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 Tuesday 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, which Pfizer and the U.S. 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 prescriptions, but follow-up tests showed interaction problems involving some two dozen other popular medications, including Viagra.
Tough to Pinpoint
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.
Still, some doctors are getting worried about drug interactions.
"Now it looks like there's something going on here. Where there's smoke, there's fire," says Charles Curry, chief of cardiology at Howard University's College of Medicine in Washington. He worries in particular about combining Viagra with medicines for high blood pressure and drugs to treat nighttime urination problems that often accompany prostate disease." You add Viagra to that equation ... it worries me," he says.
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 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.
Huge Launch
But in just 10 weeks on the market, roughly 1.7 million new prescriptions for the drug have been written -- an astounding launch that makes the emergence of unforeseen side effects, and drug interactions, but 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.
Warning Unheeded
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. Curry of Howard University 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.
"This has given me great pause," says Mark S. Litwin, a professor of urology and public health at UCLA who sees a lot of AIDS patients. Last month the Gay and Lesbian Medical Association advised its members to start patients on 25 milligrams of Viagra, as opposed to the more common 50-milligram dose. 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.
--Rochelle Sharpe and Andrea Petersen contributed to this article.
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