One little tablet forever changed Rosemary Porta's life. The 58-year-old Pennsylvania school librarian went to her doctor in January 1999 complaining of chest congestion. Because she was allergic to amoxicillin, her physician prescribed a new antibiotic, Trovan.
As she took the medication over the next several weeks, she began to suffer from nausea, blurry vision and severe exhaustion that left her bedridden. One morning, she awakened to discover the whites of her eyes had turned yellow, her skin had an eerie, incandescent glow and her urine was dark orange--the hallmarks of catastrophic liver failure.
She was rushed to the hospital, where she clung precariously to life. Finally, in April, she had a life-saving liver transplant. But the episode took a heavy toll on Porta's health. She now takes a battery of drugs to keep her body from rejecting the donor liver. The drugs themselves cause side effects, such as tremors, and she has experienced three frightening rejection episodes. And even an inconsequential medical problem, like a yeast infection, can escalate into a crisis. "I'm living on borrowed time," says Porta. "And all I did was take a pill."
The Food and Drug Administration has since limited Trovan to treating life-threatening infections in hospitals or nursing homes. The action came too late for Porta, who never realized the medicine her doctor dispensed could be hazardous. Like many Americans, she took drug safety for granted.
Adverse drug reactions have reached epidemic proportions, killing more people each year than die on the nation's highways, and doing serious damage to millions more. This problem has taken on special significance recently: The FDA has pulled 10 drugs off the market in the past three years for safety reasons, which is unprecedented in the agency's history. Nearly 20 million patients, almost 10% of the U.S. population, were estimated to have been exposed to these drugs before their removal, according to a 1999 editorial in the Journal of the American Medical Assn.
Few people, however, are aware that their medications could be harmful, or know how to spot the warning signs and what to do if they suspect there's a problem.
Yet a 1998 University of Toronto study found that roughly 100,000 Americans die of adverse drug reactions each year, and 2.1 million more are hospitalized. The FDA received reports of more than 258,000 adverse drug events in 1999, nearly quadruple the 68,000 incidents reported a decade earlier. And FDA officials acknowledge that they're catching only a tiny fraction of these incidents.
Patients Don't Assume the Worst
One reason why the agency can't quantify the magnitude of the problem is that patients tend to discount their symptoms, chalking them up to side effects of their illness. Last year, in fact, Harvard researchers found that 18% of patients complained of drug-related complications, yet only 3% had told their doctors.
"People often have symptoms for months, but they're either reluctant to let their doctor know or they weren't sure if they just felt lousy," says Dr. David W. Bates, an associate professor of medicine at Harvard University and a coauthor of the study. "But these numbers translate to 36 million adverse drug events per year." That means nearly one out of five adult Americans who take prescription drugs experience complications.
Several factors are fueling the spike in drug side effects. In the last two decades, drugs have become medicine's primary treatment tool, and advances in our understanding of the underlying mechanisms of disease have given us an impressive arsenal of weapons against such killers as heart disease, stroke, cancer and diabetes, as well as other ills, such as depression and chronic pain, that plague millions.
This progress, however, comes with a price, says Dr. Alastair J.J. Wood, a professor of pharmacology at Vanderbilt University in Nashville. "The more potent the [drug's] effect, the more likely there are to be adverse events--there's always a trade-off."
Another development that plays a role in increasing the number of drug complications is that more new therapies are being sold first in the United States, rather than in Europe and Asia. In the early 1980s, only 2% to 3% of new drugs were introduced in the United States. By 1998, that number climbed to more than 60%, according to FDA officials, largely due to faster approvals by the agency.
This cuts both ways, though. While U.S. consumers have access to new medications more quickly, we no longer have the safety cushion of having drugs used first by large numbers of people in other countries.
Reactions Run the Gamut
Like the first model year of a car, when kinks still need to be ironed out, "the initial marketing of a drug is essentially a therapeutic experiment," says Wood.
More than half of all drugs trigger serious side effects in their first year after receiving FDA approval, according to the General Accounting Office, the investigative arm of Congress. These reactions range from tremors and heart palpitations to seizures, permanent disability, cardiac arrest and death.
It's tough to predict possible side effects in a diverse population, however. Even when companies conduct large studies of drugs--some involving as many as 6,000 to 7,000 patients--they may not detect subtle differences in the way patients respond to a drug. "If an adverse event occurs in perhaps one in 5,000, or even one in 1,000 users, it could be missed in a clinical trial but pose a serious safety problem when released to the market," noted former FDA Commissioner David A. Kessler in a 1993 JAMA article.
And drug tests often exclude pregnant women, the elderly, children and the chronically ill because they would skew the results. Consequently, once millions are consuming a medication, the potential for trouble expands exponentially.
Aggressive marketing of new drugs can exacerbate the problem by persuading doctors and patients to seek out the latest therapies more quickly. "There used to be a slow curve as physicians adopted new drugs," says Mary Nell Lehnard, a senior vice president for the Blue Cross and Blue Shield Assn. in Washington, D.C. "But now, the first-year growth in revenues for new drugs is extraordinary."
When the impotency pill Viagra debuted in March 1998, for instance, nearly 2 million men got prescriptions within the first two months. Similarly, more than 2.5 million prescriptions were written for the painkiller Duract before the product was withdrawn from the market in 1998 after four patients died of liver toxicity.
And it's not just newer drugs that can be dangerous. Virtually all prescription drugs have some type of side effects.
The acne treatment Accutane is a case in point. Since 1983, the drug, which can cause severe birth defects when taken by pregnant women, has been associated with 44 suicides in the United States, according to FDA figures. A Congressional committee held hearings in December to look into the mood-altering effects of Accutane at the urging of Rep. Bart Stupak (D-Mich.), who has blamed the drug for the recent suicide of his 17-year-old son. The FDA has not removed Accutane from the market, saying there is insufficient data to establish a direct link between the drug and the suicides.
Determining whether a patient's symptoms are caused by a drug or something else is tricky. Drug makers generally try to identify and resolve any harmful side effects before their products reach the market.
No Way to Predict Some Side Effects
It's the wild cards, though, the unexpected, catastrophic consequences that crop up later, that blindside doctors, drug makers, regulators and patients. "We're good at picking up the obvious," says Dr. Timothy P. Brewer, a Harvard epidemiologist who has studied adverse drug reactions. "But there are huge gaps in our knowledge."
Because we don't understand how many drugs work, people's health can be harmed by a medicine's side effects, often without the patient or their doctors realizing what's behind their trouble. That's what happened to Vincent Canobbio, a 32-year-old Internet executive in Silicon Valley. In May 1999, Canobbio celebrated finishing graduate school with a trip to East Africa. Upon his return, he became seriously ill.
"I was sick 24/7 for weeks on end," recalls Canobbio, who suffered from dizziness, depression, panic attacks, heart palpitations and night terrors that left him drenched in sweat.
His doctors were unable to determine the cause of the symptoms, until Canobbio consulted an expert in tropical medicine, who linked his symptoms to an antimalarial medicine, mefloquine, which Canobbio had taken for his trip. In a small percentage of people, the drug causes multiple neurological problems that persist for months. "I'm almost back to normal," says Canobbio, "but this sucked up a year of my life."