National Geographic : 2003 Apr
Ai iT donepezil HC'.' . STRENGTH INTHHEFAC OF AIZHEIMER'S'" ARICEPT(DonepezilHydrochloride Tablets) BriefSummary-see packageinsertforfullprescribing information.INDICATIONS ANDUSAGE ARICEPT'is indicated for te treatment of mildto moderate dementia of the Alzheimer'stype. CONTRAINDICATIONS ARICEPT*is conlraindicated inpatients withknownhypersensitiviy to donepezilhydrochloride or to piperidine derivatives.WARNINGSAnesthesia: ARICEPTPas a cholinesterase inhibitor,islikelytoexaggeratesuccinylcholine-type musclerelaxationduringanesthesia. Cardiovascular Conditions: Becauseof theirpharmacologicalaction cholinesterase inhibitors may havevagotonic effectson the sinoatrialand atrioventricularnodes. Thiseffectmaymanifestas bradycardiaor heart blockin patients bothwithand withoutknownunderlyingcardiacconduction abnormalities. Syncopal episodes havebeen reportedin association withthe use of ARICEPT. Gastrointestinal Conditions: Through their primary action,cholinesterase inhibitors may be expectedto increasegastricacidsecretionduetoincreasedcholinergicactivity.Therefore,patientsshould be monitoredcloselyforsymptomsofactiveoroccultgastrointestinalNeeding, especiallythoseat increased risk fordevelopingulcers, e.g., those witha historyof ulcerdisease or those receivingconcurrent nonsteroidalanti-inflammatory drugs (NSAIDS).Clinicalstudies ofARICEPThaveshownno 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,whentheyoccur, appear more requentlywith the 10mg/day dose than withthe 5 mg/daydose. Inmost cases, these effectshave been mildand transient, sometimes lastingone tothreeweeks,andhaveresolvedduring continueduse ofARICEPT'. GenitoulhaixAlthoug notobservedin clinicaltrialsofARICEPP,cholinomimetics maycausebladder outflowobstruction. Ierolo l Condition: SeizuresCholinomimetics arebelievedtohavesome potentialto cause generalizedconvulsions. However,seizureactivityalso maybe a manifestationof Alzheimers Disease.PulmonaryCondons :Becauseoftheircholinomimelic actions, cholinesterase inhibitors should be prescribed withcaretopatients witha historyofasthma or obstructivepulmonary diseasePRECAUTIONS Drug-Drug Interactions DrusrHighly Bound to Plasma Proteins: Drugdisplacement studies havebeen performed in vitrobetweenthis highlybound drug (96%) and other drugs such as furosemide,digoxin, and warfarin.ARICEPTPal concentrations of 0.3-10 pg/mLdid not affect the binding of furosemide (5 pgmL), digoxin (2 ng/mL), and warfarin(3 ug/mL) to human albumin. Similarly,the binding ofARICEPT'to human albumin was not affected b furosemide, digoxin, and warfarin. EffectolARICEPF on the Metabolism ofOther Drugs: o in vivoclinicaltrialshaveinvestigatedtheeffectofARICEPTIon theclearanceofdrugs metabolized by CYP3A4(e.g . cisapride terenadine) o CYP2D6(eg. imipramine).However,in vitro studies show a lowrateofbinding to these enzymes (meanKi about 50-130 pM),that,giventhe therapeutic plasma concentrations o donepezil (164 M indicates littlelikeliood of interference.Whether ARICEPThhas any potentialforenzymeinduction is notknown.Eftct ot Other Drugs on the Metabolism of ARICEPT': Ketoconazoleand quinidine, inhibitors of CYP450,3A4and 2D6, respectively,inhibitdonepezil metabolism in vitro.Whetherthereisa clinicaleffectofthese inhibitors is notknown.InducersofCYP2D6andCYP3A4(eg., phenyn, caiamazepie dexamethasone, ritampi, andphenobarbital) couldincreasetherateofeliminatonofARICEPT. Use w hl Because oftheirmechanismofaction cholinesterase inhibitorshavethe potentialto interferewith e activityof anticholinergic medicationsUse with Cholinomimetcs andOther Cholnesterase Inhibitors: A synergislic effect maybe expectedwhencholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blockingagents orcholinergic agonists such as bethanechol. Carclnogenesis, Mutageness, Impairment of Fertility Carcinogenicitystudies 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 claslogenic effectswereobserved. Donepezilwasnot clastogenic inthe in vivomouse micronucleus test. Donepezilhad no effecton fertilityin rats at doses up to 10mg/kg/day (approximately8 times the maximumrecommended human dose ona mg/m basis). Pregnancy PrgnancyCategoyC: Teratologystudies conducted inpregnant rats at doses up to 16mkg/day approximately 3 times the maximumrecommended human dose on a mg/m basis) and in pregnant rabbits at doses up to 10mg/kg/day (approximately 16times the maximumrecommended human dose ona m 'g/ basis) did notdisclose any evidence fora teratogenic potentialof donepezil.However,in a study in which pregnantratsweregivenupto 10mg/gday approximatelyy 8 imesthemaximumrecommendedhuman dose on a mg/m 2 basis) fromday1 ofgestationthrough y20postpartum, therewasa slightincrease in stillbirthsanda slight decrease inpup survivalthroughdy 4 postpartumat this dose; the nextlower dose tested was3 mg/kg/day. Thereare no adequate or wellcontrolled studies in pregnant women. ARICEPTPshould be used during pregnancy onlyif the potentialbenefitjustifies the potentialriskto thefetus Nursing Mohers It isnotknownwhetherdonepezilis excretedinhumanbreastmilk.ARICEPT" has no indicationforuse in nursing mothers. Pediatric Use Thereare no adequate and well controlled trials to document the safelyand efficacyofARICEPT*in anyillness occurring in children. ADVERSEREACTIONS Adverse Events Leading to Discoanuaton Theratesofdiscontinuation fromcontrolledclinicaltrialsofARICEPT*due to adverse events fortheARICEPT"5 mg/day treatment groups were comparable to those of placebo-treatment groups at approximately5%. The rate of discontinuation of patients who received7-day escalations from5 mg/day to 10mg/day was higher at 13%. Themost common adverse events leadingto discontinuation, definedas those occurring in at least 2% ofpatients and at twicethe incidence seen inplacebo patients, are shown inTable1. Table 1. Most Frequent Adverse Events Leading to Withdrawal from Controlled Clinical Trials by Dose Group Dose Group Placebo 5 mg/day ARICEPP 10 mg/day ARICEPTP 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 Use of ARICEPT' Themost common adverse events, definedas those occurring at a frequencyofat least 5% inpatients receiving10mg/day and twicethe placebo rate,arelargelypredicted byARICEPT's cholinomimetic effects.Theseincludenausea, diarrhea, insomnia, vomiting,musclecramp,aigueandanorexia.These adverse events were often of mildintensityand transient, resolving during continued ARICEPT' treatmentwithoutthe need fordose modificationThereis evidence to suggest thatthe frequencyof these common adverse events may be affectedby the rate of titration.An open-label study was conducted with269 patients whoreceivedplacebointhe 15-and30-weekstudies. Thesepatientswere titratedtoa dose of10 mg/day overa 6-weekperiod.Therates ofcommon adverse events werelower than those seen inpatients titratedto 10mg/day overone weekinthecontrolledclinicaltrialsand were comparable to those seen inpatients on5 mg/day. See Table2 fora comparison ofthe most common adverse events followingone and sixweekli rationregimens. Table 2. Comparison of Rates of Adverse Events in Patients Titrated to 10 mg/day Over 1 and 6 Weeks Adverse Event Placo titat n day Onei^msllinCMSIs ek lion 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% cAoBseEmnitoRdapotad in C arroilled Trials Theevents citedreflectexperience gained under closely monitored conditions ofclinicaltrials in ahighlyselected patientpopulation. Inactualclinical practiceor in otherclinicaltrials, these frequency estimates maynot apply,as the conditions ofuse, reporting behavior,and the kinds ofpatients treatedmaydiffer.Table3 lists treatment emergent signs and symptoms thatwerereportedin atleast2% ofpatients in placebo-controlled trialswhoreceived ARICEPT* andforwhichthere ofoccurrencewasgreaterforARICEPTassigned thanplaceboassigned patients.Ingeneral,adverse events occurredmorefrequentlyinfemalepatients andwithadvancingage Table 3. Adverse Events Reported InControlled 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 ipa A}IC P 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 yncope 1 2 Dgestve 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 Urogenlal System Frequent Urination 1 2 Other Adverse Events Observed During Clinical Trials ARICEPT'has been administered to over1700 individualsduring clinicaltrialsworldwide.Approximately1200ofthese patients havebeen treatedforat least 3 months and more than 1000 patients havebeen treated forat least 6 months Controlledand uncontrolledtrials intheUnitedStates includedapproximately900 patients. Inregards tothe hihest dose of10mg/day,this populationincludes650 patientstreatedfor3 months, 475 patients treatedfor6 months and116patients treatedforover 1year Therange of patientexposure is from1 to 1214days. Treatmentemergent signs and symptoms thatoccurred during 3 controlled clinicaltrials and two open-label trials in the United States were recorded as adverse events by the clinical investigatorsusing terminologyoftheirownchoosing. Toprovidean overallestimate ofthe proportion ol individuals havingsimilar types of events the events weregrouped into a smaller number of standardized categories using a modifiedCOSTARTdictionaryand eventfrequencies werecalculated across all studies These categories are used in the listing below.The frequencies represent the proportion of900 patients fromthese trials whoexperienced thateventwhilereceivingARICEPT'. All adverse events occurring at leasttwiceare included, exceptforthose already listed inTables2 or 3 COSTART termstoogeneraltobeinformative, oreventslesslikelyto bedrugcaused. Eventsareclassified bybody system andlisted using the followingdefinitions:frequentadverseevents-those occurring in at least 1/100 patients; infrequent adverseevents-those occurring in 1/100 to1/1000 patients. Theseadverseeventsare not necessarilyrelatedtoARICEPT'treatmentandinmost cases wereobserved at a similarfrequencyin lacebtreatedpalients inthecontrolledstudies. Noimportantadditionaladverse eventswereseenin studiesconductedoutsidetheUnitedSlates.Bodyas a Whole: Frequent influenza, chest pain,toothache;Infrequent lever,edema faceperiorbitaledema, herniahiatal,abscess, cellulitis, chills, generalized coldness, head fullness, listlessness. Cardiovascular System: Frequent: hypertension, vasodilation,atrialfibrillation,hotashes, hypotension;Infrequentnginapecoris, pstura hypotension,myocardialinlarclion,AVblock(firstdegree),congestiveheartfailure,arteris, braycarda, peripheralvascular disease, supraventricular tachycardia,deep veinthrombosis. Digestive System: Frequent fecalincontinence, gastrointestinal bleeding, bloat, e pigastic painI euent: erctalion, gingivitis,increasedappetite,flatulence,periodontalabscess, liiasisiv us, drooling, ry mouth,feversore, gasritis, irritablecolon,tongueedema,epigasric distress, gastroenteritis,increased transaminases,hemorroids, ileus,increasedthirst,aundice, len, pydipsia, duodenalulcer,stomach uler.Endocrine Sysiem: ah diabetes metus gar Hemic aidl i System anemahtr thbcyemia, r ocpenia eosinopilia, erythrocylopena. etaboi and Nutitonal Disoders Freuertdehydration; nf gout,hpkalemia, increasedcreatine kinase,hyperglycemia, weightincraseincreased lactatede rgenase. usculoskeletal System: Frequent bone fracture; nfrequent muscle weakness, musce asciculation.Nervous System: Frequent:delusions tremor irritability,paresthesia, aggression, vertigo,ataxia,increased libido,restlessness, abnormal crying, nervousness, aphia; nrequent cereovascular accident,inlracranialhemorrhage, transient ischeic affack,emotional ability,neuralgia, coldness (localized)muscle spasm, dysphoria, gaitabnormality, hypertonia, hypokinesia neurodermatitis, numbness (localized), paranoia, dysartria, dysphasia, hostility, decreased libido,melancholia, emotionalwithdrawal, nytagmus, pacing Respiratory System: Frequent:dyspnea,sore throat,bronchitis;nis, post nasal drip,pneumonia, hyperventilation, pulmonarycongestion, wheezinghypoxia,pharyngitis, pleurisy, pulmonary collapse, sleep apea, snoring. Skin and Appendages: Frequent.: prurius diaphoresis urticariaInfrequent deatiis, erythema,skindiscoloration, h erkeraosis,alopeca, fungaldermatitis, es zoser, hirsuism, skinstriae,nig sweats,skinulcer.Special Senses: Frequent cataract,eye irritation,vision blurred; Infrequent dryeyes, glaucoma, earache, tinnitus, blephaitis, decreased hearing, retinalhemorrhage, otitisextema,oftis media,badtaste,conjunctivalhemorrhage,ear buzzingmotionsickness, spots before eyes. Urogental System: Frequent urinaryincontinence,nocturia Infrequent:dysuria,hemalura, urinaryurgency, metrorrhagia,cystitis,enuresis, prose hypertrophy,pyeloneprilis, inabilitytoempty bladder, breast tibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure vaginitis. Postlntroductln Reports Voluntaryreprts ofadverse events allyassociated withARICEPT thathavebeenreceivedsince marketintroductionthatare notlistedabovend thatthereis inadeuate data to determine the causal relationship withthe drug include the following:abdominal pain, agitation,cholecystitis, confusion, convulsions, hallucinations, heartblock (all types), hemolyti anemia,hepatitis,hyoatremia, neurolepticmalignantsyndrome,pancreatitis,andrash O RDOSAGE Because strategies forthe management of overdose are continually evolving, it Is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdue of any drug. Asin anycase ofoverdose, generalsupportive measures should be utilized.Overdosagewithciholinesterase inhibitorscan resultin cholinergiccrisis characterizedby severenausea, vomiting,salivation,sweating,bradycardia,hypotension, respiratory depression,collapseandconvulsions.Increasingmuscleweaknessis apossibilityand mayresultindeath if respiratorymuscles are involved.Tertiaryanticholinergics such as atropine maybe used as an antidote forARICEPP"overdosage. Intravenousatropinesulfate litratedtoeffectis recommended: an initialdose of 1.0 to 2.0 mg IVwithsubsequent doses based upon clinical response. Atypical responses inblood pressure andheartratehavebeenreported withothercholinomimetics whenco administered withquaternary anticholinergics such as glycopyrrolate. II is not knownwhether ARICEPT'and/or its metabolites can be removedbydialysis (hemodialysis, peritonealdialysis, or hemoliltration).Dose-related signs oftoxicityin animals includedreduced spontaneous movement, proneposition,staggeringgait,lacrimation,clonicconvulsions,depressed respiration,salivation,miosis, tremors, fasciculation and lowerbodysurfacetemperature. Fha ) Elsl Inc. I .S.I'.an..ar ..rti.al 200177RevisedDecember2000 Tat,,NJ01666 'i w H N-flkt NYM0I1 ARICEPT isaregisered trademarkor EisaiCo., Ltd EL187X01GB 0 2003 Eia Inc.and PfizerInc. Allrightsreserved.