Alzancer ezytab

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALZANCER EASYTAB

Composition:

Active substance: donepezil hydrochloride;

One orodispersible tablet contains 5 mg or 10 mg of donepezil hydrochloride;

Excipients: polyvinylpyrrolidone Kollidon CL, sodium metabisulfite (E 223), colloidal anhydrous silicon dioxide, aspartame (E 951), polyvinylpyrrolidone Kollidon CL-F, sodium stearyl fumarate, magnesium stearate, Pharmaburst C1* mixture, Prosolv SMCC HD 90**;

*Pharmaburst C1 mixture: mannitol (E 421), sorbitol (E 420), crospovidone, colloidal hydrated silicon dioxide;

**Prosolv SMCC HD 90 mixture: microcrystalline cellulose, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Orodispersible tablets.

Main physicochemical properties:

5 mg orodispersible tablets: white, round tablets, embossed with "ALZ" on one side and "5" on the other;

10 mg orodispersible tablets: white, round tablets, embossed with "ALZ" on one side and "10" on the other.

Pharmacotherapeutic group. Drugs 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 exceeds its ability to inhibit butyrylcholinesterase activity by 1000-fold. Butyrylcholinesterase is primarily found outside the central nervous system (CNS).

Alzheimer's Disease Dementia

In patients with Alzheimer's disease participating in clinical trials, administration of donepezil hydrochloride at doses of 5 mg or 10 mg once daily, after reaching steady-state concentrations, resulted in inhibition of acetylcholinesterase activity (measured in erythrocyte membrane) by 63.6% and 77.3%, respectively. Inhibition of acetylcholinesterase in erythrocytes 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 evaluate certain aspects of cognitive function. The ability of donepezil hydrochloride to modify the progression of the underlying neuropathological features of the disease has not been studied. Therefore, the effect of donepezil on the progression of the disease cannot be assessed.

The efficacy of donepezil treatment was evaluated in four placebo-controlled studies—two 6-month studies and two 1-year studies.

In the 6-month clinical study, efficacy analysis was based on a composite of three criteria: score on the ADAS-Cog scale (a measure of cognitive function), score on the Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+ scale, a measure of global function), and score on the functional assessment subscale evaluating activities of daily living in the presence of dementia symptoms (a measure of ability to perform social activities, household tasks, hobbies, and self-care).

Patients were considered to have responded to treatment if they met all the following criteria:

Response: Improvement in ADAS-Cog score by at least 4 points, no worsening in CIBIC+ score, and no worsening in the functional assessment subscale score for activities of daily living in the presence of dementia symptoms.

* p<0.05;

** p<0.01.

Donepezil caused a dose-dependent statistically significant increase in the proportion of patients who showed a response to treatment.

Pharmacokinetics.

Absorption

After oral administration, maximum plasma concentration (Cmax) is reached in 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 a 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 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 into 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, resulting in multiple metabolites, some of which have not 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 due to unchanged donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11%, the only metabolite with 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 the primary routes of elimination are biotransformation and urinary 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 an elimination half-life of approximately 70 hours.

Gender, race, and smoking history did not have a 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 patient populations 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's disease.

Contraindications.

Hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to 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. 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 shown that ketoconazole and quinidine (inhibitors of CYP3A4 and CYP2D6, 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 donepezil concentration 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 having anticholinergic properties. There is also a possibility of mutual enhancement of effect when co-administered with drugs such as succinylcholine, other neuromuscular blockers, cholinergic agonists, or beta-blockers capable of affecting cardiac conduction.

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 agents 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 patients with severe Alzheimer's dementia, other types of dementia, or other types of memory impairment (e.g., age-related cognitive decline) has not been studied.

Anesthesia

As a cholinesterase inhibitor, donepezil hydrochloride may potentiate succinylcholine-induced neuromuscular blockade during anesthesia.

Cardiovascular disorders

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

Dizziness and seizures have been reported. When evaluating such patients, the possibility of cardiac conduction block or prolonged pauses in sinus rhythm should be considered. Post-marketing reports have documented QTc interval prolongation and torsade de pointes (see section "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Caution is recommended in patients with pre-existing QTc interval prolongation or a family history of QTc prolongation, patients taking drugs known to affect the QTc interval, patients with cardiac conditions (e.g., uncompensated heart failure, recent myocardial infarction, bradyarrhythmias), or those with electrolyte imbalances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be required.

Gastrointestinal disorders

Close monitoring is advised in patients at risk of developing ulcers, such as those with a history of peptic ulcer disease or patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical trials 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 with donepezil.

Neurological conditions

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

Malignant neuroleptic syndrome (MNS)

MNS is a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels, which 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 signs and symptoms suggestive of MNS or unexplained high fever without other clinical manifestations of MNS develop, treatment should be discontinued.

Lung function disorders

Since cholinesterase inhibitors have cholinomimetic activity, they should be used with caution in patients with asthma or a history of obstructive lung disease.

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

Severe hepatic impairment

Data in patients with severe hepatic impairment are lacking.

Mortality 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 designed 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 overall 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 individuals with existing vascular disease. Analysis of all serious non-fatal and fatal vascular events showed no difference in event frequency between the donepezil hydrochloride and placebo groups.

In all Alzheimer's disease trials (n=4146), as well as when combining these Alzheimer's disease trials with other dementia trials including those in vascular dementia (total n=6888), the mortality rate in the placebo groups numerically exceeded that in the donepezil hydrochloride groups.

Aspartame

The medicinal product contains aspartame, which is a source of phenylalanine. It may be harmful for individuals with phenylketonuria.

Use during pregnancy or breastfeeding.

Pregnancy

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

Animal studies have shown no teratogenic effects, but signs of toxicity were observed during the peri- and postnatal periods. The potential risk for humans remains unknown.

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

Breastfeeding period

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

Ability to influence 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.

Dosage and Administration

Adult patients, including elderly patients

Treatment should be initiated at a dose of 5 mg once daily. The 5 mg daily dose should be maintained for at least one month to allow for optimal early clinical response assessment and to achieve steady-state concentration of donepezil hydrochloride. After clinical evaluation following one month of treatment with 5 mg daily, the dose of donepezil 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 treatment of such patients. The disease should be diagnosed according to generally accepted guidelines.

Donepezil therapy should only be initiated if a caregiver is available who will regularly 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

For patients with renal impairment, the same dosing regimen can be followed, as the clearance of donepezil hydrochloride is not altered in this condition.

Due to possible 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.

Administration method

The medication should be taken orally in the evening, just before bedtime. The tablet should be placed on the tongue and allowed to disintegrate before swallowing, with or without water, depending on patient preference.

In case of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Adverse reactions"), administration of the medication in the morning may be considered.

Children

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

Overdose

The known single oral lethal dose of donepezil hydrochloride in mice and rats is approximately 45 and 32 mg/kg, respectively, which is about 225 and 160 times the maximum recommended human dose (10 mg/day). In animals, dose-dependent signs of cholinergic stimulation were observed, including decreased spontaneous motor activity, prone position, ataxia, lacrimation, clonic convulsions, respiratory depression, salivation, miosis, fasciculations, and decreased skin temperature.

Overdose of cholinesterase inhibitors may lead to a cholinergic crisis characterized by severe nausea, vomiting, salivation, increased sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Progressive muscle weakness may occur, which could be fatal 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 antidotes in case of donepezil overdose. Intravenous administration of atropine sulfate is recommended with dose titration to effect: 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 removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

Adverse Reactions

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

Adverse reactions reported at a frequency exceeding that of single cases 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).

*In patients being evaluated for syncope or seizures, consider the possibility of heart block or prolonged sinus pauses (see section "Special precautions for use").

**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 treatment with donepezil.

****Cases of rhabdomyolysis have been reported independently of CNS events and with close temporal association to the initiation of donepezil treatment and dose increases.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

7 tablets per blister pack. 4 blister packs in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Nobel Ilac Sanayi Ve Ticaret A.S.

Manufacturer's address and location of operations.

Sankaklar Quarter, Eskikarakoca Avenue No: 299, 81100 Duzce, Turkey.