Can Patients Take Memantine and Aricept (Donepezil) Together?
Yes, patients can and should take memantine and donepezil together for moderate to severe Alzheimer's disease, as combination therapy provides superior clinical outcomes compared to either medication alone. 1
Evidence for Combination Therapy
Efficacy Benefits
The combination of memantine and donepezil demonstrates statistically significant and clinically meaningful improvements across multiple domains:
Cognition: Patients receiving combination therapy show significant improvements on cognitive measures (Severe Impairment Battery and ADAS-cog) compared to donepezil alone (P < 0.0001 for moderate-to-severe AD; P = 0.008 for moderate AD). 2
Global Function: Combination therapy produces significant benefits on global clinical status measures (CIBIC-plus) in patients with Alzheimer's disease. 3
Activities of Daily Living: The combination significantly improves functional capacity on ADL scales (P = 0.02 for moderate-to-severe; P = 0.04 for moderate AD). 2
Behavioral Symptoms: Patients on combination therapy show improvements in neuropsychiatric symptoms and reduced caregiver distress, particularly at 12 weeks of treatment. 3
Clinical Trial Evidence
Multiple randomized controlled trials specifically evaluated patients receiving donepezil who were then randomized to add either memantine or placebo:
In a 24-week trial, all participants received donepezil for at least 6 months before randomization, demonstrating that adding memantine to stable donepezil therapy provides additional benefit. 3
The effect sizes for combination therapy are clinically meaningful, with standardized mean differences of 0.36 for cognition, 0.21 for function, and 0.23 for global status in moderate-to-severe AD. 2
Prevention of Clinical Worsening
Combination therapy substantially reduces the risk of marked clinical deterioration:
Significantly fewer patients on memantine plus donepezil experienced concurrent worsening across cognition, function, and global status compared to donepezil alone (8.7% vs 20.4%, P = 0.0002). 2
For moderate AD specifically, only 5.9% showed marked worsening with combination therapy versus 15.0% with donepezil alone (P = 0.006). 2
Safety Profile
Tolerability
The combination of memantine and donepezil is well-tolerated with no significant increase in serious adverse events: 1
Adverse event rates are similar between combination therapy and monotherapy groups. 2
Common side effects include diarrhea, dizziness, and influenza, occurring at manageable frequencies. 4
Withdrawal rates due to adverse events range from 8-13% with combination therapy, comparable to placebo groups (5-17%). 3
Important Safety Caveat
The FDA label notes that animal studies showed increased neurodegeneration with memantine-donepezil combination compared to memantine alone, but the relevance of these findings to humans is unknown. 5, 6 Despite this preclinical finding, extensive clinical trial data in humans demonstrates safety and efficacy of the combination.
Dosing Considerations
Low-dose approach: Donepezil 5 mg/day combined with memantine may provide similar efficacy to higher doses with better tolerability, fewer adverse reactions (11.11% vs 27.87%), and better quality of life outcomes. 7
Standard dosing: Donepezil 10 mg/day with memantine 20 mg/day (or 28 mg extended-release) is the most studied regimen. 4, 2
Fixed-dose combination: A once-daily memantine ER 28 mg/donepezil 10 mg formulation is available and bioequivalent to separate administration. 4
Clinical Application
Use combination therapy when:
- Patients have moderate to severe Alzheimer's disease (MMSE < 20). 2
- Patients are already stable on donepezil therapy. 3, 8
- The goal is to maximize cognitive, functional, and behavioral benefits while minimizing clinical deterioration. 1
The American Academy of Neurology recommends combination therapy for moderate to severe Alzheimer's disease based on significant improvements in cognition, daily functioning, and behavioral symptoms. 1