Table 1FDA alerts and actions related to ESA prescribing

DateNotification TypeContent Change
June 2004Addition of clinical trial results and warning to labelAdded descriptions of clinical trial results showing risks for tumor promotion and increased mortality among cancer patients who were receiving ESAs in the treatment of chemotherapy-induced anemia; an additional warning advised physicians of increased thromboembolic event risks with ESAs in the oncology setting.
November 2006FDA Alert regarding clinical trial resultsThe “Correction of Hemoglobin and Outcomes in Renal Insufficiency” (CHOIR) study50 showed that patients treated with an ESA and dosed to a target Hb of 13.5 g/dL were at a significantly increased risk for serious and life-threatening cardiovascular complications, compared to control Hb target of 11.3 g/dL; the alert emphasized then current dosing recommendation that the target Hb not exceed 12 g/dL.
March 2007New black box warning; updated warnings, and a change to the dosage and administrationHighlights the risk of death and serious cardiovascular events when the Hb target is greater than 12 g/dL and in specific patient categories; recommends avoiding serious cardiovascular and arterial and venous thromboembolic events using the lowest possible ESA dose to reach the lowest Hb level possible to avoid RBC transfusions. Added warnings about increased mortality, cardiovascular events, tumor progression and uncontrolled hypertension. Recommended withholding ESA dose if Hb increase exceeds 12 g/dL or rises by 1g/dL in any 2-week period.
November 2007Expanded black box warning and more specific dosing languageRevisions warn that data are not sufficient to exclude the possibility of shortened survival and tumor progression in patients with cancer when ESAs are dosed to reach a Hb level between 10 and 12 g/dL. Added information that ESAs caused tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid, and non–small-cell lung cancer when they received a dose that attempted to achieve Hb ≥12 g/dL.
March 2008Changed black box warning, modified labeling informationDescribed the results of two additional studies37,51 showing increased mortality and more rapid tumor progression in patients with nonadvanced breast and cervical cancers when dosed to target Hb of ≥12 g/dL.
July 2008Expanded black box warning; dosing language modifiedESAs should not be used in cancer patients receiving chemotherapy if a cure is anticipated. Also included is a statement that ESAs are not to be administered when Hb levels are ≥ 10 g/dL. Language was removed that seemed to imply that it was safe to continue treating patients until their Hb increased to 12 g/dL.
February 2010Announcement of risk evaluation and mitigation strategy (REMS)The FDA requires all ESAs to be prescribed and used under the ESA APPRISE (Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program, part of a REMS, to ensure safe use of the drugs. ESA manufacturers must ensure that only those hospitals and healthcare professionals who have enrolled and completed training in the ESA APPRISE program will prescribe and dispense ESAs to patients with cancer. The ESA APPRISE program began on March 24, 2010.
June 2011More conservative dosing guidelines for ESA use in treating anemia in patients CKD added to black box warning.In controlled trials with CKD patients, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL. Thus, the recommended hemoglobin level for starting ESA treatment is less than 10 g/dL.

From: Introduction

Cover of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment
Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update [Internet].
Comparative Effectiveness Reviews, No. 113.
Grant MD, Piper M, Bohlius J, et al.

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