FORMULATION:

Each Film-coated tablet contains:

Donepezil hydrochloride ………………. 5 mg/ 10 mg

DESCRIPTION:

White to off white round, biconvex, film coated tablet, plain on both sides.

INDICATIONS:

Donepezil hydrochloride (Servonex) tablets are indicated for the symptomatic treatment of mild-moderately severe alzheimer’s disease

and vascular dementia (associated with a CV disease).

ADMINISTRATION AND DOSAGE:

Adults/Elderly:

Treatment is initiated at 5 mg/day (once-a-day dosing). Donepezil hydrochloride (Servonex) tablets 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 of Donepezil hydrochloride (Servonex) tablets 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 hydrochloride (Servonex) tablet 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, dose escalation should be performed according to individual

tolerability. There are no data for patients with severe hepatic impairment.

Children:

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

ADVERSE 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, < 1/10), uncommon (>1/1,000, < 1/100) rare (>1/10,000, <1/1,000); very rare

(<1/10000) and not known (cannot be estimated from available data).

Infections and infestations:

Common:

Common cold

Metabolism and nutrition disorders:

Common:

Anorexia

Psychiatric disorders:

Common:

Hallucinations, Agitation and Aggressive behaviour **

Nervous system disorders:

Common:

Syncope *, Dizziness

Uncommon:

Seizure *

Rare:

Extra pyramidal symptoms

Cardiac disorders:

Uncommon:

Bradycardia

Rare:

Sino-atrial block, Atrioventricular block

Gastrointestinal disorders:

Very common:

Diarrhoea, Nausea

Common:

Vomiting, Abdominal disturbance

Uncommon:

Gastrointestinal haemorrhage, Gastric and duodenal ulcers

Hepato-biliary disorders:

Rare:

Liver dysfunction including hepatitis***

Skin and subcutaneous tissue disorders:

Common:

Rash, pruritus

Musculoskeletal, connective tissue and bone disorders:

Common:

Muscle cramps

Renal and urinary disorders:

Common:

Urinary incontinence

General disorders and administration site conditions:

Very common:

Headache

Common:

Fatigue, Pain

Investigations:

Uncommon:

Minor increase in serum concentration of muscle creatine kinase

Servonex Tablets/PH/F

Injury and poisoning:

Common:

Accident

*In investigating patients for syncope or seizure the possibility of heart block or long sinusal pauses should be considered

**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 hydrochloride (Servonex) tablets should be considered.

DRUG INTERACTIONS:

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.

PRECAUTIONS:

The use of Donepezil hydrochloride (Servonex) tablet in patients with severe Alzheimer’s dementia, other types of dementia or other types

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

Anaesthesia:

Donepezil hydrochloride (Servonex) tablet, 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 (Servonex) tablets 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 HCl, 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 hydrochloride (Servonex) tablets 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.

Lactose and Glucose:

Donepezil hydrochloride (Servonex) tablets contain lactose and maize starch. Patients with rare hereditary

problems of galactose intolerance, the lactose deficiency or glucose-galactose malabsorption should not take this medicinal product.

CONTRAINDICATIONS:

Donepezil hydrochloride (Servonex) tablet is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.

OVERDOSAGE:

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 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.

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 (Servonex) tablet 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).

PHARMACOKINETICS:

Donepezil hydrochloride is well absorbed from the gastrointestinal tract, maximum plasma concentrations being achieved within 3 to 4 hours after ingestion. It is about 95% bound to plasma proteins, mainly albumin. Donepezil undergoes partial metabolism via the cytochrome P450 isoenzyme CYP3A4, and to a lesser extent by CYP2D6, to 4 major metabolites. About 11% of a dose is present in plasma as 6-O-desmethyldonepezil, which has similar activity to the parent compound. Over 10 days, about 57% of a dose is recovered from the urine as unchanged drug and metabolites, and about 15% from the faeces; 28% remains unrecovered suggesting accumulation.