Difelikefalin-associated adverse drug event signals: a real-world pharmacovigilance study from the FAERS database

BACKGROUND AND OBJECTIVE: Difelikefalin, a peripherally acting selective κ-opioid receptor agonist, is approved for treating chronic kidney disease-associated pruritus (CKD-aP) in adults on hemodialysis. However, real-world data on its adverse drug events (ADEs) remain limited. This study aimed to systematically identify ADE signals associated with difelikefalin in hemodialysis patients using the FAERS database, to generate hypotheses for subsequent clinical validation and provide targeted evidence for safe clinical application of difelikefalin in this vulnerable population. METHODS: ADE reports related to difelikefalin were extracted from the FAERS database (2022-2025). Drug names were standardized using Medex UIMA, and ADEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analyses, including the reporting odds ratio (ROR) and proportional reporting ratio (PRR), were employed to detect ADE signals. RESULTS: A total of 328 difelikefalin-related ADE reports were included, which is limited by the relatively recent approval and limited real-world use of this agent. Demographically, male patients (49.09%) outnumbered females (24.09%), and the vast majority of patients with clear age data were aged 65 years or older. Clinically, the most frequent outcomes were 'other serious' events (46.01%), hospitalization (33.46%), and death (15.59%). At the System Organ Class (SOC) level, Nervous system disorders (ROR = 3.4) and Psychiatric disorders (ROR = 2.99) showed the strongest ADE signals. At the Preferred Term (PT) level, high-risk signals included mental status changes (ROR = 85.65), disorientation (ROR = 33.62), electric shock sensation (ROR = 32.09), somnolence (ROR = 16.25), fall (ROR = 8.46), and fracture (ROR = 21.06). We also identified several rare ADE signals unreported in phase III clinical trials (e.g. electric shock sensation, disorientation) with significant disproportional reporting. CONCLUSION: This pharmacovigilance study identifies potential neuropsychiatric safety signals associated with difelikefalin, with a particularly elevated risk in elderly patients. These findings identify elderly hemodialysis patients as the high-risk group for difelikefalin-related ADEs, and suggest the need for targeted clinical monitoring strategies for this population; all signals require prospective cohort studies to validate potential causal relationships.