{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:19:24Z","timestamp":1790619564475,"version":"4.1.0"},"reference-count":109,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Chronic obstructive pulmonary disease (COPD) is commonly managed alongside multimorbidity, polypharmacy, recurrent treatment escalation, and older age, all of which increase vulnerability to drug\u2013drug interactions (DDIs). We aimed to synthesize the main DDI domains relevant to COPD pharmacotherapy and to distinguish harmful DDIs from beneficial combination therapy and formal compatibility findings. Methods: We performed a narrative review using structured literature searches and citation tracking to evaluate COPD-related studies. We prioritized direct COPD-specific DDI evidence, while also including mechanistic, class-specific, and contextual studies when direct evidence was lacking. Retained evidence included observational cohorts, prescribing studies, pharmacokinetic trials, case reports, and systematic reviews. Results: The reviewed literature indicates that DDI vulnerability in COPD is driven less by isolated drug pairs than by overall regimen complexity, multimorbidity, aging, fragmented prescribing, and high-intensity treatment periods such as exacerbations, hospitalization, and discharge. Key DDI domains included cardiopulmonary co-treatment, QT-related vulnerability, and potential or clinically relevant interactions amplified during exacerbations. Inhaled therapies are not universally interaction-free, particularly with strong metabolic inhibitors. Psychotropics, frailty, dementia, and palliative care further increase clinical complexity. However, beneficial bronchodilator combinations and formal compatibility studies demonstrate that not all multidrug COPD regimens are harmful. Conclusions: In COPD, DDI assessment should focus on the full treatment regimen and not be limited to a set of iconic drug pairs. Clinicians must focus on exacerbation-related prescribing, QT-active drugs, theophylline exposure, psychotropic co-medication, and vulnerable subgroups such as older, frail, and palliative patients. Pharmacist-supported drug review, drug reconciliation, and selective deprescribing are key strategies for reducing clinically relevant DDI burden in COPD.<\/jats:p>","DOI":"10.3390\/pharmaceutics18060640","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T02:32:28Z","timestamp":1779676348000},"page":"640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Polypharmacy and Drug\u2013Drug Interactions in Chronic Obstructive Pulmonary Disease: A Narrative Clinical Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4064-5871","authenticated-orcid":false,"given":"Maria-Medana","family":"Dr\u0103goi","sequence":"first","affiliation":[{"name":"Center for Drug Data Analysis, Cheminformatics, and the Internet of Medical Things, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"},{"name":"Doctoral School of Pharmacy, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8113-6071","authenticated-orcid":false,"given":"Florina-Diana","family":"Goldi\u0219","sequence":"additional","affiliation":[{"name":"Center for Drug Data Analysis, Cheminformatics, and the Internet of Medical Things, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"},{"name":"Doctoral School of Pharmacy, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1156-8825","authenticated-orcid":false,"given":"Sabina-Oana","family":"Vasii","sequence":"additional","affiliation":[{"name":"Center for Drug Data Analysis, Cheminformatics, and the Internet of Medical Things, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"},{"name":"Doctoral School of Pharmacy, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2449-3452","authenticated-orcid":false,"given":"Daiana","family":"Colib\u0103\u0219anu","sequence":"additional","affiliation":[{"name":"Center for Drug Data Analysis, Cheminformatics, and the Internet of Medical Things, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"},{"name":"Doctoral School of Pharmacy, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2075-3275","authenticated-orcid":false,"given":"Liana","family":"Suciu","sequence":"additional","affiliation":[{"name":"Center for Drug Data Analysis, Cheminformatics, and the Internet of Medical Things, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"},{"name":"Department II\u2014Pharmacology, Physiology and Physiopathology, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8575-0131","authenticated-orcid":false,"given":"Angela","family":"Caunii","sequence":"additional","affiliation":[{"name":"Center for Drug Data Analysis, Cheminformatics, and the Internet of Medical Things, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"},{"name":"Department I\u2014Clinical Pharmacy and Drug Analysis, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3084-6301","authenticated-orcid":false,"given":"Lucre\u021bia","family":"Udrescu","sequence":"additional","affiliation":[{"name":"Center for Drug Data Analysis, Cheminformatics, and the Internet of Medical Things, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"},{"name":"Department I\u2014Clinical Pharmacy and Drug Analysis, Victor Babe\u015f University of Medicine and Pharmacy Timi\u015foara, 300041 Timi\u015foara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, March 18). Chronic Obstructive Pulmonary Disease (COPD). Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/chronic-obstructive-pulmonary-disease-(copd)."},{"key":"ref_2","unstructured":"Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2026, March 18). Global Strategy for Prevention, Diagnosis and Management of COPD: 2026 Report. Available online: https:\/\/goldcopd.org\/wp-content\/uploads\/2026\/01\/GOLD-REPORT-2026-v1.3-8Dec2025_WMV2.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41533-025-00419-9","article-title":"Prevalence, diagnostic accuracy, and healthcare utilization patterns in patients with COPD in primary healthcare: A population-based study","volume":"35","author":"Vila","year":"2025","journal-title":"npj Prim. Care Respir. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1164\/rccm.202003-0625ST","article-title":"Pharmacologic management of chronic obstructive pulmonary disease. An official American Thoracic Society clinical practice guideline","volume":"201","author":"Nici","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rosenwasser, Y., Berger, I., and Loewy, Z.G. (2022). Therapeutic approaches for chronic obstructive pulmonary disease (COPD) exacerbations. Pathogens, 11.","DOI":"10.3390\/pathogens11121513"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1513\/pats.200709-148ET","article-title":"Comorbidities in chronic obstructive pulmonary disease","volume":"5","author":"Chatila","year":"2008","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1183\/09031936.00171614","article-title":"COPD comorbidities network","volume":"46","author":"Divo","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_8","first-page":"PA3607","article-title":"Cardiovascular comorbidities in chronic obstructive pulmonary disease patients","volume":"50","author":"Udrescu","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mariniello, D.F., D\u2019Agnano, V., Cennamo, D., Conte, S., Quarcio, G., Notizia, L., Pagliaro, R., Schiattarella, A., Salvi, R., and Bianco, A. (2024). Comorbidities in COPD: Current and future treatment challenges. J. Clin. Med., 13.","DOI":"10.3390\/jcm13030743"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e001798","DOI":"10.1136\/bmjresp-2023-001798","article-title":"Comorbidities and mortality among patients with chronic obstructive pulmonary disease","volume":"10","author":"Skajaa","year":"2023","journal-title":"BMJ Open Respir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/S2213-2600(23)00261-8","article-title":"COPD and multimorbidity: Recognising and addressing a syndemic occurrence","volume":"11","author":"Fabbri","year":"2023","journal-title":"Lancet Respir. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e018404","DOI":"10.1136\/bmjopen-2017-018404","article-title":"Examining patterns of multimorbidity, polypharmacy and risk of adverse drug reactions in chronic obstructive pulmonary disease: A cross-sectional UK Biobank study","volume":"8","author":"Hanlon","year":"2018","journal-title":"BMJ Open"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"240099","DOI":"10.1183\/20734735.0099-2024","article-title":"Diagnosis and management of comorbid disease in COPD","volume":"21","author":"Cronin","year":"2025","journal-title":"Breathe"},{"key":"ref_14","first-page":"440","article-title":"Polypharmacy in Patients With COPD: A Scoping Review","volume":"12","author":"Upadhyay","year":"2025","journal-title":"Chronic Obstr. Pulm. Dis. J. COPD Found."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s40266-023-01038-0","article-title":"Pharmacotherapies in older adults with COPD: Challenges and opportunities","volume":"40","author":"Matera","year":"2023","journal-title":"Drugs Aging"},{"key":"ref_16","first-page":"234","article-title":"Polypharmacy among older individuals with COPD: Trends between 2000 and 2015 in Quebec, Canada","volume":"16","author":"Sirois","year":"2019","journal-title":"COPD J. Chronic Obstr. Pulm. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s40780-021-00222-x","article-title":"Association between medication adherence and health-related quality of life in patients with chronic obstructive pulmonary disease","volume":"7","author":"Moradkhani","year":"2021","journal-title":"J. Pharm. Health Care Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2848","DOI":"10.1093\/jac\/dkz221","article-title":"Improving antibacterial prescribing safety in the management of COPD exacerbations: Systematic review of observational and clinical studies on potential drug interactions associated with frequently prescribed antibacterials among COPD patients","volume":"74","author":"Wang","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"920","DOI":"10.5114\/aoms.2014.46212","article-title":"Potential drug-drug interactions in hospitalized patients with chronic heart failure and chronic obstructive pulmonary disease","volume":"10","author":"Roblek","year":"2014","journal-title":"Arch. Med. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3390\/arm91010008","article-title":"Evaluation of drug interactions in hospitalized patients with respiratory disorders in Greece","volume":"91","author":"Spanakis","year":"2023","journal-title":"Adv. Respir. Med."},{"key":"ref_21","first-page":"100468","article-title":"Are there any potential drug-drug interactions with oral inhaler medications: A retrospective study","volume":"15","author":"Tezcan","year":"2024","journal-title":"Explor. Res. Clin. Soc. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4397","DOI":"10.1111\/bcp.14862","article-title":"Drug metabolism in severe chronic obstructive pulmonary disease: A phenotyping cocktail study","volume":"87","author":"McNeill","year":"2021","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1001\/jama.2010.672","article-title":"Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease","volume":"303","author":"Rothberg","year":"2010","journal-title":"JAMA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jpainsymman.2020.01.009","article-title":"Chronic obstructive pulmonary disease: A palliative medicine review of the disease, its therapies, and drug interactions","volume":"60","author":"Weiss","year":"2020","journal-title":"J. Pain Symptom Manag."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1183\/09031936.00126107","article-title":"Palliative and end-of-life care for patients with severe COPD","volume":"32","author":"Curtis","year":"2008","journal-title":"Eur. Respir. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/S0140-6736(17)32127-X","article-title":"Palliative care and management of troublesome symptoms for people with chronic obstructive pulmonary disease","volume":"390","author":"Maddocks","year":"2017","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.coph.2018.03.011","article-title":"Pharmacological mechanisms leading to synergy in fixed-dose dual bronchodilator therapy","volume":"40","author":"Calzetta","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s40264-014-0262-8","article-title":"Consensus recommendations for systematic evaluation of drug\u2013drug interaction evidence for clinical decision support","volume":"38","author":"Scheife","year":"2015","journal-title":"Drug Saf."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1345\/aph.1H423","article-title":"Proposal for a new tool to evaluate drug interaction cases","volume":"41","author":"Horn","year":"2007","journal-title":"Ann. Pharmacother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.artmed.2017.01.004","article-title":"Identification of adverse drug-drug interactions through causal association rule discovery from spontaneous adverse event reports","volume":"76","author":"Cai","year":"2017","journal-title":"Artif. Intell. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Peabody, J.W., Ganesan, D., Valdenor, C., Paculdo, D., Schrecker, J., Westerfield, C., and Heltsley, R. (2023). Randomized prospective trial to detect and distinguish between medication nonadherence, drug-drug interactions, and disease progression in chronic cardiometabolic disease. BMC Prim. Care, 24.","DOI":"10.1186\/s12875-023-02042-4"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1111\/crj.13434","article-title":"Clinical characteristics and outcomes of polypharmacy in chronic obstructive pulmonary disease patients: A cross-sectional study from Crete, Greece","volume":"15","author":"Ierodiakonou","year":"2021","journal-title":"Clin. Respir. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.pupt.2018.06.004","article-title":"The pharmacological treatment of chronic comorbidities in COPD: Mind the gap!","volume":"51","author":"Pedone","year":"2018","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.2147\/COPD.S136256","article-title":"Treatment burden, clinical outcomes, and comorbidities in COPD: An examination of the utility of medication regimen complexity index in COPD","volume":"12","author":"Negewo","year":"2017","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1111\/ggi.13115","article-title":"Poor adherence to chronic obstructive pulmonary disease medications in primary care: Role of age, disease burden and polypharmacy","volume":"17","author":"Vetrano","year":"2017","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.annepidem.2023.12.003","article-title":"Non-adherence to COPD medications and its association with adverse events: A longitudinal population based cohort study of older adults","volume":"96","author":"Weir","year":"2024","journal-title":"Ann. Epidemiol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hom\u0119towska, H., \u015awi\u0105toniowska-Lonc, N., Klekowski, J., Chabowski, M., and Jankowska-Pola\u0144ska, B. (2022). Treatment adherence in patients with obstructive pulmonary diseases. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph191811573"},{"key":"ref_38","first-page":"7","article-title":"Drug\u2013Drug Interactions in COPD Therapy: A Community Pharmacy Study","volume":"127","author":"Ardelean","year":"2025","journal-title":"Proceedings"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/bcp.13087","article-title":"Optimizing identification and management of COPD patients\u2013reviewing the role of the community pharmacist","volume":"83","author":"Maguire","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.pupt.2018.01.011","article-title":"Compatibility of medication with PRISCUS criteria and identification of drug interactions in a large cohort of patients with COPD","volume":"49","author":"Graf","year":"2018","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s11845-019-02155-9","article-title":"Risk factors for potential drug-drug interactions in patients with chronic obstructive pulmonary disease","volume":"189","author":"Stojadinovic","year":"2020","journal-title":"Ir. J. Med. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1007\/s11096-019-00913-4","article-title":"Drug-related problems among hospitalized patients with COPD in mainland China","volume":"41","author":"Li","year":"2019","journal-title":"Int. J. Clin. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.jamda.2022.02.020","article-title":"Prevalence of Pharmacologic Treatments for Chronic Obstructive Pulmonary Disease in Relation of Diagnosis of Dementia Among Nursing Homes Residents","volume":"23","author":"Elli","year":"2022","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_44","first-page":"1053","article-title":"Long QT and death in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease is not related to electrolyte disorders","volume":"2019","author":"Rahamim","year":"2019","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1056\/NEJMoa1713901","article-title":"Once-daily single-inhaler triple versus dual therapy in patients with COPD","volume":"378","author":"Lipson","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1056\/NEJMoa1916046","article-title":"Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD","volume":"383","author":"Rabe","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"108292","DOI":"10.1016\/j.rmed.2025.108292","article-title":"Comparing major COPD triple therapy trials using a structured multi-criteria decision analysis: A deep dive into patient populations and outcomes","volume":"247","author":"Cazzola","year":"2025","journal-title":"Respir. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ejphar.2015.05.020","article-title":"Pharmacological interaction between LABAs and LAMAs in the airways: Optimizing synergy","volume":"761","author":"Calzetta","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ejphar.2014.10.025","article-title":"Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi","volume":"745","author":"Cazzola","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ejphar.2017.07.026","article-title":"Pharmacological characterization of the interaction between umeclidinium and vilanterol in human bronchi","volume":"812","author":"Calzetta","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.pupt.2018.03.001","article-title":"The pharmacokinetics of three doses of budesonide\/glycopyrronium\/formoterol fumarate dihydrate metered dose inhaler compared with active controls: A phase I randomized, single-dose, crossover study in healthy adults","volume":"50","author":"Darken","year":"2018","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"159","DOI":"10.2147\/COPD.S40859","article-title":"Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: A randomized and open-label study","volume":"8","author":"Mehta","year":"2013","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2200302","DOI":"10.1183\/13993003.00302-2022","article-title":"Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with COPD: A systematic review and meta-analysis","volume":"61","author":"Yang","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Ruan, Z., Wang, C., Yuan, S., Fan, Y., Xu, B., Cong, X., Li, D., and Miao, Q. (2025). High-risk adverse events in two types of single inhaler triple-therapy: A pharmacovigilance study based on the FAERS database. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1460407"},{"key":"ref_55","unstructured":"(2026, April 29). ICH Harmonised Guideline Drug Interaction Studies M12, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Available online: https:\/\/database.ich.org\/sites\/default\/files\/ICH_M12_Step4_Guideline_2024_0521_0.pdf."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3487","DOI":"10.2147\/COPD.S150887","article-title":"Doxofylline is not just another theophylline!","volume":"12","author":"Matera","year":"2017","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"160123","DOI":"10.1183\/16000617.0123-2016","article-title":"Effectiveness and safety of concurrent beta-blockers and inhaled bronchodilators in COPD with cardiovascular comorbidities","volume":"26","author":"Corrao","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1183\/13993003.01847-2015","article-title":"Beta-blockers in COPD: Time for reappraisal","volume":"48","author":"Lipworth","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00059-019-4834-3","article-title":"Pulmonary and cardiac drugs: Clinically relevant interactions","volume":"44","author":"Olschewski","year":"2019","journal-title":"Herz"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.hrtlng.2018.09.015","article-title":"The prevalence of prolonged QTc increases by GOLD stage, and is associated with worse survival among subjects with COPD","volume":"48","author":"Nilsson","year":"2019","journal-title":"Heart Lung"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1161\/CIRCULATIONAHA.109.192704","article-title":"Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation","volume":"121","author":"Drew","year":"2010","journal-title":"Circulation"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1007\/s11096-018-0692-y","article-title":"Development of a risk model for predicting QTc interval prolongation in patients using QTc-prolonging drugs","volume":"40","author":"Bindraban","year":"2018","journal-title":"Int. J. Clin. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Cattaneo, D., Torre, A., Schiuma, M., Civati, A., Casalini, G., Gori, A., Antinori, S., and Gervasoni, C. (2024). Management of polypharmacy and potential drug\u2013drug interactions in patients with pulmonary aspergillosis: A 2-year study of a multidisciplinary outpatient clinic. J. Fungi, 10.","DOI":"10.3390\/jof10020107"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"105250","DOI":"10.1016\/j.phrs.2020.105250","article-title":"Meta-analysis on outcome-worsening comorbidities of COVID-19 and related potential drug-drug interactions","volume":"161","author":"Awortwe","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"105904","DOI":"10.1016\/j.rmed.2020.105904","article-title":"The effect of doxofylline in asthma and COPD","volume":"164","author":"Cazzola","year":"2020","journal-title":"Respir. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"D1265","DOI":"10.1093\/nar\/gkad976","article-title":"DrugBank 6.0: The DrugBank knowledgebase for 2024","volume":"52","author":"Knox","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1345\/aph.1E651","article-title":"The potential role of roflumilast: The new phosphodiesterase-4 inhibitor","volume":"40","author":"Karish","year":"2006","journal-title":"Ann. Pharmacother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/j.1365-2125.2009.03478.x","article-title":"Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects","volume":"68","author":"Nassr","year":"2009","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1177\/0091270010370590","article-title":"Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide","volume":"51","author":"Lahu","year":"2011","journal-title":"J. Clin. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1177\/0091270010368282","article-title":"No dose adjustment on coadministration of the PDE4 inhibitor roflumilast with a weak CYP3A, CYP1A2, and CYP2C19 inhibitor: An investigation using cimetidine","volume":"51","author":"Gleiter","year":"2011","journal-title":"J. Clin. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1365-2125.2006.02762.x","article-title":"Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects","volume":"63","author":"Nassr","year":"2007","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00228-022-03433-9","article-title":"Inhalation therapies in COPD\u2014adverse drug reactions impact on emergency department presentations","volume":"79","author":"Bergs","year":"2023","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s12931-019-1113-z","article-title":"Evaluation of systemic absorption and bronchodilator effect of glycopyrronium bromide delivered by nebulizer or a dry powder inhaler in subjects with chronic obstructive pulmonary disease","volume":"20","author":"Leaker","year":"2019","journal-title":"Respir. Res."},{"key":"ref_74","unstructured":"(2026, April 28). SPIRIVA\u00ae HandiHaler\u00ae (Tiotropium Bromide Inhalation Powder), Prescribing Information, U.S. Food and Drug Administration, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2009\/021395s029lbl.pdf."},{"key":"ref_75","unstructured":"(2026, April 28). SEEBRI\u2122 NEOHALER\u00ae (Glycopyrrolate) Inhalation Powder, for Oral Inhalation Use, Prescribing Information, U.S. Food and Drug Administration, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2015\/207923lbl.pdf."},{"key":"ref_76","unstructured":"(2026, April 28). TUDORZA\u00ae PRESSAIR\u00ae (Aclidinium Bromide Inhalation Powder), for Oral Inhalation Use, Prescribing Information, U.S. Food and Drug Administration, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/202450s012lbl.pdf."},{"key":"ref_77","unstructured":"(2026, April 28). INCRUSE ELLIPTA (Umeclidinium Inhalation Powder), for Oral Inhalation Use, Prescribing Information, U.S. Food and Drug Administration, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/205382s010lbl.pdf."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1186\/s40064-015-1218-x","article-title":"Iatrogenic Cushing syndrome and adrenal insufficiency during concomitant therapy with ritonavir and fluticasone","volume":"4","author":"Epperla","year":"2015","journal-title":"Springerplus"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Siraj, R.A. (2025). COPD and comorbid mental health: Addressing anxiety, and depression, and their clinical management. Medicina, 61.","DOI":"10.3390\/medicina61081426"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1111\/j.1440-1843.2012.02148.x","article-title":"Treatments for anxiety and depression in patients with chronic obstructive pulmonary disease: A literature review","volume":"17","author":"Cafarella","year":"2012","journal-title":"Respirology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s41030-024-00277-9","article-title":"Do antidepressants worsen COPD outcomes in depressed patients with COPD?","volume":"10","author":"Kaplan","year":"2024","journal-title":"Pulm. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"S366","DOI":"10.4103\/indianjpsychiatry.indianjpsychiatry_25_22","article-title":"Management of psychiatric disorders in patients with respiratory diseases","volume":"64","author":"Bhattacharyya","year":"2022","journal-title":"Indian J. Psychiatry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1139\/jpn.0312","article-title":"Interactions between the cytochrome P450 system and the second-generation antipsychotics","volume":"28","author":"Prior","year":"2003","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.jpsychires.2024.04.001","article-title":"Influence of CYP2C19 and CYP2D6 on side effects of aripiprazole and risperidone: A systematic review","volume":"174","author":"Schaars","year":"2024","journal-title":"J. Psychiatr. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1080\/17425255.2022.2086121","article-title":"Drug\u2013drug interactions involving antipsychotics and antihypertensives","volume":"18","author":"Buzea","year":"2022","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Cojocaru, A., Braha, A., Jeleriu, R., Andreescu, N.I., Puiu, M., Ageu, L., Folescu, R., Zamfir, C.L., and Nussbaum, L.A. (2024). The Implications of Cytochrome P450 2D6\/CYP2D6 Polymorphism in the Therapeutic Response of Atypical Antipsychotics in Adolescents with Psychosis\u2014A Prospective Study. Biomedicines, 12.","DOI":"10.3390\/biomedicines12030494"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"100338","DOI":"10.1016\/j.ejpsy.2025.100338","article-title":"Heterogeneity in the association between CYP2D6 genotype and antipsychotic-induced extrapyramidal symptoms: A systematic review","volume":"40","author":"Luca","year":"2026","journal-title":"Eur. J. Psychiatry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1001\/jamapsychiatry.2016.3793","article-title":"Association between antipsychotic agents and risk of acute respiratory failure in patients with chronic obstructive pulmonary disease","volume":"74","author":"Wang","year":"2017","journal-title":"JAMA Psychiatry"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Goldi\u0219, F.D., Vasii, S.O., Ardelean, S.M., Udrescu-Milosav, M., and Udrescu, L. (2026). PsychoPharm Aggregated Risk Score (PARS): A multidimensional tool to flag high-risk pharmacotherapy in psychiatric patients. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1782968"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1365-2710.2007.00793.x","article-title":"Inappropriate prescribing in the elderly","volume":"32","author":"Gallagher","year":"2007","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.2165\/00002018-200124140-00005","article-title":"Asthma medications and their potential adverse effects in the elderly","volume":"24","author":"Newnham","year":"2001","journal-title":"Drug Saf."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Buda, V., Prelipcean, A., Cristescu, C., Roja, A., Dalleur, O., Andor, M., Danciu, C., Ledeti, A., Dehelean, C.A., and Cretu, O. (2021). Prescription habits related to chronic pathologies of elderly people in primary care in the western part of Romania: Current practices, international recommendations, and future perspectives regarding the overuse and misuse of medicines. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18137043"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2147\/CIA.S233270","article-title":"Potentially inappropriate prescriptions in ambulatory elderly patients living in rural areas of Romania using STOPP\/START (version 2) criteria","volume":"15","author":"Buda","year":"2020","journal-title":"Clin. Interv. Aging"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s10354-018-0633-3","article-title":"Polypharmacy in palliative care\u2014COPD and multimorbidity: A case report","volume":"168","author":"Rowhani","year":"2018","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1093\/ajhp\/zxaa216","article-title":"Emerging role of pharmacists in managing patients with chronic obstructive pulmonary disease","volume":"77","author":"Hudd","year":"2020","journal-title":"Am. J.-Health-Syst. Pharm."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.rmed.2016.07.010","article-title":"Impact of community pharmacists in COPD management: Inhalation technique and medication adherence","volume":"118","author":"Hesso","year":"2016","journal-title":"Respir. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.2147\/COPD.S383914","article-title":"Effectiveness of hospital pharmacist interventions for COPD patients: A systematic literature review and logic model","volume":"17","author":"Lin","year":"2022","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/jac5.70006","article-title":"Impact of pharmacist management on chronic obstructive pulmonary disease in a family medicine residency clinic","volume":"8","author":"Figueras","year":"2025","journal-title":"J. Am. Coll. Clin. Pharm."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"100231","DOI":"10.1016\/j.chpulm.2025.100231","article-title":"A Pharmacist-Led Intervention to Increase Inhaler Access and Reduce Hospital Readmission (PILLAR): A Randomized Controlled Trial","volume":"31","author":"Parrott","year":"2026","journal-title":"CHEST Pulm."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Suciu, L., Ardelean, S.M., Udrescu, M., Goldi\u015f, F.D., H\u00e2nda, D., Tuic\u0103, M.M., Vasii, S.O., and Udrescu, L. (2024). Categorical Analysis of Database Consistency in Reporting Drug\u2013Drug Interactions for Cardiovascular Diseases. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16030339"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Colib\u0103\u0219anu, D., Ardelean, S.M., Goldi\u0219, F.D., Dr\u0103goi, M.M., Vasii, S.O., Maksimovi\u0107, T., Colib\u0103\u0219anu, \u0218., \u0218oica, C., and Udrescu, L. (2025). Unveiling Drug-Drug interactions in dental patients: A retrospective Real-World study. Dent. J., 13.","DOI":"10.3390\/dj13060255"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1016\/j.chest.2021.10.032","article-title":"The role of palliative care in COPD","volume":"161","author":"Iyer","year":"2022","journal-title":"Chest"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Kowalczys, A., Bohdan, M., Wilkowska, A., Paw\u0142owska, I., Paw\u0142owski, L., Janowiak, P., Jassem, E., Lelonek, M., Grucha\u0142a, M., and Soba\u0144ski, P. (2022). Comprehensive care for people living with heart failure and chronic obstructive pulmonary disease\u2014Integration of palliative care with disease-specific care: From guidelines to practice. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.895495"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.2147\/COPD.S74641","article-title":"Palliative care in COPD: An unmet area for quality improvement","volume":"10","author":"Vermylen","year":"2015","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"giad011","DOI":"10.1093\/gigascience\/giad011","article-title":"The curse and blessing of abundance\u2014the evolution of drug interaction databases and their impact on drug network analysis","volume":"12","author":"Udrescu","year":"2023","journal-title":"GigaScience"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Vasii, S.O., Colib\u0103\u0219anu, D., Goldi\u0219, F.D., Ardelean, S.M., Udrescu, M., Iliescu, D., Mali\u021ba, D.C., Ioni\u021b\u0103, I., and Udrescu, L. (2026). Onco-Hem Connectome\u2014Network-Based Phenotyping of Polypharmacy and Drug\u2013Drug Interactions in Onco-Hematological Inpatients. Pharmaceutics, 18.","DOI":"10.3390\/pharmaceutics18020146"},{"key":"ref_107","unstructured":"(2026, April 29). Guideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation, European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-and-simulation_en.pdf."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/cpt.1013","article-title":"Physiologically based pharmacokinetic model qualification and reporting procedures for regulatory submissions: A consortium perspective","volume":"104","author":"Shebley","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Jia, G., Ren, C., Wang, H., and Fan, C. (2024). Prediction of drug\u2013drug interactions between roflumilast and CYP3A4\/1A2 perpetrators using a physiologically-based pharmacokinetic (PBPK) approach. BMC Pharmacol. Toxicol., 25.","DOI":"10.1186\/s40360-023-00726-2"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/6\/640\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:24:22Z","timestamp":1780460662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/6\/640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,23]]},"references-count":109,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["pharmaceutics18060640"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18060640","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,23]]}}}