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FDA is taking further measures to strengthen its recent public warning
that treatment of obesity with a combination of fenfluramine and phentermine has been
associated with the development of serious cardiac valvular disease. Based on further
reporting of abnormalities in mitral, aortic, and tricuspid heart valves of patients
taking these two appetite suppressants and/or the chemically-related product,
dexfenfluramine, the agency has requested that the manufacturers of phentermine,
fenfluramine, and dexfenfluramine stress this potential risk in a black box warning in the
drugs' labeling and in patient package inserts (patient information sheets). FDA again
reiterates that, until these concerns are further clarified, these products should only be
used in people with significant obesity and not in people with minimal obesity.
Phentermine and fenfluramine, which are approved as single agents for short-term (a few
weeks) obesity therapy, have recently been widely prescribed "off-label" in
combination and for long-term management of obesity. In July, researchers at the Mayo
Clinic reported 24 cases of cardiac valvular disease in women who took the combination
therapy for an average of about 12 months. Cardiac valvular disease is usually a rare
finding in people in the age range of these 24 patients. Simultaneously, FDA advised that
it had received reports of 9 further cases of valvulopathy associated with the off-label
use. Subsequently, FDA issued a Public Health Advisory to over 700,000 health care
practitioners and institutions warning them of this new concern with these products.
In its July 8th Advisory, the FDA also asked -- and continues to request -- all health
care professionals to report any such cases and other toxicities associated with the use
of the three drugs to FDA's MedWatch program (1-800-FDA-1088/fax 1-800-FDA-0178) or to the
respective pharmaceutical manufacturers. Such reporting allows FDA to better determine the
scope of this problem, to better work with the academic community and the manufacturers in
determining the reason(s) for this problem, and to better determine the most appropriate
regulatory response to this concern.
Thanks to the reporting of health care professionals, as of August 22, FDA has received
reports of 82 cases (including Mayo's 24 cases) of cardiac valvular disease in patients --
two of whom were men -- on combination fenfluramine and phentermine. These reports have
been from 23 different states. Severity of the cardiac valvular disease was graded as
moderate or severe in over three-fourths of the cases, and two of the reports described
deterioration from no detectable heart murmur to need for a valve replacement within
one-and-a-half years. Sixteen of these 82 patients required surgery to repair their heart
valves. At least one of these patients died following surgery to repair the valves. (The
agency's findings, as of July 31, are described in more detail in the current issue of The New England Journal of Medicine,
which also carries the Mayo study.)
Five additional reported cases of cardiac valvular disease were associated with exposure
to fenfluramine followed by dexfenfluramine, both in combination with phentermine; and 1
additional case was associated with exposure to the combination of all 3 drugs given at
the same time.
In addition, there have been reports of cardiac valvular problems associated with the use
of fenfluramine alone (n=2) and dexfenfluramine alone (n=7). However, no reports have yet
been received of these heart problems developing when fenfluramine or phentermine are used
as single agents for the duration presently approved.
In addition, FDA is working with the Centers for Disease
Control and Prevention, the National Institutes of
Health, and the Mayo Clinic researchers to develop
methods to investigate the scope and cause(s) of this problem. Some epidemiologic studies
using on-going trials and various data bases are already underway. Other prospective
studies are presently being designed.
In the meantime, although the cause-effect relationship between the use of these drugs and
the development of cardiac valvular disease has not been conclusively established, FDA
wants to make sure that these serious potential risks of combination and long-term therapy
with these products is known to both the prescribers and their patients. The agency
therefore has requested the manufacturers of these products to revise the drugs' approved
labels to emphasize the new safety information in a prominent, black boxed warning at the
beginning of the label. This new black box warning will warn prescribers of these new
concerns and reiterate the fact that the safety and efficacy of the combined use of these
products and the use of the products for longer than presently approved has not been
established. In addition, the FDA has requested that manufacturers quickly develop patient
package inserts to alert potential users to the same facts and concerns.
FDA continues to be highly concerned about these reports of serious heart problems in
association with the use of these products. FDA will continue to work with the
manufacturers, the professional organizations representing those who primarily prescribe
these products, and consumer groups to use all methods possible to disseminate fully
safety and efficacy information about these products. Since the warnings that went out in
July, reduced sales of fenfluramine and phentermine have thus far suggested approximately
a 40 percent decline in their combination use in the United States.
FDA continues to explore further options available to it - other than those already
mentioned - to assure that patients are able to make fully informed decisions about the
use of these drugs.
Further updates will be issued as further data and/or regulatory activities occur with
these products.
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