Clinical UM Guideline
|Subject:||Recombinant Erythropoietin Products|
|Guideline #:||CG-DRUG-05||Current Effective Date:||07/09/2013|
|Status:||Revised||Last Review Date:||05/09/2013|
Erythropoietin (EPO) is a hormone naturally produced in the body, primarily by the kidneys, which stimulates the bone marrow to produce red blood cells (RBCs). If the body does not produce enough EPO, severe anemia can occur. This often occurs in people whose kidneys are not functioning properly. EPO is used to treat severe anemia in chronic kidney disease or other conditions, such as acquired immune deficiency syndrome (AIDS), cancer, or surgery. This document addresses recombinant, or man-made, erythropoietin products:
*NOTE: On February 23, 2013, the manufacturers of peginesatide along with the U.S. Food & Drug Administration (FDA), notified the public of a voluntary recall of all lots of peginesatide (Omontys) due to post marketing results of serious hypersensitivity reactions, including life-threatening or fatal anaphylaxis.
Epoetin alfa may be considered medically necessary when the criteria below are met:
Epoetin alfa may also be considered medically necessary when the criteria below are met:
Darbepoetin alfa may be considered medically necessary when the criteria below are:
Peginesatide is considered medically necessary when the criteria below are met:
Not Medically Necessary:
Use of epoetin alfa or darbepoetin alfa is considered not medically necessary for all of the following:
Use of peginesatide is considered not medically necessary for all of the following:
The following codes for treatments and procedures applicable to this document are included below for informational purposes. A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
|J0881||Injection, darbepoetin alfa, 1 microgram (non-ESRD use) [Aranesp]|
|J0882||Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis) [Aranesp]|
|J0885||Injection, epoetin alfa (for non-ESRD use), 1000 units [Epogen, Procrit]|
|J0886||Injection, epoetin alfa, 1000 units (for ESRD on dialysis) [Epogen, Procrit]|
|J0890||Injection, peginesatide, 0.1 mg (for ESRD on dialysis) [Omontys]|
|Q4081||Injection, epoetin alfa, 100 units (for ESRD on dialysis) [Epogen, Procrit]|
|S9537||Home therapy; hematopoietic hormone injection therapy (e.g., erythropoietin, G-CSF, GM-CSF), per diem [when specified as erythropoietin]|
|EA||Erythropoetic stimulating agent (ESA) administered to treat anemia due to anti-cancer chemotherapy|
|EB||Erythropoetic stimulating agent (ESA) administered to treat anemia due to anti-cancer radiotherapy|
|EC||Erythropoetic stimulating agent (ESA) administered to treat anemia not due to anti-cancer radiotherapy or anti-cancer chemotherapy|
|ICD-10 Diagnosis||ICD-10-CM draft codes; effective 10/01/2014:|
Anemia is a condition that occurs when the number of RBCs is below the normal level. Oxygen is carried throughout the body by RBCs. Tissue hypoxia, the lack of adequate oxygenation to the tissues, usually triggers erythropoietin, an endogenous hormone normally produced primarily by the kidneys, to stimulate the bone marrow and increase production of RBCs, also called erythropoiesis. Treatment of anemia includes correcting the underlying causes of anemia, blood transfusions or administering recombinant erythropoietin products, also called erythropoietin stimulating agents (ESAs). An adequate diagnostic workup to identify treatable causes of anemia should be performed prior to treatment of anemia.
Early studies of erythropoietin products utilized hematocrit as an objective measure. However, many studies have converted to hemoglobin as a measurable objective instead of hematocrit in clinical trials. Response to ESA therapy may be assessed by the rise in hemoglobin or hematocrit, or the abatement of further decline. Individual characteristics and diagnosis should be considered when determining whether a response to therapy has occurred. When response has not occurred, discontinuation of therapy should be considered.
Darbepoetin Alfa and Epoetin Alfa
The FDA approved epoetin alfa for the treatment of anemia in chronic kidney disease and in individuals with non-myeloid malignancies where the anemia is due to the effect of concomitantly administered myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Epoetin alfa is also FDA approved for treatment of anemia in zidovudine-treated HIV-infected individuals, and to reduce allogeneic blood transfusions in noncardiac, nonvascular surgical cases that are at high risk for perioperative transfusions with significant, anticipated blood loss (Product Information Labels, 2012).
In 2002, the FDA approved darbepoetin alfa, another ESA for the treatment of anemia in chronic kidney disease and in individuals with non-myeloid malignancies where the anemia is due to the effect of concomitantly administered chemotherapy. Darbepoetin alfa is closely related to erythropoietin and is produced by recombinant DNA technology and Chinese hamster ovary (CHO) cells. Darbepoetin alfa is composed of a 165-amino acid protein containing 5 N-linked oligosaccharide chains compared to the 3 chains in the recombinant ESAs. Because darbepoetin alfa is long acting, less frequent dosing is required (weekly or biweekly for individuals on dialysis). Glaspy and colleagues (2001) performed randomized trials to confirm the data from dose-finding studies, which suggest darbepoetin alfa can be administered effectively as infrequently as once per chemotherapy cycle (weekly or once every three weeks). Comparative studies were performed to evaluate darbepoetin alfa in individuals with cancer (Glaspy, 2001; Hedenus, 2002; Kotasek, 2000, 2001, 2003; Pirker, 2001).
The safety and efficacy of both darbepoetin and epoetin alfa are similar in anemia of chronic kidney disease or chemotherapy-induced anemia (Allon, 2002; Herrington, 2005). There are no reported trials comparing the two formulations of epoetin (Product Information Labels, 2012). There is no data to make a recommendation regarding the use of the epoetin alfa products over darbepoetin alfa for the treatment of the anemia of chronic renal failure and the treatment in individuals with non-myeloid malignancies with chemotherapy induced anemia.
Initial studies explored the use of erythropoietin in a variety of settings, testing various dosing and scheduling regimens. These trials typically were small in size and used a variety of regimens and schedules. Some failed to demonstratesignificant benefit, perhaps because of the populations enrolled, the study design, or the limitations of the agent as a therapy. While there is evidence to support the use of ESAs to treat anemia related to chronic kidney disease and anemia in individuals with non-myeloid cancer receiving chemotherapy, studies have reported adverse outcomes in unlabeled indications which resulted in warnings from the FDA in March and November 2007.
In August 2008, the Product Information Labels for ESAs were updated, as the FDA invoked authority to address the risk of increased mortality and poorer tumor outcomes when ESAs are given to individuals receiving treatment for head and neck cancer, breast cancer, non-small cell lung cancer, or cervical cancer, and in anemic individuals not receiving chemotherapy for cancer. Data from multiple trials demonstrated ESA use decreased locoregional control or progression-free survival and overall survival. The use of the lowest dose of epoetin alfa or darbepoetin alfa to achieve and maintain the lowest hemoglobin concentration to avoid the need for red blood cell (RBC) transfusion was recommended.
A Cochrane Review (Bohlius, 2009) included analysis of 53 ESA trials with a total of 13, 933 individuals with cancer. There were 1,530 deaths on-study, and 4,993 overall. The authors concluded ESAs "increased on-study mortality and worsened overall survival."
The FDA announced in February 2010, a requirement that "All ESAs are to be prescribed and used under a risk management program, known as a risk evaluation and mitigation strategy (REMS), to ensure the safe use of these drugs." The action was taken as studies had shown "ESAs can increase the risk of tumor growth and shorten survival in patients with cancer who use these products. Studies also show ESAs can increase the risk of heart attack, heart failure, stroke or blood clots in patients who use these drugs for other conditions" (FDA, 2010). The drug manufacturer, Amgen, developed an ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology program for healthcare professionals who prescribe ESAs to individuals with cancer. Currently, providers who prescribe ESA for oncologic indications must enroll in the ESA APRISE program and receive training.
In June 2011, the Product Information Labels for the ESAs were updated in collaboration with the FDA. Data from controlled clinical trials of individuals with CKD included increased risks for death, serious adverse cardiovascular reactions and stroke when hemoglobin targets of 11g/dL or greater were utilized. The trial data did not identify a hemoglobin target level, ESA dose, or dosing strategy that did not increase risk. Additional label recommendations for ESA use in individuals with CKD not on dialysis include "the rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal." Additional recommendations for individuals with CKD from the Product Information Labels include (2012) "Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events. Individualize dosing and use the lowest dose of ESA sufficient to reduce the need for RBC transfusion."
In the presence of adequate iron stores, the time to reach the target hematocrit is a function of the baseline hematocrit and the rate of hematocrit rise. The rate of increase in hematocrit is dependent upon the dose of ESA administered and individual variation. To ensure effective erythropoiesis, adequate iron stores must be continually maintained. Functional iron deficiency, with normal ferritin levels, but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. The product labels note the iron status, including transferrin saturation and serum ferritin should be evaluated prior to initiation and during ESA therapy. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL. "Majority of patients with CKD will require supplemental iron during the course of ESA therapy" to adequately support erythropoiesis (Product Information Labels, 2012).
In March 2012, the FDA approved peginesatide (Omontys®), the first new ESA administered in a once per month intravenous (IV) or subcutaneous (subq) injection for the treatment of anemia in chronic kidney disease in adults on dialysis. Peginesatide binds to and activates the human erythropoietin receptor and stimulates erythropoiesis in human red cell precursors, resulting in increases in the reticulocyte count, followed by increases in hemoglobin. The rate of hemoglobin increase varies among individuals and is dose dependent. Peginesatide is not indicated and is not recommended for the following use (Product Information Label, 2012):
The safety and efficacy of peginesatide was demonstrated in individuals with chronic kidney disease on dialysis in two randomized, active-controlled, open-label, multi-center clinical trials that evaluated the maintenance of hemoglobin concentrations in participants who were being treated with another ESA (epoetin alfa or epoetin beta) at the time of study entry. The pivotal trial results are currently unpublished in the peer-reviewed medical literature. According to the Product Information Label for peginesatide (2012), the trials randomly selected a total of 1,608 participants with hemoglobin levels initially stabilized by ESA to receive either peginesatide once monthly or to continue their current ESA (epoetin) treatment. Results showed peginesatide was as safe and effective as epoetin in maintaining hemoglobin levels within the studies' pre-specified range of 10 to 12 g/dL. In both studies, the proportion of participants receiving transfusions was similar in each treatment group. Both studies had a pre-specified, prospective, pooled analysis of a composite cardiovascular safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia. In participants receiving peginesatide, 22.8% experienced one of these events compared to 24.4% receiving epoetin (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.77, 1.17). The most common side effects observed in 10% or more of participants on dialysis and treated with peginesatide were diarrhea, vomiting, hypertension and joint, back, leg or arm arthralgias.
Peginesatide is provided under a REMS program to manage known or potential serious risks associated with treatment of individuals with CKD who are on dialysis to ensure that the benefits of peginesatide outweigh its risks. Individuals with CKD who were not on dialysis experienced increased cardiovascular events.
However, on February 23, 2013, the manufacturers of peginesatide, along with the FDA, notified the public of a voluntary recall of all lots of peginesatide (Omontys®) due to post marketing results of serious hypersensitivity reactions, including life-threatening or fatal anaphylaxis. To date, the rate of fatal reaction following the initial dose of IV peginesatide have been reported in 0.02% of individuals. The overall hypersensitivity rate of reactions reported is approximately 0.2% with a third "Of these being serious in nature including anaphylaxis requiring prompt medical intervention and in some cases hospitalization. Dialysis organizations are instructed to discontinue use."
Chronic Kidney Disease
In 2006, the Correction of Hemoglobin and Outcomes in Renal insufficiency (CHOIR) trial published the results of an open label, randomized trial of 1432 individuals with chronic kidney disease. Seven hundred fifteen individuals were assigned to achieve a hemoglobin level of 13.5 g/dL and 717 individuals were assigned to achieve a level of 11.3 g/dL. Two hundred twenty-two composite events were recorded with 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (CHF) (45.5%), 25 myocardial infarctions (MI) (11.3%) and 23 strokes (10.4%). Seven individuals (3.2%) were hospitalized for CHF and had an MI on the same day. One participant (0.5%) died after having a stroke. Hospitalization for CHF and death accounted for 74.8% of the events. The study was terminated early in May 2005 at the second interim analysis due to the results and other factors. The conclusion to this clinical trial was the use of 13.5 g/dL as a hemoglobin target as compared to 11.3 g/dL, was associated with increased risk and no improvement in the quality of life (Singh, 2006).
Drüeke and colleagues published the results of the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) in 2006. Six hundred and three individuals with stage 3 or 4 chronic kidney disease were randomly assigned to different cohorts and observed for approximately 3 years. Individuals in cohort 1 were immediately treated with epoetin beta until a target hemoglobin level of 13-15.0 g/dL was achieved. Participants in cohort 2 initiated epoetin beta when the hemoglobin level fell below 10.5 g/dL and to maintain a hemoglobin level of 10.5 -11.5 g/dL. The complete correction of anemia did not reduce the risk of cardiovascular events in either cohort. However, there was a higher prevalence of headaches and vascular disorders related to hypertensive episodes in cohort 1 (Drüeke, 2006).
Pfeffer (2009) reported results from the randomized, double-blind, Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT). The international, multi-center trial enrolled individuals with type 2 diabetes, chronic kidney disease and a hemoglobin level less than or equal to 11 g/dL. Of the evaluable 4038 individuals enrolled, 2012 were randomized to the darbepoetin alfa treatment group and 2026 were randomized to the placebo group. The study was completed in March 2009 with a median follow-up of 29.1 months. The overall median baseline hemoglobin was 10.4 g/dL. The median achieved hemoglobin was significant at 12.5 g/dL in the treatment group compared to 10.6 g/dL hemoglobin in the control group (P<0.001). The composite outcome of death or a nonfatal cardiovascular event was not statistically significant between the groups. However, "Fatal or nonfatal stroke was more likely to occur in the patients assigned to darbepoetin alfa (101 patients [5.0%] vs. 53 patients [2.6%]; hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001) (Pfeffer, 2009)."
In the interim after the TREAT trial, the Anaemia Working Group of European Renal Best Practice (ERBP; Locatelli, 2010) provided suggestions for clinical practice prior to the Kidney Disease Improving Global Outcomes (KDIGO) international guideline update. Although the ERBP maintains "Hb values of 11-12 g/dL should be generally sought in the CKD population without intentionally exceeding 13 g/dL." The ERBP group suggested,
In patients with type 2 diabetes not undergoing dialysis (and probably in diabetics at all CKD stages), more caution is needed when treating anaemia with ESA therapy. In diabetic patients with a history of stroke, a lower target is more sensible (10-12 g/dL), balancing the risk-benefit of treatment and the desired Hb target in the individual patient. It is also of paramount importance to involve the patient in the decision making, and seek their personal views after a discussion about the benefits/risks of treatment.
In the KDIGO Anemia Work Group 2012 guideline update, the recommendation when initiating and maintaining ESA therapy, includes "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, and hypertension)." The Work Group recommends ESAs are not to be used to intentionally increase the hemoglobin above 13 g/dL. The guidelines also suggest for adults with CKD, ESAs not be used to maintain hemoglobin above 11.5 g/dL.
The "Efficacy and safety of peginesatide for the maintenance treatment of anemia in patients with chronic renal failure who were receiving hemodialysis and were previously treated with epoetin study" was comprised of two similarly designed phase III randomized, controlled trials known as EMERALD 1 and EMERALD 2. Participants on hemodialysis were assigned to monthly peginesatide or continued epoetin three times a week to achieve and maintain hemoglobin levels between 10.0 and 12.0 g/dL for 52 weeks or more. Sequential randomization was stratified by mean screening hemoglobin levels ≤ 11.4 g/dL vs. ≥ 11.5 g/dL. The primary efficacy end point was the change from baseline hemoglobin level to the mean level during the evaluation period. The composite safety endpoint included death from any cause, stroke, myocardial infarction or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia. In EMERALD 1, 793 participant data was available for analysis, with 524 participants in the peginesatide group and 269 in the epoetin group. In EMERALD 2, a total of 815 participants were randomized, with 542 participants assigned to peginesatide therapy and 273 to epoetin therapy. The prespecified noninferiority criterion were met with the mean changes from baseline hemoglobin level to the mean level during the evaluation period of -0.24±0.96 g/dL for the peginesatide group and -0.09±0.92 g/dL in the epoetin group in EMERALD 1. The mean change in the EMERALD 2 study for the peginesatide group was -0.07±1.01 g/dL and -0.17±1.00 g/dL for the epoetin group. Adverse events in both EMERALD studies were similar between the peginesatide group and the epoetin group (94.6% vs. 93.0%). Serious adverse events were reported in 53.7% (572 participants) in the peginesatide group and 57.0% (309 participants) in the epoetin group. The authors noted peginesatide was noninferior to epoetin alfa to treat anemia in individuals receiving hemodialysis. Limitations of the study included high dropout rates, open-label design and "soft" endpoint for cardiovascular risk.
The National Kidney Foundation (NKF) Work Group modified the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease in 2007. The NKF recommended hemoglobin target in individuals on dialysis and nondialysis should not be greater than 13 g/dL. However, based on the reported adverse events, the FDA Black Box Warning on the product information labels (2012) state individuals experienced greater risks for death, serious adverse cardiovascular reactions and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL for individuals with CKD on dialysis. The labels also note no trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
Individuals with CRF Not Requiring Dialysis
Four clinical trials were conducted in individuals with CRF not on dialysis involving 181 individuals treated with epoetin for approximately 67 patient-years of experience. These participants responded to epoetin therapy in a manner similar to that observed in individuals on dialysis. Individuals with CRF not on dialysis demonstrated a dose-dependent and sustained increase in hematocrit when epoetin was administered by either an IV or SC route, with similar rates of rise of hematocrit when epoetin was administered by either route. Moreover, epoetin doses of 75 to 150 Units/kg per week have been shown to maintain hematocrits of 36% to 38% for up to 6 months. Based on the reported adverse events, the FDA Black Box Warning on the product information labels (2012) for epoetin and darbepoetin state: "Consider initiating ESA treatment only when the hemoglobin level is less than 10 g/dL. If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of ESA, and use the lowest dose of ESA sufficient to reduce the need for RBC transfusions."
Based on phase II trial results (Macdougall, 2011), two randomized, controlled, open-label studies called PEARL 1 and PEARL 2 "Peginesatide for the correction of anemia in patients with chronic renal failure not on dialysis and not receiving treatment with erythropoiesis-stimulating agents" were conducted. The two industry sponsored, phase III trials were similarly designed, noninferiority trials to evaluate the safety and efficacy of peginesatide. Individuals with two consecutively measured hemoglobin levels between 8.0 and 11.0 g/dL were randomized in a 1:1:1 ratio to subcutaneous peginesatide 0.025 mg/kg or 0.04 mg/kg every 4 weeks, or darbepoetin 0.75µg/kg every 2 weeks. Randomization was stratified by hemoglobin levels at screening (≤ 10.4g/dL or ≥ 10.5 g/dL). The goal was hemoglobin levels to be increased and maintained between 11.0 and 12.0 g/dL. The primary endpoint for efficacy was the mean change in hemoglobin level from baseline to the mean level during the evaluation period. Noninferiority was established if the lower limit of the CI was -1.0/dL or higher. The prospectively planned assessment of cardiovascular risk included endpoints of death, stroke, myocardial infarction, or a serious adverse event of congestive heart failure, unstable angina, or arrhythmia. A total of 490 randomized participants in PEARL 1 and 493 participants in PEARL 2 received one or more doses of study drug and were used in the analysis populations. In PEARL 1, 24.2% of the combined peginesatide treated 326 participants and 23.8% of the 164 darbepoetin treated participants withdrew prematurely from the study. Premature withdrawal rates from PEARL 2 were 24.8% from the 330 peginesatide treated participants and 14.7% of the 163 darbepoetin treated participants. The median duration of follow-up in PEARL 1for the combined peginesatide groups were 81.4 weeks and in the darbepoetin group 82.1 weeks, and in PEARL 2, peginesatide groups were 67.9 weeks and darbepoetin was 79.1 weeks. In PEARL 1, the mean change from baseline hemoglobin level to the mean level during the 12-week evaluation period were: in the lower starting dose peginesatide group 1.39±0.87 g/dL, in the higher starting dose peginesatide group 1.64±0.97 g/dL, and for darbepoetin 1.37±0.86 g/dL. In PEARL 2, the mean changes were: 1.50±0.90 g/dL in the lower starting dose peginesatide group, 1.68±0.96 g/dL in the higher starting dose peginesatide group, and for darbepoetin 1.35±1.00 g/dL. The noninferiority criteria were met. However, peginesatide had higher event rates compared to darbepoetin in death (8.8% vs. 6.7%), unstable angina (2.4% vs. 0.9%) and arrhythmia (5.6% vs. 4.0%). Additionally, higher incidences of back pain (12% vs. 6.7%), acute renal failure (8.5% vs. 4.3%) and anemia rates (3.5% vs. 1.5%) were noted with peginesatide compared to darbepoetin. The authors note "the need for additional data to clarify the benefit-risk profile of peginesatide in this population" (Macdougall, 2013).
In a comparative, multi-center, phase II clinical trial, Macdougall and colleagues (2011) assessed the efficacy and safety of peginesatide in correcting renal-related anemia in a cohort of 139 individuals with nondialysis chronic kidney disease. Participants who had not received treatment with ESAs in the 12 weeks before initiation of the study drug were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (IV or subq), and frequency of administration (every four or two weeks). Across all cohorts, 96% of participants achieved a hemoglobin response. A dose-response relationship was evident for hemoglobin increase. Comparable subq and IV peginesatide doses produced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions >13 g/dl tended to occur more frequently with dosing every two weeks than they did with dosing every four weeks. The range of final median doses in the every four weeks dosing groups was 0.019 to 0.043 mg/kg. Across all cohorts, 20% of participants reported serious adverse events (one participant, a possible drug-related serious event) and 81% reported adverse events (11.5% reported possible drug-related events); these events were consistent with those routinely observed in this population. The authors suggested that peginesatide administered every four weeks can increase and maintain hemoglobin in individuals with nondialysis chronic kidney disease. At this time, the FDA has not approved the use of peginesatide for this indication. Additional long-term data in larger study populations are required to determine the efficacy and safety of peginesatide in these individuals with nondialysis chronic kidney disease.
Efficacy in individuals with anemia due to concomitant chemotherapy was demonstrated based on reduction in the requirement for red blood cell (RBC) transfusions. ESA use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or well being. ESAs are not indicated for use in individuals receiving hormonal agents, biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy. According to the product information, ESAs are not indicated for "patients receiving myelosuppressive therapy when the anticipated outcome is cure, due to the absence of studies that adequately characterize the impact of ESAs on progression-free and overall survival" (Product Information Labels, 2012). Data from clinical trials "suggest that ESAs may promote tumor growth in an off-target manner. For this reason, these agents should not be used when the anticipated outcome is cure (NCCN, 2012)." In addition, the product labels (2012) include warnings of "increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESA."
In 2010, the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) updated the clinical practice guidelines for the use of epoetin and darbepoetin in individuals with cancer. ASCO/ASH consider the recommendations to apply to both epoetin alfa and darbepoetin. In addition the FDA considers the agents to be included in the same pharmacologic drug class. Guideline recommendations remind clinicians to carefully weigh the risks of thromboembolism in individuals for whom epoetin or darbepoetin is prescribed. Randomized clinical trials and systematic reviews demonstrate an increased risk of thromboembolism (Rizzo, 2010) in those treated with either epoetin or darbepoetin. ASCO/ASH recommend epoetin as a treatment option for individuals with chemotherapy associated anemia with a hemoglobin that is decreased to less than 10 g/dL to decrease transfusion. Depending on additional clinical and anemia circumstances, red blood cell (RBC) transfusion is also an option (Rizzo, 2010). Epoetin can be titrated to achieve the lowest concentration or "appropriate hemoglobin level sufficient to avoid transfusion or the increase exceeds 1 g/dL in any 2-week period to avoid excessive ESA exposure (Rizzo, 2010)." They conclude the evidence from clinical trials supports the use of epoetin thrice weekly (150U/kg/tiw) or 40,000 U weekly subcutaneously. With either dosing regimen, ASCO/ASH recommend that dose escalation be considered for those not responding to the initial dose. In the absence of response (e.g., a less than 1 to 2g/dL increase in hemoglobin), continuing beyond the 6-8 week treatment period does not appear to be beneficial (Rizzo, 2007; 2010).
The Agency for Healthcare Research and Quality (AHRQ, 2006) conducted a comparative effectiveness review of epoetin alfa and darbepoetin alfa for managing anemia in individuals undergoing cancer treatment by analyzing seven comparative trials of epoetin alfa versus darbepoetin alfa in addition to analyzing other trials of the individual agents versus control. AHRQ released a study in May 2006 in which it concluded there is no clinically significant difference between epoetin alfa and darbepoetin alfa in hemoglobin response, transfusion reduction, and thromboembolic events. The AHRQ study also found both epoetin alfa and darbepoetin alfa reduce the need for blood transfusions in individuals with chemotherapy-induced anemia compared to individuals managed with transfusion alone (Seidenfeld, 2006). This review is currently in the process of being updated.
The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guideline in Oncology™ (2012) recommends general asymptomatic and symptomatic categories of clinical presentations in addition to hemoglobin levels for consideration of blood transfusions. The guideline recommends transfusions for asymptomatic individuals with cormorbidities or high-risk and individuals who are symptomatic. ESA therapy is recommended for the prevention of transfusion in individuals with symptomatic anemia and does not recommend the use of ESAs beyond the treatment period where cancer-related therapies are provided. NCCN acknowledged the difficulties specifically defining the duration of chemotherapy related anemia. However, NCCN defined a treatment period as following initiation of chemotherapy and continuing 6 weeks after the completion of chemotherapy. If no hemoglobin response is noted at 8 to 9 weeks ESAs should be discontinued and RBC transfusion should be considered (NCCN, 2012).
Hepatitis C Virus (HCV)
The combination of interferon (IFN) and ribavirin (RBV) has shown sustained virological responses (SVR) in individuals with HCV. Side effects of the combination treatment include anemia which can be significant and may result in dose reduction or discontinuation of therapy. The IFN/RBV dose reduction has been associated with a decreased likelihood of early virological response (EVR) and sustained responses. In a randomized trial 185 anemic individuals treated with combination therapy (interferon [IFN] and RBV) for HCV were evaluated in 2 treatment phases (Afdhal, 2004). The first phase was 8-weeks long, double-blind, placebo-controlled comparing epoetin alfa versus placebo. The second phase was 8 weeks long, open-label, and allowed a modified crossover. The primary efficacy of RBV dosing at the end of the first phase was met with 88% of the study cohort treated with epoetin alfa maintained the RBV dosing. The difference was significant as 60% (P < 0.001) of the placebo group maintained the RBV dosing. The investigators reported quality of life (QOL) scores and hemoglobin levels were significantly improved for the epoetin treatment group versus the placebo group.
Dieterich and colleagues (2003) reported results of 64 individuals treated with RBV/IFN randomized to epoetin or standard of care (SOC). At week 16, the mean change for RBV dosing was -34mg/day for the epoetin alfa cohort compared to -146mg/day for the SOC group. At the completion of the 24 week study, 83% of the epoetin-alfa treatment group maintained RBV dosing compared to 54% of the participants receiving SOC. Hemoglobin levels were significantly higher (13.8g/dL) in the treatment group versus 11.4 g/dL in the SOC group (P<0.0001).
In the 2011 American Association for the Study of Liver Diseases practice guideline update of genotype 1 chronic hepatitis C virus infection, it was noted dose reduction of antiviral medications should be the initial response to manage anemia. However, it was noted with longer duration of antiviral therapy, the frequency of anemia is likely to be greater. The potential benefits and risks must be weighed when considering the use of ESAs (Ghany 2011).
Four placebo-controlled studies enrolling 297 individuals with hemoglobin less than 10 g/dL and HIV infection receiving concomitant therapy with zidovudine were included in the FDA approval analysis. In the subgroup of participants with pre-study endogenous serum erythropoietin levels ≤ 500 mUnits/mL, erythropoietin alfa reduced the mean cumulative number of units of blood transfused per participant by approximately 40% as compared to the placebo group. There was a statistically significant reduction (p < 0.003) in RBC transfusion requirements in individuals treated with erythropoietin alfa compared to the placebo-treated cohort whose mean weekly zidovudine dose was ≤ 4200 mg/week. Approximately 17% of the participants in the treatment cohort with endogenous serum erythropoietin levels less than or equal to 500 mUnits/mL achieved a hemoglobin of 12.7 g/dL without administration of RBC transfusions or significant reduction in zidovudine dose. In the subgroup of participants in the treatment group whose pre-study endogenous serum erythropoietin levels were greater than 500 mUnits/mL, when compared to the corresponding placebo-treated participants, the erythropoietin alfa therapy did not reduce RBC transfusion requirements or increase hemoglobin (Product Information Label, 2012).
NCCN (2012) recommends the use of epoetin and darbepoetin for the treatment of anemia in individuals with myelodysplastic syndrome (MDS) who have serum EPO levels ≤ 500 mU/ml, normal cytogenetics and <15% marrow ringed sideroblasts. It was noted higher epoetin doses were required (40,000 – 60,000 units) one to three times a week subcutaneously. Darbepoetin doses were subcutaneous 150 to 300 mcg/kg/week with response rates in low risk individuals ranging from 40% to 60%. Clinical trial data suggested overall response rates from darbepoetin were similar to or higher compared to epoetin alfa.
Other Proposed Uses:
Anemia of Prematurity
A 2006 Cochrane study addressed the early use of erythropoietin for preventing red blood cell transfusions in preterm or low birth weight infants (Ohlsson, 2006). Two thousand seventy-four preterm infants enrolled in 23 studies were reviewed. The authors noted statistically significant heterogeneity in the studies. There were small reductions in the use of red blood cell transfusions, but the reductions were "of limited clinical importance." There was a significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) in the individuals treated with epoetin. A similar trend was noted in non-significant results for ROP of any stage. The authors concluded early administration of epoetin alfa in preterm infants was not recommended.
In another Cochrane review (Aher, 2006), two high quality, randomized, double-blind studies enrolled 262 infants and evaluated early versus late use of erythropoietin for preventing red blood cell transfusions in preterm infants. The authors concluded there was a non-significant reduction in the use of one or more units of blood transfusion or the number of transfused units per infant. There was a significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) in individuals treated with epoetin alfa.
Although the American Hospital Formulary Services® (AHFS®, 2013) note epoetin alfa appears it may be beneficial in the treatment of anemia of prematurity, but "optimal patient selection criteria remain to be more fully elucidated."
AHFS (2013) also notes epoetin alfa has been used in a limited number of individuals with Gaucher's disease, Castleman's disease, anemia of prolonged acute renal failure, and in high dosages for the correction of ineffective hematopoiesis associated with paroxysmal nocturnal hemoglobinuria. However, further investigation is required to determine the safety and effectiveness of ESAs in these conditions.
Reduction of Events by Darbepoetin Alfa in Heart Failure [RED-HF] was an industry sponsored, phase III double-blind, controlled trial that randomized 2278 participants with mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) and systolic heart failure to receive darbepoetin alfa or placebo to achieve a hemoglobin target of 13 g/dL. With a median follow-up of 28 months, the study was terminated on September 1, 2012. The primary composite outcome was death from any cause or hospitalization for worsening heart failure, which occurred in 50.7% (576 participants) of the darbepoetin alfa group and 49.5% (565 participants) in the placebo group (darbepoetin group hazard ratio 1.01; 95% CI, 0.90 to 1.13; P=0.87). Adverse thromboembolic events were reported in 13.5% (153 participants) in the darbepoetin treatment group versus 10.0% (114 participants) in the placebo group (P=0.01). The investigators concluded darbepoetin alfa therapy did not improve clinical outcomes in individuals with systolic heart failure and mild-to-moderate anemia (Swedberg, 2012).
Traumatic Brain Injury
Talving and colleagues (2010) reported on a retrospective matched case control study of individuals who suffered severe traumatic brain injury (sTBI). Eighty-nine individuals with sTBI who received ESA in the surgical intensive care unit were matched 1 to 2 to case controls (178 individuals). The primary outcome was mortality and secondary endpoints included acute respiratory distress syndrome, pneumonia, sepsis, acute renal failure, deep venous thrombosis and pulmonary embolism. Overall mortality was 18% with individuals treated with ESA experiencing significantly lower in-hospital mortality compared to the controls (7.9% compared to 24.2%). There were no statistically significant differences in the secondary endpoints or in the transfusion requirements between the two study groups. However, there was a trend toward "increased complications, in particular renal failure and thromboembolic events noted in the ESA+ cases" (Talving, 2010). The authors concluded these results require validation through large randomized controlled trials.
Warnings and Adverse Events (Product Information Labels, 2012)
Black Box warnings from the FDA Product Information Labels (2012) include the following:
Warnings: ESAs increase the risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access and tumor progression or recurrence.
Chronic Kidney Disease (darbepoetin, epoetin and peginesatide):
Cancer (darbepoetin and epoetin):
Perisurgery (epoetin): Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended.
In two double-blind, placebo-controlled orthopedic studies, increased incidences of DVT were detected in individuals receiving epoetin alfa (11%) versus the placebo group (6%). The increased DVT rates were noted in the individuals with pretreatment hemoglobin greater than 13g/dL (Product Information Labels, 2012).
Epoetin and darbepoetin have been associated with pure red cell aplasia (PRCA) and severe anemia, with or without cytopenias, associated with neutralizing antibodies to erythropoietin. The Product Information Labels for epoetin and darbepoetin warn, in the event of severe anemia and low reticulocyte count, individuals should be evaluated for causative factors which may include assays for binding and neutralizing antibodies. The manufacturers note, if antibody-mediated anemia is confirmed, then all recombinant erythropoietin products should be permanently discontinued as there is a potential for cross-reactivity with other erythropoietin. PRCA has been reported predominantly in individuals with chronic renal failure, but it has also been reported related to treatment for anemia and hepatitis C therapy. No cases of PRCA developed in individuals receiving peginesatide during the clinical trials (Product Information Labels, 2012).
ESAs are contraindicated in individuals with uncontrolled hypertension. ESA therapies may increase the risk of hypertensive encephalopathy, seizures, thrombotic and other serious events. Hypertension associated with rapid increases in hemoglobin (Hgb) has been rarely noted in individuals with cancer treated with ESA, but may occur. Hypertensive encephalopathy and seizures have been observed in individuals with chronic renal failure. Blood pressure should be monitored carefully, and hypertension should be aggressively controlled, particularly in individuals with an underlying history of hypertension or cardiovascular disease. During treatment, the Hgb should be monitored twice a week until it becomes stable. The dose of ESAs should be decreased if the Hgb increase exceeds 1g/dL in any 2-week period or the Hgb exceeds recommended target. Higher risks of cardiovascular events may be associated with higher hemoglobin and/or higher rates of rise in the hemoglobin (Product Information Labels, 2012).
Anemia: A condition of having too few red blood cells. Healthy red blood cells carry oxygen throughout the body. If the blood is low on red blood cells, the body does not get enough oxygen.
Biologic agent:Includes antibodies, interleukins and vaccines; a substance that is made from a living organism or its products and is used in the prevention, diagnosis, or treatment of cancer and other diseases.
Chronic kidney disease: Slow and progressive loss of kidney function over several years, often resulting in permanent kidney failure. May also be called chronic renal failure.
Endogenous: Originating from within the body.
End Stage Renal Disease (ESRD): Persistent decline in renal function as documented by falling creatinine clearance in an individual diagnosed with a renal disease whose natural history is progression to renal impairment requiring treatment to replace the work of the failed kidneys (for example, dialysis or transplant).
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Web Sites for Additional Information|
Erythropoietin Stimulating Agents (ESA)
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Revised||05/09/2013||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Revised||05/08/2013||Hematology/Oncology Subcommittee review. Clarified criterion A and abbreviation in Clinical Indications. Added information regarding FDA recall for peginesatide. Updated Discussion/General Information, References, Websites for Additional Information.|
|01/01/2013||Updated Coding section with 01/01/2013 HCPCS changes; removed Q2047 deleted 12/31/2012.|
|Revised||05/10/2012||MPTAC review. Reformatted Position Statements and clarified hemoglobin levels in criteria. Added medically necessary indication for new FDA approved drug peginesatide. Updated Discussion/General Information, References, Websites for Additional Information, and Index. Updated Coding section with 07/01/2012 HCPCS changes.|
|Revised||08/18/2011||MPTAC review. Updated Clinical Indications for CKD to align with the updated FDA label. Reduced the hgb threshold for continued use. Discussion/General Information, References and Websites.|
|Reviewed||05/18/2011||Hematology/Oncology Subcommittee review. Updated Discussion/General Information, Coding, References and Websites.|
|Reviewed||05/12/2010||Hematology/Oncology Subcommittee review. Replaced "patient" with "individual" in clinical indications and reformatted CRF criteria for epoetin alfa and darbepoetin alfa. Clarified hypertension criteria. Updated Discussion/General Information to include FDA REMS program for oncologic indications. Updated coding, references and websites.|
|Reviewed||05/20/2009||Hematology/Oncology Subcommittee review. Formatting changes and clarification of Position Statements. Removed dosing tables and Place of Service. Updated Discussion/General Information. Updated references and websites.|
|Revised||08/28/2008||MPTAC review. Criteria revised in response to FDA warnings. Added not medically necessary criteria for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Clarified previous not medically necessary statement to include "hormonal agents, biologic products, or radiotherapy" unless receiving concomitant myelosuppressive chemotherapy. Added not medically necessary criteria for unlisted indications and for lack of response in cancer patients treated with chemotherapy. Updated coding section with 10/01/2008 ICD-9 changes.|
|Revised||05/14/2008||Hematology/Oncology Subcommittee review. Removed hematocrit criteria from medically necessary criteria. Updated references and websites.|
|Revised||11/28/2007||Hematology/Oncology Subcommittee review. Criteria revised in response to FDA warnings. Removed "biologic agents" from medical necessity statements. Added medically necessary indications with criteria for treatment of anemia in hepatitis C and chronic inflammatory diseases. Added Web Site section. Updated references and discussions/general information. Updated Coding section to include 01/01/2008 HCPCS changes.|
|Revised||05/16/2007||Hematology/Oncology Subcommittee review. Criteria clarified. Added definition section. Updated references and discussions/general information.|
|Revised||03/16/2007||Hematology/Oncology Subcommittee review. Criteria revised in response to FDA warnings. Updated references and discussion/general information.|
|Revised||03/08/2007||MPTAC review. Medical necessity criteria revised to be congruent with FDA label for Hgb targets. Updated references and discussion/general information section.|
|Reviewed||12/07/2006||MPTAC annual review. Updated references and discussion/general information section. No change to guideline position. Coding updated; removed HCPCS J0880, Q0136, Q0137, Q4054, Q4055 deleted 12/31/05.|
|Revised||03/23/2006||MPTAC review. (Added black box warning).|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
Last Review Date
|WellPoint Health Networks, Inc.|
(Procrit®, Epogen®, Epo)
|Pharmacology Toolkit||Darbepoetin Alfa (Aranesp®)|
(Procrit®, Epogen®, Epo)