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FDA EPO Safety Alert- FDA modifies dosing recommendations for Erythropoiesis-Stimulating Agents : Cites increased risk of cardiovascular events when used to treat chronic kidney disease
 
 
  FDA NEWS RELEASE
For Immediate Release: June 24, 2011
 
"The use of ESAs can increase the risk for stroke, heart attack, heart failure, blood clots, and death.....Healthcare professionals should weigh the possible benefits of using ESAs to decrease the need for red blood cell transfusions in CKD patients against the increased risks for serious cardiovascular events, and should inform their patients of the current understanding of potential risks and benefits."
 
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. 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
 
FDA Drug Safety Communication: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease
 
[6-24-2011] The U.S. Food and Drug Administration (FDA) is informing healthcare professionals of modified recommendations for more conservative dosing of Erythropoiesis-Stimulating Agents (ESAs) in patients with chronic kidney disease (CKD) to improve the safe use of these drugs. FDA has made these recommendations because of data showing increased risks of cardiovascular events with ESAs in this patient population. The manufacturer has revised the Boxed Warning, Warnings and Precautions, and Dosage and Administration sections of the labels for the ESAs to include this new information.
 
More than 20 million people aged 20 years or older in the United States have CKD.1 Patients with CKD lose the ability to make red blood cells and become anemic. The ESAs treat certain types of anemia by stimulating the bone marrow to produce red blood cells and by decreasing the need for blood transfusions. Drugs in the ESA class are epoetin alfa (marketed as Epogen and Procrit) and darbepoetin alfa (marketed as Aranesp).
 
Healthcare professionals should weigh the possible benefits of using ESAs to decrease the need for red blood cell transfusions in CKD patients against the increased risks for serious cardiovascular events, and should inform their patients of the current understanding of potential risks and benefits. Therapy should be individualized to the patient and the lowest possible ESA dose given to reduce the need for transfusions.
 
Treatment with ESAs in CKD has also been discussed at FDA Advisory Committee meetings in September 2007 and October 2010.
 
FDA is continuing to evaluate the safety of ESAs and is requiring the manufacturer to conduct additional trials. FDA will update the public when more information is available.
 
Additional Information for Patients with CKD
· The use of ESAs can increase the risk for stroke, heart attack, heart failure, blood clots, and death.
· The ESA Medication Guide (Epogen/Procrit or Aranesp) contains information on the benefits and risks of using these drugs.
· · Patients should have blood tests while using ESAs. The test results may help guide treatment and lower the risks of using these drugs. A healthcare professional will indicate how often to have blood tests.
· Questions or concerns about ESAs should be discussed with a healthcare professional.
· Side effects experienced with ESAs should be reported to the FDA MedWatch program, using the information at the bottom of the page in the "Contact Us" box.
 
Additional Information for Healthcare Professionals who Treat Patients with CKD
·
· Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular events and has not been shown to provide additional patient benefit.
· No clinical trial to date has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
· The ESA Medication Guide (Epogen/Procrit or Aranesp) should be provided to each patient or their representative when an ESA is dispensed.
·
· The lowest ESA dose sufficient to reduce the need for red blood cell transfusions should be used.
· For patients with CKD not on dialysis:
 
· Consider initiating ESA treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: - The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell transfusion; and - Reducing the risk of alloimmunization and/or other red blood cell transfusion-related risks is a goal.
· If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of ESA and use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions.
 
· For patients with CKD 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.
· When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly.
· For patients who do not respond adequately over a 12-week escalation period, increasing the ESA dose further is unlikely to improve response and may increase risks. · Adverse events involving ESAs should be reported to the FDA MedWatch program, using the information at the bottom of the page in the "Contact Us" box.
 
Table of Key Trials

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CAD = coronary artery disease; CHF = congestive heart failure; CHOIR = Correction of Hemoglobin and Outcomes in Renal Insufficiency trial; CI = confidence interval; MI = myocardial infarction; TREAT = Trial to Reduce Cardiovascular Events with Aranesp Therapy.
 
Treatment with ESAs in CKD was discussed at the Joint Meeting of the FDA Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, held on September 11, 2007, and at the FDA Cardiovascular and Renal Drugs Advisory Committee Meeting, held on October 18, 2010 (for complete reviews and background information discussed at these meetings see: " class="body">September 11, 2007 AC meeting and October 18, 2010 AC meeting).
 
References
 
· Centers for Disease Control and Prevention. National Chronic Kidney Disease Fact Sheet: General Information and National Estimates on Chronic Kidney Disease in the United States, 2010. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2010.
 
- Related Information
 
· Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)
· FDA modifies dosing recommendations for Erythropoiesis-Stimulating Agents FDA press release (6/24/2011)
· FDA Response to Citizen Petition 6/24/2011
· Cardiovascular & Renal Drugs Advisory Committee 2007
· October 18, 2010: Cardiovascular and Renal Drugs Advisory Committee Meeting Announcement
· Aranesp Medication Guide (PDF - 102KB)
· Procrit Medication Guide (PDF - 134KB)
Epogen Medication Guide (PDF - 141KB)
 
 
 
 
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