National Geographic : 2005 Dec
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 historyof recent myocardialinfarction(MI),recent stroke, or established periph eral arterial disease, PLAVIXhas been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatalor not),new MI(fatal or not),and other vascular death. * AcuteCoronarySyndrome For patients withacute coronary syndrome (unstable angina/non-Q -wave MI)including patients who are to be managed medicallyand those who are to be managed withpercutaneous coronary intervention (withor without stent) or CABG,PLAVIX has been shown to decrease the rate ofa com bined endpoint of cardiovascular death, MI,or stroke as wellas the rate of a combined endpoint of cardiovascular death, MI,stroke, or refractoryischemia. CONTRAINDICATIONS Theuse of PLAVIXiscontraindicated in the followingconditions: * Hypersensitivityto the drug substance or any component ofthe product. * Activepathological bleeding suchas peptic ulceror intracranial hemorrhage. WARNINGS Thrombotic thrombocytopenic purpura (TTP):TTPhas been reported rarelyfollowinguse ofPLAVIX, sometimes after a short exposure (<2 weeks).TTPisa serious condition and requires urgent referral to a hematologist for prompt treatment. It is characterized bythrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs]seen on peripheral smear), neurological findings, renaldysfunction, and fever.TTPwas not seen during clopidogrel's clinicaltrials, whichincluded over 17,500clopidogrel-treated patients. In world-wide postmarketing experience, however,TTPhas been reported at a rate of about four cases per million patients exposed,or about 11 cases per million patient-years. The background rate is thought to be about four casesper millionperson-years. (See ADVERSE REACTIONS.) PRECAUTIONS General PLAVIXprolongs the bleeding time and therefore should be usedwithcaution in patients who may beat riskof increased bleeding from trauma, surgery,or other pathological conditions (particularly gastrointestinal and intraocular). Ifa patient is to undergo electivesurgeryand an antiplatelet effect is not desired, PLAVIXshould be discontinued 5 daysprior to surgery. Dueto the riskof bleeding and undesirable hematological effects,bloodcell count determination and/or other appropriate testing should be promptly considered, whenever suchsuspected clinical symptoms arise during the course oftreatment (see ADVERSE REACTIONS). In patients with recent TIAor stroke who are at highriskfor recurrent ischemicevents, the combi nation of aspirin and PLAVIXhas not been shown to be more effectivethan PLAVIXalone, but the combination has been shown to increase major bleeding. GIBleeding:In CAPRIE,PLAVIXwasassociated witha rate of gastrointestinal bleeding of 2.0%,vs. 2.7%on aspirin. In CURE,the incidence of major gastrointestinal bleeding was 1.3%vs0.7%(PLAVIX + aspirin vs.placebo + aspirin, respectively).PLAVIXshould be used withcaution in patients who have lesionswitha propensity to bleed(suchas ulcers).Drugsthat might induce such lesionsshould be usedwithcaution in patients taking PLAVIX. Usein HepaticallyImpaired Patients: Experienceis limitedin patients withseverehepatic disease, who mayhave bleeding diatheses. PLAVIXshould be usedwithcaution in this population. Use in Renally-impaired Patients: Experienceis limitedin patients withsevererenal impairment. PLAVIXshould be used withcaution inthis population. Information for Patients Patients should betold that they maybleed more easilyand it maytake them longerthan usual to stop bleeding when they take PLAVIXor PLAVIXcombined withaspirin, and that they should report any unusual bleeding to their physician.Patientsshouldinformphysiciansand dentists that they are takingPLAVIXand/or anyother product knownto affectbleeding before any surgeryisscheduled and before any newdrug istaken. DrugInteractions Studyof specificdrug interactions yielded the followingresults: Aspirin:Aspirindid not modifythe clopidogrel-mediated inhibition ofADP-inducedplatelet aggrega tion. Concomitant administration of 500 mg of aspirin twicea day for 1 daydid not significantly increase the prolongation of bleeding time induced by PLAVIX. PLAVIX potentiated the effectofaspirin on collagen-induced platelet aggregation. PLAVIXand aspirinhave been administered together for up to one year. Heparin:Ina study in healthy volunteers, PLAVIXdid not necessitate modification of the heparin dose or alter the effectof heparin on coagulation. Coadministration of heparin had no effecton inhi bitionofplatelet aggregationinduced byPLAVIX. Nonsteroidal Anti-Inflammatory Drugs(NSAIDs):Inhealthy volunteers receivingnaproxen, concomi tant administration ofPLAVIXwasassociated withincreased occultgastrointestinal bloodloss.NSAIDs and PLAVIXshould becoadministered withcaution. Warfarin:Becauseof theincreased riskof bleeding, the concomitant administration of warfarin with PLAVIXshould be undertaken withcaution. (SeePRECAUTIONS- General.) Other Concomitant Therapy:No clinicallysignificantpharmacodynamic interactions were observed when PLAVIXwas coadministered withatenolol, nifedipine, or bothatenolol and nifedipine. The pharmacodynamic activityof PLAVIXwas also not significantlyinfluencedbythe coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline were not modifiedby the coadministration of PLAVIX(clopidogrel bisulfate). At highconcentrations in vitro, clopidogrelinhibits P45o(2C9).Accordingly,PLAVIXmay interfere withthe metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data withwhichto predict the magnitude ofthese interactions. Cautionshould be usedwhen any of these drugs iscoadministered withPLAVIX. Inaddition to the above specificinteraction studies, patients entered into clinicaltrials withPLAVIX received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (includinginsulin),antiepileptic agents, hormone replacement therapy, heparins (unfractionated and LMWH)and GPIIb/lllaantagonists without evidence ofclinicallysignificant adverse interactions. The useof oral anticoagulants, non-study anti platelet drug and chronic NSAIDswas not allowed in CUREand there are no data on their concomi tant usewithclopidogrel. Drug/Laboratory TestInteractions Noneknown. Carcinogenesis, Mutagenesis, Impairment of Fertility Therewas no evidence of tumorigenicity when clopidogrelwasadministered for78 weeksto mice and 104weeksto rats at dosages up to 77 mg/kgper day,whichafforded plasma exposures >25 times kbat c bman.sa .tthe. recommended dailydose of 75 mg. Clopidogrelwas not genotoxic infour in vitro tests (Amestest, DNA-repairtest in rat hepatocytes, gene mutation assayinChinesehamster fibroblasts, and metaphase chromosome analysisof human lymphocytes) and in one in vivotest (micronucleus test byoral route in mice). Clopidogrelwas found to have no effecton fertilityof male and female rats at oral doses up to 400 mg/kgper day(52times the recommended human dose on a mg/m 2 basis). Pregnancy PregnancyCategoryB. Reproductionstudies performedin rats and rabbitsat dosesup to 500and300 mg/kglday(respectively,65 and 78 times the recommended dailyhuman dose on a mg/m 2 basis), revealedno evidenceof impairedfertilityorfetotoxicitydue to clopidogrel.Thereare, however,no ade quate and well-controlledstudies in pregnant women.Becauseanimal reproduction studies are not alwayspredictiveofa human response,PLAVIX shouldbeusedduring pregnancyonlyif clearlyneeded. NursingMothers Studiesin rats have shown that clopidogreland/or its metabolites are excreted inthe milk. It is not knownwhether this drug isexcretedin human milk.Becausemanydrugs are excretedinhuman milk and becauseof the potential forserious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman. Pediatric Use Safetyand effectivenessin the pediatric population have not been established. Geriatric Use Ofthe total number ofsubjects in controlled clinicalstudies, approximately 50%of patients treated withPLAVIXwere 65years ofage and over.Approximately16%of patients treated with PLAVIX were 75years ofage and over. Theobserved difference in riskofthrombotic events withclopidogrel plusaspirin versus placebo plus aspirin by age categoryis provided in Figure3 (see CLINICAL STUDIES).Theobserved difference in riskof bleeding events withclopidogrelplusaspirin versus placebo plusaspirin by age categoryis providedin Table3 (see ADVERSE REACTIONS). ADVERSE REACTIONS PLAVIXhas been evaluated for safetyin more than 17,500patients, including over 9,000 patients treated for1 year or more. Theoveralltolerability ofPLAVIXinCAPRIEwas similar to that of aspirin regardless of age,gender and race, withan approximately equal incidence (13%)of patients with drawing from treatment because of adverse reactions. The clinicallyimportant adverse events observed inCAPRIEand 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%forPLAVIXcompared to 0.5%foraspirin. InCURE,PLAVIXuse withaspirin wasassociated withan increase in bleeding compared to placebo with aspirin (seeTable3). Therewasan excessin major bleeding in patients receivingPLAVIXplus aspirin compared withplacebo plusaspirin, primarily gastrointestinal and at puncture sites.Theinci dence ofintracranial hemorrhage (0.1%),and fatal bleeding (0.2%),were the same in both groups. The overall incidence of bleeding is described inTable3 for patients receivingboth PLAVIXand aspirin inCURE, Table3: CUREIncidence of bleeding complications (%patients) Event PLAVIX Placebo P-value (+ aspirin)* (+ aspirin)* (n=6259) (n=6303) Majorbleeding - 3.7 t 2.7 § 0.001 Life-threatening bleeding 2.2 1.8 0.13 Fatal 0.2 0.2 5 g/dLhemoglobin drop 0.9 0.9 Requiringsurgicalintervention 0.7 0.7 Hemorrhagicstrokes 0.1 0.1 Requiringinotropes 0.5 0.5 Requiringtransfusion (>4 units) 1.2 1.0 Other major bleeding 1.6 1.0 0.005 Significantlydisabling 0.4 0.3 Intraocular bleeding with significant lossof vision 0.05 0.03 Requiring2-3units of blood 1.3 0.9 Minorbleeding 5.1 2.4 <0.001 * Other standard therapies were usedas appropriate. t Lifethreatening and other major bleeding. t Majorbleeding event rate for PLAVIX+ aspirinwas 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%,265 to <75 years = 4.1%,>75 years 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 rates for placebo + aspirin byage were:<65 years = 2.1%,>65 to <75 years = 3.1%,>75 years3.6% Ledto interruption of study medication. Ninety-twopercent (92%)ofthe patients in the CUREstudy receivedheparin/LMWH, and the rate of bleeding in these patients wassimilar to the overallresults. Therewasno excessin major bleeds within sevendaysafter coronary bypassgraft surgeryinpatients who stopped therapy more than five daysprior to surgery(event rate 4.4% PLAVIX+ aspirin; 5.3% placebo + aspirin).Inpatients whoremained on therapy within fivedaysof bypass graft surgery,the event rate was9.6%for PLAVIX+ aspirin, and 6.3%for placebo + aspirin. Neutropenia/agranulocytosis: Ticlopidine,a drug chemicallysimilarto PLAVIX, is associated witha 0.8%rate of severeneutropenia (lessthan 450 neutrophils/pL).In CAPRIEsevere neutropenia was observedin six patients, four on PLAVIXand twoon aspirin.Twoof the 9599patients who received PLAVIXand none ofthe 9586patients who receivedaspirinhad neutrophil counts ofzero.Oneof the four PLAVIXpatients in CAPRIEwas receivingcytotoxicchemotherapy, and another recoveredand returned to the trialafter onlytemporarily interrupting treatment withPLAVIX (clopidogrelbisulfate).In CURE,the numbers of patients withthrombocytopenia (19PLAVIX + aspirinvs.24 placebo + aspirin)or neutropenia (3vs.3)weresimilar. Althoughthe riskof myelotoxicitywithPLAVIX(clopidogrelbisulfate) thus appears to be quite low, this possibilityshould be considered when a patient receivingPLAVIXdemonstrates feveror other signof infection. Gastrointestinal: Overall,the incidence of gastrointestinal events (e.g . abdominal pain, dyspepsia, gastritis and constipation) in patients receivingPLAVIX(clopidogrelbisulfate) was 27.1%,compared to 29.8%inthose receivingaspirin in the CAPRIEtrial. Inthe CUREtrial the incidence ofthese gastroin testinal eventsfor patients receivingPLAVIX + aspirinwas 11.7%compared to 12.5%for those receiving placebo + aspirin. In the CAPRIEtrial,the incidence of peptic, gastric or duodenal ulcerswas 0.7%forPLAVIX(clopido grel bisulfate) and 1.2%foraspirin. In the CUREtrial the incidence of peptic, gastricor duodenal ulcerswas 0.4%forPLAVIX+ aspirin and 0. 3 %for placebo + aspirin. Casesof diarrhea were reported in the CAPRIEtrial in4.5%ofpatients inthe PLAVIX groupcompared to 3.4%inthe aspiringroup. However,these were rarelysevere(PLAVIX=0.2% and aspirin=0.1%).Inthe CUREtrial,the incidenceof diarrhea forpatients receivingPLAVIX+ aspirinwas2.1%compared to2.2% forthose receivingplacebo + aspirin. In the CAPRIEtrial,the incidence of patients withdrawing from treatment because ofgastrointesti nal adverse reactions was 3.2%for PLAVIXand 4.0%for aspirin. Inthe 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 Other SkinDisorders:Inthe CAPRIEtrial, the incidence of skinand appendage disorders in patients receivingPLAVIXwas 15.8%(0.7%serious);the corresponding rate in aspirin patients was 13.1%(0.5%serious).Inthe CUREtrial the incidence of rash or other skin disorders in patients receivingPLAVIX+ aspirin was 4.0%compared to 3.5%for those receivingplacebo + aspirin.