Instructions for Donex orally dispersible tablets 10 mg No. 30
Composition
active ingredient: donepezil hydrochloride;
1 tablet contains donepezil hydrochloride 5 mg or 10 mg;
Excipients: polacrilin potassium; microcrystalline cellulose; lactose monohydrate; monosodium citrate anhydrous; aspartame (E 951); croscarmellose sodium; colloidal anhydrous silicon dioxide; magnesium stearate.
Dosage form
Orodispersible tablets.
Main physicochemical properties:
5 mg tablets: round, flat, beveled-edge tablets, white to off-white in color, embossed with "5" on one side and plain on the other side;
10 mg tablets: round, flat, beveled edge tablets, white to off-white in colour, debossed with “10” on one side and plain on the other side.
Pharmacotherapeutic group
Drugs used in dementia. Cholinesterase inhibitors. ATX code N06D A02.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Donepezil hydrochloride is a specific, reversible inhibitor of acetylcholinesterase, the major type of cholinesterase in the brain. In vitro, donepezil hydrochloride has been shown to be 1000 times more potent at inhibiting the activity of this enzyme than it is at inhibiting the activity of butyrylcholinesterase, which is predominantly located outside the central nervous system (CNS).
Alzheimer's dementia
It is known that in patients with Alzheimer's disease who participated in clinical trials, the administration of donepezil at a dose of 5 mg or 10 mg 1 time per day resulted in inhibition of acetylcholinesterase activity (which was determined in the cell membrane of erythrocytes) by 63.6% and 77.3%, respectively. It was shown that the inhibition of acetylcholinesterase in erythrocytes by donepezil hydrochloride correlated with changes in the ADAS-cog score (Alzheimer's Disease Assessment Scale for Cognitive Function), which allows to test some aspects of cognitive function. The ability of donepezil hydrochloride to modify the course of the main neurological syndromes has not been studied. Therefore, it is impossible to assess the effect of donepezil on the progression of this disease.
The efficacy of donepezil treatment was studied in four placebo-controlled studies: two studies of 6 months duration and two studies of 1 year duration.
It is known that in a 6-month clinical study, the effectiveness of donepezil treatment was analyzed based on a combination of three criteria: the number of points on the ADAS-Cog scale (an indicator of cognitive function), the number of points on the scale for assessing the patient's condition by a doctor or caregivers (the CIBIC+ scale, an indicator of general function), and the number of points on the subscale for assessing daily activities with clinical signs of dementia (an indicator of the ability to perform social activities, housework, favorite activities, and self-care).
Patients who meet the criteria below will be considered to have responded to treatment.
Response: improvement in the ADAS-Cog score by at least 4 points, no deterioration in the CIBIC+ score, no deterioration in the subscale for assessing daily activities with clinical signs of dementia.
| Patient groups | Reaction (%) |
Population grouped by treatment assigned n = 365 | All patients evaluated n = 352 |
| Placebo group | 10% | 10% |
| Donepezil 5 mg group | 18%* | 18%* |
| Donepezil 10 mg group | 21%* | 22%** |
* p < 0.05;
**p<0.01.
Donepezil caused a dose-dependent, statistically significant increase in the relative number of patients who responded to treatment.
Pharmacokinetics.
Absorption
After oral administration, the maximum plasma concentration Cmax is reached after approximately 3-4 hours. Plasma concentration and area under the concentration-time curve (AUC) increase in proportion to the dose. The terminal half-life is approximately 70 hours, so multiple once-daily dosing results in a gradual achievement of steady-state concentrations. Steady-state concentrations are reached approximately within 3 weeks of initiation of treatment. Once steady-state is reached, donepezil hydrochloride concentrations and the associated pharmacodynamic activity remain virtually unchanged throughout the day.
Food does not affect the absorption of donepezil hydrochloride.
Distribution
Donepezil hydrochloride is approximately 95% bound to plasma proteins. The extent of plasma protein binding of the active metabolite 6-O-desmethyldonepezil is unknown. The distribution of donepezil hydrochloride in various body tissues has not been studied in detail. However, a mass balance study in healthy male volunteers showed that approximately 28% of the label remained unrecovered 240 hours after a single administration of 5 mg of 14C-labeled donepezil hydrochloride. This suggests that donepezil hydrochloride and/or its metabolites may persist in the body for more than 10 days.
Donepezil hydrochloride can be excreted unchanged in the urine or metabolized in the liver by cytochrome P450 isoenzymes to form many metabolites, not all of which have been identified. After a single dose of 5 mg of 14C-labeled donepezil hydrochloride, the plasma radioactivity, expressed as a percentage of the administered dose, was mainly due to intact donepezil hydrochloride (30%), 6-O-desmethyldonepezil (11%, the only metabolite that exhibits the same activity as donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyldonepezil (7%) and the glucuronide conjugate of 5-O-desmethyl-donepezil (3%). Approximately 57% of the total administered radioactivity was recovered in the urine (17% as unchanged donepezil) and 14.5% was recovered in the feces, indicating that biotransformation and urinary excretion were the major routes of elimination. There was no evidence of enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.
The decrease in plasma concentrations of donepezil occurs with a 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 were similar in patients and in young healthy volunteers.
In patients with mild to moderate hepatic impairment, steady-state concentrations of donepezil were increased, with AUC increasing by 48% and mean Cmax increasing by 39% (see section 4.2).
Indication
The drug Donex®, orodispersible tablets, is indicated for the symptomatic treatment of mild to moderate Alzheimer's dementia.
Contraindication
Hypersensitivity to donepezil hydrochloride, piperidine derivatives or to any of the excipients of the drug.
Interaction with other medicinal products and other types of interactions
Donepezil hydrochloride and/or any of 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, in particular isoenzyme 3A4 and to a lesser extent isoenzyme 2D6, are actively involved in the metabolism of donepezil. In vitro drug interaction studies have shown that ketoconazole and quinidine, which are inhibitors of CYP3A4 and 2D6, 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 in healthy volunteers, ketoconazole increased the mean blood concentration of donepezil by approximately 30%. Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol, may decrease the blood concentration of donepezil. The extent of the induction or inhibition is unknown, and such combinations should be used with caution. Donepezil hydrochloride may interact with drugs with anticholinergic activity, reducing their effect. Synergistic activity may occur when Donex® is administered concomitantly with succinylcholine, other muscle relaxants, cholinergic agonists or beta-blockers that affect cardiac conduction.
Cases of QTc prolongation and torsade de pointes have been reported with donepezil. Caution is advised when donepezil is used concomitantly with other medicinal products known to prolong the QTc interval and 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).
Application features.
The use of donepezil in dementia in patients with severe Alzheimer's disease, other types of dementia, or other types of memory impairment (e.g., age-related cognitive decline) has not been studied.
Anesthesia: Donepezil, as a cholinesterase inhibitor, may enhance muscle relaxation when depolarizing muscle relaxants (succinylcholine type) are used during anesthesia.
Syncope and seizures have been reported. When examining such patients, special attention should be paid to the state of the cardiac conduction system and the possibility of conduction block or long sinus node pauses should be considered.
QTc prolongation and torsade de pointes have been reported in the post-marketing setting (see sections 4.5 and 4.8).
Caution is advised in patients with a history of QTc prolongation or a family history of QTc prolongation, in patients taking medications that affect the QTc interval, in patients with cardiac disease (e.g., decompensated heart failure, recent myocardial infarction, bradyarrhythmias) or electrolyte disturbances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be necessary.
Gastrointestinal disorders: Patients at increased risk of developing ulcers should be closely monitored for gastrointestinal symptoms, particularly those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs. However, in clinical trials with donepezil, there was no increase in the incidence of gastric and duodenal ulcers or gastrointestinal bleeding compared to placebo.
Genitourinary disorders: Cholinomimetics may cause urinary outflow disturbances, although such disturbances were not observed in clinical studies with donepezil.
Neurological disorders: Epileptic seizures: Cholinomimetics are thought to have the ability to induce generalized seizures. However, such seizures may also be a manifestation of Alzheimer's disease itself.
Cholinomimetics have the potential to exacerbate or cause extrapyramidal disorders.
Neuroleptic malignant syndrome (NMS)
NMS is a life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic dysfunction, altered consciousness, and elevated serum creatine phosphokinase, particularly in patients receiving concomitant antipsychotic therapy. NMS may be complicated by myoglobinuria (rhabdomyolysis) and acute renal failure. Treatment should be discontinued if the patient develops signs and symptoms suggestive of NMS or if a high fever of unknown etiology occurs without additional clinical manifestations.
Pulmonary diseases: Cholinesterase inhibitors, due to their cholinomimetic effects, should be administered with caution to patients with a history of bronchial asthma or chronic obstructive pulmonary disease.
Donepezil is not recommended for use with other acetylcholinesterase inhibitors, agonists or antagonists of the cholinergic system.
Significant hepatic impairment: There are no data in patients with significant hepatic impairment.
Mortality in clinical trials in patients with vascular dementia: Three clinical trials of 6 months duration were reported in patients meeting the NINDS-AIREN criteria for probable or possible vascular dementia. The NINDS-AIREN criteria were designed to identify patients whose dementia was likely to be due exclusively to vascular causes and to exclude patients with Alzheimer's disease. In the first study, the incidence of fatal events was 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, the incidence of death was 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, the incidence of death was 11/648 (1.7%) with donepezil hydrochloride 5 mg and 0/326 (0%) with placebo. In all three vascular dementia studies, the incidence of death in the pooled donepezil hydrochloride group (1.7%) was quantitatively higher than in the placebo group (1.1%), but this difference was not statistically significant. The majority of deaths in patients receiving either donepezil hydrochloride or placebo were due to various vascular causes, as would be expected in the elderly with pre-existing vascular disease. In an analysis of all serious non-fatal and fatal vascular events, there was no difference in the incidence of these events between the donepezil hydrochloride and placebo groups.
In studies of donepezil hydrochloride in Alzheimer's disease (n = 4146) and pooled data from Alzheimer's disease and dementia studies, including vascular dementia studies (total n = 6888), the incidence of deaths in the placebo groups was quantitatively higher than in the donepezil hydrochloride groups.
The drug Donex® contains lactose, therefore it is not recommended for use in patients with rare hereditary or acquired disorders such as fructose or galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.
The drug contains aspartame, a derivative of phenylalanine, which is dangerous for patients with phenylketonuria.
Use during pregnancy or breastfeeding.
Pregnancy
There are no reliable data on the use of donepezil in pregnant women.
It is known that in animal experiments there was no teratogenic effect, but there were signs of toxicity in the peri- and postnatal period. The potential risk for humans remains unknown.
Donepezil is not recommended for use during pregnancy unless clearly necessary.
Breastfeeding period
Donepezil is known to be excreted in the milk of rats. Studies in lactating women have not been conducted, so it is unknown whether donepezil hydrochloride is excreted in human milk. Therefore, women should discontinue breastfeeding during treatment with donepezil.
The ability to influence the reaction speed when driving vehicles or other mechanisms.
Since donepezil may cause fatigue, dizziness, muscle cramps, especially at the beginning of treatment or when the dose is increased, it may have a minor or moderate adverse effect on the ability to drive and use machines.
However, dementia may also impair a patient's ability to drive or operate machinery. Accordingly, the physician should regularly assess the patient's ability to drive or operate complex mechanical devices during treatment with donepezil.
Application features
The use of donepezil in dementia in patients with severe Alzheimer's disease, other types of dementia, or other types of memory impairment (e.g., age-related cognitive decline) has not been studied.
Anesthesia: Donepezil, as a cholinesterase inhibitor, may enhance muscle relaxation when depolarizing muscle relaxants (succinylcholine type) are used during anesthesia.
Cardiovascular disorders: Cholinesterase inhibitors, due to their pharmacological action, may have a vagotonic effect on heart rate (e.g., bradycardia). This effect may be of particular importance in patients with sick sinus syndrome or other supraventricular conduction disorders, such as sinoatrial or atrioventricular block.
Syncope and seizures have been reported. When examining such patients, special attention should be paid to the state of the cardiac conduction system and the possibility of conduction block or long sinus node pauses should be considered.
QTc prolongation and torsade de pointes have been reported in the post-marketing setting (see sections 4.5 and 4.8).
Caution is advised in patients with a history of QTc prolongation or a family history of QTc prolongation, in patients taking medications that affect the QTc interval, in patients with cardiac disease (e.g., decompensated heart failure, recent myocardial infarction, bradyarrhythmias) or electrolyte disturbances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be necessary.
Gastrointestinal disorders: Patients at increased risk of developing ulcers should be closely monitored for gastrointestinal symptoms, particularly those with a history of peptic ulcer disease or those taking nonsteroidal anti-inflammatory drugs. However, in clinical trials with donepezil, there was no increase in the incidence of gastric and duodenal ulcers or gastrointestinal bleeding compared to placebo.
Genitourinary disorders: Cholinomimetics may cause urinary outflow disturbances, although such disturbances were not observed in clinical studies with donepezil.
Neurological disorders: Epileptic seizures: Cholinomimetics are thought to have the ability to induce generalized seizures. However, such seizures may also be a manifestation of Alzheimer's disease itself.
Cholinomimetics have the potential to exacerbate or cause extrapyramidal disorders.
Neuroleptic malignant syndrome (NMS)
Pulmonary diseases: Cholinesterase inhibitors, due to their cholinomimetic effects, should be administered with caution to patients with a history of bronchial asthma or chronic obstructive pulmonary disease.
Donepezil is not recommended for use with other acetylcholinesterase inhibitors, agonists or antagonists of the cholinergic system.
Significant hepatic impairment: There are no data in patients with significant hepatic impairment.
Mortality in clinical trials in patients with vascular dementia: Three clinical trials of 6 months duration were reported in patients meeting the NINDS-AIREN criteria for probable or possible vascular dementia. The NINDS-AIREN criteria were designed to identify patients whose dementia was likely to be due exclusively to vascular causes and to exclude patients with Alzheimer's disease. In the first study, the incidence of fatal events was 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, the incidence of death was 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, the incidence of death was 11/648 (1.7%) with donepezil hydrochloride 5 mg and 0/326 (0%) with placebo. In all three vascular dementia studies, the incidence of death in the pooled donepezil hydrochloride group (1.7%) was quantitatively higher than in the placebo group (1.1%), but this difference was not statistically significant. The majority of deaths in patients receiving either donepezil hydrochloride or placebo were due to various vascular causes, as would be expected in the elderly with pre-existing vascular disease. In an analysis of all serious non-fatal and fatal vascular events, there was no difference in the incidence of these events between the donepezil hydrochloride and placebo groups.
In studies of donepezil hydrochloride in Alzheimer's disease (n = 4146) and pooled data from Alzheimer's disease and dementia studies, including vascular dementia studies (total n = 6888), the incidence of deaths in the placebo groups was quantitatively higher than in the donepezil hydrochloride groups.
Precautions regarding auxiliary ingredients
The drug Donex® contains lactose, therefore it is not recommended for use in patients with rare hereditary or acquired disorders such as fructose or galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.
The drug contains aspartame, a derivative of phenylalanine, which is dangerous for patients with phenylketonuria.
Use during pregnancy or breastfeeding
Pregnancy
There are no reliable data on the use of donepezil in pregnant women.
It is known that in animal experiments there was no teratogenic effect, but there were signs of toxicity in the peri- and postnatal period. The potential risk for humans remains unknown.
Donepezil is not recommended for use during pregnancy unless clearly necessary.
Breastfeeding period
Donepezil is known to be excreted in the milk of rats. Studies in lactating women have not been conducted, so it is unknown whether donepezil hydrochloride is excreted in human milk. Therefore, women should discontinue breastfeeding during treatment with donepezil.
Ability to influence reaction speed when driving vehicles or other mechanisms
Since donepezil may cause fatigue, dizziness, muscle cramps, especially at the beginning of treatment or when the dose is increased, it may have a minor or moderate adverse effect on the ability to drive and use machines.
However, dementia may also impair a patient's ability to drive or operate machinery. Accordingly, the physician should regularly assess the patient's ability to drive or operate complex mechanical devices during treatment with donepezil.
Method of administration and doses
Adults/elderly
Treatment should begin with a dose of 5 mg once a day.
Treatment should be initiated and continued under the supervision of a physician experienced in the diagnosis and treatment of Alzheimer's dementia. The diagnosis should be made in accordance with generally accepted guidelines. Treatment with donepezil should only be initiated if the patient has a caregiver who will regularly monitor the patient's intake of the drug. Supportive treatment should be continued as long as the patient is showing a therapeutic effect. Therefore, the clinical benefit of donepezil treatment should be reassessed regularly. Treatment should be discontinued when the therapeutic effect is no longer observed. Individual response to donepezil cannot be predicted.
After discontinuation of treatment, the positive effect of donepezil gradually decreases.
Kidney and liver dysfunction
The same dosing regimen can be used in patients with renal impairment, as this impairment does not affect the clearance of donepezil hydrochloride.
Due to the possible increase in systemic exposure in mild to moderate hepatic impairment (see section 5.2), the dose should be adjusted according to individual tolerability. There are no data available in patients with significant hepatic impairment.
Method of application
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 the patient's preference.
In case of sleep disturbances, including unusual dreams, nightmares or insomnia (see section "Adverse reactions"), taking the drug in the morning may be considered.
Children.
The drug Donex® is not recommended for use in children under 18 years of age.
Overdose
The lethal single oral dose of donepezil hydrochloride in mice and rats is known to be on average 45 and 32 mg/kg, respectively, which is approximately 225 and 160 times the maximum recommended human dose (10 mg/day). In animals, dose-dependent signs of cholinergic stimulation were observed, which included decreased spontaneous motor activity, prone position, unsteadiness of gait, lacrimation, clonic convulsions, respiratory depression, salivation, miosis, fasciculations, and decreased skin temperature.
Overdose of cholinesterase inhibitors can lead to cholinergic crisis, which is characterized by severe nausea, vomiting, salivation, increased sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Muscle weakness may occur, which can be fatal due to respiratory muscle failure.
As with any drug overdose, general supportive measures should be taken. Tertiary anticholinergic agents, such as atropine, may be used as an antidote for donepezil overdose. Intravenous atropine sulfate is recommended, titrated to achieve a therapeutic effect. The initial dose is 1-2 mg intravenously, and subsequent doses should be titrated according to clinical response. Atypical blood pressure and heart rate responses have been reported with other cholinomimetics administered concomitantly with quaternary anticholinergic agents, such as glycopyrrolate. It is unknown whether donepezil hydrochloride and/or its metabolites are dialysable (hemodialysis, peritoneal dialysis or hemofiltration).
Side effects
The most common side effects are diarrhea, muscle cramps, fatigue, nausea, vomiting, and insomnia.
The frequency of the following adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).
Infections and infestations: common – cold;
Metabolism and digestion: often - anorexia.
Psychiatric disorders: often - hallucinations**, agitation**, aggressive behavior**, sleep disorders, nightmares**; frequency unknown - increased libido, hypersexuality.
Nervous system disorders: Common: syncope*, dizziness, insomnia; uncommon: convulsions*; rare: extrapyramidal disorders; very rare: neuroleptic malignant syndrome (NMS); frequency unknown: pleurothotonus (Pisa syndrome).
On the part of the heart: infrequently - bradycardia; rarely - sinoatrial block, atrioventricular block; frequency unknown - polymorphic ventricular tachycardia, including torsade de pointes, prolongation of the QT interval on the ECG.
From the gastrointestinal tract: very often - diarrhea, nausea; often - vomiting, abdominal discomfort; infrequently - gastrointestinal bleeding, gastric and duodenal ulcers, hypersalivation.
Hepatobiliary disorders: rarely - liver dysfunction, including hepatitis***.
Skin and subcutaneous tissue disorders: often - rash, itching.
Musculoskeletal and connective tissue disorders: often - muscle cramps; very rarely - rhabdomyolysis****.
Renal and urinary disorders: often - urinary incontinence.
Systemic disorders and reactions at the injection site: very often - headache; often - fatigue, pain.
Injury, poisoning and procedural complications: often - accident, including falls.
* When examining patients with syncope or epileptic seizures, the possibility of conduction block or long sinus node pauses should be considered (see section "Special instructions").
** Hallucinations, agitation, and aggressive behavior have been reported to resolve after dose reduction or discontinuation of treatment.
*** In cases of liver dysfunction of unknown cause, it is recommended to consider discontinuing donepezil.
**** Rhabdomyolysis has been reported to occur independently of SNS, with a clear temporal relationship to the initiation of donepezil treatment and dose escalation.
Expiration date
3 years
Storage conditions
Keep out of reach 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.
Vacation category
According to the recipe.
Producer
Genepharm SA
Location of the manufacturer and address of its place of business
18th km Marathonos Ave, Pallini Attica, 15351, Greece
