Initial Memantine Dosing for Patients Already on Donepezil
For geriatric patients with moderate to severe Alzheimer's disease already on stable donepezil therapy, initiate memantine at 5 mg once daily and titrate by 5 mg increments weekly to the target maintenance dose of 10 mg twice daily (20 mg/day total). 1
Standard Titration Schedule
The FDA-approved dosing regimen follows a structured weekly escalation 1:
- Week 1: 5 mg once daily
- Week 2: 5 mg twice daily (10 mg/day total)
- Week 3: 10 mg in morning, 5 mg in evening (15 mg/day total)
- Week 4 and beyond: 10 mg twice daily (20 mg/day total)
A minimum of 1 week should be observed at each dose level before advancing to the next increment 1. This gradual titration minimizes adverse effects while achieving therapeutic levels.
Evidence Supporting Combination Therapy
The landmark trial establishing this approach demonstrated that adding memantine 20 mg/day to stable donepezil therapy in moderate to severe AD patients produced statistically significant improvements in cognition (SIB scores), activities of daily living (ADCS-ADL19), global outcomes (CIBIC-Plus), and behavioral symptoms compared to donepezil alone 2. This combination represents a rational therapeutic strategy targeting two distinct neurotransmitter systems—NMDA receptor antagonism and cholinesterase inhibition 3.
Multiple guidelines explicitly recommend this combination approach for patients with moderate to severe AD who continue to decline on cholinesterase inhibitor monotherapy 4. The American College of Physicians supports memantine at 20 mg/day dosing for this population 5.
Dose Adjustments for Renal Impairment
Critical caveat: For patients with severe renal impairment (estimated creatinine clearance ≈30 mL/min), reduce the target dose to 5 mg twice daily (10 mg/day total) rather than the standard 20 mg/day 5, 1. Memantine is primarily renally eliminated, and conditions that raise urine pH can further decrease urinary elimination, resulting in increased plasma levels 1.
Safety and Tolerability Profile
Combination therapy with memantine and donepezil demonstrates excellent tolerability 2, 3:
- Treatment discontinuation rates due to adverse events were actually lower with memantine addition (7.4%) compared to placebo (12.4%) in the pivotal trial 2
- A postmarketing surveillance study of 158 patients found 98% tolerated the combination well over 4 months, with no serious adverse drug reactions reported 3
- Most common adverse effects (≥5%) include dizziness, headache, confusion, and constipation 1
Recent evidence suggests that when combining with memantine, lower donepezil doses (5 mg/day) may provide similar efficacy to higher doses (10 mg/day) while reducing adverse reactions (11.11% vs 27.87%) and improving sleep quality 6. However, this should only be considered if the patient is not already stable on donepezil 10 mg/day.
Timeline for Assessment
Allow 6-12 months of combination therapy before fully assessing treatment response 4. Benefits typically emerge within 3 months, but some patients require longer observation periods 4. Use comprehensive assessments including physician global assessment, caregiver reports, and functional/behavioral measures rather than relying solely on brief cognitive tests 7.
Common Pitfalls to Avoid
- Do not start memantine at full dose: The 20 mg/day target must be reached through gradual weekly titration to minimize side effects 1
- Do not discontinue donepezil when adding memantine: Continuing the cholinesterase inhibitor provides additive benefit; memantine alone is inferior to combination therapy 4
- Do not underdose memantine: The full 20 mg/day dose (or 10 mg/day in severe renal impairment) is necessary for optimal therapeutic effect 5, 4
- Do not expect dramatic improvement: Set realistic expectations—the goal is slowing decline and stabilization, not reversal of symptoms 4, 7