Association Between Off-Label Drug Use and Adverse Drug Events in Adults

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A new study finds that off-label drug use is associated with higher rates of adverse drug events in adults.

Off-label use of prescription drugs is known to be associated with adverse drug events (ADEs) in children and for the first time, a link has been shown between off-label use of medications and ADEs in adults.

In a new study published in JAMA Internal Medicine, Canadian researchers said their data show caution should be used when prescribing drugs for off-label uses that lack strong scientific evidence. The study is the first to use electronically documented treatment indications and treatment outcomes to measure off-label use and ADE occurrence.

The rate of ADEs for off-label use (19.7 per 10,000 person-months) was higher than that for on-label use (12.5 per 10,000 person-months) (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.30-1.60). After adjusting for important patient and drug characteristics, off-label use without strong scientific evidence had a higher ADE rate (21.7 per 10,000 person-months) than on-label use (AHR, 1.54; CI, 1.37-1.72). Off-label use with strong scientific evidence had the same risk for ADEs as on-label use (AHR, 1.10; 95% CI, 0.88-1.38).


Risks for ADEs were higher for drugs approved from 1982 to 1995 and for those used by women, patients receiving 5 to 7 drugs, and patients receiving cardiovascular drugs and anti-infective drugs.

The study followed more than 46,000 patients who received over 151,300 prescribed drugs from primary care clinics in Quebec, Canada, using the Medical Office of the XXIst Century (MOXXI) electronic health record (EHR), which supports documentation of treatment indications and treatment outcomes. Prescriptions dispensed from January 1, 2005, through December 30, 2009, were followed up from the date of the prescription to the date the drug’s use was discontinued, treatment ended, or follow-up ended.

MOXXI EHRs require physicians to document the treatment indication for each new electronic prescription, the reasons for dose changes, drug discontinuation orders, and the nature of any ADEs. Reasons for all discontinuations of drug use are recorded and classified. The indication recorded for each prescription was classified as off-label or on-label according to the Health Canada database. For each off-label drug indication, the level of evidence supporting the drug’s overall efficacy was categorized. Thus, investigators created 2 variables: on- or off-label use; and off-label use with and without strong scientific evidence. Drug class and the year the drug was approved were measured as potential risk factors; other risk factors were age, measures of comorbidity, patient’s sex, and number of drugs taken.

“We found that 4 in 5 off-label prescriptions lacked strong scientific evidence, and this group had higher rates of ADEs,” the authors noted. “Off-label use may be clinically appropriate given the complexity of the patient’s condition, the lack of alternative effective drugs, or after exhausting approved drugs. However, a lack of physician knowledge of approved treatment indications was shown to be one factor for off-label prescribing.”

The researchers recommended that future EHRs be designed to enable postmarketing surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs.