Off-Label Drug Use Linked to More Adverse Events

Diana Swift

November 10, 2015

The off-label use of prescription drugs is associated with more adverse drug events (ADEs) in adults than on-label use, especially when off-label indications are not backed by solid data, according to a study published online November 2 in JAMA Internal Medicine.

"This study is, to our knowledge, the first to systematically evaluate the association between off-label use of drugs and the risk for ADEs in an adult population," Tewodros Eguale, MD, PhD, an epidemiologist at McGill University, Montreal, Quebec, Canada, and associate professor in the School of Pharmacy at MCPHS University, Boston, Massachusetts, and colleagues write.

On the basis of their findings, Dr Eguale and colleagues suggest that "[c]aution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence."

The researchers used data from electronic health records from a community-based clinical information system to identify 46,021 adults (mean age, 58.2 years; 60.8% women) who received 151,305 prescribed drugs from primary care clinics in the province of Quebec from 2005 to 2009. The records documented treatment indications and outcomes.

Although the majority of the prescriptions (88.2%) were for approved use, 9.5% involved off-label use without strong supportive evidence, and 2.3% were off-label but had strong evidence to support the indication.

The authors identified 3484 ADEs in the cohort, for an overall ADE incidence rate of 13.2 per 10,000 person-months.

However, the ADE rate for off-label use was higher than for on-label use, at 19.7 per 10,000 person-months vs 12.5 per 10,000 person-months (adjusted hazard ratio [AHR], 1.44; 95% confidence interval [CI], 1.30 - 1.60).

When analyzed by strength of evidence supporting the off-label use, the researchers found that use unsupported by strong scientific evidence had a higher ADE rate, at 21.7 per 10,000 person-months (AHR, 1.54; 95% CI, 1.37 - 1.72), compared with on-label use. Off-label use indicated by solid scientific evidence had a rate of 13.2 per 10,000 person-months, which was virtually the same as its on-label counterpart (AHR, 1.10; 95% CI, 0.88 - 1.38).

The risk for adverse events rose with the number of prescription drugs individual patients used. In those receiving five to seven drugs, for example, the rate was 12.1 per 10,000 person-months (AHR, 3.23; 95% CI, 2.66 - 3.92). Those taking eight or more medications had a more than fivefold increased risk for ADEs compared with patients who used one or two drugs.

The most commonly reported ADEs related to drug classes targeting the gastrointestinal tract, as well as the nervous, respiratory, and musculoskeletal systems. ADEs associated with the most frequently used off-label drugs included the following: akathisia from taking gabapentin for neurogenic pain, agitation associated with amitriptyline hydrochloride for migraine, hallucinations with trazodone hydrochloride for insomnia, QT interval prolongation with the use of quetiapine fumarate for depression, and weight gain with olanzapine for depression.

The ADE risk was higher for drugs approved from 1981 to 1995, at 14.4 per 10,000 person-months (AHR, 1.62; 95% CI, 1.45 - 1.80). It was also greater for medications used by women (14.3 per 10,000 person-months; AHR, 1.17; 95% CI, 1.06 - 1.28) and cardiovascular drugs (15.9 per 10,000 person-months; AHR, 3.30; 95% CI, 2.67 - 4.08). Anti-infectives had the highest risk for adverse events (66.2 per 10,000 person-months; AHR, 6.33; 95% CI, 4.58 - 8.76), which was more than six times that of gastrointestinal drugs. Drugs approved after 1995 had ADE rates 55% higher than drugs approved before 1981 (AHR, 1.55; 95% CI, 1.39 - 1.73).

The authors note the potential for undocumented medication-related symptoms missed by physicians and unreported by patients. Furthermore, there was no measurement of the cost of ADEs, although the study estimated that the mean cost of treating an ADE in hospital would range from $759 to $1214.

"[P]hysicians and physician organizations should recognize the enormity of the problem and be active participants in the promotion of cautious prescribing of drugs for off-label uses lacking strong scientific evidence," Dr Eguale and colleagues write.

They conclude that well-designed electronic health records can ease problems relating to the postmarketing surveillance of drugs; "namely, the lack of an explicit link between prescribed drugs and their indication for use and the underreporting of ADEs."

They recommend that future records design incorporate such safety surveillance of indications and outcomes.

"Timely" and "Informative"

Calling the McGill study "particularly timely" in light of a federal judge's First Amendment–based decision in August 2015 ruling against the US Food and Drug Administration's restrictions on off-label drug promotion of a fish-oil supplement, two editorialists describe it as "the most extensive and informative study to evaluate the safety of off-label drug use in an adult population to date."

In an invited commentary, Chester B. Good, MD, MPH, and Walid F. Gellad, MD, MPH, from the Center for Health Equity Research and Promotion, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, point out that in 2001 to 2002, an estimated 21% of office-based prescriptions were off-label.

In addition, a 2003 Knight Ridder investigative news series documented ADEs in the off-label use of antipsychotics to treat behavioral issues in elderly patients with dementia, anticonvulsants to treat bipolar disorder, terbutaline for premature labor, and fluoxetine hydrochloride for pain.

Dr Good and Dr Gellad also note that France has passed a law to monitor off-label drug use and study the benefit–risk ratios of these uses in collaboration with the pharmaceutical industry.

However, in many clinical circumstances, off-label prescribing serves the patient's best interests, and such use may even be the standard of care.

"Digoxin is approved for rate control in atrial fibrillation, whereas use of metoprolol is off-label. However, metoprolol, but not digoxin, is first-line therapy for rate control in evidence-based clinical guidelines," they write.

But given that off-label prescribing can be inappropriate and harmful, they warn that the US Food and Drug Administration "and the courts must carefully consider [the study's] findings as they contemplate guidance that would relax regulations to permit promotion of drugs beyond their labeled indications."

The authors have disclosed no relevant financial relationships. Dr Good reported serving as an unpaid adviser to the FDA Drug Safety Oversight Board, and Dr Gellad reported serving as his alternate to this board.

JAMA Intern Med. Published online November 2, 2015. Article abstract, Commentary extract


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