ARICEPT® Oral Solution
(Donepezil Hydrochloride)

ARICEPT® (donepezil hydrochloride) is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C₂₄H₂₉NO₃HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane.

Each 1mL of ARICEPT® Oral Solution contains 1 mg of donepezil hydrochloride. ARICEPT® Oral Solution also contains sorbitol solution 70%, povidone K-30, citric acid anhydrous, sodium citrate dihydrate, sodium benzoate, methylparaben, propylene glycol, sodium metabisulfite, purified water and strawberry flavor.

Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's Disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.

The effectiveness of ARICEPT® as a treatment for Alzheimer's Disease is demonstrated by the results of randomized, double-blind, placebo-controlled clinical investigations in mild, moderate and severe patients with Alzheimer's Disease.

The effectiveness of ARICEPT® as a treatment for Alzheimer's Disease is demonstrated by the results of two randomized, double-blind, placebo-controlled clinical investigations in patients with Alzheimer's Disease (diagnosed by NINCDS and DSM III-R criteria, Mini-Mental State Examination ≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2). The mean age of patients participating in ARICEPT® trials was 73 years with a range of 50 to 94. Approximately 62% of patients were women and 38% were men. The racial distribution was white 95%, black 3% and other races 2%.

In a study of 30 weeks duration, 473 patients were randomized to receive single daily doses of placebo, 5 mg/day or 10 mg/day of ARICEPT®. The 30-week study was divided into a 24-week double-blind active treatment phase followed by a 6-week single-blind placebo washout period. The study was designed to compare 5 mg/day or 10 mg/day fixed doses of ARICEPT® to placebo. However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment was started following an initial 7-day treatment with 5 mg/day doses.

In a study of 15 weeks duration, patients were randomized to receive single daily doses of placebo or either 5 mg/day or 10 mg/day of ARICEPT® for 12 weeks, followed by a 3-week placebo washout period. As in the 30-week study, to avoid acute cholinergic effects, the 10 mg/day treatment followed an initial 7-day treatment with 5 mg/day doses.

The effectiveness of ARICEPT® as a treatment for severe Alzheimer's Disease is demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted in Sweden (24-Week Study) in patients with probable or possible Alzheimer's Disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10. Two hundred and forty eight (248) patients with severe Alzheimer's disease were randomized to ARICEPT® or placebo. For patients randomized to ARICEPT®, treatment was initiated at 5 mg once daily for 28-days and then increased to 10 mg once daily. At the end of the 24-week treatment period, 90.5% of the ARICEPT® -treated patients were receiving the 10 mg dose. The mean age of patients was 84.9 years with a range of 59 to 99. Approximately 77 % of patients were women and 23 % were men. Almost all patients were Caucasian. Probable AD was diagnosed in the majority of the patients (83.6% of ARICEPT®-treated patients and 84.2% of placebo-treated patients).

ARICEPT® Oral Solution is bioequivalent to ARICEPT® Tablets. Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1-10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of ARICEPT® Tablets. Administration of ARICEPT® Oral Solution to healthy volunteers with a high-fat meal decreased C_max by 17% and increased T_max by 1 hour, while the AUC_0-72 was similar under fed and fasted conditions. This delay in absorption and decrease in exposure is not likely to be clinically significant; therefore ARICEPT® Oral Solution can be taken without regard to meals.

The elimination half life of donepezil is about 70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4-7 fold and steady state is reached within 15 days. The steady state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha₁ - acid glycoprotein (about 21%) over the concentration range of 2-1000 ng/mL.

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of ¹⁴C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug.

ARICEPT® is indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild to moderate Alzheimer's Disease, as well as in patients with severe Alzheimer's Disease.

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

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

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®.

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® have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

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. In most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT®.

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

Seizures: Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's Disease.

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

ARICEPT® Oral Solution contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than nonasthmatic people.

(see Clinical Pharmacology: Clinical Pharmacokinetics: Drug-drug Interactions)

Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.

A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.

No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil hydrochloride conducted in CD-1 mice at doses up to 180 mg/kg/day (approximately 90 times the maximum recommended human dose on a mg/m² basis), or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses up to 30mg/kg/day (approximately 30 times the maximum recommended human dose on a mg/m² basis).

Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria, or in a mouse lymphoma forward mutation assay in vitro. In the chromosome aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were observed. Donepezil was not clastogenic in the in vivo mouse micronucleus test and was not genotoxic in an in vivo unscheduled DNA synthesis assay in rats.

Donepezil had no effect on fertility in rats at doses up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m² basis).

There are no adequate and well-controlled trials to document the safety and efficacy of ARICEPT® in any illness occurring in children.

Alzheimer's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical studies with ARICEPT® was 73 years; 80% of these patients were between 65 and 84 years old and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse events reported by patient groups ≥ 65 years old and < 65 years old.

Adverse Events Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of ARICEPT® due to adverse events for the ARICEPT® patients were approximately 12% compared to 7% for placebo patients.

The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of ARICEPT® patients and at twice the incidence seen in placebo patients, 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 Frequent Adverse Clinical 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 ARICEPT® and twice the placebo rate, are largely predicted by ARICEPT®'s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT® treatment without the need for dose modification.

Adverse Events Reported in Controlled Trials

Table 4 uls treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT® and for which the rate of occurrence was greater for ARICEPT® assigned than placebo assigned patients.

Other Adverse Events Observed During Clinical Trials

ARICEPT® has been administered to over 600 patients with severe Alzheimer's Disease during clinical trials of at least 6 months duration, including 3 double blind placebo controlled trials, one of which had an open label extension. All adverse events occurring at least twice are included, except for those already uled in Table 4, COSTART terms too general to be informative, or events less likely to be drug caused. Events are classified by body system using the COSTART dictionary and uled using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. 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.

Body as a Whole:Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia.

Cardiovascular System:Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly.

Digestive System:Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage.

Endocrine System:Infrequent: diabetes mellitus.

Hemic and Lymphatic System:Frequent: anemia; Infrequent: leukocytosis.

Metabolic and Nutritional Disorders:Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased.

Musculoskeletal System:Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia.

Nervous System:Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia.

Respiratory System:Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma.

Skin and Appendages:Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash

Special Senses:Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder.

Urogenital System:Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria.

Voluntary reports of adverse events temporally associated with ARICEPT® that have been received since market introduction that are not uled above, and that there is inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.

 Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.

As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for ARICEPT® overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether ARICEPT® and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation and lower body surface temperature.

The dosages of ARICEPT® shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.

The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. 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 10 mg of ARICEPT® might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.

Evidence from the controlled trials indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events than the 5 mg dose. In open label trials using a 6 week titration, the frequency of these same adverse events was similar between the 5 mg and 10 mg dose groups. Therefore, because steady state is not achieved for 15 days and because the incidence of untoward effects may be influenced by the rate of dose escalation, treatment with a dose of 10 mg should not be contemplated until patients have been on a daily dose of 5 mg for 4 to 6 weeks.

Each teaspoon (5 mL) of ARICEPT® Oral Solution contains a 5 mg dose. Patients should be instructed as to how to measure their dose of ARICEPT® Oral Solution in teaspoons.

ARICEPT® Oral Solution should be taken in the evening, just prior to retiring.

ARICEPT® Oral Solution can be taken with or without food.

ARICEPT® Oral Solution is a clear, colorless to light yellow solution containing 1 mg of donepezil hydrochloride in each mL (1 mg/mL). Each teaspoon (5mL) contains 5 mg of donepezil hydrochloride.

NDC#62856-851-30          300 mL HDPE Bottles

Storage: Store at controlled room temperature, 15°C to 30°C (59°F to 86°F).

R_X only

ARICEPT® is a registered trademark of Eisai Co., Ltd.

Manufactured and Marketed by Eisai Inc., Teaneck, NJ 07666

Marketed by

Pfizer Inc, New York, NY 10017

© 2006 Eisai Inc.

Printed in U.S.A.

Revised October 2006