Donepezil 10mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Donepezil hydrochloride
Available from:
Mylan
ATC code:
N06DA02
INN (International Name):
Donepezil hydrochloride
Dosage:
10mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04110000; GTIN: 5016695003078
Authorization number:
PL 04569/1062

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Donepezil hydrochloride 5mg and 10mg Orodispersible Tablets

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.

The full name of this medicine is Donepezil hydrochloride

5mg and

10mg Orodispersible

Tablets

but within the leaflet it will be referred to as Donepezil tablets.

What is in this leaflet

What Donepezil tablets are and what they are used for

What you need to know before you take Donepezil tablets

How to take Donepezil tablets

Possible side effects

How to store Donepezil tablets

Contents of the pack and other information

1.

What Donepezil tablets are and what they are used for

Donepezil tablets belong to a group of medicines called acetylcholinesterase inhibitors. It is used to

treat the symptoms of dementia in people diagnosed as having mild to moderately severe Alzheimer's

disease. Donepezil tablets are for use in adult patients only.

2.

What you need to know before you take

Do not take Donepezil tablets 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

Treatment with Donepezil tablets should only be started and supervised by

a doctor with experience in diagnosing and treating Alzheimer's dementia.

Talk to your doctor or pharmacist before taking Donepezil tablets if you:

have ever had

stomach or duodenal ulcers

, or if you are taking non steroidal anti-

inflammatory drugs (NSAIDS)

have ever had a

seizure

. Donepezil may have the potential to cause fits or seizures. Your doctor

will monitor your symptoms

have a

heart condition

(especially if you have an irregular heart beat, sick sinus syndrome, or

other conditions that affect the rhythm of the heart), as Donepezil tablets may slow down your

heart rate

have

asthma

or other long term

lung disease

have ever had

liver disease

have

difficulty passing urine

are going to have an

operation

that requires you to have a general anaesthetic, as the dose of

the medication used in anaesthesia may need to be adjusted

have any involuntary or abnormal movements of the tongue, face or body (extrapyramid

symptoms). Donepezil tablets may indce or exacerbate extrapyramidal symptoms.

Donepezil tablets 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

Donepezil tablets. In cases of unexplained liver dysfunction your doctor may consider to stop

treatment with Donepezil tablets.

Tell your doctor or pharmacist the name of your caregiver. Your caregiver will help you to take your

medicine as it is prescribed.

Children and Adolescents

Donepezil is not recommended for children and adolescents.

Other medicines and Donepezil tablets

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

medicines. This is especially important for

medicines to treat pain and inflammation e.g. acetylsalicylic acid, non steroidal anti-

inflammatory drugs (NSAIDs) such as ibuprofen, or diclofenac sodium

medicines obtained without a prescription, e.g. herbal remedies

antibiotics such as erythromycin or rifampicin

anti-fungal medicine, such as ketoconazole or itraconazole

muscle relaxants, such as succinylcholine

anti-depressants such as fluoxetine

anticonvulsants, such as phenytoin or carbamazepine

medication for a heart condition, such as quinidine, or high blood pressure, such as beta

blockers (e.g. propranolol and atenolol)

other medicines that act the same way as Donepezil tablets (such as galantamine or

rivastigmine), and some medicines for diarrhoea, Parkinson’s disease, asthma or urinary

incontinence (such as tolterodine).

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 Donepezil tablets. This is because your medicine

may affect the amount of anaesthetic needed.

Donepezil tablets with alcohol

You must avoid drinking alcohol while you are being treated with Donepezil tablets, because it could

reduce the effect of Donepezil tablets.

Pregnancy and breast-feeding

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 this medicine.

Donepezil tablets should not be used during pregnancy unless your doctor decides that it is clearly

necessary.

Donepezil tablets should not be used while breast-feeding.

Driving and using machines

Donepezil tablets and the disease may impair your ability to drive or operate machinery. The medicine

can cause fatigue, dizziness and muscle cramp especially in the beginning of treatment, and if affected

you must not drive or operate machinery. You should discuss this with your doctor before performing

these activities.

Donepezil tablets contain lactose and aspartame

Donepezil tablets contain lactose. If you have been told by your doctor that you have an intolerance

to some sugars, contact your doctor before taking this medicinal product.

Donepezil tablets also contain aspartame (E951), a source of phenylalanine. This may be harmful for

people with phenylketonuria.

3.

How to take Donepezil tablets

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

if you are not sure.

The tablet should be placed on your tongue and allowed to disintegrate before swallowing, with or

without water, according to your preference.

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 will recommend. Usually, you will start by taking one 5mg

tablet every night before you go to bed. After one month, your doctor may tell you to take one 10mg

tablet every night before you go to bed. The maximum recommended dose is 10mg each night.

No dosage adjustment is required if you have kidney problems.

If you have a mild to moderate liver disease, your doctor may need to adjust your dose.

If you have severe liver problems, you should take extra care with Donepezil tablets (see section 2

“What you need to know before you take”). In cases of unexplained liver dysfunction under treatment

with Donepezil tablets, withdrawal of Donepezil tablets should be considered.

You should always follow your doctor's advice about how and when to take your medicine. Do not

alter the dose yourself without your doctor's advice. Do not stop taking the tablets unless told to do so

by your doctor.

For how long should you take Donepezil tablets

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.

If you take more Donepezil tablets than you should

Do not take more tablets than the doctor has told you. Contact your doctor or hospital immediately if

you take more than you should. Always take the tablets and the carton with you to the hospital so that

the doctor knows what has been taken.

Symptoms of overdose may include nausea, vomiting, drooling, sweating, slow heartbeat,

,low blood

pressure (light-headedness or dizziness when standing),

difficulty breathing, muscle weakness,

fainting and seizures.

If you forget to take Donepezil tablets

Do not take a double dose to make up for a forgotten dose.

If you forget to take a tablet, just take one tablet the following day at the usual time. If you forget to

take your medicine for more than one week, call your doctor before taking any more medicine.

If you stop taking Donepezil tablets

When treatment is stopped the beneficial effects of Donepezil tablets will decrease gradually. Do not

stop taking your tablets, even if you are feeling well, unless your doctor tells you.

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.

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 feeling or being sick, loss of appetite,

feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine

(which may affect up to 1 in 1,000 users)

stomach or duodenal ulcers. The symptoms of ulcers are stomach pain and discomfort

(indigestion) felt between the navel and the breast bone

(which may affect up to 1 in 100 users)

bleeding in the stomach or intestines. This may cause you to pass black tar like stools or visible

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

seizures (fits) or convulsions (which may affect up to 1 in 100 users)

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:

Very common

side effects which may affect more than 1 in 10 users:

diarrhoea

nausea (feeling sick)

headache.

Common

side effects which may affect up to 1 in 10 users:

common cold

loss of appetite

hallucinations (seeing or hearing things that are not really there), aggressive behaviour, unusual

dreams including nightmares, agitation, which have resolved on dose-reduction or

discontinuation of treatment

dizziness, sleeplessness, fainting

vomiting, abdominal disturbance

itching, rash

muscle cramp

urinary incontinence

fatigue, pain

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

Uncommon

side

effects which may affect up to 1 in 100 users:

slow heart beat

minor increase of the muscle enzyme creatine kinase in blood tests.

Rare

side

effects which may affect up to 1 in 1,000 users:

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

limbs

cardiac disturbances

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme

at: www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Donepezil tablets

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 after EXP. The

expiry date refers to the last day of that month.

Store in the original blister in order to protect from moisture.

This medicinal product does not require any special temperature 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 Donepezil tablets contain

The active substance is donezepil hydrochloride. Each orodispersible tablet contains 5mg or

10mg donepezil hydrochloride.

The other ingredients are polacrilin potassium; microcrystalline cellulose; lactose monohydrate;

monosodium citrate anhydrous; aspartame (E951); croscarmellose sodium; silica colloidal

anhydrous; magnesium stearate

What Donepezil tablets look like and contents of the pack

Donepezil hydrochloride 5mg Orodispersible tablets are white to off-white round, flat tablets with

bevelled edges, embossed with ‘5’ on one side..

Donepezil hydrochloride 10mg Orodispersible tablets are white to off-white round, flat tablets with

bevelled edges, embossed with ‘10’ on one side..

Pack sizes:

28 orodispersible tablets

Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavíkurvegur 76-78

220 Hafnarfjörður

Iceland

Manufacturer

Genepharm S.A.

km Marathonos Avenue

Pallini 15351, Attiki

Greece

This leaflet was last revised in February 2019

If you would like a leaflet with larger text, please contact 01271

385257.

Logo Actavis

Pil Spec no

Actavis, Barnstaple, EX32 8NS, UK

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Donepezil Hydrochloride 10 mg Orodispersible Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 10 mg tablet contains 10 mg donepezil hydrochloride (as monohydrate),

equivalent to 9.12 mg of donepezil free base.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Orodispersible tablet

Donepezil Hydrochloride 10 mg are yellow coloured round flat bevelled edged

tablets, debossed with “DL 10” on one side and “M” on the other side

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Donepezil Hydrochloride 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

donepezil

hydrochloride

increased

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.

Renal or 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.

Paediatric population

Donepezil

hydrochloride

recommended

children

adolescents below 18 years of age.

Method of administration

For oral use.

Donepezil Hydrochloride should be taken orally, in the evening, just prior to

retiring.

The tablet should be placed on the tongue and allowed to disintegrate before

swallowing with or without water, according to patient preference.

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,

cholinesterase

inhibitor,

likely

exaggerate

succinylcholine-type muscle relaxation during anaesthesia.

Cardiovascular conditions

Because

their

pharmacological

action,

cholinesterase

inhibitors

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,

potentially

life-threatening

condition

characterised

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

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

their

cholinomimetic

actions,

cholinesterase

inhibitors

should

prescribed with care to patients with a 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

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

studies

combined

donepezil

hydrochloride

group

(1.7%)

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 less than 1 mmol sodium (23 mg) per tablet, that is to

say essentially ‘sodium-free.’

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

donepezil

hydrochloride

affected

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

other

CYP3A4

inhibitors,

such

itraconazole

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

cholinergic

agonists

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.

Studies in animals have not shown teratogenic effect but have shown pre and post

natal toxicity (see section 5.3). The potential risk for humans is unknown.

Donepezil

hydrochloride

should

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 (<1/10000) and not known

(cannot be estimated from available data).

System Organ

Class

Very

Common

Common

Uncommon

Rare

Very Rare

Infections and

infestations

Common cold

Metabolism

and nutrition

disorders

Anorexia

Psychiatric

disorders

Hallucination

Agitation **

Aggressive

behaviour**

Abnormal

dreams and

Nightmares**

Nervous

system

disorders

Syncope*

Dizziness

Insomnia

Seizure*

Extrapyramida

l symptoms

Neuroleptic

Malignant

Syndrome

Cardiac

disorders

Bradycardia

Sino-atrial

block

Atrioventricul

ar block

Gastrointestina

l disorders

Diarrhoea

Nausea

Vomiting

Abdominal

disturbance

Gastrointestin

haemorrhage

Gastric and

duodenal

ulcers

Salivary

hypersecretion

Hepatobiliary

disorders

Liver

dysfunction

including

hepatitis***

Skin and

subcutaneous

tissue

disorders

Rash

Pruritis

Musculoskelet

al 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

* 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.

cases

unexplained

liver

dysfunction,

withdrawal

donepezil

hydrochloride should be considered.

**** Rhabdomyolysis has been reported to occur independently of neuroleptic

malignant

syndrome

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

Yellow

Card

Scheme

www.mhra.gov.uk/yellowcard.

4.9

Overdose

Donepezil hydrochloride is a specific reversible acetylcholinesterase inhibitor.

estimated

median

lethal

dose

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

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 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 (haemodialysis, peritoneal dialysis, or haemofiltration).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: anti-dementia drugs; anticholinesterases, ATC

code: N06DA02.

Mechanism of action

Donepezil

hydrochloride

specific

reversible

inhibitor

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 which is present mainly

outside the central nervous system.

Alzheimer's Dementia

patients

with

Alzheimer's

Dementia

participating

clinical

trials,

administration

single

daily

doses

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

combination

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

deterioration

Activities

Daily

Living

Schedule

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%**

* 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

area

under

curve

rise

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 and the related pharmacodynamic activity show

little variability over the course of the day.

Food did not affect the absorption of donepezil hydrochloride.

Distribution

Read the complete document

Public Assessment Report

UKPAR

Donepezil hydrochloride 5mg film-coated tablets

Donepezil hydrochloride 10mg film-coated tablets

(Donepezil hydrochloride)

UK Licence No: PL 20416/0485-0486

Crescent Pharma Limited

.

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

2

LAY SUMMARY

Donepezil hydrochloride 5mg film-coated tablets

Donepezil hydrochloride 10mg film-coated tablets

(donepezil hydrochloride)

This is a summary of the Public Assessment Report (PAR) for Donepezil hydrochloride 5mg film-coated

tablets (PL 20416/0485) and Donepezil hydrochloride 10mg film-coated tablets (PL 20416/0486). It

explains how Donepezil hydrochloride 5mg and 10mg film-coated tablets were assessed and their

authorisation recommended, as well as their conditions of use. It is not intended to provide practical

advice on how to use Donepezil hydrochloride 5mg and 10mg film-coated tablets.

The products will be collectively referred to as Donepezil hydrochloride tablets throughout the

remainder of this public assessment report (PAR).

For practical information about using Donepezil hydrochloride tablets, patients should read the package

leaflet or contact their doctor or pharmacist.

What are Donepezil hydrochloride tablets and what are they used for?

Donepezil hydrochloride tablets are 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

difficult to carry out their normal daily activities.

This medicine is for use in adult patients only.

These applications are the same as Donepezil hydrochloride 5 mg and 10 mg film-coated tablets

(PL 19156/0047 and 0048) which are already authorised.

The company (Jubilant Pharmaceuticals nv) that makes Donepezil hydrochloride 5 mg and 10 mg film-

coated tablets (PL 19156/0047 and 0048) has agreed that its scientific data can be used as a basis for

the grant of identical licences for Donepezil hydrochloride tablets.

How do Donepezil hydrochloride tablets work?

This medicine contains the active ingredient 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

acetylcholine.

How are Donepezil hydrochloride tablets used?

The pharmaceutical form of this medicine is a film-coated tablet and the route of administration is oral

(by mouth).

The patient should always take this medicine exactly as their doctor or pharmacist has told them.

The patient should check with their doctor or pharmacist if they are not sure.

Usually, the patient will start by taking 5mg every night. After one month, their doctor may tell them to

take 10mg donepezil hydrochloride every night.

The patient should swallow their Donepezil hydrochloride tablet with a drink of water before they go to

bed at night.

The tablet strength the patient will take may change depending on the length of time they have been

taking the medicine and on what the patient’s doctor recommends. The maximum recommended dose

is 10mg each night.

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

3

The patient must not alter the dose themselves without their doctor´s advice.

The patient’s doctor or pharmacist will advise them on how long they should continue to take their

tablets. The patient will need to see their doctor from time to time to review their treatment and assess

their symptoms.

This medicine can only be obtained with a prescription.

For further information on how Donepezil hydrochloride tablets are used, refer to the package leaflet

and Summaries of Product Characteristics available on the Medicines and Healthcare products

Regulatory Agency (MHRA) website.

What benefits of Donepezil hydrochloride tablets have been shown in studies?

Donepezil hydrochloride tablets are considered identical to previously authorised Donepezil

hydrochloride 5 mg and 10 mg film-coated tablets (PL 19156/0047 and 0048) with the same benefits

and risks. So, no new studies have been provided for Donepezil hydrochloride tablets, but cross-

reference is made to the studies for Donepezil hydrochloride 5 mg and 10 mg film-coated tablets (PL

19156/0047 and 0048).

What are the possible side effects from Donepezil hydrochloride tablets?

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

Donepezil hydrochloride tablets is considered to be identical to the previously authorised applications

for Donepezil hydrochloride 5 mg and 10 mg film-coated tablets (PL 19156/0047 and 0048) with the

same benefits and risks.

For a full list of all the side effects reported with Donepezil hydrochloride tablets see section 4 of the

package leaflet, available on the Medicines and Healthcare products Regulatory Agency (MHRA)

website.

For the full list of restrictions, see the package leaflet.

Why was Donepezil hydrochloride tablets approved?

The MHRA decided that the benefits of Donepezil hydrochloride tablets are greater than the risks and

recommended that it is approved for use.

What measures are being taken to ensure the safe and effective use of Donepezil hydrochloride

tablets?

A Risk Management Plan has been developed to ensure that Donepezil hydrochloride tablets are used

as safely as possible. Based on this plan, safety information has been included in the Summaries of

Product Characteristics and the package leaflet for Donepezil hydrochloride tablets including the

appropriate precautions to be followed by healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals reported by

patients/healthcare professionals will be monitored/reviewed continuously.

Other information about Donepezil hydrochloride tablets

Marketing Authorisations were granted in the UK on 29 October 2018.

The full PAR for Donepezil hydrochloride tablets follows this summary.

For more information about treatment with Donepezil hydrochloride tablets read the package leaflet or

contact your doctor or pharmacist.

This summary was last updated in December 2018.

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

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TABLE OF CONTENTS

Introduction

Page 6

Quality aspects

Page 6

Non-clinical aspects

Page 8

Clinical aspects

Page 8

User consultation

Page 8

Overall conclusion, benefit/risk assessment

and recommendation

Page 8

Table of content of the PAR update

Page 14

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

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I

INTRODUCTION

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Crescent Pharma Limited

Marketing Authorisations for the medicinal products Donepezil hydrochloride tablets

(PL 20416/0485-0486) on 29 October 2018. These products are prescription only medicines (POM)

indicated for the symptomatic treatment of mild to moderately severe Alzheimer´s dementia.

These applications were submitted as simple abridged (informed consent) applications according to

Article 10c of Directive 2001/83/EC, as amended.

The applications cross-refer to the medicinal products Donepezil hydrochloride 5 mg and 10 mg film-

coated tablets which were first authorised to the marketing authorisation holder (MAH) Jubilant

Pharmaceuticals nv on 12 March 2010 (PL 19156/0047 and 0048).

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.

No new data were submitted nor were necessary to be submitted for these applications, as the data are

identical to the data for the previously granted cross-referenced products.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place for this product type at all sites responsible for the manufacture and assembly of this product.

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

6

II

QUALITY ASPECTS

II.1

Introduction

These are abridged applications for Donepezil hydrochloride tablets (PL 20416/0485-0486)

submitted under Article 10c of Directive 2001/83/EC, as amended.

The applications cross-refer to the medicinal products Donepezil hydrochloride 5 mg and 10

mg film-coated tablets which were first authorised to the marketing authorisation holder (MAH)

Jubilant Pharmaceuticals nv on 12 March 2010 (PL 19156/0047 and 0048).

II.2.

Drug Substance

Drug substance specifications

The proposed drug substance specifications are consistent with the details registered for the

cross-reference products.

II.3.

Medicinal Product

Name

The proposed product names for these applications are Donepezil hydrochloride 5mg and

10mg film-coated tablets. The products have been named in line with current requirements.

Strength, pharmaceutical form, route of administration, container and pack sizes

Each film-coated tablet contains 5 mg of donepezil hydrochloride (equivalent to 4.56 mg of

donepezil) or 10 mg donepezil hydrochloride (equivalent to 9.12 mg of donepezil) as the active

ingredient. Both strengths of the finished product are packaged into cardboard boxes

containing PVC/aluminium blisters with 28 tablets.

The proposed shelf life of the unopened product is 3 years. This medicinal product does not

require any special storage conditions.

The proposed packaging, shelf-life and storage conditions are consistent with the details

registered for the cross-reference product.

Legal status

Prescription only medicine (POM).

Marketing Authorisation Holder/Contact Persons/Company

Crescent Pharma Limited, Units 3 & 4, Quidhampton Business Units, Polhampton Lane,

Overton, Hants RG25 3ED, UK.

The Qualified Person (QP) responsible for pharmacovigilance is stated and a satisfactory CV

has been provided.

Manufacturers

The proposed manufacturing sites are consistent with those registered for the cross-reference

products and evidence of Good Manufacturing Practice (GMP) compliance has been provided.

Qualitative and quantitative composition

The proposed composition is consistent with the details registered for the cross-reference

products.

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

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Manufacturing process

The proposed manufacturing processes are consistent with the details registered for the

cross-reference products and the maximum batch size is stated.

Finished product/shelf-life specifications

The proposed finished product specifications are in line with the details registered for the

cross-reference products.

TSE Compliance

With the exception of lactose monohydrate none of the excipients used contain material of

animal or human origin. The supplier of lactose monohydrate has confirmed that it is sourced

from healthy animals under the same conditions as milk for human consumption.

Bioequivalence

No bioequivalence data are required to support these simple abridged applications because

the proposed products are manufactured to the same formulae utilising the same processes as

the cross-reference products, Donepezil hydrochloride 5 mg and 10 mg film-coated tablets (PL

19156/0047 and 0048).

Expert Report

The applicant cross-refers to the data for Donepezil hydrochloride 5 mg and 10 mg film-coated

tablets (PL 19156/0047 and 0048) to which these applications are claimed to be identical. This

is acceptable.

Product Names and Appearance

See Section II.3 ‘Medicinal Product; Name’ for details of the proposed product names. The

appearance of the products is identical to that of the cross-reference products.

II.4

Discussion on chemical, pharmaceutical and biological aspects

The data submitted with these applications is acceptable. The grant of Marketing

Authorisations is recommended.

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

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III

NON-CLINICAL ASPECTS

Introduction

As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended,

no new non-clinical data have been supplied and none are required.

Ecotoxicity/environmental risk assessment (ERA)

Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As

the applications are identical to those of the already authorised products, it is not expected that

environmental exposure will increase following approval of the Marketing Authorisations for the

proposed products.

Discussion on the non-clinical aspects

The grant of Marketing Authorisations is recommended.

IV

CLINICAL ASPECTS

Introduction

As these are abridged applications submitted under Article 10c of Directive 2001/83/EC, as amended,

no new clinical data have been supplied and none are required.

Risk Management Plan (RMP)

The MAH has submitted a risk management plan, in accordance with the requirements of Directive

2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to

identify, characterize, prevent or minimise risks relating to Donepezil hydrochloride tablets.

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP are

listed below:

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.

Discussion on the clinical aspects

The grant of Marketing Authorisations is recommended.

V

User consultation

A user consultation with target patient groups on the package information leaflet (PIL) has been

performed on the basis of a bridging report making reference to the PIL Donepezil hydrochloride IPCA

5 mg and 10 mg film-coated tablets (Ipca Produtos Farmaceuticos Unipessoal Lda; NL/H/2626/001-

002/DC). The bridging report submitted by the applicant is acceptable.

VI

Overall conclusion, benefit/risk assessment and recommendation

The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been

identified. The applicant’s products are identical to the cross-reference products. Extensive clinical

experience with donepezil hydrochloride is considered to have demonstrated the therapeutic value of

the compound. The benefit/risk balance is, therefore, considered to be positive.

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

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Summaries of Product Characteristics (SmPC), Patient Information Leaflets (PIL) and Labels

The SmPCs and PIL are consistent with the details registered for the cross-reference products.

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and

Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

The approved labelling for this medicine is presented below:

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

10

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

11

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

12

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

PL 20416/0485-0486

13

PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

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PAR Donepezil hydrochloride 5mg and 10mg film-coated tablets

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Annex 1

Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

Scope

Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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