Withdrawal of Fenfluramine (Pondimin)
and Dexfenfluramine (Redux)

  1. What is “fen-phen”?
Fen-phen refers to the use in combination
of fenfluramine and phentermine. Phentermine has also been used  in
combination with dexfenfluramine (“dexfen-phen”). Fenfluramine (“fen”)
and phentermine (“phen”) are prescription medications  that have been
approved by the FDA for many years as appetite suppressants for the short-term
(a few weeks) management of  obesity. Phentermine was approved in
1959 and fenfluramine in 1973. Dexfenfluramine (Redux) was approved in
1996 for use as an appetite suppressant in the management of obesity. Recently,
some physicians have prescribed fenfluramine or dexfenfluramine in combination
with phentermine, often for extended periods of time, for use in weight
loss programs. Use of drugs in ways other than described in the FDA-approved
label is called “off-label use.” In the case of   fen-phen and
dexfen-phen, no studies were presented to the FDA to demonstrate either
the effectiveness or safety of the drugs taken in combination. 

  2. What is the difference between fenfluramine and
      dexfenfluramine?
Fenfluramine (Pondimin) contains dexfenfluramine
and levofenfluramine. Levofenfluramine may have some activities not directly
related to appetite suppression. Dexfenfluramine (Redux) contains only
dexfenfluramine. 

  3. What is the new evidence that prompted withdrawal of
      fenfluramine and dexfenfluramine?
On July 8, 1997, the Mayo Clinic reported
24 patients developed heart valve disease after taking fen-phen. In five
patients who underwent valve replacement surgery, the diseased valves were
found to have distinctive features similar to those seen in carcinoid syndrome.
The cluster of unusual cases of valve disease in fen-phen users suggested
that there might be an association between fen-phen use and valve disease. 

On July 8, FDA issued a Public Health Advisory
that described the Mayo findings. The Mayo findings were reported in the
August 28 issue of the New England Journal of Medicine, along with an FDA
letter to the editor describing additional cases. FDA has received over
100 reports (including the original 24 Mayo cases) of heart valve disease
associated mainly with fen-phen. There were also  reports of cases
of heart valve disease in patients taking only fenfluramine or dexfenfluramine.
No cases meeting FDA’s definition of a case were reported in patients taking
phentermine alone. 

Within the past several weeks, additional
information received by the FDA has raised more concern. Most of the cases
previously brought to the FDA’s attention were in patients who had symptoms
of heart disease. Recently, FDA has received reports from five physicians
who had performed heart studies (echocardiograms) on patients who had received
fen-phen or dexfen-phen and did not have symptoms of heart disease. Of
291 asymptomatic patients screened, about 30 percent had abnormal valve
findings, primarily aortic regurgitation. Based on these data, the manufacturers
have agreed to withdraw the products from the market and FDA has recommended
that patients stop taking the drugs. 

  4. Why isn’t phentermine being withdrawn from the market?
At the present time, no cases of heart valve
disease meeting FDA’s case definition have been reported with phentermine
alone. Analysis of the data points to an association of heart valve disease
with fenfluramine and dexfenfluramine. 

  5. Why wasn’t this problem discovered  earlier?
The type of valve disease that FDA believes
may be associated with fenfluramine and dexfenfluramine is an extremely
unusual type of drug reaction. Because valve disease is not usually associated
with drug use, it is not    normally screened for in human
clinical testing of drugs. Since valvular heart disease is not screened
for in clinical trials, it would usually not be detected unless patients
developed symptoms. No cases were detected in 500 patients followed for
one year in a clinical trial of dexfenfluramine. Furthermore, asymptomatic
heart valve disease (heart valve disease without symptoms) would not likely
be detected in patients taking the drugs as part of a weight loss program.
The number of patients who have been reported to have symptoms of heart
valve disease associated with recent exposure to the drugs has been very
small, compared to the number of recent prescriptions, although there may
be a delay in the development of symptoms. And even in symptomatic patients,
the link between the symptoms and drug use may not be obvious because such
a reaction is not common. These factors may explain why this problem was
not discovered earlier. 

During the last few years, there has been
a marked increase in amount and duration of use of fenfluramine, as it
became widely prescribed as part of the fen-phen regimen.. 

In 1992, articles were published about study
results suggesting that the combined use of phentermine and fenfluramine
would result in significant weight loss when used over an extended period
of time. The results of these studies were not reviewed by FDA, and the
conclusion about long-term use of the combination of drugs has not received
FDA approval. The increased magnitude and duration of use probably led
to an increase in the number of cases of  symptomatic heart valve
disease, which may have contributed    to the recent recognition
of this association. 

With respect to dexfenfluramine (Redux), which
was approved on April 29, 1996, the labeling states that safety has not
been shown for longer than one year of  use. This reflects the length
of the study upon which    dexfenfluramine was approved.
It was a one-year European study of 1,000 subjects, half of whom were treated
with dexfenfluramine. The study population was 80 percent women with an
average age of 41. Heart disease was not noted in the study. A follow-up
study directed toward uncovering heart disease after termination of the
study was not performed because there was no reason to believe at that
time that the heart was affected. In addition, dexfenfluramine had been
marketed in Europe for over a decade without detection of an association
between dexfenfluramine and heart valve problems. FDA is currently trying
to obtain such follow-up. 

  6. What is valvular heart disease?
The heart contains four major valves that
regulate the flow of blood through the heart and to the lungs and general
circulation. Disease may cause excessive tightness (stenosis) or leakiness
(regurgitation) of the valves. In the case of valve disease associated
with fenfluramine and dexfenfluramine, leakiness is the problem. Valvular
damage may ultimately produce severe heart and/or lung disease. 

  7. What is the relationship of  fenfluramine and
      dexfenfluramine to heart disease?
Patients who have taken those drugs may have
hanges in their heart valves that cause leakiness and backflow of blood.
If this is severe, the heart has to work harder. This may cause problems
in heart function. However, the full medical implications of this relationship,
especially in the asymptomatic patients, is not fully understood. 

  8. What are the signs and symptoms of valvular heart
      disease?
The patient may have no symptoms. The physician
may hear a new heart murmur (abnormal sound as the blood flows over a valve),
or the changes may be detected with a painless, non-invasive special heart
test called an echocardiogram. An echocardiogram is usually performed by
a cardiologist. If the disease is severe, the patient may experience such
symptoms as shortness of breath, excessive tiredness, chest pain, fainting,
and swelling of the legs (edema). 

  9. Is the valve disease reversible?
It is not known at this time. One report has
been submitted to FDA in which the valve disease appeared to improve. However,
we encourage those people who have taken fenfluramine or dexfenfluramine
to contact their physician and discuss the appropriate follow-up, even
after stopping    their medicine. The full medical implications
of these findings are not known at this time, especially as they relate
to the asymptomatic valvular changes. The FDA and other government agencies,
the manufacturers, and medical researchers will aggressively follow this
concern and keep patients and health care providers informed of what is
learned about the natural history of the valvular disease caused by these
medications. 

10. How is valvular disease treated?
It depends on the degree of damage. Medications
may help the heart function. If the damage is severe, the valves may have
to be replaced surgically. 

11. Should I stop taking fen-phen, fenfluramine or
      dexfenfluramine right now?
Yes, this is the FDA’s recommendation. Although
we believe these drugs can be stopped at once for most persons, you should
consult your physician about whether he/she advises you to taper the dosage
over, for example, a 1 to 2 week period. The manufacturers of these drugs
are withdrawing fenfluramine and dexfenfluramine from the marketplace,
effective September 15, as the concerns about the effects of these drugs
on heart valves continue to grow. The drugs will no longer be available
in pharmacies. Though the potential long-term medical implications are
not known at  this time as there are still a number of unanswered
questions, the FDA and the manufacturers believe it is in the best interest
of the patients that they stop taking these medications. Please be aware
that at present this recommendation does not apply to phentermine taken
alone. 

12. Should I get an echocardiogram if  I’ve been taking
      fenfluramine or dexfenfluramine?
You should consult your physician about having
an echocardiogram. Your physician’s recommendation will depend upon your
symptoms, if any, his or her examination of you and your history of exposure
to these drugs. 

13. Does “herbal fen-phen” have the same problem?
Herbal fen-phen is a product that does not
contain fenfluramine, dexfenfluramine, or phentermine. Products called
“herbal fen-phen” often contain a combination of ephedra (an ephedrine
containing herb) and    caffeine, but may also contain other
herbal ingredients. FDA has not reviewed these herbal products for safety
or efficacy. Ephedrine is pharmacologically different from fenfluramine
and dexfenfluramine. 

14. Can selective serotonin reuptake inhibitor (SSRI)
      antidepressants such as Prozac, Zoloft,
Luvox and Paxil be

      substituted for fenfluramine in the
phen/fen combination?

FDA has not reviewed the safety or efficacy
of such combinations and has not approved their use. These drugs are active
in serotonin metabolism but have somewhat different activity than fenfluramine
and dexfenfluramine. No currently available weight-loss drugs have been
studied adequately in combinations to permit a recommendation by FDA for
combined use. 

15. I have heard the FDA recently denied a citizen petition that
      sought to suspend the approval of
Redux

      (dexfenfluramine). Why did the FDA
deny that request?

The citizen petition did not contain any dditional
medical information that was not already known. The FDA had taken appropriate
actions based on the knowledge at that time. Since that time, more information
has been obtained that raised enough additional concerns to warrant withdrawal
of Redux from the market. 

16. Is this just a disease of women?
Though the majority of cases of which FDA
is aware are women, there is no reason at present to believe that men are
not also at risk. Most of the use of these products is in women, so what
we have seen to date could be only a reflection of the usage patterns of
the products. FDA advises that both male and female patients consult their
health care professionals. 

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Healthy Weight Journal 

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