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LIGHTS OF PRESCRIBING INFORMATIONe highlights do not include all the inormation needed to use LETAIRIS tablets saely and efectively.ull prescribing inormation or LETAIRIS.RIS (ambrisentan) tabletsl U.S. Approval: 2007
WARNING: CONTRAINDICATED IN PREGNANCY
See ull prescribing inormation or complete boxed warning.
AIRIS can be prescribed and dispensed only through a restricted distribution program
TAIRIS Education and Access Program [LEAP]) because of this risk:aycausefetalharmiftakenduringpregnancy(4.1).
xcludepregnancybeforethestartoftreatment(2.2).
reventpregnancyduring treatmentand forone monthafter stopping treatmentbyhe use of two acceptable methods of contraception unless the patient has had a tubalterilization orchooses touse a CopperT 380A IUD orLNg 20IUS, inwhichcasenodditionalcontraceptionisneeded(2.2,5.1).
NT MAJOR CHANGES
edWarning,PotentialLiverInjuryremoval03/2011rningsandPrecautions,PotentialLiverInjuryremoval(5.1)03/2011rningsandPrecautions,PrescribingandDistributionProgramforLETAIRIS(5.1)03/2011rningsandPrecautions,PulmonaryVeno-occlusiveDisease(5.5)10/2010
CATIONS AND USAGE
RIS isan endothelinreceptorantagonistindicated forthe treatmentof pulmonaryarterialhypertension(WHOGroup1)toimproveexerciseabilityanddelayclinicalworsening.StudiesestablishingeectivenessdedpredominantlypatientswithWHOFunctionalClassII-IIIsymptomsandetiologiesofidiopathicorheritable64%)orPAHassociatedwithconnectivetissuediseases(32%)(1).
AGE AND ADMINISTRATION
atetreatmentat5mgoncedailywithorwithoutfood,andconsiderincreasingthedoseto10mgoncedailymgistolerated(2.1).
Treatwomenofchildbearingpotentialonlyafteranegativepregnancytestandtreatonlywomenwhoareutwoacceptablemethodsof contraceptionunlessthepatienthashada tubalsterilizationorchoosestouCopperT380AIUDorLNg20IUS,inwhichcasenoadditionalcontraceptionisneeded.Obtainmonthlypregntests(2.2,5.1).Notrecommendedinpatientswithmoderateorseverehepaticimpairment(2.3,8.7).
DOSAGE FORMS AND STRENGTHS
5mgand10mglm-coated,unscoredtablets(3).
CONTRAINDICATIONS
DonotadministerLETAIRIStoapregnantwomanbecauseitcancausefetalharm(4.1).
WARNINGS AND PRECAUTIONS
LETAIRISisavailableonlythroughaspecialrestricteddistributionprogram(5.1).Fluidretentionmayrequireintervention(5.2).Decreasesinspermcounthavebeenobservedinpatientstakingendothelinreceptorantagonists(5.3).Decreasesin hemoglobin have beenobservedwithin therst fewweeks;measurehemoglobinat initiaat1month,andperiodicallythereafter(5.4).IfpatientsdevelopacutepulmonaryedemaduringinitiationoftherapywithLETAIRIS,considerthepossibiliunderlyingpulmonaryveno-occlusivediseaseanddiscontinuetreatmentifnecessary(5.5).
ADVERSE REACTIONS
Mostcommonplacebo-adjustedadverse reactionsare peripheral edema, nasal congestion, sinusitis, uspalpitations,nasopharyngitis,abdominalpain,andconstipation(6.1).
ToreportSUSPECTEDADVERSEREACTIONS,contactGileadSciences,Inc.at(1-800-GILEAD5,OptionFDAat1-800-FDA-1088orwww.fda.gov/medwatch.
DRUG INTERACTIONS
Multipledoseco-administrationofambrisentanandcyclosporineresultedinanabout2-foldincr eaambrisentanexposureinhealthyvolunteers.Whenco-administeredwithcyclosporine,limitthedoseto5m
oncedaily(7).USE IN SPECIFIC POPULATIONS
PregnancyCategoryX:LETAIRISiscontraindicatedinpregnantwomen(4.1and8.1).Nursingmothers:BreastfeedingwhilereceivingLETAIRISisnotrecommended(8.3).
See17forPATIENTCOUNSELINGINFORMATIONandFDA-approvedpatientlabeling(MedicationGu
Revised:07/
PRESCRIBING INFORMATION: CONTENTS*NING: CONTRAINDICATED IN PREGNANCY
ICATIONSANDUSAGE
SAGEANDADMINISTRATION
AdultDosage
WomenofChildbearingPotential
Pre-existingHepaticImpairmentSAGE FORMS AND STRENGTHS
NTRAINDICATIONS
PregnancyCategoryX
RNINGSANDPRECAUTIONS
PrescribingandDistributionProgramforLETAIRIS
FluidRetention
DecreasedSpermCounts
HematologicalChanges
PulmonaryVeno-occlusiveDisease
VERSE REACTIONS
ClinicalTrialsExperience
PostmarketingExperience
UGINTERACTIONS
E IN SPECIFIC POPULATIONSPregnancy
NursingMothers
8.4PediatricUse
8.5GeriatricUse
8.6RenalImpairment
8.7HepaticImpairment
10OVERDOSAGE
11DESCRIPTION
12CLINICALPHARMACOLOGY
12.1MechanismofAction
12.2Pharmacodynamics
12.3Pharmacokinetics
13NONCLINICALTOXICOLOGY
13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility
14CLINICALSTUDIES
14.1PulmonaryArterialHypertension(PAH)
14.2Long-termTreatmentofPAH
16HOWSUPPLIED/STORAGEANDHANDLING
17PATIENTCOUNSELINGINFORMATION
17.1ImportanceofPreventingPregnancy
17.2HepaticEects
17.3HematologicalChange
17.4Administration
17.5FDA-ApprovedMedicationGuide
PRESCRIBING INFORMATION
WARNING: CONTRAINDICATED IN PREGNANC Y
ETAIRISisverylikelytoproduceseriousbirthdefectsifusedbypregnantwomen,asthiseecthas
een seen consistently when it is administered to animals [see Contraindications (4.1)].Pregnancy
mustthereforebeexcludedbeforetheinitiationoftreatmentwithLETAIRISandpreventedduring
eatment and for one month after stopping treatment by the use of two acceptable methods of con-
aception unless the patient has had a tubal sterilization or chooses to use a Copper T 380A IUD or
Ng20IUS,inwhichcasenoadditionalcontraceptionisneeded.Obtainmonthlypregnancytests.
Becauseoftheriskofbirthdefects,LETAIRISisavailableonlythroughaspecialrestricteddistribu
tionprogramcalledtheLETAIRISEducationandAccessProgram(LEAP),bycalling1-866-664-LEAP
(5327).OnlyprescribersandpharmaciesregisteredwithLEAPmayprescribeanddistributeLETAIRIS
Inaddition,LETAIRISmaybedispensedonlytopatientswhoareenrolledinandmeetallcondition
of LEAP[see Warnings and Precautions (5.1)].
*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.
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DICATIONSANDUSAGE
RISisindicatedforthetreatmentofpulmonaryarterialhypertension(PAH)(WHOGroup1)toimproveseabilityanddelayclinicalworsening.StudiesestablishingeectivenessincludedpredominantlypatientswithFunctionalClassII-IIIsymptomsand etiologiesof idiopathicor heritablePAH(64%)orPAHassociatedwith
ectivetissuediseases(32%).
SAGEANDADMINISTRATION
dultDosagetetreatmentat5mgoncedailywithorwithoutfood,andconsiderincreasingthedoseto10mgoncedailyifistolerated.
tsmaybeadministeredwithorwithoutfood.Tabletsshouldnotbesplit,crushed,orchewed.Doseshigherthangoncedailyhavenotbeenstudiedinpatientswithpulmonaryarterialhypertension(PAH).
WomenofChildbearingPotentialwomenofchildbearingpotentialonly after anegativepregnancytestandtreatonlywomenwhoare using
acceptablemethodsofcontraceptionunlessthepatienthashada tubalsterilizationorchoosestouseaerT 380A IUDor LNg20 IUS,in whichcase noadditional contraceptionis needed. Pregnancytests shouldtainedmonthlyinwomenofchildbearingpotentialtakingLETAIRIS [see Contraindications (4.1) and Warnings
recautions (5.1)].re-existingHepaticImpairmentRISisnotrecommendedinpatientswithmoderateorseverehepaticimpairment[see Use in Specifc Populations.ThereisnoinformationontheuseofLETAIRISinpatientswithmildhepaticimpairment;however,exposuretoisentanmaybeincreasedinthesepatients.
SAGE FORMS AND STRENGTHS
RISisavailableas5mgand10mglm-coated,unscoredtablets.
NTRAINDICATIONS
regnancyCategoryXRISmaycausefetalharmwhenadministeredtoapregnantwoman.Ambrisentanwasteratogenicatoraldoses5mg/kg/dayinratsand7mg/kg/dayinrabbits;itwasnotstudiedatlowerdoses.Inbothspecies,therewerermalitiesofthelowerjawandhardandsoftpalate,malformationoftheheartandgreatvessels,andfailureofationofthethymusandthyroid.Teratogenicityisaclasseectofendothelinreceptorantagonists.TherearenoontheuseofLETAIRISinpregnantwomen.
RISiscontraindicatedinwomenwhoareormaybecomepregnant.Ifthisdrugisusedduringpregnancy,orifthentbecomespregnantwhiletakingthisdrug,thepatientshouldbeapprisedofthepotentialhazardtoafetus.ancymustbeexcludedbeforetheinitiationoftreatmentwithLETAIRISandpreventedduringtreatmentand
nemonthafterstoppingtreatmentbythe useoftwoacceptablemethodsofcontraception.IfthepatienthastubalsterilizationorchoosestouseaCopperT380AIUDorLNg20IUSforpregnancyprevention,noadditionalaceptionisneeded[see Dosage and Administration (2.2), and Warnings and Precautions (5.1)].
RNINGSANDPRECAUTIONS
rescribingandDistributionProgramforLETAIRISuseoftheriskofbirthdefects,LETAIRISisavailableonlythroughaspecialrestricteddistributionprogramcalledTAIRISEducationandAccessProgram(LEAP).Onlyprescribersandpharmaciesregisteredwith LEAPmayprescribeistributeLETAIRIS.Inaddition,LETAIRISmaybedispensedonlytopatientswhoareenrolledinandmeetalltionsofLEAP.
rollinLEAP,prescribersmust completetheLEAPPrescriberEnrollmentandAgreementFormindicatingagreementeLEAPPrescriberEnrollmentandAgreementFormforfullprescribingphysicianagreement):
dthePrescribingInformation(PI)andMedicationGuideforLETAIRIS.llallpatientsinLEAPandre-enrollpatientsaftertherst12monthsoftreatmentandannuallythereafter.ewtheLETAIRISMedicationGuideandpatienteducationbrochure(s)witheverypatient.catepatientson therisksof LETAIRIS,includingthe riskof teratogenicity[see Boxed Warning, Warnings andautions (5), and Adverse Reactions (6)].cateandcounselwomenofchildbearingpotentialtousehighlyreliablecontraceptionduringLETAIRIStreatmentforonemonthafterstoppingtreatment.IfthepatienthashadatubalsterilizationorchoosestouseaCopperT
AIUDorLNg20IUSforpregnancyprevention,noadditionalcontraceptionisneeded.Womenwhodonotchooseof thesemethodsshouldalwaysusetwoacceptableformsof contraceptiononehormonemethod andoneiermethod,ortwobarriermethodswhereonemethodisthemalecondom.ceptablehormone methods include: progesteroneinjectables, progesteroneimplants, combinationoralntraceptives,transdermalpatch,andvaginalring.ceptablebarriermethodsinclude:diaphragm(withspermicide),cervicalcap(withspermicide),andthemalecondom.rtnersvasectomymustbeusedalongwithahormonemethodorabarriermethod.ucateand counselwomenof childbearingpotentialon theuse ofemergencycontraceptionin theeventofprotectedsexorknownorsuspectedcontraceptivefailure[see Boxed Warning, Contraindications (4.1)].
womenofchildbearingpotential,orderandreviewapregnancytestpriortoinitiationofLETAIRIStreatmentandthlyduringtreatment.
erandreviewtestsforserumliverenzymesasclinicallyindicatedsincesomemembersofthispharmacologicclasshepatotoxic.nselpatientswhofailtocomplywiththeprogramrequirements.fyLEAPofanyadverseeventsorifanypatientbecomespregnantduringLETAIRIStreatment.
luidRetentionheraledemaisaknownclasseectofendothelinreceptorantagonists,andisalsoaclinicalconsequenceofPAH
worseningPAH.Intheplacebo-controlledstudies,therewasanincreasedincidenceofperipheraledemainpatients
edwithdosesof5or10mgLETAIRIScomparedtoplacebo [see Adverse Reactions (6)].Mostedemawasmildtorateinseverity,anditoccurredwithgreaterfrequencyandseverityinelderlypatients.
dition, there have beenpost-marketingreportsof uid retentionin patientswith pulmonaryhypertension,ringwithinweeksafterstartingLETAIRIS.Patientsrequiredinterventionwithadiuretic,uidmanagement,or,incases,hospitalizationfordecompensatingheartfailure.
icallysignicantuidretentiondevelops,withorwithoutassociatedweightgain,furtherevaluationshouldbertakentodeterminethecause,suchasLETAIRISorunderlyingheartfailure,andthepossibleneedforspecicmentordiscontinuationofLETAIRIStherapy.
ecreasedSpermCounts-monthstudyofanotherendothelinreceptorantagonist,bosentan,25malepatientswithWHOfunctionalclassdIVPAHandnormalbaselinespermcountwereevaluatedforeectsontesticularfunction.Therewasadeclineermcountofatleast50%in25%ofthepatientsafter3or6monthsoftreatmentwithbosentan.Onepatientopedmarkedoligospermiaat3monthsandthespermcountremainedlowwith2follow-upmeasurementsoverubsequent6weeks.Bosentanwasdiscontinuedandafter2monthsthespermcounthadreturnedtobaselines.In 22patientswhocompleted6 monthsof treatment,spermcountremainedwithinthenormalrangeandangesinspermmorphology,spermmotility,or hormonelevelswereobserved.Basedon thesendingsandnicaldata [see Nonclinical Toxicology (13.1)]fromendothelinreceptorantagonists,itcannotbeexcludedthatthelinreceptorantagonistssuchasLETAIRIShaveanadverseeectonspermatogenesis.
ematologicalChanges
asesinhemoglobinconcentrationandhematocrithavefollowedadministrationofotherendothelinreceptoronistsandwereobservedinclinicalstudieswithLETAIRIS.Thesedecreaseswereobservedwithintherstfew
weeksoftreatmentwithLETAIRIS,andstabilizedthereafter.ThemeandecreaseinhemoglobinfrombaseltreatmentforthosepatientsreceivingLETAIRISinthe12-weekplacebo-controlledstudieswas0.8g/dL.
Markeddecreasesinhemoglobin(>15%decreasefrombaselineresultinginavaluebelowthelowerlimiwereobservedin7%ofa llpatientsreceivingLETAIRIS(and10%of patientsreceiving10mg)comparpatientsreceivingplacebo.Thecauseofthedecreaseinhemoglobinisunknown,butitdoesnotappeartohemorrhageorhemolysis.
MeasurehemoglobinpriortoinitiationofLETAIRIS,atonemonth,andperiodicallythereafter.Initiationotherapy is notrecommendedfor patientswith clinicallysignicant anemia. If a clinicallysignicanthemoglobinisobservedandothercauseshavebeenexcluded,considerdiscontinuingLETAIRIS.
5.5PulmonaryVeno-occlusiveDiseaseIfpatientsdevelopacutepulmonaryedemaduringinitiationoftherapywithvasodilatingagentssuchaspossibilityofpulmonaryveno-occlusivediseaseshouldbeconsidered,andifconrmedLETAIRISshouldbedisco
6 ADVERSE REACTIONS
6.1ClinicalTrialsExperienceSeeWarnings and Precautions (5.4)fordiscussionofhematologicalchanges.
Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedint
trialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreeobservedinpractice.
SafetydataforLETAIRISwereobtainedfromtwo12-week,placebo-controlledstudiesinpatientswithPAandARIES-2)andfournonplacebo-controlledstudiesin483patientswithPAHwhoweretreatedwithdo5,or10mgoncedaily.TheexposuretoLETAIRISinthesestudiesrangedfrom1dayto4 years(N=4186monthsandN=343foratleast1year).
InARIES-1andARIES-2,atotalof261patientsreceivedLETAIRISatdosesof2.5,5,or10mgoncedailyandreceivedplacebo.Theadverseeventsthatoccurredin>3%ofthepatientsreceivingLETAIRISandweremonLETAIRISthanplaceboareshowninTable1.
Table1AdverseEventsin>3%ofPAHPatientsReceivingLETAIRISandMoreFrequentthan
Placebo(N=132)
LETAIRIS(N=261)
Adverse event n (%) n (%) Placebo-adjus
Peripheraledema 14(11) 45(17) 6
Nasalcongestion 2(2) 15(6) 4
Sinusitis 0(0) 8(3) 3
Flushing 1(1) 10(4) 3Palpitations 3(2) 12(5) 3
Nasopharyngitis 1(1) 9(3) 2
Abdominalpain 1(1) 8(3) 2
Constipation 2(2) 10(4) 2
Dyspnea 4(3) 11(4) 1
Headache 18(14) 38(15) 1
Note: This table includes all adverse events >3% incidence in the combined LETAIRIS treatment group and more rethe placebo group, with a dierence o 1% between the LETAIRIS and placebo groups.
Mostadversedrugreactionsweremildtomoderateandonlynasalcongestionwasdose-dependent.
Fewnotabledierencesintheincidenceofadversedrugreactionswereobservedforpatientsbyageorseedemawassimilarinyoungerpatients(3xupperlimitofnwere0%onLETAIRISand2.3%onplacebo.Inpractice,casesofhepaticinjuryshouldbecarefullyevaluate
Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum LiverEnzyme AbnInanuncontrolled,open-labelstudy,36patientswhohadpreviouslydiscontinuedendothelinreceptoran(ERAs:bosentan,aninvestigationaldrug,orboth)duetoaminotransferaseelevations>3xULN weretLETAIRIS.Priorelevationswerepredominantlymoderate,with64%ofthe ALTelevations8xULN.Eightpatientshadbeenre-challengedwithbosentanand/ortheinvestigationaalleighthadarecurrenceofaminotransferaseabnormalitiesthatrequireddiscontinuationofERAtherapyhadtohavenormalaminotransferaselevelsonentrytothisstudy.Twenty-veofthe 36patientswerealprostanoid and/orphosphodiesterasetype 5 (PDE5) inhibitortherapy.Twopatientsdiscontinued earloneofthepatientswithaprior8xULNelevation).Oftheremaining34patients,onepatientexperieaminotransferaseelevationat12weeksonLETAIRIS5mgthatresolvedwithdecreasingthedosageto2.5thatdidnotrecurwithlaterescalationsto10mg.Withamedianfollow-upof13monthsandwith50%oincreasingthedoseofLETAIRISto10mg,nopatientswerediscontinuedforaminotransferaseelevations.uncontrolledstudydesigndoesnotprovideinformationaboutwhatwouldhaveoccurredwithre-adminipreviouslyused ERAsorshowthatLETAIRIS ledtofewer aminotransferaseelevationsthanwouldhavewiththosedrugs,the studyindicatesthatLETAIRISmaybe tried inpatientswho haveexperiencedas
aminotransferaseelevationsonotherERAsafteraminotransferaselevelshavereturnedtonormal.6.2PostmarketingExperienceThefollowingadversereactionswereidentiedduringpostapprovaluseofLETAIRIS:Fluidretention[see WPrecautions (5.2)],heartfailure(associatedwithuidretention),hypersensitivity(e.g.,angioedema,rash)nausea,andvomiting.
Elevationsofliveraminotransferases(ALT,AST)havebeenreportedwithLETAIRISuse;inmostcasesalternoftheliverinjurycouldbeidentied(heartfailure,hepaticcongestion,hepatitis,alcoholuse,hepatotoxicmOtherendothelinreceptorantagonistshavebeenassociatedwithelevationsofaminotransferases,hepatocasesofliverfailure[see Adverse Reactions (6.1)].DiscontinueLETAIRISif>5xULNorifelevationsareaccobilirubin>2xULN,orbysignsorsymptomsofliverdysfunctionandothercausesareexcluded.
Becausethesereactionswerereportedvoluntarilyfromapopulationofuncertainsize,itis notpossiblestimatethefrequencyorestablishacausalrelationshiptodrugexposure.
7DRUGINTERACTIONS
Multiple dose co-administration of ambrisentan and cyclosporine resulted in an approximately 2-finambrisentanexposureinhealthyvolunteers;therefore,limitthe doseofambrisentanto5 mgonceco-administeredwithcyclosporine[see Clinical Pharmacology (12.3)].
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IN SPECIFIC POPULATIONS
regnancyancyCategoryX[see Contraindications (4.1)].
ursingMothersotknownwhetherambrisentanisexcretedinhumanmilk.BreastfeedingwhilereceivingLETAIRISisnotmended.Apreclinicalstudyinratshasshowndecreasedsurvivalofnewbornpups(midandhighdoses)andsontesticlesizeandfertilityof pups(highdose)followingmaternaltreatmentwithambrisentanfromlatetionthroughweaning.Dosestestedwere17x,51x,and170x(low,mid,highdose,respectively)themaximumumandoseof10mgonamg/mm2basis.
ediatricUseyandeectivenessofLETAIRISinpediatricpatientshavenotbeenestablished.
eriatricUsetwoplacebo-controlledclinicalstudiesofLETAIRIS,21%ofpatientswere65yearsoldand5%were75old.Theelderly(age65years)showedlessimprovementinwalkdistanceswithLETAIRISthanyoungerpatientsuttheresultsofsuchsubgroupanalysesmustbeinterpretedcautiously.Peripheraledemawasmorecommoninderlythaninyoungerpatients.
enalImpairmentmpactofrenal impairment onthe pharmacokinetics ofambrisentanhas beenexamined using apopulationmacokineticapproachinPAHpatientswithcreatinineclearancesrangingbetween20and150mL/min.Therewas
nicantimpactofmildormoderaterenalimpairmentonexposuretoambrisentan [see Clinical Ph armacology].DoseadjustmentofLETAIRISinpatientswithmildormoderaterenalimpairmentisthereforenotrequired.isnoinformationontheexposuretoambrisentaninpatientswithsevererenalimpairment.
mpactofhemodialysisonthedispositionofambrisentanhasnotbeeninvestigated.
epaticImpairmentuenceofpre-existinghepaticimpairmentonthepharmacokineticsofambrisentanhasnotbeenevaluated.
usethereis in vitroandin vivoevidenceofsignificantmetabolicandbiliarycontributiontotheeliminationbrisentan,hepaticimpairmentwouldbeexpectedtohavesignicante fectsonthepharmacokineticsofsentan[see Clinical Pharmacology (12.3)].LETAIRISisnotrecommendedinpatientswithmoderateorsevereicimpairment.ThereisnoinformationontheuseofLETAIRISinpatientswithmildpre-existingimpairedliveron;however,exposuretoambrisentanmaybeincreasedinthesepatients[see Dosage andAdministration (2.3)].
VERDOSAGEisnoexperiencewithoverdosageofLETAIRIS.ThehighestsingledoseofLETAIRISadministeredtohealthy
teerswas100mgandthehighestdailydoseadministeredtopatientswithPAHwas10mgoncedaily.Inhealthyteers,singledosesof 50mgand100 mg(5to 10timesthemaximumrecommendeddose)wereassociatedheadache, ushing,dizziness,nausea,and nasal congestion. Massiveoverdosagecouldpotentially result inensionthatmayrequireintervention.
SCRIPTIONRISisthebrandnameforambrisentan,anendothelinreceptorantagonistthatisselectivefortheendothelinA(ETA)receptor.Thechemicalnameofambrisentanis(+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-phenylpropanoicacid.IthasamolecularformulaofC22H22N2O4andamolecularweightof378.42.Itcontainsachiralcenterdeterminedtobethe(S)congurationandhasthefollowingstructuralformula:
Ambrisentanisawhitetoo-white,crystallinesolid.ItisacarboxylicacidwithapKaof4.0.AmbrisentanispracticallyinsolubleinwaterandinaqueoussolutionsatlowpH.Solubilityincreasesin aqueoussolutionsathigherpH.Inthesolidstateambrisentanisverystable,isnothygroscopic,andisnotlightsensitive.
LETAIRISis availableas 5 mgand 10 mglm-coated tablets foronce-dailyoral administration. The tablets include the following inactive ingredients:croscarmellose sodium, lactose monohydrate, magnesium stearate andmicrocrystallinecellulose.Thetabletsarelm-coatedwitha coatingmaterialcontainingFD&CRed#40aluminumlake,lecithin,polyethyleneglycol,polyvinylalcohol, talc, and titanium dioxide. Each square, pale pink LETAIRIS tabletcontains5 mgof ambrisentan.Eachoval,deeppink LETAIRIStablet contains10mgofambrisentan.LETAIRIStabletsareunscored.
INICALPHARMACOLOGYMechanismofActionhelin-1(ET-1)isapotentautocrineandparacrinepeptide.Tworeceptorsubtypes,ETAandETB ,mediatethesofET-1inthevascularsmoothmuscleandendothelium.TheprimaryactionsofETAarevasoconstrictionandcelleration,whilethepredominantactionsofETBarevasodilation,antiproliferation,andET-1clearance.
ientswithPAH,plasmaET-1concentrationsareincreasedasmuchas10-foldandcorrelatewithincreasedmeanatrialpressureanddiseaseseverity.ET-1andET-1mRNAconcentrationsareincreasedasmuchas9-foldintheissueofpatientswithPAH,primarilyintheendotheliumofpulmonaryarteries.ThesendingssuggestthatET-1layacriticalroleinthepathogenesisandprogressionofPAH.
isentanisahighanity(Ki=0.011nM)ETAreceptorantagonistwithahighselectivityfortheETAversusETBtor(>4000-fold).TheclinicalimpactofhighselectivityforETAisnotknown.
Pharmacodynamicsac Electrophysiologyndomized,positive-andplacebo-controlled,parallel-groupstudy,healthysubjectsreceivedeitherLETAIRIS10mgfollowedbyasingledoseof40mg,placebofollowedbyasingledoseofmoxioxacin400mg,orplaceboalone.RIS10mgdailyhadnosignicanteectontheQTcinterval.The40mgdoseofLETAIRISincreasedmeanQTcatby5mswithanupper95%condencelimitof9ms.ForpatientsreceivingLETAIRIS5-10mgdailyandnottakingbolicinhibitors,nosignicantQTprolongationisexpected.
Pharmacokineticsharmacokineticsofambrisentan(S-ambrisentan)inhealthysubjectsaredoseproportional.Theabsoluteailabilityofambrisentanisnotknown.AmbrisentanisabsorbedwithpeakconcentrationsoccurringapproximatelyrsafteroraladministrationinhealthysubjectsandPAHpatients.Fooddoesnotaectitsbioavailability. In vitro
esindicatethatambrisentanisasubstrateofP-gp.Ambrisentanishighlyboundtoplasmaproteins(99%).Thenationofambrisentanispredominantlybynon-renalpathways,buttherelativecontributionsofmetabolismandyeliminationhavenotbeenwellcharacterized.Inplasma,theAUCof4-hydroxymethylambrisentanaccountsproximately4%relativetoparentambrisentanAUC.The in vivoinversionofS-ambrisentantoR-ambrisentanligible.Themeanoralclearanceofambrisentanis38mL/minand19mL/mininhealthysubjectsandinPAH
nts,respectively.Although ambrisentan hasa 15-hourterminalhalf-life, themean troughconcentrationofsentanatsteady-stateisabout15%ofthemeanpeakconcentrationandtheaccumulationfactorisabout1.2ong-termdailydosing,indicatingthattheeectivehalf-lifeofambrisentanisabout9hours.
Interactionsro studieseswithhumanlivertissueindicatethatambrisentanismetabolizedbyCYP3A,CYP2C19,anduridinehosphateglucuronosyltransferases(UGTs)1A9S,2B7S,and1A3S. In vitrostudiessuggestthatambrisentanis
strateoftheOrganicAnionTransportingPolypeptidesOATP1B1andOATP1B3,andasubstratebutnotaninhibitorlycoprotein(P-gp).Druginteractionsmightbeexpectedbecauseofthesefactors;however,aclinicallyrelevantctionhasbeendemonstratedonlywithcyclosporine[see Drug Interactions (7)]. Ambrisentandoesnotinhibitoredrugmetabolizingenzymesatclinicallyrelevantconcentrations.
o studiesectsofotherdrugsonambrisentanpharmacokineticsandtheeectsofambrisentanontheexposuretootherareshowninFigure2andFigure3,respectively.
Figure2EectsofOtherDrugsonAmbrisentanPharmacokinetics
Figure3EectsofAmbrisentanonOtherDrugs
13NONCLINICALTOXICOLOGY
13.1Carcinogenesis,Mutagenesis,ImpairmentofFertilityOralcarcinogenicitystudiesofuptotwoyearsdurationwereconductedatstartingdosesof10,30,and60inrats(8to48timesthemaximumrecommendedhumandose[MRHD]onamg/m2basis)andat50,150akg/dayinmice(28to140timestheMRHD).Intheratstudy,thehighandmid-dosemaleandfemalegroudosesloweredto40and20mg/kg/day,respectively,inweek51becauseofeectsonsurvival.Thehighdosfemalesweretakenodrugcompletelyinweeks69and93,respectively.Theonlyevidenceofambrisentacarcinogenicitywasapositivetrendinmalerats,forthecombinedincidenceofbenignbasalcelltumorancarcinomaofskin/subcutisinthemid-dosegroup(high-dosegroupexcludedfromanalysis),andtheoccumammarybroadenomasinmalesinthehigh-dosegroup.Inthemousestudy,highdosemaleandfemaletheirdosesloweredto150mg/kg/dayinweek39andweretakenodrugcompletelyinweek96(males)(females).Inmice,ambrisentanwasnotassociatedwithexcesstumorsinanydosedgroup.
Positivendingsofclastogenicityweredetected,atdrugconcentrationsproducingmoderatetohightoxichromosomeaberrationassayinculturedhumanlymphocytes.Therewasnoevidenceforgenetictoxicityofamwhentestedin vitroinbacteria(Amestest)orin vivoinrats(micronucleusassay,unscheduledDNAsynthe
Thedevelopmentof testiculartubularatrophyandimpairedfertilityhasbeen linkedto thechronicadmof endothelinreceptor antagonists inrodents.Testicular tubulardegenerationwas observed in rats tambrisentanfortwoyearsatdoses10mg/kg/day(8-foldMRHD).Increasedincidencesoftesticularndalsoobservedinmicetreatedfortwoyearsatdoses50mg/kg/day(28-foldMRHD).Eectsonspermcoumorphology,matingperformanceandfertilitywereobservedinfertilitystudiesinwhichmaleratsweretrambrisentanatoraldosesof300mg/kg/day(236-foldMRHD).Atdosesof10mg/kg/day,observationshistopathologyintheabsenceoffertilityandspermeectswerealsopresent.
14CLINICALSTUDIES
14.1PulmonaryArterialHypertension(PAH)Two12-week,randomized,double-blind,placebo-controlled,multicenterstudieswereconductedin393pPAH(WHOGroup1).ThetwostudieswereidenticalindesignexceptforthedosesofLETAIRISandthegeograoftheinvestigationalsites.ARIES-1comparedonce-dailydosesof5mgand10mgLETAIRIStoplacebo,wcomparedonce-dailydosesof2.5mgand5mgLETAIRIStoplacebo.Inbothstudies,LETAIRISorplacebowtocurrenttherapy,whichcouldhaveincludedacombinationofanticoagulants,diuretics,calciumchannedigoxin,butnotepoprostenol,treprostinil,iloprost,bosentan,orsildenal.Theprimarystudyendpointw
walkdistance.Inaddition,clinicalworsening,WHOfunctionalclass,dyspnea,andSF-36HealthSurveywePatientshadidiopathicorheritablePAH(64%)orPAHassociatedwithconnectivetissuediseases(32%),H(3%),oranorexigenuse(1%).TherewerenopatientswithPAHassociatedwithcongenitalheartdisease.
PatientshadWHOfunctionalclassI(2%),II(38%),III(55%),orIV(5%)symptomsatbaseline.Themeanagwas50years,79%ofpatientswerefemale,and77%wereCaucasian.
SubmaximalExerciseAbilityResultsofthe6-minutewalkdistanceat12weeksfortheARIES-1andARIES-2studiesareshowninTable2a
Table2ChangesfromBaselinein6-MinuteWalkDistance(meters)
ARIES-1 ARIES-2
Placebo(N=67) 5mg(N=67) 10mg(N=67) Placebo(N=65) 2.5mg(N=64) 5
Baseline 34273 34077 34278 34386 34784
Meanchangefrombaseline -879 2383 4463 -1094 2283 Placebo-adjustedmeanchangefrombaseline 31 51 32
Placebo-adjustedmedianchangefrombaseline 27 39 30
p-valuea 0.008
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Figure4MeanChangein6-MinuteWalkDistance
change rom baseline in 6-minute walk distance in the placebo and LETAIRIS groupss are expressed as mean standard error o the mean.
thstudies,treatmentwithLETAIRISresultedin asignicantimprovementin6-minutewalkdistanceforeachdoseTAIRISand theimprovements increasedwith dose.An increase in6-minutewalk distance was observed aftereksoftreatmentwithLETAIRIS,withadose-responseobservedafter12weeksoftreatment.ImprovementsinwalkcewithLETAIRISweresmallerforelderlypatients(age65)thanyoungerpatientsandforpatientswithsecondaryPAHorpatientswithidiopathicorheritablePAH.Theresultsofsuchsubgroupanalysesmustbeinterpretedcautiously.
ectsofLETAIRISonwalkdistancesattroughdruglevelsarenotknown.Becauseonlyoncedailydosingwasedintheclinicaltrials,theecacyandsafetyofmorefrequentdosingregimensforLETAIRISarenotknown.Ifseabilityisnotsustainedthroughoutthedayinapatient,considerotherPAHtreatmentsthathavebeenstudied
morefrequentdosingregimens.
cal WorseningtoclinicalworseningofPAHwasdenedastherstoccurrenceofdeath,lungtransplantation,hospitalization
AH,atrialseptostomy,studywithdrawalduetotheadditionofotherPAHtherapeuticagentsorstudywithdrawaloearlyescape.Earlyescapewasdenedasmeetingtwoormoreofthefollowingcriteria:a20%decreaseinthenutewalkdistance;anincreaseinWHOfunctionalclass;worseningrightventricularfailure;rapidlyprogressingogenic,hepatic, orrenal failure; orrefractory systolichypotension.The clinicalworsening events duringtheeektreatmentperiodoftheLETAIRISclinicaltrialsareshowninTable3andFigure5.
Table 3 Time to Clinical Worsening
ARIES-1 ARIES-2
Placebo(N=67)
LETAIRIS(N=134)
Placebo(N=65)
LETAIRIS(N=127)
calworsening,no.(%) 7(10%) 4(3%) 13(22%) 8(6%)
rdratio 0.28 0.30
lue,Fisherexacttest 0.044 0.006
lue,Log-ranktest 0.030 0.005
ion-to-treat populationPatients may have had more than one reason or clinical worsening.nal p-values
wasasignicantdelayinthetimetoclinicalworseningforpatientsreceivingLETAIRIScomparedtoplacebo.tsinsubgroupssuchastheelderlywerealsofavorable.
Figure5TimetoClinicalWorsening
Time rom randomization to clinical worsening with Kaplan-Meier estimates o the proportions o ailures in ARIES-1 anp-values shown are the log-rank comparisons oLETAIRIS to placebo stratifed by idiopathic or heritable PAH and nonnon-heritable PAH patients
14.2Long-termTreatmentofPAHThelong-termfollow-upofthepatientswhoweretreatedwithLETAIRISinthetwopivotalstudiesandtheiextension(N=383)showsthat95%werestillaliveatoneyearand94%werestillreceivingLETAIRISmonotherauncontrolledobservationsdonotallowcomparisonwithagroupnotgivenLETAIRISandcannotbeusedtothelong-termeectofLETAIRIS.
16HOWSUPPLIED/STORAGEANDHANDLING
LETAIRISmaybeprescribedonlythroughtheLETAIRISEducationandAccessProgram(LEAP)bycalling1-86(5327)orbyloggingontowww.letairis.com.Adverseeventscanalsobereporteddirectlyviathisnumber
LETAIRISlm-coated,unscoredtabletsaresuppliedasfollows:
PackageConguration
TabletStrength
NDC No.Description o Tablet;Debossed on Tablet;
Size
30c oun tbl is te r 5mg 61958 -0 801-2Squareconvex;palepink;
5onside1andGSIonside6.6mmSquare
30c oun tbl is te r 10mg 61958 -0 802-2Ovalconvex;deeppink;
10onside1andGSIonside9.8mmx4.9mmOval
only
Storeat25C(77F);excursionspermittedto15-30C(59-86F)[see USP controlled room temperature].Stinitsoriginalpackaging.
17PATIENTCOUNSELINGINFORMATION
Asapartofpatientcounseling,doctorsmustreviewtheLETAIRISMedicationGuidewitheverypatieApproved Medication Guide (17.5)].
17.1ImportanceofPreventingPregnancyPatientsshouldbeadvisedthatLETAIRISmaycausefetalharm.LETAIRIStreatmentshouldonlybeinitiate
ofchildbearingpotentialfollowinganegativepregnancytest.WomenofchildbearingpotentialshouldbeinformedoftheimportanceofmonthlypregnancytestsandtusehighlyreliablecontraceptionduringLETAIRIStreatmentandforonemonthafterstoppingtreatment.IhashadatubalsterilizationorchoosestouseaCopperT380AIUDorLNg20IUSforpregnancyprevention,ncontraceptionisneeded.Womenwhodonotchooseoneofthesemethodsshouldalwaysusetwoacceptacontraceptiononehormonemethodandonebarriermethod,ortwobarriermethodswhereonemethodcondom.Acceptablehormonemethodsinclude:progesteroneinjectables,progesteroneimplants,combincontraceptives,transdermalpatch,andvaginalring.Acceptablebarriermethodsinclude:diaphragm(withcervicalcap(withspermicide),andthemalecondom.Partnersvasectomymustbeusedalongwithahormorabarriermethod.
Patientsshouldbeinstructedtoimmediatelycontacttheirphysicianiftheysuspecttheymaybe pregnant.counselwomenofchildbearingpotentialonuseofemergencycontraceptionforpatientswhomhavehadunproorknownorsuspectedcontraceptivefailure [see Warnings and Precautions (5.1)].
17.2HepaticEectsSomemembersofthispharmacologicalclassarehepatotoxic.Patientsshouldbeeducatedonthesymptomsofliverinjury(suchasanorexia,nausea,vomiting,fever,malaise,fatigue,rightupperquadrantabdominald
jaundice,darkurineoritching)andinstructedtoreportanyofthesesymptomstotheirphysician.
17.3HematologicalChangePatientsshouldbeadvisedoftheimportanceofhemoglobintesting.
17.4AdministrationPatientsshouldbeadvisednottosplit,crush,orchewtablets.
17.5FDA-ApprovedMedicationGuide*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.
GileadSciences,Inc.,FosterCity,CA94404
RevisedJuly2011
LETAIRISisaregisteredtrademarkofGileadSciences,Inc.GileadandtheGileadlogoaretrademarksofGileInc.Otherbrandsnotedhereinarethepropertyoftheirrespectiveowners.
2011GileadSciences,Inc.
GS22-081-008
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Medication GuideMedication Guide
LETAIRIS(le-TAIR-is) (ambrisentan)Tablets
ReadthisMedicationGuidebeforeyoustarttakingLETAIRISandeachtimeyougeta
rell.Theremaybenewinformation.ThisMedicationGuidedoesnottaketheplaceof
talkingwithyourdoctoraboutyourmedicalconditionoryourtreatment.
What is the most important information I should know
aboutLETAIRIS?
Seriousbirthdefects.
LETAIRIS can cause serious birth deects i taken during pregnancy. Women mustnot be pregnant when they start taking LETAIRIS or become pregnant duringtreatment.WomenwhoareabletogetpregnantmusthaveanegativepregnancytestbeforebeginningtreatmentwithLETAIRISandeachmonthduringtreatment.Yourdoctorwilldecidewhentodothetest,dependingonyourmenstrualcycle.
Women who are able to get pregnant must use two acceptable orms o birthcontrol, during LETAIRIS treatment and or one month ater stopping LETAIRIS.I you have had a tubal sterilization or have an IUD, these methods can beused alone and no other orm o birth control is needed. Talkwithyourdoctororgynecologist(adoctorwhospecializesinfemalereproduction)tondoutabouthowtopreventpregnancy. Do not have unprotected sex. Talk to your doctor orpharmacist right away i you have unprotected sex or i you think your birthcontrol has ailed. Tell your doctor right away i you miss a menstrual period or
think you may be pregnant.
LETAIRISisavailableonlythrougharestrictedprogramcalledtheLETAIRISEducation
andAccessProgram(LEAP).ToreceiveLETAIRIS,youmusttalktoyourdoctor,understand
thebenetsandrisksofLETAIRIS,andagreetoalloftheinstructionsintheLEAPprogram.
WhatisLETAIRIS?
LETAIRISisaprescriptionmedicinetotreatpulmonaryarterialhypertension(PAH),
whichishighbloodpressureinthearteriesofyourlungs.
LETAIRIScanimproveyourabilitytoexerciseanditcanhelpslowdowntheworsening
ofyourphysicalconditionandsymptoms.
WhoshouldnottakeLETAIRIS?
Do not take LETAIRIS i:
you are pregnant, plan to become pregnant, or become pregnant duringtreatment with LETAIRIS. LETAIRIS can cause serious birth deects.(SeeWhatithemost important information I should know about LETAIRIS?) Serious birtdefectsfromLETAIRIShappenearlyinpregnancy.
Tell your doctor about all your medical conditions and all the medicines you
take including prescription and nonprescription medicines.LETAIRISandothe
medicinesmayaecteachothercausingsideeects.Donotstartanynewmedicine
untilyoucheckwithyourdoctor.
Especially tell your doctor i you take the medicine cyclosporine (Gengra, Neora
Sandimmune).YourdoctormayneedtochangeyourdoseofLETAIRIS.Youshouldnot
takemorethan5mgofLETAIRISeachdayifyoualsotakecyclosporine.
LETAIRIShasnotbeenstudiedinchildren.
HowshouldItakeLETAIRIS?
LETAIRISwillbemailedtoyoubyaspecialtypharmacy.Yourdoctorwillgiveyou
completedetails.
TakeLETAIRISexactlyasyourdoctortellsyou.DonotstoptakingLETAIRISunlessyourdoctortellsyou.
YoucantakeLETAIRISwithorwithoutfood.
Donotsplit,crushorchewLETAIRIStablets.
ItwillbeeasiertoremembertotakeLETAIRISifyoutakeitatthesametimeeachday.
IfyoutakemorethanyourregulardoseofLETAIRIS,callyourdoctorrightaway.
Ifyoumissadose,takeitassoonasyourememberthatday.Takeyournextdoseattheregulartime.Donottaketwodosesatthesametimetomakeupforamisseddose.
WhatshouldIavoidwhiletakingLETAIRIS?
Do not get pregnant whiletakingLETAIRIS.(SeetheseriousbirthdefectssectionoWhatisthemostimportantinformationIshouldknowaboutLETAIRIS?)Ifyoumissamenstrualperiod,orthinkyoumightbepregnant,callyourdoctorrightaway.
Breasteeding is not recommended whiletakingLETAIRIS.ItisnotknowniLETAIRIScanpassthroughyourmilkandharmyourbaby.
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2011 Gilead Sciences, Inc. All rights reserved. LET10176 July 2011
LETAIRIS is a registered trademark of Gilead Sciences, Inc. Gilead and
the Gilead logo are trademarks of Gilead Sciences, Inc.
Printed on recycled paper.
WhatarethepossiblesideeectsofLETAIRIS?
Serious side efects o LETAIRIS include:
Serious birth deects. (SeeWhatisthemostimportantinformationIshouldknowaboutLETAIRIS?)
Swelling all over the body (uidretention)canhappenwithinweeksafterstartingLETAIRIS.Tellyourdoctorrightawayifyouhaveanyunusualweightgain,tiredness,ortroublebreathingwhiletakingLETAIRIS.Thesemaybesymptomsofaserioushealthproblem.Youmayneedtobetreatedwithmedicineorneedtogotothehospital.
Sperm count reduction.Reducedspermcountshavebeenobservedinsomementaking
adrugsimilartoLETAIRIS,aneectwhichmightimpairtheirabilitytofatherachild.Tellyourdoctorifremainingfertileisimportanttoyou.
Low red blood cell levels (anemia)canhappenduringtherstweeksafterstartingLETAIRIS.YourdoctorwilldobloodteststocheckyourredbloodcellsbeforestartingLETAIRIS.YourdoctormayalsodothesetestsduringtreatmentwithLETAIRIS.
The most common side efects o LETAIRIS are:
Swellingofhands,legs,anklesandfeet(peripheraledema)
Stuynose(nasalcongestion)
Inamednasalpassages(sinusitis)
Hotashesorgettingredintheface(ushing)
Feelingyourheartbeat(palpitations)
RedandsorethroatandnoseStomachpain
Constipation
Shortnessofbreath
Headache
SomemedicinesthatarelikeLETAIRIScancauseliverproblems.TellyourdoctorifyougetanyofthesesymptomsofaliverproblemwhiletakingLETAIRIS:
lossofappetite
nauseaorvomiting
fever
achiness
generallydonotfeelwellpainintheupperrightstomach(abdominal)area
yellowingofyourskinorthewhitesofyoureyes
darkurine
itching
Tellyourdoctorifyouhaveanysideeectthatbothersyouorthatdoesnotgoaway.
ThesearenotallofthepossiblesideeectsofLETAIRIS.Formoreinformation,ask
yourdoctororpharmacist.
Callyourdoctorformedicaladviceaboutsideeects.Youmayreportsideeectsto
FDAat1-800-FDA-1088.
HowshouldIstoreLETAIRIS?
StoreLETAIRISat59Fto86F(15Cto30C),inthepackageitcomesin.
KeepLETAIRISandallmedicinesoutofthereachofchildren.
General information about LETAIRIS
MedicinesaresometimesprescribedforpurposesotherthanthoselistedinaMedicatio
Guide.DonotuseLETAIRISforaconditionforwhichitwasnotprescribed.Donotgive
LETAIRIStootherpeople,eveniftheyhavethesamesymptomsthatyouhave.Itmayharmthem.
ThisMedicationGuidesummarizesthemostimportantinformationaboutLETAIRIS.Ifyou
wouldlikemoreinformation,askyourdoctor.Youcanaskyourdoctororpharmacistfo
informationaboutLETAIRISthatiswrittenforhealthcareprofessionals.
For more inormation, call 1-866-664-LEAP (5327) or visit www.letairis.com o
www.gilead.com.
WhataretheingredientsinLETAIRIS?
Active ingredient:ambrisentan
Inactive Ingredients:croscarmellosesodium,lactosemonohydrate,magnesiumstearat
andmicrocrystallinecellulose.Thetabletsarelm-coatedwithacoatingmaterialcontainin
FD&CRed #40aluminum lake,lecithin,polyethyleneglycol,polyvinylalcohol, talc,and
titaniumdioxide.
RevisedMarch2011
ThisMedication Guide hasbeen approvedby theU.S. FoodandDrug Administration
GileadSciences,Inc.,FosterCity,CA94404
LETAIRISisaregisteredtrademarkofGileadSciences,Inc.GileadandtheGileadlogoare
trademarksof GileadSciences, Inc.Otherbrandsnotedherein arethepropertyof the
respectiveowners.
2011GileadSciences,Inc.GS22-081-008