New Dosing Guidelines for Erythropoiesis-Stimulating Agents

Mark Crane

Disclosures

June 24, 2011

June 24, 2011 — The US Food and Drug Administration (FDA) today urged more conservative dosing guidelines for erythropoiesis-stimulating agents (ESAs) when used to treat anemia in patients with chronic kidney disease (CKD).

The recommendations are in response to clinical trials showing an increased risk for cardiovascular events, such as heart attack, stroke, thrombosis, and death, when ESAs are dosed to achieve a normal or nearly normal blood hemoglobin level, Robert C. Kane, MD, acting deputy director for safety, Division of Hematology Products, Center for Drug Evaluation and Research, said during a telephone news conference today.

The new guidelines are being added to the boxed warning and other sections of the package insert. In addition, ESAs have not been shown to improve quality of life, fatigue, or patient well-being, the FDA said in a news release.

ESAs are synthetic versions of a human protein known as erythropoietin, which stimulates primitive cells in the bone marrow to produce red blood cells and decreases the need for blood transfusion, according to the FDA.

Epoetin alfa and darbepoetin alfa are in the ESA drug class.

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.

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

"Health care practitioners should carefully consider when to begin treatment with an ESA and actively monitor dosing in patients with [CKD], keeping in mind the increased risk for serious cardiovascular events, and should talk to their patients about these potential risks," John Jenkins, MD, director of the Office of New Drugs, said in the release. "The goal is to individualize therapy and use the lowest ESA dose possible to reduce the need for red blood cell transfusions."

Product labels for ESAs have recommended dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL in patients with CKD. The new package insert removes this previous concept of a "target hemoglobin range."

The revised package insert for ESA products now recommends that physicians and their patients with CKD 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.

"Serious risks have been demonstrated when the hemoglobin level is higher than 11 [g/dL]," said Dr. Kane. "The intention of the labeling change is to encourage flexibility in individual dosing for each patient's needs. Evidence shows some reduction in the amount of transfusions with ESAs, but they do not appear to prevent it. Each physician, after observing his patient over a period of time, has to individualize that decision."

For patients with anemia of CKD who are not on dialysis, the FDA recommends that physicians 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, physicians should reduce or interrupt the dose of ESA.

For patients who are on dialysis, the FDA recommends that physicians initiate ESA treatment when the hemoglobin level is less than 10 g/dL, and reduce or interrupt the dose if the hemoglobin level approaches or exceeds 11 g/dL.

The new recommendations 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 for serious adverse cardiovascular events, such as heart attack and stroke, and provided no additional benefit to patients.

No clinical trial to date has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks, FDA said.

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 for ESAs.

Adverse effects related to ESAs should be reported to MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm, or by mail to MedWatch, FDA, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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