Nobel Ilac




Full Prescribing Info
Donepezil hydrochloride.
Each orodispersible tablet contains: Donepezil hydrochloride 5 mg.
Each orodispersible tablet contains: Donepezil hydrochloride 10 mg.
Pharmacotherapeutic group: Cholinesterase inhibitors.
Pharmacology: Pharmacodynamics: Donepezil hydrochloride is a selective and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride is, in vitro over 1000 times more potent, an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme that is present mainly outside the central nervous system.
Clinical studies: Mild and moderate Alzheimer's disease: In patients with Alzheimer's Dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of donepezil hydrochloride produced steady-state inhibition of acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6% and 77.3%, respectively when measured post dose. The inhibition of acetylcholinesterase (AChE) in red blood cells by donepezil hydrochloride has been shown to correlate to changes in ADAS-cog, a sensitive scale that examines selected aspects of cognition. The potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus, donepezil hydrochloride can not be considered to have any effect on the progress of the disease.
Efficacy of treatment of Alzheimer's Dementia with donepezil has been investigated in four placebo-controlled trials, 2 trials of 6-month duration and 2 trials of 1-year duration.
In the 6 months clinical trial, an analysis was done at the conclusion of donepezil treatment.
In this analysis, a combination of three efficacy criteria has been used. The ADAS-Cog (a measure of cognitive performance), the Clinician Interview Based Impression of Change with Caregiver Input (CIBIC+ - a measure of global function) and the Activities of Daily Living Subscale of the Clinical Dementia Rating Scale (CDR - a measure of capabilities in community affairs, home and hobbies and personal care).
Pharmacokinetics: Absorption: Maximum plasma levels (Cmax) are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve (AUC) rise in proportion to the dose. The terminal disposition half-life is approximately 70 hours, thus, administration of multiple single-daily doses results in gradual approach to steady-state. Approximate steady-state is achieved within 3 weeks after initiation of therapy. Once at steady-state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day.
Food does not affect the absorption of donepezil hydrochloride.
Distribution: Donepezil hydrochloride is approximately 95% bound to human plasma proteins. The plasma protein binding of the active metabolite 6-O-desmethyldonepezil is not known.
The distribution of donepezil hydrochloride in various body tissues has not been definitively studied. However, in a mass balance study conducted in healthy male volunteers, 240 hours after the administration of a single 5 mg dose of 14C-labelled donepezil hydrochloride, approximately 28% of the label remained unrecovered. This suggests that donepezil hydrochloride and/or its metabolites may persist in the body for more than 10 days.
Biotransformation: Donepezil hydrochloride is both excreted in the urine intact and metabolised by the cytochrome P450 system to multiple metabolites, not all of which have been identified.
Following administration of a single 5 mg dose of 14C-labelled donepezil hydrochloride, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil hydrochloride (30%), 6-O-desmethyldonepezil (11% - only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyldonepezil (7%) and the glucuronide conjugate of 5-O-desmethyldonepezil (3%).
Elimination: Its plasma half life is approximately 70 hours. Approximately 57% of the total administered radioactivity was recovered from the urine (17% as unchanged donepezil), and 14.5% was recovered from the faeces, suggesting biotransformation and urinary excretion as the primary routes of elimination There is no evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.
Donepezil hydrochloride is indicated in the symptomatic treatment of mild to moderate Alzheimer's Dementia.
Dosage/Direction for Use
Adults/Elderly: The treatment is started with single dose of 5 mg daily. The dose of 5 mg/day should be continued for at least one month in order to receive the earliest clinical responses to the treatment and to reach the steady state concentrations of donepezil hydrochloride. The dose of Donepezil can be increased to the single dose of 10 mg/day after the evaluation of the clinical response obtained with 5 mg dose for one month. The highest recommended dose is 10 mg. The doses above 10 mg/day have not been studied in clinical trials.
Should the treatment be interrupted, a gradual decrease is seen in the beneficial effects of Donepezil. No "rebound" or withdrawing effect has been noticed after the sudden interruption of the treatment.
Or as prescribed by the physician.
Route of administration: Donepezil should be orally taken as daily single dose just before going to bed.
The tablet should be placed onto the tongue, left to dissolve and swollen with a glass of water or without water according to the preference of the patient.
Additional information for special populations: Renal impairment: As the clearance of donepezil hydrochloride is not affected from renal impairment, a similar regime can be applied in these patients.
Hepatic impairment: The dose adjustment should be done according to the personal tolerability due to possible increase in exposure to medicine in case of mild and moderate hepatic impairment.
In a study performed on 10 individuals with stable alcoholic cirrhosis and 10 healthy individuals with the same age and sex the clearance of donepezil hydrochloride decreased 20% in cirrhosis patients in comparison to healthy individuals.
Pediatric population: Donepezil hydrochloride is not recommended to be used in children as its efficacy and safety have not been proven in children.
Geriatric population: No study has been performed to examine the relationship between the pharmacokinetics of donepezil hydrochloride and age. However, the average plasma concentrations monitored in elderly patients with Alzheimer was comparable to that of young healthy volunteers during the treatment.
Symptoms of overdose/Cholinergic crisis: Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.
Treatment: As in any case of overdose, general supportive measures should be utilised. Tertiary anticholinergics such as atropine (an intravenous starting dose of 1 to 2 mg may be followed by next doses depending on the clinical response) may be used as an antidote for donepezil hydrochloride overdosage. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (haemodialysis, peritoneal dialysis, or haemofiltration).
Donepezil is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives or any other ingredients of this medicine.
Special Precautions
The treatment should be started and directed by a doctor who is experienced in the diagnosis of Alzheimer's Dementia and in the treatment of the disease. The diagnosis should be done in compliance with the approved directives (eg. DSM IV, ICD 10).
Donepezil treatment should only be started when there is a responsible person (a relative of the patients, caregiver etc.) who can regularly monitor the medicine intake of the patient.
The treatment should be continued as long as the patient has therapeutical benefits from the medicine. Therefore, the clinical advantages of donepezil should be re-evaluated in certain time intervals. When there is no evidence showing the presence of the therapeutic effect left, the medicine should be stopped. The response that individuals will give to donepezil cannot be expected beforehand.
The use of donepezil hydrochloride in patients with other dementia types and other Memory disorders (eg. Amnestic Mild Cognitive Impairment) is still under evaluation.
Anaesthesia: Being a cholinesterase inhibitor, donepezil hydrochloride may increase the succinylcholine type of muscle relaxation during anaesthesia.
Cardiovascular conditions: Vagotonic effects (like bradycardia) may occur on the heartbeat due to the pharmacological effects of the cholinesterase inhibitors. The potential of this effect to be seen may be particularly important for patients with "sick sinus syndrome" and other supraventricular cardiac conduction disorders like sinoatrial or atrioventricular block.
There are reports of syncope and convulsions. Heart block or long sinus remission should be considered while examining these patients.
Gastrointestinal conditions: Cholinomimetics may increase the production of gastric acid. Patients with ulcer history or with high risk of ulcer development such as patients taking concomitant non-steroidal antiinflammatory drug (NSAID) should be closely followed in terms of the symptoms. On the other hand, no increase was observed in the incidence of peptic ulcer or gastrointestinal bleeding in clinical studies comparing donepezil hydrochloride and placebo.
Genito-urinary system: Cholinomimetics may lead to bladder outlet obstruction although this has not been observed in the clinical studies performed with donepezil hydrochloride.
Central nervous system: Attacks: It is believed that cholinomimetics has a potential to cause generalized convulsions. However, the attacks may also be an indicator of Alzheimer's disease. Cholinomimetics have a potential to induce or increase the extrapyramidal symptoms.
Pulmonary system: Cholinesterase inhibitors should be used with care in patients with a history of asthma or obstructive pulmonary disease depending on its cholinomimetic effects.
The concomitant use of donepezil hydrochloride with other acetylcholinesterase (AchE) inhibitors, cholinergic system agonists or antagonists should be avoided.
Effects on ability to drive and use machines: Alzheimer's Dementia may lead to impairment in driving performance and increase the ability to use machines.
Additionally, donepezil may cause tiredness, dizziness and muscle cramps especially at the beginning or during dose increasement. The doctor managing the treatment should regularly evaluate the ability of patients taking donepezil treatment for driving or using complex machines.
Use In Pregnancy & Lactation
General recommendation: Pregnancy: Pregnancy category: C.
Women of childbearing potential/Birth control (Contraception).
There is no sufficient and fully-controlled study performed on pregnant women. Donepezil should not be used during pregnancy unless it is definitely necessary.
Breastfeeding: It is not known whether donepezil hydrochloride passes into human milk and there is no study performed in breastfeeding women. Donepezil should not be used in breastfeeding women.
Fertility: Donepezil hydrochloride had no effect on fertility in rats.
Adverse Reactions
The most common adverse effects are diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia.
The frequency of Alzheimer patients from each stage experiencing adverse effects who use donepezil hydrochloride are given as follows.
Adverse reactions reported as more than an isolated case are listed as follows, by system organ class and by frequency. 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), unknown (cannot be expected from the available data).
Infections and infestations: Common: Cold.
Metabolism and nutritional disorders: Common: Anorexia.
Psychiatric disorders: Common: Hallucination**, agitation**, aggressive behaviours**, abnormal dreams.
Nervous system disorders: Common: Syncope*, dizziness, insomnia. Uncommon: Seizure*. Rare: Extrapyramidal symptoms. Very Rare: Neuroleptic Malignant Syndrome.
Cardiac disorders: Uncommon: Bradycardia. Rare: Sino-atrial block, atrioventricular block.
Gastrointestinal disorders: Very common: Diarrhoea, nausea. Common: Vomiting, abdominal discomfort. Uncommon: Gastrointestinal bleeding, gastric and duodenal ulcers.
Hepato-biliary disorders: Rare: Hepatic dysfunction including hepatitis***.
Diseases of skin and subcutaneous tissue: Common: Urticaria, rash.
Musculoskeletal disorders and diseases of connective tissues and bones: Common: Muscle cramps. Very rare: Rhabdomyolysis.
Hepato-biliary disorders: Common: Urinary incontinence.
General disorders and administration-site diseases: Very common: Headache. Common: Pain, weakness.
Investigations: Uncommon: Minor increase in serum concentration of muscle creatine kinase.
Injury and poisoning: Common: Accident.
* In investigating patients for syncope or seizure the possibility of heart block or long sinusal pauses should be considered.
** Reports of hallucinations, abnormal dreams, nightmares, agitation and aggressive behaviour have resolved on dose-reduction or discontinuation of treatment.
*** In cases of unexplained liver dysfunction, withdrawal of Donepezil should be considered.
Drug Interactions
The concomitant use of donepezil hydrochloride and other cholinesterase inhibitors should be avoided.
Donepezil hydrochloride and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, digoxin, thioridazine, risperidone and sertraline in human.
Donepezil hydrochloride is not affected by its concomitant use with digoxin, cimetidine, thioridazine, risperidone and sertraline.
The enzyme inducers like rifampicin, carbamazepine and alcohol may decrease the donepezil levels. Since the significance of the inhibitory or inducing effect is not known, such drug combinations should be used with care.
Donepezil hydrochloride has a potential to interact with medicines with anticholinergic activity. There is also a potential of synergistic activity in concomitant treatments with medicines with succinylcholine, other agents blocking neuromuscular end plate or cholinergic agonists or beta blockers having effects on cardiac conduction.
Caution For Usage
Instructions for Use/Handling: No special requirements.
Store at temperatures not exceeding 30°C.
ATC Classification
N06DA02 - donepezil ; Belongs to the class of anticholinesterases. Used in the management of dementia.
Orodispersible tab 5 mg (white coloured, round, one face "ALZ" engraved, one face "5" engraved) x 28's. 10 mg (white coloured, round, one face "ALZ" engraved, one face "10" engraved) x 28's.
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