FDA Strengthens Boxed Warnings, Approves Other Safety Labeling Changes for Erythropoiesis-Stimulating Agents (ESAs)

FDA Strengthens Boxed Warnings, Approves
Other Safety Labeling Changes for
Erythropoiesis-Stimulating Agents (ESAs)
November 2007

The U.S. Food and Drug Administrationapproved revised
boxed warnings and other safety-related product labeling
changes for erythropoiesis-stimulating agents (ESAs), which
treat certain types of anemia. These new statements address
the risks that the drugs Aranesp, Epogen and Procrit pose to
patients with cancer and patients with chronic kidney failure.

The labeling changes, which incorporate advice from FDA
advisory committees and expand upon labeling changes made
in March 2007, also include a statement that symptoms of
anemia, fatigue and quality of life have not been shown to
improve in patients with cancer who are treated with ESAs.

Epogen, Procrit and Aranesp are approved to treat anemia in
patients with chronic kidney failure and anemia caused by
chemotherapy in certain patients with cancer. Epogen and
Procrit are also approved for use in certain patients with
anemia who are scheduled to undergo major surgery to reduce
blood transfusions during or shortly after surgery and for the
treatment of anemia caused by zidovudine (AZT) therapy in HIV
patients.
For Patients with Cancer

For patients with cancer, the new boxed warnings emphasize
that ESAs caused tumor growth and shortened survival in
patients with advanced breast, head and neck, lymphoid and
non-small cell lung cancer when they received a dose that
attempted to achieve a hemoglobin level of 12 grams per
deciliter (g/dL) or greater.

The boxed warnings also emphasize that no clinical data are
available to determine whether there is a similar risk of
shortened survival or increased tumor growth for patients with
cancer who receive an ESA dose that attempts to achieve a
hemoglobin level of less than 12 g/dL. This is the hemoglobin
level commonly achieved in clinical practice.

Health care providers determine whether a patient is anemic
and decide on ESA dosing by measuring how much of the
protein known as hemoglobin is present in a patient's red blood
cells.

An earlier boxed warning, approved in March, described the
results of six studies demonstrating that survival was shorter
and tumors progressed faster when ESAs were used to
achieve hemoglobin levels of 12 g/dL or greater in cancer
patients.

This new boxed warning also clarifies that ESAs should only be
used in patients with cancer when treating anemia specifically
caused by chemotherapy and not for other causes of anemia.
Moreover, it states that ESAs should be discontinued once the
patient's chemotherapy course has been completed.

"Health care professionals need to consider the risks of
increased tumor progression and decreased survival in patients
with cancer when prescribing ESAs," said Janet Woodcock,
M.D., FDA's deputy commissioner for scientific and medical
programs, chief medical officer and acting director of its Center
for Drug Evaluation and Research. "ESAs should be used in
patients with cancer only when their anemia is due to
chemotherapy and only at the lowest dose necessary to avoid
the need for blood transfusions."

The FDA is working with the manufacturer to design and
conduct clinical trials of different dosing regimens and tumor
types to further characterize potential tumor progression
associated with ESAs.

For Patients with Chronic Kidney Failure

For patients with chronic kidney failure, the new boxed warning
states that ESAs should be used to maintain a hemoglobin level
between 10 g/dL to 12 g/dL. Maintaining higher hemoglobin
levels in patients with chronic kidney failure increases the risk
for death and for serious cardiovascular reactions such as
stroke, heart attack or heart failure, the boxed warning states.

In addition to the boxed warning, the new labeling provides
specific instructions for dosage adjustments and hemoglobin
monitoring for chronic kidney failure patients who do not
respond to ESA treatment with an adequate increase in their
hemoglobin levels.

The new labeling also emphasizes that there are no data from
controlled trials demonstrating that ESAs improve symptoms of
anemia, quality of life, fatigue, or patient well-being for patients
with cancer or for patients with HIV undergoing AZT therapy.

In March 2007 the FDA approved labeling changes and issued
a public health advisory outlining the new safety information
about ESAs. Safety concerns regarding ESAs were discussed
during May 2004 and May 2007 meetings of FDA's Oncologic
Drug Advisory Committee and a September 2007 joint meeting
of FDA's Cardiovascular and Renal Drugs Advisory Committee
and the Drug Safety and Risk Management Advisory
Committee. ESA product labeling was previously revised in
1997, 2004 and 2005 to reflect new safety information.

The agency is currently reviewing a proposed Medication Guide
that will better communicate the safety and effectiveness of
ESAs to patients and will replace the existing patient labeling.

ESAs are a bioengineered version of a natural protein made in
the kidney that stimulates the bone marrow to produce more red
blood cells. These drugs are manufactured by Amgen Inc.,
Thousand Oaks, Calif. Procrit is marketed and distributed by
Ortho Biotech LP of Bridgewater, N.J, a subsidiary of Johnson
& Johnson.

For more information:
http://www.fda.gov/cder/drug/infopage/RHE/default.htm

ALL RIGHTS RESERVED 2007