(1243) Benefits and Risks Associated with Off-label Prescribing of Common Medications: A Trazodone Case Study

Objectives: The U.S. Food and Drug Administration (FDA) is pivotal in approving medications for specific uses. Nevertheless, physicians retain the authority to prescribe drugs for “off-label” applications, diverging from uses that the FDA has determined to be safe and effective. Since the formal drug approval process is time-consuming, this practice gives patients prompt access. These patients, however, may face unknown risks due to the inadequate exploration of the off-label safety profile. Moreover, companies may lack economic incentive to conduct clinical trials for a drug’s off-label indications. Currently, around 20% of prescriptions are used off-label. A prime example of a commonly used off-label medication is trazodone hydrochloride, a serotonin antagonist-reuptake inhibitor (SARI). Initially approved to treat major depressive disorder (MDD) in adults, the brand product has been discontinued. Generic versions, however, remain on the market and are primarily used off-label. With over 25 million trazodone prescriptions filled annually, trazodone serves as an essential case study for exploring the evidence behind the safety and efficacy of off-label indications. The objective of this study is to examine the safety and efficacy of trazodone hydrochloride as an off-label medication by assessing the quality of off-label trazodone clinical trials and analyzing off-label incident reports.

Methods: ​​To begin, a search within the FDA Adverse Event Reporting System (FAERS) was conducted to identify off-label incident reports. The reports indicating trazodone as the sole suspect product active ingredient by reason for use were recorded. To further this research, clinicaltrials.gov and published literature will be explored to identify research on off-label trazodone use. The clinical trials of off-label use will be examined for adequacy of sample size, the presence of a control group, evidence of trazodone’s effectiveness against a placebo, and adherence to the National Institutes of Health’s requirements. These data will compare the reported risks of off-label use with evidence from clinical trials.

Results: Of the 7,239 incident reports submitted to the FAERS database for trazodone as an isolated suspect ingredient, only 460 reports listed the on-label use of MDD or depression symptoms as a reason for use. 1,089 reports, more than double, are associated with trazodone’s most common off-label use—insomnia or sleep disorder.

According to clinicaltrials.gov, only 24 of the 29 posted U.S.-based trials that use trazodone as a treatment isolated the effects of trazodone from other studied treatments. Of those 24 studies, only 11 (45.8%) were completed. Over half of these 11 studies (54.5%, n=11) list sample size as a primary limitation in their study, and over a third of these trials (36.4%, n=11) had sample sizes under 50.

Conclusions: Preliminary findings underscore the heightened risks associated with off-label usage of trazodone in comparison to its designated use and a lack of published research about trazodone off-label. Of the research that is available, very few trials have sufficient sample sizes to use the results as evidence for off-label prescribing. Establishing the justification for these risks requires a thorough investigation into the safety and efficacy of off-label usage. Given the widespread prescription of trazodone, the potential exposure of millions of patients to adverse effects necessitates urgent attention. Further investigation is warranted to scrutinize the evidence provided by clinical trials to support off-label prescribing of trazodone. This inquiry holds the potential to lay the groundwork for more robust and meticulously executed clinical trials, not only for trazodone, but also for other psychiatric medications employed off-label. This investigation will help to assess the adequacy of the existing regulatory framework in safeguarding the welfare of patients.