CJN volume 28 issue 4 Cover and Back matter

Table 2. Comparison ol Rates ol Adverse Events in Patients Treated with 10 ittgfdiy alter 1 and f Weeks ol Initial Treatment with 5 mg/day PHARMACOLOGIC CLASSIFICATION Cholineslerase Inhibitor ACTION AND CLINICAL PHARMACOLOGY ARICEPT (donepezil 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 from the basal forebrain lo the cerebral cortex and hippocampus. The resulting hypofunction oi these pathways is thought lo account for some of the clinical manifestations of dementia. Donepezil is postulated to exert Js Iherapeotic effect by enhancing cholinergic function. This is accomplished by increasing the concentration ot acetylcholine (ACh) through reversible inhibition of its hydrolysis by acetylcholinesterase (AchE). If this proposed mechanism ol 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 of patients 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 oi Alzheimer's disease. CONTRAINDICATIONS ARICEPT (donepezil hydrochloride) is conlraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives WARNINGS Aoaesmesia; ARICEPT (donepezil hydrochloride), as a cholioesterase inhibitor, is likely to exaggerate soccinylcholine-lype muscle relaxation during anaesthesia, Heuralegical (Milim: 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 Ihe risk of seizures. However, seizure activity may also be a manifestation of Alzheimer's disease. The risk/benefit of ARICEPT treatment for patients witti a history of seizure disorder must therefore be carefully evaluated. AHICEPT has not been studied in patients with moderatelv severe or severe Alzheimer's disease, non-Alzheimer dementias or individuals with Parkinsonian features. The efficacy and safety ol ARICEPT in these patient populations is unknown Afanavy Cetiiilisis: Because of their cholinomimetic action, cholineslerase inhibitors should be prescribed w i care lo patients with a history ol asthma or obstructive pulmonary disease. ARICEPT has not been studied in patients under treatment lor these conditions and should therefore be used with particular caution in such patients. Catiiimcalat: Because pi their pharmacological action, cholineslerase inhibitors may have vagotonic effects on heart rate (e.g., bradycardia). The potential tor fie action may beparticulartyimportantto patients with"sicksinussyndrome"orother supraventricular cardiac conduction conditionslnciinical trials, mostpatientswithserious cardiovascular conditions were excluded. Palients such as those with controlled hypertension (DBP<9S mmHg), right bundle branch blockage, and pacemakers were included. Therelore, 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 recommended that ARICEPT should not be used in palients with cardiac conduction abnormalities (except lor riglrt bundle branch block) incloding 'sick sinus syndrome" and those with unexplained syncopal episodes. CaHrantelto/: Through their primary action, cholineslerase inhibitors may be expected lo increase gastric acid secretion due to increased cholinergic activity. Therefore, patients at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drags (NSAIDs) incloding high doses ol acetylsalicylic acid (ASA), shoold be monitored lor symptoms of active or occult gastrointestinal bleeding. Clinical studies ol ARICEPT have shown no increase, relative lo placebo in the incidence ot elder 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, naosea and vomiting. These effects, when they occur, appear more frequently w i the 10 mg dose than w i the S mg dose. In most cases, these effects have usually been mild and transient, sometimes lasting one -to-three weeks and have resolved duriog conlinoed use ol ARICEPT, (See ADVERSE REACTIONS Section) Treatment with the S mg/day dose for 4-6 weeks prior lo increasing Ihe dose to 10 mg/day is associated with a lower incidence ol gastrointestinal intolerance. Sieileaiiaaif Although not observed in clinical trials of ARICEPT. cholinomimetics may cause bladder ootflow obstruction. PRECAUTIONS Concomitant Use w i other Dregs: Use uilliMiiMiaeieia: Because of their mechanism ol action, cholineslerase inhibitors have the potential to interfere with the activity ol anticholinergic medications. Use twin Cialiitaiaimelies and oiler CAl//ieslerase/itilcs,'Asynergisfceftecl may be expected when cholioesterase inhibitorsare given concurrenllywisoccinylcholine. similar heoromoscoiarblocking agents or cholinergic agonists such as bethanechol list tilt oiler ftyenoatlive Drugs; Few pabents in controlled clinical trials received neuroleptics, antidepressants or anticnnvulsants; there is thos limited information concerning the interaction of ARICEPT with these drugs. Use in Patiants>85 years Bill: In controlled clinical stodies with 5 and 10 mg of ARICEPT, 536 palients were between the ages of 65 to 84, and 37 palienis were aged 15 years or older. In Alzheimer's disease palienis, nausea, diarrhea, vomiting, insomnia, latigoe and anorexia increased w i dose and age and the incidence appeared to be greater lo female patients. Since cholineslerase inhibitors as well as Alzheimer's disease can be associated w i significant weight loss, caution is advised regarding the nse of ARICEPT in low body weight elderly patients, especially in those > !5 years old Useie flderlv Mitels M l Cemtsit Disease: There is limiled safely information lor ARICEPT in palieots with mild-to-moderate Alzheimer's disease aod significant comorbidity. The ose ol ARICEPT in Alzheimer's disease patients with chronic illnesses common among the geriatric popolation, shoold be considered only alter careful risk/benefit assessment and include close monitoring for adverse events. Caution is advised regarding the use of ARICEPT doses above 5 mg io this patient population. flena/ry a/id Hepaticallv Impaired: There is limited information regarding the pharmacokinetics of ARICEPT in renally and hepatically impaired Alzheimer's disease patients. Close monitoring foradverseeffects in Alzheimer'sdisease patients with renal or hepatic disease beingtreated with ARICEPTistherefore recommended. Drug-Drug Interactions: Pharmacokinetic studies, limited to short-term, single-dose studies in yoong subjects evaluated the potential of ARICEPT for interaction with theophylline, cimetidine, warfarin and digoxin administration. No significant effects on the pharmacokinetics of these drugs were observed. Similar stodies in elderly patients were not dene. Drugs Wigo/y flound Is Plasma Pialiits: Drag displacement stodies have been performed in vifrobetween donepezil. a highly bound drug (96%) and other drags socb asturosemide, digoxin, and warfarin. Donepezil al concentrations ol 0.3 10 pj/mL did not ailed Ihe binding ol lorosemide (5 pg/mL), digoxin (2 ng/mL) and warfarin (3 pg/mL) to human albumin. Similarly, Ihe binding of donepezil to homan albumin was not affected by lorosemide, digoxio and warfarin. Bled o/AMCEPTon Ik Htleeilim tlOliei Bites: It # 0 studies showa low rale of donepezil binding to CYP3A4 andCVP 2D6isoeozymes (mean Ki about 50 139 uK), which, giveo Ihe therapeutic plasma concentrations ol donepezil (164 nfvi), indicates lie likelihood of interferences. In a pharmacokinetic study involving 18 healthy volunteers, the administration of ARICEPT at a dose of 5mg/day for 7 days had no clinically significant effect on Ihe pharmacokinetics of ketoconazole. No other clinical tnals have been conducted to investigate the effect of ARICEPT on the clearance of drugs metabolized by CYP 3A4 (e.g., cisapride, terfenadine) or by CYP 2D6 (e.g., imipramine). It is not known whether ARICEPT has any potential lor enzyme induction. lleclel Older Drugstie M H t a i l K t P J : Ketoconazole and quinidine, inhibitors of CVP 459,3A4 and 2D6. respectively, inhibrt donepezil metabolism in nta In a pharmacokinetic study, 18 healthy volunteers received 5 mg/day ARICEPT together w i 200 mg/day ketoconazole lor 7 days. In these volunteers, mean donepezil plasma concentrations were increased by about 39-367.. Inducers olCT2D6and CYP 3A4 (e.g" pbenyloin, carbamazepine, dexamettiasone, rifampin and phenobarbital) coold increase Ihe rale ol elimination ol ARICEPT. Pharmaookioelic sludies demonstrated that the metabolism ol ARICEPT is not significantly affected by concurrent administration ol digoxin or cimetidine Use in Pregnancy and Daisies Mol/rers: The safety of ARICEPT during pregnancy and lactation has not been established and therefore, it should not be used in women of cbildbearing potential or in horsing mothers unless, in Ihe opinion of the physician, the potential benefits to Ihe patient outweigh the possible hazards to the tetus or the infant. Teratology stodies condocted in pregnant rats at doses of up lo 16 mg/kg/day and in pregnant rabbits at doses of up to 10 mg/

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