Donek

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

Composition:

Active substance: donepezil hydrochloride;

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

Excipients: polacrilin potassium; microcrystalline cellulose; lactose monohydrate; sodium citrate anhydrous; aspartame (E 951); sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Orodispersible tablets.

Main physicochemical properties:

5 mg tablets: round, flat tablets with bevelled edges, white to almost white, with "5" embossed on one side and smooth on the other;

10 mg tablets: round, flat tablets with bevelled edges, white to almost white, with "10" embossed on one side and smooth on the other.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Dementia in Alzheimer's disease

In patients with Alzheimer's disease participating in clinical studies, administration of donepezil at doses of 5 mg or 10 mg once daily has been shown to inhibit 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), which assesses 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 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 (measure of cognitive function), score on the Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+) scale (measure of global function), and score on the functional assessment scale for activities of daily living in dementia (measure of ability to perform social, household, leisure, and self-care activities).

Patients were considered responders to treatment if they met 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 score for activities of daily living in dementia.

* p < 0.05;
** p < 0.01.

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

Pharmacokinetics.

Absorption

After oral administration, peak 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 results in 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 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 persist in the body for more than 10 days.

Metabolism/Excretion

Donepezil hydrochloride may be excreted unchanged in urine or metabolized in the liver 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, 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 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 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 history of smoking 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, mean plasma concentrations in elderly patients were similar to those 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.

Donex® dispersible tablets are indicated for symptomatic treatment of mild to moderate Alzheimer's type dementia.

Contraindications.

Hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients of the medicinal product.

Interaction with other medicinal products and other types 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 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 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 enzyme-inducing or inhibiting effects remains unknown; therefore, caution should be exercised when using such drug combinations. Donepezil hydrochloride may affect drugs with anticholinergic activity, reducing their effect. Synergistic effects may occur when Donex® is administered concomitantly with succinylcholine, other muscle relaxants, cholinergic agonists, or beta-blockers that affect 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 dementia due to Alzheimer's disease, other types of dementia, or other forms of memory impairment (e.g., age-related cognitive decline) has not been studied.

Anesthesia: Donepezil, as a cholinesterase inhibitor, may potentiate muscle relaxation when depolarizing neuromuscular blocking agents (of the succinylcholine type) are used 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. In evaluating such patients, special attention should be paid to the cardiac conduction system, and the possibility of conduction block or prolonged sinus node pauses should be considered.

Post-marketing reports have documented QTc interval prolongation and torsade de pointes (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Caution is recommended when administering donepezil to patients with a history of QTc interval prolongation or a family history of QTc prolongation, patients taking medications known to affect the QTc interval, patients with cardiac conditions (e.g., uncompensated heart failure, recent myocardial infarction, bradyarrhythmia), or those with electrolyte imbalances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be required.

Gastrointestinal disorders: Patients at increased risk of developing ulcers, particularly those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs (NSAIDs), should be closely monitored for gastrointestinal tract status. However, in clinical trials with donepezil, no increased incidence of peptic ulcer disease of the stomach or duodenum or gastrointestinal bleeding was observed compared to placebo.

Urinary system disorders: Cholinomimetics may cause urinary outflow obstruction, although such events were not observed in clinical trials with donepezil.

Neurological disorders: Seizures: Cholinomimetics are considered to have the potential to induce generalized seizures. However, such seizures may also be a manifestation of Alzheimer's disease itself.

Cholinomimetics may exacerbate or induce extrapyramidal disorders.

Malignant neuroleptic syndrome (MNS)

MNS is a life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic nervous system dysfunction, altered consciousness, and elevated serum creatine phosphokinase levels, particularly in patients receiving concomitant antipsychotic therapy. MNS may be complicated by myoglobinuria (rhabdomyolysis) and acute renal failure. Treatment should be discontinued if signs or symptoms suggestive of MNS occur, or if unexplained high fever develops without additional clinical manifestations.

Pulmonary diseases: Cholinesterase inhibitors, due to their cholinomimetic effects, should be used with caution in patients with a history of bronchial asthma or chronic obstructive pulmonary disease.

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

Severe hepatic impairment: Data in patients with severe hepatic impairment are lacking.

Mortality in clinical trials involving patients with vascular dementia: Three 6-month clinical trials have been 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 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. When analyzing all serious non-fatal and fatal vascular events, no difference in event frequency was observed between the donepezil hydrochloride and placebo groups.

According to data from studies of donepezil hydrochloride in Alzheimer's disease (n = 4146), as well as pooled data from Alzheimer's disease studies and dementia studies, including those in vascular dementia (total n = 6888), the mortality rate in the placebo groups was numerically higher than in the donepezil hydrochloride groups.

Precautions regarding excipients

The medicinal product Donex® contains lactose and therefore should not be used in patients with rare hereditary or acquired conditions such as fructose intolerance, galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

The product contains aspartame, a phenylalanine derivative, which may be harmful to patients with phenylketonuria.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

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

Breastfeeding period

Donepezil is excreted in rat milk. Studies in breastfeeding women have not been conducted; therefore, it is 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.

Since donepezil may cause fatigue, dizziness, and muscle cramps, particularly at the beginning of treatment or when the dose is increased, it may have a slight to moderate adverse effect on the ability to drive a car or operate other machinery.

At the same time, dementia itself may impair a patient's ability to drive a car or operate mechanical devices. Therefore, during treatment with donepezil, the physician should regularly assess the patient's ability to drive or operate complex mechanical equipment.

Method of Administration and Dosage

Adults / 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 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 one month of treatment at 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 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 in the management of such patients. Diagnosis should be established according to accepted guidelines. 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 periodically re-evaluated. 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 this condition 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. There is no available data for patients with severe hepatic impairment.

Method of Administration

Donex® should be taken orally in the evening, 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 cases of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Adverse Reactions"), administration in the morning may be considered.

Children

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

Overdose

The oral median lethal dose (LD₅₀) 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 with cholinesterase inhibitors may result in a cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Muscle weakness may occur, which could be fatal due to paralysis of respiratory muscles.

As with overdose of any other drug, general supportive measures should be employed. In cases of donepezil overdose, tertiary anticholinergic agents such as atropine may be used as antidotes. Intravenous atropine sulfate is recommended, with gradual dose titration until therapeutic effect is achieved. The initial dose is 1–2 mg intravenously; 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 concomitantly with quaternary anticholinergic agents such as glycopyrrolate. It remains unknown whether donepezil hydrochloride and/or its metabolites are dialyzable (hemodialysis, peritoneal dialysis, or hemofiltration).

Adverse Reactions

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

The frequency of the following adverse reactions is defined as: 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 based on 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 disorders; very rare – neuroleptic malignant syndrome (NMS); frequency not known – pleurosthotonos (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 – diarrhea, nausea; common – vomiting, abdominal discomfort; uncommon – gastrointestinal hemorrhage, gastric and duodenal ulcers, hypersalivation.

Hepatobiliary disorders: rare – liver 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 kinase concentration.

Injury, poisoning and procedural complications: common – accidental injury, including falls.

* In patients presenting with syncope or epileptic seizure, conduction block or prolonged sinus node pauses should be considered (see section "Special precautions for use").

** Hallucinations, agitation, and aggressive behavior were reported to resolve after dose reduction or discontinuation of treatment.

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

**** Cases of rhabdomyolysis have been reported occurring independently of NMS, with a clear temporal relationship to the initiation of donepezil treatment and dose escalation.

Shelf life. 3 years

Storage conditions. Keep out of reach and sight of children. No special storage conditions required.

Packaging. 10 tablets in a blister; 3 or 6 blisters in a cardboard pack.

14 tablets in a blister; 2 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. Jenepharm SA

Manufacturer's address and location of operations.

18th km Marathon Avenue, Pallini Attiki, 15351, Greece