Off-label use of hydrochlorothiazide in neonatology: impact of tablet adaptation techniques on dose accuracy

Abstract Purpose: To investigate the occurrence, preparation practices, and physicochemical characteristics of hydrochlorothiazide tablet adaptations performed in neonatal intensive care units (NICUs) in northeastern Brazil, aiming to characterize clinical manipulation practices and assess their potential implications for the quality, dose accuracy, stability, and safety of compounded preparations intended for neonatal use. Methods: A three-phase study was conducted comprising: (i) a prospective cohort in a NICU to determine the frequency of hydrochlorothiazide tablet adaptations among hospitalized neonates; (ii) a survey with NICU healthcare professionals to characterize routine manipulation practices and preparation techniques; and (iii) laboratory simulations reproducing the reported methods, followed by physicochemical characterization to evaluate preparation homogeneity and dose accuracy. Results: Among 300 hospitalized neonates, frequent hydrochlorothiazide tablet adaptations were identified, highlighting the widespread use of manipulated formulations in neonatal care. Three primary preparation techniques were reported: tablet dispersion, crushing, and disintegration. Experimental analyses demonstrated substantial variability among techniques, resulting in inconsistent drug distribution and clinically relevant differences in delivered doses. Conclusion: Hydrochlorothiazide tablet adaptations demonstrated poor homogeneity and considerable dose variability, potentially compromising therapeutic effectiveness and medication safety. These findings reinforce the need for standardized preparation protocols and the development of age-appropriate neonatal formulations.