TOO MUCH OF A GOOD THING? DOCTOR CHALLENGES DRUG MANUAL

When doctors need information about what dose of medicine to
prescribe, they usually consult a fat navy blue book called the
Physicians' Desk Reference -- P.D.R. for short -- which is an
extensive compilation of data about drugs from their
manufacturers.

But the doses recommended in the P.D.R. may be too high for many
people and may cause adverse reactions, ranging from dizziness and
nausea all the way to death, according to an article published last
month in the journal Postgraduate Medicine. For many drugs --
including Viagra, Prozac and some medicines used to treat high blood
pressure, allergies, insomnia and high cholesterol -- smaller doses
would work just as well as the standard ones, with far less risk of
bad reactions, said the author of the article, Dr. Jay S. Cohen, an
associate professor of psychiatry at the University of California at
San Diego.

"Side effects drive a lot of people out of treatment that they need,"
Dr. Cohen said, noting that people with chronic conditions like high
blood pressure, headaches and depression often give up trying to treat
their illnesses when they find that the cure is worse than the
disease. But if doctors were to individualize dosages for each
patient, more people might take their medicine.

Dr. Cohen said he became aware of the problem because he encountered
many patients who suffered from side effects even though they had
taken what were supposedly the correct doses of medicine. When Dr.
Cohen consulted medical journals and textbooks, he discovered studies
showing that many patients were helped by smaller than usual amounts
of medication. And many of his own patients did better with reduced
doses.

He said his findings helped explain a study published last year by
other researchers, who reported that drug reactions in hospitals were
among the nation's leading causes of death, killing more than 100,000
Americans a year. The deaths that the team studied were not due to
medication errors by doctors or patients; they occurred in people
taking doses thought to be correct.

But Dr. Cohen thinks many of the patients died because they were
taking too much medicine: the "correct" doses were too strong for
them. People vary greatly in their sensitivity to drugs, he said, and
one person's remedy may be another's overdose. Although weight, age
and sex help determine how a dose of medicine will affect someone, it
is also possible for two people who are identical in those traits to
react quite differently to the same dose of the same drug. Dosing
guidelines from drug companies may be right for most people, but too
high for "large subsets of patients," Dr. Cohen said.

Dosing guidelines generally tend to be too high because they are based
on studies conducted in limited numbers of patients by drug companies
when they are seeking approval for new products, Dr. Cohen said. For
those studies to run efficiently, doses need to be high enough to show
as quickly as possible that the drug works. But later, after the drug
is approved, far more people take it, sometimes along with other
drugs, and individual differences begin to show up. That information
does not always make it into the P.D.R., Dr. Cohen said.

Dr. Peter Honig, deputy director of the office of postmarketing risk
assessment at the Food and Drug Administration, said, "We learn a lot
about a drug after it's been approved. I think we would agree with
that. I think he makes some good points. Individualized dosing is the
way to go. But it's not well taught in medical school."

Dr. David Bates, an associate professor of medicine at the Harvard
Medical School, called Dr. Cohen's idea an interesting hypothesis.

"In the elderly, it's clear that you want to start with lower doses,"
said Dr. Bates, who has written about adverse reactions for medical
journals. "In them in particular it's quite clear that you get in
trouble if you use a 'one size fits all' dosing, which doctors have
tended to do. It may well be for younger people, too, that there's
considerable variability in the way drugs are broken down."

Doctors are taught to "start low, go slow," Dr. Bates said, when
prescribing medicines for people over 60 or 65, but that the advice
may apply to younger patients as well.

Dr. Raymond Woosley, chairman of the department of pharmacology at
Georgetown University in Washington, called Dr. Cohen's article "an
outstanding paper, and a very important message."

Dr. Woosley named several drugs with recommended doses that he
considered too high, including Viagra and the over-the-counter allergy
medicine Chlortrimeton. In addition, he said, the AIDS drug AZT was
first marketed at doses that turned out to be far too high and that
had to be reduced.

Dr. Cohen said doctors might identify some people at risk for
reactions by asking patients whether they had ever had an adverse
reaction to a drug and whether they considered themselves unusually
sensitive to medications or prone to side effects. Having a strong
reaction to a little bit of alcohol or caffeine may also be a clue
that a patient will be very sensitive to medicines, he said.

Drugs that have caused trouble in the past should be avoided, he said,
and people who seem very sensitive to medicines can be started on low
doses, which can be gradually increased if necessary. Some pills, but
not capsules, can be cut to fine-tune doses.

But Dr. Woosley said that in his experience a bad reaction to one
medicine could not be used to predict how a patient would fare with
others.

Dr. Cohen cautioned that patients should not begin tinkering with
doses of prescription drugs on their own. He said they needed to work
with doctors to adjust the doses safely. With some drugs, doses cannot
be changed: for example, antibiotics, antivirals and other medications
used to treat infections must be taken full strength, according to the
directions on the label. And in emergencies, he said, it is always
safest to stick with the recommended doses.

A spokesman for Medical Economics Inc., publisher of the P.D.R., said
that the information in the book was supplied by drug manufacturers
and approved by the Food and Drug Administration.

Dr. Carl Peck, a former director of the Center for Drug Evaluation and
Research at the Federal drug agency, said, "One dose fits all is a
marketing myth, but it's the holy grail that every drug company tries
to achieve."

While at the drug agency, Dr. Peck conducted a study that showed that
some drugs did come to market from 1980 to 1993 with dosing advice
that had to be lowered. But, he said, that is less likely to occur
today because during the last decade drug manufacturers have begun to
study ranges of doses in the trials done before drugs are approved.

Some newer drugs, like cholesterol lowering agents and a nose spray
for allergies, come with labeling that gives a recommended dose range
and advises doctors to try to find the lowest effective dose. Dr. Peck
is now director of the center for drug development science at the
Georgetown University Medical Center.

"The whole issue of getting the dose right has become an important
focus for the F.D.A.," Dr. Peck said, "and I think the F.D.A. and the
drug companies are making a good-faith effort to do better these days."