Acenocoumarol Drug Information, Professional

22/11/2016
AcenocoumarolDrugInformation,Professional
Anticoagulants(Systemic)
Thismonographincludesinformationonthefollowing:
1)Acenocoumarol*
2)Anisindione
3)Dicumarol
4)Warfarin
Note:SeealsoindividualAntithrombinIII(Systemic),Ardeparin(Systemic),Dalteparin(Systemic),
Danaparoid(Systemic),Enoxaparin(Systemic),andHeparin(Systemic)monographs.
INN:
DicumarolDicoumarol
BAN:
AcenocoumarolNicoumalone
VACLASSIFICATION
Primary:BL114
Commonlyusedbrandname(s):Coumadin4Miradon2Sintrom1Warfilone4.
Othercommonlyusednamesare
nicoumaloneacenocoumarol*
anddicoumaroldicumarol
Note:Foralistingofdosageformsandbrandnamesbycountryavailability,seeDosageFormssection(s).
*NotcommerciallyavailableintheU.S.
NotcommerciallyavailableinCanada.
Category:
Anticoagulant
Indications
Note:BracketedinformationintheIndicationssectionreferstousesthatarenotincludedinU.S.productlabeling.
Generalconsiderations
Thismonographincludesinformationontwotypesofanticoagulantscoumarinderivatives(acenocoumarol,
https://www.drugs.com/mmx/acenocoumarol.html
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dicumarol,warfarin)andindanedionederivatives(anisindione).Warfarinisusuallytheoralanticoagulantofchoice.
Ingeneral,becauseoftheirhigherriskofhemorrhage,indanedionederivativesareusedonlywhenanoral
anticoagulantisindicatedbutuseofcoumarinderivativesisnotpossible{33}0{05}9.Dicumarolisseldomused
becauseofitsunpredictableresponseandhighincidenceofgastrointestinalsideeffects{05}8.
Decisionsaboutwhethertouseanticoagulantsshouldtakeintoaccountthebalancebetweenpotentialbenefits
(preventionofthromboembolism,reducedmortality)andrisks(hemorrhage,possibleincreasedmortality){05}7.The
presenceorabsenceofriskfactors(e.g.,advancedage,historyofbleedingorstroke,diabetes,hypertension{05}6)
stronglyinfluencesboththedecisionaboutwhethertoinitiateanticoagulanttherapyandthechoiceofanticoagulant.
Multipleindicationsalsomaybepresent(e.g.,atrialfibrillationinpatientswithprostheticheartvalves{05}5)andmay
affecttreatmentdecisions.
Severaloftheindicationsfortheoralanticoagulantsareidenticaltothoseforaspirin,heparin,otherantithrombotic
agents,otherplateletaggregationinhibitors,andthrombolyticagents.Choiceofagentmaydependonthespecific
condition,associatedriskfactors,anddesiredeffect.Insomecases,oralanticoagulantsmaybeusedincombination
with,orsequentiallywith,oneormoreoftheseagents.
Sincethefulltherapeuticeffectsoforalanticoagulantsisdelayedforseveraldays,heparinistheagentofchoice
whenanimmediateanticoagulanteffectisrequired.Oralanticoagulantsareusedwhentreatmentisnoturgentor
forlongtermanticoagulanttherapyfollowinginitialheparinorthrombolytictherapy.
Warfarininjectionisusedwhencoumarinanticoagulanttherapyisdesiredinpatientswhocannottakeoralwarfarin
{05}4.
Accepted
Thrombosis(prophylaxisand/ortreatment)or
Thromboembolism(prophylaxisand/ortreatment)Anticoagulantsareindicatedforprophylaxisand/ortreatmentof
venous[orarterial]thrombosis(anditsextension)andpulmonaryembolism{05}3{05}2{05}1{05}0{03}9{03}8{03}7
{03}6{03}5.Deepveinthrombosis(DVT)orpulmonaryembolism(treatment)
Oralanticoagulantsareusedduringandfollowinginitialheparintherapy{03}4{03}3{03}2todecreasetheriskof
extension,recurrence,ordeath.
Note:Oralanticoagulanttherapyisusuallyinitiatedatthesametimeasheparintherapy,oratleastoverlappedwith
heparintherapyheparintherapyiswithdrawnwhenatherapeuticprothrombintimehasbeenmaintainedforan
appropriateperiod{03}1.
DVTorpulmonaryembolism(prophylaxis)
Oralanticoagulantsareusedtopreventthromboemboliccomplicationsaftersurgery{03}0{02}9{02}8,althoughlow
dosesubcutaneousheparinisusedmorecommonly{02}7.
Note:Perioperativewarfarinisrecommendedinselectedveryhighriskgeneralsurgerypatients{02}6.
Warfarinmaybestartedpreoperativelyinpatientsundergoingelectivetotalhipreplacementortotalknee
replacementsurgery,andcontinuedpostoperatively{02}5{02}4.
Warfarinmaybestartedpreoperativelyorimmediatelypostoperativelyinpatientsundergoinghipfracturesurgery
{02}3.
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Lowdosewarfarinisrecommendedinpatientswithlongtermindwellingcentralveincatheterstopreventaxillary
subclavianvenousthrombosis{02}2{02}1.
Atrialfibrillation
Anticoagulantsareindicatedforprophylaxisand/ortreatmentofthromboemboliccomplications(ischemicstroke)
associatedwithatrialfibrillation{02}0{02}9{02}8{02}7{02}6{02}5{02}4{02}3{02}2{02}1{02}0{90}9.Theyarestrongly
recommendedinpatientsathighriskofstroke(includingpatientswithrecentstroke,transientischemicattack,or
systemicembolismpoorleftventricularfunctionageover75yearshypertensionrheumaticmitralvalvedisease
mechanicalortissueprostheticheartvalves){90}8.
Note:Inpatientswithoneormorelowerriskfactors(diabetesmellitus,coronaryarterydisease,age65to75years,
thyrotoxicosis),thedecisionaboutwhethertouseoralanticoagulantsshouldbalancetherelativeefficacy(compared
toaspirin)againsttheriskofhemorrhage{90}7{90}6{90}5.
Oralanticoagulanttherapyisstronglyrecommendedfor3weeksbeforeelectivecardioversionofchronicatrial
fibrillation,andshouldbecontinueduntilnormalsinusrhythmhasbeenmaintainedfor4weeks{90}4{90}3,toreduce
theriskofpostconversionemboli.Similarantithrombotictherapymayalsobeconsideredatthetimeofcardioversion
inatrialflutter{90}2{90}1,butantithrombotictherapyisnotrecommendedforcardioversionofchronic
supraventriculartachycardia{90}0.
Myocardialinfarction
Anticoagulantsareindicatedaftermyocardialinfarctiontoreducetheriskofdeath,recurrentmyocardialinfarction,
andthromboemboliceventssuchasstrokeorsystemicembolization{01}9{01}8{01}7{01}6{01}5{01}4{01}3.
Note:Anticoagulantsareusedafterinitialheparintherapy,primarilyinhighriskpatientssuchasthosewithshock,
congestiveheartfailure,prolongedarrhythmias(especiallyatrialfibrillation),previousmyocardialinfarction,orhistory
ofsystemicorpulmonarythromboembolism{01}2.
Theriskofcardioembolicstrokemaybedecreasedbyoralanticoagulants,buttheriskofhemorrhagicstrokemaybe
increased{01}1.Additionalstudiesareneededtohelpidentifysubgroupsofpatientsmostlikelytobenefitfrom
anticoagulanttherapy{01}0.
Ischemia,myocardial
Oralanticoagulantsareindicated,aloneorincombinationwithaspirin,forprimarypreventionofthrombotic
complicationsofcoronaryarterydisease{02}9{02}8{02}7{02}6{02}5{02}4inpatientswithouthistoryofmyocardial
infarction,stroke,ortransientischemicattacksbutwithincreasinglevelsofrisk{02}3{02}2.
Note:Becauseoftheriskofcerebralhemorrhagewithcombineduseofaspirinandanticoagulants,aswellasthe
costsandcomplexityofwarfarintherapy,aspirinmonotherapyisusuallyrecommended.Lowdosewarfarintherapy
isrecommendedasanalternativetoaspirinformenathighriskofcardiovascularevents,topreventthoseevents
andreduceallcausemortality{02}1.Combinationtherapywithaspirinandlowdosewarfarinmaybeconsideredin
menatveryhighrisk{02}0.
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Prostheticheartvalves
Anticoagulantsareindicatedforprophylaxisand/ortreatmentofthromboemboliccomplicationsassociatedwith
tissueandmechanicalcardiacvalvereplacement{03}9{03}8{03}7{03}6{03}5{03}4{03}3{03}2.
Note:Concurrentuseofaspirinmayincreaseeffectivenessinpatientswhoexperienceembolisminspiteof
adequateanticoagulanttherapy{03}1{03}0{09}9{09}8{09}7butisassociatedwithanincreasedriskofhemorrhageif
theinternationalnormalizedratio(INR)isnotkeptatalowlevel{09}6{09}5{09}4.
[Valvularheartdisease]
Anticoagulantsareusedincertainpatientswithvalvularheartdiseasetopreventsystemicembolization{09}3{09}2
{09}1{09}0{48}9.
Note:Warfarinisstronglyrecommendedinrheumaticmitralvalvediseaseinpatientswhohaveeitherahistoryof
systemicembolismorwhohaveparoxysmalorchronicatrialfibrillation{48}8{48}7{48}6.Longtermwarfarintherapy
shouldbeconsideredinrheumaticmitralvalvediseaseinpatientswithnormalsinusrhythmiftheleftatrialdiameter
exceeds5centimeters{48}5.
Longtermwarfarintherapyisnotrecommendedinaorticvalvediseaseunlessthereisconcomitantmitralvalve
disease,atrialfibrillation,orahistoryofsystemicembolism{48}4.
Longtermwarfarintherapyisstronglyrecommendedinmitralvalveprolapse,butonlyinpatientswhohave
documentedsystemicembolism,chronicorparoxysmalatrialfibrillation,orrecurrenttransientischemicattacks
despiteaspirintherapy{48}3{48}2{48}1.
Longtermwarfarintherapyisrecommendedinmitralannularcalcification,butonlyinpatientswithsystemic
embolismnotdocumentedtobecalcificembolismorinpatientswithassociatedatrialfibrillation{48}0{01}9.
Longtermwarfarintherapyisstronglyrecommendedinpatentforamenovale(PFO)andatrialseptalaneurysmin
patientswithunexplainedsystemicembolismortransientischemicattacksanddemonstrablevenousthrombosisor
pulmonaryembolism,unlessvenousinterruptionorsurgicalclosureofthePFOispreferable{01}8.
Longtermwarfarintherapymaybecontinuedifinfectiveendocarditisoccursinpatientswithmechanicalprosthetic
valves,unlesstherearespecificcontraindications,becauseofthehighincidenceofsystemicthromboembolismin
thesepatients{01}7{01}6however,theriskofintracranialhemorrhageissignificantwiththistherapy{01}5{01}4.The
therapeuticdecisionregardinguseofanticoagulanttherapywhensystemicembolismoccursduringthecourseof
infectiveendocarditisinvolvinganativeorbioprostheticheartvalveshouldinvolveconsiderationofcomorbidfactors
(atrialfibrillation,evidenceofleftatrialthrombus,evidenceandsizeofvalvularvegetations)aswellasthesuccessof
antibiotictherapy{01}3{01}2.
[Vasculardisease,peripheral]
Oralanticoagulantsareused,followinginitialheparinization,topreventrecurrentthromboembolisminperipheral
arterialocclusivedisease{01}1{01}0{02}9.Theyarenotindicatedforroutineprophylaxisafterintrainguinalbypass
andothervascularreconstructionsbutareindicated,usuallyincombinationwithaspirin,inpatientsathighriskof
graftthrombosis{02}8.
Acceptancenotestablished
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Thereareinsufficientdatatoevaluatesafetyandefficacyoforalanticoagulantsforpreventionofworseningor
recurrenceofacuteischemic(atherothrombotic)stroke(i.e.,noncardioembolicstroke){02}7{02}6.AteffectiveINRs,
theriskofhemorrhageappearstooutweighthepotentialbenefit{02}5{02}4.
Thereareinsufficientdatatodetermineefficacyoforalanticoagulantsforpreventionofocclusionofsaphenous
veinsusedincoronaryarterybypassgraftsaspirintherapy,however,iswellestablished{02}3.
Althoughthereisagoodtheoreticalbasisforuseofanticoagulantsintheprimarytreatmentofcancer,efficacyhas
notbeenestablishedinclinicaltrials{02}2.
Unaccepted
Warfarinisnolongerrecommendedforuseinthepreventionofsubacutethrombosisafterintracoronarystent
placement,becausestudieshaveshownthatthecombinationofaspirinandticlopidineismoreeffective{02}1.
Pharmacology/Pharmacokinetics
Physicochemicalcharacteristics:
Chemicalgroup
Coumarinderivatives:Acenocoumarol,dicumarol,warfarin.
Indanedionederivative:Anisindione.
Molecularweight
Acenocoumarol:353.33{02}0
Anisindione:252.27{03}9
Dicumarol:336.3{03}8
Warfarinsodium:330.32{03}7
Mechanismofaction/Effect:
Bothcoumarinandindanedionederivativesareindirectactinganticoagulants{03}6.Theypreventtheformationof
activeprocoagulationfactorsII,VII,IX,andX{03}5{03}4,aswellastheanticoagulantproteinsCandS{03}3{03}2
{03}1,intheliverbyinhibitingthevitaminKmediatedgammacarboxylationofprecursorproteins{03}0{09}9.These
agentshavenodirectthrombolyticeffect{09}8anddonotreverseischemictissuedamage,althoughtheymaylimit
extensionofexistingthrombiandpreventsecondarythromboemboliccomplications{09}7.
CommerciallyavailablewarfarinisaracemicmixtureofRandSenantiomers.TheSenantiomerhas2to5times
theanticoagulantactivityoftheRenantiomer{09}6{09}5{09}4{09}3butalsohasmorerapidclearance{09}2{09}1.
Absorption:
AcenocoumarolRapidbioavailabilityisatleast60%{09}0.
AnisindioneAccumulationdoesnotoccurwithrepeateddosing{48}9.
DicumarolIrregular{48}8.
WarfarinRapidlyandcompletelyabsorbedfromthegastrointestinaltract{48}7{48}6{48}5.Therate,butnotthe
extent,ofwarfarinabsorptionisdecreasedbyfood{48}4{48}3.
Proteinbinding:
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AcenocoumarolVeryhigh(98.7%),primarilytoalbumin{48}2.
DicumarolVeryhigh(approximately97%),toalbumin{48}1.
WarfarinVeryhigh(approximately99%),primarilytoalbumin{48}0{01}9{01}8.AffinityoftheRisomerishigher
thanthanoftheSisomer,whichcouldresultinstereospecificdisplacementfrombindingbyothermedications{01}7.
Biotransformation:
Hepatic{01}6{01}5{01}4{01}3.Enterohepaticrecirculationofwarfarinoccurs{01}2.
AcenocoumarolAtleasttwometabolicpathwaysareinvolved,oxidationandreductiontopharmacologically
inactivemetabolites.Oxidationproducestwohydroxylatedmetabolites.Reductionoftheketoneproducestwo
differentalcoholmetabolitesreductionofthenitriteproducesanaminemetabolite,amajorportionofwhichis
furthertransformedtothecorrespondingacetamidemetabolite.Anadditionalunidentifiedstronglypolarmetabolite
fractionhasalsobeendetected.{01}1
WarfarinStereoselectivemetabolismbyhepaticmicrosomalenzymestoinactivehydroxylatedmetabolitesandby
reductasestoreducedmetabolites(warfarinalcohols),whichhaveminimalanticoagulantactivity{01}0{02}9.The
majorhepaticisoenzymeinvolvedappearstobeCYP2C9{02}8{02}7.
Halflife:
Acenocoumarol:
8to11hours{02}6{02}5.
Dicumarol:
1to2days{02}4.
Warfarin:
Distribution:6to12hours{02}3.
Elimination:Approximately1weekafterasingledosehowever,theeffectivehalflifeis20to60hours(mean,about
40hours){02}2{02}1.Thehalflifeis37to89hoursfortheRenantiomerand21to43hoursfortheSenantiomer
{02}0{03}9.
Onsetofaction:
Anisindione:
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Effectonprothrombintime(PT):Prolonged,within6hours,to50%ofbaselineprothrombinactivityprothrombin
activitydecreasesslowlythereafter{03}8.
Dicumarol:
Inductionofhypoprothrombinemia:36to48hours{03}7.
EffectonPT:1to5days{03}6.
Warfarin(oral):
EffectonPT:Within24hours{03}5{03}4.
Note:Fulltherapeuticactionisdelayeduntilcirculatingcoagulationfactorsareremovedbynormalcatabolism,
whichoccursatdifferentratesforeachfactor{03}3.AlthoughPTmaybeprolongedwhenfactorVII(whichhasthe
shortesthalflife)isdepleted,itisbelievedthatpeakantithromboticeffectsarenotachieveduntilallfourfactorsare
removed{03}2.
ProlongedPTmayreflectearlydepletionoffactorVIIratherthanpeakantithromboticeffects{03}1.Useofaninitial
loadingdosemightalsoproducethiseffecthowever,loadingdosescurrentlyarenotrecommended.
Timetopeakplasmaconcentration
AcenocoumarolWithin1to3hours{03}0.
Dicumarol1to9hours{14}9.
WarfarinOral:Within4hours{14}8.
Peakplasmaconcentration
AcenocoumarolFollowingasingledoseof10mg:0.3mcgpermL{14}7.Bothpeakplasmaconcentrationsand
areasundertheconcentrationtimecurve(AUCs)areproportionaltothesizeofthedoseoverarangeof8to16mg
{14}6.
Note:Becauseplasmaconcentrationsachievedarevariableamongpatients,thereisnodirectcorrelationbetween
plasmaconcentrationandeffectonPT{14}5.
Timetopeakeffect:
EffectonPT:
Acenocoumarol:36to48hours{14}4.
{14}3
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Anisindione:48to72hours,to15to30%ofbaseline{14}3.
Warfarin:Oralorintravenous72to96hours{14}2{14}1{14}0.
Durationofaction:
Acenocoumarol:Within48hours{33}9{33}8.
Anisindione:1to3days{33}7.
Dicumarol:5to6days{33}6.
Warfarin:Singledose2to5days{33}5{33}4{33}3.
Elimination:
Primarilyrenal,almostentirelyasmetabolites{33}2{33}1{33}0{14}9,andtoalesserextentbiliary{14}8.
Acenocoumarol
Renal,60%{14}7.
Fecal,29%{14}6.
Warfarin
Renal,upto92%{14}5.
Indialysis
Halflifeofwarfarinissignificantlydecreasedinhemodialysis{14}4.
PrecautionstoConsider
Carcinogenicity
Anisindione:Longtermstudieshavenotbeendone{14}3.
Warfarin:Studieshavenotbeendone{14}2{14}1.
Mutagenicity
Anisindione:Noinformationisavailable{14}0.
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Warfarin:Studieshavenotbeendone{14}9{14}8.
Pregnancy/Reproduction
Pregnancy
Coumarinandindanedionederivativeanticoagulantscrosstheplacenta{14}7{14}6.Concentrationsofwarfarinin
fetalplasmaarenearlyashighasmaternalconcentrations{14}5.
Congenitalmalformationshavebeenreportedininfantsofmotherswhotookwarfarinduringthefirsttrimester,
includingasyndromecharacterizedbyseverenasalhypoplasia{14}4{14}3{14}2{14}1{14}0andstippledepiphyseal
calcificationsthatresemblechondrodysplasiapunctata{33}9{33}8{33}7{33}6,aswellascentralnervoussystem
(CNS)abnormalities,includingdorsalmidlinedysplasia(characterizedbyagenesisofthecorpuscallosum,Dandy
Walkermalformation,andmidlinecerebellaratrophy),andventralmidlinedysplasia(characterizedbyopticatrophy)
{33}5.Mentalretardation,blindness,andotherCNSabnormalitieshavebeenreportedininfantsborntomothers
takingtheseagentsduringthesecondandthirdtrimesters{33}4{33}3{33}2.Otherrareteratogeniceffectsinclude
urinarytractanomalies,suchassinglekidney,asplenia,anencephaly,spinabifida,cranialnervepalsy,
hydrocephalus,cardiacdefectsandcongenitalheartdisease,polydactyly,deformitiesoftoes,diaphragmatichernia,
cornealleukoma,cleftpalate,cleftlip,schizencephaly,andmicrocephaly{33}1{33}0.
Spontaneousabortionandstillbirthhaveoccurred,aswellaslowbirthweightandgrowthretardation{01}9.In
addition,fetalorneonatalhemorrhage{01}8{01}7{01}6{01}5,fetaldeathfromhemorrhageinutero{01}4{01}3,and
increasedriskofmaternalhemorrhage{01}2duringthesecondandthirdtrimestershavebeenreported.Thereis
someevidencethatembryopathyoccursonlywithoralanticoagulantadministrationbetweenthe6thand12thweeks
ofgestation{01}1{01}0.
ThepolymorphisminthefactorVgene,knownasfactorVLeiden,thatcausesactivatedproteinCresistanceto
anticoagulanttherapyisassociatedwithanincreasedincidenceofvenousthrombosiscasesduringpregnancy{01}9
{01}8{01}7{01}6{01}5.Pregnancyisconsideredahighriskstate,andanticoagulanttreatmentshouldbeadjusted
accordingly,whenthesegeneticfactorsarepresent{01}4{01}3.
Ingeneral,cliniciansrecommendthatcoumarinorindanedionederivativeanticoagulantsnotbeusedatanytime
duringpregnancy{01}2{01}1{01}0{22}9.Womenofchildbearingpotentialshouldbeinformedoftherisksofbecoming
pregnantwhilereceivingacoumarinorindanedionederivative{22}8.Ifthepatientbecomespregnantduring
anticoagulanttherapy,thepossibilityofterminationofthepregnancymaybeconsidered{22}7.
Ifananticoagulantisrequiredduringpregnancy,heparinmaybepreferredbecauseitdoesnotcrosstheplacenta
{22}6.Forpatientsreceivingacoumarinorindanedionederivativewhowishtobecomepregnant,someclinicians
recommendconversiontoheparintherapypriortoconception,whileothersrecommendcarefulmonitoringofthe
patientandconversiontoheparinassoonaspregnancyisconfirmed{22}5.
Anisindione:FDAPregnancyCategoryX{22}4.
Warfarin:FDAPregnancyCategoryX{22}3{22}2.
Laboranddelivery
Ifacoumarinorindanedionederivativeisusedduringthethirdtrimester,itshouldbediscontinuedafterthe37th
weekofgestation{22}1,andheparinsubstitutedifmaternalanticoagulationisrequired{22}0,toreducetheriskof
fetalhemorrhageduringlaborandofneonatalhemorrhagefollowingdelivery.Anticoagulantsalsoincreasetherisk
{48}9
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ofmaternalhemorrhageduringorfollowingdelivery{48}9.Anticoagulanttherapymaybereinstated5to7days
postpartum{48}8.
Postpartum
Administrationofanticoagulantsintheimmediatepostpartumperiodmayincreasetheriskofmaternalhemorrhage
{48}7.
Breastfeeding
Acenocoumarolisdistributedintobreastmilk,butinquantitiesthataretoosmallfordetection{48}6.
Warfarinisdistributedintobreastmilkonlyinitsinactiveform{48}5{48}4studiesininfantswhowerebreastfed
whiletheirmothersweretakingwarfarindidnotfindanyeffectonprothrombintime(PT){48}3{48}2{48}1.
Pediatrics
Safetyandefficacyofwarfarininchildrenyoungerthan18yearsofagehavenotbeenestablishedinrandomized,
controlledclinicaltrials{48}0,althoughsuchtrialsarecurrentlybeingconducted{03}9.However,useofwarfarinin
childreniswelldocumentedforprophylaxisandtreatmentofthromboembolism{03}8{03}7{03}6{03}5.
Infants,especiallyneonates,maybemoresusceptibletotheeffectsofanticoagulantsbecauseofvitaminK
deficiency{03}4{03}3.LevelsofvitaminKdependentcoagulantfactorsandinhibitorsatbirthareapproximately50%
ofthoseinadults,similartothelevelinadultsreceivingoralanticoagulanttherapy{03}2{03}1.LevelsofvitaminK
dependentproteinsincreaserapidlyaftertheneonatalperiod,towithintheadultrangebytheageof6months,but
averagevaluesareapproximatley20%belowadultvaluesuntilthelateteenageyears{03}0{05}9.Asaresult,there
isapossibilitythattheoptimalgoaloftheinternationalnormalizedratio(INR)foranticoagulanttherapywillbelower
inchildrenthaninadults{05}8{05}7.
BreastfedinfantsareverysensitivetooralanticoagulantsbecauseofthelowconcentrationsofvitaminKinbreast
milk.Somechildrenareresistanttooralanticoagulanteffectsbecauseofimpairedabsorption,useoftotalparenteral
nutrition,oruseofnutrientformulassupplementedwithvitaminK{05}6{05}5.
BecausetherehavebeenreportsofdifficultyinachievingandmaintainingtherapeuticPT/INRrangesinpediatric
patients,morefrequentmonitoringisrecommended{05}4{05}3{05}2{05}1.
Studiesinanimalssuggestthatanticoagulantsgivenduringperiodsofrapidbonegrowth(i.e.,mainlyinchildren)
{05}0{01}9{01}8mightcauseboneabnormalitiessimilartothosethatoccurininfantswhosemothersreceived
anticoagulantsduringpregnancy(hypoplasiaofthenasalbridgeanddistalphalangesandexcessiveirregular
calcificationsinepiphysesandvertebrae){01}7{01}6.Studiesinhumanshavenotbeendone{01}5{01}4.
Geriatrics
Geriatricpatientsmaybemoresusceptibletotheeffectsofanticoagulants,increasingtheriskofhemorrhage{01}3
{01}2.Geriatricpatientsmayhaveadvancedvasculardiseasethataltershemostaticmechanisms,hepaticfunction
impairmentthatdecreasesprocoagulantfactorsynthesisoranticoagulantmetabolism{01}1,ortheymayhaverenal
functionimpairment{01}0.Lowermaintenancedosesthanthoseusuallyrecommendedforadultsmayberequired
forthesepatients{02}9.
WarfarinAlthoughtherearenoagerelateddifferencesinpharmacokineticsofracemicwarfarin,thereissome
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evidenceofaslightdecreaseinclearanceoftheRenantiomerinelderlypatients.Inaddition,elderlypatients(60
yearsofageandover)appeartobemoresensitivetothePT/INReffectsofwarfarin{02}8.
Pharmacogenetics
Certainhereditaryorfamilialconditionsthatpredisposeanindividualtothrombosismayaffectindicationsfor,aswell
asdoseanddurationof,anticoagulanttherapy{02}7{02}6.ThesemayincludefactorVLeiden(apolymorphisminthe
factorVgene)oraprothrombingenemutation{02}5,whichcausesactivatedproteinCresistance,deficiencyof
proteinCorS,deficiencyofantithrombinIII,hyperhomocysteinemia,anddysfibrinogenemia{02}4{02}3{02}2.Astudy
hasconfirmedastrongassociationbetweenmultiplegeneticdefectsandtheriskofvenousthrombosis{02}1{02}0.In
addition,patientswithhereditaryorfamilialproteinCdeficiencymaybeatincreasedriskofdevelopmentofskinor
tissuenecrosis{17}9{17}8{17}7{17}6.
HeterozygosityforthefactorVLeidenmutationisbetween1and8.5%inCausasians(includingEuropean){17}5
{17}4,Jewish,IsraeliArab,andIndianpopulations,butdoesnotappeartooccurinAfricanBlacks,Chinese,
Japanese,orNativeAmericanpopulations{17}3.Incidenceoftheprothrombingenemutations(GtoAtransversion
ofposition20210inthe3untranslatedregion)hasbeenreportedtobe2%intheNetherlands{17}2.
SomepatientsexhibitresistancetoanticoagulanttherapybecauseofgeneticvariationsinthevitaminKreceptorsite
{17}1{17}0.Dosesmuchhigherthanthoseusuallyrecommendedmayberequiredtoachievesuccessful
anticoagulationinthesepatients.
Dental
Bleedingfromgingivaltissuemayoccurinanticoagulatedpatients{17}9.
Anticoagulanttherapyincreasestheriskoflocalizedhemorrhageduringandfollowingoralsurgicalprocedures.
Consultationwiththeprescribingphysicianmaybeadvisablepriortooralsurgery,todeterminewhetheratemporary
dosagereductionorwithdrawalofanticoagulanttherapyisfeasible.Also,localmeasurestominimizebleeding
shouldbeusedatthetimeofsurgery.{17}8
Surgical
Carefulmonitoringanddosageadjustmentarerequiredbecauseinterruptionofanticoagulanttherapymay
precipitatethromboembolism{17}7,whilecontinuationoffulldosetherapyisassociatedwithariskofhemorrhage
{17}6.Itisrecommendedthattheoperativesitebesufficientlylimitedtopermiteffectiveuseoflocalproceduresfor
hemostasis(includingabsorbablehemostaticagents,sutures,andpressuredressings)ifnecessary{17}5.
Asevereelevation(morethan50seconds)inactivatedpartialthromboplastintime(aPTT),withPT/INRinthe
desiredrange,maybeanindicationofincreasedriskofpostoperativehemorrhage{17}4.
Druginteractionsand/orrelatedproblems
Theinteractionsbetweenanticoagulantsandotherspecificmedicationsarecomplexandsometimesmultipleor
conflicting,andmayvarydependingondose,duration,intermittentversuschronicuse,andotherfactors{17}3.The
useofmultiplemedicationswithadditiveorconflictingeffectsfurthercomplicatespredictionoftheeffect.Therefore,
theneteffectmaybeunpredictable{17}2{17}1{17}0.Decisionsregardingdosageadjustmentoftheanticoagulant
shouldbebasedonprothrombintime(PT)and/orinternationalnormalizedratio(INR)determinations{03}9{03}8
wheneverpossible.However,itisimportanttokeepinmindthatsomemedicationsmayincreasetheriskofbleeding
withoutaffectingthePT.
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Somemedicationeffectsthatmayincreasetheriskofbleedingduringanticoagulanttherapybutthatarenot
associatedwithanincreaseinPTincludeinhibitionofplateletaggregation,inhibitionofplateletformation,
hypoprothrombinemia,effectsonvascularintegrity,gastrointestinalulcerationorhemorrhage,thrombocytopenia,
anddirectanticoagulanteffects.{03}7
Clinicaleffectsfromaninteractionmaybeapparentimmediatelyormaytakeseveraldaysorweekstoappear{03}6.
Thestrengthoftheeffectofinteractingmedicationsmayberelatedtoanumberoffactors,includingdose,duration
oftherapy,andevenrelativeeffectontheSorRisomerofwarfarin{03}5{03}4.Thesignificanceanddurationof
effectalsodependonthetypeofinteractionforexample,displacementfromplasmaproteinbindingwillproducean
initialincreaseinanticoagulantconcentration,butanewequilibriumisestablishedwithinafewdays,sotheeffectis
oflimitedsignificance{03}3{03}2.
Onlybriefinformationaboutdocumentedinteractionsbetweenanticoagulantsandothermedicationshasbeen
providedinthismonograph.Inaddition,informationregardingthepotentialmechanismoftheinteractionsis
frequentlyconflictingandincomplete.Foradditionalinformationabouttheinteractionslistedbelow,pleasereferto
thecorrespondingUSPDImonographand/orthemedicalliterature.
Inadditiontothelistedinteractions,thereisapossibilitythattheriskofhemorrhagemaybeincreasedbyconcurrent
useofanymedicationthatmayinhibitplateletaggregationorcausehypoprothrombinemia,thrombocytopenia,or
gastrointestinalulceration.Conversely,thereisapossibilitythatmedicationsthatpromotebloodclottingmay
interferewiththeanticoagulanteffect.
Becauseofthepossibleseriousconsequencesofinterferencewithanticoagulanttherapy,increasedmonitoringof
thePT/INR{03}1isrecommendedonaddition,dosagechange,orwithdrawalofanymedicationfromtheregimenof
apatientstabilizedonacoumarinorindanedionederivative,orifthedosageofaconcurrentlyusedmedicationis
changed.Anticoagulantdosagemustbeadjustedasnecessarytopreventhemorrhageorlossofeffect.Also,
substantialalterationofinitialanticoagulantdosagemaybenecessarywhenanticoagulanttherapyisinitiatedina
patientreceivingamedicationknowntocausesignificantalterationofanticoagulanteffect.{03}0
Thefollowingdruginteractionsand/orrelatedproblemshavebeenselectedonthebasisoftheirpotentialclinical
significance(possiblemechanisminparentheseswhereappropriate)notnecessarilyinclusive(=majorclinical
significance).
Note:Combinationscontaininganyofthefollowingmedications,dependingontheamountpresent,mayalso
interactwiththismedication.
Acetaminophen,chronichighdoseusage(effectsofanticoagulantsmaybeincreased{09}9{09}8{09}7{09}6{09}5
{09}4thiseffectisunlikelytooccurwithoccasionaluseorchronicuseoflessthan2gramsofacetaminophenper
day{09}3)
Alcohol,acuteintoxication(effectsofanticoagulantsmaybeincreased{09}2{09}1{09}0{17}9{17}8becauseof
inhibitionofhepaticmetabolismotheracuteeffectsofalcoholonthelivermayalsobeinvolved)
Alcohol,chronicabuse(effectsofanticoagulantsmaybedecreased{17}7{17}6{17}5{17}4{17}3{17}2becauseof
acceleratedmetabolismofanticoagulantsecondarytostimulationofhepaticmicrosomalenzymeactivity{17}1{17}0
{03}9however,increasedactivityisalsopossibleinadvancehepaticcirrhosis{03}8{03}7{03}6)
{03}5 {03}4 {03}3 {03}2 {03}1 {03}0 {04}9
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Allopurinol(effectsofanticoagulantsmaybeincreased{03}5{03}4{03}3{03}2{03}1{03}0{04}9becauseofinhibition
ofhepaticmetabolism)
Amiodarone(effectsofanticoagulantsmaybeincreased{04}8{04}7{04}6{04}5{04}4{04}3{04}2{04}1,possibly
becauseofinhibitionofhepaticmetabolism{04}0{03}9potentiationisreportedtooccurwithin3to4weeksafter
initiationofamiodaronetherapyandpersistsupto4monthsfollowingwithdrawalofamiodarone{03}8)
Anabolicsteroids{03}7{03}6{03}5{03}4{03}3{03}2{03}1{03}0,especially17alphaalkylatedcompounds{04}9,or
Androgens{04}8{04}7or
Danazol{04}6{04}5{04}4(effectsofanticoagulantsareincreasedwithin2to3daysdosagereductionofthe
anticoagulantmaybenecessary{04}3)
Anesthetics,inhalation(effectsofanticoagulantsmaybeincreased{04}2{04}1{04}0)
Antibiotics(seealsoindividualantibioticentries)(theoretically,effectsofanticoagulantsmaybeincreased
becauseofdecreasedvitaminKsynthesissecondarytoalterationsinintestinalflora{23}9{23}8{23}7{23}6{23}5{23}4
{23}3{23}2{23}1however,significantpotentiationisveryrareifdietaryintakeofvitaminKisadequate{23}0{33}9)
Anticonvulsants,hydantoin(effectsofanticoagulantsmaybeincreasedbecauseofdisplacementofanticoagulant
fromproteinbindingsites{33}8{33}7{33}6{33}5{33}4{33}3{33}2{33}1)
(effectsofanticoagulantsmaybedecreasedwithcontinuedconcurrentusebecauseofacceleratedmetabolism
ofanticoagulantsecondarytostimulationofhepaticmicrosomalenzymeactivity{33}0{08}9{08}8{08}7{08}6{08}5)
(hepaticmetabolismofhydantoinanticonvulsants,especiallyphenytoin,maybedecreased,leadingtoincreased
anticonvulsantplasmaconcentrations,halflife,andriskoftoxicity{08}4{08}3{08}2{08}1)
Antidiabeticagents,sulfonylurea,includingglimepiride{08}0(effectsofanticoagulantsmaybeincreased{23}9
{23}8{23}7{23}6{23}5initiallybecauseofdisplacementofanticoagulantfromproteinbindingsites)
(hepaticmetabolismoftheantidiabeticagentmaybedecreased,especiallybydicumarol,leadingtoincreased
plasmaconcentrationandhalflife,hypoglycemiceffect,andriskoftoxicityoftheantidiabeticagent{23}4{23}3{23}2
{23}1)
Antifungals,azole(effectsofanticoagulantsmaybeincreased{23}0{33}9{33}8{33}7{33}6{33}5{33}4{33}3)
Antiinflammatorydrugs,nonsteroidal(NSAIDs)(effectsofanticoagulantsmaybeincreased{33}2{33}1{33}0
{36}9{36}8{36}7{36}6{36}5{36}4{36}3becauseofdisplacementofanticoagulantfromproteinbinding{36}2sitesby
fenoprofen,indomethacin,meclofenamate,mefenamicacid,phenylbutazone,orsulindac,andpossiblyother
NSAIDs{36}1inaddition,phenylbutazonemayinhibithepaticmetabolismoftheanticoagulant{36}0{41}9)
(inhibitionofplateletaggregationbyNSAIDs{41}8{41}7[exceptmeclofenamateandmefenamicacid]mayresultin
increasedriskofhemorrhageriskofgastrointestinalulcerationandhemorrhagecausedbyNSAIDsmaybe
{41}6 {41}5 {41}4
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increased{41}6{41}5{41}4theseeffectscannotbeshownbymeasurementofPT)
Antineoplastics{41}3or
Radiationtherapy,recent{41}2(theeffectofindividualagentsisdifficulttopredictbecauseofthecommonuseof
combinationtherapy{41}1mechanismsfortheobservedeffectsgenerallyhavenotbeendetermined)
(effectsofanticoagulantsmaybeincreasedordecreasedbycyclophosphamide{41}0{33}9ormercaptopurine
{33}8)
(effectsofanticoagulantsmaybeincreasedbybicalutamide{33}7,etoposide{33}6,flutamide{33}5{33}4{33}3,
fluorouracil{33}2{33}1{33}0,ifosfamide{11}9{11}8{11}7{11}6,methotrexate{11}5,nilutamide{11}4,tamoxifen{11}3{11}2
{11}1{11}0{47}9,andvindesine{47}8)
(effectsofanticoagulantsmaybedecreasedbyaminoglutethimide{47}7{47}6{47}5{47}4,whichmayinduce
hepaticenzymes{47}3{47}2{47}1)
(antineoplasticsthatcausethrombocytopeniamayalsoincreasetheriskofbleeding[seealso
Thrombocytopeniacausingmedications])
(imbalancesincoagulationfactorshavebeennotedwiththeuseofpegaspargase,predisposingthepatientto
bleedingand/orthrombosis{47}0cautionshouldbeusedwhenadministeringanyconcurrentanticoagulanttherapy
{90}9ithasalsobeensuggestedthatbloodcoagulationfactorXIIIparticipatesinthecrosslinkingbetweenfibrins
andbetweenfibrinandasparaginase)
Antithyroidagents(effectsofanticoagulantsmaybeincreasedparadoxically{90}8{90}7{90}6becauseof
decreasedhepaticsynthesisofprocoagulantfactorsthiseffectmaydependonantithyroiddosageandsubsequent
thyroidstatusofthepatient{90}5)
Cephalosporins,secondandthirdgeneration(effectsofanticoagulantsmaybeincreased{90}4{90}3{90}2
becauseofdecreasedvitaminKsynthesis{90}1{90}0)
(concurrentuseofanticoagulantswithcefamandole,cefmetazole,cefoperazone,orcefotetanmayincreasethe
riskofbleeding{03}9becausetheNmethylthiotetrazole[NMTT]sidechainonthesemedicationsmayinhibitthe
metabolismofanticoagulants{03}8however,criticalillness,poornutritionalstatus,andthepresenceofliverdisease
maybemoreimportantriskfactorsforhypoprothrombinemiaandbleeding{03}7)
Chloralhydrate(initially,effectsofanticoagulantsmaybeincreased{03}6{03}5{03}4becauseofdisplacementof
anticoagulantfromproteinbindingsites{03}3{03}2{03}1{03}0{04}9{04}8however,withcontinueduse,anticoagulant
activitymayreturntobaselinelevelorbedecreasedasanewequilibriumwarfarinconcentrationisestablished{04}7
{04}6{04}5{04}4{04}3)
Chloramphenicol(effectsofanticoagulantsmaybeincreased{04}2{04}1{04}0becauseofinhibitionofhepatic
metabolism)
Cholestyramine(effectsofanticoagulantsmaybedecreased{03}9{03}8{03}7{03}6{03}5{03}4{03}3{03}2{03}1
{03}0 {04}9
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becauseofdecreasedabsorptionfromthegastrointestinaltract{03}0{04}9andinterferencewithenterohepatic
circulation{04}8)
(effectsofanticoagulantsmaybeincreased{04}7{04}6{04}5{04}4{04}3becauseofdecreasedvitaminK
absorptionorsynthesis{04}2)
Cimetidine(effectsofanticoagulantsmaybeincreased{04}1{04}0{03}9{03}8{03}7{03}6{03}5{03}4{03}3because
ofinhibitionofhepaticmetabolism)
Cinchophen(effectsofanticoagulantsmaybeincreased{03}2{03}1{03}0{06}9)
Cisapride(effectsofacenocoumarolmaybeincreasedbecauseofincreasedabsorptionfromthegastrointestinal
tract{06}8)
Clofibrate(effectsofanticoagulantsmaybeincreased{06}7{06}6{06}5{06}4{06}3{06}2{06}1{06}0{03}9{03}8,
possiblybecauseofalterationofprocoagulantfactorsynthesisorcatabolism{03}7ordisplacementofanticoagulant
fromproteinbindingsites{03}6)
Corticosteroids,glucocorticoid,or
Corticotropin(effectsofanticoagulantsmaybeincreased{03}5{03}4{03}3ordecreased{03}2{03}1{03}0{06}9{06}8
{06}7byanunknownmechanism)
Dextrothyroxine(effectsofanticoagulantsmaybeincreased{06}6{06}5{06}4{06}3{06}2becauseofalterationof
procoagulantfactorsynthesisorcatabolismandincreasedreceptoraffinityfortheanticoagulantthiseffectmay
dependonthethyroidstatusofthepatient)
Diflunisal(effectsofanticoagulantsmaybeincreased{06}1{06}0{03}9,possiblyinpartbecauseofdisplacement
ofanticoagulantfromproteinbindingsites{03}8)
Disopyramide(effectsofanticoagulantsmaybeincreased{03}7{03}6{03}5{03}4ordecreased{03}3{03}2byan
unknownmechanism)
Disulfiram(effectsofanticoagulantsmaybeincreased{03}1{03}0{06}9{06}8{06}7{06}6{06}5{06}4{06}3
disulfirammayactinthelivertodirectlyincreasethehypoprothrombinemiainducingactivityofcoumarinderivatives
{06}2)
Diuretics(effectsofanticoagulantsmaybedecreased{06}1{06}0{03}9{03}8{03}7{03}6becauseofreductionof
plasmavolumeleadingtoconcentrationofprocoagulantfactorsintheblood{03}5)
(effectsofanticoagulantsmaybeincreasedbyethacrynicacid{03}4{03}3{03}2{03}1{03}0{06}9,possiblyinpart
becauseofdisplacementofanticoagulantfromproteinbindingsitesclinicalsignificancehasnotbeendetermined)
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Erythromycins(effectsofanticoagulantsmaybeincreased{06}8{06}7{06}6becauseofinhibitionofenzymatic
metabolism)
Estrogens(effectsofanticoagulantsmaybedecreasedbecauseofincreasedhepaticsynthesisofprocoagulant
factors{06}5)
(useofestrogensinpatientswiththrombophilicdisorderstendstoincreasetheriskofthrombosis,especiallyin
patientswithactivatedproteinCresistanceduetofactorVLeidenmutation{06}4{06}3)
Estrogensandprogestins(oralcontraceptives)(effectsofanticoagulantsmaybedecreased{06}2{06}1{06}0{03}9
becauseofincreasedhepaticsynthesisofprocoagulantfactorsbyestrogenshowever,increasedeffectshavealso
beenreported{03}8)
(useofestrogencontainingoralcontraceptivesinpatientswiththrombophilicdisorderstendstoincreasetherisk
ofthrombosis,especiallyinpatientswithactivatedproteinCresistanceduetofactorVLeidenmutation{03}7{03}6)
Ethchlorvynol(effectsofanticoagulantsmaybedecreased{03}5{03}4{03}3{03}2{03}1{03}0{06}9becauseof
acceleratedmetabolismofanticoagulantsecondarytostimulationofhepaticmicrosomalenzymeactivity)
Fluoroquinolones(effectsofanticoagulantsmaybeincreased{06}8{06}7{06}6)
Fluoxetine(effectsofanticoagulantsmaybeincreased{06}5{06}4,possiblyinpartbecauseofdisplacementof
anticoagulantfromproteinbindingsites)
Fluvoxamine{06}3{06}2{06}1(concurrentusewithwarfarinfor2weeksresultedinwarfarinplasmaconcentration
increasesofupto98%andprolongedprothrombintime)
Gemfibrozil(effectsofanticoagulantsmaybeincreased{06}0becauseofinhibitionofhepaticmetabolism)
Glucagon(effectsofanticoagulantsmaybeincreased{03}9{03}8{03}7{03}6{03}5{03}4however,dosagereduction
ofwarfarinisrecommendedonlywithglucagondosesabove25mgperdayfor2ormoredays{03}3,whichare
rarely,ifever,used)
Glutethimide(effectsofanticoagulantsmaybedecreased{03}2{03}1{03}0{08}9{08}8{08}7becauseof
acceleratedmetabolismofanticoagulantsecondarytostimulationofhepaticmicrosomalenzymeactivity{08}6{08}5)
Griseofulvin(effectsofanticoagulantsmaybedecreased{08}4{08}3{08}2{08}1{08}0{08}9{08}8becauseof
acceleratedmetabolismofanticoagulantsecondarytostimulationofhepaticmicrosomalenzymeactivity{08}7)
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Heparin{08}6{08}5or
Heparin,lowdensity,including:
Ardeparin{08}4
Dalteparin{08}3
Danaparoid{08}2
Enoxaparin{08}1(theanticoagulantactivityofheparinorlowdensityheparinsmayresultinanincreasedriskof
hemorrhagelowdensityheparinsandlowdosesofheparindonotprolongPT{08}0{58}{59})
(heparinmayprolongPTwhenitisgivenasanintravenousbolusoriffulltherapeuticdosesaregiven
subcutaneouslytominimizeproblems,itisrecommendedthatbloodforthePTtestbedrawnjustpriorto,or5
hoursafter,theintravenousbolusdoseor24hoursofsubcutaneousinjectionofafulltherapeuticdoseofheparin
{01}{02}{03}{05})
Hepaticenzymeinducers(seeAppendixII)(effectsofanticoagulantsmaybedecreased{01}{02}{03}{05}{08}
{09}{10}{33}{82}becauseofinductionofhepaticmicrosomalenzymestheeffectofprimidonemaybecausedbya
barbituratemetabolite)
Hepatotoxicmedications(effectsofanticoagulantsmaybeincreased{01}{02}{03}becauseofslowmetabolism
andimpairedsynthesisofclottingfactors)
HMGCoAreductaseinhibitors(concurrentusehasbeenreportedtoincreasebleedingand/orPT{03}{09}{10}
{17}{60}{61}{62}{63})
Influenzavirusvaccine(effectsofanticoagulantshavebeenreportedtobeincreased{01}{02}{03}{09}{10}{17}
{33}however,recentstudieshavefailedtoshowasignificantimpactofinfluenzavirusvaccineonthelaboratoryor
clinicaleffectofwarfarin{09},andpatientstakingthesemedicationscanbevaccinatedsafelywithoutspecial
precautionsormonitoring{84})
Intrauterinedevices(IUDs),copper{64}orprogesterone(administrationofanticoagulantsduringIUDusemay
increasetheriskofabnormaluterinebleedingandanemiasecondarytomenorrhagiaand/orhypermenorrhea{64}
theriskofabnormaluterinebleedingincreasesaroundthetimeofIUDinsertionandlessenswithcontinueduse,
althoughspottingmaypersist)
Isoniazid(effectsofanticoagulantsmaybeincreased{10}{17}{33}{86}becauseofinhibitionofhepatic
metabolism)
Lepirudin(effectsofanticoagulantsmaybeincreasedgradualreductionindoseand/orinfusionrateoflepirudin
isrecommendedpriortoswitchingtoanoralanticoagulant{80})
Metronidazole(effectsofanticoagulantsmaybeincreased{01}{02}{03}{05}{08}{09}{10}{17}{33}{86}becauseof
inhibitionofhepaticmetabolism{10}{33})
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Nalidixicacid(effectsofanticoagulantsmaybeincreased{01}{02}{03}{05}{09}{10}{33},possiblyinpartbecause
ofdisplacementofanticoagulantfromproteinbindingsites)
Olsalazine(mayincreasethePT{03})
Omeprazole(inhibitionofthecytochromeP450enzymesystembyomeprazole,especiallyinhighdoses,may
causeadecreaseinhepaticmetabolismofanticoagulants,whichmayresultindelayedeliminationandincreased
bloodconcentrations{03}{17}{66}{86})
Opioid(narcotic)analgesics(effectsofanticoagulantsmaybeincreasedwithprolongeduse{01}{02}{03}{10}{17}
{33})
Paroxetine(apharmacodynamicinteractionmayoccurthatcausesanincreasedbleedingdiathesisdespite
unalteredPT{03}{67}sincethereislittleclinicalexperience,cautionisadvisedwhentheseagentsareused
concomitantly)
Penicillins(inhibitionofplateletaggregationbyhighdoseparenteralpenicillinsmayresultinincreasedriskof
hemorrhage{03}{10}thiseffectcannotbeshownbymeasurementofPT)
(dicloxacillinandnafcillinmaydecrease{03}{08}{10}{17}{33}theeffectsofanticoagulantsbyinducinghepatic
enzymes{10}{33})
Pentosan(becausepentosanhasweakanticoagulantactivity,theriskofhemorrhagemaybeincreased{77})
Pentoxifylline(pentoxifyllineinhibitsplateletaggregationandhasalsocausedprolongationofPTandbleeding{69}
concurrentusewithanyofthesemedicationsmayincrease{01}{02}{03}{69}theriskofbleedingbecauseofadditive
interferencewithbloodclotting)
Plateletaggregationinhibitors(effectsofanticoagulantsmaybeincreased{01}{02}{03}{05}{08}{10}theeffect
willnotbereflectedinPT)
Plicamycin{89}(effectsofanticoagulantsmaybeincreasedbecauseofplicamycin'shypoprothrombinemic
effect)
(interferencewithplateletformationbyplicamycinmayresultinincreasedriskofhemorrhagethiseffectcannot
beshownbymeasurementofPT)
Propafenone(concurrentuseresultsinasignificantincrease[approximately39%]inmeansteadystatewarfarin
plasmaconcentrations,withacorrespondingincreaseinPTofapproximately25%{03}{10}{17}{70}{86})
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Propranolol(effectsofanticoagulantsmaybeincreased{09}{17}{33}{86})
Quinidine(effectsofanticoagulantsmaybeincreased{01}{02}{03}{05}{09}{10}{17}{33}becauseofalterationof
procoagulantfactorsynthesis{10}however,decreasedanticoagulanteffecthasalsobeenreported{09}{10})
Quinine(effectsofanticoagulantsmaybeincreased{01}{02}{03}{05}{09}{10}becauseofdecreasedhepatic
synthesisofprocoagulantfactors)
Repaglinide(effectsofanticoagulantsmaybeincreasedbecauseofdisplacementfromplasmaproteinbinding
sites{81})
Rifabutin(rifampinisstructurallyrelatedtorifabutinrifampinisknowtodecreasetheactivityofmanydrugsdueto
itshepaticenzymeinducingpropertiesrifabutinappearstobealesspotentenzymeinducerofthehepatic
cytochromeP450systemthanrifampindruginteractionsdataareunavailableforrifabutinitselftherefore,itis
recommendedthatpatientstakingrifabutinconcurrentlywithanticoagulantsbemonitoredsincethesignificanceof
possibledruginteractionsisnotknown{71})
Salicylates,includingbismuthsubsalicylate{55}(effectsofanticoagulantsmaybeincreased{01}{02}{03}{09}{10}
{33}{55}becauseofthehypoprothrombinemiceffect[withlargedoses]{01}{10})
(inhibitionofplateletaggregationbyaspirin{10}mayresultinincreasedriskofhemorrhageriskofgastrointestinal
ulcerationorhemorrhagecausedbysalicylatesmaybeincreased{10}{33}theseeffectscannotbeshownby
measurementofPT)
Sertraline(cautioninconcurrentusewithanticoagulantsisrecommendedbecauseofpossibledisplacementof
eithermedicationfromproteinbindingsites,leadingtoincreasedplasmaconcentrationsofthefree[unbound]
medicationsandincreased{03}{72}riskofadverseeffects)
Smoking,tobacco(effectsofanticoagulantsmaybedecreased{09}{33}becauseofacceleratedmetabolismofthe
anticoagulantsecondarytostimulationofhepaticmicrosomalenzymeactivity{33})
Sucralfate(effectsofanticoagulantsmaybedecreased{03}{09}{10}{17}{33}{86})
Sulfapyridine{87}or
Sulfasalazine{88}(anticoagulantsmaybedisplacedfromproteinbindingsitesand/ormetabolismmaybe
inhibitedbysulfonamides,resultinginincreasedorprolongedeffectsand/ortoxicitydosageadjustmentsmaybe
necessaryduringandaftersulfonamidetherapy)
Sulfinpyrazone(effectsofanticoagulantsmaybeincreased{01}{02}{05}{08}{09}{10}{17}{33}{86}becauseof
inhibitionofhepaticmetabolism{09}{10}{33}anddisplacementoftheanticoagulantfromproteinbindingsites{08}
{10}
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{10}abiphasicresponse,withdecreasedanticoagulationoccurringfollowinginitialpotentiation,hasbeenreported
{10}{33}{86}thereasonfortheeffectisunclearsinceotherreportsindicateonlypotentiationoftheanticoagulant
effect{10})
(inhibitionofplateletaggregationbysulfinpyrazonemayresultinincreasedriskofhemorrhage{09}riskof
gastrointestinalulcerationorhemorrhagecausedbysulfinpyrazonemaybeincreasedtheseeffectscannotbe
shownbymeasurementofPT)
Sulfonamides,longacting,includingcotrimoxazole{17}{86}(effectsofanticoagulantsmaybeincreased{01}{02}
{03}{05}{09}{10}{17}{33},possiblyinpartbecauseofdisplacementofanticoagulantfromproteinbindingsites)
Tamsulosin(cautionisrecommendedwhenusedwithwarfarinbecauseofinconclusiveresultsfrominvitroandin
vivostudies{78})
Thrombocytopeniacausingmedications(effectsofanticoagulantsmaybeincreased{01}{02})
Thrombolyticagents(thrombolyticeffectmayleadtohemorrhage{01}{03}concurrentuseisnotrecommended
{14},althoughsequentialusemaybeindicated{08})
(anticoagulantsarerecommendedtopreventadditionalthrombusformationfollowingthrombolytictherapyfor
mostindications{08}however,followingintravenousthrombolytictherapyforacutecoronaryarterialocclusion,the
needforanticoagulantadministrationshouldbedeterminedonanindividualbasisifananticoagulantis
administeredunderthesecircumstances,carefulmonitoringofthepatientisrecommendedbecauseoftheriskof
hemorrhage)
Thyroidhormones(effectsofanticoagulantsmaybeincreased{01}{02}{03}{05}{09}{33}becauseofalterationof
procoagulantfactorsynthesisorcatabolism{09}{33}andincreasedreceptoraffinityforanticoagulantthiseffectmay
dependupondosageandsubsequentthyroidstatusofthepatient)
Ticlopidine(thepossibilityofadditiveeffectsonbloodclottingmechanismleadingtoanincreasedriskof
bleedingcannotbediscounted{03}particularlycarefulclinicalmonitoringofthepatientisrecommendedif
concurrentuseisnecessary)
(inonestudy,concurrentadministrationofwarfarinandticlopidinewasassociatedwithanincreasedriskof
medicationinducedcholestatichepatitis{03}{10})
Valproicacidor
Divalproex(effectsofanticoagulantsmaybeincreasedbyvalproicacid{03}becauseofdecreasedhepatic
synthesisofprocoagulantfactors)
(inhibitionofplateletaggregationbydivalproexorvalproicacidmayresultinincreasedriskofhemorrhagethis
effectcannotbeshownbymeasurementofPT)
{03} {09} {10} {16}
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VitaminE(effectsofanticoagulantsmaybeincreased{03}{09}{10}{16}withconcurrentuseofhighdosesof
vitaminE{10})
VitaminK(effectsofanticoagulantsmaybedecreased{03}{08}{09}{10}{17}becauseofincreasedhepatic
synthesisofprocoagulantfactorsincreasedvitaminKintakecanoccurduringweightreductiondietshighingreen
vegetables,certainvegetableoils,orvitaminKcontainingsupplements{16}{17}{33}{86})
Zafirlukast(theconcurrentuseofasingle25mgwarfarindosewithmultipledosesofzafirlukastresultedinan
increaseofapproximately35%inthemeanPT,duetoaninhibitionofthecytochromeP4502C9isoenzyme{03}
{73})
Zileuton(concurrentadministrationofzileutonandwarfarinresultsinaclinicallysignificantincreaseinthePT
{03}{79})
Laboratoryvaluealterations
Thefollowinghavebeenselectedonthebasisoftheirpotentialclinicalsignificance(possibleeffectinparentheses
whereappropriate)notnecessarilyinclusive(=majorclinicalsignificance):
Withdiagnostictestresults
Urinalysis,spectrophotometric{01}(testsbasedoncolorchangesmaybeinterferedwithbecausealkalineurine
mayturnredorangefollowingadministrationofanisindione{01}acidificationoftheurinetopH4eliminatesthis
color{01})
Activatedpartialthromboplastintime(aPTT)(maybeincreasedbywarfarin,evenintheabsenceofheparin,but
interferencewithheparinanticoagulationduringinitialcombinedtherapyisofminimalclinicalsignificance{03})
Hepaticenzymevalues(mayrarelybeincreased{03})
Medicalconsiderations/Contraindications
Themedicalconsiderations/contraindicationsincludedhavebeenselectedonthebasisoftheirpotentialclinical
significance(reasonsgiveninparentheseswhereappropriate)notnecessarilyinclusive(=majorclinical
significance).
Note:Manyoftheconditionslistedbelowarecommonriskfactorsthatunderlietheconditionforwhichthe
anticoagulanttherapyisindicated.Therelativeeffectonthedecisiontoprescribeanticoagulantsdependsonthe
specificconditionforwhichanticoagulanttherapyisbeingcontemplated.Decisionsaboutwhethertouse
anticoagulantsshouldbalancetheriskofhemorrhageassociatedwiththeconditionagainstthepotentialclinical
benefitofanticoagulanttherapy.{02}
ForconditionsthatalterthePT,carefulmonitoringofPTand/orinternationalnormalizedratio(INR)andappropriate
adjustmentofanticoagulantdosearerecommended.Forconditionsinwhichtheeffectonbleedingmaynotbe
reflectedinthePT/INR,carefulmonitoringofthepatientforindicationsofbleedingisrecommended.
Thepresenceofmultlipleunderlyingconditionswithadditiveorconflictingeffectsmaycomplicatepredictionofthe
effectonresponsetotheanticoagulant.Theneteffectmaybeunpredictable{03}.Decisionsregardingdosage
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adjustmentoftheanticoagulantshouldbebasedonPT/INRdeterminationsandobservationforpossiblebleeding
{03}.
Astrongassociationhasbeenfoundbetweensingleormultiplegeneticdefects(e.g.,factorVLeiden,prothrombin
mutation,antithrombinIIIdeficiency)andriskofthrombosis{13}{15},whichindicatesthatoneormoreofthese
defectsmaybepresentinindividualswiththrombophilicconditions.However,theseeffectsmayalsobesubclinical
andpatientsmaybeasymptomaticuntiltheirfirstthromboticevent{14}{15}.
Inadditiontothespecificconditionslistedbelow,cautionisrecommendedwithuseofanticoagulantsinany
conditionassociatedwithariskofhemorrhage,necrosis,and/organgrene{02}{03}.
Exceptunderspecialcircumstances,thesemedicationsshouldnotbeusedwhenthefollowingmedical
problemsexist:
Abortion,threatenedorincomplete{01}{03}(increasedriskofuncontrollablehemorrhage)
Aneurysm,cerebralordissectingaorta{01}{02}{03}(increasedriskofuncontrollablehemorrhage)
Bleeding,active{01}(increasedriskofuncontrollablehemorrhage)
Blooddyscrasias,hemorrhagic,suchas:
Thrombocytopenia{01}{02}{03}{15}or
Hemophilia{01}or
Hemorrhagictendency,other{01}{02}{03},including:
Leukemia{01}
Polycythemiavera{01}{02}{03}
Purpura{01}(increasedriskofhemorrhage)
(inpatientswithheparininducedthrombocytopenia,casesofvenouslimbischemia,necrosis,andgangrenehave
occurredwhenheparintherapywasdiscontinuedandwarfarintherapyinitiated{03}sequelaehaveincluded
amputationoftheinvolvedareaand/ordeath{03})
Cerebrovascularhemorrhage,confirmedorsuspected{01}{02}{03}(increasedriskofuncontrollable
hemorrhage)
Eclampsiaorpreeclampsia{01}{02}{03}(increasedriskofhemorrhage)
Hypertension,severeuncontrolledand/ormalignant{01}{02}{03}(increasedriskofcerebralhemorrhage)
Neurosurgery,recentorcontemplated{01}{02}{03}or
Ophthalmicsurgery,recentorcontemplated{01}{02}{03}or
Surgery,major,other,especiallyifresultinginlargeopensurfaces{02}{03}(increasedriskofuncontrollable
hemorrhage)
(althoughanticoagulantsaregenerallycontraindicatedfollowingmajorsurgery,theymayberequiredfollowing
orthopedic(hip)surgerytoreducetheriskofthromboembolism{08})
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Pericardialeffusion{01}{02}{03}or
Pericarditis{01}{02}{03}(increasedriskofseverehemorrhagicpericardialeffusionsandpericardialtamponade)
Riskbenefitshouldbeconsideredwhenthefollowingmedicalproblemsexist
Allergicoranaphylacticdisorders,severe{02}
Antiphospholipidsyndrome{03}{13}{15}or
AntithrombinIIIdeficiency{13}{14}{15}(mayreducetheeffectivenessoftheanticoagulant)
Biliaryfistula{01}(mayincreasethepatient"sresponsetotheanticoagulant,leadingtoanincreasedriskof
bleeding)
Cancer,especiallygastrointestinal{02}{03}{13}{15}{33}(venousthrombosisassociatedwithcancermaybe
resistanttoanticoagulanttherapy{13})
Carcinoma,visceral{01}{02}(mayincreasethepatient"sresponsetotheanticoagulant,leadingtoanincreased
riskofbleeding)
Childbirth,recent{02}(increasedriskofhemorrhage)
Collagenvasculardisease{02}{03}(mayincreasethepatient"sresponsetotheanticoagulant,leadingtoan
increasedriskofbleeding)
Conditionsthatmayresultinlesscompliancebyunsupervisedoutpatients{01},suchas:
Alcoholism,active{02}{03}
Emotionalinstability
Psychosis,unsupervised{02}{03}
Senility,unsupervised{02}{03}
Uncooperativepatient{02}{03}
Congestiveheartfailure{01}{02}{03}{08}{15}(mayincreasethepatient"sresponsetotheanticoagulant,leadingto
anincreasedriskofbleeding)
Coumarinresistance,hereditary{03}(responsetocoumarinanticoagulantsmaybedecreased)
Diabetesmellitus,severe{02}{03}(increasedriskofhemorrhage)
Diarrhea,prolonged{02}{03}(mayincreasethepatient"sresponsetotheanticoagulant,leadingtoanincreased
riskofbleeding)
{01} {02} {03}
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Dietaryinsufficiency,prolonged{01}{02}{03},especially:
Steatorrhea{02}{03}{16}{33}orlowfatdiet{33}
VitaminKdeficiencyormalabsorption{01}{02}{03}{16}{33}(mayincreasethepatient"sresponsetothe
anticoagulant,leadingtoanincreasedriskofbleeding)
Dietshighinphylloquinone(e.g.,greenleafyvegetables,certainvegetableoils,supplements)(maydecreasethe
anticoagulanteffect{16})
Diverticulitis{01}
Edema{02}{03}(mayreducetheeffectivenessoftheanticoagulant)
Endocarditis,subacutebacterial{01}{02}{03}(increasedriskofhemorrhageintoinfarctedarea)
Fever{01}{02}{03}{33}(mayincreasethepatient"sresponsetotheanticoagulant,leadingtoanincreasedriskof
bleeding)
Hepaticfunctionimpairment{01}{02}{03}(mayincreasethepatient"sresponsetotheanticoagulant,boththrough
impairedsynthesisofclottingfactors{08}{33}anddecreasedmetabolism{03},leadingtoanincreasedriskof
bleeding)
Hepatitis,infectious{01}{02}{03}(mayincreasethepatient"sresponsetotheanticoagulant,leadingtoanincreased
riskofbleeding)
Hyperhomocystinemia{13}{14}{15}(mayreducetheeffectivenessoftheanticoagulant)
Hyperlipidemia,includinghypercholesterolemia{01}{02}{03}(mayreducetheeffectivenessoftheanticoagulant)
Hypertension,moderate{01}{02}{03}
Hyperthyroidism{01}{02}{03}{08}{33}(mayincreasethepatient'sresponsetotheanticoagulant,leadingtoan
increasedriskofbleeding)
Hypoprothrombinemia{01}(mayincreasethepatient"sresponsetotheanticoagulant)
Hypothyroidism{01}{02}{03}(mayreducetheeffectivenessoftheanticoagulant)
Infection{01}{02}{03}or
Disturbancesofintestinalflora,suchassprue{01}{02}{03}(mayincreasethepatient"sresponsetothe
anticoagulant)
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Procedures(medicalordental)inwhichtheriskofbleedingorhemorrhageispresent{02}{03},suchas:
Anesthetics,regionalorlumbarblock{01}{02}{03}
Catheters,indwelling{02}{03}{15}
Drainagetubesinanyorificeorwound{01}{02}
Spinalpuncture{02}{03}(increasedriskofuncontrollablehemorrhage)
ProteinCdeficiency,hereditary,familial,orclinical,knownorsuspected{02}{03}{08}{14}{15}or
ProteinSdeficiency,hereditaryoracquired{03}or
Otherconditionspredisposingtotissuenecrosis{02}(increasedriskofanticoagulantinducedtissuenecrosis{01}
{02}{03}{08}{14}{37},althoughpatientswithproteinCdeficiencymayrequirelongtermanticoagulanttherapyto
preventrecurrentthrombusformation{14}administrationofheparin,proteinCconcentrate,orfreshfrozenplasma
duringthefirstfewdaysoforalanticoagulanttherapymayreducetheriskoftissuenecrosiscausedbyproteinC
deficiency{02}{03}{14})
(proteinCdeficiencyshouldbesuspectedifthereisahistoryofrecurrentepisodesofthromboembolicdisorders
inthepatientorthefamily{02})
Renalfunctionimpairment(possibleincreasedriskofhemorrhage{01}{02}{03}however,dosageadjustmentis
usuallynotrequired{03}{05}{17})
(innephroticsyndrome,decreasedhalflifeanddecreasedeffectmayoccurasaresultofhypoproteinemia{03}
{08}{15}{17})
Sensitivitytotheanticoagulantprescribed{03}
Trauma{02}{03}{15},especiallytothecentralnervoussystem(CNS)(increasedriskofinternalhemorrhage)
Tuberculosis,active{02}(increasedriskofhemorrhage)
Ulcerationorotherlesions,active,of:
Gastrointestinaltract{01}{02}{03},includingulcerativecolitis{01}
Respiratorytract{02}{03}
Urinarytract{02}{03}(increasedriskofhemorrhage)
Ulcerationorotherlesionsofgastrointestinaltract,historyof{02}(increasedriskofhemorrhage)
Vasculitis{02}{03}(increasedriskofhemorrhage)
Wounds,openulcerative,traumatic,orsurgical{01}{02}(increasedriskofhemorrhage)
Cautionisalsorecommendedinseverelydebilitatedpatients,whomaybemoresensitivetotheeffectsof
anticoagulants{03}.
{01}
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Cautionisalsorecommendedduringprolongedhotweather,duringwhichtheriskofbleedingmaybeincreased{01}
{02}{03}.
Patientmonitoring
Thefollowingmaybeespeciallyimportantinpatientmonitoring(othertestsmaybewarrantedinsomepatients,
dependingoncondition=majorclinicalsignificance):
Forallanticoagulants
Bloodinurine
Occultbloodinstool(determinationsrecommendedatperiodicintervalsduringtherapy)
Prothrombintime(PT)and/or
Internationalnormalizedratio(INR)(determinationofPT/INRistheprimarymeansofestablishingcorrectdose
determinationsarerecommendedpriortoinitiationoftherapy,at24hourintervalswhilemaintenancedosageis
beingestablished{08}{90},thengraduallylessfrequentlyforthedurationoftherapy{08}{90}additionalPT/INR
determinationsarerecommendedwhenpatientsareswitchedtodifferentbrandsorformulations,andwhenever
othermedicationsareinitiated,changed,takenirregularly,ordiscontinued{03}{90})
(PT/INRmonitoringgenerallyisnotdoneduringfixedlowdosewarfarintherapy)
(theavailabilityofportablePTmonitorshasmadepointofcareselfmonitoringbythepatientfeasibleinselected
circumstances,followinginitialdosagestabilization,asanadjuncttoregularmonitoringbymedicalprofessionals{33}
{90})
(PTreflectsdepressionofvitaminKdependentfactorsII,VII,andXPTisoftenreportedbylistingthevaluein
secondsalongwiththecontrolvalueinsecondsalternately,PTmaybereportedastheratiooftheprolonged
[therapeutic]valuetothecontrolvalue)
(theonestagePTtestistheusualtestusedthereisinterlaboratoryvariabilityintypes[sensitivity]ofrabbitbrain
thromboplastins,aswellasonestagemethods,usedtodeterminePT{03}{08}theappropriatetherapeuticPT
rangeusedtodetermineandadjustanticoagulantdosageshouldbebasedontheexperienceofthespecific
laboratory{03}aclearunderstandingoftheparticularmethod[e.g.,QuickonestagePT]{02}isimportantinorderto
facilitateappropriateanticoagulantdosageadjustment{03})
(theINRprovidesacommonbasisforcommunicationofPTresultsandinterpretationoftherapeuticrangesthe
INRsystemisbasedonalogarithmicrelationshipbetweenthePTratiosofthetestandreferencepreparationthe
InternationalReferencePreparation[IRP]isasensitivethromboplastinreagentpreparedfromhumanbraintissue
theINRisthePTratiothatwouldbeobtainediftheIRP,whichhasanInternationalSensitivityIndex[ISI]of1.0,
wereusedtoperformthetesttheINRiscalculatedas:INR=(observedPTratio)ISI,wheretheISIisthecorrection
factorintheequationthatrelatesthePTratioofthelocalreagenttothereferencepreparationandisameasureof
thesensitivityofagiventhromboplastintoreductionofvitaminKdependentcoagulationfactorsthelowertheISI,
themoresensitivethereagentandthecloserthederivedINRwillbetotheobservedPTratio{03}{08})
(withtherabbitbrainthromboplastinscurrentlycommerciallyavailableinNorthAmerica,PTvaluesof1.2to1.5
timesthecontrolvalueareequivalenttoINRvaluesof2to3timesthecontrolvalue{08},andPTvaluesof1.5to2
timesthecontrolvalueareequivalenttoINRvaluesof3to4.5timesthecontrolvaluethromboplastinswith
recombinanttissuefactor,whichhaveanISofapproximately1[andthusaPTratioessentiallyequivalenttothe
ISR]haverecentlybeenintroduced{33}forotherthromboplastins,theINRcanbecalculatedusingtheISI[available
fromthemanufacturer]asacalibrationfactor{03}{33})
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Foranisindione(inadditiontotheabove)
Hematopoieticfunction{01}and
Hepaticfunction{01}and
Protein,urinary{01}and
Renalfunction{01}(determinationsmaybeadvisableatperiodicintervalsduringanisindionetherapybecauseof
theriskofblooddyscrasias,hepatotoxicity,andnephrotoxicityassociatedwithphenindione[ananticoagulant
chemicallyrelatedtoanisindionethatisnolongeravailable]{01})
Side/AdverseEffects
Note:Differencesinfrequencyofside/adverseeffectsbetweenanticoagulantsmayreflecteitherlackofclinicaluse
dataoractualpharmacologicdistinctionsamongagents{01}.
Studiesinanimalssuggestthatanticoagulantsgivenduringperiodsofrapidbonegrowth(i.e.,mainlyinchildren)
mightcauseboneabnormalitiessimilartothosethatoccurininfantswhosemothersreceivedanticoagulantsduring
pregnancy(hypoplasiaofthenasalbridgeanddistalphalangesandexcessiveirregularcalcificationsinepiphyses
andvertebrae){19}{50}.Studiesinhumanshavenotbeendone{19}{50}.
Althoughnotalloftheside/adverseeffectslistedbelowhavebeendocumentedwithanisindione,theyhavebeen
reportedwithphenindione,anindanedionederivativethatisnolongercommerciallyavailable.Otheradverseeffects
orabnormalitiesreportedwithphenindioneincludeaccommodationparalysis(blurredvisionorotherproblems),
aplasticanemia,eosinophilia,leukocytosis,thrombocytopenia,atypicalmononuclearcells,redcellaplasia,presence
ofleukocyteagglutinins,andexfoliativedermatitis.Becauseanisindioneischemicallyrelatedtophenindione,these
side/adverseeffectsshouldbeconsideredpotentialside/adverseeffectsofanisindionealso.{01}
Thefollowingside/adverseeffectshavebeenselectedonthebasisoftheirpotentialclinicalsignificance(possible
signsandsymptomsinparentheseswhereappropriate)notnecessarilyinclusive:
Thoseindicatingneedformedicalattention
Incidencedoserelated
Symptomsofminorbleeding
Bloodinurine{01}{02}{05}{26}{48}
epistaxis{01}{03}(nosebleeds)
gingivalbleeding{03}(bleedingfromgumswhenbrushingteeth)
petechiae{01}(pinpointredspotsonskin)
unusualbleedingorbruising{01}
unusuallyheavybleedingoroozingfromcutsorwounds{03}{26}
uterinebleeding,excessive{01}{02}{05}(unusuallyheavyorunexpectedmenstrualbleeding)
Symptomsofmajororinternalbleedingorhemorrhage
{01} {02}
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Adrenalhemorrhage{01}{02}(abdominalorstomachpaindiarrheadizzinessorfaintingheadachelossof
appetitenauseawithorwithoutvomitingnervousnessweakness)
bleedingintojoints{03}(jointpain,stiffness,orswelling)
gastrointestinalbleeding{01}{05}{08}{48}(black,tarrystoolsbloodinstoolsbloodyvomitorvomitthatlookslike
coffeegroundsconstipation)
hepatichemorrhage{01}{05}(asymptomatic)
hypotensionorshock{03}(dizzinessorfainting)
intracranialhemorrhage{08}{22}{34}
includingspinalhemorrhage{01}{08}(confusiondizzinessheadache,continuingorseverenauseaandvomiting
paralysisparesthesiasweakness)
ophthalmichemorrhage{05}(bleedingineyeblurredvision)
ovarianhemorrhageattimeofovulation{02}(abdominalorstomachpain)
pericardialhemorrhage{01}{08}(chestpain)
pulmonarybleeding(coughingupbloodshortnessofbreath)
retroperitonealbleeding{34}{01}(abdominalpainorswellingbackpainorbackaches)
Note:Fatalornonfatalbleedingorhemorrhagecanoccurfromanytissueororgan{01}{02}{04}{09}.Signs,
symptoms,andseverityvarydependingonthesiteandextentofbleeding{01}{02}{03}{04}.Therefore,bleeding
shouldbeconsideredasapotentialcauseofanysignorsymptomnototherwiseexplainable{04}.
Incidenceofbleedingorhemorrhagedependsondoseanddurationofanticoagulanttherapy{01}{02}{03}{24}{33}
{34}{49},aswellasage{22}{24}{34}andothermedicationsandunderlyingconditions{01}{02}{24}{33}{34}{49}.
IncidenceisincreasedatanINRover3{24}{33}{34}{37}{50},althoughbleedingmaynotalwayscorrelatewithPT
{01}{02}.Incidenceofhemorrhageisnotincreasedwithuseoffixedlowdosewarfarin(1mgperday),which
producesanINRof1.3to1.9{34}.
Adrenalhemorrhagemayresultinacuteadrenalinsufficiency{02}.Diagnosismaybedifficultbecausetheinitial
symptoms(abdominalpain,apprehension,diarrhea,dizzinessorfainting,headache,lossofappetite,nauseaor
vomiting,andweakness)arenonspecificandvariable.
Theoccurrenceofgastrointestinalorgenitourinaryhemorrhageduringanticoagulanttherapy,especiallyifthe
prothrombintime(PT)iswithinthetherapeuticrange,mayindicatethepresenceofanunderlyingoccultlesionsuch
asatumororulcer{02}{05}{09}{33}{34}{37}.
Gastrointestinalbleedingmayalsobeasymptomofulceration{01}.
Constipationmaybeasymptomofhemorrhageinducedparalyticileusorintestinalobstructioncausedby
submucosalorintramuralhemorrhage{02}.
Intracranialhemorrhage(ICH)includesintracerebral,subdural/epidural,andsubarachnoidhemorrhageand
commonlyresultsinfatalities{22}{29}.IncidenceofICHappearstobedoserelatedhowever,ithasbeenreported
atINRswellwithinthetherapeuticrange{22}.Neurologicdeficitsmayevolverapidlyorslowly(over6to24hours)
asthebleedingevolvesandexpandsslowly{22}{29}.
Withanisindione,thepossibilityexiststhatunusualbleedingorbruisingmayalsoindicatethrombocytopenia{01}.
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Incidencelessfrequent
Dermatitis,allergic{01}{02}{03}{08}{09}{48}(skinrash,hives,and/oritching)rarewithdicumarolandwarfarin
{48}
fever{01}{02}{08}{09}
leukopenia{02}(feverorchillscoughorhoarsenesslowerbackorsidepainpainfulordifficulturination)
Incidencerare
Agranulocytosis{01}(feverorchillscoughorhoarsenesslowerbackorsidepainpainfulordifficulturination)
withanisindione
calcification,trachealortracheobronchial{03}(troubleinbreathing)withlongtermwarfarin{03}
hepatotoxicity{01}{03}{05}{09}(usuallyasymptomaticandseenonlaboratorytests{03}darkurineyelloweyesor
skin)
lipidemboli
includingsystemicatheroemboliandcholesterolmicroemboli{03}
necrosisand/organgrene,hemorrhagic,ofskinandothertissues{01}{02}{03}{05}{08}{09}{33}{48}{50}(sores
onskin,especiallyonthighs,breasts,penis,orbuttocks{09}{48})
purpletoessyndrome{01}{02}{03}{08}{48}(blueorpurpletoespainintoes)
renaldamage,withresultantedemaandproteinuria{01}(bloodyorcloudyurinedifficultorpainfulurination
suddenincreaseordecreaseinamountofurineswellingofface,feet,and/orlowerlegs)
sores,ulcers,orwhitespotsinmouthorthroat{01}{03}
vasculitis{03}(feveritchingskinsoresorblisters)
Note:Systemicatheroemboliandcholesterolmicroembolicanpresentwithavarietyofsignsandsymptoms,
includingpurpletoessyndromelivedoreticularisrashgangreneabruptandintensepainintheleg,foot,ortoes
footulcersmyalgiapenilegangreneabdominalpain,flankpain,orbackpainhematuriarenalinsufficiency
hypertensioncerebralischemiaspinalcordinfarctionpancreatitissymptomssimulatingpolyarteritisoranyother
sequelaeofvascularcompromiseduetoembolicocclusion.Themostcommonlyinvolvedvisceralorgansarethe
kidneys,followedbythepancreas,spleen,andliver.Somecaseshaveprogressedtonecrosisordeath.{03}
Necrosisiscausedbythrombosisofthevenulesandcapillarieswithinthesubcutaneousfat{01}{03}{08}{33}{50}.It
usuallyoccursonthe3rdto8thdayoftherapy{01}{02}{03}{08}{33}{48}andmaybemorefrequentinpatientswith
proteinCdeficiency{08}{14}{33}.Initiallesions,whicharepainful,areerythematousorecchymoticwithasharply
demarcatedborder,subsequentlydevelopingbullaewithfullthicknessskinnecrosis{48}.Itisimportanttodetermine
whethernecrosisiscausedbytheanticoagulantorbyanunderlyingdisease{01}{02}{03}.Inseverecases,
debridementorevenamputationofaffectedtissue,limb,breast,orpenismaybenecessary{01}{02}{03}{08}{09}
{48}.Fatalitieshaveoccurred{01}{02}{03}{09}.
Purpletoessyndromemaydevelop3to10weeksafterinitiationofanticoagulanttherapy{03}{08}itresultsfrom
systemiccholesterolmicroembolization{03}{48}.Anticoagulanttherapymayenhancethereleaseofatheromatous
plaqueemboli,whichmayincreasetheriskofpurpletoessyndromeandothercomplicationsofsystemiccholesterol
embolization{03}{08}{48}.Purplespotsmayblanchwithpressureorelevationoftheleg{03}{48}.Thesyndromeis
{03}
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usuallyreversiblebutinsomecasesmayprogresstogangreneornecrosis{03}.
Thoseindicatingneedformedicalattentiononlyiftheycontinueorarebothersome
Incidencelessfrequentorrare
Bloatedstomachorgas{03}
coldintolerance{03}
diarrhea{01}{02}{03}{05}{08}{09}morefrequentwithdicumarol{09}
lossofappetite{01}{02}
nauseaorvomiting{01}{02}{03}{05}{08}{09}morefrequentwithdicumarol{09}
stomachcrampsorpain{01}{02}{03}
Thosenotindicatingneedformedicalattention
Incidencelessfrequentorrare
Alopeciaofscalp{01}{02}{03}{05}{08}{09}{48}(lossofhaironscalp)withlongtermuse
orangeredcolorinalkalineurinewithanisindione{01}
Overdose
Forspecificinformationontheagentsusedinthemanagementofanticoagulantoverdose,seetheVitaminK
(Systemic)andFactorIX(Systemic)monographs.
Formoreinformationonthemanagementofoverdoseorunintentionalingestion,contactaPoisonControl
Center(seePoisonControlCenterListing).
Clinicaleffectsofoverdose
Thefollowingeffectshavebeenselectedonthebasisoftheirpotentialclinicalsignificance(possiblesignsand
symptomsinparentheseswhereappropriate)notnecessarilyinclusive:
Earlysignsofoverdose
Overtorsuspectedbleeding{03}
includingpetechiae{01}(pinpointredspotsonskin),unusualbleedingorbruising{01}
unusuallyheavybleedingoroozingfromcutsorwounds{03}
uterinebleeding,excessive{01}{02}{05}(unusuallyheavyorunexpectedmenstrualbleeding)
Possiblesymptomsofinternalbleeding
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Adrenalhemorrhage{01}{02}(abdominalorstomachpaindiarrheadizzinessorfaintingheadachelossof
appetitenauseawithorwithoutvomitingnervousnessweakness)
bleedingintojoints{03}(jointpain,stiffness,orswelling)
gastrointestinalbleeding{01}{05}{08}{48}(black,tarrystoolsbloodinstoolsbloodyvomitorvomitthatlookslike
coffeegroundsconstipation)
genitourinarybleeding{01}{05}{48}
includingurinarybleeding{01}{02}{05}{48}(bloodinurine),orovarianhemorrhageattimeofovulation{02}
(abdominalorstomachpain)
hepatichemorrhage{01}{05}(asymptomatic)
hypotensionorshock{03}(dizzinessorfainting)
intracranialhemorrhage{08}{22}{34}
includingspinalhemorrhage{01}{08}(confusiondizzinessheadache,continuingorseverenauseaandvomiting
paralysisparesthesiasweakness)
ophthalmichemorrhage{05}(bleedingineyeblurredvision)
pericardialhemorrhage{01}{08}(chestpain)
pulmonarybleeding{01}(coughingupbloodshortnessofbreath)
retroperitonealbleeding{34}(abdominalpainorswellingbackpainorbackaches)
Treatmentofoverdose
Ifexcessiveincreasesinprothrombintime(PT)and/orinternationalnormalizedratio(INR),withoutbleedingor
prospectivesurgery,occur,theINRshouldbereducedtoasafelevel(e.g.,lessthan5){03}{33}.Ifseriousbleeding
ispresent,theINRshouldbereducedto1assoonaspossible{33}.Ifelectivesurgeryorurgentsurgeryisrequired,
theINRcanbereducedto1to1.5atthetimeofsurgery{33}.
ReductionofINRcanusuallybeaccomplishedbytemporarilywithdrawinganticoagulanttherapyand,ifnecessary,
administeringoralorparenteralvitaminK1{01}{03}{23}{24}{33}.Reversalofanticoagulationisnotmaximalfor24to
48hoursafterwithholdingtheanticoagulant,untilsynthesisoffullycarboxylatedcoagulationproteinsiscomplete{08}
{23}.Forseriousoverdoseorlifethreateningbleeding,whenimmediaterestorationofclottingfactorsisnecessary,
transfusionoffreshplasma{01}{03}{24}{33}orprothrombin(factorIX)complexconcentrate{03}{23}{24}{33}along
withvitaminK1maybenecessary.Useofthesebloodproductsisassociatedwithanincreasedriskofhepatitisand
otherviraldiseases{03}{24}useofprothrombincomplexisalsoassociatedwithanincreasedriskofthrombosis{03}.
UseofpurifiedfactorIXcomplexpreparations(CoagulationFactorIX[HumanorRecombinant])isnot
recommendedbecausetheywillnotincreaseconcurrentlydepressedlevelsoffactorII,factorVII,andfactorX{03}.
Packedredbloodcellsmaybeadministeredforsignificantbloodloss{03}.Althoughwholebloodmaybegivenif
bloodlosshasbeenextensive,transfusionofwholebloodwillnotelevateprocoagulantfactorconcentrations
sufficientlytoeliminatetheneedforadministrationofplasmaorprothrombincomplexconcentrate.Cautionand
carefulmonitoringarerecommendedduringinfusionofbloodorplasmatoavoidprecipitatingpulmonaryedemain
elderlypatientsorpatientswithcardiacdisease{03}{24}.
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VitaminK1Overcomestheanticoagulanteffectbecauseitisreducedthroughadifferentwarfarinresistant
enzymesystem{33}.Repeateddosesmaybenecessary{08}.ThefactthatlargedosesofvitaminK1(5mgor
more)willreducetheresponsetosubsequentanticoagulanttherapyforuptoaweekorlongermustbekeptinmind
{03}{08}{23}{24}{33}.AlthoughresumptionofanticoagulanttherapycanproducetherapeuticPT/INRwithcareful
dosageadjustment,heparinmaybepreferableforinitialtherapyand/orifrapidanticoagulationisdesired{03}{08}.
Freshwholebloodorplasma200to500mLmayberequired{03}.
ProthrombincomplexconcentrateAfactorIXproduct(FactorIXComplexUSP)thatmayalsocontainclinically
usefulquantitiesoffactorsII,VII,andX.Mayalsocontainotherproteins,includingproteinsCandShighmolecular
weightkininogenandsmallquantitiesofactivatedclottingfactorsII,VII,IX,orX{85}.Theusualdoseis1500Units
{85}.
PatientConsultation
Asanaidtopatientconsultation,refertoAdviceforthePatient,Anticoagulants(Systemic).
Inprovidingconsultation,consideremphasizingthefollowingselectedinformation(=majorclinicalsignificance):
Beforeusingthismedication
Conditionsaffectinguse,especially:
Sensitivitytotheanticoagulantprescribed
PregnancyPossibilityofbirthdefectsorbleedinginthefetusorbleedinginthemothernotbecomingpregnant
duringtherapywithoutfirstdiscussingwithphysiciantellingphysicianimmediatelyifpregnancyissuspected{03}
UseinchildrenInfantsmaybemoresensitivetotheeffectsofanticoagulants
UseintheelderlyElderlypatients(60yearsofageandolder)maybemoresensitivetotheeffectsof
anticoagulants
Othermedicationsofanykind
Othermedicalproblems
Properuseofthismedication
Compliancewiththerapytakingatsametimeeachday{08}{09}
Regularvisitstophysicianorclinictocheckprogress{01}{03}possibilityofmonitoringPT/INRandadjusting
dosageathomeforsomepatients{90}
Properdosing
Misseddose:Takingassoonaspossiblenottakingifnotremembereduntilnextdaynotdoublingdoseskeepinga
recordofdosestakentoavoidmistakeskeepingrecordofmisseddosestogivephysician{03}{04}
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Properstorage
Precautionswhileusingthismedication
Informingallphysicians,dentists,and/or{90}pharmaciststhatanticoagulantisbeingused
Checkingwithphysicianimmediatelyifanysignsorsymptomsofbleedingoccur
Nottaking,stopping,orchangingothermedications,includingoverthecounter(OTC)medications,withoutfirst
discussingwithphysician{01}{03}
Carryingorwearingidentificationindicatinguseofanticoagulant{02}{03}
Notengaginginactivitiesthatmayleadtoinjury{03}
Cautioninactivitieswithriskofcuttingorbleeding(e.g.,shaving)
Minimizingalcoholconsumption{03}
Eatinganormal,balanceddietcautionwithweightlossdietsnotchangingdiet,takingvitamins,orusing
nutritionalsupplementswithoutfirstdiscussingwithphysicianbecauseofpossiblealterationofanticoagulanteffect
bysubstantialchangesinintakeofvitaminK{03}
Checkingwithphysicianifunabletoeatforseveraldaysorifcontinuinggastricupset,diarrhea,orfeveroccurs{03}
Cautioninprolongedhotweather{03}
Cautionwhenanticoagulanttherapyisdiscontinued,andforseveraldaysafterwithdrawaloftherapy,asblood
clottingreturnstonormal{03}
Side/adverseeffects
Signsandsymptomsofpotentialsideeffects,especiallybleedingorhemorrhage,allergicdermatitis,fever,
leukopenia,agranulocytosis(foranisindione),trachealortracheobronchialcalcification,hepatotoxicity,lipidemboli
includingsystemicatheroemboliandcholesterolmicroemboli,necrosisand/organgrene,purpletoessyndrome,
renaldamage,soresinmouthorthroat,andvasculitis
Checkingwithphysicianifredorangecolorofurineoccurswithanisindionenotharmfulbutmayinterferewith
certainurinetests
GeneralDosingInformation
Dosageshouldbeadjustedtoachievethegoalofimpedingthecoagulationorclottingmechanismtothepointthat
thrombosiswillnotoccurbutspontaneousbleedingwillbeavoided{02}.
Patientcomplianceisessentialtothesafeuseofthesemedications.Thepatientmustberesponsibleandwillingto
dealwiththedemandsoftherapywiththesemedications.{45}
Determinationofdoseiscomplicatedbythenarrowtherapeuticwindowandwidevariabilityindoseresponseto
warfarin{12}{17}.Ithasbeenestimatedthat20to25%ofpatientsneverachieveastabletherapeuticdose{17}.
Dosageofanticoagulantsmustbeindividualizedandshouldbeadjustedaccordingtoprothrombintime(PT)and/or
{90}
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internationalnormalizedratio(INR)determinations.{90}Determinationsofclottingtime,bleedingtime,or
anticoagulantplasmaconcentrationarenoteffectivemeasuresformonitoringanticoagulanttherapy{03}.However,it
isimportanttokeepinmindthatcertainmedicationsormedicalconditionsmayincreaseriskofhemorrhagewithout
increasingPT(e.g.,bycausinginhibitionofplateletaggregationorthrombolysis).MonitoringofPT/INRmustbe
accompaniedbycarefulmonitoringforpossiblebleedingorhemorrhage,andanticoagulantdosageadjusted
accordingly.{17}{90}
Somepatientsmayexhibitresistancetoanticoagulanttherapybecauseofgeneticpredisposition{03}{33},acquired
resistance(e.g.,antiphospholipidantibodies){03}{13},oranincreasedrateofanticoagulantmetabolismand
excretion{08}.Dosesmuchhigherthanthoseusuallyrecommendedmayberequiredtoachievesuccessful
anticoagulationinthesepatients.Thepresenceofacquiredorhereditarycoumarinresistanceshouldbeconsidered
iflargedailydosesarerequiredtomaintainthepatient'sPT/INRwithinanormaltherapeuticrange{03}.
Somepatientsmayexhibitunusualsensitivitytotheeffectsofwarfarin.Thecausehasbeenpostulatedtobevitamin
Kdepletionbutthishasnotbeenstudied.{03}
Manufacturers"dosagerecommendationsmayincludeadministrationofaninitiallargeloadingdose,whichis
graduallyreducedtothemaintenancelevelaccordingtoPT/INRdeterminations{01}{02}.However,manyclinicians
donotrecommenduseoflargeloadingdosesbecauseoftheincreasedriskofhemorrhage,{03}andbecausea
morerapidanticoagulanteffectcanbeachievedbyinitiatingtherapywithheparin{03}.
ThetherapeuticvalueofthePTwaspreviouslyconsideredtobe1.5to2.5timesthecontrolvalue{08}.Becausethe
rabbitbrainthromboplastinscurrentlyusedintheU.S.forPTdeterminationsarelesssensitivethanthehumanbrain
thromboplastinsusedpreviously,theoptimaltherapeuticvalueofthePTisnowconsideredtobe1.3to1.5timesthe
controlvalue.However,inthepresenceofaveryhighriskofthromboembolism(e.g.,inpatientswithahistoryof
recurrentsystemicembolismorpatientswithmechanicalheartvalves),maintainingthePTat1.5to2timesthe
controlvaluemaybenecessary.
ThetargetINRforanygivenindicationcanbedefinedingeneral,butmayvarydependingonseverityofthe
condition,associatedriskfactorsforthrombosis,riskfactorsformajorhemorrhage,combinationtherapywithother
agents,andotherrelevantconditions.ForspecificguidelinesconcerningINRvaluesindeterminingtheappropriate
doseofanticoagulanttherapy,theprescribershouldrefertotheliteratureortopublishedguidelines{53},suchas
thosedevelopedin1998bytheFifthAmericanCollegeofChestPhysicians(ACCP)ConsensusConferenceon
AntithromboticTherapy{52}.
Ingeneral,anINRof2to3isrecommendedforpreventionortreatmentofvenousthromboembolism{03}{20}{37},
includingpulmonaryembolism,atrialfibrillation{03}{08}{09}{38}{44},valvularheartdisease{08}{39},orwith
bioprostheticheartvalves{08}{09}{40}.AnINRof2.5to3.5isrecommendedaftermyocardialinfarction{03}{23}{33},
inpatientswithmechanicalprostheticheartvalves{03}{08}{09}{12}{33},orincertainpatientswiththrombosisand
theantiphospholipidsyndrome{12}{33}.HigherINRmayberecommendedforrecurrentsystemicembolism{03}.
EffectivenessofwarfarinisreducedatINRsoflessthan2,althoughsomebenefitcanbeobtainedinsome
conditions(e.g.,preventionofdeepveinthrombosisinpatientswithindwellingcentralveincatheters)withfixedlow
dosewarfarin(1mgperday)atanINRof1.3to2{23}{33}.
IncreasedmonitoringofPT/INRisrecommendedwhenanynewmedication,includingnonprescription(overthe
counter[OTC]),isaddedtoorwithdrawnfromtheregimenofapatientstabilizedonacoumarinorindanedione
anticoagulant,orwhenthedosageofaconcurrentlyusedmedicationischanged.Anticoagulantdosagemustbe
adjustedasnecessarytopreventhemorrhageorlossofeffect.Also,substantialalterationofinitialanticoagulant
dosagemaybenecessarywhenanticoagulanttherapyisinitiatedinapatientreceivingamedicationknowntocause
significantalterationofanticoagulanteffect.
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Whenanticoagulanttherapyisinitiatedwithheparinandcontinuedwithacoumarinorindanedioneanticoagulant,it
isrecommendedthatbothagentsbegivenconcurrentlyuntilPT/INRdeterminationsindicateanadequateresponse
tothecoumarinorindanedioneanticoagulant{02}{08}.However,thefactthatheparinmayprolongthePTmustbe
keptinmind.Subcutaneousorbolusintravenousadministrationoffulltherapeuticdosesofheparinmayprolongthe
PTconsiderablybecauseofthehighconcentrationsofheparinachievedintheblood.Ontheotherhand,continuous
intravenousinfusionoffulltherapeuticdosesorsubcutaneousadministrationoflow(prophylactic)dosesusuallydo
notincreasethePTbymorethanafewseconds.TominimizeproblemsininterpretingPTtestresults,itis
recommendedthatbloodforthePTtestbedrawnjustpriorto,oratleast5hoursafter,abolusintravenousdoseor
24hoursaftersubcutaneousadministrationofafulltherapeuticdoseofheparin{01}{02}{03}{05}.Also,thefactthat
reductioninPTmayreflectearlydepletionoffactorVIIratherthanpeakantithromboticeffectsofcoumarinor
indanedionederivativesmustbekeptinmind{33}.Somecliniciansrecommendcontinuationofheparintherapyfor
upto4to5daysafterinitiationoftherapywithacoumarinorindanedioneanticoagulanttoensurethatpeak
antithrombogenicactivityhasbeenreached{20}.
Durationofanticoagulanttherapythatisappropriateforanygivenindicationcanbedefinedingeneral,butmayvary
widelydependingontheseverityofthecondition,associatedriskfactorsforthrombosis,riskfactorsformajor
hemorrhage,combinationtherapywithotheragents,andotherrelevantconditions{03}{13}{14}{37}{40}.Forspecific
guidelinesconcerningINRvaluesasanaidindeterminingtheappropriatedurationofanticoagulanttherapy,the
prescribershouldrefertotheliteratureortopublishedguidelines{13}{53},suchasthosedevelopedin1998bythe
FifthAmericanCollegeofChestPhysicians(ACCP)ConsensusConferenceonAntithromboticTherapy{52}.
Becauseoftheriskofreboundhypercoagulability(whichmaynotbedetectedbyclottingtests)whenanticoagulant
therapyisdiscontinued{09}{31},gradualwithdrawalover3to4weeksisrecommended{01}{05}{31}.
Diet/Nutrition
DietaryvitaminKfluctuationsareespeciallyimportantinpatientstakinglowdosewarfarin{16}.
LossofanticoagulanteffectmayoccurinapreviouslystabilizedpatientfollowingincreasedintakeofvitaminKfrom
dietarysources(greenleafyvegetablessuchasbroccoli,cabbage,collardgreens,kale,lettuce,orspinachand
certainvegetableoils)orvitaminKcontainingmultiplevitaminsornutritionalsupplements{16}{17}{23}{33}.
IncreasedanticoagulanteffectmayoccurinapreviouslystabilizedpatientifprolongedmalnutritionorvitaminC
deficiencydevelops,orifdiarrhea,otherillness,orchangesindietresultingindecreasedintakeorabsorptionof
vitaminKoccurduringtherapy{23}.
Forparenteraldosageformofwarfarinonly
Itisrecommendedthatparenteralwarfarinbeadministeredbyslowintravenousinjection(over1to2minutes)intoa
peripheralvein{03}.
Intramuscularadministrationofwarfarinisnotrecommended{03}.
Forpreventionortreatmentofadverseeffects
IfexcessiveincreasesinPT/INR,withoutbleedingorprospectivesurgery,occur,theINRshouldbereducedtoa
safelevel(e.g.,lessthan5){03}{33}.Ifseriousbleedingispresent,theINRshouldbereducedto1assoonas
possible{33}.ReductionofINRmaybeaccomplishedbytemporarilywithdrawinganticoagulanttherapy,
administeringvitaminK1,and,inlifethreateningsituations,bytransfusingfreshplasmaorprothrombincomplex
concentrate{24}{33}.(SeeTreatmentofoverdoseformoreinformation.)Ifelectiveorurgentsurgeryisrequired,the
INRcanbereducedto1to1.5atthetimeofsurgery{33}.
Itisrecommendedthatintramuscularinjectionsofconcomitantmedicationsbeavoidedwheneverpossible,because
oftheriskofhematoma{05},orbeadministeredintheupperextremitiestoensureeasyaccessformanual
{03}
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compression,inspectionsforbleeding,anduseofpressurebandages{03}.
Ifacuteadrenalhemorrhageorinsufficiencyissuspected,anticoagulanttherapyshouldbediscontinued,plasma
cortisolconcentrationsmeasured,andhighdoseintravenouscorticosteroidtherapy(preferablywithhydrocortisone,
sinceotherglucocorticoidsmaynotprovidesufficientsodiumretention)institutedimmediately{02}.Delayof
treatmentwhilelaboratoryconfirmationofthediagnosisisawaitedmayprovefatalforthepatient{02}.Ithasbeen
proposedthatabdominalcomputerizedaxialtomographic(CAT)scanningmaybeusefulindiagnosingthiscondition
morerapidly.{90}
Itisrecommendedthatcoumarinorindanedioneanticoagulanttherapybediscontinuedatthefirstsignof
anticoagulantinducedtissuenecrosis{01}{02}{03}{09}{48}.Ifnecessary,anticoagulanttherapycanbecontinued
withheparinmonotherapy{01}{02}{03}{09}{48}.Nouniformlyeffectivetreatmentforanticoagulantinducedtissue
necrosishasbeenestablished{01}{02}{03},althoughsomesuccesshasbeenachievedwithreintroductionof
warfarinatlowdosesincombinationwiththerapeuticdosesofheparin,withgradualincreasesinwarfarindoseover
severalweeks{14}{33},orwithuseofproteinCconcentrateorfreshfrozenplasmauntilstableanticoagulationis
achieved{14}.ThisapproachmaypreventanabruptfallinproteinCconcentrationsbeforefactorsII,IX,andX
concentrationscanfall{14}{33}.
Itisrecommendedthatanticoagulanttherapybewithdrawn(andreplacedbyheparinifnecessary)atthefirstsign
of:Agranulocytosis{01}
Hypersensitivity{01}
Intracranialhemorrhage
(aggressivetreatmentisnecessarybecauseoftheslowevolutionandgrowthofthebleedingareainabouthalfof
thecases{22})
Purpletoessyndrome{48}
Systemicatheroemboliorcholesterolmicroemboli{03}.
ACENOCOUMAROL
SummaryofDifferences
Anothercommonlyusednameisnicoumalone.
Coumarinderivative.
Pharmacology/pharmacokinetics:
SeePharmacology/Pharmacokinetics.
OralDosageForms
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ACENOCOUMAROLTABLETS
Usualadultdose
Oral,1to10mgperday,asindicatedbyPT/INRdeterminations{05}.
Usualpediatricdose
Dosagehasnotbeenestablished.
Strength(s)usuallyavailable
U.S.
Notcommerciallyavailable.
Canada
1mg(Rx)[Sintrom]
4mg(Rx)[Sintrom(scored)]
Packagingandstorage:
Storebelow40C(104F),preferablybetween15and30C(59and86F),unlessotherwisespecifiedby
manufacturer.
Auxiliarylabeling:
Donottakeothermedicineswithoutadvicefromyourdoctor.
ANISINDIONE
Indanedionederivative.
Precautions:
LaboratoryvaluealterationsAlkalineurinemayturnredorange.
Side/adverseeffects:
SeeSide/AdverseEffects.
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OralDosageForms
ANISINDIONETABLETS
Usualadultdose
Oral,25to250mgaday,asindicatedbyPT/INRdeterminations{01}.
Usualpediatricdose
U.S.
50mg(Rx)[Miradon(scored)(lactose)]
Canada
Storebelow40C(104F),preferablybetween15and30C(59and86F),unlessotherwisespecifiedby
manufacturer.
Auxiliarylabeling:
DICUMAROL
Coumarinderivative.
Incidenceofgastrointestinalside/adverseeffectsmaybehigher.
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OralDosageForms
DICUMAROLTABLETSUSP
Usualadultdose
Oral,25to200mgaday,asindicatedbyPT/INRdeterminations{02}.
Usualpediatricdose
U.S.
25mg(Rx)[Generic](lactose)
Canada
Storebelow25C(77F).
Auxiliarylabeling:
WARFARIN
Coumarinderivative.
OralDosageForms
WARFARINSODIUMTABLETSUSP
Note:Withtherecentavailabilityofgenericformulationsofwarfarin,thepossibilityexistsforvariationsin
{17}
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bioavailability(e.g.,tabletdissolution){17}andthustheactivityofdifferentcommercialpreparations.Switching
brandsshouldbeavoidedwheneverpossible{17}.Ifaswitchtoadifferentbrandoccurs,thepatient'sPT/INR
shouldbemonitoredanddosageadjustedifnecessary{03}{09}{17}.
Usualadultdose
Regulardose(adjusted)therapy
Initial:Oral,2to5mgperday,thedosagebeingadjustedaccordingtoPT/INRdeterminations{03}{04}.
Maintenance:Oral2to10mgperday,asindicatedbyPT/INRdeterminations{03}{04}.
Lowdose(fixed)therapy
Oral,1mgperday{23}{33}.
Note:Therehavebeenanumberofreportsofuseoffixedlowdosewarfarin(1mgperday)forprophylaxisofdeep
veinthrombosis(e.g.,inpatientswithindwellingcentralveincatheters){08}{23}{33}{36}{41}.However,resultsof
studiesdonotsupportuseoffixedlowdosewarfarinfortreatmentofpatientswithacutemyocardialinfarctionor
atrialfibrillation{33}.
Usualpediatricdose
Dosagehasnotbeenestablished{11}{47}{90}.
U.S.
1mg(Rx)[Coumadin(scored)(lactose)][Generic](maycontainlactose)
2.5mg(Rx)[Coumadin(scored)(lactose)][Generic](maycontainlactose)
3mg(Rx)[Coumadin(scored)(lactose)]
7.5mg(Rx)[Coumadin(scored)(lactose)][Generic](maycontainlactose)
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Canada
2.5mg(Rx)[Coumadin(scored)(lactose)]
5mg(Rx)[Coumadin(scored)(lactose)][Warfilone(scored)(tartrazine)]
Storebetween15and30C(59and86F),unlessotherwisespecifiedbymanufacturer.Protectfromlight.
Auxiliarylabeling:
ParenteralDosageForms
WARFARINSODIUMFORINJECTIONUSP
Usualadultdose
Initial
Intravenous(overonetotwominutesintoaperipheralvein),2to5mgperday,thedosagebeingadjusted
accordingtoPT/INRdeterminations{03}{04}.
Maintenance
Intravenous(overonetotwominutesintoaperipheralvein),2to10mgperday,asindicatedbyPT/INR
determinations{03}{04}.
Usualpediatricdose
Size(s)usuallyavailable:
U.S.
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5mg(Rx)[Coumadin(sodiumphosphate,dibasic,heptahydrate)(sodiumphosphate,monobasic,monohydrate)
(sodiumchloride)(mannitol)(sodiumhydroxide)]
Canada
5mg(Rx)[Coumadin(sodiumphosphate,dibasic,heptahydrate)(sodiumphosphate,monobasic,monohydrate)
(sodiumchloride)(mannitol)(sodiumhydroxide)]
Storebetween15and30C(59and86F){03}{06},unlessotherwisespecifiedbymanufacturer.Donotrefrigerate
{03}{06}.Protectfromlight{03}{06}.
Preparationofdosageform:
Warfarinsodiumforinjectionispreparedforadministrationbyadding2.7mLofsterilewaterforinjectiontothe5mg
vial,producingasolutioncontaining2mgofwarfarinsodiumpermL{03}{06}.
Stability:
Itisrecommendedthatthereconstitutedsolutionbeusedwithin4hours{03}{06}.Anyunusedportionshouldbe
discarded{03}.
Incompatibilities:
Warfarinsodiumsolutionsareincompatiblewithamikacinsulfate,epinephrinehydrochloride,metaraminoltartrate,
oxytocin,promazinehydrochloride,tetracyclinehydrochloride,andvancomycinhydrochloride{08}.
Someadsorptionofwarfarinsodiumbypolyvinylchloridehasbeendemonstratedwhenthewarfarinwasdissolved
in0.9%sodiumchlorideinjectionor5%glucoseinjection{08}.
Revised:5/18/99
References
1.Miradonpackageinsert(ScheringUS),Rev7/92,Rec3/96.
2.Dicumaroltabletspackageinsert(AbbottUS),Rev1/95,Rec4/96.
3.Coumadinpackageinsert(DuPontMerckUS),Rev4/98,Rec8/98.
4.Warfarinsodiumtabletspackageinsert(BarrUS),Rev1/97.
5.Sintrompackageinsert(GeigyCanada),Rev1/88,Rec8/98.
6.Coumadinpackageinsert(DuPontMerckCanada),Rev1/28/98.
7.Warfilonepackageinsert(MerckFrosstCanada),Rev6/94,Rec4/96.
8.HardmanJG,LimbirdLE,MolinoffPB,etal(eds).Goodman&Gilman'sthepharmacologicalbasisof
therapeutics,9thed.NewYork:McGrawHill1996:134759.
42/47
22/11/2016
9.ReynoldsJEF,editor.Martindale:theextrapharmacopoeia,31sted.London:TheRoyalPharmaceuticalSociety
1996.p.79138081085019156928996572.
10.StockleyIH.Druginteractions:asourcebookofadverseinteractions,theirmechanisms,clinicalimportanceand
management.London:BlackwellScientificPublications1991.p.156211.
11.AndrewM,BrookerLA,GinsbergJS,etal.2.Coagulation:clinicalproblemsinanticoagulationtherapy.
Proceedingsofthe39thAmericanHematologicalSocietyannualmeeting1997.Availableat
http://www.hematology.org/education/hema97/andrew.pdf
12.HirshJ.Platelets,hemostasis,andcoagulation.HamWassermanLecture.Anticoagulants:theoldandthenew.
http://www.hematology.org/education/hema97/hirsh.pdf
13.GriffinJH,MotulskyA,HirshJ.Diagnosisandtreatmentofhypercoagulablestates.Proceedingsofthe39th
AmericanHematologicalSocietyannualmeeting1997.Availableat
http://www.hematology.org/education/hema97/griffin.pdf
14.HandinRI,SchulmanS,GinsbergJ,etal.Anticoagulanttherapy.Proceedingsofthe39thAmerican
HematologicalSocietyannualmeeting1997.Availableat
http://www.hematology.org/education/hema97/handin.pdf
15.BauerKA,GoodnightSH,RidkerPM.Hypercoagulablestatestranslationofriskfactorstoclinicalpractice.
http://www.hematology.org/education/hema97/bauer.pdf
16.SadowskiJA,BoothSL,MannKg,etal.Chapter2.StructureandmechamismofactivationofvitaminK
antagonists.In:PollerL,HirshJ,editors.Oralanticoagulants.London:Arnold1996.p.119.
17.HolbrookAM,WellsPS,CrowtherNR.Chapter3.Pharmacokineticsanddruginteractionswithwarfarin.In:
PollerL,HirshJ,editors.Oralanticoagulants.London:Arnold1996.p.3048.
18.Amarylproductinformation(HoechstMarionRousselUS).PDRPhysicians'deskreference.52nded.1998.
Montvale,NJ:MedicalEconomicsCoInc1998.p.11936.
19.VermeerC,KnapenMJH,HamulyakK.Chapter6.EffectsofvitaminKandoralanticoagulantsonhumanbone
metabolism.In:PollerL,HirshJ,editors.Oralanticoagulants.London:Arnold1996.p.7683.
20.GeertsWH,JayRM.Chapter9.Oralanticoagulantsinthepreventionandtreatmentofvenous
thromboembolism.In:PollerL,HirshJ,editors.Oralanticoagulants.London:Arnold1996.p.97122.
21.TurpieAGG.Chapter12.Valvularheartdiseaseandheartvalveprostheses.In:PollerL,HirshJ,editors.Oral
anticoagulants.London:Arnold1996.p.1439.
22.HartRG,SolomonDH,AndersonDC.Chapter13.Oralanticoagulationforpreventionofstrokeandcerebral
embolism.In:PollerL,HirshJ,editors.Oralanticoagulants.London:Arnold1996.p.15066.
23.HirshJ,PollerL.Chapter14.Practicaldosingconsiderationswithwarfarinandoptimaltherapeuticrange.In:
24.LevineMN.Chapter15.Hemorrhagiccomplicationsoforalanticoagulanttherapy.In:PollerL,HirshJ,editors.
Oralanticoagulants.London:Arnold1996.p.18091.
43/47
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25.LetskyEA.Chapter16.Oralanticoagulantsinpregnancy.In:PollerL,HirshJ,editors.Oralanticoagulants.
London:Arnold1996.p.192215.
26.MassicotteMP,BrookerLA,MarzinottoV,etal.Chapter17.Oralanticoagulationtherapyinchildren.In:PollerL,
HirshJ,editors.Oralanticoagulants.London:Arnold1996.p.21627.
27.ZacharskiLR,RicklesFR.Chapter18.Warfarininthetreatmentofcancer.In:PollerL,HirshJ,editors.Oral
28.LoweGDO,StottDJ.Chapter19.Oralanticoagulationintheelderly.In:PollerL,HirshJ,editors.Oral
29.AzeradMA,VermylenJ.Chapter20.Indicationsandresultswithcombinedwarfarinandantiplateletdrugs.In:
30.SchecterAD,FusterV,ChesebroJH.Chapter21.Anticoagulantsincardiomyopathy.In:PollerL,HirshJ,
editors.Oralanticoagulants.London:Arnold1996.p.25963.
31.PalaretiG,CoccheriS.Chapter22.Reboundhypercoagulabilityafterdiscontinuationoforalanticoagulants.In:
32.GuyattGH,CookDJ,SackettDL,etal.Gradesofrecommendationsforantithromboticagents.FifthACCP
ConsensusConferenceonAntithromboticTherapy.Chest1998Nov114(5Suppl):441S444S.
33.HirshJ,DalenJE,AndersonDR,etal.Oralanticoagulants:mechanismofaction,clinicaleffectiveness,and
optimaltherapeuticrange.FifthACCPConsensusConferenceonAntithromboticTherapy.Chest1998Nov
114(5Suppl):445S469S.
34.LevineMN,RaskobG,LandefeldS,etal.Hemorrhagiccomplicationsofanticoagulanttreatment.FifthACCP
35.GinsbergJS,HirshJ.Useofantithromboticagentsduringpregnancy.FifthACCPConsensusConferenceon
AntithromboticTherapy.Chest1998Nov114(5Suppl):524S530S.
36.ClagettGP,AndersonFA,GeertsW,etal.Preventionofvenousthromboembolism.FifthACCPConsensus
ConferenceonAntithromboticTherapy.Chest1998Nov114(5Suppl):531S560S.
37.HyersTM,AgnelliG,HullRd,etal.Antithrombotictherapyforvenousthromboembolicdisease.FifthACCP
38.LaupacisA,AlbersG,DalenJ,etal.Antithrombotictherapyinatrialfibrillation.FifthACCPConsensus
39.SalemDN,LevineHJ,PaukerSG,etal.Antithrombotictherapyinvalvularheartdisease.FifthACCPConsensus
40.SteinPD,AlpertJS,DalenJE,etal.Antithrombotictherapyinpatientswithmechanicalandbiologicalprosthetic
heartvalves.FifthACCPConsensusConferenceonAntithromboticTherapy.Chest1998Nov114(5Suppl):
602S610S.
41.CairnsJA,TherouxP,LewisHD,etal.Antithromboticagentsincoronaryarterydisease.FifthACCPConsensus
44/47
22/11/2016
42.SteinPD,DalenJE,GoldmanS,etal.Antithrombotictherapyinpatientswithsaphenousveinandinternal
mammaryarterybypassgrafts.FifthACCPConsensusConferenceonAntithromboticTherapy.Chest1998Nov
114(5Suppl):658S665S.
43.JacksonMR,ClagettGP.Antithrombotictherapyinperipheralarterialocclusivedisease.FifthACCPConsensus
44.AlbersGW,EastonJD,SaccoRL,etal.Antithromboticandthrombolytictherapyforischemicstroke.FifthACCP
45.EckmanMH,LevineHJ,SalemDN,etal.Makingdecisionsaboutantithrombotictherapyinheartdisease:
decisionanalysisandcosteffectivenessissues.FifthACCPConsensusConferenceonAntithromboticTherapy.
Chest1998Nov114(5Suppl):699S714S.
46.PopmaJJ,WeitzJ,BittlJA,etal.Antithrombotictherapyinpatientsundergoingcoronaryangioplasty.FifthACCP
47.MichelsonAD,BovillE,MonagleP,etal.Antithrombotictherapyinchildren.FifthACCPConsensusConference
onAntithromboticTherapy.Chest1998Nov114(5Suppl):748S769S.
48.SpandorferJM,MerliGJ.Outpatientanticoagulationissuesfortheprimarycarephysician.MedClinNorthAm
1996Mar80(2):47591.
49.BeckerRC,AnsellJ.Antithrombotictherapy:anabbreviatedreferenceforclinicians.ArchInternMed1995155:
14961.
50.HirshJ,FusterV.Guidetoanticoagulanttherapy.Part2:oralanticoagulants.Circulation1994889:146980.
51.CanadaJR,editor.USPdictionaryofUSANandinternationaldrugnames1998.Rockville,MD:TheUnited
StatesPharmacopeialConventionInc1997.p.17,56,2323,784.
52.DalenJE,HirshJ,editors.FifthACCPConsensusConferenceonAntithromboticTherapy.Chest1998Nov
114(5Suppl):entireissue.
53.PollerL,HirshJ,editors.Oralanticoagulants.London:Arnold1996.
54.Cytadrenproductinformation(NovartisUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
MedicalEconomicsCoInc1998.p.18389.
55.PeptoBismolproductinformation(Procter&GambleUS).In:PDRPhysicians'deskreference.52nded.1998.
56.Prozacproductinformation(DistaUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
57.Normifloproductinformation(WyethAyerstUS).In:PDRPhysicians'deskreference.52nded.1998.
58.Fragminproductinformation(Pharmacia&UpjohnUS).In:PDRPhysicians'deskreference.52nded.1998.
45/47
22/11/2016
59.Lovenoxproductinformation(RhonePoulencRorerUS).In:PDRPhysicians'deskreference.52nded.1998.
60.Lescolproductinformation(NovartisUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
61.Mevacorproductinformation(MSDUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
62.Pravacholproductinformation(BristolMyersSquibbUS).In:PDRPhysicians'deskreference.52nded.1998.
63.Zocorproductinformation(MSDUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
64.ParaGardT380Aproductinformation(OrthoMcNeilUS).In:PDRPhysicians'deskreference.52nded.1998.
65.Duractproductinformation(WyethAyerstUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,
NJ:MedicalEconomicsCoInc1998.p.30357.
66.Prilosecproductinformation(AstraMerckUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,
67.Paxilproductinformation(SmithKlineBeechamUS).In:PDRPhysicians'deskreference.52nded.1998.
68.Oncasparproductinformation(RhonePoulencRorerUS).In:PDRPhysicians'deskreference.52nded.1998.
69.Trentalproductinformation(HoechstMarionRousselUS).In:PDRPhysicians'deskreference.52nded.1998.
70.Rythmolproductinformation(KnollUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
71.Mycobutinproductinformation(Pharmacia&UpjohnUS).In:PDRPhysicians'deskreference.52nded.1998.
72.Zoloftproductinformation(PfizerUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
73.Accolateproductinformation(ZenecaUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
74.Luvoxproductinformation(SolvayUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
75.Casodexproductinformation(ZenecaUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
76.Orgaranproductinformation(OrganonUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
46/47
22/11/2016
77.Elmironproductinformation(BakerNortonUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,
78.Flomaxproductinformation(BoehringerIngelheimUS).In:PDRPhysicians'deskreference.52nded.1998.
79.Zyfloproductinformation(AbbottUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
80.Refludanpackageinsert(HoechstMarionRousselUS),Rev3/98,Rec3/98.
81.Prandinpackageinsert(NovoNordiskUS),Rev12/28/97,Rec2/19/98.
82.Priftinproductinformation(HoechstMarionRousselUS).In:PDRPhysicians'deskreference.53rded.1999.
83.Nilandronproductinformation(HoechstMarionRousselUS).In:PDRPhysicians'deskreference.52nded.
1999.Montvale,NJ:MedicalEconomicsCoInc1998.p.12224.
84.FluShieldpackageinsert(WyethAyerstUS),Rev5/96,Rec4/97.
85.Konyne80packageinsert(CutterUS),Rev4/91,Rec4/12/93.
86.WellsPS,HolbrookAM,CrowtherNR,etal.Interactionsofwarfarinwithdrugsandfood.AnnInternMed1994
121:67683.
87.Sulfapyridinepackageinsert(LillyUS),Rev2/12/86,Rec12/23/88.
88.Sulfasalazinepackageinsert(KenralCanada),Rev9/20/91,Rec11/4/93.
89.Mithracinproductinformation(BayerUS).In:PDRPhysicians'deskreference.52nded.1998.Montvale,NJ:
MedicalEconomicsCoInc1998.p6235.
90.Panelconsensus,4/99.
91.Panelcomment,4/99.
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