New Zealand - English - Medsafe (Medicines Safety Authority)
New Zealand Datasheet
1 PRODUCT NAME
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
Donepezil tablets are indicated for the treatment of vascular dementia (dementia associated
with cerebrovascular disease).
4.2 Dose and method of administration
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
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
In order to allow the earliest clinical responses to treatment to be assessed and to allow
maintained for at least one month. Donepezil tablets can be increased to a dose of
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
Precautions - Paediatric use).
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 as it is a cholinesterase inhibitor.
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.
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.
symptoms of active or occult gastrointestinal bleeding.
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
consciousness and elevated serum creatine phosphokinase levels; additional signs may
include myoglobinuria (rhabdomyolysis) and acute renal failure.
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.
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
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
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.
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
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
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
metabolism of donepezil hydrochloride is not significantly affected.
With concomitant treatment of donepezil hydrochloride and involving such medications as
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
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.
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.
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
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
Body System/Adverse Event
Percentage of Patients with any Adverse
Body as a Whole
Pain, various locations
Haematological and Lymphatic System
Metabolic and Nutritional
Body System/Adverse Event (continued)
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.
Digestive System: abdominal disturbance, bloating, constipation, drooling, dry mouth,
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,
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
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
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
Overall, the investigators judged the majority of adverse events to be mild or moderate in
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
Warnings and Precautions - Mortality in Subjects with Vascular Dementia).
Neuroleptic malignant syndrome has been associated with the use of donepezil.
There have also been post-marketing reports of abdominal pain, agitation, aggressive
hallucinations, hepatitis, heart block, haemolytic anaemia, hyponatraemia, pancreatitis and,
seizure. However, there is inadequate data to determine the causal relationship with
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
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.
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.
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.
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.
Administration of 5mg or 10mg of donepezil hydrochloride in single daily doses to patients
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
Donepezil reaches peak plasma concentration in 3 to 4 hours and has a relative oral
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
approximate steady-state is achieved within 3 weeks. Over the course of the day at steady-
affected either by time of administration (morning versus evening dose) or by food.
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
Therefore donepezil and/or its metabolites may persist in the body for more than 10 days.
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.
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).
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.
concentrations of donepezil.
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 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
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.
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.
6.3 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
7 MEDICINE SCHEDULE
Prescription Only Medicine.
REX Medical Limited
PO Box 18-119
(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
Summary of new information
Fertility section added
Reporting of adverse events added
Poison information centre contact added