Dementis - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 91.75 mg, starch corn 20,00 mg, cellulose microcrystalline 15,00 mg, hydroxypropyl cellulose 3.00 mg, magnesium stearate 0.25 mg (tablet core weight: 135.00 mg);

sheath (sepilymer 752 white): hypromellose 2.00 mg, microcrystalline cellulose 1.60 mg, macrogol stearate 0.40 mg, titanium dioxide E171 1.00 mg (theoretical weight 140.00 mg).

For a dosage of 10 mg:

active substance: donepezil hydrochloride (Cipla Ltd, India) 10.00 mg;

Excipients: lactose monohydrate 183.50 mg, corn starch 40.00 mg, microcrystalline cellulose 30.00 mg, hydroxypropylcellulose 6.00 mg, magnesium stearate 0.50 mg (tablet core weight: 270.00 mg);

sheath (transparent film 003): hypromellose 3.00 mg, microcrystalline cellulose 2.40 mg, macrogol stearate 0.60 mg; Sheath (dry desperate 3244 yellow): hypromellose 2.40 mg, microcrystalline cellulose 0.40 mg, titanium dioxide E171 1.00 mg, iron oxide yellow E172 0.20 mg (theoretical weight 280.00 mg).

Description:

For a dosage of 5 mg: white, round, slightly biconcave film-coated tablets.

For the dosage of 10 mg: yellow, round, biconvex film-coated tablets.

Pharmacotherapeutic group:Cholinesterase inhibitor

ATX: & nbsp

N.06.D.A.02 Donepezil

Pharmacodynamics:

Donepezil is a selective, reversible enzyme inhibitor acetylcholinesterase, which is an prevalent type 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.

Inhibiting cholinesterase in the brain, donepezil blocks the disintegration of acetylcholine, which performs the transfer of excitation in the central nervous system (CNS). After a single dose of donepezil in doses at mg or 10 mg, the degree of inhibition of acetylcholinesterase activity (estimated on the model of erythrocyte membranes) was 63.6 and 77.3%, respectively. The inhibition of acetylcholinesterase in erythrocytes under the influence of donepezil correlates with changes in the scale ADAS-cog (a scale of assessment of cognitive functions in Alzheimer's disease).The ability of donepezil hydrochloride to change the course of concomitant neurologic changes has not been investigated. Thus, it can not be assumed that donepezil affects the progression of the disease.

The efficacy of donepezil was investigated in four placebo-controlled trials, two six-month and two-year trials.

In a six-month clinical trial, the analysis was performed using three performance criteria after completion of donepezil administration. A scale was used ADAS-Cog (indicator of cognitive function): a scale of impressions of the clinician about changes based on interviews and data obtained from carers of patients (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 scale ADAS-Cog not less than 4 points, no deterioration on the scale CIBIC, no deterioration in the subscale of the daily activity of the clinical scale of the assessment of dementia.

	% answer
	Patients to whom treatment was prescribed (ITT - Intent to treat), n=365	Population, the analysis of which was possible, n=352
Placebo group	10%	10%
Group receiving donepezil HC1 5 mg	18%*	18%*
Group receiving donepezil HC1 5 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

The maximum concentration (C_mOh) donepezil in the plasma is achieved approximately 3-4 hours after ingestion. Plasma concentration and area under the concentration-time curve (AUC) increase in proportion to the dose. Half-life T_1/2 is approximately 70 hours, so the systematic use of single doses leads to a stable concentration, which is achieved approximately 3 weeks after the initiation of therapy. The equilibrium concentration of donepezil in plasma and the pharmacodynamic effect associated with it vary very little during the day. The intake of food does not affect the absorption of donepezil.

Distribution

Approximately 95% of donepezil binds to plasma proteins. Information on binding to plasma proteins of its active metabolite 6-O-desmethyldonepezil is absent. Distribution donepezil in various tissues of the body has been studied insufficiently.In the distribution studies on healthy male volunteers, it was found that after taking a single dose of 5 mg of labeled ¹⁴C-donepezil hydrochloride, 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.

Metabolism and excretion

Donepezil is excreted by the kidneys in both unchanged form and in the form of numerous metabolites formed by cytochrome P450 enzymes not all of which are identified. After a single dose of 5 mg of labeled ¹⁴C-donepezil hydrochloride concentration of unchanged donepezil in plasma - 30% of the dose, 6-O-desmethyldonepezil - 11% (the only metabolite with similar activity with donepezil hydrochloride), donepezil-cis-II9%, 5-O-desmethyl-donepezil - 7% and glucuronide of the conjugate 5-O-desmethyldonepezil - 3%. 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 biotransfomation and excretion by the kidneys are the primary way of elimination. There are no data confirming the enterohepatic recirculation of donepezil and / or its metabolites.

The half-life of donepezil is about 70 hours.

Gender, ethnicity and smoking do not have a significant effect on the concentration of donepezil in plasma. Donepezil pharmacokinetics was not formally studied in healthy elderly patients, nor in patients with Alzheimer's dementia 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 Elevated equilibrium concentrations of donepezil in blood plasma can be observed.

Indications:

Symptomatic treatment of dementia of the Alzheimer's type of mild or moderate severity.

Contraindications:

- Individual hypersensitivity to any component of the drug or a piperidine derivative;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (since the formulation contains lactose monohydrate);

- children under 18 years of age (safety and efficacy have not been studied).

Carefully:

They are used with caution in patients with obstructive lung diseases in history (including bronchial asthma),with cardiac arrhythmias (possibly a vagotonic effect on the heart rate, in particular bradycardia), with an increased risk of ulcers (a history of peptic ulcer disease or concomitant therapy with nonsteroidal anti-inflammatory drugs), with general anesthesia, while taking with cholinergic inhibitors or other cholinesterase inhibitors , in patients with convulsions and convulsions in an anamnesis, hepatitis or other liver diseases, difficulty in withdrawing urine or kidney disease of moderate t tin.

Pregnancy and lactation:

Pregnancy

The experience of using the drug in humans during pregnancy and during the period there is no breastfeeding. Studies in animals have not revealed donepezil, but was established peri-and postnatal toxicity. The potential risk to humans is unknown.

Therefore, the drug should not be used during pregnancy, except when it is absolutely necessary.

Breastfeeding period

In rats donepezil is excreted with milk. It is not known whether the drug is excreted in human breast milk, such studies have not been conducted.If it is necessary to take the drug during lactation, it is necessary to resolve the issue of stopping breastfeeding.

Dosing and Administration:

Inside.

Take in the evening (before going to bed), drinking with a sufficient amount of water (100 ml).

Adults / Seniors

Initial dose is 5 mg once a day (at night). A dose of 5 mg / day should be taken at least 1 month before reaching equilibrium concentrations of donepezil in plasma and assessing the clinical effect. After a month, if necessary, the dose can be increased to 10 mg once a day.

The maximum daily dose 10 mg.

Duration of therapy is determined by the doctor.

In case of missed regular dose the next dose is taken at the usual time (do not take two doses at the same time). In case of repeated admission of the drug (break more than 1 week), you should consult your doctor.

Treatment should be prescribed and conducted by a specialist doctor who has experience in managing patients with dementia of the Alzheimer's type. The diagnosis should be made in accordance with generally accepted criteria (for example, DSM IV - Diagnostic and Statistical Manual on Mental Disorders of the Fourth Revision, ICD 10 - International Classification of Diseases of the Tenth Revision).Treatment can be conducted only in the presence of persons caring for the patient, able to regularly monitor the intake of the drug. Treatment is conducted as long as there is a therapeutic effect that 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.

Information about the "withdrawal syndrome" in the event of a sudden discontinuation of donepezil is not.

Patients with impaired renal and hepatic function

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

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.

Children and teens

The drug is 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.There was also reported dizziness, headache, pain, accidents and colds. In most cases, these phenomena pass and do not require discontinuation of the drug.

Side effects are listed below in descending frequency according to the organ classification: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥ 1/10000, <1/1000), very rarely (<1/10000) or observed with an unknown frequency (the frequency can not be estimated from the available data).

Infections and parasitic diseases: often: runny nose.

Disorders from the metabolism and nutrition: often: anorexia.

Disorders of the psyche: often: hallucinations **, agitation **, aggressive behavior **, abnormal dreams, nightmarish dreams **.

Disturbances from the nervous system: often: fainting *, dizziness, insomnia; infrequently: convulsive attacks *; rarely: extrapyramidal disorders; very rarely: malignant neuroleptic syndrome.

Heart Disease: infrequently: bradycardia; rarely: sinoatrial and atrioventricular block.

Disorders from the gastrointestinal tract: very often: diarrhea, nausea; often: vomiting, indigestion; infrequently: gastrointestinal bleeding, stomach and duodenum ulcers.

Disturbances from the liver and bile ducts: rarely: a violation of the liver, including hepatitis ***.

Disturbances from the skin and subcutaneous tissue: often: a rash, itchy skin.

Disturbances from musculoskeletal and connective tissue: often: muscle spasms; very rarely: rhabdomyolysis ****.

From the side of the kidneys and urinary tract: often: urinary incontinence.

General disorders and disorders at the site of administration: very often: headache; often: fatigue, pain of different localization.

Impact on the results of laboratory and instrumental studies: infrequently: a slight increase in the concentration of muscle creatine kinase in the blood serum.

Trauma, intoxication and complications of manipulation: often: accident.

* When examining patients with syncope or convulsive seizures, the possibility of cardiac blockade or prolonged sinus pauses should be considered.

** In reported cases of hallucinations, agitation and aggressive behavior, abnormal dreams and nightmares, these manifestations ceased after a dose reduction or drug withdrawal.

*** If there is a violation of the liver function of the unexplained etiology, the possibility of drug cancellation should be considered.

**** There were reports of rhabdomyolysis, which developed independently of the malignant neuroleptic syndrome, in close connection either with the onset of donepezil, or with increasing doses.

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.

Overdose:

Overdose with donepezil can lead to a cholinergic crisis.

Symptoms: cholinergic crisis (severe nausea, vomiting, excessive salivation, sweating, bradycardia, lowering of blood pressure, respiratory depression, loss of consciousness, convulsions). Possible myasthenia gravis, which can lead to a fatal outcome in the event of injury to the respiratory muscles.

Treatment: in cases of an alleged overdose symptomatic therapy is indicated. As an antidote, it is possible to use tertiary anticholinergics,in particular atropine sulfate in an initial dose of 1-2 mg intravenously, followed by titration of the dose - depending on the effect. It is not known whether the donepezil and / or its metabolites in dialysis (hemodialysis, peritoneal dialysis or hemofiltration).

Interaction:

When prescribing donepezil it is necessary to take into account the risk of unknown interactions with other agents until now.

Donepezil and / or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin in humans. The simultaneous administration of digoxin or cimetidine does not affect the metabolism of donepezil.

In vitro studies have shown that isoenzymes 3A4 and to a small extent 2D6 cytochrome P450 are involved in the metabolism of donepezil. Conducted drug studies in vitro show that ketoconazole and quinidine, inhibitors respectively CYP3A4 and 2D6, suppress the metabolism donepezil. Thus, these and other inhibitors CYP3A4, such as intraconazole and erythromycin, and inhibitors CYP2D6, such as fluoxetine can suppress metabolism donepezil. In studies on healthy volunteers, ketoconazole increased the donepezil concentration by approximately 30%. Inductors of enzymes, such as rifampicin, phenytoin, carbamazepine and ethanol can reduce the concentration of donepezil in the blood. Since the magnitude of the inhibitory or inducing effect is unknown, caution should be exercised on such combinations of drugs.

Donepezil can affect the activity of drugs with anticholinergic activity. Donepezil may exhibit synergistic activity for drugs such as succinylcholine, other neuromuscular blockers or cholinergic agonists or β-blockers that affect the cardiac conduction system.

Special instructions:

It is impossible to predict an individual reaction to donepezil therapy. The efficacy of donepezil in patients with severe dementia of the Alzheimer type, other types of dementia, or other types of memory impairment (eg, age-related deterioration of cognitive function) has not been studied.

Anesthesia: being an inhibitor of cholinesterase, donepezil can enhance muscle relaxation of succinyl type during anesthesia.

Cardiovascular diseases: donepezil can have a vagotonic effect on heart rate (in particular, cause bradycardia). The potential for this action may be important for patients with sinus syndrome weakness or other disorders of supraventricular conduction, such as sinoatrial or atrioventricular block.

Gastrointestinal diseases: being a holinomimetic, donepezil can increase the secretion of acid in the stomach, so patients at risk of developing ulcers (for example, patients with a history of peptic ulcer disease or receiving non-steroidal anti-inflammatory drugs) should be carefully monitored. At the same time, in placebo-controlled studies donepezil there was no increase in the incidence of peptic ulcers or gastrointestinal bleeding.

Genitourinary system: being a holinomimetic, donepezil may cause difficulty in outflow of urine.

Neurological diseases: being a holinomimetic, donepezil can cause generalized convulsions, but the appearance of seizures can also be a manifestation of Alzheimer's disease. How holinomimetic donepezil may exacerbate or cause extrapyramidal disorders.

Impairment of lung function: cholinesterase inhibitors, in connection with their pharmacological action, should be administered with caution to patients with a history of asthma or obstructive pulmonary disease. It should avoid concomitant administration of donepezil and other acetylcholinesterase inhibitors, as well as agonists or antagonists of the cholinergic system.

Severe liver dysfunction: There is no data on the use in patients with severe hepatic impairment.

Malignant neuroleptic syndrome: this is a potentially life-threatening disorder characterized by hyperthermia (fever), muscle rigidity, autonomic nervous system disorders, altered consciousness, elevated levels of serum creatinine phosphokinase. Additional symptoms may include myoglobinuria (rhabdomyolysis) and acute renal failure. There are very rare reports of the development of malignant neuroleptic syndrome associated with the use of donepezil, especially in patients also receiving concomitant therapy with antipsychotic drugs.

If the patient develops signs and symptoms of a malignant neuroleptic syndrome or if an unexplained high temperature is present without additional clinical manifestations, treatment should be discontinued.

Mortality in clinical studies of vascular dementia: Three clinical trials of 6 months duration were conducted with the participation of patients meeting the criteria NINDS-AIREN possible or probable vascular dementia (DM). Criteria NINDS-AIIJEN Developed to identify patients in whom dementia can 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 5 mg of donepezil hydrochloride, 5/206 (2.4%) in the group receiving 10 mg of donepezil hydrochloride 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 5 mg of donepezil hydrochloride, 3/215 (1.4%) in the group receiving 10 mg of donepezil hydrochloride 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 5 mg of donepezil hydrochloride, 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 pooled studies of Alzheimer's disease (n = 414), 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 placebo groups are numerically greater than those in the groups treated with donepezil hydrochloride.

The drug contains lactose, therefore it is not recommended for persons suffering from lactase deficiency, galactoseemia or glucose / galactose malabsorption syndrome.

Effect on the ability to drive transp. cf. and fur:

The drug has an effect on psychophysical abilities. Dementia Alzheimer's type itself can be accompanied by a violation of the ability to drive and use sophisticated technology. In addition, the drug can cause fatigue, dizziness, muscle cramps (especially at the beginning of treatment or when the dose is exceeded). The ability of a patient to drive a car or use sophisticated equipment should be evaluated by a doctor.

Form release / dosage:

Tablets, film-coated, 5 mg and 10 mg.

Packaging:

For a dosage of 5 mg: For 14 tablets in PVC / PVDC-aluminum blister. For 2 or 7 blisters together with the instructions for use are placed in a cardboard box.

For the dosage of 10 mg: For 7 tablets in PVC / PVDC-aluminum blister. For 4 or 14 blisters together with the instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003741

Date of registration:19.07.2016

Expiration Date:19.07.2021

The owner of the registration certificate:Elpen Pharmaceutical Co. InkElpen Pharmaceutical Co. Ink Greece

Manufacturer: & nbsp

ELPEN Pharmaceutical Co. Ltd. Inc. Greece

Representation: & nbspSVYCH LLC SVYCH LLC Russia

Information update date: & nbsp23.03.2017

Illustrated instructions

Instructions

Dementis (Dementis)