Aricept: Package Insert and Label Information

ARICEPT- donepezil hydrochloride tablet, film coated
ARICEPT ODT- donepezil hydrochloride tablet, orally disintegrating
Eisai Inc.

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

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.

3 DOSAGE FORMS AND STRENGTHS

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.

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 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 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 reaction 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.

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)]

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
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