Comparative Efficacy and Safety of First-Versus Second- Generation Over-the-Counter Antihistamines: A Review

Background: Oral H1-antihistamines remain among the most frequently purchased over- the-counter (OTC) medications worldwide for allergic and non-allergic conditions. Despite evolving clinical guidelines favoring newer agents, sedating first-generation antihistamines continue to be widely used. Objective: To critically evaluate and compare the clinical efficacy and safety profiles of first- and second-generation OTC H1-antihistamines, with special consideration of vulnerable populations and real-world self-medication patterns. Methods: This narrative review integrates findings from randomized clinical trials, systematic reviews, pharmacovigilance databases, observational cohort studies, and professional guideline statements. Outcomes assessed include symptom control in allergic rhinitis and chronic urticaria, effectiveness in viral upper respiratory infections, central nervous system (CNS) and cardiovascular safety, fall risk in older adults, pediatricsafety, and public health implications of OTC access. Results: ‘For allergic rhinitis and chronic urticaria, second-generation antihistamines provide symptom relief comparable to or greater than first-generation agents, with substantially fewer adverse effects. First-generation drugs demonstrate modest benefit in common cold–related rhinorrhea and sneezing but are consistently associated with sedation, psychomotor impairment, anticholinergic burden, delirium risk, falls, and cardiovascular concerns in high-risk groups. Modern second-generation agents exhibit minimal CNS penetration and strong cardiac safety at recommended doses, although post- marketing surveillance continues to monitor rare adverse signals associated with specific molecules. Conclusion: In routine allergy management, second-generation OTC antihistamines represent the preferred first-line option due to a more favorable balance between efficacy and safety. First-generation agents should be restricted to short-term, carefully selected circumstances and avoided in populations at increased risk of adverse outcomes.