FDA Modifies Dosing Recommendations for Erythropoiesis-Stimulating Agents

Cites increased risk of cardiovascular events when used to treat chronic kidney disease

SILVER SPRING, Md., June 24, 2011 /PRNewswire-USNewswire/ -- The U.S. Food and Drug Administration today recommended more conservative dosing guidelines for Erythropoiesis-Stimulating Agents (ESAs) when used to treat anemia in patients with chronic kidney disease (CKD) because of the increased risks of cardiovascular events such as stroke, thrombosis, and death.

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ESAs are synthetic versions of a human protein known as erythropoietin, which stimulates primitive cells in the bone marrow to produce red blood cells, the main oxygen-carrying cells in the blood. Blood hemoglobin is a laboratory measure of the number of red blood cells in the blood. Anemia is an abnormally low hemoglobin value.

ESAs are approved to treat some forms of anemia resulting from CKD, chemotherapy and certain other conditions. Drugs in the ESA class are epoetin alfa, marketed as Epogen and Procrit, and darbepoetin alfa, marketed as Aranesp.

The modified recommendations are being added to the Boxed Warning and other sections of the package insert in response to clinical trials showing an increased risk of cardiovascular events, such as heart attack and stroke, when ESAs are dosed to achieve a normal or nearly normal blood hemoglobin level. In addition, ESAs have not been shown to improve quality of life, fatigue, or patient well-being.

"Health care practitioners should carefully consider when to begin treatment with an ESA and actively monitor dosing in patients with chronic kidney disease, keeping in mind the increased risk for serious cardiovascular events, and should talk to their patients about these potential risks," said John Jenkins, M.D., director of the Office of New Drugs in the FDA's Center for Drug Evaluation and Research. "The goal is to individualize therapy and use the lowest ESA dose possible to reduce the need for red blood cell transfusions."

According to the Centers for Disease Control and Prevention, more than 20 million people aged 20 years or older in the United States have CKD.

Until now, product labels for ESAs have recommended dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 grams/deciliter (g/dL) in patients with CKD. The modified package insert removes this previous concept of a "target hemoglobin range."

As a result, the package insert for ESA products now recommends that:

Physicians and their patients with chronic kidney disease should weigh the possible benefits of using ESAs to decrease the need for red blood cell transfusions against the increased risks for serious adverse cardiovascular events. For each patient, individualize dosing and use the lowest dose of ESA sufficient to reduce the need for transfusion.

For patients with the anemia of chronic kidney disease NOT on dialysis

• Consider starting ESA treatment only when the hemoglobin level is less than 10 g/dL and when certain other considerations apply.
• If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of ESA.

For patients with the anemia of chronic kidney disease on dialysis

• Initiate ESA treatment when the hemoglobin level is less than 10 g/dL.
• If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of ESA.

Initiate means to give a first dose of ESA. This advice does not define how far below 10 g/dL is appropriate for an individual to initiate. This advice also does not recommend that the goal is to achieve a hemoglobin of 10 g/dL or a hemoglobin above 10 g/dL. Individualize dosing for each patient.

The modified recommendations for dosing ESAs in patients with CKD are based on data from clinical trials including TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy), which showed that using ESAs to target a hemoglobin level of greater than 11 g/dL increased the risk of serious adverse cardiovascular events, such as heart attack and stroke, and provided no additional benefit to patients.

The use of ESAs to treat anemia in patients with CKD was discussed at the joint meeting of the Cardiovascular Drugs Advisory Committee and the Drug Safety and Risk management Advisory Committee on Sept. 11, 2007, and at the Cardiovascular and Renal Drugs Advisory Committee meeting on Oct. 18, 2010.

In addition to revising the package insert, the FDA is issuing a Drug Safety Communication informing health care professionals about its modified recommendations and issuing a response to a related Citizen Petition. The FDA will continue to evaluate the safety of ESAs and is requiring the manufacturer, Amgen Inc., to conduct additional trials.

The FDA is also approving modifications to the existing Risk Evaluation and Mitigation Strategy, or REMS, for ESAs. A REMS is a program that FDA may require to manage serious risks of marketed drugs.

Amgen is based in Thousand Oaks, Calif.

For more information:

FDA Drug Safety Communication

http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm

Joint Meeting of the Cardiovascular Drugs Advisory Committee and the Drug Safety and Risk management Advisory Committee, Sept. 11, 2007 http://www.fda.gov/ohrms/dockets/ac/cder07.htm#CardiovascularRenal

Cardiovascular and Renal Drugs Advisory Committee Oct. 18, 2010 http://www.fda.gov/AdvisoryCommittees/Calendar/ucm226531.htm

Media Inquiries: Karen Riley, 301-796-4674
Consumer Inquiries: 888-INFO-FDA

SOURCE U.S. Food and Drug Administration