Aripil 10 mg Film-Coated Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Donepezil hydrochloride
Available from:
McDermott Laboratories Ltd t/a Gerard Laboratories
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:
PA0577/099/002
Authorization date:
2008-10-03

Page 2 of 7

Package leaflet: Information for the patient

Aripil 5 mg Film-coated Tablets

Aripil 10 mg Film-coated Tablets

donepezil hydrochloride

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 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

What Aripil is and what it is used for

What you need to know before you take Aripil

How to take Aripil

Possible side effects

How to store Aripil

Contents of the pack and other information

1.

What Aripil is and what it is used for

Aripil contains the active substance donepezil hydrochloride, which belongs to a group of medicines called

acetylcholinesterase inhibitors. Donepezil hydrochloride increases the levels of a substance (acetylcholine) in

the brain involved in memory function by slowing down the breakdown of that substance.

It is used to treat the symptoms of dementia in people diagnosed as having mild to moderately severe

Alzheimer’s disease.

Symptoms of the illness include increasing memory loss, confusion and behavioural changes. As a result,

sufferers of Alzheimer’s disease find it more difficult to carry out their normal daily activities.

It is for use only in adult patients.

2.

What you need to know before you take Aripil

Do not take Aripil:

if you are allergic to donepezil, to piperidine derivative medicines (your doctor or pharmacist can advise

on this) or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor or pharmacist before taking Aripil if you suffer or have ever suffered from any of the

following conditions:

a heart rate or rhythm problem (e.g. an irregular heartbeat, sick sinus syndrome, or other conditions that

affect the rate or rhythm of the heart). Aripil may slow down your heart rate

stomach or duodenal (gut) ulcers

difficulty passing urine

fits or seizures: Aripil may have the potential to cause fits or seizures. Your doctor will monitor your

symptoms

stiffness, shaking or uncontrollable movement especially of the face and tongue but also of the limbs

(which may have occurred after taking certain medicines and referred to ‘extrapyramidal’ or

‘Parkinson’s’ like effects)

Page 3 of 7

asthma or other long term lung problems

liver problems.

Children and adolescents

Children and adolescents under the age of 18 years of age should not take this medicine.

Other medicines and Aripil

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines,

including medicines taken without a prescription. In particular, tell your doctor or pharmacist if you are

taking any of the following:

other Alzheimer’s disease medicines e.g. galantamine

antidepressants (e.g. fluoxetine)

erythromycin (an antibiotic)

rifampicin (for treatment of tuberculosis)

antifungal medicines e.g. ketoconazole, itraconazole

carbamazepine or phenytoin (for the control of epilepsy)

medication for heart conditions e.g. quinidine, beta blockers (e.g. propanolol and atenolol)

pain killers or treatment for arthritis e.g. acetylsalicylic acid (aspirin), non-steroidal anti-

inflammatory drugs (NSAIDs) such as ibuprofen, or diclofenac

anticholinergics (medicines which typically cause dry mouth, blurred vision and/or drowsiness) e.g.

tolterodine (used for bladder problems).

If you are going to have an operation, including dental surgery, that requires you to have an anaesthetic, tell

your doctor, dentist, hospital staff or the anaesthetist that you are taking this medicine.

Aripil with alcohol

Take special care if drinking alcohol whilst taking this medicine as alcohol can reduce the effect of

donepezil.

Pregnancy and breast-feeding

If you are pregnant, think you may be pregnant or are planning to have a baby, do not take this medicine

before speaking to your doctor for advice. Donepezil should not be used in pregnancy unless clearly

necessary.

Aripil should not be used while breast-feeding.

Driving and using machines

Do not drive or operate machinery if you feel dizzy, sleepy or get muscle cramps while taking this medicine.

Alzheimer’s disease may also impair your ability to drive or operate machinery. You must not perform these

activities unless your doctor tells you that it is safe to do so.

Aripil contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before

taking this medicine.

3.

How to take Aripil

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

Page 4 of 7

Tell the doctor the name of your caregiver. Your caregiver will help you take your medicine as it is

prescribed.

Adults

The recommended starting dose is 5 mg of Aripil taken once a day for at least one month. Your doctor may

increase this to 10 mg of Aripil taken once a day. The maximum recommended daily dose is 10 mg. If you

experience an increase in side effects while taking 10 mg each day, tell your doctor or pharmacist.

Use in patients with liver and kidney disease

For adults with mild to moderate liver disease, your doctor may need to adjust your dose. No dosage

adjustment is required if you have kidney problems.

Method of administration:

Take your Aripil by mouth with a drink of water in the evening before you go to sleep.

Your doctor will advise you on how long you should continue to take your tablets. You will need to see your

doctor regularly to review your treatment and assess your symptoms. You can take this medicine with or

without food.

If you take more Aripil than you should

Do not take more than one tablet each day. Contact your doctor or nearest hospital casualty department

immediately if you take more tablets than you should. Take the container and any remaining tablets with you

to the hospital so the doctor knows what has been taken.

If you take more Aripil than you should, you might have symptoms such as feeling sick (nausea), being sick

(vomiting), salivation, sweating, slow heart rate (bradycardia), low blood pressure (light-headedness or

dizziness when standing), breathing problems, losing consciousness, convulsions (fits). You could also suffer

from an increased muscles weakness which may be a life threatening condition if respiratory muscles are

involved.

If you forget to take Aripil

If you forgot to take a tablet, just take one tablet the following day 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, contact your doctor before taking any more

medicine.

If you stop taking Aripil

When treatment is stopped the beneficial effects of Aripil will decrease gradually.

Do not stop taking your tablets without first discussing with your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or go to the nearest hospital emergency department immediately if you notice any of

the following serious side effects:

Page 5 of 7

Uncommon (may affect up to 1 in 100 people)

bleeding in the stomach, guts or bowel, or ulcers of the stomach or duodenum (gut). If you are sick you

may notice fresh blood or coffee like grounds in the sick, or you may pass black tarry stools or fresh

blood from the rectum (back passage)

seizures (fits).

Rare (may affect up to 1 in 1,000 people)

liver problems including hepatitis (inflammation of the liver). You may notice dark urine, pale stools,

yellowing of the skin and whites of the eyes (jaundice), feel sick and have a fever

changes to your heart beat, such as changes to the rhythm, or ‘missed’ beats, which may be signs of

problems with the electrical signals in your heart.

Very rare (may affect up to 1 in 10,000 people)

fever with muscle stiffness, sweating or a lowered level of consciousness (a disorder called "Neuroleptic

Malignant Syndrome").

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).

Other side effects include:

Very common (may affect more than 1 in 10 people):

diarrhoea

feeling sick

headache.

Common (may affect up to 1 in 10 people):

being sick

muscle cramps

feeling tired

insomnia (difficulty sleeping)

common cold

anorexia (loss of appetite)

hallucinations (seeing or hearing things that are not real)

unusual dreams including nightmares

agitation

aggressive behaviour

fainting

feeling dizzy

abdominal pain or discomfort

skin rash and itching

passing urine uncontrollably

pain

accidents (patients may be more prone to falls and accidental injury).

Uncommon (may affect up to 1 in 100 people):

slow heartbeat

an increase in the levels of a substance called creatine kinase in your blood which is involved in

metabolism which may be seen in blood tests

increased salivation in the mouth.

Rare (may affect up to 1 in 1,000 people):

extrapyramidal symptoms (EPS) which include involuntary movements, tremors and rigidity, body

restlessness, muscle contractions and changes in breathing and heart rate

Page 6 of 7

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 Aripil

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 carton and blister/bottle after EXP. The

expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Aripil contains

The active substance is donepezil hydrochloride.

- Aripil 5 mg Film-coated Tablet: Each tablet contains 5 mg donepezil hydrochloride (equivalent to 4.56

mg donepezil).

Aripil 10 mg Film-coated Tablet: Each tablet contains 10 mg donepezil hydrochloride (equivalent to 9.12

mg donepezil).

- The other ingredients are

Tablet core: lactose monohydrate (see section 2, ‘Aripil contains lactose’), maize starch,

hydroxypropylcellulose, microcrystalline cellulose and magnesium stearate

Tablet coating: hypromellose, titanium dioxide (E171) and macrogol.

What Aripil looks like and contents of the pack

Your medicine is in the form of a film-coated tablet.

Aripil 5mg Film-coated Tablets are white, film-coated, round tablets marked with “DL” over “5” on one side

and “G” on the reverse.

Aripil 10mg Film-coated Tablets are white, film-coated, round tablets marked with “DL” over “10” on one

side and “G” on the reverse.

Aripil 5 mg Film-coated Tablets are available in blisters containing 7, 10, 28, 30, 56, 60, 84, 98, 100 film-

coated tablets, calendar packs of 28 and 98 and blister unit dose of 50 x1.

Aripil 5 mg Film-coated Tablets are also available in bottles containing 100 and 250 film-coated tablets.

Aripil 10 mg Film-coated Tablets are available in blisters containing 10, 28, 30, 56, 60, 84, 98, 100 film-

coated tablets, calendar packs of 28 and 98 and blister unit dose of 50 x1.

Aripil 10 mg Film-coated Tablets are also available in bottles containing 100 and 250 film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Marketing Authorisation Holder:

McDermott Laboratories Ltd. t/a Gerard Laboratories, 35/36 Baldoyle Industrial Estate, Grange Road,

Dublin 13, Ireland

Page 7 of 7

Manufacturers:

McDermott Laboratories Ltd. t/a Gerard Laboratories, 35/36 Baldoyle Industrial Estate, Grange Road,

Dublin 13, Ireland.

Generics [UK] Ltd, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom.

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria

“Donepezil HCL “Arcana” 5 mg - Filmtabletten” “Donepezil HCL Arcana 10 mg -

Filmtabletten”

Belgium

“Donepezil Mylan” 5 mg filmomhulde tabletten” “Donepezil Mylan 10 mg

filmomhulde tabletten”

Czech Republic

“Donepezil Mylan 5 mg” “Donepezil Mylan 10 mg”

Denmark

“Donepezil Mylan”

Finland

“Donepezil Mylan”

France

“DONEPEZIL MYLAN 5 mg, comprimé pelliculé” “DONEPEZIL MYLAN 10 mg,

comprimé pelliculé”

Greece

“DONEPEZIL/MYLAN”

Hungary

“Donepezil Mylan 5 mg filmtabletta” “Donepezil Mylan 10 mg filmtabletta”

Ireland

“Aripil 5mg Film-coated Tablets” “Aripil 10mg Film-coated Tablets”

Italy

“DONEPEZIL MYLAN GENERICS”

Poland

“Pamigen”

Portugal

“Donepezilo Mylan”

Spain

“Donepezilo MYLAN 5 mg comprimidos recubiertos con pelìcula EFG” “Donepezilo

Mylan 10 mg comprimidos recubiertos con pelìcula EFG”

Sweden

“Donepezil Mylan”

“Donepezil Hydrochloride 5mg Film-coated Tablets” “Donepezil Hydrochloride

10mg Film-coated Tablets”

This leaflet was last revised in July 2017

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Aripil 10 mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 10 mg film-coated tablet contains 10 mg donepezil hydrochloride (equivalent to 9.12 mg of donepezil).

Excipient with known effect

Each 10 mg film-coated tablet contains 174.3 mg lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Aripil 10 mg are white, film-coated, round tablets embossed with “DL” over “10” on one side and “G” on the reverse,

approximately 9 mm in diameter.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

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

4.2 Posology and method of administration

Posology

Adults/Elderly:

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 donepezil hydrochloride 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

hydrochloride 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 hydrochloride 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 hydrochloride cannot be

predicted.

Upon discontinuation of treatment, a gradual abatement of the beneficial effects of donepezil hydrochloride is seen.

Paediatric population

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

Renal or hepatic impairment

A similar dose schedule can be followed for patients with renal impairment, as clearance of donepezil hydrochloride is

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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

For oral use.

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

4.3 Contraindications

Hypersensitivity to the active substance, piperidine derivatives or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

The use of donepezil hydrochloride 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 hydrochloride, 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

non-steroidal anti-inflammatory drugs (NSAIDs) should be monitored for symptoms. However, the clinical studies

with donepezil hydrochloride 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 hydrochloride, 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

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history of asthma or obstructive pulmonary disease.

The administration of donepezil hydrochloride 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 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.

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 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 that have effects on cardiac conduction.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of donepezil hydrochloride in pregnant women.

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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 hydrochloride should not be used during pregnancy unless clearly necessary.

Breast-feeding

Donepezil hydrochloride 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 hydrochloride should

not breast feed.

4.7 Effects on ability to drive and use machines

Donepezil hydrochloride 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 hydrochloride 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 hydrochloride 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), not known (cannot be estimated from the available data).

System Organ

Class

Very

Common

Common

Uncommon

Rare

Very Rare

Infections and

infestations

Common cold

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

Diarrhoea

Vomiting

Gastrointestinal

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* 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, abnormal dreams, nightmares, agitation and aggressive behaviour have resolved on dose-

reduction or discontinuation of treatment.

*** In cases of unexplained liver dysfunction, withdrawal of donepezil hydrochloride 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: http://www.hpra.ie; e-mail: medsafety@hpra.ie.

4.9 Overdose

Donepezil hydrochloride is a specific reversible acetylcholinesterase inhibitor.

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.

disorders

Nausea

Abdominal

disturbance

haemorrhage

Gastric and

duodenal ulcers

Salivary

hypersecretion

Hepatobiliary

disorders

Liver

dysfunction

including

hepatitis***

Skin and

subcutaneous

tissue disorders

Rash

Pruritus

Musculoskeletal

and connective

tissue 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,

poisoning and

procedural

complications

Accident

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Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterised by severe nausea, vomiting,

salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle

weakness is a possibility and may result in death if respiratory muscles are involved.

As in any case of overdose, general supportive measures should be utilised. Tertiary anticholinergics such as atropine

may be used as an antidote for donepezil hydrochloride 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 (hemodialisys, peritoneal dialysis or hemofiltration).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-dementia drugs, anticholinesterases, 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 in vitro over 1000 times more potent an inhibitor of this enzyme than of

butylcholinesterase, an enzyme which 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 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 hydrochloride cannot be considered to have any effect on the progress of the disease.

Efficacy of treatment of Alzheimer’s Dementia with donepezil hydrochloride 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 hydrochloride 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

Donepezil 5 mg group

18%*

18%*

Donepezil 10 mg group

21%*

22%**

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* p<0.05

** p<0.01

Donepezil hydrochloride 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-O-desmethyldonepezil 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

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) 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 hydrochloride 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

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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

Hydroxypropylcellulose

Cellulose, microcrystalline

Magnesium stearate

Film coating

Hypromellose

Titanium dioxide (E171)

Macrogol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVdC/Aluminium blisters containing 10, 28, 30, 56, 60, 84, 98, 100 film-coated tablets.

Calendar packs containing 28 and 98 film-coated tablets.

Blister unit dose of 50x1 film-coated tablets

Polypropylene tablet container with polyethylene caps containing 100 and 250 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

McDermott Laboratories Ltd. Trading as Gerard Laboratories

35/36 Baldoyle Industrial Estate

Grange Road

Dublin 13

8 MARKETING AUTHORISATION NUMBER

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PA0577/099/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 3rd October 2008

Date of last renewal: 26th June 2013

10 DATE OF REVISION OF THE TEXT

October 2017

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