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Newsday, 3/23/04

FDA TO DRUGMAKERS: SUICIDE WARNING URGED

Amid reports raising worries about teens on antidepressants, agency seeks tougher wording on the labels

by Jamie Talan

Federal regulators yesterday asked pharmaceutical companies to strengthen the wording on labels on 10 antidepressants to warn the drugs may heighten risk of suicide.

"We don't know yet if there is a link between antidepressant use and suicide," said Dr. Thomas Laughren, team leader of the Food and Drug Administration's psychopharmacology group. But yesterday's recommendation comes on the heels of an FDA advisory committee's recommendation last month to add the warning while the committee continues to investigate. Laughren said the warning is intended for all ages, not just children and teenagers.

"This is a good warning," said Dr. Harold Koplewicz, director of New York University's Child Study Center in Manhattan, and an expert on childhood depression. Koplewicz said 11 million prescriptions for antidepressants were written last year, most probably issued by primary care doctors.

"We have very effective medicines, but doctors need to know how to use them," Koplewicz said. Side effects, such as anxiety, generally occur in the first few months on the drugs. This period is a critical window for observing whether patients are improving on the prescribed drug and dosage.

Medicines for which the new warning is recommended are Prozac, Zoloft, Paxil, Luvox, Celexa, Lexapro, Wellbutrin, Effexor, Serzone and Remeron.

The only medicine tested and FDA- approved for teenage depression is Prozac. It and two other selective serotonin reuptake inhibitors, or SSRIs, Zoloft and Luvox, are approved for obsessive-compulsive disorder in young people.

But anecdotal reports of suicides among young people taking SSRIs have appeared in recent years, sparking a debate on the safety of these medicines. Last year, the drug regulatory agency in the United Kingdom banned Paxil for use in children. The FDA quickly put together an advisory committee to review the science.

Now, the FDA has asked psychiatrists specializing in teenage suicide to go case by case through 25 papers, clinical trials that represent more than 4,000 young people, some of whom were reported to have made some suicidal gesture during the studies.

Psychiatrists at Columbia University College of Physicians and Surgeons, as well as others nationwide, will re-evaluate each case. "While we are trying to figure this out, we are urging doctors to be more cautious," Laughren said.

Dr. David Fassler, a child psychiatrist at the University of Vermont, appreciates the new warning, but worries that the attention may frighten some parents and reduce the likelihood that they seek help for their children. "That would be a tragedy," said Fassler, who thinks medicine, in conjunction with some form of talk therapy, can be extremely helpful. "One of the biggest risks is not treating at all," he said.

The 10 Drugs

The Food and Drug Administration yesterday asked makers of these antidepressants to add labels urging that patients on the drugs be monitored for signs they are at risk of suicide.

Prozac (fluoxetine)

Zoloft (sertraline)

Paxil (paroxetine)

Luvox (fluvoxamine)

Celxa (citalopram)

Lexapro (escitalopram)

Wellbutrin (bupropion)

Effexor (venlafaxine)

Serzone (nefazodone)

Remeron (mirtazapine)

SOURCE: FDA

Copyright 2004, Newsday, Inc.

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New York Times, 3/23/04

REGULATORS WANT ANTIDEPRESSANTS TO LIST WARNING

by Gardiner Harris

Patients taking antidepressants can become suicidal in the first weeks of therapy, and physicians should watch patients closely when first giving the drugs or changing dosages, federal regulators said yesterday.

The warnings are part of a public health advisory issued by the Food and Drug Administration and are a reminder that antidepressants, taken by millions around the world, are not without risks. The agency is asking drug manufacturers to place detailed caveats about the drugs' side effects prominently on their labels.

The agency's decision to issue such a broad warning was a surprise. Top FDA officials have long insisted that their decisions are driven only by clear-cut evidence from well-run clinical trials. But in a conference call with reporters yesterday, agency officials said that no studies had shown a convincing link between drug therapy and suicide. Suicide is such a rare side effect that studies on the subject have been difficult to interpret, the regulators said.

Still, the agency issued the advisory anyway.

"It warns physicians that patients' depression may become worse," said Dr. Russell Katz, the agency's chief of neurological drugs, "that they may develop suicidal thinking or behavior after the initiation of treatment."

A series of secret studies, which were conducted by drug companies and became public last year, seemed to show that depressed children and teenagers given antidepressants were more likely to become suicidal than those given placebos. The studies also showed that most antidepressants were not effective in treating depression in children and teenagers. Those studies are still under review at the agency.

Nevertheless, a scientific advisory panel urged the agency last month to issue stronger warnings about the possibility that teenagers and children given the drugs could become suicidal. Studies in adults have found no link between the drugs and suicide, but the agency included adults in the warnings, in part because of anecdotal stories at advisory meetings last month. Dr. Katz said "a number of witnesses said that these were experiences that they had with adults, too."

"We think this is good advice whether the drugs did it or not," said Dr. Robert Temple, associate director of medical policy at the agency. "If someone commits suicide, it doesn't really matter whether it's the drug or the underlying disease. In either case, you need to pay attention."

Some psychiatrists said the new warnings were likely to slow sales, which amounted to about $12 billion worldwide in 2002, and would change how the drugs were prescribed. Prozac, from Eli Lilly, is one of the most widely prescribed drugs of all time. Zoloft, from Pfizer, had $3.1 billion in sales last year, making it one of the world's top-selling medicines.

Dr. Jeffrey Lieberman, a professor of psychiatry and pharmacology at the University of North Carolina, said that the agency's action suggested that antidepressants had become too popular and physicians too casual about dispensing them.

"I think the effect of these warnings will be to have physicians become a bit more conservative in using these drugs," Dr. Lieberman said. "They'll start limiting their use of them just to patients who are clearly depressed with clinically significant symptoms as opposed to those who have very mild symptoms."

Dr. Regina Casper, a professor of psychiatry at Stanford, said that family physicians had become far too confident in the drugs' safety. Patients who are given their first prescription for an antidepressant should see their doctor at least once a week and perhaps more frequently, something family physicians rarely have time for, she said.

"I think this will have a real sobering effect among family practice doctors," Dr. Casper said.

The warnings also tell physicians to be particularly careful to evaluate whether patients have bipolar illness, also known as manic-depression. Antidepressant therapy for such patients can cause a manic episode, the label states.

While suicide is already mentioned in a rarely read portion of a sheet included with prescriptions for the antidepressants, the new discussion of suicide will be placed in the drug's warning section, the most important, widely read and prominent section of the label. To further ensure that doctors will read the material, part of it will be in boldface. The label is the primary way the FDA communicates with physicians about the safety and efficacy of drugs.

Jennifer Yoder, a spokeswoman for Lilly, said the company would comply with the agency's request.

"It's important that patients keep today's announcement from the FDA in perspective," Ms. Yoder said. "Depression is a serious public health issue, and it takes great courage for patients to begin treatment in the first place."

Dr. Catherine Clary, a Pfizer vice president, said the company would work closely with the agency to come up with label changes for Zoloft. A spokeswoman for GlaxoSmithKline, the maker of Paxil, said the company was studying the request. The companies are almost certain to adopt the agency's proposed changes.

While the FDA does not have the power to require the changes, if the manufacturers refuse to go along, the agency can declare their drugs mislabeled and force their removal. Because every antidepressant introduced in the past 15 years is included in the warning, no company is at a disadvantage. Indeed, even drugs like the GlaxoSmithKline antidepressant Wellbutrin, also known as Zyban, that have not been linked with suicide were included.

The drugs in the warning are: Prozac; Zoloft; Paxil; Wellbutrin; Luvox, from Solvay; Celexa and Lexapro, from Forest Laboratories Inc.; Effexor, from Wyeth; Serzone, from Bristol-Myers Squibb; and Remeron, from Akzo Nobel.

The dispute about whether popular antidepressants cause some patients to become suicidal or violent has been continuing for 14 years. In 1990, a Harvard psychiatrist wrote a paper suggesting that some of his patients had become acutely suicidal after taking Prozac. More testimonials followed. But a 1991 scientific advisory panel concluded that there was no convincing evidence.

The studies in children raised the issue again last year, and health authorities in Britain told physicians that with the exception of Prozac, the drugs should not be used in teenagers or children. Still, studies show that teenage suicides have declined sharply in countries where antidepressant therapy has become widespread, suggesting that the drugs prevent many more deaths than they may cause.

Dr. Madhukar Trivedi, director of the mood disorders program at University of Texas Southwestern Medical School at Dallas, said he worried that the new warnings might make depressed patients afraid of their pills. "The consequences for not treating depression are very high," Dr. Trivedi said.

The agency advisory says: "Health care providers should carefully monitor patients receiving antidepressants for possible worsening of depression and suicidality, especially at the beginning of therapy or when the dose either increases or decreases."

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity and severe restlessness are also possible side effects, the advisory adds.

The agency decided against following British regulators in suggesting that physicians should avoid the drugs' use in children. Only Prozac has been shown to be effective in treating depression in children, but that does not mean the other drugs do not work, officials said.

"What we don't know for sure is what is the best thing to do for a child who's depressed," Dr. Temple of the FDA said. "Depression has its own liabilities. It can be a fatal illness. What we don't know is whether the long-term benefits outweigh the risks."

Copyright 2004 The New York Times Company