ARICEPT*

Donepezil hydrochloride

5 mg, 10 mg tablets

Presentation

ARICEPT film-coated, round tablets, containing either 5 mg or 10 mg donepezil hydrochloride equivalent to 4.56 mg or 9.12 mg donepezil free base, respectively. ARICEPT 5 mg tablets: white film-coated debossed tablets, marked "ARICEPT" on one side and "5" on the other side. ARICEPT 10 mg tablets: yellow film-coated debossed tablets, marked "ARICEPT" on one side and "10" on the other side.

The inactive ingredients are lactose, maize starch, microcrystalline cellulose, hydroxypropyl cellulose and magnesium stearate. The film coating contains talc, polyethylene glycol, hydroxypropyl methylcellulose and titanium dioxide.

Additionally, the 10 mg tablet contains yellow iron oxide (synthetic) as a colouring agent.

Uses

Actions

Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride is over 1000 times more potent an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme which is present mainly outside the central nervous system.

In patients with Alzheimer's dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of donepezil hydrochloride produced steady-state inhibition of acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6% and 77.3%, respectively when measured post dose. The inhibition of acetylcholinesterase (AChE) in red blood cells by donepezil hydrochloride has been shown to correlate to changes in ADAS-cog, a sensitive scale which examines selected aspects of cognition. The potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been studied.

In the clinical trials, an analysis was done at the conclusion of 6 months of donepezil treatment using a combination of three efficacy criteria: the ADAS-Cog (a measure of cognitive performance), the Clinician Interview Based Impression of Change with Caregiver Input (a measure of global function) and the Combined Activities of Daily Living Domains of the Clinical Dementia Rating Scale (a measure of capabilities in community affairs, home and hobbies and personal care).

Patients who fulfilled the criteria listed below were considered treatment responders.

*p<0.05

**p<0.01

Donepezil produced a dose-dependent statistically significant increase in the percentage of patients who were judged treatment responders.

Pharmacokinetics

Absorption

Maximum plasma levels are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve rise in proportion to the dose. The terminal disposition half-life is approximately 70 hours, thus, administration of multiple single-daily doses results in gradual approach to steady state. Approximate steady-state is achieved within 3 weeks after initiation of therapy. Once at steady-state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day.

Food did not affect the absorption of donepezil hydrochloride.

Distribution

Donepezil is approximately 95% bound to human plasma proteins. The plasma protein binding site of the active metabolite 6-O-desmethyldonepezil is not known. The distribution of donepezil in various body tissues has not been definitively studied. However, in a mass balance study conducted in healthy male volunteers, 240 hours after the administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, approximately 28% of the label remained un-recovered. This suggests that donepezil and/or its metabolites may persist in the body for more than 10 days.

Metabolism/Excretion

Donepezil is both excreted in the urine intact and metabolized by the cytochrome P450 system to multiple metabolites, not all of which have been identified. Following administration of a single 5 mg dose of ¹⁴C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (30%), 6-O-desmethyl donepezil (11% - only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%) and the glucuronide conjugate of 5-O-desmethyl donepezil (3%). Approximately 57% of the total administered radioactivity was recovered from the urine (17% as unchanged donepezil), and 14.5% was recovered from the feces, suggesting biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to suggest enterohepatic recirculation of donepezil and/or any of its metabolites. Plasma donepezil concentrations decline with a half-life of approximately 70 hours. Gender, race and smoking history have no clinically significant influence on plasma concentrations of donepezil. The pharmacokinetics of donepezil have not been formally studied in healthy elderly subjects or in Alzheimer's patients. However mean plasma levels in patients closely agree with those of young healthy volunteers.

Indications

ARICEPT (donepezil hydrochloride) is indicated for the treatment of mild to moderately severe Alzheimer's Dementia.

Dosage and Administration

The dosages of ARICEPT shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once daily. Although there is no statistically significant evidence that a greater treatment effect is obtained from the use of the 10 mg dose, there is a suggestion, based on analysis of group data, that some additional benefits may accrue to some patients from the use of the higher dose.

Treatment is initiated at 5 mg/day (once-a-day dosing). ARICEPT should be taken orally, in the evening, just prior to retiring. The 5 mg/day dose should be maintained for at least one month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of donepezil to be achieved. Following a one-month clinical assessment of treatment at 5 mg/day, the dose of ARICEPT can be increased to 10 mg/day (once-a-day dosing).

The maximum recommended daily dose is 10 mg. Doses greater than 10 mg/day have not been studied in clinical trials.

Upon discontinuation of treatment, a gradual abatement of the beneficial effects of ARICEPT is seen. There is no evidence of a rebound effect after abrupt discontinuation of therapy.

A similar dose schedule can be followed for patients with renal or mild to moderate hepatic impairment as clearance of donepezil is not significantly affected by these conditions.

Use In Children

Donepezil hydrochloride is not recommended for use in children.

Contraindications

Donepezil hydrochloride is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.

Warnings and Precautions

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be made according to accepted guidelines (e.g., DSM IV, ICD 10). Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of donepezil hydrochloride should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Individual response to donepezil hydrochloride cannot be predicted. The use of donepezil in patients with severe Alzheimer's dementia, other types of dementia or other types of memory impairment (e.g., age-related cognitive decline), has not been established.

Anesthesia

Donepezil hydrochloride, as a cholinesterase inhibitor, may exaggerate succinylcholine-type muscle relaxation during anesthesia.

Cardiovascular Conditions

Because of the pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important to patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions, such as sinoatrial or atrioventricular block.

Gastrointestinal Conditions

Patients at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDS), should be monitored for symptoms. However, the clinical studies with donepezil hydrochloride showed no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Genitourinary

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

Neurological Conditions

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.

The administration of donepezil hydrochloride concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided.

Preclinical Safety Data

General

Extensive testing in experimental animals has demonstrated that donepezil hydrochloride causes few effects other than the intended harmacological effects consistent with its action as a cholinergic stimulator.

Mutagenicity

Donepezil hydrochloride is not mutagenic in bacterial and mammalian cell mutation assays. Some clastogenic effects were observed in vitro at concentrations overtly toxic to the cells and more than 3000 times the steady-state plasma concentrations. No clastogenic or other genotoxic effects were observed in the mouse micronucleus model in vivo. Full-life carcinogenicity studies of donepezil hydrochloride have been completed in mice and rats. No evidence of a tumorigenic effect was seen when donepezil hydrochloride was given to mice for at least 88 weeks at doses up to 180 mg/kg/day (900 times the maximal recommended human dose on a mg/kg basis), or to rats for at least 104 weeks at doses up to 30 mg/kg/day (150 times the maximal recommended human dose on a mg/kg basis).

Fertility

Donepezil hydrochloride had no effect on fertility in rats, and was not teratogenic in rats or rabbits, but had a slight effect on still births and early pup survival when administered to pregnant rats at 50 times (body mass basis) the human dose (see Use in Pregnancy and Lactation).

Use in Pregnancy and Lactation

Teratology studies conducted in pregnant rats at doses up to about 80 times the human dose (body mass basis) and in pregnant rabbits at doses up to approximately 50 times the human dose did not disclose any evidence for teratogenic potential. However, in a study in which pregnant rats were given approximately 50 times the human dose from day 17 of gestation through day 20 postpartum, there was a slight increase in stillbirths and a slight decrease in pup survival through day 4 postpartum. No effect was observed at the next lower dose tested, approximately 15 times the human dose.

There are no adequate or well-controlled studies in pregnant women. Donepezil should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether donepezil hydrochloride is excreted in human breast milk and there are no studies in lactating women. Donepezil has no indication for use in nursing mothers.

Driving, Use of Machinery

Alzheimer's dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, donepezil can cause fatigue, dizziness and muscle cramps, mainly when initiating or increasing the dose. The ability of Alzheimer patients on donepezil to continue driving or operating complex machines should be routinely evaluated by the treating physician.

Adverse Effects

Most adverse events are mild in severity and transient in nature. The most common (incidence = 5% and twice the frequency of placebo) were diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia.

Other common adverse events (incidence = 5% and = placebo) were headache, pain, accident, common cold, abdominal disturbance and dizziness.

Cases of syncope, bradycardia, sinoatrial block and atrioventricular block were observed.

No notable abnormalities in laboratory values associated with treatment were observed except for minor increases in serum concentrations of creatinine kinase.

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 that 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.

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 included nausea, diarrhoea, 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 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 behaviour, 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 ARICEPT-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 at Least 2% of Patients Receiving ARICEPT and at a Higher Frequency than Placebo-treated Patients

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 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 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 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, oedema face, periorbital oedema, hernia hiatal, abscess, cellulitis, chills, generalised 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: faecal 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 oedema, epigastric distress, gastroenteritis, increased transaminases, haemorrhoids, ileus, increased thirst, jaundice, melaena, polydipsia, duodenal ulcer, stomach ulcer.

Endocrine System

Infrequent: diabetes mellitus, goitre.

Haemic and Lymphatic System

Infrequent: anaemia, 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 haemorrhage, transient ischaemic attack, emotional lability, neuralgia, coldness (localised), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localised), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing.

Respiratory System

Frequent: dyspnoea, sore throat, bronchitis;

Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnoea, snoring.

Skin and Appendages

Frequent: pruritus, diaphoresis, urticaria;

Infrequent: dermatitis, erythema, skin discolouration, 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 haemorrhage, otitis externa, otitis media, bad taste, conjunctival haemorrhage, ear buzzing, motion sickness, spots before eyes

Urogenital System

Frequent: urinary incontinence, nocturia;

Infrequent: dysuria, haematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.

Post-marketing Experience

There have been post-marketing reports of hallucinations, agitation, aggressive behavior, seizure, hepatitis, gastric ulcer, duodenal ulcer, and gastrointestinal hemorrhage.

Interactions

The clinical experience with donepezil hydrochloride is presently limited and all possible interactions may not yet have been observed. The prescribing physician should be aware of new, as yet unknown interactions with donepezil. Donepezil hydrochloride and/or any of its metabolites does not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil hydrochloride is not affected by concurrent administration of digoxin or cimetidine. In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil. Drug interaction studies performed in vitro show that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil metabolism. Therefore these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil. In two studies in healthy volunteers, ketoconazole increased mean donepezil concentrations by about 30%. These increases are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway and are not likely to be clinically relevant. Administration of donepezil had no effect on the pharmacokinetics of ketoconazole.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care. Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving such medications as succinylcholine, other neuro-muscular blocking agents or cholinergic agonists or beta blocking agents which have effects on cardiac conduction.

Overdosage

Animal Study Data

The estimated median lethal dose of donepezil hydrochloride following administration of a single oral dose in mice and rats is 45 and 32 mg/kg, respectively, or approximately 225 and 160 times the maximum recommended human dose of 10 mg per day. Dose-related signs of cholinergic stimulation were observed in animals and included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, fasciculation and lower body surface temperature.

Cholinergic Crisis

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.

Treatment

As in any case of overdosage, general supportive measures should be utilized. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil hydrochloride 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 donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

Pharmaceutical Precautions

Store Below 30°C (86°F)

Package Quantities

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