HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ARICEPT safely and effectively. See full prescribing information for ARICEPT Tablets and ARICEPT Orally Disintegrating Tablets (ODT).
ARICEPT® (donepezil hydrochloride) tablets
Initial U.S. Approval: 1996
RECENT MAJOR CHANGES
Addition of new dosage strength: ARICEPT 23mg
INDICATIONS AND USAGE
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 (1.0).
DOSAGE AND ADMINISTRATION
Mild to Moderate Alzheimer's Disease - 5mg or 10mg administered once daily (2.1)
Moderate to Severe Alzheimer's Disease - 10mg or 23mg administered once daily (2.2)
A dose of 10mg once daily can be administered once patients have been on a daily dose of 5mg for 4 to 6weeks. A dose of 23mg once daily can be administered once patients have been on a dose of 10mg once daily for at least 3months (2.3).
DOSAGE FORMS AND STRENGTHS
Tablets: 5mg, 10mg and 23mg (3)
Orally Disintegrating Tablets (ODT): 5mg and 10mg (3)
CONTRAINDICATIONS
Patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives (4)
WARNINGS AND PRECAUTIONS
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 23mg 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).
ADVERSE REACTIONS
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.
DRUG INTERACTIONS
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).
USE IN SPECIFIC POPULATIONS
Based on animal data, ARICEPT may cause fetal harm (8.1).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
Revised: 11/2010
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FULL PRESCRIBING INFORMATION: CONTENTS*
*Sections or subsections omitted from the full prescribing information are not listed
RECENT MAJOR CHANGES
1. INDICATIONS AND USAGE
2. DOSAGE AND ADMINISTRATION
2.1. Mild to Moderate Alzheimer's Disease
2.2. Moderate to Severe Alzheimer's Disease
2.3. Titration
3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5. WARNINGS AND PRECAUTIONS
5.1. Anesthesia
5.2. Cardiovascular Conditions
5.3. Nausea and Vomiting
5.4. Peptic Ulcer Disease and GI Bleeding
5.5. Weight Loss
5.6. Genitourinary Conditions
5.7. Neurological Conditions: Seizures
5.8. Pulmonary Conditions
6. ADVERSE REACTIONS
6.1. Clinical Studies Experience
6.2. Postmarketing Experience
7. DRUG INTERACTIONS
7.1. Effect of ARICEPT on the Metabolism of Other Drugs
7.2. Effect of Other Drugs on the Metabolism of ARICEPT
7.3. Use with Anticholinergics
7.4. Use with Cholinomimetics and Other Cholinesterase Inhibitors
8. USE IN SPECIFIC POPULATIONS
8.1. Pregnancy
8.3. Nursing Mothers
8.4. Pediatric Use
8.5. Geriatric Use
8.6. Lower Weight Individuals
10. OVERDOSAGE
11. DESCRIPTION
12. CLINICAL PHARMACOLOGY
12.1. Mechanism of Action
12.2. Pharmacokinetics
13. NONCLINICAL TOXICOLOGY
13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2. Animal Toxicology
14. CLINICAL STUDIES
14.1. Mild to Moderate Alzheimer's Disease
14.2. Moderate to Severe Alzheimer's Disease
16. HOW SUPPLIED/STORAGE AND HANDLING
16.1 ARICEPT Tablets
16.2. ARICEPT ODT
17. PATIENT COUNSELING INFORMATION
ARICEPT PATIENT PACKAGE INSERT
PRINCIPAL DISPLAY PANEL - ARICEPT 5MG TABLETS
PRINCIPAL DISPLAY PANEL - ARICEPT 10MG TABLETS
PRINCIPAL DISPLAY PANEL - ARICEPT 23MG TABLETS
PRINCIPAL DISPLAY PANEL - ARICEPT ODT 5MG TABLETS
PRINCIPAL DISPLAY PANEL - ARICEPT ODT 10MG TABLETS
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FULL PRESCRIBING INFORMATION
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.
2. DOSAGE AND ADMINISTRATION
ARICEPT should be taken in the evening, just prior to retiring.
ARICEPT can be taken with or without food.
The 23mg 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.
2.1. Mild to Moderate Alzheimer's Disease
The dosages of ARICEPT shown to be effective in controlled clinical trials are 5mg and 10mg administered once per day.
The higher dose of 10mg did not provide a statistically significantly greater clinical benefit than 5mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10mg of ARICEPT might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10mg is a matter of prescriber and patient preference.
2.2. Moderate to Severe Alzheimer's Disease
ARICEPT has been shown to be effective in controlled clinical trials at doses of 10mg and 23mg administered once daily. Results of a controlled clinical trial in moderate to severe Alzheimer's Disease that compared ARICEPT 23mg once daily to 10mg once daily suggest that a 23mg dose of ARICEPT provided additional benefit.
2.3. Titration
The recommended starting dose of ARICEPT is 5mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5mg dose. In open-label trials using a 6week titration, the type and frequency of these same adverse events were similar between the 5mg and 10mg dose groups. Therefore, because ARICEPT steady state is achieved about 15days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10mg should not be administered until patients have been on a daily dose of 5mg for 4 to 6weeks. A dose of 23mg once daily can be administered once patients have been on a dose of 10mg once daily for at least 3months.
3. DOSAGE FORMS AND STRENGTHS
ARICEPT is supplied as film-coated, round tablets containing 5mg, 10mg, or 23mg of donepezil hydrochloride.
The 5mg tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side.
The 10mg tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side.
The 23mg 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 5mg or 10mg of donepezil hydrochloride.
The 5mg orally disintegrating tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side.
The 10mg orally disintegrating tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side.
4. CONTRAINDICATIONS
ARICEPT is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.
5. WARNINGS AND PRECAUTIONS
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 10mg/day dose than with the 5mg/day dose, and more frequently with the 23mg dose than with the 10mg dose. Specifically, in a controlled trial that compared a dose of 23mg/day to 10mg/day in patients who had been treated with donepezil 10mg/day for at least three months, the incidence of nausea in the 23mg group was markedly greater than in the patients who continued on 10mg/day (11.8%vs. 3.4%, respectively), and the incidence of vomiting in the 23mg group was markedly greater than in the 10mg group (9.2%vs. 2.5%, respectively). The percent of patients who discontinued treatment due to vomiting in the 23mg group was markedly higher than in the 10mg 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 5mg/day to 10mg/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 23mg/day showed an increase, relative to 10mg/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 23mg/day compared to 2.5% of patients assigned to 10mg/day. Compared to their baseline weights, 8.4% of patients taking 23mg/day were found to have a weight decrease of ≥7% by the end of the study, while 4.9% of patients taking 10mg/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.
6. ADVERSE REACTIONS
6.1. Clinical Studies Experience
ARICEPT 5mg/day and 10mg/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 5mg/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 5mg/day to 10mg/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 Table1.
Table 1. Most Frequent Adverse Events Leading to Discontinuation from Controlled Clinical Trials by Dose Group
Dose Group
Placebo
5mg/day ARICEPT
10 mg/day ARICEPT
Patients Randomized
355
350
315
Event/%Discontinuing
Nausea
1%
1%
3%
Diarrhea
0%
<1%
3%
Vomiting
<1%
<1%
2%
Most Frequent Adverse Events Seen in Association with the Use of ARICEPT
The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving 10mg/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 events were often of mild intensity and transient, resolving during continued ARICEPT treatment without the need for dose modification.
There is evidence to suggest that the frequency of these common adverse events may be affected by the rate of titration. An open-label study was conducted with 269patients who received placebo in the 15 and 30-week studies. These patients were titrated to a dose of 10mg/day over a 6-week period. The rates of common adverse events were lower than those seen in patients titrated to 10mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5mg/day.
See Table2 for a comparison of the most common adverse events following one and six week titration regimens.
Table 2. Comparison of Rates of Adverse Events in Mild to Moderate Patients Titrated to 10mg/day over 1 and 6Weeks
