full prescribing information let10176 july 2011

7/28/2019 Full Prescribing Information LET10176 July 2011

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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


4/6

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


5/6

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.


6/6

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

full prescribing information let10176 july 2011

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