Can an elderly patient with dementia who is on Exelon (rivastigmine) be safely started on Rexulti (brexpiprazole), and what dosing and monitoring are recommended?

Combining Rexulti (Brexpiprazole) with Exelon (Rivastigmine) in Elderly Dementia Patients

Yes, an elderly patient with dementia on Exelon (rivastigmine) can be safely started on Rexulti (brexpiprazole) for agitation, but only after exhausting non-pharmacological interventions and with careful consideration of the FDA black box warning for increased mortality in dementia patients. 1

Critical Safety Warning

The FDA label for brexpiprazole carries a black box warning: elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death, and brexpiprazole is not approved for dementia-related psychosis 1. However, brexpiprazole received FDA approval specifically for agitation associated with dementia due to Alzheimer's disease, making it the first and only approved pharmacologic agent for this indication in the United States 2, 3.

When to Consider Adding Brexpiprazole

Brexpiprazole should only be added when:

• The patient exhibits severe agitation that is dangerous or causes significant distress 4
• Non-pharmacological interventions have been systematically attempted and documented as insufficient 4
• Reversible medical causes (pain, infections, constipation, urinary retention, metabolic disturbances) have been ruled out and treated 5, 4
• The increased mortality risk has been discussed with the patient's surrogate decision maker 4, 1

Dosing Recommendations

For agitation in dementia due to Alzheimer's disease:

• Starting dose: 0.5 mg once daily 1
• Titration: Increase to 1 mg daily after 1 week, then to 2 mg daily after another week 1
• Target dose: 2-3 mg once daily 1, 2
• Maximum dose: 3 mg once daily for this indication 1
• Administration: Once daily with or without food 1

Important: Brexpiprazole is a maintenance medication and should NOT be used "as needed" or as a PRN treatment for breakthrough agitation 2.

Dose Adjustments Required

For renal impairment (CrCl < 60 mL/minute):

• Maximum dose is 2 mg once daily 1

For moderate to severe hepatic impairment:

• Maximum dose is 2 mg once daily 1

For drug interactions:

• Brexpiprazole is a major substrate of CYP2D6 and CYP3A4 1, 2
• If the patient is on strong CYP2D6 or CYP3A4 inhibitors, administer half the recommended dosage 1
• If on both strong/moderate CYP2D6 AND strong/moderate CYP3A4 inhibitors, administer one-quarter of the recommended dosage 1

Compatibility with Rivastigmine

There are no direct contraindications to combining brexpiprazole with rivastigmine. The 2025 Lancet Healthy Longevity guidelines explicitly state that pharmacological treatment for dementia (including cholinesterase inhibitors like rivastigmine) should be continued regardless of frailty status, with careful monitoring of risks and benefits 5. Rivastigmine may offer additive benefit in rapid cognitive decliners 5.

The key consideration is that rivastigmine can produce side effects such as dizziness and weight loss 5, which may be additive with brexpiprazole's side effects. Close monitoring is essential.

Monitoring Requirements

During the first 12 weeks:

• Assess agitation severity at baseline using the Cohen-Mansfield Agitation Inventory (CMAI) or Neuropsychiatric Inventory Questionnaire (NPI-Q) 4
• Evaluate response within 4 weeks of initiating treatment using the same quantitative measure 4
• Monitor for common adverse effects: dizziness, headaches, insomnia, nasopharyngitis, somnolence, urinary tract infections 2
• Monitor for extrapyramidal symptoms, falls, weight changes, metabolic changes, and QT prolongation 4, 6
• Perform daily in-person examination to evaluate ongoing need and assess for side effects 4

Long-term monitoring:

• Clinical trials demonstrated that brexpiprazole was generally well tolerated for up to 24 weeks 7, 6
• Attempt taper within 3-6 months to determine if still needed 4
• If no clinically significant response after 4 weeks at adequate dose, taper and withdraw the medication 4

Expected Efficacy

Clinical trials found brexpiprazole 2-3 mg/day demonstrated significant improvements in agitation, with approximately a 5-point greater reduction on the CMAI total score at week 12 compared with placebo 2. Patients showed continued improvement in agitation over 24 weeks of treatment 7.

Common Pitfalls to Avoid

• Do not use brexpiprazole as a PRN medication - it is a maintenance medication requiring daily dosing 2
• Do not skip the systematic investigation of reversible medical causes before adding brexpiprazole 5, 4
• Do not continue indefinitely without reassessment - attempt taper within 3-6 months 4
• Do not ignore the black box warning - discuss mortality risk with surrogate decision makers before initiating 1, 4
• Do not forget dose adjustments for renal/hepatic impairment or drug interactions 1

Safety Profile

Over 12 weeks in pooled trials, 51.1% of participants on brexpiprazole reported at least one treatment-emergent adverse event (TEAE) compared to 45.9% on placebo 6. Headache was the only TEAE with incidence ≥5% (7.6% brexpiprazole vs. 9.3% placebo) 6. The incidences of cerebrovascular TEAEs (0.5% vs. 0.3%), cardiovascular TEAEs (3.7% vs. 2.3%), extrapyramidal symptom-related TEAEs (5.3% vs. 3.1%), and somnolence/sedation TEAEs (3.7% vs. 1.8%) were generally similar between brexpiprazole and placebo 6.

Six (0.9%) participants on brexpiprazole and one (0.3%) on placebo died during the 12-week trials; causes of death were not considered related to brexpiprazole and were generally in line with those expected in Alzheimer's disease 6.