CJN volume 31 issue 3 Cover and Back matter

Once-a-dayTable 2. Comparison of Raits ol Adverse Events In Patients Treated with 11 mg/d after 1 and E Weeks ol Initial Treatment with S mg/d No Inilial Treatment PHARMACOLOGIC CLASSIFICATION: Cholnesterase Intiilor.ACTION AND CLINICAL PHARMACOLOGY: ARICEPT (donepezil hydrochloride) is a piperidine-oased, reversible inhibitor ol tire enzyme acetylcholinesterase (AC«E).A consistenl pathological change in Alzheimer's disease is the degeneration ot cholioergie neuronal pathways that project Iron the basal lorebraii to the cerebral cote and hippocampus.The resulting typotunction ol these pathways is thought to account tor some ol the olinical manifestations ol dementia.Donepezil is postulated lo exert its therapeutic effect by enhancing cholinergic function.This is accomplished by increasing Ibe concentration of acetylcholine |ACh| through reversible inhibition ot its hydrolysis by AChE.II this proposed mechanism ol action is correct, donepezil's effect may lessen as the disease process advances and lewer cholinergic neurons remain functionally intact.There is no evidence that donepezil alters the course ol the underlying dementing process.INDICATIONS AND CLINICAL OSE: ARICEPT (dooepezfl hydrochloride) is indicated for the symptomatic treatment ol patients wih mild-to-moderate dementia of Ibe Alzheimer's type.Efficacy ol ARICEPT in patients with mild-lo-moderale Alzheimer's disease was established in two 24-week and one 54-week placebo-controlled trials.ARICEPT tablets should only be prescribed by (or following ooosoltafion with) clinicians who are experienced in Ibe diagnosis and management ol Alzheimer's disease.CONTRAINDICATIONS: ARICEPT (dooepezil hydrochloride) is contraiidicated in patients with tnown hypersensitivity to donepezil hydrochloride or to piperidine derivatives.WARNINGS: Aneslfes/a: ARICEPT (donepezil hydrochloride), as a cholineslerase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.ftoroloeical Condi/ions: Seizures: Some cases ol seizures have beeo reported with the use of ARICEPT in clinical trials and from spontaneous Adveise Reaction reporting.Cholinomimetics can cause a reduction ol seizure threshold, increasing the risk ol seizures.However, seizure activity may also be a manifestation ol Alzheimer's disease.The risk/benefit of ARICEPT treatment for patients with a history ol seizure disorder must therefore be carefully evaluated.ARICEPT has not been studied in patients with non-Alzheimer dementias dr individuals wih Parkinsonian features.The efficacy and safety of ARICEPT in these patients are unknown.Putmary tortus: Because ot their cholinomimetic action, cholineslerase inhibitors should be prescribed wrib care to patents with a history of asthma or obstructive pulmonary disease.ARICEPT has not been studied in patients under treatmenl for these conditions and should therefore be osed with particular caution in soch patients.Cardiovascular: Because ol their phaimacokxjical action, chotnesterase inhibitors may nave vagotonic effects or heart rale (rip, bradycardia).The potential lor the action may be particularly important to patients with 'sick sinus syndrome' or other supraventricular cardiac conduction cordons.In clinical trials, most patients wih serious cardiovascular conditions were excluded.Patents such as those with controlled hypertension (DSP* mmBj), right bundle branch blockage and pacemakers were Included.Therefore, caution shouU be taken in treating patents with active coronary artery disease and congestive heart failure.Syncopal episodes have teen reported in association wih the use ol ARICEPT.It is recommended that ARICEPT should not be used in patients with cardac conduction abnormalities (except lor right buridle branch bfock) including "sick sinus syndrome" and Ihose wih unexplained syncopal episodes.Caslrailesliia): Through their primary action, cbolineslerase inhibilors may be expected to increase gastric acid secretion due Id increased cholinergic activity-Therefore.patents at increased risk lor developing ulcers, e.g.. Ihose with a history of ulcer disease dr Ihose receiving concurrent nonsteroidal antiinflammatory drugs (NSAIDs) including high doses ol acetylsalicylic acid (ASA), should be monitored for symptoms of active or occult gastrointestinal bleeding.Clinical stodies ot ARICEPT have shown no increase, relative lo placebo in the incidence ol either peptic ulcer disease or gastrointestinal bleeding (see ADVERSE REACTIONS section) ARICEPT, as a predictable consequence of its pharmacological properties, has teen showo to produce, in controlled clioical trials ii patieols with Alzheimer's disease, diarrhea, nausea and vomiting.These (fleets, when they occur, appear more frequently with the 10 mg dose than wilt the 5 mj dose.In most cases, these effects have usually been mild and transient, sometimes lasting 1 lo 3 weeks and have resnlved duiiny continued use ol ARICEPT (See ADVERSE REACTIONS seclion).Treatment with the 5 mg/d dose loi 4-6 weeks prior to increasing the dose lolOmg/d is associated withalower incidence of gastrointestinal intolerance.Ge/ri/oirrrnary: Although not observed in clinical trials of ARICEPT.cholinomimetics may cause bladder outflow obstruction PRECAUTIONS: Concomitant Use with Olher Drugs: Use lilt Anl/ctol/nerpics: Because ol their mechanism of action, cbolineslerase inbibitors have the potential to interfere with Ihe activity ol anticholinergic medications, list wilt CWrnoraelrcs aid Otter CMinesferase M H g r s : A synergistic effect may be expected when cholineslerase inhibilors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as oethanechot list will Offer Psyetoaclive Onjr.few patients in controlled clinical trials received neuroleptics, antidepressants or anticonvulsants.There is thus limited informalion concerning the interaction of ARICEPT with these drags.Use in Calient > IS liars Old: In controlled clinical studies with S and I) mg of ARICEPT, S3B patients were between the ages ol 65 to 84, aid 3/ patients were aged 85 years or elder.In Alzheimer's disease patients, nausea, diarrhea, vomiting, insomnia, fatigue and anorexia increased with dose and age and the incidence appeared Id be greater in female patients.Since cholioesterase inhibitors as wefl as Alzheimer's disease can be associated wih significant weight loss, caution is advised regarding the ose ol ARICEPT in low body weight elderly patients, especially in those >S5 yeats old.Vie in llleilf Pal/eils nit Comtriid disease: There is limited safety information lot ARICEPT in patients with mild-td-modetate Alzbeimir's disease and significant comorbidty.The use ol ARICEPT in Alzheimer's disease patients wih chronic illnesses common among the geriatric popolation, should be considered only after careful risk/benefit assessment and include close mooitoring forarjverse events.Caution isadvised regarding the use of ARICEPT dosesabove 5 mg inthis patient population.Bena/fy-antfWenafrcaWy-Jmparrerf.There is limited information regarding Ibe pharmacokinetics ol ARICEPT in renally-and hepaticaly-impaited Alzheimer's disease patients.Close monitoring loradverse effects in Alzheimer's disease patients wih renal or hepatic disease being Healed with ARICEPT is therefore recommended.Drnj-Orug Interactions: Pharmacokinetic studies, limited to short-term, single-dose stodies in young subjects evaluated the potential ol ARICEPT lor interaction with theophylline, cimetidine, warfarin and digoxin administration No significant effects on Ihe pharmacokinetics ot these drugs were observed.Similar sludies io elderly patients were npl dpne.Dries N/jnly l o u d lo tenia Proteins; Drag displacement studies have been performed in vitro between donepezil, a highly boond drag (96%) and other drugs such as furosemide.digoxin and warfarin.Donepezil at concentrations of 0.3-10 pg/mL did not afteel the binding ot furosemide (5 pg/mL), digoxin (2 ng/mL) and warfarin (3 pg/ml) to human albumin.Similarly, Ihe binding of donepezil to humao albomin was not affected by furosemide, digoxin and warfarin, fffeel i l M l t l on Ite H U h l of Offer Brigs: In vitro studies show a low rate ol donepezil binding to CVP 3A4 and CVP 2D6 isoenzymes (meao Ki abool 50-130 plf).which, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood ol interferences.In a pharmacokinetic study involving I I health) volunteers, the administration of ARICEPT at a dose of 5 mg/d for 7 days had no clinically significant elfecl on the pharmacokinetics ol xetoconazole.No olhei clinical trials have been conducted lo invesligate Ihe effect of ARICEPT on the clearance of drugs metabolized by CVP 3A4 (e.g.Icisapride.terfenadine)orbyC¥P206(e.g., imipramine).ltisnotknownwhetfierARICEPThasanypotentialforenzymeinduction.fffecfofOfRerfrrugsonfneMefabofi'sm ilAI/CMKetoconazoleaodgoioidioe, inhibilors ofCYP450,3A4and2D6, respectively, inhibitdonepezilmetabolism in vitro.Inapnaimacokineticsludy.llhealy volunteers received 5 mg/d ARICEPT together with 200 mg/d keloconazole lor 7 days.In these volunteers, mean donepezil plasma concentrations were increased by about 30-36%.Inducers of CYP 2DE and CVP 3A4 (e.g., phenjtoin.catbamazepine, dexametbasone, rifampin and phenobarbital) could increase the rale ol elimination of ARICEPT.Pharmacokinetic studies demonstrated thai Ibe metabolism of ARICEPT is not significantly affected by coocurrenl administration ol digoxin or cimetidine.Use it Pregnancy and fcsiij Bolter: 'H safety of ARICEPT during pregnancy and lactation has not been established and therefore, if should not be used in women of childbearing potential or in noising mothers unless, in Ihe opinion ol Ihe physician, Ihe potential benefits to Ihe patient outweigh He possible hazards lo the letus or Ihe inlant.Teratology sludies conducted in pregnant rats al doses ol up lo It mg/kg/d and in pregnant rabbis at dose

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