June 10, 1998 12:55 AM
Viagra Poses Unanticipated Risks When Taken With Other Medications
From The Wall Street Journal
Two months and nearly two million men into the Viagra
craze, concern is growing about the possibility of
unanticipated side effects and adverse reactions when
the impotency pill is taken with other medications.
Federal regulators yesterday disclosed 10 more deaths
of men who were taking Pfizer Inc.'s new drug, in
addition to the six deaths already reported. In several of
the 16 cases, the patients were taking other medications
that hadn't been formally tested with Viagra in human
trials.
That raises an unsettling prospect: What if Viagra is
hazardous when taken with other medications that Pfizer
and the Food and Drug Administration have yet to
identify?
The latest reports underscore a vulnerability in marketing
all new drugs: While pharmaceuticals manufacturers test
their concoctions on several thousand subjects to
monitor side effects and efficacy, the real experiment
begins only after a drug hits the market and vastly more
people begin taking it. The problem is more acute than
ever in an age when TV ads, public-relations blitzes and
intense media coverage accelerate demand for a new
drug.
A similar concern arose this week when Roche Holding
AG withdrew from the market Posicor, the highly touted
hypertension drug it began selling in the U.S. 10 months
ago. The original human trials of Posicor led to warnings
against using it with only three other prescription
medications, but follow-up tests showed interaction
problems involving some two dozen other popular
medications, including Viagra.
Determining which drugs -- if any -- may have interacted
adversely with others is difficult. Many of the Viagra
patients who died were also taking such widely used
drugs as insulin for diabetes, Pravachol for lowering
cholesterol, Hytrin for the prostate and Tenormin and
Cardizem for high blood pressure. Three were given
nitroglycerin for chest pains, despite warnings from
Pfizer not to combine Viagra with nitrates. The youngest
victim, a 48-year old who began having chest pains
during sexual activity, was given nitroglycerin in the
ambulance. His chest pains subsided, but soon returned.
His heart stopped in the emergency room, according to
the FDA report.
Both the company and FDA officials continue to say
they believe Viagra is safe and effective. The deaths are
a minuscule percentage of patients who have taken the
drug, they note, and many of the victims already suffered
from life-threatening illnesses.
For now the biggest risk to Viagra patients appears to
be the strain of sexual intercourse rather than the drug
itself: In several of the deaths, men died of a heart attack
or stroke within hours of taking Viagra and having sex.
Male impotence is often a side effect of more serious
cardiovascular problems, and Viagra has made possible
the resumption of strenuous physical activity -- sex --
among a particularly vulnerable population.
Pfizer tested Viagra on 3,000 men for a period of up to
a year and ran formal drug-interaction studies with about
10 other drugs, including Maalox, an antacid;
erythromycin, an antibiotic; Warfarin, a blood thinner;
Tolbutamide, a diabetes drug and Cimetidine, an
anti-ulcer drug, according to its application to the FDA.
But in just 10 weeks on the market, roughly 1.7 million
new prescriptions for the drug have been filled -- an
astounding launch that makes the emergence of
unforeseen side effects, and drug interactions, inevitable,
some experts say.
"Just because the FDA says a drug is safe and effective,
don't be surprised when problems crop up," says
Raymond Woosley, chairman of the department of
pharmacology at Georgetown University Medical
Center in Washington.
While the FDA has some input, it is largely up to
manufacturers to design drug trials and determine which
interactions to study. It typically costs half a billion
dollars to take a drug from drawing board to pharmacy
shelf, and human trials are among the most costly steps.
Manufacturers usually limit the trials to a few thousand
people, hoping that numbers will be large enough to
yield data on the most common problems.
Sometimes this falls short. American Home Products
Corp. in 1996 introduced Redux, the first obesity pill in
more than 20 years, but later pulled it from the market
because of unanticipated heart-valve problems. Hoechst
AG's Seldane allergy medication was withdrawn this
winter after 12 years of sales because it clashed with too
many other drugs. In the early 1980s Eli Lilly & Co.
scrapped Oraflex after the arthritis drug was linked to
70 deaths, and Johnson & Johnson withdrew the Zomax
painkiller after severe allergic reactions killed five
patients.
Even drugs that aren't withdrawn from the market
frequently have to be relabeled with new warnings when
side effects or drug interactions crop up after the drugs
have been approved, says Georgetown's Dr. Woosley.
"It's impossible to catch everything in clinical trials," adds
Brian Strom, an epidemiologist at the University of
Pennsylvania School of Medicine in Philadelphia
In testing Viagra for drug interactions, Pfizer focused
primarily on medications it suspected might pose
problems. The No. 1 suspect was nitrates commonly
taken by heart patients, because both nitrates and
Viagra dilate blood vessels by acting on the same
chemical mechanism.
Pfizer excluded nitrate patients from the main Viagra
trials to avoid such risks. It separately studied about 20
volunteers, confirming the dangers. The Viagra label
carries a prominent warning against mixing the drug with
nitrates (as well as a warning about the cardiovascular
risk of sex). Nevertheless four known deaths since
Viagra hit the market involved patients taking nitrates.
Now doctors have other concerns. At least five of the
men who died on the new drug were also taking some
type of medicine to control high blood pressure. One
73-year-old man who collapsed during sex and died of
a heart attack and stroke had been put on Hytrin, an
Abbott Laboratories drug used to treat prostate
problems and hypertension, only two weeks before his
death. A 74-year-old man using Hytrin and several other
medications died suddenly when his heart and lungs
stopped working the morning after he took Viagra, the
FDA said.
Pfizer didn't specifically test Viagra on patients who also
were on Hytrin, which racked up almost 10 million
prescriptions in 1997. Pfizer also didn't test Viagra
against Merck & Co.'s Vasotec (20.3 million
prescriptions last year) and two Pfizer-made drugs,
Procardia XL (15.3 million) and Cardura (7.8 million).
Instead, Pfizer chose to test Viagra in patients taking its
own hot-selling medication, Norvasc.
Pfizer conducted a study of 16 patients taking both
Norvasc and Viagra and found that they experienced the
same drop in blood pressure as patients taking Viagra
alone. Beyond that formal study, Pfizer questioned 880
patients in the main trials who were taking as many as 50
different blood-pressure drugs and learned of no major
problems.
Norvasc is immensely popular, running up 19.7 million
prescriptions last year, according to IMS Health, a
health-care information firm in Plymouth Meeting, Pa.
But Dr. Charles Curry, chief of cardiology at Howard
University's College of Medicine In Washington, argues
that Norvasc was a poor choice for interaction tests. It
is a "calcium channel blocker" that dilates blood vessels
by relaxing smooth-muscle tissue, and the drug has only
a gradual effect, lowering blood pressure over days or
weeks. "I would think Viagra would be least likely to
harm someone on that," Dr. Curry says.
Ian Osterloh, chief of the Viagra clinical trials for Pfizer,
defends using Norvasc and says that drug was chosen
because it is so widely used. In addition, patients in the
study took the two drugs in a sequence that was
designed to maximize the chances that adverse
interactions would occur, and none did. Still, Pfizer says
it may conduct an additional interaction study with
another hypertension drug to make patients "feel
comfortable with (extra) data," a spokeswoman says.
Debora Farber, associate director of the Jules Stein Eye
Institute at the University of California at Los Angeles. is
currently testing Viagra on animals to see if it can harm
their eyesight. "We are very, very concerned that
something could happen in patients taking Viagra for
long periods of time," she says. Pfizer says it has done
extensive studies on Viagra's potential for eye-related
side effects in humans and has found nothing, other than
the occasional and temporary blue-green tinge to vision.
Other doctors are wary of possible side effects in HIV
patients who take protease inhibitors, because these
powerful AIDS drugs and Viagra are metabolized by the
same enzyme system in the liver. Of special concern is
Abbott Laboratories' Norvir, an especially potent
inhibitor that puts higher demands on the liver.
Pfizer plans to study the interaction between protease
inhibitors and Viagra but hasn't said when the work will
begin, which drugs will be tested and how many subjects
will be involved.
AIDS doctors also are concerned that Viagra could
interact with other medications used to treat problems
associated with HIV, particularly anabolic steroids and
testosterone. "Putting added stress on the liver could be
detrimental," says Donald I. Abrams, an AIDS
oncologist in San Francisco who is cautious about
putting patients on that mix.
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