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.