<P>However,onefatalcaseofklebsiellapneumoniasepsisoccurredinapatienttakingteri?unomide14mgfor1.7years.Fatalinfectionshavebeenreportedinthepost-marketingsetting,inpatientsreceivingle?unomide,especiallyPneumocystisjirovecipneumoniaandaspergillosis.Mostofthereportswereconfoundedbyconcomitantimmunosuppressanttherapyand/orcomorbidillnesswhich,inadditiontorheumatoiddisease,maypredisposepatientstoinfection.InclinicalstudieswithAUBAGIO,cytomegalovirushepatitisreactivationhasbeenobserved. InclinicalstudieswithAUBAGIO,casesoftuberculosishavebeenobserved.PriortoinitiatingAUBAGIO,screenpatientsforlatenttuberculosisinfectionwithatuberculinskintest.AUBAGIOhasnotbeenstudiedinpatientswithapositivetuberculosisscreen,andthesafetyofAUBAGIOinindividualswithlatenttuberculosisinfectionisunknown.Forpatientstestingpositiveintuberculosisscreening,treatbystandardmedicalpracticepriortotherapywithAUBAGIO. Vaccination NoclinicaldataareavailableontheefficacyandsafetyofvaccinationsinpatientstakingAUBAGIO.Vaccinationwithlivevaccinesis,however,notrecommended.Thelonghalf-lifeofAUBAGIOshouldbeconsideredwhencontemplatingadministrationofalivevaccineafterstoppingAUBAGIO. Malignancy Theriskofmalignancy,particularlylymphoproliferativedisorders,isincreasedwiththeuseofsomeimmunosuppressivemedications.Thereisapotentialforimmunosuppressionwithteri?unomide.NoapparentincreaseintheincidenceofmalignanciesandlymphoproliferativedisorderswasreportedintheAUBAGIOclinicaltrials,butlargerandlonger-termstudieswouldbeneededtodeterminewhetherthereisanincreasedriskofmalignancyorlymphoproliferativedisorderswithAUBAGIO.5.5PeripheralNeuropathy Inplacebo-controlledstudies,peripheralneuropathy,includingbothpolyneuropathyandmonon-europathy(e.g.,carpaltunnelsyndrome),wasreportedmorefrequentlyinpatientstakingAUBAGIOthaninpatientstakingplacebo.Inone108-weekplacebo-controlledstudyin1086patientswithmultiplesclerosis,theincidenceofperipheralneuropathycon?rmedbynerveconductionstudieswas1.2(4patients)and1.9(6patients)on7mgand14mgofAUBAGIO,respectively,comparedwith0onplacebo.Treatmentwasdiscontinuedin2patientswithpolyneuropathy,oneoneachdose;oneofthemrecoveredfollowingtreatmentdiscontinuation.Theothercasesofperipheralneuropathydidnotresolvewithcontinuedtreatment.Therehavealsobeenreportsofperipheralneuropathyinpatientsreceivingle?unomide. Ageolderthan60years,concomitantneurotoxicmedications,anddiabetesmayincreasetheriskforperipheralneuropathy.IfapatienttakingAUBAGIOdevelopssymptomsconsistentwithperipheralneuropathy,suchasbilateralnumbnessortinglingofhandsorfeet,considerdiscontinuingAUBAGIOtherapyandperforminganacceleratedeliminationprocedureseeWarningsandPrecautions(5.3).5.6AcuteRenalFailure Inplacebo-controlledtrials,10of844(1.2)ofAUBAGIO-treatedsubjectshadtransientacuterenalfailurewithacreatininemeasurementincreasedby100ormoreoftheirbaselineserumcreatininevalue,comparedto0of421placebo-treatedsubjects.Sevenofthe10subjectshadanadircreatinineclearancelessthan30cc/minute.Ineachofthe10subjects,theserumcreatininelevelwasnormalonthenextreportedmeasurement(6–48daysfromtheincreaseincreatinine)withcontinuedteri?unomideuse.Theseincreasedcreatininemeasurementsoccurredbetween12weeksand2yearsafter?rstdoseofteri?unomide.Ofthe6subjectswithavailableserumpotassiummeasurements,3(50)hadhyperkalemia(measurementsof6.7,>7.3,and>7.3mmol/L).Noassociatedsymptomsweredocumented. AUBAGIOcausesincreasesinrenaluricacidclearancewithmeandecreasesinserumuricacidof20–30.Acuteuricacidnephropathyisalikelyexplanationforthecasesoftransientacuterenalfailureseenwithteri?unomide.Althoughsymptomsassociatedwithacuteuricacidnephropathy,suchasloinpainor?ankpain,werenotreported,thisinformationwasnotsystematicallycollected.Noincitingfactors,suchasdehydration,exercise,orincreaseinphysicalactivityinthe30dayspriortotheadverseeventwerereported,butthisinformationwasnotsystematicallycollected.5.7Hyperkalemia Inplacebo-controlledtrials,treatment-emergenthyperkalemia>7.0mmol/Loccurredin8/829(1.0)ofteri?unomide-treatedsubjects,comparedto1/414(0.2)ofplacebo-treatedsubjects.Twoteri?unomide-treatedsubjectshadhyperkalemia>7.0mmol/Lwithacuterenalfailure.Possiblecausesinothercaseswerenotdocumented.CheckserumpotassiumlevelinAUBAGIO-treatedpatientswithsymptomsofhyperkalemiaorwithacuterenalfailure.5.8SkinReactions RarecasesofStevens-Johnsonsyndromeandtoxicepidermalnecrolysishavebeenreportedinpatientswithrheumatoidarthritisreceivingle?unomide.Asimilarriskwouldbeexpectedforteri?unomideseeClinicalPharmacology(12.3)inthefullprescribinginformation.IfapatienttakingAUBAGIOdevelopsanyoftheseconditions,stopAUBAGIOtherapyandperformanacceleratedeliminationprocedureseeWarningsandPrecautions(5.3).5.9BloodPressureIncrease Inplacebo-controlledstudies,meanchangefrombaselineinsystolicbloodpressurewas2.9mmHgand2.7mmHgforAUBAGIO7mgand14mg,respectively,and-1.3mmHgforplacebo.Thechangefrombaselineindiastolicbloodpressurewas1.4mmHgand1.3mmHgforAUBAGIO7mgand14mg,respectively,and-0.9mmHgforplacebo.Hypertensionwasreportedasanadversereactionin4ofpatientstreatedwith7mgor14mgofAUBAGIO,comparedwith2onplacebo.CheckbloodpressurebeforestartofAUBAGIOtreatmentandperiodicallythereafter.ElevatedbloodpressureshouldbeappropriatelymanagedduringtreatmentwithAUBAGIO.5.10RespiratoryEffects Interstitiallungdiseaseandworseningofpre-existinginterstitiallungdiseasehavebeenreportedduringtreatmentwithle?unomide.Asimilarriskwouldbeexpectedforteri?unomideseeClinicalPharmacology(12.3)inthefullprescribinginformation.Interstitiallungdiseasemaybefatal.Interstitiallungdiseasemayoccuracutelyatanytimeduringtherapyandhasavariableclinicalpresentation.Newonsetorworseningpulmonarysymptoms,suchascoughanddyspnea,withorwithoutassociatedfever,maybeareasonfordiscontinuationofthetherapy andforfurtherinvestigationasappropriate.Ifdiscontinuationofthedrugisnecessary,considerinitiationofanacceleratedeliminationprocedureseeWarningsandPrecautions(5.3).5.11ConcomitantUsewithImmunosuppressiveorImmunomodulatingTherapiesCo-administrationwithantineoplastic,orimmunosuppressivetherapiesusedfortreatmentof multiplesclerosishasnotbeenevaluated.Safetystudiesinwhichteri?unomidewasconcomi- tantlyadministeredwithotherimmunemodulatingtherapiesforuptooneyear(interferonbeta, glatirameracetate)didnotrevealanyspeci?csafetyconcerns.Thelongtermsafetyofthese combinationsinthetreatmentofmultiplesclerosishasnotbeenestablished. InanysituationinwhichthedecisionismadetoswitchfromAUBAGIOtoanotheragentwith aknownpotentialforhematologicsuppression,itwouldbeprudenttomonitorforhematologic toxicity,becausetherewillbeoverlapofsystemicexposuretobothcompounds.Useofan acceleratedeliminationproceduremaydecreasethisrisk,butmayalsopotentiallyresultin returnofdiseaseactivityifthepatienthadbeenrespondingtoAUBAGIOtreatmentsee WarningsandPrecautions(5.3). 6.ADVERSEREACTIONSThefollowingseriousadversereactionsaredescribedelsewhereintheprescribinginformation: •HepatotoxicityseeContraindications(4.1)andWarningsandPrecautions(5.1)•BoneMarrowEffects/ImmunosuppressionPotential/InfectionsseeWarningsandPrecau-tions(5.4)•PeripheralNeuropathyseeWarningsandPrecautions(5.5)•AcuteRenalFailureseeWarningsandPrecautions(5.6)•HyperkalemiaseeWarningsandPrecautions(5.7)•SeriousSkinReactionsseeWarningsandPrecautions(5.8)•BloodPressureEffectsseeWarningsandPrecautions(5.9)•RespiratoryEffectsseeWarningsandPrecautions(5.10)ThemostfrequentadversereactionsforAUBAGIO(incidence=10and=2greaterthan placebo)intheplacebo-controlledstudieswereALTincreased,alopecia,diarrhea,in?uenza, nausea,andparesthesia.Alopeciawasthemostcommoncauseofdiscontinuationbecauseof adverseeventsincontrolledclinicalstudiesascomparedtoplacebo(0.5and1.4ofpatients onAUBAGIO7mgand14mg,respectively,and0onplacebo). Ifdesired,teri?unomidecanberapidlyclearedfromthebodybytheuseofanaccelerated eliminationprocedureseeWarningsandPrecautions(5.3). 6.1ClinicalTrialExperience Atotalof844patientsonteri?unomide(7mgor14mgoncedaily)constitutedthesafety populationinthepooledanalysisofplacebocontrolledstudiesinpatientswithrelapsingforms ofMS(RMS).Approximately72ofpatientswerefemaleandthemeanagewas38years. Study1wasa108-weekplacebo-controlledclinicalstudyin1086RMSpatientstreatedwith teri?unomide7mg(n=368),teri?unomide14mg(n=358),orplacebo(n=360). Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionrates observedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrials ofanotherdrugandmaynotre?ecttheratesobservedinclinicalpractice. Table1AdverseReactionsinStudy1(occurringin=2ofpatients,andreportedforteri?unomide7mgor14mgat=2higherratethanforplacebo) Teri?unomide PRIMARYSYSTEMORGANCLASSPreferredTerm() 14mg(N=358)7mg(N=368)Placebo(N=360) INFECTIONSANDINFESTATIONS In?uenza12910 Upperrespiratorytractinfection997 Bronchitis856 Sinusitis644 Cystitis421 Gastroenteritisviral421 Oralherpes422 BLOODANDLYMPHATICSYSTEMDISORDERS Neutropenia420.3 Leukopenia120.3 IMMUNESYSTEMDISORDERS Seasonalallergy321 PSYCHIATRICDISORDERS Anxiety432 NERVOUSSYSTEMDISORDERS Headache192218 Paraesthesia1098 Sciatica311 Burningsensation321 Carpaltunnelsyndrome310.3 EYEDISORDERS Visionblurred331 Conjunctivitis131 CARDIACDISORDERS Palpitations231 AUBAGIO® (teri?unomide)tabletsfororaladministration S:7 S:10 T:8.25 T:10.875 B:8.5 B:11.125 US.TEF.13.10.023A-size.indd 610/28/13 12:06 PM</p> <UL><LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/1/1/">Front-Cover</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/2/2/">Inside-Front-Cover</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/3/3/">Page-3</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/4/4/">Page-4</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/5/5/">Page-5</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/6/6/">Page-6</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/7/7/">Page-7</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/8/8/">Page-8</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/9/9/">Page-9</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/10/10/">Page-10</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/11/11/">Page-11</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/12/12/">Page-12</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/13/13/">Page-13</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/14/14/">Page-14</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/15/15/">Page-15</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/16/16/">Page-16</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/17/17/">Page-17</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/18/18/">Page-18</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/19/19/">Page-19</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/20/20/">Page-20</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/21/21/">Page-21</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/22/22/">Page-22</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/23/23/">Page-23</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/24/24/">Page-24</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/25/25/">Page-25</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/26/26/">Page-26</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/27/27/">Page-27</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/28/28/">Page-28</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/29/29/">Page-29</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/30/30/">Page-30</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/31/31/">Page-31</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/32/32/">Page-32</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/33/33/">Page-33</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/34/34/">Page-34</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/35/35/">Page-35</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/36/36/">Page-36</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/37/37/">Page-37</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/38/38/">Page-38</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/39/39/">Back-Cover</a></LI> <LI><a href="http://www.mzines.net/publications/704/x/sitemap.xml" target="_blank">site map</a></LI> </UL>

 

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