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12. Aricep Prescribing Information
Aricep 5mg/10mg
NAME OF THE PRODUCT
guidelines (e.g. DSM IV, ICD 10). Therapy with donepezil should only be started if a care-giver is available who will regularly monitor drug intake for the 1. QUALITATIVE AND QUANTITATIVE COMPOSITION
patient. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. 5 mg donepezil hydrochloride tablets each containing 4.56 mg Therefore, the clinical benefit of donepezil should be reassessed on a regular basis. Discontinuation should 10 mg donepezil hydrochloride tablets each containing 9.12 mg be considered when evidence of a therapeutic effect is no longer present. Individual response to donepezil cannot be predicted. The use of ARICEP in patients with 2. PHARMACEUTICAL FORM
severe Alzheimer's dementia, other types of dementia or other types of memory impairment (e.g., age-related Film-Coated tablets
cognitive decline), has not been investigated. 5 mg donepezil as white, round, biconvex tablets embossed ‘5’ on Anaesthesia: ARICEP, as a cholinesterase inhibitor, is 10 mg donepezil as yellow, round, biconvex tablets embossed ‘10’ likely to exaggerate succinylcholine-type muscle 3. CLINICAL
PARTICULARS
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 ARICEP tablets are indicated for the symptomatic treatment of mild important to patients with “sick sinus syndrome” or other to moderately severe Alzheimer's dementia. supraventricular cardiac conduction conditions, such as ARICEP tablets are indicated for the symptomatic treatment of vascular dementia (dementia associated with cerebrovascular There have been reports of syncope and seizures. In investigating such patients the possibility of heart block 4.2 Posology and method of administration or long sinusal pauses should be considered. Gastrointestinal Conditions: Patients at increased risk Treatment is initiated at 5 mg/day (once-a-day dosing). ARICEP for developing ulcers, e.g., those with a history of ulcer should be taken orally, in the evening, just prior to retiring. The 5 disease or those receiving concurrent nonsteroidal anti- mg/day dose should be maintained for at least one month in order inflammatory drugs (NSAIDs), should be monitored for to allow the earliest clinical responses to treatment to be assessed symptoms. However, the clinical studies with ARICEP and to allow steady-state concentrations of donepezil hydrochloride showed no increase, relative to placebo, in the to be achieved. Following a one-month clinical assessment of incidence of either peptic ulcer disease or treatment at 5 mg/day, the dose of ARICEP 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 Genitourinary: Although not observed in clinical trials of ARICEP, cholinomimetics may cause bladder outflow Upon discontinuation of treatment, a gradual abatement of the beneficial effects of ARICEP is seen. There is no evidence of a Neurological Conditions: Seizures: Cholinomimetics are rebound effect after abrupt discontinuation of therapy. believed to have some potential to cause generalised convulsions. However, seizure activity may also be a A similar dose schedule can be followed for patients with renal impairment, as clearance of donepezil hydrochloride is not affected Cholinomimetics may have the potential to exacerbate Pulmonary Conditions: Because of their cholinomimetic ARICEP is not recommended for use in children. actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or ARICEP is contraindicated in patients with a known hypersensitivity The administration of ARICEP concomitantly with other to donepezil hydrochloride, piperidine derivatives, or to any inhibitors of acetylcholinesterase, agonists or excipients used in the formulation. ARICEP is contraindicated in antagonists of the cholinergic system should be 4.4 Special warnings and special precautions for use Severe Hepatic Impairment: There are no data for patients with severe hepatic impairment. Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's 4.5 Interaction with other medicinal products and other dementia. Diagnosis should be made according to accepted Donepezil hydrochloride and/or any of its metabolites does not inhibit the metabolism of theophylline, warfarin, System Organ
Common Uncommon Rare
Teratology studies conducted in pregnant rats at doses up to approximately 80 times the human dose and in pregnant rabbits at doses up to approximately 50 times the human dose did not disclose any evidence for a teratogenic potential. However, in a study in which pregnant rats were given approximately 50 times the human dose from day 17 of gestation through day 20 postpartum, there was a slight increase in stillbirths and a slight decrease in pup survival through day 4 postpartum. No effect was observed at the next lower dose tested, approximately 15 times the human dose. amidal should not be used during pregnancy. For donepezil no clinical data on exposed pregnancies Lactation: It is not known whether donepezil hydrochloride is excreted in human breast milk and there are no studies in lactating women. Therefore, women on 4.7 Effects on ability to drive and use machines Alzheimer’s 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 ability of Alzheimer patients on donepezil to continue driving or operating complex machines should be routinely evaluated by the treating physician. The most common adverse events are diarrhoea, muscle cramps, fatigue, nausea, vomiting and *In investigating patients for syncope or seizure the possibility of heart block or long sinusal pauses **Reports of hallucinations, agitation and aggressive behaviour have resolved on dose- reduction or discontinuation of treatment. ***In cases of unexplained liver dysfunction, withdrawal of ARICEP should be considered. Inform your doctor in case of any adverse reactions cimetidine or digoxin in humans. The metabolism of donepezil hydrochoride 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 The estimated median lethal dose of donepezil metabolism of donepezil. Drug interaction studies performed in vitro hydrochloride following administration of a single oral show that ketoconazole and quinidine, inhibitors of CYP3A4 and dose in mice and rats in 45 and 32 mg/kg, respectively, 2D6 respectively, inhibit donepezil metabolism. Therefore, these or approximately 225 and 160 times the maximum and other CYP3A4 inhibitors, such as itraconazole and recommended human dose of 10 mg per day. Dose- erythromycin, and CYP2D6 inhibitors, such as fluoxetine could related signs of cholinergic stimulation were observed in inhibit the metabolism of donepezil. In a study in healthy volunteers, animals and included reduced spontaneous movement, ketoconazole increased mean donepezil concentrations by about prone position, staggering gait, lacrimation, clonic 30%. Enzyme inducers, such as rifampicin, phenytoin, convulsions, depressed respiration, salivation, miosis, carbamazepine and alcohol may reduce the levels of donepezil. fasciculation and lower body surface temperature. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care. Donepezil Overdosage with cholinesterase inhibitors can result in hydrochloride has the potential to interfere with medications having cholinergic crisis characterized by severe nausea, anticholinergic activity. There is also the potential for synergistic vomiting, salivation, sweating, bradycardia, hypotension, activity with concomitant treatment involving medications such as respiratory depression, collapse and convulsions. succinylcholine, other neuro-muscular blocking agents or Increasing muscle weakness is a possibility and may cholinergic agonists or beta blocking agents which have effects on result in death if respiratory muscles are involved. As in any case of overdose, general supportive measures should be utilised. Tertiary anticholinergics such as atropine may be used as an antidote for ARICEP within 3 weeks after initiation of therapy. Once at overdosage. Intravenous atropine sulphate titrated to effect is steady-state, plasma donepezil hydrochloride recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent concentrations and the related pharmacodynamic doses based upon clinical response. Atypical responses in blood activity show little variability over the course of the day. pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anti- Food did not affect the absorption of donepezil cholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Distribution: Donepezil hydrochloride is approximately 95% bound to human plasma proteins. The plasma 4. PHARMACOLOGICAL PROPERTIES
protein binding of the active metabolite 6-O-desmethyl donepezil is not known. The distribution of donepezil hydrochloride in various body tissues has not be 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-labeled Donepezil hydrochloride is a specific and reversible inhibitor of donepezil hydrochloride, approximate- ly 28% of the acetylcholinesterase, the predominant cholinesterase in the brain. label remained unrecovered. This suggests that Donepezil hydrochloride is in vitro over 1000 times more potent an donepezil hydrochloride and/or its metabolites may inhibitor of this enzyme than of butyrylcholinesterase, an enzyme persist in the body for more than 10 days. which is present mainly outside the central nervous system. Metabolism/Excretion: Donepezil hydrochloride is both In patients with Alzheimer's dementia participating in clinical trials, excreted in the urine intact and metabolised by the administration of single daily doses of 5 mg or 10 mg of ARICEP cytochrome P450 system to multiple metabolites, not all produced steady-state inhibition of acetylcholinesterase activity of which have been identified. Following administration (measured in erythrocyte membranes) of 63.6% and 77.3%, of a single 5 mg dose of 14C-labeled donepezil respectively when measured post dose. The inhibition of hydrochloride, plasma radioactivity, expressed as a acetylcholinesterase (AChE) in red blood cells by donepezil percent of the administered dose, was present primarily hydrochloride has been shown to correlate to changes in ADAS- as intact donepezil hydrochloride (30%), 6-O-desmethyl cog, a sensitive scale which examines selected aspects of donepezil (11% - only metabolite that exhibits activity cognition. The potential for donepezil hydrochloride to alter the similar to donepezil hydrochloride), donepezil-cis-N- course of the underlying neuropathology has not been studied. oxide (9%), 5-O-desmethyl donepezil (7%) and the Thus ARICEP can not be considered to have any effect on the glucuronide conjugate of 5-O-desmethyl donepezil (3%). Approximately 57% of the total administered radioactivity was recovered from the urine (17% as unchanged Efficacy of treatment with ARICEP has been investigated in four donepezil), and 14.5% was recovered from the faeces, placebo-controlled trials, 2 trials of 6-month duration and 2 trials of suggesting biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to In the 6-month clinical trial, an analysis was done at the conclusion suggest enterohepatic recirculation of donepezil of donepezil treatment using a combination of three efficacy criteria: hydrochloride and/or any of its metabolites. the ADAS-cog (a measure of cognitive performance), the Clinician Interview Based Impression of Change with Caregiver Input (a Plasma donepezil concentrations decline with a half-life 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 Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of Patients who fulfilled the criteria listed below were considered donepezil has not been formally studied in healthy elderly subjects or in Alzheimer’s patients. However mean plasma levels in patients closely agreed with Improvement of ADAS-cog of at least 4 points No deterioration of Activities of Daily Living Patients with mild to moderate hepatic impairment had Subscale of the Clinical Dementia Rating Scale increased donepezil steady state concentrations; mean AUC by 48% and mean Cmax by 39% (see section 4.2). 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 Section 4.9 above). 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 ARICEP produced a dose-dependent statistically significant the mouse micronucleus model in vivo. There was no increase in the percentage of patients who were judged treatment evidence of oncogenic potential in long term carcinogenicity studies in either rats or mice. 5.2 Pharmacokinetic properties - General characteristics Donepezil hydrochloride had no effect on fertility in rats and was not teratogenic in rats or rabbits, but had a Absorption: Maximum plasma levels are reached approximately 3 to slight effect on still births and early pup survival when 4 hours after oral administration. Plasma concentrations and area administered to pregnant rats at 50 times the human 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 6. PHARMACEUTICAL PARTICULARS
approach to steady-state. Approximate steady-state is achieved Lactose monohydrate, maize starch, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate. The film coating contains talc, macrogol, hypromellose and titanium dioxide. Additionally, the 10 mg tablet contains yellow iron oxide. Use upon physician’s prescription only. Read carefully the instruction before using. For further information, please ask for your doctor’s This medicine should be used before the expiration

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