Gastrointestinal and Skin Safety Evaluation of Pirfenidone versus Nintedanib: An Analysis of Real-World Pharmacovigilance and Randomized Controlled Trials

Abstract This study compares their safety profiles using real-world pharmacovigilance data and meta-analysis to guide clinical use. Adverse drug event (ADE) reports for pirfenidone (2008-Q1 2025) and nintedanib (2014-Q1 2025) were extracted from the FAERS database via OpenVigil 2.1. ADE signals were analyzed using MedDRA's system organ class (SOC) and preferred terms (PT), with reporting odds ratio (ROR) for signal detection. Randomized controlled trials (RCTs) were retrieved from Cochrane, PubMed, Embase, and ClinicalTrials.gov, and meta-analysis was performed using RevMan 5.3. Pirfenidone and nintedanib were associated with 26,353 and 9,809 ADE reports, respectively, primarily in patients aged ≥ 65. Gastrointestinal disorders were common for both, but nintedanib showed fewer skin-related ADRs. Gender-based differences were observed: nintedanib's gastrointestinal ADRs varied by gender, while pirfenidone's skin-related ADRs differed significantly. Most reports originated from the U.S. Meta-analysis of 10 RCTs (6 pirfenidone, 4 nintedanib) showed both drugs slowed forced vital capacity (FVC) decline and reduced respiratory-related mortality. Nintedanib demonstrated superior efficacy in reducing acute exacerbations (RR = 0.57, 95%CI [0.34–0.98], I²=47%). Both drugs primarily caused gastrointestinal ADRs (e.g., nausea, vomiting), with pirfenidone linked to more photosensitivity reactions. Integrated pharmacovigilance and RCT analyses highlight the safety profiles of pirfenidone and nintedanib, offering evidence for clinical decision-making in IPF treatment.