Amenamevir inhibitor indicated for herpes zoster, has practical advantages in routine care. However, neuropsychiatric safety in real-world settings remains incompletely characterized. To examine whether amenamevir is associated with disproportionate reporting of noninfectious encephalopathy/delirium in a national spontaneous reporting system, a retrospective pharmacovigilance study of adult reports in the Japanese Adverse Drug Event Report database was conducted. Signals were evaluated using the Standard MedDRA Query for noninfectious encephalopathy/delirium analyzed hierarchically as broad (higher sensitivity) and narrow (higher specificity). Disproportionality metrics included reporting odds ratio (ROR), proportional reporting ratio, and empirical Bayes geometric mean with pre-specified thresholds. Among 695,635 adult reports, 358 involved amenamevir. For the broad definition, amenamevir was associated with disproportionate reporting for brain-related adverse events. For the narrow definition, signals were attenuated (ROR 2.15; 95% confidence interval, CI: 1.02–4.55) and lower bound of the 95% CI of empirical Bayes geometric mean (EB05) did not exceed 2. This design disentangles heterogeneity at the preferred term level, indicating that wider signals were largely attributable to mixed phenotypes, whereas specificity and sample size materially modulated apparent signal strength. In the Japanese Adverse Drug Event Report database, amenamevir demonstrated a definition-dependent association—robust under the broad phenotype and attenuated under the narrow phenotype—a pattern that is consistent with the trade-off between sensitivity and specificity in signal detection. Because spontaneous-report analyses are inherently hypothesis-generating rather than causal, the current findings support the importance of clinical vigilance for neuropsychiatric events and highlight the need for further research to verify the observed relationships.
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