COMPOSITION:

active substance:

donepezil;

1 tablet contains donepezil hydrochloride 5 mg or 10 mg;

excipients:

lactose monohydrate, microcrystalline cellulose, copovidone K 28, partially pregelatinized starch, magnesium stearate, Opadry II White 31G58920 (talc, titanium dioxide (Е 171), hypromellose, polyethylene glycol, lactose monohydrate).

INDICATIONS:

Symptomatic

treatment of mild to moderately severe Alzheimer’s dementia.

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DOSAGE:

In adults, treatment is initiated at 5 mg/day (once-a-day dosing). Servonex® tablets should be taken orally, in the evening, just prior to retiring. The 5 mg/day dose should be maintained for at least 1 month in order to allow steady-state concentrations of donepezil hydrochloride to be achieved and to allow the earliest clinical responses to treatment to be assessed. Following a one-month clinical assessment of treatment at 5 mg/day, the dose of Servonex® 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.

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 – International Classification of Diseases, 10th revision).

Therapy with donepezil should only be started at availability of caregiver 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 Servonex® is seen.

Renal and hepatic impairment. An accepted dose schedule can be followed for patients with renal impairment and with mild to moderate hepatic impairment, as clearance of donepezil hydrochloride is not affected by this condition.

ADVERSE REACTIONS:

The most common adverse events were diarrhea, muscle cramps, fatigue, nausea, vomiting, and insomnia. Frequencies are defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (>1/10 000, <1/1000), very rare (<1/10000, including isolated reports).

Infections and infestations: common – rhinitis.

Metabolism and nutrition disorders:

common – anorexia.

Psychiatric disorders:

common – hallucinations, agitation, aggressive behavior.

Nervous system disorders:

common – syncope, dizziness, insomnia, uncommon – seizure; rare – extrapyramidal symptoms.

Cardiac disorders:

uncommon – bradycardia; rare – sinoatrial block, atrioventricular block.

Gastrointestinal disorders:

very common – nausea, diarrhea; common – vomiting, dyspepsia; uncommon – gastric and duodenal ulcers, gastrointestinal hemorrhage.

Hepatobiliary disorders:

rare – liver dysfunction including hepatitis.

Skin and subcutaneous tissue disorders:

common – rash, pruritis.

Musculoskeletal, connective tissue and bone disorders:

common – muscle cramps.

Renal and urinary disorders:

common – urinary incontinence.

General disorders:

common – headache; common – fatigue, pain.

Investigations:

common – minor increase in muscle creatine phosphokinase (CPK).

Injury and poisoning:

common – accident.

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Drug interactions:

Donepezil does not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin.

The metabolism of donepezil is not affected by concurrent administration of digoxin or cimetidine.

The cytochrome P450 isoenzymes 3A4, and less 2D6, are involved in the metabolism of donepezil. Ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil metabolism. Therefore, these and other enzyme inhibitors, such as itraconazole, erythromycin, fluoxetine, could inhibit the metabolism of donepezil. In a study with healthy volunteers, ketoconazole increased serum donepezil concentrations by about 30 %. Yet, this is unlikely to influence the clinical effects.

Concurrent use of donepezil does not affect the ketoconazole pharmacokinetics.

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 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 muscle relaxants or cholinergic agonists and beta blocking agents that have effects on cardiac conduction.

Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary ammonium compounds such as glycopyrrolate.

Pregnancy and lactation:

Servonex® should not be used during pregnancy. 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 breastfeed.

Children:

Servonex® is not recommended for use in children.

PRECAUTIONS:

The efficacy of Servonex® 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.

Servonex®, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 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.

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.

Although not observed in clinical trials, cholinomimetics may cause acute urine retention.

Cholinomimetics are also believed to have some potential to cause generalized convulsions. However, seizure activity at drug intake may also be a manifestation of Alzheimer’s disease. Because of cholinomimetic action of cholinesterase inhibitors, donepezil should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

The administration of Servonex® concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided.

The drug contains lactose, therefore patients with rare inherited forms of lactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use it.

Ability to influence reaction velocity while driving or operating any other mechanisms.

Alzheimer’s 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 at dose increasing. The treating physician should evaluate the ability of patients on donepezil to continue driving or operating complex machines upon assessment of the individual reaction of the patient.

Overdose:

Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, arterial hypotension, respiratory depression, collapse, and convulsions. Increasing muscle weakness is possible and may result in death if respiratory muscles are involved.

Symptomatic treatment is used. Tertiary amines such as atropine may be used as an antidote for Servonex® overdosage. Intravenous atropine sulphate titrated to effect is recommended:

an initial dose of 1 – 2 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 ammonium compounds such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

Ability to influence reaction velocity while driving or operating any other mechanisms.

Alzheimer’s 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 at dose increasing. The treating physician should evaluate the ability of patients on donepezil to continue driving or operating complex machines upon assessment of the individual reaction of the patient.

CONTRAINDICATIONS:

It is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.

PHARMACOLOGICAL PROPERTIES:

Pharmacodynamics.

Donepezil is a specific and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. When inhibiting cholinesterase in the brain, donepezil blocks acetylcholine degradation that transmits nervous excitation to CNS. Donepezil is over 1000 times more potent an inhibitor of acetylcholinesterase than of butyrylcholinesterase, an enzyme which is present in structures mainly outside the central nervous system.

Administration of single daily doses of 5 mg or 10 mg of donepezil produced inhibition of acetylcholinesterase activity (measured in erythrocyte membranes) of 63,6 % and 77,3 %, respectively when measured post dose.

The inhibition of acetylcholinesterase in red blood cells by donepezil has been shown to correlate to changes in ADAS-cog, a sensitive scale which examines selected aspects of cognition at Alzheimer’s dementia.

Pharmacokinetics.

Maximum plasma levels are reached approximately 3 to 4 hours after administration. Plasma concentrations and area under the curve rise in proportion to the dose. Half-life elimination period 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.

Donepezil hydrochloride is approximately 95 % bound to plasma proteins. The distribution of donepezil in various body tissues has not been definitively studied. Potentially, donepezil hydrochloride and its metabolites may persist in the body for more than 10 days.

Metabolism/Excretion. Donepezil hydrochloride is excreted intact in the urine and is biotransformed 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 percentage of intact donepezil hydrochloride was 30 % of the administered dose, along with 11 % of 6-O-desmethyldonepezil (the only metabolite with similar to donepezil hydrochloride activity), 9 % of donepezil-cis-N-oxide, 7 % of 5-O-desmethyldonepezil, and 3 % of the glucuronide conjugate of 5-O-desmethyl-donepezil. Approximately 57 % of the total administered radioactive dose was found in the urine (17 % as unchanged donepezil), and 14,5 % was found in the faeces, suggesting biotransformation and urinary excretion to be 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.

Mean plasma levels in elderly patients closely agreed with those of young healthy volunteers.

Mild to moderate hepatic impairment, like renal disorder, does not have any significant impact of donepezil clearance.

PHARMACEUTICAL CHARACTERISTICS:

General physico-chemical properties:

white to off-white round, biconvex, film coated tablets, plain on both sides.

Shelf-life:

2 years.

Storage:

Store at temperature below 25 °С. Keep out of reach of children.

Package:

14 tablets in blister. 2 blisters in carton pack.

10 tablets in blister. 3 blisters in carton pack.

Conditions of supply:

By prescription.