Does Route of Administration Matter for Gepant Safety? A Comparative Disproportionality Analysis of Intranasal Zavegepant Using the FDA Adverse Event Reporting System

Background Zavegepant shares a pharmacological target with oral gepants but has distinct pharmacokinetics and a unique intranasal route. While oral safety profiles are well defined, the real-world impact of the intranasal route on systemic sparing effects remains under-investigated. This study compared the real-world safety profiles of zavegepant and oral gepants. Methods We performed a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) from April 2023 to September 2025. Zavegepant was compared with a pooled cohort of oral gepants (rimegepant, ubrogepant, atogepant) and with rimegepant individually. Robust signals of disproportionate reporting (SDRs) were defined using the Bayesian Information Component lower bound (IC025 > 0). Results The analysis revealed a clear safety dichotomy. Zavegepant was associated with a “mucosal injury signature,” showing robust SDRs for nasal discomfort (IC025 = 2.94), throat irritation (2.38), vomiting (1.11), and dysgeusia (4.44). In contrast, rimegepant showed robust SDRs for Raynaud’s phenomenon (1.53) and somnolence (0.75). The pooled oral class exhibited a systemic profile dominated by functional gastrointestinal disorders (constipation IC025 = 0.81, dyspepsia IC025 = 0.71) and vascular events. Notably, none of these systemic signals emerged as robust SDRs for zavegepant. Conclusions While associated with local toxicity, zavegepant appears to offer a potential “systemic sparing” profile, avoiding the constipating and vascular reporting signals linked to oral CGRP blockade. These findings are strictly hypothesis-generating and warrant epidemiological confirmation. Appropriate pharmacoepidemiological studies are required before formal clinical guidelines can be established.