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5.01.04 Erythropoiesis-Stimulating Agents

Medical Policy    
Section
Prescription Drug
Original Policy Date
12/01/95
Last Review Status/Date
Reviewed with literature search/9:2014
Issue
9:2014
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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor synthesized by cells near the renal tubules in response to changes in the blood oxygen concentration. When a patient is anemic, the ability of the blood to carry oxygen is decreased. An oxygen-sensing protein in the kidney detects the decrease in blood oxygen concentration and induces the production of EPO, which then acts on the erythroid cell line in the bone marrow to stimulate hematopoiesis, thereby effectively increasing blood hemoglobin (Hb) concentrations. Suppression of erythropoietin production or suppression of the bone marrow response to erythropoietin results in anemia in several disease processes, including chronic kidney disease (CKD), many types of cancer treatment, other chronic diseases, and use of certain drugs. The severity of anemia is defined by blood Hb concentration. Normal ranges are 12 to 16 g/dL in women and 14 to 18 g/dL in men. Mild anemia is defined as Hb from 10 g/dL to the lower limit of normal ranges, while moderate anemia is 8 to 10 g/dL. Severe anemia is defined as Hb of 8 g/dL or less.

Erythropoiesis-stimulating agents (ESAs) are produced using recombinant DNA technologies. They were initially developed as replacement therapy to treat anemia due to endogenous erythropoietin deficiency that commonly occurs in individuals with chronic renal failure (CRF) secondary to CKD. Patients with CRF will become severely anemic and experience severe fatigue and reduced exercise tolerance unless treated with blood transfusions or an ESA. Partial correction of anemia by ESA treatment of patients with CRF reduces the need for red blood cell (RBC) transfusions and enhances physical functioning.

In cancer, anemia occurs with varying degrees of frequency and severity. It occurs most commonly in genitourinary, gynecologic, lung, and hematologic malignancies. Anemia may be directly related to cancer type or to its treatment. Oncologic anemia occurs by a variety of mechanisms: (1) Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B12) essential for red cell production.(2) Antibodies and/or immunoregulatory abnormalities associated with certain tumor types (most commonly, B-cell malignancies) may cause increased erythrocyte destruction (hemolysis).(3) Tumors may cause blood loss via tissue invasion, for example gastrointestinal bleeding from colon cancer.(4) Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment.(5) In more advanced cases, there may be marrow replacement with tumor or amyloid.(6) However, marrow dysfunction can occur even in the absence of frank invasion.(7) Inflammatory proteins from interactions between the immune system and tumor cells are thought to cause inappropriately low erythropoietin production and poor iron utilization, as well as a direct suppression of red cell production. The treatment of cancer also may cause anemia: (1) radical cancer surgery can result in acute blood loss; and (2) radiotherapy and many cytotoxic chemotherapeutic agents suppress marrow to varying degrees. Damage is due to a variety of mechanisms. For example, alkylating agents cause cumulative DNA damage; antimetabolites damage DNA indirectly; and platinum-containing agents appear to damage erythropoietin-producing renal tubule cells.

RBC transfusion is the traditional approach to quickly ameliorate anemia symptoms. However, it carries risk for several potential adverse events. The highest adverse event risk (1 per 432 whole blood units transfused) is for transfusion-related acute lung injury (TRALI). Adverse events due to errors in transfusion (for example, type mismatch) are estimated to occur at a rate of 1 per 5000 to 10,000 units of blood transfused. Current transfusion medicine and blood bank practices have significantly reduced the risk of transmissible infections, primarily due to better donor selection and screening for infectious diseases. Estimated risks per unit of blood transfused for transmission of hepatitis B virus (<1 in 400,000), hepatitis C virus (<1 in 1,000,000), human immunodeficiency virus (HIV) (<1 in 1,000,000), and bacterial contaminants (1 per 10,000 to 100,000) have fallen dramatically since the early 1990s. Therefore, although the initial impetus to commercialize erythropoietin replacement products was based on reduction in the risks associated with blood transfusion, current practices have mitigated many of those risks. Nonetheless, blood shortages, transfusion errors, and the risk for alloimmunization and TRALI provide sufficient rationale for use of ESA therapy in appropriately indicated patients.

Four ESA products have been licensed in the United States:

Epoetin alfa is manufactured, distributed, and marketed by Amgen, Inc. under the proprietary name, Epogen®. The same epoetin alfa product manufactured by Amgen Inc. is also marketed and distributed by Janssen Products, LP, a subsidiary of Johnson and Johnson, under the proprietary name, Procrit®. Under a contractual agreement with Amgen, Janssen Products LP has rights to develop and market Procrit® for any indication other than for treatment of anemia associated with CRF in patients on dialysis or use in diagnostic test kits. Epogen® and Procrit® have identical labeling information for all FDA-approved indications.

  • A second ESA, darbepoetin alfa, is marketed solely by Amgen, under the proprietary name, Aranesp®.
  • The third ESA product, peginesatide, was codeveloped and commercialized by Affymax Inc. and Takeda Pharmaceuticals, who market it under the proprietary name, Omontys®. In February 2013, Affymax, Takeda, and FDA announced a voluntary recall of all lots of peginesatide due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis. FDA currently lists peginesatide (Omontys®) as discontinued.
  • Epoetin beta is currently unavailable in the U.S. However, a methoxy pegylated (PEG) form of epoetin beta, called “continuous erythropoietin receptor activator” or CERA, has a prolonged halflife that permits once monthly dosing. PEG-epoetin beta was FDA-approved in 2007 and is marketed outside the U.S. by Hoffmann-LaRoche under the proprietary name Mircera®. Due to a copyright infringement lawsuit brought by Amgen in 2009, U.S. sales have been prohibited until mid-2014.

Epoetin alfa and epoetin beta have the same amino acid sequence as endogenous erythropoietin but differ from each other in glycosylation(2) ; clinical effects are considered interchangeable.(2,3) Darbepoetin alfa is similar to endogenous erythropoietin but has 2 additional oligosaccharide chains. In contrast, peginesatide lacks any amino acid sequence homology to erythropoietin. It is a synthetic dimer of identical 21-amino acid peptides bound to a linker and to polyethylene glycol, with a total molecular
weight of approximately 45,000 Da. (The molecular weight of endogenous erythropoietin is approximately 34,000 Da.) However, the epoetins, darbepoetin, and peginesatide all have pharmacologic actions similar to those of the endogenous hormone. Each binds to and activates the human erythropoietin receptor and thus increases the number of RBCs and the blood concentration of hemoglobin, when given to individuals with functioning erythropoiesis. Both epoetin alfas, PEG-epoetin beta, and darbepoetin are FDA-approved to treat anemia in patients with CKD who are on dialysis or not on dialysis. Peginesatide is approved only for adult patients with anemia from CKD who are on dialysis. Epoetin alfa and darbepoetin also are approved for other indications (see Policy section).

Regulatory Status

The major regulatory timelines for approval actions pertaining to new indications are summarized next:

Epoetin alfa (Epogen®/Procrit®):

  • 1989: Approved for use in patients with anemia due to CRF
  • 1991: Approved for use in zidovudine-treated, HIV-infected patients
  • 1993: Approved for chemotherapy-induced anemia in patients with nonmyeloid malignancies
  • 1996: Approved for presurgical use in certain patients undergoing surgery

Darbepoetin alfa (Aranesp®):

  • 2001: Approved for use in patients with anemia due to CRF
  • 2002: Approved for chemotherapy-induced anemia in patients with nonmyeloid malignancies

Peginesatide (Omontys®):

  • 2012: Approved for use in adults with anemia due to CKD who are on dialysis
  • 2013: Voluntary recall of all lots due to postmarketing reports of serious hypersensitivity

Methoxy polyethylene glycol (PEG) epoetin-beta (Mircera®)

  • 2007: Approved for use in patients with anemia due to CRF who are on dialysis or not on dialysis
  • 2009: Injunction prohibiting U.S. sales until mid-2014 due to copyright infringement
  • 2014: Resumption of U.S. sales anticipated

 

 


Policy

The use of epoetin alfa, darbepoetin, or pegylated (PEG)-epoetin beta may be considered medically necessary for:

  • treatment of anemia associated with chronic kidney disease.a,b,c

The use of PEG-epoetin beta is investigational for all other indications.

The use of epoetin alfa or darbepoetin may be considered medically necessary for:

  • treatment of anemia in cancer patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapya,b;
  • treatment of anemia related to therapy with AZT (zidovudine) in HIV-infected patientsa;
  • reduction of allogeneic blood transfusion in surgery patientsa;
  • treatment of patients after allogeneic bone marrow transplantation;
  • treatment of patients with myelodysplastic syndromes to reduce transfusion dependency; and
  • treatment of patients with hepatitis C and anemia related to ribavirin treatment.

In the medically necessary conditions noted above, the following criteria also apply:

  • The lowest dose of ESAs should be used in order to avoid red blood cell transfusions;
  • ESAs should not be used to raise the hemoglobin (Hb) level above 12 g/dL; and
  • ESA therapy should not be administered without adequate iron stores.

For medically necessary use in cancer patients, these additional FDA criteria also apply:

  • Epoetin alfa or darbepoetin therapy should not be initiated at Hb levels of 10 g/dL or higher; and
  • Epoetin alfa or darbepoetin treatment should be discontinued after completion of a myelosuppressive chemotherapy course.

The use of epoetin alfa or darbepoetin is investigational for:

  • treatment of patients after high-dose chemotherapy with autologous stem-cell support;
  • treatment of noniatrogenic chronic anemia of cancer; and
  • other cancer-associated anemia excepted as noted above.

aFDA-approved label for epoetin alfa (Epogen®, Procrit®).
bFDA-approved label for darbepoetin alfa (Aranesp®).
cFDA-approved label for PEG-epoetin beta (Mircera®).


Policy Guidelines

Throughout this Policy, unless otherwise stated:

  • The term ESA refers to epoetin alfa (Epogen®, Procrit®) and darbepoetin alfa (Aranesp®).
  • Nonmyeloid malignancies include solid tumors and the nonmyeloid hematologic malignancies myeloma, lymphoma, and chronic lymphocytic leukemia.

Administration
ESAs and pegylated (PEG)-epoetin beta are to be administered according to current FDA-approved labeling for each product, using recommended hemoglobin (Hb) levels for starting, stopping, and dose adjustment. This includes decreasing the dose of ESA as the Hb approaches the target level.

Before commencing ESA or PEG-epoetin beta therapy, the patient’s iron stores, blood ferritin, and transferrin saturation should be evaluated, adjusted, and maintained within normal physiological limits. ESA or PEG-epoetin beta therapy should not be  administered without adequate iron stores.

Blood Pressure Monitoring
Blood pressure should be adequately controlled before initiation of ESA therapy and closely monitored and controlled during treatment. ESAs and PEG-epoetin beta are contraindicated in patients with uncontrolled hypertension.

Discontinuation
Erythropoiesis-Stimulating Agents
Patients with myelodysplastic syndromes should be initially limited to a 3-month trial period with ESA. If no response to ESA is observed, ongoing therapy would be futile.

ESAs and PEG-Epoetin Beta
Patients with chronic kidney disease who do not respond adequately over a 12-week dose escalation period should not have their ESA or PEG-epoetin beta dose increased further. Increasing ESA or PEGepoetin beta dose further is unlikely to improve response and may increase risks; the lowest ESA or PEG-epoetin beta dose that maintains adequate Hb to avoid recurrent red blood cell transfusions should be used. Other causes of anemia should be evaluated. If responsiveness does not improve, discontinue
ESA or PEG-epoetin beta therapy.

Risk Evaluation and Mitigation Strategy
Epoetin alfa and darbepoetin must be prescribed and dispensed in accordance with a risk evaluation and mitigation strategy (REMS) drafted by the manufacturer and approved by FDA.(1)

REMS for epoetin alfa and darbepoetin alfa each comprises elements to assure safe use and an implementation system.

  • ESA manufacturers must ensure that all hospitals and healthcare professionals who prescribe and/or dispense ESAs to patients with cancer have enrolled and completed training in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program. The ESA APPRISE program began on March 24, 2010 after FDA’s initial approval of separate but similar REMS for epoetin alfa and darbepoetin alfa on February 16, 2010. Both REMS were subsequently modified, most recently on December 31, 2013.
  • Healthcare providers and hospitals that prescribe and/or dispense an ESA for chronic kidney disease (CKD) must provide each patient with a copy of the REMS Medication Guide included in the product label and ensure that patients are adequately informed of the risks associated with ESA treatment. However, prescribers are not required to enroll in and complete the ESA APPRISE program.

PEG-epoetin beta does not have a REMS.

On March 27, 2012, FDA approved a REMS for peginesatide with a communication plan as its only component. The plan’s goal was to inform all healthcare professionals who might prescribe the drug that peginesatide is indicated only for adult patients with CKD on dialysis, and of potentially fatal risks associated with its use in CKD patients not on dialysis. Peginesatide is currently discontinued.

 


Benefit Application
BlueCard/National Account Issues

Erythropoietin is adjudicated under the drug benefit as an injectable.


Rationale

Two 1995 TEC Assessments (Myelodysplastic Syndrome and Chronic Anemia of Cancer [tab 10]; Allogeneic Bone Marrow Transplantation or High-Dose Chemotherapy with Autologous Stem-Cell Support [tab 11]) provided the basis for the original policy statements regarding these 2 settings. The most recent literature review was performed for the period through August 5, 2014.

Primary data sources for oncology included a 2006 comparative meta-analysis on the outcomes of epoetin or darbepoetin for managing anemia in patients undergoing cancer treatment prepared for the Agency for Healthcare Research and Quality (AHRQ) and the 2005 AHRQ report, updated in 2013(3-5); a meta-analysis using individual patient data for outcomes of erythropoiesis-stimulating agent (ESA) therapy in patients with cancer,(6,7) with additional outcomes reported in 2012(8) ; American Society of Clinical
Oncology/American Society of Hematology (ASCO/ASH) 2010 clinical practice guidelines on the use of epoetin and darbepoetin to treat chemotherapy-associated anemia(9) ; 2007 briefing documents available from the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC)(2); and a 2007 Decision Memorandum from the Centers for Medicare and Medicaid Services on the use of ESAs for nonrenal disease indications.(10)

Information on the use of ESAs in chronic renal failure (CRF) was obtained from several sources including 2007 briefing documents from a joint meeting of FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) and Drug Safety and Risk Management Advisory Committee (DSRMAC) to reassess ESA risks(11); and, a meta-analysis of blood hemoglobin (Hb) targets for patients with CRFassociated anemia.(12) FDA-approved labels for ESAs available (or soon to be available) in the United
States comprised additional data sources for this Policy, in particular, recommended dosing information for the different clinical settings covered.(13-16)

The 2010 ASCO/ASH clinical practice guideline for the use of ESAs considers epoetin and darbepoetin, used at dosages recommended in current FDA-approved package inserts, to be equivalent with respect to effectiveness and safety. Epoetin and darbepoetin are identical with respect to: (1) indications for use in chemotherapy-induced anemia, (2) Hb limits for adjusting doses, initiating or discontinuing treatment, (3) warnings and cautions to consider, and (4) increased rates of thromboembolic events in the
experimental arms of separate trials on each product versus controls/placebo.(9)

Chronic Kidney Disease (Chronic Renal Failure)
Epoetin Alfa, Epoetin Beta, and Darbepoetin

At initial approval of epoetin in 1989, the primary objective of treatment was to raise Hb concentration sufficiently to avoid transfusion, with a target range of 9 to 10 g/dL in anemic patients with chronic kidney disease (CKD). The first National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines in 1997 recommended an Hb concentration of 11 g/dL, a level that was increased by subsequent NKF-KDOQI anemia guidelines, to 11 to 13 g/dL in 2007.17 With increased experience in the
use of ESAs, it became unclear whether higher Hb target concentrations, including normalization, would yield additional benefits, in particular in physical function and improved cardiovascular outcomes. Clinical doubts increased with publication of the first large randomized controlled trial (RCT) of Hb normalization using epoetin alfa in hemodialysis patients (Normal Hematocrit Cardiac Trial [NHCT]).(18) NHCT showed a trend toward increased mortality risk and significantly increased risk for vascular access thrombosis with ESA treatment to a hematocrit (Hct) target of 42%. Subsequently, 4 published RCTs in hemodialysis patients with end-stage renal disease (ESRD) and 8 in nondialysis patients with CKD found improved physical function at higher Hb targets, but none demonstrated significant improvements in cardiovascular end points or mortality.(19)

The Epogen®/Procrit® label was modified in 1996 to include results of the NHCT study that showed a higher mortality rate for anemic dialysis patients randomized to an Hct of 42%, compared with an Hct of 30%. Ten years later, the CHOIR study reported worse cardiovascular outcomes for anemic CRF patients who were not undergoing dialysis and who were randomized to a target Hb of 13.5 g/dL, compared with an Hb of 11.3 g/dL.(20) Subsequent analyses of outcomes in CHOIR showed shorter times to progression
of kidney disease and higher rates of renal replacement therapy and death among patients randomized to the higher Hb target.(21) The CREATE study, also reported in 2006, was similar to CHOIR but enrolled fewer patients.(22) CREATE did not demonstrate statistically significant differences in adverse cardiovascular outcomes for the higher Hb group, but the general trend of major cardiovascular outcomes was similar to the CHOIR findings. The 2009 TREAT study randomized 4038 patients with type 2 diabetes mellitus, Hb of 11 g/dL or less, and CKD not on dialysis.(23) Patients in 1 arm were treated with darbepoetin to a target Hb of 13 g/dL, and those in the other arm received darbepoetin only if Hb fell below 9 g/dL. Risks for 2 end points were not significantly different between arms: death or a cardiovascular event (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.94 to 1.17; p=0.41) and death or ESRD (HR=1.06; 95% CI, 0.95 to 1.19; p=0.29). However, fatal or nonfatal stroke was significantly increased among patients randomized to the higher Hb target (HR=1.92; 95% CI, 1.38 to 2.68; p<0.001). Multivariate analysis found no statistically significant relationship of increased stroke risk to any baseline characteristic; to effects on blood pressure, Hb, or platelet count; or to darbepoetin dose.(24) 

A 2012 meta-analysis by Vinhas et al included only large RCTs (N >500) with a minimum duration of 1 year.(25) Outcomes of interest were vascular access thrombosis, stroke, progression to ESRD, and allcause mortality. Five trials (7902 patients), including the CHOIR, CREATE, NHCT, and TREAT trials, were identified. Mean or median follow-up duration ranged from 14 to 36 months. As shown in Table 1, higher Hb targets were associated with increased risks of vascular access thrombosis and stroke but not with progression to ESRD or all-cause mortality.

Table 1. Results of Meta-Analysis by Vinhas et al(25)

Outcome

n/N

Relative Risk a

95% CI

I2b

Vascular access thrombosis

2/1829

1.34

1.16 to 1.55

0%

Stroke

4/7305

1.74

1.32 to 2.28

0%

Progression to ESRD

3/6073

1.09

0.99 to 1.20

0%

All-cause mortality

5/7902

1.15

0.98 to 1.35

0%

CI: confidence interval; ESRD: end-stage renal disease; n/N: number of trials/number of patients.
aRelative risk for outcome at higher Hb targets (13.0-15.0 g/dL) compared with lower Hb targets (9.5-11.5 g/dL).
bDescribes the proportion of total variation across studies that is due to heterogeneity rather than chance.

 

N

Initial Dose

Results

 

 

 

 

%
Respondersa

Mean
∆Hb,b g/dL

Correction trials in patients not receiving ESA therapy

Macdougall 2008 (ARCTOS)30,c

 

 

 

 

  PEG-epoetin beta

162

0.6 µ/kg SC q2wk

98

2.15

  Darbepoetin

162

0.45 µ/kg SC qwk

96

2.00

  P value

 

 

<0.001d

<0.001e

Klinger 2007 (AMICUS)31

 

 

 

 

  PEG-epoetin beta

135

0.4 µ/kg IV q2wk

93

2.70

  Epoetin alfa/beta

46

Per product label IV 3x/wk

91

2.56

  P value

 

 

<0.001d

<0.001e

Maintenance trials in patients receiving ESA therapy

Levin  2007 (MAXIMA)32

 

 

 

 

 

 

  • PEG-epoetin beta dose based on maintenance ESA dose
  • Comparator ESA dose was continuation of maintenance dose

 

 

  PEG-epoetin beta IV q2wk

223

-

-0.71

  PEG-epoetin beta IV q4wk

224

-

-0.25

  Epoetin alfa/beta IV q1-3x/wk

226

-

-0.75

  P value vs control

 

-

<0.001ef

Sulowicz 2007 (PROTOS)33

 

 

 

  PEG-epoetin beta SC q2wk

190

76

-0.03

  PEG-epoetin beta SC q4wk

191

66

-0.13

  Epoetin alfa/beta SC q1-3x/wk

191

72

-0.11

  P value

 

_g

<0.001ef

Canaud 2008 (STRIATA)34

 

 

 

  PEG-epoetin beta IV q2wk

157

66

0.06

  Darbepoetin IV q1-2wk

156

72

-0.12

  P value

 

0.25h

<0.001e

Spinowitz 2008 (RUBRA)35

 

 

 

  PEG-epoetin beta SC/IV q2wk

168

69

0.09

  Epoetin alfa/beta SC/IV q1-2wk

168

68

-0.03

  P value

 

-

<0.001e

 

In 2012, the American Society of Nephrology released its evidence-based recommendations for the “Choosing Wisely” campaign to improve patient care and resource use.(26) Citing the evidence reviewed here, the Society included the following among its top 5 recommendations: “Do not administer erythropoiesis-stimulating agents to CKD patients with hemoglobin levels ≥10 g/dL without symptoms of anemia.”

A 2014 Cochrane review included 8 trials (total N=2051) that compared darbepoetin with epoetin (alfa or beta) in adults with anemia due to CKD.(27) No statistically significant differences were observed in random effects meta-analyses of final Hb or mean change in Hb level, overall mortality, cardiovascular events or cardiovascular mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis. Risk of bias was rated as moderate to high, and statistical heterogeneity was minimal (I2 =0%) for all outcomes.

Pegylated Epoetin Beta

FDA’s 2007 approval of PEG-epoetin beta (Mircera®) was based on 6 phase 3, international, open-label, RCTs in patients with anemia due to CKD16 (see Table 2). In 2 trials (total N=505), patients were not receiving ESA therapy (correction trials), and in 6 trials (total N=1894), Hb was stable on maintenance
ESA therapy (maintenance trials). All but1 trial (ARCTOS) enrolled dialysis-dependent patients. The primary efficacy outcome in all trials was maintenance of Hb levels over 24 to 52 weeks, adjusted for baseline Hb and center, in the intent-to-treat and per protocol patient samples. For this outcome, the trials
demonstrated noninferiority of PEG-epoetin beta once or twice monthly to epoetin (alfa or beta) 1 to 3 times weekly (AMICUS, MAXIMA, PROTOS, RUBRA) and to darbepoetin weekly or twice monthly (ARCTOS and STRIATA). In the correction trials (ARCTOS and AMICUS), median time to response was
longer in the PEG-epoetin beta groups (43 days and 57 days, respectively) compared with the darbepoetin (29 days) and epoetin (31 days) groups.

Although target Hb ranges in these trials included levels that have since been associated with increased mortality in CKD (ie, >11 g/dL),(28) FDA’s summary review of safety (based on 1789 PEG-epoetin beta treated patients [64% for >1 year] and 948 ESA-treated patients) reported that mortality was similar
between the 2 groups (10% vs 11%, respectively).(29) Incidence of serious adverse events also was similar between groups (37% vs 40%, respectively), although serious bleeding events (5.2% vs 4%), serious gastrointestinal bleeding events (1.2% vs 0.2%), and thrombocytopenia less than 100x10(9) platelets/L
(7.5% vs 4.4%) occurred more commonly in PEG-epoetin beta-treated patients. FDA reviewers attributed these imbalances to the greater proportion of patients on hemodialysis in the PEG-epoetin beta group (84% vs 80%), and considered the risks of hemorrhage and thrombocytopenia similar to or slightly
increased above that for other ESAs. Trials excluded patients with poorly controlled hypertension; 27% of enrolled patients required increases in antihypertensive therapy.(16)

 

ESA: erythropoiesis-stimulating agents; Hb: hemoglobin; IV: intravenous; PEG: pegylated; q2wk: every 2 weeks; q4wk: every 4 weeks; SC: subcutaneous.
aDefined as:

  • ARCTOS: Hb level ≥11 g/dL and increased ≥1.0 g/dL from baseline at 28 wk; target Hb 11-13 g/dL
  • AMICUS: Hb level ≥11 g/dL and increased ≥1.0 g/dL from baseline at 24 wk; target Hb 11-13 g/dL
  • PROTOS, STRIATA: Mean Hb within ±1 g/dL of baseline values through 52 wk; target Hb 10-13.5 g/dL

bChange from baseline Hb at 24 wk (AMICUS), 28 wk (ARCTOS), 36 wk (MAXIMA, STRIATA, RUBRA), or 52 wk (PROTOS).
cPatients with stage 3 or 4 CKD (creatinine clearance <59 mL/min) who were not on dialysis.
dFor noninferiority to a predefined minimum of 60%.
eFor noninferiority to comparator; noninferiority margin for difference in mean Hb level (PEG-epoetin beta minus comparator), -0.75 g/dl.
fBoth comparisons.
gTrial investigators did not report statistical testing. Neither PEG-epoetin beta group was statistically different from comparator by x2 test (author calculation; p=0.52 for q2wk PEG-epoetin beta, p=0.36 for q4wk PEG-epoetin beta).
hChi-square test.
iTrial investigators did not report statistical testing. There was no statistical difference between groups by x2 test (author calculation; p=0.88).

A 2014 Cochrane review included random effects meta-analyses of the 5 trials in dialysis patients listed in Table 2 and reported no statistical between-group differences in final Hb level (compared with epoetin), overall mortality, blood transfusions, or adverse events due to hypertension or vascular access
thrombosis.(36) In the STRIATA trial, final Hb level was statistically higher in the PEG-epoetin group compared with the darbepoetin group (mean difference, 0.30 g/dL [95% CI, 0.05 to 0.55]). Risk of bias was rated as low to moderate, and statistical heterogeneity was low to moderate (I2 range, 0%-34%).

Since FDA approval, subsequent short-term trials (24-40 weeks; total N=841) have replicated the findings of the pivotal correction trials in patients on hemodialysis(37) and not on hemodialysis,(38,39) and of the pivotal maintenance trials in patients on hemodialysis.(40,41) Of 324 nondialysis patients in the ARCTOS correction trial, 296 (96%) entered a 24-week extension study.(42) Patients who responded to PEG-epoetin beta biweekly (n=145) were rerandomized 1:1 to biweekly or monthly dosing to maintain Hb between 11 to 13 g/dL. Mean (SD) Hb levels were 11.9 (0.9) g/dL, 11.7 (0.9) g/dL, and 11.9 (1.0) g/dL in the PEG-epoetin biweekly, PEG-epoetin monthly, and darbepoetin (weekly or biweekly) groups (n=151), respectively. Within-patient variation in Hb levels was similar across groups.

Peginesatide

FDA approved Omontys® (peginesatide) to treat anemia in CKD patients on dialysis in March 2012 based on 2 randomized active-controlled noninferiority trials, which were summarized in a TEC Specialty Pharmacy Report.(43) The first trial, EMERALD-1, enrolled 803 patients in the United States, and controls
received epoetin alfa (Epogen®, Procrit®). The second trial, EMERALD-2, enrolled 823 patients in the United States and Europe, and controls received epoetin alfa or epoetin beta (not available in the United States). Adults on dialysis for at least 3 months with stable Hb concentrations (between 10.0 g/dL and
12.0 g/dL) on ESA therapy for at least 8 weeks were eligible for randomization to peginesatide once monthly or continued epoetin 1 to 3 times weekly for 36 weeks. Results for the primary efficacy outcome (between-arm difference of the change from baseline Hb to the mean value during weeks 29 to 36 [the
evaluation period], with a noninferiority margin of -1.0 g/dL) demonstrated the noninferiority of peginesatide in each trial (-0.15 g/dL in EMERALD-1, +0.10 in EMERALD-2). The relative risk (RR) for red blood cell (RBC) transfusion also did not differ significantly between arms (RR=1.21; 95% CI, 0.76 to
1.92 in EMERALD 1; RR=0.79; 95% CI, 0.50 to 1.24 in EMERALD-2).

Two other trials (PEARL-1 and PEARL-2; total N=656 randomized to peginesatide, N=327 to darbepoetin) were conducted for patients with CKD who were not on dialysis. The trials prospectively evaluated cardiovascular risk of ESAs. The 4 trials together were powered for a primary safety outcome,
which was to rule out an increase of 30% or more in the risk of the composite safety end point, based on a 2-sided 90% CI. The composite safety end point comprised death, stroke, myocardial infarction, and hospitalization for congestive heart failure, unstable angina or arrhythmia. Incidence of the composite
safety outcome did not differ significantly between groups randomized to peginesatide or active comparator (HR=1.06; 95% CI, 0.89 to 1.26). In an analysis limited to the 2 trials of patients on dialysis (EMERALD-1 and -2), the 2 groups again did not differ with respect to incidence of the composite safety
end point (HR=0.95; 90% CI, 0.79 to 1.13). However, peginesatide significantly increased the incidence of this composite safety end point in a pooled analysis of the 2 trials for patients not on dialysis (PEARL-1 and -2; HR=-1.32; 90% CI, 1.02 to 1.72). Cardiovascular harms in the nondialysis population were
considered unacceptably high and the indication was abandoned. The risk evaluation and mitigation strategy (REMS) communication plan developed by the manufacturer and approved by FDA (see Policy Guidelines section) was designed to inform health care providers who might prescribe peginesatide of
these findings. Note also that thus far, no data are available on safety or efficacy of peginesatide for any other ESA indications (eg, patients with a nonmyeloid malignancy who are anemic while receiving palliative chemotherapy, HIV patients who are anemic while receiving zidovudine, or perisurgical patients
unable to donate autologous blood).

On February 23, 2013, Affymax, Takeda, and FDA announced a voluntary recall of all lots of peginesatide due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis.(44) Serious reactions occurred within 30 minutes of the first dose of peginesatide; serious reactions after subsequent
doses have not been reported. Among approximately 25,000 patients who received peginesatide postapproval, the estimated overall incidence of hypersensitivity reactions was 2 per 1000, and the estimated incidence of fatal reactions was 2 per 10,000. FDA currently lists peginesatide (Omontys®) as
“Discontinued” on its website (Drugs@FDA).

Section Summary

Three ESAs are FDA-approved for use in patients with CRF: epoetin alfa, pegylated epoetin beta (PEGepoetin beta), and darbepoetin alfa; PEG-epoetin beta is expected to be available in the U.S. soon. Placebo-controlled clinical trials have established that epoetin alfa and darbepoetin alfa effectively
increase Hb concentrations and decrease the need for blood transfusions. Evidence does not support an improvement in other clinical outcomes such as mortality, morbidity, functional status, or quality of life (QOL). Some trials and a meta-analysis published in 2012 have reported increased cardiovascular events
and/or increased mortality in patients treated with ESAs. These trials generally have treated to a Hb of 12 g/dL or higher. The optimal target Hb is unclear, and it is uncertain whether treating to lower Hb levels avoids the increase in adverse events. Both peginesatide and PEG-epoetin beta have been compared
with other ESAs in randomized trials. Peginesatide has shown noninferiority to epoetin for adult patients with CRF on dialysis. There are no trials reporting benefit for peginesatide for other indications or in pediatric patients with kidney disease. Currently, peginesatide is unavailable and should not be used.
PEG-epoetin beta has shown noninferiority to epoetin and darbepoetin for correcting or maintaining Hb levels in RCTs of patients on dialysis or not on dialysis. In meta-analyses of trials in dialysis patients, no statistical differences were reported in overall mortality, blood transfusions, or adverse events due to
hypertension or venous access thrombosis. PEG-epoetin beta currently is unavailable in the U.S.

Oncology
Epoetin Alfa, Epoetin Beta, and Darbepoetin

In 1993, FDA approved Procrit®/Epogen® (epoetin alfa) to treat anemia in patients receiving cancer chemotherapy based on data from 2 multicenter randomized placebo-controlled, double-blind clinical trials; 1 enrolled 344 adult patients and the second enrolled 222 pediatric patients, and an additional
pooled analysis of 6 smaller double-blind RCTs enrolled a total of 131 patients. Patients in all 3 studies received at least 12 weeks of concurrent chemotherapy and were randomized (1:1) to receive Procrit®/Epogen® or placebo subcutaneously for 12 weeks. Overall, the data showed a reduction in the
proportion of patients requiring blood transfusion during the second and third months of epoetin treatment.

The approval of Aranesp® (darbepoetin alfa) in 2002 for the treatment of anemia associated with cancer chemotherapy was based on demonstration of a significant reduction in the proportion of patients transfused during chemotherapy from week 5 through the end of treatment. Study 980297, a phase 3,
double-blind, placebo-controlled randomized (1:1) multicenter, multinational trial of darbepoetin alfa enrolled 314 anemic patients with previously untreated non-small cell or small cell lung cancer receiving at least 12 weeks of platinum-containing chemotherapy.

After the first approval of an ESA) for treatment of chemotherapy-associated anemia in 1993, additional data became available regarding increased risks of mortality and possible tumor promotion from the use of ESAs. Increased mortality has been observed in patients with cancer (BEST, ENHANCE, 20000161,
EPO-CAN-20 studies) when ESA treatment strategies were designed to achieve and maintain Hb levels above 12 g/dL.(9) In addition, ESA treatment strategies intended to achieve and maintain Hb levels above 12 g/dL have demonstrated poorer tumor outcomes (BEST, ENHANCE, DAHANCA studies). More
recently, a 2009 meta-analysis using individual patient data on 13,933 subjects from 53 RCTs reported significantly greater on-study mortality (HR=1.17; 95% CI, 1.06 to 1.30) and poorer survival to end of follow-up (HR=1.06; 95% CI, 1.00 to 1.12), with little heterogeneity between trials.(6,7) Results were
qualitatively similar when the analysis was limited to 10,441 patients receiving concurrent chemotherapy in 38 trials, and there was little evidence for a difference between trials of patients receiving different chemotherapy regimens.

Data from multiple trials, consistent with data presented to ODAC in May 2004, led to revised product labeling with broader and more detailed warnings against ESA treatment strategies targeting Hb levels above 12 g/dL. More recent data, including the individual patient data meta-analysis summarizedearlier,(6,7) suggested that factors such as the planned Hb ceiling for stopping ESA therapy had little influence on increased mortality resulting from ESA treatment. Although risks of Hb targets greater than needed to avoid transfusions are now well-established, data from adequate, well-controlled studies employing
recommended ESA doses and Hb targets are as yet insufficient to assess effects on survival or tumor promotion. The only data provided to FDA which used the recommended dose and Hb target was from Amgen Study 20010103, which demonstrated significantly shorter survival in cancer patients receiving
ESAs compared with those supported by transfusion alone. However, this study was not adequately designed to assess effects on tumor promotion or on thrombotic risks.

Despite these caveats, data from available studies were sufficient for FDA to reassess the safety of ESAs in patients with cancer and to re-evaluate the net clinical benefit of ESAs in this setting.

Results of the updated AHRQ comparative effectiveness review (2013) were consistent with those reported in 2006.(3) Among patients receiving chemotherapy and/or radiotherapy for malignancy, use of ESAs to treat anemia reduced the risk of transfusion and increased the risk of thromboembolic events
and on-study mortality. Both thromboembolic events and on-study mortality were reduced (but not eliminated) when ESA treatment was initiated at Hb less than 10 g/dL. Although the reviewed evidence incorporated higher baseline and target Hb levels than those currently recommended, sensitivity analyses
suggested that these findings were robust. QOL, as assessed by the Functional Assessment of Cancer Therapy (FACT) fatigue scale, was improved in patients receiving ESAs, but the magnitude of improvement was less than the minimal clinically important difference of 3 points. Fifteen included trials
did not support an association between ESA use and tumor response or progression; meta-analysis was not possible due to varying outcome definitions.

The AHRQ update incorporated the individual patient data meta-analysis previously described.(6,7) Despite differing inclusion criteria and methodologies, additional analyses of these data by Tonia et al (2012)(8) supported results of the updated AHRQ review, as shown in Table 3.



                                                               2013 AHRQ3                               

2012 Individual Patient Data8

 

n/N

Result (95% CI)

n/N

Result (95% CI)

Transfusions, RR

18/10,809

0.58 (0.53 to 0.64)

70/16,093

0.65 (0.62 to 0.68)

Thromboembolic events, RRa

37/12,570

1.51 (1.30 to 1.74)

57/15,278

1.52 (1.33 to 1.73)

On-study mortality, HRa

37/11,266

1.17 (1.04 to 1.31)

70/15,935

1.17 (1.06 to 1.29)

Tumor response, RRa

15/5577

Not pooledb

15/5012

1.02 (0.98 to 1.06)

FACT-fatigue, mean difference

14/3643

2.74c (1.69 to 3.78)

18/4965

2.08c (1.43 to 2.72)

Overall survival, HR for death

44/14,278

1.04 (0.99 to 1.10)

78/19,003

1.05 (1.00 to 1.11)

Hypertension, RR

16/4318

1.48 (1.07 to 2.06)

31/7228

1.12 (0.94 to 1.33)

Thrombocytopenia/hemorrhage, RRa

12/3714

1.17 (1.01 to 1.36)

21/4507

1.21 (1.04 to 1.42)

CI: confidence interval; FACT: Functional Assessment of Cancer Therapy; HR: hazard ratio; n/N: number of trials/number of patients; RR: relative risk.
aResults are similar between the 2 analyses.
bNo evidence of an association with erythropoiesis-stimulating agents.
cPoint estimate is less than the minimal clinically important difference (3 points).

A 2014 meta-analysis examined the incidence of thromboembolic events in patients with solid and hematologic cancers who received ESAs, and found a similar result.(45) Gao et al pooled 51 RCTs (12,115 patients) and reported a 75% increased odds of thromboembolic events among patients receiving ESAs
(pooled odds ratio, 1.75; 95% CI, 1.50 to 2.05; I2 =0%).

Pegylated Epoetin Beta

PEG-epoetin beta is not FDA-approved for anemia due to cancer chemotherapy,(16) and Hoffmann-LaRoche, manufacturer of PEG-epoetin beta, has not sought this indication.(29) A 2010 phase 2, open-label RCT by Gascon et al compared 3 doses of subcutaneous PEG-epoetin beta with subcutaneous
darbepoetin in 153 patients who were receiving first-line chemotherapy for stage 3B or 4 non-small-cell lung cancer.(46) Baseline Hb at screening was 11 g/dL or less. PEG-epoetin beta was administered every 3 weeks, and darbepoetin was administered weekly or every 3 weeks. The primary efficacy outcome, mean change from baseline Hb during weeks 5 to 13, did not differ between groups and indicated inadequate treatment responses in all groups (0.17 g/dL and 0.26 g/dL in the PEG-epoetin beta and darbepoetin groups, respectively). At week 12, the trial was terminated due to more deaths in the 3 PEG-epoetin beta groups compared with the darbepoetin group (29 [25%] of 114 patients vs 4 [10%] of 39 patients, respectively). Post hoc analyses did not convincingly demonstrate that baseline imbalances accounted for the mortality difference.

Section Summary

Epoetin alfa and darbepoetin alfa are approved for patients with anemia associated with concurrent cancer chemotherapy. These ESAs effectively increase Hb concentrations and decrease the need for blood transfusions in patients with anemia caused by cancer chemotherapy. The evidence does not
support an improvement in other clinical outcomes such as mortality, morbidity, functional status, or QOL. Some trials have reported higher thromboembolic events and/or mortality in cancer patients treated with ESAs, and 2 meta-analyses published in 2012 and 2013 also reported increases in mortality and
thromboembolic events. Trials that reported increased adverse events have generally treated to a Hb of 12 g/dL or higher, and adverse events appear to be correlated with higher treatment targets. However, it is unclear whether treating to a lower Hb reduces or eliminates these adverse events. These concerns
over potential harm from ESAs have led FDA to reassess the risk/benefit ratio and to modify the labeled indications. Current FDA labeling recommends against starting ESA therapy in a cancer patient whose Hb exceeds 10 g/dL.

PEG-epoetin beta is not FDA-approved for patients with anemia due to cancer chemotherapy. A phase 2 RCT demonstrated increased mortality among patients with advanced non-small cell lung cancer who received PEG-epoetin beta compared with those who received darbepoetin.

ESAs for Treatment of Hepatitis C-Related Anemia

Standard treatment for hepatitis C infection includes ribavirin. Anemia related to ribavirin use often is the limiting step in treatment. Options for treatment of ribavirin-related anemia are reduction in the dose of ribavirin and use of ESAs and/or blood transfusions as needed. However, a reduction in ribavirin dose
has been associated with less favorable response rates, and some experts therefore prefer using ESAs to maintain full-dose ribavirin. Evidence on the benefit of using ESAs for this purpose comprises several RCTs, some of which are reviewed next.

At least 2 RCTs randomized patients with hepatitis C and ribavirin-related anemia to epoetin alfa or usual care. The larger of these was conducted by Afdhal et al (2004).(47) This trial included 185 patients with a Hb level of 12 g/dL or less who received 8 weeks of epoetin alfa at a dose of 40,000 units weekly.
Outcomes included the proportion of patients who were able to maintain full-dose treatment with ribavirin, mean Hb level, and QOL as measured by 36-Tiem Short-Form Health Survey. More patients in the epo group (88%) than in the usual care group (60%, p<0.001) were able to maintain full-dose ribavirin.
Increase in mean Hb level also was higher in the epo group (2.2 g/dL) than in the usual care group (0.1 g/dL, p<0.001). Improvement in QOL was significantly greater for the epo group on 7 of 8 domains, with incremental improvement ranging from 1.3 to 10.0 for patients on epoetin.

A second RCT by Dieterich et al (2003) was similar to the Afdhal trial.(48) Dieterich et al enrolled 64 patients with hepatitis C and ribavirin-related anemia, as defined by Hb less than 12 g/dL. Patients were followed for 16 weeks and treated with epoetin alfa 40,000 units weekly. Primary end points were ribavirin
dose and Hb level. Mean ribavirin dose decreased less in the epoetin group (-34 mg/d) than in the usual care group (-146 mg/d), but this difference was not statistically significant (p=0.06). More patients in the epo group (83%) than in the usual care group (54%, p=0.02) were able to maintain full-dose ribavirin.
Mean Hb level was higher in the epo group (13.8 g/dL) than in the usual care group (11.4 g/dL, p<0.001).

A third RCT by Shiffman et al (2007) evaluated ESAs for anemia in patients with hepatitis C who were treated with ribavirin.(49) This trial randomized 150 patients to 3 groups at the onset of treatment: (1) ribavirin at standard dose; (2) ribavirin at standard dose plus epoetin alfa; and (3) ribavirin at higher dose
plus epoetin alfa. Primary end points were reduction in ribavirin dose and the proportion of patients with a sustained virologic response (SVR). Fewer patients treated with epoetin required dose reduction (10%) compared with patients not treated with epo (40%, p<0.05), but the proportion of patients with SVR did
not differ between groups.

Section Summary

RCTs of ESAs versus placebo for patients with hepatitis C and ribavirin-related anemia have demonstrated that use of ESAs can improve Hb levels and allow more patients to maintain treatment at full ribavirin doses. One RCT also reported improvement in QOL for patients treated with ESAs. Improvements in these parameters may lead to health outcome benefits, although no study has reported an improvement in clinical outcomes such as SVR or survival.

Postapproval FDA Regulatory Actions
In November 2006, FDA issued a Public Health Advisory regarding the serious cardiovascular risks from ESA therapy in patients with CKD evidenced in the CHOIR study and the NHCT study.(50) Subsequently, FDA received reports of increased risks associated with ESAs used to treat anemia in cancer patients
who were receiving or not receiving chemotherapy, as well as a report of thrombotic risks in patients receiving ESAs in the perisurgical setting. These data prompted reassessment of the safety information contained in the Aranesp®, Epogen®, and Procrit® labels and culminated in the approval of revised
labels on March 9, 2007. Product labels have been revised and updated subsequently, most recently in December 2013.(50)

Regarding dosage information, periodic reassessment of ESA safety has determined that clinical data do not support a therapeutic Hb target free of risk for mortality. Consequently, revised “Dosage and Administration” sections of the product label deleted any specific therapeutic Hb or Hct "target" range for
ESAs. Instead, revised labels recommended that prescribers use the lowest ESA dose that will gradually increase Hb concentration to the lowest level sufficient to avoid the need for RBC transfusion. For anemic CRF patients, this recommendation was primarily based on the NHCT and CHOIR study findings, as well as the lack of data for any specific Hb or Hct threshold or range. Clinical data did not identify specific Hb or Hct levels that directly correlated with a "reduction in the need for red blood cell transfusion," the main treatment benefit supporting ESA efficacy. The March 2007 label revision allowed prescribers to use their clinical judgment in determining the "lowest level sufficient to avoid the need for red blood cell transfusion."

On November 8, 2007, FDA revised the product labeling for epoetin alfa and darbepoetin alfa.(11) These revisions clarified the evidence for safety and effectiveness of these products and provided more explicit directions and recommendations for their use. These recommendations were consistent with those made during the May 10, 2007 ODAC and the September 11, 2007 CRDAC and DSRMAC meetings. Revisions included strengthened boxed warnings and “Warnings and Precautions” sections, and changes to the “Indications and Usage,” “Clinical Trials Experience”, and “Dosage and Administration” sections of the product labels. Product labels for Epogen®/Procrit® and Aranesp® have been revised many times since then. The revised black box warnings and limitations of use shown next reflect current labeling for these ESAs.(13-15) Although the Mircera® product label has not been updated since 2007, “Warnings” for use in CRF are similar to those listed next.(16)

Cancer

  • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small-cell lung, head, and neck, lymphoid, and cervical cancers.
  • Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense an ESA to patients with cancer.
  • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.
  • Use ESAs only for anemia from myelosuppressive chemotherapy.
  • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • Discontinue after the completion of a chemotherapy course.

Chronic Renal Failure

  • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a Hb level of greater than 11 g/dL.
  • No trial has identified a Hb target level, ESA dose, or dosing strategy that does not increase these risks.
  • Use the lowest Epogen®/Procrit® or Aranesp® dose sufficient to reduce the need for RBC
    transfusions.

Perisurgery (Epogen®/Procrit® only)

Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended.

Limitations of Use

Epogen®/Procrit® and Aranesp® have not been shown to improve QOL, fatigue, or patient well-being (for any indication).

Epogen®/Procrit® and Aranesp® are not indicated for use:

  • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • As a substitute for RBC transfusions in patients who require immediate correction of anemia

Epogen®/Procrit® also is not indicated for use:

  • In patients scheduled for surgery who are willing to donate autologous blood.
  • In patients undergoing cardiac or vascular surgery.

On February 23, 2013, FDA announced a voluntary recall of all lots of peginesatide (Omontys®) due to postmarketing reports of serious hypersensitivity reactions, including anaphylaxis. Peginesatide is currently discontinued.

Clinical Input Received Through Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or
academic medical centers, unless otherwise noted.

Responses were received from 4 academic medical centers and 2 specialty societies in 2012. Reviewers agreed with the current medically necessary indications. There was support among reviewers for treatment of patients with hepatitis C and ribavirin-related anemia. For investigational indications,
reviewers agreed with the current policy statements.

Summary of Evidence

This policy is based on available clinical trial evidence, as well as on recommendations for use from the Food and Drug Administration (FDA) and from specialty societies. Erythropoiesis-stimulating agents (ESAs) have been used extensively in patients with anemia due to cancer chemotherapy or renal failure.
Initial trials of epoetin alfa and darbepoetin alfa established that these agents effectively increase hemoglobin (Hb) concentrations and decrease the need for blood transfusions. However, these agents also have been associated with increases in thromboembolic events and/or mortality, especially when the
target Hb for treatment is higher. These concerns over potential harm from ESAs led FDA to reassess the risk/benefit ratio and to modify labeled indications. Modifications include treating to a lower target Hb and limiting ESA use in cancer to patients receiving myelosuppressive treatment with palliative intent whose Hb concentration is less than 10 g/dL. These additional recommendations have led to more limitations on ESA use and enhanced surveillance systems that are intended to closely monitor and mitigate the risk of adverse events.

Based on these factors, epoetin alfa and darbepoetin alfa may be considered medically necessary for patients with chronic renal failure (CRF) when used under the guidelines in the policy statement. Epoetin alfa and darbepoetin alfa may be considered medically necessary in patients on dialysis and not on
dialysis and in pediatric patients with renal disease. For patients with cancer chemotherapy-associated anemia, epoetin alfa and darbepoetin may be considered medically necessary when used under the guidelines in the policy statement. For patients with hepatitis C and anemia related to ribavirin treatment,
epoetin and darbepoetin may be considered medically necessary as a method for avoiding dose reduction of ribavirin.

Pegylated (PEG)-epoetin beta is a long-acting epoetin that is FDA-approved for patients with anemia due to CRF. Evidence for this indication comprises RCTs in patients on dialysis or not on dialysis that showed noninferiority to standard ESAs for correction or maintenance of Hb levels. Meta-analyses in dialysis
patients reported no difference in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. Based on this evidence, PEG-epoetin beta may be considered medically necessary for treatment of anemia due to CRF. For treatment of anemia due to cancer chemotherapy, 1 phase 2 trial showed increased mortality with PEG-epoetin beta compared with darbepoetin. PEG-epoetin beta is expected to become available in the United States soon.

Practice Guidelines and Position Statements
ESAs in Chronic Kidney Disease

In 2007, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative updated its evidence-based, consensus guidelines for the treatment of anemia in chronic kidney disease.(17) The guidelines reviewed evidence for epoetin alfa, epoetin beta, and darbepoetin. Updated recommendations
included Hb target of 11 to 12 g/dL (consensus recommendation); target Hb should not exceed 13 g/dL (guideline supported by moderately strong evidence). Guideline authors provided no specific Hb level at which to initiate ESA therapy and emphasized that treatment decisions should be individualized
(consensus recommendation).

ESAs in Oncology

Table 4 summarizes current clinical practice guidelines published jointly by the American Society of Clinical Oncology and the American Society of Hematology9 and from the National Comprehensive Cancer Network, version 2.2015.51

  Table 4. Summary of Current Guidelines for Treatment of Anemia in Patients With Cancer

 

American Society of Clinical Oncology/American Society of Hematology 2010 Clinical Practice Guideline

National Comprehensive Cancer Network Guidelines, Cancer and Chemotherapy-Induced Anemia

(v. 2.2014)

ESAs are indicated for:

ESAs are a recommended treatment option for patients with chemotherapy-associated anemia; red blood cell transfusion may also be an option. ESAs are also a treatment option for patients with lower risk myelodysplastic syndrome (MDS) who are not undergoing concurrent chemotherapy. “Although the FDA label now limits the indication for ESA use to patients receiving chemotherapy for palliative intent . . . determining the treatment intent requires clinical judgment of an individual patient’s circumstances.”

  • Based on patient preference and values, patients undergoing palliative treatment or myelosuppressive chemotherapy without curative intent may be treated with ESAs using FDA-approved indications/dosing/dosing adjustments, under REMS guidelines, with informed consent of patient OR may be treated with red blood cell transfusions per provided guidelines.
  • Patients with anemia due to myelosuppressive chemotherapy should be assessed for risk of adverse events due to anemia and need for initial transfusion.

ESAs are NOT indicated for:

  • Clinicians should consider other correctable causes of anemia before considering ESA therapy.
  • Recommends against using ESAs to treat anemia associated with malignancy in patients (excepting those with lower risk myelodysplastic syndrome [MDS]) who are not receiving concurrent myelosuppressive chemotherapy.

ESA treatment is not recommended when patients are treated with myelosuppressive chemotherapy with curative intent.

ESA treatment symptom outcomes

Evidence does not conclusively show that ESA use leads to improved quality of life as can be perceived and valued by patients; recommends that the goal of ESA use should be to avoid transfusions.

Not discussed.

Risk evaluation and mitigation strategy

Notes requirement

Notes requirement

Hb levels for ESA initiation

Recommended when Hb level has decreased to <10 g/dL. Whether or not to initiate treatment when Hb is between 10 and 12 g/dL should be determined by clinical judgment, consideration of ESA risks and benefits (transfusion avoidance), and patient preferences. Transfusion is also an option.

If Hb is <11 g/dL or >2 g/dL below baseline, an evaluation for possible causes of anemia is suggested. If a cause is not identified, then anemia due to myelosuppressive chemotherapy is considered.

Span of ESA treatment

Recommends discontinuing ESA treatment when chemotherapy concludes, per FDA guidelines.

Physicians are advised not to administer ESAs outside the treatment period of cancer-related chemotherapy.

ESA dosing modifications

  • Recommends ESA starting doses and dose adjustments follow FDA guidelines, noting that alternative doses and schedules have not improved medical outcomes.
  • Refers to product label directing clinicians to use the lowest possible ESA dose (ie, minimize ESA exposure) to reach the lowest Hb level sufficient to avoid RBC transfusions.

Dosing and titration directions for epoetin-alfa and darbepoetin-alfa are reproduced from the FDA-approved labels; alternative dosing regimens are provided, eg, every 2 or 3 weeks instead of weekly injections

Hb target

Hb can be raised to the lowest Hb level needed to avoid RBC transfusions. An optimal target Hb cannot be determined from the available evidence.

No Hb target is mentioned; notes that the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to a target Hb <12 g/dL.

Iron

Iron studies at baseline and periodically during treatment may be valuable to minimize the need for ESA treatment, maximize improvement of symptoms, or determine the reason for failure to respond.

Iron studies and supplementation of functional iron deficiency are recommended for patients treated with ESAs.

Thromboembolic risk

Caution is urged in the use of these agents with patients judged to be at high risk for thromboembolic events, and regarding ESA use together with therapies that increase risk of thromboembolic events.

Patients with previous risk factors for thrombosis may be at higher risk when administered ESAs and should undergo risk assessment; the risk of ESA-associated thrombosis is independent of Hb levels.

Response to treatment

If a patient does not respond to ESAs after 6-8 weeks, despite a dose increase, ESA therapy should be discontinued and the clinician should investigate possible underlying tumor progression, iron deficiency, or other causes of the anemia.

ESA therapy should be discontinued if a patient shows no response despite iron supplementation after 8-9 weeks of treatment.

ESA: erythrocyte stimulating agent; FDA: U.S. Food and Drug Administration; Hb: hemoglobin; MDS: myelodysplastic syndrome; RBC: red blood cell; REMS: risk evaluation and mitigation strategy.

U.S. Preventive Services Task Force Recommendations

Erythropoiesis stimulating agents for the treatment of anemia due to chronic kidney disease, cancer chemotherapy, or ribavirin treatment of hepatitis C infection is not a preventive service.

Medicare National Coverage

In July 2007, Centers for Medicare and Medicaid Services (CMS) released a Decision Memorandum on the use of ESAs for nonrenal disease indications (CAG-00383N).(10) Safety concerns such as thrombosis, cardiovascular events, tumor progression, and reduced survival, derived from clinical trials in several cancer and noncancer populations, prompted CMS to review its coverage of ESAs. CMS reviewed a large volume of scientific literature, including basic science research, to see if safety findings observed in
RCTs could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. Based on this review, CMS proposed conditions of coverage based on expression of erythropoietin receptors. However, the scientific understanding of this mechanism is controversial and requires additional study.

CMS also reviewed comments on ESAs for treatment of myelodysplastic syndrome (MDS), a precursor of acute myeloid leukemia (AML) in many patients. CMS retains interest in these specific issues but does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease and has decided at this time to make no national coverage determination (NCD) on ESAs in MDS.

CMS has determined that evidence is sufficient to conclude that ESA treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on the underlying disease or because the underlying disease increases the risk of adverse effects related to ESA use. These conditions include:

  • Any anemia in cancer or cancer treatment patients due to folate deficiency, vitamin B12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis
  • Anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers
  • Anemia of cancer not related to cancer treatment
  • Any anemia associated only with radiotherapy
  • Prophylactic use to prevent chemotherapy-induced anemia
  • Prophylactic use to reduce tumor hypoxia
  • Patients with erythropoietin-type resistance due to neutralizing antibodies
  • Anemia due to cancer treatment if patients have uncontrolled hypertension

CMS also determined that ESA treatment for anemia secondary to myelosuppressive anticancer chemotherapy in solid tumors, multiple myeloma, lymphoma and lymphocytic leukemia is reasonable and necessary under the following specified conditions only:

  • The hemoglobin (Hb) level immediately before initiation or maintenance of ESA treatment is less than 10 g/dL (or the hematocrit [Hct] is <30%).
  • The starting dose for ESA treatment is the recommended FDA-labelled starting dose (no more than 150 U/kg 3 times weekly for epoetin alfa and 2.25 mcg/kg weekly for darbepoetin alpha). Equivalent doses may be given over other approved time periods.
  • Maintenance of ESA therapy is the starting dose if the Hb level remains below 10 g/dL (or Hct is <30%) 4 weeks after initiation of therapy and the increase in Hb is greater than 1 g/dL (Hct >3%).
  • For patients whose Hb increases less than 1 g/dL (Hct <3%) compared with pretreatment baseline over 4 weeks of treatment and whose Hb level remains less than 10 g/dL after 4 weeks of treatment (or Hct is <30%), the recommended FDA-labelled starting dose may be increased once by 25%. Continued use of the drug is not reasonable and necessary if Hb increases less than 1 g/dL (Hct <3%) compared with pretreatment baseline after 8 weeks of treatment.
  • Continued administration of the drug is not reasonable and necessary if there is a rapid rise in Hb greater than 1 g/dL (Hct >3%) over 2 weeks of treatment unless Hb remains below or subsequently falls to less than 10 g/dL (Hct <30%). Continuation and reinstitution of ESA therapy must include a dose reduction of 25% from the previously administered dose.
  • ESA treatment duration for each course of chemotherapy includes the 8 weeks after the last dose of myelosuppressive chemotherapy in a chemotherapy regimen.

PEG-epoetin beta is not addressed in the Decision Memorandum or NCD.(52)

This decision by CMS allows local Medicare contractors to continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD.

References: 

  1. U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS), page last
    updated:  8/01/2014 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm
    . Accessed August 2014.
  2. U.S. Food and Drug Administration. FDA Briefing Document, May 10, 2007 Oncologic Drugs Advisory Committee. Continuing reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for
    the treatment of anemia associated with cancer chemotherapy. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf. Accessed July 2014.
  3. 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. http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=1481. Accessed July 2014.
  4. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated metaanalysis of 57 studies including 9353 patients. J Natl Cancer Inst. May 17 2006;98(10):708-714. PMID 16705125
  5. 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 2006.
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  6. 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. PMID 19588423
  7. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. May 2 2009;373(9674):1532-1542. PMID
    19410717
  8. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012;12:CD003407. PMID 23235597
  9. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. Nov 20 2010;28(33):4996-5010. PMID 20975064
  10. Centers for Medicare and Medicaid Services (CMS). Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N), July 30, 2007. http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=203&ver=12&NcaName=Erythropoiesis+Stimulating+Agents+&bc=BEAAAAAAIAAA. Accessed July 2014.
  11. U.S. Food and Drug Administration. FDA Briefing Document, September 11, 2007 Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Committee. Reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with chronic renal failure. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4315b1-01-FDA.pdf. Accessed July 2014.
  12. Strippoli GF, Craig JC, Manno C, et al. Hemoglobin targets for the anemia of chronic kidney disease: a metaanalysis of randomized, controlled trials. J Am Soc Nephrol. Dec 2004;15(12):3154-3165. PMID 15579519
  13. Amgen Inc. Epogen® (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, April 2014. http://www.epogen.com/. Accessed July 2014.
  14. Amgen Inc. Procrit® (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, December 2013. http://www.procrit.com/. Accessed July 2014.
  15. Amgen Inc. Aranesp® (darbepoetin alfa) injection for intravenous or subcutaneous use prescribing information, December 2013. http://www.aranesp.com. Accessed July 2014.
  16. Hoffmann-La Roche, Inc. Mircera® (methoxy polyethylene glycol-epoetin beta) solution for injection: intravenous (IV) or subcutaneous (SC) use prescribing information, November 2007. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/125164lbl.pdf. Accessed July 2014.
  17. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. Sep 2007;50(3):471-530. PMID 17720528
  18. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. Aug 27 1998;339(9):584-590. PMID 9718377
  19. Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol. Nov 2007;2(6):1274-1282. PMID 17942772
  20. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. Nov 16 2006;355(20):2085-2098. PMID 17108343
  21. Inrig JK, Barnhart HX, Reddan D, et al. Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. Am J Kidney Dis. Sep 2012;60(3):390-401. PMID 22537421
  22. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. Nov 16 2006;355(20):2071-2084. PMID 17108342
  23. 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. Nov 19 2009;361(21):2019-2032. PMID 19880844
  24. Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation. Dec 20 2011;124(25):2903-2908. PMID 22104547
  25. Vinhas J, Barreto C, Assuncao J, et al. Treatment of anaemia with erythropoiesis-stimulating agents in patients with chronic kidney disease does not lower mortality and may increase cardiovascular risk: a meta-analysis. Nephron Clin Pract. 2012;121(3-4):c95-101. PMID 23182871
  26. Williams AW, Dwyer AC, Eddy AA, et al. Critical and honest conversations: the evidence behind the "Choosing Wisely" campaign recommendations by the American Society of Nephrology. Clin J Am Soc Nephrol. Oct 2012;7(10):1664-1672. PMID 22977214
  27. Palmer SC, Saglimbene V, Craig JC, et al. Darbepoetin for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2014;3:CD009297. PMID 24683046
  28. Walker RG, Strippoli GF. A pegylated epoetin in anaemia of renal disease: non-inferiority for an unvalidated surrogate. Lancet. Oct 20 2007;370(9596):1395-1396. PMID 17950848
  29. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Office Director Memo: application number BLA 125164. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/125164TOC.cfm. Accessed August 2014.
  30. Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol. Mar 2008;3(2):337-347. PMID 18287255
  31. 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. Dec 2007;50(6):989-1000. PMID 18037099
  32. Levin NW, Fishbane S, Canedo FV, et al. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet. Oct 20 2007;370(9596):1415-1421. PMID 17950856
  33. Sulowicz W, Locatelli F, Ryckelynck JP, et al. Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clin J Am Soc Nephrol. Jul 2007;2(4):637-646. PMID 17699476
  34. Canaud B, Mingardi G, Braun J, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrol Dial Transplant. Nov 2008;23(11):3654-3661. PMID 18586762
  35. Spinowitz B, Coyne DW, Lok CE, et al. C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. Am J Nephrol. 2008;28(2):280-289. PMID 18004064
  36. Hahn D, Cody JD, Hodson EM. Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients. Cochrane Database Syst Rev. 2014;5:CD003895. PMID 24872328
  37. Oh J, Joo KW, Chin HJ, et al. Correction of anemia with continuous erythropoietin receptor activator in Korean patients on long-term hemodialysis. J Korean Med Sci. Jan 2014;29(1):76-83. PMID 24431909
  38. Vankar SG, Dutta P, Kohli HS, et al. Efficacy & safety of continuous erythropoietin receptor activator (CERA) in treating renal anaemia in diabetic patients with chronic kidney disease not on dialysis. Indian J Med Res. Jan 2014;139(1):112-116. PMID 24604046
  39. 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. Dec 2011;26(12):3980-3986. PMID 21505096
  40. Al-Ali FS, El-Sayed Abdelfattah M, Fawzy AA, et al. Erythropoietin-stimulating agents in the management of anemia of end-stage renal disease patients on regular hemodialysis: A prospective randomized comparative study from Qatar. Hemodial Int. Jun 3 2014. PMID 24894344
  41. Hirai T, Nishizawa Y, Nakazono H, et al. Hemoglobin maintenance and dosing strategies using intravenous continuous erythropoietin receptor activator in Japanese hemodialysis patients. Ther Apher Dial. Oct 2013;17(5):498-503. PMID 24107278
  42. Kessler M, Martinez-Castelao A, Siamopoulos KC, et al. C.E.R.A. once every 4 weeks in patients with chronic kidney disease not on dialysis: The ARCTOS extension study. Hemodial Int. Apr 2010;14(2):233-239. PMID 19888948
  43. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). TEC Specialty Pharmacy Reports 2012. Peginesatide: #6-2012.
  44. U.S. Food and Drug Administration. MedWatch Safety Information and Adverse Event Reporting. Omontys (peginesatide) Injection by Affymax and Takeda: Recall of All Lots - Serious Hypersensitivity Reactions. February 23, 2013.
    http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm340895.htm?source=govdelivery. Accessed July 2014.
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  46. Gascon P, Pirker R, Del Mastro L, et al. Effects of CERA (continuous erythropoietin receptor activator) in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy: results of a phase II study. Ann Oncol. Oct 2010;21(10):2029-2039. PMID 20335369
  47. Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology. May 2004;126(5):1302-1311. PMID 15131791
  48. Dieterich DT, Wasserman R, Brau 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. Nov 2003;98(11):2491-2499. PMID 14638354
  49. Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha. Hepatology. Aug 2007;46(2):371-379. PMID 17559152 
  50. U.S. Food and Drug Administration. Postmarket Drug Safety Information for Patients and Providers: Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp).
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  52. Centers for Medicare and Medicaid Services (CMS). National Coverage Determination (NCD) for Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions (110.21), July 30, 2007. http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=322&ncdver=1&bc=AgAAQAAAAAAAAA%3D%3D&&. Accessed July 2014.

Codes

Number

Description

CPT 

96365

Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour

 

96372

Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

ICD-9 Procedure 

99.29 

Injection or infusion of other therapeutic or prophylactic substance 

ICD-9 Diagnosis 

042 

HIV disease 

  070.44, 070.54 Chronic hepatitis C codes

 

238.71-238-75

Neoplasm of uncertain behavior of other and unspecified sites and tissues; other lymphatic and hematopoietic tissues (includes myelodysplastic syndrome)

 

285.9 

Anemia, unspecified (There is no classification for anemia specifically related to renal failure, AZT use, or chemotherapy) 

 

585.1-585.9

Chronic renal failure; code range

  V42.81-V42.82 Status post-transplant of bone marrow (V42.81) or peripheral stem cells (V42.82)

HCPCS 

J0881 Injection, darbepoetin alfa, 1 mcg (non-ESRD use)
  J0882 Injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis)

 

J0885 

Injection, epoetin alfa, (for non-ESRD use), 1000 units 

 

J0886 

Injection, epoetin alfa, 1000 units (for ESRD on dialysis)
  Q2047 Injection, peginesatide, 0.1mg (for ESRD on dialysis)

 

Q4081

Injection, epoetin alfa, 100 units (for ESRD on dialysis)

  Q9972 Injection, epoetin beta, 1 microgram (for ESRD on dialysis) (new code effective 10/01/14)
  Q9973 Injection, epoetin beta, 1 microgram (non-ESRD use) (new code effective 10/01/14)
ICD-10-CM (effective 10/1/15) B18.2 Chronic viral hepatitis C
  B20 Symptomatic HIV
  D46.9 Myelodysplastic syndromes
  D47.0 – D47.9 Other neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue, code range
  D63.1 Anemia in chronic kidney disease (EPO resistant anemia)
  D64.2 Secondary sideroblastic anemia due to drugs and toxins
  D64.81 Anemia due to antineoplastic chemotherapy
  N18.1 – N18.9 Chronic renal failure, code range
  Z94.81 Bone marrow transplant status
  Z94.84 Stem cells transplant status
ICD-10-PCS (effective 10/1/15)     ICD-10-PCS codes are only used for inpatient services. There are no ICD-10-PCS codes for drugs.
  3E033GC, 3E043GC, 3E053GC, 3E063GC Administration, introduction, percutaneous, other therapeutic substance, code by body part (peripheral vein, central vein, peripheral artery, or central artery)

Type of Service 

Prescription Drug
 
(Injection) 

Place of Service 

Inpatient
 
Outpatient
 
Physician’s office 
Home
 


Index

Anemia, Treatment with Erythropoietin
EPO (Erythropoietin)
Epoetin Alfa
Erythropoietin (EPO)
ESA (Erythropoiesis-Stimulating Agents)
Growth Factors, Hematopoietic, Erythropoietin
Hematopoietic Growth Factors, Erythropoietin  


Policy History

 

Date Action Reason
12/01/95 Add to Prescription Drug section New policy
12/18/02 Replace Policy Policy retired
12/14/05 Replace Policy – coding update only CPT and HCPCS codes updated
02/14/08 Replace policy Policy returned to active review and updated with literature search. Policy revised extensively to reflect recent publications, guidelines and FDA regulatory actions. Policy statements and guidelines updated to reflect new information about initiation of therapy, target Hb levels, and dosing. Reference numbers 1 to 17 added. Policy title changed to Erythropoesis Stimulating Agents (ESAs).
5/12/11 Replace policy Policy revised with literature search; minor qualifying statements added to the Policy statements unchanged, criteria added related to use in patients with cancer. References 3, 17, and 18 added; reference 20 updated
9/13/12 Replace policy Policy updated with literature review, references 3, 4, 13, 18-23 added. Additional medical necessary indication added for peginesatide for treatment of anemia in patients with chronic renal failure on dialysis
12/13/12 Replace policy Policy updated with results of clinical vetting and literature review on treatment of hepatitis C-related anemia; references 23-25 added. Additional medically necessary indication added for treatment of patients with hepatitis C and anemia related to ribavirin treatment.
12/12/13 Replace policy Policy updated with literature review through November 12, 2013; references 3, 6, 23- 24, and 26-27 added; references 2, 8-10, 12-15, and 31-32 updated.; reference 13 (Omontys prescribing information) deleted. Peginesatide (Omontys) deleted from policy statements since it is no longer available. Policy statements otherwise unchanged.
9/11/14 Replace policy Policy updated with literature review through August 5, 2014; references1, 16, 27-42, 46, and 52 added; 2-3, 5, 10-11, 13-15, 44, and 50-51 updated. Information about pegylated (PEG) epoetin beta (Mircera®) added and medically necessary policy statement updated to include PEG-epoetin beta for treatment of anemia associated with chronic kidney disease; PEG-epoetin beta is investigational for all other uses.