Yanjing Zhang ¹ Chunhua Zhou ^1,2 Yan LIU ¹ Yupei Hao ¹ Jing Wang ¹ Bingyu Song ^2,3 Jing Yu ^1*

• ¹ Department of Clinical Pharmacy, The First hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
• ² The First hospital of Hebei Medical University, Shijiazhuang, China
• ³ Hebei Medical University, Shijiazhuang, Hebei Province, China

Background: Lumateperone has been approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia in adults since 2019, however, there is still a lack of data report on adverse reactions in real-world settings. Conducting data mining on adverse events (AEs) associated with Lumateperone and investigating the risk factors for serious AEs can provide valuable insights for its clinical practice.Methods: AE reports in the FDA Adverse Event Reporting System (FAERS) from 2019 Q4 (FDA approval of Lumateperone) to 2024 Q1 were collected and analyzed. Disproportionality in Lumateperone-associated AEs was evaluated using the following parameters: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Univariate and multivariate logistic regression analyses were conducted to identify the risk factors for Lumateperone-induced severe AEs.Results: A total of 2,644 reports defined Lumateperone as the primary suspected drug was collected, including 739 reports classified as severe AEs and 1905 reports as non-severe AEs. The analysis revealed that 130 preferred terms (PTs) with significant disproportionality were based on the four algorithms, 67 (51.53%) of which were not included in the product labeling, affecting 6 systems and organs. In addition, dizziness (81 cases) was the most reported Lumateperone-associated severe AEs, and tardive dyskinesia showed the strongest signal (ROR = 186.24). Logistic regression analysis indicated that gender, bipolar II disorder, and concomitant drug use are independent risk factors for Lumateperone-associated severe AEs. Specifically, female patients had a 1.811-fold increased risk (OR=1.811 [1.302, 2.519], P=0.000), while patients with bipolar II disorder had a 1.695-fold increased risk (OR=1.695 [1.320, 2.178], P=0.000). Conversely, concomitant use of CYP3A4 inhibitors or drugs metabolized by CYP3A4 was associated with a decreased risk of severe AEs (OR=0.524 [0.434, 0.633], P=0.000). Conclusion: Collectively, this study provides critical insights into the safety profile of Lumateperone. It highlights the need for cautious use in high-risk populations, such as females and individuals with bipolar II disorder, and emphasizes the importance of monitoring for AEs, including dizziness and tardive dyskinesia. Healthcare also should remain alert to potential AEs not listed in the prescribing information to ensure medical safety.