ARICEPT (donepezil hydrochloride) is indicated for: symptomatic treatment of patients with mild to moderate dementia of the Alzheimer's type.

Efficacy of ARICEPT in patients with mild to moderate Alzheimer's disease was established in two 24 week and one 54-week placebo-controlled trials.

ARICEPT tablets should only be prescribed by (or following consultation with) clinicians who are experienced in the diagnosis and management of Alzheimer's disease.

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

Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (eg, bradycardia). The potential for this action may be particularly important to patients with “sick sinus syndrome” or other supraventricular cardiac conduction conditions.

In clinical trials in Alzheimer's disease, most patients with serious cardiovascular conditions were excluded. Patients such as those with controlled hypertension (DBP<95 mmHg), right bundle branch blockage, and pacemakers were included. Therefore, caution should be taken in treating patients with active coronary artery disease and congestive heart failure. Syncopal episodes have been reported in association with the use of ARICEPT. It is recommended that ARICEPT should not be used in patients with cardiac conduction abnormalities (except for right bundle branch block) including “sick sinus syndrome” and those with unexplained syncopal episodes.

Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients at increased risk for developing ulcers, eg, those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDS) including high doses of acetylsalicylic acid (ASA), should be monitored for symptoms of active or occult gastrointestinal bleeding. Clinical studies of ARICEPT have shown no increase, relative to placebo in the incidence of either peptic ulcer disease or gastrointestinal bleeding (see Adverse Reactions).

ARICEPT, as a predictable consequence of its pharmacological properties, has been shown to produce, in controlled clinical trials in patients with Alzheimer's disease, diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 10 mg dose than with the 5 mg dose. In most cases, these effects have usually been mild and transient, sometimes lasting 1 to 3 weeks and have resolved during continued use of ARICEPT (see Adverse Reactions). Treatment with the 5 mg/day dose for 4-6 weeks prior to increasing the dose to 10 mg/day is associated with a lower incidence of gastrointestinal intolerance.

Although not observed in clinical trials of ARICEPT, cholinomimetics may cause bladder outflow obstruction.

There is limited information regarding the pharmacokinetics of ARICEPT in hepatically impaired Alzheimer disease patients (see Action and Clinical Pharmacology, Pharmacokinetics).

Close monitoring for adverse effects in patients with hepatic disease being treated with ARICEPT is therefore recommended.

Some cases of seizures have been reported with the use of ARICEPT in clinical trials and from spontaneous Adverse Reaction reporting. Cholinomimetics can cause a reduction of seizure threshold, increasing the risk of seizures. However, seizure activity may also be a manifestation of Alzheimer's disease. The risk/benefit of ARICEPT treatment for patients with a history of seizure disorder must therefore be carefully evaluated.

ARICEPT has not been studied in patients with Parkinsonian features. The efficacy and safety of ARICEPT in these patients are unknown.

ARICEPT, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

There is limited information regarding the pharmacokinetics of ARICEPT in renally impaired Alzheimer disease patients (see Action and Clinical Pharmacology, Pharmacokinetics).

Close monitoring for adverse effects in patients with renal disease being treated with ARICEPT is therefore recommended.

Because of their cholinomimetic action, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. ARICEPT has not been studied in patients under treatment for these conditions and should therefore be used with particular caution in such patients.

The safety of ARICEPT during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or in nursing mothers unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus or the infant.

Teratology studies conducted in pregnant rats at doses of up to 16 mg/kg/day and in pregnant rabbits at doses of up to 10 mg/kg/day did not disclose any evidence for a teratogenic potential of ARICEPT.

There are no adequate and well-controlled trials to document the safety and efficacy of ARICEPT in any illness occurring in children. Therefore, ARICEPT is not recommended for use in children.

In controlled clinical studies with 5 and 10 mg of ARICEPT, 536 patients were between the ages of 65 to 84, and 37 patients were aged 85 years or older. In Alzheimer's disease patients, nausea, diarrhea, vomiting, insomnia, fatigue and anorexia increased with dose and age and the incidence appeared to be greater in female patients. Since cholinesterase inhibitors as well as Alzheimer's disease can be associated with significant weight loss, caution is advised regarding the use of ARICEPT in low body weight elderly patients, especially in those ≥85 years old.

There is limited safety information for ARICEPT in patients with mild to moderate Alzheimer's disease and significant comorbidity. The use of ARICEPT in Alzheimer's disease patients with chronic illnesses common among the geriatric population, should be considered only after careful risk/benefit assessment and include close monitoring for adverse events. Caution is advised regarding the use of ARICEPT doses above 5 mg in this patient population.

Three clinical trials, each of 6 months duration, were conducted to evaluate the safety and efficacy of ARICEPT for the symptomatic treatment of individuals meeting the NINDS-AIREN criteria for probable or possible vascular dementia. The NINDS-AIREN criteria are designed to identify patients with dementia that appears to be due solely to vascular causes, and to exclude patients with Alzheimer's disease. ARICEPT was not shown to be an effective treatment for patients with vascular dementia in two of these clinical trials.

The safety profile from these controlled clinical trials in vascular dementia patients indicates that the rate of occurrence of treatment emergent adverse events overall was higher in vascular dementia patients (86%) than in Alzheimer's disease patients (75%). This was seen in both ARICEPT-treated subjects and placebo-treated subjects and may relate to the greater number of co-morbid medical conditions in the vascular dementia population.

In two of the clinical trials there was a higher rate of mortality among patients treated with ARICEPT, during double-blind treatment; this result was statistically significant for one of these two trials. For the three vascular dementia studies combined, the mortality rate in the ARICEPT group (1.7%, 25/1475) was numerically higher than in the placebo group (1.1%, 8/718), but this difference was not statistically significant.

These results are summarized as follows: (see Table 1).

Table 1: ARICEPT

Mortality Rates in ARICEPT Vascular Dementia Clinical Trials

Study	Placebo	ARICEPT 5 mg	p-valueb	ARICEPT 10 mg	p-valueb
307	3.5% (7/199)	1.0% (2/198)	0.17	2.4% (5/206)	0.57
308	0.5% (1/193)	1.9% (4/208)	0.37	1.4% (3/215)	0.62
319	0% (0/326)	1.7% (11/648)	0.02	a	NA
Combined	1.1% (8/718)	1.7% (25/1475)			0.35

^a. No 10 mg ARICEPT treatment arm in Study 319.
^b. p-values are for 5 mg donepezil vs placebo and 10 mg donepezil vs placebo.

The majority of deaths in patients taking either ARICEPT or placebo appear to have resulted from various vascular related causes, which may be expected in this elderly, fragile, population with co-morbid vascular disease. In the three combined vascular dementia clinical trials there were similar proportions of patients with serious AEs in both treatment groups (approximately 15%), and similar proportions of patients with serious cardiovascular or cerebrovascular adverse events (non-fatal and fatal, approximately 8%). The proportion of patients who had a fatal cardiovascular or cerebrovascular adverse event was numerically higher in the ARICEPT group than in the placebo group, but this difference was not statistically significant across the three trials.

There is no evidence of an increase risk of mortality when ARICEPT is used in patients with mild to moderate Alzheimer's disease.

A total of 747 patients with mild to moderate Alzheimer's disease were treated in controlled clinical studies with ARICEPT (donepezil hydrochloride). Of these patients, 613 (82%) completed the studies. The mean duration of treatment for all ARICEPT groups was 132 days (range 1-356 days).

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 the 10 mg/day dose after only a 1 week initial treatment with 5 mg/day ARICEPT 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 the incidence seen in placebo patients, are shown in Table 2.

Table 2: ARICEPT

Most Frequent Adverse Events Leading to Withdrawal from Controlled Clinical Trials by Dose Group

Dose Group	Placebo	5 mg/day ARICEPT	10 mg/day ARICEPT
Number of Patients Randomized	355	350	315
Events/% Discontinuing
Nausea	1%	1%	3%
Diarrhea	0%	<1%	3%
Vomiting	<1%	<1%	2%

The most common adverse events, 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 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 duration of treatment with an initial 5 mg daily dose prior to increasing the dose to 10 mg/day. An open label study was conducted with 269 patients who received placebo in the 15- and 30-week studies. These patients received a 5 mg/day dose for 6 weeks prior to initiating treatment with 10 mg/day. The rates of common adverse events were lower than those seen in controlled clinical trial patients who received 10 mg/day after only a 1 week initial treatment period with a 5 mg daily dose, and were comparable to the rates noted in patients treated only with 5 mg/day.

See Table 3 for a comparison of the most common adverse events following 1- and 6-week initial treatment periods with 5 mg/day ARICEPT.

Table 3: ARICEPT

Comparison of Rates of Adverse Events in Patients Treated with 10 mg/day after 1 and 6 weeks of Initial Treatment with 5 mg/day

Adverse Event	No Initial Treatment		1-Week Initial Treatment with 5 mg/day	6-Week Initial Treatment with 5 mg/day
	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

The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.

Table 4 lists treatment-emergent signs and symptoms (TESS) that were reported in at least 2% of patients from placebo-controlled clinical trials who received ARICEPT and for which the rate of occurrence was greater for ARICEPT than placebo-assigned patients. In general, adverse events occurred more frequently in female patients and with advancing age.

Table 4: ARICEPT

Adverse Events Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving ARICEPT and at a Higher Frequency than Placebo-treated Patients

During the premarketing phase, ARICEPT has been administered to over 1700 individuals for various lengths of time during clinical trials worldwide. Approximately 1200 patients have been treated for at least 3 months, and more than 1000 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 115 patients treated for over 1 year. The range of patient exposure is from 1 to 1214 days.

Treatment-emergent signs and symptoms that occurred during 3 placebo-controlled clinical trials and 2 open-label trials were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the studies were integrated and the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900 patients from these trials who experienced that event while receiving ARICEPT. All adverse events occurring at least twice are included. Adverse events already listed in Table 3 and Table 4 are not repeated here (ie, events occurring at an incidence >2%). Also excluded are COSTART terms too general to be informative, or events less likely to be drug-caused. Events are classified by body system and listed as occurring in ≥1% and <2% of patients (ie, in 1/100 to 2/100 patients: frequent) or in <1% of patients (ie, in 1/100 to 1/1000 patients: infrequent). These adverse events are not necessarily related to ARICEPT treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.