The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.
The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.
Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."
Based on dialysis status, the new recommendations are as follows:
• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.
The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.
• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."
Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.
ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.
The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.
He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.
The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.
Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.
Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.
The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.