Off-Label Drug Use Makes Adverse Events More Likely


Patients prescribed drugs for indications that the FDA has not approved face a 44% greater risk for adverse drug events.

Patients prescribed drugs for indications that the FDA has not approved face a 44% greater risk for adverse drug events.

Tewodros Eguale, MD, PhD, an associate professor at MCPHS University in Boston, told Pharmacy Times that these recent findings should encourage pharmacists to advise their patients about the risk of off-label prescribing, especially when there is little scientific evidence backing the efficacy of an unapproved use.

Dr. Eguale and his fellow researchers analyzed a cohort of 46,021 patients who received 151,305 medications. The prescriptions were dispensed between January 2005 and December 2009, and a follow-up was conducted when the drug was discontinued, when the treatment ended, or at the end of the follow-up period on December 30, 2010.

The researchers found 3484 adverse drug events in more than 46,000 patients. Most of the events occurred in the first year (around 70%), and of those events, half occurred in the first 3 months.

The rate of adverse drug events was higher for off-label use than it was for on-label use (19.7 per 10,000 person-months versus 12.5).

The rate of adverse drug events was higher still for off-label use lacking strong scientific evidence (21.7 per 10,000).

This is especially relevant considering that 4 in 5 off-label prescriptions lack strong scientific evidence, according to the researchers.

The study authors did acknowledge that off-label drug use can be appropriate in certain circumstances, such as when there is a lack of alternative effective drugs or when the health care team has exhausted all other options of approved drugs. They found that off-label drug use with strong scientific evidence had the same risk for adverse drug events as on-label use.

“However, a lack of physician knowledge of approved treatment indications was shown to be one factor for off-label prescribing,” the researchers noted. “Physicians are finding it difficult to keep up with rapidly changing medication information, and this lack of knowledge is affecting treatment of patients.”

The risk for adverse events was higher when the drugs were approved between 1981 and 1995, when they were used by women, when the patients were taking 5 to 7 medications, and when patients received cardiovascular drugs or anti-infectives, the authors found.

Those who took 8 or more drugs faced a more than 5-fold increase in risk for adverse drug events than patients taking 1 or 2 medications, according to the researchers.

Meanwhile, anti-infectives led to a more than 6-fold increase in the risk for adverse drug events compared with gastrointestinal tract drugs.

One of the reasons why rates of adverse drug events are higher for women could be related to the fact that women are more likely than men to be prescribed an off-label treatment, according to Dr. Eguale.

While the study involved Canadian patients, Dr. Egaule told Pharmacy Times that there was a “very good parallel” between Canada and the United States, so the results could be applicable to US patients, as well.

He also said that the study should be of interest to pharmacists because it was able to consider treatment indications.

“While our study focused on the effect of off-label use on adverse drug events, the overall setup of the study and the inclusion of treatment indication in the prescription has more advantage to the pharmacist and to the patient,” Dr. Eguale said.

Since pharmacists are the last line of defense against medication errors like wrong doses or the wrong drug, knowing the treatment indication can help pharmacists identify errors more easily, Dr. Eguale explained.

Knowing the indication can also help facilitate the medication reconciliation process and decrease the time pharmacists spend contacting prescribers, which can allow for more pharmacist productivity.

Treatment indications can also help pharmacists target patients with specific disease states and spur discussions about off-label drug use.

The researchers suggested that electronic health records should allow for treatment indications and outcomes to monitor the safety of on- and off-label use.

To the researchers’ knowledge, this is the first study to look at the association between off-label drug use and the risk for adverse events among adults, and also the first study to use electronically documented treatment indications and outcomes to measure off-label drug use and adverse events.

The findings were published in JAMA Internal Medicine.

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