Food and Drug Administration - March 9, 2007
Richard Klein, Kimberly Struble

The drugs affected by the safety update are darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit). (ESAs are genetically engineered forms of the naturally occurring human protein, erythropoietin. Natural erythropoietin is made by the kidney and increases the number of red blood cells).

FDA and the manufacturer of these products have agreed on revised product labeling that includes updated warnings, a new black box warning, and modifications to the dosing instructions. The new black box warning advises physicians to monitor red blood cell levels (hemoglobin) and to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid the need for blood transfusions. Physicians and patients should carefully weigh the risks of ESAs against transfusion risks.

Recently completed studies describe an increased risk of death, blood clots, strokes, and heart attacks in patients with chronic kidney failure when ESAs were given at higher than recommended doses. In other studies, more rapid tumor growth occurred in patients with head and neck cancer who received these higher doses.

In studies where ESAs were given at recommended doses, an increased risk of death was reported in patients with cancer who were not receiving chemotherapy and an increased risk of blood clots was observed in patients following orthopedic surgery.

"The agency is in the process of re-evaluating the safety of Aranesp, Epogen, and Procrit on the basis of the results of recent clinical studies," said Steven Galson, M.D. director of FDA's Center for Drug Evaluation and Research. "The new studies provide significant new information for both prescribers and patients, and the new information applies to all ESAs, which share the same mechanism of action. The safety of these products will be discussed when the Oncologic Drugs Advisory Committee (ODAC) meets in May and further revisions to the labeling may occur after that meeting."

Safety concerns from earlier ESA studies were discussed during a 2004 meeting of the ODAC. Product labeling was previously revised in 1997, 2004, and 2005 to reflect new safety information.

The three drugs are approved to treat anemia in patients with chronic kidney failure and in patients with cancer whose anemia is caused by chemotherapy. Epogen and Procrit are approved for patients scheduled for major surgery to reduce potential blood transfusions and for the treatment of anemia due to zidovudine therapy in HIV patients. ESAs are not approved to treat the symptoms of anemia - including fatigue - in cancer patients, surgical patients, or those with HIV.

All three drugs are manufactured by Amgen Inc. of Thousand Oaks, California. Procrit is marketed and distributed by Ortho Biotech LP, a subsidiary of Johnson & Johnson.

The FDA Public Health Advisory

Erythropoiesis-Stimulating Agents (ESAs)

Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)

Recent reports of studies with erythropoiesis-stimulating agents (ESAs) have shown a higher chance of serious and life-threatening side effects and greater number of deaths in patients treated with these agents. ESAs stimulate the bone marrow to make more red blood cells and are FDA approved for use in reducing the need for blood transfusions in patients with chronic kidney failure, patients with cancer on chemotherapy, patients scheduled for major surgery (except heart surgery) and patients with HIV that are using AZT. Because all ESAs work the same way, the findings from these studies apply to all ESAs; the FDA is re-evaluating the safe use of this drug class.

Patients currently using or considering the use of an ESA should know the following:

• A higher chance of death and an increased rate of tumor growth were reported in patients with advanced head and neck cancer receiving radiation therapy and in patients with metastatic breast cancer receiving chemotherapy, when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.

• A higher chance of death was reported and no fewer blood transfusions were received when ESAs were given to patients with cancer and anemia not receiving chemotherapy.

• A higher chance of death was reported and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in patients with chronic kidney failure when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.

• A higher chance of blood clots was reported in patients who were scheduled for major surgery and given ESAs. ESAs are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer, surgical patients and patients with HIV.

• If you have any questions you should talk with your health care provider.

Important study results include the following:

• Patients with chronic kidney failure had an increased number of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).

• Patients with head and neck cancer receiving radiation therapy had faster tumor growth when ESAs were adjusted to maintain hemoglobin levels higher than 12 g/dL.

• Patients with cancer not receiving chemotherapy died sooner and had no fewer blood transfusions when ESAs were given according to the dosing recommendations for cancer patients receiving chemotherapy.

• Patients scheduled for orthopedic surgery who received ESAs to reduce blood transfusions during and after surgery had more blood clots than those not given an ESA.

Physicians who prescribe ESAs should consider the important study results above and:

• Adjust the dose of ESA to maintain the lowest hemoglobin level necessary to avoid the need for transfusions.

• Monitor patients' hemoglobin levels to ensure they do not exceed 12 g/dL;

• Understand that ESAs are given to decrease the chances of receiving transfusions;

• Understand that ESAs have not been shown to improve the outcomes of chemotherapy treatment (e.g., better tumor shrinkage, delay in tumor growth or longer time for survival);

• Consider both the risks of transfusions and those of ESAs when deciding to prescribe an ESA; and

• Understand that ESAs should not be given to treat the symptoms of anemia, including shortness of breath, dizziness, fatigue, low energy, or poor quality of life.

FDA and Amgen, the manufacturer of these products, and Ortho Biotech Products, L.P, a Johnson & Johnson Pharmaceuticals Research and Development subsidiary, the distributor of Procrit, have agreed to change the labeling for Aranesp, Epogen, and Procrit to reflect the new safety information and to provide additional instructions for their use.

FDA-approved uses of ESAs are: for the treatment of anemia in chronic kidney failure patients, in patients with cancer whose anemia is caused by chemotherapy, in patients with HIV whose anemia is caused by AZT (zidovudine), and to reduce the number of transfusions in patients scheduled for major surgery (except heart surgery).

You can find more details about the use of ESAs in FDA's Information for Healthcare Professional.

The FDA asks health care professionals and patients to report serious side effects after using ESAs to the FDA through the MedWatch program by phone (1-800-FDA-1088) or by the Internet at http://www.fda.gov/medwatch

A Questions and Answers on Erythropoiesis-stimulating Agents (ESAs) page has been added to the FDA website at http://www.fda.gov/cder/drug/infopage/RHE/qa.htm to address questions and likely further explain the issue.

Richard Klein | Office of Special Health Issues | Food and Drug Administration

Kimberly Struble | Division of Antiviral Drug Products | Food and Drug Administration

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SOURCE: Food and Drug Administration (FDA).

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