Doenza-sanovel

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOENZA-sanovel (DOENZA-sanovel)

Composition:

Active substance: donepezil;

1 tablet contains donepezil hydrochloride 5 mg;

Excipients: microcrystalline cellulose (PH101), lactose monohydrate, maize starch, hydroxypropylcellulose, magnesium stearate;

Coating: Opadry White Y-1-7000 (hypromellose 5 cP methocel E5 LV, polyethylene glycol 400, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets.

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

Pharmacological properties.

Pharmacodynamics.

Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, the primary cholinesterase in the brain. Donepezil inhibits this enzyme approximately 1,000 times more potently than butyrylcholinesterase—an enzyme primarily found outside the central nervous system.

Inhibition of acetylcholinesterase by donepezil hydrochloride in erythrocytes correlates with changes in the ADAS-cog—a sensitive scale assessing specific aspects of cognitive function. The ability of donepezil hydrochloride to modify the underlying neuropathology of the disease has not been studied. Therefore, it is considered that donepezil hydrochloride does not affect the progression of the disease.

Pharmacokinetics.

Absorption. Peak plasma concentration is reached approximately 3–4 hours after administration. Plasma concentrations and the area under the pharmacokinetic curve increase proportionally with dose. The terminal elimination half-life is approximately 70 hours; thus, once-daily dosing leads gradually to a steady state, which is 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.

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

Metabolism/Excretion. Donepezil hydrochloride is excreted unchanged in urine and undergoes biotransformation via the cytochrome P450 system, forming several metabolites, not all of which have been identified.

After a single 5 mg dose of 14C-labeled donepezil hydrochloride, unchanged donepezil accounted for 30% of the administered dose in plasma, 6-O-desmethyl donepezil (the only metabolite with activity similar to donepezil hydrochloride) for 11%, donepezil-cis-N-oxide for 9%, 5-O-desmethyl donepezil for 7%, and the glucuronide conjugate of 5-O-desmethyl donepezil for 3%. Approximately 57% of the administered radioactive dose was excreted in urine (17% as unchanged donepezil) and 14.5% in feces. This indicates that the primary elimination pathways are biotransformation and renal excretion. There is no information on the potential for enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.

Special patient populations. Sex, race, and smoking do not have a significant effect on plasma concentrations of donepezil hydrochloride. Pharmacokinetics of donepezil have not been studied in official trials in healthy elderly volunteers or in patients with Alzheimer's disease or vascular dementia. However, mean plasma levels in elderly patients are comparable to those in young healthy volunteers.

Elevated steady-state concentrations of donepezil hydrochloride are observed in patients with mild to moderate hepatic impairment.

Clinical characteristics.

Indications.

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

Contraindications.
Known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipient of the medicinal product. Pregnancy.

Interaction with other medicinal products and other forms of interactions.

Clinical experience with donepezil is limited; therefore, all possible interactions with other drugs are not known. The physician should be aware of the potential for new, yet unknown interactions with donepezil.

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 the metabolism of donepezil involves cytochrome P450 isoenzymes 3A4 and, to a lesser extent, 2D6. In vitro interaction studies indicate that ketoconazole and quinidine, which are inhibitors of CYP3A4 and CYP2D6 respectively, inhibit the metabolism of donepezil. Therefore, these and other CYP3A4 inhibitors (e.g., itraconazole, erythromycin), as well as CYP2D6 inhibitors (e.g., fluoxetine), may suppress the metabolism of donepezil. In a study involving healthy volunteers, ketoconazole increased mean plasma concentrations of donepezil by approximately 30%. However, this is unlikely to affect clinical outcomes. Enzyme inducers (e.g., rifampicin, phenytoin, carbamazepine, alcohol) may reduce donepezil levels. Since the extent of inhibitory or inductive effects is unknown, such drug combinations should be used with caution. Donepezil hydrochloride may potentially affect the action of drugs with anticholinergic activity. There is also a possibility of synergy when donepezil is used concomitantly with drugs such as succinylcholine, other neuromuscular blocking agents, cholinomimetics, or beta-blockers affecting cardiac conduction. Atypical changes in blood pressure and heart rate may occur with concomitant use of donepezil and other cholinomimetics or quaternary anticholinergics (e.g., glycopyrrolate).

Cases of QT interval prolongation and torsade de pointes ventricular tachycardia have been reported with donepezil use. Caution is recommended when donepezil is used concomitantly with other medicinal products that prolong the QT interval. Clinical monitoring (ECG) may be necessary. Examples of such medicinal products 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.

The efficacy of the drug Doenza has not been studied in patients with severe dementia due to Alzheimer's disease, other types of dementia, or other types of memory impairment (e.g., age-associated memory impairment).

Analgesia. As a cholinesterase inhibitor, donepezil may intensify neuromuscular blockade of the succinylcholine type during anesthesia.

Cardiovascular disorders. Due to their pharmacological action, cholinesterase inhibitors may exert a vagotonic effect on heart rate (e.g., bradycardia). Such disturbances are particularly significant in patients with sick sinus syndrome or other supraventricular conduction abnormalities, such as sinoatrial or atrioventricular block. Cases of dizziness and seizures have also been reported.

Post-marketing reports include QT interval prolongation and torsades de pointes (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Patients with a history or family history of QT interval prolongation, those taking medicinal products affecting the QT interval, or those with cardiac conditions (e.g., uncompensated heart failure, myocardial infarction, bradyarrhythmia) or electrolyte imbalances (hypokalemia, hypomagnesemia) may require clinical monitoring (ECG).

Gastrointestinal disorders. Patients at risk of ulcer development, such as those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs (NSAIDs), should be monitored. However, clinical studies have shown no increased incidence of peptic ulcer formation or gastrointestinal bleeding with donepezil use.

Urinary system disorders. Cholinomimetics may potentially cause urinary outflow obstruction from the bladder (although no such cases have been reported).

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

Cholinomimetics may exacerbate or induce extrapyramidal symptoms.

Pulmonary disorders. Due to cholinomimetic activity, cholinesterase inhibitors should be used with caution in patients with asthma or a history of obstructive pulmonary diseases.

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

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

Mortality in vascular dementia studies

In all Alzheimer's disease trials, as well as in combined analyses of Alzheimer's disease trials with other dementia trials including those in vascular dementia, the mortality rate in placebo-treated groups numerically exceeded that in groups treated with donepezil hydrochloride.

Malignant neuroleptic syndrome (MNS)

Malignant neuroleptic syndrome occurs very frequently in patients receiving neuroleptics and taking donepezil. Dangerous symptoms such as hyperthermia, muscle rigidity, autonomic nervous system dysfunction, altered consciousness, and elevated creatine phosphokinase levels may occur, especially in patients receiving concomitant antipsychotic therapy. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. Treatment should be discontinued if a patient develops signs and symptoms suggestive of MNS or presents with unexplained high fever without other clinical manifestations.

This medicinal product contains lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take Doenza-sanovel.

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient data on the use of donepezil in pregnant women; therefore, Doenza-sanovel should not be taken 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 influence reaction speed when driving or operating machinery

Dementia may impair the ability to drive or operate machinery. Alzheimer-type dementia may impair the ability to drive vehicles or operate machinery. Additionally, donepezil may cause fatigue, dizziness, and muscle cramps, primarily at the beginning of treatment or when the dose is increased. The ability of patients with Alzheimer's disease to drive or operate complex machinery should be regularly assessed by a physician.

Method of Administration and Dosage

The medicinal product Doenza-Sanovel should be taken orally, in the evening, immediately before bedtime. In cases of sleep disturbances, including unusual dreams, nightmares, or insomnia (see section "Side Effects"), administration in the morning may be considered.

Adults/Elderly patients. Treatment should be initiated at a dose of 5 mg/day (once daily). Doenza-Sanovel should be administered at a dose of 5 mg/day for at least one month to assess early signs of clinical efficacy and to achieve steady-state concentrations of donepezil hydrochloride. After clinical evaluation of the efficacy of the 5 mg/day dose over one month, the dose may be increased to 10 mg/day (once daily). The maximum recommended daily dose is 10 mg. The use of doses higher than 10 mg/day has not been studied in clinical trials.

Treatment should be conducted under the supervision of a physician experienced in the diagnosis of Alzheimer's disease and 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). Treatment should only be initiated when a caregiver is available who will consistently supervise the patient's tablet intake.

Maintenance therapy should continue as long as a therapeutic effect is observed. If no therapeutic effect is observed, discontinuation of the medication should be considered.

Renal impairment. Patients with renal impairment may use the medication according to the same regimen, as the clearance of donepezil hydrochloride is not altered in such conditions.

Hepatic impairment. Due to the potential for increased exposure in mild to moderate hepatic impairment, dose escalation should be performed with careful consideration of individual tolerability.

There are no data available on the use of the medication in patients with severe hepatic impairment.

Children.

Doenza-Sanovel is not recommended for use in children and adolescents under 18 years of age.

Overdose.

Overdose of cholinesterase inhibitors may lead to a cholinergic crisis characterized by severe nausea, vomiting, salivation, increased sweating, bradycardia, arterial hypotension, respiratory depression, collapse, and seizures. Progressive muscle weakness may occur, which can be fatal if respiratory muscles are affected.

As with any overdose, general symptomatic treatment is indicated. Anticholinergic agents of the tertiary amine group, such as atropine, may be used as antidotes in case of donepezil hydrochloride overdose. Intravenous administration of atropine sulfate is recommended, with dose titration to effect: the initial dose is 1.0–2.0 mg intravenously, followed by dose adjustments based on clinical response. When other cholinomimetics are used concomitantly with anticholinergic agents of the quaternary ammonium compounds group (e.g., glycopyrrolate), atypical changes in blood pressure and heart rate have been observed. It is not known whether donepezil hydrochloride and/or its metabolites are removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

Adverse Reactions

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

The adverse reactions reported are listed below by system organ class and frequency. Frequency categories are 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), and not known (cannot be estimated from available data).

Infections and infestations:
Common – cold symptoms, rhinitis.

Metabolism and nutrition disorders:
Common – anorexia.

Psychiatric disorders:
Common – hallucinations,* agitation, aggressive behavior,** excitement,** sleep disturbances, and nightmares;
Not known – increased libido, hypersexuality.

Nervous system disorders:
Common – syncope,* dizziness, insomnia;
Uncommon – convulsions,* epileptic seizures;
Rare – extrapyramidal symptoms;
Very rare – CNS;
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.

Gastrointestinal disorders:
Very common – diarrhea, nausea;
Common – vomiting, abdominal discomfort;
Uncommon – gastrointestinal hemorrhage, gastric and duodenal ulcer, hypersalivation.

Hepatobiliary disorders:
Rare – liver function abnormalities, 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 – injuries, falls.

* In patients presenting with syncope or convulsions, consideration should be given to the possibility of cardiac block or prolonged sinus pauses (see section "Special precautions for use").

** Reports of hallucinations, excitement, 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 CNS events and in close temporal association with the initiation of donepezil treatment and dose increases.

Shelf life. 3 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C.

Packaging. 14 tablets in a blister pack. 1 blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Sanovel Ilac San. ve Tic. A.S., Turkey.

Manufacturer's address and place of business.
Balaban Quarter, Cihanger Sokak, No: 10, Istanbul, 34580, Silivri District, Turkey.