Dementis, 5 mg 28 pcs.

Pharmacological group: Cholinesterase inhibitor.

Pharmacodynamics

Donepezil is a selective, reversible inhibitor of the enzyme acetylcholinesterase, which is the predominant type of cholinesterase in the brain. In vitro, donepezil inhibits this enzyme more than 1,000 times stronger than butyrylcholinesterase, an enzyme that is mainly located outside the central nervous system.

Inhibiting cholinesterase in the brain, donepezil blocks the breakdown of acetylcholine, which carries out excitation transmission in the central nervous system (CNS). After a single dose of donepezil at doses of 5 mg or 10 mg, the degree of inhibition of acetylcholinesterase activity (evaluated on the red blood cell membrane model) was 63.6% and 77.3%, respectively. Inhibition of acetylcholinesterase in erythrocytes by donepezil correlates with changes in ADAS-cog scale (Alzheimer’s disease cognitive assessment scale). The ability of donepezil hydrochloride to change the course of concomitant neurological changes has not been investigated. Thus, donepezil cannot be considered to affect disease progression.

Pharmacokinetics

Intake

The maximum plasma concentration (Cmax) of donepezil is reached approximately 3-4 hours after oral administration. Plasma concentration and area under the concentration-time curve (AUC) increase in proportion to dose. The half-life of the T1/2 is approximately 70 hours, so systematic use of single doses leads to a stable concentration that is reached within approximately 3 weeks after the start of therapy. The equilibrium plasma concentration of donepezil and its associated pharmacodynamic effects vary very little during the day. Food intake has no effect on the absorption of donepezil.

Distribution

About 95% of donepezil is bound to plasma proteins. There is no information about the binding to plasma proteins of its active metabolite 6-Q-desmethyl donepezil. The distribution of donepezil in various body tissues has not been studied sufficiently. In distribution studies on healthy male volunteers, it was found that after a single dose of 5 mg of 14C-labeled donepezil hydrochloride, approximately 28% of the dose was detected in the body 240 hours after administration. This indicates that donepezil and/or its metabolites may persist in the body for more than 10 days.

Metabolism and excretion

Donepezil is excreted by the kidneys both unchanged and in the form of numerous metabolites formed by cytochrome P450 enzymes, not all of which have been identified. After a single dose of 5 mg of 14C-labeled donepezil hydrochloride, the plasma concentration of unchanged donepezil is 30% of the administered dose, that of 6-O-desmethyl donepezil – 11% (the only metabolite, with similar activity to donepezil hydrochloride), donepezil-cis-N-oxide 9%, 5-O-desmethyl-donepezil 7%, and 5O-desmethyl-donepezil glucuronide conjugate ‑3%. Approximately 57% of the administered dose was found in the urine (17% unchanged) and 14.5% in the feces, concluding that biotransformation and excretion by the kidneys was the primary route of elimination. There are no data to support enterohepatic recirculation of donepezil and/or its metabolites.

The elimination half-life of donepezil is approximately 70 h.

Gender, ethnicity and smoking have no significant effect on the plasma concentration of donepezil. The pharmacokinetics of donepezil has not been formally studied in healthy elderly or in patients with Alzheimer’s type dementia or vascular dementia. However, the mean plasma concentration of donepezil in these patients was consistent with that determined in healthy volunteers.

In patients with mild to moderate hepatic impairment, elevated equilibrium plasma concentrations of donepezil may be observed.

Indications

Symptomatic treatment of mild to moderate Alzheimer’s type dementia.

Pharmacological effect

Pharmacological group: Cholinesterase inhibitor.

Pharmacodynamics

Donepezil is a selective, reversible inhibitor of the enzyme acetylcholinesterase, which is the predominant type of cholinesterase in the brain. In vitro, donepezil inhibits this enzyme more than 1000 times more potently than butyrylcholinesterase, an enzyme that is primarily located outside the central nervous system.

By inhibiting cholinesterase in the brain, donepezil blocks the breakdown of acetylcholine, which transmits excitation in the central nervous system (CNS). After a single dose of donepezil in doses of 5 mg or 10 mg, the degree of inhibition of acetylcholinesterase activity (assessed in the erythrocyte membrane model) was 63.6 and 77.3%, respectively. Inhibition of acetylcholinesterase in erythrocytes by donepezil correlates with changes in ADAS-cog (Alzheimer’s Disease Cognitive Assessment Scale). The ability of donepezil hydrochloride to alter the course of concomitant neurological changes has not been studied. Thus, donepezil cannot be considered to influence disease progression.

Pharmacokinetics

Suction

The maximum concentration (Cmax) of donepezil in plasma is reached approximately 3–4 hours after oral administration. Plasma concentration and area under the concentration-time curve (AUC) increase proportionally to the dose. The half-life T1/2 is approximately 70 hours, so systematic use of single doses leads to a stable concentration, which is achieved approximately within 3 weeks after the start of therapy. The steady-state plasma concentration of donepezil and its associated pharmacodynamic effects vary very little throughout the day. Eating does not affect the absorption of donepezil.

Distribution

Approximately 95% of donepezil is bound to plasma proteins. There is no information on plasma protein binding of its active metabolite 6-Q-desmethyldonepezil. The distribution of donepezil in various tissues of the body has not been sufficiently studied. In distribution studies in healthy male volunteers, it was found that following a single 5 mg dose of labeled 14C-donepezil hydrochloride, approximately 28% of the dose was detectable in the body 240 hours after administration. This indicates that donepezil and/or its metabolites may persist in the body for more than 10 days.

Metabolism and excretion

Donepezil is excreted by the kidneys both unchanged and in the form of numerous metabolites formed by cytochrome P450 enzymes, not all of which have been identified. After a single dose of 5 mg of 14C-labeled donepezil hydrochloride, the concentration of unchanged donepezil in plasma is 30% of the dose taken, 6-O-desmethyldonepezil is 11% (the only metabolite with similar activity to donepezil hydrochloride), donepezil-cis-N-oxide is 9%, 5-O-desmethyl-donepezil is 7% and glucuronide conjugate 5-O-desmethyldonepezil – 3%. Approximately 57% of the administered dose was found in urine (17% unchanged) and 14.5% in feces, leading to the conclusion that biotransformation and renal excretion are the primary route of elimination. There is no evidence to support enterohepatic recycling of donepezil and/or its metabolites.

The half-life of donepezil is approximately 70 hours.

Gender, ethnicity and smoking do not have a significant effect on donepezil plasma concentrations. The pharmacokinetics of donepezil have not been formally studied in healthy elderly patients or in patients with dementia of the Alzheimer’s type or vascular dementia. However, the mean plasma concentrations of donepezil in these patients were consistent with those measured in healthy volunteers.

Increased steady-state plasma concentrations of donepezil may be observed in patients with mild or moderate hepatic impairment.

Special instructions

Individual response to donepezil therapy cannot be predicted. The effectiveness of donepezil in patients with severe Alzheimer’s type dementia, other types of dementia, or other types of memory impairment (eg, age-related cognitive decline) has not been studied.

Anesthesia: As a cholinesterase inhibitor, donepezil may enhance succinyl-type muscle relaxation during anesthesia.

Cardiovascular disease: donepezil may have a vagotonic effect on heart rate (in particular, causing bradycardia). The potential for such an effect may be important in patients with sick sinus syndrome or other supraventricular conduction disorders such as sinoatrial or atrioventricular block.

Gastrointestinal diseases: As a cholinomimetic, donepezil may increase gastric acid secretion, so patients at risk of developing ulcers (for example, patients with a history of peptic ulcers or those receiving non-steroidal anti-inflammatory drugs) should be closely monitored. However, in placebo-controlled studies of donepezil, there was no increase in the incidence of peptic ulcers or gastrointestinal bleeding.

Genitourinary system: Being a cholinomimetic, donepezil may cause difficulty in the outflow of urine.

Neurological diseases: Being a cholinomimetic, donepezil can cause generalized seizures, but the appearance of seizures may also be a manifestation of Alzheimer’s disease. As a cholinomimetic, donepezil may enhance or cause extrapyramidal disorders.

Impaired pulmonary function: Cholinesterase inhibitors, due to their pharmacological effects, should be prescribed with caution to patients with a history of asthma or obstructive pulmonary disease.

The simultaneous administration of donepezil and other acetylcholinesterase inhibitors, as well as agonists or antagonists of the cholinergic system, should be avoided.

Severe liver impairment: There are no data on use in patients with severe liver impairment.

Neuroleptic malignant syndrome: This is a potentially life-threatening disorder that is characterized by hyperthermia (fever), muscle rigidity, autonomic nervous system disturbances, altered consciousness, and elevated serum creatinine phosphokinase levels. Additional symptoms may include myoglobinuria (rhabdomyolysis) and acute renal failure.

There are very rare reports of the development of neuroleptic malignant 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 neuroleptic malignant syndrome or has an unexplained high fever without additional clinical manifestations, treatment should be discontinued.

Mortality in Vascular Dementia Clinical Trials: Three 6-month clinical trials were conducted in patients meeting the NINDS-AIREN criteria for possible or probable vascular dementia (VaD). The NINDS-AIREN criteria are designed to identify patients whose dementia may be due to vascular causes only and to exclude patients with Alzheimer’s disease.

In the first study, the incidence of death was 2/198 (1%) in the donepezil hydrochloride 5 mg group, 5/206 (2.4%) in the donepezil hydrochloride 10 mg group, and 7/199 (3.5%) in the placebo group. In the second study, the incidence of death was 4/208 (1.9%) in the donepezil hydrochloride 5 mg group, 3/215 (1.4%) in the donepezil hydrochloride 10 mg group, and 1/193 (0.5%) in the placebo group. In the third study, the incidence of death was 11/648 (1.7%) in the donepezil hydrochloride 5 mg group and 0/326 (0%) in the placebo group.

The incidence of death in all donepezil hydrochloride groups in the three diabetes trials (1.7%) was numerically higher than in the placebo group (1.1%), but this difference was not statistically significant. The majority of deaths in patients receiving donepezil hydrochloride or placebo were due to various vascular events, which are expected in this population of elderly individuals with underlying vascular disease. Analysis of all serious non-fatal and fatal vascular events did not reveal a difference in the incidence of their occurrence in the groups receiving donepezil hydrochloride and placebo.

In the pooled Alzheimer’s disease studies (n=4,146) and the same Alzheimer’s disease studies plus vascular dementia studies (6,888 total patients), mortality rates in the placebo groups were numerically superior to those in the donepezil hydrochloride groups.

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

Impact on the ability to drive vehicles and operate machinery

The drug affects psychophysical abilities. Dementia of the Alzheimer’s type may itself be accompanied by impaired ability to drive a car and use complex equipment. In addition, the drug may cause fatigue, dizziness, and muscle cramps (especially at the beginning of treatment or if the dose is exceeded). The patient’s ability to drive a car or use complex machinery should be assessed by a physician.

Active ingredient

Donepezil

Composition

1 tablet contains:

Active substance:

Donepezil hydrochloride (Cipla Ltd, India) 5.00 mg

Excipients:

Lactose monohydrate 91.75 mg, corn starch 20.00 mg, microcrystalline cellulose 15.00 mg, hydroxypropylcellulose 3.00 mg, magnesium stearate 0.25 mg (tablet core weight 135.00 mg); shell (sepifilm 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).

Pregnancy

Pregnancy

There is no experience of using the drug in humans during pregnancy and breastfeeding. Animal studies have not revealed a teratogenic effect of donepezil, however, peri- and postnatal toxicity has been established. The potential risk to humans is unknown.

Therefore, the drug should not be used during pregnancy, unless treatment is absolutely necessary.

Breastfeeding period

In rats, donepezil is excreted in milk. It is unknown whether the drug is excreted in human breast milk and no such studies have been conducted. If it is necessary to take the drug during lactation, it is necessary to decide on stopping breastfeeding.

Contraindications

– Individual hypersensitivity to any component of the drug or piperidine derivatives;

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

– Children under 18 years of age (safety and effectiveness of use have not been studied).

With caution

Use with caution in patients with a history of obstructive pulmonary diseases (including bronchial asthma), with cardiac arrhythmias (possible vagotonic effect on heart rate, in particular bradycardia), with an increased risk of developing ulcers (history of peptic ulcer or concomitant therapy with non-steroidal anti-inflammatory drugs), during general anesthesia, when taken simultaneously with anticholinergics or other inhibitors cholinesterase, in patients with a history of seizures and convulsions, hepatitis or other liver diseases, difficulty passing urine, or moderate kidney disease.

Side Effects

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

Side effects are listed below in descending order of frequency of occurrence according to the organ classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000) or observed with an unknown frequency (frequency cannot be estimated from available data).

Infections and parasitic diseases: often: runny nose.

Metabolic and nutritional disorders: often: anorexia.

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

Nervous system disorders: often: fainting*, dizziness, insomnia; uncommon: seizures*; rarely: extrapyramidal disorders; very rare: neuroleptic malignant syndrome.

Cardiac disorders: uncommon: bradycardia; rarely: sinoatrial and atrioventricular block.

Gastrointestinal disorders: very common: diarrhea, nausea; often: vomiting, dyspepsia; uncommon: gastrointestinal bleeding, gastric and duodenal ulcers.

Disorders of the liver and biliary tract: rarely: impaired liver function, including hepatitis***.

Skin and subcutaneous tissue disorders: often: rash, itching.

Musculoskeletal and connective tissue disorders: common: muscle spasms; very rare: rhabdomyolysis****.

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

General disorders and disorders at the injection site: very often: headache; often: fatigue, pain of various localizations.

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

Injuries, intoxications and complications of manipulations: often: accident.

Interaction

When prescribing donepezil, the risk of hitherto unknown interactions with other agents must be taken into account.

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

In vitro studies have shown that cytochrome P450 isoenzymes 3A4 and, to a small extent, 2D6 are involved in the metabolism of donepezil. In vitro studies of the drug show that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6, respectively, suppress the metabolism of donepezil. Therefore, these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine, may inhibit the metabolism of donepezil. In studies in healthy volunteers, ketoconazole increased donepezil concentrations by approximately 30%. Enzyme inducers such as rifampicin, phenytoin, carbamazepine and ethanol may reduce the concentration of donepezil in the blood. Since the magnitude of the inhibitory or inducing effect is unknown, such drug combinations should be used with extreme caution.

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

Overdose

An overdose of donepezil can lead to a cholinergic crisis.

Symptoms: cholinergic crisis (severe nausea, vomiting, profuse salivation, sweating, bradycardia, decreased blood pressure, respiratory depression, loss of consciousness, convulsions). Increasing myasthenia gravis is possible, which can be fatal if the respiratory muscles are damaged.

Treatment: in cases of suspected overdose, symptomatic therapy is indicated. Tertiary anticholinergics can be used as an antidote, 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 donepezil and/or its metabolites are removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration).

Storage conditions

At a temperature not exceeding 25 °C.
Keep out of the reach of children.

Shelf life

3 years.
The drug should not be used after the expiration date indicated on the package.

Manufacturer

Elpen Pharmaceutical Co. Inc., Greece