Dementile is for use in adult patients only.

Dementile is indicated for the symptomatic treatment of mild to moderately severe Alzheimer's dementia.

Adults/Elderly:

Treatment is initiated at 5 mg/day (once-a-day dosing). Dementile should be taken orally, in the evening, just prior to retiring. The 5 mg/day dose should be maintained for at least one month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of donepezil hydrochloride to be achieved. Following a one-month clinical assessment of treatment at 5 mg/day, the dose of Dementile can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses greater than 10 mg/day have not been studied in clinical trials.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be made according to accepted guidelines (e.g. DSM IV, ICD 10). Therapy with donepezil should only be started if a caregiver is available who will regularly monitor drug intake for the patient. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of donepezil should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Individual response to donepezil cannot be predicted.

Upon discontinuation of treatment, a gradual abatement of the beneficial effects of donepezil is seen.

Renal and hepatic impairment:

A similar dose schedule can be followed for patients with renal impairment, as clearance of donepezil hydrochloride is not affected by this condition.

Due to possible increased exposure in mild to moderate hepatic impairment, dose escalation should be performed according to individual tolerability.

There are no data for patients with severe hepatic impairment.

Children:

Dementile is not recommended for use in children.

If you forget to take Dementile:

If you forget to take a tablet, just take one tablet the following day at the usual time. Do not take a double dose to make up for a forgotten tablet.

If you forget to take your medicine for more than one week, call your doctor before taking any more medicine.

The use of Dementile in patients with severe dementia, other types of dementia or other types of memory impairment (e.g., age-related cognitive decline), has not been investigated.

Anaesthesia: Dementile, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.

Cardiovascular Conditions: Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important to patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions, such as sinoatrial or atrioventricular block.

There have been reports of syncope and seizures. In investigating such patients the possibility of heart block or long sinusal pauses should be considered.

Gastrointestinal Conditions: Patients at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), should be monitored for symptoms. However, the clinical studies with donepezil showed no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Genitourinary: Although not observed in clinical trials of donepezil, cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions: Seizures: Cholinomimetics are believed to have some potential to cause generalised convulsions. However, seizure activity may also be a manifestation of Alzheimer's disease.

Cholinomimetics may have the potential to exacerbate or induce extrapyramidal symptoms.

Pulmonary Conditions: Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

The administration of Dementile concomitantly with other inhibitors of acetyl-cholinesterase, agonists or antagonists of the cholinergic system should be avoided.

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

Dementile contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Cardiovascular conditions
Because of their pharmacological action, cholinesterase inhibitors may have vagotonic  effects on heart rate (e.g., bradycardia). The potential for this action may be particularly  important to patients with "sick sinus syndrome" or other supraventricular cardiac  conduction conditions, such as sinoatrial or atrioventricular block. 
There have been reports of syncope and seizures. In investigating such patients the  possibility of heart block or long sinusal pauses should be considered. 
There have been post-marketing reports of QTc interval prolongation and Torsade de  Pointes (see sections 4.5 and 4.8). Caution is advised in patients with pre-existing or family  history of QTc prolongation, in patients treated with drugs affecting the QTc interval, or in  patients with relevant pre-existing cardiac disease (e.g. uncompensated heart failure, recent  myocardial infarction, bradyarrhythmias), or electrolyte disturbances (hypokalaemia,  hypomagnesaemia). Clinical monitoring (ECG) may be required

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 affected by concurrent administration of digoxin or cimetidine. In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil. Drug interaction studies performed in vitro show that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil metabolism. Therefore these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine, could inhibit the metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by about 30%.

Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care. Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving medications such as succinylcholine, other neuro-muscular blocking agents or cholinergic agonists or beta blocking agents that have effects on cardiac conduction.

Cases of QTc interval prolongation and Torsade de Pointes have been reported for  donepezil. Caution is advised when donepezil is used in combination with other medicinal  products known to prolong the QTc interval and clinical monitoring (ECG) may be required. 

Examples include

• Class IA antiarrhythmics (e.g. quinidine).
• Class III antiarrhythmics (e.g. amiodarone, sotalol).
• Other antipsychotics (e.g. phenothiazine derivatives, sertindole, pimozide,  ziprasidone).
• Certain antibiotics (e.g. clarithromycin, erythromycin, levofloxacin, moxifloxacin)

Pregnancy: There are no adequate data from the use of donepezil in pregnant women. Studies in animals have not shown teratogenic effect but have shown peri and post natal toxicity. The potential risk for humans is unknown. Dementile should not be used during pregnancy unless clearly necessary.

Lactation: Donepezil is excreted in the milk of rats. It is not known whether donepezil hydrochloride is excreted in human breast milk and there are no studies in lactating women. Therefore, women on donepezil should not breast feed.

Pharmacotherapeutic group

Anti-dementia drugs, Anticholinesterases

ATC Code

N06DA02

Donepezil hydrochloride is a specific 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.

Alzheimer's Dementia

In patients with Alzheimer's Dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of Dementile 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 which examines selected aspects of cognition. The potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus Dementile cannot be considered to have any effect on the progress of the disease.

Efficacy of treatment with Dementile 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 using a combination of three efficacy criteria: the ADAS-Cog (a measure of cognitive performance), the Clinician Interview Based Impression of Change with Caregiver Input (a measure of global function) and the Activities of Daily Living Subscale of the Clinical Dementia Rating Scale (a measure of capabilities in community affairs, home and hobbies and personal care).

Patients who fulfilled the criteria listed below were considered treatment responders.

Response =   Improveement of ADAS-Cog of at least 4 points

                       No deterioration of CIBIC+

                       No Deterioration of activities of Daily Living Subscale of the Clinical Dementia Rating Scale

* p<0.05

** p<0.01

Dementile produced a dose-dependent statistically significant increase in the percentage of patients who were judged treatment responders.

Absorption:

Maximum plasma levels are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve 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 did 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.

Metabolism/Excretion:

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-desmethyl donepezil (11% - only metabolite that exhibits activity similar to 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 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.

Plasma donepezil concentrations decline with a half-life of approximately 70 hours.

Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil has not been formally studied in healthy elderly subjects or in Alzheimer's or vascular dementia patients. However mean plasma levels in patients closely agreed with those of young healthy volunteers.

Patients with mild to moderate hepatic impairment had increased donepezil steady state concentrations; mean AUC by 48% and mean C_max by 39 %.

Extensive testing in experimental animals has demonstrated that this compound causes few effects other than the intended pharmacological effects consistent with its action as a cholinergic stimulator. Donepezil is not mutagenic in bacterial and mammalian cell mutation assays. Some clastogenic effects were observed in vitro at concentrations overtly toxic to the cells and more than 3000 times the steady-state plasma concentrations. No clastogenic or other genotoxic effects were observed in the mouse micronucleus model in vivo. There was no evidence of oncogenic potential in long term carcinogenicity studies in either rats or mice.

Donepezil hydrochloride had no effect on fertility in rats, and was not teratogenic in rats or rabbits, but had a slight effect on still births and early pup survival when administered to pregnant rats at 50 times the human dose.

Not applicable.

Store below 30° C

Do not use beyond the expiry date or if the product shows any sign of deterioration.

Not applicable