Off-Label Drug Use and Adverse Drug Events

Study Questions:

What is the off-label use of prescription drugs and its effect on adverse drug events (ADEs) in an adult population?


A cohort of 46,021 patients who received 151,305 incident prescribed drugs was assembled from primary care clinics in Quebec, Canada, using the Medical Office of the XXIst Century electronic health record, 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 use was discontinued, the end of treatment, or the end of follow-up (December 30, 2010). Off-label prescription drug use with and without strong scientific evidence was assessed. The main outcomes measure was adverse drug events in off-label use with and without strong scientific evidence. Analysis used multivariate marginal Cox proportional hazards regression for clustered data with the drug as the unit of analysis.


A total of 3,484 ADEs were found in the 46,021 study patients, with an incidence rate of 13.2 per 10,000 person-months. 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% confidence interval [CI], 1.30-1.60). Off-label use lacking strong scientific evidence had a higher ADE rate (21.7 per 10,000 person-months) compared with on-label use (AHR, 1.54; 95% CI, 1.37-1.72). However, 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). The risks for ADEs were higher for drugs approved from 1981 to 1995 (14.4 per 10,000 person-months; AHR, 1.62; 95% CI, 1.45-1.80) and for those used by women (14.3 per 10,000 person-months; AHR, 1.17; 95% CI, 1.06-1.28), patients receiving 5-7 drugs (12.1 per 10,000 person-months; AHR, 3.23; 95% CI, 2.66-3.92), and patients receiving cardiovascular drugs (15.9 per 10,000 person-months; AHR, 3.30; 95% CI, 2.67-4.08) and anti-infectives (66.2 per 10,000 person-months; AHR, 6.33; 95% CI, 4.58-8.76). Patients with a 1-unit increase in the continuity of care index had a 19% increase in ADEs (AHR, 1.19; 95% CI, 1.12-1.26).


The authors concluded that off-label use of prescription drugs is associated with ADEs.


This study reports that off-label use of drugs was associated with ADEs after adjusting for important patient and drug characteristics. Furthermore, there was a risk gradient with higher rates of ADEs for off-label uses lacking strong scientific evidence. It is imperative that physicians and physician organizations recognize the significance of the problem and participate actively in the promotion of cautious prescribing of drugs for off-label uses lacking strong scientific evidence. In the future, electronic health records may allow postmarketing surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs.

Clinical Topics: Prevention

Keywords: Cardiovascular Agents, Continuity of Patient Care, Drug Labeling, Electronic Health Records, Off-Label Use, Prescription Drugs, Primary Prevention, Treatment Outcome

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