[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.
ESA label changes
The ESA labels now warn:
- In controlled trials with CKD patients, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL.
- No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
ESA labels now recommend:
- For patients with CKD, consider starting ESA treatment when the hemoglobin level is less than 10 g/dL. 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 and use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions. Adjust dosing as appropriate.
The drug label previously recommended that ESAs should be dosed to achieve and maintain hemoglobin levels within the target range of 10 to 12 g/dL in CKD patients. This target concept has been removed from the label.
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.
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.
- 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.
- 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:
o 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.
o 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:
o Initiate ESA treatment when the hemoglobin level is less than 10 g/dL.
o 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.
|Normal Hematocrit Study (NHS) (N = 1265)||CHOIR (N = 1432)||TREAT (N = 4038)|
|Time Period of Trial||1993 to 1996||2003 to 2006||2004 to 2009|
|Population||CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa||CKD patients not on dialysis with hemoglobin
< 11="" g/dl="" not="" previously="" administered="" epoetin="">
|CKD patients not on dialysis with type II diabetes, hemoglobin
≤ 11 g/dL
|Hemoglobin Target; Higher vs. Lower (g/dL)||14.0 vs. 10.0||13.5 vs. 11.3||13.0 vs. ≥ 9.0|
|Median (Q1, Q3) Achieved Hemoglobin Level (g/dL)||12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7)||13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6)||12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3)|
|Primary Endpoint||All-cause mortality or non-fatal MI||All-cause mortality, MI, hospitalization for CHF, or stroke||All-cause mortality, MI, myocardial ischemia, heart failure, and stroke|
|Hazard Ratio or Relative Risk (95% CI)||1.28 (1.06 - 1.56)||1.34 (1.03 - 1.74)||1.05 (0.94 - 1.17)|
|Adverse Outcome for Higher Target Group||All-cause mortality||All-cause mortality||Stroke|
|Hazard Ratio or Relative Risk (95% CI)||1.27 (1.04 - 1.54)||1.48 (0.97 - 2.27)||1.92 (1.38 - 2.68)|
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: September 11, 2007 AC meeting and October 18, 2010 AC meeting).
- 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.
- Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)
- FDA Drug Safety Podcast for Healthcare Professionals: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease
- FDA modifies dosing recommendations for Erythropoiesis-Stimulating Agents
- FDA Response to Citizen Petition
- October 18, 2010: Cardiovascular and Renal Drugs Advisory Committee Meeting Announcement
- Aranesp Medication Guide
- Procrit Medication Guide
- Epogen Medication Guide