CJN volume 31 issue 1 Cover and Back matter

PHARMACOLOGIC CLASSIFICATION: Cholineslerase Inhibitor ACTION AND CLINICAL PHARMACOLOGY: ARICEPT (donepezil hydrochloride) isa piperidirre-based. reversible inhibitor ol the enryme acetylcholinesterase (AChE).A consistent pathological change in Alzheimer's disease is the degeneration ot cholinergic neuronal pathways that project trom the basal lorebrain to the cerebral cote and hippocampus.The resulting bypofnnction ot these pathways is thought to acconnt tor some ol the clinica manifestations ol dementia.Donepezil is postulated to exert its therapeutic efiect by enhancing cholinergic function.This is accomplished hy increasing the concentration of acetylcholine (ACh) through reversible inhibition of its hydrolysis by AChE.If this proposed mechanism of action is correct, donepezils 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 tor the symptomatic treatment ol patients «ilh mild-to-moderate dementia of the Alzheimer' s type.Efficacy of ARICEPT in patients with mild-to-moderate 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 consultation with) clinicians who are experienced in the diagnosis and management ol Alzheimer's disease.CONTRAINDICATIONS: ARICEPT (donepezil hydrochloride) is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.WARNINGS: keslhesie: ARICEPT (donepezil hydrochloride), as a cholineslerase inhibitor, is likely to exaggerate succinylcholioe-type muscle relaxation during anesthesia.neurological Cnnditions: 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 ol seizure threshold, increasing the risk of seizures.However, seizure activity may also be a manifestation ot Alzheimer's disease.The nsk/benefil 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 or individuals with Parkinsonian features.The efficacy and safety of ARICEPT in these patients are unknown.Puktmq Conditions: Because of fheir cholinomimetic action, cholinesterase inhibitors should he 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.Cardiovascular Because of their pharmacological action, cholineslerase inhibitors may have vagotonic effects on heart rate (e.g" bradycardia).The potential for this action may be particularly important*) patents with "sick sinus syndrome" or other supraventricular cardiac conduction conditions.In clinical trials, most patients w i senous cardiovascular conditions were excluded.Patients such as those with controlled hypertension (DBP<95 mmHg), nght bundle branch blockage and pacemakers were included.Theretdre, caution should be taken 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 recommended thai ARICEPT should not be used in patients with cardiac conduction abnormalities (except for right bundle branch block) including "sick sinus syndrome" and those with unexplained syncopal episodes.Saslro'mteslinal: Through their primary action, cholineslerase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity.Therefore patients at increased nskfor developing ulcers, e.g., those with a history of ulcer disease df those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) including high ddses el acelylsalicylic acid (ASA), should be monitored lor symptoms of active ot occult gastrointestinal bleeding.Clinical studies ot ARICEPT have shown no increase, relative to placebo in the incidence ol either peptic ulcer disease dr 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 t to 3 weeks and have resolved during continued use ol ARICEPT (See ADVERSE REACTIONS section).Treatment with the S mg/d dose for 4-8 weeks prior lo increasing Ihe dose to 10 mg/d is assaciated with a lower incidence of gastrointestinal intolerance.Gtoitonrinar/: Although not observed in clinical trials of ARICEPT, cholinomimetics may cause bladder outflow obstruction, PRECAUTIONS: Concomitant Ose with Other Drugs: (lie i i Mcnolineroits: Because of their mechanism ol action, cholinesterase nhitiitors have the potential to interfere with the activity of anticholinergic medications.Use viith Cholinomimetics and Bitter Cholioesletase lonioitors: A synergistic effect may be expected when cholinesterase inhibdorsare given concurrently with succinylcboline, similar neuromuscular blocking agents er cholinergic agonists such as bethanechol.Use fillr ( l e r Rn/ctoitfn tojs: Few patients in controlled clinical trials received neuroleptics, antidepressants or anticonvulsants.There is thus limited information concerning the interaction ot ARICEPT with these drugs.Use in Patients > 05 fears Hit In controlled clinical studies with 5 and 10 mg of ARICEPT, 536 patients were between the ages of 65 to 84, and 37 patients were aged 85 years or older.In Alzheimer's disease patients, nausea, diarrhea, vdmiting, insomnia, fatigue and anorexia increased with dbse and age and the incidence appeared Id be greater in female patienfs.Since cholineslerase inhibitors as well as Alzheimer's disease can be associated with significant weight toss, caution is advised regarding the use ol ARICEPT in low body weight elderly patients, especially in those >85 years old. Use m Irdertf Patients mm I m o t i i i Disease:There is limited safety information lor ARICEPT in patients with mild-to-moderate Alzheimer's disease and significant comorbidity.The use df ARICEPT in Alzheimer's disease patients with chronic illnesses common among the geriatric population, should he ccnsidered only after carefol risk/benefit assessment and include close monitoring foradverseevents.CautionisadvisedregardingtheuseofARICEPTdosesabove5mginthispatienipopulation.flena///-arn/ffepai/caffy-frnpa/rec':Thereislimited intormati o n regarding Ihe pharmacokinetics ol ARICEPT in renaily-andhepalica|-impairedAlzheimeftdiseasi patients, Clpse monitoring loradverseefficlsin Alzheimer's disease patients with renal or hepatic disease being treated with ARICEPT is therefore recommended.Dreg-Drug Interactions: Pharmacokinetic studies, limited to short-term, single-dose studies in young subjects evaluated the potential ot ARICEPT for interaction with theophylline, cimetidine, warfarin and digoxin administration.No significant effects on the pharmacokinetics ol these drags were observed.Similar studies in elderly patients were nel done.Unas Hnjtn) l e w i to Plasma Proteins: 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 ot furosemide (5 pg/mL), digoxin (2 ngM) and warfarin (3 ug/mL) to human albumin.Similarly, the binding of donepezil to human albumin was not affected by lurosemide, digoxin and warfarin.i S e c t o l W l f l on frti Metabolism of OfcOrnns: In vitro studies show a low rate of donepezil binding to CVP 3A4 and CYP 2D6 isoenzymes (mean Ki about 50-130 pM), which, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little Likelihood ol interferences.In a pharmacokinetic study involving 18 heallhy volunteers, the administration ot ARICEPT at a dose of 5 mg/d for 7 days had no clinically significant effect on the pharmacokinetics of keloconazole.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)orbyCYP2D6(e.g.,imipramine).ItisnotknownwhetherARICEPThasany potentialforeniymeinduction, Frrec(o/0(nerOmjso/ifAierWe/a*o/(sm oMfl/CEPTKetoconazole and quinidine, inhibitors of CVP450.3A4 and 2D6.respectively, inhibit donepezil metabolism in vitro.In a pharmacokineticstudy. 18 healthy 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%, loducers of CVP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamelhasone, rifampin and phenobarhital) 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 Projianty aoltimum (Wrier: The safely of ARICEPT during pregnancy and lactation has not been established and therefore, if should nol be used in women of cbildbearing potential or in norsing mothers unless, in the opininn pt the physician, Ihe potential benefits to the patient outweigh the possible hazards to the fetus or the infant Teratology studies conducted in pregnant rats at ddses of up to 16 mg/kg/d and in pregnant rabbits at doses of up to 10 mg/kg/d did nol disclose any evidence for a teratogenic potential ]! ARICEPT Pediatric Use: There are no adequate and we

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