Neuropsychiatric Adverse Events Associated with Acyclovir, Valacyclovir, and Famciclovir: A Pharmacovigilance Study Using the FDA Adverse Event Reporting System (FAERS)

Background/Objectives: Acyclovir, valacyclovir, and famciclovir are widely used antiviral agents, but comparative data on neuropsychiatric adverse event reporting are limited. This study’s aim was to compare neuropsychiatric adverse event reporting among acyclovir, valacyclovir, and famciclovir and to evaluate the influence of demographic and temporal factors. Methods: A retrospective pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System (FAERS, Q4 2003–Q3 2025). Unique reports in which acyclovir, valacyclovir, or famciclovir was the primary suspect drug were analyzed. Disproportionality was assessed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC). Between-drug differences in the proportion of neuropsychiatric reports were examined using multivariable logistic regression adjusted for age, sex, region (with Japan as a separate category), and reporting year, together with overlap and inverse probability weighting and sensitivity analyses. A narrow clinical phenotype (encephalopathy/neurotoxicity, altered consciousness/delirium, hallucination/psychosis, and seizure) was the primary outcome, and a broad System Organ Class (SOC)-based definition was a secondary outcome. Results: Of 16,071 unique primary-suspect reports (acyclovir, 6641; valacyclovir, 8980; famciclovir, 450), 4942 (30.8%) contained at least one nervous system or psychiatric Preferred Term (broad definition), and 2471 (15.4%) contained the narrow phenotype. All three drugs showed strong disproportionality signals for encephalopathy-related terms (e.g., toxic encephalopathy ROR 71.63 for acyclovir and 123.39 for valacyclovir; neurotoxicity ROR 55.74 and 48.57, respectively). For the primary narrow phenotype, reporting did not differ between valacyclovir and acyclovir (aOR 1.06, 95% CI 0.96–1.17) and was not higher for famciclovir (aOR 0.72, 95% CI 0.54–0.96; adjusted p = 0.055). Only with the secondary broad definition was the adjusted proportion of neuropsychiatric reports higher for valacyclovir (aOR 1.15, 95% CI 1.07–1.24) and famciclovir (aOR 1.41, 95% CI 1.14–1.75) than for acyclovir. The valacyclovir difference was confined to reports from Japan (aOR 1.88, 95% CI 1.52–2.33) and was absent elsewhere (aOR 1.06, 95% CI 0.98–1.15; interaction p < 0.001), whereas the famciclovir excess reflected non-specific terms such as dizziness and headache. Older age was independently associated with neuropsychiatric reporting (narrow phenotype: aOR 2.52, 95% CI 2.24–2.82). Conclusions: Acyclovir, valacyclovir, and famciclovir share a consistent, encephalopathy-dominated neuropsychiatric reporting signal in FAERS. Apparent between-drug differences depended on the case definition and on reports from Japan and should not be interpreted as differences in neurotoxic risk. Clinical vigilance for encephalopathy is warranted with all three agents, particularly in older patients, while recognizing that FAERS data cannot establish causality or absolute risk.