Clinical UM Guideline

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 1 of 22

Subject: Recombinant Erythropoietin Products Guideline #: CG-DRUG-05 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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 2 of 22

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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 3 of 22

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;

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 4 of 22

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 Injection, darbepoetin alfa, 1 microgram (non-ESRD use) [Aranesp] J0882 Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis) [Aranesp] J0885 Injection, epoetin alfa (for non-ESRD use), 1000 units [Epogen, Procrit] J0887 Injection, epoetin beta, 1 microgram, (for ESRD on dialysis) [Mircera] J0888 Injection, epoetin beta, 1 microgram, (for non-ESRD use) [Mircera] Q4081 Injection, epoetin alfa, 100 units (for ESRD on dialysis) [Epogen, Procrit] S9537 Home therapy; hematopoietic hormone injection therapy (e.g., erythropoietin, G-CSF,

GM-CSF), per diem [when specified as erythropoietin] Modifiers EA Erythropoetic stimulating agent (ESA) administered to treat anemia due to anti-cancer

chemotherapy EB Erythropoetic stimulating agent (ESA) administered to treat anemia due to anti-cancer

radiotherapy EC Erythropoetic stimulating agent (ESA) administered to treat anemia not due to anti-cancer

radiotherapy or anti-cancer chemotherapy ICD-10 Diagnosis 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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 5 of 22

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 HIV-infected individuals, and to reduce allogeneic blood transfusions in noncardiac, nonvascular surgical cases that are at high risk for perioperative transfusions with significant, anticipated blood loss (Product Information Labels, 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 2007. In August 2008, the Product Information Labels for ESAs were updated, as the FDA invoked authority to address the risk of increased mortality and poorer tumor outcomes when ESAs are given to individuals receiving treatment for head and neck cancer, breast cancer, non-small cell lung cancer, or cervical cancer, and in anemic individuals not receiving chemotherapy for cancer. Data from multiple trials demonstrated ESA use decreased locoregional control or progression-free survival and overall survival. The use of the lowest dose of epoetin alfa or darbepoetin

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 6 of 22

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 transfusion-related 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).

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 7 of 22

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-2014. 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 2006. 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 13-15.0 g/dL was achieved. Participants in cohort 2 initiated epoetin beta when the hemoglobin level fell below 10.5 g/dL and to maintain a hemoglobin level of 10.5-11.5 g/dL. The complete correction of anemia did not reduce the risk of cardiovascular events in either cohort. However, there was a higher prevalence of headaches and vascular disorders related to hypertensive episodes in cohort 1 (Drüeke, 2006). Pfeffer (2009) reported results from the 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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 8 of 22

(KDIGO) international guideline update. Although the ERBP maintains “Hb values of 11-12 g/dL should be generally sought in the CKD population without intentionally exceeding 13 g/dL,” the ERBP group suggested:

In patients with type 2 diabetes not undergoing dialysis (and probably in diabetics at all CKD stages), more caution is needed when treating anaemia with ESA therapy. In diabetic patients with a history of stroke, a lower target is more sensible (10-12 g/dL), balancing the risk-benefit of treatment and the desired Hb target in the individual patient. It is also of paramount importance to involve the patient in the decision making, and seek their personal views after a discussion about the benefits/risks of treatment.

In the KDIGO Anemia Work Group 2012 guideline update, the 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 2007. The NKF recommended hemoglobin target in individuals on dialysis and nondialysis should not be greater than 13 g/dL. However, based on the reported adverse events, the FDA Black Box Warning on the product information labels (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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 9 of 22

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 glycol-epoetin 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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 10 of 22

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 cancer-related 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).

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 11 of 22

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 placebo-treated 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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 12 of 22

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 double-blind, controlled trial that randomized 2278 participants with mild-to-moderate anemia (hemoglobin level, 9.0 to 12.0 g per deciliter) and systolic heart failure to receive darbepoetin alfa or placebo to achieve a hemoglobin target of 13 g/dL. With a median follow-up of 28 months, the study was terminated on September 1, 2012. The primary composite outcome was death from any cause or hospitalization for worsening heart failure, which occurred in 50.7% (576 participants) of the darbepoetin alfa group and 49.5% (565 participants) in the placebo group (darbepoetin group hazard ratio 1.01; 95% CI, 0.90 to 1.13; p=0.87). Adverse thromboembolic events were reported in 13.5% (153 participants) in the darbepoetin treatment group versus 10.0% (114 participants) in the placebo group (p=0.01). The investigators concluded darbepoetin alfa therapy did not improve clinical outcomes in individuals with systolic heart failure and mild-to-moderate anemia (Swedberg, 2012). 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

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 13 of 22

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, 0.49-0.96; p=0.03) and shortened the hospitalization time (MD, -7.59; 95% CI, -9.71 to -5.46; p<0.0001) for patients with TBI. Pooled results of favorable outcome (RR 1.00; 95% CI, 0.88-1.15; p=0.97) and deep vein thrombosis (DVT; RD 0.00, 95% CI, -0.05 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 well-designed 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):

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 14 of 22

• 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 www.esa-apprise.com or call 1-866-284-8089 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:

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 15 of 22

• 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.

Definitions 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:

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 16 of 22

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):1302-1311.

2. 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):546-555.

3. 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):4009-4017.

4. Carson JL, Carless PA, Hebert PC. Outcomes using lower vs. higher hemoglobin thresholds for red blood cell transfusion. JAMA. 2013; 309(1):83-84.

5. 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):23-29.

6. 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):2491-2499.

7. 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):2071-2084.

8. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Brit J Cancer. 2001; 84(Suppl 1):3-10.

9. 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):17-23.

10. Hedenus M, Adriansson M, San Miguel J, et al.; Darbepoetin Alfa 20000161 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):394-403.

11. 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):1255-1260.

12. Herrington, JD, Davidson, Tomita DK, et al. Utilization of darbepoetin alfa and epoetin alfa for chemotherapy-induced anemia. Am J Health Syst Pharm. 2005; 62(1):54-62.

13. 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):989-1000.

14. 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):817-824.

15. 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):5960-5972.

16. 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. 2016 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):94-103.

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 17 of 22

18. Navaneethan SD, Bonifati C, Schena FP, Strippoli GF. Evidence for optimal hemoglobin targets in chronic kidney disease. J Nephrol. 2006; 19(5):640-647.

19. Ohls RK, Kamath-Rayne BD, Christensen RD, et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics. 2014; 133(6):1023-1030.

20. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2011; 361(21):2019-2032.

21. Robertson, CS, Hannay HJ, Yamal JM, et al.; Epo Severe TBI Trial Investigators. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury a randomized clinical trial. JAMA. 2014; 312(1):36-47.

22. Roger SD, Locatelli F, Woitas RP, et al. C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis. Nephrol Dial Transplant. 2011; 26(12):3980-3986.

23. Shenouda G, Zhang Q, Ang KK, et al. Long-term results of radiation therapy oncology group 9903: a randomized phase 3 trial to assess the effect of erythropoietin on local-regional control in anemic patients treated with radiation therapy for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2015;91(5):907-915.

24. Sherman M, Cohen L, Cooper MA, et al. Clinical recommendations for the use of recombinant human erythropoietin in patients with hepatitis C virus being treated with ribavirin. Can J Gastroenterol. 2006; 20(7): 479-485.

25. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006; 355(20):2085-2098.

26. Smith RE Jr, Aapro MS, Ludwig H, et al. Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol. 2008; 26(7):1040-1050.

27. Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013; 368(13):1210-1219.

28. Talving P, Lustenberger T, Kobayashi L, et al. Erythropoiesis stimulating agent administration improves survival after severe traumatic brain injury: a matched case control study. Ann Surg. 2010; 251(1):1-4.

29. Thamer M, Zhang Y, Kaufman J, et al. Similar outcomes for two anemia treatment strategies among elderly hemodialysis patients with diabetes. J Endocrinol Diabetes. 2014;1(2).

30. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007; 25(9):1027-1032.

31. Younossi ZM, Nader FH, Bai C, et al. A phase II dose finding study of darbepoetin alpha and filgrastim for the management of anaemia and neutropenia in chronic hepatitis C treatment. J Viral Hepat. 2008; 15(5):370-378.

32. Zhang Y, Thamer M, Kaufman J, et al. Comparative effectiveness of two anemia management strategies for complex elderly dialysis patients. Med Care. 2014; 52 Suppl 3:S132-S139.

Government Agency, Medical Society, and Other Authoritative Publications: 1. Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm

and/or low birth weight infants. Cochrane Database Syst Rev. 2006;(3):CD004865. 2. Aher SM, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth

weight infants. Cochrane Database Syst Rev. 2006;(3):CD004868.

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 18 of 22

3. Aranesp [Product Information], Thousand Oaks, CA. Amgen; Updated on July 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103951s5363lbl.pdf. Accessed on August 20, 2016.

4. Bath PM, Sprigg N, England T. Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke. Cochrane Database Syst Rev. 2013;(6):CD005207.

5. Bohlius J, Schmidlin K, Brillant C, et al. Erythropoietin or darbepoetin for patients with cancer - meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009;(3):CD007303.

6. Bohlius J, Langensiepen S, Schwarzer G, et al. Erythropoietin for patients with malignant disease. Cochrane Database Syst Rev. 2004;(3):CD003407.

7. Centers for Medicare and Medicaid Services. National Coverage Determination: Erythropoiesis stimulating agents (ESAs) in cancer and related neoplastic conditions. NCD #110.21. Effective July 30, 2007. Available at: http://www.cms.hhs.gov/mcd/index_list.asp?list_type=ncd. Accessed on August 20, 2016.

8. Cody JD, Daly C, Campbell MK, et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre-dialysis patients. Cochrane Database Syst Rev. 2001;(4):CD003266.

9. Cody JD, Daly C, Campbell MK, et al. Frequency of administration of recombinant human erythropoietin for anaemia of end stage renal disease in dialysis patients. Cochrane Database Syst Rev. 2002;(2):CD003895.

10. Darbepoetin Alfa. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated May 26, 2015. Available at: http://www.micromedexsolutions.com. Accessed on August 20, 2016.

11. Darbepoetin Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised March 19, 2015. Accessed on September 29, 2015.

12. Epoetin Alfa. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 12, 2014. Available at: http://www.micromedexsolutions.com. Accessed on August 20, 2016.

13. Epoetin Alfa Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 22, 2014. Accessed on September 29, 2015.

14. Epogen [Product Information], Thousand Oaks, CA. Amgen; Updated December 31,2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103234s5323lbl.pdf. Accessed on August 20, 2016.

15. Ghany MG, Nelson DR, Strader DR, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatol. 2011; 54(4):1433-1444.

16. Grant MD, Piper M, Bohlius J, et al. Epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment: comparative effectiveness update. Comparative Effectiveness Review No. 113. (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-2007-10058-I.) AHRQ Publication No. 13-EHC077-EF. Rockville, MD: Agency for Healthcare Research and Quality; April 2013. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/170/1480/cancer-anemia-treatment-report-130425.pdf. Accessed on August 20, 2016.

17. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Inter., Suppl. 2012; 2:279-335.

18. Locatelli F, Aljama P, Canaud B, et al.; Anaemia Working Group of European Renal Best Practice (ERBP). Target haemoglobin to aim for with erythropoiesis-stimulating agents: a position statement by ERBP following publication of the Trial to reduce cardiovascular events with Aranesp therapy (TREAT) study. Nephrol Dial Transplant. 2010; 25(9):2846-2850.

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 19 of 22

19. Martí-Carvajal AJ, Agreda-Pérez LH, Solà I, Simancas-Racines D. Erythropoiesis-stimulating agents for anemia in rheumatoid arthritis. Cochrane Database Syst Rev. 2013;(2):CD000332.

20. Mircera [Product Information], Nutley, NJ. Hoffmann-La Roche Inc.; Revised August 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125164s070lbl.pdf. Accessed on August 20, 2016.

21. National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®). © 2015 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 29, 2015. • Cancer- and chemotherapy-induced anemia. (V.1.2017). Revised August 18, 2016. • Myelodysplastic syndromes. (V.1.2016). Revised May 28, 2015.

22. National Kidney Foundation (NKF). Kidney Disease Outcomes Quality Initiative (KDOQI). KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007; 50(3):471-530.

23. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2014;(4):CD004863.

24. Palmer SC, Saglimbene V, Craig JC, et al. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2014;(3):CD009297.

25. Palmer SC, Saglimbene V, Mavridis D, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2014;(12):CD010590.

26. Procrit (Epoetin alfa) [Product Information], Raritan, New Jersey: Ortho Biotech, Inc. Revised December 31, 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103234s5323lbl.pdf. Accessed on August 20, 2016.

27. Qaseem A, Humphrey LL, Fitterman N, et al.; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013; 159(11):770-779.

28. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010; 28(33):4996-5010.

29. Rizzo JD, Somerfield MR, Hagerty KL, et al.; American Society of Clinical Oncology; American Society of Hematology. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol. 2008; 26(1):132-149.

30. Seidenfeld J, Piper M, Bohlius J, et al. Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. Comparative effectiveness review No. 3. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-02-0026). Rockville, MD: Agency for Healthcare Research and Quality. May 23, 2006.

31. Sun X, Patnode CD, Williams, C, et al. Interventions to improve patient adherence to hepatitis C treatment: comparative effectiveness. Comparative Effectiveness Review No. 91. (Prepared by the Oregon Evidence based Practice Center under Contract No. 290-2007-10057-I.) AHRQ Publication No. 13- EHC009-EF. Rockville, MD: Agency for Healthcare Research and Quality. December 2012.

32. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;(12):CD003407.

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 20 of 22

33. U.S. Food and Drug Administration. FDA drug safety communication. Updated July 26, 2016. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM109375Accessed on August 20, 2016. • Erythropoiesis-stimulating agents (ESAs): procrit, epogen and aranesp. February 16, 2010. • Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in

chronic kidney disease. June 24, 2011. Websites for Additional Information 1. National Cancer Institute. Available at: http://www.cancer.gov/types/myeloproliferative/hp/myelodysplastic-

treatment-pdq . Accessed on August 20, 2016. • Myelodysplastic Syndromes Treatment (PDQ®). Updated August 12, 2015. • Fatigue (PDQ). Updated May 7, 2015.

2. National Institute of Diabetes and Digestive and Kidney Diseases. Updated July 17, 2015. Available at: http://www2.niddk.nih.gov/. Accessed on August 20, 2016.

Index Aranesp Darbepoetin Alfa Epoetin Alfa Epogen Erythropoietin Stimulating Agents (ESA) Mircera Procrit The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. History

Status Date Action Reviewed 11/03/2016 Medical Policy & Technology Assessment Committee (MPTAC) review. Reviewed 11/02/2015 Hematology/Oncology Subcommittee review. Updated Rationale,

Definitions References and History sections. Updated formatting in the “Clinical Indications” section.

Reviewed 11/05/2015 MPTAC review. Reviewed 11/04/2015 Hematology/Oncology Subcommittee review. Updated

Discussion/General Information, References and History sections. Updated Coding section with 01/01/2016 HCPCS changes; removed J0886 deleted 12/31/2015; also removed ICD-9 codes.

Reviewed 08/06/2015 MPTAC review. Updated Description, Discussion/General Information, Reference and Website sections.

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 21 of 22

01/01/2015 Updated Coding section with 01/01/2015 HCPCS changes; removed Q9972, Q9973 deleted 12/31/2014.

Revised 08/14/2014 MPTAC review. Added clinical indications for methoxy polyethylene glycol-epoetin beta (Mircera). Updated Discussion/General Information, References, Websites for Additional Information. Updated Coding section with 10/01/2014 HCPCS changes.

Revised 05/15/2014 MPTAC review. Revised 05/14/2014 Hematology/Oncology Subcommittee review. Clinical indications

removed for peginesatide (Omontys) as the drug has been discontinued by the manufacturer.

Revised 05/09/2013 MPTAC review. Revised 05/08/2013 Hematology/Oncology Subcommittee review. Clarified criterion A and

abbreviation in Clinical Indications. Added information regarding FDA recall for peginesatide. Updated Discussion/General Information, References, Websites for Additional Information.

01/01/2013 Updated Coding section with 01/01/2013 HCPCS changes; removed Q2047 deleted 12/31/2012.

Revised 05/10/2012 MPTAC review. Reformatted Position Statements and clarified hemoglobin levels in criteria. Added medically necessary indication for new FDA approved drug peginesatide. Updated Discussion/General Information, References, Websites for Additional Information, and Index. Updated Coding section with 07/01/2012 HCPCS changes.

Revised 08/18/2011 MPTAC review. Updated Clinical Indications for CKD to align with the updated FDA label. Reduced the hgb threshold for continued use. Discussion/General Information, References and Websites.

Reviewed 05/19/2011 MPTAC review. Reviewed 05/18/2011 Hematology/Oncology Subcommittee review. Updated

Discussion/General Information, Coding, References and Websites. Reviewed 05/13/2010 MPTAC review. Reviewed 05/12/2010 Hematology/Oncology Subcommittee review. Replaced “patient” with

“individual” in clinical indications and reformatted CRF criteria for epoetin alfa and darbepoetin alfa. Clarified hypertension criteria. Updated Discussion/General Information to include FDA REMS program for oncologic indications. Updated coding, references and websites.

Reviewed 05/21/2009 MPTAC review. Reviewed 05/20/2009 Hematology/Oncology Subcommittee review. Formatting changes and

clarification of Position Statements. Removed dosing tables and Place of Service. Updated Discussion/General Information. Updated references and websites.

Revised 08/28/2008 MPTAC review. Criteria revised in response to FDA warnings. Added not medically necessary criteria for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Clarified previous not medically necessary statement to include “hormonal agents, biologic

Clinical UM Guideline CG-DRUG-05 Recombinant Erythropoietin Products

Federal and State law, as well as contract language, and Medical Policy take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to implement a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card. Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan. CPT Only – American Medical Association Page 22 of 22

products, or radiotherapy” unless receiving concomitant myelosuppressive chemotherapy. Added not medically necessary criteria for unlisted indications and for lack of response in cancer patients treated with chemotherapy. Updated coding section with 10/01/2008 ICD-9 changes.

Revised 05/15/2008 MPTAC review. Revised 05/14/2008 Hematology/Oncology Subcommittee review. Removed hematocrit

criteria from medically necessary criteria. Updated references and websites.

Revised 11/29/2007 MPTAC review. Revised 11/28/2007 Hematology/Oncology Subcommittee review. Criteria revised in response

to FDA warnings. Removed “biologic agents” from medical necessity statements. Added medically necessary indications with criteria for treatment of anemia in hepatitis C and chronic inflammatory diseases. Added Web Site section. Updated references and discussions/general information. Updated Coding section to include 01/01/2008 HCPCS changes.

Revised 05/17/2007 MPTAC review. Revised 05/16/2007 Hematology/Oncology Subcommittee review. Criteria clarified. Added

definition section. Updated references and discussions/general information.

Revised 03/16/2007 MPTAC review. Revised 03/16/2007 Hematology/Oncology Subcommittee review. Criteria revised in response

to FDA warnings. Updated references and discussion/general information. Revised 03/08/2007 MPTAC review. Medical necessity criteria revised to be congruent with

FDA label for Hgb targets. Updated references and discussion/general information section.

Reviewed 12/07/2006 MPTAC annual review. Updated references and discussion/general information section. No change to guideline position. Coding updated; removed HCPCS J0880, Q0136, Q0137, Q4054, Q4055 deleted 12/31/05.

Revised 03/23/2006 MPTAC review. Added black box warning. Revised 07/14/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger

WellPoint Harmonization.

Pre-Merger Organizations Last Review Date

Document Number Title

Anthem, Inc. No document WellPoint Health Networks, Inc.

08/05/2004 Pharmacology Toolkit Erythropoietin (Procrit®, Epogen®, Epo)

12/02/2004 Pharmacology Toolkit Darbepoetin Alfa (Aranesp®)

12/02/2004 Clinical Guideline Erythropoietin (Procrit®, Epogen®, Epo)