Donepezil 5mg orodispersible tablets sugar free

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:
5mg
Pharmaceutical form:
Orodispersible tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04110000; GTIN: 5016695004525
Authorization number:
PL 04569/1061

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Package leaflet: Information for the patient

Donepezil Hydrochloride 5 mg Orodispersible Tablets

Donepezil Hydrochloride 10 mg Orodispersible 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 Donepezil Hydrochloride is and what it is used for

What you need to know before you take Donepezil Hydrochloride

How to take Donepezil Hydrochloride

Possible side effects

How to store Donepezil Hydrochloride

Contents of the pack and other information

1.

What Donepezil Hydrochloride is and what it is used for

Donepezil Hydrochloride contains the active substance donepezil hydrochloride. Donepezil

hydrochloride 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 in adult patients only.

2.

What you need to know before you take Donepezil Hydrochloride

Do not take Donepezil Hydrochloride

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 Donepezil Hydrochloride if you suffer, or

have ever suffered, from any of the following conditions:

heart rate or rhythm problem

(e.g. an irregular heart beat or other conditions that affect

the rate or rhythm of the heart)

stomach or duodenal (gut) ulcers

difficulty passing urine

fits or seizures

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 as ‘extrapyramidal’ or ‘Parkinson’s’ like effects)

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 Donepezil Hydrochloride

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any

other medicines. In particular, tell your doctor or pharmacist if you are taking any of the

following:

other Alzheimer’s disease medicines, e.g. galantamine

anticholinergics (medicines which typically cause dry mouth, blurred vision and/or

drowsiness) e.g. tolterodine (used for bladder problems)

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. propranolol and

atenolol)

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

anti-inflammatory drugs NSAID) such as ibuprofen or diclofenac

muscle relaxants e.g. diazepam

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.

Donepezil Hydrochloride with alcohol

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

effect of donepezil hydrochloride.

Pregnancy and breast-feeding

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

medicine before speaking to your doctor for advice. Donepezil Hydrochloride should not be

used in pregnancy unless clearly necessary.

Women taking this medicine should not breast-feed.

Driving and using machines

Do not drive or operate machinery if you feel dizzy, sleepy/tired or get muscle cramps while

taking this medicine.

Alzheimer’s disease may also 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.

3.

How to take Donepezil Hydrochloride

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

doctor or pharmacist if you are not sure.

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 taken once a day, normally in the evening before you

go to bed, for at least one month.

After one month, your doctor may increase this to 10 mg taken once a day, normally in the

evening before you go to bed.

The maximum daily dose is 10 mg.

Use in patients with liver and kidney disease

For adults with mild to moderate liver problems, your doctor may need to adjust your dose.

No dosage adjustment is normally required if you have kidney problems.

Use in children or adolescents

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

Method of administration

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

with or without water, according to your preference. You can take this medicine with or

without food.

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 Hydrochloride 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 that the doctor knows what has been taken.

Symptoms of taking more than you should include feeling and being sick, salivation,

sweating, slow heart rate, low blood pressure (light-headedness or dizziness when standing),

breathing problems, losing consciousness, seizures (fits) or convulsions and muscle weakness.

If you forget to take Donepezil Hydrochloride

If you forget 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 Donepezil Hydrochloride

When treatment is stopped the beneficial effects of Donepezil Hydrochloride 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 your nearest hospital casualty department straight away if you

have any of the following serious side effects:

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 (poo) 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), you may

feel sick and have a fever)

changes in heart rhythm or a very slow heart rate.

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 in sleeping)

common cold

anorexia (loss of appetite)

hallucinations (seeing or hearing things that are not really there)

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.

Rare (

may affect up to 1 in 1,000 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

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 Hydrochloride

Keep this medicine out of the sight and reach of children.

This medicine does not require any special storage conditions.

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.

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 Hydrochloride contains

The active substance is donepezil hydrochloride.

- Donepezil Hydrochloride 5 mg Orodispersible Tablets: Each tablet contains 5 mg

donepezil hydrochloride (equivalent to 4.56 mg donepezil).

- Donepezil Hydrochloride 10 mg Orodispersible Tablets: Each tablet contains 10 mg

donepezil hydrochloride (equivalent to 9.12 mg donepezil).

The other ingredients are mannitol (E421); silica colloidal anhydrous;

hydroxypropylcellulose; acesulfame potassium; glycine; sodium starch glycolate;

crospovidone (Type A);microcrystalline cellulose; magnesium stearate.

Donepezil Hydrochloride 10 mg Orodispersible Tablets also contain yellow iron oxide

(E172).

What Donepezil Hydrochloride looks like and contents of the pack

Your medicine is in the form of an orodispersible tablet.

Donepezil Hydrochloride 5 mg Orodispersible Tablets are white coloured round flat bevelled

edged tablets, marked with “DL 5” on one side and “M” on the other side.

Donepezil Hydrochloride 10 mg Orodispersible Tablets are yellow coloured round flat

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

Donepezil Hydrochloride 5 mg and 10 mg Orodispersible Tablets are available in blister

packs of 7, 10, 14, 28, 30, 50, 56, 60, 84, 98, 100, 120 and 180 orodispersible tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Mylan, Potters Bar, Hertfordshire, EN6 1TL, UK

Manufacturers

McDermott Laboratories Ltd. T/A Gerard Laboratories, 35/36 Baldoyle Industrial Estate,

Grange Road, Dublin 13, Ireland.

Mylan Hungary Kft., H-2900, Komárom, Mylan utca.1, Hungary.

This leaflet was last revised in 04/2016

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Object 1

Donepezil Hydrochloride 5 mg Orodispersible

Tablets

Summary of Product Characteristics Updated 14-Jul-2017 | Generics UK T/A Mylan

1. Name of the medicinal product

Donepezil Hydrochloride 5 mg Orodispersible Tablets

2. Qualitative and quantitative composition

Each 5 mg tablet contains 5 mg donepezil hydrochloride (as monohydrate), equivalent to 4.56 mg of

donepezil free base.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Orodispersible tablet

Donepezil Hydrochloride 5 mg are white coloured round flat bevelled edged tablets, debossed with “DL

5” 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 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.

Patients with 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 is not recommended for use in children.

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 excipients listed in section 6.1.

4.4 Special warnings and precautions for use

The use of donepezil hydrochloride in patients with severe 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 nonsteroidal 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 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.

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.

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 (<1/10000) 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

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

Hepatobiliary

disorders

Liver

dysfunction

including

hepatitis***

Skin and

subcutaneous

tissue disorders

Rash

Pruritis

Musculoskeletal

and connective

tissue disorders

Muscle cramps

Rhabdomyolysis****

Renal and

urinary disorders

Urinary

incontinence

General disorders

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.

*** 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 the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard.

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.

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

(haemodialysis, peritoneal dialysis, or haemofiltration).

5. Pharmacological properties

5.1 Pharmacodynamic properties

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

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

cholinesterase in the brain. Donepezil hydrochloride is in vitro over 1000 times more potent an inhibitor

of this enzyme than of butyrylcholinesterase, an enzyme 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 Schedule 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%**

* 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 14C-labelled donepezil hydrochloride, approximately 28% of the

label remained unrecovered. This suggests that donepezil hydrochloride and/or its metabolites may persist

in the body for more than 10 days.

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-desmethyldonepezil (11% - only metabolite that exhibits activity similar to

donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyldonepezil (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 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

Mannitol

Silica colloidal anhydrous

Hydroxypropylcellulose

Acesulfame potassium

Glycine

Sodium starch glycolate (Type A)

Crospovidone (Type A)

Cellulose, microcrystalline

Magnesium stearate

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

Cold form foil OPA/Alu/PVC-Alu blisters in packages of 7, 10, 14, 28, 30, 50, 56, 60, 84, 98, 100, 120

and 180 orodispersible tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7. Marketing authorisation holder

Generics [UK] Limited t/a Mylan

Station Close,

Potters Bar,

Hertfordshire, EN6 1TL,

United Kingdom

8. Marketing authorisation number(s)

PL 04569/1061

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 30/04/2010

Date of latest renewal: 30/03/2016

10. Date of revision of the text

04/2016

Company Contact Details

Generics UK T/A Mylan

Address

Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

http://www.mylan.com

+44 (0)1707 261 803

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)1707 261 803

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