Objective: In the US, approved therapies for mild to moderate Alzheimer's disease (AD) currently comprise three cholinesterase inhibitors (ChEIS: donepezil, galantamine, and rivastigmine), while the N-methyl-D-aspartate (NMDA) receptor antagonist memantine and the ChEI donepezil are approved for moderate to severe AD. The purpose of this study is to review the safety and tolerability of the ChEIs and memantine, based upon manufacturers' data found in prescribing information (PI) documents.
Design: Current PI documents for donepezil, galantamine, rivastigmine, and memantine were obtained from American manufacturers' websites, accessed in September, 2007. Adverse events (AEs) data for each drug versus placebo were compiled and analyzed using odds ratios.
Results: A review of PI data indicated that all three ChEIs are associated with cholinomimetic effects. Nausea (2-8%) and vomiting (1-5%) were reported across all ChEI trials as the most common reasons for trial discontinuation. Dizziness, anorexia, and diarrhea were also commonly experienced; however, a recent study suggests improved tolerability with transdermal administration of rivastigmine. The most frequently reported AEs in memantine trials were dizziness, headache, and confusion. There were no AEs that lead to trial discontinuation in more than one percent of memantine-treated patients and at a frequency greater than that observed in placebo-treated patients.
Conclusions: Data from this review suggest that gastrointestinal side effects are typical of ChEIs. Problems with rivastigmine tolerability may be reduced by transdermal administration. Memantine provides a distinctive tolerability profile. It is important to note that this study sought to overcome the lack of direct-comparison trials by analyzing the data presented by each company in its own PI material; however, caution should be exercised when comparing values obtained from different trials or trial groups.
Keywords: Alzheimer's disease; cholinesterase inhibitor; memantine; tolerability.