Donemac 5

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Donemac 5 (Donemac 5) Donemac 10 (Donemac 10)

Composition:

Active substance: donepezil hydrochloride;

5 mg tablets:

One film-coated tablet contains 5 mg of donepezil hydrochloride;

Excipients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating Opadry White 02H58708 / Instacoat Universal White A05D02075: hypromellose, propylene glycol, talc, titanium dioxide (E 171);

10 mg tablets:

One film-coated tablet contains 10 mg of donepezil hydrochloride;

Excipients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating Opadry Yellow 02H82475 / Instacoat Universal Yellow A05D02076: hypromellose, propylene glycol, talc, titanium dioxide (E 171), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets: round, biconvex, film-coated tablets, white or almost white in color, with "ML 89" engraved on one side and a smooth surface on the other;

10 mg tablets: round, biconvex, film-coated tablets, yellow in color, with "ML 88" engraved on one side and a smooth surface on the other.

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

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, a neurotransmitter responsible for nerve impulse transmission in the central nervous system (CNS). Donepezil inhibits acetylcholinesterase more than 1000 times more potently than butyrylcholinesterase, which is predominantly found in tissues outside the CNS.

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

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

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, 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 reaching steady state, plasma concentrations of donepezil hydrochloride and the associated pharmacodynamic activity remain almost unchanged throughout the day. Food does not affect the absorption of donepezil hydrochloride.

Distribution. The elimination half-life of donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) ranges from 0.13 to 0.19 L/h/kg. After multiple dosing, donepezil accumulates in plasma, and steady state is achieved within 15 days. The steady-state volume of distribution is 12–16 L/kg. Donepezil is approximately 96% bound to human plasma proteins, primarily to albumin (about 75%) and alpha-1 acid glycoprotein (about 21%) over a concentration range of 2–1000 ng/mL.

Metabolism/Elimination. 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, 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 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 major elimination pathways are metabolism and renal excretion. There was no evidence of enterohepatic recirculation of donepezil hydrochloride or any of its metabolites.

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

Gender, race, and smoking history had no clinically significant effect on plasma concentrations of donepezil hydrochloride. 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.

For symptomatic treatment of mild to moderate Alzheimer's type dementia.

Contraindications.

The medicinal product is contraindicated in patients with hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Donepezil hydrochloride and/or any of 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 CYP450 isoenzymes 3A4 and, to a lesser extent, 2D6 of cytochrome P450 are involved in the metabolism of donepezil. Results of in vitro interaction studies indicate that ketoconazole and quinidine, which are inhibitors of CYP3A4 and 2D6 respectively, inhibit the metabolism of donepezil. Therefore, these agents and other CYP3A4 inhibitors (e.g., itraconazole, erythromycin), as well as CYP2D6 inhibitors (e.g., fluoxetine), may suppress donepezil metabolism. In a study involving healthy volunteers, ketoconazole increased mean plasma concentrations of donepezil by approximately 30%.

Enzyme inducers (e.g., rifampicin, phenytoin, carbamazepine, alcohol) may reduce donepezil levels. Since the extent of inhibitory or inductive effects is unknown, such combinations should be used with caution.

Donepezil hydrochloride may affect drugs with anticholinergic activity. In addition, synergistic effects may occur when donepezil is administered concomitantly with drugs such as succinylcholine, other neuromuscular blockers, cholinergic agonists, or beta-blockers that affect cardiac conduction (see section "Special precautions for use").

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 efficacy of donepezil in patients with severe dementia due to Alzheimer's disease, other types of dementia, and other types of memory impairment (e.g., age-associated cognitive decline) has not been studied.

Anesthesia. As a cholinesterase inhibitor, donepezil may potentiate succinylcholine-type muscle relaxation during anesthesia.

Cardiovascular disorders. Due to their pharmacological action, cholinesterase inhibitors may exert a vagotonic effect on heart rate (e.g., may cause 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 conduction abnormalities or prolonged sinus 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 prescribing to patients with known QTc interval prolongation or a family history of QTc prolongation, patients taking medicinal products affecting 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 risk of developing ulcers, such as those with a history of peptic ulcer disease or those receiving nonsteroidal anti-inflammatory drugs (NSAIDs), should be closely monitored. However, in clinical trials of donepezil, no increased incidence of peptic ulcers or gastrointestinal hemorrhage was observed compared to placebo.

Genitourinary system. Cholinomimetics may cause difficulty in urinary voiding, although this effect has not been observed in clinical studies of donepezil.

Neurological disorders. Cholinomimetics are considered to have some potential to provoke generalized seizures. However, seizure activity may also be a manifestation of Alzheimer's disease.

Cholinomimetics may exacerbate or induce extrapyramidal symptoms.

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

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

Severe hepatic impairment. There are no data available for patients with severe hepatic impairment.

Mortality in clinical trials involving patients with 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 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.

In all Alzheimer's disease trials (n = 4146), as well as in pooled analyses of Alzheimer's disease trials combined with 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). There are very few reports of MNS associated with donepezil, particularly in patients concurrently taking neuroleptic agents. MNS is a life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic dysfunction, altered consciousness, and elevated serum creatine and phosphokinase levels. Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. Treatment should be discontinued if symptoms suggestive of MNS or unexplained high fever without other clinical manifestations occur.

Special warnings regarding excipients. The medicinal product Donemak contains lactose. Therefore, this product is not recommended for patients with rare hereditary conditions such as fructose intolerance, galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

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 should not be used during pregnancy except in cases of extreme necessity.

Breastfeeding period

Donepezil passes into the milk of rats. 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 while receiving donepezil therapy.

Ability to influence reaction speed while driving or operating machinery.

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

Dementia may impair the ability to drive or operate machinery. In addition, donepezil may cause fatigue, dizziness, and muscle cramps, particularly at the beginning of treatment and during dose escalation. The ability of patients taking donepezil to drive or operate complex machinery should be periodically assessed by a physician.

Method of Administration and Dosage

Adults

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 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 in clinical trials.

Treatment should be initiated and monitored by a physician specialized in the diagnosis and treatment of dementia associated with Alzheimer's disease. Diagnosis should be made according to established guidelines (e.g., DSM-IV, ICD-10). Treatment with donepezil may be initiated only 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 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 effects of donepezil gradually diminish.

Renal and Hepatic Impairment

The same dosage regimen may be used in 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 to moderate hepatic impairment (see section "Pharmacokinetics"), dose escalation should be based on individual tolerability. There is no information available regarding patients with severe hepatic impairment.

Method of Administration

Donepezil hydrochloride should be taken orally in the evening, just before bedtime. In cases of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Adverse Reactions"), consideration may be given to administering the medication in the morning.

Children

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

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. Muscle weakness may occur, which can be fatal if respiratory muscles are affected.

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

As with overdose of any other drug, general supportive measures should be taken. In cases of donepezil hydrochloride overdose, tertiary anticholinergic agents such as atropine may be used as antidotes. Intravenous administration of atropine sulfate at an initial dose of 1–2 mg is recommended, with gradual dose increases based on clinical response until therapeutic effect is achieved. When other cholinomimetics have been administered concomitantly with quaternary anticholinergic agents such as glycopyrrolate, atypical changes in blood pressure and heart rate have been reported. It is unknown whether donepezil hydrochloride and/or its metabolites are dialyzable (hemodialysis, peritoneal dialysis, or hemofiltration).

Side effects.

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

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

Infections and infestations: common – upper respiratory tract infection, rhinitis.

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 – 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 – 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 – 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 seizure, conduction block or prolonged sinus node pauses should be considered (see section "Special precautions for use").

** Hallucinations, agitation, and aggressive behavior have been 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 independently of NMS and in close temporal association with the initiation of donepezil treatment and dose escalation.

Reporting suspected adverse reactions

Reporting of 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 are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister, 3 or 5 blisters per cardboard pack.

Prescription category. Prescription-only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and location of operations.

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.