Aricept

Food does not have an influence on the rate and extent of donepezil hydrochloride absorption.

Interactions with laboratory tests have not been established.

Interactions with herbal products have not been established.

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

Drug displacement studies have been performed in vitro between donepezil, a highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. Donepezil at concentrations of 0.3-10 µg/mL did not affect the binding of furosemide (5 µg/mL), digoxin (2 ng/mL) and warfarin (3 µg/mL) to human albumin. Similarly, the binding of donepezil to human albumin was not affected by furosemide, digoxin and warfarin.

In vitro studies show a low rate of donepezil binding to CYP 3A4 and CYP 2D6 isoenzymes (mean Ki about 50-130 µM), which, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interferences. In a pharmacokinetic study involving 18 healthy volunteers, the administration of ARICEPT at a dose of 5 mg/day for 7 days had no clinically significant effect on the pharmacokinetics of ketoconazole. No other clinical trials have been conducted to investigate the effect of ARICEPT on the clearance of drugs metabolized by CYP 3A4 (eg, cisapride, terfenadine) or by CYP 2D6 (e.g., imipramine).

It is not known whether ARICEPT has any potential for enzyme induction.

Pharmacokinetic studies, limited to short-term, single-dose studies in young subjects evaluated the potential of ARICEPT for interaction with theophylline, cimetidine, warfarin and digoxin administration. No significant effects on the pharmacokinetics of these drugs were observed. Similar studies in elderly patients were not done.

Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. In a pharmacokinetic study, 18 healthy volunteers received 5 mg/day ARICEPT together with 200 mg/day ketoconazole for 7 days. In these volunteers, mean donepezil plasma concentrations were increased by about 30%-36%.

Inducers of CYP 2D6 and CYP 3A4 (eg, phenytoin, carbamazepine, dexamethasone, rifampin and phenobarbital) could increase the rate of elimination of ARICEPT.

Pharmacokinetic studies demonstrated that the metabolism of ARICEPT is not significantly affected by concurrent administration of digoxin or cimetidine.

Few patients in controlled clinical trials received neuroleptics, antidepressants or anticonvulsants. There is thus limited information concerning the interaction of ARICEPT with these drugs.

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

Adverse events are more common in individuals of low body weight, in patients ≥85 years old and in females. It is recommended that ARICEPT be used with caution in these patient populations. In elderly women of low body weight, the dose should not exceed 5 mg/day.

In a population of cognitively-impaired individuals, safe use of this and all other medications may require supervision.

ARICEPT should be taken once daily in the morning or evening. It may be taken with or without food.

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

The recommended initial dose of ARICEPT or ARICEPT RDT is 5 mg taken once daily. Therapy with the 5 mg dose should be maintained for 4-6 weeks before considering a dose increase, in order to avoid or decrease the incidence of the most common adverse reactions to the drug (see Adverse Reactions) and to allow plasma levels to reach steady state. Based on clinical judgement, the 10 mg daily dose may be considered following 4-6 weeks of treatment at 5 mg/day. The maximum recommended dose is 10 mg taken once daily.

Following initiation of therapy or any dosage increase, patients should be closely monitored for adverse effects.

ARICEPT tablets should be swallowed whole with water.

ARICEPT RDT should be placed on the tongue and allowed to disintegrate before swallowing with water.

A total of 573 patients with severe Alzheimer’s disease were treated in controlled clinical studies with ARICEPT. Of these patients, 441 (77%) completed the studies. The duration of double blind treatment in all studies was 24 weeks. The mean duration of treatment for all ARICEPT groups was 148.4 days (range 1-231 days). The mean daily dose of ARICEPT was 7.5 mg/day.

In clinical trials of patients with severe Alzheimer’s disease, most patients with significant comorbid conditions were excluded. 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 should include close monitoring for adverse events.

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, cholecystitis, convulsions, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, pancreatitis, and rash.

(≥1% and <2%) fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; (<1%) 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.

(<1%) anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia.

In controlled clinical trials in severe Alzheimer’s disease, the rate of discontinuation due to adverse events was 11.3% in patients treated with ARICEPT compared to 6.7% in the placebo group. The most common adverse events that led to discontinuation, more often in patients treated with ARICEPT than placebo, were diarrhea, nausea, vomiting, urinary tract infection, decreased appetite, and aggression. Each of these adverse events led to discontinuation of less than 2% of patients treated with ARICEPT.

(≥1% and <2%) cataract, eye irritation, blurred vision; (<1%) 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.

Patients were exposed to ARICEPT in 2 open-label extension mild to moderate Alzheimer’s disease studies (n=885) of over 2 years. In 1 of the studies, 763 patients who previously completed 1 of 2 placebo-controlled studies of 15 or 30 weeks duration continued to receive ARICEPT and were evaluated for safety and neuropsychological evaluations for up to 152 weeks; the safety profile of ARICEPT in this extension study remained consistent with that observed in placebo-controlled trials. Following 1 and 2 years of treatment, 76% (n=580) and 49% (n=374) of these patients, respectively, were still receiving therapy (cumulative Weeks 48 and 108).

(≥1% and <2%) abrasion, pruritus, diaphoresis, urticaria; (<1%) dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer.

(≥1% and <2%) bone fracture; (<1%) muscle weakness, muscle fasciculation.

(≥1% and <2%) influenza, chest pain, toothache; (<1%) fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, head pressure, listlessness.

(≥1% and <2%) hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; (<1%) angina pectoris, postural hypotension, myocardial infarction, premature ventricular contraction, arrhythmia, AV Block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thromboses.

Results from the controlled clinical trials indicate that the incidence of adverse events such as vomiting, urinary tract infection, urinary incontinence, pneumonia, falls, decreased appetite, aggression, restlessness, hallucination and confusion may be higher in ARICEPT and placebo-treated patients with severe Alzheimer’s disease than in patients with mild to moderate Alzheimer’s disease.

Other adverse events that occurred with an incidence of at least 2% in ARICEPT treated patients and at an equal or lower rate than in placebo treated patients included: abdominal pain, fatigue, gastroenteritis, excoriation, dizziness, anxiety and depression.

(<1%) diabetes mellitus, goiter.

(≥1% and <2%) delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, libido increased, restlessness, abnormal crying, nervousness, aphasia; (<1%) 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, seizures.

(≥1% and <2%) urinary incontinence, nocturia; (< 1%) dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.

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).

In Study 315, which was a 24 week, randomized, placebo controlled study in severe Alzheimer’s patients, at the end of double-blind treatment 229 patients entered open label ARICEPT treatment for up to an additional 12 weeks. Therefore, at the end of the open label phase, 111 patients had received up to 36 weeks of ARICEPT treatment and 118 patients had received up to 12 weeks of ARICEPT treatment.

The most commonly affected body systems, types and frequencies of adverse events reported during 12 weeks of open label ARICEPT treatment were similar to what was observed during 24 weeks of double-blind treatment.

Gastrointestinal adverse events (diarrhea, nausea, vomiting, anorexia) were reported at a higher frequency in patients who received up to12 weeks of ARICEPT treatment. Other adverse events reported at higher frequencies in the patients treated with ARICEPT for up to 12 weeks included infection, insomnia, pneumonia, fever, dizziness, hypertension, asthenia, tremor, pharyngitis, hallucinations, convulsions and cysts.

In patients treated with ARICEPT for up to 36 weeks, accidental injury, urinary incontinence and urinary tract infections were reported at higher frequencies.

(≥1% and <2%) dehydration; (<1%) gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase.

During the premarketing phase, ARICEPT has been administered to over 1700 individuals with mild to moderate Alzheimer’s disease 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 of patients with mild to moderate Alzheimer’s disease 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.

(≥1% and <2%) dyspnea, sore throat, bronchitis; (<1%) epistaxis, postnasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring.

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.

The elimination half-life of ARICEPT (donepezil hydrochloride) at recommended doses is approximately 70 hours, thus, in the case of overdose, it is anticipated that prolonged treatment and monitoring of adverse and toxic reactions will be necessary. As in any case of overdose, general supportive measures should be utilized.

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 observed in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, fasciculation, and lower body surface temperature.

Each white, film-coated tablet, embossed with the name “ARICEPT” and the strength, contains: donepezil HCl 5 mg equivalent to donepezil free base 4.56 mg. Nonmedicinal ingredients: cornstarch, hydroxypropylcellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose; film-coating: hypromellose, polyethylene glycol, talc and titanium dioxide. HDPE bottles of 30. Boxed blister strips of 7, 14 and 28 (combination of 2 strips of 14).

Each yellow, uncoated, rapidly disintegrating tablet, embossed with the name “ARICEPT” and the strength, contains: donepezil HCl 10 mg equivalent to donepezil free base 9.12 mg. Nonmedicinal ingredients: κ-carrageenan, iron oxide, mannitol, polyvinyl alcohol and silica colloidal anhydrous. Boxed blister strips of 7, 28 and 30.

Each white, uncoated, rapidly disintegrating tablet, embossed with the name “ARICEPT” and the strength, contains: donepezil HCl 5 mg equivalent to donepezil free base 4.56 mg. Nonmedicinal ingredients: κ-carrageenan, mannitol, polyvinyl alcohol and silica colloidal anhydrous. Boxed blister strips of 7, 28 and 30.

Each yellow, film-coated tablet, embossed with the name “ARICEPT” and the strength, contains: donepezil HCl 10 mg equivalent to donepezil free base 9.12 mg. Nonmedicinal ingredients: cornstarch, hydroxypropylcellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose; film-coating: hypromellose, iron oxide, polyethylene glycol, talc and titanium dioxide. HDPE bottles of 30. Boxed blister strips of 7, 14 and 28 (combination of 2 strips of 14).

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.

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.

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.

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

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.

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.

In controlled clinical studies with 5 and 10 mg ARICEPT in patients with mild to moderate Alzheimer’s disease, there were 536 patients between the ages of 65 to 84, and 37 patients aged 85 years or older treated with ARICEPT. In controlled clinical trials of patients with severe Alzheimer’s disease there were 158 patients who were 74 years of age or less, 276 patients between the ages of 75 and 84, and 139 patients aged 85 years or older treated with ARICEPT. 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 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.

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.

There is limited safety information for ARICEPT in patients with mild to moderate or severe 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.

In severe Alzheimer’s disease, the possibility of comorbid vascular disease and risk factors for vascular adverse events and mortality should be considered.

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

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.

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.

In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil was decreased by 20% relative to 10 healthy age and sex matched subjects.

Donepezil hydrochloride is about 96% bound to human plasma proteins, mainly to albumins (~75%) and α₁-acid glycoprotein (~21%) over the concentration range of 2 to 1000 ng/mL.

ARICEPT (donepezil hydrochloride) is a piperidine-based, reversible inhibitor of the enzyme acetylcholinesterase (AChE).

A consistent pathological change in Alzheimer's disease is the degeneration of cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. The resulting hypofunction of the cholinergic systems is thought to account for some of the clinical manifestations of dementia. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine (ACh) through reversible inhibition of its hydrolysis by AChE.

There is no evidence that donepezil alters the course of the underlying dementing process.

No specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of donepezil. However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese and Caucasians) did not affect the clearance of donepezil.

In a study of 4 patients with moderate to severe renal impairment (Cl_cr <22 mL/min/1.73 m²) the clearance of donepezil did not differ from that of 4 age and sex matched healthy subjects.

No formal pharmacokinetic study was conducted to examine age and gender related differences in the pharmacokinetic profile of donepezil. However, mean plasma donepezil concentrations measured during therapeutic drug monitoring of elderly male and female patients with Alzheimer's disease are comparable to those observed in young healthy volunteers.

Donepezil hydrochloride is extensively metabolized and is also excreted in the urine as parent drug. The rate of metabolism of donepezil hydrochloride is slow and does not appear to be saturable. There are 4 major metabolites—2 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 a single 5 mg dose of ¹⁴C-labelled donepezil hydrochloride, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as unchanged donepezil hydrochloride (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% of the total administered radioactivity was recovered from the urine and 15% was recovered from the feces (total recovery of 72%) over a period of 10 days. Approximately 28% of the labelled donepezil remained uncovered, with about 17% of the donepezil dose recovered in the urine as parent drug.

Neither food nor time of dose administration (ie, morning versus evening dose) have an influence on the rate and extent of donepezil hydrochloride absorption.

The effect of achlorhydria on the absorption of donepezil hydrochloride is unknown.