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Background and objective: Drug-interaction alert systems are commonly used in community pharmacies to identify potential drug–drug interactions. However, depending on the software default setting, pharmacists may override alerts because they are too numerous. We explored the handling of drug-interaction alerts by community pharmacies in Switzerland. Methods: Data were collected by 15 trained pharmacy students in 15 Swiss community pharmacies. The medication history and the drug-interaction alerts of 600 patients who had ≥2 drugs on prescription were assessed, and the pharmacists in charge were interviewed about their management of drug-interaction alerts. Results: In the 15 pharmacies studied, the computer systems were programmed to flag only ‘severe’ drug interactions in four, ‘severe or moderate’ in six or ‘severe, moderate or minor’ in five pharmacies. The median frequency of drug-interaction alerts increased with decreasing default severity level from 0.5 to 40, respectively, to 76 per 40 patient visits and pharmacy. Because of these default settings, 277 (35·2%) of 787 potential drug-interaction alerts on new or repeated prescriptions were overridden by the computer systems. Only 256 (32·5%) of 787 potential drug interactions emerged from new prescriptions. The alert systems produced 656 alerts of which 146 were irrelevant because of multiple alerting of the same interaction or of drug combinations currently no longer taken. Of the 510 remaining relevant drug-interaction alerts, 289 (56·7%) were overridden by community pharmacists without any action taken. If the pharmacist took care of a patient's prescription him- or herself (as opposed to just controlling a prescription after a technician took care of the patient), fewer drug-interaction alerts were overridden by the pharmacist [Odds ratio (OR) 0·6, 95% confidence interval (CI) 0·42–0·98; P = 0·042). Technical overrides (by default settings) and pharmacists’ overrides together accounted for 71·9% (566 of 787 potential drug interactions). Of the remaining 211 interactions alerts, 87 (41·2%) were checked more closely by consulting the literature, contacting the prescribing physician or discussion with the patient. This led to 55 (63·2%) interventions (close monitoring, adjustment of dose or ingestion time, therapy stop or switching to alternative therapy). Determinants associated with action taken after an interaction alert were potential high severity (severe or moderate) (OR 3·34, 95% CI 1·77–6·31; P < 0·001) and alert flagged for the first time (OR 3·76, 95% CI 1·98–7·14; P < 0·001). All severe potential drug interactions ( n = 10) generated an alert and all caused an intervention. Conclusions: Pharmacists override a substantial proportion of drug-interaction alerts of minor or moderate potential severity by ignoring them or by programming the system to only flag drug interactions of potentially high severity. More sophisticated systems with improved sensitivity and specificity are required. Until these become available, it is important to ensure that at least potentially severe drug interactions are not missed; a goal that seems to be largely achieved. [ABSTRACT FROM AUTHOR]