Alzepil

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALZEPIL (ALZEPIL®)

Composition:

Active substance: donepezil;

1 film-coated tablet contains 5 mg or 10 mg of donepezil hydrochloride;

Excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol 400.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg film-coated tablets: white or almost white, round, biconvex, film-coated tablets, odorless or nearly odorless, with an engraved stylized letter E and beneath it the number 381 on one side;

10 mg film-coated tablets: white or almost white, round, biconvex, film-coated tablets, odorless or nearly odorless, with an engraved stylized letter E and beneath it the number 382 on one side.

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

Pharmacological Properties

Pharmacodynamics

Donepezil is a selective and reversible inhibitor of acetylcholinesterase, the primary type of cholinesterase in the brain. By inhibiting cholinesterase in the brain, donepezil prevents the breakdown of acetylcholine, which mediates nerve impulse transmission in the central nervous system. Donepezil inhibits acetylcholinesterase more than 1000 times more potently than butyrylcholinesterase, which is predominantly found in structures outside the central nervous system.

After a single dose of 5 mg or 10 mg of donepezil, the degree of inhibition of acetylcholinesterase activity in erythrocyte membranes is approximately 63.6% and 77.3%, respectively.

Inhibition of erythrocyte acetylcholinesterase by donepezil correlates with changes in the ADAS-cog scale (Alzheimer's Disease Assessment Scale–cognitive subscale).

Pharmacokinetics

Maximum plasma concentration (Cmax) is reached approximately 3–4 hours after administration. Plasma concentrations and the area under the pharmacokinetic curve (AUC) increase proportionally with dose. The elimination half-life is approximately 70 hours; therefore, once-daily dosing gradually leads to steady-state conditions, which are achieved within 3 weeks of starting therapy.
At steady state, plasma concentrations of donepezil hydrochloride and the corresponding pharmacodynamic activity change only slightly throughout the day. Food does not affect the absorption of donepezil hydrochloride.

Donepezil is approximately 95% bound to plasma proteins. Distribution of donepezil into various tissues has not been fully studied. Theoretically, donepezil and its metabolites may be retained in the body for up to 10 days.

Metabolism/Excretion. Donepezil hydrochloride is excreted unchanged in urine and undergoes biotransformation via the cytochrome P450 system, forming numerous metabolites, some of which have not been fully characterized.

After a single oral dose of 5 mg of 14C-labeled donepezil hydrochloride, unchanged donepezil hydrochloride accounts for 30% of the administered dose in plasma,
6-O-desmethyl donepezil – 11% (the only metabolite with activity similar to donepezil hydrochloride), donepezil-cis-N-oxide – 9%, 5-O-desmethyl donepezil – 7%, and glucuronide conjugate of 5-O-desmethyl donepezil – 3%. Approximately 57% of the administered radioactive dose is 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 is no information available on the possibility of enterohepatic recirculation of donepezil hydrochloride or any of its metabolites. The decline in plasma concentrations of donepezil hydrochloride occurs with an elimination half-life of approximately 70 hours. Plasma levels of donepezil in patients are comparable to those observed in healthy young volunteers. Mild to moderate hepatic impairment, as well as renal impairment, do not significantly affect the clearance of donepezil.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate Alzheimer's disease.

Contraindications.

Hypersensitivity to donepezil hydrochloride, piperidine derivatives, or any 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. The metabolism of donepezil hydrochloride is not altered by concomitant administration of digoxin or cimetidine. In vitro studies have shown that donepezil metabolism is mediated by the cytochrome P450 isoenzyme 3A4 and, to a lesser extent, 2D6. In vitro drug interaction studies have demonstrated that ketoconazole and quinidine (inhibitors of CYP3A4 and 2D6, respectively) inhibit donepezil metabolism. Therefore, these and other CYP3A4 inhibitors such as itraconazole and erythromycin, as well as CYP2D6 inhibitors such as fluoxetine, may inhibit donepezil metabolism. In a study involving healthy volunteers, ketoconazole increased the mean concentration of donepezil by approximately 30%. Enzyme inducers such as rifampicin, phenytoin, carbamazepine, and alcohol may reduce donepezil concentrations. Since the magnitude of the inhibitory or inductive effect is unknown, such drug combinations should be used with caution. Donepezil hydrochloride has the potential for drug interactions with agents exhibiting anticholinergic effects. There is also a possibility of mutual potentiation of effects when used concomitantly with drugs such as succinylcholine, other neuromuscular blockers, cholinergic agonists, or beta-blockers capable of affecting 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 advised when using donepezil concomitantly with other medicinal products that prolong the QTc interval; clinical monitoring (ECG) may be required. Examples of such agents include:

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

Special precautions for use.

Treatment should be initiated and continued under the supervision of a physician experienced in the diagnosis of Alzheimer's disease and the management of such patients. The disease must be diagnosed according to generally accepted guidelines (e.g., DSM-IV, ICD-10 – International Classification of Diseases, 10th revision). Therapy with donepezil may be initiated only if there is a caregiver who will consistently supervise the patient's intake of tablets. Maintenance therapy should be continued as long as a therapeutic benefit is observed. Therefore, the clinical effect of donepezil should be evaluated regularly. If no therapeutic benefit is observed, discontinuation of the drug should be considered. Individual response to donepezil cannot be predicted. The efficacy of donepezil in patients with severe Alzheimer's dementia, other types of dementia, or other types of memory impairment (e.g., age-associated cognitive decline) has not been studied.

Anesthesia

As a cholinesterase inhibitor, Aricept (donepezil) may potentiate succinylcholine-type neuromuscular blockade during anesthesia.

Cardiovascular disorders

Due to their pharmacological action, cholinesterase inhibitors may exert vagotonic effects on heart rate (e.g., causing bradycardia). This possibility is particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction abnormalities (e.g., sinoatrial or atrioventricular block).

Dizziness and seizures have been reported. In evaluating such patients, the possibility of cardiac block or prolonged pauses in sinus rhythm should be considered.

In the post-marketing period, cases of 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").

Use with caution in patients with a history of QTc interval prolongation or a family history of QTc prolongation, in patients taking drugs affecting the QTc interval, in patients with cardiac conditions (e.g., uncompensated heart failure, recent myocardial infarction, bradyarrhythmia), or with electrolyte imbalances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be required.

Gastrointestinal disorders

Close monitoring is recommended in patients at risk of ulcer development, such as those with a history of peptic ulcer or patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical studies of donepezil, no increased incidence of peptic ulcers or gastrointestinal bleeding was observed compared to placebo.

Urinary system disorders

Cholinomimetics may cause urinary outflow obstruction, although this effect has not been observed in clinical studies of donepezil.

Neurological conditions

Cholinomimetics are considered to have some potential to cause generalized seizures. However, seizure activity may also be a manifestation of Alzheimer's disease. Cholinomimetics may exacerbate or induce extrapyramidal symptoms.

Pulmonary function disorders

Cholinesterase inhibitors should be administered with caution to patients with asthma or a history of obstructive pulmonary disorders.

Concomitant use of Aricept with other acetylcholinesterase inhibitors, cholinergic agonists, or antagonists should be avoided.

Severe hepatic impairment

Data in patients with severe hepatic impairment are lacking.

Fatalities in clinical trials of vascular dementia

Three 6-month clinical trials were conducted in patients meeting NINDS-AIREN criteria for probable or possible vascular dementia. The NINDS-AIREN criteria were developed to identify patients whose dementia may be exclusively due to vascular causes and to exclude patients with Alzheimer's disease. In the first study, mortality rates were 2/198 (1%) with donepezil hydrochloride 5 mg, 5/206 (2.4%) with donepezil hydrochloride 10 mg, and 7/199 (3.5%) with placebo. In the second study, mortality rates were 4/208 (1.9%) with donepezil hydrochloride 5 mg, 3/215 (1.4%) with donepezil hydrochloride 10 mg, and 1/193 (0.5%) with placebo. In the third study, mortality rates were 11/648 (1.7%) with donepezil hydrochloride 5 mg and 0/326 (0%) with placebo. Across all three studies in vascular dementia, the mortality rate in the combined donepezil hydrochloride group (1.7%) was numerically higher than in the placebo group (1.1%), but this difference was not statistically significant. Most deaths in patients receiving either donepezil hydrochloride or placebo were due to various vascular causes expected in elderly patients with existing vascular disease. When analyzing all serious non-fatal and fatal vascular events, no difference in event frequency was observed between donepezil hydrochloride and placebo groups.

In all Alzheimer's disease trials (n = 4146), as well as in the combined analysis of Alzheimer's disease trials and other dementia trials including vascular dementia studies (total n = 6888), the mortality rate in the placebo groups was numerically higher than in the donepezil hydrochloride groups.

Malignant neuroleptic syndrome (MNS)

MNS is a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic nervous system dysfunction, altered consciousness, and elevated serum creatine phosphokinase levels, which 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 other clinical features of MNS, treatment should be discontinued.

Use during pregnancy or breastfeeding.

Pregnancy.

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

Donepezil should not be used during pregnancy.

Breastfeeding.

It is unknown whether donepezil hydrochloride is excreted in human breast milk; studies in breastfeeding women have not been conducted. Therefore, women taking donepezil should discontinue breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Donepezil has minimal or moderate influence on the ability to drive vehicles or operate machinery. Alzheimer's-type dementia itself may impair the ability to drive or operate machinery. Additionally, donepezil may cause increased fatigue, dizziness, and muscle cramps, primarily at the beginning of treatment or when the dose is increased. The ability of patients taking donepezil to drive or operate complex machinery should be periodically assessed by a physician.

Method of Administration and Dosage

Adult and elderly patients

Treatment should be initiated at a dose of 5 mg once daily. Alzepil should be administered orally in the evening, immediately before bedtime. In case of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Adverse Reactions"), consideration should be given to administering Alzepil in the morning. The 5 mg daily dose should be maintained for at least one month to allow for the earliest possible clinical response to treatment based on assessment and to achieve a steady-state concentration of donepezil hydrochloride. After clinical evaluation of treatment with a 5 mg daily dose for one month, the donepezil 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 in clinical trials.

Treatment should be initiated and continued under the supervision of a physician experienced in the diagnosis of Alzheimer's type dementia and the management of such patients. The disease should be diagnosed according to generally accepted guidelines (e.g., DSM IV or ICD-10 – International Classification of Diseases, 10th revision).

Donepezil therapy should only be initiated when a caregiver is available who will consistently supervise the patient’s intake of tablets.

Maintenance treatment may be continued as long as the patient continues to derive therapeutic benefit. Therefore, the clinical benefit of donepezil should be regularly assessed. If evidence of therapeutic effect is no longer observed, discontinuation of the drug should be considered. Individual response to donepezil cannot be predicted.

Upon discontinuation of treatment, a gradual decline in the beneficial effects of donepezil is observed.

Renal and hepatic impairment

The same dosing regimen may be used for patients with impaired renal function, as the clearance of donepezil hydrochloride is not altered in this condition.

Due to the potential for increased exposure in patients with mild to moderate hepatic impairment, dose escalation should be based on individual tolerability. Data in patients with severe hepatic impairment are lacking.

Children
Alzepil is not recommended for use in children under 18 years of age, as the safety of the drug has not been studied in this population.

Overdose

Overdose with cholinesterase inhibitors may lead to a cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Progressive muscle weakness may occur, which could result in a fatal outcome if respiratory muscles are affected.

As with any overdose, general supportive measures should be applied. Tertiary anticholinergic agents such as atropine may be used as an antidote in case of donepezil overdose. Intravenous administration of atropine sulfate with dose titration to effect is recommended: initial dose of 1 to 2 mg intravenously, followed by further dosing based on clinical response. Atypical responses in blood pressure and heart rate have been reported when other cholinomimetics are used concomitantly with quaternary anticholinergic agents such as glycopyrrolate. It is unknown whether donepezil hydrochloride and/or its metabolites can be effectively removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

Adverse Reactions

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

In individuals with individual hypersensitivity to any component of the medicinal product, hypersensitivity reactions are possible.

Adverse reactions reported at a frequency higher than isolated case reports are listed below by system organ class and frequency. Frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); and frequency not known (cannot be estimated based on available data).

*When examining patients due to syncope or seizures, consider the possibility of heart 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, consider discontinuing donepezil therapy.

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

Reporting of adverse reactions following marketing authorization of the medicinal product is of great importance. This enables ongoing monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of therapeutic effect via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store at a temperature not exceeding 30 °C in a place inaccessible to children.

Packaging. 14 film-coated tablets in a blister; 2 or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Egis Pharmaceuticals PLC.

Manufacturer's address.
1165 Budapest, Bekenyefalda St. 118-120, Hungary.