Objective: To summarize safety data obtained in pivotal clinical trials of galantamine.
Design: Data on adverse events from 33 clinical trials conducted with galantamine in 2,578 patients with Alzheimer’s disease (AD) and 360 subjects without AD, some of whom had renal or hepatic impairment, were entered into an integrated safety database. Trials included those conducted in the United States and international trials. An in-depth evaluation of worldwide literature and postmarketing data was also conducted.
Materials and methods: All randomized subjects who took at least one dose of trial medication were included in the safety analysis. Standard definitions for adverse events and serious adverse events, as described in the Harmonized Tripartite Guideline for Good Clinical Practice from the International Commission on Harmonization, were used. Because of the potential cholinergic side effects elicited by cholinesterase inhibitors at the neuromuscular junction, muscle weakness and associated symptoms, as well as cardiovascular safety, were fully evaluated.
Results: In patients who experienced adverse events, galantamine administration commonly led to cholinergic side effects of the sort typically seen with this class of therapeutic agents, primarily gastrointestinal effects; these symptoms typically disappeared with continuing galantamine administration. The overall rate of serious adverse events in the double-blind trials was low and was similar between galantamine- and placebo-treated patients. No unexpected adverse events emerged. The literature evaluation did not reveal any new safety or toxicity concerns. Two events potentially related to negative chronotropism, bradycardia and syncope, occurred more frequently in patients receiving galantamine 32 mg/day than in placebo patients or patients at 16 and 24 mg (the 32-mg/day dose exceeds current dosing recommendations). In drug interaction studies, potential drug interactions were identified, then incorporated into the proposed labeling.
Conclusions: The database from 3 of the initial trials of galantamine in patients with AD showed an overall high frequency of comorbidities, as expected for the elderly population included in the trials. The US Centers for Disease Control and Prevention, using data from the National Health and Nutrition Examination Survey, estimated numbers of patients using 2 or more prescription drugs as 51% among those 65 to 74 years of age and 60% in those 75 years of age and older (16% of those 75 years of age and older use 5 or more prescription drugs). The observed low frequency of serious adverse events, comparable to placebo, in the galantamine pivotal trials as well as in the postmarketing surveillance data suggests that as long as recommendations and precautions indicated in the labeling are followed, galantamine is generally safe to use in elderly patients with comorbidities and concomitant medications. Efficacy was also demonstrated in these trials, according to other reports.
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