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Akron Univ. School of Law

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Saturday, August 16, 2008

Behind the FDA's "Black Box" Warnings

The Los Angeles Times discusses why Cipro and similar antibiotics are given the FDA's strictest label, while epilepsy drugs Lyrica, Depakote and Topamax may have escaped.  Karen Ravn writes,

Cipro Two groups of drugs were under the Food and Drug Administration spotlight last month. Both have been associated with rare but serious side effects, and both were candidates for a "black box" warning, the strongest the FDA issues short of taking a drug off the market. Although one was hit with this safety advisory, the other may have escaped. We look at these drugs and their different fates.

Fluoroquinolones

This class of powerful antibiotics had a black box warning added to its résumé. The best-known is probably Cipro, produced by Bayer, which won fame in 2001 as an anthrax treatment, although it's mostly used for urinary tract infections. Another in wider use is Levaquin by Ortho-McNeil, used for respiratory infections.

The risks: Fluoroquinolones are associated with tendon problems, including tendinitis and, more seriously, ruptured tendons (usually the Achilles) that may require surgery and extensive rehab.

The connection is "not exactly intuitive," says Dr. Sidney Wolfe, director of health research at the consumer advocacy group Public Citizen, which campaigns actively on drug safety issues. Although no one can explain why the connection exists, evidence for it has been adding up for years, with problems often reported by patients who are over 60 or have had kidney, heart or lung transplants. This is a different group from those most apt to experience tendon troubles -- namely, thirtysomething jocks.
In the years that these drugs have been marketed, 407 ruptures were reported as of the end of 2007, as were 341 cases of tendinitis, according to Public Citizen. Adverse drug reactions are generally reported about 10% of the time, and in a case like this, where the drug is not a natural suspect, reporting may be even lower.

What happened: Public Citizen petitioned the FDA two years ago to require black box warnings on the professional labels for fluoroquinolones. The group also asked the agency to require medication guides highlighting the warning for consumers as well as "Dear Doctor" letters, alerts sent from drugmakers to doctors, advising them of the new warning. Since the FDA had not acted by January, the organization sued the agency.

Between 2001 and 2004, the FDA added warning information -- but not a black box warning -- to the professional labels provided to doctors for fluoroquinolones, updating the information in that warning as recently as 2007. The assumption is that doctors will discuss warnings with their patients. But injury reports persisted. So last month the agency decided to order black box warnings on the professional labels. It also ordered medication guides to tell patients about the new warning, and it sent out information sheets to more than 100,000 physicians and 170 medical organizations to let them know. It did not order drug makers to send Dear Doctor letters.

Will a black box warning be useful? Though some fluoroquinolone-associated ruptures occur suddenly, many are preceded by a week or two of discomfort. This implies that forewarned patients can quite possibly forestall injury if they stop taking the drug when they notice something is wrong, as the FDA advises on its professional labels. But the FDA and patient advocate groups have been concerned that not enough patients were heeding, or even noticing, earlier, lesser warnings.

"This risk has been around for a long time, and doctors know about it," says Dr. Paul Seligman, director of the FDA's safety policy and communications staff. "We needed to get patients more aware and engaged."

Will a black box warning be harmful? No one seems to think so. The FDA suggests patients switch to another antibiotic at the first sign of trouble.

Should the FDA have done more? Wolfe says the agency should have ordered Dear Doctor letters because that's the only way to be sure all doctors will know about the black box warning.

But -- speaking on his own, not on behalf of the FDA -- Seligman says black box warnings plus medication guides are sufficient and may be more effective than Dear Doctor letters. "Medication guides go out with a prescription every time it's refilled. That makes sure patients see it," he says. "Dear Doctor letters just go out once."

Dr. Frances Richmond, director of the School of Pharmacy Regulatory Science program at USC, sees why the FDA drew the line where it did. The black box warning already tells doctors to be very careful, she says. But the agency has to be careful not to get "real excited" too often. "Doctors will pay more attention to Dear Doctor letters if they just come out on occasion so they sort of imply, 'Oh, my God, this is something terrible.' "

Antiepileptic drugs

Among the drugs under review by an advisory committee to the FDA were Lyrica, produced by Pfizer; Depakote, produced by Abbott Laboratories; and Topamax, produced by Johnson & Johnson. Although classified as antiepileptic drugs, they are also prescribed for psychiatric disorders, such as bipolar disorder, as well as other medical conditions.

The risks: An analysis of 199 placebo-controlled trials of 11 drugs with a total of almost 28,000 patients found that these drugs were associated with an increased risk of suicidality (suicidal behavior or suicidal thoughts): 0.37% of patients taking one of the drugs had an incident of suicidality compared with 0.24% of patients taking placebos. Most of these incidents were suicidal thoughts, although four suicides occurred, all by patients taking a drug.

Patients taking the drugs for epilepsy were about twice as likely to have incidents of suicidality as those taking them for other reasons.

What happened: The advisory committee recommended to the FDA that medication guides should be provided to patients for all antiepileptic drugs that are taken long-term -- not just those included in the analysis -- but that a black box warning should not be required. The FDA doesn't have to follow a committee's advice but usually does.

Would a black box warning be useful or harmful? Requiring a black box warning could have "unreasonable" effects, says Dr. Larry Goldstein, a professor of medicine at Duke University and acting chairman of the antiepileptic drug advisory committee. "It could make people so afraid of using the drug that patients who should be treated wouldn't be treated."

Though this is a concern held by many doctors, Wolfe thinks it's unfounded. He says most patients would use the information to their advantage, by switching to another drug or staying in touch with their doctors or counselors.

A study published this year in the Archives of General Psychiatry may have bearing on this question. It looked at the effects of a black box warning about the risk of suicidality in youths taking antidepressants.

The FDA required the warning to be added to professional labels in October 2004, after evidence was found of increased suicidal thinking and behavior early in the treatment of patients ages 18 to 24 taking certain antidepressants. (The risk was a lot higher than the risk associated with antiepileptics, Seligman says.)

The study of black box effects found that from the time the warning was ordered until the end of 2005, antidepressant use by youths fell about 10% a year. "The effects were not as large as some psychiatrists, especially child psychiatrists, had feared," says lead author Dr. Mark Olfson, professor of clinical psychiatry at Columbia University. But he says the study can't answer "the important question concerning the trade-offs between unnecessarily exposing a child to a small increased risk of suicidality and the risk of doing nothing for a child impaired by depression."

"These warnings," Olfson says, "have a potential for both benefit and harm."

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