Composition, form of production and packaging
Tablets covered with a film coating of white or almost white color, round, biconcave, engraved "E381" on one side, odorless or almost odorless.
1 tab.
donepezil hydrochloride monohydrate 5.21 mg,
which corresponds to the content of donepezil hydrochloride 5 mg
Excipients: microcrystalline cellulose - 96 mg, low-substituted hydroxypropylcellulose (L-HPC B1) - 24 mg, magnesium stearate - 1 mg, opadrai Y-1-7000 white - 3 mg, hypromellose - 1.875 mg, titanium dioxide - 0.9375 mg, macrogol 400 - 0.1875 mg.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
Tablets coated with a white or nearly white-colored film shell are round, biconvex, with engraved "E382" on one side, odorless or almost odorless.
1 tab.
Donepezil hydrochloride monohydrate 10.42 mg,
which corresponds to the content of donepezil hydrochloride 10 mg
Excipients: microcrystalline cellulose - 192 mg, low-substituted hydroxypropylcellulose (L-HPC B1) - 48 mg, magnesium stearate - 2 mg, opadrai Y-1-7000 white - 6 mg, hypromellose - 3.75 mg, titanium dioxide - 1.875 mg, macrogol 400 - 0.375 mg.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
PHARMACHOLOGIC EFFECT
Selective reversible inhibitor of acetylcholinesterase, which is the main predominant type of cholinesterase in the brain. In vitro donepezil inhibits this enzyme more than 1000 times stronger than butyrylcholine esterase, an enzyme that is located mainly outside the central nervous system.
A single dose of 5 mg or 10 mg in the equilibrium state is accompanied by inhibition of cholinesterase activity (estimated on the model of erythrocyte membranes) by 63.6% and 77.3%, respectively. The ability of donepezil hydrochloride to inhibit the activity of erythrocyte cholinesterase 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 change the course of concomitant neurologic changes has not been investigated. Thus, it can not be considered that donepezil affects the progression of the disease.
The efficacy of donepezil was investigated in four placebo-controlled studies, two six-month and two-year-old studies.
In a six-month clinical study, the analysis was performed using three performance criteria after completion of donepezil administration. The ADAS-Cog scale was used (cognitive function indicator); a scale of impressions of the clinician about changes based on interviews and data obtained from carers of the patient (an indicator of the overall level of function); subscale daily activity of the clinical scale of the evaluation of dementia (an indicator of the patient's ability to participate in the life of society, do household chores, favorite things, serve himself).
Patients who met the criteria listed below were considered responders to treatment.
Response = improvement in the ADAS-Cog score by at least 4 points, no deterioration in the CIBIC scale, no deterioration in the subscale of the daily activity of the clinical scale of the dementia assessment.
% Answer
Patients who were prescribed treatment ("HTT - Intent to treat"), n = 365 Population, the analysis of which was possible, n = 352
Placebo group 10% 10%
Group receiving donepezil hydrochloride at a dose of 5 mg of 18% * 18% *
Group receiving donepezil hydrochloride at a dose of 10 mg 21% * 22% **
* p <0.05, ** p <0.01
Donepezil hydrochloride caused a dose-dependent, statistically significant increase in the percentage of patients who were recognized as responding to treatment.
PHARMACOKINETICS
Suction
After ingestion C max, donepezil in blood plasma is reached after about 3-4 hours. Concentrations in plasma and AUC increase in proportion to the dose. The intake of food does not affect the absorption of donepezil. In the equilibrium state, the donepezil concentration in the plasma and the corresponding pharmacodynamic activity vary slightly during the day.
Distribution
Binding to plasma proteins - 95%. The binding of plasma to the active metabolite 6-O-desmethyldonepezil is not known.
The distribution of donepezil in tissues has not been specifically studied. In one study involving healthy male volunteers, it was found that after a single administration of labeled 14 C-donepezil hydrochloride at a dose of 5 mg, 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, an equilibrium state is achieved within 3 weeks after initiation of therapy.
Metabolism and excretion
After a single administration of a labeled 14 C-donepezil hydrochloride at a dose of 5 mg, the concentration of unchanged donepezil in plasma is 30% of the dose taken, 6-O-desmethyldone-peryl-11% (the only metabolite having similar activity with donepezil hydrochloride), donepezil-cis-N- oxide - 9%, 5-O-desmethyldonepezil - 7% and glucuronide conjugate 5-O-desmethyldonepezil - 3%.
Donepezil is excreted by the kidneys both in unchanged form 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 urine (17% in unchanged form) and 14.5% in feces, on the basis of which it was concluded that biotransformation and excretion by the kidneys is the primary way of elimination. There are no data confirming the enterohepatic recirculation of donepezil and / or its metabolites. T 1/2 is approximately 70 hours.
Pharmacokinetics in specific patient groups
Sex, ethnicity and smoking do not significantly affect the concentration of donepezil in plasma. Donepezil pharmacokinetics was not formally studied in healthy elderly patients, nor in patients with dementia of Alzheimer's type or vascular dementia. However, the average concentration of donepezil in blood plasma in these patients corresponded to the concentration determined in healthy volunteers.
In patients with mild or moderate impairment of liver function, an increase in C ss of donepezil in blood plasma can be observed.
INDICATIONS
- symptomatic treatment of dementia of the Alzheimer's type of mild and moderate.
DOSING MODE
The drug is taken orally, preferably in the evening before bedtime.
Treatment should be started and carried out under the supervision of a doctor who has experience in the diagnosis and treatment of Alzheimer's dementia. The diagnosis should be based on accepted recommendations, for example, DSM-IV, ICD-10. Treatment donepezilom can start only if there are persons caring for the patient, able to regularly monitor the intake of the drug.
Adults, incl. elderly patients
Treatment begins with the use of the drug at a dose of 5 mg 1 time / day and continues for at least 4 weeks to achieve C ss donepezil and assess the early clinical effect of therapy.
After 1 month, the dose of Alzepyl В® can be increased to 10 mg 1 time / day, which is the maximum recommended daily dose. Doses in excess of 10 mg / day in clinical studies have not been studied.
Supportive therapy can be continued as long as the therapeutic effect remains, which should be evaluated regularly. In the absence of a therapeutic effect, treatment should be considered.
After drug cancellation, a gradual decrease in the beneficial effect of treatment can 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.
In connection with the possible increase in exposure for mild or moderate liver dysfunction, the dose should be increased taking into account individual tolerability. There are no data on the use of the drug in patients with severe impairment of liver function .
The drug Alzepil В® is not intended for the treatment of children and adolescents .
SIDE EFFECT
The most common adverse events are diarrhea, muscle cramps, fatigue, nausea, vomiting and insomnia. There was also reported dizziness, headache, pain, accidents and colds. In most cases, these phenomena pass and do not require discontinuation of the drug.
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 disturbances: often - hallucinations **, agitation **, aggressive behavior **, abnormal dreams, nightmarish dreams **.
From the nervous system: very often - headache; often - fainting *, dizziness, insomnia; infrequently, seizures *; rarely - extrapyramidal symptoms; very rarely - ZNS.
From the side of the cardiovascular system: infrequently bradycardia; rarely - sinoatrial blockade, AV blockade.
From the digestive system: very often - diarrhea, nausea; often - vomiting, dyspepsia, anorexia; infrequently - bleeding from the digestive tract, ulcers of the stomach and duodenum; rarely - a violation of liver function, incl. hepatitis***.
From the skin and subcutaneous tissues: often - a rash, itchy skin.
From the musculoskeletal system: often - muscle spasms; very rarely - rhabdomyolysis ****.
From the urinary system: often - urinary incontinence.
From laboratory and instrumental studies: infrequently - a slight increase in the activity of the muscle isoform of CK in the blood serum.
Other: often - a runny nose, fatigue, pain, accident.
* When examining patients with syncope or convulsive seizures, the possibility of cardiac blockade or prolonged sinus pauses should be considered.
** When registering cases of hallucinations, agitation and aggressive behavior, abnormal dreams and nightmares, it was reported that these manifestations ceased after a dose reduction or drug withdrawal.
*** If there is a violation of the liver function of the unexplained etiology, consider the possibility of abolishing Alzepyl В® .
**** There were reports of rhabdomyolysis, which developed independently of the ZNS, in close temporal connection either with the onset of donepezil, or with an increase in the dose.
Providing data on alleged adverse reactions of the drug is very important, allowing continuous monitoring of the risk / benefit ratio of the drug. Medical workers should be provided with information on any suspected adverse reactions at the contacts indicated at the end of the instruction, as well as through the national information collection system.
CONTRAINDICATIONS
- children and adolescence under 18 years (due to lack of clinical data);
- hypersensitivity to the components of the drug;
- hypersensitivity to piperidine derivatives.
PREGNANCY AND LACTATION
The experience of using the drug in women during pregnancy and during breastfeeding is absent.
Studies in animals did not reveal the teratogenic effect of donepezil, but peri- and postnatal toxicity was established. The potential risk to humans is unknown.Therefore, the Alzepyl В® drug should not be used during pregnancy, unless it is absolutely necessary.
In rats, donepezil is excreted with milk. It is not known whether the drug is excreted in breast-feeding women; such studies have not been conducted. If it is necessary to use the drug during lactation, the question of stopping breastfeeding should be resolved.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with impaired renal function do not need to change the treatment regimen, because this condition does not affect the clearance of donepezil.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With mild or moderate violations of the liver function, the dose should be increased taking into account individual tolerability. There are no data on the use of the drug in patients with severe impairment of liver function .
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
SPECIAL INSTRUCTIONS
The donepezil efficacy has not been established in patients with Alzheimer's dementia, severe dementia, other dementia, or memory impairment (eg, with an age-related decline in cognitive function).
Alzepyl В® is an inhibitor of cholinesterase, and therefore the drug can enhance succinylcholine muscle relaxation during anesthesia.
Disorders from the cardiovascular system
Cholinesterase inhibitors, in connection with their pharmacological action, may have vagotonic effects on the heart rate (for example, cause bradycardia). The possibility of such an action should be particularly taken into account in the SSA or other violations of AV-conduction, for example, with a sinoatrial blockade or AV blockade.
There were reports of fainting and seizures. When examining such patients, one should consider the possibility of cardiac blockade or long pauses in the sinus rhythm.
Dysfunction of the digestive tract
Patients with an increased risk of developing ulcers, for example having a history of peptic ulcer disease or receiving concomitant treatment with NSAIDs, need to be monitored to detect symptoms of ulceration. However, clinical trials of donepezil, in comparison with placebo, did not reveal an increase in the incidence of peptic ulcers or gastrointestinal bleeding.
urinary system
Cholinomimetics can cause a disturbance in the outflow of urine from the bladder, but such effects have not been observed in donepezil clinical trials.
Neurological conditions
It is believed that holinomimetiki have some propensity to provoke generalized seizures. However, convulsive activity may also be a manifestation of Alzheimer's disease.
Cholinomimetics can exacerbate or cause extrapyramidal symptoms.
ZNS
ZNS is a potentially life-threatening disorder characterized by hyperthermia (fever), muscle rigidity, autonomic nervous system disorders, altered consciousness, increased activity of CK in serum. Additional symptoms may include myoglobinuria (rhabdomyolysis) and acute renal failure.
There are very few reports of the development of CNS associated with the use of donepezil, especially in patients also receiving concomitant therapy with antipsychotic drugs.
If a patient develops signs and symptoms of the ZNS or if there is an unexplained high fever without additional clinical manifestations, treatment should be discontinued.
Dysfunction of the lungs
Cholinesterase inhibitors, in connection with their pharmacological action, should be administered with caution to patients who have a history of asthma or obstructive pulmonary disease. Avoid simultaneous administration of Alzepil В® and other acetylcholinesterase inhibitors, as well as agonists or antagonists of the cholinergic system.
Severe liver dysfunction
There are no data on the use of the drug in patients with severe impairment of liver function.
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 may be associated only with vascular causes and exclusion of patients with Alzheimer's disease.
In the first study, the incidence of death was 2/198 (1%) in the group receiving donepezil hydrochloride at a dose of 5 mg, 5/206 (2.4%) in the group receiving donepezil hydrochloride at a dose of 10 mg and 7/199 (3.5% ) in the placebo group. In the second study, the incidence of death was 4/208 (1.9%) in the group receiving donepezil hydrochloride at a dose of 5 mg, 3/215 (1.4%) in the group receiving donepezil hydrochloride at a dose of 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 at a dose of 5 mg and 0/326 (0%) in the placebo group. The incidence of death in all groups receiving donepezil hydrochloride in three studies of diabetes (1.7%) was numerically higher than in the placebo group (1.1), but this difference was not statistically significant. Most deaths of patients taking donepezil hydrochloride or placebo resulted from various vascular disorders that are expected in this population of elderly people with concomitant vascular lesions. The analysis of all serious non-fatal and fatal vascular disorders did not reveal a difference in their incidence in the groups receiving donepezil hydrochloride and placebo.
In the combined materials of Alzheimer's research (n = 4146), as well as the same studies of Alzheimer's disease with the addition of studies of vascular dementia (the total number of patients 6888), the death rates in the placebo groups are numerically superior to those in the donepezil hydrochloride group.
Impact on the ability to drive vehicles and manage mechanisms
Donepezil in an insignificant or medium degree affects the ability to drive vehicles and work with mechanisms.
Dementia Alzheimer's type itself can be accompanied by a disruption in the ability to drive and use machinery. The question of the ability of a patient with Alzheimer's dementia during taking donepezil to drive a car or use complex techniques should be decided by the doctor after assessing the patient's individual response to treatment.
OVERDOSE
It is estimated that the median lethal dose of donepezil hydrochloride after single oral administration in mice and rats respectively equal to 45 mg / kg and 32 mg / kg, which is approximately 225 and 160 times higher than the maximum recommended human dose for 10 mg / kg / day. The animals were observed dose-related signs of cholinergic stimulation system, which include the reduction of spontaneous motility, prone posture, swaying gait, lacrimation, clonic convulsions, respiratory depression, salivation, miosis, fasciculation and reducing the temperature of the body surface.
symptoms:cholinesterase inhibitors overdose may lead to cholinergic crisis, characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, convulsions and collapse. May increase muscle weakness that can lead to death in the defeat of the respiratory muscles.
Treatment: As in any case of overdose, it is necessary to appoint a general supportive treatment. Tertiary anticholinergics, e.g., atropine, may be used as antidotes in overdose Alzepil preparation В®. Recommended / v atropine sulfate in increasing doses to achieve the effect, first administered 1-2 mg / kg / a, after which additional doses depending on the clinical response. Atypical reaction of blood pressure and heart rate were recorded when administered in conjunction with other cholinomimetics quaternary anticholinergics, eg glycopyrrolate. Unknown whether removal of Donepezil hydrochloride and / or its metabolites by dialysis (hemodialysis, peritoneal dialysis or hemofiltration).
DRUG INTERACTION
Donepezil and / or its metabolism products do not inhibit the metabolism of theophylline, warfarin, cimetidine, digoxin. Simultaneous treatment with digoxin or cimetidine did not affect the metabolism of donepezil.
Studies in vitro have shown that the metabolism of donepezil used cytochrome P450 isozymes involved - 3A4, and to a lesser extent - 2D6. Ketoconazole and quinidine, are inhibitors of CYP3A4 and CYP2D6, respectively, inhibit the metabolism of donepezil. Consequently, these and other inhibitors of CYP3A4, such as itraconazole, and erythromycin, and CYP2D6 inhibitors such as fluoxetine, can inhibit the metabolism of donepezil. In healthy volunteers, ketoconazole increased mean concentrations of donepezil is about 30%. Enzyme inducers such as rifampicin, phenytoin, carbamazepine and ethanol can cause a reduction in the concentration of donepezil. Since the degree of such an inhibiting or inducing action is unknown, use similar means in combination with donepezil with caution.
Donepezil has an effect on the action of drugs with anticholinergic activity. Furthermore, while the use of donepezil can increase the effects of succinylcholine, muscle relaxants or other agonists of cholinergic receptors and beta-blockers affecting cardiac conduction.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of reach of children at a temperature not higher than 30 В° C. She
