Alzepil film-coated tablets 5 mg blister No. 28

Instructions Alzepil film-coated tablets 5 mg blister No. 28

Composition

active ingredient: donepezil;

1 film-coated tablet contains donepezil hydrochloride 5 mg or 10 mg;

Excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, magnesium stearate, hypromellose, titanium dioxide (E171), macrogol 400.

Dosage form

Film-coated tablets.

Main physicochemical properties:

film-coated tablets, 5 mg: white or almost white, round biconvex, film-coated tablets, odorless or almost odorless, engraved on one side with a stylized letter E and the number 381 below it;

Film-coated tablets, 10 mg: white or almost white, round biconvex, film-coated tablets, odorless or almost odorless, engraved on one side with a stylized letter E and the number 382 below it.

Pharmacotherapeutic group

Drugs used in dementia. Cholinesterase inhibitors. ATX code N06D A02.

Pharmacological properties

Pharmacodynamics

A selective and reversible inhibitor of acetylcholinesterase, the main type of cholinesterase in the brain. By inhibiting cholinesterase in the brain, donepezil blocks the breakdown of acetylcholine, which carries out the transmission of nerve impulses in the CNS. Donepezil inhibits acetylcholinesterase more than 1000 times more potently than butyrylcholinesterase, which is found in structures located mostly outside the central nervous system.

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

Inhibition of acetylcholinesterase in erythrocytes by donepezil correlates with changes in the ADAS-cog scale (Alzheimer's Disease Assessment Scale for Cognitive Function).

Pharmacokinetics

The maximum concentration (Cmax) in the blood plasma is reached approximately 3-4 hours after taking the drug. Plasma concentrations and the area under the pharmacokinetic curve (AUC) increase in proportion to the dose. The half-life is about 70 hours, so repeated administration of the drug once a 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 hydrochloride in the blood plasma and the corresponding pharmacodynamic activity change little during the day. Food does not affect the absorption of donepezil hydrochloride.

Donepezil is approximately 95% bound to plasma proteins. The distribution of donepezil in various tissues has not been studied sufficiently. 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 cytochrome P450 system to form numerous metabolites, some of which have not been identified.

After a single administration of 5 mg of 14C-labeled donepezil hydrochloride, the proportion of unchanged donepezil hydrochloride in plasma is 30% of the administered dose, 6-O-desmethyldonepezil - 11% (the only metabolite with similar activity to donepezil hydrochloride), donepezil-cis-N-oxide - 9%, 5-O-desmethyldonepezil - 7% and the glucuronide conjugate of 5-O-desmethyldonepezil - 3%. Approximately 57% of the administered radioactive dose was recovered in the urine (17% as unchanged donepezil) and 14.5% in the feces, indicating that biotransformation and urinary excretion are the primary routes of elimination. There is no information on the possibility of enterorenal recirculation of donepezil hydrochloride and/or any of its metabolites. The decrease in plasma concentrations of donepezil hydrochloride occurs with a half-life of approximately 70 hours. The average plasma levels of donepezil in patients correspond to those in healthy young volunteers. Mild to moderate hepatic impairment and renal impairment do not significantly affect the clearance of donepezil.

Indication

Symptomatic treatment of mild to moderate Alzheimer's disease.

Contraindication

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

Interaction with other medicinal products and other types of interactions

Donepezil hydrochloride and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil hydrochloride is not altered by concomitant administration of digoxin or cimetidine. In vitro studies have shown that donepezil is metabolized by cytochrome P450 isoenzyme 3A4 and, to a lesser extent, 2D6. In vitro drug interaction studies have shown that ketoconazole and quinidine (inhibitors of CYP3A4 and 2D6, respectively) inhibit the metabolism of donepezil. Thus, these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, as well as CYP2D6 inhibitors, such as fluoxetine, may inhibit the metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased the mean concentration of donepezil by approximately 30%. Enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol may decrease donepezil concentrations. Since the magnitude of the inhibitory or inducing effect is unknown, such drug combinations should be used with caution. Donepezil hydrochloride has the potential for drug interactions with drugs that have anticholinergic effects. There is also the possibility of mutual potentiation of the effects when drugs such as succinylcholine, other neuromuscular blocking agents, cholinergic agonists or beta-blockers that may affect cardiac conduction are administered concomitantly with donepezil.

Cases of atypical changes in blood pressure and heart rate have been described when other cholinomimetics and quaternary anticholinergics, such as glycopyrrolate, were used concomitantly with donepezil.

Application features

Treatment should be initiated and continued under the supervision of a physician experienced in the diagnosis and management of Alzheimer's disease. The diagnosis should be made in accordance with generally accepted guidelines (e.g. DSM-IV, ICD-10 – International Classification of Diseases, 10th edition). Donepezil therapy should only be initiated if there is a caregiver who will continuously monitor the patient's tablet intake. Supportive therapy should be continued as long as the patient remains on treatment. Therefore, the clinical effect of donepezil should be regularly assessed. If no therapeutic effect is observed, discontinuation of the drug should be considered. Individual response to donepezil cannot be predicted. The efficacy of donepezil in patients with severe Alzheimer's dementia, other types of dementia and other types of memory impairment (e.g. age-related cognitive decline) has not been studied.

Anesthesia

As a cholinesterase inhibitor, Alzepil is able to enhance succinylcholine myorelaxation during anesthesia.

Cardiovascular disorders

Due to their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (e.g., bradycardia). The possibility of such disturbances is of particular importance in patients with sick sinus syndrome or other supraventricular conduction disorders (e.g., sinoatrial or atrioventricular block).

Dizziness and seizures have been reported. When examining such patients, the possibility of heart block or long pauses in sinus rhythm should be considered.

Gastrointestinal disorders

Patients at risk of developing ulcers, such as those with a history of peptic ulcer disease or those receiving nonsteroidal anti-inflammatory drugs (NSAIDs), should be closely monitored. However, in clinical trials with donepezil, there was no increase in the incidence of peptic ulcers or gastrointestinal bleeding compared to placebo.

Diseases of the genitourinary system

Cholinomimetics may cause impaired urinary outflow from the bladder, although this effect was not observed in clinical studies with donepezil.

Neurological conditions

Cholinomimetics are thought to have some role in causing generalized seizures. However, seizure activity may also be a manifestation of Alzheimer's disease. Cholinomimetics may exacerbate or cause extrapyramidal symptoms.

Lung function impairment

Cholinesterase inhibitors should be prescribed with caution to patients with asthma or a history of obstructive pulmonary disease.

The simultaneous use of Alzepil with other acetylcholinesterase inhibitors, agonists or antagonists of the cholinergic system should be avoided.

Severe liver failure

There are no data in patients with severe hepatic impairment.

Three clinical trials of 6 months duration were conducted in patients who met the NINDS-AIREN criteria for probable or possible vascular dementia. The NINDS-AIREN criteria were designed to identify patients whose dementia was likely to be due exclusively to vascular causes and to exclude patients with Alzheimer's disease. In the first trial, the incidence of fatal events was 2/198 (1%) with donepezil hydrochloride 5 mg, 5/206 (2.4%) with donepezil hydrochloride 10 mg, and 7/199 (3.5%) with placebo. In the second study, the incidence of death was 4/208 (1.9%) with donepezil hydrochloride 5 mg, 3/215 (1.4%) with donepezil hydrochloride 10 mg, and 1/193 (0.5%) with placebo. In the third study, the incidence of death was 11/648 (1.7%) with donepezil hydrochloride 5 mg and 0/326 (0%) with placebo. In all three vascular dementia studies, the incidence of death in the pooled donepezil hydrochloride group (1.7%) was quantitatively higher than in the placebo group (1.1%), but this difference was not statistically significant. The majority of deaths in patients receiving either donepezil hydrochloride or placebo were due to various vascular causes, as would be expected in the elderly with pre-existing vascular disease. In an analysis of all serious non-fatal and fatal vascular events, there was no difference in the incidence of these events between the donepezil hydrochloride and placebo groups.

In all Alzheimer's disease studies (n=4146), and when these Alzheimer's disease studies were combined with other dementia studies, including vascular dementia studies (total n=6888), the incidence of deaths in the placebo groups was quantitatively higher than in the donepezil hydrochloride groups.

Neuroleptic malignant syndrome (NMS)

NMS has been reported to occur very rarely in association with donepezil, particularly in patients receiving concomitant neuroleptics. Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms suggestive of NMS or an unexplained high fever without additional clinical manifestations of NMS, treatment should be discontinued.

Use during pregnancy or breastfeeding

It is not recommended to use the drug during pregnancy or breastfeeding.

Ability to influence reaction speed when driving vehicles or other mechanisms

Donepezil has minor or moderate influence on the ability to drive and use machines. Alzheimer's dementia may impair the ability to drive and use machines. In addition, donepezil may cause fatigue, dizziness and muscle cramps, mainly at the beginning of treatment or when the dose is increased. The ability of patients taking donepezil to drive or use machines should be assessed by a physician in accordance with the established procedure.

Method of administration and doses

Adult and elderly patients.

Treatment should be initiated at a dose of 5 mg/day (once daily). Alzepil should be taken orally in the evening, immediately before bedtime. The dose of 5 mg/day should be maintained for at least one month to ensure the earliest possible clinical response to treatment and to achieve steady-state concentrations of donepezil hydrochloride. After clinical evaluation of treatment with 5 mg/day for 1 month, the dose of donepezil may be increased to 10 mg/day (once daily).

The maximum recommended daily dose is 10 mg. Doses exceeding 10 mg/day have not been studied in clinical trials.

Maintenance treatment may be continued as long as the patient is receiving therapeutic benefit. Therefore, the clinical benefit of donepezil should be regularly assessed. If evidence of therapeutic benefit is no longer observed, discontinuation of the drug should be considered. Individual response to donepezil cannot be predicted.

Upon discontinuation of treatment, a gradual decrease in the beneficial effect of donepezil is observed.

Renal and hepatic impairment

The same dosing regimen can be followed for patients with impaired renal function, as the clearance of donepezil hydrochloride is not altered in this condition.

Due to the possible increase in exposure in mild to moderate hepatic impairment, dose escalation should be based on individual tolerability. There are no data in patients with severe hepatic impairment.

Children

Alzepil is not recommended for use in children.

Overdose

As with any overdose, general supportive measures should be employed. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil overdose. Intravenous atropine sulfate titrated to effect is recommended: initial dose 1 to 2 mg intravenously, with subsequent dosing according to clinical response. Atypical reactions in blood pressure and heart rate have been reported when other cholinomimetics are used concomitantly with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration).

Adverse reactions

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 reported with a frequency greater than isolated cases are listed below by system organ class and by frequency. The frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).

*When evaluating patients for syncope or seizures, the possibility of heart block or prolonged sinus pauses should be considered (see section "Special warnings and precautions for use").

**Reports of hallucinations, agitation, and aggressive behavior that resolved after dose reduction or discontinuation of the drug.

***In cases of unexplained hepatic dysfunction, discontinuation of donepezil treatment should be considered.

Expiration date

5 years.

Storage conditions

Store at a temperature not exceeding 30 °C out of the reach of children.

Packaging

14 film-coated tablets in a blister; 2 or 4 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

CJSC Pharmaceutical Plant EGIS/EGIS Pharmaceuticals PLC.

Location of the manufacturer and its business address

1165, Budapest, Bokenyfoldiut. 118-120, Hungary.