Study finds <1% of prescriptions that violate black box warningscause adverse drug events

An observational study of 51 outpatient practices found that about 7 in 1,000 outpatients were administered a prescription that violated an FDA black box warning and that <1% of those patients had an adverse drug event (ADE) as a result.

The study, published in the Archives of Internal Medicine, involved 40 hospital-based clinics, 4 community health centers, and 7 community-based practices in the Boston, Mass, region in 2002 and tested the frequency of adverse drug-drug, drug-laboratory, and drug-disease interactions among patients by examining electronic health records (EHRs).

"Although a few outpatients seem to receive prescriptions in violation of black box warnings for drug-drug, drug-laboratory, and/or drug-disease interactions, the absolute number of outpatients at risk is substantial," the authors stated.

After multivariate analysis, researchers found patients most likely to receive medications in violation of a black box warning were aged ≥75 years (OR=1.94; 95% CI, 1.08–3.48; P<.05), female (OR=1.37; 95% CI, 1.25–1.50; P<.05), receiving care from a community health center (OR=1.89; 95% CI, 1.05–3.39; P<.05) or a hospital-based clinic (OR=1.79; 95% CI, 1.02–3.12; P<.05), and had ≥7 medical problems on their EHRs when the medication with the black box warning was prescribed (OR=1.93; 95% CI, 1.30–2.86; P<.05).

To measure the frequency of ADEs, the EHRs of a random sample of 575 patients who received a medication in violation of the black box warning were reviewed. Among the 575 patients, a total of 583 warning violations were identified. After excluding 92 apparent violations because the medication was not given in violation of the black box warning and an additional 124 cases because insufficient data were available in order to determine whether an ADE had occurred, a total of 367 black box warning violations were examined.

Four ADEs related to black box warning violations were identified (1.1%; 95% CI, 0.03%–2.15%; P<.05) with an additional 92 potential ADEs (25.1%; 95% CI, 20.6%–29.5%; P<.05) and 154 medication errors (42.0%; 95% CI, 36.9%–47.0%; P<.05) identified by researchers. Four ADEs were not related to a black box warning violation (1.1%; 95% CI, 0.03%–2.15%; P<.05).

The drug most often prescribed in violation of its black box warning was propoxyphene, which had 115 cases (31.3%) resulting in 2 ADEs. Other drugs associated with frequent black box warning violations included azathioprine, carbamazepine, lithium carbonate or citrate, metformin, triamterene, and valproate. The seven drugs accounted for a total of 1,745 black box warning violations (74.1%).

A limitation identified by the authors was the lack of access to patient data beyond that which was contained in their EHRs. Consequently, whether an ADE had occurred in a subject could not be determined in approximately 20% of the random sample analyzed, thus causing potential underestimation of ADEs as outpatients may not have reported symptoms caused by an ADE while receiving care.

According to researchers, the "vague" wording of some black box warnings needs to be clarified to diminish ADE risk, especially with the expected spread of computerized means to track patients' health history. In their initial univariate analysis, researchers found that 1,486 prescriptions (59.8%; P<.001) in violation of black box warnings were given by either primary care medical doctors, nurse practitioners, or physician assistants.

"The Food and Drug Administration should make these warnings more specific, so they are readily understandable by providers, and so that such providers can easily take action to avoid violating the warnings," the authors stated. "Because of the increasing use of EHRs, the warnings should be mapped to terms that make them computable."

Prior studies cited by the researchers obtained startlingly different results, demonstrating that prescribers "fail to adhere to black box warnings much more frequently than was observed in our study."

SOURCE Lasser KE, Seger DL, Yu DT, et al. Adherence to black box warning for prescription medications in outpatients. Arch Intern Med. 2006;166: 338–344.