UnitedHealthcare Erythropoiesis-Stimulating Agents Policy Update

Coverage Criteria

Anemia Due to Chronic Kidney Disease - Patients Receiving Dialysis

Covered when ALL of the following are met

Initial therapy: Patient is on dialysis; Hematocrit is less than 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsHct<30%

Continuation therapy: Patient is on dialysis; Documentation of positive clinical response to ESA therapy; Hematocrit remains less than 33%; Reauthorization will be for no more than 12 monthsHct<33%

ESAs are unproven to treat anemia of CKD in patients on dialysis for a hematocrit ≥33%

Anemia Due to Chronic Kidney Disease - Patients Not Receiving Dialysis

Covered when ALL of the following are met

Initial therapy: Patient is not on dialysis; Hematocrit is less than 30% at initiation of therapy; The rate of hematocrit decline indicates likelihood of requiring an RBC transfusion; Therapeutic goal is reducing the risk of alloimmunization and/or other RBC transfusion-related risks; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsHct<30%

Continuation therapy: Patient is not on dialysis; Documentation of positive clinical response to ESA therapy; Therapeutic goal is reducing the risk of alloimmunization and/or other RBC transfusion-related risks; Hematocrit remains less than 30% for continuation of therapy; Reauthorization will be for no more than 12 monthsHct<30%

ESAs are unproven to treat anemia of CKD in patients not on dialysis for a hematocrit >30%

Anemia Due to Cancer Chemotherapy

Aranesp, Epogen, Procrit, Retacrit covered when ALL of the following are met

Initial therapy: Hematocrit less than or equal to 30% at initiation of therapy; Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency) and there is documentation of normal iron stores; And one of the following: patient has moderate to severe CKD; OR undergoing palliative treatment; OR receiving myelosuppressive chemotherapy not given with curative intent; OR receiving myelosuppressive chemotherapy with curative intent AND patient is refusing blood transfusion(s); Initial authorization will be for no more than 12 monthsHct<=30%

Mircera is unproven for this indication; ESAs are unproven when anticipated outcome is cure except for transfusion refusal or when anemia can be managed by transfusion

Continuation therapy: Documentation of positive clinical response to ESA therapy; Hematocrit remains less than or equal to 30% for continuation of therapy; Reauthorization will be for no more than 12 monthsHct<=30%

Anemia Associated With Myelodysplastic Syndromes (MDS)

Aranesp, Epogen, Procrit, Retacrit covered when ALL of the following are met

Initial therapy: Serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit is less than or equal to 30% at initiation of therapy; No evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Treatment of lower risk (IPSS-R Very Low, Low, Intermediate) disease with symptomatic anemia; And one of the following: del(5q) chromosomal abnormality present; OR patient without del(5q) and ring sideroblasts <15% (or <5% with SF3B1 mutation); OR patient without del(5q) and ring sideroblasts ≥15% (or ≥5% with SF3B1) and no response to Reblozyl (luspatercept); Initial authorization will be for no more than 12 monthsEPO<=500 mU/mL; Hct<=30%

Continuation therapy: Documentation of positive clinical response to ESA therapy; Serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit remains less than or equal to 36% for continuation of therapy; Reauthorization will be for no more than 12 monthsEPO<=500 mU/mL; Hct<=36%

Anemia Associated With Myeloproliferative Neoplasms - Myelofibrosis

Covered when ALL of the following are met

Initial therapy: Serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit is less than or equal to 30% at initiation of therapy; Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsEPO<=500 mU/mL; Hct<=30%

Anemia Associated With Zidovudine Treatment in HIV-Infected Patients

Epogen, Procrit, Retacrit covered when ALL of the following are met

Initial therapy: Patient is receiving zidovudine administered at less than or equal to 4,200 mg/week; Endogenous serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit is less than 30% at initiation of therapy; Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsZDV<=4200 mg/week; EPO<=500 mU/mL; Hct<30%

Continuation therapy: Documentation of positive clinical response to ESA therapy; Patient is receiving zidovudine ≤4,200 mg/week; Endogenous serum erythropoietin level less than or equal to 500 mUnits/mL; Hematocrit remains less than or equal to 36% for continuation of therapy; Reauthorization will be for no more than 12 monthsEPO<=500 mU/mL; Hct<=36%

Anemia Associated With Hepatitis C With Ribavirin and Interferon Therapy

Epogen, Procrit, Retacrit covered when ALL of the following are met

Initial therapy: Patient is receiving ribavirin and interferon therapy; Hematocrit is less than or equal to 30% at initiation of therapy; Patient does not have evidence of other causes of anemia (e.g., iron deficiency, hemolysis, vitamin B12 deficiency); Initial authorization will be for no more than 12 monthsHct<=30%

Continuation therapy: Documentation of positive clinical response to ESA therapy; Patient remains on ribavirin and interferon therapy; Hematocrit remains less than or equal to 36% for continuation of therapy; Reauthorization will be for no more than 12 monthsHct<=36%

Preoperative Use to Reduce Allogeneic Blood Transfusions (Perioperative)

Epogen, Procrit, Retacrit covered perioperatively when ALL of the following are met

Perioperative criteria: Perioperative hematocrit is greater than 30% and less than or equal to 39%; Patient is expected to require at least 2 units of blood during the surgical procedure; Patient is at high risk for blood loss during surgery; Patient is unable or unwilling to donate autologous blood; Surgery procedure is elective, noncardiac, and nonvascular; Authorization will be for no more than 3 monthsHct>30% and <=39%

ESAs are unproven for patients willing to donate autologous blood pre-operatively or undergoing cardiac/vascular surgery

ESA use in chronic kidney disease (CKD)

Covered when ALL of the following are met (CKD context):

CKD ESA initiation and maintenance: 1) Indication: anemia attributable to CKD appropriate for ESA therapy (CKD ND, CKD 5D) AND 2) Hemoglobin and clinical thresholds: for CKD ND generally do not initiate if Hb ≥ 10.0 g/dL; if Hb < 10.0 g/dL, individualize decision based on symptoms, rate of Hb decline, iron status, transfusion risk, and prior iron response AND 3) Maintenance targets: generally do not maintain Hb > 11.5 g/dL in adults and do not intentionally increase Hb > 13 g/dL AND 4) Monitoring: Hb measured at least monthly during initiation, then at least every 3 months during maintenance for CKD ND (monthly for CKD 5D).see text

Follow KDIGO recommendations for dosing adjustments, administration route, and hyporesponsiveness management.

ESA use in cancer and myelodysplastic syndromes (MDS)

Covered when ALL of the following are met (oncology/MDS context):

ESA use in cancer/chemotherapy-induced anemia: 1) Indication: symptomatic anemia due to myelosuppressive chemotherapy (lymphoid malignancies, solid tumors) OR myelodysplastic syndromes/myeloproliferative neoplasms as specified by guideline AND 2) Not for patients receiving non-myelosuppressive therapy, not receiving therapy, or where curative-intent chemotherapy is being given (ESAs not indicated) AND 3) In non-curative chemotherapy, use per FDA indications/dosing/REMS with documented informed consent and counseling on risks/benefits AND 4) Consider ESA versus transfusion risks; discontinue ESA after chemotherapy completion or loss of response; permanently discontinue if antibody-mediated anemia occurs.see text

Be aware of evidence of increased thromboembolism and possible mortality signal in some studies; target Hb generally ≤ 12 g/dL in MDS and avoid exceeding recommended targets.

Management of Poor ESA Responsiveness

Guidance for patients with initial or acquired ESA hyporesponsiveness

Manage and individualize therapy: Evaluate and treat specific causes of poor ESA response. For patients who remain hyporesponsive despite correcting treatable causes, individualize therapy considering decline in Hb, continuing ESA with consideration of doses required, or use of blood transfusions.

Not graded guidance; weigh risks and benefits.

Adjuvant Therapies

Adjuvant treatments to avoid with ESA therapy

Adjuvant therapies not recommended: Do not use androgens as an adjuvant to ESA treatment; Suggest not using adjuvants including vitamin C, vitamin D, vitamin E, folic acid, L-carnitine, and pentoxifylline.

Recommendations per work group guidance.

Evaluation for Pure Red Cell Aplasia (PRCA)

Investigate and stop ESA when antibody-mediated PRCA is suspected

PRCA diagnostic triggers: If on ESA therapy for more than 8 weeks and patient develops: sudden rapid decrease in hemoglobin at a rate of 0.5 to 1.0 g/dL per week or requirement of transfusions at approximately 1 to 2 per week; with normal platelet and white cell counts; and absolute reticulocyte count less than 10,000/µL, investigate for antibody-mediated PRCA.Rate: 0.5–1.0 g/dL/week; Retic<10,000/µL

Not graded.

Actions when antibody-mediated PRCA suspected: Stop ESA therapy and contact manufacturer for assays for binding and neutralizing anti-erythropoietin antibodies; consider peginesatide to treat antibody-mediated PRCA as recommended by the work group.

Stopping ESA is a 1A recommendation; peginesatide recommendation noted as 1B.

ESAs are explicitly listed as unproven in several oncology-related contexts where trial data indicate potential harm or lack of benefit. These exclusions include patients receiving curative-intent chemotherapy (except when the patient refuses transfusion), patients receiving hormonal agents, biologic products, or radiotherapy alone (unless also receiving concomitant myelosuppressive chemotherapy), and patients who require immediate correction of anemia as a substitute for red blood cell transfusion. ESAs are also considered unproven for patients undergoing cardiac or vascular surgery, patients scheduled to donate autologous blood, and patients whose anemia can be managed by transfusion.

Use of ESAs in oncology is limited to specific scenarios and requires careful counseling and documentation. ESAs are recommended only for anemia due to myelosuppressive chemotherapy for lymphoid malignancies and selected solid tumors and for certain hematologic conditions (MDS, myeloproliferative neoplasms). In non‑curative chemotherapy settings, ESA use should follow FDA indications/REMS and include documented informed consent discussing risks and benefits. Multiple randomized trials and meta-analyses have shown increased thromboembolic risk and, in some studies, worse survival when ESAs are used to target higher hemoglobin ranges; these safety signals underpin recommendations to limit ESA use in many oncology patients.

ESAs are not indicated for patients with cancer who are not receiving myelosuppressive therapy or who are receiving non‑myelosuppressive therapy. They are also inappropriate when chemotherapy is given with curative intent (except when the patient refuses transfusion) or when an identified, treatable cause of anemia exists. For cancer patients with coexisting CKD, ESA use should follow CKD guidance and include a careful risk/benefit assessment; avoid ESA initiation when alternative management (including transfusion) is appropriate.

The guideline work group recommends against routine use of androgens as adjuvants to ESA therapy. In addition, the work group suggests avoiding several other adjuvant agents (including vitamin C, vitamin D, vitamin E, folic acid, L‑carnitine, and pentoxifylline) because evidence does not support their role as effective adjuncts to improve ESA responsiveness.

Continuation of ESA therapy requires documentation of ongoing clinical benefit and adherence to hematocrit/hemoglobin thresholds specific to the indication. For dialysis patients, continuation criteria include documented response with Hct <33%. For non‑dialysis CKD patients, continuation is supported when there is a positive clinical response and the hematocrit remains 30% for continuation. In CKD generally, guideline work groups advise avoiding maintenance of hemoglobin above 11.5 g/dL and not intentionally increasing hemoglobin above 13 g/dL, and recommend individualized decisions about initiation when Hb is near 10.0 g/dL.

Trials and systematic reviews in cancer populations demonstrate safety risks when targeting higher hemoglobin levels with ESAs. Randomized studies reported decreased survival and increased fatal thrombotic events when ESAs were titrated to hemoglobin targets in the 12–14 g/dL range; meta-analyses also report increased thromboembolic risk and signals for higher mortality in some analyses. These findings support conservative hemoglobin targets and careful patient selection in oncology.

In chronic kidney disease patients who are not dialysis dependent, the work group suggests not initiating ESA therapy when Hb ≥ 10.0 g/dL. If Hb is < 10.0 g/dL, initiation should be individualized based on symptoms, rate of decline, iron status, and transfusion risk. Maintenance recommendations include avoiding routine use to maintain Hb above 11.5 g/dL and not intentionally increasing Hb > 13 g/dL.

The policy lists specific adjuvant therapies that are not recommended to be used with ESAs. These include androgens (recommendation 1B) and a suggested avoidance of vitamin C, vitamin D, vitamin E, folic acid, L‑carnitine, and pentoxifylline (suggestion 2D), reflecting limited evidence for benefit as ESA adjuncts.

Initial Therapy Criteria

Initial therapy

Initial therapy covered when indication-specific entry criteria are satisfied (hematocrit/EPO thresholds, exclusion of other causes of anemia, and indication-specific conditions).

See indication-specific initial rules: Refer to Diagnosis-Specific Criteria sections for CKD (dialysis and non-dialysis), cancer chemotherapy, MDS, myelofibrosis, zidovudine-associated anemia, hepatitis C-associated anemia, and perioperative use for exact initiation requirements and authorization durations.varies by indication

Initial authorizations commonly limited to ≤12 months (perioperative ≤3 months)

Perioperative initiation

Surgical/preoperative use

Preoperative ESA course: Multiple-dose ESA regimens given in weeks before surgery can reduce transfusion rates in hip/knee arthroplasty; trials used subcutaneous dosing beginning ~3 weeks pre-op with monitoring and withheld final dose if Hb exceeded trial-specified thresholds; weigh thrombosis risk and cost-effectiveness and use prophylaxis as indicated.

Continuation Therapy Criteria

Continuation therapy general rule

Continuation coverage conditions vary by indication but generally require documentation of clinical response and adherence to specified hematocrit or serum erythropoietin thresholds.

General continuation: Documentation of positive clinical response to ESA therapy; Maintain indication-specific hematocrit and/or serum erythropoietin thresholds as defined in diagnosis-specific sections; Reauthorization typically for no more than 12 monthsindication-specific

See individual indication criteria

CKD continuation considerations

Continuation considerations in CKD/darbepoetin trial:

TREAT continuation findings: Darbepoetin alfa increased mean hemoglobin and reduced transfusions but was associated with higher rates of fatal or nonfatal stroke compared with placebo; continuation decisions should weigh reduced transfusion need against increased cerebrovascular events.

Step Therapy Requirements

Step	Requirement	Notes / Failure criteria
1
Trial of Reblozyl (luspatercept-aamt) required prior to initiation of ESA therapy for patients with myelodysplastic syndromes who are without del(5q) and have ring sideroblasts ≥15% (or ≥5% with an SF3B1 mutation).
Failure to demonstrate no response to Reblozyl (i.e., patient still responsive) is considered lack of eligibility for ESA per this step; applies only when del(5q) is absent and ring sideroblasts meet the specified thresholds.

Step	Requirement	Notes / Failure criteria
1
Trial of iron therapy/ferrous supplementation and optimization of standard measures (e.g., correct iron deficiency) before initiating ESA for patients with iron-responsive anemia.
If iron deficiency is not corrected or there is an adequate hemoglobin response to iron, ESA initiation is not indicated; insufficient response to iron (or continued transfusion need) supports ESA consideration.

Step	Requirement	Notes / Failure criteria
1
Avoid repeated ESA dose escalations beyond doubling the initial or previously stable dose when addressing hyporesponsiveness; evaluate and correct treatable causes of poor response prior to further dose escalation.
If Hb does not increase after appropriate weight-based dosing and correction of reversible causes, further escalation beyond double the initial/stable dose is discouraged; persistent lack of response may prompt consideration of transfusion or individualized management.

Step	Requirement	Notes / Failure criteria
1
Individualize ESA therapy decisions for patients who remain hyporesponsive despite correction of treatable causes; avoid use of adjuvant agents that the work group recommends against (androgens) or suggests not using (vitamin C, vitamin D, vitamin E, folic acid, L-carnitine, pentoxifylline).
Use of the listed adjuvants is not recommended and should not be used as the strategy to overcome ESA hyporesponsiveness; persistent inadequate response should prompt alternative strategies such as transfusion or expert consultation.

Provider Actions and Requirements

Prior Authorization

Prior Authorization Required

Prior authorization required per diagnosis-specific criteria for initial and continuation therapy. Initial authorizations are generally limited to specified durations (commonly up to 3 months for perioperative use and up to 12 months for most indications); reauthorization/continuation requests must document ongoing eligibility and are typically limited to similar intervals (eg, up to 12 months).

Initial authorization durations: typically ≤ 12 months for CKD, MDS, myelofibrosis, HIV-related anemia, hepatitis C–related anemia; ≤ 3 months for perioperative use.
Reauthorization: requires documentation of positive clinical response and will generally be for ≤ 12 months (CKD, MDS, HIV, hepatitis C, myelofibrosis).

Prior Authorization

Prior Authorization for ESA Therapy

Prior authorization is required to ensure appropriate use of erythropoiesis-stimulating agents (ESAs) given evidence of increased mortality and thromboembolic events in some cancer and CKD populations. Requests should demonstrate that use meets diagnosis-specific coverage criteria and guideline-based indications.

Prior authorization ensures alignment with FDA and guideline indications (eg, oncology use limited to myelosuppressive chemotherapy contexts per FDA/NCCN).

Coding and Thresholds

Applicable HCPCS/J-codes and Q-codesHCPCS

J0881	Injection, darbepoetin alfa, 1 mcg (non-ESRD use)
J0882	Injection, darbepoetin alfa, 1 mcg (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

Hematocrit / Hemoglobin thresholds — Initiation and continuation

Common initiation thresholdHematocrit < 30% (approx. Hgb < 10 g/dL using Hct = 3 × Hgb)

Dialysis continuation limitHematocrit remains < 33% for continuation in patients receiving dialysis

Non-dialysis continuation limit (typical)Hematocrit remains < 30% for continuation in patients not on dialysis

Perioperative entry rangePerioperative Hct > 30% and ≤ 39% (specific perioperative criteria apply)

Hemoglobin thresholds — CKD initiation and maintenance

CKD ND initiation recommendationDo not generally initiate ESA therapy in adult CKD non-dialysis patients with Hb ≥ 10.0 g/dL; individualize decision when Hb < 10.0 g/dL

Site of Care

Billing Rule

Document subcutaneous (office) administration and monitoring plan

Subcutaneous administration is used in outpatient, preoperative, and HCV trial settings; when administering in the office, document the route and monitoring plan because outpatient SC dosing with monitoring for thrombotic risk and hemoglobin response was used in trials.

Document the planned route (SC) and monitoring for hemoglobin response and thrombotic risk when requesting office-administered ESA.
Include perioperative dosing plan and Hb monitoring schedule if for preoperative use.

Billing Rule

Specify route (IV vs SC) and CKD status for infusion‑center administration

When requesting ESA administration in an infusion center, indicate the route (IV or SC) and CKD setting because the guideline suggests IV or SC for CKD 5HD and SC for CKD ND and CKD 5PD.

Specify CKD stage and rationale for IV vs SC route in the request.

Biosimilar and Product Notes

Billing Rule

Submit appropriate HCPCS/J‑ or Q‑code; Retacrit has specific Q‑codes

When billing, use the appropriate HCPCS/J- or Q-code for the specific ESA product and indication; Retacrit is listed among covered ESAs with specific Q‑codes for ESRD and non‑ESRD use.

Use J0881–J0888 or Q4081/Q5105/Q5106 as applicable to the product and ESRD status.
Include clinical indication and dialysis status on claims to support correct code assignment.

Billing Rule

Use only approved ESAs; for copies, use true biosimilars

Use only ESAs approved by an independent regulatory agency and, for non‑reference products, use true biosimilars rather than unapproved 'copy' versions; document product approval status when requested.

Provide biosimilar product name and evidence of regulatory approval (e.g., prescribing information) if billing a biosimilar.
Do not request coverage for unapproved 'copy' ESA products.

Background

Anemia has multiple etiologies including blood loss, decreased marrow production, and hemolysis. Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa, darbepoetin alfa, and methoxy polyethylene glycol‑epoetin beta (CERA) are recombinant erythropoietin analogs that stimulate red blood cell production. Darbepoetin and MPG‑epoetin beta have molecular modifications that extend half‑life compared with epoetin alfa. ESA therapy requires assessment and correction of reversible causes of anemia (for example iron deficiency) and ongoing monitoring of hemoglobin/hematocrit during initiation and maintenance.

Definitions

ESA — Erythropoiesis-stimulating agents

Definition - ESA classErythropoiesis-stimulating agents (epoetin alfa, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta/CERA, and biosimilars)

Common brand examplesAranesp (darbepoetin alfa); Epogen/Procrit (epoetin alfa); Mircera (methoxy polyethylene glycol-epoetin beta); Retacrit (epoetin alfa biosimilar)

Primary useUsed to stimulate red blood cell production to reduce transfusion needs in select indications (CKD, chemotherapy-induced anemia, MDS, others)

epoetin alfa

Mechanism/definitionEpoetin alfa is a recombinant form of endogenous erythropoietin that stimulates red blood cell production

Examples/brandsMarketed as Epogen and Procrit (epoetin alfa)

Operational Notes & Provider Summary

Note

Revision History

2026-04-01Template update / operationalLatest

Policy template and state applicability were updated; content/language pertaining to Louisiana was removed and the References section was refreshed; prior policy version CS2025D0028Q was archived.