CJN volume 28 issue 1 Cover and Back matter

with 1D mg/day after 1 and 6 Weeks ol Initial Treatment with S mgfiay PHARMACOLOGIC CLASSIFICATION Cholinesterase Inhibitor ACTION AND CLINICAL PHARMACOLOGY APJCEPT [donepea 1 hydrochloride) is a piperidine-based, reversible inhibitor of the enzyme acetylcholinesterase, A consistent pathological change in Alzheimer's disease is the degeneration of cholinergic neuronal pathways that project trom the basal forebrain to the cerebral cortex and hippocampus.The resulting hypofunction of these pathways is thought to account for some of the clinical manifestations of dementia, Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function.This is accomplished by increasing the concentration of acetylcholine (ACh) through reversible inhibition of 9s hydrolysis by acetylcholinesterase (ME).II this proposed mechanism of action is correct, donepezil's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact.There is no evidence that donepezil alters the course of the underlying dementing process.INDICATIONS AND CLINICAL USE ARICEPT (donepezil hydrochloride) is indicated for the symptomatic treatment ol palients with mild-to-moderate dementia of the Alzheimer's type.ARICEPT tablets should only be prescribed by (or following consultation with) clinicians who are experienced in the diagnosis and management of Alzheimer's disease.CONTRAINDICATIONS ARICEPT (donepezil hydrochloride) is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.WARNINGS Aiaesliesia; ARICEPT (donepezil hydrochloride), as a cholinesterase inhibitor, is likely to exaggerate succinylohoioe-type muscle relaxation during anaesthesia Hennlnaissl Cflim'/iois: Seizures: Some cases of seizures have been reported with the use of ARICEPT in clinical trials and from spontaneous Adverse Reaction reporting Cholinomimetics can cause a reduction of seizure threshold, increasing the risk of seizures.However, seizure activity may also be a manifestation of Alzheimer's disease.The risk/benefit of ARICEPT treatment for patients with a history of seizure disorder must therefore be carefully evaluated.ARICEPT has not been studied in patients with moderately severe or severe Alzheimer's disease, non-Alzheimer dementias or individuals with Parkinsonian leatures.The efficacy and safety of ARICEPT in these patient populations is unknown.M i l i a r y £i«dili»is; Because of their cholinomimetic action, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.ARICEPT has not been studied in patients under treatment for these conditions and should therefore be used with particular caution in such patients.Card/ovascalar: 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.In clinical tnals.most patients with senous cardiovascular conditions were excluded.Patients such as those with controlled hypertension (DBP<95 mmHg), right bundle branch blockage, and pacemakers were included.Therefore, caution should betaken in treating patients with active coronary artery disease and congestive heart failure.Syncopal episodes have been reported in association with the use of ARICEPT.It is •ecommended that ARICEPT should not be used in patients with cardiac conduction abnormalities (except for nghl bundle branch block) including "sick sinus syndrome" and those with unexplained syncopal episodes.telrainleslmai; Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity.Therefore, palients at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) including high doses of acetylsalicylic acid (ASA), should be monitored for symptoms of active or occult gastrointestinal bleeding.Clinical studies of ARICEPT have shown no increase, relative to placebo in the incidence of either peptic ulcer disease or gastrointestinal bleeding, (See ADVERSE REACTIONS Section) ARICEPT, as a predictable consequence of its pharmacological properties, has been shown to produce, in controlled clinical trials in patients with Alzheimer's disease, diarrhea, nausea and vomiting.These effects, when they occur, appear more frequently with the 10 mg dose than with the 5 mg dose.In most cases, these effects have usually been mild and transient, sometimes lasting one -to-three weeks and have resolved during continued use ol ARICEPT.(See ADVERSE REACTIONS Section) Treatment with the 5 mg/day dose lor 4-6 weeks prior to increasing the dose to 10 mg/day is associated with a lower incidence of gastrointestinal intolerance, fidtknwy: Although not observed in clinical trials of ARICEPT, cholinomimetics may cause bladder outflow obstruction.PRECAUTIONS Concomitant Use with ether Drugs: Use uilnkkklinitiici: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.Use villi tklinmimelicsani diner CWineslerase M/iitosrA synergistic effect may be expected when cholinesterase inhibitors are given concurrently with suecinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.Use v#3 liner PspmeM Bines: Few patients in controlled clinical trials received neuroleptics, antidepressants or anticonvulsants: there is thus limited information concerning the interaction of ARICEPT with these drugs.Use in Petiitits>85 rears Did: In controlled clinical studies with S and 11 mg of ARICEPT, 536 patients were between the ages of 85 to 14, and 3? palients were aged 8S years or older.In Alzheimer's disease patients, nausea, diarrhea, vomiting, insomnia, fatigue and anorexia increased with dose and age and the incidence appeared to be greater in female patients.Since cholinesterase inhibitors as well as Alzheimer's disease can be associated with significant weight loss, caution is advised regarding the use of ARICEPT in low body weight elderly patients, especially in those > 15 years old.Use i« Elmtrly M a i l s ml» Come-*/ Disease: There is limited safety information for ARICEPT in patients with mild-to-moderate Alzheimer's disease and significant comorbidity.The use of ARICEPT in Alzheimer's disease patients with chronic illnesses common among the geriatric population, should be considered only after careful risk/benefit assessment and include close monitoring for adverse events.Caution is advised regarding the use of ARICEPT doses above 5 mg in this patient population.fleiaiiy aid Weiaticaiiy impaired: There is limited information regarding the pharmacokinetics of ARICEPT in renally and hepatically impaired Alzheimer's disease patients.Close monitoring foradverse effects in Alzheimer's disease patients with renal or hepaticdisease being treated with ARICEPT is therefore recommended.Drug-Drug Interactions: Pharmacokinetic studies, limited to short-term, single-dose studies in young subjects evaluated the potential of ARICEPT for interaction with theophylline, cimetidine, warfarin and digoxin administration.No sigohicant effects on the pharmacokinetics of these drugs were observed.Similar studies in elderly patients were not done, tojsiiijtly faicd foPiasnra Pieleins: Drug displacement studies have been performed in vitro between donepezil, a highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin, Donepezil at concentrations of 0,3 • 10 ug/mL did not affect the binding of furosemide (5 ug/mL).digoxin (2 ng/mL) and warfarin (3 ug/mL) to human albumin.Similarly, the binding of donepezil to human albumin was not affected by furosemide, digoxin and warfarin.Effectel M E P T n Ilia Meliklim »l Older Drills: In nlro studies show a low rate of donepezil binding to CVP3A4 and CYP 206 isoenzymes (mean Ki about SO • 130 uM), which, given thetherapeutic plasma concentrations ol donepezil (164 nM), indicates little likelihood of interferences.In a pharmacokinetic study involving 18 healthy volunteers, the administration of ARICEPT at a dose of Smg/day for 1 days had no clinically significant (fleet on the pharmacokinetics ol ketoconazole.No other clinical trials have been conducted to investigate the effect of ARICEPT on the clearance of drugs metabolized by CVP 3A4 (e.g., cisapride, terfenadine) or by CYP 2D6 (e.g., imipramine).It is not known whether ARICEPT has any potential for enzyme induction, [heel if Olki Inns i» lire Meiatolisij tMUCtFI: Ketoconazole and guinidine, inhibitors of CVP 450,3A4 and ZD6, respectively, inhibit donepezil metabolism in # o .In a pharmaepkinetic study, 1! healthy volunteers received 5 mg/day ARICEPT together with 300 mg/day ketoconazole for 7 days.In these volunteers, mean donepezil plasma concentrations were increased by about 30-38%.Inducers of CYP 3D6and CVP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rilampin and phenobartital) could increase the rate of elimination of ARICEPT, Pharmacokinetic studies demonstrated that the metabolism of ARICEPT is not significantly affected by concurrent administration ol digoxin or cimetidine.Use in Pieeimq aid Hirsiij Miliars.'Thesafety of ARICEPT during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or in nursing mothers unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus or the infant.Teratology studies conducted in pregnant rats at doses of up to 16 mg/tg/day and in pregnant rabbits at doses ol up to to mj/kg/day did not disclose any evidence fora teratogenic potential of ARICEPT

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