1. Dosage
1.1. Adults
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. Acetylcholinesterase inhibitors (ACIs) exert pharmacologic effects by increasing availability of intrasynaptic acetylcholine in the presence of intact cholinergic neurons. All available ACIs are FDA-approved in adults for the management of mild to moderate Alzheimer’s dementia, while donepezil is also FDA-approved for management of severe Alzheimer’s disease. Additionally, rivastigmine (Exelon) is FDA-approved for use in mild-to-moderate dementia associated with Parkinson’s disease.
A combination product containing donepezil and memantine extended-release (Namzaric) is also FDA-approved for use in patients with moderate to severe Alzheimer’s dementia stabilized on donepezil and memantine. Memantine, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, exerts pharmacologic effects by blocking glutamate activity, the key excitatory neurotransmitter in the central nervous system. Glutamate 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. ACI monotherapy and combination therapy recommended dosages are summarized in Table 1 and Table 2, respectively. Dosages exceeding these recommendations will be reviewed.
| Drug Name | Dosage Form and Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| donepezil (Adlarity®) | transdermal patch (5 mg/24 hours, 10 mg/24 hours) | Mild to severe Alzheimer’s dementia | One 10 mg/24 hours transdermal patch weekly (10 mg/day) |
| donepezil (Aricept, generics) | tablets (5 mg, 10 mg, 23 mg) | mild to moderate Alzheimer’s dementia | 10 mg/day, as a single dose |
| orally disintegrating tablets (5 mg, 10 mg) | 10 mg/day, as a single dose | ||
| moderate to severe Alzheimer’s dementia | 23 mg/day, as a single dose | ||
| galantamine (Razadyne, Razadyne ER, generics) |
immediate-release tablets (4 mg, 8 mg, 12 mg) oral solution (4 mg/ml) |
mild to moderate Alzheimer’s dementia | 24 mg/day, in 2 divided doses |
| extended-release capsules (8 mg, 16 mg, 24 mg) | mild to moderate Alzheimer’s dementia | 24 mg/day once daily | |
| rivastigmine (Exelon, generics) | immediate-release capsules (1.5 mg, 3 mg, 4.5 mg, 6 mg) | mild to moderate Alzheimer’s dementia | 12 mg/day, in 2 divided doses |
| mild/ moderate Parkinson’s disease dementia | 12 mg/day, in 2 divided doses | ||
| transdermal (extended-release) patch (4.6 mg/24 h, 9.5 mg/24 h, 13.3 mg/24 h) | Mild to severe Alzheimer’s dementia | 13.3 mg/24 h | |
| mild/ moderate Parkinson’s disease dementia | 13.3 mg/24 h |
| Treatment Indication | Drug Name | Dosage Form and Strength | Maximum Recommended Dosage |
|---|---|---|---|
| moderate to severe Alzheimer’s dementia in patients stabilized on donepezil alone or memantine and donepezil | memantine extended-release/donepezil (Namzaric) | capsules (7 mg/10 mg, 14 mg/10 mg, 21 mg/10 mg, 28 mg/10 mg) | 28 mg/10 mg once daily |
Although not FDA-approved, ACIs have also been evaluated for use in vascular dementia, dementia with Lewy bodies, post stroke aphasia, and memory improvement in multiple sclerosis patients11-14 .
1.1.1. Renal Impairment
Patients prescribed galantamine with moderate renal impairment [creatinine clearance (CrCl) 9-59 ml/min] should have doses titrated cautiously; dosages should not exceed 16 mg daily. Galantamine is not recommended for use in patients with severe renal impairment (CrCl less than 9 ml/min)1,2,5-7 .
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 or donepezil 10 mg once daily without memantine may utilize memantine/donepezil combination therapy in doses not exceeding 14 mg/10 mg daily1,2,10.
1.2. Pediatrics
ACIs and memantine/donepezil combination therapy are not recommended for use in children, as adequate, well-controlled clinical trials have not documented safety and efficacy of these agents for any disease state in the pediatric population1-10.