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Pharmacological properties

a selective and reversible inhibitor of acetylcholinesterase, which is the main type of cholinesterase in the brain. inhibiting cholinesterase in the brain, donepezil blocks the breakdown of acetylcholine, which transmits nervous excitation to the central nervous system. donepezil inhibits acetylcholinesterase more than 1000 times stronger than butyrylcholinesterase contained in structures located mainly outside the central nervous system.

After a single dose of donepezil in doses of 5 or 10 mg, the degree of inhibition of acetylcholinesterase activity is assessed in erythrocyte membranes and is 63.6 and 77.3%, respectively.

Inhibition of acetylcholinesterase in red blood cells by donepezil correlates with changes in the ADAS-cog scale (a scale for evaluating cognitive function in Alzheimers disease).

Pharmacokinetics Cmax in blood plasma is achieved 3-4 hours after taking the drug. Plasma concentrations and AUC increase in proportion to dose. T½ is about 70 hours, therefore, repeated use of the drug 1 time per day gradually leads to an equilibrium state, which is achieved within 3 weeks from the start of therapy. In the equilibrium state, the concentration of donepezil in the blood plasma and the corresponding pharmacodynamic activity vary slightly during the day. Food does not affect the absorption of donepezil.

Donepezil binds to plasma proteins by 95%. The distribution of donepezil in different tissues has not been studied enough. Theoretically, donepezil and its metabolites can persist in the body for up to 10 days.

Metabolism / excretion. Donepezil hydrochloride is excreted unchanged in the urine and undergoes biotransformation by the P450 cytochrome system with the formation of numerous metabolites; some of them are not installed.

After a single administration of 5 mg of donepezil labeled 14C, the proportion of unchanged donepezil in blood plasma is 30% of the administered dose, 6-O-desmethyldonepezil is 11% (the only metabolite that has similar activity with donepezil), donepezil-cis-M-oxide is 9%, 5-O-desmethyldonepezil - 7% and glucuronic conjugate of 5-O-desmethyldonepezil - 3%. About 57% of the administered radioactive dose was detected in urine (17% in the form of unchanged donepezil) and 14.5% in feces; this suggests that the primary routes of drug excretion are biotransformation and urinary excretion. There is no evidence of the possibility of enterorenal recirculation of donepezil and / or any of its metabolite. Decreased plasma donepezil concentration occurs with T½ about 70 hours. Average levels of donepezil in the blood plasma of patients correspond to those in healthy young volunteers. Impaired liver function of mild to moderate degree, as well as impaired renal function, do not significantly affect donepezil clearance.

Indications

Symptomatic treatment of mild to moderate Alzheimers disease.

Application

Adult and elderly patients. treatment begins with a dose of 5 mg / day (once a day). Alzepil should be taken orally in the evening, immediately before bedtime. doses of 5 mg / day should be adhered to for at least 1 month to ensure the earliest possible clinical response to treatment according to the evaluation results and to achieve an equilibrium concentration of donepezil. after a clinical evaluation of treatment at a dose of 5 mg / day for 1 month, the dose of donepezil can be increased to 10 mg / day (once a day). The maximum recommended daily dose is 10 mg. doses in excess of 10 mg / day have not been studied in clinical studies.

Supportive care can be continued as long as there is a therapeutic benefit. Therefore, the clinical benefit of donepezil should be regularly evaluated. If there is no more evidence of a therapeutic effect, consider discontinuing the drug. An individual response to donepezil is impossible to predict.

When canceling treatment, a gradual decrease in the severity of the beneficial effect of donepezil is noted.

Impaired renal and hepatic function. For patients with impaired renal function, the same dosage regimen can be followed, since the donepezil clearance will not change with this condition.

Due to the possible increase in exposure with mild or moderate liver failure, an increase in dose should be carried out depending on the individual tolerance of the drug. Data on patients with severe liver failure are not available.

Contraindications

Hypersensitivity to donepezil hydrochloride, piperidine derivatives or any excipients of the drug.

Side effects

The most common side effects are diarrhea, muscle cramps, fatigue, nausea, vomiting, and insomnia.

In individuals with individual intolerance to any component of the drug, hypersensitivity reactions are possible.

Adverse reactions recorded with a frequency exceeding the level of rare cases are listed below in the categories System-Organ-Class and in frequency. The frequency is defined as follows: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000, 1/1000); very rarely (1/10 000) and the frequency is unknown (it is impossible to estimate based on available data).

System-organ-class Often Often Infrequently Rarely Rarely
Infections and infestations   Colds, rhinitis      
Metabolic and nutritional disorders   Anorexia      
From the psyche   Hallucinations **, arousal **, aggressive behavior **, state of anxiety      
From the nervous system   Syncope *, dizziness, insomnia Epileptic seizures, convulsions * Extrapyramidal symptoms Malignant antipsychotic syndrome, nightmares, unusual dreams
From the cardiovascular system     Bradycardia Sinoatrial block, AV block, stroke  
From the digestive system Nausea, diarrhea Vomiting, dyspepsia, abdominal discomfort Gastrointestinal bleeding, gastric and duodenal ulcer (the risk of formation increases with combined use with NSAIDs)    
On the part of the liver and biliary tract       Hepatic dysfunction, including hepatitis ***  
On the part of the skin and subcutaneous tissue   Rash, itching      
From the musculoskeletal system and connective tissue   Muscle cramps      
From the kidneys and urinary tract   Urinary incontinence      
General disorders and reactions at the injection site Headache Fatigue, pain      
Abnormalities identified as a result of the survey     A slight increase in the plasma concentration of muscle CPK    
Injuries, poisoning and procedural complications   Injuries      

* When examining patients for syncope or seizures, cardiac blockade or prolonged sinus pauses should be considered (see SPECIAL INSTRUCTIONS).

** Hallucinations, agitation, and aggressive behavior reported after a dose reduction or drug withdrawal have been reported.

*** In cases of hepatic dysfunction, which is not explained by obvious reasons, consideration should be given to stopping treatment with donepezil.

special instructions

Treatment should be started and carried out under the supervision of a physician with experience in diagnosing and treating Alzheimers disease. the disease must be diagnosed according to generally accepted recommendations (for example, dsm, iv, icd 10 - international classification of diseases, 10th edition). therapy with donepezil can only be started if there is a person caring for the patient who will constantly monitor the intake of tablets. maintenance therapy should be continued until the patient is noted

Tags: Donepezil