Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)]
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.
This information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this when additional information or analyses become available.
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.
- ESAs shortened the overall survival and/or time-to-tumor progression in patients with various cancers
- Risks of shortened survival and tumor progression have not been excluded when ESAs are dosed with the intent to achieve hemoglobin levels <12g/dL
- Use the lowest dose of [Aranesp/EPOGEN/PROCRIT] needed to avoid red blood cell transfusions. Do not exceed the upper safety limit for hemoglobin levels of 12 g/dL and
- Reduce the ESA dose by 25% when hemoglobin reaches a level needed to avoid transfusion
- Withhold dosing with an ESA when hemoglobin level exceeds 12 g/dL
- Restart dosing at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required
- Use ESAs only for the treatment of anemia due to concomitant myelosuppressive chemotherapy
- Discontinue treatment with an ESA following the completion of a course of chemotherapy
- Use of ESAs in cancer patients have not been demonstrated in controlled clinical trials to improve the symptoms of anemia, quality of life, fatigue, or well-being.
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
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.