Adverse Drug Reactions Reported With Cholinesterase Inhibitors: An Analysis of 16 Years of Individual Case Safety Reports From VigiBase.
BACKGROUND
No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market.


OBJECTIVE
To describe ChEI related ADRs in Alzheimer's disease (donepezil, rivastigmine, and galantamine) and characterize their seriousness as reported by national pharmacovigilance systems to VigiBase, a World Health Organization International Drug Monitoring Program database, between 1998 and 2013.


METHODS
All ChEI RELATED REPORTS: , submitted to VigiBase between 1998 and 2013 from THE FIVE CONTINENTS: were extracted. Analyses were carried out for general, serious, and nonserious ADRs.


RESULTS
A total of 18 955 reports (43 753 ADRs) FROM 58 COUNTRIES: were reported: 60.1% in women; mean age 77.4 ± 9.1 years. Most reports originated from Europe (47.6%) and North America (40.4%). Rivastigmine and donepezil were involved in MOST: reports (41.4% each). The most frequently reported ADRs were neuropsychiatric (31.4%), gastrointestinal (15.9%), general (11.9%), and cardiovascular (11.7%) disorders. During the 2006-2013 period, serious ADRs remained more often reported than nonserious ones; the most serious were neuropsychiatric (34.0%), general (14.0%), cardiovascular (12.1%), and gastrointestinal (11.6%) disorders. Medication errors were reported in 2.0% of serious cases. Death occurred in 2.3% of the reports.


CONCLUSIONS
This international pharmacovigilance study highlights the ADR pattern induced by ChEIs. Neuropsychiatric events were the most frequently reported ADRs. Serious cardiovascular events were frequently reported, suggesting that their significance has probably been previously underestimated. Given the frailty of the patients and the frequent comedications, caution is advised before introducing a ChEI.
Centre de Recherche du CHU de Québec, Canada Université Laval, Québec, Canada.
Edeltraut
E
Kröger
Service de Pharmacologie-Toxicologie-Pharmacovigilance, Limoges, France.
Marie
M
Mouls
McGill University, Montréal, Canada Centre for Clinical Epidemiology Jewish General Hospital-Lady Davis Research Institute, Montréal, Canada Donald Berman Maimonides Geriatric Centre, Montréal, Canada.
Machelle
M
Wilchesky
Utrecht University, Netherlands.
Mieke
M
Berkers
Centre de Recherche du CHU de Québec, Canada.
Pierre-Hugues
PH
Carmichael
Jeroen-Bosch Ziekenhuis, 's-Hertogenbosch, Netherlands EMGO Institute for Health and Care Research VU University Medical Center Amsterdam, Netherlands.
Rob
R
van Marum
Utrecht University, Netherlands.
Patrick
P
Souverein
Utrecht University, Netherlands University Medical Centre, Utrecht, Netherlands.
Toine
T
Egberts
Service de Pharmacologie-Toxicologie-Pharmacovigilance, Limoges, France Université de Limoges, Limoges, France marie-laure.laroche@chu-limoges.
Marie-Laure
ML
Laroche
D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy; D002800:Cholinesterase Inhibitors / Q000009:adverse effects*; D000077265:Donepezil; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology*; D005060:Europe; D005260:Female; D005702:Galantamine / Q000009:adverse effects; D006801:Humans; D007189:Indans / Q000009:adverse effects; D008297:Male; D008508:Medication Errors; D009656:North America; D060735:Pharmacovigilance; D010880:Piperidines / Q000009:adverse effects; D000068836:Rivastigmine / Q000009:adverse effects; D014944:World Health Organization
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil; D000068836:Rivastigmine
Alzheimer’s disease; VigiBase; adverse drug reactions; cholinesterase inhibitors; pharmacovigilance