1.1. Adults
Memantine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, is FDA-approved for use in the palliative management of moderate-to-severe Alzheimer’s disease. Glutamate, the key excitatory neurotransmitter in the central nervous system, is released into synapses when certain neurons die and activates NMDA receptors, causing over excitation, an influx of calcium ions and, ultimately, death of downstream neurons. NMDA receptor activation is thought to be one of the main causes of neurodegeneration in various types of dementia, including Alzheimer’s-associated dementia. Memantine exerts pharmacologic effects by binding to NMDA receptors thus blocking activation by glutamate. However, memantine has not been shown to delay or prevent neurodegeneration in Alzheimer’s disease patients1-4.
Memantine is available as an immediate-release (IR) tablet and solution as well as extended-release (ER) capsule. A combination product containing donepezil and memantine extended-release (Namzaric®) is also available for use in patients with moderate to severe Alzheimer’s dementia stabilized on donepezil. Acetylcholinesterase inhibitors like donepezil exert pharmacologic effects by increasing availability of intrasynaptic acetylcholine in the presence of intact cholinergic neurons. Alzheimer’s disease is associated with significant losses in cholinergic neurons and decreased concentrations of acetylcholine, a neurotransmitter significantly involved in learning and memory processes.
Recommended memantine and memantine/donepezil dosages are summarized in Table 1. Patient profiles documenting dosages exceeding these recommendations will be reviewed.
In patients with severe renal impairment (creatinine clearance 5-29 mL/min, based on Cockcroft-Gault equation), the memantine target IR dose should be reduced to 5 mg orally twice daily, while memantine ER maximum dosages should not exceed 14 mg once daily. Patients with severe renal impairment (CrCl 5-29 mL/min) stabilized on memantine 5 mg twice daily immediate-release or 14 mg daily extended-release and donepezil 10 mg daily may utilize memantine/donepezil combination therapy in doses not exceeding 14 mg/10 mg daily.
| Drug Name | Dosage Form/Strength | Titration Dose ^ | Maximum Recommended Dosage |
|---|---|---|---|
| memantine IR* (Namenda®) | 5 mg, 10 mg tablets 2 mg/ml oral solution |
Week 1: 5 mg orally once daily Week 2: 5 mg orally twice daily Week 3: 10 mg in am, 5 mg in pm Week 4: 10 mg orally twice daily |
20 mg/day, in divided doses |
| memantine ER+ (Namenda XR®) | 7 mg, 14 mg, 21 mg, 28 mg capsules | Week 1: 7 mg orally once daily Week 2: 14 mg orally once daily Week 3: 21 mg orally once daily Week 4: 28 mg orally once daily |
28 mg/day as a single dose |
Legend:
- *IR = immediate-release
- +ER = extended-release
- ^Titrate in weekly intervals to next dose, only if previous dose tolerated
| Drug Name | Dosage Form/Strength | Titration Dose^ | Maximum Recommended Dosage |
|---|---|---|---|
| memantine extended-release/donepezil (Namzaric®) | 7 mg/10 mg, 14 mg/ 10 mg, 21 mg/ 10 mg, 28 mg/ 10 mg capsules |
|
28 mg/10 mg once daily |
Legend:
- ^ Titrate in weekly intervals to next dose, only if previous dose tolerated
- * Titration schedule indicated for patients who are stabilized on donepezil and not currently on memantine
While Tariot et al. have shown beneficial improvements in cognitive and behavioral performance when memantine is administered in combination with donepezil, a recent trial by Howard and cohorts and systematic review by Tricco et al. revealed that monotherapy with memantine or donepezil was significantly better than no therapy, but combined therapy did not produce significant improvements in cognitive and functional outcomes compared to donepezil alone. Although not FDA-approved, memantine therapy has demonstrated some efficacy in treating mild-to-moderate vascular dementia and Parkinson’s disease dementia. Memantine has been approved as an extended-release formulation to simplify the dosage regimen and improve compliance/adherence.