Program - 39th Canadian Congress of Neurological Sciences - Calgary, AB

Once-a-dayTable 2, Comparison of Rates of Adverse Events io Patients Treated with 10 mg/d after 1 and 6 Weeks of Initial Treatment with 5 mg/d PHARMACOLOGIC CLASSIFICATION: Ctoieesterase Inhibitor.ACTION AND CLINICAL PHARMACOLOGY: AfllCEPT (dooepezil hydrochloride) i s 1 piperidine-tased, reversible inhibitor of the enzyme acetylcholinesterase (AChE).A consisteot pathological change in Alzheimer's disease is the degeneration of cholinergic neoronal pathways that project from the basal forebrain to the cerebral cortex aod hippocampus.The resulting hypofunction of these pathways is thought to account for some of the clinical manifestations of dementia, Dooepezil is postulated lo exert its Iherapeitic effect by enhancing cholinergic function.This is accomplished by increasing the concentration of acetylcholine (ACh) through reversible iohibition of its hydrolysis by AChE, It this proposed mechanism of actioo i s correct, dooepezil's effect may lessen as the disease process advances aod fewer cholinergic oeurons remain tunctiooilly iotact.There is no evidence that dooepezil alters the course oi the underlying dementing process, INDICATIONS AID CLINICAL USE: ARICEPT (dooepezil hydrochloride) is indicated for the symptomatic treatment of patients with mild-to-rhdderate dementia of the Alzheimer' s type.Efficacy of ARICEPT in patients with mild-to-moderate Alzheimer's disease wis established io two 24-week aid one 54-week placebo-controlled trills, ARICEPT tablets should ooly be prescribed by (dr following consultation with) clinicians who are experienced io the diagnosis aod maoagement of Alzheimer's disease.CONTRAINDICATIONS: ARICEPT (dooepezil hydrochloride) is conlraiodioated in patients with known hypersensitivity to dooepezil hydrdchloride or to pipeline derivatives.WARNINGS: Anesfcsij: ARICEPT (dooepezil hydrochloride), as a cholinesterase inhibitor, is likely to exaggerate succinjlctolioe-type muscle relaxation during anesthesia.Aiwoliiicil Ciil/lims; Seitires: Some cases of seizures have been reported with the use of ARICEPT in clinical frills and from spontaneous Adverse Reaction reporting.Cholinomimetics can cause a reduction ol seizure threshold, increasing the risk df seizures.However, seizure activity may also be i maoifestatioo of Alzheimer's disease.The risk/benefit ol ARICEPT treatment for patients with a history ot seizure disorder must therefore be carefully evaluated ARICEPT his oot been studied in patients with non-Alzheimer dementias or individuals with Parkiosonian features.The efficacy and safety of ARICEPT in these patients are unknown.Pirtiiiiry M M : lecause ol their cholinomimetic action, cholinesterase inhibitors should be prescribed with care to patients with i history of asthma or obstructive pulmonary disuse.ARICEPT his not leeo studied in pifients under treatment for these conditions and should therefore be used with particular caution in such patients, Ciriimsulu:Because of their pharmacological action, cholinesterase inbibnors may have vagotooic effects oo heart rate (e.g., bradycardia).The potential for this action may be particularly important to patients with "sick sinus syndrome' or other supraventricular cardi ac cooductioo oondifioos.lo clinical trials, most patients with serious tirdioviscular coodiioos were excluded.Patieots such as those with controlled hypertension (DBP<95 mmHg), right bundle branch bl ockage and pacemakers were included.Therefore, caution should be takeo i o treating patieots with active coronary artery di sease snd congestive heart failure.Syncopal episodes have been reported i o association: with the use of ARICEPT.It i s recommended that ARICEPT should not be used in patieots with cardiic conduction abnormalities (except tor right boodle branch block) including "sick sious syndrome" and those w«h unexplained syncopal episodes. Sislwiilisliiil:Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increised cholinergic activity.Therefore, patients at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent noosferoidal anti-inflammatory drugs (NSAIDs) iocluding 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 ol its pharmacological properties, has beeo shown to produce, io controlled clinical trials in patients with Alzheimer's disease, diarrhea, nausea and vomiting.These effects, when they occur, appear more frequently with the 1D mg dose than with the 5 mg dose.In most cases, these effects have usually been mild and transient, sometimes lasting f to 3 weeks and have resolved during continued use of ARICEPT (See ADVERSE REACTIONS seclioo).Treatment with the S mg/d dose for 4-6 weeks prior to increasing the dose fo 10 mg/d is associated with a lower incidence of gastrointestinal intolerance, Genrtiirrfiary: Although oot observed in clinical trials of ARICEPT.cholinomimetics may cause bladder outflow obslructioo.PRECADTIDNS: Concomitant Ose with Other Drugs: Use nft AilrcWinergies: Because of Iheir mechanism Df action, cholinesterase inhibitors have the potential to interfere wilt the activity of anticholinergic medications, lise lill G M M M b and titer f M l w i U m i MiMirs: A synergistic effect may be expected when cholinesterase inhibitors are giveo concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.Use » 1 Ofcr ftitinifiw Jriis; 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 M i l l s > 85 fears Oil: lo controlled clinical studies with 5 and ID mg of AfllCEPT, 536 patients were between the ages of 65 to 84. and 3? patients were aged 85 years or older.In Alzheimer's disease patieots, nausea, diarrhea, vomiting, insomnia, fatigue aod anorexia increased with dose and age and the ioeideoce appeared to be greater in female patients.Since cholinesterase iohibifors as well as Alzheimer's disease can be associated with significant weight loss, caution is advised regarding He use of ARICEPT in low body weight elderly patients, especially in Hose >!5 years old.Use i i Elderly M u l l m'll C i i w B flisease.'There is limited safety information for ARICEPT io patients with mild-to-moderate Alzheimer's disease and significant comorbidity.T he use of ARICEPT in Alzheimer's disease patients with chronic illnesses commoo amoog the geriatric population, should be considered only after careful risk/benefit assessment aod include clcse monitoring foradverse events.Caution is advised regarding the use of ARICEPT doses above 5 mg in this patient popuFation.Hena//)r-a , nrfHejBa , tfC3//v-fmin' a/reo' :Thefe is limited information regarding the ptarmacokioetics ol AfllCEPT in renally-and hepatically-impaired Alzheimer's disease patients.Clnse mooitoring for adverse effects in Alzheimer's disease patients with renal or hepatic disease beiog 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 ioferaction with theophylline, cimetidine, warfarin and digoxio administratioo, lo sigoilicant (fleets oo the pharmacokioetics of these drugs were observed.Similar studies in elderly patients were oot done, Dnis fliin/y tad In tana Proteins: Drug displacement studies have been performed in vitro betweeo dooepezil, a highly bound drug (96%) and other drugs such as furosemide, digoxin and warfarin, Dooepezil at concentrations of 0,3-10 pg/mL did oof affect the binding of furosemide (5 pg/mL), digoxin (2 ng/ml) aod warfarin (3 pg/mL) to human albumin.Similarly, the binding of dooepezil to human albomin was not affected by furosemide, drgoxin and warfarin, fffeef i/Afl/CfPTorr lie Afe/aiiO'sit of Oiler Ori/is; In vitro studies show a low rate of dooepezil binding to CTP 3A4 aod CYP 2D6 isoenzymes (mean Ki about 50-130 uM).which, given the therapeutic plasma cootentrations ol ddoepezil (164 nil), indicates little likelihood of interferences, lo a pharmacokinetic study involving 18 healthy volunteers, the administration of ARICEPT at a dose of 5 mg/d for 7 days had no clioically significant effect on the pharmacokinetics of kelocooazole, lo other clinical trials have been conducted fo investigate He effect of ARICEPT on the clearance of drugs metabolized by CYP 3A4 (e.g., cisapride, terfenadine)orbyCYP2D6(e.g.,imipramine).It is oolknowo whether AfllCEPT has any potential for enzyme induction, fffeil of Oiler tongs on the nTetalilisni nlMf.PI: kelocooazole and gumidine, inhibitors of CYP 450,3A4and2D6, respectively, iohibit dooepezil metabolism in vitro.In a pharmacokinetic study, 1S healthy volunteers received 5 mg/d ARICEPT together with 300 mg/d letoconazole for 7 days.In tbese volunteers, mean dooepezil plasma concentrations were increased by about 30-36%.Inducers of CYP 2DB aod CYP 3A4 (e.g., pheoytoio, carbamazepioe, dexamethasone, rifampin and phenobarbifal) could increase the rate of elimioatioo of ARICEPT, Pharmacokinetic studies demonstrated that the metabolism of ARICEPT is oot significantly affected by concurrent administration of digoxio or cimetidine.listiiPreiMiey end A t a g Mo/her: The safely oi ARICEPT duriog pregnancy and lactation has not been established and therefore, it should not be used io women of childbearing potential or in nursing mothers unless, in the opioion of the physiciao, the poteotial beoefits to Ihe palient outweigh the possible hazards to the fetus or the infant.Teratology studies cooducted i o pregna

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