Original Investigation
Health Care Reform
January 2016

Association of Off-label Drug Use and Adverse Drug Events in an Adult Population

Author Affiliations
  • 1Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
  • 2Department of Medicine, McGill University, Montreal, Quebec, Canada
  • 3Division of General Medicine and Primary Care, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 4Department of Social and Administrative Pharmacy, Schoool of Pharmacy, MCPHS University, Boston, Massachusetts
  • 5Department of Mathematics and Statistics, McGill University, Montreal, Quebec, Canada

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Intern Med. 2016;176(1):55-63. doi:10.1001/jamainternmed.2015.6058

Importance  Off-label use of prescription drugs has been identified as an important contributor to preventable adverse drug events (ADEs) in children. Despite concerns regarding adverse outcomes, to date, no systematic investigation of the effects of off-label drug use in adult populations has been performed.

Objective  To monitor and evaluate off-label use of prescription drugs and its effect on ADEs in an adult population.

Design, Setting, and Participants  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). Data were analyzed from January 5, 2012, to March 15, 2015.

Exposures  Off-label prescription drug use with and without strong scientific evidence.

Main Outcomes and Measures  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.

Results  A total of 3484 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% 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 to 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).

Conclusions and Relevance  Off-label use of prescription drugs is associated with ADEs. Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence. Future electronic health records should be designed to enable postmarket surveillance of treatment indications and treatment outcomes to monitor the safety of on- and off-label uses of drugs.