School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
Regional Pharmacovigilance Center, Korean Pharmaceutical Association, Seoul, Republic of Korea.
J Pineal Res. 2024 Mar;76(2):e12949. doi: 10.1111/jpi.12949.
Melatonin, a pineal hormone that modulates circadian rhythms, sleep, and neurotransmitters, is widely used to treat sleep disorders. However, there are limited studies on the safety of melatonin. Therefore, we aimed to present the overall patterns of adverse events (AEs) following melatonin administration and identify potential safety signals associated with melatonin. Using VigiBase, a global individual case safety report (ICSRs) database managed by the World Health Organization (WHO), we conducted a retrospective, observational, pharmacovigilance study of melatonin between January 1996 and September 2022. Disproportionality analysis was conducted using two comparator settings: all other drugs and other sleep medications. We used multivariable logistic regression to estimate reporting odds ratios (RORs) with 95% confidence intervals (CIs) to compare the frequencies of AEs reporting between melatonin and each comparator setting. Furthermore, we assessed adverse events of special interests (AESIs) that could potentially be associated with melatonin. Signals were identified when the following criteria were met: cases ≥3, x ≥ 4, IC025 ≥ 0, and the lower end of the 95% CI of ROR > 2. These signals were then compared with the AE information on the drug labels provided by regulatory bodies. A total of 35 479 AE reports associated with melatonin were identified, with a higher proportion of reports from females (57.1%) and individuals aged 45-64 years (20.8%). We identified 21 AEs that were commonly detected as safety signals in the disproportionality analyses, including tic, educational problems, disturbance in social behavior, body temperature fluctuation, and growth retardation. In AESI analyses, accidents and injuries (adjusted ROR 2.97; 95% CI, 2.80-3.16), fall (2.24; 2.12-2.37), nightmare (4.90; 4.37-5.49), and abnormal dreams (3.68; 3.19-4.25) were detected as a signal of melatonin when compared to all other drugs, whereas those signals were not detected when compared to other sleep medications. In this pharmacovigilance study, exogenous melatonin showed safety profiles comparable to other sleep medications. However, several unexpected potential safety signals were identified, underscoring the need for further investigation at the population level.
褪黑素是一种调节昼夜节律、睡眠和神经递质的松果腺激素，被广泛用于治疗睡眠障碍。然而，关于褪黑素的安全性研究有限。因此，我们旨在展示褪黑素给药后不良事件（AE）的总体模式，并确定与褪黑素相关的潜在安全信号。我们使用世界卫生组织（WHO）管理的全球个体病例安全报告（ICSR）数据库 VigiBase，对 1996 年 1 月至 2022 年 9 月期间的褪黑素进行了回顾性、观察性、药物警戒研究。使用两个比较器设置（所有其他药物和其他睡眠药物）进行了比例失调分析。我们使用多变量逻辑回归来估计报告比值比（ROR）及其 95%置信区间（CI），以比较褪黑素与每个比较器设置之间 AE 报告的频率。此外，我们评估了可能与褪黑素相关的特殊关注不良事件（AESI）。当满足以下标准时确定信号：病例数≥3、x≥4、IC025≥0.05 和 ROR 的 95%CI 下限>2。然后将这些信号与监管机构提供的药物标签上的 AE 信息进行比较。共确定了 35479 例与褪黑素相关的 AE 报告，其中女性（57.1%）和 45-64 岁人群（20.8%）的报告比例较高。在比例失调分析中，我们确定了 21 种常见的安全信号 AE，包括抽搐、教育问题、社会行为障碍、体温波动和生长迟缓。在 AESI 分析中，与所有其他药物相比，事故和伤害（调整后的 ROR 2.97；95%CI，2.80-3.16）、跌倒（2.24；2.12-2.37）、噩梦（4.90；4.37-5.49）和异常梦境（3.68；3.19-4.25）被检测为褪黑素的信号，而与其他睡眠药物相比，这些信号未被检测到。在这项药物警戒研究中，外源性褪黑素显示出与其他睡眠药物相当的安全性特征。然而，发现了一些意想不到的潜在安全信号，这表明需要在人群水平上进一步研究。
