Oral Second-Generation H1-Antihistamine Regimens for Allergic Rhinitis: Systematic Review and Network Meta-Analysis of Effects and Estimability.

Background/Objectives: Comparative effects of oral second-generation H1-antihistamines vary by rhinitis category, outcome, and treatment period. We assessed evidence structure, estimability, and differentiation among regimens. Methods: PubMed, Embase, Web of Science Core Collection, CENTRAL, WHO ICTRP, ClinicalTrials.gov, and the EU Clinical Trials Register were searched on 1-3 July 2026 for records through 30 June 2026. Eligible studies were natural-exposure randomized trials. Continuous outcomes were analyzed using covariance-aware generalized least squares, and binary harms were analyzed using Bayesian arm-level models. RoB 2, CINeMA, and ROB-MEN were applied in duplicate. Registration was retrospective. Results: Sixty-one reports generated 66 report-randomization entries from 64 cohorts (34,831 participants); 35 model-ready randomizations informed nine structures. In seasonal allergic rhinitis, six of seven TNSS estimates, two of three ocular estimates, and four RQLQ estimates favored active treatment. Any-adverse-event estimates were imprecise. Under the primary prior, cetirizine yielded a WDAE OR of 0.25 (95% CrI 0.08-0.66), but predictive classification was prior-sensitive. Of 34 continuous active-active comparisons, seven were directly informed and 27 indirect-only. All 147 estimable binary active-active contrasts were reported as secondary derivations: 141 CrIs included one and six excluded one, all indirect-only and not formally appraised with CINeMA. Six of 14 regimen-level nodes contributed only to tolerability structures, precluding balanced regimen-specific benefit-harm assessment. All 89 estimable comparisons within the defined CINeMA appraisal scope were rated very low; two non-estimable effects were not evaluable. Conclusions: Predominantly placebo-anchored and sparse evidence established neither a reliable regimen hierarchy nor therapeutic equivalence. Findings were hypothesis-generating, and somnolence remained an evidence gap. No external funding supported conduct; NEXUS PEOPLE, S.L. funded the APC. OSF registration was retrospective: doi:10.17605/OSF.IO/DPT5N.