Pending Policies - Prescription Drugs


Erythropoiesis-Stimulating Agents (ESAs)

Number:RX501.069

Effective Date:02-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

NOTE: A form is available for optional use to assist in requesting review for consideration of coverage of ESAs. The form is available on the Provider / Forms page of the applicable Blue Cross Blue Shield web site, i.e., BCBSIL.com, BCBSMT.com, BCBSNM.com, BCBSOK.com, or BCBSTX.com.

General Criteria for Erythropoiesis-Stimulating Agents (ESAs)

Erythropoiesis-Stimulating Agents (ESAs) may be considered medically necessary, when ALL of the following criteria are met:

A. Prior to starting ESA therapy, the patient’s iron stores should be evaluated, and blood ferritin should be at least 100 ng/mL (nanograms per milliliter) OR transferrin saturation should be at least 20%—initial and ongoing ESA therapy should not be administered unless iron stores are maintained; and

B. The ESA dose should be the lowest dose that will gradually increase Hgb (hemoglobin) concentration to the lowest level sufficient to avoid the need for red blood cell (RBC) transfusion; and

C. Blood pressure is adequately controlled and closely monitored before and during ESA therapy; and

D. Either one of the following:

i. For use in cancer patients, ESA therapy should not be initiated until the Hgb (hemoglobin) level is approaching or has fallen below 10 g/dL; and ESA therapy should not be used to raise the Hgb level above 12 g/dL; or

ii. For use in chronic kidney failure (including end-stage renal disease-ESRD), therapy may be initiated to reduce the need for red cell transfusions when Hgb has dropped below 10 g/dL (no target Hgb is recommended, but levels of 11 g/dL or greater should be avoided); and

E. Drug-specific criteria listed below must be met.

Epoetin Alfa (Epogen®, Procrit®)—Drug-Specific Criteria

When the General Criteria (listed above) are met, the use of Epoetin alfa may be considered medically necessary for treatment of anemia:

1. Associated with chronic kidney failure (including end-stage renal disease—ESRD); or

2. In cancer patients with metastatic non-myeloid malignancies:

a) Patient is undergoing myelosuppressive chemotherapy; and

b) Anemia is caused by myelosuppressive chemotherapy; and

c) Anemia is not due to other factors, e.g., iron or folate deficiencies, hemolysis, gastrointestinal bleeding, or underlying hemolytic disease (e.g., sickle cell anemia, thalassemia, porphyria); and

d) Anticipated outcome of myelosuppressive therapy is not cure; or

3. Related to therapy with AZT (zidovudine) in HIV-infected (human immunodeficiency virus) patients, when the endogenous serum erythropoietin level is ≤ 500 mUnits/ml; or

4. To reduce the need for allogeneic blood transfusion in pre-operative surgery patients who meet all of the following criteria:

a) Scheduled for elective, non-cardiac, non-vascular surgery, and

b) Hgb < 13 g/dL, and

c) Not a candidate for autologous blood transfusion, and

d) High risk for significant perioperative blood loss; or

5. Following allogeneic bone marrow transplantation; or

6. In patients with myelodysplastic syndromes to reduce transfusion dependency; or

7. Of prematurity:

a) Birth weight <1500 gm or gestational age <33 weeks, and

b) Hematocrit (Hct) <33%); or

8. Associated with Hepatitis C that is being treated with the combination of ribavirin and interferon alfa or ribavirin and peg interferon, and:

a) Other causes of anemia have been ruled out; and

b) Patient has failed to respond (i.e., severe anemia) within two weeks after reducing the dose of Ribavirin by 200 mg/day from the initial dose (NOTE: Use of erythropoietin may be considered prior to dose reduction for the following: 1) documented evidence of cirrhosis, or 2) post liver transplant, or 3) HIV co-infection); and

c) Hgb<10 g/dL, or patient is symptomatic and has Hgb < 11 g/dL.

Authorization Limits for Epoetin Alfa: Continued therapy requires clinical documentation of ongoing need every 12 weeks for treatment of anemia secondary to chemotherapy. Documentation should include the current Hgb and current test(s) for iron stores (i.e., blood ferritin OR transferrin saturation).

Darbepoetin Alfa (Aranesp®)—Drug-Specific Criteria

When the General Criteria (listed above) are met, the use of Darbepoetin alfa may be considered medically necessary for treatment of anemia:

1. Associated with chronic kidney failure (including end-stage renal disease—ESRD); or

2. In cancer patients with metastatic non-myeloid malignancies:

a) Patient is undergoing myelosuppressive chemotherapy; and

b) Anemia is caused by myelosuppressive chemotherapy; and

c) Anemia is not due to other factors, e.g., iron or folate deficiencies, hemolysis, gastrointestinal bleeding, or underlying hemolytic disease (e.g., sickle cell anemia, thalassemia, porphyria); and

d) Anticipated outcome of myelosuppressive therapy is not cure; or

3. In patients with myelodysplastic syndromes to reduce transfusion dependency.

Authorization Limits for Darbepoetin Alfa: Continued therapy requires clinical documentation of ongoing need every 12 weeks for treatment of anemia secondary to chemotherapy. Documentation should include the current Hgb and current test(s) for iron stores (i.e., blood ferritin OR transferrin saturation).

Pegylated (PEG)-epoetin beta (Mircera®)—Drug Specific Criteria

When the General Criteria (listed above) are met, Pegylated (PEG)-epoetin beta may be considered medically necessary for treatment of anemia associated with chronic kidney disease (CKD).

The use of PEG-epoetin beta (Mircera) is considered experimental, investigational and/or unproven for all other indications.

The use of an Erythropoiesis-Stimulating Agent (ESA) is considered experimental, investigational and/or unproven for any other indication, including but not limited to treatment of:

Patients following high-dose chemotherapy with autologous stem-cell support; or

Non-iatrogenic chronic anemia of cancer; or

Other cancer-associated anemia (excepted as noted above); or

Aplastic anemia; or

Any other type of anemia (except as noted above) including, but not limited to, anemia secondary to:

o Deficiency (e.g., iron, folate, B12);

o Hemolysis;

o Bleeding (e.g., occult, gastrointestinal);

o Hemolytic disease (e.g., sickle cell anemia, thalassemia, porphyria);

o Castleman’s disease;

o Gaucher’s disease;

o HIV, when anemia is due to factors other than AZT (zidovudine) therapy (e.g., iron or folate deficiency, hemolysis, gastrointestinal bleeding, etc); or

o Pregnancy.

Description:

Throughout this Policy, unless otherwise stated, nonmyeloid malignancies include solid tumors and the nonmyeloid hematologic malignancies include myeloma, lymphoma, and chronic lymphocytic leukemia.

Background

Endogenous erythropoietin 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 endogenous erythropoietin, which then acts on the erythroid cell line in the bone marrow to stimulate hematopoiesis, thereby effectively increasing blood hemoglobin (Hgb) 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 Hgb concentration. Normal ranges are 12 to 16 g/dL in women and 14 to 18 g/dL in men. Mild anemia is defined as Hgb from 10 g/dL to the lower limit of normal ranges, moderate anemia is 8 to 10 g/dL, and severe anemia is 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 patients 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 RBC 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 (e.g., gastrointestinal bleeding from colon cancer).

4. Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, and 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 RBC production.

Cancer treatments 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, this approach 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 (e.g., 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), 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 risks of alloimmunization and TRALI provide sufficient rationale for the 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, under the proprietary name, Epogen. The same epoetin alfa product manufactured by Amgen is also marketed and distributed by Janssen Products, a subsidiary of Johnson and Johnson, under the proprietary name, Procrit. Under a contractual agreement with Amgen, Janssen Products 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 U.S. Food and Drug Administration (FDA)-approved indications.

A second ESA, darbepoetin alfa, is marketed solely by Amgen, under the proprietary name, Aranesp.

The third ESA product, peginesatide, was codeveloped and commercialized by Affymax 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 post- marketing 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 half-life that permits once monthly dosing. PEG-epoetin beta was FDA approved in 2007 under the brand name Mircera. Mircera sales in the United States were prohibited from 2009 until 2015 due to a copyright infringement lawsuit, however, Hoffmann-La Roche is now manufacturing and supplying the drug to Galencia, and it is currently available.

Epoetin alfa and epoetin beta have the same amino acid sequence as endogenous erythropoietin but differ from each other in glycosylation; clinical effects are considered interchangeable. 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 Hgb, when given to individuals with functioning erythropoiesis. Both brands of epoetin alfas, PEG-epoetin beta, and darbepoetin alfa 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 alfa also are approved for other indications.

Regulatory Status

The major regulatory timelines for approval actions for 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 non?myeloid 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 non?myeloid 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 post-marketing 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

2015: Resumption of U.S. sales

Recommendations for Use of ESAs

Administration of ESAs

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

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 PEG-epoetin beta dose further is unlikely to improve response and may increase risks; the lowest ESA or PEG-epoetin beta dose that maintains adequate Hgb 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 (REMS)

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 the FDA.

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, the 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.

On April 13, 2017, the FDA announced the elimination of the risk evaluation and mitigation strategy (REMS) for Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin). (55)

Rationale:

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, which was prepared for the Agency for Healthcare Research and Quality (AHRQ), and the 2005 AHRQ report, updated in 2013 (3); a meta-analysis using individual patient data for outcomes of erythropoiesis-stimulating agent (ESA) therapy in patients with cancer, (5, 6) with additional outcomes reported in 2012 (7); 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 (8); 2007 briefing documents available from the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC); and a 2007 Decision Memorandum from the Centers for Medicare and Medicaid Services on the use of ESAs for nonrenal disease indications.

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; and, a meta-analysis of blood hemoglobin (Hgb) targets for patients with CRF-associated anemia. (11) FDA-approved labels for ESAs available in the United States comprised additional data sources for this policy, in particular, recommended dosing information for the different clinical settings covered.

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) Hgb 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. (8)

Chronic Kidney Disease and Anemia

Epoetin Alfa, Epoetin Beta, and Darbepoetin

At initial approval of epoetin in 1989, the primary objective of treatment was to raise Hgb 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 Hgb concentration of 11 g/dL, a level that was increased by subsequent NKF-KDOQI anemia guidelines, to 11 to 13 g/dL in 2007. (16) With increased experience in the use of ESAs, it became unclear whether higher Hgb target concentrations, including normalization, would yield additional benefits, in particular, physical function and improved cardiovascular outcomes. Clinical doubts increased with publication of the first large randomized controlled trial (RCT) of Hgb normalization using epoetin alfa in hemodialysis patients (Normal Hematocrit Cardiac Trial [NHCT]). (17) 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 Hgb targets, but none demonstrated significant improvements in cardiovascular end points or mortality. (18)

The Epogen/Procrit labeling 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%. In 2006, the CHOIR study reported worse cardiovascular outcomes for anemic CRF patients who were not undergoing dialysis and who were randomized to a target Hgb of 13.5 g/dL, compared with an Hgb of 11.3 g/dL. (19) 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 Hgb target. (20) The CREATE study, also reported in 2006, was similar to CHOIR but enrolled fewer patients. (21) CREATE did not demonstrate statistically significant differences in adverse cardiovascular outcomes for the higher Hgb 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, Hgb of 11 g/dL or less, and CKD not on dialysis. (22) Patients in 1 arm were treated with darbepoetin to a target Hgb of 13 g/dL, and those in the other arm received darbepoetin only if Hgb 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 Hgb 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, Hgb, or platelet count; or to darbepoetin dose. (23)

A 2012 meta-analysis by Vinhas et al. included only large RCTs (N>500) with a minimum duration of 1 year. (24) Outcomes of interest were vascular access thrombosis, stroke, progression to ESRD, and all- cause mortality. Five trials (7902 patients), including the CHOIR, CREATE, NHCT, and TREAT trials, were identified. Mean or median duration of follow-up ranged from 14 to 36 months. As shown in Table 1, higher Hgb 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. (24)

Outcome

n/N

Relative Riska

95% CI

I2 b

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.

a Relative risk for outcome at higher Hgb targets (13.0-15.0 g/dL) compared with lower Hgb targets (9.5-11.5 g/dL).

b Describes the proportion of total variation across studies that is due to heterogeneity rather than chance.

In 2012, the American Society of Nephrology released its evidence-based recommendations for the “Choosing Wisely” campaign to improve patient care and resource use. (25) Citing the evidence reviewed, 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. (26) No statistically significant differences were observed in random effects meta-analyses of final Hgb or mean change in Hgb 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

The 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 CKD (see Table 2). In 2 trials (total N=505), patients were not receiving ESA therapy (correction trials), and in 6 trials (total N=1894), Hgb was stable on maintenance ESA therapy (maintenance trials). All but 1 trial (ARCTOS) enrolled dialysis-dependent patients. The primary efficacy outcome in all trials was maintenance of Hgb levels over 24 to 52 weeks, adjusted for baseline Hgb and center, in the intention-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, STRIATA). In the correction trials (ARCTOS, 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 Hgb ranges in these trials included levels that have since been associated with increased mortality in CKD (i.e., >11 g/dL), (27) 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). 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 100 x109 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.

Table 2. Pivotal Trials of PEG-Epoetin Beta

N

Initial Dose

Results

% Respondersa

Mean

ΔHgbb, g/dL

Correction trials in patients not receiving ESA therapy

Macdougall 2008 (ARCTOS) (29) 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) (30)

PEG-epoetin beta

135

0.4 µ/kg IV q2wk

93

2.70

Epoetin alfa/beta

46

Per product label IV 3 µ/wk

91

2.56

P value

<0.001d

<0.001e

Maintenance trials in patients receiving ESA therapy

Levin 2007 (MAXIMA) (31)

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

<0.001e,f

Sulowicz 2007 (PROTOS) (32)

PEG-epoetin beta SC q2wk

190

PEG-epoetin beta dose

based on maintenance

ESA dose

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 vs control

-g

<0.001e,f

Canaud 2008 (STRIATA) (33)

PEG-epoetin beta IV q2wk

157

Comparator ESA dose was continuation of maintenance dose

66

0.06

Darbepoetin IV q1-2wk

156

72

-0.12

P value

0.25h

<0.001e

Spinowitz 2008 (RUBRA) (34)

PEG-epoetin beta SC/IV q2wk

168

69

0.09

Epoetin alfa/beta SC/IV q1-

2wk

168

68

-0.03

P value

-i

<0.001e

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

a Defined as:

ARCTOS: Hgb level ≥11 g/dL and increased ≥1.0 g/dL from baseline at 28 wk; target Hgb 11-13 g/dL

AMICUS: Hgb level ≥11 g/dL and increased ≥1.0 g/dL from baseline at 24 wk; target Hgb 11-13 g/dL

PROTOS, STRIATA: Mean Hgb within ±1 g/dL of baseline values through 52 wk; target Hgb 10-13.5 g/dL

b Change from baseline Hgb at 24 wk (AMICUS), 28 wk (ARCTOS), 36 wk (MAXIMA, STRIATA, RUBRA), or 52 wk (PROTOS).

c Patients with stage 3 or 4 CKD (creatinine clearance <59 mL/min) who were not on dialysis.

d For noninferiority to a predefined minimum of 60%.

e For noninferiority to comparator; noninferiority margin for difference in mean Hgb level (PEG-epoetin beta minus comparator), -0.75 g/dl.

f Both comparisons.

g Trial investigators did not report statistical testing. Neither PEG-epoetin beta group was statistically different from comparator by χ2 test (author calculation; p=0.52 for q2wk PEG-epoetin beta, p=0.36 for q4wk PEG-epoetin beta).

h Chi-square test.

i Trial investigators did not report statistical testing. There was no statistical difference between groups by χ2 test (author calculation; p=0.88).

A 2014 Cochrane review included random effects meta-analyses of the 5 trials that enrolled dialysis patients listed in Table 2 and reported no statistical between-group differences in final Hgb level (compared with epoetin), overall mortality, blood transfusions, or adverse events due to hypertension or vascular access thrombosis. (35) In the STRIATA trial, final Hgb 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%). Another systematic review published in 2014 evaluated the efficacy of PEG-epoetin beta versus darbepoetin for treatment of anemia in patients with CKD who are not dialysis-dependent. (36) This review included 4 RCTs (total N=1155 patients) and concluded that there were no differences between PEG-epoetin beta and darbepoetin on the change in Hgb levels.

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 (91%) 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 Hgb between 11 to 13 g/dL. Mean (SD) Hgb 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 Hgb levels was similar across groups.

Peginesatide

The 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 Hgb 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 Hgb 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. (43) 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 the FDA 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 (e.g., patients with a non?myeloid malignancy who are anemic while receiving palliative chemotherapy, HIV patients who are anemic while receiving zidovudine, or perisurgical patients unable to donate autologous blood).

On February 23, 2013, Affymax, Takeda, and the FDA announced a voluntary recall of all lots of peginesatide due to post-marketing 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. The FDA currently lists peginesatide (Omontys) as “Discontinued” on its website (Drugs@FDA).

Comparative Efficacy of Different ESAs

While there are RCTs that directly compare different ESAs, the evidence base on the comparative efficacy of different ESAs is incomplete. A Cochrane network meta-analysis was published in 2014 that attempted to use indirect comparisons via network meta-analysis to evaluate comparative efficacy. (45) This analysis included RCTs that compared one ESA with placebo, no treatment, or another ESA for the treatment of CKD. A total of 56 studies involving 15,596 patients were included in the review, the majority of which were judged to have high or uncertain risk of bias. The network meta-analysis did not allow conclusions on the comparative efficacy of different agents in preventing blood transfusions. There were very few studies that included patient-reported outcomes (e.g., quality of life) and as a result, the evidence base was also insufficient to make conclusions on these other outcomes.

Section Summary: Chronic Kidney Disease and Anemia

Three ESAs are FDA-approved for use in patients with CRF: epoetin alfa, PEG-epoetin beta, and darbepoetin alfa. Placebo-controlled clinical trials have established that epoetin alfa and darbepoetin alfa effectively increase Hgb 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 an Hgb of 12 g/dL or higher. The optimal target Hgb is unclear, and it is uncertain whether treating to lower Hgb 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 Hgb levels in RCTs of patients on dialysis or not on dialysis. In meta-analyses of trials involving dialysis patients, no statistical differences were reported in overall mortality, blood transfusions, or adverse events due to hypertension or venous access thrombosis. Evidence on comparative effectiveness of the different agents is lacking. A Cochrane network meta-analysis was not able to make any conclusions on comparative effectiveness due to limited comparative evidence.

Cancer-Related Anemia

Epoetin Alfa, Epoetin Beta, and Darbepoetin

In 1993, The 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 Hgb levels above 12 g/dL. (8) In addition, ESA treatment strategies intended to achieve and maintain Hgb 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. (5, 6) 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 Hgb levels above 12 g/dL. More recent data, including the individual patient data meta-analysis summarized earlier, (5, 6) suggested that factors such as the planned Hgb ceiling for stopping ESA therapy had little influence on increased mortality resulting from ESA treatment. Although risks of Hgb targets greater than needed to avoid transfusions are now well-established, data from adequate, well-controlled studies employing recommended ESA doses and Hgb 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 Hgb 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 the FDA to reassess the safety of ESAs in patients with cancer and to re-evaluate the net clinical benefit of ESAs in this setting.

Results of the updated AHRQ comparative effectiveness review (2013) were consistent with those reported in 2006. 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 Hgb less than 10 g/dL. Although the reviewed evidence incorporated higher baseline and target Hgb 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. (5, 6) Despite differing inclusion criteria and methodologies, additional analyses of these data by Tonia et al. (2012) (7) supported results of the updated AHRQ review, as shown in Table 3.

Table 3. 2013 AHRQ Report and 2012 Individual Patient Data: Comparison of Updated Results

2013 AHRQ

2012 Individual

Patient Data (7)

n/N

Result

(95% CI)

n/N

Result

(95% CI)

Transfusions, RR

38/10,809

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.

a Results are similar between the 2 analyses.

b No evidence of an association with erythropoiesis-stimulating agents.

c Point 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. (46) 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, and Hoffmann- LaRoche, manufacturer of PEG-epoetin beta, has not sought this indication. 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. (47) Baseline Hgb 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 Hgb 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: Cancer-Related Anemia

Epoetin alfa and darbepoetin alfa are approved for patients with anemia associated with concurrent cancer chemotherapy. These ESAs effectively increase Hgb 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 an Hgb 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 Hgb 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 Hgb 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.

Hepatitis C Infection Treated With Ribavirin–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 therefore, some experts 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 controlled trials randomized patients with hepatitis C virus and ribavirin-related anemia to epoetin alfa or usual care. The larger of these was conducted by Afdhal et al. (2004). (48) This trial included 185 patients with an Hgb 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 Hgb level, and QOL as measured by 36-item Short-Form Health Survey. More patients in the epoetin group (88%) than in the usual care group (60%, p<0.001) were able to maintain full-dose ribavirin. Increase in mean Hgb level also was higher in the epoetin 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 epoetin 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) (49) was similar to the Afdhal trial. Dieterich et al. enrolled 64 patients with hepatitis C and ribavirin-related anemia, as defined by Hgb 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 Hgb 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 epoetin group (83%) than in the usual care group (54%, p=0.02) were able to maintain full-dose ribavirin. Mean Hgb level was higher in the epoetin 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. (50) 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 epoetin (40%, p<0.05), but the proportion of patients with SVR did not differ between groups.

Section Summary: Hepatitis C Infection Treated With Ribavirin–Related Anemia

RCTs of ESAs versus placebo for patients with hepatitis C and ribavirin-related anemia have demonstrated that use of ESAs can improve Hgb levels and allow more patients to maintain treatment at full 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, as evidenced in the CHOIR and NHCT studies. 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 labeling for Aranesp, Epogen, and Procrit 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.

Regarding dosage information, periodic reassessment of ESA safety has determined that clinical data do not support a therapeutic Hgb target free of risk for mortality. Consequently, revised “Dosage and Administration” sections of the product label deleted any specific therapeutic Hgb or Hct "target" range for ESAs. Instead, revised labels recommended that prescribers use the lowest ESA dose that will gradually increase Hgb 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 Hgb or Hct threshold or range. Clinical data did not identify specific Hgb 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. (10) 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. Although the Mircera product label has not been updated since 2007, “Warnings” for use in CRF are similar to those listed next.

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 use 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 an Hgb level of greater than 11 g/dL.

No trial has identified an Hgb 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, the 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.

Summary of Evidence

The evidence for erythropoiesis-stimulating agents (ESAs; e.g., epoetin alfa, pegylated epoetin beta, darbepoetin) in individuals who have chronic kidney disease and anemia includes randomized controlled trials (RCTs) and systematic reviews of RCTs. Relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. All 3 ESAs have been studied and approved for this use. Most of the evidence has demonstrated a decrease in the need for blood transfusions but has failed to demonstrate any significant improvement in other clinical outcomes, including mortality, morbidity, functional status, or quality of life. Many studies have, in fact, demonstrated increased mortality risk and increased risk for venous access thrombosis and stroke, prompting U.S. Food and Drug Administration (FDA) warnings and a risk evaluation and mitigation strategy. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence for ESAs (e.g., epoetin alfa, darbepoetin) in individuals who have cancer-related anemia includes RCTs and systematic reviews of RCTs. Relevant outcomes are symptoms, morbid events, medication use, and treatment-related mortality and morbidity. The available trials have demonstrated an increase in hemoglobin concentration and a decrease in the need for blood transfusions. However, the evidence has also demonstrated increased mortality rates and possible tumor promotion, as well as increased risk of thromboembolic events, when target hemoglobin levels were above 12 g/dL. Epoetin alfa and darbepoetin are the ESAs approved for use in treatment of cancer-related anemia; pegylated epoetin beta is not FDA approved for this indication, as studies have demonstrated increased mortality and no significant improvement in clinical outcomes. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence for ESAs (e.g., epoetin alfa, darbepoetin) in individuals who have hepatitis C infection treated with ribavirin includes RCTs. Relevant outcomes are quality of life and medication use. Evidence from RCTs demonstrates that treatment with ESAs improves the ability to maintain full-dosing of ribavirin, as anemia is often a limiting effect for treatment. There may also be a positive effect on quality of life, although this is less certain. Epoetin alfa and darbepoetin are the ESAs approved for this use. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

National Kidney Foundation

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. (16) The guidelines reviewed evidence for epoetin alfa, epoetin beta, and darbepoetin. Updated recommendations included Hgb target of 11 to 12 g/dL (consensus recommendation); target Hgb should not exceed 13 g/dL (guideline supported by moderately strong evidence). Guideline authors provided no specific Hgb level at which to initiate ESA therapy and emphasized that treatment decisions should be individualized (consensus recommendation).

American Society of Clinical Oncology et al.

Table 4 summarizes current clinical practice guidelines published jointly by the American Society of Clinical Oncology and the American Society of Hematology (8) and from the National Comprehensive Cancer Network (v.2.2016).

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

ASCO/ASH

2010 CLINICAL Practice Guideline

NCCN Guidelines

Cancer, Chemotherapy-Induced Anemia (v.2.2016)

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 is not recommended when patients are not receiving therapy or palliative treatment, or those on non-myelosuppressive therapy.

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 (REMS)

Notes requirement

Notes requirement

Hgb levels for ESA initiation

Recommended when Hgb level has decreased to <10 g/dL. Whether or not to initiate treatment when Hgb 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 Hgb 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 (i.e. minimize ESA exposure) to reach the lowest Hgb 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, e.g., every 2 or 3 weeks instead of weekly injections.

Hgb target

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

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

ASCO: American Society of Clinical Oncology; ASH: American Society of Hematology ESA: erythropoiesis- stimulating agent; FDA: U.S. Food and Drug Administration; Hgb: hemoglobin; MDS: myelodysplastic syndrome; NCCN: National Comprehensive Cancer Network; RBC: red blood cell; REMS: risk evaluation and mitigation strategy.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J0881, J0882, J0885, J0887, J0888, J0890, S9537, Q4081

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. 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. Available at<http://www.fda.gov> (accessed August 12, 2015).

2. 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.) Rockville, MD, April 2013.

3. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. May 17 2006; 98(10):708-714. PMID 16705125

4. 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, May 2006.

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. PMID 19588423

6. 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

7. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012; 12:CD003407. PMID 23235597

8. 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

9. Centers for Medicare and Medicaid Services (CMS). Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N), July 30, 2007. Available at<http://www.cms.gov> (accessed August 12, 2015).

10. U.S. Food and Drug Administration. FDA Briefing Document, September 11, 2007 Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Committee. Reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with chronic renal failure. Available at<http://www.fda.gov> (accessed August 12, 2015).

11. Strippoli GF, Craig JC, Manno C, et al. Hemoglobin targets for the anemia of chronic kidney disease: a meta- analysis of randomized, controlled trials. J Am Soc Nephrol. Dec 2004; 15(12):3154-3165. PMID 15579519

12. Amgen Inc. Epogen® (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, April 2014. Available at<http://www.epogen.com> (accessed August 12, 2015).

13. Amgen Inc. Procrit® (epoetin alfa) injection for intravenous or subcutaneous use prescribing information, December 2013. Available at<http://www.procrit.com> (accessed August 12, 2015).

14. Amgen Inc. Aranesp® (darbepoetin alfa) injection for intravenous or subcutaneous use prescribing information, December 2013. Available at<http://www.aranesp.com>. (accessed August 12, 2015).

15. Hoffmann-La Roche, Inc. Mircera® (methoxy polyethylene glycol-epoetin beta) solution for injection: intravenous (IV) or subcutaneous (SC) use prescribing information, November 2007. Available at<http://www.accessdata.fda.gov> (accessed August 12, 2015).

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Office Director Memo: application number BLA 125164. Available at <http://www.accessdata.fda.gov> (accessed August 12, 2015).

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. Alsalimy N, Awaisu A. Methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa for anemia in non-dialysis-dependent CKD: a systematic review. Int J Clin Pharm. Dec 2014; 36(6):1115-1125. PMID 25288147

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). Chicago, Illinois: Blue Cross Blue Shield Association. 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. Available at<http://www.fda.gov> (accessed August 12, 2015).

45. 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. PMID 25486075

46. Gao S, Ma JJ, Lu C. Venous thromboembolism risk and erythropoiesis-stimulating agents for the treatment of cancer-associated anemia: a meta-analysis. Tumour Biol. Jan 2014; 35(1):603-613. PMID 23959477

47. 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

48. 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

49. 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

50. 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

51. 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). Available at<http://www.fda.gov> (accessed August 12, 2015).

52. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: cancer- and chemotherapy-induced anemia, version 1.2016. Available at<http://www.nccn.org> (accessed August 12, 2015).

53. 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. Available at<http://www.cms.gov> (accessed August 12, 2015).

54. Erythropoiesis-Stimulating Agents. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (March 2016) Prescription Drug 5.01.04.

55. U.S. FDA 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) – 2017. Available at<https://www.fda.gov> (accessed July 2017).

Policy History:

Date Reason
2/15/2018 Document updated with literature review. The following changes to Coverage were made: Peginesatide (Omontys®)—Drug Specific Criteria was removed. The following Coverage statement was added: The use of PEG-epoetin beta (Mircera) is considered experimental, investigational and/or unproven for all other indications.
6/1/2016 Reviewed. No changes.
9/15/2015 Document updated with literature review. The following was added to Coverage: When the General Criteria are met, Pegylated (PEG)-epoetin beta may be considered medically necessary for treatment of anemia associated with chronic kidney disease (CKD). Authorization limit of “every 24 weeks for chronic renal failure” was removed for Epogen, Procrit and Aranesp.
7/1/2014 Reviewed. No changes.
6/1/2013 Document updated with literature review. Coverage unchanged. Rational completely revised.
7/1/2012 CPT/HCPCS codes updated. The following was added regarding a new FDA approved drug: “Peginesatide (Omontys) may be considered medically necessary for treatment of anemia due to chronic kidney disease in adult patients on dialysis.” Also, the following general criteria bullet was added: “For use in chronic kidney failure (including end-stage renal disease-ESRD), therapy may be initiated to reduce the need for red cell transfusions when Hgb has dropped below 10 g/dL (no target Hgb is recommended, but levels of 11 g/dL or greater should be avoided).” Two general criteria bullets were merged into the following one bullet: “For use in cancer patients, ESA therapy should not be initiated until the Hgb (hemoglobin) level is approaching or has fallen below 10 g/dL; and ESA therapy should not be used to raise the Hgb level above 12 g/dL.”
4/15/2012 The following change(s) were made: Normal thyroid function and control of hypertension were removed from the Coverage criteria and were placed in the Rationale section.
9/1/2011 The general criteria for ESA therapy changed from needing both blood ferritin and transferrin saturation to needing either blood ferritin OR transferrin saturation. The following statement was added to the documentation requirements for continued ESA therapy: Documentation should include the current Hgb and current test(s) for iron stores (i.e., blood ferritin OR transferrin saturation).
1/1/2011 Document updated with literature review. The following changes were made: 1) ESAs may be considered medically necessary in cancer patients with metastatic non-myeloid malignancies who are undergoing myelosuppressive chemotherapy, anemia is caused by the chemotherapy, anemia is not due to other factors, and anticipated outcome of myelosuppressive therapy is not cure; 2) For ESAs related to AZT in HIV-infected patients, requirement was added that the endogenous serum erythropoietin level is ≤ 500 mUnits/ml; 3) Aplastic anemia and any other type of anemia were added to the list of examples of experimental, investigational and unproven indications; 4) Continued therapy requires clinical documentation of ongoing need every 12 weeks for treatment of anemia secondary to chemotherapy, and every 24 weeks for chronic renal failure; 5) A form is available for optional use to assist in requesting review for consideration of coverage of ESAs. The form is available on the Provider / Forms page of the applicable Blue Cross Blue Shield web site.
11/15/2008 New medical document

Archived Document(s):

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