What are the side effects of memantine and donepezil in elderly patients with Alzheimer’s disease?

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Last updated: February 25, 2026 • View editorial policy

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Side Effects of Memantine and Donepezil

Both donepezil and memantine are generally well-tolerated in elderly patients with Alzheimer's disease, with donepezil primarily causing gastrointestinal side effects (nausea, vomiting, diarrhea) and cardiac effects (bradycardia), while memantine causes similar gastrointestinal symptoms plus dizziness and headache, though notably memantine may actually reduce agitation rather than cause it. 1, 2

Donepezil Side Effects

Gastrointestinal Effects

  • Nausea, vomiting, and diarrhea are the most common side effects, occurring more frequently with the 10 mg dose than the 5 mg dose 2, 3
  • These gastrointestinal effects are mild and transient in most cases and can be significantly reduced by taking donepezil with food 3
  • Anorexia may also occur 2

Cardiovascular Effects

  • Bradycardia is a notable side effect, occurring in approximately 10% of patients 4
  • Physicians should exercise special care when prescribing donepezil with other drugs known to cause bradycardia 4

Neuropsychiatric Effects

  • Initial increase in agitation may occur in some patients but typically subsides after a few weeks 3, 5
  • This initial agitation should not be confused with sustained anxiety worsening 5
  • Nightmares can occur 1
  • Seizures are a theoretical risk with cholinomimetics, though seizures may also represent disease progression 3

Other Effects

  • Weakness occurs in approximately 5% of patients 4
  • Convulsions occur in approximately 4% of patients 4
  • No hepatotoxicity occurs with donepezil, unlike tacrine 3

Withdrawal Rates

  • Withdrawal rates due to adverse effects are low with donepezil 2

Memantine Side Effects

Gastrointestinal Effects

  • Nausea, vomiting, and diarrhea occur with memantine, similar to donepezil 1, 2
  • Gastrointestinal symptoms occur in approximately 4-18% of participants 2

Neurological Effects

  • Dizziness occurs in 6.1% of memantine-treated patients versus 3.9% with placebo 2
  • Headache occurs in 5.5% of memantine-treated patients versus 4.3% with placebo 2

Behavioral Effects

  • Agitation is listed as a side effect (4-18% incidence), but importantly, memantine actually shows a protective effect against agitation compared with placebo 1, 2
  • Memantine significantly reduces the frequency of agitation across multiple randomized trials 2

Cardiovascular Effects

  • Bradycardia occurs in approximately 7% of patients 4
  • Hypertension is not an expected adverse effect at standard therapeutic doses (20 mg/day oral or 28 mg extended-release) 2

Withdrawal Rates

  • Withdrawal rates due to adverse effects range from 9-12% in treatment groups compared to 7-13% in placebo groups, indicating no excess discontinuations attributable to memantine 1, 2

Combination Therapy (Donepezil + Memantine)

Safety Profile

  • The combination is well-tolerated with no significant increase in serious adverse events compared to monotherapy 2
  • Adverse event rates are similar between combination therapy and monotherapy groups 2
  • Memantine is well-tolerated both as monotherapy and when combined with donepezil 2

Specific Benefits

  • The combination shows particular benefit for behavioral symptoms and caregiver distress at 12 weeks 2
  • Patients on combination therapy show improvements in neuropsychiatric symptoms 2

Dose-Dependent Considerations

  • High-dose donepezil (10 mg/day) combined with memantine may lead to decreased sleep quality and increased risk of adverse reactions compared to low-dose donepezil (5 mg/day) with memantine 6
  • The total incidence of adverse reactions with low-dose combination (11.11%) is significantly lower than high-dose combination (27.87%) 6

Important Clinical Caveats

Monitoring and Management

  • Start donepezil at 5 mg once daily in the evening with food to minimize side effects 5
  • Increase to 10 mg daily after 4-6 weeks only if the initial dose is tolerated 5
  • Counsel patients and caregivers that any initial agitation typically resolves within the first few weeks 5

Drug Interactions

  • Both medications require special care when prescribed with other drugs that cause bradycardia or reduce the epileptogenic threshold 4
  • Conflicting evidence exists regarding interactions with cimetidine, theophylline, warfarin, and digoxin for donepezil 3

Special Populations

  • Most adverse drug events with both donepezil and memantine are associated with elderly people, even if they do not receive any other treatment 4
  • If hypertension develops in a patient on memantine, assess for progression of underlying vascular disease and potential drug-drug interactions rather than attributing it to memantine 2

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Guideline

Memantine Treatment for Moderate to Severe Alzheimer's Disease

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

3
Guideline

Donepezil Side Effects and Precautions

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

5
Guideline

Donepezil's Impact on Anxiety in Dementia Patients

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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