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<h4>Background</h4>Nurse-led monitoring of patients for signs and symptoms associated with documented 'undesirable effects' of medicines has potential to prevent avoidable harm, and optimise prescribing.<h4>Intervention</h4>The Adverse Drug Reaction Profile for polypharmacy (ADRe-p) identifies and documents putative adverse effects of medicines commonly prescribed in primary care. Nurses address some problems, before passing ADRe-p to pharmacists and prescribers for review, in conjunction with prescriptions.<h4>Objectives</h4>We investigated changes in: the number and nature of residents' problems as recorded on ADRe-p; prescription regimens; medicines optimisation: and healthcare costs. We explored aetiologies of problems identified and stakeholders' perspectives.<h4>Setting and participants</h4>In three UK care homes, 19 residents completed the study, December 2018 to May 2019. Two service users, three pharmacists, six nurses gave interviews.<h4>Methods</h4>This mixed-method process evaluation integrated data from residents' ADRe-ps and medicines charts, at the study's start and 5-10 weeks later.<h4>Results</h4>We recruited three of 27 homes approached and 26 of 45 eligible residents; 19 completed ADRe-p at least twice. Clinical gains were identified for 17/19 residents (mean number of symptoms 3 SD 1.67, range 0-7). Examples included management of: pain (six residents), seizures (three), dyspnoea (one), diarrhoea (laxatives reduced, two), falls (two of five able to stand). One or more medicine was de-prescribed or dose reduced for 12/19 residents. ADRe administration and review cost ~£30 in staff time. ADRe-p helped carers and nurses bring residents' problems to the attention of prescribers.<h4>Implications</h4>ADRe-p relieved unnecessary suffering. It supported carers and nurses by providing a tool to engage with pharmacists and prescribers, and was the only observable strategy for multidisciplinary team working around medicines optimisation. ADRe-p improved care by: a) regular systematic checks and problem documentation; b) information transfer from care home staff to prescribers and pharmacists; c) recording changes.<h4>Registration</h4>NLM Identifier NCT03955133; ClinicalTrials.gov.