Alzepil pills 10mg №28

Film Coated Tablets white or almost white, round, biconvex, engraved with "E382" on one side, odorless or almost odorless.

Excipients: microcrystalline cellulose - 192 mg, low substituted hydroxypropyl cellulose (L-HPC B1) - 48 mg, Magnesium stearate - 2 mg, opadry Y-1-7000 white - 6 mg, hypromellose - 3.75 mg, titanium dioxide - 1.875 mg, macrogol 400 - 0.375 mg.

Anticholinesterase agent

Mechanism of action

Selective reversible acetylcholinesterase inhibitor, which is the main predominant type of cholinesterase in the brain. In vitro, donepezil inhibits this enzyme more than 1000 times stronger than butyrylcholinesterase, an enzyme that is mainly outside the central nervous system.

A single dose of 5 mg or 10 mg in an equilibrium state is accompanied by inhibition of cholinesterase activity (estimated on the erythrocyte membrane model) by 63.6% and 77.3%, respectively. The ability of donepezil hydrochloride to inhibit erythrocyte cholinesterase activity correlates with changes in the results on the ADAS-cog scale, which is a sensitive tool for assessing changes in cognitive function.The ability of donepezil hydrochloride to alter the course of concomitant neurological changes has not been investigated. Thus, donepezil cannot be considered to affect the progression of the disease.

The effectiveness of donepezil was investigated in four placebo-controlled studies, two six-month and two one-year.

In a six-month clinical study, the analysis was performed using three criteria of efficacy after completion of the administration of donepezil. The ADAS-Cog scale (cognitive performance indicator) was used; Clinician's impressions scale of changes based on interviews and data from caregivers (an indicator of overall function); a subscale of the daily activity of the clinical scale for assessing dementia (an indicator of the patient's ability to participate in society, do household chores, beloved, serve themselves).

Patients who achieved the following criteria were considered responders.

Answer = improvement on the ADAS-Cog scale by at least 4 points, no deterioration on the CIBIC scale, no deterioration on a subscale of the daily activity of the clinical scale for assessing dementia.

* p <0.05, ** p <0.01

Donepezil hydrochloride caused a dose-dependent, statistically significant increase in the percentage of patients who were found to be responders.

Suction

After ingestion C_max Donepezil in plasma is reached after about 3–4 hours. Plasma concentrations and AUC increase in proportion to the dose. Eating does not affect the absorption of donepezil. In equilibrium, the concentration of donepezil in plasma and the corresponding pharmacodynamic activity change slightly during the day.

Distribution

Plasma protein binding - 95%. The binding of plasma proteins of the active metabolite - 6-O-desmethyldoneepesil is unknown.

Distribution of donepezil in tissues was not specifically studied. In one study involving healthy male volunteers, it was found that after a single injection of labeled ¹⁴C-donepezil hydrochloride in a dose of 5 mg of approximately 28% of the dose was determined in the body 240 hours after administration. This indicates that donepezil and / or its metabolites can persist in the body for more than 10 days.

With the systematic use of single doses equilibrium is achieved within 3 weeks after the start of therapy.

Metabolism and excretion

After a single administration of the labeled ¹⁴C-donepezil hydrochloride in a dose of 5 mg, the concentration of unchanged Donepezil in plasma is 30% of the dose taken, 6-O-desmethyldonepesyl - 11% (the only metabolite with similar activity with donepezil hydrochloride), donepezil-cis-N-oxide - 9%, 5-O-desmethyldonepesyl - 7% and the glucuronide conjugate 5-O-desmethyldoneepesyl - 3%.

Donepezil is excreted by the kidneys both unchanged and in the form of numerous metabolites formed by cytochrome P450 enzymes, not all of which are identified.Approximately 57% of the administered dose was found in the urine (17% in unchanged form) and 14.5% in the feces, on the basis of which it was concluded that biotransformation and excretion by the kidneys is the primary way of elimination. There is no evidence to support the enterohepatic recirculation of donepezil and / or its metabolites. T_1/2 is approximately 70 h.

Pharmacokinetics in Special Patient Groups

Gender, ethnicity, and smoking do not significantly affect plasma concentrations of donepezil. The pharmacokinetics of donepezil has not been formally studied in either healthy elderly or in patients with Alzheimer's-type dementia or vascular dementia. However, the average concentration of donepezil in the blood plasma of these patients corresponded to the concentration determined in healthy volunteers.

Patients with mild or moderate liver dysfunction may experience elevated C_ss donepezil in blood plasma.

Indications and usage

- symptomatic treatment of mild to moderate Alzheimer's-type dementia.

The drug is taken orally, preferably in the evening before bedtime.

Treatment should begin and be carried out under the supervision of a physician experienced in the diagnosis and treatment of Alzheimer's-type dementia. The diagnosis should be based on accepted recommendations, for example, DSM-IV, ICD-10. Treatment with donepezil can be started only if there are people who care for the patient and are able to monitor the drug regularly.

Adults, includingelderly patients

Treatment begins with the use of the drug in a dose of 5 mg 1 time / day and continue for at least 4 weeks to reach C_ss donepezil and evaluate the early clinical effect of therapy.

After 1 month, the dose of Alzepil^® can be increased to 10 mg 1 time / day, which is the maximum recommended daily dose. Doses exceeding 10 mg / day have not been studied in clinical studies.

Maintenance therapy can continue as long as the therapeutic effect persists, which should be regularly evaluated. In the absence of a therapeutic effect, the possibility of discontinuation of treatment should be considered.

After drug withdrawal, a gradual decrease in the beneficial effect of treatment may be observed.

Patients with impaired renal function do not need to change the treatment regimen, because This condition does not affect the clearance of donepezil.

Due to the possible increase in exposure at mild or moderate hepatic impairment increase the dose should be based on individual tolerance. There are no data on the use of the drug in patients with severe liver dysfunction.

Drug Alzepil^® not intended for treatment children and teenagers.

The most common adverse events are diarrhea, muscle cramps, fatigue, nausea, vomiting, and insomnia. Dizziness, headache, pain, accidents, and colds have also been reported.In most cases, these phenomena disappear and do not require cessation of drug administration.

Determination of the frequency of adverse reactions: 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), the frequency is unknown (it is impossible to estimate from the available data).

Mental disorders: often - hallucinations **, agitation **, aggressive behavior **, abnormal dreams, nightmarish dreams **.

From the nervous system: very often - a headache; often - fainting *, dizziness, insomnia; infrequently - convulsive seizures *; rarely extrapyramidal symptoms; very rarely - ZNS.

Since the cardiovascular system: infrequently - bradycardia; rarely - sinoatrial block, AV block.

From the digestive system: very often - diarrhea, nausea; often - vomiting, dyspepsia , anorexia; infrequently - bleeding from the gastrointestinal tract, gastric ulcer and duodenal ulcer; rarely - liver dysfunction, incl. hepatitis***.

Skin and Subcutaneous Tissues: often - rash, skin itch.

From the musculoskeletal system: often - muscle spasms; very rarely - rhabdomyolysis ****.

From the urinary system: often - urinary incontinence.

From the laboratory and instrumental studies: infrequently, a slight increase in the activity of the muscle isoform of CK in the serum.

Other: often - runny nose, fatigue, pain, accident.

* When examining patients with fainting or convulsive seizures, consider the possibility of cardiac block or prolonged sinus pauses.

** When registering cases of the development of hallucinations, agitation and aggressive behavior, abnormal dreams and nightmares, it was reported that these manifestations ceased after dose reduction or discontinuation of the drug.

*** In case of impaired liver function of unknown etiology, the possibility of discontinuing the drug Alzepil should be considered.^®.

**** There were reports of rhabdomyolysis, which developed independently of the NNS, in a tight temporal relationship, either with the start of donepezil or with an increase in dose.

Providing data on the estimated adverse reactions of the drug is a very important point, allowing continuous monitoring of the risk / benefit ratio of the drug. Health workers should provide information on any suspected adverse reactions to the contacts listed at the end of the manual, as well as through the national information collection system.

- children's and teenage age up to 18 years (due to the lack of clinical data);

- hypersensitivity to the drug;

- hypersensitivity to piperidine derivatives.

Experience with the use of the drug in women during pregnancy and during breastfeeding is missing.

Animal studies did not reveal the teratogenic effect of donepezil, however, peri- and postnatal toxicity was established. The potential risk to humans is unknown.Therefore, the drug Alzepil^® should not be used during pregnancy, unless treatment is absolutely necessary.

In rats, donepezil is excreted in milk. It is not known whether the drug is excreted in breast milk in lactating women; such studies have not been conducted. If necessary, the use of the drug during lactation should decide on the termination of breastfeeding.

At mild or moderate hepatic impairment increase the dose should be based on individual tolerance. There are no data on the use of the drug in patients with severe liver dysfunction.

Application for violations of kidney function

Patients with impaired renal function do not need to change the treatment regimen, because This condition does not affect the clearance of donepezil.

Contraindicated in children and adolescents under 18 years of age.

The effectiveness of donepezil has not been established in patients with severe dementia of Alzheimer's type, other types of dementia or memory impairment (for example, with age-related cognitive decline).

Alzepil^® is an inhibitor of cholinesterase, in connection with which the drug can enhance succinylcholine muscle relaxation during anesthesia.

Violations of the cardiovascular system

Cholinesterase inhibitors, due to their pharmacological action, can have vagotonic effects on heart rate (for example, cause bradycardia).The possibility of such an action should be especially taken into account in case of SSS or other violations of AV-conduction, for example, in case of a sinoatrial blockade or AV-blockade.

Reported fainting and convulsive seizures. When examining such patients, consideration should be given to the possibility of heart block or long pauses in the sinus rhythm.

Gastrointestinal dysfunction

Patients with an increased risk of developing ulcers, for example, having a history of peptic ulcer disease or receiving concomitant NSAIDs , should be monitored for signs of ulcer formation. However, clinical trials donepezil, compared with placebo, did not reveal an increase in the frequency of peptic ulcers or Gastrointestinal bleeding .

urinary system

Cholinomimetics can cause disturbance of urine outflow from the bladder, however, such effects have not been observed in clinical trials donepezil.

Neurological conditions

It is believed that cholinomimetics have a certain propensity to provoke generalized convulsive seizures. However, seizure activity can also be a manifestation of Alzheimer's disease.

Cholinomimetics can exacerbate or cause extrapyramidal symptoms.

ZNS

ZNS is a potentially life-threatening disorder, which is characterized by hyperthermia (fever), muscle rigidity, autonomic nervous system disorders, altered consciousness, and elevated CK activity in blood serum.Additional symptoms may include myoglobinuria (rhabdomyolysis) and acute renal failure .

There are very rare reports of the development of NNS associated with the use of donepezil, especially in patients also receiving concomitant antipsychotic therapy.

If the patient has developed signs and symptoms of MNS or an unexplained fever is present without additional clinical manifestations, treatment should be discontinued.

Impaired lung function

Cholinesterase inhibitors, due to their pharmacological action, should be prescribed with caution in patients with a history of asthma or obstructive pulmonary disease. The simultaneous administration of Alzepil should be avoided.^® and other acetylcholinesterase inhibitors, as well as cholinergic system agonists or antagonists.

Severe abnormal liver function

There are no data on the use of the drug in patients with severe liver dysfunction.

Mortality in clinical studies of vascular dementia

Three clinical trials with a duration of 6 months were conducted with the participation of patients meeting the criteria of NINDS-AIREN for possible or probable vascular dementia (DM). The NINDS-AIREN criteria are designed to identify patients in whom dementia can only be associated with vascular causes and to exclude patients with Alzheimer's disease.

In the first study, the death rate was 2/198 (1%) in the group receiving donepezil hydrochloride 5 mg, 5/206 (2.4%) in the group receiving donepezil hydrochloride 10 mg and 7/199 (3.5% ) in the placebo group.In the second study, the death rate was 4/208 (1.9%) in the group receiving donepezil hydrochloride 5 mg, 3/215 (1.4%) in the group receiving donepezil hydrochloride 10 mg and 1/193 (0.5% ) in the placebo group. In the third study, the incidence of death was 11/648 (1.7%) in the group receiving donepezil hydrochloride in a dose of 5 mg, and 0/326 (0%) in the placebo group. The incidence of death in all groups receiving donepezil hydrochloride was three times higher in diabetes (1.7%) than in the placebo group (1.1), but this difference was not statistically significant. Most of the deaths of patients taking donepezil hydrochloride or placebo occurred as a result of various vascular disorders that are expected in this population of elderly people with concomitant vascular lesions. Analysis of all serious non-lethal and fatal vascular disorders did not reveal differences in the frequency of their occurrence in the groups receiving donepezil hydrochloride and placebo.

In the pooled materials of Alzheimer's disease studies (n = 4146), as well as the same Alzheimer's disease studies with the addition of vascular dementia studies (the total number of patients is 6888), the mortality rates in the placebo groups outnumbered those in the groups that received donepezil hydrochloride.

Influence on ability to drive motor transport and control mechanisms

Donepezil has a slight or moderate effect on the ability to drive and operate machinery.

Dementia of the Alzheimer's type may itself be accompanied by impaired ability to drive and use technology. The question of the ability of a patient with dementia of the Alzheimer's type while administering donepezil to drive a car or using a complex technique must be decided by the doctor after evaluating the patient's individual response to treatment.

According to existing estimates, the median lethal dose of donepezil hydrochloride after a single ingestion in mice and rats is 45 mg / kg and 32 mg / kg, respectively, which is approximately 225 and 160 times higher than the maximum recommended dose for a human being of 10 mg / kg / day. The animals showed dose-dependent signs of stimulation of the cholinergic system, which included a decrease in spontaneous mobility, a prone body position, a staggering gait, tearing, clonic convulsions, respiratory depression, drooling, miosis, fasciculation, and a decrease in body surface temperature.

Symptoms: An overdose of cholinesterase inhibitors can lead to a cholinergic crisis characterized by severe nausea, vomiting, drooling, sweating, bradycardia, hypotension, respiratory depression, collapse and seizures. May increase muscle weakness, which can lead to death with the defeat of the respiratory muscles.

Treatment: as in any case of overdose, a general supportive treatment should be prescribed.Tertiary anticholinergic drugs, for example, atropine, can be used as antidotes for overdose of the drug Alzepil^®. It is recommended in / in the introduction of atropine sulfate in increasing doses to achieve the effect: first, 1-2 mg / kg of IV is administered, followed by additional doses, depending on the clinical response. Atypical reactions of blood pressure and heart rate were registered with the introduction of other cholinomimetics together with quaternary anticholinergic drugs, for example, glycopyrrolate. It is not known whether donepezil hydrochloride and / or its metabolites can be eliminated by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

Donepezil and / or its metabolic products do not inhibit the metabolism of theophylline, Warfarin , cimetidine, Digoxin . Simultaneous administration of digoxin or cimetidine does not affect the metabolism of donepezil.

In vitro studies have shown that cytochrome P450 - 3A4 isoenzymes and, to a lesser extent, 2D6, are used in the metabolism of donepezil. Ketoconazole and quinidine, which are inhibitors of CYP3A4 and CYP2D6, respectively, inhibit donepezil metabolism. Consequently, these and other CYP3A4 inhibitors, such as itraconazole and Erythromycin , and CYP2D6 inhibitors, such as Fluoxetine , can inhibit donepezil metabolism. In healthy volunteers, ketoconazole increased the average concentration of donepezil by about 30%. Enzyme inducers such as rifampicin, phenytoin, Carbamazepine and ethanol can cause a decrease in the concentration of donepezil.Since the extent of such an inhibitory or inducing action is unknown, such agents should be used in combination with donepezil with caution.

Donepezil has an effect on the action of drugs with anticholinergic activity. In addition, with the simultaneous use of donepezil may enhance the action of succinylcholine, other muscle relaxants or cholinergic receptor agonists and beta-blockers that affect cardiac conduction.

The drug should be stored out of the reach of children at a temperature not higher than 30 ° C.