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ARICEPT

SCHEDULING STATUS:
Schedule 5

PROPRIETARY NAME
(and dosage form):

ARICEPT
Donepezil Hydrochloride

ARICEPT 5 mg Tablets
ARICEPT 10 mg Tablets

COMPOSITION
Each ARICEPT 5 mg tablet contains 5 mg donepezil hydrochloride
Each ARICEPT 10 mg tablet contains 10 mg donepezil hydrochloride
Aricept tablets contain the following inactive ingredients: lactose monohydrate, maize starch, microcrystalline cellulose, hydroxypropyl cellulose and magnesium stearate. The film coating contains talc, polyethylene glycol, hydroxypropyl methycellulose and titanium dioxide. Additionally, the 10 mg tablet contains yellow iron oxide (synthetic) as a colouring agent.

PHARMACOLOGICAL CLASSIFICATION
A 5.3 Cholinomimetics (cholinergics)

PHARMACOLOGICAL ACTION
Donepezil hydrochloride is a 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 Aricept 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 correspond closely to the effects in the cerebral cortex. In addition, significant correlation was demonstrated between plasma levels of donepezil hydrochloride, AChE inhibition and change in ADAS-cog, a sensitive and well validated scale which examines cognitive performance - including memory, orientation, attention, reason, language and praxis.
Absorption:
Oral administration of Aricept produces predictable plasma concentrations with maximal values achieved approximately 3 to 4 hours after dose 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 the 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.
Neither food nor time of administration (morning versus evening dose) affect the absorption of donepezil hydrochloride.
Distribution:
The steady state volume of distribution is 12 L/kg. Donepezil hydrochloride is approximately 96% bound to human plasma proteins. The distribution of donepezil hydrochloride 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-labelled donepezil hydrochloride, approximately 28% of the label remained unrecovered.
This suggests that donepezil hydrochloride and/or any of it’s metabolites may persist in the body for more than 10 days. The average CSF:plasma ratio for both doses, expressed as a percent of the concentration in plasma, was 15.7%.
Metabolism / Excretion:
Donepezil hydrochloride is both excreted in the urine intact and metabolised 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 - labelled donepezil hydrochloride, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil hydrochloride (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 and 14.5% was recovered from the faeces, suggesting biotransformation and urinary excretion as the primary routes of elimination.
There is no evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.
Plasma donepezil concentrations decline with a half-life of approximately 70 hours. Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil hydrochloride.
Mechanism of Action:
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. If this proposed mechanism of action is correct, donepezil’s effect may lessen as the disease process advances and fewer cholinergic neurons remain intact. There is no evidence that donepezil alters the course of the underlying process.
The enzyme AChE also occurs peripherally in red blood cells; therefore measurement of AChE activity in erythrocyte membranes provides an index for donepezil hydrochloride pharmacodynamics. This surrogate marker has been evaluated in several human pharmacokinetic/pharmacodynamic trials and in controlled clinical trials. The population plasma donepezil hydrochloride concentrations and AChE inhibition measurements verified that patients in clinical trials experienced exposure to donepezil hydrochloride and its pharmacodynamic actions as predicted.
Results from therapeutic drug monitoring showed no apparent relationship between plasma concentration and adverse drug reactions.

INDICATIONS
Aricept tablets are indicated for the symptomatictreatment of mild or moderate dementia in Alzheimer’s disease.

CONTRA-INDICATIONS
Aricept is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.
The safety of Aricept in pregnancy and lactation has not been established.
Aricept is not recommended for use in children.

WARNINGS
Treatment should be initiated and supervised by a doctor experienced in the diagnosis and treatment of Alzheimer’s dementia. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of Aricept should be reassesed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Individual response to Aricept cannot be predicted.
The use of Aricept 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.
Anaesthesia: Aricept, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.
Cardiovascular Conditions: Because of their 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. 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 of developing ulcers. e.g. those with a history of ulcer disease or those receiving concurrent nonsteriodal 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 diarrhoea, nausea and vomiting. These effects, when they occur, appeared 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 generalised convulsions. However, seizure activity may also 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. The administration of Aricept concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided.

DRUG-DRUG INTERACTIONS:
See Side Effects and Special Precautions
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 metabolised by CYP3A4 (e.g. cisapride, terfenadine) or by CYP2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 microM), 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.
Effect of Other Drugs on the Metabolism of Aricept: Ketoconazole and quinidine, inhibitors of CYP450 3A4 and 2D6 respectively, inhibit donepezil metabolism in vitro. Therefore these and other CYP3A4 inhibitors, such as itraconazole and erythromycin and CYP2D6 inhibitors such as fluoxetine, could inhibit the metabolism of donepezil. Whether there is a clinical effect of these inhibitors is not known. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by 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. Inducers of CYP2D6 and CYP3A4 (e.g. phenytoin, carbamazepine, alcohol, dexamethasone, rifampicin and phenobarbital) could increase the rate of elimination of Aricept.
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 or beta blocking agents which have an effect on cardiac conduction.

DOSAGE AND DIRECTIONS FOR USE
Adults/Elderly:
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 hydrochloride 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.
Renal & Hepatic Impairment:
A similar dose schedule can be followed for patients withrenal or mild to moderate hepatic impairment as clearance of donepezil hydrochloride is not affected by these conditions.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
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, diarrhoea, insomnia, vomiting, muscle cramps, fatigue and anorexia. These adverse events were often of mild intensity and transient, resolving during continued Aricept treatment without the need for dose modification. Other common adverse events observed were common cold, abdominal disturbance, bradycardia, sinoatrial block, atrioventricular block and minor changes in serum concentrations of muscle creatinine kinase There is evidence to suggest that the frequency of these common adverse events may be affected by rate of dose titration.
The following treatment emergent signs and symptoms 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 than placebo assigned patients: headache, pain (various locations), syncope, ecchymosis, weight decrease, arthritis, dizziness, depression, abnormal dreams, agitation, somnolence, frequent urination. In general, adverse events occurred more frequently in female patients and with advancing age.
The following adverse events have occurred in at least 1/100 patients in the clinical trial programme. 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: influenza, chest pain, toothache
Cardiovascular system: hypertension, vasodilation, atrial fibrillation, hot flushes, hypotension
Digestive system: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain
Metabolic and nutritional disorders: dehydration
Musculoskeletal: bone fracture
Nervous system: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia
Respiratory system: dyspnoea, sore throat, bronchitis
Skin and appendages: pruritis, diaphoresis, urticaria
Special senses: cataract, eye irritation, vision blurred
Urogenital system: urinary incontinence, nocturia
The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice, these frequency estimates may not apply, as conditions of use, reporting behaviour and the kinds of patients treated may differ.
There have been post-marketing reports of hallucinations, agitation, seizure, hepatitis, gastric ulcer, duodenal ulcer.
Interactions:
Drugs Highly Bound to Plasma Proteins: Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin and warfarin. Aricept at concentrations of 0.3-10 micrograms/mL did not affect the binding of furosemide (5 micrograms/mL), digoxin (2 micrograms/mL), and warfarin (3 micrograms/mL) to human albumin. Similarly, the binding of Aricept to human albumin was not affected by furosemide, digoxin and warfarin.
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 metabolised 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 microM), 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 and digoxin. No significant effects on the pharmacokinetics of these drugs were observed.
Effects of Other Drugs on the Metabolism of Aricept: Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of these inhibitors is not known. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by 30%. These increases are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway are not likely to be clinically relevant. Administration of donepezil had no effect on the pharmacokinetics of ketoconazole. 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.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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.
Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterised 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.
As in any case of overdose, general supportive measures should be utilised. Tertiary anticholinergics such as atropine may be used as an antidote for Aricept overdosage. Intravenous atropine sulphate 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).

IDENTIFICATION

Aricept 5 mg:	White, round, biconvex, film-coated tablets embossed with the word “ARICEPT”on the one side and “5”on the other side
Aricept 10 mg:	Yellow, round, biconvex, film-coated tablets embossed with the word “ARICEPT” on the one side and “10”on the other side

PRESENTATION

Aricept 5 mg tablets:	Blister strips (PVC/foil) of 2 x 14
Aricept 10 mg tablets:	Blister strips (PVC/foil) of 2 x 14

STORAGE INSTRUCTIONS
Store below 30°C. Keep out of the reach of children.

REGISTRATION NUMBERS

Aricept 5 mg tablets:	32/5.3/0315
Aricept 10 mg tablets:	32/5.3/0316

NAME AND BUSINESS ADDRESS OF APPLICANT
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
SANDTON, 2196

DATE OF PUBLICATION OF THIS PACKAGE INSERT
29 December 1997

Updated on this site: February 2005
Source: Pharmaceutical Industry
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