National Geographic : 2006 Feb
PLAVIX® Rxonly clopidogrel bisulfate tablets BriefSummary of PrescribingInformation Rev.May2005 INDICATIONS ANDUSAGE PLAVIX(clopidogrelbisulfate) is indicated forthe reduction ofatherothrombotic events as follows: * Recent MI,Recent Stroke or Established Peripheral Arterial Disease Forpatients witha historyofrecent myocardialinfarction (Ml),recent stroke, or established periph eral arterialdisease, PLAVIXhas been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatalor not),newMI(fatalor not),and other vascular death. * AcuteCoronarySyndrome For patients with acute coronary syndrome (unstable angina/non-Q -wave MI)including patients whoare to be managed medicallyand those who are to be managed withpercutaneous coronary intervention (withor without stent) orCABG,PLAVIXhas been shownto decrease the rate of a com bined endpoint ofcardiovascular death, Mi,or stroke as wellas the rate of a combined endpoint of cardiovascular death, MI,stroke,or refractoryischemia. CONTRAINDICATIONS Theuse of PLAVIXiscontraindicatedinthe following conditions: * Hypersensitivity tothe drugsubstanceoranycomponentof the product. * Activepathologicalbleedingsuchaspepticulceror intracranialhemorrhage. WARNINGS Thromboticthrombocytopenicpurpura(TTP):TTPhasbeenreportedrarelyfollowing use of PLAVIX, sometimesaftera shortexposure(<2weeks).TTPisa seriousconditionandrequiresurgent referral to a hematologistfor prompttreatment.It is characterized bythrombocytopenia, microangiopathic hemolyticanemia(schistocytes [fragmentedRBCs]seenon peripheralsmear),neurologicalfindings, renaldysfunction,andfever.TTPwasnotseenduring clopidogrel'sclinicaltrials,whichincludedover 17,500clopidogrel-treatedpatients.Inworld-widepostmarketing experience, however,TTPhasbeen reportedat a rateof aboutfour casespermillion patientsexposed,or about11 casesper million patient-years. Thebackgroundrateis thoughtto beaboutfour casesper million person-years. (See ADVERSE REACTIONS.) PRECAUTIONS General PLAVIXprolongsthe bleedingtimeandthereforeshouldbe usedwithcaution inpatientswhomay beat riskof increased bleedingfromtrauma,surgery,or otherpathologicalconditions(particularly gastrointestinalandintraocular).If a patientis to undergo electivesurgeryandanantiplateleteffect isnot desired,PLAVIX shouldbediscontinued5 dayspriorto surgery. Dueto the riskof bleedingandundesirable hematologicaleffects,bloodcell count determination and/orother appropriatetestingshouldbepromptlyconsidered,wheneversuchsuspectedclinical symptomsariseduringthecourseoftreatment(seeADVERSE REACTIONS). In patientswithrecentTIAor strokewhoareat highriskfor recurrentischemicevents,the combi nation of aspirinandPLAVIXhasnot beenshownto be moreeffectivethanPLAVIX alone,but the combinationhasbeenshownto increasemajorbleeding. GI Bleeding:InCAPRIE,PLAVIXwasassociatedwitha rateofgastrointestinalbleedingof 2.0%,vs. 2.7%on aspirin.InCURE,the incidenceof majorgastrointestinalbleedingwas1.3%vs0.7%(PLAVIX + aspirinvs.placebo+ aspirin,respectively).PLAVIXshouldbe usedwith cautionin patientswho havelesionswitha propensityto bleed(suchasulcers).Drugsthat mightinducesuchlesionsshould beused withcaution in patientstakingPLAVIX. Usein HepaticallyImpairedPatients:Experienceis limitedin patientswithseverehepaticdisease, whomayhavebleedingdiatheses.PLAVIXshouldbe usedwithcautioninthis population. Usein Renally-impaired Patients:Experienceis limitedin patientswith severerenalimpairment. PLAVIXshouldbeused withcaution inthis poulation. Informationfor Patients Patientsshouldbetoldthat theymaybleedmoreeasilyandit maytakethem longerthan usualto stopbleedingwhentheytakePLAVIXor PLAVIXcombinedwithaspirin,andthat theyshouldreport anyunusual bleedingto theirphysician.Patientsshouldinformphysicians anddentiststhattheyare takingPLAVIXand/oranyotherproductknownto affectbleedingbeforeanysurgeryisscheduledand beforeanynewdrugis taken. DrugInteractions Studyof specificdruginteractionsyieldedthefollowing results: Aspirin:Aspirindidnot modifythe clopidogrel-mediated inhibition ofADP-inducedplateletaggrega tion. Concomitantadministrationof 500mgof aspirintwicea dayfor 1 daydid not significantly increasetheprolongationof bleedingtimeinducedby PLAVIX.PLAVIXpotentiatedthe effectofaspirin on collagen-induced plateletaggregation. PLAVIXandaspirinhavebeenadministeredtogetherforup to oneyear. Heparin:In a studyin healthyvolunteers,PLAVIXdid not necessitatemodificationof the heparin doseor altertheeffectof heparinoncoagulation. Coadministration of heparinhadnoeffecton inhi bitionof plateletaggregation inducedbyPLAVIX. NonsteroidalAnti-InflammatoryDrugs(NSAIDs):Inhealthyvolunteersreceivingnaproxen, concomi tant administrationofPLAVIXwasassociated with increasedoccultgastrointestinalbloodloss.NSAIDs andPLAVIXshouldbecoadministered withcaution. Warfarin:Becauseoftheincreasedriskofbleeding,theconcomitantadministrationofwarfarinwith PLAVIXshould beundertaken withcaution.(SeePRECAUTIONS- General.) OtherConcomitantTherapy:No clinicallysignificantpharmacodynamic interactionswereobserved whenPLAVIX wascoadministered with atenolol,nifedipine,or bothatenololand nifedipine.The pharmacodynamic activityof PLAVIX wasalsonot significantlyinfluencedbythe coadministration of phenobarbital, cimetidineorestrogen. Thepharmacokineticsof digoxinortheophylline were not modifiedby the coadministration of PLAVIX(clopidogrelbisulfate). At highconcentrations in vitro, clopidogrelinhibits P450(2C9).Accordingly,PLAVIXmayinterfere with the metabolismof phenytoin,tamoxifen,tolbutamide,warfarin,torsemide,fluvastatin, andmanynon-steroidal anti-inflammatory agents,butthereareno datawithwhichto predictthe magnitudeoftheseinteractions.Cautionshouldbe usedwhenanyof thesedrugsiscoadministered with PLAVIX. Inadditionto theabovespecificinteractionstudies,patientsenteredinto clinicaltrialswithPLAVIX receiveda varietyof concomitantmedicationsincluding diuretics,beta-blockingagents, angiotensinconvertingenzymeinhibitors,calciumantagonists, cholesterolloweringagents, coronaryvasodilators, antidiabeticagents(includinginsulin),antiepilepticagents,hormone replacementtherapy,heparins(unfractionated andLMWH)andGPIIb/lllaantagonistswithout evidenceofclinically significantadverseinteractions. Theuse oforalanticoagulants, non-studyanti plateletdrugandchronicNSAIDswasnotallowedin CUREandtherearenodataontheir concomi tant usewith clopidogrel. Drug/Laboratory TestInteractions Noneknown. Carcinogenesis, Mutagenesis, Impairmentof Fertility Therewasnoevidenceof tumorigenicitywhenclopidogrelwasadministeredfor 78weeksto mice and104weeksto ratsat dosagesupto77 mg/kgperday,whichaffordedplasmaexposures >25 times that in humansat the recommendeddailydoseof75mg. Clopidogrelwasnot genotoxicinfour in vitrotests(Amestest,DNA-repairtestin rat hepatocytes, gene mutationassayinChinesehamsterfibroblasts, andmetaphasechromosome analysisof human lymphocytes) andinonein vivotest(micronucleustestbyoralroute in mice). Clopidogrelwasfoundto haveno effecton fertility of maleandfemaleratsat oral dosesup to 400mg/kgperday(52timesthe recommendedhumandoseon a mg/m 2basis). Pregnancy PregnancyCategoryB.Reproductionstudiesperformedinrats and rabbitsat doses upto 500and 300 mg/kg/day(respectively,65 and 78 times the recommended dailyhuman dose on a mg/m 2 basis), revealedno evidenceof impairedfertilityor fetotoxicitydue to clopidogrel.Thereare, however,noade quate and well-controlledstudies in pregnant women.Becauseanimal reproduction studies are not alwayspredictiveofa human response,PLAVIX shouldbeusedduring pregnancyonlyifdearly needed. NursingMothers Studiesin rats haveshownthat clopidogreland/or its metabolites are excretedin the milk.It is not knownwhether this drug is excretedinhuman milk.Becausemanydrugs are excretedin human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether todiscontinue nursing orto discontinue the drug, taking into account the importance ofthe drugto the nursing woman. Pediatric Use Safetyand effectivenessinthe pediatric population have not been established. Geriatric Use Ofthe total number of subjects in controlled clinicalstudies, approximately 50%of patients treated withPLAVIXwere 65 yearsof age and over.Approximately16%of patients treated with PLAVIX were 75years ofage and over. Theobserveddifference in riskofthrombotic events withclopidogrel plusaspirin versusplacebo plus aspirinby age categoryis provided in Figure3 (see CLINICAL STUDIES).The observed difference in riskof bleeding events withclopidogrelplus aspirin versusplacebo plusaspirin by age category is providedin Table 3 (seeADVERSE REACTIONS). ADVERSE REACTIONS PLAVIXhas been evaluated for safetyin more than 17,500patients, including over 9,000 patients treated for1 year or more. The overalltolerability of PLAVIXin CAPRIEwassimilar to that of aspirin regardlessof age, gender and race, withan approximately equal incidence (13%)of patients with drawing from treatment because of adverse reactions. The clinicallyimportant adverse events observedinCAPRIEand CUREare discussed below. Hemorrhagic:In CAPRIEpatients receivingPLAVIX, gastrointestinal hemorrhage occurred at a rate of 2.0%,and required hospitalization in0.7% .In patients receivingaspirin, the corresponding rates were 2 . 7 %and 1.1%,respectively.The incidence of intracranial hemorrhage was0.4%for PLAVIX compared to 0.5%foraspirin. In CURE,PLAVIXuse withaspirinwasassociated withan increase inbleeding compared to placebo withaspirin(see Table3). There wasan excessin major bleeding in patients receivingPLAVIXplus aspirincompared withplaceboplusaspirin, primarilygastrointestinal and at puncture sites. The inci dence of intracranial hemorrhage (0.1%),and fatal bleeding (0.2%),were the same inboth groups. The overallincidence of bleeding is described in Table 3 for patients receivingboth PLAVIXand aspirin in CURE, Table3: CUREIncidence of bleeding complications (%patients) Event Majorbleeding f Life-threatening bleeding Fatal 5 g/dL hemoglobin drop Requiringsurgicalintervention Hemorrhagicstrokes Requiringinotropes Requiringtransfusion (24 units) Other major bleeding Significantlydisabling Intraocular bleeding with significantlossofvision Requiring2-3units of blood Minorbleeding PLAVIX (+ aspirin)* (n=6259) 3.7t 2.2 0.2 0.9 0.7 0.1 0.5 1.2 Placebo (+ aspirin)* (n=6303) 2.7§ 1.8 0.2 0.9 0.7 0.1 0.5 1.0 1.6 1.0 0.4 0.3 0.05 0.03 1.3 0.9 5.1 2.4 P-value 0.001 0.13 0.005 <0.001 * Other standard therapies were usedas appropriate. f Lifethreatening and other major bleeding. $ Majorbleeding event rate for PLAVIX+ aspirin was dose-dependent on aspirin: <100 mg=2.6%; 100-200mg= 3.5%;>200 mg=4.9% Majorbleeding event rates for PLAVIX+ aspirin byage were: <65 years= 2.5%,>65to <75 years = 4.1%,>75years 5.9% § Majorbleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg=2.0%; 100-200mg= 2.3%;>200 mg=4.0% Majorbleeding event ratesfor placebo + aspirin byage were:<65 years= 2.1%,>65 to <75 years = 3.1%,275 years 3.6% T Ledto interruption of studymedication. Ninety-twopercent (92%)ofthe patients inthe CUREstudy receivedheparin/LMWH, and the rate of bleeding inthese patients wassimilar to the overallresults. Therewasnoexcessin major bleeds withinsevendaysafter coronary bypassgraft surgeryinpatients whostopped therapy more than fivedaysprior to surgery (event rate 4.4%PLAVIX+ aspirin; 5.3% placebo + aspirin).In patients who remained on therapy within five daysofbypassgraft surgery,the event rate was 9.6%for PLAVIX + aspirin,and 6.3%for placebo + aspirin. Neutropenia/agranulocytosis: Ticlopidine,a drug chemicallysimilar to PLAVIX,is associatedwitha 0.8%rate of severe neutropenia (lessthan 450 neutrophils/pL).In CAPRIEsevere neutropenia was observedin sixpatients, fouron PLAVIXand twoon aspirin. Twoofthe 9599patients who received PLAVIX and none ofthe 9586patients who receivedaspirinhad neutrophil counts of zero.Oneof the four PLAVIXpatients in CAPRIEwas receivingcytotoxicchemotherapy, and another ecoveredand returned tothe trial afteronlytemporarily interrupting treatment withPLAVIX (clopidogrelbisulfate) in CURE,the numbers ofpatients withthrombocytopenia (19PLAVIX + aspirin vs.24placebo + aspirin)or neutropenia (3vs.3)were similar. Althoughthe riskof myelotoxicitywithPLAVIX(clopidogrelbisulfate) thus appears to bequite low, this possibilityshould be considered when a patient receivingPLAVIXdemonstrates fever or other signofinfection. Gastrointestinal: Overall,the incidenceof gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) inpatients receivingPLAVIX(clopidogrelbisulfate) was27.1%,compared to 29.8%inthose receivingaspirin inthe CAPRIEtrial. Inthe CUREtrial the incidence ofthese gastroin testinal ev ientsrpatients receivingPLAVIX + aspirinwas11.7%compared to 12.5%forthose receiving placebo+ aspirin. Inthe CAPRIEtrial,the incidence of peptic, gastricor duodenal ulcerswas0.7%forPLAVIX(clopido grel bisulfate) and 1.2%for aspirin.In the CUREtrial the incidence of peptic, gastric or duodenal ulcerswas0.4%for PLAVIX+ aspirin and 0.3%for placebo + aspirin. Casesof diarrhea were reported inthe CAPRIEtrial in4.5%of patients inthe PLAVIXgroup compared to 3.4%inthe aspiringroup. However,these were rarelysevere(PLAVIX=0.2% and aspirin=0.1%).Inthe CUREtrial,the incidenceofdiarrhea forpatients receivingPLAVIX + aspirinwas2.1%compared to 2.2% forthose receivingplacebo+ aspirin. In the CAPRIEtrial, the incidence of patients withdrawing from treatment because of gastrointesti nal adverse reactions was 3.2%for PLAVIXand 4.0%for aspirin. In the CUREtrial, the incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 0.9%for PLAVIX+ aspirin compared with0.8%for placebo + aspirin. Rashand OtherSkinDisorders:In the CAPRIEtrial,the incidence of skinand appendage disorders in patients receivingPLAVIXwas 15.8%(0.7%serious);the corresponding rate in aspirin patients was 1 3 .1%(0.5%serious).In the CUREtrial the incidence of rash or other skin disorders in patients receivingPLAVIX+ aspirin was4.0%compared to 3.5%for those receivingplacebo + aspirin.