LABELS HIDE DIET DRUG MIXTURE RISK - U.S. RESEARCH

BOSTON (Reuters) - Outdated labeling hides a popular diet drug's
dangerous side effects when combined with antidepressants such as
Prozac or cold remedies like Sudafed, researchers said Friday.

The diet drug phentermine -- the ``phen'' in the now banned
combination fen-phen -- has been used in the United States since 1961
and remains on the market. It is widely prescribed to treat obesity, a
problem that afflicts some 65 million Americans.

But the U.S. Food and Drug Administration has never updated the drug's
warning label to include crucial information, according to researchers
at the Massachusetts Institute of Technology and the Massachusetts
College of Pharmacy. Phentermine blocks the body's ability to remove
serotonin from the blood stream.

Serotonin is involved in transmitting nerve impulses, and the
antidepressant and anti-obesity drugs are designed to enhance that
effect. But too much serotonin can damage blood vessels, particularly
in the lungs, cause cracks in heart valves and lead to
hypertension.

The body has two ways of removing serotonin: by absorption into blood
platelets that use it for clotting and through the
serotonin-destroying enzyme monoamine oxidase, or MAO.

Some drugs block serotonin from being taken in by platelets; others
block the activity of MAO. By using two of the drugs at the same time,
the body's ability to keep serotonin in check is destroyed.

Phentermine is an MAO inhibitor, something researchers noted in the
1970s, but that fact was never added to the drug's warning label, MIT
scientist Tim Maher said.

``To this day, if you ask 1,000 physicians or pharmacists if
phentermine is an MAO inhibitor, they will say no. This information
was buried. It never surfaced after the 1970s, and we're reconfirming
it now,'' Maher said.

``Because this information is still omitted from the drug's label,
many patients are now taking it with another serotonin-uptake blocker,
Prozac, to lose weight,'' Maher said.

Other serotonin-uptake blockers such as pseudoephedrine, found in
Sudafed, phenylpropanolamine, used in Acutrim, and ephedrine, a
bronchial relaxant, may also be taken by people already using
phentermine, Maher's colleague Richard Wurtman said. The labels on
those products clearly state they should not be taken if the patient
is also using an MAO inhibitor.

``What good does it do to say, 'Never give with an MAO inhibitor,' if
you don't know that an MAO inhibitor is in what you're prescribing?''
asked Wurtman, co-inventor of the anti-obesity drug Redux, the ``fen''
in fen-phen, which was withdrawn from the market in 1997. MIT holds
the patent on Redux, also known as dexfenfluramine.

American Home Products is the target of dozens of class-action suits
resulting from its manufacture of the diet drugs fenfluramine and
dexfenfluramine, which were recalled last September. The company faces
billions of dollars in potential liability after the FDA warned the
two drugs might cause heart valve abnormalities.

Wurtman said if U.S. doctors had known phentermine was an MAO
inhibitor, ``they never would have prescribed the drugs together.''

A spokesman for Eli Lilly, makers of Prozac, the decade's most popular
antidepressant, said that in the 11 years the product had been
available, ``there has been no such report of an adverse reaction.''

Last September, Lilly sent Nutri/System Weight-Loss Centers a kind of
cease-and-desist letter when the Pennsylvania diet company launched an
advertising campaign promoting the use of Prozac with
phentermine.

``That was done not because we had any reports of adverse reactions
but because we did not conduct safety tests for that use,'' Lilly
spokesman Greg Keuterman said.

Dr. Judi Sills of Warner-Lambert, makers of Sudafed, said, ''We have
30 years of past data, and we have not had any reports of people who
are on Sudafed and other products resulting in such an adverse
reaction'' as hypertension or damage to heart valves.

FDA spokeswoman Ivy Kupec, while declining to comment on the specifics
of phentermine, said the agency had the ability to update labeling
information. ``We require new information on labels when we learn of
adverse events through clinical trials or reports,'' she said.

Both Maher and Wurtman expect to meet with FDA officials after they
present the results of their research at the International Congress of
Obesity next week in Paris.

The pair's rediscovery of phentermine's MAO-inhibiting effects was
serendipitous. Maher was researching the problems associated with
fen-phen, while Wurtman wanted to see whether phentermine affected
another chemical in the blood.

Maher quickly found the 1970s reports that phentermine was an MAO
inhibitor, and Wurtman noted a spike in serotonin levels in volunteers
for his experiment. They looked at the other drugs because Maher said
they ``have similar chemical structures to fenfluramine.''

Checked-by: Patrick Henry