Precedex (Dexmedetomidine hydrochloride) - RxList

doses ranging from 0.2 to 1 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation. For awake fiberoptic ... Precedex GenericName:dexmedetomidinehydrochlorideBrandName:Precedex LastupdatedonRxList:3/23/2021 home drugsa-zlist sideeffectsdrugcenterprecedex(dexmedetomidinehydrochloride)drug PROFESSIONAL CONSUMER SIDEEFFECTS DrugDescription Indications&Dosage SideEffects DrugInteractions Warnings&Precautions Overdosage&Contraindications ClinicalPharmacology MedicationGuide DrugDescription WhatisPrecedexandhowisitused? Precedexisaprescriptionmedicineusedasasedativebeforeand/orduringsurgicalandotherprocedures.Precedexmaybeusedaloneorwithothermedications. PrecedexbelongstoaclassofdrugscalledSedatives. ItisnotknownifPrecedexissafeandeffectiveinchildren. WhatarethepossiblesideeffectsofPrecedex? Precedexmaycauseserioussideeffectsincluding: loworhighbloodpressure, slowheartrate,and abnormalheartrate Getmedicalhelprightaway,ifyouhaveanyofthesymptomslistedabove. ThemostcommonsideeffectsofPrecedexinclude: loworhighbloodpressure, slowheartrate, nausea, drymouth, irregularheartbeat, fever, vomiting, lowbloodplasma, fluidbuildupbetweenlungsandchest, agitation, anemia, fastheartrate, chills, highbloodsugar, lowbloodoxygen, extremelyelevatedbodytemperature, completeorpartialcollapseofalung, post-procedurebleeding, lowbloodcalcium, decreasedurination, wheezing, swellingoftheextremities, acidaccumulationinthebody,and fluidinthelungs Tellthedoctorifyouhaveanysideeffectthatbothersyouorthatdoesnotgoaway. ThesearenotallthepossiblesideeffectsofPrecedex.Formoreinformation,askyourdoctororpharmacist. DESCRIPTION Precedex(dexmedetomidinehydrochloride)injectionisasterile,nonpyrogenicsolutionsuitableforintravenousinfusionfollowingdilution.Precedex(dexmedetomidinehydrochloride)in0.9%SodiumChlorideInjectionisasterile,nonpyrogenicreadytousesolutionsuitableforintravenousinfusion.DexmedetomidinehydrochlorideistheS-enantiomerofmedetomidineandischemicallydescribedas(+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazolemonohydrochloride.Precedexhasamolecularweightof236.7andtheempiricalformulaisC13H16N2•HClandthestructuralformulais: DexmedetomidinehydrochlorideisawhiteoralmostwhitepowderthatisfreelysolubleinwaterandhasapKaof7.1.Itspartitioncoefficientin-octanol:wateratpH7.4is2.89. PrecedexInjectionissuppliedasaclear,colorless,isotonicsolutionwithapHof4.5to7.0.EachmLcontains118mcgofdexmedetomidinehydrochlorideequivalentto100mcg(0.1mg)ofdexmedetomidineand9mgofsodiumchlorideinwaterandistobeusedafterdilution.Thesolutionispreservative-freeandcontainsnoadditivesorchemicalstabilizers. Precedexin0.9%SodiumChlorideInjectionissuppliedasaclear,colorless,isotonicsolutionwithapHof4.5to8.0.EachmLcontains4.72mcgofdexmedetomidinehydrochlorideequivalentto4mcg(0.004mg)ofdexmedetomidineand9mgsodiumchlorideinwaterandisreadytobeused.Thesolutionispreservative-freeandcontainsnoadditivesorchemicalstabilizers. Indications&Dosage INDICATIONS IntensiveCareUnitSedation Precedex™isindicatedforsedationofinitiallyintubatedandmechanicallyventilatedpatientsduring treatmentinanintensivecaresetting.Precedexshouldbeadministeredbycontinuousinfusionnotto exceed24hours. Precedexhasbeencontinuouslyinfusedinmechanicallyventilatedpatientspriortoextubation,during extubation,andpost-extubation.ItisnotnecessarytodiscontinuePrecedexpriortoextubation. ProceduralSedation Precedexisindicatedforsedationofnon-intubatedpatientspriortoand/orduringsurgicalandother procedures. DOSAGEANDADMINISTRATION DosingGuidelines Precedexdosingshouldbeindividualizedandtitratedtodesiredclinicalresponse. Precedexisnotindicatedforinfusionslastinglongerthan24hours. Precedexshouldbeadministeredusingacontrolledinfusiondevice. DosageInformation Table1:DosageInformation INDICATION DOSAGEANDADMINISTRATION InitiationofIntensiveCare UnitSedation Foradultpatients:aloadinginfusionofonemcg/kgover10minutes. Foradultpatientsbeingconvertedfromalternatesedativetherapy:a loadingdosemaynotberequired[seeDosageInformation]. Forpatientsover65yearsofage:adosereductionshouldbe considered[seeUseInSpecificPopulations]. Foradultpatientswithimpairedhepatic-function:adosereduction shouldbeconsidered[seeUseInSpecificPopulations,CLINICALPHARMACOLOGY]. MaintenanceofIntensive CareUnitSedation Foradultpatients:amaintenanceinfusionof0.2to0.7mcg/kg/hour. Therateofthemaintenanceinfusionshouldbeadjustedtoachievethe desiredlevelofsedation. Forpatientsover65yearsofage:adosereductionshouldbe considered[seeUseInSpecificPopulations]. Foradultpatientswithimpairedhepaticfunction:adosereduction shouldbeconsidered[seeUseInSpecificPopulations,CLINICALPHARMACOLOGY] InitiationofProcedural Sedation Foradultpatients:aloadinginfusionofonemcg/kgover10minutes. Forlessinvasiveproceduressuchasophthalmicsurgery,aloading infusionof0.5mcg/kggivenover10minutesmaybesuitable. Forawakefiberopticintubationinadultpatients:aloadinginfusion ofonemcg/kgover10minutes. Forpatientsover65yearsofage:aloadinginfusionof0.5mcg/kg over10minutes[seeUseInSpecificPopulations]. Foradultpatientswithimpairedhepaticfunction:adosereduction shouldbeconsidered[seeUseInSpecificPopulations,CLINICALPHARMACOLOGY]. MaintenanceofProcedural Sedation Foradultpatients:themaintenanceinfusionisgenerallyinitiatedat 0.6mcg/kg/hourandtitratedtoachievedesiredclinicaleffectwith dosesrangingfrom0.2to1mcg/kg/hour.Therateofthemaintenance infusionshouldbeadjustedtoachievethetargetedlevelofsedation. Forawakefiberopticintubationinadultpatients:amaintenance infusionof0.7mcg/kg/hourisrecommendeduntiltheendotrachealtube issecured. Forpatientsover65yearsofage:adosereductionshouldbe considered[seeUseInSpecificPopulations]. Foradultpatientswithimpairedhepaticfunction:adosereduction shouldbeconsidered[seeUseInSpecificPopulations,CLINICALPHARMACOLOGY]. DosageAdjustment Duetopossiblepharmacodynamicinteractions,areductionindosageofPrecedexorotherconcomitant anesthetics,sedatives,hypnoticsoropioidsmayberequiredwhenco-administered[seeDRUGINTERACTIONS]. Dosagereductionsmayneedtobeconsideredforadultpatientswithhepaticimpairment,andgeriatric patients[seeWARNINGSANDPRECAUTIONS,UseInSpecificPopulations,CLINICALPHARMACOLOGY]. PreparationOfSolution StrictaseptictechniquemustalwaysbemaintainedduringhandlingofPrecedex. Parenteraldrugproductsshouldbeinspectedvisuallyforparticulatematteranddiscolorationpriorto administration,wheneversolutionandcontainerpermit. PrecedexInjection,200mcg/2mL(100mcg/mL) Precedexmustbedilutedwith0.9%sodiumchlorideinjectiontoachieverequiredconcentration (4mcg/mL)priortoadministration.Preparationofsolutionsisthesame,whetherfortheloadingdose ormaintenanceinfusion. Topreparetheinfusion,withdraw2mLofPrecedexInjection,andaddto48mLof0.9%sodium chlorideinjectiontoatotalof50mL.Shakegentlytomixwell. Precedexin0.9%SodiumChlorideInjection,80mcg/20mL(4mcg/mL),200mcg/50mL(4 mcg/mL)And400mcg/100mL(4mcg/mL) Precedexin0.9%SodiumChlorideInjectionissuppliedinglasscontainerscontainingapremixed, readytousedexmedetomidinehydrochloridesolutionin0.9%sodiumchlorideinwater.Nofurther dilutionofthesepreparationsarenecessary. AdministrationWithOtherFluids Precedexinfusionshouldnotbeco-administeredthroughthesameintravenouscatheterwithbloodor plasmabecausephysicalcompatibilityhasnotbeenestablished. Precedexhasbeenshowntobeincompatiblewhenadministeredwiththefollowingdrugs:amphotericin B,diazepam. Precedexhasbeenshowntobecompatiblewhenadministeredwiththefollowingintravenousfluids: 0.9%sodiumchlorideinwater 5%dextroseinwater 20%mannitol LactatedRinger'ssolution 100mg/mLmagnesiumsulfatesolution 0.3%potassiumchloridesolution CompatibilityWithNaturalRubber CompatibilitystudieshavedemonstratedthepotentialforabsorptionofPrecedextosometypesof naturalrubber.AlthoughPrecedexisdosedtoeffect,itisadvisabletouseadministrationcomponents madewithsyntheticorcoatednaturalrubbergaskets. HOWSUPPLIED DosageFormsAndStrengths PrecedexInjection PrecedexInjection,200mcg/2mLdexmedetomidine(100mcg/mL)inaglassvial.Tobeusedafter dilution. PrecedexIn0.9%SodiumChlorideInjection PrecedexInjection,80mcgdexmedetomidine/20mL(4mcg/mL)dexmedetomidineina20mLglass vial.Readytouse. PrecedexInjection,200mcgdexmedetomidine/50mL(4mcg/mL)dexmedetomidineina50mLglass bottle.Readytouse. PrecedexInjection,400mcgdexmedetomidine/100mL(4mcg/mL)dexmedetomidineina100mLglass bottle.Readytouse. StorageAndHandling PrecedexInjection Precedex(dexmedetomidinehydrochloride)injection200mcg/2mL(100mcg/mL)isavailablein2mL clearglassvials.Thestrengthisbasedonthedexmedetomidinebase.Vialsareintendedforsingleuse only. NDCNo. Container Size 0409-1638-02 Vial 2mL PrecedexIn0.9%SodiumChlorideInjection Precedex(dexmedetomidinehydrochloridein0.9%SodiumChloride)injectionisavailable as80mcg/20mL(4mcg/mL),200mcg/50mL(4mcg/mL)and400mcg/100mL(4mcg/mL)in20mL clearglassvials,50mLand100mLclearglassbottles,respectively.Containersareintendedforsingle useonly. NDCNo. Container Size 0409-1660-20 Vial 20mL 0409-1660-50 Bottle 50mL 0409-1660-10 Bottle 100mL Storeatcontrolledroomtemperature,25°C(77°F)withexcursionsallowedfrom15to30°C(59to 86°F).[SeeUSP.] ManufacturedandDistributedby:Hospira,Inc.LakeForest,IL60045USA.Revised:May2016 QUESTION Abouthowmuchdoesanadulthumanbrainweigh? SeeAnswer SideEffects SIDEEFFECTSThefollowingclinicallysignificantadversereactionsaredescribedelsewhereinthelabeling:Hypotension,bradycardiaandsinusarrest[seeWARNINGSANDPRECAUTIONS]Transienthypertension[seeWARNINGSANDPRECAUTIONS]ClinicalTrialsExperienceBecauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionsratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinpractice.Mostcommontreatment-emergentadversereactions,occurringingreaterthan2%ofpatientsinbothIntensiveCareUnitandproceduralsedationstudiesincludehypotension,bradycardiaanddrymouth.IntensiveCareUnitSedationAdversereactioninformationisderivedfromthecontinuousinfusiontrialsofPrecedexforsedationintheIntensiveCareUnitsettinginwhich1,007adultpatientsreceivedPrecedex.Themeantotaldosewas7.4mcg/kg(range:0.8to84.1),meandoseperhourwas0.5mcg/kg/hr(range:0.1to6.0)andthemeandurationofinfusionof15.9hours(range:0.2to157.2).Thepopulationwasbetween17to88yearsofage,43%≥65yearsofage,77%maleand93%Caucasian.Treatment-emergentadversereactionsoccurringatanincidenceof>2%areprovidedinTable2.Themostfrequentadversereactionswerehypotension,bradycardiaanddrymouth[seeWARNINGSANDPRECAUTIONS].Table2:AdverseReactionswithanIncidence>2%-AdultIntensiveCareUnitSedationPopulation<24hours*AdverseEventAllPrecedex(N=1007)(%)RandomizedPrecedex(N=798)(%)Placebo(N=400)(%)Propofol(N=188)(%)Hypotension25%24%12%13%Hypertension12%13%19%4%Nausea9%9%9%11%Bradycardia5%5%3%0AtrialFibrillation4%5%3%7%Pyrexia4%4%4%4%DryMouth4%3%1%1%Vomiting3%3%5%3%Hypovolemia3%3%2%5%Atelectasis3%3%3%6%PleuralEffusion2%2%1%6%Agitation2%2%3%1%Tachycardia2%2%4%1%Anemia2%2%2%2%Hyperthermia2%2%3%0Chills2%2%3%2%Hyperglycemia2%2%2%3%Hypoxia2%2%2%3%Post-proceduralHemorrhage2%2%3%4%PulmonaryEdema1%1%1%3%Hypocalcemia1%1%02%Acidosis1%1%1%2%UrineOutputDecreased1%1%02%SinusTachycardia1%1%1%2%VentricularTachycardia<1%1%1%5%Wheezing<1%1%02%EdemaPeripheral<1%01%2%*26subjectsintheallPrecedexgroupand10subjectsintherandomizedPrecedexgrouphadexposureforgreaterthan24hoursAdversereactioninformationwasalsoderivedfromtheplacebo-controlled,continuousinfusiontrialsofPrecedexforsedationinthesurgicalintensivecareunitsettinginwhich387adultpatientsreceivedPrecedexforlessthan24hours.Themostfrequentlyobservedtreatment-emergentadverseeventsincludedhypotension,hypertension,nausea,bradycardia,fever,vomiting,hypoxia,tachycardiaandanemia(seeTable3).Table3:Treatment-EmergentAdverseEventsOccurringin>1%ofAllDexmedetomidine-TreatedAdultPatientsintheRandomizedPlacebo-ControlledContinuousInfusion<24HoursICUSedationStudiesAdverseEventRandomizedDexmedetomidine(N=387)Placebo(N=379)Hypotension28%13%Hypertension16%18%Nausea11%9%Bradycardia7%3%Fever5%4%Vomiting4%6%AtrialFibrillation4%3%Hypoxia4%4%Tachycardia3%5%Hemorrhage3%4%Anemia3%2%DryMouth3%1%Rigors2%3%Agitation2%3%Hyperpyrexia2%3%Pain2%2%Hyperglycemia2%2%Acidosis2%2%PleuralEffusion2%1%Oliguria2%<1%Thirst2%<1%Inacontrolledclinicaltrial,PrecedexwascomparedtomidazolamforICUsedationexceeding24hoursdurationinadultpatients.Keytreatmentemergentadverseeventsoccurringindexmedetomidineormidazolamtreatedpatientsintherandomizedactivecomparatorcontinuousinfusionlong-termintensivecareunitsedationstudyareprovidedinTable4.Thenumber(%)ofsubjectswhohadadose-relatedincreaseintreatment-emergentadverseeventsbymaintenanceadjusteddoseraterangeinthePrecedexgroupisprovidedinTable5.Table4:KeyTreatment-EmergentAdverseEventsOccurringinDexmedetomidine-orMidazolam-TreatedAdultPatientsintheRandomizedActiveComparatorContinuousInfusionLong-TermIntensiveCareUnitSedationStudyAdverseEventDexmedetomidine(N=244)Midazolam(N=122)Hypotension156%56%HypotensionRequiringIntervention28%27%Bradycardia242%19%BradycardiaRequiringIntervention5%1%SystolicHypertension328%42%Tachycardia425%44%TachycardiaRequiringIntervention10%10%DiastolicHypertension312%15%Hypertension311%15%HypertensionRequiringIntervention†19%30%Hypokalemia9%13%Pyrexia7%2%Agitation7%6%Hyperglycemia7%2%Constipation6%6%Hypoglycemia5%6%RespiratoryFailure5%3%RenalFailureAcute2%1%AcuteRespiratoryDistressSyndrome2%1%GeneralizedEdema2%6%Hypomagnesemia1%7%†Includesanytypeofhypertension1HypotensionwasdefinedinabsolutetermsasSystolicbloodpressureof<80mmHgorDiastolicbloodpressureof<50mmHgorinrelativetermsas≤30%lowerthanpre-studydruginfusionvalue2Bradycardiawasdefinedinabsolutetermsas<40bpmorinrelativetermsas≤30%lowerthanpre-studydruginfusionvalue3HypertensionwasdefinedinabsolutetermsasSystolicbloodpressure>180mmHgorDiastolicbloodpressureof>100mmHgorinrelativetermsas≥30%higherthanpre-studydruginfusionvalue4Tachycardiawasdefinedinabsolutetermsas>120bpmorinrelativetermsas≥30%greaterthanpre-studydruginfusionvalueThefollowingadverseeventsoccurredbetween2and5%forPrecedexandMidazolam,respectively:renalfailureacute(2.5%,0.8%),acuterespiratorydistresssyndrome(2.5%,0.8%),andrespiratoryfailure(4.5%,3.3%).Table5.Number(%)ofAdultSubjectsWhoHadaDose-RelatedIncreaseinTreatmentEmergentAdverseEventsbyMaintenanceAdjustedDoseRateRangeinthePrecedexGroupPrecedex(mcg/kg/hr)AdverseEvent≤0.7*(N=95)>0.7to≤1.1*(N=78)>1.1*(N=71)Constipation6%5%14%Agitation5%8%14%Anxiety5%5%9%EdemaPeripheral3%5%7%AtrialFibrillation2%4%9%RespiratoryFailure2%6%10%AcuteRespiratoryDistressSyndrome1%3%9%*AveragemaintenancedoseovertheentirestudydrugadministrationProceduralSedationAdversereactioninformationisderivedfromthetwotrialsforproceduralsedation[seeClinicalStudies]inwhich318adultpatientsreceivedPrecedex.Themeantotaldosewas1.6mcg/kg(range:0.5to6.7),meandoseperhourwas1.3mcg/kg/hr(range:0.3to6.1)andthemeandurationofinfusionof1.5hours(range:0.1to6.2).Thepopulationwasbetween18to93yearsofage,ASAI-IV,30%≥65yearsofage,52%maleand61%Caucasian.Treatment-emergentadversereactionsoccurringatanincidenceof>2%areprovidedinTable6.Themostfrequentadversereactionswerehypotension,bradycardia,anddrymouth[seeWARNINGSANDPRECAUTIONS].Pre-specifiedcriteriaforthevitalsignstobereportedasadversereactionsarefootnotedbelowthetable.ThedecreaseinrespiratoryrateandhypoxiawassimilarbetweenPrecedexandcomparatorgroupsinbothstudies.Table6:AdverseReactionswithanIncidence>2%—ProceduralSedationPopulationAdverseEventPrecedex(N=318)(%)Placebo(N=113)(%)Hypotension154%30%RespiratoryDepression237%32%Bradycardia314%4%Hypertension413%24%Tachycardia55%17%Nausea3%2%DryMouth3%1%Hypoxia62%3%Bradypnea2%4%1HypotensionwasdefinedinabsoluteandrelativetermsasSystolicbloodpressureof<80mmHgor≤30%lowerthanpre-studydruginfusionvalue,orDiastolicbloodpressureof<50mmHg2Respiratorydepressionwasdefinedinabsoluteandrelativetermsasrespiratoryrate(RR)<8beatsperminuteor>25%decreasefrombaseline3Bradycardiawasdefinedinabsoluteandrelativetermsas<40beatsperminuteor≤30%lowerthanpre-studydruginfusionvalue4HypertensionwasdefinedinabsoluteandrelativetermsasSystolicbloodpressure>180mmHgor≥30%higherthanpre-studydruginfusionvalueorDiastolicbloodpressureof>100mmHg5Tachycardiawasdefinedinabsoluteandrelativetermsas>120beatsperminuteor≥30%greaterthanpre-studydruginfusionvalue6HypoxiawasdefinedinabsoluteandrelativetermsasSpO2<90%or10%decreasefrombaselinePostmarketingExperienceThefollowingadversereactionshavebeenidentifiedduringpost-approvaluseofPrecedex.Becausethesereactionsarereportedvoluntarilyfromapopulationofuncertainsize,itisnotalwayspossibletoreliablyestimatetheirfrequencyorestablishacausalrelationshiptodrugexposure.HypotensionandbradycardiawerethemostcommonadversereactionsassociatedwiththeuseofPrecedexduringpost-approvaluseofthedrug.Table7:AdverseReactionsExperiencedDuringPost-ApprovalUseofPrecedexSystemOrganClassPreferredTermBloodandLymphaticSystemDisordersAnemiaCardiacDisordersArrhythmia,atrialfibrillation,atrioventricularblock,bradycardia,cardiacarrest,cardiacdisorder,extrasystoles,myocardialinfarction,supraventriculartachycardia,tachycardia,ventriculararrhythmia,ventriculartachycardiaEyeDisordersPhotopsia,visualimpairmentGastrointestinalDisordersAbdominalpain,diarrhea,nausea,vomitingGeneralDisordersandAdministrationSiteConditionsChills,hyperpyrexia,pain,pyrexia,thirstHepatobiliaryDisordersHepaticfunctionabnormal,hyperbilirubinemiaInvestigationsAlanineaminotransferaseincreased,aspartateaminotransferaseincreased,bloodalkalinephosphataseincreased,bloodureaincreased,electrocardiogramTwaveinversion,gammaglutamyltransferaseincreased,electrocardiogramQTprolongedMetabolismandNutritionDisordersAcidosis,hyperkalemia,hypoglycemia,hypovolemia,hypernatremiaNervousSystemDisordersConvulsion,dizziness,headache,neuralgia,neuritis,speechdisorderPsychiatricDisordersAgitation,confusionalstate,delirium,hallucination,illusionRenalandUrinaryDisordersOliguria,polyuriaRespiratory,ThoracicandMediastinalDisordersApnea,bronchospasm,dyspnea,hypercapnia,hypoventilation,hypoxia,pulmonarycongestion,respiratoryacidosisSkinandSubcutaneousTissueDisordersHyperhidrosis,pruritus,rash,urticariaSurgicalandMedicalProceduresLightanesthesiaVascularDisordersBloodpressurefluctuation,hemorrhage,hypertension,hypotension DrugInteractions DRUGINTERACTIONSAnesthetics,Sedatives,Hypnotics,OpioidsCo-administrationofPrecedexwithanesthetics,sedatives,hypnotics,andopioidsislikelytoleadtoanenhancementofeffects.Specificstudieshaveconfirmedtheseeffectswithsevoflurane,isoflurane,propofol,alfentanil,andmidazolam.NopharmacokineticinteractionsbetweenPrecedexandisoflurane,propofol,alfentanilandmidazolamhavebeendemonstrated.However,duetopossiblepharmacodynamicinteractions,whenco-administeredwithPrecedex,areductionindosageofPrecedexortheconcomitantanesthetic,sedative,hypnoticoropioidmayberequired.NeuromuscularBlockersInonestudyof10healthyadultvolunteers,administrationofPrecedexfor45minutesataplasmaconcentrationofoneng/mLresultedinnoclinicallymeaningfulincreasesinthemagnitudeofneuromuscularblockadeassociatedwithrocuroniumadministration.DrugAbuseAndDependenceControlledSubstancePrecedex(dexmedetomidinehydrochloride)isnotacontrolledsubstance.DependenceThedependencepotentialofPrecedexhasnotbeenstudiedinhumans.However,sincestudiesinrodentsandprimateshavedemonstratedthatPrecedexexhibitspharmacologicactionssimilartothoseofclonidine,itispossiblethatPrecedexmayproduceaclonidine-likewithdrawalsyndromeuponabruptdiscontinuation[seeWARNINGSANDPRECAUTIONS]. Warnings&Precautions WARNINGSIncludedaspartofthe"PRECAUTIONS"SectionPRECAUTIONSDrugAdministrationPrecedexshouldbeadministeredonlybypersonsskilledinthemanagementofpatientsintheintensivecareoroperatingroomsetting.DuetotheknownpharmacologicaleffectsofPrecedex,patientsshouldbecontinuouslymonitoredwhilereceivingPrecedex.Hypotension,Bradycardia,AndSinusArrestClinicallysignificantepisodesofbradycardiaandsinusarresthavebeenreportedwithPrecedexadministrationinyoung,healthyadultvolunteerswithhighvagaltoneorwithdifferentroutesofadministrationincludingrapidintravenousorbolusadministration.ReportsofhypotensionandbradycardiahavebeenassociatedwithPrecedexinfusion.Someofthesecaseshaveresultedinfatalities.Ifmedicalinterventionisrequired,treatmentmayincludedecreasingorstoppingtheinfusionofPrecedex,increasingtherateofintravenousfluidadministration,elevationofthelowerextremities,anduseofpressoragents.BecausePrecedexhasthepotentialtoaugmentbradycardiainducedbyvagalstimuli,cliniciansshouldbepreparedtointervene.Theintravenousadministrationofanticholinergicagents(e.g.,glycopyrrolate,atropine)shouldbeconsideredtomodifyvagaltone.Inclinicaltrials,glycopyrrolateoratropinewereeffectiveinthetreatmentofmostepisodesofPrecedex-inducedbradycardia.However,insomepatientswithsignificantcardiovasculardysfunction,moreadvancedresuscitativemeasureswererequired.CautionshouldbeexercisedwhenadministeringPrecedextopatientswithadvancedheartblockand/orsevereventriculardysfunction.BecausePrecedexdecreasessympatheticnervoussystemactivity,hypotensionand/orbradycardiamaybeexpectedtobemorepronouncedinpatientswithhypovolemia,diabetesmellitus,orchronichypertensionandinelderlypatients.Inclinicaltrialswhereothervasodilatorsornegativechronotropicagentswereco-administeredwithPrecedexanadditivepharmacodynamiceffectwasnotobserved.Nonetheless,cautionshouldbeusedwhensuchagentsareadministeredconcomitantlywithPrecedex.TransientHypertensionTransienthypertensionhasbeenobservedprimarilyduringtheloadingdoseinassociationwiththeinitialperipheralvasoconstrictiveeffectsofPrecedex.Treatmentofthetransienthypertensionhasgenerallynotbeennecessary,althoughreductionoftheloadinginfusionratemaybedesirable.ArousabilitySomepatientsreceivingPrecedexhavebeenobservedtobearousableandalertwhenstimulated.Thisaloneshouldnotbeconsideredasevidenceoflackofefficacyintheabsenceofotherclinicalsignsandsymptoms.WithdrawalIntensiveCareUnitSedationWithadministrationupto7days,regardlessofdose,12(5%)Precedexadultsubjectsexperiencedatleast1eventrelatedtowithdrawalwithinthefirst24hoursafterdiscontinuingstudydrugand7(3%)Precedexadultsubjectsexperiencedatleast1event24to48hoursafterendofstudydrug.Themostcommoneventswerenausea,vomiting,andagitation.Inadultsubjects,tachycardiaandhypertensionrequiringinterventioninthe48hoursfollowingstudydrugdiscontinuationoccurredatfrequenciesof<5%.Iftachycardiaand/orhypertensionoccursafterdiscontinuationofPrecedexsupportivetherapyisindicated.ProceduralSedationInadultsubjects,withdrawalsymptomswerenotseenafterdiscontinuationofshort-terminfusionsofPrecedex(<6hours).ToleranceAndTachyphylaxisUseofdexmedetomidinebeyond24hourshasbeenassociatedwithtoleranceandtachyphylaxisandadose-relatedincreaseinadversereactions[seeADVERSEREACTIONS].HepaticImpairmentSincePrecedexclearancedecreaseswithseverityofhepaticimpairment,dosereductionshouldbeconsideredinpatientswithimpairedhepaticfunction[seeDOSAGEANDADMINISTRATION].NonclinicalToxicologyCarcinogenesis,Mutagenesis,ImpairmentOfFertilityCarcinogenesisAnimalcarcinogenicitystudieshavenotbeenperformedwithdexmedetomidine.MutagenesisDexmedetomidinewasnotmutagenicinvitro,ineitherthebacterialreversemutationassay(E.coliandSalmonellatyphimurium)orthemammaliancellforwardmutationassay(mouselymphoma).Dexmedetomidinewasclastogenicintheinvitrohumanlymphocytechromosomeaberrationtestwith,butnotwithout,ratS9metabolicactivation.Incontrast,dexmedetomidinewasnotclastogenicintheinvitrohumanlymphocytechromosomeaberrationtestwithorwithouthumanS9metabolicactivation.AlthoughdexmedetomidinewasclastogenicinaninvivomousemicronucleustestinNMRImice,therewasnoevidenceofclastogenicityinCD-1mice.ImpairmentOfFertilityFertilityinmaleorfemaleratswasnotaffectedafterdailysubcutaneousinjectionsofdexmedetomidineatdosesupto54mcg/kg(lessthanthemaximumrecommendedhumanintravenousdoseonamcg/m2basis)administeredfrom10weekspriortomatinginmales,and3weekspriortomatingandduringmatinginfemales.UseInSpecificPopulationsPregnancyPregnancyCategoryCTherearenoadequateandwell-controlledstudiesofPrecedexuseinpregnantwomen.Inaninvitrohumanplacentastudy,placentaltransferofdexmedetomidineoccurred.Inastudyinthepregnantrat,placentaltransferofdexmedetomidinewasobservedwhenradiolabeleddexmedetomidinewasadministeredsubcutaneously.Thus,fetalexposureshouldbeexpectedinhumans,andPrecedexshouldbeusedduringpregnancyonlyifthepotentialbenefitsjustifythepotentialrisktothefetus.Teratogeniceffectswerenotobservedinratsfollowingsubcutaneousadministrationofdexmedetomidineduringtheperiodoffetalorganogenesis(fromgestationday5to16)withdosesupto200mcg/kg(representingadoseapproximatelyequaltothemaximumrecommendedhumanintravenousdosebasedonbodysurfacearea)orinrabbitsfollowingintravenousadministrationofdexmedetomidineduringtheperiodoffetalorganogenesis(fromgestationday6to18)withdosesupto96mcg/kg(representingapproximatelyhalfthehumanexposureatthemaximumrecommendeddosebasedonplasmaareaunderthetime-curvecomparison).However,fetaltoxicity,asevidencedbyincreasedpost-implantationlossesandreducedlivepups,wasobservedinratsatasubcutaneousdoseof200mcg/kg.Theno-effectdoseinratswas20mcg/kg(representingadoselessthanthemaximumrecommendedhumanintravenousdosebasedonabodysurfaceareacomparison).Inanotherreproductivetoxicitystudywhendexmedetomidinewasadministeredsubcutaneouslytopregnantratsat8and32mcg/kg(representingadoselessthanthemaximumrecommendedhumanintravenousdosebasedonabodysurfaceareacomparison)fromgestationday16throughweaning,loweroffspringweightswereobserved.Additionally,whenoffspringofthe32mcg/kggroupwereallowedtomate,elevatedfetalandembryocidaltoxicityanddelayedmotordevelopmentwasobservedinsecondgenerationoffspring.LaborAndDeliveryThesafetyofPrecedexduringlaboranddeliveryhasnotbeenstudied.NursingMothersItisnotknownwhetherPrecedexisexcretedinhumanmilk.Radio-labeleddexmedetomidineadministeredsubcutaneouslytolactatingfemaleratswasexcretedinmilk.Becausemanydrugsareexcretedinhumanmilk,cautionshouldbeexercisedwhenPrecedexisadministeredtoanursingwoman.PediatricUseSafetyandefficacyhavenotbeenestablishedforProceduralorICUSedationinpediatricpatients.Oneassessor-blindedtrialinpediatricpatientsandtwoopenlabelstudiesinneonateswereconductedtoassessefficacyforICUsedation.ThesestudiesdidnotmeettheirprimaryefficacyendpointsandthesafetydatasubmittedwereinsufficienttofullycharacterizethesafetyprofileofPrecedexforthispatientpopulation.TheuseofPrecedexforproceduralsedationinpediatricpatientshasnotbeenevaluated.GeriatricUseIntensiveCareUnitSedationAtotalof729patientsintheclinicalstudieswere65yearsofageandover.Atotalof200patientswere75yearsofageandover.Inpatientsgreaterthan65yearsofage,ahigherincidenceofbradycardiaandhypotensionwasobservedfollowingadministrationofPrecedex[seeWARNINGSANDPRECAUTIONS].Therefore,adosereductionmaybeconsideredinpatientsover65yearsofage[seeDOSAGEANDADMINISTRATION,CLINICALPHARMACOLOGY].ProceduralSedationAtotalof131patientsintheclinicalstudieswere65yearsofageandover.Atotalof47patientswere75yearsofageandover.HypotensionoccurredinahigherincidenceinPrecedex-treatedpatients65yearsorolder(72%)and75yearsorolder(74%)ascomparedtopatients<65years(47%).Areducedloadingdoseof0.5mcg/kggivenover10minutesisrecommendedandareductioninthemaintenanceinfusionshouldbeconsideredforpatientsgreaterthan65yearsofage.HepaticImpairmentSincePrecedexclearancedecreaseswithincreasingseverityofhepaticimpairment,dosereductionshouldbeconsideredinpatientswithimpairedhepaticfunction[seeDOSAGEANDADMINISTRATION,CLINICALPHARMACOLOGY]. Overdosage&Contraindications OVERDOSEThetolerabilityofPrecedexwasstudiedinonestudyinwhichhealthyadultsubjectswereadministereddosesatandabovetherecommendeddoseof0.2to0.7mcg/kg/hr.Themaximumbloodconcentrationachievedinthisstudywasapproximately13timestheupperboundaryofthetherapeuticrange.Themostnotableeffectsobservedintwosubjectswhoachievedthehighestdoseswerefirstdegreeatrioventricularblockandseconddegreeheartblock.Nohemodynamiccompromisewasnotedwiththeatrioventricularblockandtheheartblockresolvedspontaneouslywithinoneminute.FiveadultpatientsreceivedanoverdoseofPrecedexintheintensivecareunitsedationstudies.Twoofthesepatientshadnosymptomsreported;onepatientreceiveda2mcg/kgloadingdoseover10minutes(twicetherecommendedloadingdose)andonepatientreceivedamaintenanceinfusionof0.8mcg/kg/hr.Twootherpatientswhoreceiveda2mcg/kgloadingdoseover10minutes,experiencedbradycardiaand/orhypotension.OnepatientwhoreceivedaloadingbolusdoseofundilutedPrecedex(19.4mcg/kg),hadcardiacarrestfromwhichhewassuccessfullyresuscitated.CONTRAINDICATIONSNone. ClinicalPharmacology CLINICALPHARMACOLOGYMechanismOfActionPrecedexisarelativelyselectivealpha2-adrenergicagonistwithsedativeproperties.Alpha2selectivityisobservedinanimalsfollowingslowintravenousinfusionoflowandmediumdoses(10-300mcg/kg).Bothalpha1andalpha2activityisobservedfollowingslowintravenousinfusionofhighdoses(≥1,000mcg/kg)orwithrapidintravenousadministration.PharmacodynamicsInastudyinhealthyvolunteers(N=10),respiratoryrateandoxygensaturationremainedwithinnormallimitsandtherewasnoevidenceofrespiratorydepressionwhenPrecedexwasadministeredbyintravenousinfusionatdoseswithintherecommendeddoserange(0.2–0.7mcg/kg/hr).PharmacokineticsFollowingintravenousadministration,dexmedetomidineexhibitsthefollowingpharmacokineticparameters:arapiddistributionphasewithadistributionhalf-life(t1/2)ofapproximately6minutes;aterminaleliminationhalf-life(t1/2)ofapproximately2hours;andsteady-statevolumeofdistribution(Vss)ofapproximately118liters.Clearanceisestimatedtobeapproximately39L/h.Themeanbodyweightassociatedwiththisclearanceestimatewas72kg.Dexmedetomidineexhibitslinearpharmacokineticsinthedosagerangeof0.2to0.7mcg/kg/hrwhenadministeredbyintravenousinfusionforupto24hours.Table8showsthemainpharmacokineticparameterswhenPrecedexwasinfused(afterappropriateloadingdoses)atmaintenanceinfusionratesof0.17mcg/kg/hr(targetplasmaconcentrationof0.3ng/mL)for12and24hours,0.33mcg/kg/hr(targetplasmaconcentrationof0.6ng/mL)for24hours,and0.70mcg/kg/hr(targetplasmaconcentrationof1.25ng/mL)for24hours.Table8:Mean±SDPharmacokineticParametersParameterLoadingInfusion(min)/TotalInfusionDuration(hrs)10min/12hrs10min/24hrs10min/24hrs35min/24hrsDexmedetomidineTargetPlasmaConcentration(ng/mL)andDose(mcg/kg/hr)0.3/0.170.3/0.170.6/0.331.25/0.70t1/2*,hour1.78±0.302.22±0.592.23±0.212.50±0.61CL,liter/hour46.3±8.343.1±6.535.3±6.836.5±7.5Vss,liter88.7±22.9102.4±20.393.6±17.099.6±17.8AvgCss#,ng/mL0.27±0.050.27±0.050.67±0.101.37±0.20Abbreviations:t1/2=half-life,CL=clearance,Vss=steady-statevolumeofdistribution*Presentedasharmonicmeanandpseudostandarddeviation#MeanCss=Averagesteady-stateconcentrationofdexmedetomidineThemeanCsswascalculatedbasedonpost-dosesamplingfrom25to9hourssamplesfor12hourinfusionandpost-dosesamplingfrom25to18hoursfor24hourinfusionsTheloadingdosesforeachoftheaboveindicatedgroupswere0.5,0.5,1and2.2mcg/kg,respectively.DexmedetomidinepharmacokineticparametersafterPrecedexmaintenancedosesof0.2to1.4mcg/kg/hrfor>24hoursweresimilartothepharmacokinetic(PK)parametersafterPrecedexmaintenancedosingfor<24hoursinotherstudies.Thevaluesforclearance(CL),volumeofdistribution(V),andt1/2were39.4L/hr,152L,and2.67hours,respectively.DistributionThesteady-statevolumeofdistribution(Vss)ofdexmedetomidinewasapproximately118liters.Dexmedetomidineproteinbindingwasassessedintheplasmaofnormalhealthymaleandfemalesubjects.Theaverageproteinbindingwas94%andwasconstantacrossthedifferentplasmaconcentrationstested.Proteinbindingwassimilarinmalesandfemales.ThefractionofPrecedexthatwasboundtoplasmaproteinswassignificantlydecreasedinsubjectswithhepaticimpairmentcomparedtohealthysubjects.Thepotentialforproteinbindingdisplacementofdexmedetomidinebyfentanyl,ketorolac,theophylline,digoxinandlidocainewasexploredinvitro,andnegligiblechangesintheplasmaproteinbindingofPrecedexwereobserved.Thepotentialforproteinbindingdisplacementofphenytoin,warfarin,ibuprofen,propranolol,theophyllineanddigoxinbyPrecedexwasexploredinvitroandnoneofthesecompoundsappearedtobesignificantlydisplacedbyPrecedex.EliminationMetabolismDexmedetomidineundergoesalmostcompletebiotransformationwithverylittleunchangeddexmedetomidineexcretedinurineandfeces.BiotransformationinvolvesbothdirectglucuronidationaswellascytochromeP450mediatedmetabolism.Themajormetabolicpathwaysofdexmedetomidineare:directN-glucuronidationtoinactivemetabolites;aliphatichydroxylation(mediatedprimarilybyCYP2A6withaminorroleofCYP1A2,CYP2E1,CYP2D6andCYP2C19)ofdexmedetomidinetogenerate3-hydroxy-dexmedetomidine,theglucuronideof3-hydroxy-dexmedetomidine,and3-carboxy-dexmedetomidine;andN-methylationofdexmedetomidinetogenerate3-hydroxyN-methyl-dexmedetomidine,3-carboxyN-methyl-dexmedetomidine,anddexmedetomidine-N-methylO-glucuronide.ExcretionTheterminaleliminationhalf-life(t1/2)ofdexmedetomidineisapproximately2hoursandclearanceisestimatedtobeapproximately39L/h.Amassbalancestudydemonstratedthatafterninedaysanaverageof95%oftheradioactivity,followingintravenousadministrationofradiolabeleddexmedetomidine,wasrecoveredintheurineand4%inthefeces.Nounchangeddexmedetomidinewasdetectedintheurine.Approximately85%oftheradioactivityrecoveredintheurinewasexcretedwithin24hoursaftertheinfusion.FractionationoftheradioactivityexcretedinurinedemonstratedthatproductsofN-glucuronidationaccountedforapproximately34%ofthecumulativeurinaryexcretion.Inaddition,aliphatichydroxylationofparentdrugtoform3-hydroxy-dexmedetomidine,theglucuronideof3-hydroxy-dexmedetomidine,and3-carboxylicacid-dexmedetomidinetogetherrepresentedapproximately14%ofthedoseinurine.N-methylationofdexmedetomidinetoform3-hydroxyN-methyldexmedetomidine,3-carboxyN-methyldexmedetomidine,andN-methylO-glucuronidedexmedetomidineaccountedforapproximately18%ofthedoseinurine.TheN-Methylmetaboliteitselfwasaminorcirculatingcomponentandwasundetectedinurine.Approximately28%oftheurinarymetaboliteshavenotbeenidentified.SpecificPopulationsMaleAndFemalePatientsTherewasnoobserveddifferenceinPrecedexpharmacokineticsduetogender.GeriatricPatientsThepharmacokineticprofileofPrecedexwasnotalteredbyage.TherewerenodifferencesinthepharmacokineticsofPrecedexinyoung(18–40years),middleage(41–65years),andelderly(>65years)subjects.PatientsWithHepaticImpairmentInsubjectswithvaryingdegreesofhepaticimpairment(Child-PughClassA,B,orC),clearancevaluesforPrecedexwerelowerthaninhealthysubjects.Themeanclearancevaluesforpatientswithmild,moderate,andseverehepaticimpairmentwere74%,64%and53%ofthoseobservedinthenormalhealthysubjects,respectively.Meanclearancesforfreedrugwere59%,51%and32%ofthoseobservedinthenormalhealthysubjects,respectively.AlthoughPrecedexisdosedtoeffect,itmaybenecessarytoconsiderdosereductioninsubjectswithhepaticimpairment[seeDOSAGEANDADMINISTRATION,WARNINGSANDPRECAUTIONS].PatientsWithRenalImpairmentDexmedetomidinepharmacokinetics(Cmax,Tmax,AUC,t1/2,CL,andVss)werenotsignificantlydifferentinpatientswithsevererenalimpairment(creatinineclearance:<30mL/min)comparedtohealthysubjects.DrugInteractionStudiesInVitroStudiesInvitrostudiesinhumanlivermicrosomesdemonstratednoevidenceofcytochromeP450mediateddruginteractionsthatarelikelytobeofclinicalrelevance.AnimalToxicologyAnd/OrPharmacologyTherewerenodifferencesintheadrenocorticotropichormone(ACTH)-stimulatedcortisolresponseindogsfollowingasingledoseofdexmedetomidinecomparedtosalinecontrol.However,aftercontinuoussubcutaneousinfusionsofdexmedetomidineat3mcg/kg/hrand10mcg/kg/hrforoneweekindogs(exposuresestimatedtobewithintheclinicalrange),theACTH-stimulatedcortisolresponsewasdiminishedbyapproximately27%and40%,respectively,comparedtosaline-treatedcontrolanimalsindicatingadose-dependentadrenalsuppression.ClinicalStudiesThesafetyandefficacyofPrecedexhasbeenevaluatedinfourrandomized,double-blind,placebo-controlledmulticenterclinicaltrialsin1,185adultpatients.IntensiveCareUnitSedationTworandomized,double-blind,parallel-group,placebo-controlledmulticenterclinicaltrialsincluded754adultpatientsbeingtreatedinasurgicalintensivecareunit.Allpatientswereinitiallyintubatedandreceivedmechanicalventilation.ThesetrialsevaluatedthesedativepropertiesofPrecedexbycomparingtheamountofrescuemedication(midazolaminonetrialandpropofolinthesecond)requiredtoachieveaspecifiedlevelofsedation(usingthestandardizedRamsaySedationScale)betweenPrecedexandplacebofromonsetoftreatmenttoextubationortoatotaltreatmentdurationof24hours.TheRamsayLevelofSedationScaleisdisplayedinTable9.Table9:RamsayLevelofSedationScaleClinicalScoreLevelofSedationAchieved6Asleep,noresponse5Asleep,sluggishresponsetolightglabellartaporloudauditorystimulus4Asleep,butwithbriskresponsetolightglabellartaporloudauditorystimulus3Patientrespondstocommands2Patientcooperative,oriented,andtranquil1Patientanxious,agitated,orrestlessInthefirststudy,175adultpatientswererandomizedtoreceiveplaceboand178toreceivePrecedexbyintravenousinfusionatadoseof0.4mcg/kg/hr(withallowedadjustmentbetween0.2and0.7mcg/kg/hr)followinganinitialloadinginfusionofonemcg/kgintravenousover10minutes.ThestudydruginfusionratewasadjustedtomaintainaRamsaysedationscoreof≥3.Patientswereallowedtoreceive“rescue”midazolamasneededtoaugmentthestudydruginfusion.Inaddition,morphinesulfatewasadministeredforpainasneeded.Theprimaryoutcomemeasureforthisstudywasthetotalamountofrescuemedication(midazolam)neededtomaintainsedationasspecifiedwhileintubated.PatientsrandomizedtoplaceboreceivedsignificantlymoremidazolamthanpatientsrandomizedtoPrecedex(seeTable10).AsecondprospectiveprimaryanalysisassessedthesedativeeffectsofPrecedexbycomparingthepercentageofpatientswhoachievedaRamsaysedationscoreof≥3duringintubationwithouttheuseofadditionalrescuemedication.AsignificantlygreaterpercentageofpatientsinthePrecedexgroupmaintainedaRamsaysedationscoreof≥3withoutreceivinganymidazolamrescuecomparedtotheplacebogroup(seeTable10).Table10:MidazolamUseasRescueMedicationDuringIntubation(ITT)StudyOnePlacebo(N=175)Precedex(N=178)p-valueMeanTotalDose(mg)ofMidazolam19mg5mg0.0011*  Standarddeviation53mg19mgCategorizedMidazolamUse  0mg43(25%)108(61%)<0.001**  0–4mg34(19%)36(20%)  >4mg98(56%)34(19%)ITT(intent-to-treat)populationincludesallrandomizedpatients*ANOVAmodelwithtreatmentcenter**Chi-squareAprospectivesecondaryanalysisassessedthedoseofmorphinesulfateadministeredtopatientsinthePrecedexandplacebogroups.Onaverage,Precedex-treatedpatientsreceivedlessmorphinesulfateforpainthanplacebo-treatedpatients(0.47versus0.83mg/h).Inaddition,44%(79of178patients)ofPrecedexpatientsreceivednomorphinesulfateforpainversus19%(33of175patients)intheplacebogroup.Inasecondstudy,198adultpatientswererandomizedtoreceiveplaceboand203toreceivePrecedexbyintravenousinfusionatadoseof0.4mcg/kg/hr(withallowedadjustmentbetween0.2and0.7mcg/kg/hr)followinganinitialloadinginfusionofonemcg/kgintravenousover10minutes.ThestudydruginfusionwasadjustedtomaintainaRamsaysedationscoreof≥3.Patientswereallowedtoreceive“rescue”propofolasneededtoaugmentthestudydruginfusion.Inaddition,morphinesulfatewasadministeredasneededforpain.Theprimaryoutcomemeasureforthisstudywasthetotalamountofrescuemedication(propofol)neededtomaintainsedationasspecifiedwhileintubated.PatientsrandomizedtoplaceboreceivedsignificantlymorepropofolthanpatientsrandomizedtoPrecedex(seeTable11).AsignificantlygreaterpercentageofpatientsinthePrecedexgroupcomparedtotheplacebogroupmaintainedaRamsaysedationscoreof≥3withoutreceivinganypropofolrescue(seeTable11).Table11:PropofolUseasRescueMedicationDuringIntubation(ITT)Placebo(N=198)Precedex(N=203)p-valueMeanTotalDose(mg)ofPropofol513mg72mg<0.0001*  Standarddeviation782mg249mgCategorizedPropofolUse  0mg47(24%)122(60%)<0.001**  0–50mg30(15%)43(21%)  >50mg121(61%)38(19%)*ANOVAmodelwithtreatmentcenter**Chi-squareAprospectivesecondaryanalysisassessedthedoseofmorphinesulfateadministeredtopatientsinthePrecedexandplacebogroups.Onaverage,Precedex-treatedpatientsreceivedlessmorphinesulfateforpainthanplacebo-treatedpatients(0.43versus0.89mg/h).Inaddition,41%(83of203patients)ofPrecedexpatientsreceivednomorphinesulfateforpainversus15%(30of198patients)intheplacebogroup.Inacontrolledclinicaltrial,PrecedexwascomparedtomidazolamforICUsedationexceeding24hoursduration.Precedexwasnotshowntobesuperiortomidazolamfortheprimaryefficacyendpoint,thepercentoftimepatientswereadequatelysedated(81%versus81%).Inaddition,administrationofPrecedexforlongerthan24hourswasassociatedwithtolerance,tachyphylaxis,andadose-relatedincreaseinadverseevents[seeADVERSEREACTIONS].ProceduralSedationThesafetyandefficacyofPrecedexforsedationofnon-intubatedpatientspriortoand/orduringsurgicalandotherprocedureswasevaluatedintworandomized,double-blind,placebo-controlledmulticenterclinicaltrials.Study1evaluatedthesedativepropertiesofPrecedexinpatientshavingavarietyofelectivesurgeries/proceduresperformedundermonitoredanesthesiacare.Study2evaluatedPrecedexinpatientsundergoingawakefiberopticintubationpriortoasurgicalordiagnosticprocedure.InStudy1,thesedativepropertiesofPrecedexwereevaluatedbycomparingthepercentofpatientsnotrequiringrescuemidazolamtoachieveaspecifiedlevelofsedationusingthestandardizedObserver’sAssessmentofAlertness/SedationScale(seeTable12).Table12:Observer’sAssessmentofAlertness/SedationAssessmentCategoriesResponsivenessSpeechFacialExpressionEyesCompositeScoreRespondsreadilytonamespokeninnormaltoneNormalNormalClear,noptosis5(alert)LethargicresponsetonamespokeninnormaltoneMildslowingorthickeningMildrelaxationGlazedormildptosis(lessthanhalftheeye)4Respondsonlyafternameiscalledloudlyand/orrepeatedlySlurringorprominentslowingMarkedrelaxation(slackjaw)Glazedandmarkedptosis(halftheeyeormore)3RespondsonlyaftermildproddingorshakingFewrecognizablewords--2Doesnotrespondtomildproddingorshaking---1(deepsleep)PatientswererandomizedtoreceivealoadinginfusionofeitherPrecedex1mcg/kg,Precedex0.5mcg/kg,orplacebo(normalsaline)givenover10minutesandfollowedbyamaintenanceinfusionstartedat0.6mcg/kg/hr.Themaintenanceinfusionofstudydrugcouldbetitratedfrom0.2mcg/kg/hrto1mcg/kg/hrtoachievethetargetedsedationscore(Observer’sAssessmentofAlertness/SedationScale≤4).Patientswereallowedtoreceiverescuemidazolamasneededtoachieveand/ormaintainanObserver’sAssessmentofAlertness/SedationScale≤4.Afterachievingthedesiredlevelofsedation,alocalorregionalanestheticblockwasperformed.DemographiccharacteristicsweresimilarbetweenthePrecedexandcomparatorgroups.EfficacyresultsshowedthatPrecedexwasmoreeffectivethanthecomparatorgroupwhenusedtosedatenon-intubatedpatientsrequiringmonitoredanesthesiacareduringsurgicalandotherprocedures(seeTable13).InStudy2,thesedativepropertiesofPrecedexwereevaluatedbycomparingthepercentofpatientsrequiringrescuemidazolamtoachieveormaintainaspecifiedlevelofsedationusingtheRamsaySedationScalescore≥2(seeTable9).PatientswererandomizedtoreceivealoadinginfusionofPrecedex1mcg/kgorplacebo(normalsaline)givenover10minutesandfollowedbyafixedmaintenanceinfusionof0.7mcg/kg/hr.Afterachievingthedesiredlevelofsedation,topicalizationoftheairwayoccurred.Patientswereallowedtoreceiverescuemidazolamasneededtoachieveand/ormaintainaRamsaySedationScale≥2.DemographiccharacteristicsweresimilarbetweenthePrecedexandcomparatorgroups.ForefficacyresultsseeTable13.Table13:KeyEfficacyResultsofProceduralSedationStudiesStudyLoadingInfusionTreatmentArmNumberofPatientsEnrolleda%NotRequiringMidazolamRescueConfidencebIntervalontheDifferencevs.PlaceboMean(SD)TotalDose(mg)ofRescueMidazolamRequiredConfidencebIntervalsoftheMeanRescueDoseStudy1Dexmedetomidine0.5mcg/kg1344037(27,48)1.4(1.7)-2.7(-3.4,-2.0)Dexmedetomidine1mcg/kg1295451(40,62)0.9(1.5)-3.1(-3.8,-2.5)Placebo633–4.1(3.0)–Study2Dexmedetomidine1mcg/kg555339(20,57)1.1(1.5)-1.8(-2.7,-0.9)Placebo5014–2.9(3.0)–aBasedonITTpopulationdefinedasallrandomizedandtreatedpatientsbNormalapproximationtothebinomialwithcontinuitycorrection MedicationGuide PATIENTINFORMATIONPrecedexisindicatedforshort-termintravenoussedation.Dosagemustbeindividualizedandtitratedtothedesiredclinicaleffect.Bloodpressure,heartrateandoxygenlevelswillbemonitoredbothcontinuouslyduringtheinfusionofPrecedexandasclinicallyappropriateafterdiscontinuation.WhenPrecedexisinfusedformorethan6hours,patientsshouldbeinformedtoreportnervousness,agitation,andheadachesthatmayoccurforupto48hours.Additionally,patientsshouldbeinformedtoreportsymptomsthatmayoccurwithin48hoursaftertheadministrationofPrecedexsuchas:weakness,confusion,excessivesweating,weightloss,abdominalpain,saltcravings,diarrhea,constipation,dizzinessorlight-headedness. 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