Donepezil

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Donepezil hydrochloride 10 mg
Available from:
REX Medical Ltd
INN (International Name):
Donepezil hydrochloride 10 mg
Dosage:
10 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Donepezil hydrochloride 10 mg Excipient: Colloidal silicon dioxide Croscarmellose sodium Lactose monohydrate Magnesium stearate Microcrystalline cellulose Opadry yellow 04F52201 Purified water Starch
Units in package:
Blister pack, PVC/PE/PVDC/AI, 10 tablets per blister strip, Sample pack, 30 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Cipla Ltd
Therapeutic indications:
Donepezil tablets are indicated for the treatment of mild, moderate and severe Alzheimer's disease.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PE/PVDC/AI, 10 tablets per blister strip, Sample pack - 30 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PE/PVDC/AI, 10 tablets per blister strip - 90 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PE/PVDC/AI, 10 tablets per blister strip - 100 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, PVC/PE/PVDC/AI, 10 tablets per blister strip - 250 tablets - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-7722a
Authorization date:
2006-06-30

New Zealand Datasheet

1 PRODUCT NAME

Donepezil

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Donepezil hydrochloride 5mg and 10mg tablets.

3 PHARMACEUTICAL FORM

Donepezil film-coated tablets for oral administration are supplied containing 5 mg donepezil

hydrochloride, equivalent to 4.56 mg donepezil free base, or 10 mg donepezil hydrochloride,

equivalent to 9.12 mg donepezil free base.

Donepezil 5mg tablets are white, circular, biconvex film-coated tablets, embossed ‘DPZ’ on

one side and ‘5’ on the other side. The tablet diameter is approximately 7.1 mm.

Donepezil 10mg tablets are yellow, circular, biconvex film-coated tablets, embossed ‘DPZ’

on one side and ‘10’ on the other side. The tablet diameter is approximately 9.1 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Donepezil tablets are indicated for the treatment of mild, moderate and severe Alzheimer's

disease.

Donepezil tablets are indicated for the treatment of vascular dementia (dementia associated

with cerebrovascular disease).

4.2 Dose and method of administration

Adults/Elderly

It is recommended that the diagnosis and treatment of Alzheimer’s disease should be

initiated and supervised by a doctor with appropriate experience in Alzheimer’s disease.

Individual patient response to donepezil therapy cannot be predicted.

Where a therapeutic benefit for the patient exists, then treatment should be continued.

Where there is no longer evidence of a therapeutic effect, discontinuation of therapy should

be considered. The physician should periodically assess the therapeutic effect using input

from the patient and caregiver. Donepezil usage in patients with other types of memory

impairment (e.g. age-related cognitive decline) or other types of dementia has not been

established.

5mg and 10mg dosages of donepezil hydrochloride administered once daily in controlled

clinical trials have been shown to be effective. With the 10mg dose per day there is no

statistically significant evidence that a greater treatment effect is obtained from this higher

dose versus the 5mg/day, however based on analysis of group data there is a suggestion

that some additional benefits may accrue to some patients using 10mg/day.

Initial treatment should be started at 5mg/day once a day. Donepezil tablets should be taken

in the evening, orally, just prior to retiring. Donepezil tablets can be taken with or without

food.

In order to allow the earliest clinical responses to treatment to be assessed and to allow

steady-state

concentrations

donepezil

achieved,

5mg/day

dosage

should

maintained for at least one month. Donepezil tablets can be increased to a dose of

10mg/day

(once-a-day

dosing)

after

one-month

clinical

assessment

treatment

5mg/day.

10mg per day is the maximum recommended daily dose. No doses over 10mg per day have

been studied in clinical trials.

After discontinuation of treatment using donepezil tablets a gradual abatement of the

beneficial effects of donepezil tablets occurs. After abrupt cessation of therapy there is no

evidence of any rebound effect.

Renal & Hepatic Impairment

For patients with mild to moderate hepatic or renal impairment, a similar dose schedule can

be followed as the clearance of donepezil is not significantly affected by these conditions.

Use in Children

usage

Donepezil

tablets

children

recommended

(see Warnings

Precautions - Paediatric use).

4.3 Contraindications

Any known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any of

the excipients is a contraindication for Donepezil tablets.

4.4 Special warnings and precautions for use

Anaesthesia

Donepezil

hydrochloride

exaggerate

succinylcholine-type

muscle relaxation

during

anaesthesia as it is a cholinesterase inhibitor.

Cardiovascular Conditions

Vagotonic effects on heart rate (e.g. bradycardia) may be induced by cholinesterase

inhibitors such as donepezil. The potential risk for this action may be increased particularly in

patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions,

such as atrioventricular or sinoatrial block.

Gastrointestinal Conditions

Cholinesterase inhibitors such as donepezil will cause an increase in cholinergic activity.

This increase in activity may be likely to cause an increase in gastric secretions. The clinical

studies with donepezil hydrochloride did not show an increased incidence of either peptic

ulcer disease or gastrointestinal bleeding as compared to the placebo. However, patients

with certain risk factors such as a history of ulcer disease or those receiving concurrent

nonsteroidal anti-inflammatory drugs (NSAIDS) may be more likely to develop ulcers.

Patients

with

risk

factors

should

closely

monitored

stomach

ulcers,

including

symptoms of active or occult gastrointestinal bleeding.

Genitourinary

Cholinomimetics may cause bladder outflow obstruction, however this was not observed in

clinical trials of donepezil hydrochloride.

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS) has been reported in patients treated with donepezil

with or without concomitant antipsychotic medication. NMS is a potentially life-threatening

condition

characterised

hyperthermia,

muscle

rigidity,

autonomic

instability,

altered

consciousness and elevated serum creatine phosphokinase levels; additional signs may

include myoglobinuria (rhabdomyolysis) and acute renal failure.

Neurological Conditions

Cholinomimetics may have some potential to cause generalised convulsions. However, it is

difficult to attribute this event to the administration of donepezil alone as seizure activity may

also be a manifestation of Alzheimer's disease. Cholinomimetics have the potential to

exacerbate or induce extrapyramidal symptoms.

Pulmonary Conditions

Cholinesterase inhibitors such as donepezil should be prescribed with caution to patients

with a history of asthma or obstructive pulmonary disease because of their cholinomimetic

actions.

The co-administration of other inhibitors of acetylcholinesterase, agonists or antagonists of

the cholinergic system and donepezil hydrochloride should be avoided.

Mortality in Subjects with Vascular Dementia

Three clinical trials studying patients meeting the NINDS-AIREN criteria for probable or

possible vascular dementia (VaD) and excluding patients with a diagnosis of Alzheimer's

disease were conducted for 6 months duration.

In the first study, the mortality rates were 7/199 (3.5%) on placebo, 5/206 (2.4%) on

donepezil hydrochloride 10mg, and 2/198 (1.0%) on donepezil hydrochloride 5mg. In the

second study, the mortality rates were 1/193 (0.5%) on placebo, 3/215 (1.4%) on donepezil

hydrochloride 10mg and 4/208 (1.9%) on donepezil hydrochloride 5mg. In the third study,

the mortality rates were 0/326 (0%) on placebo (p<0.02), and 11/648 (1.7%) on donepezil

hydrochloride 5mg.

For the three VaD studies combined, the mortality rate in the placebo group (1.1%) was

smaller numerically than the donepezil hydrochloride group (1.7%) however, there was no

significant difference statistically. Various vascular related causes appeared to be the reason

for the majority of deaths in patients taking either donepezil hydrochloride or placebo. This is

to be expected in the elderly population with underlying vascular disease. There was no

difference in the rate of occurrence of all serious non-fatal and fatal vascular events as

analysed in the donepezil hydrochloride group relative to placebo.

Mortality in Subjects with Alzheimer’s Disease

In the current approved indications of mild, moderate and severe Alzheimer's disease there

is no evidence of an increased risk of mortality. When Alzheimer's disease studies were

pooled (n=4146), the mortality rate in the placebo group numerically exceeded that in the

donepezil hydrochloride group.

Paediatric Use

Donepezil tablets are not recommended for use in children.

4.5 Interaction with other medicines and other forms of interaction

Drugs Highly Bound to Plasma Proteins

In vitro drug displacement studies have been performed between donepezil hydrochloride

which is a highly bound drug (96%) and other drugs such as warfarin, frusemide, and

digoxin. Donepezil hydrochloride did not affect the binding of warfarin (3µg/mL), frusemide

(5µg/mL), digoxin (2ng/mL) to human albumin at donepezil hydrochloride concentrations of

0.3-10µg/mL. Similarly the binding of donepezil hydrochloride to human albumin was not

affected by warfarin, frusemide, and digoxin.

Effect of Donepezil Hydrochloride on the Metabolism of Other Drugs

effect

donepezil

hydrochloride

clearance

other

drugs that

also

metabolised by CYP 3A4 (e.g. terfenadine, cisapride) or CYP 2D6 (e.g. imipramine) has not

been established as there have been no in vivo clinical trials. Given the therapeutic plasma

concentrations of donepezil (164 nM) with in vitro studies and the low rate of binding to these

enzymes (mean Ki about 50-130 µM), there is little indication of likelihood of interference. It

is not known whether donepezil hydrochloride has any potential for enzyme induction.

No significant effects on the pharmacokinetics of digoxin theophylline, cimetidine or warfarin

were observed in formal pharmacokinetic studies evaluating the potential for interactions

with donepezil hydrochloride.

Sertraline, thioridazine or risperidone metabolism is not inhibited by donepezil hydrochloride

and/or any of its metabolites

Donepezil hydrochloride administered for 21 days in a study of Parkinson's disease patients

on optimal treatment with L-dopa/carbidopa, had no effect on L-dopa or carbidopa blood

levels. No effects on motor activity were observed in this study.

Effect of Other Drugs on the Metabolism of Donepezil Hydrochloride

Donepezil metabolism in vitro is inhibited by ketoconazole and quinidine (which are inhibitors

CYP450,

CYP3A4

CYP2D6,

respectively).

cytochrome

P450

isoenzymes;

CYP3A4 and to a lesser extent CYP2D6 are involved in the metabolism of donepezil during

in vitro studies. These and other CYP2D6 inhibitors (e.g. fluoxetine) and CYP3A4 inhibitors

(e.g. erythromycin and itraconazole) could inhibit the metabolism of donepezil.

It is not known if these inhibitors have a clinical effect. In healthy volunteers, in two studies

the mean donepezil concentrations increased by about 30% with ketoconazole. These

increases are not likely to be clinically relevant and are smaller than those produced by

ketoconazole for other agents sharing the CYP3A4 pathway. The pharmacokinetics of

ketoconazole was not affected by administration of donepezil.

Inducers of CYP2D6 and CYP3A4 (e.g. carbamazepine phenytoin, rifampicin Phenobarbital,

alcohol and dexamethasone) could increase the rate of elimination of donepezil. Such drug

combinations that effect this CYP 2D6 and CYP 3A4 pathway should be used with care as

the magnitude of inhibition or induction is unknown.

Formal pharmacokinetic studies with donepezil hydrochloride and concurrent administration

digoxin,

cimetidine,

thioridazine,

risperidone

sertraline

demonstrated

that

metabolism of donepezil hydrochloride is not significantly affected.

With concomitant treatment of donepezil hydrochloride and involving such medications as

succinylcholine,

other

neuro-muscular

blocking

agents

cholinergic

agonists

beta

blocking agents which have effects on cardiac conduction, there is also the potential for

synergistic activity. However in an in vitro study, donepezil hydrochloride had minimal effects

on hydrolysis of succinylcholine.

4.6 Fertility, pregnancy and lactation

Pregnancy

No evidence of teratogenic potential of donepezil was found in teratology studies conducted

in pregnant rats at doses up to 16 mg/kg/day and in pregnant rabbits at doses up to 10

mg/kg/day. This dose in rats resulted in a systemic drug exposure in excess of human

values, however, the extent of systemic drug exposure is not known in the rabbits.

Treatment of pregnant rats with an oral donepezil dose of 10mg/kg/day from late gestation to

the end of lactation resulted in a slight increase in incidence of stillborn pups, and slightly

reduced pup survival through day 4 postpartum.

In pregnant women, there are no adequate or well-controlled studies. A decision to use

donepezil should be made by the physician in pregnancy, only if the potential benefit justifies

the potential risk to the foetus.

Breast feeding

Oral treatment of donepezil in nursing rats did show excretion of donepezil and/or its

metabolites into milk, with milk concentrations similar to those in plasma. It is not known

whether donepezil hydrochloride is excreted in human breast milk and there are no studies

in lactating women. Based on the studies of rats, women on donepezil should not breast

feed as there is a possibility of donepezil being excreted in milk.

Fertility

In rats up to 10 mg/kg/day donepezil hydrochloride had no effect on fertility. At the maximum

recommended human clinical dose of 10 mg/day in male and female rats based on AUC, the

rats achieved a tissue exposure equivalent to approximately twice that in humans

4.7 Effects on ability to drive and use machines

Driving performance and the ability to use machinery may be compromised in patients with

Alzheimer's disease and vascular dementia. Donepezil can cause muscle cramps, dizziness

and fatigue, mainly when initiating or increasing the dose. Patient’s ability to continue driving

or operating complex machines of patients should be routinely evaluated by the physician.

4.8 Undesirable effects

Mild to Moderately Severe Alzheimer's Disease Clinical Trials

Most adverse events are mild in severity and transient. The most common (incidence ≥ 5%

and twice the frequency of placebo) were diarrhoea, fatigue, insomnia, muscle cramps,

nausea and vomiting. Other common adverse events (incidence ≥ 5% and ≥ placebo) were

abdominal disturbance, accident, common cold, dizziness, headache and pain. More rarely,

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

Adverse events including asthenia was observed during long-term but not the short-term

trials (incidence ≥ 5% and twice the frequency of placebo).

Minor increases in serum concentrations of creatinine kinase were the only observed notable

abnormality in laboratory values associated with treatment.

Adverse Events Leading to Discontinuation

The rate of donepezil hydrochloride discontinuation for the 5mg/day treatment group was

very similar to that of the placebo group at approximately 5% in clinical trials of mild to

moderate Alzheimer’s disease. Treatment discontinuation rate was higher (13%) in patients

who received rapid escalations in dose from 5mg/day to 10mg/day over 7 days. Nausea,

vomiting and diarrhoea were the most common reasons for discontinuing therapy.

These symptoms were generally mild and transient resolving within 2 days in those patients

who did not discontinue therapy and continued usage at the 10 mg/day dose rate. There is

evidence to suggest that the rate of titration may affect the frequency of these common

adverse events.

Table 1:

In Controlled Clinical Trials of Patients Receiving Donepezil Hydrochloride; Adverse Events

Reported in at Least 2% of patients and at a Higher Frequency than Placebo-Treated

Patients

Body System/Adverse Event

Donepezil

Placebo

(n=747)

(n=355)

Percentage of Patients with any Adverse

Event

74%

72%

Body as a Whole

Accident

Fatigue

Headache

Pain, various locations

Cardiovascular

Syncope

Digestive System

Anorexia

Diarrhoea

Nausea

Vomiting

Haematological and Lymphatic System

Ecchymosis

Metabolic and Nutritional

Weight Decrease

Musculoskeletal System

Arthritis

Muscle Cramps

Body System/Adverse Event (continued)

Donepezil

Placebo

Nervous System

Abnormal Dreams

Depression

<1%

Dizziness

Insomnia

Somnolence

<1%

Urogenital

Frequent urination

Other Adverse Events Observed During Clinical Trials

Clinical investigators recorded signs and symptoms experienced by the patients receiving

donepezil using their own terminology. The following summarises adverse events that

occurred at least twice, with the exception of those already listed in the previous table and

judged to be possibly, or definitely, related to donepezil hydrochloride treatment.

Frequent adverse events: - those occurring in at least 1/100 patients and infrequent

adverse events - those occurring in 1/100 to 1/1000 patients are included.

Body as a Whole: infection, generalised weakness, assault, influenza.

Cardiovascular

System:

angina

pectoris,

flushes,

hypertension,

hypotension,

vasodilation.

Digestive System: abdominal disturbance, bloating, constipation, drooling, dry mouth,

epigastric

pain,

eructation,

faecal

incontinence,

flatulence,

gastrointestinal

bleeding,

increased appetite, stomach upset, increased transaminases.

Metabolic and Nutritional Disorders: oedema of extremities, dehydration.

Musculoskeletal System: weakness in muscles.

Nervous System: abnormal crying, agitation, anxiety, aphasia, ataxia, coldness (localised),

confusion, delusions, hallucinations, hypokinesia, irritability, increased libido, muscle spasm,

nervousness, paraesthesia, paranoia, restlessness (localised), tremor, aggression, vertigo,

wandering.

Respiratory System: coughing, dyspnoea, rhinitis.

Skin and Appendages: abrasion, diaphoresis, puritus, rash.

Special Senses: cataract, ear disorder, vision blurred.

Urogenital System: nocturia, urinary incontinence, urinary tract infection.

Severe Alzheimer's Disease Clinical Trials

In controlled clinical studies, a total of 573 patients with severe Alzheimer's disease were

treated with donepezil hydrochloride. Of these patients, 441 (77%) completed the studies.

The mean duration of treatment for all donepezil hydrochloride groups was 148.4 days

(range 1-231 days).

For severe Alzheimer’s disease the incidence profile for adverse events was similar to that of

mild to moderate Alzheimer's disease. The most common adverse events, defined as those

occurring at a frequency of at least 5% in patients and twice the placebo rate, were

aggression,

diarrhoea,

nausea.

Other

less

common

adverse

events

leading

discontinuation included aggression, decreased appetite, diarrhoea, nausea, urinary tract

infection, and vomiting.

There were no adverse events occurring in at least 2% of patients and adverse events seen

with

donepezil

hydrochloride

therapy

numbered

twice

incidence

seen

placebo

patients. In clinical trials the rate of discontinuation in severe Alzheimers due to adverse

events was 11.3% in patients treated with donepezil hydrochloride, compared to 6.7% in the

placebo group.

Overall, the investigators judged the majority of adverse events to be mild or moderate in

intensity.

Vascular Dementia Clinical Trials

The types and relative proportions of adverse events associated with donepezil were similar

in the patients with Alzheimer’s disease and vascular dementia in a comparison of the

studies. In the combined vascular dementia studies the mortality rate in the placebo group

(1.1%)

numerically

lower

than

in the

donepezil

hydrochloride

group (1.7%)

(see

Warnings and Precautions - Mortality in Subjects with Vascular Dementia).

Post-marketing Experience

Neuroleptic malignant syndrome has been associated with the use of donepezil.

There have also been post-marketing reports of abdominal pain, agitation, aggressive

behaviour,

cholecystitis,

duodenal

ulcer,

gastric

ulcer,

gastrointestinal

haemorrhage,

hallucinations, hepatitis, heart block, haemolytic anaemia, hyponatraemia, pancreatitis and,

seizure. However, there is inadequate data to determine the causal relationship with

donepezil hydrochloride.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Animal Study Data

Following administration of a single oral dose in mice, rats and dogs, the estimated median

lethal dose of donepezil hydrochloride is 45, 32 and 15mg/kg, respectively, or approximately

225, 160 and 75 times the maximum recommended human dose of 10 mg per day. In

animals dose-related signs of cholinergic stimulation were observed and included reduced

spontaneous movement, prone position, lacrimation, staggering gait, clonic convulsions,

salivation, depressed respiration, fasciculation, lower body surface temperature, and miosis.

Cholinergic Crisis

A cholinergic crisis can result from overdosage with cholinesterase inhibitors. This is

characterised by bradycardia, collapse, convulsions, hypotension, respiratory depression,

salivation, severe nausea, sweating and vomiting. If respiratory muscles are involved,

increased muscle weakness is a possibility and may result in death.

Treatment

General

supportive

measures

should

utilised,

with

most

overdoses.

Donepezil

hydrochloride

overdosage

counteracted

with

tertiary

anticholinergics

such

atropine. Intravenous atropine sulfate titrated to effect is recommended with an initial dose of

1.0 to 2.0 mg IV with subsequent doses based on clinical response. Co-administration of

quarternary anticholinergics (such as glycopyrrolate) with other cholinomimetics has caused

atypical responses in blood pressure and heart rate. It is not known whether dialysis

(peritoneal dialysis, haemofiltration or haemodialysis) can remove donepezil hydrochloride

and/or its metabolites.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-dementia drugs; anticholinesterase; ATC-code N06DA02.

Alzheimer’s disease is associated with a relative decrease in cholinergic system activity in

the cerebral cortex and other areas of the brain. Donepezil hydrochloride is understood to

exert its therapeutic effect in the central nervous system by enhancing cholinergic function.

This

accomplished

reversible

inhibition

acetylcholine

hydrolysis

acetylcholinesterase, which increases the concentration of acetylcholine.

Donepezil hydrochloride was found in vitro to be over 1000 times more potent an inhibitor of

acetylcholinesterase than of butyrylcholinesterase, an enzyme which is present mainly

outside the central nervous system.

Alzheimer's Disease

Administration of 5mg or 10mg of donepezil hydrochloride in single daily doses to patients

with

Alzheimer’s

dementia,

clinical

trials,

produced

steady-state

inhibition

acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6% and 77.3%,

respectively when measured post dose. The donepezil hydrochloride induced inhibition of

acetylcholinesterase (AChE) 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, change in ADAS-cog and AChE inhibition. ADAS-cog is a

sensitive and well validated scale which examines cognitive performance including attention,

language, memory, orientation, praxis and reason.

5.2 Pharmacokinetic properties

Absorption

Donepezil reaches peak plasma concentration in 3 to 4 hours and has a relative oral

bioavailability

100%.

Plasma

concentrations

area

under

curve

rises

proportionally according to dose and therefore the oral administration of donepezil produces

highly predictable plasma concentrations.

Administration of multiple single-daily doses results in a gradual approach to steady state as

terminal

disposition

half-life

approximately

hours.

After

initiation

therapy,

approximate steady-state is achieved within 3 weeks. Over the course of the day at steady-

state,

related

pharmacodynamic

activity

plasma

donepezil

hydrochloride

concentrations

show

little

variability. The

absorption

donepezil

hydrochloride

affected either by time of administration (morning versus evening dose) or by food.

Distribution

Donepezil hydrochloride is approximately 96% bound to human plasma proteins. The steady

state volume of distribution is 12L/kg. The donepezil distribution in various body tissues has

not been studied definitively. In healthy male volunteers after a single 5mg dose of C

labeled donepezil hydrochloride in a mass balance study 240 hours after administration,

approximately 28% of the label remained un-recovered. Expressed as a percentage of the

concentration

plasma,

average

CSF:plasma

ratio

both

doses,

15.7%.

Therefore donepezil and/or its metabolites may persist in the body for more than 10 days.

Metabolism

Donepezil is extensively metabolised into four major metabolites, two of which are known to

be active and a number of minor metabolites, not all of which have been identified.

Donepezil’s

three

human

metabolites

have

undergone

extensive

safety

testing

animals. These metabolites comprise an N-oxidation product and two O-demethylated

derivatives. Donepezil is metabolised by CYP450 isoenzymes, CYP3A4 and CYP2D6 and

undergoes glucuronidation. Donepezil’s rate of metabolism is slow and does not appear to

be saturable. Formal pharmacokinetic studies are consistent with these results which show

that donepezil and/or its metabolites do not inhibit the metabolism of warfarin, theophylline,

digoxin, or cimetidine in humans. Concurrent administration of cimetidine or digoxin in

pharmacokinetic studies does not affect the metabolism of donepezil. (See Interactions).

Excretion

Donepezil is excreted in the urine intact. Plasma radioactivity expressed as a percent of the

administered dose, following administration of C

-labeled donepezil, was present primarily

as intact donepezil (53%), 6-O-desmethyl donepezil (11%), which has been reported to

inhibit AChE to the same extent as donepezil in vitro and was found in the plasma at

concentrations equal to about 20% of donepezil.

Over a period of 10 days, approximately 57% of the total radioactivity was recovered in urine

and faeces, with about 17% of the donepezil dose recovered in the urine as unchanged,

while 28% remained unrecovered. Donepezil plasma concentrations decline with a half-life

of approximately 70 hours. There is no evidence to suggest enterohepatic recirculation of

donepezil and/or any of its metabolites.

Sex,

smoking

history

race

have

clinically

significant

influence

plasma

concentrations of donepezil.

Pharmacokinetic/dynamic properties

Donepezil in the central nervous system, as an inhibitor of AChE, augments cholinergic

function, thereby providing its therapeutic benefit. AChE activity in erythrocyte membranes

provides a measurement index for donepezil pharmacodynamics as the enzyme AChE also

occurs peripherally in red blood cells. In several human pharmacokinetic/pharmacodynamic

controlled clinical trials, this surrogate marker has been evaluated.

In clinical trials the red blood cell AChE inhibition measurements and the population plasma

donepezil

concentration

measurements

verified

that

patients

experienced

exposure

donepezil hydrochloride and its pharmacodynamic actions as predicted.

There was no apparent relationship from therapeutic drug monitoring shown between

plasma concentration and adverse drug reactions.

5.3 Preclinical safety data

Mutagenicity

Following oral administration in rat primary hepatocyte cultures, donepezil did not induce

unscheduled DNA synthesis. With in vitro assays (bacterial and in the mouse lymphoma

forward mutation) donepezil hydrochloride was non mutagenic. In cultures of Chinese

hamster lung cell, using the chromosome aberration test, some clastogenic effects were

observed in the in vivo mouse micronucleus model.

Carcinogenicity

In long-term studies in rats and mice with dietary dosing of donepezil there was no evidence

found of carcinogenicity. The mice had peak plasma concentrations of up to 17 times that in

humans at the maximum recommended clinical dose of 10 mg/day and the rats had peak

plasma concentrations from 6-19 times the maximum human recommended dose.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Colloidal silicon dioxide, Croscarmellose sodium, Lactose monohydrate, Magnesium

stearate, Microcrystalline cellulose, Opadry yellow 04F52201, Purified water, Starch.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Shelf life is 36 months (3 years) from manufacture.

6.4 Special precautions for storage

Store at or below 25°C.

6.5 Nature and contents of container

Donepezil 5 mg and 10 mg tablets are available in blisters of 90, 100 or 250 tablets.

6.6 Special precautions for disposal and other handling

Not applicable.

7 MEDICINE SCHEDULE

Prescription Only Medicine.

8 SPONSOR

REX Medical Limited

PO Box 18-119

Glen Innes

Auckland

(09) 574 6060

(09) 574 6070

9 DATE OF FIRST APPROVAL

12 August 2010

10 DATE OF REVISION OF THE TEXT

17 September 2018

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Fertility section added

Section added

Reporting of adverse events added

Poison information centre contact added

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