FICHADEMEDICAMENTO

Theophylline,Aminophylline
Elixophyllin|QuibronT|QuibronT/SR|Respbid|SloBid...
InformacinproporcionadaporGoldStandard

Description:Theophyllineisaxanthinederivativethatisusedbothorallyorintravenouslyinthetreatmentofasthmaand
bronchospasm.Theophyllineoccursnaturallyinteaandischemicallysimilartocaffeineandtheobromine.Theophyllinewasintroduced
in1900totreatasthma,butitsusedidnotbecomewidespreaduntilafter1936,anditwasnotapprovedbytheFDAuntil1940.During
the1970sand1980s,theophyllinedosingwasintensivelystudied,itspharmacokineticswereaccuratelydescribed,andsustainedrelease
preparationsweremarketed.Currently,sustainedreleasetheophyllineisconsideredanalternate,butnotpreferred,therapytotheuse
ofinhaledcorticosteroids(ICSs)inthetreatmentofmildpersistentasthma(step2care)accordingtothe2007guidelinesoftheExpert
PaneloftheNationalAsthmaEducationandPreventionProgram.33558Inaddition,thePanelrecommendstheophyllineasanalternate,
adjuncttherapywithlowdoseICSforpatientswithinadequatelycontrolledmoderatepersistentasthma(step3care).Analternate
treatmentinstep4careincludesthecombineduseoftheophyllineandICS.Modestclinicaleffectivenessaswellastheneedfor
monitoringtheophyllinelevelsshouldbetakenintoconsiderationwhenevaluatingthebenefitsandrisksoftheophyllinecomparedto
otherasthmatreatments.TheophyllineandaminophyllinearenotrecommendedforthetreatmentofstableCOPDduetolowefficacy
andadversereactionsunlessotherlongactingbronchodilatorsareunavailableornotaffordable.InCOPDexacerbation,intravenous
theophyllineoraminophyllineareconsideredsecondlinetherapy,onlytobeusedwhenasufficientresponsetoinhaledshortacting
bronchodilatorscannotbeobtained.50604Bothimmediateandsustainedreleaseoraldosageformsaremarketedandtheseshouldnot
beconfused.InJanuary1996,theFDAissuedafinalrulestatingthatOTCcombinationproductscontainingtheophyllinearenot
generallyrecognizedassafeandeffective.Asaresult,thesecombinationproductswerereformulated.InMay2002,allTheoDur
productswerediscontinuedbythemanufacturerTheoDurSprinkleshavebeendiscontinuedsinceJanuary1995.
MechanismofAction:Despitedecadesofresearch,themechanismofactionfortheophyllineisstillbeingdebated.Whileits
bronchoprotectiveeffectsaremostwellknown,theophyllineappearstoalsopossessantiinflammatoryandimmunomodulatoryactions.
24634Theophyllinerelaxesthesmoothmuscleofthebronchialairwaysandpulmonarybloodvessels.Inpatientswithasthma,

theophyllinereducesairwayresponsivenesstohistamine,methacholine,adenosine,andallergen.24634Theabilityoftheophyllineto
controlchronicasthma,however,isdisproportionatelygreaterthanisexplainablebyitsrelativelyweakbronchodilatoryaction.24634
Theophyllinemayevenpossessantiinflammatoryactionsasevidencedbyitsabilitytoattenuatelatephasereactionsinasthma.23579
Regardingitsbiochemicalaction,originally,itwasbelievedthattheophyllineexerteditseffectsviatheinhibitionoftypeIIIortypeIV
phosphodiesterase(PDE)whichisresponsibleforbreakingdowncyclicAMPinsmoothmusclecells.Whiletheophyllinedoespossess
thisproperty,itisnegligibleattherapeuticserumconcentrationsandthereisnoevidencethatintracellularconcentrationsof
theophyllineinairwaysmoothmusclecellsarehigherthanserumconcentrations.DrugsthatexertgreaterinhibitionofPDEthan
theophylline(e.g.,dipyridamole,papaverine)havenobronchodilatoreffect.
Otherexplanationstheophylline'sactionhavebeenproposedincludingchangesinsmoothmusclecalciumionconcentration,inhibition
ofhistaminereleaseandadenosineantagonism.Adenosineantagonismhasbeenconsideredasanexplanationfortheophylline's
bronchodilatingeffects.Supportingthistheoryarethefactsthatadenosineandtheophyllinearestructurallysimilar,adenosinecan
provokebronchoconstrictioninasthmaticpatients,andadenosinecanantagonizetheophyllineinducedbronchodilation.Inaddition,
theophyllinecanantagonizeadenosine'sactionsinothertissues.However,controversysurroundsthisexplanationalso.23579
Contradictingthetheorythattheophyllinebronchodilationismediatedbyadenosineantagonismisthefactthatenprofylline,another
xanthinethatisfivetimesaspotentabronchodilatorastheophylline,doesnotantagonizeadenosine.23579Thus,cliniciansdonot
believeadenosineantagonismexplainsthebronchoprotectiveactionsoftheophylline.24634
Actionsoftheophyllineotherthanbronchodilation,particularlythosethatareexcitatory,mayindeedbeafunctionofadenosine
antagonism,however.SinceadenosineisaCNSdepressant,antagonismofadenosinemayexplaintheophylline'sstimulantactiononthe
medullaryrespiratorycenter,increasingthesensitivitytocarbondioxide.Furthersupportofadenosineantagonismasanexplanation
fortheextrapulmonaryactionsoftheophyllinewasdemonstratedbytheophylline'sabilitytoattenuatemethotrexateinduced

neurotoxicity,asyndromebelievedduetoelevatedadenosineCNSconcentrations.24089Asabronchodilator,theophylline'scellular
mechanismofactionisstilluncertain.
Theophyllinerelaxesothertypesofsmoothmusclebutcanstimulatecardiacandskeletalmusclecontraction.Increasedcardiacoutput
canleadtodiuresis,buttolerancemaydeveloptothiseffect.OtherextrapulmonaryeffectsattributedtotheophyllineincludeCNS
stimulation,improveddiaphragmaticcontractility,andprostaglandininhibition.Acentralmechanismappearstoberesponsiblefor
theophylline'sabilitytoreducecentralsleepapneainpatientswithheartfailure.24649
Pharmacokinetics:Theophyllinecanbeadministeredorallyorintravenously.Whenrapidattainmentoftherapeuticserum
concentrationsisdesired,IV"loading"dosescanbegiven,althoughoraladministrationwithregularreleasetabletsisequallyeffective.
Unboundtheophyllineserumconcentrationsareusuallyintherangeof612mcg/mlandconcentrationsshouldbeobtainedin
patientswithlowproteinbinding(i.e.,neonates,hepaticcirrhosis).Steadystateserumconcentrationsarereachedin3065hoursin
adults.Aminophylline,asaltoftheophylline,istheformfrequentlyusedforIVtherapy.Since100mgofaminophyllineisequivalentto
80mgoftheophylline,errorsindosingarepossible,andcliniciansshouldcarefullyassessdoseadjustmentsandcalculationswhen
switchingbetweenaminophyllinedoseformsandtheophyllinedoseforms.

Proteinbindingisapproximately40%forhealthyadultsandislowerinneonatesandpatientswithhepaticimpairment.Targetpeak
serumconcentrationrangesforneonatesforthetreatmentofapneaarethereforelowerthanthoseofadults,duetoagreaterproportion
offree"active"theophylline.Unboundtheophyllineisdistributedthroughoutextracellularbodyfluidsandtissues,however,distribution
intobodyfatispoor.Theophyllinereadilycrossestheplacentaandthebloodbrainbarrierandisexcretedintobreastmilk.

AffectedcytochromeP450isoenzymesanddrugtransporters:CYP1A2,CYP2E1,CYP3A4
TheophyllineisprimarilymetabolizedbyCYP1A2isoenzymes,withsecondarypathwaysbyCYP2E1andCYP3A4.Invitrodatasuggest
thatwhilemetabolismismediatedbyCYP1A2atlowplasmaconcentrations,metabolismshiftstoCYP2E1athigherconcentrations,and
metabolismbyCYP3A4isminor,independentoftheophyllineplasmaconcentration.34671Themanufacturerstatesthattheophyllineis
asubstrateofhepaticenzymesCYP1A2,2E1,and3A3withoutmentionof3A450760however,cytochromeP450genomeexpertsno
longersupporttheexistenceofCYP3A3andinsteadattributethisisoformtoacodingerroroforavariantofCYP3A4.5607534673Since
thetherapeuticrangeisnarrow,itisprudenttomonitortheophyllineserumconcentrationsuponinitiation,dosageadjustment,or
discontinuationofmedicationsthatmayalterthefunctionofCYP1A2,CYP2E1,and/orCYP3A4isoforms.

Intheprematureneonate,theophyllineismetabolizedtocaffeineinsignificantamounts,andthiscompoundcanaccumulateduetoits
longhalflife.Eliminationisusuallyafirstorderprocess,butzeroordereliminationhasbeenreportedinsomecases.Theophyllines'
halflifevarieswithpatientage,hepaticfunction,smokingstatus,anddruginteractions.Nonsmokingadultsusuallyhaveahalflifeof
6.510.5hours.Metabolitesareeliminatedrenally,withonlyabout10%excretedasunchangedtheophylline.

RouteSpecificPharmacokinetics
OralRoute
Theophyllineisgenerallywellabsorbedafteroraladministration.Regular(i.e.,nonsustainedrelease)tabletsproducepeakserum
concentrationswithin60minutesafteradministration.Liquidsandsuspensionsareabsorbedmorerapidly.Sustainedrelease
preparationsvaryintherateofabsorption.Foodcandelaytherate,butnottheextent,ofabsorptionofsomesustainedrelease
products.Largevolumesoffluidcanincreaseabsorption.

Peakconcentrationsshouldusuallyoccur12hoursafteroraldosing.Serumconcentrationsof1020mcg/ml(55110micromoles/L)
generallyareregardedastherapeutic,however,theFDAhasnowloweredthetargetpeakconcentrationrangeto1015mcg/mlto
minimizetheriskofadversereactions.Mostcliniciansuse815mcg/mlasthetargetrange.

SpecialPopulations
HepaticImpairment
Cirrhosiscanprolongthehalflifeoftheophyllinetoaslongas24hours.
Pediatrics
Inchildrenage19years,thehalflifeoftheophyllinecanbeasshortas45hours.Neonates(<3monthsold)haveamuchhigherrate
ofexcretionofunchangedtheophylline(approximately50%).

Other
Smoking
Insmokers,thehalflifeoftheophyllinecanbeasshortas45hours.

Corpulmonale
Corpulmonalecanprolongthehalflifeoftheophyllinetoaslongas24hours.

Pulmonaryedema
pulmonaryedemacanprolongthehalflifeoftheophyllinetoaslongas24hours.
Lastrevised:August31,2016

IndicacionesyDosificacin
asthma
bronchospasmprophylaxis
chronicobstructivepulmonarydisease(COPD)
emphysema
neonatalapnea
sleepapnea
statusasthmaticus
Fortreatmentofreversibleairwaysobstruction(i.e.,forbronchospasmprophylaxis)associatedwithasthmaor
chronicobstructivepulmonarydisease(COPD)(e.g.,emphysemaorchronicbronchitis):
NOTE:Calculateinitialmg/kgdosebasedonidealbodyweightastheophyllinedistributespoorlyintobodyfat.4423244286
foradjuncttreatmentofacuteexacerbationsofthesymptomsandreversibleairflowobstructionassociatedwith
asthmaandotherchroniclungdiseases(e.g.,COPD)alongwithinhaledbeta2selectiveagonistsandsystemic
corticosteroids:
Intravenouscontinuousinfusionmaintenancedosage(dosageisexpressedastheophylline):
Adults>=60years:Initially,0.3mg/kg/hourIV.Give0.2mg/kg/hourIVtopatientswithCHF,corpulmonale,liverdysfunction,
sepsiswithmultiorganfailure,shock,orotherfactorsforreducedtheophyllineclearance.Reduceddosesmaybeneededinpatients
receivingotherdrugsthatdecreasetheophyllineclearance.Adjustdosagebasedonsubsequentserumconcentrationsdonotexceed
400mg/dayunlessserumconcentrationandpatientconditionindicatetheneedforahigherdosage.44232InacuteCOPDexacerbation,
intravenoustheophylline/aminophyllineisconsideredsecondlinetherapy,onlytobeusedwhenasufficientclinicalresponsedoesnot
occurwiththeuseofshortactinginhaledbronchodilators.50604
Adults<60yearsandAdolescents>=16years:Initially,0.4mg/kg/hourIVuptoamaximumof900mg/dayinotherwisehealthy
nonsmokersalthoughnospecificdosingguidanceisavailable,patientswhosmokemayrequireanincreaseddoseassmokingincreases
drugclearance(seePharmacokineticsandPrecautions).Give0.2mg/kg/hourIV(upto400mg/day)topatientswithCHF,cor
pulmonale,liverdysfunction,sepsiswithmultiorganfailure,shock,orotherfactorsforreducedtheophyllineclearance.Reduceddoses
maybeneededinpatientsreceivingotherdrugsthatdecreasetheophyllineclearance.Adjustdosagebasedonsubsequentserum
concentrations.44232InacuteCOPDexacerbation,intravenoustheophylline/aminophyllineisconsideredsecondlinetherapy,onlyto
beusedwhenasufficientclinicalresponsedoesnotoccurwiththeuseofshortactinginhaledbronchodilators.50604
Children>=12yearsandAdolescents<=15years:Initially,0.5mg/kg/hourIVinotherwisehealthynonsmokers(upto900mg/day)
0.7mg/kg/hrIVinsmokers.Reduceddosesmaybeneededinpatientsreceivingotherdrugsthatdecreasetheophyllineclearance.Dose
at0.2mg/kg/hourIV(upto400mg/day)inpatientswithcardiacdecompensation,corpulmonale,liverdysfunction,sepsiswith
multiorganfailure,orshock.Adjustdosagebasedonsubsequentserumconcentrations.44232
Children9to11years:Initially,0.7mg/kg/hourIV.Reduceddosesmaybeneededinpatientsreceivingotherdrugsthatdecrease
theophyllineclearance.Give0.2mg/kg/hourIV(upto400mg/day)topatientswithcardiacdecompensation,corpulmonale,liver
dysfunction,sepsiswithmultiorganfailure,orshock.Adjustdosagebasedonsubsequentserumconcentrations.44232
Children1to8years:Initially,0.8mg/kg/hourIVreduceddosesmaybeneededinpatientsreceivingotherdrugsthatdecrease
theophyllineclearance.Doseat0.2mg/kg/hourIV(upto400mg/day)inpatientswithcardiacdecompensation,corpulmonale,liver

dysfunction,sepsiswithmultiorganfailure,orshock.Adjustdosagebasedonsubsequentserumconcentrations.44232.
Infants6to52weeks:Calculateinitialdosageusingthefollowingequation:(0.008xageinweeks)+0.21=theophyllinedosagein
mg/kg/hourIVreduceddosesmaybeneededinpatientswithriskfactorsforreducedtheophyllineclearance(e.g.,cimetidinetherapy,
cardiacorliverdysfunction,renaldysfunctionininfants<3months).Adjustdosagebasedonsubsequentserumconcentrations.44232
formaintenancetherapyofasthmaorCOPDusingoraldosage:
Oralmaintenancedosage(dosageisexpressedastheophyllineusingimmediatereleaseproducts):
Adults,Adolescents,andChildren>45kg:Initially,300mg/dayPOindivideddosesevery68hours.After3days,iftolerated,
increasedoseto400mg/dayPOindivideddosesevery68hours.After3moredays,iftolerated,increasedoseto600mg/dayPOin
divideddosesgivenevery68hours.Adjustdosetomaintaintherapeuticrangedosesof4001600mg/dayPOmaybeneeded.Do
notexceed400mg/dayinpatientswithriskfactorsfordecreasedtheophyllineclearance,suchastheelderly(>60years),andinthose
whocannotreceiverecommendedserumconcentrationmonitoring.Considersmaller,morefrequentdosesofimmediaterelease
productsoruseofextendedreleaseproductsinpatientswithrapidmetabolism,identifiedbyhigherthanaveragedoserequirements.
4428644288AnNIHexpertpanelrecommendsinitialdoseforasthmaof10mg/kg/day(max:300mg/day)POwithtitrationtoserum

concentrationof515mcg/ml(usualmax:800mg/dayinpatients>=12yearsand16mg/kg/dayinchildren111).44295Duetolow
efficacyandmoreadversereactions,theophyllineisnotrecommendedforuseinstableCOPDunlessotherinhaledlongacting
bronchodilatorsareunavailableornotaffordable.50604
ChildrenandAdolescents<=15yearsoldand<=45kg:Initially,1214mg/kg(max300mg)perdayPOindivideddosesevery46
hours.After3days,iftolerated,mayincreaseto16mg/kg(max:400mg)perdayindivideddosesevery46hours.After3moredays,
iftoleratedandifneeded,increasedoseto20mg/kg(max:600mg)perdayindivideddosesevery46hours.Adjustdosetomaintain
therapeuticrange(e.g.,dosesof1036mg/kg/dayPOinchildren19yearsmaybeneeded).Donotexceed16mg/kg(max:400mg)
perdayinpatientswithriskfactorsfordecreasedtheophyllineclearanceorwhocannotreceiverecommendedserumconcentration
monitoring.4428644288AnNIHexpertpanelrecommendsinitialdoseforasthmaof10mg/kg/day(max:300mg/day)POwithtitration
toserumconcentrationof515mcg/ml(usualmax:800mg/dayinpatients>=12yearsand16mg/kg/dayinchildren111).44295
NeonatesandInfantsupto52weeksold:Calculateinitialdoseusingthefollowingequation:[(0.2xageinweeks)+5]x(kgbody
weight)=theophyllinedosageinmg/dayPO.Ininfantsupto26weeksold,dividedoseandadministerevery8hoursandininfants>
26weeksold,dividedoseandadministerevery6hours.Considerincreasedmonitoringanddosereductionsininfants<3monthswith
renaldysfunction.Adjustdosetomaintainasteadystateserumconcentrationof510mcg/mlinneonatesand1015mcg/mlin
infants.4428644288AnNIHexpertpanelrecommendsinitialdoseforasthmaof10mg/kg/dayPOwithtitrationtotheophyllineserum
concentrationof515mcg/ml,usualmaxinmg/kg/day=[(0.2xageinweeks)+5].44295
Oralmaintenancedosage(dosageisexpressedastheophyllineusingextendedreleasedosageforms,e.g.,TheolairSR):
NOTE:Extendedreleaseformulationsareintendedonlyforchronicdiseasemanagementdonotuseintreatmentofacutesymptomsof
asthmaandreversiblebronchospasm.44293
Adults>=60years:Initially,300mg/dayPOindivideddosesevery812hours.After3days,iftolerated,increasedosageto400
mg/dayPOindivideddosesevery812hours.Adjustdosetomaintaintherapeuticrange.Donotexceed400mg/dayunlessserum
concentrationandpatientconditionindicateneedforhigherdose.Considersmaller,morefrequentdosesinpatientswithrapid
metabolism,identifiedbyhigherthanaveragedoserequirements.44293AnNIHexpertpanelrecommendsinitialdoseforasthmaof10
mg/kg/day(max:300mg/day)POwithtitrationtotheophyllineserumconcentrationof515mcg/ml.44295Duetolowefficacyand
moreadversereactions,theophyllineisnotrecommendedforuseinstableCOPDunlessotherinhaledlongactingbronchodilatorsare
unavailableornotaffordable.50604
Adults<60years,Adolescents,andChildren>=6yearsand>45kg:Initially,300mg/dayPOindivideddosesevery812hours.
After3days,iftolerated,increaseto400mg/dayPOindivideddosesevery812hoursthenafter3moredays,iftolerated,increaseto
600mg/dayindivideddosesevery812hours.Adjustdosetomaintaintherapeuticrangedosesof4001600mg/dayPOmaybe
needed.Donotexceed400mg/dayinpatientswithriskfactorsfordecreasedtheophyllineclearanceandinthosewhocannotreceive
recommendedserumconcentrationmonitoring.Considersmaller,morefrequentdosesinpatientswithrapidmetabolism,identifiedby
higherthanaveragedoserequirements.44293AnNIHexpertpanelrecommendsinitialdoseforasthmaof10mg/kg/day(max:300
mg/day)POwithtitrationtoserumconcentrationof515mcg/ml(usualmax:800mg/dayinpatients>=12yearsand16mg/kg/day
inchildren111).44295Duetolowefficacyandmoreadversereactions,theophyllineisnotrecommendedforuseinstableCOPDunless
otherinhaledlongactingbronchodilatorsareunavailableornotaffordable.50604
Children>=6yearsandAdolescents<=15yearsoldand<=45kg:Initially,1214mg/kg(max:300mg)perdayPOindivideddoses
every812hours.After3days,iftolerated,mayincreasedoseto16mg/kg(max:400mg)perdayPOindivideddosesevery812
hours.After3moredays,iftolerated,increasedoseto20mg/kg(max:600mg)perdayPOindivideddosesevery812hours.Adjust
dosetomaintaintherapeuticrangedosesof1036mg/kg/dayPOinchildren<9yearsand4001600mg/dayPOinpatients>=16
yearsmaybeneeded.Donotexceed16mg/kg/dayupto400mg/dayinpatientswithriskfactorsfordecreasedtheophyllineclearance

orwhocannotreceiverecommendedserumconcentrationmonitoring.44293AnNIHexpertpanelrecommendsinitialdoseforasthma
of10mg/kg/day(max:300mg/day)POwithtitrationtotheophyllineserumconcentrationof515mcg/ml(usualmax:800mg/dayin
patients>=12yearsand16mg/kg/dayinchildren111).44295
Oralmaintenancedosage(dosageisexpressedastheophyllineusingcontrolledreleasedosage,e.g.,Theo24Capsules):
NOTE:Extendedreleaseformulationsareintendedonlyforchronicdiseasemanagementdonotuseintreatmentofacutesymptomsof
asthmaandreversiblebronchospasm.44293
Adults,Adolescents,andChildren>=12yearsand>45kg:Initially,300400mg/dayPOevery24hourseveningdosingisnot
recommended.After3days,iftolerated,increasedosageto400600mg/dayPOevery24hours.Adjustdosetomaintaintherapeutic
rangedosesof4001600mg/dayPOmaybeneeded.Donotexceed400mg/dayinpatientswithriskfactorsfordecreased
theophyllineclearance,suchastheelderly(>60years),andinthosewhocannotreceiverecommendedserumconcentration
monitoring.Considertwicedailydosinginpatientswithrapidmetabolismandwhorepeatedlyhavesymptomsattheendofa24hour
dosinginterval.44294AnNIHexpertpanelrecommendsinitialdoseforasthmaof10mg/kg/day(max:300mg/day)POwithtitrationto
serumconcentrationof515mcg/ml(usualmax:800mg/day).44295Duetolowefficacyandmoreadversereactions,theophyllineis
notrecommendedforuseinstableCOPDunlessotherinhaledlongactingbronchodilatorsareunavailableornotaffordable.50604
Children>12yearsandAdolescents<16yearsand<45kg:Initially,1214mg/kg(max:300mg)perdayPOevery24hoursevening
dosingisnotrecommended.After3days,iftolerated,mayincreasedoseto16mg/kg(max:400mg)perday.After3moredays,if
toleratedandifneeded,increaseto20mg/kg(max:600mg)perday.Adjustdosetomaintaintherapeuticrange.Donotexceed16
mg/kg/dayupto400mg/dayinpatientswithriskfactorsfordecreasedtheophyllineclearanceorwhocannotreceiverecommended
serumconcentrationmonitoring.Considertwicedailydosinginpatientswithrapidmetabolismandwhorepeatedlyhavesymptomsat
theendofa24hourdosinginterval.44294AnNIHexpertpanelrecommendsinitialdoseforasthmaof10mg/kg/day(max:300
mg/day)POwithtitrationtoserumconcentrationof515mcg/ml(usualmax:800mg/day).44295
Forthetreatmentofacuteexacerbationsofreversibleairwaysobstruction(includingstatusasthmaticus)in
patientswhoarenotrespondingtofirstlinetherapies:
NOTE:Althoughreferencetextscontinuetolistthisindication,severalstudieshavefailedtodemonstrateabenefitoftheophyllinein
themanagementofacutebronchospasm.TheFDAnolongerincludesacutebronchospasmasanapprovedindication.Mostclinicians
donotfeeltheophyllineiswarrantedinthetreatmentofacutebronchospasmunlessthepatientisnotrespondingtoothertreatments.
24634TheNationalAsthmaEducationandPreventionProgramdoesnotrecommendtheophyllineforacuteexacerbationsbecauseit

appearstoprovidenoadditionalbenefittooptimalinhaledbeta2agonisttherapyandmayincreaseriskofadverseeffects.33558
Intravenousloadingdosage(dosageisexpressedastheophylline):
Adults,Adolescents,andChildren:4.6mg/kgIVloadingdoseinfusedover30minutesinapatientwhohasreceivednotheophyllinein
theprevious24hourswillproduceanaveragepeakserumtheophyllineconcentrationof10mcg/ml(range616mcg/ml)calculate
mg/kgdosebasedonidealbodyweight.Inpatientswhohavereceivedtheophyllinewithintheprevious24hours,atheophyllineserum
concentrationmustbedrawnandloadingdose,ifneeded,calculatedaccordingly.44232Ifdosingwiththeophyllineiscontinued,follow
maintenancedosagebelow.
Oralloadingdosage(dosageisexpressedastheophyllineNOTEdonotusesustainedreleasedosageforms):
Adults,Adolescents,andChildren:5mg/kgPOloadingdoseusinganimmediatereleaseproductinapatientwhohasreceivedno
theophyllineintheprevious24hourswillproduceanaveragepeakserumtheophyllineconcentrationof10mcg/ml(range515
mcg/ml)calculatemg/kgdosebasedonidealbodyweight.44286Ifdosingwiththeophyllineiscontinued,followmaintenancedosage
below.
Forthetreatmentofneonatalapneaofprematuritywhennonpharmacologictherapiesareineffective:
NOTE:Caffeineisthepreferredagentforthisindication(seeCaffeinemonograph)theophyllineisusedasanalternative.
Intravenousloadingdosage(theophyllineonly):
PrematureNeonates:Aloadingdoseof4mg/kg(theophylline)IVinfusedover2030minuteswillproduceanaveragepeakserum
theophyllineconcentrationof810mcg/ml.Ifdosingwiththeophyllineiscontinued,followmaintenanceIVorPOdosage
recommendations.
Intravenousororalsyrupmaintenancedosage(theophyllineonly):
PrematureNeonates,postnatalage>=24days:Initially,1.5mg/kg(theophylline)IVorPOevery12hours.Peaksteadystateserum
theophyllineconcentrationsshouldaverage8mcg/ml(range510mcg/ml)forneonatalapnea.Monitorclinicalstatusand
theophyllineserumconcentrationsfrequently.Dosageoftheophyllinemustbeindividualized.
PrematureNeonates,postnatalage<24days:Initially,1mg/kg(theophylline)IVorPOevery12hours.Peaksteadystateserum
theophyllineconcentrationsshouldaverage8mcg/ml(range510mcg/ml)forneonatalapnea.Monitorclinicalstatusand

theophyllineserumconcentrationsfrequently.Dosageoftheophyllinemustbeindividualized.
Forthetreatmentofsleepapneainpatientswithchronicheartfailureinducedsystolicdysfunction:
Oraldosage(dosageisexpressedastheophyllineusingextendedreleasedosageforms):
Adults:Theeffectsoftheophyllineorplacebowereevaluatedin15menwithstableheartfailureanddocumentedsleepapnea.
Treatmentwiththeophyllineresultedinaconsiderablereductioninperiodicbreathingandepisodesofsleepapnea.Inthisstudy,
theophyllinewasadministeredasTheoDurtablets(NOTE:nolongercommerciallyavailable)3.3mg/kgPOtwicedailyfor5days.
Meanserumtheophyllineconcentrationonday5was11+/2mcg/ml(range6.914.9mcg/ml).24649
TherapeuticDrugMonitoring:
Thedosageoftheophyllinemustbeindividualized.Initialdosageshouldbebasedonleanbodyweightanddosageadjustments
shouldbebasedonserumtheophyllineconcentrations.Thetargetsteadystateserumtheophyllineconcentrationsgenerallyrange
from515mcg/mlininfants,children,andadults.
Alwaysmonitorserumtheophyllineconcentrationswithin1224hoursofbeginninganintravenouscontinuousinfusion.
ThefollowinggeneraldosingguidelinesareadaptedfromtherevisedFDAlabelingchangesfortheophyllineoraldosageforms
from1995,HendelesL,WeinbergerM.Theophylline:Astateoftheartreview.Pharmacother19833:244.
23486,andtheNIHExpertPanelReport2:GuidelinesfortheDiagnosisandManagementofAsthma,July1997.24901RiskFactorsfor

ReducedTheophyllineClearance:
Manydrugswillreducetheclearanceandmetabolismoftheophyllinesignificantly(seeDrugInteractions).Thefollowingagegroups
exhibitreducedtheophyllineclearance:theelderly(>60yearsofage)andneonates,particularlyprematureneonates.Thefollowing
diseasestatesareassociatedwithreducedtheophyllineclearance:corpulmonalecongestiveheartfailurehepaticdisease(cirrhosis,
cholestasisoracutehepatitis)andfever.Otherfactorsassociatedwithdecreasedtheophyllineclearanceincludethethirdtrimesterof
pregnancy,sepsiswithmultipleorganfailure,andhypothyroidism.Carefulattentiontodosereductionandfrequentserumtheophylline
concentrationmonitoringarerequired.
RiskFactorsforIncreasedTheophyllineClearance:
Somedrugswillincreasetheclearanceandmetabolismoftheophyllinesignificantly(seeDrugInteractions),includingthesmokingof
tobacco.Thefollowingdiseasestatesareassociatedwithincreasedtheophyllineclearance:hyperthyroidismandcysticfibrosis.Careful
attentiontodoseadjustmentandfrequentserumtheophyllineconcentrationmonitoringmayberequired.
RoutineDosageAdjustmentGuidelines(basedonserumtheophyllineconcentrations):
Steadystateserumtheophyllineconcentration<9.9mcg/ml:
Ifsymptomsarenotcontrolledandcurrentdosageistolerated,increasedosebyabout25%andrecheckconcentrationafter3days.Ifa
serumtheophyllineconcentrationisobtainedbeforesteadystateisachievedatagivendosage,donotincreasethemaintenancedose
evenifconcentrationis<10mcg/ml.
Steadystateserumtheophyllineconcentration=1014.9mcg/ml:
Ifsymptomsarecontrolledandcurrentdosageistolerated,maintaindoseandrechecktheophyllineconcentrationat612month
intervals.Ifsymptomsarenotcontrolledandcurrentdosageistolerated,consideraddingadditionalmedicationtotreatment.
Steadystateserumtheophyllineconcentration=1519.9mcg/ml:
Toprovideagreatermarginofsafety,considerdecreasingdoseby10%evenifcurrentdoseistolerated.
Steadystateserumtheophyllineconcentration=2024.9mcg/ml:
Decreasedoseby25%evenifnoadverseeffectsarepresentandrecheckconcentrationafter3days.
Steadystateserumtheophyllineconcentration=2530mcg/ml:
Skipnextdoseandreducesubsequentdosesbyatleast25%evenifnoadverseeffectsarepresentandrecheckconcentrationafter3
days.Ifpatientissymptomatic,considerwhetheroverdosetreatmentmaybenecessary.
Steadystateserumtheophyllineconcentration>30mcg/ml:
Holdtheophylline,treatasanoverdoseasnecessary(consultspecializedresources).Monitorthepatientandobtainserialtheophylline
concentrationsevery24hourstogaugetheeffectivenessoftherapyandtoguidefurthertreatmentdecisions.Iftheophyllineisresumed
later,decreasepreviousdosebyatleast50%andrecheckconcentrationafter3days.
MaximumDosageLimits:

Theophyllinehasanarrowtherapeuticindex.Themaximumdosageisindividualizedbasedontherapeuticdrugconcentration
monitoringandassessmentofefficacyandsafetyparameters(seeTherapeuticDrugMonitoring).Thefollowingaresomegeneral
guidelinesinchronicuse(dosageexpressedastheophylline):
Adults
<60years:Individualizedosage400mg/dayPOifriskfactorsfordecreasedclearancearepresentorrecommendedserum
concentrationmonitoringisnotpossible.
>=60years:400mg/dayPO.
Geriatric
400mg/dayPO.
Adolescents
>=16years:Individualizedosage400mg/dayPOifriskfactorsfordecreasedclearancearepresentorrecommendedserum
concentrationmonitoringisnotpossible.
<16years:Individualizedosage16mg/kg/dayupto400mg/dayPOifriskfactorsfordecreasedclearancearepresentor
recommendedserumconcentrationmonitoringisnotpossible.
Children
Individualizedosage16mg/kg/dayupto400mg/dayPOifriskfactorsfordecreasedclearancearepresentorrecommendedserum
theophyllineconcentrationmonitoringisnotpossible.
Infants
Mustindividualizedosage.
Neonates
Mustindividualizedosage.
PatientswithHepaticImpairmentDosing
Reduceddosageisneededinpatientswithliverdisease,includingcirrhosisandacutehepatitis.Maximuminitialdose=0.2mg/kg/day
IV(theophylline)inpatients>=1year.Donotexceed400mg/dayIV,400mg/dayPOinpatients>=16years,or16mg/kg/dayupto
400mg/dayPOinpatients<16yearsunlessserumtheophyllineconcentrationandpatientconditionwarranthigherdosecareful
attentiontodosereductionandfrequentmonitoringofserumtheophyllineconcentrationsarerequired.
PatientswithRenalImpairmentDosing
Reduceddosageisneededinneonatesandinfants<3monthsasroughly50%oftheadministeredtheophyllinedoseisexcreted
unchangedintheurineinthispopulationcarefulattentiontodosereductionandfrequentmonitoringofserumtheophylline
concentrationsarerequired.Inadults,children,andinfants>3monthsofage,nodosageadjustmentisnecessary.
nonFDAapprovedindication
Lastrevised:October10,2013

Administracin
GeneralAdministrationInformation
Forstorageinformation,seethespecificproductinformationwithinthetheHowSuppliedsection.
RouteSpecificAdministration
OralAdministration
Forfasterabsorption,administertheophyllinewithafullglassofwateronanemptystomach3060minutesbeforemealsor2
hoursaftermeals.Ifgastrointestinalirritationoccurs,administerwithfoodorantacids.

OralSolidFormulations
Entericcoatedortimedreleasecapsulesortablets:Donotcrushorchew.Forpatientswithdifficultyswallowing,thecapsule
formulationsmaybeopenedandmixedwithsoftfooddonotcheworcrushmedicationbeads.
Theo24capsules:Administeronanemptystomachadministrationwithahighfatcontentmealmayincreasethepeakserum
theophyllineconcentration('dosedumping')whichcouldresultintoxicity.Administrationisusuallyinthemorningatapproximately
thesametimedailywhentwodosesperdayareprescribed,administertheseconddose1012hoursafterthemorningdoseand
beforetheeveningmeal.
UniDurTablets:Donotcrushorchew.Maybeadministeredoncedaily,intheAMorinthePMandwithoutregardtomeals.When
twodosesperdayareprescribed,administertheseconddose12hoursafterthemorningdose.

OralLiquidFormulations
Elixir,solution,syrup:Administertheophyllineusingacalibratedmeasuringdevicetoensureaccuratedosing.

InjectableAdministration
Visuallyinspectparenteralproductsforparticulatematteranddiscolorationpriortoadministrationwheneversolutionand
containerpermit.Discardsolutionifitisnotclear.
Donotuseifcrystalsarepresent.
44232

IntravenousAdministration
Intravenousloadingdosebolus:
Ifthepatienthasreceivedanytheophyllinewithin24hours,obtainserumtheophyllineconcentrationpriortoadministrationofa
theophyllineloadingdose.
Manufacturersrecommendadministeringthebolusdoseover30minutes.
Monitorpatientclinicallyasappropriateduringinfusion.
Obtaintheophyllineserumconcentration30minutesafteradministrationofintravenousloadingdosetoassesstheneedforand
sizeofsubsequentloadingdoses,ifclinicallyindicated,andforguidanceofcontinuingtherapy.
44232

Intravenouscontinuousinfusion:
Infusionrateshouldbeindividualizedandisdependentoninterpatientvariabilityoftheophyllineclearance(seeDosage).
Monitorpatientclinicallyasappropriateduringinfusion.
Obtaintheophyllineserumconcentrationatoneexpectedhalflifeafterstartingtheconstantinfusionandagain12to24hours
later,thenmonitorevery24hoursduringinfusion.
44232

Parmetrosdemonitorizacin
LFTs
PFTs
serumtheophyllineconcentrations
serumtheophyllineconcentrations

Contraindicaciones

Contraindicaciones
acidemia
breastfeeding
cardiacarrhythmias
cardiacdisease
cholestasis
corpulmonale
cornhypersensitivity
coronaryarterydisease
cysticfibrosis
fever
gastritis
gastroesophagealrefluxdisease(GERD)
geriatric
heartfailure
hepaticdisease
hepatitis
hiatalhernia
hyperthyroidism
hypothyroidism
hypoxemia
infants
myocardialinfarction
neonates
pepticulcerdisease
pregnancy
prostatichypertrophy
pulmonaryedema
renalimpairment
seizuredisorder
sepsis
shock
tobaccosmoking

Theophyllinecanaltertheresultsofsomecommonlaboratorytests.Serumconcentrationslevelsofglucose,uricacid,freefattyacids
(cholesterol,HDL),andurinaryfreecortisolexcretionmayallbereportedlyincreased.Also,transientdecreasesintriiodothyronine
levelshavebeenreported.Theclinicianshouldbeawareofthesealterationsandshouldweightheclinicalimportanceofthesechanges
tothebenefitsoftheophyllinetherapy.
Patientswithcardiacdiseaseshouldbemonitoredmorecloselyforadversereactionstotheophylline.Lowerdosesmaybenecessaryfor
patientswithcongestiveheartfailure,includingcorpulmonale,duetodecreasedtheophyllineclearance(>=50%decrease).Also,
theophyllinecanexacerbateexistingcardiacarrhythmiasandshouldbeusedwithcautioninpatientsatrisk.Similarly,because
theophyllinecanincreaseoxygendemand,itshouldbeprescribedcarefullyinpatientswithcoronaryarterydisease,especiallythose
withahistoryofmyocardialinfarction.
Patientswithhypothyroidism,acutepulmonaryedema,sepsiswithmultipleorganfailure,orshockmayhavedecreasedtheophylline
clearance.Anypatientswithanyoftheaboveconditionsshouldbemonitoredcarefullywhilereceivingtheophylline.
Increasedtheophyllineclearancemayoccurinpatientswithhyperthyroidismorcysticfibrosis.Hypercalcemiahasbeenreportedina
patientwithhyperthyroiddiseaseattherapeutictheophyllineconcentrations.Anypatientswithcysticfibrosisorconditionsaffectingthe
thyroidshouldbemonitoredcarefullywhilereceivingtheophylline.
Patientswithuncorrectedacidemiacanhaveanincreaseinthevolumeofdistributionoftheophyllineduetoadecreaseinplasma
proteinbinding.Unboundserumtheophyllineconcentrationsshouldbemonitoredinthesepatientstoavoidtoxicity.
Sincetheophyllineismetabolizedhepatically,dosesmayneedtobelowerinpatientswithmoderatetoseverehepaticdiseasesuchas
cirrhosis,acutehepatitis,cholestasis,oralcoholicliverdisease.Patientswhoregularlyconsumeethanolbutdonotexhibitoverthepatic
dysfunctionmayactuallyrequirelargerdosesthannormal.Theelderlymayalsohavereducedhepaticmetabolism,andtheirdoses
shouldgenerallybelowerwithcautioustitration.Dosesshouldbedecreasedinininfantsunder1yearofage,especiallypremature
neonatesduetoalessdevelopedhepaticmetabolism.Also,sinceneonatesandyounginfantshaveahigherpercentageofunchanged
theophyllineexcretedviathekidneys(approximately50%innewbornsascomparedto10%inthoseolderthan3months),neonatesand
infantslessthan3monthswithrenalimpairmentrequirelowerdoses.4423244288
Tobaccosmokinghasbeenshowntoincreasetheclearanceoftheophyllinebyabout50%inyoungadulttobaccosmokersandabout
80%inelderlytobaccosmokers.Also,passivesmokeexposuremaycauseaanincreaseintheophyllineclearancebyupto50%.Because
theeffectoftobaccoonhepaticmicrosomalenzymesisnotrelatedtothenicotinecomponent,suddensmokingcessationmayresultina
reducedclearanceoftheophylline,despitetheinitiationofnicotinereplacementproducts.Following1weekofabstinencefromchronic
tobaccosmoking,theophyllineclearancemaydecreasebyroughly40%,leadingtoanincreaseinserumtheophyllineconcentrations.
Theophyllineserumconcentrationsshouldbemonitoredcarefullywhenchangesinsmokingstatusoccur.
Prolongedfeverhasbeenreportedtoreducetheophyllineclearance.Lowerdosesshouldbeconsideredintheseconditions.
Theophyllinealsoshouldbeusedcautiouslyinpatientswithrespiratoryinfectionorseverehypoxemia.
Sincetheophyllinecanstimulategastricsecretions,itshouldbeusedwithcautioninpatientswithgastritisoractivepepticulcerdisease.
Theophyllinemayaggravatesymptomsrelatedtohiatalherniaorgastroesophagealrefluxdisease(GERD).
Theophyllinerelaxessmoothmuscleandcanincreaseurinaryretention,soitshouldbeusedwithcautioninpatientswithprostatic
hypertrophy.Useoftheophyllineinitiallycancauseadiureticeffect.
TheophyllineisclassifiedasaFDApregnancyriskcategoryCdrug.442884429346999Theophyllinehasnotbeenproventobeteratogenic
inhumans,butuseduringpregnancymayleadtopotentiallydangerousserumtheophyllineandcaffeineconcentrationsinneonates,as
wellastachycardia,irritability,andothersymptomsoftheophyllinetoxicity.Decreasedtheophyllineclearancehasbeenreportedduring
thethirdtrimesterofpregnancy.Despitetheseprecautions,theophyllineisconsideredanalternativetherapytoinhaledcorticosteroids
formildpersistentasthmaduringpregnancyaccordingtothe2004guidelinesoftheNationalAsthmaEducationandPrevention
Program(NAEPP)AsthmaandPregnancyWorkingGroup.Ifused,itisrecommendedthatserumtheophyllineconcentrationsbe
regularlymonitoredandmaintainedbetween512mcg/mL.Itshouldbenotedthatinhaledcorticosteroidsarethepreferredtreatment
duetothepotentialtoxicitiesoftheophylline,includingsideeffectsanddruginteractions.31822However,maintainingapreviously
establishedtreatmentregimenmaybemorebeneficialtothepatient.Therefore,selectionofanypharmacologictreatmentforasthma
controlduringpregnancyshouldincludethespecificneedsofthepatient,basedonanindividualevaluation,andconsiderationofthe

potentialbenefitsorriskstothefetus.
Theophyllineisexcretedinbreastmilkinconcentrationssimilartotheserumconcentrationofthemother.Neonateswhosemothers
havebeentakingtheophyllineduringpregnancyorwhilebreastfeedingshouldbemonitoredcarefully.Breastfedinfantswhose
mothersaretakingtheophyllinemayexperienceirritabilityorothermildsignsoftoxicityhowever,seriousadverseeventsareunlikely
unlessthemotherhastoxicserumconcentrations.442884429346999Theophyllineisconsideredanalternativetherapytoinhaled
corticosteroidsformildpersistentasthmaduringpregnancyandlactationaccordingtothe2004guidelinesoftheNationalAsthma
EducationandPreventionProgram(NAEPP)AsthmaandPregnancyWorkingGroup.Ifused,itisrecommendedthatserum
theophyllineconcentrationsberegularlymonitoredandmaintainedbetween512mcg/mL.31822TheAmericanAcademyofPediatrics
considerstheophyllinetobeusuallycompatiblewithbreastfeeding.27500Considerthebenefitsofbreastfeeding,theriskofpotential
infantdrugexposure,andtheriskofanuntreatedorinadequatelytreatedcondition.Ifabreastfeedinginfantexperiencesanadverse
effectrelatedtoamaternallyingesteddrug,healthcareprovidersareencouragedtoreporttheadverseeffecttotheFDA.
Theophyllineiscontraindicatedinpatientswhohavedemonstratedahypersensitivityreactiontotheophyllineoranycomponentinthe
commercialproduct.Somepremixedtheophyllineindextroseintravenousinfusionsmaybemanufacturedusingcornorcornproducts
andmaybecontraindicatedinpatientswithcornhypersensitivity.
Theophyllineshouldbeusedcautiouslyinpatientswithahistoryofseizuredisorderduetotheriskofexacerbatingtheircondition.
Theclearanceoftheophyllineisdecreasedbyanaverageof30%inhealthygeriatricadultsvsyoungeradultsclearancemaybefurther
significantlydecreasedifconcomitantdiseasestatesorotherfactorsforreducedclearancearepresent.Carefulconsiderationmustbe
giventothebenefitsandrisksoftheophyllineoraminophyllineuseandtheneedformoreintensivemonitoringofserumtheophylline
concentrationsinolderadultpatientsmorethan60yearsofage.Ifthetotaldailydoseisnotappropriatelyreduced,severeand
potentiallyfataltheophyllinetoxicitycanoccur.4428850760AccordingtotheBeersCriteria,theophyllineisconsideredapotentially
inappropriatemedication(PIM)foruseingeriatricpatientswithinsomniaandshouldbeavoidedduetothepotentialfordruginduced
CNSstimulanteffects.60515
Lastrevised:January29,2016

Interacciones
Acyclovir
Adenosine
Albendazole
Allopurinol
Alphainterferons
Amiodarone
Anagrelide
Aprepitant,Fosaprepitant
Atazanavir
AtazanavirCobicistat
Barbiturates
Benzodiazepines
Betaagonists
Betablockers
Bupropion

Caffeine
Carbamazepine
Cetirizine
Cimetidine
Ciprofloxacin
Clarithromycin
Cobicistat
CobicistatElvitegravirEmtricitabineTenofovirAlafenamide
CobicistatElvitegravirEmtricitabineTenofovirDisoproxilFumarate
Colesevelam
Darunavir
DarunavirCobicistat
DasabuvirOmbitasvirParitaprevirRitonavir
Dichlorphenamide
Diltiazem
Dirithromycin
Disulfiram
Dronabinol,THC
Dyphylline
Echinacea
ElbasvirGrazoprevir
Erythromycin
Ethotoin
Famotidine
Febuxostat
Flavocoxid,FlavocoxidCitratedZincBisglycinate
Fluconazole
Fluvoxamine
Fosphenytoin
GeneralAnesthetics
GreenTea
Guarana
InfluenzaVirusVaccine
InterferonGamma1b

Isoniazid,INH
Ivacaftor
Ketoconazole
Lansoprazole
Levofloxacin
Lithium
LumacaftorIvacaftor
Methotrexate
Mexiletine
Modafinil
Nabilone
ObeticholicAcid
OmbitasvirParitaprevirRitonavir
Osimertinib
Phenytoin
Prednisone
Primidone
Propafenone
Quinine
RadiopaqueContrastAgents
Ranitidine
Regadenoson
Rifampin
Riociguat
Ritonavir
Rofecoxib
Roflumilast
Ropivacaine
Sevelamer
St.John'sWort,Hypericumperforatum
Sympathomimetics
Tacrine
Tacrolimus
Thyroidhormones

Ticlopidine
tobacco
Troleandomycin
Verapamil
Zafirlukast
Zileuton
NOTE:TheophyllineisprimarilymetabolizedbyCYP1A2isoenzymes,withsecondarypathwaysbyCYP2E1andCYP3A4.Invitrodata
suggestthatwhiletheophyllinemetabolismismediatedbyCYP1A2atlowtheophyllineplasmaconcentrations,metabolismshiftsto
CYP2E1athigherconcentrations,andmetabolismbyCYP3A4isminor,independentoftheophyllineplasmaconcentration.11530The
manufacturerstatesthattheophyllineisasubstrateofhepaticenzymesCYP1A2,2E1,and3A3withoutmentionof3A450760however,
cytochromeP450genomeexpertsnolongersupporttheexistenceofCYP3A3andinsteadattributethisisoformtoacodingerrorofora
variantofCYP3A4.1153111532Sincethetherapeuticrangeisnarrowfortheophylline,itisprudenttomonitortheophyllineserum
concentrationsuponinitiation,dosageadjustment,ordiscontinuationofmedicationsthatmayalterthefunctionofCYP1A2,CYP2E1,
and/orCYP3A4isoforms.
CaffeineisaCNSstimulant.4666Theconcurrentadministrationofcaffeinetopatientstakingtheophyllinemayproduceexcessive
caffeinelikesideeffects,suchasnausea,irritabilityornervousness.Adverseeffectssuchastremors,insomnia,seizures,orcardiac
arrhythmiasarealsopossiblewhenexcessivedosagesofcaffeinearetakenconcurrentlywiththeophylline.Patientstakingtheophylline
shouldavoidmedicationscontainingcaffeinewhenpossible.6856Patientsmayalsoneedtolimittheirintakeofcaffeinecontaining
beveragesorfoods(e.g.,coffee,greentea,otherteas,colas,orchocolate)toavoidcaffeinelikesideeffects.Inneonates,theophyllineis
metabolizedtocaffeineinitiatingcaffeineaftertheophyllinetherapyishaltedmayresultincaffeinetoxicityinneonatesifserum
caffeinelevelsarenotmonitoredpriortotheinitiationofcaffeinetherapy.Concurrentuseoftheophyllinewithcaffeineinneonatesis
notrecommendedduetothepotentialforadditivetoxicity.
Caffeineand,toasmallextent,theophyllineareactiveconstituentsofguarana.4679Theconcurrentadministrationofguaranato
patientstakingtheophyllinemayproduceexcessivecaffeinelikesideeffects,suchasnausea,irritabilityornervousness.Adverseeffects
suchastremors,insomnia,seizures,orcardiacarrhythmiasarealsopossiblewhenexcessivedosagesofguaranaaretakenconcurrently
withtheophylline.Patientstakingtheophyllineshouldavoidmedicationsordietarysupplementscontainingguarana.Patientsmayalso
needtolimittheirintakeofguaranacontainingbeveragestoavoidcaffeinelikesideeffects.
Dyphyllineisaxanthinederivative6977andshouldnotbeadministeredwithothermethylxanthines(e.g.,theophylline,aminophylline
andothers)duetotheduplicativenatureoftherapyandthepotentialincreasedriskformethylxanthinerelatedsideeffects,suchas
nausea,irritabilityornervousness.Adverseeffectssuchasdiarrhea,tremors,insomnia,seizures,orcardiacarrhythmiasarealso
possiblewhenexcessivedosagesofmethylxanthinesaretaken.
Methylxanthines,suchastheophyllineoraminophylline,competitivelyblocktheeffectsofadenosine.Ifpossible,stopuseof
methylxanthinesatleast5halflivespriortoadministeringadenosine.Patientsreceivingtheophylline,aminophyllineshouldbe
monitoredforadenosineefficacylargerdosesofadenosinemayberequiredtoachieveantiarrhythmicgoalsinsomepatients.In
addition,theophylline,aminophyllinemayincreasetheriskofseizuresassociatedwithadenosineavoidmethylxanthineuseinpatients
whohaveexperiencedanadenosineassociatedseizure.465443606
Methylxanthines,suchastheophyllineoraminophylline,arenonspecificadenosinereceptorantagonistsandmayinterferewiththe
vasodilationactivityofadenosinereceptoragonists,suchasregadenoson.Patientsshouldavoidanydrugscontainingtheophylline,
aminophyllineforatleast12hoursbeforeregadenosonadministration.Methylxanthinesattenuatetheduration,butnotthepeak
increaseofcoronarybloodflowproducedbyregadenosonaminophyllinemaybeusedtoattenuatesevereorpersistentadverse
reactionsofregadenoson.Aminophyllineinjected1minuteafterregadenosoninsubjectsundergoingcardiaccatheterizationwasshown
toshortenthedurationofthecoronarybloodflowresponseasmeasuredbypulsedwaveDopplerultrasonography.Inaddition,
theophylline,aminophyllinemayincreasetheriskofseizuresassociatedwithregadenosonavoidmethylxanthineuseinpatientswho
haveexperiencedaregadenosonassociatedseizure.33906

Propranololandperhapsotherbetablockerscandecreasethehepaticclearanceoftheophylline,predisposingpatientstotheophylline
toxicity.50760Propranololinhibitstheophyllinehepaticdemethylation.Atenololandnadololdonotimpairtheophyllineclearance,
however,betablockers,particularlynonspecificbetablockers,opposetheeffectsoftheophyllineonbronchialsmoothmuscle.
Ophthalmicbetablockerssuchaslevobunololandtimolol,shouldnotbediscountedasbeingfreeofinteractingwiththeophyllinesince
systemiceffectscanbeseenafterophthalmicadministration.Thus,bothpharmacokineticandpharmacodynamicinteractionsoccur
betweentheophyllineandbetablockers.
Allopurinolinlargedoses(i.e.,600mg/dayorgreater)candecreasetheophyllineclearance.6857Itappearsthatthesignificanceofthis
druginteractiondependsonthedoseofallopurinolasdosesof300mg/dayhavebeenshowntonotaffecttheophyllineclearance.
TheophyllineisprimarilymetabolizedintheliverbytheCYP1A2isoenzyme.Cimetidineiswellknowntoinhibitthehepaticmetabolism
theophylline.Ingeneral,otherH2antagonists,suchasranitidineorfamotidine,donotinteractwiththeophylline,butatleastone
reportexistsoftheophyllinetoxicityoccurringduringranitidinetherapyandasmallstudydocumentedasignificantdecreasein
theophyllineclearanceaftertherapywithfamotidine.321
Thecalciumchannelblockersdiltiazem,nifedipine(conflictingdata),andverapamil37425000havebeenreportedtodecrease
theophyllineclearance.ThemechanismifmostlikelyreducedcytochromeP450metabolismoftheophylline.Diltiazemandverapamil
areknownCYP3A4inhibitors.TheophyllineispartiallymetabolizedbyCYP3A4however,CYP1A2istheprimarymetabolicpathway.
Aninteractionwiththeophyllineisunlikelytobeclinicallyimportantfornifedipine,andthereductionintheophyllineclearanceis
modest(about1020%)forverapamilanddiltiazem.Theinteractionbetweentheophyllineandverapamilappearstobedoserelated
verapamilhasbeenreportedtoreducetheophyllineclearanceby818%whengivenindosesrangingfrom40to120mg.3742Inseveral
studies,diltiazemhasbeenshowntomodestlyreduce(range1122%)thetotalclearanceoftheophylline,withanassociatedincreasein
halflife.Inonesmallclinicalstudy,diltiazemdidnotsignificantlyincreasetheophyllineserumconcentrationsduringchronictherapy
(i.e.,meanserumtheophyllinelevel13.6vs.14mcg/mlwithandwithoutdiltiazem,respectively).3743Sincethetherapeuticrangeis
narrowfortheophylline,itisprudenttomonitortheophyllineserumconcentrationsduringdiltiazemorverapamiltherapy.
Disulfiraminhibitsthehepatichydroxylationanddemethylationoftheophylline,therebyincreasingtheserumlevelsoftheophylline
andincreasingtheriskfortheophyllinetoxicity.Patientsshouldbemonitoredfortheophyllinetoxicityifdisulfiramisaddedto
theophyllinetherapy.Iftheophyllineisaddedafterdisulfiramisbegunanddisulfiramislaterdiscontinued,subtherapeutictheophylline
serumconcentrationscanresult.347573475850760Inaddition,somepreparationsoftheophyllineoraminophyllineelixirmaycontain
significantamountsofethanol,whichcancausereactionswithdisulfiramreadlabelscarefully.
Macrolideantibioticssuchasclarithromycin,erythromycin,andtroleandomycincaninhibittheophyllineoraminophyllineclearanceby
inhibitingthecytochromeP450CYP3Aisoenzymes.5587Thelabelingfortheophyllineproductsstatesthattheophyllineclearancemay
bedecreasedbyupto35%whencertainmacrolides(i.e.,clarithromycin,erythromycinortroleandomycin)areprescribedconcurrently
theseinteractionscanbeclinicallyimportant.50760Theseinteractionsareparticularlysignificantwhentheophyllineserum
concentrationsarealreadyinthehightherapeuticrange(i.e.,>15mcg/ml).62Ifclarithromycin,erythromycin,ortroleandomycinare
usedwithaminophyllineortheophyllinetherapy,patientsshouldbemonitoredforelevatedtheophyllinelevelsand/ortheophylline
toxicity.Theophyllineoraminophyllinemayincreasetherenalclearanceoferythromycin,butthisinteractionshouldnotbeclinically
significantandshouldnotinterferewithantimicrobialeffectofthemacrolide.Theliteraturereportsdifferencesamongthemacrolides
intheirabilitiestoinhibitCYP450enzymesand,thus,tocauseclinicallysignificantdrugdruginteractions.Ofthemacrolides,
azithromycinanddirithromycindonotinhibitcytochromeP450enzymesandarenotimplicatedinclinicallysignificantdrugdrug
interactionswiththeophyllineoraminophylline.1059384654075587However,theophyllinelevelsshouldbemonitoredinselected
patientsreceivingdirithromycin,particularlyinpatientswiththeophyllineconcentrationsinthehightherapeuticrange.5642Nodosage
adjustmentoftheophylline(oraminophylline)isrequiredwhenazithromyciniscoadministered.5588
Isoniazid,INHmayreducetheophyllineclearance.6599Althoughdataregardingthisdruginteractionareconflicting,itappearsthatthis
canbeexplainedbythedurationofisoniazidadministration.Largerdosesofisoniazidandlongerdurationofisoniazidadministration
aremorelikelytoaffecttheophyllinepharmacokinetics.Atleastonepatientdevelopedtheophyllinetoxicityasaresultofthis
interactionwithisoniazid.
MexiletineisaninhibitorofCYP1A2isoenzymes,andmayreduceCYP1A2mediatedtheophyllinemetabolism.4718Mexiletinehasbeen
showntodecreasetheophyllineclearance,increasetheophyllineconcentrations,andproducetheophyllinetoxicity.Lowerdosesof

theophyllineshouldbeusedinpatientsreceivingmexiletineorwhenmexiletineisadded.5007
Ciprofloxacinreducestheclearanceoftheophyllineby31%.Monitortheophyllinelevelsifconcurrentadministrationcannotbeavoided.
Seriousandfatalreactionshaveoccurredinpatientsreceivingconcurrentciprofloxacinandtheophylline.Thesereactionshaveincluded
cardiacarrest,seizure,statusepilepticus,andrespiratoryfailure.Althoughsimilarseriousadversereactionshavebeenreportedin
patientsreceivingtheophyllinealone,thepossibilitythatthesereactionsmaybepotentiatedbyciprofloxacincannotbeeliminated.
CiprofloxacinisCYP1A2inhibitorandtheophyllineisasubstrateofCYP1A2.Accordingtothemanufactureroftheophylline,no
clinicallysignificantinteractionisexpectedwithlomefloxacin,norfloxacin,orofloxacin.2876444294Somefluoroquinolonesreducethe
hepaticclearanceoftheophylline.Inacrossoverstudyofhealthyvolunteers,levofloxacindidnotsignificantlyaffecttheplasma
concentration,AUC,orotherpharmacokineticparametersofintravenouslyadministeredtheophylline.Nevertheless,because
concomitantadministrationofotherquinoloneswiththeophyllinehasresultedinincreasedserumtheophyllineconcentrationswitha
subsequentincreaseinriskofseizures,theophyllinelevelsshouldbecloselymonitoredwhenlevofloxaciniscoadministered.28421
FluvoxamineinhibitstheactivityofthehepaticisozymeCYP1A2.4718Drugsknowntobemetabolizedviathisenzymeincludethe
methylxanthinescaffeineandtheophylline.Themanufactureroffluvoxaminehasnotedthatfluvoxaminedecreasestheclearanceof
theophyllinethreefold.47184Therefore,iftheophyllineiscoadministeredwithfluvoxamine,thetheophyllinedailydosageshouldbe
reducedbyonethirdandplasmatheophyllineconcentrationsshouldbemonitored.Patientsshouldreportanyincreasein
methylxanthineinducedsideeffects,liketremor,nausea,orvomitingpromptly.47184
LansoprazoleismetabolizedbythecytochromeP450system.IthasbeenshownthatoneofthespecificisozymesresponsibleisCYP3A4,
whichisalsoafactorinthemetabolismoftheophyllinehowever,theprimarypathwayfortheophyllinemetabolismisCYP1A2.
Concomitantuseoftheophyllineandlansoprazolehascausedasmallincrease(10%)intheclearancerateoftheophylline.5142Therapy
withtheophyllinecouldrequireadjustmentwhentherapywithlansoprazoleisstoppedorstarted.
TheophyllineisprimarilymetabolizedintheliverbytheCYP1A2isoenzyme,andalsobytheCYP3A4isoenzyme.4718Thefollowing
drugscanstimulatethehepaticmetabolismoftheophyllineifusedconcurrently:barbiturates4722,carbamazepine4743,ethotoin4741,
phenytoinorfosphenytoin4742,primidone4718,andrifampin4718.Duetothelonghalflifeofphenobarbital,severaldaysof
phenobarbitaltherapymaybenecessarybeforeanyeffectontheophyllinepharmacokineticsisseen.Theophyllinedosesmayneedtobe
increasedifanyofthesedrugsareadded.Moreimportantly,serioustheophyllinetoxicitycanresultifanyofthesedrugsare
discontinuedandthedoseoftheophyllineisnotcorrespondinglydecreased.Theophylline,inturn,mayinhibittheabsorptionof
phenytoin.
Theophyllineusedconcurrentlywithinhaledgeneralanestheticsmayincreasetheriskofcardiacarrhythmias.50760Whenketamineand
theophyllinearegivenconcurrentlyaclinicallysignificantreductionintheseizurethresholdisobservedunpredictableextensortype
seizureshavebeenreportedwithconcurrentadministration.
Betaagonistsarecommonlyusedinconjunctionwithaminophyllineortheophyllinetherapy.ConcomitantusecancauseadditiveCNS
stimulationsomepatientsmayexperiencetremorornervousnesswithcombineduse.Moreseriouseffectsarerare,butmayresultin
additivecardiovasculareffectssuchasincreasedbloodpressureandheartrate.Methylxanthinederivatives(e.g.,theophylline,
aminophylline)mayrarelyaggravatethehypokalemiceffectseenwithbetaagonists.Considercheckingpotassiumlevelsifclinically
indicated.2831850760440263290144979
Concurrentadministrationoftheophyllineoraminophyllinewithsomesympathomimeticscanproduceexcessivestimulationand
effectssuchasnervousness,irritability,orinsomnia.Seizuresorcardiacarrhythmiasarealsopossible.Theherbalsympathomimetic
ephedra,Mahuangmaypotentiallyincreasetheriskofdevelopingcardiacarrhythmiasifthisherbistakenwiththeophylline.5241
Ticlopidinewasshowntosignificantlydecreasetheophyllineclearanceandsignificantlyincreasetheophyllinehalflife(from8.6to12.2
hours)inhealthyvolunteers.1501Dosesoftheophyllinemayneedtobereducedifticlopidineisadded.
AlthoughinfluenzavirusvaccinehasbeenreportedtoinhibittheclearanceofmedicationsmetabolizedbycytochromeP450including
theophyllineoraminophylline,thereportsconcerningpossibletoxicityareconflicting.7587Mostrecentreportshavenotednoadverse
clinicaloutcomesfromtheuseofinfluenzavirusvaccineinpatientstakingthesemedications7587theuseofthesemedicationsshould
notprohibitinfluenzaimmunizationifindicated.However,becauseanoccasionalpredisposedpatientmayexperienceanincreaseinthe

effectsoftheophyllineoraminophylline,monitoringfortheophyllinetoxicitymaybewarrantedatemporarydosageadjustmentmaybe
neededifaninteractionoccurs.
Alphainterferons,whenadministeredsystemically,maydecreasetheclearanceoftheophyllineresultinginincreasedplasmalevels.6858
Concomitantuseofinterferonalfa2borpeginterferonalfa2bwiththeophyllinemayresultina100%increaseintheophylline
concentrations.Interferonalfa2ainhibitionoftheophyllineclearancemayberelatedtothedoseofinterferonhigherdoseshavebeen
showntoexertamoredramaticeffect.Asimilarinteractionmayoccurifthepatientisreceivinginterferongamma1b.50760
Theophyllinecanincreaserenalclearanceoflithium,reducingitstherapeuticeffectiveness.6978Cliniciansshouldbealerttolossof
lithiumtherapeuticeffectivenessiftheophyllineisadded.
Althoughlimiteddataareavailable,itappearsthatpropafenoneaffectstheophyllineclearance.6996Inseveralpatients,theophylline
concentrationsincreasedaftertheadditionofpropafenoneandinatleastonepatient,symptomsoftheophyllinetoxicitywere
suspected.Untilmoredataareavailable,lowerdosesoftheophyllineshouldbeconsideredinpatientsreceivingpropafenone.
Serumtheophyllineconcentrationshavebeenreportedtobelowerduringconcomitantadministrationofprednisone,buttheactual
magnitudeoftheinteractionwasslight.6997
Fluconazoleincreasestheserumconcentrationsoftheophylline.Inonestudy(manufacturerdata),thepharmacokineticsof
theophyllineweredeterminedfromasingleIVdoseofaminophylline(6mg/kg)beforeandafterfluconazole200mgPOoncedailyfor
14daysin16normalmalevolunteers.SignificantincreasesintheophyllineAUC,Cmax,andhalflifewerereportedwithacorresponding
decreaseinclearance.Themean+/SDtheophyllineAUCincreased21+/16%theCmaxincreased13+/17%andtheophylline
clearancedecreased16+/11%.Theophyllinehalflifeincreasedfrom6.6+/1.7hoursto7.9+/1.5hours.Serumtheophylline
concentrationsshouldbemonitoredcloselyiffluconazoleisadded.5405
Ketoconazolehasbeenreportedtodecreasetheophyllineserumconcentrationswhentheophyllinewasadministeredorallyassustained
releasetablets,however,nointeractionwasnotedwhentheophyllinewasadministeredIV.6998Sinceketoconazoleiswellknownto
inhibitthehepaticmetabolismofmanydrugsandtheophyllineconcentrationswouldbeexpectedtoincrease,itissuspectedthat
ketoconazolemayhaveinterferedwithoralbioavailabilityoftheophylline.Astheseresultsarebasedonasinglecasereport,additional
clinicaldataarenecessary.
TheophyllineAUCandCmaxweredecreasedby43%and32%,respectively,whencoadministeredwithritonavir.Higherdosagesof
theophyllinemayberequired.47165
Correctionofhypothyroidismtotheeuthyroidstatemayprecipitatecertaindruginteractions.Forexample,hypothyroidismcauses
decreasedclearanceoftheophylline,whichreturnstonormalintheeuthyroidstate.Theophyllinedosageadjustmentsmaybeneeded
whencoadministeredwiththyroidhormones.43942
Zileuton,a5lipoxygenaseinhibitor,caninteractwiththeophyllinebyinhibitingtheophyllinemetabolismandclearance.Concomitant
administrationoftheophyllineandzileutoninnormalvolunteersresultedinasignificantincreaseinpeakandtroughconcentrationsof
theophylline,anapproximatedoublingoftheophyllineAUC,aprolongedtheophyllinehalflife(24%increase),andasignificantdecline
intheophyllineclearance.6999Onaverage,adoublingofprevioustheophyllineconcentrationsoccurswhenzileutonisaddedtoan
existingtheophyllineregimen.5415Theophyllinerelatedadverseeffectsoccurmorefrequentlyinpatientsreceivingconcomitant
zileuton.5415Toavoidtheophyllinetoxicity,thetheophyllineoraminophyllinedosagemustbereducedbyapproximately50%when
zileutonisprescribedtoanexistingregimen.5415Inpatientstakingzileutoninwhomtheophyllineoraminophyllineareadded,patients
shouldreceiveadjusteddosingordosingintervalsoftheophyllineoraminophylline.5415Serumtheophyllineconcentrationsshouldbe
monitored.5415
Zafirlukast,aleukotrienereceptorantagonist,inhibitstheCYP2C9andCYP3A4hepaticmicrosomalisozymes.Zafirlukastwasoriginally
reportednottohavesignificantinteractionpotentialwiththeophylline(primarilyCYP1A2substrate,butalsometabolizedbyCYP3A4).
However,acaseofapatientexperiencingincreasedtheophyllinelevelswithclinicalsignsandsymptomsoftoxicityaftertheadditionof
zafirlukasttoanexistingtheophyllineregimenhasbeenreported,andtheinteractionhasbeenconfirmedbyrechallenge.2129
Monitoringforsignsandsymptomsoftoxicity,aswellasclosemonitoringofserumtheophyllinelevels,isadvisablewhenzafirlukastis
usedincombinationwiththeophylline.

Despitethelackofdocumentedinteractionswithsevelamer,thepotentialforreduceddrugabsorptioncouldresultinclinical
significancefororaldrugswithanarrowtherapeuticrange,withthepotentialforlossofefficacy.Thesedrugscouldinclude
theophylline.Thepotentialfordruginteractionswithoralconcomitantmedicationscanbeminimizedbyadministeringotherdrugsat
least1hourbeforeor3hoursafteradministrationofsevelamerdoses.4827
ModafinilinducesinducesCYP3A4andhasthepotentialtoinduceotherhepaticmicrosomalenzymessuchasCYP1A2.41243Thedrug
mayinducethemetabolismofsomenarrowtherapeuticindexmedications.TheophyllineisprimarilymetabolizedbyCYP1A2
isoenzymes,withsecondarypathwaysbyCYP2E1andCYP3A4(minor).1153111532Patientsontheophyllineoraminophyllinemayneed
tobemonitoredforreducedmethylxanthineefficacywhenmodafinilisaddedtotherapy.
AninteractionbetweentheophyllineandSt.John'swort,Hypericumperforatumhasbeenreported.Awomanwhowason1600mg/day
POoftheophyllinedevelopedlowerthanexpectedserumtheophyllineconcentrations(i.e.,9.2mcg/ml)itwasnotedthatsherecently
hadinitiatedselftreatmentwithSt.John'swort.After1weekofdiscontinuationoftheSt.John'swort,thepatient'sserumtheophylline
concentrationsroseto19.2mcg/ml.2719ItappearsthatSt.John'swortmayincreasethemetabolismoftheophyllineorrelated
methylxanthines(e.g.,caffeine)throughinductionofthehepaticCYP1A2isoenzyme.Usecautionwheninitiatingordiscontinuingthe
useofSt.John'swortinanypatientstabilizedontheophylline.
Inasmallnumberofpatientswitheitherleukemiaorlymphomaandacutemethotrexateneurotoxicity,theophyllineattenuated
methotrexateinducedneurotoxicity,asyndromebelievedduetoelevatedadenosineCNSconcentrations.657Thiseffectoftheophylline
onmethotrexatetoxicityisconsistentwiththeabilityoftheophyllinetoantagonizeadenosinereceptors,however,thisdoesnotsuggest
thattheophyllinewouldantagonizethetherapeuticactionsofmethotrexate.
A33yearoldmanhadelevationinserumcreatinineandintroughconcentrationsoftacrolimusafterinitiationoftheophylline600mg
daily.Theserumcreatinineandtacrolimustroughconcentrationsfurtherincreaseddespitetheophyllinedosagereductionto300mg
dailyfor4dayseachweek.Althoughthetheophyllineserumconcentrationsrangedfrom26.7mg/L,theophyllinewasdiscontinued
withsubsequentnormalizationofserumcreatinineandtacrolimustroughconcentrations.Onrechallenge,additionoftheophylline125
mgdailytoastabledrugregimenincreasedthesystemictacrolimusexposurefrom25to142ng/h/mloverthefirst10hoursaftera
tacrolimusdose.Thepeaktheophyllineconcentrationwas4.3mg/L.Themechanismfortheproposedinteractionisnotknownbutis
hypothesizedtobeduetoinhibitionofCYP3A4bytacrolimus.Closelymonitorserumtacrolimusconcentrations,serumcreatinine
concentrations,andrenalfunctioninpatentswhoarestabilizedontacrolimusiftheophyllineoraminophyllineisadded,changedor
discontinued.6179
AgentsthatarealsometabolizedbycytochromeP4501A2,suchastheophylline,maydecreasethemetabolismofropivacainethrough
competitiveinhibition.5040
Noclinicallysignificantinteractionsoccurredwhencetirizinewascoadministeredwithalowdose(i.e.,400mgPOoncedailyfor3
days)oftheophyllinealthough,cetirizineclearancewasslightly(16%)reduced.5607Perthemanufacturer,itispossiblethatlarger
theophyllinedosescouldhaveagreatereffectoncetirizinepharmacokinetics.Thedispositionoftheophyllineisunalteredbycetirizine
administration.Noclinicalinteractionsbetweentheophyllineandcetirizinehavebeendocumented.
Rofecoxib12.5,25,and50mg/daygivenfor7daysincreasedtheAUCandhalflifeoftheophylline,whiledecreasingtheoralclearance
oftheophylline,inhealthysubjectsfollowingasingle300mgoraltheophyllinedoseonday6ofrofecoxibadministration.Adequate
monitoringoftheophyllinelevelsshouldbeconsideredwhentherapywithrofecoxibisinitiatedorchangedinpatientsreceiving
theophylline.4797
TobaccosmokecontainspolycyclicaromatichydrocarbonsthatinducehepaticCYP450microsomalenzymes(e.g.,CYP1A1,CYP1A2,
CYP2E1)tobaccosmokingresultsinanincreasedclearanceoftheophyllinethatisclinicallysignificant.5056Becausetheeffecton
hepaticmicrosomalenzymesisnotrelatedtothenicotinecomponentoftobacco,thesuddencessationoftobaccosmokingmayresultin
areducedclearanceoftheophylline,despitetheinitiationofanicotinereplacementproduct.Followingoneweekofabstinencefrom
chronictobaccosmoking,theophyllineclearancemaydecreasebyroughly40%,leadingtoanincreaseinserumtheophylline
concentrations.Theophyllineserumconcentrationsshouldbemonitoredcarefullywhenchangesinsmokingstatusoccur.No
interactionisexpectedtodirectlyoccurfromtheuseofnicotinereplacementproductswiththeophyllineoraminophylline.

Increasedtheophyllinemetabolismhasbeenreportedwithsmokingofmarijuana,theinteractionissimilarineffecttothatofsmoking
tobacco,whichmaysubstantiallydecreasetheophyllineserumconcentrations.7588Thisinteractionmayalsooccurwithdronabinol,
THCandnabilonewhicharesyntheticanalogsofanaturallyoccurringsubstancefoundinmarijuana.71859044However,itisalso
probablethatcompoundsproducedviathesmokingprocess(i.e.,hydrocarbons)mayberesponsibleforthereducedtheophyllinelevels
seenwithmarijuanasmoking,asoccurswithtobaccosmokingthesmokecontainshydrocarbonsthatinducehepaticCYP450
microsomalenzymes.50567588Conversely,becausetheeffectofmarijuanasmokingonhepaticmicrosomalenzymesmayberelatedto
theactionsofhydrocarbonsversusthecannabinoidcomponent,suddencessationofhabitualmarijuanasmokingmayresultina
reducedclearanceoftheophylline.Itmaybeadvisabletocloselymonitortheophyllineconcentrationswheneverasignificantchangein
marijuanasmokingstatusoccurs.7588
Theophyllinehasbeenreportedtocounteractthepharmacodynamiceffects(e.g.,sedativeandanxiolyticeffects)ofdiazepam.A
proposedmechanismiscompetitivebindingoftheophyllinetoadenosinereceptorsinthebrain.Whetherasimilarinteractionoccurs
withotherbenzodiazepinesisnotknown.Iftheophyllinetherapyisinitiatedordiscontinued,monitortheclinicalresponseto
benzodiazepines.4764
Usecautioniftheophylline,aminophyllineandaprepitant,fosaprepitantareusedconcurrentlyandmonitorforanincreasein
theophyllineoraminophyllinerelatedadverseeffectsandalteredserumlevelsforseveraldaysafteradministrationofamultiday
aprepitantregimen.TheophyllineandaminophyllineareCYP3A4substrates.Aprepitant,whenadministeredasa3dayoralregimen
(125mg/80mg/80mg),isamoderateCYP3A4inhibitorandinducersubstitutionoffosaprepitant115mgIVonday1ofthe3day
regimenmaylessentheinhibitoryeffectsofCYP3A4.TheAUCofasingledoseofanotherCYP3A4substrate,midazolam,increasedby
2.3foldand3.3foldondays1and5,respectively,whencoadministeredwitha5dayoralaprepitantregimen.Aftera3dayoral
aprepitantregimen,theAUCofmidazolamincreasedby25%onday4,anddecreasedby19%and4%ondays8and15,respectively,
whengivenondays1,4,8,and15.Asasingle40mgoraldose,theinhibitoryeffectofaprepitantonCYP3A4isweak,withtheAUCof
midazolamincreasedby1.2foldthemidazolamAUCincreasedby1.5foldafterasingle125mgdoseoforalaprepitant.Aftersingle
dosesofIVfosaprepitant,themidazolamAUCincreasedby1.8fold(150mg)and1.6fold(100mg)lessthana2foldincreaseinthe
midazolamAUCisnotconsideredclinicallyimportant.Afteradministration,fosaprepitantisrapidlyconvertedtoaprepitantandshares
thesamedruginteractions.306764002750760
AlbendazolehasbeenshowntoinducethehepaticCYP1Amicrosomalenzymes(e.g.,CYP1A1,CYP1A2)inhumanhepatomacells.While
thepharmacokineticsoftheophylline(givenasaminophylline5.8mg/kgIVinfusedover20minutes)wereunchangedfollowingasingle
oraldoseofalbendazole(400mgPO)in6healthysubjectsnodataareavailableforrepeatedcoadministrationofthesedrugs.4768Itis
possiblethattheprescriptionofalbendazolemayresultinanincreasedclearanceoftheophylline.Conversely,thediscontinuationof
albendazoletherapymayresultinareducedclearanceoftheophylline,leadingtoanincreaseinserumtheophyllineconcentrations.
Theophyllineserumconcentrationsandthepatient'sclinicalstatusshouldbemonitoredcarefullywhenalbendazoleisprescribedand
ondiscontinuationofalbendazoletherapy.
Useofmedicationsthatlowertheseizurethresholdshouldbecarefullyevaluatedwhenconsideringintrathecalradiopaquecontrast
agents.Theophyllineaminophyllineshouldbediscontinuedatleast48hoursbeforemyelographyandshouldnotberesumedforat
least24hourspostprocedure.54425698
TheophyllineisprimarilymetabolizedbyCYP1A2isoenzymes,withasecondarypathwaybyCYP3A4.4718Amiodaroneisaninhibitorof
theseisoenzymes,andcanreducetheophyllinemetabolism.4718495050018329Itisprudenttomonitorforsignsandsymptomsof
toxicity,aswellasserumtheophyllineconcentrations,duringcoadministrationwithamiodarone.
TheophyllineisprimarilymetabolizedintheliverbytheCYP1A2isoenzyme.Tacrinesignificantlydecreasestheophyllineclearance,
apparentlybyinhibitingCYP1A2.5076057058Coadministrationoftacrinewiththeophyllineincreasedtheophyllineeliminationhalflife
andaverageplasmatheophyllineconcentrationsbyapproximately2fold.41680Anticipatingtheinteractionandreducingthe
theophyllinedosebeforetacrineinitiationcanhelplimittheriskoftoxicity.Ifbothmedicationsareinitiatedconcurrentlyorif
theophyllineisbeinginitiatedinapatientreceivingtacrine,theinitialdosageoftheophyllinemayneedtobereducedby2550%to
avoidtoxicity.Closemonitoringoftheophyllinelevelsisrequiredduringconcomitanttherapywithtacrine.Theophyllinedosereduction
maybenecessary.
Theophylline,aminophyllineismetabolizedbybothCYP1A2andCYP3A4.InvivodataindicatethatechinaceamayinhibitCYP1A2,

inducehepaticCYP3A4,andinhibitintestinalCYP3A4.Theefficacyandsafetyoftheophylline,aminophyllineifusedincombination
withechinaceaareunknownhowever,closemonitoringofpatientsforchangesinefficacyortoxicitymaybeprudentiftheophylline,
aminophyllineisusedincombinationwithechinacea,untilmoredataareavailable.75668894
AnagrelidehasbeenshowntoinhibitCYP1A2.Intheory,coadministrationofanagrelidewithsubstratesofCYP1A2,including
theophylline,aminophylline,couldleadtoincreasesintheserumconcentrationsofthesedrugsandthus,adverseeffects.Patients
receivinganagrelideandtheophylline,aminophyllineconcomitantlyshouldbemonitoredforincreasedtoxicityoftheophylline,
aminophylline.6912
Invitro,flavocoxid,flavocoxidcitratedzincbisglycinatedemonstrateda23%inhibitionofCYP1A2isoenzymes.8954Thisinhibition
couldpotentiallybeclinicallyrelevant,especiallywhenflavocoxid,flavocoxidcitratedzincbisglycinateiscoadministeredwithCYP1A2
substratesthathaveanarrowtherapeuticindexsuchastheophylline,aminophylline.4718Untilmoredataareavailable,itmaybe
prudenttomonitorforpotentialadverseeffectsoftheophyllineoraminophyllinewhencoadministeredwithflavocoxid,flavocoxid
citratedzincbisglycinate.
Themanufacturerforcolesevelamsuggestsmonitoringserumdrugconcentrationsand/orclinicaleffectsforthosedrugsforwhich
alterationsinserumbloodconcentrationshaveaclinicallysignificanteffectonsafetyorefficacy.7576Tominimizepotentialfor
interactions,consideradministeringoraldrugswithanarrowtherapeuticindexsuchastheophyllineatleast4hoursbefore
colesevelam.
Thecoadministrationoftheophylline,aminophyllinewithquininemayincreasetheCmaxandAUCofquinineanddecreasetheAUCof
theophylline,aminophylline.Inastudyof20healthysubjectsreceivingmultipledosesofquinineandasingledoseoftheophylline,the
quininemeanCmaxwasincreasedby13%,andtheAUCwasincreasedby14%.Also,inastudyof19subjectsreceivingmultipledosesof
quinineandasingledoseoftheophylline,themeantheophyllineAUCdecreasedby10%however,therewasnochangeinmeanCmax.
ThisinteractionmaybeduetothepotentialinductionoftheCYP1A2isoenzymebyquinineastheCYP1A2isoenzymeistheprimary
routeofmetabolismfortheophylline,aminophylline.Coadministrationdoesnotrequireanydosagechangeshowever,sideeffectsof
quinineshouldbemonitoredandplasmaconcentrationsoftheophyllineshouldbefrequentlymonitoredtoensuretherapeutic
concentrations.31403
Bupropionisassociatedwithadoserelatedriskofseizures.4781Extremecautionisrecommendedduringconcurrentuseofotherdrugs
thatmaylowertheseizurethresholdsuchastheophylline.4781Themanufacturerrecommendslowinitialdosingandslowdosage
titrationifthiscombinationmustbeusedthepatientshouldbecloselymonitored.Inaddition,whenbupropionisusedforsmoking
cessation,itshouldbenotedthatcessationofsmokingmayresultinelevatedserumconcentrationsofsomedrugsthatarehepatically
metabolized,suchastheophyllineoraminophylline,duetoloweredinductionofhepaticoxidativemicrosomalenzymes(tobaccosmoke
induceshepaticenzymes).Downwarddosageadjustmentsofsuchdrugsandmorefrequentmonitoringmayberequiredduring
smokingcessation.
Althoughnodosingadjustmentsarerecommended,usecautioniffebuxostatandtheophylline,aminophyllineareusedconcurrently.By
inhibitingxanthineoxidase,febuxostatalterstheophyllinemetabolism.Inastudyconductedinhealthyadults,coadministrationof
febuxostat(80mgPOdaily)resultedinincreasedtheophyllineCmax(6%)andAUC(6.5%).Thesechangeswerenotconsidered
statisticallysignificant.Anapproximately400foldincreaseintheamountof1methylxanthine(amajormetaboliteoftheophylline)
excretedintheurinewasalsonoted.Thelongtermeffectsofthisincreasedexposureareunknown.35002
Patientswithhyperthyroidismmayexhibitacceleratedclearanceoftheophylline.Correctionofhyperthyroidismcanleadtoadecrease
intheophyllineclearanceasthepatientbecomeseuthyroidviatheuseofagentssuchasmethimazoleorpropylthiouracil,PTU.5176
Theophyllineserumconcentrationsshouldbemonitoredcloselyduringtheinitialstagesoftreatmentforhyperthyroidism.
Druginteractionstudieswereperformedwithroflumilastandotherdrugslikelytobecoadministeredordrugscommonlyusedas
probesforpharmacokineticinteraction.Nosignificantdruginteractionswereobservedwhen500mcgoralroflumilastwas
administeredwiththeophylline,aminophylline.Whileapharmacokineticinteractiondidnotoccur,patientswereprohibitedfrom
takingtheophyllineinroflumilastclinicaltrials.4355145296CurrentguidelinesinthemanagementofpatientswithCOPDdonot
recommendcouseoftheophyllineoraminophyllinewithroflumilast,presumablyduetoapharmacodynamiceffect(additiveactionson
cyclicAMP)andthepotentialforsimilarsideeffectprofiles(e.g.,diarrhea,weightloss,appetitechanges,nausea,headache).45296

Cautioniswarrantedwhencobicistatisadministeredwiththeophyllineaminophyllineasthereisapotentialforelevatedtheophylline
concentrations.Clinicalmonitoringforadverseeffectsisrecommendedduringcoadministration.Theophyllineisasubstrateof
CYP3A4cobicistatisaCYP3A4inhibitor.5076058000
Cautioniswarrantedwhendarunavirisadministeredwiththeophyllineaminophyllineasthereisapotentialforelevatedtheophylline
concentrations.Clinicalmonitoringforadverseeffectsisrecommendedduringcoadministration.Theophyllineisasubstrateof
CYP3A4darunavirisaCYP3A4inhibitor.5076032432
Cautioniswarrantedwhendarunavircobicistatisadministeredwiththeophyllineaminophyllineasthereisapotentialforelevated
theophyllineconcentrations.Clinicalmonitoringforadverseeffectsisrecommendedduringcoadministration.Theophyllineisa
substrateofCYP3A4darunavirandcobicistatareCYP3A4inhibitors.507605800058763
Cautioniswarrantedwhenatazanavirisadministeredwiththeophyllineaminophyllineasthereisapotentialforelevatedtheophylline
concentrations.Clinicalmonitoringforadverseeffectsisrecommendedduringcoadministration.Theophyllineisasubstrateof
CYP3A4atazanavirisaCYP3A4inhibitor.5076028142
Cautioniswarrantedwhenatazanavircobicistatisadministeredwiththeophyllineaminophyllineasthereisapotentialforelevated
theophyllineconcentrations.Clinicalmonitoringforadverseeffectsisrecommendedduringcoadministration.Theophyllineisa
substrateofCYP3A4atazanavirandcobicistatareCYP3A4inhibitors.507605800058761
Cautioniswarrantedwhencobicistatelvitegraviremtricitabinetenofovirdisoproxilfumarateisadministeredwiththeophylline
aminophyllineasthereisapotentialforelevatedtheophyllineconcentrations.Clinicalmonitoringforadverseeffectsisrecommended
duringcoadministration.TheophyllineisasubstrateofCYP3A4cobicistatisaCYP3A4inhibitor.5076051664
Cautioniswarrantedwhencobicistatelvitegraviremtricitabinetenofoviralafenamideisadministeredwiththeophylline
aminophyllineasthereisapotentialforelevatedtheophyllineconcentrations.Clinicalmonitoringforadverseeffectsisrecommended
duringcoadministration.TheophyllineisasubstrateofCYP3A4cobicistatisaCYP3A4inhibitor.5076060269
Coadministrationofriociguatandphosphodiesteraseinhibitors,includingspecificphosphodiesterase5inhibitors(sildenafil,tadalafil,
vardenafil)andnonspecificphosphodiesteraseinhibitors(dipyridamole,Aspirin,ASAdipyridamole,theophylline,aminophylline,or
guaifenesintheophylline)iscontraindicatedduetotheriskofhypotension.Clinicalexperiencewithotherphosphodidesterase
inhibitors(e.g.,milrinone,cilostazol,androflumilast)islimited.Theadditionofriociguattoastablesildenafilregimen(20mgthree
timesaday)resultedinadditivehemodynamiceffectsinanexploratoryinteractionstudyin7patientswithpulmonaryarterial
hypertension(PAH).AmongpatientswithPAHonstablesildenafiltreatmentandriociguattherewasonedeath,possiblyrelatedtothe
combinationofthesedrugs,andahighrateofdiscontinuationforhypotension.56096
Usecautionwhenadministeringivacaftorandtheophylline,aminophyllineconcurrently.IvacaftorisaninhibitorofCYP3Aand
theophyllineandaminophyllinearepartiallymetabolizedbyCYP3A.Coadministrationcantheoreticallyincreasetheophyllineor
aminophyllineexposureleadingtoincreasedorprolongedtherapeuticeffectsandadverseeventshowever,theclinicalimpactofthis
hasnotyetbeendetermined.4852434671
Concomitantuseoftheophyllineandlumacaftorivacaftorisnotrecommended.Lumacaftorivacaftormaydecreasethesystemic
exposureoftheophylline,anarrowtherapeuticindexdrug.Theclinicalsignificanceofthisinteractionisunclear.Lumacaftorivacaftor
isapotentCYP3Ainducer.TheophyllineisprimarilymetabolizedbyCYP1A2,withsecondarypathwaysbyCYP3AandCYP2E1.Invitro
datasuggestsmetabolismbyCYP3Aisminor.However,sincethetherapeuticrangeoftheophyllineisnarrow,ifconcurrentusecannot
beavoided,monitortheophyllineserumconcentrationscloselyandadjustthedoseaccordingly.346715076059891
Usedichlorphenamideandtheophylline,aminophyllinetogetherwithcaution.Dichlorphenamideincreasespotassiumexcretionand
cancausehypokalemiaandshouldbeusedcautiouslywithotherdrugsthatmaycausehypokalemiaincludingtheophylline,
aminophylline.Measurepotassiumconcentrationsatbaselineandperiodicallyduringdichlorphenamidetreatment.Ifhypokalemia
occursorpersists,considerreducingthedichlorphenamidedoseordiscontinuingdichlorphenamidetherapy.60122
Concurrentadministrationoftheophyllineaminophyllinewithombitasvirparitaprevirritonavirshouldbeapproachedwithcaution

andcarefulmonitoring.Ritonavirhasbeenshowntoreduceplasmatheophyllineconcentrationsanincreaseintheophyllinedosage
mayberequired.Ifthesedrugsareusedtogether,therapeuticdrugmonitoringshouldbeconsidered.4716560002
Concurrentadministrationoftheophyllineaminophyllinewithdasabuvirombitasvirparitaprevirritonavirshouldbeapproached
withcautionandcarefulmonitoring.Ritonavirhasbeenshowntoreduceplasmatheophyllineconcentrationsanincreasein
theophyllinedosagemayberequired.Ifthesedrugsareusedtogether,therapeuticdrugmonitoringshouldbeconsidered.4716558664
Avoidtheconcomitantuseofosimertinibwiththeophylline,aminophyllineduetotheriskofeitherincreasedordecreasedtheophylline
exposure.OsimertinibisbothaCYP3Ainducer(PregnaneXdependent)andcompetitiveinhibitor,aswellasaCYP1A2inducer
theophylline,aminophyllineisasensitiveCYP3AandCYP1A2substrate.Coadministrationmayincreasetheophyllinerelatedadverse
reactionsand/ordecreasetheefficacyoftheophylline,aminophylline,althoughclinicalstudiesofosimertinibwithCYP3AandCYP1A2
substrateshavenotbeenconducted.6029750760
Administeringtheophylline,aminophyllinewithelbasvirgrazoprevirmayresultinelevatedtheophyllineplasmaconcentrations.
TheophyllineisaminorsubstrateofCYP3AgrazoprevirisaweakCYP3Ainhibitor.Ifthesedrugsareusedtogether,closelymonitorfor
signsofadverseevents.6052350760
ObeticholicacidmayincreasetheexposuretoconcomitantdrugsthatareCYP1A2substrates,suchastheophylline,aminophylline.
Sincethetherapeuticrangeisnarrow,itisprudenttomonitortheophyllineserumconcentrationsuponinitiation,dosageadjustment,or
discontinuationofmedicationsthatmayalterthefunctionofCYP1A2.3467160840
Cautionisadvisedwhenadministeringtheophylline,aminophyllinewithacyclovir.TheophyllineisprimarilymetabolizedbyCYP1A2
acyclovirisaweakinhibitorofCYP1A2.Takingthesedrugtogethermayincreasetheserumconcentrationoftheophylline.Sincethe
therapeuticrangeoftheophyllineisnarrow,itisprudenttomonitortheophyllineserumconcentrationsuponinitiation,dosage
adjustment,ordiscontinuationofmedicationsthatmayalterthefunctionofCYP1A2.346716113056579
Lastrevised:August31,2016

Reaccionesadversas
abdominalpain
agitation
anorexia
anxiety
atrialfibrillation
atrialflutter
atrialtachycardia
cardiacarrest
contactdermatitis
diarrhea
diuresis
dizziness
exfoliativedermatitis
gastroesophagealreflux
headache
hematemesis

hyperactivity
hypercalcemia
hypokalemia
hypotension
insomnia
irritability
metabolicacidosis
nausea
palpitations
prematureventricularcontractions(PVCs)
restlessness
seizures
sinustachycardia
supraventriculartachycardia(SVT)
urticaria
ventriculartachycardia
vomiting
AdverseGIreactionscanbeeitheralocalirritanteffectonthegastricmucosaoracentrallymediatedeffect.Transientcaffeinelike
adversereactions,suchasnauseaandvomiting,canoccurespeciallyduringinitiationoftheophylline.Initiatetheophyllineatalowdose
andslowlytitratetodecreasetheoccurrenceofthesereactions.Thesereactionsmaypersistinasmallpercentageofpatients(<3%
pediatricsand<10%adults).Areductionindosagemayeliminatecaffeinelikeadversereactions,butiftheycontinueorbecomesevere,
theophyllinemayhavetobediscontinued.Diarrheahasalsobeenreportedasanadversereactioninpatientswiththerapeuticserum
concentrationsoftheophylline.Nausea/vomitingandabdominalpainmaybecausedbygastroesophagealreflux,andthiseffectismore
likelytooccurifthepatientislyingdown.Children2yearsoldandunder,theelderly,anddebilitatedpatientsaremorelikelytosuffer
fromthiseffect.OtherGIeffectsincludeabdominalcramps,anorexia,andpossiblehematemesis.Localirritationcanbeminimizedby
takingtheoraldrugbeforeoraftermeals,withafullglassofwaterormilk,orwithantacids.BothadverseGIandCNSeffectscanbe
minimizedifthedoseistitratedoveraperiodof1week.Repetitivevomitingmayindicatetheophyllinetoxicityandshouldbe
investigated.Instudiesevaluatingsignsandsymptomsoftheophyllineoverdose,vomitingwasreportedin7393%ofpatientsaftera
largesingleingestion(acuteoverdose)and3061%ofpatientsaftermultipleexcessivedoses(chronicoverdose).44288
Transientcaffeinelikeadversereactions,suchasheadacheandinsomnia,canoccurespeciallyduringinitiationoftheophylline
however,moreseriousevents(i.e.,lifethreateningseizures)canalsooccur,particularlyatelevatedserumconcentrations.Seizures
occurringinpatientswithserumtheophyllineconcentrations<20mcg/mlareusuallymilderthanthoseoccurringinpatientswith
supratherapeurticserumconcentrations(e.g.,transient,resolvewithoutanticonvulsanttherapy,anddonotresultinneurological
residual).ThesereactionsaremorelikelytooccurinchildrenthaninadultsandarealsomorelikelyfollowingrapidIVadministration
orinpatientswithexcessivetheophyllineserumconcentrations.Seriousreactionscanoccurwithoutantecedentminorsymptoms.To
minimizetheoccurrenceofthecaffeinelikeadverseeffects,initiatetheophyllineatalowdoseandslowlytitrate.Thesereactionsmay
persistinasmallpercentageofpatients(<3%pediatricsand<10%adults).Areductionindosagemayeliminatecaffeinelikeadverse
reactions,butiftheycontinueorbecomesevere,theophyllinemayhavetobediscontinued.Irritability,restlessness,andtremorhave
alsobeenreportedasadversereactionsinpatientswiththerapeuticserumconcentrationsoftheophylline.AdditionaladverseCNS
effectsincludeanxiety,agitation,dizziness,andhyperactivity.44288
Theophyllineisaweakdiureticandinotrope,andcancauseamilddiuresis.44288

Hypercalcemiahasbeenreportedinapatientwithhyperthyroiddiseaseattherapeutictheophyllineconcentrations.44288
Severeallergicskinreactions,suchasexfoliativedermatitis,candeveloprarelyaftersystemadministrationofaminophyllineinpatients
previouslysensitizedtoethylenediamineviatopicaladministrationofanethylenediaminecontainingproduct.Urticariaorcontact
dermatitiscandevelopinindividualswhophysicallyhandleaminophyllinefromahypersensitivitytotheethylenediaminesalt.44232
Allergicreactionsmaynotbecomeevidentfor1224hoursafterinitiationoftreatment.
Theophyllinecanaffectthecardiovascularsystem.Itdecreasesperipheralresistance,increasescardiacoutput,andcausesacentral
vagaleffect.44288Palpitations,sinusbradycardia,extrasystoles,hypotension,ventriculartachycardia,prematureventricular
contractions(PVCs),andcardiacarresthavebeenreported.Althoughcardiovasculareffectsaregenerallymildandtransient,serious
reactions,suchasventriculararrhythmias,candevelopwithoutwarning.Patientsshouldbecarefullymonitored.
Theophyllinetoxicityappearstooccuratlowerserumconcentrationsafterchronicovermedicationthanafteracuteoverdose.2358023581
Inaddition,acuteoverdosepatientsaremorelikelytoexhibithypotension,hypokalemia,and/ormetabolicacidosisthanarepatients
receivingchronicovermedication.23580Patientssufferingchronicovermedicationcandevelopseizuresandseriousarrhythmiaswith
serumconcentrationsof2870mcg/ml.23580Cardiacarrhythmiasincludeatrialfibrillationoratrialflutter,multifocalatrial
tachycardia,sinustachycardia,supraventriculartachycardia(SVT),prematureventricularcontractions(PVCs),andotherventricular
arrhythmiaswithhemodynamicinstability.Instudiesevaluatingsignsandsymptomsoftheophyllineoverdose,sinustachycardiawas
themostcommoncardiacsymptomoccurringin86100%ofpatientsafteralargesingleingestion(acuteoverdose)and62100%of
patientsaftermultipleexcessivedoses(chronicoverdose).Multifocalatrialtachycardiaandatrialflutterhavebeenreportedatserum
concentrations>=15mcg/mlinpatientswithhypoxiasecondarytoCOPD.44288
Lastrevised:January10,2013

Clasificaciones
RespiratoryAgents
Methylxanthines

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