Patients receiving prescriptions for off-label indications were 54% more likely to experience an adverse event that warranted discontinuation of that agent. However, off-label use backed by strong scientific evidence had the same risk for ADEs as did on-label use (AHR 1.10; 95% CI, 0.88-1.38). There were higher risks for ADEs in drugs approved from 1981 to 1995, in drugs used by women, and in patients receiving polypharmacy (five to seven drugs). Agents most associated with ADEs were cardiovascular and anti-infective, and the most common ADEs affected the gastrointestinal tract and nervous, respiratory, and musculoskeletal systems.
In an accompanying editorial, Good and Gellad4 placed the issues into broader perspective. They cited an August, 2015 ruling of a Manhattan judge in the case of Amarin Pharma, which sought to promote icosapent ethyl (approved for the indication of hypertriglyceridemia) for broader, cardiovascular benefits.5 The ruling allowed Amarin to provide truthful, albeit off-label, information regarding the drug. Their right to do this, according to the ruling, was protected by First-Amendment freedom of speech. The question raised by the editorial is whether freedom of speech is appropriate if health and lives might be placed at risk. The authors likened this to “yelling ‘fire’ in a crowded theater without imminent danger” and discussed both sides of this complex conundrum.
They noted that appropriate off-label prescription is not only common but is actually standard of care and recommended by evidence-based guidelines (eg, metoprolol as first-line therapy for rate control in atrial fibrillation).4 Moreover, off-label use sometimes precedes approval for a given indication (eg, thalidomide, originally approved for treatment of leprosy in 1998, was used off-label for treatment of multiple myeloma and in 2006, received FDA-approval for that indication). Thus, off-label use of drugs may actually constitute good medical practice.