INDICATIONS AND USAGE ARICEP T® 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. CONTRAINDICATIONS ARICEPT® is contraindicated in patients
with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives. WARNINGS Anesthesia: ARICEPT®, as a cholinesterase inhibitor,
is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 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®. Gastrointestinal Conditions: 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®. Genitourinary: Although not observed in clinical
trials of ARICEPT®, cholinomimetics may cause bladder outflow obstruction. 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. 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. PRECAUTIONS Drug-Drug Interactions (see Clinical Pharmacology: Clinical Pharmacokinetics: Drug-drug
Interactions) Effect of ARICEPT® on the Metabolism of Other Drugs: No in vivo clinical trials have investigated the effect of ARICEPT® on the
clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding
to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of
interference. Whether ARICEPT® has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of ARICEPT®
for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of ARICEPT® on the pharmacokinetics of these drugs were
observed. Effect of Other Drugs on the Metabolism of ARICEP T®: Ketoconazole and quinidine, inhibitors of C YP450, 3A4 and 2D6, respectively,
inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7-day crossover study in 18 healthy volunteers,
ketoconazole (200 mg q.d.) increased mean donepezil ( 5 mg q.d.) concentrations (AUCO- 24 and Cmax) by 36%. The clinical relevance of this increase in
concentration is unknown. Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could
increase the rate of elimination of ARICEPT®. Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT® is not significantly affected
by concurrent administration of digoxin or cimetidine. Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have
the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A
synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or
cholinergic agonists such as bethanechol. Carcinogenesis, Mutagenesis, Impairment of Fertility 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 30 mg/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). Pregnancy Pregnancy Category C: Teratology studies conducted in pregnant rats at doses up to 16
mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/m2 basis) and in pregnant rabbits at doses up to 10 mg/kg/day
(approximately 16 times the maximum recommended human dose on a mg/m2 basis) did not disclose any evidence for a teratogenic potential of donepezil.
However, in a study in which pregnant rats were given up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2
basis) from day 17 of gestation through day 20 postpartum, there was a slight increase in still births and a slight decrease in pup survival through day
4 postpartum at this dose; the next lower dose tested was 3 mg/kg/day. There are no adequate or well-controlled studies in pregnant women. ARICEPT®
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether donepezil
is excreted in human breast milk. ARICEPT® has no indication for use in nursing mothers. Pediatric Use There are no adequate and well-controlled trials
to document the safety and efficacy of ARICEPT® in any illness occurring in children. Geriatric Use Alzheimer’s disease is a disorder occurring primarily
in individuals over 55 years of age. The mean age of the 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 the 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 REACTIONS 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® 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 the incidence seen
in placebo patients, are shown in Table 1. Table 1. Most Frequent Adverse Events Leading to Withdrawal from Controlled Clinical Trials
by Dose Group (Placebo, 5 mg/day ARICEPT®, and 10 mg/day ARICEPT®, respectively); Patients Randomized (355, 350, 315);
Event/% Discontinuing: Nausea (1%, 1%, 3%); Diarrhea (0%, <1%, 3%); Vomiting (<1%, <1%, 2%). 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 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
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. Table 2. Comparison of rates of adverse events in patients titrated to 10 mg/day over 1
and 6 weeks (No titration: Placebo [n=315], No titration: 5 mg/day [n=311], One week titration: 10 mg/day [n=315], Six week titration:
10 mg/day [n=269], respectively): 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%). 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 ARICEPT®
and for which the rate of occurrence was greater for ARICEP T® assigned than placebo assigned patients. In general, adverse events occurred more frequently
in female patients and with advancing age. Table 3. Adverse Events Reported in Controlled Clinical Trials in Mild to Moderate Alzheimer’s
Disease in at Least 2% of Patients Receiving ARICEPT® and at a Higher Frequency than Placebo-treated Patients (Body
System/Adverse Event: Placebo [n=355], ARICEPT® [n=747], respectively): Percent of Patients with any Adverse Event: 72, 74.
Body as a Whole: Headache ( 9, 10); Pain, various locations ( 8, 9); Accident ( 6, 7); Fatigue ( 3, 5). Cardiovascular System: Syncope ( 1, 2). Digestive
System: Nausea ( 6, 11); Diarrhea ( 5, 10); Vomiting ( 3, 5); Anorexia ( 2, 4). Hemic and Lymphatic System: Ecchymosis ( 3, 4). Metabolic and
Nutritional Systems: Weight Decrease ( 1, 3). Musculoskeletal System: Muscle Cramps ( 2, 6); Arthritis ( 1, 2). Nervous System: Insomnia ( 6, 9);
Dizziness ( 6, 8); Depression (< 1, 3); Abnormal Dreams (0, 3); Somnolence (< 1, 2). Urogenital System: Frequent Urination ( 1, 2). Other Adverse Events
Observed During Clinical Trials. ARICEPT® 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
ARU00239 © 2007 Eisai Inc. and Pfizer Inc.
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 3 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 ARICEPT®. All adverse events occurring at least t wice 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 caused. 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 ARICEPT® 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 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 lists 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. Table 4. Adverse Events Reported in Controlled Clinical Trials
in Severe Alzheimer’s Disease in at Least 2% of Patients Receiving ARICEPT® and at a Higher Frequency than Placebo-treated
Patients (Body System/Adverse Event: Placebo [n=392], ARICEPT® [n=501], respectively): Percent of Patients with any Adverse
Event: 73, 81. Body as a Whole: Accident ( 12, 13); Infection ( 9, 11); Headache ( 3, 4); Pain ( 2, 3); Back Pain ( 2, 3); Fever ( 1, 2); Chest Pain (< 1, 2).
Cardiovascular System: Hypertension ( 2, 3); Hemorrhage ( 1, 2); Syncope ( 1, 2). Digestive System: Diarrhea ( 4, 10); Vomiting ( 4, 8); Anorexia ( 4,
8); Nausea ( 2, 6). Hemic and Lymphatic System: Ecchymosis ( 2, 5). Metabolic and Nutritional Systems: Creatine Phosphokinase Increased ( 1,
3); Dehydration ( 1, 2); Hyperlipemia (< 1, 2). Nervous System: Insomnia ( 4, 5); Hostility ( 2, 3); Nervousness ( 2, 3); Hallucinations ( 1, 3); Somnolence
( 1, 2); Dizziness ( 1, 2); Depression ( 1, 2); Confusion ( 1, 2); Emotional Lability ( 1, 2); Personality Disorder ( 1, 2). Skin and Appendages: Eczema ( 2, 3).
Urogenital System: Urinary Incontinence ( 1, 2). 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 t wice are included, except for those already listed 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 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 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. Postintroduction Reports
Voluntary reports of adverse events temporally associated with ARICEPT® that have been received since market introduction that are not listed 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.
OVERDOSAGE 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 lo wer body surface temperature.
