ARICEPT 10 mg film coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Donepezil hydrochloride
Available from:
Pfizer Healthcare Ireland
ATC code:
N06DA; N06DA02
INN (International Name):
Donepezil hydrochloride
Dosage:
10 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Anticholinesterases; donepezil
Authorization status:
Marketed
Authorization number:
PA0822/002/002
Authorization date:
1997-02-25

<s5g>

Service Développement Fareva Amboise

Produit

ARICEPT TAB

Couleur:

NOIR

Code

Mock up from 8814117

Type

Bobine Simple (BSM)

Format

135 x 315 mm

Minimum font size:

9 pts

Recto: 4a + spot / Verso: 4b

Version:

3

Préparé par :

A.S.Laloux

Date:

22/11/2019

Text only is subject to market approval.

Read all of this leaflet carefully before you

start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your

doctor or pharmacist.

This medicine has been prescribed for you only.

Do not pass it on to others. It may harm them,

even if their signs of illness are the same as

yours.

If you get any of the side effects talk to your

doctor or pharmacist.This includes any possible

side effects not listed in this leaflet. See

section 4.

What is in this leaflet

1. What ARICEPT is and what it is used for

2. What you need to know before you take

ARICEPT

3. How to take ARICEPT

4. Possible side effects

5. How to store ARICEPT

6. Contents of the pack and other information

1. What ARICEPT is and what it is used for

ARICEPT contains the active substance donepezil

hydrochloride. ARICEPT (donepezil hydrochloride)

belongs to a group of medicines called

acetylcholinesterase inhibitors.

Donepezil increases the levels of a substance

(acetylcholine) in the brain involved in memory

function by slowing down the breakdown of

acetylcholine.

It is used to treat the symptoms of dementia in

people diagnosed as having mild and moderately

severe Alzheimer’s disease. The symptoms

include increasing memory loss, confusion and

behavioural changes. As a result, sufferers of

Alzheimer’s disease find it more and more difficult

to carry out their normal daily activities.

ARICEPT is for use in adult patients only.

2. What you need to know before you take

ARICEPT

Do not take ARICEPT

if you are allergic to donepezil hydrochloride,

or to piperidine derivatives, or any of the

other ingredients of this medicine (listed in

section 6).

Warnings and precautions

Talk to your doctor or pharmacist before taking

ARICEPT if you have or have had:

stomach or duodenal ulcers

seizures (fits) or convulsions

a heart condition (irregular or very slow heart

beat)

asthma or other long term lung disease

liver problems or hepatitis

difficulty passing urine or mild kidney disease

Also tell your doctor if you are pregnant or think

you might be pregnant.

Children and adolescents

ARICEPT is not recommended for use in children

and adolescents (younger than 18 years of age).

Other medicines and ARICEPT

Tell your doctor or pharmacist if you are taking,

have recently taken or might take any other

medicines. This includes medicines that your

doctor has not prescribed for you but which you

have bought yourself from a chemist/pharmacist.

It also applies to medicines you may take some

time in the future if you continue to take ARICEPT.

This is because these medicines may weaken or

strengthen the effects of ARICEPT.

In particular it is important to tell your doctor

if you are taking any of the following types of

medicines:

other Alzheimer’s disease medicines, e.g.

galantamine

pain killers or treatment for arthritis e.g. aspirin,

non-steroidal anti-inflammatory (NSAID) drugs

such as ibuprofen, or diclofenac sodium

anticholinergics medicines, e.g. tolterodine

antibiotics e.g. erythromycin, rifampicin

anti-fungal medicine e.g. ketoconazole

anti-depressants e.g. fluoxetine

anticonvulsants e.g. phenytoin, carbamazepine

medication for a heart condition e.g. quinidine,

beta-blockers (propanolol and atenolol)

muscle relaxants e.g. diazepam, succinylcholine

general anaesthetic

medicines obtained without a prescription e.g.

herbal remedies

If you are going to have an operation that requires

you to have a general anaesthetic, you should

tell your doctor and the anaesthetist that you are

taking ARICEPT. This is because your medicine

may affect the amount of anaesthetic needed.

ARICEPT can be used in patients with kidney

disease or mild to moderate liver disease. Tell

your doctor first if you have kidney or liver

disease. Patients with severe liver disease should

not take ARICEPT.

Tell your doctor or pharmacist the name of your

caregiver. Your caregiver will help you to take your

medicine as it is prescribed.

ARICEPT with food, drink and alcohol

Food will not influence the effect of ARICEPT.

ARICEPT should not be taken with alcohol

because alcohol may change its effect.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you

may be pregnant or are planning to have a baby,

ask your doctor or pharmacist for advice before

taking any medicine.

ARICEPT should not be used while breast-feeding.

Driving and using machines

Alzheimer’s disease may impair your ability to

drive or operate machinery and you must not

perform these activities unless your doctor tells

you that it is safe to do so.

Also, your medicine can cause tiredness, dizziness

and muscle cramp. If you experience any of these

effects you must not drive or operate machinery.

ARICEPT contains lactose

If you have been told by your doctor that you have

intolerance to some sugars, you should contact

your doctor before taking ARICEPT.

3. How to take ARICEPT

How much ARICEPT should you take

Always take this medicine exactly as your

doctor or pharmacist has told you. Check with

your doctor or pharmacist if you are not sure.

Initially, the recommended dose is 5 mg (one

white tablet) every night before you go to bed.

After one month, your doctor may tell you to

take 10 mg (one yellow tablet) every night

before you go to bed.

The tablet strength you will take may change

depending on the length of time you have been

taking the medicine and on what your doctor

recommends. The maximum recommended dose

is 10 mg each night.

Always follow your doctor or pharmacist’s advice

about how and when to take your medicine. Do

not alter the dose yourself without your doctor’s

advice.

How to take your medicine

Swallow your ARICEPT tablet with a drink of water

before you go to bed at night.

Use in Children and adolescents

ARICEPT is not recommended for use in children

and adolescents (younger than 18 years of age).

If you take more ARICEPT than you should

Contact your doctor or the nearest hospital

emergency department immediately if you take

more of the medicine than you should. Take this

leaflet and any remaining tablets with you.

Overdose symptoms may include nausea (feeling

sick) and vomiting (being sick), drooling,

sweating, slow heart rate, low blood pressure

(light-headedness or dizziness when standing),

Package leaflet: Information for the user

ARICEPT

5 mg Film Coated Tablets

ARICEPT

10 mg Film Coated Tablets

Donepezil Hydrochloride

Mock up from 8814117

breathing problems, losing consciousness and

seizures (fits) or convulsions.

If you forget to take ARICEPT

If you forget to take your medicine, take the next

dose at the usual time. Do not take a double dose

to make up for a forgotten tablet.

If you forget to take your medicine for more than

one week, call your doctor before taking any more

medicine.

If you stop taking ARICEPT

Do not stop taking the tablets unless told to do so

by your doctor. If you stop taking ARICEPT, the

benefits of your treatment will gradually fade away.

If you have any further questions on the use of this

medicine, ask your doctor or pharmacist.

For how long should you take ARICEPT

Your doctor or pharmacist will advise you on how

long you should continue to take your tablets. You will

need to see your doctor from time to time to review

your treatment and assess your symptoms.

4. Possible side effects

Like all medicines, this medicine can cause side

effects, although not everybody gets them.

The following side effects have been reported by

people taking ARICEPT.

Tell your doctor if you have any of these effects

while you are taking ARICEPT.

Serious side effects:

You must tell your doctor immediately if you notice

these serious side effects mentioned. You may need

urgent medical treatment.

liver damage e.g. hepatitis. The symptoms of

hepatitis are nausea (feeling sick) or vomiting

(being sick), loss of appetite, feeling generally

unwell, fever, itching, yellowing of the skin and

eyes, and dark coloured urine (may affect up to 1 in

1,000 people)

stomach or duodenal ulcers. The symptoms

of ulcers are stomach pain and discomfort

(indigestion) felt between the navel and the breast

bone (may affect up to 1 in 100 people)

bleeding in the stomach or intestines. This may

cause you to pass black tar like stools or visible

blood from the rectum (may affect up to 1 in 100

people)

seizures (fits) or convulsions (may affect up to 1 in

100 people)

fever with muscle stiffness, sweating or a

lowered level of consciousness (a disorder called

“Neuroleptic Malignant Syndrome”) (may affect up

to 1 in 10,000 people)

muscle weakness, tenderness or pain and

particularly, if at the same time, you feel unwell,

have a high temperature or have dark urine. They

may be caused by an abnormal muscle breakdown

which can be life threatening and lead to kidney

problems (a condition called rhabdomyolysis) (may

affect up to 1 in 10,000 people)

Other side effects

Very common side effects (may affect more than 1 in

10 people):

diarrhoea

headache

Common side effects (may affect up to 1 in 10

people):

muscle cramp

tiredness

difficulty in sleeping (insomnia)

the common cold

hallucinations (seeing or hearing things that are not

really there)

unusual dreams including nightmares

agitation

aggressive behaviour

fainting

dizziness

stomach feeling uncomfortable

rash

passing urine uncontrollably

pain

accidents (patients may be more prone to falls and

accidental injury)

Uncommon side effects (may affect up to 1 in 100

people):

slow heart beat

salivary hypersecretion

Rare side effects (may affect up to 1 in 1000 people):

stiffness, shaking or uncontrollable movement

especially of the face and tongue but also of the

limbs

Reporting of side effects

If you get any side effects, talk to your doctor or

pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side

effects directly via HPRA Pharmacovigilance,

Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1

6764971; Fax: +353 1 6762517. Website: www.

hpra.ie; E-mail: medsafety@hpra.ie. By reporting

side effects you can help provide more information

on the safety of this medicine.

5. How to store ARICEPT

Keep this medicine out of the sight and reach of

children.

Do not use this medicine after the expiry date which

is stated on the outer carton and blister or bottle

(EXP). The expiry date refers to the last day of that

month.

Do not store this medicine above 30°C.

Do not throw away any medicines via wastewater

or household waste. Ask your pharmacist how to

dispose of medicines you no longer use. These

measures will help to protect the environment.

6. Contents of the pack and other information

What ARICEPT film coated tablets contain

The active substance is donepezil hydrochloride.

Two different strengths of tablets are available.

Each 5 mg film coated tablet contains 5 mg

of donepezil hydrochloride and each 10 mg

film coated tablet contains 10 mg of donepezil

hydrochloride.

The other ingredients are lactose monohydrate,

maize starch, cellulose microcrystalline, hyprolose,

magnesium stearate, hypromellose, talc, Macrogol,

and titanium dioxide (E171).

Additionally, the 10 mg film coated tablet contains

synthetic yellow iron oxide (E172).

What ARICEPT looks like and contents of the pack

ARICEPT 5 mg film coated tablets are white, round,

biconvex tablets marked ‘ARICEPT’ on one side and

‘5’ on the other side.

ARICEPT 10 mg film coated tablets are yellow,

round, biconvex tablets marked ‘ARICEPT’ on one

side and ‘10’ on the other side.

ARICEPT is available in packs of :

7, 14, 28, 30, 50, 56, 60, 84, 98, 112 and 120 film

coated tablets in blister packs

28, 30 and 100 film coated tablets in HDPE bottles

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Pfizer Healthcare Ireland

9 Riverwalk

National Digital Park

Citywest Business Campus

Dublin 24, Ireland

Manufacturer:

Fareva Amboise

Zone Industrielle

29, Route des Industries

37530 Pocé-sur-Cisse

France

This medicinal product is authorised in the member

states of the EEA under the following names:

Name of the Member

State

Name of the medicinal

product

Austria, Belgium, France,

Portugal, United Kingdom,

Germany, Denmark,

Greece, Finland, Ireland &

Luxembourg

Aricept 5 mg & 10 mg Film

Coated Tablets

Italy & Sweden

Aricept

This leaflet was last revised in MM/YYYY

Ref: AR 24_0

® Trademark of and under licence agreement with

Eisai R&D Management Co., Ltd., Japan

Health Products Regulatory Authority

02 August 2019

CRN008J21

Page 1 of 7

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

ARICEPT 10 mg film coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg donepezil hydrochloride, equivalent to 9.12 mg of donepezil free base.

Excipients with known effect:174.33 mg lactose per film-coated tablet

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

ARICEPT 10 mg film coated tablets are yellow, round, biconvex tablets debossed ‘ARICEPT’ on one side and ‘10’ on the other

side.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

ARICEPT film-coated tablets are indicated for the symptomatic treatment of mild to moderately severe Alzheimer's dementia.

4.2 Posology and method of administration

Posology

Adults/Elderly people

Treatment is initiated at 5 mg/day (once-a-day dosing). 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.

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 ARICEPT is seen.

Paediatric population

ARICEPT is not recommended for use in children and adolescents below 18 years of age.

Patients with 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.

Method of administration

ARICEPT should be taken orally, in the evening, just prior to retiring.

Health Products Regulatory Authority

02 August 2019

CRN008J21

Page 2 of 7

4.3 Contraindications

Hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

The use of ARICEPT in patients with severe Alzheimers' dementia, other types of dementia or other types of memory

impairment (e.g., age-related cognitive decline), has not been investigated.

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.

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 ARICEPT

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 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.

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 ARICEPT 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

Health Products Regulatory Authority

02 August 2019

CRN008J21

Page 3 of 7

(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 Alzheimer'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.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interactions

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 agonistsor beta blocking agents that have effects on cardiac conduction.

4.6 Fertility, 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 pre and post-natal toxicity (see section 5.3 preclinical safety data). The potential risk for humans is

unknown. ARICEPT should not be used during pregnancy unless clearly necessary.

Breastfeeding

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 adverse events are diarrhoea, muscle cramps, fatigue, nausea, vomiting 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) and not known (cannot be estimated from the available data).

System Organ

Class

Very Common

Common

Uncommon

Rare

Very Rare

Infections and

Common cold

Health Products Regulatory Authority

02 August 2019

CRN008J21

Page 4 of 7

infestations

Metabolism and

nutrition

disorders

Anorexia

Psychiatric

disorders

Hallucinations

Agitation**

Aggressive

behaviour**

Abnormal

dreams and

Nightmares**

Nervous system

disorders

Syncope*

Dizziness

Insomnia

Seizure*

Extrapyramidal

symptoms

Neuroleptic

malignant

syndrome

Cardiac

disorders

Bradycardia

Sino-atrial

block

Atrioventricular

block

Gastrointestinal

disorders

Diarrhoea

Nausea

Vomiting

Abdominal

disturbance

Gastrointestinal haemorrhage

Gastric and duodenal ulcers

Salivary hypersecretion

Hepato-biliary

disorders

Liver

dysfunction

including

hepatitis***

Skin and

subcutaneous

tissue disorders

Rash

Pruritus

Musculoskeletal,

connective

tissue and bone

disorders

Muscle cramps

Rhabdomyolysis*

Renal and

urinary

disorders

Urinary

incontinence

General

disorders and

administration

site conditions

Headache

Fatigue

Pain

Investigations

Minor increase in serum

concentration of muscle creatine

kinase

Injury and

poisoning

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

hallucinations,

abnormal

dreams,

nightmares,

agitation

aggressive

behaviour

have

resolved

dose-reduction or discontinuation of treatment.

***In cases of unexplained liver dysfunction, withdrawal of ARICEPT should be considered.

****Rhabdomyolysis has been reported to occur independently of Neuroleptic Malignant syndrome and in close temporal

association with donepezil initiation or dose increase.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected

adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Health Products Regulatory Authority

02 August 2019

CRN008J21

Page 5 of 7

4.9 Overdose

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

convulsions.

Increasing

muscle

weakness

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 (haemodialysis, peritoneal

dialysis, or haemofiltration).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the

brain. Donepezil hydrochloride is i

n 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.

Alzheimer's Dementia

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 correlate to changes in ADAS-cog, a sensitive scale that examines selected aspects of

cognition. The potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been

studied. Thus ARICEPT cannot be considered to have any effect on the progress of the disease.

Efficacy of treatment of Alzheimer's Dementia with ARICEPT 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 ADAS-Cog (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

% Response ​

Intent to Treat Population

n=365

Evaluable Population

n=352

Placebo Group

ARICEPT tablets 5-mg Group

18%*

18%*

ARICEPT tablets 10-mg Group

21%*

22%**

* p<0.05

** p<0.01

Health Products Regulatory Authority

02 August 2019

CRN008J21

Page 6 of 7

ARICEPT 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

therapy.

Once

steady-state,

plasma

donepezil

hydrochloride

concentrations

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-O-desmethyl donepezil 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

C-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.

Biotransformation/ Elimination

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

C-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 (17% as unchanged donepezil),

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 C

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

Tablet core

Lactose monohydrate

Maize starch

Cellulose microcrystalline

Hyprolose

Health Products Regulatory Authority

02 August 2019

CRN008J21

Page 7 of 7

Magnesium stearate

Film coating

Talc

Macrogol

Hypromellose

Titanium dioxide “E171”

Yellow iron oxide “E172”

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Bottles: 3 years

Blisters: 4 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Bottles (HDPE) of 28, 30 and 100.

Blisters (PVC/Aluminium)

Pack sizes: 7, 14, 28, 30, 50, 56, 60, 84, 98, 112 or 120 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Pfizer Healthcare Ireland

9 Riverwalk

National Digital Park

Citywest Business Campus

Dublin 24

Ireland

8 MARKETING AUTHORISATION NUMBER

PA0822/002/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 February 1997

Date of last renewal: 14 February 2007

10 DATE OF REVISION OF THE TEXT

August 2019

Similar products

Search alerts related to this product

View documents history

Share this information