Servonex®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SERVONEX® (SERVONEX®)

Composition:

Active substance: donepezil;

1 tablet contains 5 mg or 10 mg of donepezil hydrochloride;

Excipients: lactose monohydrate, microcrystalline cellulose, copovidone K 28, pregelatinized starch, magnesium stearate, Opadry II White 31G58920 (talc, titanium dioxide (E 171), hypromellose, polyethylene glycol, lactose monohydrate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex film-coated tablets, smooth on both sides.

Pharmacotherapeutic group.

Agents used in dementia. Cholinesterase inhibitors. ATC code N06DA02.

Pharmacological properties.

Pharmacodynamics.

Donepezil hydrochloride is a specific, reversible inhibitor of acetylcholinesterase, the predominant type of cholinesterase in the brain. In vitro studies have shown that the ability of donepezil hydrochloride to inhibit this enzyme's activity is 1000 times greater than its ability to inhibit butyrylcholinesterase, which is primarily found outside the central nervous system.

Alzheimer's disease dementia

In patients with Alzheimer's disease, administration of donepezil at doses of 5 mg or 10 mg once daily at steady-state conditions resulted in inhibition of acetylcholinesterase activity (measured in erythrocyte membrane) by 63.6% and 77.3%, respectively. Inhibition of erythrocyte acetylcholinesterase by donepezil hydrochloride has been shown to correlate with changes in scores on the ADAS-cog scale (Alzheimer's Disease Assessment Scale–cognitive subscale), a sensitive instrument designed to assess certain aspects of cognitive function. The ability of donepezil hydrochloride to modify the progression of underlying neuropathological disorders has not been studied. Therefore, the effect of donepezil on the progression of this disease cannot be evaluated.

The efficacy of donepezil in the treatment of dementia has been demonstrated in four placebo-controlled trials lasting 6 months and 1 year. Donepezil was shown to produce a dose-dependent, statistically significant increase in the proportion of patients who responded to treatment, as assessed by validated scales measuring cognitive function (ADAS-cog scale), clinical global impression (CIBIC+ scale for overall function), and daily activities in the presence of clinical signs of dementia.

Pharmacokinetics.

Absorption

Following oral administration, peak plasma concentration (Cmax) is reached within approximately 3–4 hours. Plasma concentration and area under the concentration-time curve (AUC) increase proportionally with dose. The terminal elimination half-life is approximately 70 hours; therefore, repeated once-daily dosing leads to gradual attainment of steady-state concentration. Steady-state concentration is reached within approximately 3 weeks after initiation of treatment. After steady state is achieved, the concentration of donepezil hydrochloride and the associated pharmacodynamic activity remain nearly constant throughout the day.

Food does not affect the absorption of donepezil hydrochloride.

Distribution

Approximately 95% of donepezil hydrochloride is plasma protein-bound. The extent of plasma protein binding for the active metabolite, 6-O-desmethyldonepezil, is unknown. Distribution of donepezil hydrochloride into various body tissues has not been thoroughly studied. However, in a mass balance study conducted in healthy male volunteers, approximately 28% of the administered radioactivity remained unrecovered 240 hours after a single 5 mg dose of 14C-labeled donepezil hydrochloride. This suggests that donepezil hydrochloride and/or its metabolites may remain in the body for more than 10 days.

Metabolism/Excretion

Donepezil hydrochloride may be excreted unchanged in urine or undergo hepatic metabolism via cytochrome P450 isoenzymes, resulting in multiple metabolites, not all of which have been identified. After a single 5 mg dose of 14C-labeled donepezil hydrochloride, plasma radioactivity expressed as a percentage of the administered dose was primarily due to unchanged donepezil hydrochloride (30%), 6-O-desmethyldonepezil (11%, the only metabolite with activity similar to that of donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyldonepezil (7%), and the glucuronide conjugate of 5-O-desmethyl-donepezil (3%). Approximately 57% of the total administered radioactivity was recovered in urine (17% as unchanged donepezil) and 14.5% in feces, indicating that the main routes of elimination are biotransformation and renal excretion. There was no evidence of enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.

The decline in donepezil plasma concentration occurs with a half-life of approximately 70 hours.

Gender, race, and smoking history have no clinically significant effect on donepezil hydrochloride plasma concentrations. The pharmacokinetics of donepezil have not been formally studied in healthy elderly volunteers or in patients with Alzheimer's disease or vascular dementia. However, the mean plasma concentrations in elderly patients were consistent with those observed in young healthy volunteers.

In patients with mild to moderate hepatic impairment, steady-state donepezil concentrations are increased, with AUC increased by 48% and mean Cmax increased by 39% (see section "Dosage and administration").

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate Alzheimer-type dementia.

Contraindications.

Contraindicated in patients with known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or any of the excipients of the drug.

Interaction with other medicinal products and other forms of interactions.

Donepezil hydrochloride and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin in humans. Concomitant administration of digoxin or cimetidine does not affect the metabolism of donepezil hydrochloride. In vitro studies have shown that cytochrome P450 isoenzymes, particularly CYP3A4 and to a lesser extent CYP2D6, are actively involved in the metabolism of donepezil. In vitro drug interaction studies have demonstrated that ketoconazole and quinidine, which are inhibitors of CYP3A4 and CYP2D6 isoenzymes, respectively, inhibit the metabolism of donepezil. Therefore, these and other inhibitors of the CYP3A4 isoenzyme, such as itraconazole and erythromycin, as well as inhibitors of the CYP2D6 isoenzyme, such as fluoxetine, may inhibit the metabolism of donepezil. In a study involving healthy volunteers, ketoconazole increased the mean plasma concentration of donepezil by approximately 30%.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine, and alcohol, may reduce the plasma concentration of donepezil. The extent of inducing or inhibiting effects remains unknown; therefore, caution should be exercised when using such drug combinations.

Donepezil hydrochloride may affect drugs with anticholinergic activity. In addition, synergistic effects may occur when co-administered with drugs such as succinylcholine, other neuromuscular blockers, cholinergic agonists, or beta-blockers that affect cardiac conduction.

Cases of atypical changes in blood pressure and heart rate have been reported with concomitant use of donepezil and other cholinomimetics or quaternary anticholinergic agents such as glycopyrronium.

Cases of QTc interval prolongation and torsade de pointes have been reported with the use of donepezil. Caution is recommended when using donepezil concomitantly with other medicinal products that prolong the QTc interval—clinical monitoring (ECG) may be required. Examples of such medicinal products include:

• Class IA antiarrhythmics (e.g., quinidine);
• Class III antiarrhythmics (e.g., amiodarone, sotalol);
• Certain antidepressants (e.g., citalopram, escitalopram, amitriptyline);
• Other antipsychotics (e.g., phenothiazine derivatives, sertindole, pimozide, ziprasidone);
• Certain antibiotics (e.g., clarithromycin, erythromycin, levofloxacin, moxifloxacin).

Special precautions for use.

The use of donepezil in dementia due to Alzheimer's disease in its severe form, in other types of dementia, or in other types of memory impairment (e.g., in age-related cognitive decline) has not been studied.

Anesthesia

Donepezil, as a cholinesterase inhibitor, may potentiate succinylcholine-type muscle relaxation during anesthesia.

Cardiovascular disorders

Cholinesterase inhibitors, due to their pharmacological action, may exert a vagotonic effect on heart rate (e.g., cause bradycardia). This effect may be particularly important in patients with sick sinus syndrome or other supraventricular conduction disorders, such as sinoatrial or atrioventricular block.

Cases of syncope and seizures have been reported. Evaluation of such patients should consider the possibility of conduction block or prolonged sinus node pauses.

In the post-marketing period, QTc interval prolongation and torsade de pointes have been reported (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Caution is recommended in patients with personal or family history of QTc interval prolongation, in patients taking medicinal products affecting the QTc interval, in patients with cardiac conditions (e.g., uncompensated heart failure, recent myocardial infarction, bradyarrhythmia), or with electrolyte disturbances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be required.

Gastrointestinal disorders

Patients at increased risk of ulceration (e.g., those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs [NSAIDs]) should be closely monitored for symptoms. However, in clinical trials with donepezil, no increased incidence of peptic ulcer disease or gastrointestinal bleeding was observed compared to placebo.

Urinary system

Cholinomimetics may cause obstruction of the lower urinary tract, although such events were not observed in clinical trials with donepezil.

Neurological disorders

Seizures. Cholinomimetics are considered to have some potential to cause generalized seizures. However, such seizures may also be manifestations of Alzheimer's disease itself.

Cholinomimetics may exacerbate or induce extrapyramidal symptoms.

Malignant neuroleptic syndrome (MNS)

MNS – a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic dysfunction, altered consciousness, and elevated serum creatine phosphokinase levels – has been reported very rarely in association with donepezil use, particularly in patients concurrently receiving neuroleptics. Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms suggestive of MNS or presents with unexplained high fever without additional clinical features of MNS, treatment should be discontinued.

Pulmonary diseases

Due to their cholinomimetic effect, cholinesterase inhibitors should be administered with caution in patients with bronchial asthma or a history of obstructive lung disease.

Donepezil is not recommended to be taken concomitantly with other acetylcholinesterase inhibitors, or cholinergic agonists or antagonists.

Severe hepatic impairment:

Data in patients with severe hepatic impairment are lacking.

Mortality in clinical trials in vascular dementia

In clinical trials of donepezil hydrochloride in patients with vascular dementia, the mortality rate was numerically higher in the donepezil group than in the placebo group, although this difference was not statistically significant. Most deaths in patients receiving either donepezil hydrochloride or placebo were due to various vascular events expected in elderly individuals with existing vascular disease. When analyzing all serious non-fatal and fatal vascular events, no difference in event rates was observed between the donepezil hydrochloride and placebo groups.

Mortality in Alzheimer's disease trials

In Alzheimer's disease trials, as well as in pooled analyses combining these Alzheimer's disease trials with other dementia trials, including those in vascular dementia, the mortality rate in the placebo groups was numerically higher than in the donepezil hydrochloride groups.

Excipients

The medicine contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is recommended before taking this medicine.

Use during pregnancy or breastfeeding

Pregnancy

There are no reliable data on the use of donepezil in pregnant women.

In animal studies, no teratogenic effects were observed, but signs of toxicity during the perinatal and postnatal periods were noted. The potential risk for humans remains unknown.

Donepezil is not recommended during pregnancy except in cases of extreme necessity.

Breastfeeding period

Donepezil penetrates into the milk of rats. Studies in women during breastfeeding have not been conducted; therefore, it is unknown whether donepezil hydrochloride passes into human breast milk. Therefore, women should discontinue breastfeeding during treatment with donepezil.

Ability to influence reaction speed when driving or operating machinery

Donepezil has a negligible or moderate influence on the ability to drive a car or operate machinery.

Alzheimer's-type dementia may impair the ability to drive a car or operate machinery. In addition, donepezil may cause fatigue, dizziness, and muscle cramps, especially at the beginning of treatment or when the dose is increased. During treatment with donepezil, physicians should regularly assess patients' ability to drive a car or operate complex mechanical devices.

Method of administration and dosing.

Adults

Treatment should be initiated at a dose of 5 mg once daily. SERVONEX® should be taken orally in the evening, immediately before bedtime. In case of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Adverse reactions"), administration of SERVONEX in the morning may be considered.

The 5 mg daily dose should be maintained for at least 1 month to allow assessment of the initial clinical response to treatment and to achieve steady-state plasma concentrations of donepezil. After clinical evaluation of treatment with 5 mg daily for 1 month, the dose may be increased to 10 mg once daily. The maximum recommended daily dose is 10 mg. Doses exceeding 10 mg daily have not been studied.

Treatment should be initiated and supervised by a physician specialized in the diagnosis and treatment of Alzheimer's disease dementia. Diagnosis should be established according to standard guidelines (e.g., DSM-IV, ICD-10). Treatment with donepezil may only be initiated if the patient has a caregiver who will regularly monitor the patient's intake of the medication. Maintenance treatment may be continued as long as a therapeutic benefit is observed. Therefore, the clinical benefits of donepezil treatment should be regularly re-evaluated. Treatment should be discontinued when therapeutic benefit is no longer observed. Individual response to donepezil cannot be predicted.

After discontinuation of treatment, the beneficial effect of donepezil gradually diminishes.

Renal and hepatic impairment

The same dosing regimen may be used in patients with renal impairment, as such impairment does not affect the clearance of donepezil hydrochloride.

Due to the potential for increased systemic exposure in patients with mild to moderate hepatic impairment (see section "Pharmacokinetics"), dose escalation should be based on individual tolerability. Data are not available for patients with severe hepatic impairment.

Children

SERVONEX® is not recommended for use in children under 18 years of age.

Overdose

Overdose with cholinesterase inhibitors may lead to a cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and seizures. Muscle weakness may occur, which could be fatal if respiratory muscles are affected.

As with overdose of any other drug, general supportive measures should be taken. In case of donepezil overdose, tertiary anticholinergic agents such as atropine may be used as antidotes. Intravenous administration of atropine sulfate is recommended, with the dose gradually increased until therapeutic effect is achieved: the initial dose is 1–2 mg intravenously, and subsequent doses should be adjusted based on clinical response. Atypical responses in blood pressure and heart rate have been reported when other cholinomimetics were administered together with quaternary anticholinergic agents such as glycopyrrolate. The ability to remove donepezil hydrochloride and/or its metabolites by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) is unknown.

Adverse Reactions

The most commonly observed adverse effects are diarrhea, muscle spasms, increased fatigue, nausea, vomiting, and insomnia.

Hypersensitivity reactions may occur in individuals with known hypersensitivity to any component of the medicinal product.

The adverse reactions listed below are categorized by organ system and frequency of occurrence. Frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations

Common: cold.

Metabolism and nutrition disorders

Common: anorexia.

Psychiatric disorders

Common: hallucinations**, agitation**, aggressive behavior**, sleep disturbances**, nightmares**;

Frequency not known: increased libido, hypersexuality.

Nervous system disorders

Common: syncope*, dizziness, insomnia;

Uncommon: seizures*;

Rare: extrapyramidal symptoms;

Very rare: neuroleptic malignant syndrome;

Frequency not known: pleurothotonus (Pisa syndrome).

Cardiac disorders

Uncommon: bradycardia;

Rare: sinoatrial block, atrioventricular block;

Frequency not known: polymorphic ventricular tachycardia, including torsade de pointes; QT interval prolongation on ECG.

Gastrointestinal disorders

Very common: nausea, diarrhea;

Common: vomiting, dyspepsia;

Uncommon: gastrointestinal hemorrhage, gastric and duodenal ulcers, hypersalivation.

Hepatobiliary disorders

Rare: hepatic dysfunction, including hepatitis***.

Skin and subcutaneous tissue disorders

Common: rash, pruritus.

Musculoskeletal and connective tissue disorders

Common: muscle cramps;

Very rare: rhabdomyolysis****.

Renal and urinary disorders

Common: urinary incontinence.

General disorders and administration site conditions

Very common: headache;

Common: increased fatigue, pain.

Investigations

Uncommon: slight increase in serum concentration of creatine phosphokinase.

Injury, poisoning and procedural complications

Common: accidents, including falls.

*In patients presenting with syncope or seizures, cardiac block or prolonged sinus pauses should be considered (see section "Dosage and Administration").

**Reports of hallucinations, agitation, and aggressive behavior, which resolved after dose reduction or discontinuation of the drug.

***In cases of unexplained hepatic dysfunction, discontinuation of donepezil therapy should be considered.

****Cases of rhabdomyolysis have been reported independently of neuroleptic malignant syndrome and in close temporal association with the initiation of donepezil treatment and dose escalation.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

14 tablets in a blister pack. 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's address and location of operations.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriia St., 54.

INSTRUCTION

for medical use of the medicinal product

SERNEX®

(SERVONEX®)

Composition:

Active ingredient: donepezil;

1 tablet contains 5 mg or 10 mg of donepezil hydrochloride;

Excipients: lactose monohydrate, microcrystalline cellulose, copovidone K 28, pregelatinized starch, magnesium stearate, Opadry II White 31G58920 (talc, titanium dioxide (E 171), hypromellose, polyethylene glycol, lactose monohydrate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex, film-coated tablets, smooth on both sides.

Pharmacotherapeutic group.

Drugs used in dementia. Cholinesterase inhibitors. ATC code N06D A02.

Pharmacological properties.

Pharmacodynamics.

Donepezil hydrochloride is a specific, reversible inhibitor of acetylcholinesterase, the predominant type of cholinesterase in the brain. In vitro studies have shown that the ability of donepezil hydrochloride to inhibit this enzyme's activity exceeds by 1000-fold its ability to inhibit butyrylcholinesterase, which is primarily found outside the central nervous system.

Alzheimer's disease dementia

In patients with Alzheimer's disease, administration of donepezil at doses of 5 mg or 10 mg once daily, after reaching steady-state concentration, resulted in inhibition of erythrocyte membrane acetylcholinesterase activity by 63.6% and 77.3%, respectively. Inhibition of erythrocyte acetylcholinesterase by donepezil hydrochloride has been shown to correlate with changes in scores on the ADAS-cog scale (Alzheimer's Disease Assessment Scale–cognitive subscale), a sensitive instrument designed to assess certain aspects of cognitive function. The ability of donepezil hydrochloride to modify the progression of underlying neuropathological processes has not been studied. Therefore, the effect of donepezil on the progression of the disease cannot be assessed.

The efficacy of donepezil in the treatment of dementia has been demonstrated in four placebo-controlled trials lasting 6 months and 1 year. Donepezil was shown to produce a dose-dependent, statistically significant increase in the proportion of patients who responded to treatment, as measured by validated assessment scales for cognitive function (ADAS-cog scale), clinical global impression (CIBIC+ scale for overall function), and activities of daily living in the presence of clinical signs of dementia.

Pharmacokinetics.

Absorption

After oral administration, maximum plasma concentration (Cmax) is reached approximately within 3–4 hours. Plasma concentration and area under the concentration-time curve (AUC) increase proportionally with dose. The terminal elimination half-life is approximately 70 hours; therefore, once-daily dosing leads to gradual attainment of steady-state concentration. Steady-state concentration is reached within approximately 3 weeks after initiation of treatment. After steady-state is achieved, plasma concentrations of donepezil hydrochloride and the associated pharmacodynamic activity remain nearly constant throughout the day.

Food does not affect the absorption of donepezil hydrochloride.

Distribution

Approximately 95% of donepezil hydrochloride is bound to plasma proteins. The extent of plasma protein binding of the active metabolite 6-O-desmethyl donepezil is unknown. Tissue distribution of donepezil hydrochloride has not been fully characterized. However, in a mass balance study conducted in healthy male volunteers, approximately 28% of the administered radioactivity remained unrecovered 240 hours after a single 5 mg dose of 14C-labeled donepezil hydrochloride. This suggests that donepezil hydrochloride and/or its metabolites may remain in the body for more than 10 days.

Metabolism/Excretion

Donepezil hydrochloride may be excreted unchanged in urine or undergo hepatic metabolism via cytochrome P450 isoenzymes, resulting in multiple metabolites, not all of which have been fully identified. After a single 5 mg dose of 14C-labeled donepezil hydrochloride, plasma radioactivity expressed as a percentage of the administered dose was primarily attributable to unchanged donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11%, the only metabolite with activity comparable to that of donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%), and the glucuronide conjugate of 5-O-desmethyl donepezil (3%). Approximately 57% of the total administered radioactivity was recovered in urine (17% as unchanged donepezil) and 14.5% in feces, indicating that the primary routes of elimination are biotransformation and renal excretion. There was no evidence of enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.

Decrease in donepezil plasma concentration occurs with an elimination half-life of approximately 70 hours.

Sex, race, and smoking history had no clinically significant effect on donepezil hydrochloride plasma concentrations. The pharmacokinetics of donepezil have not been formally studied in healthy elderly volunteers or in patients with Alzheimer's disease or vascular dementia. However, mean plasma concentrations in patients were consistent with those observed in young healthy volunteers.

In patients with mild to moderate hepatic impairment, steady-state concentrations of donepezil were increased, with AUC increased by 48% and mean Cmax increased by 39% (see section "Dosage and administration").

Clinical characteristics.

Indications.

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

Contraindications.

Contraindicated in patients with known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or any of the excipients of the drug.

Interaction with other medicinal products and other forms of interaction.

Donepezil hydrochloride and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin in humans. Concomitant administration of digoxin or cimetidine does not affect the metabolism of donepezil hydrochloride. In vitro studies have shown that cytochrome P450 isoenzymes, particularly isoenzyme 3A4 and to a lesser extent isoenzyme 2D6, are actively involved in the metabolism of donepezil. In vitro drug interaction studies have demonstrated that ketoconazole and quinidine, which are inhibitors of CYP3A4 and CYP2D6 isoenzymes respectively, inhibit the metabolism of donepezil. Therefore, these and other inhibitors of CYP3A4 isoenzyme, such as itraconazole and erythromycin, as well as inhibitors of CYP2D6 isoenzyme, such as fluoxetine, may inhibit the metabolism of donepezil. In a study involving healthy volunteers, ketoconazole increased the mean plasma concentration of donepezil by approximately 30%.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine, and alcohol, may reduce the plasma concentration of donepezil. The extent of inducing or inhibiting effects remains unknown; therefore, caution should be exercised when using such drug combinations.

Donepezil hydrochloride may affect drugs with anticholinergic activity. In addition, synergistic effects may occur when co-administered with drugs such as succinylcholine, other neuromuscular blockers, cholinergic agonists, or beta-blockers that affect cardiac conduction.

Cases of atypical changes in blood pressure and heart rate have been reported with concomitant use of donepezil and other cholinomimetics or quaternary anticholinergic agents such as glycopyrrolate.

Cases of QTc interval prolongation and torsade de pointes have been reported with the use of donepezil. Caution is recommended when using donepezil concomitantly with other medicinal products that prolong the QTc interval—clinical monitoring (ECG) may be required. Examples of such medicinal products include:

• Class IA antiarrhythmics (e.g., quinidine);
• Class III antiarrhythmics (e.g., amiodarone, sotalol);
• Certain antidepressants (e.g., citalopram, escitalopram, amitriptyline);
• Other antipsychotics (e.g., phenothiazine derivatives, sertindole, pimozide, ziprasidone);
• Certain antibiotics (e.g., clarithromycin, erythromycin, levofloxacin, moxifloxacin).

Special precautions for use.

The use of donepezil in dementia due to severe Alzheimer's disease, in other types of dementia, or in other forms of memory impairment (e.g., in age-associated cognitive decline) has not been studied.

Anesthesia

Donepezil, as a cholinesterase inhibitor, may potentiate succinylcholine-type muscle relaxation during anesthesia.

Cardiovascular disorders

Cholinesterase inhibitors, due to their pharmacological action, may exert a vagotonic effect on heart rate (e.g., cause bradycardia). This effect may be particularly important in patients with sick sinus syndrome or other supraventricular conduction disorders, such as sinoatrial or atrioventricular block.

Cases of syncope and seizures have been reported. When evaluating such patients, the possibility of conduction block or prolonged sinus node pauses should be considered.

In the post-marketing period, QTc interval prolongation and torsade de pointes have been reported (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Caution is recommended in patients with personal or family history of QTc interval prolongation, in patients taking medicinal products known to affect the QTc interval, in patients with cardiac conditions (e.g., uncompensated heart failure, recent myocardial infarction, bradyarrhythmia), or with electrolyte disturbances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be required.

Gastrointestinal disorders

Patients at increased risk of developing ulcers, such as those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs (NSAIDs), should be closely monitored for symptoms. However, in clinical trials with donepezil, no increased frequency of peptic ulcer disease or gastrointestinal bleeding was observed compared to placebo.

Urinary system

Cholinomimetics may cause obstruction of the lower urinary tract, although such disorders were not observed in clinical studies with donepezil.

Neurological disorders

Seizures. Cholinomimetics are considered to have some potential to cause generalized seizures. However, such seizures may also be manifestations of Alzheimer's disease itself.

Cholinomimetics may exacerbate or induce extrapyramidal symptoms.

Malignant neuroleptic syndrome (MNS)

MNS – a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels – has been reported very rarely in association with donepezil use, particularly in patients concurrently receiving neuroleptics. Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms suggestive of MNS or presents with unexplained high fever without additional clinical features of MNS, treatment should be discontinued.

Lung diseases

Cholinesterase inhibitors, due to their cholinomimetic effect, should be prescribed with caution in patients with a history of bronchial asthma or obstructive lung disease.

Donepezil is not recommended to be taken concomitantly with other acetylcholinesterase inhibitors, or cholinergic agonists or antagonists.

Severe hepatic impairment:

Data in patients with severe hepatic impairment are lacking.

Mortality in clinical trials with vascular dementia

In studies using donepezil hydrochloride in patients with vascular dementia, the mortality rate was numerically higher than in the placebo group, although this difference was not statistically significant. Most deaths in patients receiving either donepezil hydrochloride or placebo were due to various vascular events expected in elderly individuals with existing vascular disease. When analyzing all serious non-fatal and fatal vascular events, no difference in event frequency was observed between the donepezil hydrochloride and placebo groups.

Mortality in Alzheimer's disease trials

In Alzheimer's disease trials, as well as in combined analyses of these Alzheimer's trials with other dementia trials, including those in vascular dementia, the mortality rate in the placebo groups was numerically higher than in the donepezil hydrochloride groups.

Excipients.

The medicine contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is recommended before taking this medicine.

Use during pregnancy or breastfeeding.

Pregnancy

There are no reliable data on the use of donepezil in pregnant women.

Animal studies did not show teratogenic effects, but signs of toxicity were observed during the peri- and postnatal periods. The potential risk to humans remains unknown.

Donepezil is not recommended during pregnancy except in cases of extreme necessity.

Period of breastfeeding

Donepezil penetrates into the milk of rats. Studies in breastfeeding women have not been conducted; therefore, it remains unknown whether donepezil hydrochloride passes into human breast milk. Thus, women should discontinue breastfeeding during treatment with donepezil.

Ability to influence the speed of reactions while driving or operating machinery.

Donepezil has a minor or moderate effect on the ability to drive a car or operate machinery.

Alzheimer-type dementia itself may impair the ability to drive a car or operate machinery. In addition, donepezil may cause fatigue, dizziness, and muscle cramps, particularly at the beginning of treatment or when the dose is increased. During treatment with donepezil, physicians should regularly assess patients' ability to drive a car or operate complex mechanical devices.

Method of Administration and Dosage

Adults

Treatment should be initiated at a dose of 5 mg once daily. SERVONEX® should be taken orally in the evening, immediately before bedtime. In case of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Adverse Reactions"), administration in the morning may be considered.

The 5 mg daily dose should be maintained for at least 1 month to allow assessment of the initial clinical response to treatment and to achieve steady-state plasma concentrations of donepezil. After clinical evaluation following 1 month of treatment with 5 mg daily, the dose may be increased to 10 mg once daily. The maximum recommended daily dose is 10 mg. Doses exceeding 10 mg daily have not been studied.

Treatment should be initiated and supervised by a physician specialized in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be established according to generally accepted guidelines (e.g., DSM-IV, ICD-10). Treatment with donepezil may only be initiated if the patient has a caregiver who will regularly monitor the patient's intake of the medication. Maintenance treatment may be continued as long as a therapeutic benefit is observed. Therefore, the clinical benefits of donepezil treatment should be regularly reassessed. Treatment should be discontinued when no further therapeutic effect is observed. Individual response to donepezil cannot be predicted.

After discontinuation of treatment, the beneficial effects of donepezil gradually diminish.

Renal and Hepatic Impairment

The same dosing regimen may be used for patients with renal impairment, as renal dysfunction does not affect the clearance of donepezil hydrochloride.

Due to the potential for increased systemic exposure in patients with mild or moderate hepatic impairment (see section "Pharmacokinetics"), dose escalation should be based on individual tolerability. Data in patients with severe hepatic impairment are not available.

Children

SERVONEX® is not recommended for use in children under 18 years of age.

Overdose

Overdose with cholinesterase inhibitors may lead to a cholinergic crisis, characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and seizures. Muscle weakness may occur, which could be fatal if respiratory muscles are affected.

As with overdose of any other drug, general supportive measures should be implemented. Atropine sulfate may be used as an antidote in cases of donepezil overdose. Intravenous administration of atropine sulfate is recommended, with the dose titrated to achieve therapeutic effect: the initial dose is 1–2 mg intravenously, and subsequent doses adjusted according to clinical response. Atypical responses in blood pressure and heart rate have been reported when other cholinomimetics were administered concomitantly with quaternary anticholinergic agents such as glycopyrrolate. The ability to remove donepezil hydrochloride and/or its metabolites by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) is unknown.

Side effects

The most commonly observed adverse effects are diarrhea, muscle spasms, increased fatigue, nausea, vomiting, and insomnia.

The adverse reactions listed below are categorized by organ systems and frequency of occurrence. The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated based on available data).

Infections and infestations

Common: colds.

Metabolism and nutrition disorders

Common: anorexia.

Psychiatric disorders

Common: hallucinations**, agitation**, aggressive behavior**, sleep disturbances**, nightmares**;

Frequency not known: increased libido, hypersexuality.

Nervous system disorders

Common: syncope*, dizziness, insomnia;

Uncommon: seizures*;

Rare: extrapyramidal symptoms;

Very rare: neuroleptic malignant syndrome;

Frequency not known: pleurothotonus (Pisa syndrome).

Cardiac disorders

Uncommon: bradycardia;

Rare: sinoatrial block, atrioventricular block;

Frequency not known: polymorphic ventricular tachycardia, including torsade de pointes; QT interval prolongation on ECG.

Gastrointestinal disorders

Very common: nausea, diarrhea;

Common: vomiting, dyspepsia;

Uncommon: gastrointestinal hemorrhage, gastric and duodenal ulcers, hypersalivation.

Hepatobiliary disorders

Rare: hepatic dysfunction, including hepatitis***.

Skin and subcutaneous tissue disorders

Common: rash, pruritus.

Musculoskeletal and connective tissue disorders

Common: muscle cramps;

Very rare: rhabdomyolysis****.

Renal and urinary disorders

Common: urinary incontinence.

General disorders and administration site conditions

Very common: headache;

Common: increased fatigue, pain.

Investigations

Uncommon: slight increase in serum creatine phosphokinase concentration.

Injury, poisoning and procedural complications

Common: accidents, including falls.

*Patients experiencing syncope or seizures should be evaluated for possible cardiac conduction block or prolonged sinus pauses (see section "Special precautions").

**Reports of hallucinations, agitation, and aggressive behavior that resolved after dose reduction or discontinuation of the drug.

***In cases of hepatic dysfunction not explained by obvious causes, discontinuation of donepezil therapy should be considered.

****Cases of rhabdomyolysis have been reported independently of neuroleptic malignant syndrome and in close temporal association with the initiation of donepezil therapy and dose increases.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug approval is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

14 tablets in a blister pack. 2 blisters per cardboard box.

10 tablets in a blister pack. 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTION

for medical use of the medicinal product

SERVONEX®

(SERVONEX®)

Composition:

Active substance: donepezil;

1 tablet contains 5 mg or 10 mg of donepezil hydrochloride;

Excipients: lactose monohydrate, microcrystalline cellulose, copovidone K 28, pregelatinized starch, magnesium stearate, Opadry II White 31G58920 (talc, titanium dioxide (E 171), hypromellose, polyethylene glycol, lactose monohydrate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex, film-coated tablets, smooth on both sides.

Pharmacotherapeutic group.

Drugs used in dementia. Cholinesterase inhibitors. ATC code N06D A02.

Pharmacological properties.

Pharmacodynamics.

Donepezil hydrochloride is a specific, reversible inhibitor of acetylcholinesterase, the predominant type of cholinesterase in the brain. In vitro studies have shown that the ability of donepezil hydrochloride to inhibit this enzyme's activity is 1000 times greater than its ability to inhibit butyrylcholinesterase activity, which is primarily located outside the central nervous system.

Alzheimer's disease dementia

In patients with Alzheimer's disease, administration of donepezil at a dose of 5 mg or 10 mg once daily, after reaching steady-state concentration, resulted in inhibition of erythrocyte membrane acetylcholinesterase activity by 63.6% and 77.3%, respectively. Inhibition of erythrocyte acetylcholinesterase by donepezil hydrochloride has been shown to correlate with changes in scores on the ADAS-cog scale (Alzheimer's Disease Assessment Scale–cognitive subscale), a sensitive scale capable of detecting certain aspects of cognitive function. The ability of donepezil hydrochloride to modify the progression of the underlying neuropathological process has not been studied. Therefore, the effect of donepezil on the progression of the disease cannot be assessed.

The efficacy of donepezil in the treatment of dementia has been demonstrated in four placebo-controlled trials of 6 months and 1 year duration. Donepezil was shown to produce a dose-dependent, statistically significant increase in the proportion of patients who responded to treatment, as assessed by validated cognitive function rating scales (ADAS-cog scale), patient condition (CIBIC+ scale for global function), and daily activities in the presence of clinical signs of dementia.

Pharmacokinetics.

Absorption

Following oral administration, peak plasma concentration (Cmax) is reached approximately within 3–4 hours. Plasma concentration and area under the concentration-time curve (AUC) increase proportionally with dose. The terminal elimination half-life is approximately 70 hours; therefore, repeated once-daily dosing leads to gradual attainment of steady-state concentration. Steady-state concentration is reached within approximately 3 weeks after initiation of treatment. After steady state is achieved, the concentration of donepezil hydrochloride and the associated pharmacodynamic activity remain virtually unchanged throughout the day.

Food does not affect the absorption of donepezil hydrochloride.

Distribution

Approximately 95% of donepezil hydrochloride is bound to plasma proteins. The extent of plasma protein binding of the active metabolite, 6-O-desmethyl donepezil, is unknown. The distribution of donepezil hydrochloride in various body tissues has not been fully studied. However, in a mass balance study conducted in healthy male volunteers, approximately 28% of the administered radioactivity remained unrecovered 240 hours after a single 5 mg dose of 14C-labeled donepezil hydrochloride. This suggests that donepezil hydrochloride and/or its metabolites may remain in the body for more than 10 days.

Metabolism/Excretion

Donepezil hydrochloride may be excreted unchanged in urine or undergo hepatic metabolism via cytochrome P450 isoenzymes, forming several metabolites, not all of which have been identified. After a single 5 mg dose of 14C-labeled donepezil hydrochloride, radioactivity in plasma, expressed as a percentage of the administered dose, was primarily due to unchanged donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11%, the only metabolite exhibiting activity similar to that of donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%), and the glucuronide conjugate of 5-O-desmethyl donepezil (3%). Approximately 57% of the total administered radioactivity was recovered in urine (17% as unchanged donepezil) and 14.5% in feces, indicating that biotransformation and renal excretion are the main elimination pathways. There was no evidence of enterohepatic recirculation of donepezil hydrochloride and/or its metabolites.

The decline in donepezil plasma concentration occurs with a half-life of approximately 70 hours.

Gender, race, and smoking history had no clinically significant effect on donepezil hydrochloride plasma concentrations. The pharmacokinetics of donepezil have not been formally studied in healthy elderly volunteers or in patients with Alzheimer's disease or vascular dementia. However, the average plasma concentration in patients was consistent with that observed in young healthy volunteers.

In patients with mild to moderate hepatic impairment, steady-state concentrations of donepezil were increased, with AUC increased by 48% and mean Cmax increased by 39% (see section "Dosage and administration").

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate Alzheimer-type dementia.

Contraindications.

Contraindicated in patients with known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Donepezil hydrochloride and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin in humans. Concomitant administration of digoxin or cimetidine does not affect the metabolism of donepezil hydrochloride. *In vitro* studies have shown that cytochrome P450 isoenzymes, particularly isoenzyme 3A4 and to a lesser extent isoenzyme 2D6, are actively involved in the metabolism of donepezil. *In vitro* drug interaction studies have demonstrated that ketoconazole and quinidine, which are inhibitors of CYP3A4 and CYP2D6 isoenzymes respectively, inhibit the metabolism of donepezil. Therefore, these and other inhibitors of CYP3A4 isoenzyme, such as itraconazole and erythromycin, as well as inhibitors of CYP2D6 isoenzyme, such as fluoxetine, may inhibit donepezil metabolism. In a study involving healthy volunteers, ketoconazole increased the mean plasma concentration of donepezil by approximately 30%.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine, and alcohol, may reduce the plasma concentration of donepezil. The extent of inducing or inhibiting effects remains unknown; therefore, caution is advised when using such combinations.

Donepezil hydrochloride may affect drugs with anticholinergic activity. In addition, synergistic effects may occur when co-administered with drugs such as succinylcholine, other neuromuscular blockers, cholinergic agonists, or beta-blockers that affect cardiac conduction.

Cases of atypical changes in blood pressure and heart rate have been reported with concomitant use of donepezil and other cholinomimetics or quaternary anticholinergic agents such as glycopyrrolate.

Cases of QTc interval prolongation and torsade de pointes have been reported with the use of donepezil. Caution is recommended when using donepezil concomitantly with other medicinal products that prolong the QTc interval—clinical monitoring (ECG) may be required. Examples of such medicinal products include:

• Class IA antiarrhythmics (e.g., quinidine);
• Class III antiarrhythmics (e.g., amiodarone, sotalol);
• Certain antidepressants (e.g., citalopram, escitalopram, amitriptyline);
• Other antipsychotics (e.g., phenothiazine derivatives, sertindole, pimozide, ziprasidone);
• Certain antibiotics (e.g., clarithromycin, erythromycin, levofloxacin, moxifloxacin).

Special precautions for use.

The use of donepezil in dementia in patients with severe Alzheimer's disease, other types of dementia, or other forms of memory impairment (e.g., age-associated cognitive decline) has not been studied.

Anesthesia

Donepezil, as a cholinesterase inhibitor, may potentiate succinylcholine-type muscle relaxation during anesthesia.

Cardiovascular disorders

Cholinesterase inhibitors, due to their pharmacological action, may exert a vagotonic effect on heart rate (e.g., cause bradycardia). This effect may be particularly significant in patients with sick sinus syndrome or other supraventricular conduction disorders, such as sinoatrial or atrioventricular block.

Cases of syncope and seizures have been reported. Evaluation of such patients should consider the possibility of conduction block or prolonged sinus node pauses.

In the post-marketing period, QTc interval prolongation and torsade de pointes have been reported (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Caution is recommended in patients with a personal or family history of QTc interval prolongation, in patients taking medicinal products affecting the QTc interval, in patients with cardiac conditions (e.g., uncompensated heart failure, recent myocardial infarction, bradyarrhythmia), or with electrolyte disturbances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be required.

Gastrointestinal disorders

Patients at increased risk of developing ulcers, such as those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs (NSAIDs), should be closely monitored for symptoms. However, in clinical studies with donepezil, no increased frequency of peptic ulcer disease or gastrointestinal bleeding was observed compared to placebo.

Urinary system

Cholinomimetics may cause obstruction of the lower urinary tract, although such disorders were not observed in clinical studies with donepezil.

Neurological disorders

Seizures. Cholinomimetics are considered to have some potential to induce generalized seizures. However, such seizures may also be manifestations of Alzheimer's disease itself.

Cholinomimetics may exacerbate or induce extrapyramidal symptoms.

Malignant neuroleptic syndrome (MNS)

MNS – a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic dysfunction, altered consciousness, and elevated serum creatine phosphokinase levels – has been very rarely reported in association with donepezil use, particularly in patients concurrently receiving neuroleptics. Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms suggestive of MNS or presents with unexplained high fever without additional clinical features of MNS, treatment should be discontinued.

Pulmonary diseases

Cholinesterase inhibitors, due to their cholinomimetic effect, should be prescribed with caution in patients with a history of bronchial asthma or obstructive lung disease.

Donepezil is not recommended to be taken concomitantly with other acetylcholinesterase inhibitors, or cholinergic agonists or antagonists.

Severe hepatic impairment:

Data in patients with severe hepatic impairment are lacking.

Fatalities in clinical trials in vascular dementia

In studies of donepezil hydrochloride in patients with vascular dementia, the number of fatal events was numerically higher than in the placebo group, although this difference was not statistically significant. Most deaths in patients receiving either donepezil hydrochloride or placebo were due to various vascular events expected in elderly individuals with existing vascular disease. When analyzing all serious non-fatal and fatal vascular events, no difference in frequency was observed between the donepezil hydrochloride and placebo groups.

Fatalities in Alzheimer's disease studies

In Alzheimer's disease studies, as well as in pooled analyses combining these Alzheimer's studies with other dementia studies, including those in vascular dementia, the mortality rate in the placebo groups was numerically higher than in the donepezil hydrochloride groups.

Excipients

The medicinal product contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

There are no reliable data on the use of donepezil in pregnant women.

Animal studies did not show teratogenic effects, but signs of toxicity in the perinatal and postnatal periods were observed. The potential risk to humans remains unknown.

Donepezil is not recommended during pregnancy except in cases of extreme necessity.

Breastfeeding period

Donepezil penetrates into the milk of rats. Studies in breastfeeding women have not been conducted; therefore, it remains unknown whether donepezil hydrochloride passes into human breast milk. Thus, women should discontinue breastfeeding during treatment with donepezil.

Ability to influence reaction speed when driving or operating machinery

Donepezil has a negligible or moderate influence on the ability to drive a car or operate machinery.

Alzheimer's-type dementia may impair the ability to drive a car or operate machinery. In addition, donepezil may cause fatigue, dizziness, and muscle cramps, especially at the beginning of treatment or when the dose is increased. During treatment with donepezil, the physician should regularly assess the patient's ability to drive a car or operate complex mechanical devices.

Method of Administration and Dosage

Adults

Treatment should be initiated at a dose of 5 mg once daily. SerVonex® should be taken orally in the evening, immediately before bedtime. In case of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Side Effects"), administration of SerVonex in the morning may be considered.

The 5 mg daily dose should be maintained for at least 1 month to allow assessment of the early clinical response to treatment and to achieve steady-state plasma concentrations of donepezil. After clinical evaluation of treatment with 5 mg daily for 1 month, the dose may be increased to 10 mg once daily. The maximum recommended daily dose is 10 mg. Doses exceeding 10 mg daily have not been studied.

Treatment should be initiated and supervised by a physician specializing in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be established according to generally accepted guidelines (e.g., DSM-IV, ICD-10). Treatment with donepezil may only be initiated if the patient has a caregiver who will regularly monitor the patient's intake of the medication. Maintenance therapy may be continued as long as a therapeutic benefit is observed. Therefore, the clinical benefits of donepezil treatment should be regularly reassessed. Treatment should be discontinued when no further therapeutic effect is observed. Individual response to donepezil cannot be predicted.

After discontinuation of treatment, the beneficial effects of donepezil gradually diminish.

Renal and Hepatic Impairment

The same dosing regimen may be used in patients with renal impairment, as such impairment does not affect the clearance of donepezil hydrochloride.

Due to the potential for increased systemic exposure in patients with mild to moderate hepatic impairment (see section "Pharmacokinetics"), dose escalation should be based on individual tolerability. Data are not available for patients with severe hepatic impairment.

Children

SerVonex® is not recommended for use in children under 18 years of age.

Overdose

Overdose with cholinesterase inhibitors may lead to a cholinergic crisis, characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and seizures. Muscle weakness may occur, which could be fatal if respiratory muscles are affected.

As with overdose of any other drug, general supportive measures should be implemented. In cases of donepezil overdose, tertiary anticholinergic agents such as atropine may be used as antidotes. Intravenous administration of atropine sulfate is recommended, with the dose gradually increased until therapeutic effect is achieved: initial dose is 1–2 mg intravenously, with subsequent doses adjusted according to clinical response. Atypical responses in blood pressure and heart rate have been reported when other cholinomimetics were administered concomitantly with quaternary anticholinergic agents such as glycopyrrolate. The ability to eliminate donepezil hydrochloride and/or its metabolites by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) is unknown.

Side effects

The most commonly observed adverse effects are diarrhea, muscle cramps, increased fatigue, nausea, vomiting, and insomnia.

The adverse reactions listed below are categorized by organ systems and frequency of occurrence. Frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations

Common: cold.

Metabolism and nutrition disorders

Common: anorexia.

Psychiatric disorders

Common: hallucinations**, agitation**, aggressive behavior**, sleep disturbances**, nightmares**;

Frequency not known: increased libido, hypersexuality.

Nervous system disorders

Common: syncope*, dizziness, insomnia;

Uncommon: seizures*;

Rare: extrapyramidal symptoms;

Very rare: neuroleptic malignant syndrome;

Frequency not known: pleurothotonus (Pisa syndrome).

Cardiac disorders

Uncommon: bradycardia;

Rare: sinoatrial block, atrioventricular block;

Frequency not known: polymorphic ventricular tachycardia, including torsade de pointes; QT interval prolongation on ECG.

Gastrointestinal disorders

Very common: nausea, diarrhea;

Common: vomiting, dyspepsia;

Uncommon: gastrointestinal hemorrhage, gastric and duodenal ulcers, hypersalivation.

Hepatobiliary disorders

Rare: hepatic dysfunction, including hepatitis***.

Skin and subcutaneous tissue disorders

Common: rash, pruritus.

Musculoskeletal and connective tissue disorders

Common: muscle cramps;

Very rare: rhabdomyolysis****.

Renal and urinary disorders

Common: urinary incontinence.

General disorders and administration site conditions

Very common: headache;

Common: increased fatigue, pain.

Investigations

Uncommon: slight increase in serum concentration of creatine phosphokinase.

Injury, poisoning and procedural complications

Common: accidents, including falls.

*Patients experiencing syncope or seizures should be evaluated for possible cardiac block or prolonged sinus pauses (see section "Special precautions").

**Reports of hallucinations, agitation, and aggressive behavior, which resolved after dose reduction or discontinuation of the drug.

***In cases of hepatic dysfunction not explained by obvious causes, discontinuation of donepezil therapy should be considered.

****Cases of rhabdomyolysis have been reported independently of neuroleptic malignant syndrome and in close temporal association with the initiation of donepezil treatment and dose escalation.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

14 tablets in a blister pack. 2 blisters per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of business activity.

54 Skryabina Street, Sumy, Sumy Oblast, 40020, Ukraine.