Prevalence, predictors, and clinical relevance of drug–drug interactions in outpatient prescribing: A national cross-sectional study

Background Drug–drug interactions (DDIs) represent a major preventable cause of medication-related harm globally. Their prevalence varies across health systems, but common drivers include polypharmacy, aging populations, and specialty-specific prescribing patterns. Large-scale pharmacoepidemiologic analyses of real-world prescription data can clarify the magnitude of the problem and inform strategies to reduce risks. Methods This retrospective study included 2,365,811 outpatient prescriptions (982,102 patients) from Tehran, Iran. The top 100 most prescribed medications were screened for potential DDIs via Micromedex®. Interactions were classified as contraindicated, major, or moderate. Logistic regression identified demographic, specialty, and prescription-level predictors. Results Potential DDIs occurred in 46.1% of prescriptions, with 57.8% of patients affected. Major DDIs (62.6%) dominated, followed by moderate (32.8%) and contraindicated (4.6%). ASA was a frequent contributor to high-risk pairs. Contraindicated interactions were largely NSAID duplications, most common in orthopedics and emergency medicine. Psychiatry and cardiology prescriptions showed the highest prevalence, while polypharmacy strongly predicted DDIs, with incremental risks amplified in older adults. Conclusions Outpatient DDIs represent a substantial burden in routine care, comparable to international reports. Prevention requires comprehensive strategies, including e-prescribing with CDSS, pharmacist-led reviews, patient education on OTC use, and policy interventions to limit reimbursement of unsafe combinations.