Warning labels on high-risk drugs ignored by doctors

In a survey of approximately 930,000 ambulatory care patients, researchers from the Department of Ambulatory Care and Prevention (of Harvard Medical School and Harvard Pilgrim Health Care) and colleagues found that 42 percent received prescriptions for drugs with Black Box Warnings (BBW), the Food and Drug Administration's strongest label for high-risk medication.

Additionally, physicians' compliance with the recommendations of the BBWs was highly variable, which suggests that better methods are needed for ensuring the safe use of medications that carry serious risks. In the categories studied, doctors' noncompliance to BBWs ranged from 0.3 percent to 49.6 percent. These results are reported online in the Nov. 18, 2005 issue of Pharmacoepidemiology and Drug Safety.

"In ambulatory care settings, approximately 1.4 billion prescriptions are written per year," said Anita Wagner, assistant professor at DACP. "Until now, there has been no information about how frequently doctors prescribe BBW drugs, nor whether prescribing is consistent with the warnings. This study tells us that these drugs are prescribed often and that in some categories, prescribing is inconsistent with the warnings."

Wagner, Richard Platt (chairman of DACP and principal investigator of the Agency for Healthcare Research and Quality–funded Prescribing Safety Study), and colleagues in HMOs across the country conducted a retrospective study over two and a half years to find out how many ambulatory care patients were prescribed drugs with BBWs and to assess compliance to these warnings. BBWs are warnings printed in a black frame in the package insert of a drug and are intended to alert prescribers to the serious risks that may be associated with certain drugs. They describe the drug's risks, can list specific precautions for its use, and must appear on all promotional materials.

To examine prescribing compliance, Wagner and colleagues examined approximately 217,000 enrollees who had received at least one of 19 BBW drugs. The researchers considered BBWs that required laboratory monitoring when a patient began taking the medication or for the duration of the prescription; were unsafe to take with other specific medications; or were unsafe to take while pregnant.

From this group, most noncompliance with BBWs occurred when patients should have received lab tests as they began a medication; 49.6 percent of all prescriptions that should have been accompanied by a lab test at the onset of a prescription were not. Recommendations for pregnancy tests were most frequently not observed (for example, when women of childbearing age were given prescriptions for acitretin, which treats severe psoriasis).

When patients needed lab monitoring while taking a medication, there was no continued monitoring for 12.8 percent of prescription times during which the BBW recommended a test.

Nine percent of prescriptions were dispensed on the same day as a drug that is considered unsafe to take simultaneously. All involved dispensing of methotrexate with non-steroidal anti-inflammatory drugs (NSAIDS) or ketorolac with other NSAIDS (11 and 7.6 percent, respectively).

Warnings that indicated a medication was unsafe to take while pregnant had excellent compliance. Women of childbearing age received almost 79,000 prescriptions for BBW drugs that should be avoided during pregnancy. Only 95, or 0.3 percent, may have occurred during pregnancy.

"We need several things to improve the effectiveness of the warnings: to be clear about the magnitude of risk that justifies a BBW and the evidence that underlies a recommendation, to communicate warnings clearly to both clinicians and patients, and to create systems that support doctors and patients in following the recommendations," Wagner said. "We believe our data shed light on adherence to BBW recommendations and provide a preliminary basis for recommendations to improve communication about the risks of medicines."

For instance, it is possible that concise and focused wording of a warning is more effective than less direct wording. Patient-specific automated alerts to BBW drugs or recommendations at the point of prescribing and dispensing may be more effective than BBWs in package inserts. Designing such a system requires complete, consistent, and current lists of BBW medicines and clinical circumstances associated with risk of morbidity and mortality. The authors of this study recommend that the FDA establish and maintain such a list.

"This will require new information about risks, about the way drugs are used in everyday practice, about effective methods of influencing clinicians' prescribing, and about ensuring that patients understand how to use their drug as safely as possible," Wagner said.