Beyond the label: Rethinking off‐label drug use in paediatrics. Towards a scientifically grounded and safer future for paediatric pharmacotherapy

Despite regulatory progress being made in the past two decades, off-label drug use in paediatrics remains pervasive, with prevalence estimated between 3% and 97% of prescriptions across different clinical settings. Off-label use-defined as prescribing outside the conditions described in the Summary of Product Characteristics (SmPC)-is often unavoidable due to the lack of authorized paediatric indications, particularly for older, off-patent drugs. The level of evidence for off-label use is strikingly low: strong evidence supports only 14% of off-label paediatric drug records, while 37% of dosing recommendations rely solely on expert consensus. This practice exposes children to increased risks of adverse drug reactions (OR 2.25; 95% CI 1.95-2.59) and dosing errors, driven by insufficient evidence on age-appropriate dosing, efficacy and safety. Children remain 'therapeutic orphans', and the true challenge lies not in the absence of marketing authorization, but in the persistent evidence gap. This narrative review examines strategies to mitigate risks associated with paediatric off-label drug use proposing a five-step framework¹: verify authorization status²; confirm unmet medical need³; assess benefit-risk balance using structured published tools⁴ ensure proportional informed consent and⁵ closing the knowledge gap. Closing knowledge gaps through research prioritization, evidence mapping and innovative methodologies such as paediatric extrapolation, modelling and simulation, real-world evidence use and innovative trial designs will enable safer, scientifically grounded off-label use. Dissemination via harmonized international paediatric drug information platforms is critical to ensure equitable access to best-evidence paediatric pharmacotherapy. Off-label use in paediatrics is a global reality demanding a paradigm shift from 'off-label' to 'on-evidence'.