Donepezil HCl Sandoz 10 mg - Filmtabletten

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/

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Public Assessment Report

Decentralised Procedure

Donepezil Hydrochloride 5mg Film Coated Tablets

Donepezil Hydrochloride 10mg Film Coated Tablets

AT/H/0883/001-002

Former UK/H/1145/01-02/DC

Applicant: Sandoz Limited

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Sandoz

Limited Marketing Authorisations (licences) for the medicinal products Donepezil

Hydrochloride 5mg and 10mg Film Coated Tablets on 25

November 2008. This is a

prescription-only medicine used to treat the symptoms of dementia in people

diagnosed as having mild to moderately severe Alzheimer’s disease.

The tablets contain the active ingredient, donepezil hydrochloride. Aricept belongs to

a group of medicines called acetylcholinesterase inhibitors. Donepezil is well

characterised in the literature. It is a specific and reversible inhibitor of

acetylcholinesterase, the predominant cholinesterase in the brain.

No new or unexpected safety concerns arose from these applications and it was

therefore judged that the benefits of taking Donepezil hydrochloride 5mg and 10mg

Film-Coated Tablets outweigh the risks; hence Marketing Authorisations have been

granted.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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TABLE OF CONTENTS

Module 1: Information about initial procedure

Page 4

Module 2: Summary of Product Characteristics

Page 5

Module 3: Product Information Leaflets

Page 21

Module 4: Labelling

Page 23

Module 5: Scientific Discussion

Page 25

1 Introduction

Page 25

2 Quality aspects

Page 27

3 Non-clinical aspects

Page 29

4 Clinical aspects

Page 29

Module 6

5 Overall conclusions

Steps taken after initial procedure

Page 34

Page 35

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Module 1

Product Name

Donepezil Hydrochloride 5mg Film Coated Tablets

Donepezil Hydrochloride 10mg Film Coated Tablets

Type of Application

Generic, Article 10.1

Active Substance

Donepezil Hydrochloride

Form

Film Coated Tablets

Strength

5mg & 10mg

MA Holder

Sandoz Limited,

37 Woolmer Way, Bordon, Hampshire, GU35 9QE,

United Kingdom

Reference Member

State (RMS)

CMS

Austria, Belgium, Czech Republic, Denmark, Germany,

Greece, Spain, Finland, France, Italy, Norway, Poland,

Portugal, Romania, Sweden, Slovak Republic and Slovenia

Procedure Number

UK/H/1145/01-02/DC

End of Procedure

July 2008

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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Module 2

Summary of Product Characteristics

The UK Summaries of Product Characteristics (SPC) for Donepezil Hydrochloride

5mg & 10mg Film Coated Tablets are as follows:

1

NAME OF THE MEDICINAL PRODUCT

Donepezil Hydrochloride 5 mg Film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg donepezil hydrochloride.

Excipients:

19 mg lactose/film-coated tablet

0.2 mg soya lecithin/film-coated tablet

For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablet

White, round (diameter 7 mm) film-coated tablet

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Donepezil is indicated for the symptomatic treatment of mild to moderately severe

Alzheimer’s dementia.

4.2

Posology and method of administration

Adults/Elderly:

Treatment is initiated at 5 mg/day (once-a-day dosing). The film-coated tablet should be taken

orally, in the evening, just prior to retiring. The 5 mg/day dose should be maintained for at

least one month in order to allow the earliest clinical responses to treatment to be assessed and

to allow steady-state concentrations of donepezil hydrochloride to be achieved. Following a

one-month clinical assessment of treatment at 5 mg/day, the dose can be increased to 10

mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses greater

than 10 mg/day have not been studied in clinical trials.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and

treatment of Alzheimer’s dementia. Diagnosis should be made according to accepted

guidelines (e.g. DSM IV, ICD 10). Therapy with donepezil should only be started if a

caregiver is available who will regularly monitor drug intake for the patient. Maintenance

treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore,

the clinical benefit of donepezil should be reassessed on a regular basis. Discontinuation

should be considered when evidence of a therapeutic effect is no longer present. Individual

response to donepezil cannot be predicted.

Upon discontinuation of treatment, a gradual abatement of the beneficial effects of donepezil

is seen.

Renal and hepatic impairment:

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

donepezil hydrochloride is not affected by this condition.

Due to possible increased exposure in mild to moderate hepatic impairment (see section 5.2),

dose escalation should be performed according to individual tolerability. There are no data for

patients with severe hepatic impairment.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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Children and adolescents:

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

4.3

Contraindications

Hypersensitivity to the active substance, piperidine derivatives, soya, peanut or to any of the

excipients.

4.4

Special warnings and precautions for use

The use of donepezil in patients with severe Alzheimer’s dementia, other types of dementia or

other types of memory impairment (e.g., age-related cognitive decline), has not been

investigated.

Anaesthesia:

Donepezil, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle

relaxation during anaesthesia.

Cardiovascular Conditions:

Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects

on heart rate (e.g. bradycardia). The potential for this action may be particularly important to

patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions,

such as sinoatrial or atrioventricular block.

There have been reports of syncope and seizures. In investigating such patients the possibility

of heart block or long sinusal pauses should be considered.

Gastrointestinal Conditions:

Patients at increased risk for developing ulcers, e.g. those with a history of ulcer disease or

those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), should be

monitored for symptoms. However, the clinical studies with donepezil showed no increase,

relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Genitourinary:

Although not observed in clinical trials of donepezil, cholinomimetics may cause bladder

outflow obstruction.

Neurological Conditions:

Seizures: Cholinomimetics are believed to have some potential to cause generalised

convulsions. However, seizure activity may also be a manifestation of Alzheimer's Disease.

Cholinomimetics may have the potential to exacerbate or induce extrapyramidal symptoms.

Pulmonary Conditions:

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with

care to patients with a history of asthma or obstructive pulmonary disease.

The administration of donepezil concomitantly with other inhibitors of acetylcholinesterase,

agonists or antagonists of the cholinergic system should be avoided.

Severe Hepatic Impairment:

There are no data for patients with severe hepatic impairment.

Mortality in Vascular Dementia Clinical Trials:

Three clinical trials of 6 months duration were conducted studying individuals meeting the

NINDS-AIREN criteria for probable or possible vascular dementia (VaD). The NINDS-

AIREN criteria are designed to identify patients whose dementia appears to be due solely to

vascular causes and to exclude patients with Alzheimer’s disease. In the first study, the

mortality rates were 2/198 (1.0%) on donepezil hydrochloride 5 mg, 5/206 (2.4%) on

donepezil hydrochloride 10 mg and 7/199 (3.5%) on placebo. In the second study, the

mortality rates were 4/208 (1.9%) on donepezil hydrochloride 5 mg, 3/215 (1.4%) on

donepezil hydrochloride 10 mg and 1/193 (0.5%) on placebo. In the third study, the mortality

rates were 11/648 (1.7%) on donepezil hydrochloride 5 mg and 0/326 (0%) on placebo. The

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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mortality rate for the three VaD studies combined in the donepezil hydrochloride group

(1.7%) was numerically higher than in the placebo group (1.1%), however, this difference was

not statistically significant. The majority of deaths in patients taking either donepezil

hydrochloride or placebo appear to result from various vascular related causes, which could be

expected in this elderly population with underlying vascular disease. An analysis of all serious

non-fatal and fatal vascular events showed no difference in the rate of occurrence in the

donepezil hydrochloride group relative to placebo.

In pooled Alzheimers’s disease studies (n= 4146), and when these Alzheimer’s disease studies

were pooled with other dementia studies including the vascular dementia studies (total n =

6888), the mortality rate in the placebo groups numerically exceeded that in the donepezil

hydrochloride groups.

Lactose and Glucose:

Donepezil hydrochloride film-coated tablets contain lactose and maize starch (source of

glucose). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5

Interaction with other medicinal products and other forms of interaction

Donepezil hydrochloride and/or any of its metabolites does not inhibit the metabolism of

theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil

hydrochloride is not affected by concurrent administration of digoxin or cimetidine. In vitro

studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are

involved in the metabolism of donepezil. Drug interaction studies performed in vitro show

that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit

donepezil metabolism. Therefore, these and other CYP3A4 inhibitors, such as itraconazole

and erythromycin, and CYP2D6 inhibitors, such as fluoxetine, could inhibit the metabolism of

donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil

concentrations by about 30%. Enzyme inducers, such as rifampicin, phenytoin, carbamazepine

and alcohol may reduce the levels of donepezil. Since the magnitude of an inhibiting or

inducing effect is unknown, such drug combinations should be used with care. Donepezil

hydrochloride has the potential to interfere with medications having anticholinergic activity.

There is also the potential for synergistic activity with concomitant treatment involving

medications such as succinylcholine, other neuro-muscular blocking agents or cholinergic

agonists or beta blocking agents which have effects on cardiac conduction.

4.6

Pregnancy and lactation

Pregnancy:

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

Studies in animals have not shown teratogenic effect but have shown peri and post natal

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

Donepezil should not be used during pregnancy unless clearly necessary.

Lactation:

Donepezil is excreted in the milk of rats. It is not known whether donepezil hydrochloride is

excreted in human breast milk and there are no studies in lactating women. Therefore, women

on donepezil should not breast-feed.

4.7

Effects on ability to drive and use machines

Donepezil has minor or moderate influence on the ability to drive and use machines.

Dementia may cause impairment of driving performance or compromise the ability to use

machinery. Furthermore, donepezil can induce fatigue, dizziness and muscle cramps, mainly

when initiating or increasing the dose. The treating physician should routinely evaluate the

ability of patients on donepezil to continue driving or operating complex machines.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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4.8

Undesirable effects

The most common undesirable effects are diarrhoea, muscle cramps, fatigue, nausea,

vomiting, headache and insomnia.

Adverse reactions reported as more than an isolated case are listed below, by system organ

class and by frequency.

Frequencies are defined as:

Very common (≥1/10)

Common (≥1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000), not known (cannot be estimated from the available data)

System Organ Class

Very

Common

Common

Uncommon

Rare

Infections and

infestations

Common cold

Metabolism and nutrition

disorders

Anorexia

Psychiatric disorders

Hallucinations**

Agitation**

Aggressive

behaviour**

Nervous system

disorders

Syncope*

Dizziness

Insomnia

Seizure*

Extrapyramidal

symptoms

Cardiac disorders

Bradycardia

Sino-atrial

block

Atrioventricula

r block

Gastrointestinal

disorders

Diarrhoea

Nausea

Vomiting

Abdominal

disturbance

Gastrointestinal

haemorrhage

Gastric and

duodenal ulcers

Hepato-biliary disorders

Liver

dysfunction

including

hepatitis***

Skin and subcutaneous

tissue disorders

Rash

Pruritis

Musculoskeletal,

connective tissue and

bone disorders

Muscle cramps

Renal and urinary

disorders

Urinary

incontinence

General disorders and

administration site

conditions

Headache

Fatigue

Pain

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System Organ Class

Very

Common

Common

Uncommon

Rare

Investigations

Minor increase in

serum

concentration of

muscle creatine

kinase

Injury and poisoning

Accident

*In investigating patients for syncope or seizure the possibility of heart block or long sinusal

pauses should be considered (see section 4.4).

**Reports of hallucinations, agitation and aggressive behaviour have resolved on dose-

reduction or discontinuation of treatment.

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

4.9

Overdose

The estimated median lethal dose of donepezil hydrochloride following administration of a

single oral dose in mice and rats is 45 and 32 mg/kg, respectively, or approximately 225 and

160 times the maximum recommended human dose of 10 mg per day.

Symptoms:

Dose-related signs of cholinergic stimulation were observed in animals and included reduced

spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions,

depressed respiration, salivation, miosis, fasciculation and lower body surface temperature.

Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by

severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory

depression, collapse and convulsions. Increasing muscle weakness is a possibility and may

result in death if respiratory muscles are involved.

Treatment:

As in any case of overdose, general supportive measures should be utilised. Tertiary

anticholinergics such as atropine may be used as an antidote for donepezil overdosage.

Intravenous atropine sulphate titrated to effect is recommended: an initial dose of 1.0 to 2.0

mg intravenous with subsequent doses based upon clinical response. Atypical responses in

blood pressure and heart rate have been reported with other cholinomimetics when 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 that is

present mainly outside the central nervous system.

In patients with Alzheimer's dementia participating in clinical trials, administration of single

daily doses of 5 mg or 10 mg of donepezil hydrochloride produced steady-state inhibition of

acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6% and 77.3%,

respectively when measured post dose. The inhibition of acetylcholinesterase (AChE) in red

blood cells by donepezil hydrochloride has been shown to correlate to changes in ADAS-cog,

a sensitive scale which examines selected aspects of cognition. The potential for donepezil

hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus

donepezil can not be considered to have any effect on the progress of the disease.

Efficacy of treatment of Alzheimer’s dementia with donepezil has been investigated in four

placebo-controlled trials, 2 trials of 6-month duration and 2 trials of 1-year duration.

In the 6 months clinical trial, an analysis was done at the conclusion of donepezil treatment

using a combination of three efficacy criteria: the ADAS-Cog (a measure of cognitive

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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 Hydrochloride

5-mg Group

18%*

18%*

Donepezil Hydrochloride 10-mg

Group

21%*

22%**

*p < 0.05

**p < 0.01

Donepezil produced a dose-dependent statistically significant increase in the percentage of

patients who were judged treatment responders.

5.2

Pharmacokinetic properties

Absorption:

Maximum plasma levels are reached approximately 3 to 4 hours after oral administration.

Plasma concentrations and area under the curve rise in proportion to the dose. The terminal

disposition half-life is approximately 70 hours, thus, administration of multiple single-daily

doses results in gradual approach to steady-state. Approximate steady-state is achieved within

3 weeks after initiation of therapy. Once at steady-state, plasma donepezil hydrochloride

concentrations and the related pharmacodynamic activity show little variability over the

course of the day.

Food did not affect the absorption of donepezil hydrochloride.

Distribution:

Donepezil hydrochloride is approximately 95% bound to human plasma proteins. The plasma

protein binding of the active metabolite 6-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.

Metabolism/Excretion:

Donepezil hydrochloride is both excreted in the urine intact and metabolised by the

cytochrome P450 system to multiple metabolites, not all of which have been identified.

Following administration of a single 5 mg dose of

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-desmethyldonepezil (3%).

Approximately 57% of the total administered radioactivity was recovered from the urine (17%

as unchanged donepezil), and 14.5% was recovered from the faeces, suggesting

biotransformation and urinary excretion as the primary routes of elimination. There is no

evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its

metabolites.

Plasma donepezil concentrations decline with a half-life of approximately 70 hours.

Sex, race and smoking history have no clinically significant influence on plasma

concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil has not been

formally studied in healthy elderly subjects, or in Alzheimer’s or vascular dementia patients.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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However, mean plasma levels in patients closely agreed with those of young healthy

volunteers.

Patients with mild to moderate hepatic impairment had increased donepezil steady state

concentrations; mean AUC by 48% and mean C

by 39% (see section 4.2).

5.3

Preclinical safety data

Extensive testing in experimental animals has demonstrated that this compound causes few

effects other than the intended pharmacological effects consistent with its action as a

cholinergic stimulator (see section 4.9). Donepezil is not mutagenic in bacterial and

mammalian cell mutation assays. Some clastogenic effects were observed in vitro at

concentrations overtly toxic to the cells and more than 3000 times the steady-state plasma

concentrations. No clastogenic or other genotoxic effects were observed in the mouse

micronucleus model in vivo. There was no evidence of oncogenic potential in long-term

carcinogenicity studies in either rats or mice.

Donepezil hydrochloride had no effect on fertility in rats, and was not teratogenic in rats or

rabbits, but had a slight effect on still-births and early pup survival when administered to

pregnant rats at 50 times the human dose (see section 4.6).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Microcrystalline cellulose,

Lactose monohydrate

Maize starch

Magnesium stearate

Tablet coat:

Polyvinyl alcohol

Talc

Titanium dioxide (E171)

Macrogol 3350

Soya lecithin

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

18 months

6 months after first opening of the HDPE-bottle

6.4

Special precautions for storage

Do not store above 25°C.

6.5

Nature and contents of container

PVC/Aluminium blister

Pack sizes of 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 98, 100, 100x1 or 120 film-coated tablets

HDPE-bottle with a PP- or a HDPE-screw cap

Pack size of 100 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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7

MARKETING AUTHORISATION HOLDER

Sandoz Limited

37 Woolmer Way

Bordon

Hampshire

GU35 9QE

8

MARKETING AUTHORISATION NUMBER(S)

PL 04416/0832

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

21/11/2008

10

DATE OF REVISION OF THE TEXT

21/11/2008

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Donepezil Hydrochloride 10 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg donepezil hydrochloride.

Excipients:

38 mg lactose/film-coated tablet

0.4 mg soya lecithin/film-coated tablet

For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablet

Yellow, round (diameter 9 mm) film-coated tablet with score line. The film-coated tablet can

be divided into equal halves.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Donepezil is indicated for the symptomatic treatment of mild to moderately severe

Alzheimer’s dementia.

4.2

Posology and method of administration

Adults/Elderly:

Treatment is initiated at 5 mg/day (once-a-day dosing). The film-coated tablet should be taken

orally, in the evening, just prior to retiring. The 5 mg/day dose should be maintained for at

least one month in order to allow the earliest clinical responses to treatment to be assessed and

to allow steady-state concentrations of donepezil hydrochloride to be achieved. Following a

one-month clinical assessment of treatment at 5 mg/day, the dose can be increased to 10

mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses greater

than 10 mg/day have not been studied in clinical trials.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and

treatment of Alzheimer’s dementia. Diagnosis should be made according to accepted

guidelines (e.g. DSM IV, ICD 10). Therapy with donepezil should only be started if a

caregiver is available who will regularly monitor drug intake for the patient. Maintenance

treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore,

the clinical benefit of donepezil should be reassessed on a regular basis. Discontinuation

should be considered when evidence of a therapeutic effect is no longer present. Individual

response to donepezil cannot be predicted.

Upon discontinuation of treatment, a gradual abatement of the beneficial effects of donepezil

is seen.

Renal and hepatic impairment:

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

donepezil hydrochloride is not affected by this condition.

Due to possible increased exposure in mild to moderate hepatic impairment (see section 5.2),

dose escalation should be performed according to individual tolerability. There are no data for

patients with severe hepatic impairment.

Children and adolescents:

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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

4.3

Contraindications

Hypersensitivity to the active substance, piperidine derivatives, soya, peanut or to any of the

excipients.

4.4

Special warnings and precautions for use

The use of donepezil in patients with severe Alzheimer’s dementia, other types of dementia or

other types of memory impairment (e.g., age-related cognitive decline), has not been

investigated.

Anaesthesia:

Donepezil, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle

relaxation during anaesthesia.

Cardiovascular Conditions:

Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects

on heart rate (e.g. bradycardia). The potential for this action may be particularly important to

patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions,

such as sinoatrial or atrioventricular block.

There have been reports of syncope and seizures. In investigating such patients the possibility

of heart block or long sinusal pauses should be considered.

Gastrointestinal Conditions:

Patients at increased risk for developing ulcers, e.g. those with a history of ulcer disease or

those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), should be

monitored for symptoms. However, the clinical studies with donepezil showed no increase,

relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Genitourinary:

Although not observed in clinical trials of donepezil, cholinomimetics may cause bladder

outflow obstruction.

Neurological Conditions:

Seizures: Cholinomimetics are believed to have some potential to cause generalised

convulsions. However, seizure activity may also be a manifestation of Alzheimer's Disease.

Cholinomimetics may have the potential to exacerbate or induce extrapyramidal symptoms.

Pulmonary Conditions:

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with

care to patients with a history of asthma or obstructive pulmonary disease.

The administration of donepezil concomitantly with other inhibitors of acetylcholinesterase,

agonists or antagonists of the cholinergic system should be avoided.

Severe Hepatic Impairment:

There are no data for patients with severe hepatic impairment.

Mortality in Vascular Dementia Clinical Trials:

Three clinical trials of 6 months duration were conducted studying individuals meeting the

NINDS-AIREN criteria for probable or possible vascular dementia (VaD). The NINDS-

AIREN criteria are designed to identify patients whose dementia appears to be due solely to

vascular causes and to exclude patients with Alzheimer’s disease. In the first study, the

mortality rates were 2/198 (1.0%) on donepezil hydrochloride 5 mg, 5/206 (2.4%) on

donepezil hydrochloride 10 mg and 7/199 (3.5%) on placebo. In the second study, the

mortality rates were 4/208 (1.9%) on donepezil hydrochloride 5 mg, 3/215 (1.4%) on

donepezil hydrochloride 10 mg and 1/193 (0.5%) on placebo. In the third study, the mortality

rates were 11/648 (1.7%) on donepezil hydrochloride 5 mg and 0/326 (0%) on placebo. The

mortality rate for the three VaD studies combined in the donepezil hydrochloride group

(1.7%) was numerically higher than in the placebo group (1.1%), however, this difference was

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not statistically significant. The majority of deaths in patients taking either donepezil

hydrochloride or placebo appear to result from various vascular related causes, which could be

expected in this elderly population with underlying vascular disease. An analysis of all serious

non-fatal and fatal vascular events showed no difference in the rate of occurrence in the

donepezil hydrochloride group relative to placebo.

In pooled Alzheimers’s disease studies (n= 4146), and when these Alzheimer’s disease studies

were pooled with other dementia studies including the vascular dementia studies (total n =

6888), the mortality rate in the placebo groups numerically exceeded that in the donepezil

hydrochloride groups.

Lactose and Glucose:

Donepezil hydrochloride film-coated tablets contain lactose and maize starch (source of

glucose). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5

Interaction with other medicinal products and other forms of interaction

Donepezil hydrochloride and/or any of its metabolites does not inhibit the metabolism of

theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil

hydrochloride is not affected by concurrent administration of digoxin or cimetidine. In vitro

studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are

involved in the metabolism of donepezil. Drug interaction studies performed in vitro show

that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit

donepezil metabolism. Therefore, these and other CYP3A4 inhibitors, such as itraconazole

and erythromycin, and CYP2D6 inhibitors, such as fluoxetine, could inhibit the metabolism of

donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil

concentrations by about 30%. Enzyme inducers, such as rifampicin, phenytoin, carbamazepine

and alcohol may reduce the levels of donepezil. Since the magnitude of an inhibiting or

inducing effect is unknown, such drug combinations should be used with care. Donepezil

hydrochloride has the potential to interfere with medications having anticholinergic activity.

There is also the potential for synergistic activity with concomitant treatment involving

medications such as succinylcholine, other neuro-muscular blocking agents or cholinergic

agonists or beta blocking agents which have effects on cardiac conduction.

4.6

Pregnancy and lactation

Pregnancy:

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

Studies in animals have not shown teratogenic effect but have shown peri and post natal

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

Donepezil should not be used during pregnancy unless clearly necessary.

Lactation:

Donepezil is excreted in the milk of rats. It is not known whether donepezil hydrochloride is

excreted in human breast milk and there are no studies in lactating women. Therefore, women

on donepezil should not breast-feed.

4.7

Effects on ability to drive and use machines

Donepezil has minor or moderate influence on the ability to drive and use machines.

Dementia may cause impairment of driving performance or compromise the ability to use

machinery. Furthermore, donepezil can induce fatigue, dizziness and muscle cramps, mainly

when initiating or increasing the dose. The treating physician should routinely evaluate the

ability of patients on donepezil to continue driving or operating complex machines.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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4.8

Undesirable effects

The most common undesirable effects are diarrhoea, muscle cramps, fatigue, nausea,

vomiting, headache and insomnia.

Adverse reactions reported as more than an isolated case are listed below, by system organ

class and by frequency.

Frequencies are defined as:

Very common (≥1/10)

Common (≥1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000), not known (cannot be estimated from the available data)

System Organ Class

Very

Common

Common

Uncommon

Rare

Infections and infestations

Common cold

Metabolism and nutrition

disorders

Anorexia

Psychiatric disorders

Hallucinations**

Agitation**

Aggressive

behaviour**

Nervous system disorders

Syncope*

Dizziness

Insomnia

Seizure*

Extrapyramidal

symptoms

Cardiac disorders

Bradycardia

Sino-atrial block

Atrioventricular

block

Gastrointestinal disorders

Diarrhoea

Nausea

Vomiting

Abdominal

disturbance

Gastrointestinal

haemorrhage

Gastric and

duodenal ulcers

Hepato-biliary disorders

Liver

dysfunction

including

hepatitis***

Skin and subcutaneous

tissue disorders

Rash

Pruritis

Musculoskeletal,

connective tissue and bone

disorders

Muscle cramps

Renal and urinary disorders

Urinary incontinence

General disorders and

administration site

conditions

Headache

Fatigue

Pain

Investigations

Minor increase in

serum

concentration of

muscle creatine

kinase

Injury and poisoning

Accident

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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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, agitation and aggressive behaviour have resolved on dose-

reduction or discontinuation of treatment.

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

4.9

Overdose

The estimated median lethal dose of donepezil hydrochloride following administration of a

single oral dose in mice and rats is 45 and 32 mg/kg, respectively, or approximately 225 and

160 times the maximum recommended human dose of 10 mg per day.

Symptoms:

Dose-related signs of cholinergic stimulation were observed in animals and included reduced

spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions,

depressed respiration, salivation, miosis, fasciculation and lower body surface temperature.

Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by

severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory

depression, collapse and convulsions. Increasing muscle weakness is a possibility and may

result in death if respiratory muscles are involved.

Treatment:

As in any case of overdose, general supportive measures should be utilised. Tertiary

anticholinergics such as atropine may be used as an antidote for donepezil overdosage.

Intravenous atropine sulphate titrated to effect is recommended: an initial dose of 1.0 to 2.0

mg intravenous with subsequent doses based upon clinical response. Atypical responses in

blood pressure and heart rate have been reported with other cholinomimetics when 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 that is

present mainly outside the central nervous system.

In patients with Alzheimer's dementia participating in clinical trials, administration of single

daily doses of 5 mg or 10 mg of donepezil hydrochloride produced steady-state inhibition of

acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6% and 77.3%,

respectively when measured post dose. The inhibition of acetylcholinesterase (AChE) in red

blood cells by donepezil hydrochloride has been shown to correlate to changes in ADAS-cog,

a sensitive scale which examines selected aspects of cognition. The potential for donepezil

hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus

donepezil can not be considered to have any effect on the progress of the disease.

Efficacy of treatment of Alzheimer’s dementia with donepezil has been investigated in four

placebo-controlled trials, 2 trials of 6-month duration and 2 trials of 1-year duration.

In the 6 months clinical trial, an analysis was done at the conclusion of donepezil treatment

using a combination of three efficacy criteria: the 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

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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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 Hydrochloride

5-mg Group

18%*

18%*

Donepezil Hydrochloride 10-mg

Group

21%*

22%**

*p < 0.05

**p < 0.01

Donepezil produced a dose-dependent statistically significant increase in the percentage of

patients who were judged treatment responders.

5.2

Pharmacokinetic properties

Absorption:

Maximum plasma levels are reached approximately 3 to 4 hours after oral administration.

Plasma concentrations and area under the curve rise in proportion to the dose. The terminal

disposition half-life is approximately 70 hours, thus, administration of multiple single-daily

doses results in gradual approach to steady-state. Approximate steady-state is achieved within

3 weeks after initiation of therapy. Once at steady-state, plasma donepezil hydrochloride

concentrations and the related pharmacodynamic activity show little variability over the

course of the day.

Food did not affect the absorption of donepezil hydrochloride.

Distribution:

Donepezil hydrochloride is approximately 95% bound to human plasma proteins. The plasma

protein binding of the active metabolite 6-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.

Metabolism/Excretion:

Donepezil hydrochloride is both excreted in the urine intact and metabolised by the

cytochrome P450 system to multiple metabolites, not all of which have been identified.

Following administration of a single 5 mg dose of

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-desmethyldonepezil (3%).

Approximately 57% of the total administered radioactivity was recovered from the urine (17%

as unchanged donepezil), and 14.5% was recovered from the faeces, suggesting

biotransformation and urinary excretion as the primary routes of elimination. There is no

evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its

metabolites.

Plasma donepezil concentrations decline with a half-life of approximately 70 hours.

Sex, race and smoking history have no clinically significant influence on plasma

concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil has not been

formally studied in healthy elderly subjects, or in Alzheimer’s or vascular dementia patients.

However, mean plasma levels in patients closely agreed with those of young healthy

volunteers.

Patients with mild to moderate hepatic impairment had increased donepezil steady state

concentrations; mean AUC by 48% and mean C

by 39% (see section 4.2).

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5.3

Preclinical safety data

Extensive testing in experimental animals has demonstrated that this compound causes few

effects other than the intended pharmacological effects consistent with its action as a

cholinergic stimulator (see section 4.9). Donepezil is not mutagenic in bacterial and

mammalian cell mutation assays. Some clastogenic effects were observed in vitro at

concentrations overtly toxic to the cells and more than 3000 times the steady-state plasma

concentrations. No clastogenic or other genotoxic effects were observed in the mouse

micronucleus model in vivo. There was no evidence of oncogenic potential in long-term

carcinogenicity studies in either rats or mice.

Donepezil hydrochloride had no effect on fertility in rats, and was not teratogenic in rats or

rabbits, but had a slight effect on still-births and early pup survival when administered to

pregnant rats at 50 times the human dose (see section 4.6).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Microcrystalline cellulose,

Lactose monohydrate

Maize starch

Magnesium stearate

Tablet coat:

Polyvinyl alcohol

Talc

Titanium dioxide (E171)

Macrogol 3350

Soya lecithin

Iron oxide yellow (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

18 months

6 months after first opening of the HDPE-bottle

6.4

Special precautions for storage

Do not store above 25°C.

6.5

Nature and contents of container

PVC/Aluminium blister

Pack sizes of 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 98, 100, 100x1 or 120 film-coated tablets

HDPE-bottle with a PP- or a HDPE-screw cap

Pack size of 100 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7

MARKETING AUTHORISATION HOLDER

Sandoz Limited

37 Woolmer Way

Bordon

Hampshire

Gu35 9QE

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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8

MARKETING AUTHORISATION NUMBER(S)

PL 04416/0833

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/11/2008

10

DATE OF REVISION OF THE TEXT

21/11/2008

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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Module 3

Patient Information Leaflet

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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Module 4

Labelling

Donepezil Hydrochloride 5mg Film Coated Tablets

Carton

Blister Foil

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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Donepezil Hydrochloride 10mg Film Coated Tablets

Carton

Blister foil

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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Module 5

Scientific discussion during initial procedure

INTRODUCTION

Based on the review of the data and the Applicant’s response to the questions raised

by RMS and CMSs on quality, safety and efficacy, the RMS considers that the

application for Donepezil hydrochloride 5mg and 10mg film-coated tablets in the

treatment of mild to moderately severe Alzheimers dementia is approvable.

These applications were submitted under Article 10.1 of Directive 2001/83 EC (as

amended), for Donepezil hydrochloride 5mg Film Coated Tablets and Donepezil

hydrochloride 10mg Film Coated Tablets. They have been shown to be generic

medicinal products of the originator products Aricept 5mg and 10mg Tablets

(Marketing Authorisation Holder: Eisai Limited, UK) which were granted licences on

February 1997 in the UK.

Donepezil hydrochloride, a piperidine derivative, is a centrally active, reversible

inhibitor of acetylcholinesterase. A deficiency of acetylcholine caused by selective

loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus is

recognized as one of the early pathophysiologic features of Alzheimer’s disease

associated with memory loss and cognitive deficits. Since the resultant cortical

deficiency of this neurotransmitter is believed to account for some of the clinical

manifestations of mild to moderate dementia, enhancement of cholinergic function

with an anticholinesterase agent, such donepezil, is one of the pharmacologic

approaches to treatment. Due to the fact that widespread degeneration of multiple

central neuronal systems eventually occurs in patients with Alzheimer’s disease, the

potentially beneficial effects of anticholinesterase agents would diminish as the

disease process advances and fewer cholinergic neurons remain functioning.

No new preclinical studies were conducted, which is acceptable given that the

applications were based on essential similarity to products that have been licensed for

over 10 years.

The RMS has been assured that acceptable standards of GMP are in place for these

product types at all sites responsible for the manufacture and assembly of this product

prior to granting its national authorisation.

For manufacturing sites outside the community, the RMS has accepted copies of

current

Certificates

satisfactory

inspection

summary

reports,

‘close-out

letters’

‘exchange

information’

issued

inspection

services

competent

authorities

those

countries

with

which

Mutual

Recognition Agreement for their own territories) as certification that acceptable

standards of GMP are in place at those non-Community sites.

The bioequivalence study was carried out in accordance with Good Clinical Practice

(GCP).

package

leaflet

been

submitted

MHRA

along

with

results

consultations with target patient groups ("user testing"), in accordance with Article 59

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-

structured and organised, easy to understand and written in a comprehensive manner.

The test shows that the patients/users are able to act upon the information that it

contains.

II. ABOUT THE PRODUCT

Name of the product in

the Reference Member

State

Name(s) of the active

substance(s) (INN)

Pharmacotherapeutic

classification

(ATC code)

Pharmaceutical form and

strength(s)

Reference numbers for

the Mutual Recognition

Procedure

Donepezil Hydrochloride 5mg Film-Coated Tablets

Donepezil Hydrochloride 10mg Film-Coated Tablets

Donepezil hydrochloride

N06D A02: anticholinesterase

5mg and 10mg Film Coated Tablets

UK/H/1145/01-02/DC

Reference Member State

United Kingdom

Member States

concerned

Marketing Authorisation

Number(s)

Name and address of the

authorisation holder

Austria, Belgium, Czech Republic, Germany, Denmark,

Greece, Spain, Finland, France, Italy, Norway, Poland,

Portugal, Romania, Sweden, Slovak Republic and Slovenia

PL 04416/0832-3

Sandoz Limited,

37 WoolmerWay, Bordon, Hampshire, GU35 9QE, UK

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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III

SCIENTIFIC OVERVIEW AND DISCUSSION

III.1

QUALITY ASPECTS

S.

Active substance

Nomenclature:

INN:

Donepezil hydrochloride

Chemical name:

(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-

piperidinyl]methyl]-1H-inden-1-one, hydrochloride

Structure:

Molecular formula

ClNO

Molecular weight

415.95 g/mol

General Properties

Characteristics: White to off-white or slightly yellow crystalline powder

Solubility

Donepezil Hydrochloride is freely soluble in chloroform, dichloromethane and in

methanol, soluble in water, sparingly soluble in ethanol, n-butanol and in acetonitrile

and very slightly soluble in acetone.

Polymorphism:

Donepezil Hydrochloride is known to exist in different polymorphic forms including

hydrates, anhydrates, crystalline and amorphous form.

Synthesis of the drug substance from the designated starting material has been

adequately described and appropriate in-process controls and intermediate

specifications are applied. Satisfactory specifications are in place for all starting

materials and reagents and these are supported by relevant certificates of analysis.

The drug substance donepezil hydrochloride is not the subject of BP or Ph.Eur

monographs. An appropriate specification is provided for the active substance

donepezil hydrochloride.

Analytical methods have been appropriately validated and are satisfactory for

ensuring compliance with the relevant specifications.

Active donepezil hydrochloride is stored in appropriate packaging that comply with

Directive 2002/72/EC (as amended), and are suitable for contact with foodstuffs.

Specifications and certificates of analysis have been provided.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

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Batch analysis data are provided and comply with the proposed specification.

Satisfactory certificates of analysis have been provided for standards used by the

active substance manufacturer during validation studies.

Appropriate stability data have been generated for drug substance stored in the same

immediate packaging as the commercial packaging. The data demonstrates the

stability of the drug substance and supports an appropriate retest period when stored

in the proposed packaging.

P.

Medicinal Product

Other Ingredients

Other ingredients consist of pharmaceutical excipients namely microcrystalline

cellulose, lactose monohydrate, maize starch and magnesium stearate. All ingredients

within the tablet body comply with relevant Ph Eur monographs.

The tablet coating contains: polyvinyl alcohol, talc, titanium dioxide (E171),

macrogol 3350, soya lecithin and (iron oxide yellow (E172)- only present in 10mg

strength). All the ingredients within the tablets coating comply with their relevant Ph

Eur monographs with the exception of lecithin which complies with USNF (US

National Formulary) and JP (Japanese Pharmacopeia).

Appropriate justification for the inclusion of each excipient has been provided.

Satisfactory certificates of analysis have been provided for all excipients.

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

from animal or human origin. The applicant has provided a declaration that milk used

in the production of lactose is sourced from healthy animals under the same

conditions as that for human consumption.

Pharmaceutical development

The objective of formulation was to develop generic film-coated tablets bioequivalent

to the reference product, Aricept 5mg and 10mg Tablets.

The objectives of the development programme were to develop a formula and a

manufacturing process for Donepezil Hydrochloride Film Coated Tablets, to produce

tablets with the following

comparable dissolution profile to the brand

bioequivalent to the brand

meet all physical and chemical specifications for the dosage form in general and

for this product.

Dissolution and impurity profiles

Dissolution and impurity profiles for all both strengths of drug product were found to be

similar to those for the reference products

.

Manufacturing Process

Satisfactory batch formulae have been provided for the manufacture of the product,

along with an appropriate account of the manufacturing process.

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Finished Product Specification

The finished product specifications proposed are acceptable. Test methods have been

described and have been adequately validated, as appropriate. Batch data have been

provided and comply with the release specification. Certificates of analysis have been

provided for any working standards used.

Container-Closure System

Donepezil hydrochloride tablets are packaged either in clear polyvinyl chloride

(PVC)/aluminium blister packs or in high density polyethylene (HDPE) containers

with a (polypropylene) PP or HDPE screw cap containing desiccant. Blister pack

presentation is available in pack sizes of 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 98, 100,

100x1 or 120 film-coated tablets and the bottle presentation is available in pack sizes

of 100 tablets. All primary product packaging complies with EU legislation regarding

contact with food.

Stability of the product

Stability studies have been performed on the six batches of 5mg strength and seven batches

of 10mg strength. All batches are packaged in the proposed commercial packaging. Stability

testing is performed according to the relevant ICH guidelines.

Based on the results of the stability studies, the applicant has proposed a shelf life of

18 months and 6months after first opening of the HDPE bottle, with storage

conditions of “Do not store above 25°C”. These are acceptable.

SPC, PIL, Labels

The SPC, PIL and Labels are pharmaceutically acceptable. A package leaflet has

been submitted to the MHRA along with results of consultations with target patient

groups ("user testing"), in accordance with Article 59 of Council Directive

2001/83/EC. The results indicate that the package leaflet is well-structured and

organised, easy to understand and written in a comprehensive manner. The test shows

that the patients/users are able to act upon the information that it contains.

Conclusion

The grant of marketing authorisations is recommended.

III.2

PRE-CLINICAL ASPECTS

No new preclinical data were supplied with this application and none are required.

Clinical experience with Donepezil HCL overrides the need for further preclinical

data. The nonclinical overview provides a satisfactory review of the relevant

preclinical pharmacological and toxicological literature.

III.3

CLINICAL ASPECTS

Introduction

This assessment report represents an evaluation of the key elements of the information

provided by the company in the dossier. For more details, the reader should refer to

the company's clinical overview and summary and to the clinical file.

The clinical overview dated 14 May 2007 has been written by a suitably qualified

person with relevant experience in the pharmaceutical industry. The report refers to

66 publications up to 2006.

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The clinical overview on the clinical pharmacology, efficacy and safety is adequate.

Clinical study reports

To support the application, the applicant has submitted a single bioequivalence study:

an open label, single dose, randomised, 2 way study of crossover design, performed

under fasting conditions. The study was performed at the 10mg dose strength.

Biowaiver

The multiple strengths exemption criterion for linear pharmacokinetics over the

therapeutic range is met.

The company’s clinical expert has provided the following justification for studying

the 10mg strength only, rather than both strengths:

The pharmacokinetics are linear

The qualitative composition is the same

The ratio between active substance and the excipients in both strengths of the

test product is the same

The dissolution rate of the highest strength of the test product in-vitro is similar

to that of the lower strength, and the dissolution rate of both of the strengths of the test

product in vitro is similar to the dissolution rates of the corresponding strengths of the

reference product.

Pharmacokinetic studies

Study 2006-24-FTA-1

Study design

A comparative, randomised, two-way, two-period, single dose crossover study

performed in fasting subjects.

Assessor's comment:

A

review

of

the

PK

characteristics

of

donepezil

indicates

that

absorption

is

predictable and it appears unlikely that the conclusion of bioequivalence would be

any different if the 5mg dose had also been studied. It is normally considered that the

highest dose strength is the most discriminatory for the purposes of bioequivalence

testing, which is the strength which has been tested here. The confidence intervals for

the bioequivalence parameters of the presented studies are within the required limits

by a substantial margin.

In conclusion the use of the 10mg strength only for the bioequivalence studies has

been adequately justified and the results of Study 2006-24-FTA-1 with the 10mg

formulation can be extrapolated to other strength 5mg, according to conditions in

Note

for

Guidance

on

the

Investigation

of

Bioavailability

and

Bioequivalence

CPMP/EWP/QWP/1401/98, section 5.4.

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Healthy, fasting, male volunteers, aged 23-44 years, were randomised to receive a

single dose of 10mg orally of either the applicant's test product or the reference

product donepezil.

The randomisation scheme was balanced for sequence and appears random.

Serum drug levels were followed for 72 hours following dosing and the schedule was

appropriate for accurate determination of AUC

0-72

and C

. The washout period

between phases was sufficiently long at 21 days.

Test and reference products

Reference:

Aricept 10mg Film Coated Tablets (Donepezil Hydrochloride) (Eisai

GmbH, Germany.)

Test :

Donepezil 10mg Film Coated Tablets (Donepezil Hydrochloride)

(HEXAL AG, Germany)

Analytical methods

Plasma samples were analysed to quantify the concentration of donepezil using a

validated LC/MS/MS bioanalytical method. The validation report has been provided.

The lower limit of quantification was 0.250 ng/ml for donepezil and 50.0 pg/ml for 6-

O-desmethyldonepezil.

Statistical methods

ANOVA for AUC

0-72

, C

max.

Non-parametric for T

. Analysis of sequence/period

effects.

Results

Table 1. Pharmacokinetic parameters for parent drug (non-transformed values;

arithmetic mean ± SD, t

max ,

median, range).

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Table 2. Pharmacokinetic parameters for parent drug (log-transformed values).

Table 3. Pharmacokinetic parameters for 6-O-desmethyldonepezil (non-transformed

values; arithmetic mean ± SD, t

max ,

median, range).

Table 4. Pharmacokinetic parameters for 6-O-desmethyldonepezil (log-transformed

values).

Assessor's comment:

These results are within conventional bioequivalence criteria, with 90% confidence

intervals between 80-125% for the parent drug only. It is noted that the data for the 6-

O-Desmethyl

metabolite

within

conventional

bioequivalence

acceptance

criteria. Displaying activity equal to that of the parent drug, this metabolite is to be

found in concentrations up to 20% that of the parent drug. There is no evidence to

suggest entero-hepatic recycling or accumulation.

From the data presented, there would seem to be two possible explanations for what is

seen:

1. Statistical - 90% CIs are very wide and include unity so there may be no

formulation difference at all.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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2. True formulation difference. The estimated 5% lower Cmax for the test product

indicates a slightly slower drug delivery, resulting in a greater proportion being

metabolised pre-systemically into the active metabolite, resulting in bioinequivalence

for the metabolite.

Either way, the active metabolite cannot be considered to contribute greatly to the

activity of this product. There have been a number of other European procedures for

donepezil products whereby the metabolites have not been assayed at all. Overall, it is

considered that this product fulfils conventional bioequivalence acceptance criteria.

Pharmacokinetic conclusion

Based on the submitted bioequivalence study Donepezil 10mg film coated tablets are

considered

bioequivalent

with

Aricept

10mg

Film

Coated

Tablets

(Donepezil

Hydrochloride) (Eisai GmbH, Germany.).

The results of Study 2006-24-FTA-1 with the 10mg formulation can be extrapolated

to the other strength, 5mg, according to conditions in Note for Guidance on the

Investigation

Bioavailability

Bioequivalence

CPMP/EWP/QWP/1401/98,

section 5.4.

Post marketing experience

Donepezil 5 and 10mg film coated tablets have a well-recognised efficacy and an

acceptable

level

safety

indications

approved

Donepezil,

corresponding products have been widely used in many countries. Therefore, the

submission of PSUR at the renewal of the marketing authorisation is supported.

Benefit-Risk Assessment

The application contains an adequate review of published clinical data and the

bioequivalence has been shown. Approval is recommended from the clinical point of

view.

SUMMARY OF PRODUCT CHARACTERISTICS

The SPCs are in line with those of the reference products and are satisfactory.

PATIENT INFORMATION LEAFLET

The PIL is satisfactory.

LABELLING

Medically satisfactory.

DISCUSSION

The application contains an adequate review of published clinical data.

Bioequivalence has been demonstrated for 10mg tablets. The results could be

extrapolated to 5mg tablets.

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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The clinical safety and efficacy of donepezil hydrochloride is well established as it

has been used extensively in clinical practice.

The SPCs are in line with those for the reference products and are satisfactory. The

PIL and labelling are medically satisfactory.

CONCLUSIONS

The grant of marketing authorisations is recommended.

IV

OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY

The important quality characteristics of Donepezil Hydrochloride 5mg & 10mg Film

Coated Tablets are well-defined and controlled. The specifications and batch

analytical results indicate consistency from batch to batch. There are no outstanding

quality issues that would have a negative impact on the benefit/risk balance.

PRECLINICAL

No new preclinical data were submitted and none are required for applications of this

type.

EFFICACY

Bioequivalence has been demonstrated between the applicant’s Donepezil

hydrochloride 10mg Film-Coated Tablets and the reference product Aricept 10mg

Tablets. (Eisai Limited). As these products meet the criteria as specified in the Note

for Guidance on the investigation of bioavailability and bioequivalence

(CPMP/EWP/QWP/1401/98), the results and conclusions of the bioequivalence study

on the 10mg strength can be extrapolated to the 5 mg strength tablets.

No new or unexpected safety concerns arise from this application.

The SPC, PIL and labelling are satisfactory.

RISK BENEFIT ASSESSMENT

The quality of the product is acceptable and no new preclinical or clinical safety

concerns have been identified. Extensive clinical experience with donepezil

hydrochloride is considered to have demonstrated the therapeutic value of the

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

PAR-Donepezil Hydrochloride 5mg & 10mg Film-Coated Tablets

AT/H/0883/001-002/DC

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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date

submitted

Application

type

Scope

Outcome

28.03.2012

Renewal

Approved

13.04.2018

RMS-Transfer

Former RMS: UK/H/1145/001-002

Approved