What is the recommended dosing regimen of memantine for moderate to severe Alzheimer’s disease, including adjustments for impaired renal function, and what are its common adverse effects?

Memantine Dosing and Clinical Profile for Moderate to Severe Alzheimer's Disease

Standard Dosing Regimen

Memantine should be initiated at 5 mg once daily and titrated weekly in 5 mg increments to the target dose of 20 mg/day (10 mg twice daily), with the option of 28 mg once-daily extended-release formulation for improved adherence. 1

Titration Schedule

• Week 1: 5 mg once daily 1
• Week 2: 10 mg/day (5 mg twice daily) 1
• Week 3: 15 mg/day (5 mg and 10 mg as separate doses) 1
• Week 4 and beyond: 20 mg/day (10 mg twice daily) - the dose proven effective in controlled trials 1
• Memantine can be taken with or without food 1
• If doses are missed for several days, retitration from lower doses may be necessary 1

Extended-Release Alternative

• Memantine ER 28 mg once daily provides higher total daily exposure than standard IR formulation and may improve adherence 2
• Capsules can be opened and sprinkled on applesauce for patients with swallowing difficulties 2

Renal Dose Adjustments

For severe renal impairment (creatinine clearance 5-29 mL/min), reduce the target dose to 5 mg twice daily (10 mg total daily). 1

• No adjustment needed for mild to moderate renal impairment 1
• Conditions that raise urine pH decrease urinary elimination and increase plasma levels, requiring monitoring 1

Hepatic Considerations

• Administer with caution in severe hepatic impairment, though specific dose adjustments are not provided 1

Common Adverse Effects

Memantine is well-tolerated with withdrawal rates of 7-10% due to adverse events, comparable to placebo rates of 11-13%. 3, 1

Most Frequent Side Effects

• Gastrointestinal symptoms: Nausea, diarrhea (4-18% of patients) 4, 1, 2
• Dizziness: 6.1% with memantine vs 3.9% with placebo 5
• Headache: 5.5% vs 4.3% with placebo 5, 2
• Agitation: Notably, memantine shows a protective effect against agitation compared to placebo 4, 3, 5

Important Safety Notes

• No individual adverse reaction led to discontinuation in ≥1% of patients at rates greater than placebo 1
• Memantine is well-tolerated both as monotherapy and in combination with cholinesterase inhibitors 3, 6
• Hypertension is not an expected adverse effect at therapeutic doses 3

Clinical Efficacy Context

Memantine demonstrates statistically significant improvements in cognition (SIB), global assessment (CIBIC-plus), activities of daily living, and behavioral symptoms in moderate to severe Alzheimer's disease. 4, 3, 6

Combination Therapy Benefits

• Adding memantine to stable donepezil therapy provides superior outcomes compared to donepezil alone 3, 6
• Combination therapy reduces marked clinical worsening by more than half (8.7% vs 20.4% with donepezil alone) 7
• Particularly effective for neuropsychiatric symptoms and caregiver distress at 12 weeks 4, 3

Magnitude of Effect

• Cognitive improvement averages 0.9 to 2.15 points on validated scales 5, 6
• Benefits are sustained and increase over long-term treatment (>1 year) 8
• May delay nursing home placement when initiated early 8

Treatment Duration and Discontinuation Considerations

• Consider discontinuation if clinically meaningful worsening occurs over 6 months without other contributing factors 3
• For patients with neuropsychiatric symptoms showing meaningful reduction, continue memantine even with cognitive decline 3
• When discontinuing, reduce dose by 50% every 4 weeks until reaching initial starting dose 3