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DONEPEZIL 5 MG ORODISPERSIBLE TABLETS

Active substance(s): DONEPEZIL HYDROCHLORIDE / DONEPEZIL HYDROCHLORIDE / DONEPEZIL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Donepezil 5 mg Orodispersible Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each orodispersible tablet contains 5 mg donepezil hydrochloride.
Excipients:
8.4 mg aspartame/orodispersible tablet
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Orodispersible tablet
White, round, flat orodispersible tablet with embossment “5” on one side and
plain on the other side

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Donepezil is indicated for the symptomatic treatment of mild to moderately
severe Alzheimer’s dementia.

4.2

Posology and method of administration
Adults/Elderly:

Treatment is initiated at 5 mg/day (once-a-day dosing). The orodispersible
tablet should be taken orally, in the evening, just prior to retiring. It should be
placed on the tongue and allowed to disintegrate before swallowing with or
without water, according to patient preference. 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 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.
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). Therapy with
donepezil should only be started if a caregiver is available who will regularly
monitor drug intake for the patient. Maintenance treatment can be continued
for as long as a therapeutic benefit for the patient exists. Therefore, the clinical
benefit of donepezil 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 cannot be predicted.
Upon discontinuation of treatment, a gradual abatement of the beneficial
effects of donepezil is seen.
Renal and hepatic impairment:
A similar dose schedule can be followed for patients with renal impairment, as
clearance of donepezil hydrochloride is not affected by this condition.
Due to possible increased exposure in mild to moderate hepatic impairment
(see section 5.2), dose escalation should be performed according to individual
tolerability. There are no data for patients with severe hepatic impairment.
Children and adolescents:
Donepezil is not recommended for use in children and adolescents below 18
years of age.

4.3

Contraindications
Known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or
to any of the excipients.

4.4

Special warnings and precautions for use

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 investigated.
Anaesthesia:
Donepezil, 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.
There have been reports of syncope and seizures. In investigating such patients the
possibility of heart block or long sinusal pauses should be considered.
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 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, 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.
Cholinomimetics may have the potential to exacerbate or induce extrapyramidal
symptoms.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially life-threatening
condition characterised by hyperthermia, muscle rigidity, autonomic instability,
altered consciousness and elevated serum creatine phosphokinase levels, has been
reported to occur very rarely in association with donepezil, particularly in patients
also receiving concomitant antipsychotics. Additional signs may include
myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs
and symptoms indicative of NMS, or presents with unexplained high fever without
additional clinical manifestations of NMS, treatment should be discontinued.
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 concomitantly with other inhibitors of
acetylcholinesterase, agonists or antagonists of the cholinergic system should be
avoided.
Severe Hepatic Impairment:
There are no data for patients with severe hepatic impairment.
Mortality in Vascular Dementia Clinical Trials:

Three clinical trials of 6 months duration were conducted studying individuals
meeting the NINDS-AIREN criteria for probable or possible vascular dementia
(VaD). The NINDS-AIREN criteria are designed to identify patients whose dementia
appears to be due solely to vascular causes and to exclude patients with Alzheimer’s
disease. In the first study, the mortality rates were 2/198 (1.0%) on donepezil
hydrochloride 5 mg, 5/206 (2.4%) on donepezil hydrochloride 10 mg and 7/199
(3.5%) on placebo. In the second study, the mortality rates were 4/208 (1.9%) on
donepezil hydrochloride 5 mg, 3/215 (1.4%) on donepezil hydrochloride 10 mg and
1/193 (0.5%) on placebo. In the third study, the mortality rates were 11/648 (1.7%) on
donepezil hydrochloride 5 mg and 0/326 (0%) on placebo. The mortality rate for the
three VaD studies combined in the donepezil hydrochloride group (1.7%) was
numerically higher than in the placebo group (1.1%), however, this difference was
not statistically significant. The majority of deaths in patients taking either donepezil
hydrochloride or placebo appear to result from various vascular related causes, which
could be expected in this elderly population with underlying vascular disease. An
analysis of all serious non-fatal and fatal vascular events showed no difference in the
rate of occurrence in the donepezil hydrochloride group relative to placebo.
In pooled Alzheimers’s disease studies (n= 4146), and when these Alzheimer’s
disease studies were pooled with other dementia studies including the vascular
dementia studies (total n = 6888), the mortality rate in the placebo groups numerically
exceeded that in the donepezil hydrochloride groups.
Aspartame:
Donepezil hydrochloride orodispersible tablets contain aspartame, a source of
phenylalanine. May be harmful for patients with phenylketonuria.

4.5

Interaction with other medicinal products and other forms of interaction
Donepezil hydrochloride and/or any of its metabolites do 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 a study in healthy
volunteers, ketoconazole increased mean donepezil concentrations by about
30%. 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 medications such as
succinylcholine, other neuro-muscular blocking agents or cholinergic agonists
or beta blocking agents which have effects on cardiac conduction.

4.6

Pregnancy and lactation
Pregnancy:
There are no adequate data from the use of donepezil in pregnant women.
Studies in animals have not shown teratogenic effect but have shown peri and
post natal toxicity (see section 5.3). The potential risk for humans is unknown.
Donepezil should not be used during pregnancy unless clearly necessary.
Lactation:
Donepezil is excreted in the milk of rats. It is not known whether donepezil
hydrochloride is excreted in human breast milk and there are no studies in
lactating women. Therefore, women on donepezil should not breast feed.

4.7

Effects on ability to drive and use machines
Donepezil has minor or moderate influence on the ability to drive and use
machines.
Dementia may cause impairment of driving performance or compromise the
ability to use machinery. Furthermore, donepezil can induce fatigue, dizziness
and muscle cramps, mainly when initiating or increasing the dose. The treating
physician should routinely evaluate the ability of patients on donepezil to
continue driving or operating complex machines.

4.8

Undesirable effects
The most common undesirable effects are diarrhoea, muscle cramps, fatigue, nausea,
vomiting, headache and insomnia.
Adverse reactions reported as more than an isolated case are listed below, by system
organ class and by frequency.
Frequencies are defined as:
Very common (≥1/10)
Common (≥1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000), not known (cannot be estimated from the available data)

System Organ Class
Infections and
infestations
Metabolism and

Very
Common

Common
Common cold
Anorexia

Uncommon

Rare

Very rare

nutrition disorders
Psychiatric disorders

Hallucinations**
Agitation**
Aggressive
behaviour**
Syncope*

Nervous system
disorders

Seizure*

Extrapyramidal
symptoms

Bradycardia

Sino-atrial
block

Dizziness
Insomnia
Cardiac disorders

Atrioventricul
ar block
Gastrointestinal
disorders

Diarrhoea

Vomiting

Gastrointestinal
haemorrhage

Abdominal
disturbance

Gastric and
duodenal ulcers

Nausea

Hepato-biliary disorders

Liver
dysfunction
including
hepatitis***

Skin and subcutaneous
tissue disorders
Musculoskeletal,
connective tissue and
bone disorders
Renal and urinary
disorders
General disorders and
administration site
conditions
Investigations

Injury and poisoning

Rash
Pruritus
Muscle cramps

Headache

Urinary
incontinence
Fatigue
Pain
Minor increase
in serum
concentration of
muscle creatine
kinase
Accident

*In investigating patients for syncope or seizure the possibility of heart block or long
sinusal pauses should be considered (see section 4.4).
**Reports of hallucinations, agitation and aggressive behaviour have resolved on
dose-reduction or discontinuation of treatment.
***In cases of unexplained liver dysfunction, withdrawal of donepezil should be
considered.

4.9

Overdose

Neuroleptic
malignant
syndrome

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.
Symptoms:
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
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 overdose, general supportive measures should be utilised.
Tertiary anticholinergics such as atropine may be used as an antidote for
donepezil overdosage. Intravenous atropine sulphate titrated to effect is
recommended: an initial dose of 1.0 to 2.0 mg intravenous with subsequent
doses based upon clinical response. Atypical responses in blood pressure and
heart rate have been reported with other cholinomimetics when coadministered with quaternary anticholinergics such as glycopyrrolate. It is not
known whether donepezil hydrochloride and/or its metabolites can be removed
by dialysis (haemodialysis, peritoneal dialysis, or haemofiltration).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: anti-dementia drugs, anticholinesterases
ATC code: N06DA02
Donepezil hydrochloride is a specific and reversible inhibitor of
acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil
hydrochloride is in vitro over 1000 times more potent an inhibitor of this
enzyme than of butyrylcholinesterase, an enzyme that 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. Thus donepezil can not be considered to
have any effect on the progress of the disease.
Efficacy of treatment of Alzheimer’s dementia with donepezil has been
investigated in four placebo-controlled trials, 2 trials of 6-month duration and
2 trials of 1-year duration.
In the 6 months clinical trial, an analysis was done at the conclusion of
donepezil treatment using a combination of three efficacy criteria: the ADASCog (a measure of cognitive performance), the Clinician Interview Based
Impression of Change with Caregiver Input (a measure of global function) and
the Activities of Daily Living Subscale 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.
Response =
Improvement of ADAS-Cog of at least 4 points
No deterioration of CIBIC
No deterioration of Activities of Daily Living Subscale of the Clinical
Dementia Rating Scale

Placebo Group
Donepezil Hydrochloride
5-mg Group
Donepezil Hydrochloride 10mg Group
*p < 0.05
**p < 0.01

% Response
Intent to Treat Population
n = 365
10%
18%*

Evaluable Population
n = 352
10%
18%*

21%*

22%**

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

5.2

Pharmacokinetic properties
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 hydrochloride is approximately 95% bound to human plasma
proteins. The plasma protein binding of the active metabolite 6-Odesmethyldonepezil is not known. 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 its metabolites may persist in the body for
more than 10 days.
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-desmethyldonepezil (11% – only metabolite that exhibits activity
similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-Odesmethyldonepezil (7%) and the glucuronide conjugate of 5-Odesmethyldonepezil (3%). Approximately 57% of the total administered
radioactivity was recovered from the urine (17% as unchanged donepezil), 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. The pharmacokinetics of
donepezil has not been formally studied in healthy elderly subjects, or in
Alzheimer’s or vascular dementia patients. However, mean plasma levels in
patients closely agreed with those of young healthy volunteers.
Patients with mild to moderate hepatic impairment had increased donepezil
steady state concentrations; mean AUC by 48% and mean Cmax by 39% (see
section 4.2).

5.3

Preclinical safety data
Extensive testing in experimental animals has demonstrated that this
compound causes few effects other than the intended pharmacological effects

consistent with its action as a cholinergic stimulator (see section 4.9).
Donepezil 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. There was no evidence of oncogenic potential in
long-term carcinogenicity studies in either rats or mice.
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 the human dose
(see section 4.6).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Aspartame (E 951)
Croscarmellose sodium
Magnesium stearate
Mannitol (E 421)
Cellulose, microcrystalline
Peppermint flavour
Silica, colloidal anhydrous
Zinc sulfate monohydrate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years
6 months after first opening of the HDPE-bottle

6.4

Special precautions for storage
Do not store above 25°C.

6.5

Nature and contents of container
PVC/Aclar/Aluminium blister
Pack sizes of 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 98 or 120 orodispersible
tablets
HDPE-bottle with a PP-screw cap
Pack size of 100 orodispersible tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Sandoz Ltd
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 04416/1118

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
19/04/2011

10

DATE OF REVISION OF THE TEXT
01/02/2013

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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