Overall, treatment-emergent adverse events (TEAEs) during the study were higher in patients receiving 23 mg/d (74%) than those receiving 10 mg/d (64%). The most common TEAEs in the 23-mg/d and 10-mg/d groups were nausea (12% vs 3%, respectively), vomiting (9% vs 3%), and diarrhea (8% vs 5%) (Table 2).22 These gastrointestinal adverse effects were more frequent during the first month of treatment and were relatively infrequent beyond 1 month. Serious TEAEs, such as falls, urinary tract infection, pneumonia, syncope, aggression, and confusional state, were noted in a similar proportion of patients in the 23-mg/d and 10-mg/d groups; most of these were considered unrelated to treatment. No drug-related deaths occurred during the study. High-dose (23 mg/d) donepezil generally was well tolerated, with a typical ChEI safety profile but superior efficacy.
A recent commentary discussed the issue of effect size and whether a 2.2-point difference on a 100-point scale (the Severe Impairment Battery [SIB]) is clinically meaningful.23 As with all anti-dementia therapies, in any cohort some patients will gain considerably more than 2.2 points on the SIB, which is clinically significant. A 6-month trial is recommended to identify these optimal responders.
Table 2
High-dose vs standard-dose donepezil: Treatment-emergent adverse events
| Adverse event | Donepezil, 23 mg/d | Donepezil,10 mg/d |
|---|---|---|
| Nausea | 12% | 3% |
| Vomiting | 9% | 3% |
| Diarrhea | 8% | 5% |
| Anorexia | 5% | 2% |
| Dizziness | 5% | 3% |
| Weight decrease | 5% | 3% |
| Headache | 4% | 3% |
| Insomnia | 3% | 2% |
| Urinary incontinence | 3% | 1% |
| Fatigue | 2% | 1% |
| Weakness | 2% | 1% |
| Somnolence | 2% | 1% |
| Contusion | 2% | 0% |
| Source: Reference 22 | ||
High-dose memantine
Memantine is an NMDA receptor antagonist, which works on glutamate, an ubiquitous neurotransmitter in the brain that serves many functions. For reasons that are not fully understood, in AD glutamate becomes excitotoxic and causes neuronal death.
Some researchers have hypothesized that if safe and well tolerated, a memantine dose >20 mg/d may have better efficacy than a lower dose. Memantine’s manufacturer has developed an extended-release (ER), once-daily formulation of memantine, 28 mg/d, to improve adherence and possibly increase efficacy.10,11 Because of memantine ER’s relatively slow absorption rate and longer median Tmax, of 12 hours, there is minimal fluctuation in plasma levels during steady-state dosing intervals compared with the immediate-release (IR) formulation.10
In a phase I study of 24 healthy volunteers that investigated the safety, tolerability, and pharmacokinetics of memantine ER, 28 mg/d, TEAEs were mild; the most common were headache, somnolence, and dizziness.10 During memantine treatment, there were no serious adverse events, potential significant changes in patients’ vital signs, or deaths.
Memantine ER plus ChEI. A multicenter, multinational, randomized, double-blind study compared memantine ER, 28 mg/d, and placebo in patients with moderate to severe AD (MMSE: 3 to 14).11 All patients were receiving concurrent, stable ChEI treatment (donepezil, rivastigmine, or galantamine) for ≥3 months before the study. Patients treated with memantine ER, 28 mg/d, and ChEI (n = 342) showed a significant improvement compared with the placebo/ChEI group (n = 335) in cognition and global functioning. Patients receiving memantine/ChEI also showed statistically significant benefits on behavior and verbal fluency testing compared with patients receiving placebo/ChEI. Memantine was well tolerated; most adverse events were mild or moderate. The most common adverse events in the memantine/ChEI group that occurred at a higher rate relative to the placebo/ChEI group were headache (5.6% vs 5.1%, respectively), diarrhea (5.0% vs 3.9%), and dizziness (4.7% vs 1.5%). There were no deaths related to memantine (Table 3).11
Memantine ER, 28 mg/d, may be tolerated better than the IR formulation because of less plasma level fluctuation during the steady-state dosing interval. Also, memantine ER, 28 mg/d, may offer better efficacy over memantine IR, 20 mg/d, because of dose-dependent cognitive, global, and behavioral effects. In addition, once-daily dosing of memantine ER may improve adherence compared with the IR formulation.24
In patients with severe renal impairment, dosage of memantine IR should be reduced from 20 mg/d to 10 mg/d.25 However, there is no available information regarding the dosing, safety, and tolerability of memantine ER, 28 mg/d, in patients with renal disease.
Table3
High-dose memantine: Treatment-emergent adverse eventsa
| Adverse event | Placebo (n = 335) | Memantine ER (n = 341) |
|---|---|---|
| Any TEAE | 214 (63.9%) | 214 (62.8%) |
| Fall | 26 (7.8%) | 19 (5.6%) |
| Urinary tract infection | 24 (7.2%) | 19 (5.6%) |
| Headache | 17 (5.1%) | 19 (5.6%) |
| Diarrhea | 13 (3.9%) | 17 (5.0%) |
| Dizziness | 5 (1.5%) | 16 (4.7%) |
| Influenza | 9 (2.7%) | 15 (4.4%) |
| Insomnia | 16 (4.8%) | 14 (4.1%) |
| Agitation | 15 (4.5%) | 14 (4.1%) |
| Hypertension | 8 (2.4%) | 13 (3.8%) |
| Anxiety | 9 (2.7%) | 12 (3.5%) |
| Depression | 5 (1.5%) | 11 (3.2%) |
| Weight increased | 3 (0.9%) | 11 (3.2%) |
| Constipation | 4 (1.2%) | 10 (2.9%) |
| Somnolence | 4 (1.2%) | 10 (2.9%) |
| Back pain | 2 (0.6%) | 9 (2.6%) |
| Aggression | 5 (1.5%) | 8 (2.3%) |
| Hypotension | 5 (1.5%) | 7 (2.1%) |
| Vomiting | 4 (1.2%) | 7 (2.1%) |
| Abdominal pain | 2 (0.6%) | 7 (2.1%) |
| Nasopharyngitis | 10 (3.0%) | 6 (1.8%) |
| Confusional state | 7 (2.1%) | 6 (1.8%) |
| Weight decreased | 11 (3.3%) | 5 (1.5%) |
| Nausea | 7 (2.1%) | 5 (1.5%) |
| Irritability | 8 (2.4%) | 4 (1.2%) |
| Cough | 8 (2.4%) | 3 (0.9%) |
| aData [n (%)] include all adverse events experienced by ≥2% patients in either group (safety population). Adverse events that were experienced at twice the rate in 1 group compared with the other are indicated by bold type ER: extended-release (28 mg); TEAE: treatment-emergent adverse event Source: Reference 11 | ||