Erythropoiesis-Stimulating Agents (ESAs) Epoetin alfa (marketed as Procrit, Epogen),
Darbepoetin alfa (marketed as Aranesp)

The FDA previously communicated safety information from clinical trials in cancer patients receiving erythropoiesis-stimulating agents (ESAs).  The FDA has received additional safety information which has been incorporated in product labeling for darbepoetin alfa (Aranesp, Amgen, Inc.) and epoetin alfa (Epogen, Amgen, Inc. and Procrit, Ortho Biotech Products LP).  These safety findings have resulted in a boxed warning and additional labeling revisions.  The information contained in the new boxed warning is summarized below:

• Use the lowest dose of ESAs that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid blood transfusions.

• ESAs increased the risk for death and for serious cardiovascular events when administered to target a hemoglobin greater than 12 g/dL.

• A higher incidence of deep venous thrombosis was documented in patients receiving epoetin alfa pre-operatively for reduction of allogeneic blood transfusions.  These patients did not receive prophylactic anticoagulation. 

• ESAs when administered to cancer patients:
  • shortened the time-to-progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a hemoglobin > 12g/dL;
    
  • shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin > 12 g/dL; and
  • increased mortality in cancer patients not receiving chemotherapy or radiation therapy when administered to target a hemoglobin of 12 g/dL.  ESAs are not indicated for this population.

A summary of the studies supporting the above recommendations are provided below:

• A randomized (1:1) trial, “Correction of Hemoglobin and Outcomes in Renal Insufficiency” (CHOIR), evaluated 1432 anemic chronic renal failure patients who were not undergoing dialysis.  Patients were assigned to epoetin alfa either targeting a maintenance hemoglobin of 13.5 g/dL or of 11.3 g/dL.  A major cardiovascular event (death, MI, stroke or hospitalization for CHF) occurred in 18% in the higher hemoglobin arm compared to 14% in the lower hemoglobin arm (HR 1.3, 95% CI: 1.0 to 1.7, p = 0.03).
  
  
• A randomized study, “Maintaining Normal Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A Survival Study” (BEST), evaluated 939 women with metastatic breast cancer receiving chemotherapy.  Patients received either weekly epoetin alfa (to maintain hemoglobin levels of 12-14 g/dL) or placebo for one year.  The study was terminated prematurely for higher mortality (8.7% vs. 3.4%) and higher fatal thrombotic event rate (1.1% vs. 0.2%) in the first 4 months in the epoetin alfa arm.   At study termination, 12-month survival rates were lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
  
  
• A phase 3, randomized, placebo-controlled study evaluated 989 patients with active malignant disease not receiving chemotherapy or radiation therapy. Patients were randomized to darbepoetin (to achieve a hemoglobin of 12 g/dL) or placebo.  No evidence of a statistically significant reduction in RBC transfusions was observed.  More deaths occurred in the darbepoetin alfa arm than in placebo (26% vs. 20%) following 16 weeks of treatment.  With a median follow-up of 4.3 months, the absolute number of deaths was greater in the darbepoetin alfa group than placebo [49% vs. 46%; HR 1.29; 95% CI: 1.08, 1.55].
  
  
• A randomized study (DAHANCA 10) evaluated 522 patients with carcinoma of the head and neck receiving radiation therapy.  Patients were randomized to either darbepoetin alfa or placebo.  An interim analysis in 484 patients demonstrated a 10% increase in loco-regional failure rate among darbepoetin alfa-treated patients (p = 0.01).  At the time of study termination, a trend toward worse survival in the darbepoetin alfa-treated arm was observed (p = 0.08).
  
  
• A trial in advanced non-small-cell-lung cancer patients, randomized to either epoetin alfa (targeting hemoglobin 12-14 g/dL) or placebo.  Following an interim analysis in 70 patients, a significant decrease in median survival was observed in the epoetin-treated arm (63 vs. 129 days; HR 1.84; p = 0.04).
  
  
• A randomized study (SPINE) evaluated 681 patients undergoing spinal surgery who received either epoetin alfa and standard of care (SOC) or SOC alone. These patients did not receive prophylactic anticoagulation.  Preliminary analysis showed a higher incidence of deep vein thrombosis in the epoetin alfa group than the SOC (4.7% vs. 2.1%).  Twelve patients in the epoetin alfa group and 7 in the SOC had additional thrombotic vascular events. These results have not been published or disseminated previously.

This new information will be discussed at the May 10, 2007 Oncologic Drugs Advisory Committee (ODAC) meeting to re-evaluate the safety and dosing of ESAs in cancer patients.

Additional modifications of the product labeling were made to the DOSAGE AND ADMINISTRATION section.  These changes emphasize that physicians should prescribe the lowest dose of ESAs that will gradually increase the hemoglobin to the lowest level sufficient to avoid blood transfusions.  

FDA reminds physicians that ESAs are approved for the reduction in red blood cell transfusions.  These products have not been shown to improve or relieve the symptoms of anemia nor to improve quality of life in patients with cancer. 

Physicians should discuss this information with patients in clinical studies and should ask patients to confirm their consent for continued participation.  Institutional Review Boards should also be advised of these findings.  Investigators should re-evaluate whether clinical investigations should continue in light of these new safety data.  FDA will be issuing a letter to IND sponsors with these recommendations.

Please see the FDA Healthcare Professional Sheet regarding evolving safety issues with ESAs, posted at http://www.fda.gov/cder/drug/infopage/RHE/default.htm . 

Full prescribing information, including the above changes, is available for Aranesp at http://www.fda.gov/cder/foi/label/2007/103951s5139lbl.pdf and for Epogen/Procrit at http://www.fda.gov/cder/foi/label/2007/103234s5122lbl.pdf .  Note that the content of the labels for Epogen and Procrit are the same except for the proprietary name.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting Program via an online form at www.fda.gov/medwatch/report.htm , by faxing (1-800-FDA-0178) or mailing the postage-paid Form 3500 available at www.fda.gov/medwatch , or by telephone (1-800-FDA-1088).

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