CJN volume 31 issue 4 Cover and Back matter

Table 2. Comparison ol Raits of Adverse Events in Patients Treated with II mjfi alter 1 and 6 Weeks ol H a l Treatment with 5 mg ( Aricept donepezil HCl 5 & 10 rag tablets JL PHARMACOLOGIC CLASSIFICATION: Cholinesteiase Minor ACTION AND CLINICAL PHARMACOLOGY: ARICEPT (donepezil hydrochloride) is a piperidne-based, reversible inhibitor ol the enzyme acetylcholinesterase (AChE). A consistent pathological change in Alzheimer's disease is the degeneration of cholinergic neuronal pathways that project tram the basal forebiain lo the cerebral cortex and hippocampus The resulting hypofunction ol these pathways is thought to account lor some ol the clinical manifestations ol dementia Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration ol acetylcholine (ACti) through reversible inhibition of its hydrolysis by AChE If this proposed mechanism ol action is correct, donepczi'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: ARBEPT (donepezil hydrochloride) is indicated lor the symptomatic treatment of patients with mild-to-moderate dementia of the Alzheimer's type. Efficacy of ARICEPT in patients with mild-lo-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 of Alzheimer's disease. CONTRAINDICATIONS: ARICEPT (donepezil hydrochloride) is contraindtaled in patents with known hypersensrtivty to donepezil hydrochloride or lo pipendine dehvahves. WARNINGS: Anesthesia ARICEPT (donepezil hydrahlondel. as a cholineslerase inhibitor, is likely lo exaggerate socdnytmoHne-type muscle relaxation during anesthesia. Neurological CoMlims: Seizins: Some cases ol seizures have been reported witti the use ol 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 ol Alzheimer's disease. The nsk/benett ol ARICEPT treatment for patients wrtti a history ol seizure disorder must therefore be carefully evaluated. ARICEPT has not been studied in patients with non-Alzheimer dementias oi individuals with Parkinsonian features. The efficacy and safety ol ARICEPT in these patients are unknown. M i w s r y Citlilitis: Because of their cholinomimetic action, cholineslerase infiibitors 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 foi these conditions and should therefore be used with particular caution in such patients M o n s c i l i r : Because of then nharmacctogd action, chctnesterasemribitors may have 'flootonic effects on Heart rate (eg., bratrycarttal-The potential for teactwi rnay be parOciJarry irnoortant to patents with 'sch sinus syndrome' or other supravermxular canUac oxiducbon ccndibons. In dinical tnats. most patients wnh senous rsrdrjvascuiar oindftions were excluded. Pabents such as those with controlled hypertension (DBP<95 mmHg), right bundle branch blrjclcacje and pacernakens were mduded. Therefore, caution sfiould be taken in treabng patients with acbve coronary artery disease and conrjestive heart failure Syncopal episodes have been reported in assoctahon with the use of ARICBT. It is recomrnended that AflCEFT should not be used in patients wnh cardiac conduction abnormalities (except for right bundle branch block) including "sick sinus syndrome' and those wrrh unexplained syncopal episodes. GistrainltstiMl: Through their primary action, cholineslerase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activrty. Therefore, patients at increased risk lor developing ulcers, eg,, those wrrh a history ot ulcer disease or those receiving concurrent nonsteroidal antHntlammatory drugs (NSAIDs) including high doses of acetylsakcylic acid lASAi. should be monitored lor symptoms of acbve or occult gastrointestinal bleeding. Clinical studies ol AHCEPT have shown no increase. relative to placebo in the incidence of either peptic ulcer disease or gastrointesbnal tjteeding (see ADVERSE REACTIONS sechoni ARICEFT. as a predictable consequence of its pharmacological properties, has been shown lo produce, in controlled clinical trials in pabents with Alzheimer s disease, diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 1Q mg dose than with the 5 mg dose. In most cases, these effects have usually been mild and transient, somebmes lasting I to 3 weeks and have resolved during continued use ol ARICEPT (See ADVERSE REACTIONS section). Treatment with the 5 mg/d dose tor 4-6 weeks prior to increasing the dose to 10 mg/d is associated with a lowei incidence of gastrointestinal intolerance Gem'touri'Mry: Although not observed in clinical trials ol ARICEPT, cholinomimetics may cause bladder outflow obstruction PRECAUTIONS: Concomitant Use wilt Other Drugs: Use ilAMtioliiwirts: Because ol then mechanism ol action, cholineslerase inhibitors have the potential to interfere vrith the activrty of anticholinergic mediations tee lift) CMiMiiwtics ind Otter CMwsferase Mrtilm: A synergistic effect may be expected when choliiiesteiase inhibitois aie given concunently wrtfi succinylcbotine, similai neuramuscular blocking agents oi cholineigic agonists such as bettianecbol Use ibt Otter ftycbojcfhe Oriel. Few pabents in controlled clinical trials received neuroleptics, antidepressants or anticonvulsants. There s thus limied information concerning the interaction ol ARICEPT wnh these drugs JJ in Pilrenb 285 fears O/rr: In controlled clinical studies wnh 5 and 10 mg ot ARICEPT, 536 patients were between the ages ot 65 to 84, and 3/ pabents were aged 85 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 cholineslerase inhibitors as well as Alzheimer's disease can be associated with significant weight loss, caution is advised regarding the use ol ARICEFT in low body weight elderly pabents. especially in those >85 years old. list in Eluirfv M i n i s Witt Comrtii H u m : There s limited safety information lor ARICEFT in pabents with mild-lo-moderate Alzheimer's disease and significant comorbtdrty The use of ARICEPT in Alzheimer's disease patients with chime illnesses common among the genatnc population, should be considered only after careful riskrtenefft assessment and include dose monitoring foi adverse events Caution is advised regarding the use IARICEPTdosesabove5mg in this patient population fmllj-ii*/ieralitall|r-lrruireif.'The!e is limiied information regarding the pharmacokinetics of ARICEFT in renally-and fiepahcally-rmpaired Alzheimer's disease patients Close monitoring for adverse effects in Alzheimer's diseasepahents wrth renal or hepatic disease 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 ot ARICEPT tor interaction with theophylline, cimetidine, warfarin and digoxin administration. No significant effects on the pharmacokinetics ot these drugs were observed Similar studies in elderly patients were not done Drugs Highly tali la Html Mints: Drug displacement studies have been performed in vitro between donepezil, a highly bound diug (96%) and othei drags such as lurosemide, digoxin and warfarin. Donepezil at concentrations of 03-10 pg/mL did not affect tit binding of lurosemide |5 pglmL), digoxin (2 ng/mL) and warfarin (3 ugfmL) to human albumin Similarly, the binding ol donepezil to human albumin was not affected by turosemide, digoxin and wartann flfttf itlFIClPJ on Die AfelaMsrti of Offter Dm/s.-In vitro slides show a low rale ol donepezil binding to CVP 3A4 and CVP 206 isoenzymes [mean Kl about 50-130 uM), which, given the therapeutic plasma concentrations ol donepezil (164 nM), indicates I n * likelihood of interferences. In a pharmacokinetic study involving 18 heathy volunteers, the administration ol ARICEPT al a dose ol 5 mg/d lor ? days had no clinically significant effect on the pharmacokinetics ol ketoconazole. No other clinical trials, have been conducted to investigate the effect ol ARICEPT on the clearance of drugs metabolized by CVP 3A4 (eg, cisapride. lerfenadine)oi by O P 206 leg, imipramine). It is not known whether ARICEPT hasanypolenhalloienzyire induction fftdo/OIAer Brigsbe AfctiWisii itxtMi^CEFr ftetrxaofiazoie andquinidine.inhioitorsofCT> 450.3A4 and 2D6. respechvefy. inhibit donepezil metabolism in vitro. I n a r^ltarinacolonetic study, 18 healthy volurrteers received 5 mg/d ARICEFT together with 200 mg/d ketoconazole for 7 days. In these volunteers, mean donepezil plasma concentratiorrs were increased by about 30-36% Inducers ol CVP 2D6 and CVP 3A4 (e.g., phenytoin, carbamazepine, dexamelhasone, nlampln and phenodaibrtal) could increase the rate ol elimination of ARICEPT Pharmacokinetic studies demonstrated that the metabolism of ARICEFT is not significantly affected by concurrent administration ol digoxin oi cimetidine Die ii Pregnancy f Nursing Afilfier The safety of ARICEPT dunng pregnancy and lactation has not been established and therelote, it should not be used in women ol childbeaiing potential or in nursing mothers unless, in the opinion of the physician, the potential benefits to the patienl outweigh the possible hazards to the tetus or the infant. Teratology studies conducted in pregnant rats at doses ol up to 16 mg/Vg/d and

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