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Objectives This study evaluated the prevalence of clinically significant drug-drug interactions (CSDDIs), off-label (OL) drug use and the associated predictors in paediatric cardiology ward.Design A cross-sectional study.Setting Hayatabad Medical Complex, Tertiary care hospital in Peshawar, Pakistan.Patients 250 patients.Methodology The Micromedex Drug-Reax tool was used to check the drug-drug interactions (DDI) and interactions of major severity were categorised as CSDDI. Association of various predictors including OL drug use with CSDDIs was evaluated using univariate and multivariate binary logistic regression.Main outcome measures Rate of drug-drug interactions, types and classification of DDI, OL prescribing in paediatrics.Result Of the total 250 paediatric patients, 127 (28.6%) patients were exposed to at least one clinically significant DDI, while 228 (91.20%) patients received at least one OL prescription. Furosemide was the most frequently prescribed drug involved in CSDDIs, while it was also one of the highly prescribed OL drugs. Multivariate analysis revealed that infant age group (OR 0.256; CI 0.080 to 0.814) with p value 0.02 and patients prescribed >5 drugs (OR 3.544; CI 1.906 to 6.589) were significantly more likely to experience CSDDIs in reference to their corresponding categories.Conclusion A high prevalence of CSDDIs and OL prescriptions was observed. OL drug presence was also observed to be a significant predictor associated with an increased risk of CSDDIs. Thus, to improve paediatric pharmacotherapy, suitable medical interventions are required to decrease OL drug use and CSDDIs.