{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T21:12:42Z","timestamp":1783631562134,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"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: Allergic rhinitis (AR) is commonly treated with intranasal and oral pharmacotherapy or allergen immunotherapy (AIT), each associated with distinct safety considerations. This study aimed to systematically evaluate and compare the safety profiles of these therapeutic approaches by analysing adverse events (AEs) reported in completed randomised controlled trials (RCTs). Methods: A meta-epidemiological analysis was conducted using completed RCTs registered in ClinicalTrials.gov up to 20 October 2023. Trials investigating intranasal drugs, oral medications, or AIT for AR were identified using predefined search terms. Adverse events were manually extracted and categorised according to treatment class and dosage. Other adverse events (OAEs) were classified using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) and Medical Dictionary for Regulatory Activities (MedDRA) terminology. Meta-analyses compared OAE incidence across treatment groups, including standard-dose, higher-dose, and placebo arms. Results: A total of 216 RCTs were included. Intranasal therapies accounted for 55.56% of trials, predominantly intranasal corticosteroids (INCS) and intranasal antihistamines (INAH). OAE incidence was 16.37% for INCS, 29.43% for INAH, and 8.71% for combination therapy. INAH was associated with higher rates of dysgeusia and nasal discomfort, while higher INCS doses were linked to an increased risk of urinary tract infections. AIT trials comprised 22.69% of studies and demonstrated higher OAE rates, particularly for sublingual immunotherapy (64.96%), followed by subcutaneous (53.98%) and intralymphatic immunotherapy (62.50%). Oropharyngeal AEs were most frequent with sublingual immunotherapy. Oral medications (18.06%) showed the lowest OAE incidence, with upper respiratory tract infections occurring more frequently with oral antihistamines. Conclusions: Among intranasal therapies, INCS demonstrated the most favourable safety profile. Sublingual immunotherapy was associated with a higher frequency of OAEs compared with other AIT modalities. Combination oral antihistamine and leukotriene receptor antagonist therapy appeared to be the safest oral treatment option. Further well-designed studies are needed to refine comparative safety assessments across AR treatments.<\/jats:p>","DOI":"10.3390\/pharmaceutics18050581","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:11:13Z","timestamp":1778271073000},"page":"581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Safety Profile of Medications for Allergic Rhinitis: A Meta-Epidemiological Analysis of Completed RCTs from ClinicalTrials.gov"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5203-2379","authenticated-orcid":false,"given":"Ivan","family":"Paladin","sequence":"first","affiliation":[{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9264-7597","authenticated-orcid":false,"given":"Mirko","family":"Maglica","sequence":"additional","affiliation":[{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5650-990X","authenticated-orcid":false,"given":"Marin","family":"Gudelj","sequence":"additional","affiliation":[{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilija","family":"Krezo \u0160ljivi\u0107","sequence":"additional","affiliation":[{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5917-5794","authenticated-orcid":false,"given":"Franko","family":"Batinovi\u0107","sequence":"additional","affiliation":[{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darko","family":"Batisti\u0107","sequence":"additional","affiliation":[{"name":"Department of ENT and Head and Neck Surgery, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly Melissa","family":"Prani\u0107","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Split School of Medicine, 21000 Split, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1016\/j.jaip.2022.07.020","article-title":"The Allergic Rhinitis and Its Impact on Asthma (ARIA) Approach of Value-Added Medicines: As-Needed Treatment in Allergic Rhinitis","volume":"10","author":"Bousquet","year":"2022","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_2","unstructured":"Pawankar, R., Holgate, S.T., Canonica, G.W., and Lockey, R.F. (2011). WAO White Book on Allergy, World Allergy Organization."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1398-9995.2007.01549.x","article-title":"A survey of the burden of allergic rhinitis in Europe","volume":"62","author":"Canonica","year":"2007","journal-title":"Allergy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.jaci.2019.06.049","article-title":"Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence","volume":"145","author":"Bousquet","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1111\/all.13317","article-title":"EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis","volume":"73","author":"Roberts","year":"2018","journal-title":"Allergy"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13223-020-00436-y","article-title":"Towards definitive management of allergic rhinitis: Best use of new and established therapies","volume":"16","author":"Hossenbaccus","year":"2020","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/all.16384","article-title":"Efficacy and safety of intranasal medications for allergic rhinitis: Network meta-analysis","volume":"80","author":"Vieira","year":"2025","journal-title":"Allergy"},{"key":"ref_8","first-page":"CD002893","article-title":"Sublingual immunotherapy for allergic rhinitis","volume":"2010","author":"Radulovic","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/lary.29586","article-title":"Subcutaneous Versus Sublingual Immunotherapy for Adults with Allergic Rhinitis: A Systematic Review with Meta-Analyses","volume":"132","author":"Tie","year":"2022","journal-title":"Laryngoscope"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yang, J., and Lei, S. (2023). Efficacy and safety of sublingual versus subcutaneous immunotherapy in children with allergic rhinitis: A systematic review and meta-analysis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1274241"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.anai.2023.07.019","article-title":"Evidence-based use of antihistamines for treatment of allergic conditions","volume":"131","author":"Linton","year":"2023","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1177\/0194599817752624","article-title":"Oral Antihistamines Alone vs in Combination with Leukotriene Receptor Antagonists for Allergic Rhinitis: A Meta-analysis","volume":"158","author":"Liu","year":"2018","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1111\/bcp.14024","article-title":"Pharmacoepidemiology: Using randomised control trials and observational studies in clinical decision-making","volume":"85","author":"Caparrotta","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.jaci.2017.03.050","article-title":"Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines\u20142016 revision","volume":"140","author":"Brozek","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_15","first-page":"635","article-title":"The Range and Scientific Value of Randomized Trials","volume":"114","author":"Lange","year":"2017","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101523","DOI":"10.1016\/j.beha.2023.101523","article-title":"The role of randomized controlled trials, registries, observational databases in evaluating new interventions","volume":"36","author":"Gale","year":"2023","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1136\/ebmed-2017-110713","article-title":"Guidelines for reporting meta-epidemiological methodology research","volume":"22","author":"Murad","year":"2017","journal-title":"Evid. Based Med."},{"key":"ref_18","unstructured":"(2025, March 22). ClinicalTrials.gov. U.S. National Library of Medicine, Available online: https:\/\/clinicaltrials.gov."},{"key":"ref_19","unstructured":"U.S. Department of Health and Human Services, National Institutes of Health, and National Cancer Institute (2017). Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0."},{"key":"ref_20","unstructured":"(2025, March 15). Medical Dictionary for Regulatory Activities (MedDRA). Version 26.1. Available online: https:\/\/www.meddra.org."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_22","unstructured":"Council for International Organizations of Medical Sciences (CIOMS) Working Group III (1995). Guidelines for Preparing Core Clinical-Safety Information on Drugs, CIOMS."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/alr.23090","article-title":"International consensus statement on allergy and rhinology: Allergic rhinitis\u20142023","volume":"13","author":"Wise","year":"2023","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.jaci.2022.01.007","article-title":"Allergen immunotherapy for long-term tolerance and prevention","volume":"149","author":"Penagos","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1016\/j.jaip.2024.09.001","article-title":"Intranasal Versus Oral Treatments for Allergic Rhinitis: A Systematic Review with Meta-Analysis","volume":"12","author":"Torres","year":"2024","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1177\/0194599819832277","article-title":"Epistaxis Risk Associated with Intranasal Corticosteroid Sprays: A Systematic Review and Meta-analysis","volume":"161","author":"Wu","year":"2019","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s40801-022-00301-x","article-title":"Adverse Drug Reactions of Intranasal Corticosteroids in the Netherlands: An Analysis from the Netherlands Pharmacovigilance Center","volume":"9","author":"Rollema","year":"2022","journal-title":"Drugs Real World Outcomes"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1177\/00034894211007222","article-title":"Adverse Events Associated with Intranasal Sprays: An Analysis of the Food and Drug Administration Database and Literature Review","volume":"130","author":"Ahsanuddin","year":"2021","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/s41577-022-00786-1","article-title":"Allergen immunotherapy: Past, present and future","volume":"23","author":"Durham","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","first-page":"108","article-title":"International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis","volume":"8","author":"Wise","year":"2018","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2500\/ajra.2017.31.4382","article-title":"Efficacy and safety of sublingual immunotherapy for allergic rhinitis in pediatric patients: A meta-analysis of randomized controlled trials","volume":"31","author":"Feng","year":"2017","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.jaci.2015.09.026","article-title":"Fold stability during endolysosomal acidification is a key factor for allergenicity and immunogenicity of the major birch pollen allergen","volume":"137","author":"Machado","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1939-4551-7-6","article-title":"Sublingual immunotherapy: World Allergy Organization position paper 2013 update","volume":"7","author":"Canonica","year":"2014","journal-title":"World Allergy Organ. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0091-6749(05)80228-3","article-title":"The role of antihistamines in upper respiratory tract infections","volume":"86","author":"Welliver","year":"1990","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Xu, Y., Zhang, J., and Wang, J. (2014). The efficacy and safety of selective H1-antihistamine versus leukotriene receptor antagonist for seasonal allergic rhinitis: A meta-analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112815"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1177\/1945892419844459","article-title":"Leukotriene Receptor Antagonist Addition to H1-Antihistamine Is Effective for Treating Allergic Rhinitis: A Systematic Review and Meta-analysis","volume":"33","author":"Seresirikachorn","year":"2019","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_38","unstructured":"World Health Organization (2023, December 15). International Clinical Trials Registry Platform (ICTRP), Available online: https:\/\/www.who.int\/clinical-trials-registry-platform\/network\/primary-registries."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1186\/s13063-022-06569-2","article-title":"Update on the clinical trial landscape: Analysis of ClinicalTrials.gov registration data, 2000\u20132020","volume":"23","author":"Gresham","year":"2022","journal-title":"Trials"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/5\/581\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:14:40Z","timestamp":1778271280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/5\/581"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["pharmaceutics18050581"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18050581","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]}}}