Precautions

Important Precautions Precaution on Special Populations Precaution Concerning Dosage & Administration (N/A) Precaution Concerning Use (N/A)

Important Precautions

Anesthesia

Donepezil hydrochloride (ARICEPT®) 23 mg tablets, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

Nausea and Vomiting

Donepezil hydrochloride (ARICEPT®), as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea, and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose, and more frequently with the 23 mg dose than with the 10 mg dose. Specifically, in a controlled trial that compared a dose of 23 mg/day to 10 mg/day in patients who had been treated with donepezil 10 mg/day for at least three months, the incidence of nausea in the 23 mg group was markedly greater than in the patients who continued 10 mg/day (11.8% vs 3.4%, respectively), and the incidence of vomiting in the 23 mg group was markedly greater than in the 10 mg group (9.2% vs 2.5%, respectively). The percent of patients who discontinued treatment due to vomiting in the 23 mg group was markedly higher than in the 10 mg group (2.9% vs 0.4%, respectively). Although in most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT, patients should be observed closely at the initiation of treatment and after dose increases.

Peptic Ulcer Disease and GI Bleeding

Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDS). Results of a controlled clinical study of Donepezil hydrochloride (ARICEPT®) 23 mg tablets showed an increase relative to donepezil hydrochloride 10 mg/day, in the incidence of peptic ulcer disease (0.4% vs. 0.2%) and gastrointestinal bleeding from any site (1.1% vs. 0.6%).

Weight Loss

Weight loss was reported as an adverse event in 4.7% of patients assigned to Donepezil hydrochloride (ARICEPT®) 23 mg tablets compared to 2.5% of patients assigned to 10 mg donepezil hydrochloride. Compared to their baseline weights, 8.4% of patients in the Donepezil hydrochloride (ARICEPT®) 23 mg tablets group were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of the group taking 10 mg donepezil hydrochloride were found to have weight loss of ≥ 7% at the end of the study.

Genitourinary Conditions

Although not observed in clinical trials of Donepezil hydrochloride (ARICEPT®), cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions: Seizures

Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer’s disease.


Precautions on Special Populations

Cardiovascular Conditions

Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of Donepezil hydrochloride (ARICEPT®) 23 mg tablets.

Pulmonary Conditions

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Mortality in Vascular Dementia Clinical Trials

Three clinical trials of 6 months duration were conducted studying individuals meeting the NINDS-AIREN criteria for probable or possible vascular dementia (VaD). The NINDS-AIREN criteria are designed to identify patients whose dementia appears to be due solely to vascular causes and to exclude patients with Alzheimer’s disease. In the first study, the Donepezil mortality rates were 2/198 (1.0%) on donepezil hydrochloride 5 mg, 5/206 (2.4%) on donepezil hydrochloride 10 mg and 7/199 (3.5%) on placebo. In the second study, the mortality rates were 4/208 (1.9%) on donepezil hydrochloride 5mg, 3/215 (1.4%) on donepezil hydrochloride 10 mg and 1/193 (0.5%) on placebo. In the third study, the mortality rates were 11/648 (1.7%) on donepezil hydrochloride 5 mg and 0/326 (0%) on placebo. The mortality rate for the three VaD studies combined in the donepezil hydrochloride group (1.7%) was numerically higher than in the placebo group (1.1%). However, this difference was not statistically significant.

The majority of deaths in patients taking either donepezil hydrochloride or placebo appear to result from various vascular related causes, which could be expected in this elderly population with underlying vascular disease. An analysis of all serious non-fatal and fatal vascular events showed no difference in the rate of occurrence in the donepezil hydrochloride group relative to placebo. In pooled Alzheimer’s disease studies (n=4146), and when these Alzheimer’s disease studies were pooled with other dementia studies including the vascular dementia studies (total n=6888), the mortality rate in the placebo groups numerically exceeded that in the donepezil hydrochloride groups.

Pediatric Use

The safety and effectiveness of Donepezil hydrochloride (ARICEPT®) 23 mg tablets in children have not been established.

Geriatric Use

Alzheimer’s disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical study with Donepezil hydrochloride (ARICEPT®) was 73 years; 80% of these patients were between 65 and 84 years old, and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse events reported by patient groups ≥ 65 years old and < 65 years old.

Lower Weight Individuals

In the controlled clinical trial, among patients in the Donepezil hydrochloride (ARICEPT®) 23 mg tablets treatment group, those patients weighing < 55 kg reported more nausea, vomiting, and decreased weight than patients weighing 55 kg or more. There were more withdrawals due to adverse events as well. This finding may be related to higher plasma exposure associated with lower weight.