Aricept Tablet, Film Coated

The most common adverse reactions in clinical studies of ARICEPT are nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 (fax 1-201-746-3207) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. Clinical Studies Experience ARICEPT 5 mg/day and 10 mg/day Mild to Moderate Alzheimer's Disease Adverse Events Leading to Discontinuation The rates of discontinuation from controlled clinical trials of ARICEPT due to adverse events for the ARICEPT 5 mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day was higher at 13%. The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients, are shown in Table 1. Table 1. Most Frequent Adverse Events Leading to Discontinuation from Controlled Clinical Trials by Dose Group Dose Group

• Cholinesterase inhibitors are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia (5.1). • Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as bradycardia or heart block (5.2). • ARICEPT can cause vomiting. Patients should be observed closely at initiation of treatment and after dose increases (5.3). • Patients should be monitored closely for symptoms of active or occult gastrointestinal (GI) bleeding, especially those at increased risk for developing ulcers (5.4). • The use of ARICEPT in a dose of 23 mg once daily is associated with weight loss (5.5). • Cholinomimetics may cause bladder outflow obstructions (5.6). • Cholinomimetics are believed to have some potential to cause generalized convulsions (5.7). • Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease (5.8). 5.1. Anesthesia ARICEPT, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 5.2. 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 ARICEPT. 5.3. Nausea and Vomiting 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 on 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. 5.4. 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). Clinical studies of ARICEPT in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Results of a controlled clinical study with 23 mg/day showed an increase, relative to 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%) 5.5. Weight Loss Weight loss was reported as an adverse event in 4.7% of patients assigned to ARICEPT in a dose of 23 mg/day compared to 2.5% of patients assigned to 10 mg/day. Compared to their baseline weights, 8.4% of patients taking 23 mg/day were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of patients taking 10 mg/day were found to have weight loss of ≥ 7% at the end of the study. 5.6. Genitourinary Conditions Although not observed in clinical trials of ARICEPT, cholinomimetics may cause bladder outflow obstruction. 5.7. 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. 5.8. 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.

ARICEPT should be taken in the evening, just prior to retiring. ARICEPT can be taken with or without food. The 23 mg tablet should not be split, crushed or chewed because this may increase its rate of absorption. Allow ARICEPT ODT to dissolve on the tongue and follow with water. ARICEPT is supplied as film-coated, round tablets containing 5 mg, 10 mg, or 23 mg of donepezil hydrochloride. The 5 mg tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side. The 10 mg tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side. The 23 mg tablets are reddish. The strength, in mg (23), is debossed on one side, and ARICEPT is debossed on the other side. ARICEPT ODT is supplied as round tablets containing either 5 mg or 10 mg of donepezil hydrochloride. The 5 mg orally disintegrating tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side. The 10 mg orally disintegrating tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side.

• Cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications (7.3). • A synergistic effect may be expected with concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists (7.4). 7.1. Effect of ARICEPT on the Metabolism of Other Drugs No in vivo clinical trials have investigated the effect of ARICEPT on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Whether ARICEPT has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of ARICEPT for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of ARICEPT on the pharmacokinetics of these drugs were observed. 7.2. Effect of Other Drugs on the Metabolism of ARICEPT Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro . Whether there is a clinical effect of quinidine is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.) increased mean donepezil (5 mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown. A small effect of CYP2D6 inhibitors was identified in a population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease. Donepezil clearance was reduced by approximately 17% in patients taking 10 or 23 mg in combination with a known CYP2D6 inhibitor. This result is consistent with the conclusion that CYP2D6 is a minor metabolic pathway of donepezil. Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT. Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT is not significantly affected by concurrent administration of digoxin or cimetidine. 7.3. Use with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. 7.4. Use with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.