Background: Polypharmacy exposes patients with comorbidities (particularly elderly patients) to an increased risk of drug-specific adverse events and drug–drug interactions. These adverse events could be avoided with the use of a computerized prescription support system in the primary care setting. The INTERCheck® software is a prescription support system developed with the aim of balancing the risks and benefits of polytherapy and examining drug–drug interactions. Objectives: This observational study used the INTERCheck® software to evaluate the incidence of adverse events and of drug–drug interactions in outpatients and inpatients receiving multiple medications. Methods: Patients were randomly enrolled from the outpatient department (n = 98) and internal medicine ward (n = 46) of S. Andrea Hospital of Rome. Polypharmacological treatment was analyzed using INTERCheck® software, and the prevalence of risk indicators and adverse events was compared between the two groups. Results: Polypharmacy (use of five or more drugs) applied to all except three cases among outpatients and one case among inpatients. A significant positive correlation was found between the number of medications and the INTERCheck® score (ρ = 0.67; p < 0.000001), and a significant negative correlation was found between the drug-related anticholinergic burden and cognitive impairment (r = − 0.30 p = 0.01). Based on the INTERCheck® analysis, inpatients had a higher score for class D (contraindicated drug combination should be avoided) than did outpatients (p = 0.01). The potential class D drug–drug interactions were associated with adverse events that caused hospitalization (χ2 = 7.428, p = 0.01). Conclusions: INTERCheck® analysis indicated that inpatients had a high risk of drug–drug interactions and a high percentage of related adverse drug events. Further prospective studies are necessary to evaluate whether the INTERCheck® software may help reduce polypharmacy-related adverse events when used in a primary care setting and thus potentially avoid related hospitalization and severe complications such as physical and cognitive decline
