Epoetin alfa (Epogen?, Procrit?)was initially approved by the U.S. Food and Drug Administration (FDA) in 1989 to treat some forms of anemia resulting from chronic kidney disease (CKD). It also is used to treat anemia in patients with HIV infection who are receiving zidovudine (Retrovir?)and in patients with cancer who are receiving chemotherapy and develop anemia. In some cases, epoetin alfa is used to to decrease the need for transfusions of red blood cells in patients who are anemic and are scheduled to undergo surgery.
Treatment of anemia is designed to elevate or maintain red blood cell levels. While epoetin alfa and a related erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa (Aranesp?), have generally been accepted for this indication, optimal hemoglobin targets have never been established.
Because of the long-standing concern that the risk of cardiovascular events such as stroke, thrombosis, and death, may be related to the rapidity of the increase in hemoglobin concentration, as well as to oscillations in hemoglobin levels and overshoots of the target concentration, the FDA earlier this week recommended a more conservative dosing guidelines for Erythropoiesis-Stimulating Agents (ESAs) when used to treat anemia in patients with chronic kidney disease (CKD).
A prime regulator
Erythropoietin or EPO, a hormone produced by the kidney, is the prime regulator stimulating primitive cells in the bone marrow to produce red blood cells, the main oxygen-carrying cells in the blood. When the body, in healty individuals, senses a decrease in red blood cells or a deficiency in the supply of oxygen, more erythropoietin is produced. This increases the number of red blood cells. However, when this natural mechanism is no longer functioning correctly, stimulating the bone marrow to produce red blood cells may become necessary.
Erythropoiesis-stimulating agents are synthetic versions of erythropoietin. Blood hemoglobin is a laboratory measure of the number of red blood cells in the blood. Anemia is an abnormally low hemoglobin value.
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.?
Chronic kidney disease
According to the Centers for Disease Control and Prevention (CDC), more than 20 million people aged 20 years or older in the United States have CKD.
Until now, product labels for Erythropoiesis-Stimulating Agents 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.?
Weighing the benefits
As a result, the package insert for Erythropoiesis-Stimulating 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 Erythropoiesis-Stimulating agents sufficient to reduce the need for transfusion.
Based on the new recommendations, patients with the anemia of chronic kidney disease not on dialysis should consider starting ESA treatment only when the hemoglobin level is less than 10 g/dL and when certain other considerations apply. And if hemoglobin levels exceeds 10 g/dL, the are adviced to reduce or interrupt the dose of Erythropoiesis-Stimulating Agents.
Patients with the anemia of chronic kidney disease on dialysis are vadvused to initiate ESA treatment when the hemoglobin level is less than 10 g/dL and when hemoglobin levels approach or exceeds 11 g/dL, to reduce or interrupt the dose of Erythropoiesis-Stimulating Agents.
Initiate means to give a first dose of Erythropoiesis-Stimulating Agents. 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 Erythropoiesis-Stimulating Agents and is requiring the manufacturers 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.
For more information:
Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents–time for a reevaluation. N Engl J Med. 2010 Jan 21;362(3):189-92. Epub 2010 Jan 6.