Shan Qing, Wang Lei, Liu Xia, Chen Yan, Li Bing, Guo Yuhang, Fu Qiang, Guo Jinmin
Department of Clinical Pharmacy, The 960 Hospital, Jinan, Shandong, China.
Jinan Key Laboratory of Individualised Clinical Drug Safety Monitoring and Pharmacovigilance Research, Jinan, China.
Front Pharmacol. 2025 Jun 18;16:1477127. doi: 10.3389/fphar.2025.1477127. eCollection 2025.
Hyperammonemic encephalopathy (HE) is a serious side effect linked to sodium valproate (VPA). Recent case studies indicate that newer antiepileptic drugs (AEDs) might also trigger HE, whether used alone or alongside VPA. This study investigated the risk factors of HE linked to 10 AEDs using data from the FDA Adverse Event Reporting System (FAERS), focusing on VPA co-administration effects.
FAERS reports from the first quarter of 2013 to the third quarter of 2024 were examined for ten frequently prescribed antiepileptic drugs (AEDs): VPA, perampanel (PER), phenytoin (PHT), carbamazepine (CBZ), topiramate (TPM), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXA), clonazepam (CZP), and zonisamide (ZNS). Hepatic event (HE) signals were evaluated using reporting odds ratios (ROR). A multivariate logistic regression analysis was conducted to assess risk factors (age, gender, indication, drug combinations). Particular attention was given to the effects of VPA in combination with LEV, TPM, olanzapine (OLZ), or quetiapine (QTP) on the risk of HE.
A total of 1,456 HE-related events were identified, with 93.06% of these events linked to AEDs. VPA had the highest association with HE (ROR = 122.14, 95% CI: 110.16-135.41), followed by PER, which was independent of VPA (ROR = 52.62). Eight additional AEDs also indicated positive associations, mainly influenced by VPA (such as TPM and LEV). Identified risk factors for HE included age (with a lower risk observed in minors, OR = 0.61, 95% CI [0.50-0.76]) and clinical indication (with a lower risk in psychiatric disorders, OR = 0.74, 95% CI [0.62-0.89]). The combination of VPA+TPM significantly raised the risk of HE (OR = 3.38, 95% CI [2.25-5.06]) without negatively impacting outcomes. Furthermore, combinations of antipsychotic medications with VPA also indicated an increased risk of HE (OLZ+VPA: OR = 1.65, 95% CI [1.18-2.30], QTP+VPA: OR = 1.95, 95% CI [1.39-2.75]).
This research underscores the possible danger of HE related to AEDs, with a particular focus on the risks tied to VPA and PER when used alone, as well as VPA in conjunction with TPM, OLZ, or QTP. It emphasizes the need to monitor ammonia levels in patients on AEDs, particularly those on polypharmacy.
高氨血症性脑病（HE）是与丙戊酸钠（VPA）相关的一种严重副作用。近期的病例研究表明，新型抗癫痫药物（AEDs）单独使用或与VPA联合使用时，也可能引发HE。本研究利用美国食品药品监督管理局不良事件报告系统（FAERS）的数据，调查了与10种AEDs相关的HE的危险因素，重点关注VPA联合用药的影响。
对2013年第一季度至2024年第三季度FAERS报告中的十种常用抗癫痫药物（AEDs）进行了审查：VPA、吡仑帕奈（PER）、苯妥英（PHT）、卡马西平（CBZ）、托吡酯（TPM）、拉莫三嗪（LTG）、左乙拉西坦（LEV）、奥卡西平（OXA）、氯硝西泮（CZP）和唑尼沙胺（ZNS）。使用报告比值比（ROR）评估肝脏事件（HE）信号。进行多因素逻辑回归分析以评估危险因素（年龄、性别、适应症、药物组合）。特别关注VPA与LEV、TPM、奥氮平（OLZ）或喹硫平（QTP）联合使用对HE风险的影响。
共识别出1456起与HE相关的事件，其中93.06%的事件与AEDs有关。VPA与HE的关联度最高（ROR = 122.14，95%CI：110.16 - 135.41），其次是PER，其与VPA无关（ROR = 52.62）。另外八种AEDs也显示出正相关，主要受VPA影响（如TPM和LEV）。确定的HE危险因素包括年龄（未成年人风险较低, OR = 0.61, 95%CI [0.50 - 0.76]）和临床适应症（精神疾病风险较低, OR = 0.74, 95%CI [0.62 - 0.89]）。VPA + TPM联合使用显著增加了HE的风险（OR = 3.38, 95%CI [2.25 - 5.06]），且未对治疗结果产生负面影响。此外，抗精神病药物与VPA联合使用也显示出HE风险增加（OLZ + VPA: OR = 1.65, 95%CI [1.18 - 2.30], QTP + VPA: OR = 1.95, 95%CI [1.39 - 2.75]）。
本研究强调了与AEDs相关的HE的潜在危险，尤其关注单独使用VPA和PER以及VPA与TPM、OLZ或QTP联合使用时的风险。它强调了对使用AEDs的患者，特别是那些联合用药的患者监测氨水平的必要性。
