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.

Intranasal corticosteroids (INCS) remain the cornerstone of pharmacologic treatment for allergic rhinitis (AR) because of their well-established anti-inflammatory efficacy and generally favorable benefit–risk profile. Nevertheless, concerns regarding local and systemic corticosteroid-related adverse events (AEs) continue to influence patient adherence, prescribing practices, and long-term treatment acceptance. In routine clinical practice, safety perception and corticosteroid-related concerns frequently influence adherence and formulation selection to a greater extent than differences in clinical efficacy, particularly in pediatric populations and in patients requiring prolonged continuous therapy. Differences in pharmacokinetic and pharmacodynamic properties, including systemic bioavailability, glucocorticoid receptor affinity, lipophilicity, protein binding, and extent of first-pass metabolism, are considered important safety profile determinants of currently available INCS formulations. Available evidence indicates that local AEs, particularly epistaxis, nasal irritation, dryness, and sensory discomfort, represent the most frequently reported treatment-related AEs across INCS formulations, although these events are generally mild, self-limiting, and infrequently treatment-limiting. Clinically significant structural nasal complications, including septal perforation or progressive mucosal injury, appear uncommon in currently available studies. Systemic AEs, including hypothalamic–pituitary–adrenal (HPA) axis suppression, ocular toxicity, growth impairment, or clinically meaningful effects on bone metabolism, have not been consistently demonstrated with currently used low-systemic-exposure formulations administered at recommended therapeutic doses. Although systemic glucocorticoid exposure has been associated with alterations in lipid metabolism, adipose tissue function, and metabolic homeostasis, currently available intranasal corticosteroids demonstrate minimal systemic exposure, making clinically relevant metabolic effects unlikely under recommended therapeutic conditions. Formulations such as mometasone furoate, fluticasone propionate, fluticasone furoate, and ciclesonide exhibit pharmacokinetic characteristics associated with minimal systemic exposure because of extensive first-pass metabolism and low oral bioavailability. Although substantial pharmacokinetic differences exist between currently available INCS formulations, direct comparative evidence demonstrating clinically meaningful superiority in systemic safety outcomes remains limited. Current evidence suggests that formulation-dependent differences are clinically more relevant with respect to local tolerability, sensory characteristics, patient preference, and long-term adherence than major systemic safety outcomes. Pediatric evidence is generally reassuring, although historical concerns regarding growth suppression associated with earlier corticosteroid formulations continue to influence clinical practice. Currently available evidence supports the use of modern INCS as effective and generally well-tolerated therapeutic options across adult and pediatric populations.