Aricept

1 INDICATIONS AND USAGE ARICEPT is indicated for the treatment of dementia of the Alzheimer’s type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease. ARICEPT is an acetylcholinesterase inhibitor indicated for the treatment of dementia of the Alzheimer’s type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s Disease ( 1 )

2 DOSAGE AND ADMINISTRATION Mild to Moderate Alzheimer’s Disease: 5 mg to 10 mg once daily ( 2.1 ) Moderate to Severe Alzheimer’s Disease: 10 mg to 23 mg once daily ( 2.2 ) 2.1 Dosing in Mild to Moderate Alzheimer’s Disease The recommended starting dosage of ARICEPT is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of ARICEPT in patients with mild to moderate Alzheimer’s disease is 10 mg per day. A dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks. 2.2 Dosing in Moderate to Severe Alzheimer’s Disease The recommended starting dosage of ARICEPT is 5 mg administered once per day in the evening, just prior to retiring. The maximum recommended dosage of ARICEPT in patients with moderate to severe Alzheimer’s disease is 23 mg per day. A dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks. A dose of 23 mg per day should not be administered until patients have been on a daily dose of 10 mg for at least 3 months. 2.3 Administration Information ARICEPT should be taken in the evening, just prior to retiring. ARICEPT can be taken with or without food. The ARICEPT 23 mg tablet should not be split, crushed, or chewed. Allow ARICEPT ODT to dissolve on the tongue and follow with water.

4 CONTRAINDICATIONS ARICEPT is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives. Known hypersensitivity to donepezil hydrochloride or to piperidine derivatives ( 4 )

Not available.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Cardiovascular Conditions [see Warnings and Precautions ( 5.2 )] Nausea and Vomiting [see Warnings and Precautions ( 5.3 )] Peptic Ulcer Disease and GI Bleeding [see Warnings and Precautions ( 5.4 )] Weight Loss [see Warnings and Precautions ( 5.5 )] Genitourinary Conditions [see Warnings and Precautions ( 5.6 )] Neurological Conditions: Seizures [see Warnings and Precautions ( 5.7 )] Pulmonary Conditions [see Warnings and Precautions ( 5.8 )] 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 Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. ARICEPT has been administered to over 1,700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months, and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1,214 days. Mild to Moderate Alzheimer ’ s Disease Adverse Reactions Leading to Discontinuation The rates of discontinuation from controlled clinical trials of ARICEPT due to adverse reactions 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 reactions 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 Common Adverse Reactions Leading to Discontinuation in Patients with Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo (n=355) % 5 mg/day ARICEPT (n=350) % 10 mg/day ARICEPT (n=315) % Nausea 1 1 3 Diarrhea 0 <1 3 Vomiting <1 <1 2 Most Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by ARICEPT’s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse reactions were often transient, resolving during continued ARICEPT treatment without the need for dose modification. There is evidence to suggest that the frequency of these common adverse reactions may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15- and 30-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse reactions were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day. See Table 2 for a comparison of the most common adverse reactions following one and six week titration regimens. Table 2. Comparison of Rates of Adverse Reactions in Mild to M oderate Patients Titrated to 10 mg/day over 1 and 6 Weeks No titration One week titration Six week titration Adverse Reaction Placebo (n=315) % 5 mg/day (n=311) % 10 mg/day (n=315) % 10 mg/day (n=269) % Nausea 6 5 19 6 Diarrhea 5 8 15 9 Insomnia 6 6 14 6 Fatigue 3 4 8 3 Vomiting 3 3 8 5 Muscle cramps 2 6 8 3 Anorexia 2 3 7 3 Table 3 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received either ARICEPT 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo. In general, adverse reactions occurred more frequently in female patients and with advancing age. Table 3. Adverse Reactions in Pooled Placebo- Controlled Clinical Trials in Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo (n=355) % ARICEPT (n=747) % Percent of Pa tients with any Adverse Reaction 72 74 Nausea 6 11 Diarrhea 5 10 Headache 9 10 Insomnia 6 9 Pain, various locations 8 9 Dizziness 6 8 Accident 6 7 Muscle Cramps 2 6 Fatigue 3 5 Vomiting 3 5 Anorexia 2 4 Ecchymosis 3 4 Abnormal Dreams 0 3 Depression <1 3 Weight Loss 1 3 Arthritis 1 2 Frequent Urination 1 2 Somnolence <1 2 Syncope 1 2 Severe Alzheimer’s Disease (ARICEPT 5 mg/day and 10 mg/day) ARICEPT has been administered to over 600 patients with severe Alzheimer’s disease during clinical trials of at least 6 months duration, including three double-blind, placebo-controlled trials, two of which had an open label extension. Adverse Reactions Leading to Discontinuation The rates of discontinuation from controlled clinical trials of ARICEPT due to adverse reactions for the ARICEPT patients were approximately 12% compared to 7% for placebo patients. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of ARICEPT patients and at twice or more the incidence seen in placebo, were anorexia (2% vs. 1% placebo), nausea (2% vs. <1% placebo), diarrhea (2% vs. 0% placebo), and urinary tract infection (2% vs. 1% placebo). Most Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving ARICEPT and at twice or more the placebo rate, are largely predicted by ARICEPT’s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse reactions were often transient, resolving during continued ARICEPT treatment without the need for dose modification. Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received ARICEPT 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo. Table 4. Adverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer’s Disease Body System/Adverse Reaction Placebo (n=392) % ARICEPT (n=501) % Percent of Patients with any Adverse Reaction 73 81 Accident 12 13 Infection 9 11 Diarrhea 4 10 Anorexia 4 8 Vomiting 4 8 Nausea 2 6 Insomnia 4 5 Ecchymosis 2 5 Headache 3 4 Hypertension 2 3 Pain 2 3 Back Pain 2 3 Eczema 2 3 Hallucinations 1 3 Hostility 2 3 Increase in Creatine Phosphokinase 1 3 Nervousness 2 3 Fever 1 2 Chest Pain <1 2 Confusion 1 2 Dehydration 1 2 Depression 1 2 Dizziness 1 2 Emotional Lability 1 2 Hemorrhage 1 2 Hyperlipemia <1 2 Personality Disorder 1 2 Somnolence 1 2 Syncope 1 2 Urinary Incontinence 1 2 Moderate to Severe Alzheimer’s Disease (ARICEPT 23 mg/day) ARICEPT 23 mg/day has been administered to over 1300 individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950 patients have been treated for at least six months. The range of patient exposure was from 1 to over 500 days. Adverse Reactions Leading to Discontinuation The rate of discontinuation from a controlled clinical trial of ARICEPT 23 mg/day due to adverse reactions was higher (19%) than for the 10 mg/day treatment group (8%). The most common adverse reactions leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with 10 mg/day are shown in Table 5. Table 5. Most Common Adverse Reactions Leading to Discontinuation in Patients with Moderate to Severe Alzheimer’s Disease Adverse Reaction 23 mg/day ARICEPT (n=963) % 10 mg/day ARICEPT (n=471) % Vomiting 3 0 Diarrhea 2 0 Nausea 2 0 Dizziness 1 0 The majority of discontinuations due to adverse reactions in the 23 mg group occurred during the first month of treatment. Most Common Adverse Reactions with ARICEPT 23 mg /day The most common adverse reactions, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia. Table 6 lists adverse reactions that occurred in at least 2% of patients who received 23 mg/day of ARICEPT and at a higher frequency than those receiving 10 mg/day of ARICEPT in a controlled clinical trial that compared the two doses. In this study, there were no important differences in the type of adverse reactions in patients taking ARICEPT with or without memantine. Table 6. Adverse Reactions in a Controlled Clinical Trial in Moderate to Severe Alzheimer’s Disease Adverse Reaction 23 mg/day ARICEPT (n=963) % 10 mg/day ARICEPT (n=471) % Percent of Patie nts with any Adverse Reaction 74 64 Nausea 12 3 Vomiting 9 3 Diarrhea 8 5 Anorexia 5 2 Dizziness 5 3 Weight Loss 5 3 Headache 4 3 Insomnia 3 2 Urinary Incontinence 3 1 Asthenia 2 1 Contusion 2 0 Fatigue 2 1 Somnolence 2 1 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARICEPT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abdominal pain, agitation, aggression, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis, QTc prolongation, and torsade de pointes.