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Erythropoiesis Stimulating Agents (ESAs)

Policy Number: MP-307

Latest Review Date: October 2020

Category:  Pharmacy                                                             

Policy Grade: A

POLICY:

The use of Epoetin Alpha, Darbepoetin Alpha or Pegylated (PEG)-Epoetin Beta may be considered medically necessary for the following patients with chronic kidney disease (CKD):

CKD with Dialysis:

  • Initiate treatment when the hemoglobin level is less than 10g/dl.
  • Reduce or interrupt treatment if hemoglobulin level approaches or exceeds 11g/dl.

CKD not on Dialysis:

  • Initiating treatment only when the hemoglobin level is less than 10g/dl and the following criteria is met:
    • The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell (RBC) transfusion      AND
    • Reducing the risk of alloimmunization and /or other RBC transfusion-related risk is a goal.
  • If the hemoglobin level exceeds 10g/dl, reduce or interrupt the dose and use lowest dose sufficient to reduce the need for RBC transfusions.

In the medically necessary conditions listed above the following also applies:

  • The lowest dose of ESAs should be used in order to avoid red blood cell transfusions

The use of PEG-Epoetin Beta is considered not medically necessary and investigational for all other indications.

The use of Epoetin Alpha or Darbepoetin Alpha, may be considered medically necessary for one of the following conditions with hemoglobin < 10 g/dL or hematocrit < 30%:

  • Anemia of concurrently-administered chemotherapy in patients with non-myeloid malignancies;
  • Anemia due to therapy with AZT in HIV-infected patients;
  • Anemia due to Ribavirin therapy in the treatment of Hepatitis C;
  • Anemic patients scheduled to undergo elective, non-cardiac, non-vascular surgery with hemoglobin > 10 g/dL to < 13g/dL and not willing or unable to donate blood
  • Anemia related to Myelodysplastic Syndrome (MDS)
  • Anemia in post-renal transplant patients

Erythropoiesis stimulating agents (ESAs) Epoetin Alpha and Darbepoetin Alpha are considered not medically necessary and investigational in the following conditions: 

  • ESA treatment beyond six weeks following the last dose of myelosuppressive chemotherapy in a chemotherapy regimen or earlier if anemia has resolved
  • Hemoglobin levels greater than 12g/dl or hematocrit greater than 36% or rapid rise in hemoglobin/hematocrit levels after two weeks of treatment
  • Anemias not induced by chemotherapy or biologic agents, excluding patients with acute leukemia
  • Anemia in cancers or HIV-infected patients due to other factors such as iron or folate deficiency, hemolysis, gastrointestinal bleeding or bone marrow fibrosis
  • Anemia is not responsive to epoetin alfa after six-eight weeks of treatment
  • Anemia that is radiation therapy induced
  • Hemolytic anemia, sickle cell disease or aplastic anemia 
  • Prophylactic use to prevent chemotherapy-induced anemia or reduce tumor hypoxia

**NOTE:  Peginesatide (Omontys®) is currently discontinued due to 2013 voluntary recall of all lots due to postmarketing reports of serious hypersensitivity.

DESCRIPTION OF PROCEDURE OR SERVICE:

Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor that regulates hemoglobin levels in response to changes in the blood oxygen concentration.  Erythropoiesis-stimulating agents (ESAs) are produced using recombinant DNA technologies and have pharmacologic properties similar to endogenous EPO.  The primary clinical use of ESAs is in patients with chronic anemia. 

Endogenous Erythropoietin and Anemia

Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor synthesized by cells near the renal tubules in response to changes in the blood oxygen concentration. When a patient is anemic, the ability of the blood to carry oxygen is decreased. An oxygen-sensing protein in the kidney detects the decrease in blood oxygen concentration and induces the production of EPO, which then acts on the erythroid cell line in the bone marrow to stimulate hematopoiesis, thereby effectively increasing blood hemoglobin (Hb) concentrations. Suppression of erythropoietin production or suppression of the bone marrow response to erythropoietin results in anemia in several disease processes, including chronic kidney disease (CKD), many types of cancer treatment, other chronic diseases, and use of certain drugs.

The severity of anemia is defined by blood Hb concentration. Normal ranges are 12 to 16g/dL in women and 14 to 18g/dL in men. Mild anemia is defined as Hb from 10g/dL to the lower limit of normal ranges, while moderate anemia is 8 to 10g/dL and severe anemia is 8g/dL or less.

Treatment

Erythropoiesis-stimulating agents (ESAs) are produced using recombinant DNA technologies. They were initially developed as replacement therapy to treat anemia due to endogenous erythropoietin deficiency that commonly occurs in individuals with chronic renal failure (CRF) secondary to CKD. Patients with CRF will become severely anemic and experience severe fatigue and reduced exercise tolerance unless treated with blood transfusions or an ESA. Partial correction of anemia by ESA treatment of patients with CRF reduces the need for red blood cell (RBC) transfusions and enhances physical functioning.

In cancer, anemia occurs with varying degrees of frequency and severity. It occurs most commonly in genitourinary, gynecologic, lung, and hematologic malignancies. Anemia may be directly related to cancer type or to its treatment. Oncologic anemia occurs by a variety of mechanisms:

  1. Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B12) essential for RBC production.
  2. Antibodies and/or immunoregulatory abnormalities associated with certain tumor types (most commonly, B-cell malignancies) may cause increased erythrocyte destruction (hemolysis).
  3. Tumors may cause blood loss via tissue invasion (e.g., gastrointestinal bleeding from colon cancer).
  4. Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, and multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment.
  5. In more advanced cases, there may be marrow replacement with tumor or amyloid.
  6. However, marrow dysfunction can occur even in the absence of frank invasion.
  7. Inflammatory proteins from interactions between the immune system and tumor cells are thought to cause inappropriately low erythropoietin production and poor iron utilization, as well as a direct suppression of RBC production.

Cancer treatments may also cause anemia: 

  1. Radical cancer surgery can result in acute blood loss.
  2. Radiotherapy and many cytotoxic chemotherapeutic agents cause marrow suppression to varying degrees.  Damage is due to a variety of mechanisms.  For example, alkylating agents cause cumulative DNA damage; anti-metabolites damage DNA indirectly; and platinum-containing agents appear to damage erythropoietin-producing renal tubule cells.

Red blood cell (RBC) transfusion is the traditional approach to quickly ameliorate anemia symptoms.  However, this approach carries several potential adverse events.  The highest adverse event risk (1 per 432 whole blood units transfused) is for transfusion-related acute lung injury (TRALI). Adverse events due to errors in transfusion (for example, type mismatch) are estimated to occur at a rate of 1 per 5000 to 10,000 units of blood transfused. Current transfusion medicine and blood bank practices have significantly reduced the risk of transmissible infections, primarily due to better donor selection and screening for infectious diseases. Estimated risks per unit of blood transfused for transmission of hepatitis B virus (<1 in 400,000), hepatitis C virus (<1 in 1,000,000), human immunodeficiency virus (HIV) (<1 in 1,000,000), and bacterial contaminants (1 per 10,000 to 100,000) have fallen dramatically since the early 1990s.  Therefore, although the initial impetus to commercialize erythropoietin replacement products was based on reduction in the risks associated with blood transfusion errors, current practices have mitigated many of those risks.  Nonetheless, blood shortages, transfusion errors, and the risk for alloimmunization and TRALI provide sufficient rationale for the use of ESA therapy in appropriately indicated patients.

ESA products have been licensed in the U.S; however, peginesatide is no longer manufactured.

  • Epoetin alfa is manufactured, distributed and marketed by Amgen, Inc. under the proprietary name, Epogen®.  The same epoetin alfa product manufactured by Amgen, Inc. is also marketed and distributed by Janssen Products, LP, a subsidiary of Johnson and Johnson, under the proprietary name, Procrit®.  Under a contractual agreement with Amgen, Janssen Products has rights to develop and market Procrit for any indication other than for treatment of anemia associated with chronic renal failure in patients on dialysis or use in diagnostic test kits.  Epogen and Procrit have identical labeling information for all U.S. Food and Drug administration (FDA)-approved indications. 
  • The second ESA, darbepoetin alfa, is marketed solely by Amgen, under the proprietary name, Aranesp®. 
  • The third ESA product, peginesatide, was co-developed and commercialized by Affymax, Inc. and Takeda Pharmaceuticals, who market it under the proprietary name, Omontys®. In February 2013, Affymax, Takeda, and FDA announced a voluntary recall of all lots of peginesatide due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis. FDA currently lists peginesatide (Omontys) as discontinued.
  • Epoetin beta is currently unavailable in the U.S. However, a methoxy pegylated (PEG) form of epoetin beta, called “continuous erythropoietin receptor activator” or CERA, has a prolonged half-life that permits once monthly dosing. PEG-epoetin beta was FDA-approved in 2007 under the brand name Mircera.  Mircera sales in the US were prohibited from 2009 until 2015 due to a copyright infringement lawsuit, Hoffmann-LaRoche is now manufacturing and supplying the drug to Galencia, and it is currently available in the United States.

Epoetin alfa and epoetin beta have the same amino acid sequence as endogenous erythropoietin but differ from each other in glycosylation; clinical effects are considered interchangeable. However, the epoetins and darbepoetin all have pharmacologic actions similar to those of the endogenous hormone. When given to individuals with functioning erythropoiesis, each binds to and activates the human erythropoietin receptor and thus increases the number of RBCs and the blood concentration of hemoglobin. Both brands of epoetin alfas, pegylated epoetin beta, and darbepoetin alfa are approved by the Food and Drug Administration (FDA) to treat anemia in patients with CKD who are on or are not on dialysis. Epoetin alfa and darbepoetin alfa also are approved for other indications.

KEY POINTS:

The most recent literature update was performed through August 27, 2020.

Summary of Evidence

For individuals who have chronic kidney disease and anemia who receive epoetin alfa, PEG- epoetin beta, or darbepoetin, the evidence includes RCTs and systematic reviews of RCTs. The relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. All three ESAs have been studied and approved for this use. Most of the evidence has demonstrated an increase in hemoglobin and a decrease in blood transfusions but has failed to demonstrate any significant improvement in clinical outcomes such as mortality and morbidity. The evidence is inconsistent in showing improvements in functional status and QOL. Many studies have demonstrated increased mortality risk and increased risk for venous access thrombosis and stroke, prompting FDA warnings. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have cancer-related anemia who receive epoetin alfa or darbepoetin, the evidence includes RCTs, comparative analyses, and systematic reviews of RCTs. The relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. The available trials have demonstrated an increase in hemoglobin concentration and a decrease in the need for blood transfusions. However, the evidence has also demonstrated increased mortality rates and possible tumor promotion, as well as increased risk of thromboembolic events when target hemoglobin levels were above 12 g/dL. Comparative analyses have shown that when the target hemoglobin level was lowered to 10 g/dL, patients experienced increased hemoglobin and decreased risk for blood transfusions. Length of follow-up was short in the comparative analyses, and mortality and adverse events were therefore not addressed. Epoetin alfa and darbepoetin are the ESAs approved for use in the treatment of cancer-related anemia; PEG-epoetin beta is not FDA-approved for this indication, because studies have demonstrated increased mortality and no significant improvement in clinical outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have hepatitis C infection treated with ribavirin who receive epoetin alfa or darbepoetin, the evidence includes RCTs. The relevant outcomes are QOL and medication use. Evidence from RCTs has demonstrated that treatment with ESAs improves the ability to maintain full-dosing of ribavirin, because anemia is often a limiting effect for treatment. There may also be a positive effect on the QOL, although this is less certain. Epoetin alfa and darbepoetin are the ESAs approved for this use. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

PRACTICE GUIDELINES AND POSITION STATEMENTS

National Kidney Foundation

The National Kidney Foundation (2012) published the Kidney Disease: Improving Global Outcomes clinical practice guidelines for anemia in chronic kidney disease (CKD). A consensus of an international group of experts created comprehensive, evidence-based guidance for the treatment of anemia in CKD. The Kidney Disease: Improving Global Outcomes recommendation on initiation and maintenance of erythropoiesis-stimulating agents (ESAs) was based on balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension). Recommendations for treatment initiation and maintenance are listed in Table 1.

Table 1. Recommendations for Initial and Maintenance Therapy for Anemia in CKD

Recommendation

LOR

Initial Therapy

“We recommend using ESA therapy with great caution, if at all, in CKD patients with

  • active malignancy
  • … a history of stroke or
  • a history of malignancy.”


1B
1B
2C

“For adult CKD ND patients with Hb concentration ≥10.0 g/dl (≥100 g/l) we suggest that ESA therapy not be initiated.”

2D

“For adult CKD ND [non-dialysis] patients with Hb [hemoglobin] concentration ≤10.0 g/dl (<100 g/l) we suggest that the decision whether to initiate ESA therapy be individualized based on the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia.

2C

“For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the Hb concentration fall below 9.0 g/dl (90 g/l) by starting ESA therapy when the hemoglobin is between 9.0-10.0 g/dl (90-100g/l).”

2B

Maintenance Therapy

“…we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adult patients with CKD.”

2C

“Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hb concentration above 11.5 g/dl (115 g/l) and will be prepared to accept the risks.”

Not graded

“…we recommend that ESAs not be used to intentionally increase the Hb concentration above 13 g/dl (130 g/l).”

1A

CKD: Chronic Kidney Disease; ESA: erythropoiesis-stimulating agent; Hb: hemoglobin; LOR: level of recommendation; ND: nondialysis.

American Society of Clinical Oncology, American Society of Hematology, and National Comprehensive Cancer Network

Table 2 summarizes current clinical practice guidelines published jointly by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (updated in 2019) and from the National Comprehensive Cancer Network (v.2.2020).

Table 2: Summary of Current Guidelines on ESA Therapy to Treat Anemia in Cancer Patients

Indications

ASCO/ASH 2019 Clinical Practice Guidelines

NCCN Guidelines (v.1.2020)

ESAs are indicated for:

  • Depending on clinical circumstances, ESAs may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin (HgB) has declined to
  • Based on patient preference and values, patients undergoing palliative treatment or myelosuppressive chemotherapy without curative intent may be treated with ESAs using FDAapproved indications/dosing/dosing adjustments OR may be treated with RBC transfusions per provided guidelines

ESAs are NOT indicated for:

  • Patients with chemotherapy-associated anemia whose cancer treatment is curative in intent (Type: EB; EQ: intermediate; SOR: strong)
  •  ESAs should not be offered to most patients with nonchemotherapy-associated anemia (Type: IC; EQ: low; SOR: strong)
  • ESA treatment is not recommended when patients are treated with myelosuppressive chemotherapy with curative intent
  • ESA treatment is not recommended when patients are not receiving therapy or palliative treatment, or those on non-myelosuppressive therapy

ESA treatment symptom outcomes

Not discussed

Not discussed

Hb levels for ESA initiation

  • ESAs may be offered to patients with lower risk myelodysplastic syndromes and a serum erythropoietin level ≤500 IU/L (Type: EB; EQ: intermediate; SOR: moderate)

If Hb is 2 g/dL below baseline, an evaluation for possible causes of anemia is suggested. If a cause is not identified, then anemia due to myelosuppressive chemotherapy is considered.

Span of ESA treatment

Not discussed

Physicians advised not to administer ESAs outside the treatment period of cancer-related chemotherapy

ESA dosing modifications

  • It is recommended that starting and modifying doses of ESAs follow FDA guidelines (Type: IC; EQ: intermediate; SOR: moderate)

Dosing and titration directions for epoetin alfa and darbepoetin alfa are reproduced from FDAapproved labels; alternative dosing regimens are provided, eg, every 2 or 3 wk instead of weekly injections

Hb target

Hgb may be increased to the lowest concentration needed to avoid or reduce the need for RBC transfusions, which may vary by patient and condition (Type: IC; EQ: intermediate: SOR: moderate)

No Hb target is mentioned; notes that the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to a target Hb

Iron

Iron replacement may be used to improve HgB response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Baseline and periodic monitoring of iron, total ironbinding capacity, transferrin saturation, or ferritin levels is recommended (Type: EB; EQ: intermediate; SOR: weak)

Iron studies and supplementation of functional iron deficiency are recommended for patients treated with ESAs. These include serum iron, TIBC, and serum ferritin. Any patient with cancer who develops a sudden loss of response to ESAs, accompanied by severe anemia and a low reticulocyte count, should be evaluated for the etiology of loss of effect

Thromboembolic risk

  • In patients with myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia, clinicians should observe the hematologic response to cancer treatment before considering an ESA. Particular caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases where risk of thromboembolic complications is increased. In all cases, blood transfusion is a treatment option that should be considered (Type: IC; EQ: low; SOR: moderate)
  • ESAs increase the risk of thromboembolism, and clinicians should carefully weigh the risks of thromboembolism and use caution and clinical judgment when considering use of these agents (Type EB; EQ: high; SOR: strong)

Patients with previous risk factors for thrombosis may be at higher risk when administered ESAs and should undergo risk assessment

Response to treatment

ESAs should be discontinued in patents who do not respond within 6 to 8 weeks. Patients who do not respond to ESA treatment should be reevaluated for underlying tumor progression, iron deficiency, or other etiologies for anemia (Type: IC; EQ: intermediate; SOR: strong)

ESA therapy should be discontinued if a patient shows no response despite iron supplementation after 8 wks of treatment. ESA dose-adjustment decisions are based on the goal of a gradual increase in Hb level that remains sufficient to avoid transfusion

EB: evidence-based; EQ: evidence quality; SOR: strength of recommendation; IC: informal conscensus;ASCO: American Society of Clinical Oncology; ASH: American Society of Hematology; ESA: erythropoiesis-stimulating agent; FDA: Food and Drug Administration; HgB: hemoglobin; NCCN: National Comprehensive Cancer Network; RBC: red blood cell; TIBC: total iron-binding capacity.

American Society of Nephrology

The American Society of Nephrology (2012) released its evidence-based recommendations for the Choosing Wisely campaign to improve patient care and resource use. The Society included the following among its top five recommendations: “Do not administer erythropoiesis-stimulating agents to CKD patients with hemoglobin levels ≥10 g/dL without symptoms of anemia.”

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS

Not applicable.

Additional Guidelines

Administration

ESAs and pegylated (PEG)-epoetin beta are to be administered according to current FDA-approved labeling for each product, using recommended hemoglobin (Hb) levels for starting, stopping, and dose adjustment. This includes decreasing the dose of ESA as the Hb approaches the target level.

Before commencing ESA or PEG-epoetin beta therapy, the patient’s iron stores, blood ferritin, and transferrin saturation should be evaluated, adjusted, and maintained within normal physiological limits. ESA or PEG-epoetin beta therapy should not be administered without adequate iron stores.

Blood Pressure Monitoring

Blood pressure should be adequately controlled before initiation of ESA therapy and closely monitored and controlled during treatment. ESAs and PEG-epoetin beta are contraindicated in patients with uncontrolled hypertension.

Discontinuation

ESAs

Patients with myelodysplastic syndromes should be initially limited to a three-month trial period with ESA. If no response to ESA is observed, ongoing therapy would be futile.

ESAs and PEG-Epoetin Beta

Patients with chronic kidney disease who do not respond adequately over a 12-week dose escalation period should not have their ESA or PEG-epoetin beta dose increased further. Increasing ESA or PEG-epoetin beta dose further is unlikely to improve response and may increase risks; the lowest ESA or PEG-epoetin beta dose that maintains adequate Hb to avoid recurrent red blood cell transfusions should be used. Other causes of anemia should be evaluated. If responsiveness does not improve, discontinue ESA or PEG-epoetin beta therapy.

Risk Evaluation and Mitigation Strategy

Clinical studies have shown that treatment with epoetin alfa and darbepoetin alfa for patients with cancer may result in shorter overall survival and/or increased risk of progression or recurrence. Additional studies of patients with chronic kidney disease and hemoglobin greater than 11 g/dL found that treatment with epoetin alfa and darbepoetin alfa resulted in increased risks of mortality or cardiovascular adverse events or stroke. In response to this data, FDA implemented a risk evaluation and mitigation strategy (REMS) in 2011 under which providers and hospitals were required to counsel patients, and each patient had to complete a provider acknowledgement form before treatment.

In April 2017, FDA eliminated the REMS for Epogen®/Procrit® and Arenesp®, stating that “the risks can be communicated by the current product prescribing information” and that “The appropriate use of ESAs is supported by the Centers for Medicare and Medicaid Services’ (CMS) National Coverage Determination, the American Society of Clinical Oncology, the American Society of Hematology clinical guidelines, which are evidence-based guidelines intended to provide a basis for the standard of care in clinical oncology.”

PEG-epoetin beta does not have a REMS.

In 2012, FDA approved a REMS for peginesatide with a communication plan as its only component. The plan’s goal was to inform all health care professionals who might prescribe the drug that peginesatide is indicated only for adults with chronic kidney disease on dialysis, as well as to warn health care professionals of potentially fatal risks associated with its use in patients with chronic kidney disease not on dialysis. Peginesatide is currently discontinued.

KEY WORDS:

Erythropoietin, erythropoietin alfa, epoetin alfa, Epogen®, Procrit®, Aranesp®, darbepoetin alfa, darbepoetin, anemia, erythropoiesis stimulating agent, ESA, Mircera®, OMONTYS®, Retacrit®

APPROVED BY GOVERNING BODIES:

Epoetin alfa (Epogen® and Procrit®)

  • 1989: Approved for use in patients with anemia due to CRF
  • 1991: Approved for use in zidovudine-treated, HIV-infected patients
  • 1993: Approved for chemotherapy-induced anemia in patients with non‒myeloid malignancies
  • 1996: Approved for presurgical use in certain patients undergoing surgery

Darbepoetin alfa (Aranesp®)

  • 2001: Approved for use in patients with anemia due to CRF
  • 2002: Approved for chemotherapy-induced anemia in patients with non‒myeloid malignancies

Peginesatide (Omontys®; Takeda Pharmaceuticals, Deerfield, IL, and Affymax):

  • 2012: Approved for use in adults with anemia due to CKD who are on dialysis
  • 2013: Voluntary recall of all lots due to postmarketing reports of serious hypersensitivity

Methoxy polyethylene glycol (PEG) epoetin-beta (Mircera®; Roche, Basel, Switzerland

  • 2007: Approved for use in patients with anemia due to CRF who are on dialysis or not on dialysis
  • 2009: Injunction prohibiting U.S. sales until mid-2014 due to copyright infringement
  • 2015: Resumption of U.S. sales

Clinical studies had shown that treatment with epoetin alfa and darbepoetin alfa for patients with cancer may result in shorter overall survival and/or increased risk of progression or recurrence. Additional studies of patients with CKD and hemoglobin greater than 11 g/dL found that treatment with epoetin alfa and darbepoetin alfa resulted in increased risks of mortality or cardiovascular adverse events or stroke. In response to this data, the FDA implemented a risk evaluation and mitigation strategy in 2011 under which providers and hospitals were required to provide counseling to patients and each patient needed to complete a provider acknowledgement form before treatment.

In April 2017, the FDA eliminated the risk evaluation and mitigation strategy for Epogen®/Procrit® and Arenesp®, citing that “the risks can be communicated by the current product prescribing information” and that “The appropriate use of ESAs is supported by the Centers for Medicare and Medicaid Services’ (CMS) National Coverage Determination, the American Society of Clinical Oncology, the American Society of Hematology clinical guidelines, which are evidence-based guidelines intended to provide a basis for the standard of care in clinical oncology.”

Postapproval FDA Regulatory Actions

In 2006, the FDA issued an advisory on the serious cardiovascular risks from ESA therapy in patients with CKD, as evidenced in the Correction of Hemoglobin and Outcomes in Renal Insufficiency and the Normal Hematocrit Cardiac Trial studies. Subsequently, the FDA received reports of increased risks associated with ESAs used to treat anemia in cancer patients who were receiving or not receiving chemotherapy, as well as a report of thrombotic risks in patients receiving ESAs in the peri-surgical setting.

Regarding dosage information, periodic reassessment of ESA safety has determined that clinical data do not support a therapeutic hemoglobin target free of risk for mortality. Consequently, revised “Dosage and Administration” sections of the product label deleted any specific therapeutic hemoglobin or hematocrit “target” range for ESAs. Instead, revised labels recommended that prescribers use the lowest ESA dose that will gradually increase hemoglobin concentration to the lowest level sufficient to avoid the need for RBC transfusion. For anemic chronic renal failure patients, this recommendation was primarily based on the Normal Hematocrit Cardiac Trial and the Correction of Hemoglobin and Outcomes in Renal Insufficiency study findings, as well as the lack of data for any specific hemoglobin or Hct threshold or range. Clinical data did not identify specific hemoglobin or hematocrit levels that directly correlated with a “…reduction in the need for red blood cell transfusion,” the main treatment benefit supporting ESA efficacy. Label revisions allowed prescribers to use their clinical judgment in determining the “…lowest level sufficient to avoid the need for red blood cell transfusion." These data prompted a reassessment of the safety information contained in the labeling for Mircera (2014), Aranesp (2017),Epogen (2017), and Procrit (2017) and culminated in the approval of revised labels. These revisions clarified the evidence for safety and effectiveness of these products and provided more explicit directions and recommendations for their use.

These recommendations were consistent with those made by the FDA in May 2007 and in September 2007. Revisions included strengthened boxed warnings and “Warnings and Precautions” sections, and changes to the “Indications and Usage,” “Clinical Trials Experience,” and “Dosage and Administration” sections of the product labels. The revised black box warnings and limitations of use shown next reflect current labeling for these ESAs.

Cancer

  • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.
  • Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense an ESA to patients with cancer.
  • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.
  • Use ESAs only for anemia from myelosuppressive chemotherapy.
  • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is a cure.
  • Discontinue following the completion of a chemotherapy course.

Chronic Renal Failure

  • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a Hb level of greater than 11 g/dL.
  • No trial has identified a Hb target level, ESA dose, or dosing strategy that does not increase these risks.
  • Use the lowest Epogen/Procrit or Aranesp dose sufficient to reduce the need for RBC transfusions.

Perisurgery (Epogen®/Procrit® Only)

  • Due to increased risk of deep venous thrombosis, prophylaxis for deep venous thrombosis is recommended.

Limitations of Use

Epogen®/Procrit® and Aranesp® have not been shown to improve QOL, fatigue, or patient well-being (for any indication).

Epogen®/Procrit® and Aranesp® are not indicated for use:

  • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is a cure.
  • As a substitute for RBC transfusions in patients who require immediate correction of anemia.

Epogen®/Procrit® also are not indicated for use:

  • In patients scheduled for surgery who are willing to donate autologous blood.
  • In patients undergoing cardiac or vascular surgery.

In May 2018, Retacrit (epoetin alfa-epbx; Pfizer) was approved by the FDA as a biosimilar of epoetin alfa for the treatment of anemia due to CKD in patients on dialysis and not on dialysis, zidovudine in patients with HIV-infection, and the effects of concomitant myelosuppressive chemotherapy. Retacrit is also indicated for the reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply.  Refer to member’s benefit plan.

FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

HCPCS:

J0881        Injection, darbepoetin alfa, 1mcg (for 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        Injectin, epoetin beta, 1 microgram, (for non-ESRD use)

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

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

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

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

REFERENCES:

  1. Afdahl NH, Dieterich DT, Pokros PJ et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology, 2004; 126(5):1302-11.
  2. AHRQ Effective Health Care.  Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment.  Executive Summary, May 23, 2006.  effectivehealthcare.ahrq.gov.
  3. Al-Ali FS, El-Sayed Abdelfattah M, Fawzy AA, et al. Erythropoietin-stimulating agents in the management of anemia of end-stage renal disease patients on regular hemodialysis: A prospective randomized comparative study from Qatar. Hemodial Int. Jun 3 2014.
  4. Alsalimy N, Awaisu A. Methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa for anemia in non-dialysis-dependent CKD: a systematic review. Int J Clin Pharm. Dec 2014; 36(6):1115-1125.
  5. Amato L, Addis A, Saulle R, et al. Comparative efficacy and safety in ESA biosimilars vs. originators in adults with chronic kidney disease: a systematic review and meta-analysis. J Nephrol. Jun 2018;31(3):321-332.
  6. American Association for Cancer Research.  Study produces conflicting findings on the use of anti-anemia drug.  www.aacr.org/home/public--media/news.aspx?d=765.
  7. Amgen. Highlights of Prescribing Information: Aranesp® (darbepoetin alfa). 2018; //pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aranesp/ckd/aranesp_pi_hcp_english.ashx. Accessed September 29, 2018.
  8. Amgen. Highlights of Prescribing Information: Epogen® (epoetin alfa). 2018; https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/epogen/epogen_pi_hcp_english.ashx. Accessed September 29, 2018.
  9. Bennett Charles L, Silver Samuel M, et al.  Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.  JAMA, February 27, 2008, Vol. 299, No. 8.
  10. 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):584-90.
  11. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Specialty Pharmacy Reports 2012. Peginesatide: #6-2012.
  12. Boccia RV, Henry DH, Belton L, et al. Efficacy and safety of darbepoetin alfa initiated at hemoglobin </=10 g/dL in patients with stage IV cancer and chemotherapy-induced anemia. Cancer Med. Dec 2016; 5(12):3445-3453.
  13. Bohlius J, Schmidlin K, Brillant C et al. Erythropoietin or darbepoetin for patients with cancer – meta-analysis based on individual patient data. Cochrane Database Syst Rev 2009; (3):CD007303.
  14. Bohlius J, Schmidlin K, Brillant C et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009; 373(9674):1532-42.
  15. Bohlius J, Weingart O, Trelle S and Engert A.  Cancer-related anemia and recombinant erythropoietin-An updated overview.  Nat Clin Pract Oncol 2006; 3(3): 152-164.
  16. Bohlius J, Wilson J, Seidenfeld J, Piper M, et al.  Recombinant human erythropoietins and cancer patients:  Updated meta-analysis of 57 studies including 9353 patients.  J Natl Cancer Inst, May 2006; 98(10): 708-714.
  17. Canaud B, Mingardi G, Braun J, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrol Dial Transplant. Nov 2008; 23(11):3654-3661.
  18. Centers for Medicare and Medicaid Services (CMS).  NCD for Erythropoiesis stimulating agents (ESAs) in cancer and related neoplastic conditions.  Medicare Coverage Database, April 7, 2008.
  19. Chustecka Zosia.  Physicians now more cautious about using erythropoietin in cancer patients.  www.medscape.com/viewarticle/555383_print.
  20. Cody JD, Hodson EM. Recombinant human erythropoietin versus placebo or no treatment for the anaemia of chronic kidney disease in people not requiring dialysis. Cochrane Database Syst Rev. Jan 20 2016(1):CD003266.
  21. Collister D, Komenda P, Hiebert B, et al. The effect of erythropoietin-stimulating agents on health-related quality of life in anemia of chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. Apr 05 2016; 164(7):472-478.
  22. Coronado Daza J, Marti-Carvajal AJ, Ariza Garcia A, et al. Early versus delayed erythropoietin for the anaemia of end-stage kidney disease. Cochrane Database Syst Rev. Dec 16 2015(12):CD011122.
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  24. Dieterich DT, Wasserman R, Brau N et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol, 2003; 98(11):2491-9.
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  46. Mhaskar R, Wao H, Miladinovic B, et al. The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents. Cochrane Database Syst Rev. Feb 04 2016; 2:CD009624.
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  50. Oh J, Joo KW, Chin HJ, et al. Correction of anemia with continuous erythropoietin receptor activator in Korean patients on long-term hemodialysis. J Korean Med Sci. Jan 2014; 29(1):76-83.
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  54. Palmer SC, Saglimbene V, Craig JC, et al. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. Mar 31 2014; 3(3):CD009297.
  55. Palmer SC, Saglimbene V, Mavridis D, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2014; 12:CD010590.
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  58. Rizzo JD, Brouwers M, Hurley P et al. American Society of Clinical Oncology/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):4996-5010.
  59. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update. Journal of Clinical Oncology, January 2008, Vol. 26, No. 1.
  60. Roger SD, Locatelli F, Woitas RP, et al. C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis. Nephrol Dial Transplant. Dec 2011; 26(12):3980-3986.
  61. Roger SD, Tio M, Park HC, et al. Intravenous iron and erythropoiesis-stimulating agents in haemodialysis: A systematic review and meta-analysis. Nephrology (Carlton). Oct 03 2016.
  62. Saglimbene V, Palmer SC, Craig JC, et al. Low versus high dose erythropoiesis-stimulating agents in hemodialysis patients with anemia: A randomized clinical trial. PLoS One. Mar 1 2017; 12(3):e0172735.
  63. Schwenger V, Morath C and Zeier M. Use of erythropoietin after solid organ transplantation.  Nephrol Dial Transplant 2007; 22(Suppl 8): viii47-viii49.
  64. Seidenfeld J, Piper M, Bohlius J et al. Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment. Comparative Effectiveness Review No. 3. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-02-0026.) Rockville, MD: Agency for Healthcare Research and Quality; May 2006. Available online at: www.ncbi.nlm.nih.gov/books/NBK42982/. Last accessed July 2014.
  65. Shehata N, Walker I, Meyer R, et al.  Treatment for anemia with erythropoietic agents in patients with non-myeloid hematological malignancies:  A clinical practice guideline.  Cancer Care Ontario, January 2007, p. 32. www.guideline.gov/summary/summary.aspx?doc_id=10583.
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  68. Skali H, Parving HH, Parfrey PS et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with darbepoetin alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation 2011; 124(25):2903-8.
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POLICY HISTORY:

Medical Policy Group, April 2008 (1)

Medical Policy Administration Committee, April 2008

Available for comment April 4-May 18, 2008

Medical Policy Group, October 2008 (3)

Medical Policy Administration Committee, November 2008

Available for comment November 20, 2008-January 5, 2009

Medical Policy Group, March 2010 (3)

Medical Policy Group, April 2011 (3): Code update

Medical Policy Administration Committee, April 2011

Available for comment April 13 – May 30, 2011

Medical Policy Group, July 2011 (3): Updated Policy, Key Points, & References

Medical Policy Administration Committee, July 2011

Available for comment July 6 through August 22, 2011

Medical Review Committee, July 2011

Medical Policy Group, October 2011 (2): Description, References updated

Medical Policy Group, June 2012 (3): Updates to Policy, Key Points, Key Words, Approved by Governing Bodies, Codes, References

Medical Policy Administration Committee, June 2012

Available for comment June 26 through August 9, 2012

Medical Policy Group, November 2012: 2013 Coding Update-added J0890- peginesatide injection-effective 1/1/2013

Medical Policy Panel, December 2012

Medical Policy Group, February 2013 (3):  Updates to Description, Key Points and References.  No change in policy statement.

Medical Policy Group, October 2013 (3): Removed ICD-9 Diagnosis codes; no change to policy statement.

Medical Policy Panel, December 2013

Medical Policy Group, December 2013 (3):  Updates to Description, Policy Statement, Key Points, Governing Bodies, and References; removed from policy statement references to Omontys® - not currently available due to voluntary recall

Medical Policy Administration Committee, February 2014

Available for comment February 5 through March 21, 2014

Medical Policy Panel, September 2014

Medical Policy Group, September 2014 (3):  2014 Updates to Description, Key Points, Governing Bodies, Current Coding & References;  Policy Statement updated to include coverage and investigational criteria for pegylated (PEG)-epoetin beta (product not yet available in US due to litigation but expected to be in fall, 2014)

Medical Policy Administration Committee, October 2014

Available for comment September 25 through November 8, 2014

Medical Policy Group, November 2014: 2015 Annual Coding update.  Added HCPCS codes J0887 and J0888 and moved deleted HCPCS codes Q9972 and Q9973 to previous coding.

Medical Policy Panel, March 2016

Medical Policy Group, April 2016 (3):  2016 Updates to Key Points, Key Words & References; removed policy criteria for dates of service prior to December 12, 2013; no change in currently effective policy statements otherwise

Medical Policy Panel, October 2017

Medical Policy Group, November 2017 (3): 2017 Updates to Description, Key Points, Additional Guidelines Section, Approved by Governing Bodies & References. Removed previous code Q2047 deleted 12/31/12. Removed policy statement for dates on or after December 12, 2013 and prior to October 1, 2014; no other changes to policy statements

Medical Policy Panel, October 2018

Medical Policy Group, December 2018 (2): 2018 Updated To Description, Key Points, and References; Keywords (added Retacrit); Current Coding (added codes Q5105 and Q5106) and moved code J0886 to previous coding section; no changes to Policy statement.

Medical Policy Panel, October 2019

Medical Policy Group, October 2019 (2): Updates to Description, Key Points, Practice Guidelines and Position Statements, and Approved by Governing Bodies. No changes to Policy Statement.

Medical Policy Panel, October 2020

Medical Policy Group, October 2020 (2): Updates to Key Points, No change to Policy Statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.