Divergent System Organ Class Safety Profiles of Isotretinoin Versus Topical Retinoids: An EudraVigilance Disproportionality Analysis

TL;DR

This study compares the safety profiles of isotretinoin and topical retinoids using EudraVigilance data, finding that isotretinoin is associated with higher reports of psychiatric and physical side effects.

Contribution

The study identifies distinct safety signals for isotretinoin compared to topical retinoids, particularly in psychiatric and musculoskeletal adverse events.

Findings

Isotretinoin showed strong over-reporting in psychiatric disorders, gastrointestinal disorders, and musculoskeletal disorders.

Psychiatric disorders had the highest disproportionality in males and adolescents aged 12–17.

Gastrointestinal and musculoskeletal signals remained significant across all age and sex strata.

Abstract

Background/Objectives: Isotretinoin remains an essential therapy for severe acne, yet its safety profile continues to raise concerns. This study analyzed adverse event reporting patterns for isotretinoin versus topical retinoids using EudraVigilance data. Methods: Aggregated ADR data for isotretinoin and four topical retinoids (tretinoin, adapalene, tazarotene, trifarotene) were retrieved from the EMA ADRreports portal (April 2025). Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals at the MedDRA system organ class (SOC) level. Significant demographic differences (age and sex; both p < 0.001) justified stratified ROR analyses for SOCs showing positive signals. Results: Among 35,030 isotretinoin and 3795 topical retinoid reports, isotretinoin showed strong over-reporting in six SOCs: psychiatric disorders (ROR 11.96; 95% CI 10.11–14.14), gastrointestinal disorders (3.88; 3.50–4.31), musculoskeletal and connective tissue disorders (2.89; 2.50–3.35), surgical and medical procedures, social circumstances, and ear and labyrinth disorders. Fourteen SOCs demonstrated significant under-reporting, including neoplasms, immune system disorders, cardiac disorders, and blood/lymphatic disorders. Stratified analyses confirmed the robustness of the positive signals. Psychiatric disorders exhibited the highest disproportionality in males (22.10; 16.11–30.31) and adolescents aged 12–17 (25.85; 13.32–50.19). Gastrointestinal and musculoskeletal signals remained significant across all age and sex strata. Conclusions: Isotretinoin presents a distinct safety profile characterized by consistently elevated reporting of psychiatric, gastrointestinal, and musculoskeletal adverse events, independent of age and sex. These results refine the comparative safety landscape of systemic versus topical retinoids and support focused pharmacovigilance monitoring.

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