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By Jay Cohen, M.D.
Part 2 of 2 (Part
1)
Over
Dose: The Case Against the Drug Companies: Prescription Drugs, Side Effects,
and Your Health
The PDR is not only the leading
drug reference among physicians, but it is also purchased by thousands
of consumers each year. Moreover, the PDR is the source for the bulk of
information contained in other consumer drug references. Yet, as I have
written in multiple professional publications, because the PDR is mainly
a collection of drug-company written package inserts, it omits a great
deal of important information.
The PDR omits or underreports
many serious side effects. It frequently omits information about proven-effective
medication dosages that are lower and safer than the doses recommended
by drug companies or usually prescribed by doctors (54-58). Many new,
important uses of medications are not even mentioned in the PDR.
Nor does the PDR provide any
guidance whatsoever in selecting between the many drugs that might be
used for medical conditions. And, although a new PDR is published each
year, many drug descriptions are not updated. Some of these descriptions
contain information that is decades old.
A glaring example was provided
in a 1997 article in the Annals of Emergency Medicine (59). This article
examined drug company guidelines in the PDR for handling overdoses of
20 drugs commonly seen in overdose situations in emergency rooms.
The study found that for 80%
of the drugs studied, the PDR guidelines for handling overdoses were inadequate.
For overdoses with nearly half of these drugs, the PDR recommended "ineffective
or frankly contraindicated" treatments that could worsen the situations
or cause unnecessary deaths.
The drug companies' influence
even extends to the FDA, which we will explore in Chapter 11. The FDA
is required to ensure the effectiveness and safety of medications, but
changes in the law and political pressure from Congress, as well as a
massive shortfall in funding, has led to weakened FDA standards. Furthermore,
some of the FDA's own policies make matters worse (60).
Funding for the FDA's monitoring of newly approved drugs is so limited
that some drug toxicities weren't identified by the agency, but by investigations
conducted by newspapers or health interest groups. Limited funding also
hampers the ongoing monitoring of important drugs with recognized risks.
After Viagra was on the market
for seven months, the FDA reported receiving 230 cases of deaths associated
with the drug (61). The FDA responded, as usual, with required changes
in Viagra's labeling -- yet, the agency hasn't provided any follow-up
reports on Viagra-related deaths or any analysis of whether the labeling
changes have helped.
Experts with drug company ties fill many important advisory positions
at the FDA. An investigation by USA Today found that more than half of
the experts on FDA advisory committees "have financial relationships
with the pharmaceutical companies that will be helped or hurt by their
decisions (62)."
Today, the FDA approves drugs
much faster, and sometimes on fewer studies, than required ten years ago
(63-65), and FDA oversight wasn't exactly robust then, as multiple drug
withdrawals in the 1980s demonstrated. Since 1997, more drugs have proven
toxic and been withdrawn than ever before.
Some of these withdrawn drugs
- Redux, Seldane,
Propulsid,
Rezulin
-- were prescribed millions of times. According to Dr. Alastair
J.J. Wood, Assistant Vice Chancellor for Research at the Vanderbilt
University Medical Center (66), "a staggering 19.8
million patients (almost 10% of the U.S. population) were
estimated to have been exposed" to just five of the ten
drugs withdrawn in this period.
Dr. Wood added, "None
of the drugs was indicated for a life-threatening condition nor, in many
cases, were they the only drugs available for that indication (67)."
Safer alternatives to these drugs existed, but intense marketing convinced
physicians to prescribe them anyway -- and to continue prescribing them
even as the FDA prepared to withdraw them.
Drug companies can profit handsomely
on such drugs. Seldane, the top-selling antihistamine in the world for
more than a decade, was on the market for thirteen years until the FDA
removed it in 1997, seven years after the drug's cardiac toxicities were
identified in 1990 (68).
Perennial top-seller Propulsid,
for heartburn, remained on the market for seven years, despite reports
of hundreds of heart arrhythmias and scores of deaths before the FDA finally
withdrew it (69).
Rezulin, a diabetes drug
withdrawn by Britain in 1997, wasn't withdrawn by the FDA until 2000,
during which hiatus Warner-Lambert earned $1.8 billion (70).
Drug company influence on regulatory
agencies isn't solely an American affair. "Some medicines are out
on the market too early, without giving practitioners sufficient time
to evaluate them," Dr. Thiery Buclin, a Swiss health official, told
Dimanche, a leading French newspaper, in April 2000.
"We have proof of too
much hastiness and sometimes lack of prudence. In 1998 alone, out of thirty
medicines launched in the Swiss market, five had to be removed. This is
a significant number of rejects, revealing a counter-productive mechanism.
The pharmaceutical industry plays the first role in this dangerous game.
With aggressive marketing, it uses heavy infantry to convince health personnel
(71)."
Aggressive marketing, slanting
research, unethical publishing of results, pressuring medical centers,
intimidating researchers, influencing physicians, limiting information,
manipulating the FDA, marketing drugs with inaccurate safety information
and inappropriate doses -- all of these have created an environment in
which medication development has become, in Dr. Angell's fitting term,
a "race to the bottom (72)."
The side-effect epidemic arises
from the very methods by which drugs are produced, and thus it involves
hundreds of medications. That's why warnings like this partial sampling
from January 1998 to January 2000 continue to appear in medical journals
and the news media:
"Correctly Prescribed
Drugs Take Heavy Toll: Millions Affected by Toxic Reactions." Washington
Post (73)
"Lawmakers Ask FDA Why
Rezulin Was Kept on Market Despite Deaths." Los Angeles Times (74)
"Hepatotoxicity Associated
with Antiretroviral Therapy in Adults Infected with HIV." Journal
of the American Medical Association (75)
"Some AIDS Patients
Are Hit by Disfiguring Fat Deposits; Protease Inhibitor Drugs Suspected."
Philadelphia Inquirer (76)
"Sudden Deaths Reported
with Orap." Worst Pills, Best Pills News (77)
"Alcohol-Acetaminophen
[Tylenol] Syndrome: Even Moderate Social Drinkers Are at Risk."
Postgraduate Medicine (78)
"Psychosis Due to Abrupt
Discontinuation of Oral Contraceptive." Primary Psychiatry (79)
"Antibiotic Linked to
Stomach Disorder in Infants." San Diego Union-Tribune (80)
"Study Links Breast
Cancer, Hormone Use." Los Angeles Times (81)
"Maker of Fen-Phen Paid
for Articles: Lawsuit Says Wyeth Hid Dangers Linked to Weigh-Loss Drugs."
Associated Press (82)
"Liver Toxicity with
Prostate Cancer Drug Eulexin." Worst Pills, Best Pills News (83)
"Trovan Associated with
Liver Injury and Death." FDA (84)
Shocking? Knowing how the drug
companies operate, it is no shock when new dangers are revealed with drugs
we've been using for decades. It is no shock when:
In 2000, the Archives of Internal
Medicine reports that anti-inflammatory drugs have been linked with congestive
heart disease (85).
In 1999, the British Medical
Journal (BMJ) reported that SSRI antidepressants (e.g., Prozac, Zoloft,
Paxil) have been linked with increased risks of gastrointestinal bleeding
(86).
A 2000 Los Angeles Times headline
announced that frequently prescribed drugs for high blood pressure (beta
blockers) have been linked with diabetes (87).
In 2000, the Annals of Internal
Medicine reported that drugs relaxing the muscles of the lower esophagus
have been linked with increased risks of esophageal cancer (88).
Unfortunately, revelations
like these aren't new. These and many more surfaced each of the thirty
years since I earned my medical degree.
Of course, these incidents represent only reported adverse effects --
the tip of the iceberg. Consider digoxin, the best-selling heart drug.
According to an article in JAMA, the FDA receives about eighty-two reports
annually involving digoxin, yet "a systematic study of Medicare records
disclose 202,211 hospitalizations for digoxin adverse effects in a 7-year
period (89)."
That's more than 28,000
reactions per year -- of which the FDA receives eighty-two.
The great tragedy of it all
is that so many side effects are avoidable. Prozac, perhaps the most famous
breakthrough drug since penicillin and insulin, serves as a perfect example.
Prescribed 24,742,000 times in 1999, Prozac causes side effects in a large
proportion of the people started on it. Sexual dysfunctions alone occur
in 33 to 50 percent or more of Prozac users (90-92).
Plus, the drug has repeatedly
been linked to incidents of psychosis, suicide, and violent behavior.
I saw some of this myself. Yet, when I began individualizing my use of
Prozac to fit the needs and tolerances of patients, side effects dropped
dramatically, and the percentage of my patients obtaining good responses
far exceeded Lilly and Company's own claims.
Pfizer developed Lipitor to be extremely powerful in lowering blood cholesterol
levels, so that with aggressive marketing, Lipitor could surpass better
established, more proven competitors. With 48,791,000 prescriptions filled
in 2000, Lipitor has accomplished this, but it has also triggered more
reports to me about side effects than the other five drugs in its class
combined.
Perhaps this is because the
standard dosage of Lipitor is so strong, it is far stronger than many
patients actually need or can tolerate.
Similar problems exist in the
way drug companies research and market many other top-selling drugs today.
There is no doubt that popular drugs such as Zocor, Vasotec, Norvasc,
Viagra, Motrin, Voltaren, Premarin, Prozac, Lipitor, Celebrex, Zestril,
Allegra, etc., are very effective -- I want to emphasize this -- but today's
methods of producing and prescribing these drugs do not include minimizing
their risks.
Of course, pharmaceutical companies
cannot study everything, but as subsequent chapters will show, current
research is woefully deficient in anticipating and avoiding foreseeable
problems -- problems that could be avoided by producing and prescribing
medications to fit people.
The drug companies reject the
assertion that their medications are not safe. "Do unsafe drugs enter
and remain in the marketplace? Absolutely not," stated Bert Spilker,
a senior vice president for the Pharmaceutical Research and Manufacturers
of America (PhRMA), according to the Los Angeles Times (93).
The drug companies also claim
that they need large earnings -- $124,835,595,000 in 1999 -- to conduct
their research. They have a point -- to a point. Aggressive research is
indeed essential. The medications produced by the pharmaceutical industry
have greatly improved the quality and length of life of millions of people.
But this explanation loses credibility when:
1. Just one of every five dollars
the drug industry collects goes to drug research:
2. Some drug companies
spend almost twice as much money for marketing and advertising than for
research;
3. Drug industry profit-taking
is so large it outstrips every other industry by far (94).
As Dr. Angell stated in a second
astonishing 2000 article in the New England Journal of Medicine ("The
Pharmaceutical Industry: To Whom Is It Accountable?"): "An industry
so important to public health and so heavily subsidized and protected
by the government has social responsibilities that should not be totally
overshadowed by its drive for profits.
There needs to be a better
balance between the interest of the shareholders and those of the public
(95)." Indeed, and this balance should begin with improving drug
research and development in order to ensure drug safety and to end the
side-effect epidemic.
The sad irony is that not only
would patients, physicians, insurers, and health care organizations benefit
from reducing the high incidence of medication side effects, but so would
the drug companies. When 50 percent or more of patients quit treatment
for conditions such as high blood pressure (96, 97), high cholesterol
(98, 99), and osteoporosis (100, 101, 101A), no one wins.
These patients become exposed
to markedly increased risks of premature disease and death, and the healthcare
system is burdened with billions in extra costs. Yet, if the priority
in producing medications wasn't expediency but maximizing the benefits
while minimizing the risks of medication treatment, many of these problems
could be avoided. And keeping patients satisfied and in treatment would
increase drug sales.
Just because side effects are
all too common, this doesn't mean they must be. In a 1999 article in JAMA,
Dr. Wood stated, "Drug safety will improve only when it is viewed
as a cooperative venture between regulator, industry, and prescriber,
when all parties are prepared to engage in open dialogue so they may learn
from the past with a view toward improving the future (102)."
This dialogue should have begun
long ago, because ending the side-effect epidemic doesn't require some
new insight or discovery: It simply requires restoring sound, practical,
scientific principles to the ways we research, develop, regulate, and
prescribe medications.
As Over Dose will demonstrate
in detail, we already have all of the information we need to do this --
to drastically reduce the occurrence of medication side effects and to
end the side-effect epidemic today.
We have so much information
that, by using it in the manner I will describe in subsequent chapters,
patients can have great influence on how medications are prescribed to
them. In doing so, they can greatly increase their chances of a positive
response to medication treatment while greatly reducing their risks.
The side effects Alex endured
should never had occurred. Once they did occur, they should have been
promptly curtailed. Alex' disorder should have been easily and quickly
controlled. This book will explain how -- and how other patients and their
physicians can do the same with their own medications.
Ten Medications Withdrawn From
The Market Since 1997
Because Of Serious, Often Lethal
Side Effects
Rezulin:
Given fast-track approval by the FDA, Rezulin was linked to sixty-three
confirmed deaths and probably hundreds more. "We have real trouble,"
an FDA physician wrote in 1997, just a few months after Rezulin's approval
(103). The drug wasn't withdrawn until 2000.
Lotronex:
Against concerns of one of its own officers, the FDA approved Lotronex
in February 2000. By the time it was withdrawn nine months later, the
FDA had received reports of ninety-three hospitalizations, multiple emergency
bowel surgeries, and five deaths (104).
Propulsid:
A top-selling drug many years, the drug was linked to hundreds of cases
of heart arrhythmias and one hundred deaths.
Redux:
Taken by millions for weight loss after its approval in April 1996, Redux
was soon linked to heart valve damage and a disabling, often lethal pulmonary
disorder. Withdrawn in September 1997.
Pondimin:
A component of Fen-Phen, the diet fad drug. Approved in 1973, Pondimin's
link to heart valve damage an a lethal pulmonary disorder wasn't recognized
until shortly before its withdrawal in 1997.
Duract:
The painkiller was withdrawn when it was linked to severe, sometimes fatal
liver failure.
Seldane:
America's and the world's top-selling antihistamine for a decade, it took
the FDA five years to recognize that Seldane was causing cardiac arrhythmias,
blackouts, hospitalizations, and deaths -- and another eight years to
withdraw it.
Hismanal:
Approved in 1988 and soon known to cause cardiac arrhythmias, the drug
was finally withdrawn in 1999.
Posicor:
For treating hypertension, the drug was linked to life-threatening drug
interactions and more than one hundred deaths. An expert on the advisory
committee said, "Posicor should not have been approved (105)."
Raxar:
Linked to cardiac toxicities and deaths.
References
Subsequent
Chapters of "Over
Dose: The Case Against The Drug Companies"
Chapter 2: How Drug Company Policies
Harm People
Chapter 3: How Drug Company Policies
Cause Problems For 50-75% Of Patients Taking Prozac
Chapter 4: When New Drugs Are Approved,
The Experiment Is Just Beginning, And You May Be Part Of It -- Viagra
Chapter 5: How The Drug Companies' Policies
Harm Women
Chapter 6: Why 50-75% Of People Quit
Taking Their Cholesterol-Lowering Medications
Chapter 7: Why 50-75% Of People Quit
Taking Their Medications for High Blood Pressure
Chapter 8: Why Seniors Are At The Greatest
Risk
Chapter 9: How The Drug Companies Slant
Drug Research Limit Information To Doctors And Consumers, And Secure
High Profits
Chapter 10: What The Drug Companies Need
To Do To End The Side-Effect Epidemic -- But Will They?
Chapter 11: What's Wrong With The FDA?
And What Can Be Done About It?
Chapter 12: What The FDA Shouldn't Do
-- Why We Need An Independent Medication Safety Monitoring System
Chapter 13: Doctors, Drugs, And Patients
Chapter 14: How You Can Avoid Side Effects
And Use Medications Safely
Jay S. Cohen, M.D., is an Associate Professor
of Family and Preventive Medicine (voluntary) at the University of California,
San Diego.
PUBLISHERS WEEKLY: "Replete with information
supported by recognized and reliable sources, this expose` and health
guide should be read by anyone taking prescription medication.... Clear,
easy narrative ... an invaluable resource for doctors and patients alike."
BOOKLIST: "A thorough, solidly based
book that deserves to be widely read by medical professionals and the
lay public."
KIRKUS REVIEWS: "A call for action
and a plan for it as well. Though not intended as a comprehensive reference,
Over Dose is a source of useful drug information, much of it tabulated
at chapter ends for easy consultation."
LOS ANGELES TIMES: "The central message
of Over Dose is that people are overmedicated. Cohen believes that the
only way for consumers to circumvent these problems is to become informed
about lower, safer drug doses. To this end, the book includes practical
advice on dozens of common prescription medications for those who are
most at-risk: the elderly, women, and children."
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