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Background and Objectives <p>The safety profile of single or dual monoamine reuptake inhibitors (MRIs) is based on longstanding post-marketing experience but remains to be established for triple MRIs that may exhibit favorable efficacy as treatment of psychiatric disorders. Here, we characterized the safety profile of the triple MRI dasotraline based on disproportionality analyses and clinical trial data.</p> Methods <p>The Food and Drug Administration Adverse Event Reporting System was queried for adverse events of commonly prescribed selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs). Bayesian disproportionality analyses were conducted to determine the Empirical Bayes Geometric Mean (EBGM) for each Medical Dictionary for Regulatory Activities (MedDRA<sup>®</sup>) preferred term (PT) within each drug class. Five randomized, double-blind, placebo-controlled Phase 2/3 studies with dasotraline were utilized to determine the pooled incidence of disproportionally reported PTs (EBGM ≥3) on dasotraline and placebo.</p> Results <p>A total of 1087, 940, 409, and 714 PTs with an EBGM ≥3 were identified for SSRIs, SNRIs, NRIs, and NDRIs, respectively. The cumulative pooled incidence of these class-related PTs was approximately 2- to 2.5-fold higher for dasotraline than placebo (SSRIs: 24.7%/9.6%; SNRIs: 50.7%/26.3%; NRIs: 56.5%/32.2%; NDRIs: 35.2%/18.2%).</p> Conclusions <p>The safety profile of the triple MRI dasotraline was not distinct from pharmacologically related classes indicated by a consistently higher incidence of class-related adverse events compared to placebo in randomized, controlled clinical trials. Bayesian disproportionality analyses utilizing post-marketing data from established drug classes can provide meaningful information for qualitative safety evaluation of drugs in clinical development.</p> ClinicalTrials.gov Identifiers: <p>NCT01692782, NCT02428088, NCT02276209, NCT02564588, NCT03107026</p>

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Characterization of the Safety Profile of the Triple Monoamine Reuptake Inhibitor Dasotraline Based on Clinical Trial Data and Disproportionality Analyses of Four Related Pharmacological Classes Using Real-World Data from the FDA Adverse Event Reporting System

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • Solomiya Gumenyuk,
  • Ajay Ogirala,
  • Steven T. Szabo,
  • Kenneth Koblan,
  • Seth C. Hopkins,
  • Mike Ufer

摘要

Background and Objectives

The safety profile of single or dual monoamine reuptake inhibitors (MRIs) is based on longstanding post-marketing experience but remains to be established for triple MRIs that may exhibit favorable efficacy as treatment of psychiatric disorders. Here, we characterized the safety profile of the triple MRI dasotraline based on disproportionality analyses and clinical trial data.

Methods

The Food and Drug Administration Adverse Event Reporting System was queried for adverse events of commonly prescribed selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs). Bayesian disproportionality analyses were conducted to determine the Empirical Bayes Geometric Mean (EBGM) for each Medical Dictionary for Regulatory Activities (MedDRA®) preferred term (PT) within each drug class. Five randomized, double-blind, placebo-controlled Phase 2/3 studies with dasotraline were utilized to determine the pooled incidence of disproportionally reported PTs (EBGM ≥3) on dasotraline and placebo.

Results

A total of 1087, 940, 409, and 714 PTs with an EBGM ≥3 were identified for SSRIs, SNRIs, NRIs, and NDRIs, respectively. The cumulative pooled incidence of these class-related PTs was approximately 2- to 2.5-fold higher for dasotraline than placebo (SSRIs: 24.7%/9.6%; SNRIs: 50.7%/26.3%; NRIs: 56.5%/32.2%; NDRIs: 35.2%/18.2%).

Conclusions

The safety profile of the triple MRI dasotraline was not distinct from pharmacologically related classes indicated by a consistently higher incidence of class-related adverse events compared to placebo in randomized, controlled clinical trials. Bayesian disproportionality analyses utilizing post-marketing data from established drug classes can provide meaningful information for qualitative safety evaluation of drugs in clinical development.

ClinicalTrials.gov Identifiers:

NCT01692782, NCT02428088, NCT02276209, NCT02564588, NCT03107026