Can I add memantine to Aricept (donepezil)?

Can You Add Memantine to Aricept (Donepezil)?

Yes, you can and should add memantine to donepezil in patients with moderate to severe Alzheimer's disease who are already on stable donepezil therapy, as this combination provides statistically significant improvements in cognition, activities of daily living, and behavioral symptoms. 1, 2, 3, 4

Evidence Supporting Combination Therapy

FDA-Approved Safety Profile

• The FDA drug label explicitly states that coadministration of memantine with donepezil does not affect the pharmacokinetics of either compound, and memantine does not affect acetylcholinesterase inhibition by donepezil 1
• In vitro studies confirm memantine does not interfere with the reversible inhibition of acetylcholinesterase by donepezil 1
• A 24-week controlled clinical study in moderate to severe Alzheimer's disease showed the adverse event profile of memantine plus donepezil was similar to donepezil alone 1

Clinical Efficacy Data

• Patients receiving combination therapy for 24 weeks experienced statistically significant improvements on the modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (mean change -2.0 vs -3.4 for placebo, P=0.03) and Severe Impairment Battery (mean change 0.9 vs -2.5 for placebo, P=0.001) 2
• Network meta-analysis of 54 trials demonstrated combination therapy was superior to placebo for cognition (MD -5.01 on ADAS-Cog; MD 9.61 on Severe Impairment Battery), global assessment (MD -2.88), daily activities (MD 13.06), and neuropsychiatric symptoms (MD -6.84) 4
• The fixed-dose combination (memantine ER 28mg/donepezil 10mg) is bioequivalent to coadministration of individual drugs and provides convenient once-daily dosing 3

Disease Stage Considerations

When to Add Memantine

• Moderate to severe Alzheimer's disease is the primary indication for adding memantine to existing donepezil therapy 5, 2, 3
• The 2022 AHA/ASA guideline suggests it may be reasonable to consider cholinesterase inhibitors for mild to moderate dementia and memantine for moderate to severe dementia after intracerebral hemorrhage 5
• Memantine shows beneficial effects on cognitive function, ADLs, and mood in moderate to severe Alzheimer disease, and improvement in cognitive function, behavior, and mood in mild to moderate vascular dementia 5

Monotherapy Considerations

• Donepezil alone demonstrates consistent efficacy across all severity levels of Alzheimer's disease and vascular dementia 5
• Memantine monotherapy shows non-significant effects in mild to moderate Alzheimer's disease (P=0.25) but significant benefits in mild to moderate vascular dementia (P<0.001) 5

Safety and Tolerability Profile

Common Adverse Events

• The combination therapy is generally well tolerated, with diarrhea, dizziness, and influenza occurring at least twice as often with memantine addition compared to placebo in donepezil-treated patients 3
• Memantine-specific side effects include headaches and dizziness, while donepezil causes nausea, diarrhea, anorexia, and cramps 5
• No significant increase in serious adverse events occurs with combination therapy compared to monotherapy 1, 3

Important Caveats

• Avoid this combination in frontotemporal dementia, as it is not recommended due to lack of evidence and potential for adverse effects, particularly in older adults 6
• The clinical relevance of statistically significant improvements remains debated, as effect sizes may not always translate to meaningful functional changes in daily life 2
• Combination therapy showed lower acceptability than monotherapy in network meta-analysis, though memantine alone was more acceptable than placebo 4

Practical Implementation

Dosing Strategy

• Start memantine at low doses and titrate gradually while maintaining stable donepezil 10mg daily 1, 3
• Target memantine dose is 28mg extended-release once daily or 10mg immediate-release twice daily 1, 3
• Consider the fixed-dose combination (Namzaric™ 28/10mg) for improved adherence in patients already stable on both medications 3

Monitoring Requirements

• Assess renal function before initiating memantine, as dose reduction is required in severe renal impairment (CrCl 5-29 mL/min) 1
• No dose adjustment needed for mild to moderate hepatic impairment, but use caution in severe hepatic impairment 1
• Regular assessment of cognitive, functional, and behavioral symptoms is essential 6