| Coverage Policy Manual | |
| Policy #: | 2013003 |
| Category: | Pharmacy |
| Initiated: | January 2013 |
| Last Review: | November 2023 |
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| Stem Cell Growth Factors, Erythropoiesis-Stimulating Agents (ESAs), Darbepoetin, Epoetin, Methoxy polyethylene glycol (PEG) epoetin-beta | |
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| Description: |
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 individuals with chronic 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 an individual 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 upon 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 12–16 g/dL in women and 14–18 g/dL in men. Mild anemia is defined as Hb from 10 g/dL to the lower limit of normal ranges, while moderate anemia is 8-10 g/dL. Severe anemia is defined as Hb 8 g/dL or below.
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. Individuals with CRF will become severely anemic, experience severe fatigue, and reduced exercise tolerance unless treated with blood transfusions or an ESA. Partial correction of anemia by ESA treatment of individuals with CRF reduces the need for red blood cell 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. Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B-12) essential for red cell production. Antibodies and/or immunoregulatory abnormalities associated with certain tumor types (most commonly, B-cell malignancies) may cause increased erythrocyte destruction (hemolysis). Tumors may cause blood loss via tissue invasion, for example gastrointestinal bleeding from colon cancer. Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment. In more advanced cases, there may be marrow replacement with tumor or amyloid. However, marrow dysfunction can occur even in the absence of frank invasion. 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 red cell production. The treatment of cancer may also cause anemia. Radical cancer surgery can result in acute blood loss.
Radiotherapy and many cytotoxic chemotherapeutic agents suppress marrow 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, it carries risk for several potential adverse events. The highest adverse event risk (1 per 432 whole blood units transfused) is that 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 5,000–10,000 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 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 10,000-100,000) have fallen dramatically since the early 1990s. Therefore, while the initial impetus to commercialize erythropoietin replacement products was based on reduction in the risks associated with blood transfusion, current practices have mitigated many of those risks. Nonetheless, blood shortages, transfusion errors, and the risk for alloimmunization and TRALI provide sufficient rationale for use of ESA therapy in appropriately indicated individuals.
Four ESA products have been licensed in the U.S. 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, LP has rights to development and marketing of Procrit for any indication other than for the treatment of anemia associated with chronic renal failure in individuals 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. A second ESA, darbepoetin alfa, is marketed solely by Amgen, under the proprietary name, Aranesp. The third ESA product, peginesatide, was codeveloped and commercialized by Affymax, Inc. and Takeda Pharmaceuticals, who market it under the proprietary name, Omontys. The fourth 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 and is marketed outside the U.S. by Hoffmann-LaRoche under the proprietary name Mircera®. Due to a copyright infringement lawsuit brought by Amgen in 2009, U.S. sales have been prohibited until mid-2014.
The epoetin alfas and epoetin beta have the same amino acid sequence as endogenous erythropoietin but differ from each other in glycosylation; clinical effects are considered interchangeable while darbepoetin alfa has two additional oligosaccharide chains. In contrast, peginesatide lacks any amino acid sequence homology to erythropoietin. It is a synthetic dimer of identical 21-amino acid peptides bound to a linker and to polyethylene glycol, with a total molecular
weight of approximately 45,000 daltons. However, the epoetins, darbepoetin, and peginesatide all have pharmacologic actions similar to those of the endogenous hormone. Each binds to and activates the human erythropoietin receptor and thus increases the number of red blood cells and the blood concentration of hemoglobin, when given to individuals with functioning erythropoiesis. All currently marketed ESAs are approved as treatment of anemia associated with CKD in adult individuals on dialysis. The two epoetin alfas and darbepoetin are also approved to treat pediatric individuals on dialysis with anemia from CKD, anemic individuals with CKD not on dialysis, and for other indications.
Pegylated (PEG)-epoetin beta is a long-acting epoetin that is FDA-approved for individuals with anemia due to CRF. Evidence for this indication comprises randomized controlled trials in individuals on dialysis or not on dialysis that showed non-inferiority to standard ESAs for correction or maintenance of Hb levels. Meta analyses in dialysis individuals reported no difference in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. Based on this evidence, PEG epoetin beta may be considered medically necessary for treatment of anemia due to CRF. For treatment of anemia due to cancer chemotherapy, one Phase 2 trial showed increased mortality with PEG-epoetin beta compared with darbepoetin. PEG-epoetin beta is expected to become available in the U.S. soon.
Regulatory Status
The major regulatory timelines for approval actions pertaining to new indications is summarized below:
Epoetin alfa (Epogen/Procrit):
Darbepoetin alfa (Aranesp):
Peginesatide (Omontys):
Methoxy polyethylene glycol (PEG) epoetin-beta (Mircera®) :
Epoetin Alfa-EPBX (Retacrit):
On February 23, 2013, Affymax, Inc. and Takeda Pharmaceutical Company Limited along with the U.S. Food and Drug Administration (FDA) announced the voluntary recall of all lots of Peginesatide (e.g., OMONTYS®) Injection due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service when rendered for oncologic indications and is managed through the oncology benefits management program.
Effective November 21, 2023
DARBEPOETIN ALFA (e.g., Aranesp)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Coverage for darbepoetin requires more than meeting specific diagnosis requirements. These additional coverage criteria are listed below under "Limitations".
Darbepoetin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is covered only for the following conditions:
Limitations:
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR an NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Recommended starting dose for individuals with CKD on dialysis:
Recommended starting dose for individuals with CKD not on dialysis:
Recommended starting dose for pediatric individuals with CKD:
Recommended starting dose for individuals with cancer on chemotherapy:
Darbepoetin alfa is available as:
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of darbepoetin, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, darbepoetin, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
EPOETIN ALFA (e.g., Procrit and Epogen)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Coverage for epoetin alfa requires more than meeting specific diagnosis requirements. These additional coverage criteria are listed below under “limitations”.
Epoetin alfa meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following diagnoses based on specific coverage guidelines:
Limitations:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Evaluate iron status before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia before initiating treatment
In pregnant women, lactating women, neonates, infants: Use only single dose vials.
Individuals with CKD: Initial dose: 50 to 100 Units/kg 3 times weekly (adults) and 50 Units/kg 3 times weekly (pediatric individuals). Individualize maintenance dose. Intravenous route recommended for patients on hemodialysis).
Individuals on Zidovudine due to HIV-infection: 100 Units/kg 3 times weekly.
Individuals with Cancer on Chemotherapy: 40,000 Units weekly or 150 Units/kg 3 times weekly (adults); 600 Units/kg intravenously weekly (pediatric patients ≥ 5 years).
Surgery Individuals: 300 Units/kg per day daily for 15 days or 600 Units/kg weekly.
Epoetin alfa is available as:
20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
This policy does not address use of epoetin use for pre-surgical individuals with hemoglobin between 10 g/dL and 13 g/dL who are scheduled to undergo major orthopedic hip or knee surgery.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Epoetin, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, Epoetin, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Epoetin Alfa-EPBX (e.g., Retacrit)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Coverage for epoetin alfa-epbx requires more than meeting specific diagnosis requirements. These additional coverage criteria are listed below under "Limitations".
Epoetin alfa-epbx meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following conditions:
Treatment of anemia due to:
Limitations:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Evaluate iron status before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia before initiating treatment.
In pregnant women, lactating women, neonates, infants: Use only single-dose vials.
Individuals with CKD: Initial dose: 50 to 100 Units/kg 3 times weekly (adults) and 50 Units/kg 3 times weekly (pediatric patients). Individualize maintenance dose. Intravenous route recommended for patients on hemodialysis.
Individuals on Zidovudine due to HIV-infection: 100 Units/kg 3 times weekly.
Individuals with Cancer on Chemotherapy: 40,000 Units weekly or 150 Units/kg 3 times weekly (adults); 600 Units/kg intravenously weekly (pediatric patients > 5 years).
Surgery Individuals: 300 Units/kg per day daily for 15 days or 600 Units/kg weekly.
Epoetin alfa-epbx is available as:
20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Epoetin alfa-epbx, for any indication or circumstance not descried above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, Epoetin alfa-epbx, for any indication or circumstance not descried above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA (e.g., Mircera)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of pegylated (PEG)-epoetin beta meets member benefit certificate primary coverage criteria for effectiveness in improving health outcomes and is covered for the following diagnoses based on specific coverage guidelines:
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR an NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
In adult patients, pegylated (PEG)-epoetin beta is administered by subcutaneous or intravenous injection.
In pediatric patients, Mircera is administered by intravenous injection only.
Pegylated (PEG)-epoetin beta is available as:
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pegylated (PEG)-epoetin beta, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, pegylated (PEG)-epoetin beta, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 1, 2022 to November 20, 2023
DARBEPOETIN ALFA (e.g., Aranesp)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Coverage for darbepoetin requires more than meeting specific diagnosis requirements. These additional coverage criteria are listed below under "Limitations".
Darbepoetin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered only for the following conditions:
Limitations:
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR an NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of darbepoetin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness including but not limited to the following:
For members with contracts without primary coverage criteria, darbepoetin for any indication not listed above as covered, including but not limited to treatment of anemia associated with Hepatitis C therapy or myelodysplastic syndrome, is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
EPOETIN ALFA (e.g., Procrit and Epogen)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Coverage for epoetin alfa requires more than meeting specific diagnosis requirements. These additional coverage criteria are listed below under “limitations”.
Epoetin alfa meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered for the following diagnoses based on specific coverage guidelines:
Limitations:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
This policy does not address use of epoetin use for pre-surgical individuals with hemoglobin between 10 g/dL and 13 g/dL who are scheduled to undergo major orthopedic hip or knee surgery.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Epoetin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness including but not limited to the following:
For members with contracts without primary coverage criteria, Epoetin is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Epoetin Alfa-EPBX (e.g., Retacrit)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Coverage for epoetin alfa-epbx requires more than meeting specific diagnosis requirements. These additional coverage criteria are listed below under "Limitations".
Epoetin alfa-epbx meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is covered only for the following conditions:
Treatment of anemia due to:
Limitations:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
RETACRIT does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is not covered for the following uses:
For members with contracts without primary coverage criteria, RETACRIT is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA (e.g., Mircera)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of pegylated (PEG)-epoetin beta meets member benefit certificate primary coverage criteria for effectiveness and is covered for the following diagnoses based on specific coverage guidelines:
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR an NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
PEG-epoetin beta does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of any indication or any circumstance other than those outlined above.
For members with contracts without primary coverage criteria, PEG-epoetin beta is considered investigational for the treatment of any indication or any circumstance other than those outlined above.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
PEGINESATIDE
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of peginesatide does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness based on manufacturer recall due to reports of serious hypersensitivity reactions, including anaphylaxis.
For members with contracts without primary coverage criteria, peginesatide is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to January 1 2022 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com.
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| Rationale: |
ESAs in Chronic Renal Failure
At initial approval of epoetin in 1989, the primary objective of treatment was to raise Hb concentration sufficiently to avoid transfusion, with a target range of 9–10 g/dL in anemic patients with chronic kidney disease (CKD). The first National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines in 1997 recommended an Hb concentration of 11 g/dL, a level that was increased by the second NKF-KDOQI anemia guidelines to 11–13 g/dL. (NKF, 2007). With increased experience in the use of ESAs, it became unclear whether higher Hb target concentrations, including normalization, would yield additional benefits, in particular in physical function and improved cardiovascular outcomes. Clinical doubts increased with publication of the first large randomized controlled trial (RCT) of Hb normalization in hemodialysis (HD) patients (Normal Hematocrit Cardiac Trial [NHCT]), that showed a trend toward increased mortality risk and significantly increased risk for vascular access thrombosis with ESA treatment to a hematocrit (HSCT) target of 42% (Besarab, 1998). Subsequently, 4 published RCTs in HD patients with end-stage renal disease (ESRD) and 8 in nondialysis patients with CKD found improved physical function at higher Hb targets, but none demonstrated significant improvements in cardiovascular endpoints or mortality (Fishbane, 2007).
The Epogen/Procrit label was modified in 1996 to include the results of the NHCT study that showed a higher mortality rate for anemic dialysis patients randomized to a hematocrit (Hct) of 42%, compared to a Hct of 30%. Ten years later, the CHOIR study reported worse cardiovascular outcomes for anemic CRF patients who were not undergoing dialysis and who were randomized to a target Hb of 13.5 g/dL, compared to a Hb of 11.3 g/dL (Singh, 2006). Subsequent analyses of outcomes for patients enrolled in CHOIR showed shorter times to progression of kidney disease and higher rates of renal replacement therapy and death among those randomized to the higher Hb target (Inrig, 2012). The CREATE study, also reported in 2006, was a study similar to CHOIR but enrolled fewer patients (Drueke, 2006). CREATE did not demonstrate statistically significant differences in adverse cardiovascular outcomes for the higher Hb group, but the general trend of the major cardiovascular outcomes was similar to the CHOIR findings. The TREAT study, (Pfeffer, 2009) reported in 2009, randomized 4,038 patients with CKD not on dialysis, type 2 diabetes mellitus, and Hb ≤11 g/dL. Patients in one arm were treated with darbepoetin to a target Hb of 13 g/dL, while those in the other arm received darbepoetin only if Hb fell below 9 g/dL. Risks for 2 endpoints were not significantly different between arms: death or a cardiovascular event (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 0.94 to 1.17; p=0.41) and death or end-stage renal disease (HR: 1.06; 95% CI: 0.95 to 1.19; p=0.29). However, fatal or non-fatal stroke was significantly increased among patients randomized to the higher Hb target (HR: 1.92; 95% CI: 1.38 to 2.68; p<0.001). Multivariate analysis found no statistically significant relationship of increased stroke risk to any baseline characteristic; to effects on blood pressure, hemoglobin (Hb), or platelet count; or to darbepoetin dose (Skali, 2011).
The FDA approved Omontys® (peginesatide) to treat anemia in CKD patients on dialysis in March 2012 based on 2 randomized active-controlled non-inferiority trials. Two trials (EMERALD-1 and EMERALD-2) evaluated the use of peginesatide for the treatment of anemia in patients with chronic kidney disease on hemodialysis (NCT00597753; NCT00597584). Two other trials (PEARL-1 and PEARL-2; total N=656 randomized to peginesatide and N=327 to darbepoetin), were conducted for patients with CKD who were not on dialysis (NCT00598273; NCT00598442). These trials have results but have not been published.
Conclusions. Three ESAs are FDA-approved for use in patients with chronic renal disease: epoetin alfa, darbepoetin alfa, and peginesatide. Placebo-controlled clinical trials have established that epoetin alfa and darbepoetin alfa effectively increase hemoglobin concentrations and decrease the need for blood transfusions. The evidence does not support an improvement in other clinical outcomes such as mortality, morbidity, functional status, or quality of life. Some trials have reported higher cardiovascular events and/or increased mortality in patients treated with ESAs. These trials have generally treated to a hemoglobin of 12g/dL or higher. The optimal target hemoglobin is unclear, and it is not certain whether treating to lower hemoglobin levels avoids the increase in adverse events.
ESAs in Oncology
In 1993, FDA approved Procrit/Epogen to treat anemia in patients receiving cancer chemotherapy based on data from 2 multicenter randomized, placebo-controlled, double-blind, clinical trials; one with 344 adult patients and the second with 222 pediatric patients, plus an additional pooled analysis of 6 smaller double-blind RCTs with a total of 131 patients. Patients in all 3 studies received at least 12 weeks of concurrent chemotherapy and were randomized (1:1) to receive Procrit/Epogen or placebo subcutaneously for 12 weeks. Overall, the data showed a reduction in the proportion of patients requiring blood transfusion during the second and third months of epoetin treatment.
The approval of Aranesp for the treatment of anemia associated with cancer chemotherapy was based on demonstration of a significant reduction in the proportion of patients transfused during chemotherapy from week 5 through the end of treatment. Study 980297, a Phase 3, double-blind, placebo-controlled, randomized (1:1) multicenter, multinational study of darbepoetin alfa enrolled 314 anemic patients with previously untreated non-small cell or small cell lung cancer receiving at least 12 weeks of platinum-containing chemotherapy.
Since the first approval of an erythropoiesis-stimulating agent (ESA) for treatment of chemotherapy-associated anemia in 1993, additional data became available regarding the increased risks of mortality and of possible tumor promotion from the use of ESAs. Increased mortality has been observed in patients with cancer (BEST, ENHANCE, 20000161, and EPO-CAN-20 studies) when ESA treatment strategies were designed to achieve and maintain Hb levels above 12 g/dL (Rizzo, 2010). In addition, ESA treatment strategies intended to achieve and maintain Hb levels above 12 g/dL have demonstrated poorer tumor outcomes (BEST, ENHANCE, and DAHANCA studies). More recently, a meta-analysis using individual patient data on 13,933 subjects from 53 RCTs (Bohlius, 2009; Bohlius, 2009) reported significantly greater on-study mortality (HR: 1.17; 95% CI: 1.06 to 1.30) and poorer survival to end of follow-up (HR: 1.06; 95% CI: 1.00 to 1.12), with little heterogeneity between trials. Results were qualitatively similar when the analysis was limited to 10,441 patients receiving concurrent chemotherapy from 38 trials, and there was little evidence for a difference between trials of patients receiving different chemotherapy regimens.
Data from multiple trials, consistent with data presented to ODAC in May 2004, led to revised product labeling with broader and more detailed warnings against ESA treatment strategies targeting Hb levels above 12 g/dL. More recent data, including the individual patient data meta-analysis summarized above, ((Bohlius, 2009; Bohlius, 2009) suggested that factors such as the planned Hb ceiling for stopping ESA therapy had little influence on increased mortality resulting from ESA treatment. While the risks of Hb targets greater than needed to avoid transfusions are now well-established, data from adequate, well-controlled studies employing the recommended ESA doses and Hb targets are as yet insufficient to assess effects on survival or tumor promotion. The only data provided to the FDA which used the recommended dose and Hb target was from Amgen Study 20010103, which demonstrated significantly shorter survival in cancer patients receiving ESAs compared to those supported by transfusion alone. However, this study was not adequately designed to assess effects on tumor promotion or on thrombotic risks.
Despite these caveats, data from available studies were sufficient for the FDA to reassess the safety of ESAs in patients with cancer and to re-evaluate the net clinical benefit of ESAs in this setting.
Conclusions. Epoetin alfa and darbepoetin alfa are approved for patients with anemia associated with concurrent cancer chemotherapy. These ESAs effectively increase hemoglobin concentrations and decrease the need for blood transfusions in patients with anemia caused by cancer chemotherapy. The evidence does not support an improvement in other clinical outcomes such as mortality, morbidity, functional status, or quality of life. Some trials have reported higher thromboembolic events and/or mortality in cancer patients treated with ESAs. While the trials that reported increased adverse events have generally treated to a hemoglobin of 12g/dL or higher, it is not clear whether treating to a lower hemoglobin reduces these adverse events. These concerns over potential harm from ESAs have led the FDA to reassess the risk/benefit ratio and to modify the labeled indications. Current FDA labeling recommends against starting ESA therapy in a cancer patient whose hemoglobin is >10 g/dL.
ESAs for treatment of hepatitis C-related anemia
Standard treatment for hepatitis C infection includes peginterferon and ribavirin. Anemia related to ribavirin use is often the limiting step in treatment. Options for treatment of ribavirin-related anemia are reduction in the dose of ribavirin, use of ESAs, and/or blood transfusions as needed. However, a reduction in ribavirin dose has been associated with less favorable response rates, and some experts therefore prefer using ESAs to maintain full-dose ribavirin. The evidence on the benefit of using ESAs for this purpose consists of a number of RCTs, several of which are reviewed below.
At least 2 RCTs have randomized patients with hepatitis C and ribavirin-related anemia to epoetin alfa or usual care. The larger of these was performed by Afdahl et al. (Afdahl, 2004) This trial included 185 patients with a hemoglobin level <12g/dL, and treated with 8 weeks of epoetin alfa at a dose of 40,000 units per week. Outcomes included the percent of patients who were able to maintain full-dose treatment with ribavirin, the mean Hgb level, and QOL as measured by the SF-36 short form instrument. The percent of patients who were able to maintain full dose ribavirin was higher in the Epo group (88%) compared to usual care (60%, p<0.001). The increase in the mean hemoglobin level was also higher for the Epo group (2.2g/dl) compared to usual care (0.1g/dl, p<0.001). The improvement in QOL was significantly greater for the Epo group on 7 of 8 domains, with the incremental improvement ranging from 1.3 to 10.0 for patients on Epo.
A second RCT by Dieterich et al. was similar to the Afdahl study (Dieterich, 2003). This study enrolled 64 patients with hepatitis C and ribavirin related anemia, as defined by a hemoglobin (Hgb) level less than 12g/dL. Patients were followed for 16 weeks and treatment with epoetin alfa was at 40,000 units/wk. The primary endpoints were the ribavirin dosage and the increase in Hgb level. The mean ribavirin dose decreased less in the epoetin group (-34mg/day) compared to usual care (-146 mg/day), but this difference was not quite statistically significant (p=0.06). A greater percent of patients in the Epo group (83%) were able to maintain full dose ribavirin compared to usual care (54%, p=0.02). The mean Hgb level was higher in the Epo group (13.8 g/dL) compared to usual care (11.4 g/dL, p<0.0001).
A third RCT by Shiffman et al. evaluated use of ESAs for hepatitis C in all patients treated with ribavirin (Shiffman, 2007). This study randomized 150 patients to 3 groups at the onset of treatment: 1) ribavirin at standard dose, 2) ribavirin at standard dose + epoetin alfa, and 3) ribavirin at higher dose + epoetin alfa. The primary endpoints were reduction in ribavirin dose and the percent of patients with a sustained viral response (SVR). A lower number of patients treated with Epo required dose reduction (10%) compared to patients not treated with Epo (40%, p<0.05), but the percent of patients with SVR did not differ between groups.
Conclusions. RCTs of ESAs versus placebo for patients with hepatitis C and ribavirin-related anemia have demonstrated that use of ESAs can improve Hgb levels and allow more patients to maintain treatment at full dosages. One RCT also reported improvement in quality of life (QOL) for patients treated with ESAs. Improvements in these parameters may lead to health outcome benefits, although no study has reported an improvement in clinical outcomes such as SVR or survival.
Postapproval FDA Regulatory Actions
In November 2006, FDA issued a Public Health Advisory regarding the serious cardiovascular risks from ESA therapy in patients with CKD evidenced in the CHOIR study and the NHCT study (FDA, 2007). Subsequently, the FDA received reports of increased risks associated with ESAs used in the treatment of chemotherapy-induced anemia among cancer patients, the use of ESAs among cancer patients not receiving chemotherapy, as well as a report of thrombotic risks among patients receiving an ESA in the perisurgical setting. These data prompted reassessment of the safety information contained in the Aranesp, Epogen, and Procrit labels and culminated in the approval of revised labels on March 9, 2007. The labels have been revised and updated subsequently, most recently in July, 2012 (FDA, 2012).
With respect to dosage information, periodic reassessments of ESA safety have determined that clinical data do not support a therapeutic Hb target free of risk for mortality. Consequently, the dosage and administration sections of the label revisions deleted references to any specific therapeutic Hb or Hct "target" range for ESAs. Instead, the label revisions recommended that prescribers use the lowest ESA dose that will gradually increase the Hb concentration to the lowest level sufficient to avoid the need for red blood cell transfusion. This recommendation was based, with respect to the use of ESAs among anemic CRF patients, predominantly upon the NHCT and CHOIR study findings, as well as the lack of data to support the safety of any specific Hb or Hct level or range. Clinical data were not available to identify specific Hb or Hct levels that directly correlated with a "reduction in the need for red blood cell transfusion," the main treatment benefit supporting ESA efficacy. The March 2007 label revision allowed prescribers to use their clinical judgment in determining the "lowest level sufficient to avoid the need for red blood cell transfusion."
On November 8, 2007, FDA revised the product labeling for epoetin alfa and darbepoetin alfa (FDA, 2007). These revisions clarified the evidence for safety and effectiveness and provided more explicit directions and recommendations to prescribers for their use. They were consistent with recommendations made at the May 10, 2007, ODAC and the September 11, 2007 meeting of the CRDAC and the DSRMAC. The revised product labeling included strengthened Boxed Warning and Warnings sections, changes to the Indications and Usage, Clinical Experience, and Dosage and Administration sections of the labeling for the 3 ESAs then available. The product labeling has been revised 10 times since then for each of these 3 ESAs. The revised Black-Box Warnings and Limitations of Use for the 3 ESAs (Aranesp, Epogen, and Procrit) shown below reflect current labeling.
Cancer
Chronic Renal Failure
Perisurgery
Limitations of Use
Epogen has not been shown to improve quality of life, fatigue, or patient well-being (for any indication).
Epogen is not indicated for use:
Patient Counseling Information
As part of the Risk Evaluation and Mitigation Strategy (REMS) approved by FDA for these 3 ESAs, patient medication guides to better communicate the risks and benefits of ESA use to patients have been developed. Although the ESA REMS and medication guides were initially developed for patients with cancer who were starting ESA therapy, the current program requires prescribers to share the medication guide and discuss information on potential harms and benefits with all patients who will receive an ESA, regardless of indication. Key points for discussion include the following:
All patients should be instructed by a healthcare provider or receive medical help right away if they have any of these symptoms of blood clots:
In addition, patients with cancer who will be treated with an ESA should be informed that their healthcare provider has received special training through the ESA APPRISE Oncology Program in order to prescribe Epogen. Before they can begin to receive an ESA, they must sign the patient-healthcare provider acknowledgment form. When they sign this form, they are stating that the healthcare provider talked with them about the risks of taking an ESA. These risks include that their tumor may grow faster and they may die sooner if they choose to take an ESA. They should also talk with their healthcare provider about:
Summary
This policy is based on the available clinical trial evidence, as well as on recommendations for use from the FDA and from specialty societies. Erythropoiesis-stimulating agents (ESAs) have been used extensively in patients with anemia due to cancer chemotherapy or renal failure. Initial trials of epoetin alfa and darbepoetin alfa established that these agents effectively increase hemoglobin concentrations and decrease the need for blood transfusions. However, some clinical trials have also reported increases in cardiovascular or thromboembolic events and/or mortality for patients treated with ESAs. These concerns over potential harm from ESAs have led the FDA to re-assess the risk/benefit ratio and to modify the labeled indications. Modifications to the labeled indications include treating to a lower target hemoglobin and limiting its use in cancer to patients receiving myelosuppressive treatment with palliative intent whose hemoglobin concentration is <10 g/dL. These additional recommendations have led to more limitations on ESA use and enhanced surveillance systems that are intended to closely monitor and mitigate the risk of adverse events.
February 2013 Update
The coverage statement has been changed in response to a recent manufacturer recall of OMONTYS® (peginesatide) Injection due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis..
2014 Update
A literature search conducted through July 2014 revealed new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2014 Cochrane review included 8 trials (total N=2051) that compared darbepoetin with epoetin (alfa or beta) in adults with anemia due to CKD (Palmer, 2014). No statistically significant differences were observed in random effects meta-analyses of final Hb or mean change in Hb level, overall mortality, cardiovascular events or cardiovascular mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis. Risk of bias was rated as moderate to high, and statistical heterogeneity was minimal (I2=0%) for all outcomes.
Pegylated Epoetin Beta
FDA’s 2007 approval of PEG-epoetin beta (Mircera®) was based on 6 Phase 3, international, open-label, RCTs in patients with anemia due to CKD (Hoffmann-La, 2007). In 2 trials (total N=505), patients were not receiving ESA therapy (correction trials), and in 6 trials (total N=1894), Hb was stable on maintenance ESA therapy (maintenance trials). All but1 trial (ARCTOS) enrolled dialysis-dependent patients. The primary efficacy outcome in all trials was maintenance of Hb levels over 24-52 weeks, adjusted for baseline Hb and center, in the intent-to-treat and per protocol patient samples. For this outcome, the trials demonstrated non-inferiority of PEG-epoetin beta once or twice monthly to epoetin (alfa or beta) 1-3 times weekly (AMICUS, MAXIMA, PROTOS, and RUBRA) and to darbepoetin weekly or twice monthly (ARCTOS and STRIATA). In the correction trials (ARCTOS and AMICUS), median time to response was longer in the PEG-epoetin beta groups (43 days and 57 days, respectively) compared with the darbepoetin (29 days) and epoetin (31 days) groups (Macdougall, 2008; Klinger, 2007; Levin, 2007; Sulowicz, 2007; Canaud, 2008; Spinowitz, 2008).
Although target Hb ranges in these trials included levels that have since been associated with increased mortality in CKD (ie, >11 g/dL) (Walker, 2007). FDA’s summary review of safety (based on 1789 PEG-epoetin betatreated patients [64% for >1 year] and 948 ESA-treated patients) reported that mortality was similar between the 2 groups (10% vs 11%, respectively) (FDA, 2014). Incidence of serious adverse events also was similar between groups (37% vs 40%, respectively), although serious bleeding events (5.2% vs 4%), serious gastrointestinal bleeding events (1.2% vs 0.2%), and thrombocytopenia less than 100 x 109 platelets/L (7.5% vs 4.4%) occurred more commonly in PEG-epoetin beta-treated patients. FDA reviewers attributed these imbalances to the greater proportion of patients on hemodialysis in the PEG-epoetin beta group (84% vs 80%), and considered the risks of hemorrhage and thrombocytopenia similar to or slightly increased above that for other ESAs. Trials excluded patients with poorly controlled hypertension; 27% of enrolled patients required increases in antihypertensive therapy (Hoffmann-La, 2007).
A 2014 Cochrane review included random effects meta-analyses of 5 trials in dialysis patients, (Macdougall, 2008; Klinger, 2007; Levin, 2007; Sulowicz, 2007; Canaud, 2008; Spinowitz, 2008), and reported no statistical between-group differences in final Hb level (compared with epoetin), overall mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis (Hahn, 2014). In the STRIATA trial, final Hb level was statistically higher in the PEG-epoetin group compared with the darbepoetin group (mean difference, 0.30 g/dL [95% CI, 0.05 to 0.55]). Risk of bias was rated as low to moderate, and statistical heterogeneity was low to moderate (I2=0%-34%).
Since FDA approval, subsequent short-term trials (24-40 weeks; total N=841) have replicated the findings of the pivotal correction trials in patients on hemodialysis (Oh, 2014) and not on hemodialysis,(Vankar, 2014; Roger, 2011) and of the pivotal maintenance trials in patients on hemodialysis (Al-Ali, 2014; Hirai, 2013). Of 324 non-dialysis patients in the ARCTOS correction trial, 296 (96%) entered a 24-week extension study (Kessler, 2010). Patients who responded to PEG-epoetin beta biweekly (n=145) were re-randomized 1:1 to biweekly or monthly dosing to maintain Hb between 11-13 g/dL. Mean SD) Hb levels were 11.9 (0.9) g/dL, 11.7 (0.9) g/dL, and 11.9 (1.0) g/dL in the PEG-epoetin biweekly, PEG-epoetin monthly, and darbepoetin (weekly or biweekly) groups (n=151), respectively. Within-patient variation in Hb levels was similar across groups.
Peginesatide
PEG-epoetin beta has shown non-inferiority to epoetin and darbepoetin for correcting or maintaining Hb levels in randomized controlled trials of patients on dialysis or not on dialysis. In meta-analyses of trials in dialysis patients, no statistical differences were reported in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. PEG -epoetin beta currently is unavailable in the U.S.
Pegylated Epoetin Beta
PEG-epoetin beta is not FDA-approved for anemia due to cancer chemotherapy,(Hoffmann-La, 2007) and Hoffmann-LaRoche, manufacturer of PEG-epoetin beta, has not sought this indication (FDA, 2014). A 2010 Phase 2, openlabel RCT by Gascon et al compared 3 doses of subcutaneous PEG-epoetin beta with subcutaneous darbepoetin in 153 patients who were receiving first-line chemotherapy for stage 3B or 4 nonsmall cell lung cancer (Gascon, 2010). Baseline Hb at screening was 11 g/dL or less. PEG-epoetin beta was administered every 3 weeks, and darbepoetin was administered weekly or every 3 weeks. The primary efficacy outcome, mean change from baseline Hb during weeks 5-13, did not differ between groups and indicated inadequate treatment responses in all groups (0.17 g/dL and 0.26 g/dL in the PEG-epoetin beta and darbepoetin groups, respectively). At week 12, the trial was terminated due to more deaths in the 3 PEG-epoetin beta groups compared with the darbepoetin group (29 [25%] of 114 patients vs 4 [10%] of 39 patients, respectively). Post-hoc analyses did not convincingly demonstrate that baseline imbalances accounted for the mortality difference.
PEG-epoetin beta is not FDA-approved for patients with anemia due to cancer chemotherapy. A Phase 2 RCT demonstrated increased mortality among patients with advanced nonsmall cell lung cancer who received PEG-epoetin beta compared with those who received darbepoetin. Pegylated (PEG)-epoetin beta is a long-acting epoetin that is FDA-approved for patients with anemia due to CRF. Evidence for this indication comprises randomized controlled trials in patients on dialysis or not on dialysis that showed non-inferiority to standard ESAs for correction or maintenance of Hb levels. Metaanalyses in dialysis patients reported no difference in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. Based on this evidence, PEG-epoetin beta may be considered medically necessary for treatment of anemia due to CRF. For treatment of anemia due to cancer chemotherapy, one Phase 2 trial showed increased mortality with PEG-epoetin beta compared with darbepoetin. PEG-epoetin beta is expected to become available in the U.S. soon.
2018 Update
A literature search conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
2019 Update
A literature search conducted through November 2019 did not reveal any new information that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023.
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