Mapping the therapeutic versatility of WHO essential medicines: a systematic analysis of off-label indications

Background: Off-label prescribing represents an important aspect of clinical practice globally. However, there are limited data on the extent, evidence base and guideline support of off-label indications among the World Health Organization’s essential medicines list (WHO EML), which serves as a cornerstone for healthcare systems, especially in low- and middle-income countries. Objectives: This study aimed to systematically analyse the prevalence, therapeutic distribution, quality of evidence and inclusion in clinical guidelines of off-label uses for drugs listed in the 2023 WHO EML. Methods: We conducted a descriptive analysis of all medications on the WHO EML using UpToDate ® Lexidrug™ database. For each medication, we extracted FDA-approved indications, identified off-label indications, the level of evidence supporting each off-label use (Level A, B, C, or G) and inclusion status in clinical practice guidelines. Off-label indications were categorized across 24 therapeutic systems, and system-to-system transitions from labelled to off-label uses were mapped. Design: Descriptive cross-sectional observational study using a structured database analysis. Results: Off-label prevalence among the WHO EML was 60.0%. The most frequent off-label use was observed in infectious diseases (30.5%) and oncology (25.2%). Most off-label uses were supported by Level C (32%) and Level B (30%) evidence, while only 11% were backed by Level A evidence. Notably, 64% of off-label uses were included in clinical guidelines, though many lacked associated evidence levels in Lexicomp. The majority of off-label uses remained within the same therapeutic system, with limited cross-system transitions. Conclusion: This first comprehensive analysis of off-label uses across the WHO EML demonstrates widespread repurposing of essential medicines with variable evidence quality.