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BOSTON, Feb. 14 - Black box warnings emblazoned on prescription-drug labels are vaguely worded and difficult for doctors to interpret and follow, according to researchers here.

They called on the FDA to sharpen the language of the black box warnings so that doctors can more easily abide by them. Some of the warnings, the researchers said, need a specialist to interpret.

Vague wording was a key reason why the doctors of 7% of patients who received a medication with a black box warning in 2002 wrote a prescription in violation of the warning, said Karen E. Lasser, M.D., of the Cambridge Health Alliance here.

While 7% may not sound like much, "the absolute number of outpatients at risk is substantial," Dr. Lasser and colleagues at Harvard Medical School concluded in the Feb. 13 issue of the Archives of Internal Medicine.

The researchers analyzed the medical records of more than 300,000 patients from 51 outpatient practices in the greater Boston area who received a prescription medication in 2002.

Of these, about 30,000 patients (10%) received a drug with a black box warning. Of the 30,000 patients, about 2,500 (7% or 0.7% of all patients in the study) were handed a prescription in violation of the warning.

On the basis of the overall rate of adverse drug events, the investigators estimated that less than 1% of the 2,500 who received a prescription in violation of the black box warnings-or about 16 study patients in all-had an adverse drug event as a result.

It is possible that the study underestimated the number of adverse drug events. The authors noted that "our study was limited by the fact that we did not have access to visit or laboratory data outside of the electronic health record. Thus, we could not determine whether an adverse drug event occurred in about a fifth of the records reviewed."

Poorly worded warnings were a likely key reason for the violations, the Boston team said. "In many cases, the warnings are vague and difficult to interpret," they said. "We found that more than half of the black box warnings required clarification from a specialist."

For example, the antiseizure drug valproate sodium (sold under a variety of U.S. brand names) contains a black box warning to check liver function test results at frequent intervals, but the warning does not specify how often to monitor such tests. Other examples of imprecise terms included in black box warnings included "advanced renal impairment," "active liver disease," and "high dose," the Boston team said.

"The Food and Drug Administration should make these warnings more specific, so that they are readily understandable by providers, and so that such providers can easily take action to avoid violating the warnings," the authors added.

A spokesperson for the FDA said the agency had no comment.

Another reason for physicians' failures to follow black box warnings may be that they conflict with established clinical practice guidelines, the investigators said. For example, American Psychiatric Association guidelines state that blood should be drawn to monitor levels of lithium (sold under a variety of U.S. brand names) every three to six months, but the drug's black box warning says levels should be monitored at least every two months.

"Remembering all these warnings is beyond the capability of the human mind," the authors added. "If providers are to consider these warnings, it is essential that at least the most frequently violated warnings be compiled and made available through decision support in electronic health records."

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