Clinical UM Guideline

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1 Subject: Guideline #: Current Effective Date: 12/28/2016 Status: Reviewed Last Review Date: 11/03/2016 Description This document addresses recombinant, or man-made, erythropoietin products: Aranesp (Darbepoetin Alfa, [Amgen, Thousand Oaks, CA]) Epogen (Epoetin Alfa, [Amgen, Thousand Oaks, CA]) Mircera (Methoxy polyethylene glycol-epoetin beta [Hoffmann-La Roche Inc., Nutley, NJ]) Procrit (Epoetin Alfa, [Ortho Biotech Products, LP, Raritan, NJ]) 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. Clinical Indications Medically Necessary: DARBEPOETIN ALFA Darbepoetin alfa may be considered medically necessary when the criteria below are met: A. The individual has a hemoglobin (Hgb) level less than 10 g/dl prior to initiation of therapy; and B. Prior to initiation of therapy, evaluation of the individual s iron status reveals: 1. transferrin saturation is at least 20%; or 2. ferritin is at least 80 ng/ml; or 3. bone marrow demonstrates adequate iron stores; and C. For individuals with hypertension, blood pressure is adequately controlled before initiation of therapy and closely monitored and controlled during therapy; and D. The individual meets at least one of the following: 1. Anemia associated with chronic kidney disease (CKD), for individuals on dialysis, to achieve and maintain hemoglobin levels within the range of 10.0 to 11.0 g/dl; or 2. Anemia associated with chronic kidney disease (CKD), for individuals not on dialysis, to achieve and maintain hemoglobin levels of 10.0 g/dl; or 3. Cancer chemotherapy known to produce anemia when all of the following are met: a. Chemotherapy is planned for a minimum of 2 months; and b. The individual has a diagnosis of non-myeloid cancer and the anticipated outcome is not cure; or CPT Only American Medical Association Page 1 of 22

2 4. Myelodysplastic syndrome with an endogenous erythropoietin level less than 500 mu/ml. EPOETIN ALFA Epoetin alfa may be considered medically necessary when the criteria below are met: A. The individual has a hemoglobin (Hgb) level less than 10 g/dl prior to initiation of therapy; and B. Prior to initiation of therapy, evaluation of the individual s iron status reveals: 1. Transferrin saturation is at least 20%; or 2. Ferritin is at least 80 ng/ml; or c) bone marrow demonstrates adequate iron stores; and C. For individuals with hypertension, blood pressure is adequately controlled before initiation of therapy and closely monitored and controlled during therapy; and D. The individual meets at least one of the following: 1. Anemia associated with chronic kidney disease (CKD), for individuals on dialysis, to achieve and maintain hemoglobin levels within the range of 10.0 to 11.0 g/dl; or 2. Anemia associated with chronic kidney disease (CKD), for individuals not on dialysis, to achieve and maintain hemoglobin levels of 10.0 g/dl; or 3. Cancer chemotherapy known to produce anemia (myelosuppressive) when all of the following are met: a. Chemotherapy is planned for a minimum of 2 months; and b. The individual has a diagnosis of non-myeloid cancer and the anticipated outcome is not cure; or 4. Myelodysplastic syndrome with an endogenous erythropoietin level less than 500 mu/ml; or 5. Zidovudine in human immunodeficiency virus (HIV)-infected individuals when the endogenous serum erythropoietin level is less than or equal to 500 munits/ml and when the dose of zidovudine is less than or equal to 4200 mg/week; or 6. Hepatitis C virus infection in individuals who are being concomitantly treated with the combination of ribavirin and interferon alfa, or ribavirin and peginterferon alfa; or 7. Myelosuppressive drugs (for example, disease modifying anti-rheumatic drugs) known to produce anemia in individuals with a diagnosis of a chronic inflammatory disease; or 8. Allogeneic bone marrow transplantation. Epoetin alfa may also be considered medically necessary when the criteria below are met: A. The individual is undergoing elective, non-cardiac, non-vascular surgery and requires epoetin alfa to reduce the need for allogeneic blood transfusions when the individual meets all of the following criteria: 1. Individual s hemoglobin levels are greater than 10.0 to less than or equal to 13.0 g/dl; and 2. Individual is at high risk for perioperative transfusions with significant, anticipated blood loss; and 3. Individual is unable or unwilling to donate autologous blood; and 4. Antithrombotic prophylaxis has been considered; and 5. Prior to initiation of therapy, evaluation of the individual s iron status reveals: a. Transferrin saturation is at least 20%; or b. Ferritin is at least 80 ng/ml; or c. Bone marrow demonstrates adequate iron stores; and 6. For individuals with hypertension, blood pressure is adequately controlled before initiation of therapy and closely monitored and controlled during therapy. METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA CPT Only American Medical Association Page 2 of 22

3 Methoxy polyethylene glycol-epoetin beta is considered medically necessary when the criteria below are met: A. The individual has a hemoglobin (Hgb) level less than 10 g/dl prior to initiation of therapy; and B. Prior to initiation of therapy, evaluation of the individual s iron status reveals: 1. Transferrin saturation is at least 20%; or 2. Ferritin is at least 80 ng/ml; or 3. Bone marrow demonstrates adequate iron stores; and C. For individuals with hypertension, blood pressure is adequately controlled before initiation of therapy and closely monitored and controlled during therapy; and D. The individual has anemia associated with chronic kidney disease (CKD) and meets one of the following: 1. Individual is on dialysis and the goal is to achieve and maintain hemoglobin levels within the range of 10.0 to 11.0 g/dl; or 2. Individual is not on dialysis and the goal is to achieve and maintain hemoglobin levels of 10.0 g/dl. Not Medically Necessary: DARBEPOETIN ALFA and EPOETIN ALFA Use of epoetin alfa or darbepoetin alfa is considered not medically necessary for all of the following: A. When the above criteria are not met; B. To treat anemia in any indication not listed above, including but not limited to anemia of prematurity; C. Continued use when the hemoglobin level exceeds 11.0 g/dl unless otherwise specified above (except when the dose of epoetin alfa or darbepoetin alfa is adjusted to achieve and maintain target hemoglobin not to exceed 11.0 g/dl); D. Use beyond 12 weeks in the absence of response in individuals with chronic kidney disease; E. Use beyond 8 weeks in the absence of response in individuals with myelodysplastic syndrome (MDS); F. Use beyond 8-9 weeks in the absence of response or if transfusions are still required in individuals with metastatic, non-myeloid cancer being treated with myelosuppressive chemotherapy agents known to produce anemia; G. To treat anemia in individuals due to other factors such as iron deficiency, folate deficiency or B12 deficiency, hemolysis, gastrointestinal bleeding, other active or occult bleeding, or underlying hematologic diseases (such as sickle cell anemia, thalassemia, and porphyria); H. As treatment in the presence of a sudden loss of response with severe anemia and a low reticulocyte count; I. To treat anemia in individuals with cancer receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy; J. To treat anemia in individuals with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure; K. Continued use beyond 6 weeks after therapy with myelosuppressive chemotherapy known to produce anemia is completed; L. Pre-operative use for individuals who are willing to donate autologous blood. METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA Use of methoxy polyethylene glycol-epoetin beta is considered not medically necessary for all of the following: A. When the above criteria are not met; CPT Only American Medical Association Page 3 of 22

4 B. Continued use when the hemoglobin level exceeds 11.0 g/dl (except when the dose of methoxy polyethylene glycol-epoetin beta is adjusted to achieve and maintain target hemoglobin not to exceed 11.0 g/dl); C. Use beyond 12 weeks in the absence of response in individuals with chronic kidney disease; D. To treat anemia in individuals due to other factors such as cancer chemotherapy, iron deficiency, folate deficiency or B12 deficiency, hemolysis, gastrointestinal bleeding, other active or occult bleeding, or underlying hematologic diseases (such as sickle cell anemia, thalassemia, and porphyria); E. As treatment in the presence of a sudden loss of response with severe anemia and a low reticulocyte count. Coding The following codes for treatments and procedures applicable to this document are included below for informational purposes. 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. HCPCS J0881 J0882 J0885 J0887 J0888 Q4081 S9537 EA EB EC ICD-10 Diagnosis Injection, darbepoetin alfa, 1 microgram (non-esrd use) [Aranesp] Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis) [Aranesp] Injection, epoetin alfa (for non-esrd use), 1000 units [Epogen, Procrit] Injection, epoetin beta, 1 microgram, (for ESRD on dialysis) [Mircera] Injection, epoetin beta, 1 microgram, (for non-esrd use) [Mircera] Injection, epoetin alfa, 100 units (for ESRD on dialysis) [Epogen, Procrit] Home therapy; hematopoietic hormone injection therapy (e.g., erythropoietin, G-CSF, GM-CSF), per diem [when specified as erythropoietin] Modifiers Erythropoetic stimulating agent (ESA) administered to treat anemia due to anti-cancer chemotherapy Erythropoetic stimulating agent (ESA) administered to treat anemia due to anti-cancer radiotherapy Erythropoetic stimulating agent (ESA) administered to treat anemia not due to anti-cancer radiotherapy or anti-cancer chemotherapy All diagnoses Discussion/General Information 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 erythropoietin products, also called erythropoietin CPT Only American Medical Association Page 4 of 22

5 stimulating agents (ESAs, such as epoetin alfa and darbepoetin) or continuous erythropoietin receptor activator (CERA, such as methoxy polyethylene glycol-epoetin beta). An adequate diagnostic workup to identify treatable causes of anemia should be performed prior to treatment of anemia. Response to therapy with erythropoietin products may be assessed by the stabilization of or rise in hemoglobin or hematocrit. Individual characteristics and diagnosis should be considered when determining whether a response to therapy has occurred. Darbepoetin Alfa and Epoetin Alfa The U.S. Food and Drug Administration (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 2 additional months of planned chemotherapy. Epoetin alfa is also FDA approved for treatment of anemia in zidovudine-treated HIVinfected 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, 2013). Darbepoetin alfa is another FDA-approved ESA for similar indications. 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 3 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, 2013). There is no data to make a recommendation regarding the use of the epoetin alfa products over darbepoetin alfa for the treatment anemia from 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 demonstrate significant 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 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 CPT Only American Medical Association Page 5 of 22

6 alfa to achieve and maintain the lowest hemoglobin concentration to avoid the need for 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 1530 deaths on-study, and 4993 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 ESAs 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 transfusionrelated risks is a goal. Additional recommendations for individuals with CKD from the Product Information Labels (2013) include: 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. A majority of patients with CKD will require supplemental iron during the course of ESA therapy to adequately support erythropoiesis (Product Information Labels, 2013). CPT Only American Medical Association Page 6 of 22

7 Methoxy Polyethylene Glycol - Epoetin Beta In 2007, the FDA approved methoxy polyethylene glycol-epoetin beta (Mircera), an erythropoietin receptor activator to treat anemia associated with chronic renal failure for individuals in the U.S., including those on dialysis and individuals not on dialysis. The label also specifies epoetin beta is not indicated and not recommended: (1) in the treatment of anemia due to cancer chemotherapy; (2) as a substitute for RBC transfusions in patients who require immediate correction of anemia (Product Information, 2014). Epoetin beta was not commercially available in the U.S. until mid Methoxy polyethylene glycol-epoetin beta may be administered intravenously or subcutaneously once every 2 weeks or once a month to attain the hemoglobin target. 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. A total of 715 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. A total of 222 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%). 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) trial in A total of 603 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 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 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 international randomized, double-blind, Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) comparing darbepoetin and placebo. The 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 CPT Only American Medical Association Page 7 of 22

8 (KDIGO) international guideline update. Although the ERBP maintains Hb values of 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 recommendations regarding initial and maintenance ESA therapy include 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 should not be used to maintain hemoglobin above 11.5 g/dl. 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 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 (2013) 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. Two large studies used observational data from the U.S. Renal Data System to compare two strategies of anemia management on individuals undergoing dialysis. The first study involved complex elderly individuals (participants at high risk for adverse cardiovascular outcomes) and the second study involved individuals with diabetes (Thamer, 2014; Zhang, 2014). The authors compared the low hematocrit (30%-34.5%) and the mid-range hematocrit (34.5%-39%) anemia management strategies from the database to emulate randomized clinical trials. Both studies found Found no differences in the rates of mortality and a cardiovascular composite endpoint between these two clinical strategies, which supports the current FDA recommendations for a target hematocrit level up to 33% in hemodialysis patients. Individuals with Chronic Renal Failure (CRF) Not Requiring Dialysis Four clinical trials were conducted in individuals with CRF not on dialysis enrolling 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 CPT Only American Medical Association Page 8 of 22

9 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. A randomized controlled trial for the correction of renal anemia in individuals with CKD (CORDATUS) study compared the use of monthly subcutaneous methoxy polyethylene glycol-epoetin beta versus weekly or biweekly subcutaneous darbepoetin alfa in individuals not on dialysis. The primary endpoint was hemoglobin response which was defined as a greater than or equal to 1g/dL hemoglobin increase compared to baseline and hemoglobin greater than or equal to 10 g/dl. Greater than 60% of the individuals treated with methoxy polyethylene glycolepoetin beta had a response in increased hemoglobin and the responses were comparable to darbepoetin alfa (Roger, 2011). Cancer Chemotherapy Efficacy in individuals with anemia due to concomitant chemotherapy was demonstrated based on reduction in the requirement for RBC transfusions. ESA use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or wellbeing. ESAs are not indicated for use in individuals receiving hormonal agents, biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy. According to the FDA 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. Examples of cancers where there is therapy with curative intent include, but are not limited to early-stage breast cancer, Hodgkin lymphoma, non-hodgkin lymphoma, testicular cancer, early-stage non-small cell lung cancer (National Comprehensive Cancer Network [NCCN ], 2014). 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. 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, 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). The guidelines conclude the evidence from clinical trials supports the use of epoetin thrice weekly (150 U/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 CPT Only American Medical Association Page 9 of 22

10 initial dose. In the absence of response (for example, less than a 1 to 2 g/dl increase in hemoglobin), continuing beyond the 6-8 week treatment period does not appear to be beneficial (Rizzo, 2007; 2010). The AHRQ review was updated with additional data from published studies and meta-analyses (Grant, 2013). The authors concluded the updated results were consistent with the 2006 review (Seidenfeld, 2006). The transfusion need was reduced with ESAs (pooled relative risk [RR] 0.58; 95% confidence interval [CI], 0.53 to 0.64: 38 trials), and the risk of thromboembolism was increased (pooled RR 1.41; 95% CI, 1.30 to 1.74; 37 trials). Fewer thromboembolic and on-study mortality adverse events were reported when delaying ESA treatment until hemoglobin was less than 10 g/dl at baseline. A total of 14 trials reporting the Functional Assessment of Cancer Therapy (FACT)-Fatigue scores had improved study participant-reported scores with ESA (increase by 2.1; 95% CI, -3.9 to 8.1) as compared to control arms (decrease by -0.6; 95% CI, -6.4 to 5.2). However, the authors concluded the magnitude of the FACT-Fatigue score difference was less than the minimal clinically important difference. An increase in mortality accompanied the use of ESAs. An important unanswered question is whether dosing practices and overall ESA exposure might influence harms. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines, 2015) recommend three general categories of asymptomatic and symptomatic clinical presentations in addition to hemoglobin levels for consideration of blood transfusions. ESA therapy is recommended for the prevention of transfusion in individuals with symptomatic anemia but the use of ESAs is not recommended beyond the treatment period where cancerrelated therapies are provided. NCCN acknowledged the difficulties specifically defining the duration of chemotherapy-related anemia and 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. 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 (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 maintaining 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 -34 mg/day for the epoetin alfa cohort compared to -146 mg/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 (13.8 g/dl) in the treatment group versus 11.4 g/dl in the SOC group (p<0.0001). CPT Only American Medical Association Page 10 of 22

11 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 that dose reduction of antiviral medications should be the initial response to manage anemia. However, it was noted that 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). HIV-infected, zidovudine-treated 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 less than or equal to 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 less than or equal to 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 placebotreated participants, the erythropoietin alfa therapy did not reduce RBC transfusion requirements or increase hemoglobin (Product Information Label, 2012). Myelodysplastic Syndrome NCCN clinical guidelines (2014) recommend the use of epoetin and darbepoetin for the treatment of anemia in individuals with myelodysplastic syndrome (MDS) who have serum EPO levels less than or equal to 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: The American Hospital Formulary Services (AHFS, 2014) note that 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. 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). A total of 2074 preterm infants enrolled in 23 studies were CPT Only American Medical Association Page 11 of 22

12 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 greater than or equal to 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 an updated review (Ohlsson, 2014), the conclusions remain unchanged, and epoetin is not recommended for routine use in preterm infants. 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 greater than or equal to 3 retinopathy of prematurity (ROP) in individuals treated with epoetin alfa. The American Hospital Formulary Services (AHFS, 2014) 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. Heart Failure Reduction of Events by Darbepoetin Alfa in Heart Failure [RED-HF] was an industry sponsored, phase III doubleblind, 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, 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). In a clinical guideline for treatment of anemia in individuals with heart disease, the American College of Physicians provides a strong recommendation against the use of erythropoiesis-stimulating agents in patients with mild to moderate anemia and congestive heart failure or coronary heart disease (Qaseem, 2013). Stroke A Cochrane Review (Bath, 2013) of colony stimulating factors (CSF) for stroke included erythropoietin in addition to other CSFs. Functional outcome after an acute or subacute ischaemic or haemorrhagic stroke treated with CSF was the primary outcome. A total of 1275 participants in 11 randomized controlled trials were included in the analysis. Three trials involving erythropoietin treatment had a total of 782 participants. The authors concluded: EPO therapy was associated with a significant increase in death by the end of the trial (odds ratio (OR) 1.98, 95% confidence interval (CI), 1.19 to 3.3, p=0.009) and a non-significant increase in serious CPT Only American Medical Association Page 12 of 22

13 adverse events. EPO significantly increased the red cell count with no effect on platelet or white cell count, or infarct volume. Traumatic Brain Injury Talving and colleagues (2010) reported on a retrospective matched case control study of individuals who suffered severe traumatic brain injury (stbi). A total of 89 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%; individuals treated with ESA experienced 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. Liu and colleagues (2016) conducted a meta-analysis to assess the effectiveness and safety of EPO in patients with TBI. The assessed outcomes included mortality, favorable neurological outcome, hospital stay, and associated adverse effects. A total of 915 individuals from five randomized controlled trials met the inclusion criteria. The overall results demonstrated that EPO significantly reduced mortality (RR 0.69, 95% CI, ; p=0.03) and shortened the hospitalization time (MD, -7.59; 95% CI, to -5.46; p<0.0001) for patients with TBI. Pooled results of favorable outcome (RR 1.00; 95% CI, ; p=0.97) and deep vein thrombosis (DVT; RD 0.00, 95% CI, to 0.05; p=1.00) did not show a significant difference. EPO was found to beneficial for the participants with TBI by reducing mortality and hospitalization time without increasing the risk of DVT. The effect of EPO for improving neurological outcomes did not reach statistical significance. The authors concluded that more welldesigned RCTs are necessary to ascertain the optimum dosage and time window of EPO treatment for patients with TBI. Warnings and Adverse Events Darbepoetin and Epoetin Alfa (Product Information Labels, 2013) 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): In controlled trials, individuals 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 ESA dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer (darbepoetin and epoetin): CPT Only American Medical Association Page 13 of 22

14 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. Prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense ESAs to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit or call for further assistance. Use the lowest dose to avoid RBC transfusion. Use ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course. 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 13 g/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 (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 1 g/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). Warnings and Adverse Events Epoetin Beta (Product Information Labels, 2014) Black Box warnings from the FDA Product Information Label (2014) include the following: Chronic Kidney Disease: CPT Only American Medical Association Page 14 of 22

15 Definitions 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 Mircera dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: Mircera is not indicated and is not recommended for the treatment of anemia due to cancer chemotherapy. A dose ranging study of Mircera was terminated early because of more deaths among patients receiving Mircera than another ESA. ESAs have shown shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid and cervical cancers. 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). Ferritin: A protein produced by metabolism that serves to store iron in the tissues releases it in a controlled fashion. Myelosuppressive: Suppression of the bone marrow's production of blood cells and platelets. Myelosuppression is a side effect of some cancer treatments Non-myeloid: Not being, involving, or affecting bone marrow. Transferrin: A protein of the beta globulin group that binds and transports iron in blood serum. References Peer Reviewed Publications: CPT Only American Medical Association Page 15 of 22

16 1. Afdhal NH, Dieterich DT, Pockros PJ, et al.; Proactive Study Group. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. 2004; 126(5): Allon M, Kleinman K, Walczyk M, et al. Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients undergoing dialysis. Clin Pharmacol Ther. 2002; 72(5): Carrera F, Lok CE, de Francisco A, et al.; PATRONUS Investigators. Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial. Nephrol Dial Transplant. 2010; 25(12): Carson JL, Carless PA, Hebert PC. Outcomes using lower vs. higher hemoglobin thresholds for red blood cell transfusion. JAMA. 2013; 309(1): Debus J, Drings P, Baurecht W, et al. Prospective, randomized, controlled, and open study in primarily inoperable, stage III non-small cell lung cancer (NSCLC) patients given sequential radiochemotherapy with or without epoetin alfa. Radiother Oncol. 2014; 112(1): Dieterich DT, Wasserman R, Bräu N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol. 2003; 98(11): Drüeke TB, Locatelli T, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006; 355(20): Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Brit J Cancer. 2001; 84(Suppl 1): Glaspy J, Jadeja JS, Justice G, et al. A dose-finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy. Br J Cancer. 2001; 84(Suppl 1): Hedenus M, Adriansson M, San Miguel J, et al.; Darbepoetin Alfa Study Group. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol. 2003; 122(3): Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. Lancet. 2003; 362(9392): Herrington, JD, Davidson, Tomita DK, et al. Utilization of darbepoetin alfa and epoetin alfa for chemotherapyinduced anemia. Am J Health Syst Pharm. 2005; 62(1): Klinger M, Arias M, Vargemezis V, et al. Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. Am J Kidney Dis. 2007; 50(6): Leuchter RH, Gui L, Poncet A, et al. Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age. JAMA. 2014; 312(8): Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol. 2005; 23(25): Liu WC, Wen L, Xie T, et al.therapeutic effect of erythropoietin in patients with traumatic brain injury: a meta-analysis of randomized controlled trials Jul 1:1-8. [Epub ahead of print]. 17. Locatelli F, Mann JF, Aldigier JC, et al. C.E.R.A. safety profile: a pooled analysis in patients with chronic kidney disease. Clin Nephrol. 2010; 73(2): CPT Only American Medical Association Page 16 of 22