Tonizep FDT

Tonizep FDT Mechanism of Action

donepezil

Manufacturer:

T. O. Chemicals

Distributor:

T. O. Chemicals
Full Prescribing Info
Action
Pharmacotherapeutic Group: Drugs for dementia. ATC Code: N06DA02.
Pharmacology: Pharmacodynamics: Donepezil hydrochloride is a specific inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. The drug binds reversibly with and inactivates cholinesterase, thus inhibiting hydrolysis of acetylcholine. As a result, the concentration of acetylcholine increases at cholinergic synapses. Donepezil hydrochloride is in vitro over 1000 times more potent an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme which is present mainly outside the central nervous system.
Alzheimer's dementia: Mild to moderately severe 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 membrane) 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 donepezil hydrochloride cannot be considered to have any effect on the progress of the disease.
Efficacy of treatment of Alzheimer's dementia with donepezil hydrochloride has been investigated in four placebo-controlled trials, 2 trials of 6-month duration and 2 trials of 1-year duration.
In the 6-month clinical trial, an analysis was done at the conclusion of donepezil hydrochloride treatment using a combination of three efficacy criteria: the ADAS-cog (a measure of cognitive performance), the Clinician's 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 (a measure of capabilities in community affairs, home and hobbies and personal care). (See Table 1.)
Patients who fulfilled the criteria listed below were considered treatment responders.
Response = Improvement 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.

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Donepezil hydrochloride produced a dose-dependent statistically significant increase in the percentage of patients who were judged treatment responders.
Severe Alzheimer's disease: Efficacy of treatment with donepezil hydrochloride in severe Alzheimer's disease has been investigated in three placebo-controlled trials of 6-month duration.
In each of the clinical trials, an analysis was done at the conclusion of donepezil hydrochloride treatment using a combination of three efficacy criteria: the total Severe Impairment Battery (SIB - a measure of cognitive performance in all three trials) score, the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+ - a measure of global function in two trials) or Clinical Global Impression of Change (CGI-I - a measure of global function in one trial) and the modified Alzheimer's Disease Cooperative Study - Activities of Daily Living inventory for severe Alzheimer's disease (ADCS-ADL-sev - a measure of function in all three trials). (See Table 2.)
Patients who fulfilled the criteria listed below were considered treatment responders.
Response = Improvement of SIB at least 4 points;
No deterioration of CIBIC+ or CGI-I;
No deterioration of ADCS-ADL-sev.

Click on icon to see table/diagram/image

Vascular dementia: Efficacy of treatment of vascular dementia with donepezil hydrochloride has been investigated in three placebo-controlled trials of 6-month duration in which the diagnostic criteria for vascular dementia proposed by the NINDS-AIREN consensus group (National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences) were used to define the population of patients studied.
An overall analysis was done at the conclusion of donepezil hydrochloride treatment using a combination of three efficacy criteria. (See Table 3.)
Patients who fulfilled the criteria listed in Table 3 were considered treatment responders.
Response = Improvement of ADAS-cog of at least 4 points and;
Improvement or no deterioration of CIBIC+ and;
Improvement or no deterioration of Clinical Dementia Rating functionality subscale.

Click on icon to see table/diagram/image

Donepezil hydrochloride produced a dose-dependent statistically significant increase in the percentage of patients who were judged treatment responders.
Pharmacokinetics: Absorption: Donepezil hydrochloride is well absorbed and food does not affect the absorption of the drug. 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 pharmacodynamics activity show little variability over the course of the day.
Distribution: Donepezil hydrochloride is approximately 96% bound to human plasma proteins (to albumin approximately 75% and α1-acid glycoprotein approximately 21%). The plasma protein binding of the active metabolite 6-O-desmethyl donepezil is not known. The steady-state volume of distribution is 12 to 16 L/kg. In a mass balance study conducted in healthy male volunteers, 240 hours after the administration of a single 5 mg dose of 14C-labeled 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 metabolized by the cytochrome P450 (CYP-450) isoenzymes 2D6 and 3A4 to multiple metabolites, not all of which have been identified. Following administration of a single 5 mg dose of 14C-labeled 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 feces, 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 hydrochloride concentrations decline with a half-life of approximately 70 hours and the mean apparent plasma clearance is 0.13 to 0.19 L/h/kg.
Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil hydrochloride 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 hydrochloride steady-state concentrations; mean AUC by 48% and mean Cmax by 39% (see Dosage & Administration).
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