The Food and Drug Administration Friday issued a public health advisory to warn care providers and patients that use of common anemia drugs can increase the risk of death and other serious problems in patients with cancer or kidney disease.

The drugs of concern are Procrit, Epogen and Aranesp, which are erythropoiesis-stimulating agents. These drugs are genetically engineered versions of a natural protein, erythropoietin, that increases the number of red blood cells.

But recent studies show that the drugs at a dose higher than indicated increased risk of death, blood clots, stroke and heart attack in patients with chronic kidney failure.   In patients with head and neck cancer, high doses of the agents promoted tumor growth.

The FDA warned that even at the dose recommended by the agency, the agents increased death risk in patients with cancer who were not on chemotherapy.   In addition, patients receiving orthopedic surgery would have a higher risk for blood clots when the drugs were given to them.

The FDA wants a new boxed warning to advise physicians to monitor red blood cell levels and to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid the need for blood transfusions.   The agency says doctors and patients need to weigh the risks of these agents against the risk of transfusions.

The safety concerns resulted from earlier ESA studies discussed during a 2004 meeting of the Oncologic Drugs Advisory Committee. Product labeling was previously revised in 1997, 2004, and 2005 to reflect new safety information.

The drugs, Aranesp, Epogen, and Procrit, are approved to treat anemia in patients with chronic kidney failure and in patients with cancer whose anemia is caused by chemotherapy.

Epogen and Procrit are indicated for patients scheduled for major surgery to reduce potential blood transfusions and for the treatment of anemia due to zidovudine therapy in HIV patients.

ESAs are not for treatment of the symptoms of anemia – including fatigue – in cancer patients, surgical patients, or those with HIV.
 
All three drugs are manufactured by Amgen Inc. based out of Thousand Oaks, California. Procrit is marketed and distributed by Ortho Biotech LP, a subsidiary of Johnson & Johnson, the FDA says.

All the following information is updated on March 9, 2007 by the FDA

FDA Public Health Advisory

Erythropoiesis-Stimulating Agents (ESAs)

Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)

Recent reports of studies with erythropoiesis-stimulating agents (ESAs) have shown a higher chance of serious and life-threatening side effects and greater number of deaths in patients treated with these agents.  ESAs stimulate the bone marrow to make more red blood cells and are FDA approved for use in reducing the need for blood transfusions in patients with chronic kidney failure, patients with cancer on chemotherapy, patients scheduled for major surgery (except heart surgery) and patients with HIV that are using AZT.  Because all ESAs work the same way, the findings from these studies apply to all ESAs; the FDA is re-evaluating the safe use of this drug class. 

Patients currently using or considering the use of an ESA should know the following:

• A higher chance of death and an increased rate of tumor growth were reported in patients with advanced head and neck cancer receiving radiation therapy and in patients with metastatic breast cancer receiving chemotherapy, when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
• A higher chance of death was reported and no fewer blood transfusions were received when ESAs were given to patients with cancer and anemia not receiving chemotherapy.   
• A higher chance of death was reported and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in patients with chronic kidney failure when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
• A higher chance of blood clots was reported in patients who were scheduled for major surgery and given ESAs.
• ESAs are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer, surgical patients and patients with HIV. 
• If you have any questions you should talk with your health care provider.

Important study results include the following:

• Patients with chronic kidney failure had an increased number of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).
• Patients with head and neck cancer receiving radiation therapy had faster tumor growth when ESAs were adjusted to maintain hemoglobin levels higher than 12 g/dL.
• Patients with cancer not receiving chemotherapy died sooner and had no fewer blood transfusions when ESAs were given according to the dosing recommendations for cancer patients receiving chemotherapy.
• Patients scheduled for orthopedic surgery who received ESAs to reduce blood transfusions during and after surgery had more blood clots than those not given an ESA. 

Physicians who prescribe ESAs should consider the important study results above and:

• Adjust the dose of ESA to maintain the lowest hemoglobin level necessary to avoid the need for transfusions.
• Monitor patients’ hemoglobin levels to ensure they do not exceed 12 g/dL;
• Understand that ESAs are given to decrease the chances of receiving transfusions; 
• Understand that ESAs have not been shown to improve the outcomes of chemotherapy treatment (e.g., better tumor shrinkage, delay in tumor growth or longer time for survival);
• Consider both the risks of transfusions and those of ESAs when deciding to prescribe an ESA; and
• Understand that ESAs should not be given to treat the symptoms of anemia, including shortness of breath, dizziness, fatigue, low energy, or poor quality of life.

FDA and Amgen, the manufacturer of these products, and Ortho Biotech Products, L.P, a Johnson & Johnson Pharmaceuticals Research and Development subsidiary, the distributor of Procrit, have agreed to change the labeling for Aranesp, Epogen, and Procrit to reflect the new safety information and to provide additional instructions for their use. 

FDA-approved uses of ESAs are: for the treatment of anemia in chronic kidney failure patients, in patients with cancer whose anemia is caused by chemotherapy, in patients with HIV whose anemia is caused by AZT (zidovudine), and to reduce the number of transfusions in patients scheduled for major surgery (except heart surgery).

You can find more details about  the use of ESAs in FDA’s Information for Healthcare Professional.

The FDA asks health care professionals and patients to report serious side effects after using ESAs to the FDA through the MedWatch program by phone (1-800-FDA-1088) or by the Internet at  http://www.fda.gov/medwatch

Questions and Answers on Erythropoiesis-stimulating Agents (ESAs)

Epoetin alfa (marketed as Procrit, Epogen)
Darbepoetin alfa (marketed as Aranesp)

What is the FDA announcing today?

The FDA is announcing new safety information about erythropoiesis-stimulating agents (ESAs).  Erythropoiesis-stimulating agents (ESAs) are man-made versions of a natural protein. The natural protein is made by the kidney and stimulates the bone marrow to produce more red blood cells.  ESAs are given to reduce the number of red blood cell transfusions administered to patients with certain serious diseases/conditions who are or may become anemic.  The new information from recently reported clinical studies includes the following:

• Chronic kidney failure patients had increased numbers of deaths and of non-fatal heart attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).
• Head and neck cancer patients receiving radiation therapy had faster tumor growth when ESAs were adjusted to maintain hemoglobin levels higher than 12 g/dL. 
• Cancer patients not receiving chemotherapy died sooner and had no fewer blood transfusions when ESAs were given according to the dosing recommendations for cancer patients receiving chemotherapy.
• Patients scheduled for orthopedic surgery who received ESAs to reduce blood transfusions during and after surgery had more blood clots than those not given an ESA

What are the FDA-approved uses for ESAs?

ESAs are approved for use in anemic patients with chronic kidney failure, for anemic patients with cancer taking chemotherapy, for anemic patients with HIV taking zidovudine (AZT), and for patients with hemoglobin levels of 10-13 g/dL prior to surgical procedures expected to require blood transfusions and who are unwilling to donate blood.

ESAs are not approved to treat the symptoms of anemia, including fatigue, tiredness, low energy, poor quality of life, shortness of breath, and dizziness.

What products are covered by FDA’s public health advisory?

The products are darbepoetin alfa and epoetin alfa. Darbepoetin alfa was approved for marketing on September 17, 2001 and is licensed and marketed by Amgen, Inc. as Aranesp.  Epoetin alfa was approved for marketing on June 1, 1989 and is also licensed by Amgen, Inc.  It is marketed under the proprietary name Procrit by Ortho Biotech L.P., a subsidiary of Johnson and Johnson Pharmaceutical Research & Development LLC (J&J PRD), and marketed under the proprietary name Epogen by Amgen, Inc.

Does this new information about safety risks apply to all of these products?

Yes, the safety risks apply to all ESAs.

What is FDA doing?

To inform the general public, FDA issued a public health advisory, a press release, and scheduled a press call.  FDA has approved revised product labeling for physicians and patients that describes new warnings and dosing information. FDA posted an “Information for Health Care Professionals” sheet to further inform prescribers and other health care professionals (http://www.fda.gov/cder/drug/infopage/RHE/default.htm). 

The Agency will present this new information to the Oncologic Drugs Advisory Committee on May 10, 2007. FDA will seek advice on the need for additional labeling changes and/or additional studies to further assess safety.

FDA informed hematologists, oncologists and nephrologists via an additional e-mail communication that will be distributed through medical professional organizations; this will be posted on FDA’s Office of Oncology Drug Products website (http://www.fda.gov/cder/Offices/OODP/default.htm), under the “What’s New” link.

FDA will issue a letter to all IND holders investigating new uses of ESAs.  This letter will describe the new data, advise discussion of this information with patients, investigators, and IRBs, and recommend re-consideration of the safety of studies in light of these new data.

FDA asked Amgen, Ortho Biotech, LP, and other ESA manufacturers to provide FDA with the results of clinical studies describing increased risks of ESAs.

FDA requested that Amgen and Ortho Biotech, LP provide an overview and update on the status of all studies investigating safety of ESAs, particularly agreed-upon post-marketing studies and studies identified at the May 2004 ODAC meeting. 

What are Amgen, Inc. and Ortho Biotech doing?

They have revised product labeling to include the new warnings and dosing recommendations and will issue the revised labeling with a Dear Health Care Provider letter. They have voluntarily agreed to suspend broadcast (radio and television) direct-to-consumer advertising for Aranesp, Procrit, and Epogen regarding uses in cancer, with the exception of safety information, under after the May 2007 ODAC meeting.  Amgen and Ortho Biotech agreed to inform all investigators conducting company-sponsored or supported studies of these data, to revise investigational drug brochures, and to participate in the May 2007 ODAC meeting. 

What should physicians and healthcare professionals do with this information?

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. 

What previous actions has FDA taken regarding safety concerns with ESAs?

The product labels for all US marketed ESAs have been updated several times since the original approvals to incorporate new safety information. The FDA has closely monitored emerging safety information and requested post-marketing studies to address actual and potential safety concerns.  These included requests for post-marketing studies to assess risks of blood clots and effects on cancer. FDA has requested and performed analyses of clinical studies to assess the relationship between safety, dose, and pharmacodynamic effects (e.g., rate of increase of red blood cells). FDA also sought advice of the ODAC in May 2004 regarding assessment of current information and design of studies to assess effects on tumor growth, increased death rate, and blood clots.

As new data became available, FDA approved labeling changes when the information available was determined to be sufficient to support the change.

Should patients consider alternative products?

Yes, the patient and his/her physician should carefully consider the risks of ESAs and the risks of red blood cell transfusions (an alternative treatment for anemia) before making a decision to use ESAs.

Why isn’t FDA removing ESAs from the market?

At this time, ESAs appear to be safe and effective when used according to the recently revised product labeling, at the recommended dose and approved indication. The revised labeling reflects the current knowledge regarding risks and benefits that patients and their physicians should consider.  The FDA continues to assess data as it becomes available. 

ESAs may be used in ways that are not FDA-approved.  Should those users be concerned in the wake of these studies?

Yes, all users of ESAs should be aware of these risks. Those taking ESAs may be at increased risk of death and of serious cardiovascular complications, including stroke, heart attack, pulmonary embolism, and deep vein thrombosis (blood clots to the heart and the blood vessels).

  What are the previously reported serious and life-threatening side effects of ESAs when used according to FDA-approved product labeling?

Serious and life-threatening side effects common to all ESAs include:

• An increased risk of blood clots in the lungs, brain and major blood vessels. 
• Pure red cell aplasia.  This is a severe anemia that results when patients become allergic to erythropoietins. 

Serious and life-threatening side effects in patients with chronic kidney failure

• Seizures
• Hypertensive encephalopathy (swelling of the brain caused by very high blood pressure)

Where can I find more information about ESAs?

Please see the ESA information web page at http://www.fda.gov/cder/drug/infopage/RHE/default.htm.

Information for Healthcare Professionals

Erythropoiesis Stimulating Agents (ESA)
[Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)]

FDA ALERT [11/16/2006, Updated 2/16/2007 and 3/09/2007]:  FDA is issuing this alert to provide new safety information for erythropoiesis-stimulating agents (ESAs) [Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa)].  Analyses of four new studies in patients with cancer found a higher chance of serious and life-threatening side effects and/or death with the use of ESAs.  These research studies were evaluating an unapproved dosing regimen, a patient population for which ESAs are not approved, or a new unapproved ESA.  In another study, patients scheduled for orthopedic surgery had a higher rate of deep venous thrombosis when treated with Procrit at the approved dose.  This new information is consistent with risks found in two clinical studies in patients with chronic renal failure treated with an unapproved regimen of an ESA that were reported in November 2006 and are summarized in the data section below. 

All ESAs have the same mechanism of action.  As a result, FDA believes these new concerns apply to all ESAs and is re-evaluating how to safely use this product class.  FDA and Amgen, the manufacturer of Aranesp, Epogen and Procrit, have changed the full prescribing information for these drugs.  The new product labeling includes a new boxed warning, updated warnings, and a change to the dosage and administration sections for all ESAs.  These changes are summarized below.

  This information reflects FDA’s preliminary analysis of data concerning this drug.  FDA is considering, but has not reached a final conclusion about, this information.  FDA intends to update this sheet when additional information or analyses become available.

  To report any serious adverse events associated with the use of these drugs, please contact the FDA MedWatch program using the contact information at the bottom of this sheet

Changes to the prescribing information for the ESAs (Aranesp, Epogen and Procrit) are summarized here:  

A New Boxed Warning providing the following information:

• Avoid serious cardiovascular and arterial and venous thromboembolic events by using the lowest dose of [Aranesp /EPOGEN/PROCRIT] that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion
• [Aranesp /EPOGEN/PROCRIT] and other ESAs increased the risk for death and for serious cardiovascular events when dosed to achieve a target a hemoglobin of greater than 12 g/dL
• Use of ESAs to achieve a target hemoglobin of 12 g/dL or greater in cancer patients: 
• shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy;
• shortened overall survival and increased deaths attributed to disease progression in patients with metastatic breast cancer receiving chemotherapy;  
• increased the risk of death in patients with active malignant disease not under treatment with chemotherapy or radiation therapy.  ESAs are not indicated for this patient population.
• Patients treated before surgery with epoetin alfa to reduce allogenic red blood cell transfusions had a higher incidence of deep venous thrombosis. Aranesp is not approved for this indication.

Additional Warnings about increased mortality, cardiovascular events, tumor progression and uncontrolled hypertension

• Increased Mortality and Cardiovascular Events – the warnings now describes the results of new studies showing an increased incidenceof thrombotic events in patients with chronic renal failure, cancer patients on chemotherapy, and surgical candidates.
• Potential for Tumor Growth Progression – A new subsection in Warnings describes the new data and emphasizes the evidence for increased rate of tumor progression. 
• Hypertension - this subsection advises against the use of ESAs in patients with uncontrolled hypertension, and describes the risks to and guidance for managing controlled hypertensive patients.

Recommendations and Considerations

Physicians and other healthcare professionals should consider the following when using ESAs:

For all patients:

• Use the lowest dose possible to gradually increase the hemoglobin concentration to avoid the need for transfusion.
• Measure hemoglobin twice a week for 2 to 6 weeks after any dosage adjustment to ensure that hemoglobin has stabilized in response to the dose change.
• Withhold the dose of the ESA if the hemoglobin increase exceeds 12 g/dL or rises by 1g/dL in any 2 week period.

For cancer patients:

• Use of an ESA in anemic cancer patients who are not on chemotherapy offered no benefit and may shorten the time to death.
• ESAs are not FDA approved to treat anemia in cancer patients not receiving chemotherapy
• There is a potential risk of shortening the time to tumor progression or disease-free survival
• ESAs are administered only to avoid red blood cell transfusions in cancer patients.  ESAs do not improve the outcome of cancer treatment and do not alleviate fatigue or increase energy.

Dosing and Monitoring Recommendations

For chronic renal failure (CRF) patients

• Measure hemoglobin twice a week after initiating treatment until hemoglobin has stabilized.

For cancer patients and zidovudine-treated HIV patients 

• Measure hemoglobin once a week after initiating treatment until hemoglobin has stabilized.

For patients with a history of cardiovascular disease or hypertension 

• Closely monitor and control blood pressure.

Patient Counseling Information

Physicians and other healthcare professionals should discuss the following with their patients:

• The goal of treatment with erythropoiesis stimulating agents (ESA) is to increase the number of red blood cells to avoid blood transfusions.
• ESAs require at least 2-6 weeks of treatment before there is an increase in the number of red blood cells.
• The effects of treatment with an ESA can be harmful in certain circumstances.
• They should keep appointments for blood tests so they can be adequately monitored.
• They need to monitor blood pressure every day (if appropriate) and to call you if there are any changes outside of the range established for the patient.
• Call you if they experience any of the following symptoms:
• Pain and/or swelling in the legs
• Worsening in shortness of breath
• Increases in blood pressure
• Dizziness or loss of consciousness
• Extreme tiredness
• Blood clots in hemodialysis vascular access ports

Data Summary

Studies in cancer patients receiving radiotherapy

In December, 2006 Amgen informed FDA of the interim results of the Danish Head and Neck Cancer Study Group trial (DAHANCA 10).  This open-label, randomized trial compared radiation therapy alone to radiation therapy plus Aranesp in the treatment of advanced head and neck cancer.  The trial assessed whether treating anemia to maintain a hemoglobin concentration of 14.0-15.5 g/dL during radiotherapy would improve loco-regional disease control. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).  Overall survival also favored those not treated with Aranesp, though this finding was not statistically significant (p=0.08). The data monitoring committee recommended the trial’s termination on December 1, 2006. See http://conman.au.dk/dahanca for additional information on the DAHANCA 10 study.  FDA will review and analyze the complete study results after they are submitted by Amgen.

This study is similar in design and in outcomes to that reported by Henke, et al. The data from the Henke study were presented at the May 4, 2004 meeting of the Oncologic Drugs Advisory Committee. The briefing information and transcript for the Advisory Committee is available at http://www.fda.gov/ohrms/dockets/ac/cder04.html#Oncologic. The increased rate of tumor progression and increased mortality reported in the Henke study were incorporated into product labeling (see: Precautions, Tumor Growth Factor Potential) in 2004.

Study in cancer patients not receiving chemotherapy

FDA was notified in January 2007 of the results of a 989 patient, multi-center, double-blind, randomized, placebo-controlled study of Aranesp (darbepoetin alfa) in anemic cancer patients who are not receiving chemotherapy. The target hemoglobin in the Aranesp treatment group was 12 g/dl. The study results provided to FDA show Aranesp did not reduce the need for red blood cell transfusions and showed an increase in mortality in patients receiving Aranesp compared to those receiving placebo (hazard ratio 1.25; 95% confidence interval: 1.04, 1.51).  FDA will review and analyze the complete study results after they are submitted by Amgen.   Additional information on the study is provided in a January 26th, 2007 Dear Health Care Professional letter sent by Amgen (see http://www.fda.gov/medwatch/safety/2007/safety07.htm#Aranesp).

FDA was notified in February 2007 of the final results of a double-blind, placebo controlled study to evaluate whether use of epoetin alpha in anemic non-small cell lung cancer patients not on chemotherapy improved their quality of life.  The epoetin alfa dose was titrated to maintain a hemoglobin level of 12 to 14 g/dL; epoetin alfa was dosed at 40,000 IU every week.  Though planned to enroll 300 patients, the study was closed to accrual in December 2003 after enrolling only 70 patients because its data monitoring committee found higher mortality in those treated with epoetin alfa.  Median time to death in those treated with epoetin alfa was 68 days and significantly shorter than the median time to death of 131 days in those treated with placebo (p = 0.04), with the majority of deaths reported as disease progression.  Also, treatment with epoetin alfa did not significantly reduce the need for red blood cell transfusion or improve quality of life.  Prognostic factors and previous treatments were reported to be well balanced between the treatment groups.  FDA will review and analyze the complete study results after they are submitted by Johnson & Johnson Pharmaceutical Research and Development.

Study in cancer patients with an investigational ESA

In February 2007 FDA was notified by Hoffmann-La Roche that it was suspending a study of a new ESA product because of safety concerns.  The study was a multi-center, randomized, dose-finding assessment of a pegylated epoetin beta product in anemic patients with Stage IIIB or IV non-small cell lung cancer who were receiving first line chemotherapy. Three dosing regimens of the investigational drug were being compared to Aranesp (given according to an FDA-approved dosing regimen). The dose of pegylated epoetin beta was titrated to maintain the hemoglobin level between 11 and 13 g/dL. An interim analysis, after randomization of 153 patients, demonstrated a numerical imbalance in the number of deaths across the four arms of the study.  FDA has not yet received the complete study results, and will review and analyze the data after they are submitted by Hoffmann-La Roche.

Study in patients undergoing surgery

FDA was notified in February 2007 of the preliminary results of a 681 patient, multi-center, randomized, open-label, non-inferiority study of Procrit (Epoetin Alfa) compared to the standard of care in adult patients undergoing elective spinal surgery.  Procrit was administered according to the dosage and administration section of the label for pretreatment hemoglobin values >10 and < 13 g/dL.  The frequency of deep venous thrombosis in patients treated with Procrit was 4.7 percent (16 patients), more than twice that of patients who received usual blood conservation care (frequency of 2.1 percent, seven patients). FDA will review and analyze the complete study results after they are submitted by Ortho Biotech, L.P.

Studies in patients with chronic renal failure

Two clinical studies and an editorial published in the New England Journal of Medicine in November, 2006 addressed safety concerns about the use of erythropoiesis stimulating agents in the treatment of anemia of chronic renal failure (CRF).  The 1,400 subject CHOIR study demonstrated increases in serious and potentially life threatening cardiovascular events when epoetin alfa (Procrit) is administered to reach higher target hemoglobin levels than lower target hemoglobin levels. The 600 subject CREATE study trended toward more cardiovascular events in a pattern similar to the CHOIR study, thus strengthening the findings of the CHOIR study.  The CREATE study examined the use of epoetin beta, a product not approved in the USA. 

The CHOIR study was a randomized, open label design in which anemic chronic kidney disease (CKD) subjects were randomized to be dosed to either a higher target hemoglobin (13.5 g/dL) or a lower target hemoglobin (11.3 g/dL).  All subjects received Procrit.  The primary endpoint was a time to event analysis for a composite cardiovascular endpoint (all cause mortality, congestive heart failure (CHF) hospitalization, non-fatal MI, or non-fatal stroke).

Procrit was administered as 10,000 U SC weekly and titration allowed to a maximum dose of 20,000 U weekly.  Overall, 715 subjects were randomized to the high hemoglobin target (13.5 g/dL) and 717 randomized to the low target (11.3 g/dL).  At the end of the study, the average hemoglobin was 12.6 g/dL for the high group and 11.3 g/dL for the low group.  The primary endpoint, composite of death, and cardiovascular events was statistically significant worse outcome in the higher target hemoglobin group (p = 0.03 by log rank test) with a hazard ratio of 1.3 [95% CI 1.03, 1.74].  The rates for the individual components of the composite primary endpoint were (high target hemoglobin vs. low target hemoglobin):

Death:                   7.3% vs 5.0% (p = 0.07)
CHF hosp:             9.0% vs 6.6% (p = 0.07)
Non-fatal MI:        2.5% vs 2.8%
Non-fatal stroke:   1.7% vs 1.7%

• The published analyses for this study found no correlation between adverse cardiovascular events and rate of rise of hemoglobin. 

The published CHOIR and supportive CREATE study findings underscore the importance of the warnings in the labeling for Procrit, Epogen, and Aranesp regarding cardiovascular risks that include thrombotic events and increased mortality observed in hemodialysis patients with cardiac disease targeted to higher hemoglobin levels (~14 g/dL), and warning regarding the increased risk of death if ESAs are dosed to raise hemoglobin levels to >12 g/dL.

Report serious adverse events to
FDA’s MedWatch reporting system by completing a form on line at
http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178),
by mail using the postage-paid address form provided online
( 5600 Fishers Lane, Rockville, MD 20852-9787),
or by telephone (1-800-FDA-1088).