Alzepil

General characteristics. Structure:

Active agent: hydrochloride donepezil monohydrate of 5,21 mg or 10,42 mg in one tablet (that there correspond 5 mg or 10 mg of donepezil of a hydrochloride);
excipients: cellulose of microcrystallic 96 mg / 192 mg, hydroxypropyl cellulose with low extent of substitution (L-HPC B1) of 24 mg / 48 mg, magnesium stearate of 1 mg / 2 mg, опадрай Y-1-7000 of white 3 mg / 6 mg: gipromelloza of 1,875 mg / 3,75 mg, titanium dioxide of 0,9375 mg / 1,875 mg, macrogoal of 400 0,1875 mg / 0,375 mg.

Description:
Tablets of 5 mg: white or almost white, round, biconvex tablets, film coated, with an engraving "Е 381" on one party, inodorous or almost inodorous.
Tablets of 10 mg: white or almost white, round, biconvex tablets, film coated, with an engraving "Е 382" on one party, inodorous or almost inodorous.

Pharmacological properties:

Pharmacodynamics. Donepezil - the selection and reversible inhibitor of acetylcholinesterase which is the main prevailing cholinesterase type in a brain. Donepezil inhibits this enzyme more than 1000 times stronger, than butyrylcholinesterase - enzyme which is in the basic outside the central nervous system.

The single dose of 5 mg or 10 mg in an equilibrium state is followed by oppression of activity of cholinesterase (it is estimated in covers of erythrocytes) for 63.6 and 77.3% respectively. Slows down progressing of Alzheimer's disease, reduces expressiveness of cognitive symptoms, in some cases recovers day activity of patients and facilitates care of them. Adjusts behavioural disturbances, reduces apathy, hallucinations and the meaningless repeating movements.

Pharmacokinetics. Absorption
 The maximum concentration (Stakh) of donepezil in a blood plasma after oral administration are reached approximately in 3-4 h. Concentration in plasma and the area under curve AUC increase in proportion to a dose. The elimination half-life of T1/2 makes about 70 hours therefore systematic use of single doses leads to achievement of an equilibrium state which is reached during 2-3 weeks after the beginning of therapy. In an equilibrium state concentration of donepezil in plasma and the corresponding pharmakodinamichesky activity slightly change during the day. Meal does not influence donepezil absorption.

Distribution
 Communication with proteins of plasma - 95%. Of communication with proteins of plasma of an active metabolite - 6-O-des-metildonepezila is unknown. Distribution was not studied. Donepezil and/or its metabolites can remain in an organism more than 10 days.

Metabolism and removal
 Donepezil is exposed to metabolism in a liver and is removed as well as its metabolites formed by system P450 cytochrome, generally kidneys in not changed look: about 57% of the entered dose are revealed in urine (17% in not changed look) and 14.5% in - fecal masses.

After a single dose of 5 mg concentration of not changed donepezil in plasma - 30% of the accepted dose, 6-O-desmetildonepezila - 11% (the only metabolite having similar activity from donepezil a hydrochloride), donepezil cis-N - oxide - 9%, 5-0-desmetildonepezila - 7% and glucuronic conjugate 5-O-desmetildonepezila - 3%. The elimination half-life of donepezil makes about 70 hours.

Floor, race and smoking have no significant effect on concentration of donepezil in plasma.

At patients with an easy or moderate abnormal liver function it can be observed the increased equilibrium concentration of donepezil in a blood plasma.

Indications to use:

Symptomatic treatment of dementia of Altsgeymerovsky type of easy, average and heavy degree.

Route of administration and doses:

Inside. Drug is recommended to be accepted in the evening before going to bed.

Treatment begin with reception 5 mg once a day and continue within not less than 4 weeks to reach equilibrium concentration of donepezil and to estimate early clinical effect of therapy.

In 1 month the drug dose Alzepil can be raised to 10 mg once a day that is the maximum recommended daily dose.

The maintenance therapy can be continued until the therapeutic effect which should be estimated regularly remains.

Patients with an abnormal liver function and kidneys
 Patients with an abnormal liver function easy and moderate severity, and also with a renal failure do not need change of the scheme of treatment since these states do not influence clearance of donepezil.

Features of use:

The maintenance therapy can be continued until the therapeutic effect remains. In this regard it is necessary to estimate effect of donepezil regularly. If drug ceases to work, it should be cancelled. After the termination of treatment gradual reduction of action of Alzepil is observed, there are no data on a syndrome of "cancellation" in case of the sharp termination of administration of drug. Individual response to therapy by donepezil cannot be predicted.

Donepezil can increase expressiveness of the neuromuscular blockade caused by the depolarizing muscle relaxants during the general anesthesia.

Inhibitors of cholinesterase can have vagotonic effect on heart rate (in particular, to cause bradycardia). Potentiality of such action can be important for patients with a sick sinus syndrome or other disturbances of supraventricular conductivity, such as sinuatrial or atrioventikulyarny blockade.

During treatment it is necessary to observe carefully patients who have a risk of development of stomach ulcer and a duodenum, for example, of patients with a peptic ulcer of a stomach in the anamnesis or the patients receiving non-steroidal anti-inflammatory drugs since cholinomimetics can strengthen secretion of hydrochloric acid in a stomach. At the same time in clinical trials increase in frequency of development of round ulcers or gastrointestinal bleeding in comparison with placebo was not noted.

Inhibitors of cholinesterase can cause an ischuria though this effect did not meet in clinical trials.

Believe that inhibitors of cholinesterase are to some extent capable to cause generalized spasms, however convulsive activity can be also display of dementia of Altsgeymerovsky type.

Considering cholinomimetic effect of inhibitors of cholinesterase, it is necessary to appoint them with care the patient with bronchial asthma or obstructive diseases of lungs in the anamnesis.

Influence on ability to control of motor transport and work with mechanisms
 Dementia of Altsgeymerovsky type itself can be followed by disturbance of ability to driving and use of a difficult technique. Besides, drug, generally in an initiation of treatment or at increase in a dose, can cause fatigue, dizziness and myotonia. A question of ability of the patient with dementia of Altsgeymerovsky type during reception of donepezil to drive the car or to use a difficult technique the doctor after assessment of individual reaction of the patient to treatment has to solve.

Side effects:

Depending on frequency side effects are defined as follows: very frequent (≥ 1/10), frequent (≥ 1/100 - <1/10), infrequent (≥ 1/1000 - ≤ 1/100), rare (≥ 1/10000 - ≤ 1/1000), very rare (≤ 1/10000).

From cardiovascular system: infrequently: bradycardia, it is rare: sinuatrial blockade, atrioventricular block.

From the central nervous system and peripheral nervous system: often: syncope *, increased fatigue, dizziness, headache, muscular spasms, sleeplessness, hallucinations, excitement, agressive behavior, infrequent: convulsive attacks *, it is rare: extrapyramidal symptoms.

From digestive tract: very frequent: diarrhea, nausea, frequent: vomiting, dyspepsia, anorexia, gastrointestinal frustration, infrequent: bleeding from digestive tract, stomach ulcer and a duodenum.

From kidneys, bodies of urination and liver: often: the urine incontience, is rare: abnormal liver function, including hepatitis.

From skin and hypodermic fabric: frequent: rash, skin itch.

Laboratory researches: infrequently: slight increase of activity of a muscular isoform of a kreatinfosfokinaza in blood serum.

Other: pain of various localization, "cold".

 * At inspection of patients with faints or convulsive attacks it is necessary to consider a possibility of cordial blockade.

Interaction with other medicines:

Donepezil and/or products of his metabolism do not inhibit metabolism of theophylline, warfarin, Cimetidinum, digoxin, thioridazine, a risperidon and sertraline. The concomitant use of digoxin, Cimetidinum, thioridazine, a risperidon and sertraline does not influence donepezil metabolism.

Use of donepezil along with a levodopa / карбидопой within 21 days did not exert impact on concentration of these drugs in blood.

Take part in metabolism of donepezil a P450 cytochrome isoenzyme - ZA4 and to a lesser extent - 2D6. Ketokonazol and the quinidine which is CYP3A4 and 2D6 inhibitors respectively suppress donepezil metabolism. Therefore, these and other CYP3A4 inhibitors, such as итраконазол both erythromycin, and CYP2D6 inhibitors, such as fluoxetine, can inhibit donepezil metabolism. At healthy volunteers кетоконазол increased average concentration of donepezil approximately for 30%. Simultaneous use of donepezil does not exert impact on pharmacokinetics of a ketokonazol.

Inductors of enzymes, such as rifampicin, Phenytoinum, carbamazepine and ethanol can cause decrease in levels of donepezil. However extent of such inhibiting or inducing action is not known therefore it is necessary to apply similar means in combination with donepezil carefully.

Donepezil exerts impact on effect of the drugs having anticholinergic activity. Besides, at simultaneous use, donepezil can strengthen effect of succinylcholine of bromide, other muscle relaxants or agonists of the cholinergic receptors and beta adrenoblockers exerting impact on conductivity of heart.

At simultaneous use of donepezil and agonists of cholinergic receptors, quarternary anticholinergic drugs, such as a glikopirroniya bromide, cases of atypical changes of arterial pressure and heart rate are described.

Contraindications:

Hypersensitivity (including to piperidine derivatives).
Pregnancy and the period of a lactation (see the section "Pregnancy and Period of a Lactation")
Children's age up to 18 years (in view of lack of clinical data)

With care: chronic obstructive pulmonary disease, bronchial asthma, disturbances of a heart rhythm, general anesthesia, peptic ulcer of a stomach and 12-perstny gut, concomitant use of NPVP, holinoblokator or other inhibitors of cholinesterase.

Pregnancy and period of a lactation
 There is no experience of use of drug during pregnancy and in the period of a lactation. It is unknown whether drug with breast milk is emitted. Therefore use during pregnancy is contraindicated, in case of need administration of drug in the period of a lactation, it is necessary to resolve an issue of the breastfeeding termination.

Overdose:

Symptoms: cholinergic crisis (the expressed nausea, vomiting, hypersalivation, the increased sweating, bradycardia, a lowering of arterial pressure, respiratory depression, a collapse, spasms). The accruing myasthenia which can lead to a lethal outcome in case of damage of respiratory muscles is possible.
Treatment: Symptomatic therapy. As an antidote atropine in/in in an initial dose of 1-2 mg can be used, then the dose is selected depending on effect. It is unknown whether donepezil and/or its metabolites at dialysis (a hemodialysis, peritoneal dialysis or haemo filtering) are removed.

Storage conditions:

Period of validity of 5 years. Not to use drug after expiry date. At a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 5 mg and 10 mg. On 14 tablets in the blister from the polyamide/ave of foil/PVC//the ave a foil or from PVH/PVDH//the ave a foil. 2 or 4 blisters are packed together with the application instruction into a cardboard pack.