Serious Adverse Drug Reactions Associated with Off-Label and Unlicensed Drug Use in Children: A 14-Year Analysis of...

Background/Objectives: Adverse drug reactions are associated with off-label (OL) and unlicensed (UL) drug use in children. Methods: We conducted a retrospective observational pharmacovigilance study based on individual case safety reports (ICSRs) and adverse drug reactions (ADRs) from VigiBase for patients aged 0-17 years to evaluate reporting patterns associated with off-label and unlicensed suspected drugs reported in Serbia. Results: Over 14 years, 2037 pediatric ICSRs comprising 4257 ADRs were reported. Infants (28 days-23 months) accounted for just over half of ICSRs, and systemic anti-infectives and vaccines dominated suspected drugs. Overall, 9.7% of ADRs were serious, including 12 fatal outcomes, with serious ADRs reported more often for non-vaccine than vaccine suspected drugs. Off-label and unlicensed suspected drug records accounted for 10.8% and 1.9% of suspected drug records, respectively, and had higher proportions of serious ADRs than on-label or licensed use (off-label 12.1% vs. on-label 9.4%, p = 0.04; unlicensed 22.9% vs. licensed 9.4%, p < 0.001). In the adjusted ICSR-level logistic regression, neonatal age was the strongest independent predictor of seriousness, with approximately threefold higher odds of a serious case compared with children (aOR 3.04, 95% CI 1.55-5.98). Conclusions: Although off-label and unlicensed drugs accounted for a minority of pediatric reports, they were associated with a higher proportion of serious reported ADRs, particularly in the neonatal period. These findings should be interpreted as pharmacovigilance reporting patterns rather than incidence-based estimates or proof of causality.