PD-1/PD-L1 Inhibitor-Induced Hyponatremia: A Real-World Pharmacovigilance Analysis Using FAERS Database

Chao Tao^1,2Qian Ding³Yan Dai¹Jinyi Lv^4,5Huanhuan He²Kun Chen¹Ke Wang^1,2Liuxuan Yang¹Xiaoqun Ren^1*Meiling Zhou^6*

• ¹Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
• ²Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan Province, China
• ³Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, China
• ⁴Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
• ⁵Rehabilitation Medicine and Engineering Key Laboratory of Luzhou, Luzhou, Sichuan Province, China
• ⁶The Affiliated Hospital of Southwest Medical University, Luzhou, China

Background: With the increasing use of programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) inhibitors in cancer treatment, hyponatremia has emerged as a notable adverse event associated with this class of drugs.We extracted adverse event reports related to PD-1/PD-L1 inhibitor-induced hyponatremia from the FDA Adverse Event Reporting System (FAERS) database, spanning from Q1 2004 to Q2 2024. The reports were analyzed for disproportionality using four methods: reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker.Signals of hyponatremia associated with nivolumab, pembrolizumab, and atezolizumab were assessed at both the Standardized MedDRA Query and preferred term levels.Results: A total of 1,339 reports of hyponatremia involving 1,274 patients were identified, with nivolumab, pembrolizumab, or atezolizumab as the primary suspected drugs. All four methods consistently indicated positive signals for hyponatremia with these drugs. Hyponatremia induced by PD-1/PD-L1 inhibitors predominantly occurred in patients aged 45 and older, with a higher incidence in males. The median onset times were 42 days for nivolumab, 35 days for pembrolizumab, and 20 days for atezolizumab.Except for atezolizumab, the median onset times for hyponatremia induced by nivolumab and pembrolizumab differed across genders and age groups.This pharmacovigilance analysis reveals the association between PD-1/PD-L1 inhibitors and hyponatremia, offering valuable insights to refine treatment strategies and improve risk management for this AE.