Pharmacological properties

Pharmacodynamics. selection and reversible inhibitor of acetylcholinesterase which is the main type of cholinesterase in a head brain. inhibiting cholinesterase in a head brain, donepezil blocks disintegration of acetylcholine which is carrying out transfer of nervous excitement to central nervous system. donepezil inhibits acetylcholinesterase 1000 times stronger, than the butyrylcholinesterase which is contained in the structures located the most part out of central nervous system.

After single dose of donepezil in a dose of 5 or 10 mg in membranes of erythrocytes and makes 63.6 and 77.3% respectively.

acetylcholinesterase Inhibition in erythrocytes under the influence of donepezil correlates with changes of a scale of ADAS-cog (a scale of assessment of cognitive functions in Alzheimer's disease).

Pharmacokinetics. The C _max in blood plasma reaches peak in ≈3–4 h after administration of drug. The C _max in blood plasma and AUC raise in proportion to a dose. The t _½ makes ≈70 h therefore repeated use of medicament of 1 times a day gradually leads to an equilibrium state that is reached during 3 weeks from the beginning of therapy. In an equilibrium state concentration of donepezil in blood plasma and the corresponding pharmakodinamichesky activity slightly change during the day. Food does not influence donepezil absorption.

Donepezil contacts proteins of blood plasma for 95%. Distribution of donepezil in different fabrics is studied insufficiently. Theoretically donepezil and its metabolites can remain in an organism up to 10 days

Metabolism/removal. Donepezil the hydrochloride is removed with urine in not changed look and is exposed to biotransformation the system of P450 cytochrome with formation of numerous metabolites; some of them are not established.

After single introduction of 5 mg of donepezil, marked ¹⁴ With, the share of not changed donepezil in blood plasma makes 30% of the entered dose, 6-O-desmetildonepezila — 11% (the only metabolite having similar activity from donepezil a hydrochloride), donepezil - cis-N-oxide — 9%, 5-O-desmetildonepezila — 7% and glucuronic conjugate 5-O-desmetildonepezila — 3%. About 57% of the entered radioactive dose are revealed in urine (17% — in the form of not changed donepezil) and 14.5% — in Calais; it demonstrated that primary ways of removal of medicament is biotransformation and excretion with urine. There are no data on a possibility of intra renal recirculation of donepezil and/or any its metabolite. Decrease in concentration of donepezil in blood plasma happens to T _½ ≈70 h

Average levels of donepezil in blood plasma of patients correspond to that at healthy volunteers of young age. The abnormal liver function of easy and average degree and also a renal failure do not affect significantly clearance of donepezil.

Indication

Symptomatic treatment of dementia of altsgeymerovsky type easy and moderate severity.

Use

Drug is appointed the adult in an initial dose of 5 mg of 1 times a day. servonex accept orally in the evening before going to bed. reception in an initial dose of 5 mg of 1 times a day is continued within 1 month before achievement of equilibrium concentration of donepezil and determination of early therapeutic effect. after clinical assessment of monthly treatment in a dose of 5 mg of 1 times a day the dose of a servonex can be raised to 10 mg of 1 times a day. the maximum recommended daily dose — 10 mg. use of doses of 10 mg of 1 times a day was not studied.

under control of the doctor having experience of diagnosis of Alzheimer's disease and treatment of such patients. The disease needs to be diagnosed according to the standard recommendations (for example DSM IV or ICD 10 — the International classification of diseases, the 10th release).

only in the presence of the person who is looking after the patient who will constantly control reception of tablets by the patient.

while the therapeutic effect of medicament remains. In this regard it is necessary to estimate effect of donepezil regularly. The expediency of the termination of treatment needs to be considered at disappearance of its effect. The individual answer to donepezil cannot be provided.

After the termination of treatment the gradual reduction of favorable effect of Servonex happens.

Renal failure and liver. It is possible to use medicament in the standard doses for treatment of patients with disturbances of functions of kidneys or with easy or moderately severe disturbances of functions of a liver as the clearance of donepezil does not change at these states.

Contraindication

It is contraindicated to patients with hypersensitivity to donepezil, derivatives of piperidine or to any of medicament excipients.

Side effects

Main side effects were diarrhea, myotonia, increased fatigue, nausea, vomiting and insomnia. criteria for evaluation of frequency of development of undesirable effects: very often (≥1/10), it is frequent (≥1/100, 1/10), sometimes (≥1/1000, 1/100), is rare (1/10,000, 1/1000), is very rare (1/10,000, including separate messages).

Infectious diseases: often — cold.

from a metabolism and metabolism: often — anorexia.

from mentality: often — hallucinations, a condition of alarm, agressive behavior.

from nervous system: often — a faint, dizziness, insomnia; sometimes — an epileptic attack; seldom — extrapyramidal symptoms.

from heart: seldom — bradycardia; seldom — sinuatrial and AV blockade.

from a GIT: very often — nausea, diarrhea; often — vomiting, dyspepsia; seldom — ulcer of stomach and duodenum, gastrointestinal bleeding.

from a gepatobiliarny system: seldom — an abnormal liver function, including hepatitis.

from skin and hypodermic fabrics: often — rash, an itching.

from a musculoskeletal system: often — myotonia.

from kidneys and urinary tract: often — urine incontinence.

General manifestations: very often — a headache; often — increased fatigue, pain.

Datas of laboratory: seldom — slight increase of muscular KFK.

Injury and poisoning: often — traumatism.

Special instructions

Efficiency of a servonex at patients with heavy dementia of Alzheimer, was not studied by other types of dementia and other types of disturbance of memory (for example age deterioration in cognitive function).

As inhibitor of Servonex cholinesterase it is capable to strengthen muscle relaxation of suktsinilkholinovy type during an anesthesia. Inhibitors of cholinesterase can have vagotonic effect on ChSS (for example bradycardia). The possibility of similar disturbances is of particular importance at patients with a sick sinus syndrome or other disturbances of supraventricular conductivity of type sinuatrial or AV blockade.

needs to observe attentively patients with presence of risk of developing an ulcer, for example persons with a round ulcer in the anamnesis or the receiving NPVP. At the same time in researches of donepezil did not observe increase in frequency of an ulcer of a GIT or gastrointestinal bleeding in comparison with placebo.

is Assumed that antikholinesterazny medicaments can cause a sharp ischuria though clinical trials did not reveal this effect.

Antikholinesterazny medicaments can cause generalized spasms also. However appearance of spasms during administration of medicament can be manifestation of Alzheimer's disease. Considering cholinomimetic effect of inhibitors of cholinesterase, patients should appoint donepezil with care with OH or obstructive disease of lungs.

Should avoid use of medicament with other inhibitors of acetylcholinesterase, agonists or antagonists of a cholinergic system.

Drug contains lactose therefore to patients with rare hereditary forms of intolerance of a galactose, insufficiency of lactase or a syndrome of glyukozo-galaktozny malabsorption it is impossible to use drug.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Dementia of altsgeymerovsky type can be followed by disturbance of ability of control of vehicles or work with a difficult technique. Besides, donepezil in an initiation of treatment or at increase in a dose can cause increased fatigue, dizziness and spasms. The doctor after assessment of individual reaction of the patient has to solve a question of control of vehicles or work with difficult mechanisms.

Use during pregnancy and feeding by a breast. Servonex it is not necessary to apply during pregnancy. It is unknown whether the hydrochloride gets into breast milk at the person of donepezil; researches at the women nursing were not conducted. The women applying donepezil should stop feeding by a breast.

Children. Servonex children as safety of use of medicament for children was not studied are not recommended to appoint.

Interaction

Donepezil does not inhibit metabolism of theophylline, warfarin, Cimetidinum, digoxin. the concomitant use of digoxin, Cimetidinum does not influence donepezil metabolism. the cytochrome isoenzyme r450 3a4 and to a lesser extent — 2d6 participates in metabolism of donepezil. ketokonazol and quinidine are inhibitors of these isoenzymes at the expense of what they suppress donepezil metabolism. other medicaments inhibiting these enzymes, for example itrakonazol, erythromycin, fluoxetine also can influence metabolism of donepezil. at healthy volunteers ketokonazol increased the level of concentration of donepezil in blood plasma by 30%. however it hardly affects clinical effects.

Concomitant use of donepezil does not influence pharmacokinetics of a ketokonozol.

Inductors of enzymes, such as rifampicin, Phenytoinum, carbamazepine and ethanol, can reduce donepezil level. However extent of decrease is not found out therefore it is necessary to use these medicaments at the same time with care.

Donepezil can have effect on the medicaments rendering anticholinergic activity. Besides, at the combined use, donepezil can strengthen action of a suktsinilkholin and other muscle relaxants or agonists of cholinergic receptors and blockers of the beta adrenoceptors affecting conductivity of heart.

At simultaneous use with donepezil of others holinomimetikiv and quarternary anticholinergic drugs, such as glycopyrolat, described cases of atypical changes of the ABP and ChSS.

Overdose of inhibitors of cholinesterase can lead

to cholinergic crisis, characterized by the profound nausea, vomiting, a sialosis raised by perspiration, bradycardia, arterial hypotension, respiratory depression, collapse and spasms. muscle weakness which accrues and can lead to a lethal outcome in case of damage of respiratory muscles is possible.

to

showed symptomatic treatment. As Servoneksa antidote at its overdose anticholinergics of group of tertiary amines can be applied (atropine). It is recommended in/in administration of Atropini sulfas which dose is titrated before achievement of effect: the initial dose makes 1–2 mg, then the dose is selected depending on clinical effect. At simultaneous use of other cholinomimetics in combination with anticholinergics of group of quarternary ammonium connections (glycopyroarmour), atypical changes of the ABP and ChSS are noted. It is unknown whether the hydrochloride and/or its metabolites at dialysis (hemodialysis, peritoneal dialysis or haemo filtration) are removed donepezil.

Storage conditions

At a temperature not above 25 °C.