Safety Profiles of Trofinetide in Pediatric Rett Syndrome Population: A Real-World Postmarketing Pharmacovigilance Analysis.

Purpose: Trofinetide, a synthetic analog of glycine-proline-glutamate, is the only approved therapy for Rett syndrome. This study evaluated the safety profile of trofinetide in pediatric patients with Rett syndrome using real-world pharmacovigilance data.

Methods: Adverse event (AE) reports were extracted from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) from Q1 2023 to Q4 2024. Disproportionality analyses were conducted using ROR, PRR, BCPNN, and MGPS to detect AE signals associated with trofinetide use in individuals under 18 years. A Weibull distribution model was applied to assess time-to-onset patterns. Subgroup analyses by age and dose, as well as sensitivity analyses excluding common co-medications, were conducted to evaluate signal consistency.

Findings: Most patients were female (95.4%), and all reports originated from the United States. Common labeled AEs were confirmed, including diarrhoea (n = 1,528; ROR = 38.1), vomiting (n = 434; ROR = 5.96), and seizures (n = 251; ROR = 5.30). Off-label signals included weight decreased (n = 135; ROR = 7.21), tremor (n = 39; ROR = 3.37), dystonia (n = 18; ROR = 4.39), and dyskinesia (n = 24; ROR = 4.53). Over 70% of AEs occurred within the first month. Hypersomnia was more frequently reported in younger children (ROR = 12.11), and higher doses were associated with psychiatric symptoms. Subgroup and sensitivity analyses confirmed the robustness of key signals.

Implications: This study provides critical real-world safety data on trofinetide use in pediatric Rett syndrome, identifying both expected and emerging AEs. Findings highlight the importance of monitoring dose-related and age-specific adverse events in clinical settings.