Directory of Drugs: Epoetin alfa - Procrit, Epogen, and Aranesp
FDA ALERT [Updated 11/8/2007]: FDA is issuing this alert to update healthcare professionals about revisions to the product labeling for the erythropoiesis-stimulating agents (ESAs) [Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa)]. These revisions are intended to clarify the evidence for safety and effectiveness and provide more explicit directions and recommendations to prescribers on their use.
The changes for use in patients with cancer include a warning to state that the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to reach a hemoglobin value of <12 g/dL. The risks for higher mortality and/or shortened time to tumor progression were demonstrated in studies where ESAs were dosed with the intent to achieve Hgb values greater than or equal to 12 g/dL as compared to placebo or observational controls. The revised labeling also includes a tabular summary of the clinical studies that demonstrated more rapid tumor growth or more deaths in those patients treated with an ESA. The table includes data on the achieved hemoglobin level in these studies, which in some cases was less than the targeted value.
The dosing recommendations for anemic patients with chronic renal failure have been revised to recommend maintaining hemoglobin levels within 10-12g/dL. Directions are also provided for patients whose Hgb level does not increase to the recommended level after following appropriate dose titrations. In addition, quality of life claims in the previous labeling were removed, with the exception of improved exercise tolerance and functional ability for chronic renal failure patients.
These revisions are consistent with recommendations made at the May 10, 2007, Oncologic Drugs Advisory Committee (ODAC) and the September 11, 2007, meeting of the Cardiovascular & Renal Drugs Advisory Committee (CRDAC) and the Drug Safety & Risk Management Advisory Committee (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. These changes are summarized below.
Recommendations and Considerations for Healthcare Professionals
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. It is important to become familiar with the recent restrictions and recommendations for dose adjustment and/or suspension added to the labeling and summarized below.
Chronic Renal Failure
HIV treated with Zidovudine
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:
Background and Data Summary
Between December 2006 and February 2007, FDA was made aware of several studies in cancer patients that showed higher mortality or shorter time to tumor progression in patients randomized to receive an ESA as compared to placebo. Some of the trials dosed patients in the ESA treatment group to achieve hemoglobin levels ≥ 12 g/dl (higher than recommended in the labeling). Other trials included anemic patients who were not on chemotherapy or radiotherapy. These studies were discussed at a May 10, 2007 meeting of the ODAC (link provided below). The ODAC recommended additional restrictions in the labeling for ESAs including specific tumor types for which adverse safety signals were observed with the use of an ESA, instructions for hemoglobin trigger level-based dose modification/suspension and instruction to discontinue use of ESAs upon completion of chemotherapy. http://www.fda.gov/ohrms/dockets/ac/cder07.htm#OncologicDrugs
Chronic Renal Failure
In November 2006, the New England Journal of Medicine published an editorial and two clinical studies in patients with chronic renal failure not on dialysis, known as the CHOIR and CREATE studies, that addressed safety concerns with the use of erythropoiesis stimulating agents in the treatment of anemia of chronic renal failure (CRF). In these studies, patients who were randomized to receive an ESA to achieve higher hemoglobin levels experienced more serious adverse cardiovascular outcomes than those who received an ESA to achieve lower hemoglobin levels.
The CHOIR and supportive CREATE study findings underscore the importance of the warnings added to the labeling for Procrit, Epogen, and Aranesp regarding cardiovascular risks, including thrombotic events observed in predialysis patients targeted to higher than recommended hemoglobin levels. The safety of ESAs in patients with chronic renal failure was discussed at the September 11, 2007 joint meeting of the CRDAC and the DSRMAC (link provided below). The committee discussed reasonable hemoglobin levels as a goal of therapy and also the need to avoid excessive doses in patients whose hemoglobin does not respond appropriately. http://www.fda.gov/ohrms/dockets/ac/cder07.htm#CardiovascularRenal
Also in February 2007, FDA received notification of the preliminary results of a multi-center, randomized, study of Procrit (Epoetin Alfa) compared to the standard of care in adult patients undergoing elective spinal surgery. The frequency of deep venous thrombosis in patients treated with Procrit was more than twice that of patients who did not receive Procrit. Physicians should consider prophylactic anticoagulation in this setting.
Date created: November 8, 2007
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