Psychiatry - November 2008 - (Page 28)

confusion. There were no AEs that lead to trial discontinuation in more than one percent of memantinetreated 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 directcomparison 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. INTRODUCTION In the United States, the cholinesterase inhibitors (ChEIs) donepezil,1,2 galantamine,3,4 and rivastigmine5–7 are approved for the treatment of mild to moderate Alzheimer’s disease (AD), while donepezil8–11 and memantine,12,13 an uncompetitive antagonist of Nmethyl-D-aspartate receptors, are indicated for patients in moderate to severe stages of the disease. All four drugs are administered orally; in addition, rivastigmine has also earned a Food and Drug Administration (FDA) approval for transdermal application.6 The ChEIs differ slightly from each other in their pharmacological profiles, which can conceivably translate into differences in drug tolerability.14 The mechanism of action of memantine is unrelated to that of the ChEIs,15 which provides for a distinctive safety and tolerability profile. Considering the variety of therapeutic options, and the fact that a typical patient with AD is also likely to receive concomitant medications for both related and unrelated illnesses,16,17 we believed it is useful to provide physicians with a compilation of safety and tolerability data for each anti-AD drug, based on the prescribing information documents provided by manufacturers. METHODS Current US prescribing information (PI) documents for donepezil,1 galantamine,3 rivastigmine,5,6 and memantine12 were obtained from American manufacturers’ websites in September 2007.18–22 The information contained in these documents was accepted as presented, and the data were not reconciled with individually published trials or meta-analyses. Quantitative data about adverse events (AEs) from each PI document were reviewed. In addition, the odds of each AE occurring in the active versus placebo group for each drug were compared by means of odds ratios (ORs),23 which are commonly used to assess the odds of experiencing a particular AE.2,4,13,24 Since the numbers of patients who experienced a particular AE were not given exactly, but provided in form of percentages rounded to the closest integer, we calculated the ORs using m-values, derived through multiplying available percentages by the total number of patients (e.g., the m-value of an AE that has been observed in 3% of the total of 1000 patients would be taken to be 30 [0.03 x 1000], although, due to the rounding, the actual number could have been as low as 25 and as high as 34). Statistical analyses were based on a simple linear logistic regression model, with treatment as the only explanatory variable. Descriptive safety data are presented without statistical analysis. RESULTS All of the information presented in this manuscript was taken directly from the PI documents for each drug, with the exception of the odds TABLE 1. AEs leading to discontinuation in donepezil clinical trials (%)* MILD TO MODERATE AD ADVERSE EVENT Placebo N/A (n=355) Any AE Anorexia Diarrhea Nausea Urinary tract infection Vomiting 5 0 1 <1 Donepezil 5mg/day (n=350) 5 <1 1 <1 Donepezil 10mg/day (n=315) 13 3 3 2 Placebo N/A N/A 7 1 0 <1 1 † SEVERE AD Donepezil 10mg/day N/A† 12 2 2 2 2 - *The most frequent AEs leading to discontinuation in at least 2% of donepezil-treated patients and at least twice the frequency seen in placebo-treated patients. †N/A: Information on the total number of patients is not provided in the PI document. Hyphens indicate that data were not reported in the PI documents (presumably below threshold cutoff). 28 Psychiatry 2008 [ N O V E M B E R ]

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Psychiatry - November 2008 Editor's Message Editorial Advisory Board Contents PsychRx Letters to the Editor Measuring Adverse Events in Psychiatry Nonsuicidal Self Injury in Adolescents Relative Tolerability of Alzheimer's Disease Treatments Biracial Identity Development and Recommendations in Therapy Depression and Cardiovascular Disease: Just an Urban Legend? Three Risk Management Basics Journal Watch Classified Advertising Information for Authors

Psychiatry - November 2008

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