less that is induced by treatment with AZT administered at 4200 mg/week or less.
  • Hb is less than 10 g/dL or Hct is less than 30% at the initiation of therapy. 
Chronic Kidney Disease (CKD)

For individuals who have anemia related to CKD when all of the following criteria are met:
  • Hb is less than 10 g/dL (or HCT is <30%) at the initiation of therapy.
  • Glomerular filtration rate (GFR) is less than 60 mL/min/1.73 m2 for 3 or more months.
MEDICALLY NECESSARY CRITERIA FOR EPOETIN ALFA (EPOGEN®, PROCRIT®) AND RELATED BIOSIMILARS (e.g., EPOETIN ALFA-EPBX [RETACRIT™])
Epoetin alfa (Epogen®, Procrit®) and related biosimilars (e.g., epoetin alfa-epbx [Retacrit™]) are considered medically necessary and, therefore, covered for the treatment of anemia associated with the following indication when the following criteria are met:

Perisurgical Adjuvant Therapy

For individuals with anemia who are undergoing elective, nonvascular, noncardiac, nonvascular surgery, when all of the following criteria are met:
  • Hb is between 10–13 g/dL (or HCT is between 30%–39%).
  • The individual is​ at high risk for perioperative blood loss. 
  • The individual is not a candidate for autologous blood transfusion.
  • The individual is expected to lose two or more units of blood.
  • The individual has been evaluated to ensure that anemia is due to chronic disease.
​CONTINUATION OF ESA THERAPY WITH EPOETIN ALFA (EPOGEN®, PROCRIT®) AND RELATED BIOSIMILARS (e.g., EPOETIN ALFA-EPBX [RETACRIT™])
During ESA therapy, many individuals eventually require supplemental iron. To guide appropriate supplementation, iron stores should be regularly monitored to ensure a transferrin saturation greater than 20% and/or serum ferritin levels greater than 100 ng/mL.

MEDICALLY NECESSARY CRITERIA FOR METHOXYPOLYETHYLENE GLYCOL-EPOETIN BETA (MIRCERA®)
Methoxypolyethylene glycol-epoetin beta (Mircera®) is considered medically necessary and, therefore, covered for the treatment of the following indications when the following criteria are met:
  • Anemia associated with chronic kidney disease in adults on hemodialysis and adults not on hemodialysis
  • Anemia associated with chronic kidney disease in pediatric individuals 3 months to 17 years of age on hemodialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA
CONTINUATION OF ESA THERAPY WITH METHOXYPOLYETHYLENE GLYCOL-EPOETIN BETA (MIRCERA®)
Methoxypolyethylene glycol-epoetin beta (Mircera®) is considered medically necessary and, therefore, covered for continuation of the treatment when the following criteria are met:
  • Professional providers use the lowest dose of ESA required to avoid RBC transfusions. During therapy, evaluation of iron status and correction or exclusion of other causes of anemia is required.
  • If Hb does not rise adequately over a 12-week escalation period: Additional dose increase is unlikely to improve response and may increase risk. Evaluate other causes of anemia and discontinue therapy if responsiveness does not improve.
NOT MEDICALLY NECESSARY CRITERIA FOR METHOXYPOLYETHYLENE GLYCOL-EPOETIN BETA (MIRCERA®)
Methoxypolyethylene glycol-epoetin beta (Mircera®) is considered not medically necessary and, therefore, not covered for any of the following indications because the available published peer-reviewed literature does not support its use:
  • Treatment of anemia due to cancer chemotherapy
  • Substitute for RBC transfusions in individuals who require immediate correction of anemia
NOT ELIGIBLE FOR REIMBURSEMENT
Peginesatide (Omontys®) is no longer manufactured and has been withdrawn from the market, as of February 23, 2013; therefore, it is not eligible for reimbursement. This drug was withdrawn from the market due to serious hypersensitivity reactions, which can be life-threatening.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of ESA therapy are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

MANDATES 

PENNSYLVANIA MEMBERS

In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents" (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.​


REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the health care professional's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Documentation supporting the indication for ESA therapy must be maintained in the individual’s medical record and made available upon request. For all individuals, this includes:
  • Assessment of, and correction for, contributing factors for anemia such as iron deficiency, underlying infection or inflammatory process, underlying hematological diseases, hemolysis, vitamin deficiencies (e.g., folic acid, B12), blood loss, aluminum intoxication)
  • Baseline Hb/HCT levels
  • Date of initiation of ESA therapy
  • Documentation of adequate iron stores
  • Individual’s weight and ESA units administered per kilogram of body weight
  • Response to ESA therapy (i.e., regular reporting of Hb/HCT to monitor response to ESA dose and documentation of transfusion requirements)
  • Medical justification for exceeding recommended doses of ESA
  • Additional information determined by indication
For rare instances when an individual's cardiac, pulmonary, or other medical condition warrants the use of ESA therapy to maintain an Hb/HCT higher than the target level discussed in this policy, documentation to support this practice must be available upon request.

BILLING REQUIREMENTS

Refer to the Coding Table in this policy for a list of modifier codes that are applicable to ESA therapy. When reporting ESA therapy, the most appropriate modifier that identifies this service must be used.

Guidelines

Because darbepoetin alfa (Aranesp®), epoetin alfa (Epogen®, Procrit®), and related biosimilars (e.g., epoetin alfa-epbx [Retacrit™]) have a similar mode of action and their structures differ only by the number of N-linked oligosaccharides on the protein, this policy does not distinguish differences for indications and contraindications, except for pretreatment of selective surgery where blood loss is anticipated due to the long-acting nature of darbepoetin alfa (Aranesp®).

The following causes of anemia must be considered, documented, and corrected (when possible) before starting erythropoiesis-stimulating agent (ESA) therapy for the medically necessary indications listed in this policy:
  • Iron deficiency
  • Underlying infection or inflammatory process
  • Underlying hematological disease
  • Hemolysis
  • Vitamin deficiencies (e.g., folic acid, B12)
  • Blood loss
  • Aluminum intoxication
ESA DOSAGE ADJUSTMENTS FOR CANCER AND RELATED NEOPLASTIC CONDITIONS
  • During ESA therapy, many individuals eventually require supplemental iron. To guide appropriate supplementation, iron stores should be regularly monitored to ensure a transferrin saturation greater than 20% and/or serum ferritin levels greater than 100 ng/mL.
  • ESA doses must be titrated according to the individual's response.
ESA DOSING AND TITRATION FOR CANCER AND RELATED NEOPLASTIC CONDITIONS
EPOETIN ALFA
(AND BIOSIMILARS)
DARBEPOETIN ALFA
INITIAL DOSE
Adult:150 U/kg SQ 3 times wkly
Pediatric: 600 U/kg IV wkly
Adult: 40,000 U SQ wkly*
Pediatric: 600 U/kg IV wkly
2.25 mcg/kg SQ wkly
500 mcg SQ every 3 wks
MAINTENANCE DOSE
If Hb remains <10 g/dL (or HCT is <30%) compared to pretreatment baseline 4 wks after initiation of therapy, and the rise in Hb is ≥1 g/dL (or HCT is ≥3%), the maintenance dose of ESA therapy should be the same as the recommended FDA starting dose.
(Same as Epoetin Alfa)
DOSE INCREASE If Hb rises <1 g/dL (or HCT rises <3%) compared to pretreatment baseline 4 wks after initiation of therapy, and Hb remains <10 g/dL (or HCT is <30%).If Hb rises <1 g/dL (or HCT rises <3%) compared to pretreatment baseline 6 wks after initiation of therapy, and Hb remains <10 g/dL (or HCT is <30%).
Adult: 300 U/kg SQ 3 times wkly
Pediatric: 900 U/kg (max 60,000 units) IV wkly
Adult: 60,000 U SQ wkly**
Pediatric: 900 U/kg (max 60,000 units) IV wkly
4.5 mcg/kg SQ wkly
No dose adjustment
DOSE REDUCTIONIf Hb rises >1 g/dL (or HCT rises >3%) in any 2-wk period, reduce dose by 25%.

If Hb reaches a level needed to avoid RBC transfusion, reduce dose by 25%.

If Hb exceeds a level needed to avoid RBC transfusion, withhold dose. When Hb approaches a level requiring RBC transfusion, reinitiate dose 25% below previous dose.		If Hb rises >1 g/dL (or HCT rises >3%) in any 2-wk period, reduce dose by 40%.

If Hb reaches a level needed to avoid RBC transfusion, reduce dose by 40%.

If Hb exceeds a level needed to avoid RBC transfusion, withhold dose. When Hb approaches a level requiring RBC transfusion, reinitiate dose 40% below previous dose.
DOSE DISCONTINUATIONContinuation of ESA therapy is not warranted if there is a rapid rise in Hb >1 g/dL (or HCT rises >3%) over any 2-wk period of treatment unless the Hb remains below or subsequently falls to <10 g/dL (or HCT is <30%). In these cases, continuation or reinstitution of ESA therapy must include a dose reduction from the previously administered dose of 25%.
Continuation of ESA therapy is not warranted if after 8 wks of treatment, the Hb rises <1 g/dL (or HCT rises <3%) compared to pretreatment baseline or if RBC transfusions are still required after 8 wks of treatment.		Continuation of ESA therapy is not warranted if there is a rapid rise in Hb >1 g/dL (or HCT rises >3%) over any 2-wk period of treatment unless the Hb remains below or subsequently falls to <10 g/dL (or HCT is <30%). In these cases, continuation or reinstitution of ESA therapy must include a dose reduction from the previously administered dose of 40%.

Continuation of ESA therapy is not warranted if after 8 wks of treatment, the Hb rises <1 g/dL (or HCT rises <3%) compared to pretreatment baseline or if RBC transfusions are still required after 8 wks of treatment.

*According to the FDA-approved prescribing information, individuals 5 to 18 years of age have a recommended starting dose of 600 U/kg intravenously weekly.
**According to the FDA-approved prescribing information, individuals 5 to 18 years of age should increase the dose to 900 U/kg (maximum 60,000 U) weekly if after 4 weeks of initiation of epoetin alfa or related biosimilars (e.g., epoetin alfa-epbx [Retacrit™]) the hemoglobin increases less than 1 g/dL and remains below 10 g/dL.

ESA DOSAGE ADJUSTMENTS FOR CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD)
  • Healthcare professionals and individuals should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events.
  • Use the lowest dose sufficient to reduce the need for red blood cell (RBC) transfusions.
  • Consider initiating treatment when the rate of Hb decline indicates the likelihood of requiring a RBC transfusion.
  • Consider initiating treatment when reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
ESA DOSING AND TITRATION FOR CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE
EPOETIN ALFA
(AND BIOSIMILARS)
DARBEPOETIN ALFA
METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA
Adults
Pediatrics on hemodialysis
converting from
INITIAL DOSE
Adults: 50–100 U/kg IV or SQ 3 times wkly

Pediatrics: 50U/kg IV or SQ 3 times wkly		On Dialysis:
Adult: 0.45 mcg/kg IV or SQ wkly or 0.75 mcg/kg IV every 2 wks
Pediatric: 0.45 mcg/kg IV or SQ wkly

Not on Dialysis:
Adult: 0.45 mcg/kg IV or SQ once at 4-wk intervals
Pediatric: 0.75 mcg/kg IV or SQ every 2 wks		0.6 mcg/kg IV or SQ every 2 wksEpoetin alfa:
4 × previous weekly epoetin alfa dose (Units)/125		Darbepoetin:
4 × previous weekly darbepoetin alfa dose (mcg)/0.55
DOSE INCREASE
If Hb rises <1 g/dL (or HCT rises <3%) compared to pretreatment baseline 4 wks after initiation of therapy, and Hb remains <10 g/dL (or HCT is <30%), the recommended FDA starting dose may be increased by 25%.

Dose should not be increased more than once every 4 weeks, but may be decreased more frequently. Avoid frequent dose adjustments.
DOSE REDUCTION
If Hb rises >1 g/dL (or HCT rises >3 %) in any 2-wk period, the ESA dose must be reduced by ≥25% as needed.

If Hb >10 g/dL in those NOT on dialysis or if Hb ≥11 g/dL in those on dialysis, the ESA dose must be interrupted or reduced.
DOSE DISCONTINUATION
If adequate response is not achieved after a 12-wk escalation period, increasing the ESA is unlikely to improve response and may increase risks. Evaluate other causes of anemia. Discontinue ESA if responsiveness does not improve.

DOSING GUIDELINES FOR MYELODYSPLASTIC SYNDROME
  • Hb must have a 1 g/dL sustained increase when compared to initiation level by the 12th week of therapy to continue therapy.
MYELODYSPASTIC SYNDROME PROGNOSTIC SCORING SYSTEMS

There are three main prognostic scoring systems:
  • International Prognostic Scoring System (IPSS)
  • Revised International Prognostic Scoring System (IPSS-R)
  • WHO classification-based Prognostic Scoring System (WPSS )
The IPSS-R enhances prognostic risk stratification and is applicable to the general myelodysplastic syndrome (MDS) population. IPSS-R Cytogenetic risk is based on cytogenic abnormalities as follows:

IPSS-R Cytogenetic risk groups†,††

Cytogenetic Prognostic Subgroups
Cytogenetic Abnormalities
Very good
-Y, del(11q)
Good
Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate
del(7q), +8, +19, i(17q), any other single or double independent clones
Poor
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities
Very poor
Complex: >3 abnormalities

IPSS-R Prognostic Score Values†

Prognostic variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very Good
Good
Intermediate
Poor
Very Poor
BM Blast %
≤2
>2%–<5%
5%–10%
>10%
Hemoglobin
≥10
8–<10
<8
Platelets
≥100
50–<100
<50
ANC
≥0.8
<0.8


IPSS-R Prognostic Risk Categories/Scores††

RISK CATEGORY
RISK SCORE
Very Low
≤​1.5
Low
>1.5–3
Intermediate
>3–4.5
High
>4.5–6
Very High
>6

†Greenberg TL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndrome. Blood. 2012;120(12):2454-2465.

††Schanz J, Tüchler H, Solé F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820-829.

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, ESAs are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in the medical policy are met.

A medication or class of medications may be a product or group contract exclusion. Individual benefits must be verified.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Initial approval for the use of epoetin alfa (Epogen®, Procrit®) as an ESA was granted by the FDA on June 1, 1989. Supplemental approvals for epoetin alfa have since been issued by the FDA.

Initial approval for the use of darbepoetin alfa (Aranesp®) as an ESA was granted by the FDA on September 19, 2001. Supplemental approvals for darbepoetin alfa have since been issued by the FDA.

Initial approval for the use of methoxy polyethylene glycol-epoetin beta (Mircera®) as an ESA was granted by the FDA on November 14, 2007. Supplemental approvals have since been issued.

Initial approval for the use of peginesatide (Omontys®) as an ESA was granted by the FDA on March 27, 2012.

On February 23, 2013, Affymax, Inc. and Takeda Pharmaceutical Company Limited, in conjunction with the FDA, initiated a voluntary recall of all lots of peginesatide (Omontys®) injection to the patient level due to recent postmarketing reports regarding seriou​s hypersensitivity reactions, including anaphylaxis, which can be life-threatening or fatal. As of August 2013, per the pharmaceutical companies, peginesatide (Omontys®) injection was still unavailable for prescribing or dispensing by healthcare professionals.

Initial approval for the use of biosimilar epoetin alfa-epbx (Retacrit™) as an ESA was granted by the FDA on May 15, 2018. Epoetin alfa (Epogen®, Procrit®) are the reference products for this biosimilar.

Description

Erythropoietin is a hormone that is produced by the kidneys, primarily in response to hypoxia. Its purpose is to stimulate bone marrow to form new red blood cells, a process called erythropoiesis. When the kidneys cannot produce enough erythropoietin, an erythropoiesis-stimulating agent (ESA) is prescribed to mimic its action. An ESA is used in the treatment of certain types of anemia to elevate or maintain the individual's red blood cell level (as demonstrated by the hemoglobin [Hb] and/or hematocrit [HCT] levels) and to decrease the need for transfusions.

Darbepoetin alfa (Aranesp®), epoetin alfa (Epogen®, Procrit®) and related biosimilars (e.g., epoetin alfa-epbx [Retacrit™]) are biologically engineered hormones produced by recombinant deoxyribonucleic acid (DNA) technology. They are erythropoietin analogues that contain the identical amino acid sequence as naturally occurring erythropoietin and have the same biological effect. Darbepoetin alfa (Aranesp®) differs from recombinant human epoetin alfa (Epogen®, Procrit®) by having two additional N-glycosylation sites. This slows the drug's clearance and makes its half-life two to three times longer, thereby requiring less frequent injections.

Methoxypolyethylene glycol-epoetin beta (Mircera®) was approved by the US Food and Drug Administration (FDA) for anemia associated with chronic kidney disease in adults, including individuals on dialysis and not on dialysis and pediatric individuals 5 to 17 years of age on hemodialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA. Methoxypolyethylene glycol-epoetin beta (Mircera®) is not indicated for the treatment of anemia due to cancer chemotherapy and is not a substitute for red blood cell transfusions in individuals who require immediate correction of anemia. Methoxypolyethylene glycol-epoetin beta (Mircera®) is an erythropoietin receptor activator with a greater activity and increased half-life compared to erythropoietin.

Peginesatide (Omontys®) is a synthetic, nonrecombinant peptide whose structure is unrelated to endogenous human erythropoietin. On February 23, 2013, Affymax, Inc. and Takeda Pharmaceutical Company Limited, in conjunction with the FDA, initiated a voluntary recall of all lots of peginesatide (Omontys®) injection to the patient level due to recent postmarketing reports regarding serious hypersensitivity reactions, including anaphylaxis, which can be life-threatening or fatal. As of May 2014, peginesatide (Omontys®)​ is currently unavailable for prescribing or dispensing by healthcare professionals.

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Hospital Formulary Service (AHFS). Drug Information 2026. Methoxy Polyethylene Glycol-Epoetin Beta. [Lexicomp Web site] 02/25/2026. Available at: https://online.lexi.com/lco/action/doc/retrieve/docid/complete_ashp/6684461 [via subscription only]. Accessed March 18, 2026​​.

American Hospital Formulary Service (AHFS). Drug Information 2026. Darbepoetin alfa. [Lexicomp Web site]. 02/25/2026. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 18, 2026.

American Hospital Formulary Service (AHFS). Drug Information 2026. Epoetin alfa. [Lexicomp Web site]. 02/25/2026​​​. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 18, 2026.

Aranesp® (darbepoetin alfa) [prescribing information]. Thousand Oaks, CA: Amgen, Inc.; 12/2024. Available online at:http://pi.amgen.com/united_states/aranesp/ckd/aranesp_pi_hcp_english.pdf. Accessed March 18, 2026.

Arora P. Chronic kidney disease. Updated 02/26/2021. Available at: http://emedicine.medscape.com/article/238798-overview. Accessed March 18, 2026.​

Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299(8):914-924.

Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med.1998;339(9):584-590.

Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98(10):708-714.

Centers for Medicare & Medicaid Services (CMS). Medicare Coverage Database. Decision memo for erythropoiesis stimulating agents (ESAs) for non-renal disease indications (CAG-00383N). [CMS Web site]. 07/30/07. Available at: http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=203&NcaName=Erythropoiesis+Stimulating+Agents+(ESAs)+for+non-renal+disease+indications&CoverageSelection=National&KeyWord=Erythropo&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAACAAAAA==&. Accessed March 18, 2026.

Centers for Medicare & Medicaid Services (CMS). Medicare Coverage Database. Monitoring of erythropoietin stimulating agents for beneficiaries with end stage renal disease. [CMS Web site]. 07/20/07. Available at: https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=11&McdName=Monitoring+of+Erythropoietin+Stimulating+Agents+for+Beneficiaries+with+End+Stage+Renal+Disease&mcdtypename=CMS+Solicitation+of+Public+Comments&MCDIndexType=4&bc=AgAEAAAAAAAA&. Accessed March 18, 2026.

Centers for Medicare & Medicaid Services (CMS). MLN Matters. MM5699: Reporting of hematocrit or hemoglobin levels on all claims for the administration of erythropoiesis stimulating agents (ESAs), implementation of new modifiers for non-ESRD ESA indications, and reporting of hematocrit or hemoglobin levels on all non-ESRD, non-ESA claims requesting payment for anti-anemia drugs. [CMS Web site]. Original: 01/01/08. (Revised: 07/01/21). Available at: http://www.cms.hhs.gov/MLNMattersArticles/downloads/MM5699.pdf. Accessed March 18, 2026.

Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (110.21). [CMS Web site]. 04/07/08. Available at: NCD - Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (110.21)​. Accessed March 18, 2026.

Centers for Medicare & Medicaid Services (CMS). Locall Coverage Determination (LCD). Billing and Coding: Erythropoiesis Stimulating Agents (ESA) (A56462) [CMS Web site]. 03/05/26. Available at:​ https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleId=56462&ver=32. Accessed March 18, 2026.​
Cervantes F, Alvarez-Larran A, Hernandez-Boluda J, et. al. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: Results in 20 patients and review of the literature. Br J Haematol. 2004;127:399-403.

Doss S, Schiller B. Peginesatide: a potential erythropoiesis stimulating agent for the treatment of anemia of chronic renal failure. Nephrol Nurs J. 2010;37(6):617-626.

Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355(20):2071-2084.

Elsevier’s Clinical Pharmacology Compendium. Darbepoetin alfa. [Clinical Key Web site]. 02/27/2025. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed March 18, 2026.

Elsevier’s Clinical Pharmacology Compendium. Epoetin alfa. [Clinical Key Web site]. 03/12/2025. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed March 18, 2026.

Elsevier’s Clinical Pharmacology Compendium. Epoetin alfa-epbx. [Clinical Key Web site]. 03/12/2025. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed March 18, 2026.

Elsevier’s Clinical Pharmacology Compendium. Methoxy Polyethylene Glycol-Epoetin Beta. [Clinical Key Web site]. 02/27/2025​. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed March 18, 2026.

Epogen® (epoetin alfa) [prescribing information]. Thousand Oaks, CA: Amgen, Inc.; 12/2024. Available at: http://pi.amgen.com/united_states/epogen/epogen_pi_hcp_english.pdf. Accessed March 18, 2026.

Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol. 2007;2(6):1274-1282.

Grannouli S, Voulgarelis M. Anemia in systemic lupus erythematosus: from pathophysiology to clinical assessment. Ann Rheum Dis. 2006;65:144-148.

Grant MD, Piper M, Bohlius J, et al. Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ) (US); 2013 Apr. Number 113. Accessed March 18, 2026.

Guagnozzi D. Anemia in inflammatory bowel disease: a neglected issue with relevant effects. World J Gastroenterol. 2014;20(13):3542-3551.

Hayes, Inc. Health Technology Assessment & Consulting. News – Clinical Study: No benefit for ESAs in patients with heart failure and anemia. March 2013.

Lexi-Drugs Compendium. Epoetin alfa-epbx. [Lexicomp Online Web site]. 02/23/2024. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 18, 2026.

Lexi-Drugs Compendium. Methoxy Polyethylene Glycol-Epoetin Beta. [Lexicomp Online Web site]. 10/01/2025. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 18, 2026.

Lexi-Drugs Compendium. Darbepoetin Alfa. [Lexicomp Online Web site]. 01/30/2026. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 18, 2026.

Lexi-Drugs Compendium. Epoetin Alfa. [Lexicomp Online Web site]. 02/13/2026​. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed March 18, 2026.

Mircera (Methoxy Polyethylene Glycol-Epoetin Beta). [prescribing information]. Gallen Switzerland​: Vifor (International) Inc; 6/2024. Available at: http://assets.procrit.com/shared/product/procrit/procrit-prescribing-information.pdf. Accessed March 18, 2026.​

Micromedex® Healthcare Series [Internet database]. DRUGDEX® Evaluations. Darbepoetin alfa. Greenwood Village, CO: Thomson Micromedex. 09/25/2023. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. Accessed March 18, 2026.

Micromedex® Healthcare Series [Internet database]. DRUGDEX® Evaluations. Epoetin alfa. Greenwood Village, CO: Thomson Micromedex. 08/20/2025​. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. Accessed March 18, 2026.

Micromedex® Healthcare Series [Internet database]. DRUGDEX® Evaluations. Peginesatide. Greenwood Village, CO: Thomson Micromedex. 02/27/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. Accessed March 18, 2026.

Micromedex® Healthcare Series [Internet database]. DRUGDEX® Evaluations. Epoetin alfa-epbx. Greenwood Village, CO: Thomson Micromedex. 08/20/2025​. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. Accessed March 18, 2026.

Micromedex® Healthcare Series [Internet database]. DRUGDEX® Evaluations. Methoxy Polyethylene Glycol-Epoetin Beta. Greenwood Village, CO: Thomson Micromedex. 05/16/2024​​. Available at: http://www.micromedexsolutions.com/micromedex2/librarian. Accessed March 18, 2026.

Micromedex® Healthcare Series [Internet database]. Drugdex® Consults. Use of erythropoiesis-stimulating agents for chemotherapy-induced anemia in adult patients with cancer: Clinical practice guidelines. Greenwood Village, CO: Thomson Micromedex. Updated: 06/10/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/704ABF/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/9B1518/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.IntermediateToDocumentLink?docId=9719&contentSetId=50&title=USE+OF+ERYTHROPOIESIS-STIMULATING+AGENTS+FOR+CHEMOTHERAPY-INDUCED+ANEMIA+IN+ADULT+PATIENTS+WITH+CANCER:+CLINICAL+PRACTICE+GUIDELINES&servicesTitle=USE+OF+ERYTHROPOIESIS-STIMULATING+AGENTS+FOR+CHEMOTHERAPY-INDUCED+ANEMIA+IN+ADULT+PATIENTS+WITH+CANCER:+CLINICAL+PRACTICE+GUIDELINES. Accessed March 18, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Cancer- and chemotherapy-induced anemia. v.3.2026. Updated 12/05/2025 [NCCN Web site]. Available at: http://www.nccn.org/professionals/physician_gls/pdf/anemia.pdf [via subscription only]. Accessed March 18, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Myelodysplastic Syndrome. v.2.2025. Updated 01/17/2025. NCCN Web site]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf Accessed March 18, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™. Myeloproliferative Neoplasms v.1.2026. Updated 01/22/2026. NCCN Web site]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf Accessed March 18, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drug & Biologics Compendium. Darbepoetin alfa. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=49. Accessed March 18, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drug & Biologics Compendium. Epoetin alfa. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=50. Accessed March 18, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drug & Biologics Compendium. Epoetin alfa-epbx . Available at: https://www.nccn.org/professionals/drug_compendium/content/. Accessed March 18, 2026.

National Kidney Foundation. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. [National Kidney Foundation Web site]. Available at: http://www.ajkd.org/article/S0272-6386(07)00934-1/pdf. Accessed March 18, 2026.

National Institute for Health and Care Excellence (NICE). Erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating anemia in people with cancer having chemotherapy (including review of TA142). London (UK): National Institute for Health and Care Excellence (NICE); 11/2014. p. 47.

Ohls R, Christensen R, Kamath-Rayne B. A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants. Pediatrics. 2013;132:e119-27.

Ohls R, Roohi M, Peceny H. A randomized, masked study of weekly erythropoietin dosing in preterm infants. J Pediatr. 2012;160(5):790-795.

Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants (Review). Cochrane Database Syst Rev. 2016. Review content assessed as up-to-date: July 1, 2013.

Procrit® (epoetin alfa) [prescribing information]. Raritan, NJ: Ortho Biotech Products, LP; 4/2024. Available at: http://assets.procrit.com/shared/product/procrit/procrit-prescribing-information.pdf. Accessed March 18, 2026.

Rizzo J, Brouwers M, Hurley P, et al. American Society of Clinical Oncology (ASCO)/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4496-5010. Available at: http://jco.ascopubs.org/content/28/33/4996.full.pdf+html. Accessed March 18, 2026.

Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098.

Strippoli GF, Craig JC, Manno C, Schena FP. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol. 2004;15(12):3154-3165.

Tsiolakidou G. Stimulating erythropoiesis in inflammatory bowel disease associated anemia. World J Gastroenterol. 2007;13(26):4798-4806.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: darbepoetin alfa (Aranesp). [FDA Web site]. 04/2024. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103951s5363lbl.pdf. Accessed March 18, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: epoetin alfa (Epogen, Procrit). [FDA Web site]. 04/2024. Available at: http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed March 18, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: peginesatide (OMONTYS). [FDA Web site]. FDA 12/2012. Available at: http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed March 18, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: epoetin alfa-epbx (Retacrit™) 06/2024. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125545s000lbl.pdf. Accessed March 18, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: methoxypolyethylene glycol-epoetin beta (Mircera®) ). [FDA Web site]. 06/2024. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed March 18, 2026​.

Weiss G, Goodnough L. Anemia in chronic disease. New Engl J Med. 2005;352(10):1011-1023.

Coding

CPT Procedure Code Number(s)
N/A
ICD - 10 Procedure Code Number(s)
N/A
ICD - 10 Diagnosis Code Number(s)

B20 Human immunodeficiency virus [HIV] disease

C94.40 Acute panmyelosis with myelofibrosis not having achieved remission

C94.41 Acute panmyelosis with myelofibrosis, in remission

C94.42 Acute panmyelosis with myelofibrosis, in relapse

C94.6 Myelodysplastic disease, not elsewhere classified

D46.1 Refractory anemia with ring sideroblasts

D46.A Refractory cytopenia with multilineage dysplasia

D46.C Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality

D47.1 Chronic myeloproliferative disease

D47.4 Osteomyelofibrosis

D61.1 Drug-induced aplastic anemia

D63.0 Anemia in neoplastic disease

D63.1 Anemia in chronic kidney disease

D63.8 Anemia in other chronic diseases classified elsewhere

D64.81 Anemia due to antineoplastic chemotherapy

D75.81 Myelofibrosis

N18.1 Chronic kidney disease, stage 1

N18.2 Chronic kidney disease, stage 2 (mild)

N18.30 Chronic kidney disease, stage 3 unspecified

N18.31 Chronic kidney disease, stage 3a

N18.32 Chronic kidney disease, stage 3b

N18.4 Chronic kidney disease, stage 4 (severe)

N18.5 Chronic kidney disease, stage 5

N18.6 End stage renal disease

N18.9 Chronic kidney disease, unspecified

HCPCS Level II Code Number(s)

J0881 Injection, darbepoetin alfa, 1 mcg (non-ESRD use)

J0882 Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis)

J0885 Injection, epoetin alfa, (for non-ESRD use), 1000 units

J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)

J0888 Injection, epoetin beta, 1 microgram, (for non ESRD use)

Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis)

Q5105 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for ESRD on dialysis), 100 units

Q5106 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for non-ESRD use), 1000 units

S9537 Home therapy; hematopoietic hormone injection therapy (e.g., erythropoietin, G-CSF, GM-CSF); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem


NOT ELIGIBLE FOR REIMBURSEMENT

THE FOLLOWING CODE REPRESENTS PEGINESATIDE WHICH IS NO LONGER MANUFACTURED AND HAS BEEN WITHDRAWN FROM THE MARKET​

J0890 Injection, peginesatide, 0.1 mg (for ESRD on dialysis)

Revenue Code Number(s)

0634 Pharmacy - Extension of 025X-Erythropoietin (EPO) <10,000 Units

0635 Pharmacy - Extension of 025X-Erythropoietin (EPO) >=10,000 Units

Modifiers

EA Erythropoetic stimulating agent (ESA) administered to treat anemia due to anticancer chemotherapy

EB Erythropoetic stimulating agent (ESA) administered to treat anemia due to anticancer radiotherapy

EC Erythropoetic stimulating agent (ESA) administered to treat anemia not due to anticancer radiotherapy or anticancer chemotherapy

EJ Subsequent claims for a defined course of therapy (e.g., EPO, sodium hyaluronate, infliximab)

GS Dosage of EPO or darbepoetin alfa has been reduced and maintained in response to hematocrit or hemoglobulin level


THE FOLLOWING CODES ARE MEDICALLY NECESSARY WHEN REPORTED WITH EA:

Erythropoetic stimulating agent (ESA) administered to treat anemia due to anticancer chemotherapy


J0881 Injection, darbepoetin alfa, 1 mcg (non-ESRD use)

J0885 Injection, epoetin alfa, (for non-ESRD use), 1000 units

Q5106 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for non-ESRD use), 1000 units


THE FOLLOWING CODES ARE NOT MEDICALLY NECESSARY WHEN REPORTED WITH EA:

Erythropoetic stimulating agent (ESA) administered to treat anemia due to anticancer chemotherapy


J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)

J0888 Injection, epoetin beta, 1 microgram, (for non ESRD use)


THE FOLLOWING CODES ARE NOT MEDICALLY NECESSARY WHEN REPORTED WITH EB:

Erythropoetic stimulating agent (ESA) administered to treat anemia due to anticancer radiotherapy.


J0881 Injection, darbepoetin alfa, 1 mcg (non-ESRD use)

J0882 Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis)

J0885 Injection, epoetin alfa, (for non-ESRD use), 1000 units

J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)

J0888 Injection, epoetin beta, 1 microgram, (for non ESRD use)

Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis)

Q5105 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for ESRD on dialysis), 100 units

Q5106 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for non-ESRD use), 1000 units


THE FOLLOWING CODES ARE MEDICALLY NECESSARY WHEN REPORTED WITH EC:

Erythropoetic stimulating agent (ESA) administered to treat anemia not due to anticancer radiotherapy or anticancer chemotherapy


J0881 Injection, darbepoetin alfa, 1 mcg (non-ESRD use)

J0882 Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis)

J0885 Injection, epoetin alfa, (for non-ESRD use), 1000 units

J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)

J0888 Injection, epoetin beta, 1 microgram, (for non ESRD use)

Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis)

Q5105 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for ESRD on dialysis), 100 units

Q5106 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for non-ESRD use), 1000 units


THE FOLLOWING CODES AND MODIFIERS ARE NOT MEDICALLY NECESSARY WHEN REPORTED WITHOUT EA, EB OR EC MODIFIER


J0881 Injection, darbepoetin alfa, 1 mcg (non-ESRD use)

J0882 Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis)

J0885 Injection, epoetin alfa, (for non-ESRD use), 1000 units

J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis)

J0888 Injection, epoetin beta, 1 microgram, (for non ESRD use)

Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis)

Q5105 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for ESRD on dialysis), 100 units

Q5106 Injection, epoetin alfa-epbx, biosimilar, (Retacrit) (for non-ESRD use), 1000 units

Coding and Billing Requirements

Policy History

Revisions From 08.00.75r:
06/15/2026
​

This version of the policy will become effective 06/15/2026​​​.​

    The policy has been updated to communicate changes based on US Food and Drug Administration (FDA​) labeling and the National Comprehensive Cancer Network (NCCN).

    ​

    Criteria have been revised for:

    • Myelodysplastic Syndrome

    • Therapy for Cancer and Related Oncologic Conditions

    • Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)

    • Mircera for anemia associated with chronic kidney disease in pediatric individuals​

    The following ICD-10 codes are added to the policy:

    B20 Human immunodeficiency virus [HIV] disease

    B97.35 Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere

    D46.1 Refractory anemia with ring sideroblasts

    D46.A Refractory cytopenia with multilineage dysplasia

    D46.C Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality

    N18.1 Chronic kidney disease, stage 1

    N18.2 Chronic kidney disease, stage 2 (mild)

    N18.30 Chronic kidney disease, stage 3 unspecified

    N18.31 Chronic kidney disease, stage 3a

    N18.32 Chronic kidney disease, stage 3b

    N18.4 Chronic kidney disease, stage 4 (severe)

    N18.5 Chronic kidney disease, stage 5

    N18.6 End stage renal disease

    N18.9 Chronic kidney disease, unspecified


    Revisions From 08.00.75q:
    11/17/2025
    ​

    This version of the policy will become effective 11/17/2025​​.​

      The policy has been updated to communicate changes based on US Food and Drug Administration (FDA​) labeling and the National Comprehensive Cancer Network (NCCN).

      ​

      Criteria have been revised for:

      • Myelodysplastic Syndrome

      • Therapy for Cancer and Related Oncologic Conditions

      The following ICD-10 codes are added to the policy:
      • C94.40 Acute panmyelosis with myelofibrosis not having achieved remission
      • C94.41 Acute panmyelosis with myelofibrosis, in remission
      • C94.42 Acute panmyelosis with myelofibrosis, in relapse
      • C94.6 Myelodysplastic disease, not elsewhere classified
      • D47.1 Chronic myeloproliferative disease
      • D47.4 Osteomyelofibrosis
      • D63.0 Anemia in neoplastic disease
      • D75.81 Myelofibrosis​

      Revisions From 08.00.75p:
      04/22/2024
      ​
      		This version of the policy will become effective 04/22/2024.​

        The policy has been updated to communicate changes based on US Food and Drug Administration (FDA​) labeling and the National Comprehensive Cancer Network (NCCN).

        Criteria has been added to the policy: 

        • Chemotherapy-Induced Anemia​

        Criteria have been revised for:

        • Myelodysplastic Syndrome
        • Perisurgical Adjuvant Therapy
        • Therapy for Cancer and Related Oncologic Conditions
          ​Criteria has been removed for 
          • Hepatitis C

          Revisions From 08.00.75o:
          ​08/24/2022
          		​This policy has been reissued in accordance with the Company's annual review process.​
          09/27/2021 

          		This version of the policy will become effective 09/27/2021​.

          The policy has been updated to communicate changes based on ​US Food and Drug Administration (FDA) labeling and the National Comprehensive Cancer Network (NCCN).

          Criteria have been revised for:
          • ​Myelodysplastic Syndrome​.
          • Perisurgical Adjuvant Therapy
          • Therapy for Cancer and Related Oncologic Conditions​
          Criteria have been removed for Acute Kidney Injury

          Revisions From 08.00.75n:
          06/03/2020This policy has been reissued in accordance with the Company's annual review process.
          01/01/2020This policy has been identified for the HCPCS code update, effective 01/01/2020.

          The following HCPCS codes have a revised narrative in this policy:

          FROM Q5105 Injection, epoetin alfa, biosimilar (Retacrit) (for ESRD on dialysis), 100 units

          TO Q5105 Injection, epoetin alfa-epbx, biosimilar (retacrit) (for esrd on dialysis), 100 units

          FROM Q5106 Injection, epoetin alfa, biosimilar (Retacrit) (for non-ESRD use), 1000 units

          TO Q5106 Injection, epoetin alfa-epbx, biosimilar (retacrit) (for non-esrd use), 1000 units

          Revisions From 08.00.75m:
          09/25/2019This policy has been reissued in accordance with the Company's annual review process.
          01/28/2019This version of the policy will become effective 01/28/2019.

          The policy has been updated to communicate changes based on US Food and Drug Administration (FDA) labeling and the National Comprehensive Cancer Network (NCCN).

          Criteria have been revised to include biosimilar epoetin alfa-epbx (Retacrit™) as an ESA.

          Not medically necessary criteria have been revised for all agents. Criteria for methoxy polyethylene glycol-epoetin beta (Mircera®) was updated to include indications for pediatric individuals, continuation therapy recommendations, and not medically necessary criteria.

          Criteria for myelodysplastic syndrome were updated per NCCN.
          _____________________________________

          Note: On 04/08/2019 the Miscellaneous Coding - Modifiers section of the Coding Table was revised to clarify which codes should be used with the EC Modifier.
          • Codes J0881, J0885, Q5106 were added as medically necessary when reported with EC. They were listed as not medically necessary in error.
          • The listing of codes considered not medically necessary when reported without the EC Modifier was removed because it was duplicative.
          These changes are retroactively effective to 01/28/2019.

          Effective 10/05/2017 this policy has been updated to the new policy template format.
          6/15/2026
          6/15/2026
          08.00.75
          Medical Policy Bulletin
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