Off-label drugs prescribed without clinical evidence call for pharmacist vigilance

February 1, 2009

Medications are often prescribed for off-label purposes without evidence of effectiveness or safety. Unsupported use is especially high for antidepressants, antipsychotics, and sedatives.

Key Points

"We wouldn't want to say that these products are being misused," said Surrey Walton, PhD, lead author and assistant professor of pharmacy administration at the University of Illinois (Chicago). "But we can say that they are being used without good evidence. Pharmacists need to pay more attention to potential uses of prescription products that are not based on evidence."

Walton and researchers at Stanford University analyzed 30 months of physician prescribing between January 2005 and June 2007, using the National Disease and Therapeutic Index maintained by IMS Health. NDTA is one of the few databases in the United States that links clinical findings and indications with prescriptions, Walton said.

The highest level of unsupported prescribing was found in connection with antipsychotics and antidepressants, according to principal investigator Randall Stafford, MD, associate professor of medicine at the Stanford Prevention Research Center. The group identified 14 drugs most in need of additional clinical research to support common off-label uses.

Seroquel (quetiapine; AstraZeneca) topped the list of drugs used off-label with inadequate evidence. The agent was approved for schizophrenia in 1997, but is commonly used to treat bipolar disorder.

Bipolar disorder is the most common off-label use found in the study, accounting for 6 of the top 14 agents. Other mental disorders and cardiovascular disease were the second most-common off-label uses, accounting for two agents each. Fibromatosis, COPD, sleep, and anemia round out the list.

"Many of the drugs and conditions on the list represent situations where inadequate response to treatment is common and where drug side effects are frequent," Stafford said. "Not only are these areas where patients and physicians are naturally interested in trying off-label therapies, but areas targeted for expansion by the makers of these drugs."

The study, published in the December 2008 issue of Pharmacotherapy (Walton SM et al. 2008;28[12]:1443-52) found that a total of 76 percent of quetiapine scripts are written for off-label uses. Stafford said with quetiapine, off-label use is even more problematic than it is with other products, as indicated by its black-box warning for dementia and suicidality in some populations, its high cost, and heavy marketing efforts by AstraZeneca.

"Off-label prescribing means that we're venturing into uncharted territory, where we lack the usual level of evidence presented to the FDA that tells us these drugs are safe and effective," he said. "When the volume of off-label use of any drug reaches the magnitude that we're documenting, it suggests a role of the pharmaceutical industry in facilitating these types of uses."

Pharmaceutical manufacturers are generally barred from promoting off-label use of approved products, but they are allowed to distribute published research that deals with off-label use. Stafford told Drug Topics that recent lawsuits have revealed systematic plans by some drugmakers to market their products for off-label use.

How, or whether, regulation of off-label use might change is not clear. In the past, patients and private third-party payers covered most of the cost for off-label drug use. With the Medicare Part D Rx drug benefit, government and taxpayers are picking up a growing part of the bill. That could spur efforts to limit off-label prescribing, at least in government-sponsored programs.

"There is clearly room for off-label use of approved drugs," Walton said. "That is clear, and we are mindful of those issues. But I would like to see a great[er] effort made toward evidence-based drug use. Once drugs are put out there by the FDA, physicians are pretty much free to use them for anything, proven or not."