Document: spc-doc_PL 04416-1213 change

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Sandoz Limited
Donepezil 5 mg Orodispersible Films	PL 04416/1213

1. NAME OF THE MEDICINAL PRODUCT

Donepezil 5 mg Orodispersible Films

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible film contains 5 mg donepezil hydrochloride.

Excipients with known effect: Each orodispersible film contains 0.48mg sucralose

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per

dose

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Orodispersible film

White to slightly yellow, rectangular (3 cm ), flexible orodispersible film

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

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 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.

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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:

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

The orodispersible film should be taken orally, in the evening, just prior to retiring. It should be placed on the tongue where it dissolves rapidly, so that it can be easily swallowed with or without water, according to patient preference. Please see below “Instructions on handling the orodispersible films”.

Instructions on handling the orodispersible films

Important: Do not handle the orodispersible film with wet hands!

a) Take the sachet, locate the arrow mark at one of the shorter sides and hold the sachet with this side facing up. The sachet is not sealed here.

b) Gently peel both parts of the sachet apart at the arrow mark. Now you can hold each between your thumb and your index finger using one hand for each part.

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in opposite directions until they are separated. The placed on one of the separated sachet parts.

d) Take the orodispersible film with dry fingers out of the sachet and put it in your mouth directly on your tongue. It will dissolve rapidly, so that it can be easily swallowed. Water may be used if desired.

4.3.    Contraindications

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

4.4.    Special warnings and precautions for use

The use of 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.

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

Gastrointestinal Conditions:

Patients at increased risk for developing ulcers, e.g. those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), should be monitored for symptoms. However, the clinical studies with donepezil showed no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Genitourinary:

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

Neurological Conditions:

Seizures: Cholinomimetics are believed to have some potential to cause generalised convulsions. However, seizure activity may also be a manifestation of Alzheimer's Disease. Cholinomimetics may have the potential to exacerbate or induce extrapyramidal symptoms.

Neuroleptic Malignant Syndrome (NMS): NMS, 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 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.

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

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.

Sucralose:

Donepezil hydrochloride orodispersible film contains sucralose, which is a sucrose derivative. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Ethanol (alcohol)

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.

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

4.6.    Fertility, pregnancy and lactation

Pregnancy:

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

Studies in animals have not shown teratogenic effect but have shown 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.

Breastfeeding:

Donepezil is excreted in the milk of rats. In humans it is not known whether donepezil hydrochloride is excreted in milk and there are no studies in lactating women. Therefore, women on donepezil should not breast feed.

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

Fertility:

In animal studies, no effects on fertility were observed (see section 5.3); however, there are no adequate data with respect to the effects on fertility in humans.

4.7.    Effects on ability to drive and use machines

Donepezil has minor or moderate influence on the ability to drive and use machines. Dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, donepezil can induce fatigue, dizziness and muscle cramps, mainly when initiating or increasing the dose. The treating physician should routinely evaluate the ability of patients on donepezil to continue driving or operating complex machines.

4.8.    Undesirable effects

The most common 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	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*	Extrapyra midal symptoms	Neuroleptic malignant syndrome
Cardiac disorders			Bradycardia	Sino-atrial block

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

				Atrioventric ular 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 Pruritus
Musculoskeletal, connective tissue and bone disorders		Muscle cramps			Rhabdomyo lysis****
Renal and urinary disorders		Urinary incontinence
General disorders and administration site conditions	Headache	Fatigue Pain
Investigations			Minor increase in serum concentration of muscle creatine kinase
Injury and poisoning		Accident

*In investigating patients for syncope or seizure the possibility of heart block or long sinusal pauses should be considered (see section 4.4).

**Reports of hallucinations, abnormal dreams and Nightmares**, 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.

**** 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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard.

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.

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

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 coadministered 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 =

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

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	10%	10%
Donepezil Hydrochloride 5-mg Group	18%*	18%*
Donepezil Hydrochloride 10mg 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 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.

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 ¹⁴C-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

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

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_max 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

Glycerol

Hypromellose

Levomenthol

Maltodextrin

Microcrystalline cellulose

Peppermint flavour

Sucralose

Titanium dioxide (E 171)

Ethanol

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf life

2 years

6.4.    Special precautions for storage

This medicinal product does not require any special storage condition.

6.5.    Nature and contents of container

PET/ALU/PE-Sachets (84x47 mm)

Each orodispersible film is individually enclosed in a sealed sachet.

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Donepezil 5 mg Orodispersible Films	PL 04416/1213

Pack sizes:

7, 10, 14, 21, 28, 30, 49, 50, 56, 60, 90, 98, 100 or 120 orodispersible films Some pack sizes also contain a PP-box for temporary storage of a few sachets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Sandoz Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 04416/1213

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 06/09/2011 Renewal of the authorization: 21/08/2015

10. DATE OF REVISION OF THE TEXT

01/12/2015

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