Alzepil pills 10 mg 28 pcs
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Active ingredients
Donepezil
Release form
Pills
Composition
1 tablet contains: donepezil hydrochloride monohydrate 10.42 mg, which corresponds to the content of donepezil hydrochloride 10 mg. Auxiliary substances: microcrystalline cellulose - 192 mg, low substituted hydroxypropylcellulose (L-HPC B1) - 48 mg, magnesium stearate - 2 mg, yadi y-1- 7000 white - 6 mg, hypromellose - 3.75 mg, titanium dioxide - 1.875 mg, macrogol 400 - 0.375 mg.
Pharmacological effect
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 CNS. 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) 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 influence the progression of the disease. Donepezil was tested for effectiveness 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 the completion 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 respondents to treatment.
Pharmacokinetics
Absorption After ingestion of C max of donepezil in the blood plasma is reached after approximately 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 is 95%. The binding of plasma proteins to the active metabolite, 6-O-desmethyldoneepesil, is unknown. Distribution of donepezil in tissues has not been specifically studied. In one study with the participation of healthy male volunteers, it was found that after a single injection of labeled 14C-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 reached within 3 weeks after the start of therapy. Metabolism and elimination After a single injection of 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-desmethyldoneepesyl - 11% (the only metabolite with similar activity with donepezil hydrochloride), donepezil-cis-N-oxide - 9%, 5-O-desmethyl onepezila - 7% and glucuronide conjugate of 5-O-desmetildonepezila - 3% .Donepezil excreted by the kidneys in unchanged form or in the form of numerous metabolites formed by cytochrome P450 enzymes, all of which are not 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. T1 / 2 is approximately 70 hours. Pharmacokinetics in special patient groups. Gender, ethnicity and smoking do not have a significant effect on 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 in these patients corresponded to the concentration determined in healthy volunteers. In patients with mild or moderate liver dysfunction, an increase in Css donepezil in the blood plasma may be observed.
Indications
- symptomatic treatment of mild to moderate Alzheimer's-type dementia.
Contraindications
- children and adolescents up to 18 years (due to lack of clinical data); - hypersensitivity to the components of the drug; - hypersensitivity to piperidine derivatives.
Use during pregnancy and lactation
The experience of using the drug in women during pregnancy and during breastfeeding is absent. Studies on animals 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.
Dosage and administration
The drug is taken orally, preferably in the evening before bedtime. The treatment should be started and carried out under the supervision of a physician with experience in the diagnosis and treatment of dementia of the Alzheimer's type. The diagnosis should be based on accepted recommendations, for example, DSM-IV, ICD-10. Treatment with donepezil can be started only if there are persons who care for the patient and are able to regularly monitor the drug intake. Adults, including Elderly patients: Treatment begins with the use of the drug in a dose of 5 mg 1 time / day and continues for at least 4 weeks to reach Css 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. Supportive therapy can be continued 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 discontinuation of the drug, 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, since this condition does not affect the clearance of donepezil. Due to the possible increase in exposure in mild or moderate liver dysfunction, increase the dosedrug should be tailored to individual tolerability. There are no data on the use of the drug in patients with severe liver dysfunction. The drug is Alzepil; not intended for the treatment of children and adolescents.
Side effects
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. The frequency of adverse reactions is determined: 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), frequency unknown (impossible to estimate according to the available data). Mental disorders: often - hallucinations **, agitation **, aggressive behavior **, abnormal dreams, nightmares **. From the nervous system: very often - headache; often - fainting *, dizziness, insomnia; infrequently - convulsive seizures *; rarely extrapyramidal symptoms; very rarely - ZNS.S 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 ***. From the skin and subcutaneous tissues: often - rash, pruritus. From the musculoskeletal system: often - muscle spasms; very rarely - rhabdomyolysis ****. From the urinary system: often - urinary incontinence. From laboratory and instrumental studies: rarely - a slight increase in the activity of the muscular isoform of CPK in the blood serum. Other: often - runny nose, fatigue, pain, accident . * When examining patients with fainting or convulsive seizures, the possibility of heart block or prolonged sinus pauses should be considered. ** When registering cases of hallucinations, agitation and aggressive behavior, abnormal of dreams and nightmares, it was reported that these manifestations stopped after reducing the dose or discontinuing the drug. *** If there is an impaired liver function of unknown etiology, the possibility of discontinuing Alzepil should be considered; **** There were reports of rhabdomyolysis developed independently , in close time connection, or with the start of reception of donepezil,or with increasing doses. Providing data on the alleged 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.
Overdose
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, posture on the body, a wavering gait, lacrimation, clonic convulsions, respiratory depression, drooling, miosis, fasciculation, and a decrease in body surface temperature. to cholinergic crisis, characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, call Apsom and cramps. May increase muscle weakness, which can lead to death with the defeat of the respiratory muscles. Treatment: as in any case of overdose, general supportive treatment should be prescribed. Tertiary anticholinergic drugs, for example, atropine, can be used as antidotes for overdosing 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).
Interaction with other drugs
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 degree of such an inhibitory or inducing action is unknown, it is necessary to use such agents in combination with donepezil with caution. Dipezil 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.
special instructions
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, and therefore the drug can enhance succinylcholine muscle relaxation during anesthesia. Cardiovascular disorders 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 SAS or other violations of AV-conduction, for example, in case of a sinoatrial blockade or AV-blockade. There were reports of fainting and convulsive seizures. When examining such patients, consideration should be given to the possibility of cardiac blockade or long pauses in the sinus rhythm. Disorders of gastrointestinal function Patients with an increased risk of developing ulcers, for example, having a history of a peptic ulcer or receiving concomitant NSAIDs, need to be observed to identify symptoms of ulceration.However, clinical trials of donepezil, compared with placebo, did not reveal an increase in the incidence of peptic ulcers or gastrointestinal bleeding. Urinary system Cholinomimetics can cause disturbance of urine outflow from the bladder, however, such effects were not observed in clinical trials of donepezil. 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. A CNSSN is a potentially life-threatening disorder that is characterized by hyperthermia (fever), muscle rigidity, disorders of the autonomic nervous system, altered consciousness, elevated CPK activity . Additional symptoms may include myoglobinuria (rhabdomyolysis) and acute renal failure. There are very rare reports of the development of NNS associated with donepezil, especially in patients also receiving concomitant antipsychotic therapy. If a patient develops signs and symptoms of NNS or there is an unexplained high temperature without additional clinical manifestations, treatment should be discontinued. Pulmonary dysfunctions Cholinesterase inhibitors, due to their pharmacology With a biological effect, patients should be prescribed with caution, with a history of asthma or obstructive pulmonary disease. The simultaneous administration of the drug Alzepil should be avoided; and other acetylcholinesterase inhibitors, as well as cholinergic system agonists or antagonists. Severe hepatic dysfunction There is no data on the use of the drug in patients with severely impaired liver function. Mortality in clinical studies of vascular dementia There were three clinical trials of 6 months duration involving NINDS- AIREN possible or probable vascular dementia (DM). The NINDS-AIREN criteria are designed to identify patients whose dementia can only be associated with vascular causes and exclude Alzheimer's patients. 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 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-fatal and fatal vascular disorders did not reveal differences in the frequency of their occurrence in groups receiving donepezil hydrochloride and placebo. In the combined materials of Alzheimer's disease studies (n = 4146), as well as the same Alzheimer's studies with the addition of vascular dementia studies (total the number of patients 6888) mortality rates in the placebo groups outnumbered those in the groups treated with donepezil hydrochloride numerically. The effect on the ability to drive motor vehicles and control The effect of the mechanisms of Donepesil on a minor or moderate degree affects the ability to drive vehicles and work with mechanisms. The Alzheimer's type dementia itself can be accompanied by a violation of the ability to drive and use equipment. 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.