Aricept Evess

Aricept Evess

donepezil

Manufacturer:

Eisai

Distributor:

Zuellig

Marketer:

HI-Eisai
Full Prescribing Info
Contents
Donepezil HCl.
Description
Each 5- and 10-mg orodispersible tablet contains donepezil HCl 5 mg and 10 mg equivalent to donepezil free base 4.56 mg and 9.12 mg, respectively.
Aricept Evess also contains the following excipients: Mannitol, anhydrous colloidal silica, k-carrageenan, polyvinyl alcohol.
Additionally, the 10-mg tablet contains yellow iron oxide as coloring agent.
Action
Pharmacotherapeutic Group: Drugs for dementia. ATC Code: N06DA02.
Pharmacology: Pharmacodynamics: Donepezil HCl is a specific and reversible inhibitor of acetylcholinesterase (AChE), the predominant cholinesterase in the brain. Donepezil HCl is in vitro over 1000 times more potent inhibitor of AChE than of butyrylcholinesterase, an enzyme which is present mainly outside the central nervous system.
Alzheimer's Dementia: Mild to Moderate Alzheimer's Disease: In patients with Alzheimer's dementia participating in clinical trials, administration of single daily doses of Aricept Evess 5 or 10 mg produced steady-state inhibition of AChE activity (measured in erythrocyte membranes) of 63.6% and 77.3%, respectively when measured post-dose. The inhibition of AChE in red blood cells by donepezil HCl has been shown to correlate to changes in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), a sensitive scale which examines selected aspects of cognition. The potential for donepezil HCl to alter the course of the underlying neuropathology has not been studied. Thus, Aricept Evess cannot be considered to have any effect on the progress of the disease. Efficacy of treatment of Alzheimer's dementia with Aricept Evess has been investigated in 4 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 3 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).
Patients who fulfilled the criteria listed as follows were considered treatment responders.
Response: Improvement of ADAS-Cog of at least 4 points; no deterioration of CIBIC and Activities of Daily Living Subscale of the Clinical Dementia Rating Scale. (See Table 1.)

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Aricept Evess 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 Aricept Evess in severe Alzheimer's disease has been investigated in 3 placebo-controlled trials of 6-month duration.
In each of the clinical trials, an analysis was done at the conclusion of donepezil treatment using a combination of 3 efficacy criteria: The total Severe Impairment Battery [(SIB), a measure of cognitive performance in all 3 trials] score, the CIBIC (a measure of global function in 2 trials) or Clinical Global Impression of Change [(CGI-I), a measure of global function in 1 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 3 trials]. Patients who fulfilled the criteria listed as follows were considered treatment responders.
Response: Improvement of SIB of at least 4 points; no deterioration of CIBIC or CGI-I and ADCS-ADL-sev. (See Table 2.)

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Vascular Dementia: Efficacy of treatment of vascular dementia with Aricept Evess has been investigated in 2 placebo-controlled trials of 6-month duration in which the diagnostic criteria for vascular dementia proposed by the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neuroscience (NINDS-AIREN) consensus group were used to define the population of patients studied.
An overall analysis was done at the conclusion of donepezil treatment using a combination of 3 efficacy criteria.
Patients who fulfilled the criteria listed as follows were considered treatment responders.
Response: Improvement of ADAS-Cog of at least 4 points; improvement or no deterioration of CIBIC and Clinical Dementia Rating functionality subscale. (See Table 3.)

Click on icon to see table/diagram/image

Aricept Evess produced statistically significant increase in the percentage of patients who were judged treatment responders.
Pharmacokinetics: Absorption: Maximum plasma levels are reached approximately 3-4 hrs after oral administration. Plasma concentrations and area under the curve (AUC) rise in proportion to the dose. The terminal disposition t½ is approximately 70 hrs, 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 HCl concentrations and the related pharmacodynamic activity show little variability over the course of the day.
Food did not affect the absorption of donepezil HCl.
Distribution: Donepezil HCl is approximately 95% bound to human plasma proteins. The plasma protein-binding of the active metabolite 6-O-desmethyl donepezil is not known. The distribution of donepezil HCl in various body tissues has not been definitively studied. However, in a mass balance study conducted in healthy male volunteers, 240 hrs after the administration of a single 5-mg dose of 14C-labeled donepezil HCl, approximately 28% of the label remained unrecovered. This suggests that donepezil HCl and/or its metabolites may persist in the body for >10 days.
Metabolism/Excretion: Donepezil HCl is both excreted in the urine intact and metabolized by the cytochrome P-450 system to multiple metabolites, not all of which have been identified. Following administration of a single 5-mg dose of 14C-labeled donepezil HCl, plasma radioactivity, expressed as a percent of the administered dose was present primarily as intact donepezil HCl (30%), 6-O-desmethyl donepezil (11%, only metabolite that exhibits activity similar to donepezil HCl), 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 HCl and/or any of its metabolites.
Plasma donepezil concentrations decline with a t½ of approximately 70 hrs.
Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil HCl. 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 maximum plasma concentration (Cmax) by 39% (see Dosage & Administration).
Toxicology: Preclinical Safety Data: 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 (see Overdosage). 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 >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 HCl had no effect on fertility in rats, and was not teratogenic in rats or rabbits, but had a slight effect on stillbirths and early pup survival when administered to pregnant rats at 50 times the human dose (see Use in pregnancy under Precautions).
Indications/Uses
Symptomatic treatment of mild, moderate and severe Alzheimer's disease; vascular dementia (dementia associated with cerebrovascular disease).
Dosage/Direction for Use
Adults and Elderly: Initiated at 5 mg/day (once-a-day dosing). The 5 mg/day dose should be maintained for at least 1 month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of donepezil HCl to be achieved. Following a 4-6 weeks clinical assessment in patients who tolerated treatment at 5 mg/day, the dose of Aricept Evess can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses >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 (eg, DSM IV, ICD 10). Therapy with donepezil should only be started if a caregiver who will regularly monitor drug intake for the patient is available. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of donepezil should be re-assessed 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 Aricept Evess is seen.
Renal and Hepatic Impairment: A similar dose schedule can be followed for patients with renal impairment, as clearance of donepezil HCl is not affected by this condition.
Due to possible increased exposure in mild to moderate hepatic impairment (see Pharmacokinetics under Actions), dose escalation should be performed according to individual tolerability. There are no data for patients with severe hepatic impairment.
Aricept Evess should be taken orally in the evening, just prior to retiring. The tablet should be placed on the tongue and allow to disintegrate before swallowing with or without water, according to patient's preference.
Overdosage
The estimated median lethal dose of donepezil HCl following administration of a single oral dose in mice and rats is 45 mg/kg and 32 mg/kg, respectively, or approximately 225 times and 160 times the maximum recommended human dose of 10 mg/day. Dose-related signs of cholinergic stimulation were observed in animals and included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, fasciculation and lower body surface temperature.
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.
As in any case of overdose, general supportive measures should be utilized. Tertiary anticholinergics eg, atropine may be used as an antidote for donepezil HCl overdosage. Intravenous atropine sulfate titrated to effect is recommended: An initial dose of 1-2 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics eg, glycopyrrolate. It is not known whether donepezil HCl and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration).
Contraindications
Known hypersensitivity to donepezil HCl, piperidine derivatives or to any of the excipients of Aricept Evess.
Use in pregnancy: Donepezil HCl is contraindicated in pregnancy.
Use in lactation: Donepezil is excreted in the milk of rats. It is not known whether donepezil HCl is excreted in human breast milk and there are no studies in lactating women. Therefore, women on donepezil should not breastfeed.
Special Precautions
The use of Aricept Evess in patients with other types of dementia and other types of memory impairment (eg, age-related cognitive decline) has not been investigated.
Anesthesia: Aricept Evess, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Cardiovascular Conditions: Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (eg, bradycardia). The potential for this action may be particularly important to patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions eg, 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 eg, 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 Aricept Evess 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 Aricept Evess, cholinomimetics may cause bladder outflow obstruction.
Neurological Conditions: Seizures: Cholinomimetics are believed to have some potential to cause generalized 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 Aricept Evess concomitantly with other inhibitors of AChE, agonists or antagonists of the cholinergic system should be avoided.
Severe Hepatic Impairment: There are no data for patients with severe hepatic impairment.
Mortality in Vascular Dementia Clinical Trials: Three clinical trials of 6-month duration were conducted studying individuals meeting the NINDS-AIREN criteria for probable or possible vascular dementia (VaD). The NINDS-AIREN criteria are designed to identify patients whose dementia appears to be due solely to vascular causes and to exclude patients with Alzheimer's disease. In the 1st study, the mortality rates were 2/198 (1%) on donepezil HCl 5 mg, 5/206 (2.4%) on donepezil HCl 10 mg and 7/199 (3.5%) on placebo. In the 2nd study, the mortality rates were 4/208 (1.9%) on donepezil HCl 5 mg, 3/215 (1.4%) on donepezil HCl 10 mg and 1/193 (0.5%) on placebo. In the 3rd study, the mortality rates were 11/648 (1.7%) on donepezil HCl 5 mg and 0/326 (0%) on placebo. The mortality rate for the 3 VaD studies combined in the donepezil HCl group (1.7%) was numerically higher than in the placebo group (1.1%), however, this difference was not statistically significant. The majority of deaths in patients taking either donepezil HCl or placebo appear to result from various vascular related causes which could be expected in this elderly population with underlying vascular disease. An analysis of all serious nonfatal and fatal vascular events showed no difference in the rate of occurrence in the donepezil HCl group relative to placebo.
In pooled Alzheimer's disease studies (n=4146), and when these Alzheimer's disease studies were pooled with other dementia studies including VaD studies (total n=6888), the mortality rate in the placebo groups numerically exceeded that in the donepezil HCl groups.
Effects on the Ability to Drive or Operate Machinery: Donepezil has minor or moderate influence on the ability to drive and use machines.
Dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, donepezil can induce fatigue, dizziness and muscle cramps, mainly when initiating or increasing the dose. The treating physician should routinely evaluate the ability of patients on donepezil to continue driving or operating complex machines.
Use in 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 postnatal toxicity (see Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is unknown. Aricept Evess should not be used during pregnancy unless clearly necessary.
Use in children: Aricept Evess is not recommended for use in children.
Adverse Reactions
The most common adverse events are diarrhea, muscle cramps, fatigue, nausea, vomiting and insomnia.
The incidence profile for adverse events for severe Alzheimer's disease is similar to that of mild to moderately severe Alzheimer's disease. Table 4 reflects the incidence of adverse events in patients receiving treatment with Aricept Evess for all stages of Alzheimer's disease.
Adverse reactions reported as more than an isolated case are listed by system organ class and by frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000) and not known (cannot be estimated from available data). (See Table 4.)

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Drug Interactions
Donepezil HCl and/or any of its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil HCl is not affected by concurrent administration of digoxin or cimetidine. In vitro studies have shown that the cytochrome P-450 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 CYP2D6 respectively, inhibit donepezil metabolism. Therefore these and other CYP3A4 inhibitors eg, itraconazole and erythromycin, and CYP2D6 inhibitors eg, fluoxetine could inhibit the metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by about 30%. Enzyme inducers eg, 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 HCl has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving medications eg, succinylcholine, other neuromuscular blocking agents or cholinergic agonists or β-blocking agents which have effects on cardiac conduction.
Storage
Store at temperatures not exceeding 30°C. Protect from light.
Shelf-Life: 3 years.
ATC Classification
N06DA02 - donepezil ; Belongs to the class of anticholinesterases. Used in the management of dementia.
Presentation/Packing
Orodispersible tab 5 mg (white, round, biconvex, embossed with "ARICEPT" on one side and "5" on the other side) x 28's. 10 mg (yellow, round, biconvex, embossed with "ARICEPT" on one side and "10" on the other side) x 28's.
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