5.01.04

Erythropoiesis-Stimulating Agents (ESAs)

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Medical Policy
Section Prescription Drug	Original Policy Date 12/01/95	Last Review Status/Date Reviewed with literature/2:2008
Issue 2:2008		Return to Medical Policy Index

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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.

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Description

Policy

The use of ESA may be  medically necessary for:

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

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

In addition, for the medically necessary use in cancer patients these additional items also apply:

• ESA therapy should not be initiated until the Hb level is approaching or has fallen below 10 g/dL; and 
• ESA duration of treatment for each course of chemotherapy is 6 to 8 weeks following the final dose of myelosuppresive chemotherapy.

The use of an ESA is investigational for:

• treatment of patients following high-dose chemotherapy with autologous stem-cell support; and
• treatment of non-iatrogenic chronic anemia of cancer

1        FDA-approved label for epoietin alfa (Epogen®, Procrit®)

2        FDA-approved label for darbepoetin alfa (Aranesp®)

Policy Guidelines

Benefit Application

Rationale

The initial search of the literature for this policy was completed through the MEDLINE database for the period of January 1990 through May 1995. The search strategy focused on references containing the following Medical Subject Headings:

 

- Anemia

- Bone-Marrow Transplantation

- Cancer

- Erythropoietin

- Erythropoietin, Therapeutic Use

- Stem-Cell Support

Research was limited to English-language journals on humans.

 

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 policy statements regarding these two settings.

This policy revision addresses use of ESAs in oncology and chronic renal failure patients. The primary data sources for oncology included a 2006 comparative meta-analysis of the use of epoetin or darbepoetin for managing anemia in patients undergoing cancer treatment prepared for the Agency for Healthcare Research and Quality (AHRQ) (1, 2); updated American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) 2007 clinical practice guidelines on the use of epoetin and darbepoetin to treat chemotherapy-associated anemia (3); 2007 briefing documents available from the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) (4); and, a 2007 Decision Memorandum from the Centers for Medicare and Medicaid services (CMS) on the use of ESAs for non-renal disease indications (5).

Information on the use of ESAs in chronic renal failure (CRF) was obtained from several sources including 2007 briefing documents from a joint meeting of the FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) and the Drug Safety and Risk Management Advisory Committee (DSRMAC) to reassess the risks of ESAs (6); and, a recent meta-analysis of Hb targets for patients with CRF-associated anemia (7). The FDA-approved labels for ESAs available in the U.S. comprise additional data sources for this Policy, in particular recommended dosing information for the different clinical settings covered (8-10).
The 2007 ASCO/ASH clinical practice guideline for the use of ESAs “considers epoetin and darbepoetin, used at dosages recommended in current U.S. FDA-approved package inserts, to be equivalent with respect to effectiveness and safety…Epoetin and darbepoetin are identical with respect to: (a) indications for use in chemotherapy-induced anemia, (b) hemoglobin (Hb) limits for adjusting doses or discontinuing treatment, (c) warnings and cautions to consider, and (d) increased rates of thromboembolic events in the experimental arms of separate trials on each product versus controls/placebo” (3).
ESAs in Chronic Renal Failure
To support the initial FDA approval of Epogen/Procrit for anemia of CKD, substantial evidence of efficacy was provided predominantly from placebo-controlled and single arm clinical studies that demonstrated the product sufficiently increased and maintained blood Hb levels to reduce the need for red blood cell transfusions. In the clinical development program for Aranesp, evidence of efficacy was provided predominantly from active comparator studies that demonstrated the product increased and maintained Hb concentrations in a manner similar to that of the comparator. In this development paradigm, blood Hb concentration served as a form of surrogate for "reduction in the need for red blood cell transfusions.”
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 9-10g/dL in anemic CKD patients. The first National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines in 1997 recommended a Hb concentration of 11 g/dL, a level that was increased by the second NKF-KDOQI anemia guidelines to 11-13 g/dL (11). 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 RCT of Hb normalization in hemodialysis (HD) patients (Normal Hematocrit Cardiac Trial [NHCT]), that showed a trend toward increased mortality risk and significantly increased risk for vascular access thrombosis with ESA treatment to a Hct target of 42% (12). Subsequently, 4 published RCTs in HD patients with end-stage renal disease (ESRD) and 8 in nondialysis patients with CKD found improved physical function at higher Hb targets but none demonstrated significant improvements in cardiovascular endpoints or mortality (13).
On the basis of the totality of results, the Epogen/Procrit label was modified in 1996 to include the results of the NHCT study that showed a higher mortality rate for anemic dialysis patients randomized to a Hct of 42%, compared to a Hct of 30%. Ten years later, the CHOIR study reported worse cardiovascular outcomes for anemic CRF patients who were not undergoing dialysis and who were randomized to a Hb of 13.5 g/dL, compared to a Hb of 11.3 g/dL (14). The CREATE study, also reported in 2006, was a study similar to CHOIR but enrolled fewer patients (15). CREATE did not demonstrate statistically significant differences in adverse cardiovascular outcomes for the higher Hb group, but the general trend of the major cardiovascular outcomes was similar to the CHOIR findings.
ESAs in Oncology
The basis of approval for Procrit/Epogen for the expanded indication of treatment of anemia associated with cancer chemotherapy in 1993 was demonstration of a reduction in the proportion of patients transfused during chemotherapy within the second and third months of chemotherapy and Epoetin alfa administration. The approval was based on data pooled from 6 randomized, placebo-controlled, double-blind, clinical trials in a total of 131 anemic cancer patients receiving at least 12 weeks of concurrent chemotherapy who were randomized (1:1) to receive Procrit or placebo subcutaneously for 12 weeks.
The approval of Aranesp for the treatment of anemia associated with cancer chemotherapy was based on demonstration of a significant reduction in the proportion of patients transfused during chemotherapy during week 5 through the end-of-treatment. Study 980297, a Phase 3, double-blind, placebo-controlled, randomized (1:1) multicenter, multinational study of darbepoetin alfa enrolled 314 anemic patients with previously untreated non-small cell or small cell lung cancer receiving at least 12 weeks of platinum-containing chemotherapy.
Since the first approval of an ESA for treatment of chemotherapy-associated anemia in 1993, additional data became available regarding the increased risks of mortality and of possible tumor promotion from the use of ESAs. Increased mortality has been observed in patients with cancer (BEST, ENHANCE, 20000161, and EPO-CAN-20 studies) when ESA treatment strategies were designed to achieve and maintain Hb levels above 12 g/dL (3). In addition, ESA treatment strategies intended to achieve and maintain Hb levels above 12 g/dL have demonstrated poorer tumor outcomes (BEST, ENHANCE, and DAHANCA studies).
Data from recent clinical trials, consistent with earlier clinical trials presented to ODAC in May 2004, led to revised product labeling that includes more expansive and detailed warnings regarding use of ESA treatment strategies that are designed to maintain Hb levels above 12 g/dL. While the risks of treatment strategies in which ESAs are used to achieve and maintain Hb levels in excess of that needed to avoid transfusions have been clearly demonstrated to be unacceptable, data from adequate, well-controlled studies employing the recommended doses of ESAs are as yet insufficient to assess effects on survival or tumor promotion. The only data provided to FDA which used the recommended dose and medication was from Amgen Study 20010103, that demonstrated significantly shorter survival in cancer patients receiving ESAs as compared those receiving transfusion support. However, this study was not adequately designed to assess effects on tumor promotion or on thrombotic risks.
Despite these caveats, data from the available body of clinical studies provided sufficient rationale for the FDA to re-assess the safety of ESAs in patients with cancer and to re-evaluate the net clinical benefit of ESAs in this setting.
2006-2007 FDA Regulatory Actions
In November, 2006 FDA issued a Public Health Advisory regarding the serious cardiovascular risks evidenced in the CHOIR study and the NHCT study (6). Subsequently, FDA received reports of increased risks associated with ESAs used in the treatment of chemotherapy-induced anemia among cancer patients, the use of ESAs among cancer patients not receiving chemotherapy as well as a report of thrombotic risks among patients receiving an ESA in the perisurgical setting. These data prompted a reassessment of the safety information contained in the ESA product labels and culminated in the approval of revised labels on March 9, 2007.
With respect to dosage information, the reassessment of ESA safety determined that clinical data did not support a specific therapeutic Hb goal, exclusive of the upper Hb limit of 12 g/dL. Consequently, the dosage and administration sections of the label revisions deleted references to any specific therapeutic Hb or Hct "target" range for ESAs. Instead, the label revisions recommended that prescribers use the lowest ESA dose that will gradually increase the Hb concentration to the lowest level sufficient to avoid the need for red blood cell transfusion. This recommendation was based, with respect to the use of ESAs among anemic CRF patients, predominantly upon the NHCT and CHOIR study findings as well as the lack of data to support the safety of any specific Hb or Hct level or range under 12 g/dL. Clinical data were not available to identify specific Hb or Hct levels that directly correlated with a "reduction in the need for red blood cell transfusion," the main treatment benefit supporting ESA efficacy. The March, 2007 label revision allowed prescribers to use their clinical judgment in determining the "lowest level sufficient to avoid the need for red blood cell transfusion."
Updated 2007 FDA Recommendations and Considerations for Healthcare Professionals
On November 8, 2007, FDA released information to update Healthcare Professionals about revisions to the product labeling for ESAs (16). These revisions are intended to clarify the evidence for safety and effectiveness and provide more explicit directions and recommendations to prescribers for their use. They are consistent with recommendations made at the May 10, 2007, ODAC and the September 11, 2007, meeting of the CRDAC and the DSRMAC. The revised product labeling includes a strengthened Boxed Warning and Warnings, changes to the Indications and Usage, Clinical Experience, and Dosage and Administration sections of the labeling for all ESAs. The changes to the prescribing information for the ESAs (Aranesp, Epogen and Procrit) summarized below expand on the revision made to the labeling and described in a Healthcare Professional sheet issued in March 2007 and include recommendations made by these FDA Advisory Committees: ODAC, CRDAC and DRSMAC.
Cancer

Chronic Renal Failure

• Risks for death and serious cardiovascular events are greater when ESAs are administered to achieve higher target hemoglobin levels (13.5 to 14 g/dL) versus lower hemoglobin levels (10 to 11.3g/dL).
• Dosing should be individualized to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL.
• If a patient is hypo-responsive (hemoglobin levels do not increase or reach the recommended range despite appropriate dose titrations over 12 weeks)
  • Do not administer higher doses and use the lowest dose that will maintain a hemoglobin level to avoid the need for recurrent blood transfusions.
  • Evaluate and treat other causes of anemia, and continue monitoring hemoglobin levels.
  • Follow instructions for dose adjustments.
  • Discontinue ESAs if the patient remains transfusion dependent.

HIV treated with Zidovudine

• Use of ESAs in anemic patients with HIV that have been treated with Zidovudine have not been demonstrated in controlled clinical trials to improve the symptoms of anemia, quality of life, fatigue, or well-being.

Patient Counseling Information
As part of a risk minimization plan, a patient Medication Guide to better communicate the risks and benefits of ESA use to patients is currently being developed.
Physicians and other healthcare professionals should discuss the following with their patients:

• The primary goal of treatment with erythropoiesis stimulating agents (ESA) is to increase the number of red blood cells in order to avoid receiving blood transfusions.
• ESAs require at least 2 weeks of treatment before there is an increase in the number of red blood cells and the dose may be adjusted periodically but not more often than every 4 weeks.
• ESAs increase their chance of blood clots and the risk of dying may be greater in certain circumstances
• They should keep appointments for blood tests so hemoglobin levels can be monitored.
• They need to monitor their blood pressure and to call you if there are any changes outside of the range that has been established for them.
• Call you if they experience any of the following symptoms:
  
  • Pain and/or swelling in the legs
  • Worsening in shortness of breath
  • Increases in blood pressure
  • Dizziness or loss of consciousness
  • Extreme tiredness
  • Blood clots in hemodialysis vascular access ports

2007 Center for Medicare and Medicaid Services (CMS) Decision Memorandum
In July 2007, CMS released a Decision Memorandum on the use of ESAs for non-renal disease indications (CAG-00383N) (5). Emerging safety concerns such as thrombosis, cardiovascular events, tumor progression, and reduced survival, derived from clinical trials in several cancer and non-cancer populations, prompted CMS to review its coverage of erythropoiesis stimulating agents (ESAs). CMS reviewed a large volume of scientific literature, including basic science research, to see if safety findings observed in RCTs could be reasonably explained in whole or in part by the actions of ESAs on normal or cancerous cells. Based on this review, CMS proposed conditions of coverage based on expression of erythropoietin receptors. However, the scientific understanding of this mechanism is controversial, and requires additional study.
CMS also reviewed comments on ESAs treatment of myelodysplastic syndrome (MDS), a precursor of acute myeloid leukemia (AML) in many patients. CMS retains interest in these specific issues, but does not differentiate ESA coverage by the erythropoietin receptor status of the underlying disease, and has decided to make no national coverage determination (NCD) at this time on ESAs in MDS.
CMS has determined that evidence is sufficient to conclude that ESA treatment is not reasonable and necessary for beneficiaries with certain clinical conditions, either because of a deleterious effect of the ESA on their underlying disease or because the underlying disease increases their risk of adverse effects related to ESA use. These conditions include:

• any anemia in cancer or cancer treatment patients due to folate deficiency, B-12 deficiency, iron deficiency, hemolysis, bleeding, or bone marrow fibrosis
• the anemia associated with the treatment of acute and chronic myelogenous leukemias (CML, AML), or erythroid cancers
• the anemia of cancer not related to cancer treatment
• any anemia associated only with radiotherapy
• prophylactic use to prevent chemotherapy-induced anemia
• prophylactic use to reduce tumor hypoxia
• patients with erythropoietin-type resistance due to neutralizing antibodies
• anemia due to cancer treatment if patients have uncontrolled hypertension.

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

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

This decision by CMS also allows local Medicare contractors to continue to make reasonable and necessary determinations on all uses of ESAs that are not determined by NCD.
2007 ASCO/ASH Guideline Update on Use of Epoetin and Darbepoetin in Patients with Cancer
As noted above, the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) have published their 2007 guideline update on use of ESAs in patients with cancer. (3) Key points of this report are summarized below:
For patients with chemotherapy-associated anemia, the Committee continues to recommend initiating an erythropoiesis-stimulating agent (ESA) as hemoglobin (Hb) approaches, or falls below, 10 g/dl, to increase Hb and decrease transfusions. ….
Starting doses and dose modifications based on response or lack thereof should follow the package insert. Continuing ESAs beyond 6 to 8 weeks … does not seem to be beneficial, and ESA therapy should be discontinued. … The Committee also cautions against ESA use for patients with cancer who are not receiving chemotherapy, since recent trials report increased thromboembolic risks and decreased survival under these circumstances.
2007 National Comprehensive Cancer Network Revised Cancer- and Treatment-Related Guidelines
In December 2007, the National Comprehensive Cancer Network (NCCN) released important updates to the NCCN Cancer- and Treatment-Related Anemia Guidelines relating to the use of ESAs (17). This is summarized as follows:

ESAs are no longer recommended for the treatment of cancer-related anemia associated with solid tumors or hematologic malignancies other than myelodysplastic syndromes (MDS). ESA therapy is an option for patients receiving myelosuppressive chemotherapy who have symptoms of anemia and hemoglobin levels of less than 11 g/dL. ESA therapy should only be considered as an option for patients receiving myelosuppressive chemotherapy without symptoms of anemia if they have hemoglobin levels less than or equal to 10 g/dL and additional risk factors for the development of symptomatic anemia requiring transfusion. When ESAs are administered to patients with cancer receiving myelosuppressive chemotherapy, the drug dosage should be titrated to achieve hemoglobin levels in the range of 10 to less than 12  <12 g/dL ="g/dL" purpose="purpose" avoiding="avoiding" red="red" blood="blood" cell="cell" transfusion.="transfusion." Use="Use" ESAs="ESAs" myelosuppressive="myelosuppressive" is="is" limited="limited" during="during" chemotherapy="chemotherapy" for="for" a="a" short="short" period="period" chemotherapy,="chemotherapy," usually="usually" within="within" 6="6" weeks="weeks" following="following" end="end" such="such" therapy.="therapy." reflect="reflect" recent="recent" evidence="evidence" indicating="indicating" decreased="decreased" survival="survival" in="in" patients="patients" with="with" cancer="cancer" receiving="receiving" ESA="ESA" therapy="therapy" changes="changes" made="made" to="to" product="product" labels="labels" of="of" these="these" agents="agents" by="by" the="the" Food="Food" and="and" Drug="Drug" Administration="Administration" (FDA).g/dL for the purpose of avoiding red blood cell transfusion. Use of ESAs in patients with cancer receiving myelosuppressive chemotherapy is limited to the period during chemotherapy and for a short period following chemotherapy, usually within 6 weeks following the end of such therapy. These changes reflect recent evidence indicating decreased survival in patients with cancer receiving ESA therapy and changes made to the product labels of these agents by the Food and Drug Administration (FDA).In order to facilitate shared physician-patient decision-making for those patients with cancer at risk of anemia requiring transfusion who will undergo myelosuppressive chemotherapy, patient counseling regarding the risks and benefits of ESA therapy is recommended.

References:

1. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006; 98:708-14.
2. 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. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
3. Rizzo DL, Somerfield MR, Hagerty KL, Seidenfeld J et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update. J Clin Oncology 2008; 28:132-49. Available online at: http://jco.ascopubs.org/cgi/content/abstract/26/1/132 ,
4. 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. Accessible at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf. Last accessed December 28, 2007.
5. Centers for Medicare and Medicaid Services, July 30, 2007 Decision memo for erythropoiesis stimulating agents (ESAs) for non-renal disease indications (CAG-00383N). Accessible at: http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203. Last accessed December 28, 2007.
6. 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. Accessible at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4315b1-01-FDA.pdf. Last accessed December 28, 2007.
7. Strippoli G, Craig JC, Manno C, et al. Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol 2004; 15:3154-65.
8. Epoetin alfa (Epogen®) Product label, 2007. Accessible at: http://www.fda.gov/cder/foi/label/2007/103234s5158lbl.pdf. Last accessed December 28, 2007.
9. Epoetin alfa (Procrit®) Product label, 2007. Accessible at: http://www.fda.gov/cder/foi/label/2007/103234s5158lbl.pdf. Last accessed December 28, 2007.
10. Darbepoetin alfa (Aranesp®) Product label, 2007. Accessible at: http://www.fda.gov/cder/foi/label/2007/103951s5164lbl.pdf. Last accessed December 28, 2007.
11. National Kidney Foundation. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Accessible at: http://www.kidney.org/professionals/kdoqi/pdf/KDOQI_finalPDF.pdf. Last accessed December 28, 2007.
12. 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. New Engl J Med 1998; 339:584-90.
13. Fishbane S, Besarab A. Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol 2007; 2:1274-82.
14. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. New Engl J Med 2006; 355:2085-98.
15. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. New Engl J Med 2006; 355:2071-84.
16. FDA Information for Healthcare Professionals 2007. Erythropoiesis stimulating agents (ESA). Accessible at: http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE200711HCP.htm. Last accessed December 28, 2007.
17. NCCN Clinical Practice Guideline in Oncology. Cancer- and treatment-related anemia. V.1.2008. Accessible at: http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf. Last accessed December 28, 2007.

Index

Policy History

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