1 INDICATIONS AND USAGE

Donepezil HCl 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

Donepezil HCl should be taken in the evening, just prior to retiring.

Donepezil HCl can be taken with or without food.

Allow Donepezil HCl ODT to dissolve on the tongue and follow with water.

2.1. Mild to Moderate Alzheimer's Disease

The dosages of donepezil HCl 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 donepezil HCl 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.

2.2. Severe Alzheimer's Disease

Donepezil HCl has been shown to be effective in controlled clinical trials at doses of 10 mg.

2.3. Titration

The recommended starting dose of donepezil HCl is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because donepezil steady state is achieved about 15 days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, 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.

3 DOSAGE FORMS AND STRENGTHS

Donepezil HCl is supplied as film-coated, round tablets containing either 5 mg or 10 mg of donepezil HCl.

The 5 mg tablets are white. The strength, in mg (5), is debossed on one side and a stylized G is debossed on the other side.

The 10 mg tablets are yellow. The strength, in mg (10), is debossed on one side and a stylized G is debossed on the other side.

Donepezil HCl 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

Donepezil HCl is contraindicated in patients with known hypersensitivity to donepezil HCl or to piperidine derivatives.

5 WARNINGS AND PRECAUTIONS

5.1. Anesthesia

Donepezil, 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 donepezil HCl.

5.3. Nausea and Vomiting

Donepezil, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting and diarrhea. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. Although in most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil HCl, 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 GI 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 donepezil HCl 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 GI bleeding.

5.5 Genitourinary Conditions

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

5.6 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.

5.7 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

Donepezil HCl 5 mg/day and 10 mg/day

Mild to Moderate Alzheimer's Disease

Adverse Events Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of donepezil HCl due to adverse events for the donepezil 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 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 Table 1.

Most Frequent Adverse Events Seen in Association with the Use of Donepezil HCl

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 donepezil'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 donepezil HCl 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 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 events 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 events following one and six week titration regimens.

Adverse Events Reported in Controlled Trials

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 3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received donepezil HCl and for which the rate of occurrence was greater for patients treated with donepezil HCl than with placebo. In general, adverse events occurred more frequently in female patients and with advancing age.

Other Adverse Events Observed During Clinical Trials

Donepezil HCl has been administered to over 1700 individuals during clinical trials worldwide. Approximately 1200 of these 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 116 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 three controlled clinical trials and two open-label trials in the United States 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 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 donepezil HCl. All adverse events occurring at least twice are included, except for those already listed in Tables 2 or 3, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system and listed 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 donepezil HCl treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States.

Body as a Whole: Frequent: influenza, chest pain, toothache; Infrequent: fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness.

Cardiovascular System: Frequent: hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris, postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis.

Digestive System: Frequent: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer.

Endocrine System: Infrequent: diabetes mellitus, goiter.

Hemic and Lymphatic System: Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia.

Metabolic and Nutritional Disorders: Frequent: dehydration; Infrequent: gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase.

Musculoskeletal System: Frequent: bone fracture; Infrequent: muscle weakness, muscle fasciculation.

Nervous System: Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing.

Respiratory System: Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring.

Skin and Appendages: Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer.

Special Senses: Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes.

Urogenital System: Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.

Severe Alzheimer's Disease

Adverse Events Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of donepezil HCl due to adverse events for the donepezil HCl-treated 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 donepezil HCl-treated 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 Frequent Adverse Events Seen in Association with the Use of Donepezil HCl

The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving donepezil HCl and at twice or more the placebo rate, are largely predicted by donepezil's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued donepezil HCl treatment without the need for dose modification.

Adverse Events Reported in Controlled Trials

Table 4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received donepezil HCl and for which the rate of occurrence was greater for patients treated with donepezil HCl than with placebo.

Other Adverse Events Observed During Clinical Trials

Donepezil HCl 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. All adverse events occurring at least twice are included, except for those already listed in Table 4, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system using the COSTART dictionary and listed 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 donepezil HCl 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: