Is off-label prescribing really harmful?

Off-label prescribing is a common practice, and, of course, when we do it we are not thinking that we are causing harm. The concept is that the regulatory agencies, after reviewing the clinical trial data, will approve the use of a medication for a specific indication at a specific dose because the benefits and risks are acceptable. Off-label means that we are using the medication in a way that is not indicated on the official drug label.

This research group looked at 46,000 patients in primary care in Quebec, Canada, to see if off-label prescribing caused harm or not; they found an increase in adverse events associated with off-label use. The adjusted hazard ratio was 1.44 (CI, 1.30–1.60); so, 44% more adverse events. However, when we consider off-label use as either having good scientific evidence to support it or not having good scientific evidence to support it, the results were quite different. As expected, the no-evidence-to-support group was associated with a higher risk of adverse events (HR, 1.54). However, if the off-label use had good scientific support, risk of adverse events was no higher compared with that associated with on-label use.

Anti-infective drugs were associated with the highest adverse event rates when used off-label (HR, 6.33); cardiovascular medications (HR, 3.30) came in second, and CNS medications (HR, 3.06) comprised the third category in terms of associated adverse events.

Also, the adverse events increased if the patients were on more medications. Compared with that for patients taking one or two medications, the hazard ratio for patients on more than eight medications was 5.29 for increased adverse events.

So, the bottom line is stay with what the medications are approved for; if we are going to go off-label, we need to make sure there are good scientific data to support that decision, and make sure that the patients are not on a lot of other medications. If we do this then we will get the good out of the medications and limit the adverse events suffered by our patients.

Abstract

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.

Journal Abstract