PRESCRIPTION FOR TROUBLE: Approved medicine is being used for the wrong purpose
November 3, 2003
BY ALISON YOUNG AND CHRIS
For the last three and a half months of her pregnancy, Tammie Snyder had a small medical device strapped to her thigh. It pumped a drug called terbutaline through her body to prevent her from going into labor too soon.
Terbutaline is an asthma drug, and the U.S. Food and Drug Administration hasn't approved its use to prevent premature labor. The FDA has warned doctors that the treatment is potentially dangerous and might not be effective. Snyder said her doctor never told her about the warning or that the FDA had approved terbutaline only to treat asthma.
A six-month investigation by the Free Press Washington bureau has found that thousands of patients are harmed each year as doctors prescribe drugs in ways the FDA never certified as safe and effective.
These legal but unapproved prescriptions are soaring. Doctors wrote 115 million such prescriptions in the past year, nearly double the number of five years ago, according to a bureau analysis of prescriptions for the country's top-selling drugs.
The practice, known as off-label prescribing, is driven by aggressive drug-company marketing, questionable research and a sometimes cavalier approach by doctors. The FDA has done little to discourage the practice and is considering whether to allow drug companies greater leeway in promoting unapproved treatments.
Doctors are giving patients epilepsy drugs for depression and hot flashes and to help them lose weight. They prescribe antidepressants to treat premature ejaculation and pain, and powerful antipsychotics for insomnia and attention deficit disorder. High blood-pressure pills are prescribed for headaches and anxiety; antibiotics are used to treat viruses.
Some drugs, in fact, are sold mostly for unapproved purposes. Eight out of 10 prescriptions for the epilepsy drug Topamax aren't for epilepsy. Thalidomide, the notorious morning-sickness drug that caused birth defects and ushered in today's FDA drug-safety rules, is on the market today, and 99 percent of its prescriptions are off-label.
Off-label prescribing is widely accepted by doctors and defended by the American Medical Association. And the practice can be appropriate, for instance, with patients who have intractable, rare or fatal illnesses. In some cases, there may be gold-standard studies backing an off-label use.
"Sometimes it may help, sometimes it may do more harm than good, and sometimes it may kill people," said Dr. Arnold Relman, a former editor of the New England Journal of Medicine.
The analysis for this series included a review of 15 top-selling drug classes. The review found that some drugs, such as cholesterol medicines, rarely are prescribed for unapproved treatments. But three-quarters of antiseizure medications are prescribed off-label, as are nearly two-thirds of antipsychotics and about one-fourth of antidepressants.
Victims of off-label prescribing said in interviews that they have suffered heart attacks and strokes, had permanent nerve damage or lost their eyesight. Most said they never were told that the FDA hadn't approved their treatments.
A review of FDA data estimates that at least 8,000 people became seriously ill last year after taking drugs off-label. The true number is likely to be many times higher.
Dr. Nancy Nielsen, an elected official of the American Medical Association, said that, in an ideal world, all drug uses would be FDA-approved.
"I'd love to have a randomized clinical trial for every drug use," she said. But she said the nature of the drug business and the FDA approval process makes that unrealistic.
Instead, she said, doctors base their knowledge on peer-reviewed research. An FDA approval, she said, doesn't represent the bulk of the scientific body of information available on a drug.
"Using a drug for an unlabeled use doesn't mean it's unsafe," she said.
Drugmakers in several cases were reluctant to discuss off-label use of their products. But those who agreed to interviews maintained that they don't push such uses.
"We don't recommend that our products be used off-label," said Doug Petkus, a spokesman for Wyeth, a drugmaker.
Risperdal and a series of attacks
George Murphy's hands, made strong by years of climbing utility poles for Houston Lighting & Power, shake with tremors. His legs, now rigid, shuffle as he pushes his walker through his studio apartment in Deer Park, Texas.
"I wish I didn't have to use this thing," he said as the walker snagged on his recliner while he was showing off his Army dog tags from World War II, a plaque for 40 years of service as a Mason, his Shriner fez and the oil paintings his wife did a few years before she died.
Murphy, 85, began having the tremors last year after he had a series of stroke-like attacks while taking Risperdal, a powerful antipsychotic drug that the FDA has approved only for treating schizophrenia.
Murphy's family practitioner in Pasadena, Texas, Dr. Dennis Yaworski, prescribed Risperdal for an off-label purpose: "cancer phobia," according to case notes from a Sept. 9, 2002, office visit.
The drug's maker, Johnson & Johnson, has marketed Risperdal heavily to doctors who treat elderly patients.
In 1999, the FDA cited Johnson & Johnson for downplaying the drug's risks to elderly people and making false and misleading claims that it could be used not just to treat schizophrenia, but also "for psychotic symptoms associated with a broad range of disorders."
While doctors are free to prescribe as they wish, the FDA prohibits drugmakers from marketing unapproved treatments.
Despite the FDA's action, Risperdal has become a popular off-label treatment for Alzheimer's disease and dementia. About 670,000 such prescriptions were written last year, up more than 350 percent from 1998, the newspaper analysis found. Sixty-five percent of Risperdal's prescriptions last year were for unapproved treatments, generating $929 million in retail sales.
Murphy had been a familiar figure at his doctor's office, complaining of stomach pains and arthritis, often convinced that any pain was a sign that he was dying of cancer. But he was otherwise fit, his daughters said, enjoying family dinners, a recent trip to an alligator festival and an active social life at his independent living center.
The FDA hasn't approved Risperdal for the treatment of hypochondria. But Murphy's family members said they weren't told this. Yaworski declined to be interviewed.
Within a month of starting the drug, Murphy had the first in a series of stroke-like events, called transient ischemic attacks, according to his family and hospital records. During the worst of them, on Nov. 14, 2002, Murphy suddenly couldn't walk, his speech became slurred and his face drooped. He became easily confused, and doctors at the hospital added dementia to his diagnoses.
Attack followed attack, but Murphy kept taking his Risperdal. He was still afraid of getting cancer, his family said.
Then in April 2003, Johnson & Johnson sent a letter to U.S. doctors warning that Risperdal may be associated with an increase in strokes when prescribed off-label to elderly dementia patients.
The public warning came nearly two years after the drugmaker privately alerted the FDA that there was a problem with Risperdal, agency officials said in response to questions for this series. It came six months after drug regulators in Canada issued a similar warning and urged doctors in that country to reassess their use of Risperdal to treat dementia.
FDA officials, in a written statement, said it took several rounds of questions to the drugmaker before they had enough evidence to get the drug company to issue the warning. Johnson & Johnson, based in New Brunswick, N.J., had no comment.
Murphy and his family have sued the company, which in court filings denies wrongdoing. His daughter, Robbie Murphy, said, "Our father has been taken away from us. Basically the last enjoyable times he could have with us are gone."
Dr. Raymond Woosley, the vice president of health sciences at the University of Arizona, said off-label prescribing puts patients at greater risk than when doctors follow a drug's FDA-approved directions.
"I have no doubt about it," said Woosley, who also is the director of one of the national centers for drug research established by the federal government. "The caveat is we can't quantify it."
Few have even tried. One study that did was published in 1999 in Great Britain.
Examining about 1,000 children, researchers found that the number of side effects among those who were taking off-label prescriptions was small, but more frequent than for those taking drugs for approved uses.
"If you give a medicine in the right dose, and with good information on how a patient with that illness will handle it, you are less likely to get an adverse drug reaction than if you are prescribing outside of those boundaries," said one of the study's authors, Imti Choonara, a professor in child health at the University of Nottingham. "Otherwise, there's no point to anybody studying medicine. You might as well say, 'Here's a medicine, take it as you like and come tell me if there is a problem.' "
Big numbers, small samplings
The national prescription data revealed a startling breadth of off-label prescribing. Virtually every drug has been prescribed that way at some point, and many are regularly.
Nielsen, of the AMA, doesn't think doctors have been cavalier about their approach. "They have been in meetings," she said. "They know it works."
But individual doctors and patients aren't in a good position to gauge the safety or effectiveness of off-label treatments, experts say. Even in the busiest of practices, doctors see too few patients to assess the drugs' range of side effects.
Medical history is filled with examples of doctors who were convinced that an off-label therapy was safe and effective, only to be proven disastrously wrong.
Often, they based their certainty on secondhand anecdotes, small published studies or observations from their own practices. Off-label prescribing can continue for years before a thorough clinical trial finds it is ineffective or even dangerous. Often such trials are never done.
Fen-Phen, an unapproved cocktail of two prescription appetite suppressants, was widely prescribed in the 1990s until the Mayo Clinic in 1997 noticed that some Fen-Phen patients were suffering from a rare heart-valve disease.
More recently, there was the rampant off-label prescribing of hormone replacements. Though the drugs were approved for treating specific menopause symptoms, such as hot flashes, doctors put millions of women on them for life. The doctors believed hormones would prevent heart disease, breast cancer and Alzheimer's disease, uses the FDA hadn't approved. They even started women on the drugs years after menopause.
A massive government-run study, the Women's Health Initiative, found that hormone replacement therapy actually increases a woman's risk of getting these diseases.
Many doctors don't believe the findings, theorizing that the study's outcome would have been different if the women in the study had started hormone therapy earlier and had taken it longer.
Despite decades of off-label prescribing, drugmakers universally deny that they push these uses at doctors.
"We don't track what you're calling prescribing for unapproved uses," said Doug Petkus, a spokesman for Wyeth pharmaceutical company. "We don't recommend that our products be used off-label."
Like Tylenol for pneumonia
Once it's on the market, a drug might be prescribed for a dozen or more unapproved conditions.
The FDA approved Topamax in 1996 as a supplemental treatment for epilepsy.
It has several potentially serious side effects. It often causes numbness and tingling in the hands and feet. It can cause depression and kidney stones. It can slow the thinking of many patients, impairing memory and making it difficult to choose words. It can cause vision problems, including a form of glaucoma that can result in blindness.
To stop epileptic seizures, the FDA deemed these risks acceptable.
The newspaper analysis of the last year of prescription data for Topamax found that doctors are giving it to patients for migraine headaches, schizophrenia, bipolar disorder, depression, pain, nerve damage and to help them lose weight.
In 1998, Topamax was prescribed only for epileptic seizures, the data show. Now, 79 percent of Topamax prescriptions are for illnesses and conditions that the drug hasn't been approved to treat, the analysis found. The drug firm has asked the FDA to approve its use for migraines.
Carolyn Bartley nearly went blind in June 2000, a week after she began taking Topamax, which her psychiatrist prescribed as a treatment for bipolar disorder, which is characterized by bouts of depression and mania.
"Everywhere I looked, it was like a watercolor painting, and somebody had smeared it," said the 44-year-old Annapolis, Md., bookkeeper. Laser surgery reduced the pressure in both eyes and restored her sight. In 2001, the drug's manufacturer -- Johnson & Johnson -- sent a letter to doctors warning about the kind of sudden glaucoma Bartley experienced.
Bartley's psychiatrist, Dr. Parviz Sahandy, said he hadn't researched the medical literature on Topamax, but that he considered it effective for bipolar disorder about 50 percent of the time.
Those who have read the studies are less certain.
"Topamax is no better than a placebo," said Dr. Joseph Goldberg, a research scientist at Zucker Hillside Hospital on Long Island, N.Y., who published a review of epilepsy drugs as treatments for bipolar disorder earlier this year while at Cornell University. "It's giving an ineffective treatment for a potentially life-threatening illness. It would be like giving Tylenol for pneumonia."
Goldberg said that even studies by Johnson & Johnson found it didn't work to treat bipolar disorder. As a result, company spokeswoman Lesley Fishman said, the drugmaker didn't seek FDA approval for treating that condition.
Over the last year, doctors wrote 586,000 Topamax prescriptions to treat bipolar disorder, the prescription data showed.
The terbutaline pump therapy prescribed to Tammie Snyder is one of many off-label drug treatments doctors use in an attempt to stop preterm labor.
Nearly 500,000 babies are born prematurely each year, but the causes and cures for preterm birth largely elude science. Most of the treatments are based on hope and a desperate desire to try something.
Dr. John Thorp Jr., a professor of obstetrics at the University of North Carolina at Chapel Hill, was part of a research team for the federal government's Agency for Healthcare Research and Quality that reviewed the scientific evidence for terbutaline and other drugs in preventing preterm labor.
Their report, published in June, found that the drugs weren't effective in prolonging pregnancy for a long term and can cause a range of harms, including heart-rhythm disorders and heart failurein mothers.
"There really is no evidence," Thorp said, noting that early contractions stop without any medical intervention 50 to 70 percent of the time.
Nonetheless, pregnant women across the country are taking these drugs.
"I think experiment is too good a word," Thorp said of the wide use of terbutaline. "It implies observation, measurement, alteration -- that you're actually conducting science. Clinical crapshoot would probably be better."
The best use of terbutaline is a series of three injections to calm contractions for about 48 hours or so, enough time to administer steroids to help the babies' underdeveloped lungs, said Dr. Washington Hill, chairman of obstetrics and gynecology at Sarasota Memorial Hospital in Florida and a member of the board of directors of the national Society for Maternal-Fetal Medicine.
But doctors still send women home with long-term prescriptions for terbutaline pills. If they were candid, Hill said, those doctors would admit: "I know it doesn't work, but it cuts down on the phone calls."
Last year, 63 percent of the more than 392,000 prescriptions for terbutaline pills were for pregnant women, despite pharmaceutical company labels that warn against the asthma drug being used this way.
While many doctors and mothers passionately believe in the treatments, especially in the terbutaline pump, the national company that is the largest provider of the therapy is ambivalent.
Dr. Gary Stanziano, the vice president for medical affairs at Matria Healthcare, based in Marietta, Ga., said he had no opinion about whether the therapy his company sold for about $10,000 a month worked. "There are studies out there that are positive and studies out there that are negative," he said.
Stanziano and Roberta McCaw, Matria general counsel, said the company is in the business of following doctors' orders, since physicians are the ones who write prescriptions for terbutaline pumps. Matria is a middleman, supplying the drug and pumps, then having its nurses hook up the women to the devices and monitor their progress. Stanziano wouldn't say how many women use Matria's pump therapy each year, but said he hadn't heard of any client seriously harmed.
Warnings were issued
In 1997, however, the FDA warned doctors that the terbutaline pump "has not been demonstrated to be effective and is potentially dangerous." Four years earlier, the FDA had warned Tokos Medical Corp., one of the two companies that merged to become Matria, about promoting unapproved preterm-labor therapies despite promises to stop.
"This case could be viewed as a conspiracy to circumvent the FDA approval process," an FDA compliance officer wrote in a memo that year.
Matria officials said they had no information about this, because it happened before the merger. They said Matria doesn't promote the off-label use of terbutaline to doctors.
Snyder said she felt betrayed by her obstetrician, Dr. Federico Mariona, a clinical professor at Wayne State University and a leader in local medical societies. Mariona didn't respond to repeated requests for an interview.
Snyder's medical records from Matria include signed consent forms that say, among other things, that some of the treatments being prescribed by her doctor may involve the use of drugs "outside of their labeling." Only after having congestive heart failure, Snyder said, did she learn what those words meant.
Her heart has improved enough that she doesn't need a transplant, but Snyder, 30, said her doctors had told her she couldn't have more children; pregnancy would be too dangerous for her heart.
Snyder and her husband, Chris, had wanted to have more children. They used in vitro fertilization to have their twins and have other frozen embryos.
Now, those embryos remain in limbo.
"I hate terbutaline," Chris Snyder said. "I hate what they did."
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