Safety Profile of Brexpiprazole Before and After FDA Approval for Agitation Associated with Alzheimer's Dementia: An FDA AEMS Pharmacovigilance Study

Background: Brexpiprazole became the first FDA-approved medication for agitation associated with Alzheimer's dementia in May 2023, expanding use into an older population vulnerable to adverse drug reactions. Real-world safety following this indication of expansion has not been well characterized. We evaluated changes in brexpiprazole adverse event reporting before and after FDA approval using the FDA Adverse Event Monitoring System (AEMS).

Methods: A retrospective pharmacovigilance study of FDA AEMS reports through 2026 Q1 was performed. Duplicate reports were removed according to FDA recommendations, and reports involving brexpiprazole as a suspected product were included. Reports were classified as pre-approval (before May 11, 2023) or post-approval (May 11, 2023 onward). Demographic, clinical, and safety variables were extracted, including age, sex, geriatric status, indication, polypharmacy, seriousness, reported outcomes, and clinically grouped MedDRA adverse reaction categories. Patient characteristics and adverse event distributions were compared between study periods using descriptive statistics and χ² or Fisher's exact tests, with prespecified subgroup analyses among older adults.

Results: Depression was the most reported indication for brexpiprazole use both before and after May 11, 2023, accounting for 45.5% and 41.1% of reports respectively, which was significantly different ( p < 0.001). Reports associated with agitation decreased from 3.3% to 2.0% (p < 0.001), while reports for Alzheimer’s diseases decreased from 4.4% to 3.0% (p < 0.001). The reports associated with schizophrenia ( p = 0.13), bipolar disorder ( p = 9.60), anxiety (p = 0.90), and unknown indications (p = 0.065) were not significantly different between the two study periods. Reported seriousness varied significantly across age groups (p < 0.001). Patients aged 75 years and older had the highest proportion of serious reports (76.8%), whereas patients younger than 18 years had the lowest (14.5%). Of the 12,591 total reports from 2015-2026, age was specified for 4,848 of them. Among the cases where age was specified, adults aged 45-64 years made up the largest percentage at 35.3%, followed by those aged 18-44 years (34.0%), 75+ years (14.1%) and 65-74 years (11.2%). Geriatric patients (65+ years) made up 9.5% of total cases (n = 1,190) with 4.4% aged 65-74 and 5.0% aged 75+ years. Pediatric patients (< 18 years) represented 2.6% of total cases. In exploratory 2023–2026 disproportionality analyses, brexpiprazole demonstrated strong reporting signals relative to the full AEMS background for tardive dyskinesia (ROR, 59.27), neuroleptic malignant syndrome (ROR, 53.72), lactation or breast discharge (ROR, 55.72), gambling (ROR, 31.39), extrapyramidal disorder (ROR, 17.15), and suicidal behavior (ROR, 9.20). Active-comparator analyses substantially attenuated several signals. Extrapyramidal-disorder reporting was lower with brexpiprazole than with aripiprazole, risperidone, quetiapine, and olanzapine, while tardive-dyskinesia reporting was similar to aripiprazole, risperidone, and olanzapine but higher than quetiapine. Falls remained disproportionately reported with brexpiprazole relative to all five selected comparators. Gambling was reported less frequently than with aripiprazole but more frequently than with the other antipsychotic comparators.

Conclusion: Despite the FDA approval of brexpiprazole for agitation associated with Alzheimer’s dementia, reporting rates for the majority of adverse reaction categories remained stable between the pre- and post-approval periods. For geriatric patients, the primary target population of this expanded indication, the safety profile showed consistent patterns in both reaction types and severity. However, advanced age remains significantly associated with higher rates of serious outcomes across the entire study period, and active-comparator analysis identified falls as the most consistent area disproportionately reported, highlighting the importance of enhanced pharmacological vigilance and optimized medical management in older adult populations.