Safety Profile of Istradefylline in Parkinson’s Disease: A Meta-Analysis of Randomized Controlled Trials and Disproportionality Analysis Using FAERS

Background Istradefylline, a selective adenosine A2A receptor antagonist, is used as an adjunct therapy to levodopa to improve motor symptoms in Parkinson’s disease (PD) patients, particularly those experiencing wearing-off phenomena. This study integrates safety data on istradefylline for the treatment of PD from randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS). Methods We performed a systematic search of PubMed, EMBASE, Ovid, MEDLINE, and ClinicalTrials.gov for RCTs on istradefylline safety in PD patients up to September 2024. A random-effects meta-analysis estimated the Peto odds ratio (OR) with 95% confidence intervals (CIs). FAERS data were analyzed through disproportionality measures, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), with signal refinement to primary suspect cases. Results The safety meta-analysis, encompassing data from 8 RCTs, reveals a significant association between istradefylline treatment and an increased risk of dyskinesia (odds ratio [OR] 1.77, 95% CI 1.32-2.36; P = 0.01), hallucinations (OR 2.08, 95% CI 1.11-3.90; P = 0.02), and nausea, when compared with placebo. In the FAERS database, 2597 patients were identified with adverse events (AEs) linked to istradefylline. Disproportionality analysis of istradefylline revealed 39 AEs strongly associated with its use, all of which were substantiated through signal refinement. The most commonly reported AEs were primarily associated with nervous system and psychiatric disorders. Conclusion This study highlights distinct AE patterns for istradefylline in trials vs real-world data, underscoring the importance of post-marketing surveillance to detect underreported AEs and validate new safety signals effectively.