Composition, structure and packing
Tablets, coated white, round, biconvex, engraved with "Aricept" on one side and "5" - on the other.
1 tab. donepezil hydrochloride 5 mg.
Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, gidroksipropiltsellyuloza, magnesium stearate. The composition of the shell: Opadry White YS-1-18134-A (gipromelloza, talc, polyethylene glycol 8000, titanium dioxide).
Film-coated tablets are yellow, round, biconvex, engraved with "Aricept" on one side and "10" - on the other. 1 tab. donepezil hydrochloride 10 mg Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, gidroksipropiltsellyuloza, magnesium stearate. The composition of the shell: Opadry yellow YS-1-12700-A (gipromelloza, talc, polyethylene glycol 8000, titanium dioxide, iron oxide pigment yellow (E172)).
Clinico-pharmacological group: selective inhibitor of acetylcholinesterase in the brain. The drug for the treatment of Alzheimer's disease.
Pharmacological action
The selective and reversible inhibitor of acetylcholinesterase, which is the predominant type of cholinesterase in the brain. Donepezil inhibits this enzyme is more than 1000 times stronger than butyrylcholinesterase, contained mainly outside the CNS. After a single dose Arisepta in doses of 5 mg or 10 mg of the degree of suppression of acetylcholinesterase activity measured in erythrocyte membranes after taking the drug, accounted for respectively 63.6% and 77.3%.
Inhibition of acetylcholinesterase in erythrocytes under the effect of donepezil correlates with changes in the scale ADAS-cog (the scale of assessments of cognitive function in Alzheimer's disease). Possible impact on neuropathological changes have not been studied.
Pharmacokinetics
Absorption
Cmax donepezil in plasma is reached after about 3-4 hours after ingestion. Plasma concentrations and AUC increased in proportion to dose. T1 / 2 from the plasma is approximately 70 hours, so if systematic use of single doses Css achieved, usually within 2-3 weeks after starting therapy. After reaching the equilibrium state concentration of donepezil hydrochloride in plasma and related pharmacodynamic effects did not significantly change during the day. Eating does not affect the absorption of donepezil hydrochloride.
Distribution
Donepezil about 95% bound to plasma proteins. Information about binding to plasma proteins of its active metabolite 6-O-desmetildonepezila no.
The distribution of donepezil in various tissues of the body sufficiently studied. It is assumed that Donepezil and / or its metabolites may persist in the body over 10 days.
Metabolism and excretion
Donepezil undergoes metabolism in the liver. The main products of metabolism of donepezil are compounds M1 and M2 (products of O-dealkylation and hydroxylation), M11 and M12 (products glyukuronirovaniya M1 and M2, respectively), M4 (a product of hydrolysis) and M6 (product N-oxidation). IQ of intrahepatic recycling of donepezil and / or products of its metabolism is not available. Donepezil is derived, as well as its metabolites, mainly in the urine: 79% of the dose found in urine and 21% - in the feces. Predominantly found in the urine Donepezil.
Pharmacokinetics in special clinical situations
Gender, race and smoking did not significantly affect the concentration of donepezil in plasma. Mean levels of donepezil in plasma of patients correspond to those in healthy young volunteers. Violations of the liver function of light and medium severity, and renal dysfunction did not significantly affect the clearance of donepezil.
Statement
symptomatic treatment of Alzheimer's type dementia of mild or moderate severity.
Dosage regimen
Adults (including elderly patients), the medication is prescribed in an initial dose of 5 mg 1 time / day. Admission to the initial dose is continued for at least 4-6 weeks to reach equilibrium concentrations of donepezil and to identify early clinical effect of therapy. After 1 month Arisepta dose may be increased to 10 mg / day, which is the maximum recommended daily dose.
Supportive therapy can continue for as long as the therapeutic effect, which should be regularly assessed. When violations of liver and kidney function correction doses are required.
Side effect
On the part of the digestive system: frequent (> 5%) - diarrhea, nausea, vomiting.
From the central nervous system and peripheral nervous system: frequent (> 5%) - fatigue, insomnia, muscle cramps.
Since the cardiovascular system: rarely - syncope, bradycardia, sinoatrial and AV-block. Other: rarely - a slight increase in concentration of muscle CK in serum. In controlled clinical studies in patients were also observed:
From the CNS: headache, dizziness, hallucinations, anxiety, aggressive behavior, epileptic seizures.
On the part of the digestive system: dyspepsia, hepatitis, gastric ulcers and duodenal ulcers and bleeding from the gastrointestinal tract.
Other: pain of different localization, accidents, cold.
Adverse events observed in controlled clinical studies, no less than 2% of patients taking Arisept, with a frequency higher than those in the placebo group.
Contraindications
Hypersensitivity to donepezil hydrochloride, the other components of the drug, as well as to piperidine derivatives. Precautions should be prescribed to patients with obstructive lung diseases in medical history (including bronchial asthma), with heart rhythm disorders, during anesthesia, and patients with high risk of developing ulcers (eg, patients with peptic ulcer or a history of receiving concomitant therapy of NSAIDs).
Avoid the simultaneous application of Arisepta with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system.
Pregnancy and lactation
Controlled studies of Arisepta during pregnancy and lactation was conducted. IQ for the withdrawal donepezil with breast milk is not. The drug should be prescribed to pregnant women only if the expected benefit of treatment exceeds the potential risk to the fetus.
Application for violations of liver function
When violations of liver function correction doses are required.
Application for violations of renal function
When violations of renal function correct doses are required.
Cautions
Treatment must be prescribed and conducted by a doctor with experience of managing patients with Alzheimer's disease. The diagnosis should be delivered in accordance with generally accepted criteria (eg, DSM IV - Diagnostic and Statistical Manual of Mental Disorders fourth revision, ICD 10 - International Classification of Diseases 10th revision). Supportive therapy can continue for as long as the therapeutic effect. If the drug ceases to act, it should be abolished. After the cessation of treatment, a gradual decrease of Arisepta, information about withdrawal syndrome in the event of an abrupt discontinuation of the drug is not.
Individual response to therapy Ariseptom impossible to predict. Effectiveness Arisepta in patients with severe dementia, Alzheimer's type, other types of dementia or other types of memory (eg, age deterioration of cognitive function) was not studied.
Arisept, as a cholinesterase inhibitor, may increase miorelaxation suktsinilholinovogo type during anesthesia. Cholinesterase inhibitors (including Arisept) may have vagotonicheskoe effect on heart rate (in particular, cause bradycardia). The potential for such an action may be important for patients with SSS or other supraventricular conduction disorders, such as the sinoatrial or AV-block.
At increased risk of developing ulcers, eg in patients with peptic ulcer history or in patients receiving concomitant therapy of NSAIDs during the treatment Ariseptom should exercise increased caution, because holinomimetiki may increase the secretion of acid in the stomach. However, in placebo-controlled studies Arisepta found no increased incidence of peptic ulcers or gastrointestinal bleeding.
It is believed that holinomimetiki the potential to cause generalized convulsions. However, the appearance of convulsions during the administration of the drug Arisept may also be a manifestation of Alzheimer's disease. Given the cholinomimetic action of cholinesterase inhibitors, Arisept be used with caution in patients with asthma or obstructive pulmonary diseases in history.
Use in Pediatrics
Safety and effectiveness Arisepta in children has not been studied, and the drug is not recommended to assign these patients.
Effects on ability to drive trucks and operate machinery
Dementia Alzheimer's type itself may be accompanied by impairments in the driving and the use of sophisticated technology.
In addition, Arisept, mostly in the beginning of treatment or at higher doses, can cause fatigue, dizziness and muscle cramps. The question of the ability of a patient with Alzheimer's type dementia during a reception Arisepta driving or using complex machinery to decide the doctor after assessing individual patient responses to treatment.
Overdose
Symptoms: cholinergic crisis (expressed as nausea, vomiting, excessive salivation, sweating, bradycardia, decrease blood pressure, respiratory depression, collapse and convulsions). Perhaps increased muscle weakness, which, with the defeat of the respiratory muscles can lead even to death.
Treatment: symptomatic therapy. As an antidote to an overdose Arisepta can use tertiary anticholinergics, including atropine in the initial dose of 1-2 mg / in, then the dose is selected depending on the effect. It is unknown whether Donepezil removed and / or its metabolites during dialysis (hemodialysis, peritoneal dialysis or hemofiltration).
Drug Interactions
Clinical experience with Arisepta limited, so the appointment of the drug should take into account the risk of the unknown to date interactions with other drugs. Donepezil hydrochloride and / or products of its metabolism did not inhibit the metabolism of theophylline, warfarin, cimetidine, digoxin, tioridazina, risperidone and sertraline. Simultaneous reception of digoxin, cimetidine, tioridazina, risperidone and sertraline does not affect the metabolism of donepezil hydrochloride.
Application Arisepta simultaneously with levodopa / carbidopa for 21 days had no effect on the concentration of these drugs in the blood.
It is not revealed any effect on locomotor activity. In the metabolism of donepezil participate CYP3A4 and to a lesser extent - CYP2D6. Ketoconazole and quinidine, an inhibitor of CYP3A4 and 2D6, respectively, inhibit the metabolism of donepezil.
Consequently, these and other inhibitors of CYP3A4, such as itraconazole and erythromycin, and inhibitors of CYP2D6, such as fluoxetine, can inhibit the metabolism of donepezil. In healthy volunteers ketoconazole increased the average concentration of donepezil by about 30%.
However, this effect was not comparable to the influence of ketoconazole on other substances, is metabolized with the participation of CYP3A4, so it is unlikely to have clinical significance. The simultaneous use of Arisepta no effect on the pharmacokinetics of ketoconazole. Inductors enzymes, such as rifampicin, phenytoin, carbamazepine, and ethanol may cause lower levels of donepezil.
However, the extent of the inhibitory or inducing action is not known, so use these tools in conjunction with Ariseptom should be cautious. Arisept may influence the action of drugs with anticholinergic activity.
In addition, while the application, Donepezil may exacerbate the effects of succinylcholine and other muscle relaxants, or cholinergic receptor agonists and beta-blockers, which affect the conductivity of the heart, although in vitro study showed that donepezil hydrochloride has minimal effect on hydrolysis of succinylcholine.
At the same time with the application of other Ariseptom holinomimetikov and quaternary anticholinergic drugs, such as glikopirrolat, described cases of atypical changes in blood pressure and heart rate.
Terms and Conditions of storage
List B. The drug should be stored out of reach of children at or above 30 ° C. Shelf life - 3 years.
Tablets, coated white, round, biconvex, engraved with "Aricept" on one side and "5" - on the other.
1 tab. donepezil hydrochloride 5 mg.
Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, gidroksipropiltsellyuloza, magnesium stearate. The composition of the shell: Opadry White YS-1-18134-A (gipromelloza, talc, polyethylene glycol 8000, titanium dioxide).
Film-coated tablets are yellow, round, biconvex, engraved with "Aricept" on one side and "10" - on the other. 1 tab. donepezil hydrochloride 10 mg Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, gidroksipropiltsellyuloza, magnesium stearate. The composition of the shell: Opadry yellow YS-1-12700-A (gipromelloza, talc, polyethylene glycol 8000, titanium dioxide, iron oxide pigment yellow (E172)).
Clinico-pharmacological group: selective inhibitor of acetylcholinesterase in the brain. The drug for the treatment of Alzheimer's disease.
Pharmacological action
The selective and reversible inhibitor of acetylcholinesterase, which is the predominant type of cholinesterase in the brain. Donepezil inhibits this enzyme is more than 1000 times stronger than butyrylcholinesterase, contained mainly outside the CNS. After a single dose Arisepta in doses of 5 mg or 10 mg of the degree of suppression of acetylcholinesterase activity measured in erythrocyte membranes after taking the drug, accounted for respectively 63.6% and 77.3%.
Inhibition of acetylcholinesterase in erythrocytes under the effect of donepezil correlates with changes in the scale ADAS-cog (the scale of assessments of cognitive function in Alzheimer's disease). Possible impact on neuropathological changes have not been studied.
Pharmacokinetics
Absorption
Cmax donepezil in plasma is reached after about 3-4 hours after ingestion. Plasma concentrations and AUC increased in proportion to dose. T1 / 2 from the plasma is approximately 70 hours, so if systematic use of single doses Css achieved, usually within 2-3 weeks after starting therapy. After reaching the equilibrium state concentration of donepezil hydrochloride in plasma and related pharmacodynamic effects did not significantly change during the day. Eating does not affect the absorption of donepezil hydrochloride.
Distribution
Donepezil about 95% bound to plasma proteins. Information about binding to plasma proteins of its active metabolite 6-O-desmetildonepezila no.
The distribution of donepezil in various tissues of the body sufficiently studied. It is assumed that Donepezil and / or its metabolites may persist in the body over 10 days.
Metabolism and excretion
Donepezil undergoes metabolism in the liver. The main products of metabolism of donepezil are compounds M1 and M2 (products of O-dealkylation and hydroxylation), M11 and M12 (products glyukuronirovaniya M1 and M2, respectively), M4 (a product of hydrolysis) and M6 (product N-oxidation). IQ of intrahepatic recycling of donepezil and / or products of its metabolism is not available. Donepezil is derived, as well as its metabolites, mainly in the urine: 79% of the dose found in urine and 21% - in the feces. Predominantly found in the urine Donepezil.
Pharmacokinetics in special clinical situations
Gender, race and smoking did not significantly affect the concentration of donepezil in plasma. Mean levels of donepezil in plasma of patients correspond to those in healthy young volunteers. Violations of the liver function of light and medium severity, and renal dysfunction did not significantly affect the clearance of donepezil.
Statement
symptomatic treatment of Alzheimer's type dementia of mild or moderate severity.
Dosage regimen
Adults (including elderly patients), the medication is prescribed in an initial dose of 5 mg 1 time / day. Admission to the initial dose is continued for at least 4-6 weeks to reach equilibrium concentrations of donepezil and to identify early clinical effect of therapy. After 1 month Arisepta dose may be increased to 10 mg / day, which is the maximum recommended daily dose.
Supportive therapy can continue for as long as the therapeutic effect, which should be regularly assessed. When violations of liver and kidney function correction doses are required.
Side effect
On the part of the digestive system: frequent (> 5%) - diarrhea, nausea, vomiting.
From the central nervous system and peripheral nervous system: frequent (> 5%) - fatigue, insomnia, muscle cramps.
Since the cardiovascular system: rarely - syncope, bradycardia, sinoatrial and AV-block. Other: rarely - a slight increase in concentration of muscle CK in serum. In controlled clinical studies in patients were also observed:
From the CNS: headache, dizziness, hallucinations, anxiety, aggressive behavior, epileptic seizures.
On the part of the digestive system: dyspepsia, hepatitis, gastric ulcers and duodenal ulcers and bleeding from the gastrointestinal tract.
Other: pain of different localization, accidents, cold.
Adverse events observed in controlled clinical studies, no less than 2% of patients taking Arisept, with a frequency higher than those in the placebo group.
Contraindications
Hypersensitivity to donepezil hydrochloride, the other components of the drug, as well as to piperidine derivatives. Precautions should be prescribed to patients with obstructive lung diseases in medical history (including bronchial asthma), with heart rhythm disorders, during anesthesia, and patients with high risk of developing ulcers (eg, patients with peptic ulcer or a history of receiving concomitant therapy of NSAIDs).
Avoid the simultaneous application of Arisepta with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system.
Pregnancy and lactation
Controlled studies of Arisepta during pregnancy and lactation was conducted. IQ for the withdrawal donepezil with breast milk is not. The drug should be prescribed to pregnant women only if the expected benefit of treatment exceeds the potential risk to the fetus.
Application for violations of liver function
When violations of liver function correction doses are required.
Application for violations of renal function
When violations of renal function correct doses are required.
Cautions
Treatment must be prescribed and conducted by a doctor with experience of managing patients with Alzheimer's disease. The diagnosis should be delivered in accordance with generally accepted criteria (eg, DSM IV - Diagnostic and Statistical Manual of Mental Disorders fourth revision, ICD 10 - International Classification of Diseases 10th revision). Supportive therapy can continue for as long as the therapeutic effect. If the drug ceases to act, it should be abolished. After the cessation of treatment, a gradual decrease of Arisepta, information about withdrawal syndrome in the event of an abrupt discontinuation of the drug is not.
Individual response to therapy Ariseptom impossible to predict. Effectiveness Arisepta in patients with severe dementia, Alzheimer's type, other types of dementia or other types of memory (eg, age deterioration of cognitive function) was not studied.
Arisept, as a cholinesterase inhibitor, may increase miorelaxation suktsinilholinovogo type during anesthesia. Cholinesterase inhibitors (including Arisept) may have vagotonicheskoe effect on heart rate (in particular, cause bradycardia). The potential for such an action may be important for patients with SSS or other supraventricular conduction disorders, such as the sinoatrial or AV-block.
At increased risk of developing ulcers, eg in patients with peptic ulcer history or in patients receiving concomitant therapy of NSAIDs during the treatment Ariseptom should exercise increased caution, because holinomimetiki may increase the secretion of acid in the stomach. However, in placebo-controlled studies Arisepta found no increased incidence of peptic ulcers or gastrointestinal bleeding.
It is believed that holinomimetiki the potential to cause generalized convulsions. However, the appearance of convulsions during the administration of the drug Arisept may also be a manifestation of Alzheimer's disease. Given the cholinomimetic action of cholinesterase inhibitors, Arisept be used with caution in patients with asthma or obstructive pulmonary diseases in history.
Use in Pediatrics
Safety and effectiveness Arisepta in children has not been studied, and the drug is not recommended to assign these patients.
Effects on ability to drive trucks and operate machinery
Dementia Alzheimer's type itself may be accompanied by impairments in the driving and the use of sophisticated technology.
In addition, Arisept, mostly in the beginning of treatment or at higher doses, can cause fatigue, dizziness and muscle cramps. The question of the ability of a patient with Alzheimer's type dementia during a reception Arisepta driving or using complex machinery to decide the doctor after assessing individual patient responses to treatment.
Overdose
Symptoms: cholinergic crisis (expressed as nausea, vomiting, excessive salivation, sweating, bradycardia, decrease blood pressure, respiratory depression, collapse and convulsions). Perhaps increased muscle weakness, which, with the defeat of the respiratory muscles can lead even to death.
Treatment: symptomatic therapy. As an antidote to an overdose Arisepta can use tertiary anticholinergics, including atropine in the initial dose of 1-2 mg / in, then the dose is selected depending on the effect. It is unknown whether Donepezil removed and / or its metabolites during dialysis (hemodialysis, peritoneal dialysis or hemofiltration).
Drug Interactions
Clinical experience with Arisepta limited, so the appointment of the drug should take into account the risk of the unknown to date interactions with other drugs. Donepezil hydrochloride and / or products of its metabolism did not inhibit the metabolism of theophylline, warfarin, cimetidine, digoxin, tioridazina, risperidone and sertraline. Simultaneous reception of digoxin, cimetidine, tioridazina, risperidone and sertraline does not affect the metabolism of donepezil hydrochloride.
Application Arisepta simultaneously with levodopa / carbidopa for 21 days had no effect on the concentration of these drugs in the blood.
It is not revealed any effect on locomotor activity. In the metabolism of donepezil participate CYP3A4 and to a lesser extent - CYP2D6. Ketoconazole and quinidine, an inhibitor of CYP3A4 and 2D6, respectively, inhibit the metabolism of donepezil.
Consequently, these and other inhibitors of CYP3A4, such as itraconazole and erythromycin, and inhibitors of CYP2D6, such as fluoxetine, can inhibit the metabolism of donepezil. In healthy volunteers ketoconazole increased the average concentration of donepezil by about 30%.
However, this effect was not comparable to the influence of ketoconazole on other substances, is metabolized with the participation of CYP3A4, so it is unlikely to have clinical significance. The simultaneous use of Arisepta no effect on the pharmacokinetics of ketoconazole. Inductors enzymes, such as rifampicin, phenytoin, carbamazepine, and ethanol may cause lower levels of donepezil.
However, the extent of the inhibitory or inducing action is not known, so use these tools in conjunction with Ariseptom should be cautious. Arisept may influence the action of drugs with anticholinergic activity.
In addition, while the application, Donepezil may exacerbate the effects of succinylcholine and other muscle relaxants, or cholinergic receptor agonists and beta-blockers, which affect the conductivity of the heart, although in vitro study showed that donepezil hydrochloride has minimal effect on hydrolysis of succinylcholine.
At the same time with the application of other Ariseptom holinomimetikov and quaternary anticholinergic drugs, such as glikopirrolat, described cases of atypical changes in blood pressure and heart rate.
Terms and Conditions of storage
List B. The drug should be stored out of reach of children at or above 30 ° C. Shelf life - 3 years.
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