FDA-approved label for epoetin alfa (Epogen, Procrit ) 2

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1 Original Issue Date (Created): July 1, 2002 Most Recent Review Date (Revised): March 25, 2014 Effective Date: June 1, 2014 I. POLICY Note: Throughout this policy, unless otherwise stated, the term ESA (erythropoiesisstimulating agents) refers to epoetin alfa (Epogen, Procrit ), and darbepoetin alfa (Aranesp ). The use of an ESA may be considered medically necessary for: treatment of anemia associated with chronic kidney disease 1,2 ; treatment of anemia in cancer patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy 1,2 ; treatment of anemia related to therapy with AZT (zidovudine) in HIV-infected patients 1 ; reduction of allogeneic blood transfusion in surgery patients 1 ; treatment of patients following allogeneic bone marrow transplantation; and treatment of patients with myelodysplastic syndromes to reduce transfusion dependency. treatment of patients with hepatitis C and anemia related to ribavirin treatment. In the medically necessary conditions noted above, the following criteria also apply: The lowest dose of ESAs should be used in order to avoid red blood cell transfusions, ESAs should not be used to raise the Hb level above 12 g/dl, and ESA therapy should not be administered without adequate iron stores. For the medically necessary use in cancer patients, these additional FDA criteria also apply: Epoetin or Darbepoetin therapy should not be initiated at Hb levels 10 g/dl and Epoetin or Darbepoetin treatment should be discontinued following the completion of a myelosuppressive chemotherapy course. 1 FDA-approved label for epoetin alfa (Epogen, Procrit ) 2 FDA-approved label for darbepoetin alfa (Aranesp ) The use of an ESA is considered investigational for: Treatment of patients following high-dose chemotherapy with autologous stem-cell support. Treatment of non-iatrogenic chronic anemia of cancer; Other cancer-associated anemia excepted as noted in the policy section Treatment of orthostatic hypotension Page 1

2 There is insufficient evidence to support a conclusion concerning the health outcomes or benefits associated with these procedures. Policy Guidelines Non-myeloid malignancies include solid tumors and the non-myeloid hematologic malignancies myeloma, lymphoma, and chronic lymphocytic leukemia. ESA treatment is to be administered according to current FDA-approved labeling for each product, using recommended Hb levels for starting, stopping, and dose adjustment. This includes decreasing the dose of ESA as the Hb approaches the target level. Prior to commencing ESA therapy, the patient s iron stores, blood ferritin, and transferrin saturation should be evaluated, adjusted, and maintained within normal physiological limits. ESA therapy should not be administered without adequate iron stores. Blood pressure should be adequately controlled prior to initiation of ESA therapy and closely monitored and controlled during treatment. Patients with myelodysplastic syndromes should be initially limited to a 3-month trial period with ESA. If no response to ESA is observed, ongoing therapy would be futile. ESAs must be prescribed and dispensed in accordance with a Risk Evaluation and Mitigation Strategy (REMS) drafted by the manufacturer and approved by the U.S. Food and Drug Administration (FDA) (available online at: roviders/ucm htm. The REMS for epoetin alfa ( PatientsandProviders/UCM pdf ) and darbepoetin alfa ( PatientsandProviders/UCM pdf ) each include a medication guide, a communication plan, elements to assure safe use, and an implementation system. ESA manufacturers must ensure that all hospitals and healthcare professionals who prescribe and/or dispense ESAs to patients with cancer have enrolled and completed training in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program. The ESA APPRISE program began on March 24, 2010 following the FDA s initial approval of separate but similar REMS for epoetin alfa and darbepoetin alfa on February 16, Both REMS were subsequently modified on June 24, 2011 and then again on May 31, 2012 and March 27, Healthcare providers and hospitals that prescribe and/or dispense an ESA for CKD must provide each patient with a copy of the REMS Medication Guide and ensure they are adequately informed of the risks associated with ESA treatment. However, they are not required to enroll in and complete the ESA APPRISE program. Page 2

3 Cross-reference: MP Off-Label Use of Prescription Drugs and Medical Devices II. PRODUCT VARIATIONS [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below [N] Capital Cares 4 Kids [N] Indemnity [N] PPO [N] SpecialCare [N] HMO [N] POS [Y] SeniorBlue HMO** [Y] FEP PPO* [Y] SeniorBlue PPO** * For Procrit and Epogen - Refer to FEP Medical Policy Manual MP EPOGEN / PROCRIT; for Aranesp refer to MP Aranesp. The FEP Medical Policy manual can be found at: ** Refer to Centers for Medicare and Medicaid (CMS) National Coverage Determination (NCD) Erythropoiesis-Stimulating Agents (ESA s) in Cancer and Related Neoplastic Conditions. Also refer to the Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Chapter 15, section for coverage of ESA s for end-stage renal disease related anemia. III. DESCRIPTION/BACKGROUND Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor that regulates hemoglobin levels in response to changes in the blood oxygen concentration. Erythropoiesisstimulating agents (ESAs) are produced using recombinant DNA technologies and have pharmacologic properties similar to endogenous EPO. The primary clinical use of ESAs is in patients with chronic anemia. Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor synthesized at the cellular level by cells near the renal tubules in response to changes in the blood oxygen concentration. When a patient is anemic, 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 (Hgb) concentrations. Mild anemia is defined as Hgb from 10 g/dl to the lower limit of normal ranges, while moderate anemia is 8-10 g/dl. Severe anemia is defined as Hgb 8 g/dl or below. Page 3

4 Erythropoiesis-stimulating agents (ESAs) are produced using recombinant DNA technologies. They were initially developed as replacement therapy to treat anemia due to endogenous erythropoietin deficiency that commonly occurs in individuals with chronic renal failure (CRF) secondary to CKD. Patients with CRF will become severely anemic, experience severe fatigue, and reduced exercise tolerance unless treated with blood transfusions or an ESA. Partial correction of anemia by ESA treatment of patients with CRF reduces the need for red blood cell 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 the red cell production. Antibodies in certain tumor types may cause increased erythrocyte destruction through 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. Marrow dysfunction can occur, however, 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 cause marrow suppression to some degree. 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 is not risk-free, with several potential associated adverse events. The highest adverse event risk (1 per 432 whole blood units) 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 B virus (<1 in 400,000), hepatitis C virus (<1 in 1,000,000), human immunodeficiency virus (HIV) (<1 in 1,000,000), and bacterial contaminants (1 per 10, ,000) have fallen dramatically since the early 1990s. Therefore, while the initial impetus for commercialization of erythropoietin replacement products was based on reduction in the risks associated with blood transfusion, current practices have mitigated many of those. Nonetheless, blood shortages, transfusion errors, and the risk for alloimmunization and TRALI provide sufficient rationale for the use of ESA therapy in appropriately indicated patients. Page 4

5 Three 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 patients on dialysis or use in diagnostic test kits. Epogen and Procrit have identical labeling information for all U.S. Food and Drug Administration (FDA) -approved indications. A second ESA, darbepoetin alfa, is marketed solely by Amgen, under the proprietary name, Aranesp. The third ESA product, peginesatide, was co-developed and commercialized by Affymax, Inc. and Takeda Pharmaceuticals, who market it under the proprietary name, Omontys. In February 2013, Affymax, Takeda, and FDA announced a voluntary recall of all lots of peginesatide due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis. FDA currently lists peginesatide (Omontys) as discontinued. The epoetins have the same amino acid sequence as endogenous erythropoietin, while darbepoetin alfa has two additional oligosaccharide chains; however, the epoetins and darbepoetin all have pharmacologic actions identical to those of the endogenous hormone. They increase the number of red blood cells, and thus the blood concentration of hemoglobin, when given to individuals with functioning erythropoiesis. Both currently marketed ESAs have been approved for use in the treatment of anemia associated with CRF, as well as other indications. The major regulatory timeline for approval actions pertaining to new indications is summarized below: Epoetin alfa (Epogen/Procrit): 1989: approved for use among anemic CRF patients 1991: approved for use among zidovudine-treated HIV-infected patients 1993: approved for use among chemotherapy-induced anemia in patients with nonmyeloid malignancies 1996: approved for presurgical use among certain patients undergoing surgery Darbepoetin alfa (Aranesp): 2001: approved for use among anemic CRF patients 2002: approved for use among chemotherapy-induced anemia in patients with nonmyeloid malignancies Peginesatide (Omontys): 2012: approved for use among anemic adults with CKD on dialysis Voluntary recall of all lots due to postmarketing reports of serious hypersensitivity Page 5

6 IV. RATIONALE Two 1995 TEC Assessments (Myelodysplastic Syndrome and Chronic Anemia of Cancer - Tab 10; Allogeneic Bone Marrow Transplantation or High-Dose Chemotherapy with Autologous Stem-Cell Support - Tab 11) provided the basis for the original policy statements regarding these two settings. The primary data sources for oncology included a 2006 comparative meta-analysis on the outcomes of epoetin or darbepoetin for managing anemia in patients undergoing cancer treatment prepared for the Agency for Healthcare Research and Quality (AHRQ) (1,2); a meta-analysis using individual patient data for outcomes of erythropoiesis-stimulating agents (ESA) therapy in patients with cancer (3,4); American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) 2010 clinical practice guidelines on the use of epoetin and darbepoetin to treat chemotherapy-associated anemia (5); 2007 briefing documents available from the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) (6); and, a 2007 Decision Memorandum from the Centers for Medicare and Medicaid services (CMS) on the use of ESAs for non-renal disease indications. (7) Information on the use of ESAs in chronic renal failure (CRF) was obtained from several sources including 2007 briefing documents from a joint meeting of the FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) and the Drug Safety and Risk Management Advisory Committee (DSRMAC) to reassess the risks of ESAs (8); and, a meta-analysis of blood hemoglobin (Hb) targets for patients with CRF-associated anemia. (9) The FDAapproved labels for ESAs available in the U.S. comprise additional data sources for this Policy, in particular, recommended dosing information for the different clinical settings covered. (10-13) The 2010 ASCO/ASH clinical practice guideline for the use of ESAs considers epoetin and darbepoetin, used at dosages recommended in current U.S. FDA-approved package inserts, to be equivalent with respect to effectiveness and safety. Epoetin and darbepoetin are identical with respect to: (a) indications for use in chemotherapy-induced anemia, (b) hemoglobin (Hb) limits for adjusting doses, initiating or discontinuing treatment, (c) warnings and cautions to consider, and (d) increased rates of thromboembolic events in the experimental arms of separate trials on each product versus controls/placebo. (5) 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 g/dl. (14) 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. Page 6

7 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%. (15) 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. (16) 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. (17) 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. (18) The CREATE study, also reported in 2006, was a study similar to CHOIR but enrolled fewer patients. (19) 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, (20) 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. (21) 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. (13, 22) The first trial, EMERALD-1, enrolled 803 patients in the U.S., and controls received epoetin alfa (Epogen, Procrit ). The second trial, EMERALD-2, enrolled 823 patients in the U.S. and Europe, and controls received epoetin alfa or epoetin beta (not available in the U.S.). Adults on dialysis for at least 3 months with stable Hb concentrations (between 10.0 g/dl and 12.0 g/dl) on ESA therapy for at least 8 weeks were eligible for randomization to peginesatide once monthly or continued epoetin 1 to 3 times weekly for 36 weeks. Results for the primary efficacy outcome (between-arm difference for the change in Hb from baseline to the mean value during weeks 29 to 36 [the evaluation period, with a non-inferiority margin of -1.0 g/dl) demonstrated the non-inferiority of peginesatide in each trial (-0.15 g/dl in EMERALD-1 and in EMERALD-2). The relative risk (RR) for red blood cell (RBC) transfusion also did not differ significantly between arms (RR: 1.21; 95% CI: 0.76 to 1.92 in EMERALD 1 and RR: 0.79; 95% CI: 0.50 to 1.24 in EMERALD-2). Page 7

8 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. These trials were summarized in a TEC Specialty Pharmacy Report. (22) The trials prospectively evaluated the cardiovascular risk of ESAs. The 4 Phase 3 trials together were powered for a primary safety outcome, which was to rule out an increase of 30% or more in the risk of the composite safety endpoint, based on 2-sided 90% confidence interval. The components of the composite safety endpoint were death, stroke, myocardial infarction, and hospitalization for congestive heart failure, unstable angina or arrhythmia. The incidence of the composite safety outcome did not differ significantly between groups randomized to peginesatide or the active comparator (HR: 1.06; 95% CI: 0.89 to 1.26). In an analysis limited to the 2 trials for patients on dialysis (EMERALD-1 and -2), the 2 groups again did not differ with respect to incidence of the composite safety endpoint (HR: 0.95; 90% CI: 0.79 to 1.13). However, peginesatide significantly increased the incidence of this composite safety endpoint in a pooled analysis of the 2 trials for patients not on dialysis (PEARL-1 and -2; HR: -1.32; 90% CI: 1.02 to 1.72). The cardiovascular harms in the nondialysis population were considered unacceptably high and the indication was abandoned. The REMS communication plan developed by the manufacturer and approved by FDA (see above, under Policy Guideline) was designed to inform healthcare providers who might prescribe peginesatide of these findings. Note also that thus far, no data are available on safety or efficacy of peginesatide for any other ESA indications (e.g., patients with a non-myeloid malignancy who are anemic while receiving palliative chemotherapy, HIV patients who are anemic while receiving zidovudine, or perisurgical patients unable to donate autologous blood). 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. Peginesatide has been compared to other ESAs in randomized trials and has shown non-inferiority to the older agents for adult patients with chronic renal failure on dialysis. There are no trials reporting benefit for peginesatide for other indications or in pediatric patients with kidney disease. 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 Page 8

9 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 , 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, , and EPO- CAN-20 studies) when ESA treatment strategies were designed to achieve and maintain Hb levels above 12 g/dl. (5) 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 (3,4) 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, (3,4) 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 , 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. Page 9

10 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. (23) 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. (24) 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). Page 10

11 A third RCT by Shiffman et al. evaluated use of ESAs for hepatitis C in all patients treated with ribavirin. (25) 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. (6) 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, The labels have been revised and updated subsequently, most recently in July, (26) 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. (8) 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 Page 11

12 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. (10,11,12) Cancer ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense an ESA to patients with cancer. To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. Use ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course. Chronic Renal Failure In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dl. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions. Perisurgery Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended. Limitations of Use Epogen has not been shown to improve quality of life, fatigue, or patient well-being (for any indication). Page 12

13 Epogen is not indicated for use: In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. In patients scheduled for surgery who are willing to donate autologous blood. In patients undergoing cardiac or vascular surgery. As a substitute for RBC transfusions in patients who require immediate correction of anemia 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 (see above, under Policy Guidelines). 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: Using Epogen can lead to death or other serious side effects. If you decide to take Epogen, your healthcare provider should prescribe the smallest dose of Epogen that is needed to reduce your chance of requiring red blood cell transfusions. You may have serious heart problems such as heart attack, stroke, heart failure, and may die sooner if you are treated with Epogen to reach a normal or near-normal hemoglobin level. You may have blood clots at any time while taking Epogen. If you are receiving Epogen for any reason and you are going to have surgery, talk to your healthcare provider about whether or not you need to take a blood thinner to lessen the chance of blood clots during or following surgery. Clots can form in blood vessels (veins), especially in your leg (DVT). Pieces of a blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus). 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: Chest pain Page 13

14 Trouble breathing or shortness of breath Pain in your legs, with or without swelling A cool or pale arm or leg Sudden confusion, trouble speaking, or trouble understanding others speech Sudden numbness or weakness in your face, arm, or leg, especially on one side of your body Sudden trouble seeing Sudden trouble walking, dizziness, loss of balance or coordination Loss of consciousness (fainting) Hemodialysis vascular access stops working 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: Why Epogen treatment is being prescribed for them. What are the chances they will require red blood cell transfusions if they do not take an ESA. What are the chances they will require red blood cell transfusions even if they do take an ESA. How taking Epogen may affect the success of their cancer treatment. After they have finished their chemotherapy course, ESA treatment should be stopped. Clinical Input Received through Physician Specialty Societies and Academic Medical Centers While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. Page 14

15 Responses were received from 4 academic medical centers and 2 specialty societies in Reviewers agreed with the current medically necessary indications. There was support among reviewers for treatment of patients with hepatitis C and ribavirin-related anemia. For investigational indications, reviewers agreed with the current policy statements. 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. Based on the above factors, epoetin alfa, darbepoetin alfa, and peginesatide may be considered medically necessary for patients with chronic renal failure when used under the guidelines in the policy statement. Peginesatide may be considered medically necessary only for adult renal patients on dialysis, while epoetin alfa and darbepoetin alfa may be considered medically necessary in patients who are not on dialysis and in pediatric patients with renal disease. For patients with cancer-associated anemia, epoetin alfa and darbepoetin may be considered medically necessary when used under the guidelines in the policy statement. For patients with hepatitis C and anemia related to ribavirin treatment, epoetin and darbepoetin may be considered medically necessary as a method for avoiding dose reduction of ribavirin. Centers for Medicare and Medicaid Services (CMS) Postapproval Decision Memorandum In July 2007, CMS released a Decision Memorandum on the use of ESAs for non-renal disease indications (CAG-00383N). (7) Safety concerns such as thrombosis, cardiovascular events, tumor progression, and reduced survival, derived from clinical trials in several cancer and non-cancer populations, prompted CMS to review its coverage of erythropoiesisstimulating agents (ESAs). CMS reviewed a large volume of scientific literature, including basic science research, to see if safety findings observed in RCTs could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. Based on this review, CMS proposed conditions of coverage based on expression of erythropoietin receptors. However, the scientific understanding of this mechanism is controversial and requires additional study. Page 15

16 CMS also reviewed comments on ESAs treatment of myelodysplastic syndrome (MDS), a precursor of acute myeloid leukemia (AML) in many patients. CMS retains interest in these specific issues but does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease and has decided to make no national coverage determination (NCD) at this time on ESAs in MDS. CMS has determined that evidence is sufficient to conclude that ESA treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include: any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers anemia of cancer not related to cancer treatment any anemia associated only with radiotherapy prophylactic use to prevent chemotherapy-induced anemia prophylactic use to reduce tumor hypoxia patients with erythropoietin-type resistance due to neutralizing antibodies anemia due to cancer treatment if patients have uncontrolled hypertension. CMS also determined that ESA treatment for the anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is only reasonable and necessary under the following specified conditions: The hemoglobin level immediately prior to initiation or maintenance of ESA treatment is <10 g/dl (or the hematocrit is <30%). The starting dose for ESA treatment is the recommended FDA label starting dose, no more than 150 U/kg/3 times weekly for epoetin and 2.25 mcg/kg/weekly for darbepoetin alpha. Equivalent doses may be given over other approved time periods. Maintenance of ESA therapy is the starting dose if the hemoglobin level remains below 10 g/dl (or hematocrit is <30%) 4 weeks after initiation of therapy and the rise in hemoglobin is >1g/dL (hematocrit >3%). For patients whose hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline over 4 weeks of treatment and whose hemoglobin level remains <10 g/dl after the 4 weeks of treatment (or the hematocrit is <30%), the recommended FDA label starting dose may be increased once by 25%. Continued use of the drug is Page 16

17 not reasonable and necessary if the hemoglobin rises <1 g/dl (hematocrit rise <3%) compared to pretreatment baseline by 8 weeks of treatment. Continued administration of the drug is not reasonable and necessary if there is a rapid rise in hemoglobin >1 g/dl (hematocrit >3%) over 2 weeks of treatment unless the hemoglobin remains below or subsequently falls to <10 g/dl (or the hematocrit is <30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose. ESA treatment duration for each course of chemotherapy includes the 8 weeks following the final dose of myelosuppressive chemotherapy in a chemotherapy regimen. This decision by CMS also allows local Medicare contractors to continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD ASCO/ASH and NCCN Clinical Guidelines on Use of Epoetin and Darbepoetin in Patients with Cancer The following table summarizes the latest clinical guidelines available from ASCO/ASH (5) and the National Comprehensive Cancer Network (NCCN). (27) American Society of Clinical Oncology/American Society of Hematology 2010 Clinical Practice Guideline National Comprehensive Cancer Network Guidelines, Cancer and Chemotherapy- Induced Anemia ESAs are indicated for: ESAs are a recommended treatment option for patients with chemotherapy-associated anemia; red blood cell transfusion may also be an option. ESAs are also a treatment option for patients with lower risk myelodysplastic syndrome (MDS) who are not undergoing concurrent chemotherapy. Although the FDA label now limits the indication for ESA use to patients receiving chemotherapy for palliative intent... determining the treatment intent requires clinical judgment of an individual patient s circumstances. Patients undergoing palliative treatment or myelosuppressive chemotherapy without curative intent may be treated with ESAs using FDA-approved indications/dosing/dosing adjustments, under REMS guidelines, with informed consent of patient OR may be treated with red blood cell transfusions per provided guidelines. Patients with anemia due to myelosuppressive chemotherapy should be assessed for risk of adverse events due to anemia, and need for initial transfusion. ESAs are NOT indicated for: Clinicians should consider other correctable causes of anemia before considering ESA therapy ESA treatment is not recommended when patients are treated with myelosuppressive chemotherapy with curative intent. Recommends against using ESAs to treat anemia associated with malignancy in patients (excepting those with lower risk myelodysplastic syndrome [MDS]) who are not receiving concurrent myelosuppressive chemotherapy. Page 17

18 ESA treatment symptom outcomes Risk evaluation and mitigation strategy (REMS) Hb levels for ESA initiation Span of ESA treatment ESA dosing modifications Hb target Iron Thromboembolic risk Response to treatment Evidence does not conclusively show that ESA use leads to improved quality of life as can be perceived and valued by patients; recommends that the goal of ESA use should be to avoid transfusions. Notes requirement Recommended when Hb level has decreased to <10 g/dl. Whether or not to initiate treatment when Hb is between 10 and 12 g/dl should be determined by clinical judgment, consideration of ESA risks and benefits (transfusion avoidance), and patient preferences. Transfusion is also an option. Recommends discontinuing ESA treatment when chemotherapy concludes, per FDA guidelines. Recommends ESA starting doses and dose adjustments follow FDA guidelines, noting that alternative doses and schedules have not improved medical outcomes. Refers to product label directing clinicians to use the lowest possible ESA dose (i.e. minimize ESA exposure) to reach the lowest hemoglobin level sufficient to avoid RBC transfusions. Hb can be raised to the lowest hemoglobin level needed to avoid RBC transfusions. An optimal target Hb cannot be determined from the available evidence. Iron studies at baseline and periodically during treatment may be valuable to minimize the need for ESA treatment, maximize improvement of symptoms, or determine the reason for failure to respond. Caution is urged in the use of these agents with patients judged to be at high risk for thromboembolic events, and regarding ESA use together with therapies that increase risk of thromboembolic events. If a patient does not respond to ESAs after 6 to 8 weeks, despite a dose increase, ESA therapy should be discontinued and the clinician should investigate possible underlying tumor progression, iron deficiency, or other causes of the anemia. Not discussed. Notes requirement If Hb is <11 g/dl or >2 g/dl below baseline, an evaluation for possible causes of anemia is suggested. If a cause is not identified, then anemia due to myelosuppressive chemotherapy is considered. Physicians are advised not to administer ESAs outside the treatment period of cancer-related chemotherapy. Dosing and titration directions for epoetin-alfa and darbepoetin-alfa are reproduced from the FDA-approved labels. No Hb target is mentioned; notes that the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to a target Hb <12 g/dl. Iron studies and supplementation of functional iron deficiency are recommended for patients treated with ESAs. Patients with previous risk factors for thrombosis may be at higher risk when administered ESAs and should undergo risk assessment; the risk of ESA-associated thrombosis is independent of Hb levels. ESA therapy should be discontinued if a patient shows no response despite iron supplementation after 8-9 weeks of treatment. Page 18

19 V. DEFINITIONS ALLOGENEIC refers to having a different genetic constitution but belonging to the same species, i.e., involves a donor and a recipient. FERRITIN is an iron storage protein found in the liver, spleen and bone marrow. HEMATOPOIESIS refers to the production and development of blood cells. IATROGENIC refers to any adverse mental or physical condition induced in a patient through the effects of treatment. MYELODYSPLASTIC SYNDROMES ARE a group of diseases in which the bone marrow does not make enough healthy blood cells. NONMYELOID REFERS to conditions not involving or affecting bone marrow. TRANSFERRIN SATURATION IS the proportion of transferrin proteins that are carrying iron. Normal range is 16%-45% in a fasting TS. VI. BENEFIT VARIATIONS The existence of this medical policy does not mean that this service is a covered benefit under the member s contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member s benefit information or contact Capital for benefit information. VII. DISCLAIMER Capital s medical policies are developed to assist in administering a member s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law. Page 19

20 VIII. REFERENCES 1. Bohlius J, Wilson J, Seidenfeld J et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006; 98(10): Seidenfeld J, Piper M, Bohlius J et al. Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. Comparative Effectiveness Review No. 3. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No ) Rockville, MD: Agency for Healthcare Research and Quality. May Available online at: Last accessed August Bohlius J, Schmidlin K, Brillant C et al. Erythropoietin or darbepoetin for patients with cancer meta-analysis based on individual patient data. Cochrane Database Syst Rev 2009; (3):CD Bohlius J, Schmidlin K, Brillant C et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009; 373(9674): Rizzo JD, Brouwers M, Hurley P et al.; American Society of Clinical Oncology; American Society of Hematology. J Clin Oncol 2010; 28(33): Available online at: Last accessed August U. S. Food and Drug Administration. FDA Briefing Document, May 10, 2007 Oncologic Drugs Advisory Committee. Continuing reassessment of the risks of erythropoiesisstimulating agents (ESAs) administered for the treatment of anemia associated with cancer chemotherapy. Available online at: Last accessed August Centers for Medicare and Medicaid Services, July 30, 2007 Decision memo for erythropoiesis stimulating agents (ESAs) for non-renal disease indications (CAG N). Available online at: Last accessed August U. S. Food and Drug Administration. FDA Briefing Document, September 11, 2007 Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Committee. Reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with chronic renal failure. Available online at: FDA.pdf. Last accessed August Strippoli G, Craig JC, Manno C et al. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol 2004; 15(12): Page 20