National Geographic : 2003 Oct
Ai (donepezil HCI).*'- ^ STRENGTH IN THE FACE OF ALZHElIMER'S" ARICEPTP(DonepezilHydrochloride Tablets) BriefSummary-see package insert forfullprescribing information.INDICATIONS ANDUSAGE ARICEPP is indicated for the treatment of mildto moderate dementia of the Alzheimer'stype. CONTRAINDICATIONS ARICEPP is contraindicated in atients withknownhypersensitivity to donepezilhydrochloride or to piperidine derivatives.WARNINGSAnesthesia: ARICEPTP, asa cholinesterase inhibitor,is likelytoexaggeratesuccinylcholine-type musclerelaxationduringanesthesia. Cardiovascular Conditions: Because of their pharmacological action,cholinesterase inhibitors mayhavevagotonic effectson the sinoatrialand atrioventricularnodes. Thiseffectmaymanifestas bradycardiaor heartblock in patientsbothwithand withoutknownunderlyingcardiacconduction abnormalities. Syncopal episodes havebeen reported in association withthe use of ARICEP®. Gastrointestinal Conditions: Through their primary action, cholinesterase inhibitors may be expectedto increasegastricacidsecretiondueto increasedcholinergicactivity.Therefore,patientsshould bemonitoredcloselyforsymptomsofactiveoroccultgastrointestinalbleeding,especiallythoseat increased risk for developingulcers, e.g., those witha history ofulcer disease or those receivingconcurrent nonsteroidalanti-inflammatorydrugs (NSAIDS).Clinicalstudies ofARICEPT ® haveshown no increase, relativeto placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. ARICEPT,as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea and vomiting. These effects,whenthey occur, appear more frequentlywith the 10 mg/day dose than withthe 5 mg/day dose. In most cases, these effectshave beenmildand transient, sometimes lastingone tothreeweeks,andhaveresolvedduring continued use ofARICEPTP. GenitourinaryAlthough not observedin clinicaltrialsofARICEPP,cholinomimetics maycause bladder outflowobstruction. Neurological Conditions: Seizures:Cholinomimeticsarebelievedtohavesome potentialto cause generalizedconvulsions. However,seizureactivityalso may be a manifestationof Alzheimer's Disease.Pulmonary Conditions: Because oftheir cholinomimetic actions, cholinesterase inhibitors should be prescribed withcare to patients witha historyofasthma or obstructive pulmonary disease. PRECAUTIONS Drug-Drug Interactions Drugs Highly Bound to Plasma Proteins: Drugdisplacement studies have been performed in vitro betweenthis highlybound drug (96%) and other drugs such as furosemide, digoxin, and warfarin.ARICEPT"at concentrations of 0.3-10 pg/mL did not affect the binding of furosemide (5 pg/mL), digoxin (2 ng/mL),and warfarin(3 pg/mL) tohuman albumin. Similarly, the binding ofARICEPP to human albumin was not affected by urosemide, digoxin, and warfarin.Effect of ARICEP1 on the Metabolism of Other Drugs: Noin vivoclinicaltrialshaveinvestigatedtheeffectofARICEPP onthe clearanceofdrugs metabolized by CYP3A4(e.g . cisapride, terfenadine) or byCYP2D6(e.g . imipramine).However,in vitrostudies show a lowrateofbinding to these enzymes (meanKiabout 50-130 pM),that, giventhe therapeutic plasma concentrations of donepezil (164 nM),indicates littlelikelihoodof interference.Whether ARICEPP ® has any potentialforenzymeinduction is not known.Effect of Other Drugs on the Metabolism of ARICEPT : Ketoconazoleand quinidine, inhibitors of CYP450,3A4and 2D6, respectively, inhibit donepezilmetabolism in vitro.Whetherthere is a clinicaleffectofthese inhibitors isnotknown.Inducers ofCYP2D6andCYP3A4(e.g ., phenytoin, carbamazepine dexamethasone, rifampin, andphenobarbital)couldincreasetherateofelimination ofARICEPP.Use withAntictolinerics Because of theirmechanism ofaction cholinesterase inhibitorshavethe potentialtointerferewiththe activityof anticholinergic medications.Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effectmay be expected whencholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blockingagents or cholinergic agonists such as bethanechol. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies ofdonepezil have not been completed. Donepezilwas not mutagenic in the Amesreverse mutation assay in bacteria.Inthe chromosome aberration test in cultures ofChinese hamster lung(CHL)cells, some clastogenic effectswere observed. Donepezilwas notclastogenic inthe in vivomouse micronucleus test. Donepezilhad noeffecton fertilityin rats at doses up to 10mg/kg/day (approximately 8 times the maximumrecommended human dose on a mg/mrbasis). Pregnancy Pregnancy Category C: Teratologystudies conducted inpregnant rats at doses up to 16mg/kg/day (approximately 13times the maximumrecommended human dose on a mg/m 2 basis) and inpregnant rabbits at doses up to 10mg/kg/day (approximately 16 times the maximumrecommended human dose ona mg/m 2 basis) did not disclose any evidence fora teratogenic potentialof donepezil.However,in a study in which pregnantrats weregivenupto10 mg/kg/day(approximately8 timesthe maximumrecommendedhuman dose on a mg/m 2 basis) fromday1 of gesation through day20postpartum,therewasa slightincrease in stillbirthsand a slight decrease inpupsurvivalthroughday4 postpartum at this dose; thenextlower dose tested was3 mg/kg/day. Thereare no adequate or wellcontrolled studies inpregnant women. ARICEPTPshould beused during pregnancy onlyif the potentialbenefitjustifies the potentialriskto thefetus.Nursing Mothers Itis notknownwhetherdonepezilis excretedinhumanbreastmilk.ARICEPTP has no indication foruse in nursing mothers. Pediatric Use Thereare no adequate and well controlled trials to document the safetyand efficacyofARICEPTPin anyillness occurring in children. ADVERSEREACTIONS Adverse Events Leading to Discontinuation Theratesofdiscontinuation fromcontrolled clinicaltrials ofARICEPTdue to adverse events forthe ARICEPT ® 5 mg/day treatment groups were comparable to those of placebo-treatment groups at approximately 5%. The rate of discontinuation of patients whoreceived7-day escalations from5 mg/day to 10 mg/day, washigher at 13%. Themost common adverse events leadingtodiscontinuation, definedas those occurring in at least 2% of patients and at twicethe incidence seen inplacebo patients, are shown in Table1. Table 1. Most Frequent Adverse Events Leading to Withdrawal from Controlled Clinical Trials by Dose Group Dose Group Placebo 5 mg/day ARICEPT 10 mg/day ARICEPP Patients Randomized 355 350 315 Event/% Discontinuing Nausea 1% 1% 3% Diarrhea 0% <1% 3% Vomiting <1% <1% 2% Most Frequent Adverse Clinical Events Seen in Association with the Ue of ARICEPP Themost common adverse events, definedas those occurring at a frequency ofat least 5% inpatients receiving 10mg/day and twicethe placebo rate,are largelypredicted byARICEPT®'s cholinomimetic effects.These includenausea, diarrhea,insomnia, vomiting,muscle cramp,fatigueandanorexia.These adverse events were often of mild intensityandtransient, resolving during continued ARICEPT ® treatment withoutthe need fordose modification.Thereis evidence to suggest thatthe frequencyof these common adverse events maybe affectedby the rateof titration. An open-label study was conducted with269 patients whoreceivedplacebointhe15-and30-weekstudies. Thesepatients were titratedtoadose of10 mg/day overa 6-week period. Therates of common adverse events werelower than those seen inpatients titratedto 10mg/day overone weekinthe controlledclinicaltrialsand were comparable to those seen inpatients on5 mg/day. SeeTable2 fora comparison ofthemost common adverse events followingone and sixweektitrationregimens. Table 2. Comparison of Rates of Adverse Events in Patients Titrated to 10 mg/day Over 1 and 6 Weeks No titration One-week titration Six-week titration Adverse Event Placebo 5 m(n315) gday 10mday 1 0mday (n=315) (n 11 (n3a- 5) (n=269) Nausea 6% 5% 19% 6% Diarrhea 5% 8% 15% 9% Insomnia 6% 6% 14% 6% Fatigue 3% 4% 8% 3% Vomiting 3% 3% 8% 5% Muscle cramps 2% 6% 8% 3% Anorexia 2% 3% 7% 3% practiceor in otherclinicaltrials, these frequency estimates maynot apply,as the conditions ofuse, reportingbehavior,and the kinds ofpatients treated maydiffer.Table3 lists treatment emergent signs and symptoms thatwerereportedin at least 2% ofpatients in placebo-controlled trialswho received ARICEPPandforwhichthe rateofoccurrencewasgreaterforARICEPPassigned thanplaceboassigned patients.Ingeneral,adverse events occurredmorefrequentlyinfemale patientsand withadvancing age. Table 3. Adverse Events Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving ARICEPT (donepezil HCI)and at a Higher Frequency than Placebo-treated Patients Body System/Adverse Event Placebo ARICEPP (n=355) (n=747) Percent of Patients with any Adverse Event 72 74 Body as a Whole Headache 9 10 Pain,various locations 8 9 Accident 6 7 Fatigue 3 5 Cardiovascular System Syncope 1 2 Digestive System Nausea 6 11 Diarrhea 5 10 Vomiting 3 5 Anorexia 2 4 Hemic and Lymphatic System Ecchymosis 3 4 Metabolic and Nutritional Systems WeightDecrease 1 3 Musculoskeletal System Muscle Cramps 2 6 Arthritis 1 2 Nervous System Insomnia 6 9 Dizziness 6 8 Depression <1 3 AbnormalDreams 0 3 Somnolence <1 2 Urogenital System Frequent Urination 1 2 Other Adverse Events Observed During Clinical Trials ARICEPT®has been administered to over1700 individualsduring clinicaltrialsworldwide.Approximately1200 ofthese patients havebeen treatedfor at least 3 months and more than 1000 patients havebeen treated for at least 6 months. Controlledand uncontrolledtrialsinthe UnitedStates includedapproximately900 patients. Inregards tothehighestdose of10mg/day,this populationincludes650patientstreatedfor3 months,475patients treatedfor6 months and 116patients treatedforover 1year. The range ofpatientexposure isfrom 1 to1214 days. Treatmentemergent signs and symptoms thatoccurred during 3controlledclinicaltrials and twoopen-label trials inthe UnitedStates were recorded as adverse events by the clinical investigatorsusing terminologyoftheirownchoosing. Toprovidean overallestimate ofthe proportion of individuals havingsimilar types of events, the events were grouped into a smaller number of standardized categories using a modifiedCOSTARTdictionary and eventfrequencies werecalculated across all studies. These categories are used in the listingbelow.The frequencies represent the proportion of900 patients fromthese trials whoexperienced that event whilereceivingARICEPTP.All adverse events occurring at least twiceare included, except forthose already listedinTables2 or 3, COSTARTtermstoogeneraltobeinformative,oreventslesslikelytobedrugcaused. Eventsareclassified bybodysystem andlisted using the followingdefinitions: frequent adverse events-those occurring in at least 1/100 patients; infrequentadverse events-those occurring in1/100 to 1/1000 patients. Theseadverseeventsare notnecessarilyrelatedtoARICEPPtreatmentandinmost cases wereobserved at a similarfrequencyinplacebo-treatedpatientsinthecontrolledstudies. Noimportantadditionaladverse eventswereseen instudiesconductedoutsidetheUnitedStates.Bodyas a Whole: Frequent influenza, chest pain,toothache;Infrequent fever,edema face,periorbitaledema, herniahiatal,abscess, cellulitis, chills, generalized coldness, head fullness, listlessness. Cardiovascular System: Frequent: hypertension, vasodilation, atrialfibrillation, hot flashes,hypotension;Infrequent:anginapectoris,postural hypotension,myocardialinfarction,AVblock(firstdegree),congestiveheartfailure,arteritis,bradycardia, peripheralvascular disease, supraventricular tachycardia,deepveinthrombosis. Digestive System: Frequent fecalincontinence, gastrointestinal bleeding, bloating,epigastricpain;Inrequent eructation, gingivitis,increasedappetite,flatulence,periodontalabscess, cholelithiasis,diverticulitis, drooling,dry mouth,feversore,gastritis,irritablecolon,tongueedema,epigastricdistress, gastroenteritis,increased transaminases,hemorrhoids,ileus,increasedthirst,jaundice,melena,polydipsia,duodenalulcer,stomach ulcer.EndocrineSystem: nfrequmntdiabetes mellitus,oiter.Hemic and ympha System: Infrequent anemia,thrombocyhemia, thrombocytopenia, eosinophilia, erythrocytopenia. Metabolic and Nutritional Disorders: Frequentdehydration;Infruentgout, hpokalemia, increasedcreatinekinase,hyperglycemia, weightincrease,increasedlactatedehydrogease. Musculoskeletal System: Frequent bone fracture; Infrequent:muscle weakness, muscle fasciculation.Nervous System: Frequent: delusions, tremor, irritability,paresthesia, aggression, vertigo,ataxia,increased libido,restlessness, abnormalcrying, nervousness, aphasia;Infrequent cerebrovascular accident, intracranialhemorrhage, transientischemic attack,emotionallability,neuralgia, coldness (localized),muscle spasm, dysphoria, gaitabnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized),paranoia, dysarthria, dysphasia, hostility,decreased libido,melancholia, emotional withdrawal,nystagmus, pacing. Respiratory System: Frequent:dyspnea,sore throat,bronchitis;Infrequent:epistaxis,post nasaldrip,pneumonia, hyperventilation, pulmonarycongestion, wheezinghypoxia,pharyngitis, pleurisy, pulmonarycollapse, sleep apnea,snoring.Skin and Appendages: Frequent.pruritus, diaphoresis, urticaria;Infrequent dermatitis,erythema,skindiscoloration, hyperkeratosis, alopecia,fungaldermatitis,herpeszoster,hirsutism, skinstriae,nightsweats,skinulcer.Special Senses: Frequent:cataract, eye irritation,vision blurred; Infrequent.dryeyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing,retinalhemorrhage, otitisexterna,otitismedia, adtaste, conjunctivalhemorrhage,earbuzzing,motionsickness, spots before eyes. Urogenital System: Frequent urinaryincontinence, nocturia;Infrequent dysuria,hematuria, urinaryurgency,metrorrhagia,cystitis,enuresis, prostate hypertrophy,pyelonephritis,inabilitytoempty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis. Postintroduction Reports Voluntaryreportsofadverse events temporallyassociated withARICEPT® thathavebeenreceivedsince marketintroductionthatarenotlistedabove, and thatthereis inadequate data to determine the causal relationship withthe drug include the following:abdominal pain, agitation,cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia,hepatitis,hyponatremia, neurolepticmalignantsyndrome,pancreatitis,andrash.OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine thelatest recommendations for the management of an overdose of any drug. Asin any case ofoverdose, generalsupportive measures should beutilized.Overdosagewithcholinesterase inhibitors canresulti nergiccrisis characterizedby severenausea, vomiting,salivation,sweating,bradycardia,hypotension, respiratory depression,collapseand convulsions.Increasingmuscleweaknessisa possibilityand mayresultindeath if respiratory muscles are involved.Tertiaryanticholinergics such as atropine may be used as an antidote forARICEPTPoverdosage. Intravenousatropine sulfatetitratedtoeffectis recommended: an initialdose of 1.0 to 2.0 mg IVwithsubsequent doses based upon clinical response. Atypical responses inblood pressure and heartratehavebeen reported withother cholinomimetics whenco administered withquaternary anticholinergics such as glycopyrrolate. It is not knownwhether ARICEPT®and/or its metabolites can be removedbydialysis (hemodialysis, peritonealdialysis, or hemofiltration).Dose-related signs oftoxicityin animals included reduced spontaneous movement, proneposition,staggeringgait,lacrimation, clonicconvulsions,depressed respiration,salivation,miosis, tremors, tasciculaion and lowerbodysurface temperature. Adverse Events Reported in Controlled Trials Theevents cited reflectexperince gained under r sa S rmaceuial 200177 RevisedDecember2000 closely monitored conditions ofclinicaltrials in a highlyselected patientpopulation. Inactualclinical Esa iN r,4 wo, ' a 2011r RevisedDecember200 ARICEPT ' is a registeredtrademark of EisaiCo., Ltd. EL187X01GB © 2003 Eisai Inc.and PfizerInc. Allrightsreserved.