Epoetin alfa and darbepoetin alfa are Erythropoiesis-Stimulating Agents (ESAs), approved for the treatment of anemia (low red blood cells) resulting from chronic kidney disease, chemotherapy, certain treatments for Human Immunodeficiency Virus (HIV), and also to reduce the number of blood transfusions during and after certain major surgeries. ESAs work like the human protein erythropoietin, which stimulates bone marrow to make red blood cells.Epoetin alfa (marketed as Procrit and Epogen) and darbepoetin alfa (marketed as Aranesp), are manufactured by Amgen, Inc.
In 2017, the FDA determined that the ESA Risk Evaluation and Mitigation Strategy (REMS), which was limited to the use of Epogen/Procrit and Aranesp to treat patients with anemia due to associated myelosuppressive chemotherapy is no longer necessary to ensure that the benefits of Epogen/Procrit and Aranesp outweigh its risks of shortened overall survival and/or increased risk of tumor progression or recurrence in patients with cancer.
The FDA made this determination based on an evaluation of the results of the REMS Assessments submitted by Amgen, Inc., and additional FDA analyses to understand the impact of the various regulatory and other actions on the use of ESAs.
The REMS Assessment showed that:
- The results from surveyed prescribers demonstrate acceptable knowledge of the product risks of decreased survival and/or the increased risk of tumor progression or recurrence and the need to counsel patients about these risks.
- The drug utilization data indicates appropriate prescribing of ESAs consistent with the intended use as a treatment alternative to RBC transfusion for anemia associated with myelosuppressive chemotherapy
The FDA conducted an evaluation of the impact of multiple actions, including the ESA REMS, on the utilization of the ESAs using sponsor-submitted data from outpatient oncology practices between 2006 and 2014. During 2004-2009, the FDA took multiple regulatory actions, including labeling changes. In 2007, the Center for Medicare and Medicaid Services (CMS) made a National Coverage Determination (NCD) to limit coverage of ESAs for non-renal disease indications. These actions coincided with:
- A decrease in the proportion of patients receiving chemotherapy using ESAs
- An increase in the proportion of patients receiving chemotherapy who initiate ESAs at a hemoglobin level <10g l,="">10g>
- An increase in the proportion of patients who initiate ESAs at a dosage consistent with product prescribing information.
Full implementation of the ESA REMS in 2011 had minimal impact on trends in these three ESA utilization metrics beyond the changes observed after the CMS coverage determination and multiple other FDA regulatory actions.
This information led the FDA to conclude it is no longer necessary to require the certification of prescribers and hospitals that prescribe and/or dispense ESAs to patients with cancer in order to ensure the benefits outweigh the risks.
The FDA has released the REMS requirements for the ESA products, Epogen/Procrit and Aranesp, and the risks can be communicated by the current product prescribing information. The appropriate use of ESAs is supported by the CMS NCD, the American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) clinical guidelines which are evidence-based guidelines intended to provide a basis for the standard of care in clinical oncology.
While the REMS is no longer necessary to ensure the benefits outweigh the risks, the serious risks of shortened overall survival and/or increased risk of tumor progression or recurrence associated with these drugs remain. The prescribing information continues to note an increased risk of tumor progression or recurrence, as well as death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access. Health care providers are encouraged to discuss the risks and benefits of using ESAs with each patient before initiating use.
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Adverse reactions or quality problems experienced with the use of these Products may be reported to the FDA's MedWatch Adverse Event Reporting program using the contact information at the bottom of this page.
History of REMS for ESAs
In 2008, FDA determined a REMS was necessary for Epogen/Procrit and Aranesp to ensure their benefits for use as a treatment alternative to RBC transfusion for anemia associated with myelosuppressive chemotherapy outweigh their risks of shortened overall survival and/or increased risk of tumor progression or recurrence in patients with cancer. This determination was made after data accumulated from numerous randomized clinical trials indicating an increase in tumor progression and shortened survival in patients with certain types of cancer. The risks were particularly concerning because of the extensive use of these products in cancer patients for uses that extended beyond the treatment of anemia due to myelosuppressive chemotherapy .The results of these trials prompted labeling changes that included a boxed warning and limitations of use. The results were also the topic of discussion at several FDA Oncologic Drugs Advisory Committee meetings. The FDA regulatory actions for ESA prescribing primarily occurred in the years 2004 through 2009. In 2007, the Centers for Medicare & Medicaid Services (CMS) made a National Coverage Determination (NCD) to limit coverage of the ESAs to patients with cancer whose hemoglobin level is less than 10 mg/dL, in addition to other safe use conditions.
The ESA REMS for Epogen/Procrit and Aranesp, approved in February 2010, jointly fall under a common implementation program, the ESA Apprise Oncology Program. The ESA REMS consisted of a Medication Guide, communication plan, elements to assure safe use, implementation system, and a timetable for submission of assessments of the REMS. The REMS required that healthcare providers that prescribe, or prescribe and dispense, ESAs for patients with cancer, become certified. It also required hospitals that dispense ESAs to patients with cancer, to become certified. Finally, the REMS required a Patient and Healthcare Provider Acknowledgement Form be completed for each patient with cancer before the new ESA treatment course to ensure patients were counseled about the benefits and risks of these products. The ESA REMS was fully implemented in 2011.
Labeling and Regulatory History from Drugs@FDA
Postmarket Safety History
- FDA Drug Safety Communication: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease [ARCHIVED] 6/24/2011
- FDA Drug Safety Podcast for Healthcare Professionals: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease [ARCHIVED] 6/27/2011
- Enforcement Discretion Letter Regarding Aranesp Medication Guide (PDF - 33KB) [ARCHIVED] 6/2/2011
- Enforcement Discretion Letter Regarding Epogen/Procrit Medication Guide (PDF - 33KB) [ARCHIVED] 6/2/2011
- Aranesp Risk Evaluation and Mitigation Strategy (REMS) (PDF - 28MB) [ARCHIVED]
- Epogen/Procrit Risk Evaluation and Mitigation Strategy (REMS) (PDF - 27.9MB) [ARCHIVED]
- FDA Announces New Safety Plan for Agents Used to Treat Chemotherapy-Related Anemia [ARCHIVED] 2/16/2010
- FDA Drug Safety Communication: Erythropoiesis-Stimulating Agents (ESAs): Procrit, Epogen and Aranesp [ARCHIVED] 2/16/2010
- Historical Information on Erythropoiesis Stimulating Agents (ESA) (marketed as Procrit, Epogen, and Aranesp) [ARCHIVED]
- Questions and Answers on Medication Guides for Erythropoiesis-Stimulating Agents (ESAs) [ARCHIVED]
- Follow Up to the January 3, 2008 Communication About an Ongoing Safety Review Erythropoiesis-Stimulating Agents (ESAs) Epoetin alfa (marketed as Procrit, Epogen) Darbepoetin alfa (marketed as Aranesp) 10/1/2008 [ARCHIVED]
- Early Communication about an Ongoing Safety Review of Epoetin Alfa [ARCHIVED] 9/26/2008
- CMS Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications 7/30/2007