Is it appropriate to use Rexulti (brexpiprazole) for agitation in a patient with dementia, given the increased risk of mortality?

The Pharmacist's Concern is Valid: Rexulti Carries a Black Box Warning for Increased Mortality in Dementia Patients

Rexulti (brexpiprazole) does carry an FDA black box warning for increased mortality in elderly patients with dementia-related psychosis, BUT it is specifically FDA-approved for agitation associated with dementia due to Alzheimer's disease at doses of 2-3 mg/day 1. This creates a nuanced clinical situation that requires careful understanding.

Understanding the Black Box Warning vs. FDA Approval

The FDA label explicitly states: "Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease" 1.

Key distinction: Rexulti is NOT approved for general dementia-related psychosis, but IS specifically approved for agitation in Alzheimer's dementia. This represents a carefully considered risk-benefit analysis by the FDA based on clinical trial data.

When Rexulti Use is Appropriate

According to APA guidelines, antipsychotic use in dementia should only occur when 2:

• Symptoms are severe, dangerous, and/or cause significant distress to the patient
• Nonpharmacological interventions have been reviewed and found insufficient
• Risk-benefit discussion has occurred with the patient (if feasible) and surrogate decision-maker
• Treatment plan is documented and person-centered

Brexpiprazole should be initiated at low doses (starting 0.5-1 mg/day) and titrated to the effective dose of 2-3 mg/day 1.

The Evidence Supporting Rexulti's Approval

Clinical trials demonstrated that brexpiprazole 2-3 mg/day produced:

• Statistically significant reduction in agitation (approximately 4.5-5 point greater improvement on CMAI scores versus placebo) 3
• Generally well-tolerated safety profile with adverse event rates of 51.1% vs 45.9% for placebo over 12 weeks 4
• Low mortality rates: 6 deaths (0.9%) on brexpiprazole vs 1 (0.3%) on placebo over 12 weeks; causes were not considered treatment-related and were consistent with expected Alzheimer's disease mortality 4

Critical Safety Considerations

Mortality risk context: While the class carries increased mortality risk, the actual trial data showed:

• Deaths occurred at rates expected in Alzheimer's populations
• No deaths were attributed directly to brexpiprazole treatment
• The 24-week extension trial had zero deaths 4

Common adverse effects (incidence ≥5%): headache (7.6%), with generally low rates of:

• Cerebrovascular events (0.5%)
• Extrapyramidal symptoms (5.3%)
• Somnolence/sedation (3.7%)
• Cardiovascular events (3.7%) 4

Clinical Decision Algorithm

Use Rexulti when:

1. Patient has confirmed Alzheimer's dementia with severe, dangerous agitation
2. Nonpharmacological approaches have been attempted and documented as insufficient
3. Risk-benefit discussion documented with surrogate decision-maker
4. No contraindications (e.g., severe hepatic/renal impairment without dose adjustment)
5. Monitoring plan established for response and adverse effects

Do NOT use Rexulti when:

1. Agitation is mild or manageable with nonpharmacological approaches
2. Dementia is not due to Alzheimer's disease (off-label, higher risk)
3. Patient has dementia-related psychosis without significant agitation
4. Adequate risk-benefit discussion has not occurred

Addressing the Pharmacist's Refusal

The pharmacist should dispense Rexulti if:

• The indication is specifically for agitation in Alzheimer's dementia (not general dementia-related psychosis)
• The prescription is within FDA-approved dosing (2-3 mg/day maintenance)
• Documentation suggests appropriate use per guidelines

The prescriber should:

• Clearly document the indication as "agitation associated with dementia due to Alzheimer's disease"
• Document that nonpharmacological approaches were attempted
• Document risk-benefit discussion with family/surrogate
• Provide this context to the pharmacist if questioned

Monitoring Requirements

Per APA guidelines 2:

• Assess response with quantitative measures (e.g., CMAI, CGI-S)
• If no response after 4 weeks at adequate dose: taper and discontinue
• If significant side effects occur: review risk-benefit and consider tapering
• If positive response: discuss ongoing need with family, as continued exposure carries risks

Common Pitfalls to Avoid

1. Using Rexulti "as needed": This is a maintenance medication requiring daily dosing, not PRN use 5
2. Ignoring drug interactions: Major substrate of CYP2D6 and CYP3A4; dose adjustment required with strong inhibitors 1
3. Failing to adjust for renal/hepatic impairment: Maximum 2 mg/day for CrCl <60 mL/min or moderate-severe hepatic impairment 1
4. Not documenting the specific indication: Generic "dementia" is insufficient; must specify "agitation in Alzheimer's dementia"

Bottom line: The black box warning reflects class-wide concerns about antipsychotic use in dementia, but Rexulti's specific FDA approval for Alzheimer's-related agitation represents a determination that benefits outweigh risks in this narrow indication when used appropriately. The pharmacist's concern demonstrates appropriate vigilance, but refusal to dispense for the FDA-approved indication with proper documentation would be inappropriate.