HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PROAIR HFA safely and effectively. See full prescribing information for PROAIR HFA Inhalation AerosolPROAIR HFA (albuterol sulfate) INHALATION AEROSOLInitial U.S. Approval: 1981 RECENT MAJOR CHANGES

Dosage and Administration (2.3) 03/12 INDICATIONS AND USAGE PROAIR HFA Inhalation Aerosol is a beta2-adrenergic agonist indicated for:• Treatmentorpreventionofbronchospasminpatients4yearsofageandolderwithreversibleobstructiveairwaydisease.(1.1)

• Preventionofexercise-inducedbronchospasminpatients4yearsofageandolder.(1.2)

DOSAGE AND ADMINISTRATION

Fororalinhalationonly• Treatmentorpreventionofbronchospasminadultsandchildren4yearsofageandolder:2inhalationsevery4to6hours.Insomepatients,oneinhalationevery4hoursmaybesufficient.(2.1)

• Preventionofexercise-inducedbronchospasm inadultsandchildren4yearsofageandolder:2inhalations15to30minutesbeforeexercise.(2.2)

• Priminginformation:PrimePROAIRHFAbeforeusingforthefirsttime,orwhentheinhalerhasnotbeenusedformorethan2weeks.ToprimePROAIRHFA,re-lease3spraysintotheairawayfromtheface.Shakewellbeforeeachspray.(2.3)

• Cleaninginformation:At leastonceaweek,washtheactuatorwithwarmwater,shakeoffexcess,andairdrythoroughly.(2.3)

• PROAIRHFAinhalershouldbediscardedwhenthedosecounterdisplays0oraftertheexpirationdateontheproduct,whichevercomesfirst.(2.3)

DOSAGE FORMS AND STRENGTHS

InhalationAerosol: Each actuationdelivers 108mcgof albuterol sulfate from theactuatormouthpiece(equivalentto90mcgofalbuterolbase).Suppliedin8.5-gcan-istercontaining200actuations.(3) CONTRAINDICATIONS

HypersensitivitytoalbuterolandanyotherPROAIRHFAInhalationAerosolCompo-nents.(4)

WARNINGS AND PRECAUTIONS

• Life-threateningparadoxicalbronchospasmmayoccur.DiscontinuePROAIRHFAimmediatelyandtreatwithalternativetherapy.(5.1)

• NeedformoredosesofPROAIRHFAthanusualmaybeasignofdeteriorationofasthmaandrequiresreevaluationoftreatment. (5.2)

• PROAIRHFAisnotasubstituteforcorticosteroids.(5.3)• Cardiovasculareffectsmayoccur.Usewithcautioninpatientssensitivetosympatho-mimeticdrugsandpatientswithcardiovascularorconvulsivedisorders.(5.4, 5.7)

• Excessiveusemaybefatal.Donotexceedrecommendeddose.(5.5)• Immediatehypersensitivityreactionsmayoccur.DiscontinuePROAIRHFAimme-diately.(5.6)

• Hypokalemiaandchangesinbloodglucosemayoccur.(5.7, 5.8) ADVERSE REACTIONS

Mostcommonadversereactions(≥3.0%and>placebo)areheadache,tachycardia,pain,dizziness,pharyngitis,andrhinitis.(6.1)To report SUSPECTED ADVERSE REACTIONS, contact Teva Respiratory, LLC at 1-888-482-9522 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS

• Other short-acting sympathomimetic aerosol bronchodilators and adrenergicdrugs:Maypotentiateeffect.(7)

• Beta-blockers:May decrease effectiveness of PROAIRHFA and produce severebronchospasm.Patientswithasthmashouldnotnormallybe treatedwithbeta-blockers.(7.1)

• Diuretics,ornon-potassiumsparingdiuretics:MaypotentiatehypokalemiaorECGchanges.Considermonitoringpotassiumlevels.(7.2)

• Digoxin:Maydecreaseserumdigoxinlevels.Considermonitoringdigoxinlev-els.(7.3)

• Monoamineoxidase(MAO)inhibitorsandtricyclicantidepressants:Maypotentiateeffectofalbuterolon thecardiovascularsystem.Consideralternative therapy inpatientstakingMAOsortricyclicantidepressants.(7.4)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.Revised: 05/12

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE1.1Bronchospasm1.2Exercise-InducedBronchospasm

2 DOSAGE AND ADMINISTRATION2.1Bronchospasm2.2Exercise-InducedBronchospasm2.3AdministrationInformation

3 DOSAGE FORMS & STRENGTHS4 CONTRAINDICATIONS5 WARNINGS & PRECAUTIONS5.1ParadoxicalBronchospasm5.2DeteriorationofAsthma5.3UseofAnti-inflammatoryAgents5.4CardiovascularEffects5.5DoNotExceedRecommendedDose5.6ImmediateHypersensitivityReactions5.7CoexistingConditions5.8Hypokalemia

6 ADVERSE REACTIONS6.1ClinicalTrialsExperience6.2PostmarketingExperience

7 DRUG INTERACTIONS7.1Beta-Blockers7.2Diuretics7.3Digoxin7.4MonoamineOxidaseInhibitorsorTricyclicAntidepressants

8 USE IN SPECIFIC POPULATIONS8.1Pregnancy8.2LaborandDelivery

8.3NursingMothers8.4PediatricUse8.5GeriatricUse

10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1MechanismofAction12.2Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility13.2AnimalToxicologyand/orPharmacology

14 CLINICAL STUDIES14.1BronchospasmAssociatedwithAsthma14.2Exercise-InducedBronchospasm

16 HOW SUPPLIED/STORAGE & HANDLING17 PATIENT COUNSELING INFORMATION17.1FrequencyofUse17.2PrimingandCleaning17.3DoseCounter17.4ParadoxicalBronchospasm17.5ConcomitantDrugUse17.6CommonAdverseEvents17.7Pregnancy17.8GeneralInformationonUse17.9FDA-ApprovedPatientLabeling

*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.

1 INDICATIONS AND USAGE1.1 BronchospasmPROAIRHFA InhalationAerosol is indicated for the treatmentorprevention

ofbronchospasm inpatients4 yearsof ageandolderwith reversibleobstructiveairwaydisease.

1.2 Exercise-Induced BronchospasmPROAIRHFA InhalationAerosol is indicated for the prevention of exercise-

inducedbronchospasminpatients4yearsofageandolder.2 DOSAGE AND ADMINISTRATION

2.1 BronchospasmFortreatmentofacuteepisodesofbronchospasmorpreventionofsymptoms

associatedwithbronchospasm,theusualdosageforadultsandchildren4yearsandolderistwoinhalationsrepeatedevery4to6hours.Morefrequentadministrationoralargernumberofinhalationsisnotrecommended.Insomepatients,oneinhalationevery4hoursmaybesufficient.

2.2 Exercise-Induced BronchospasmTheusualdosageforadultsandchildren4yearsofageorolderistwoinhala-

tions15to30minutesbeforeexercise.2.3 Administration InformationAdministerPROAIRHFAbyoralinhalationonly.Shakewellbeforeeachspray.

Tomaintainproperuseofthisproductandtopreventmedicationbuild-upandblock-age,itisimportanttofollowthecleaningdirectionscarefully.

Priming:Primetheinhalerbeforeusingforthefirsttimeandincaseswheretheinhalerhasnotbeenusedformorethan2weeksbyreleasingthreespraysintotheair,awayfromtheface.

Cleaning: AswithallHFA-containingalbuterol inhalers, tomaintainproperuseofthisproductandtopreventmedicationbuild-upandblockage,itisimportanttocleantheplasticmouthpieceregularly.Theinhalermayceasetodelivermedicationiftheplasticactuatormouthpieceisnotproperlycleanedanddried.Toclean:Washtheplasticmouthpiecewithwarmrunningwaterfor30seconds,shakeoffexcesswater,andairdrythoroughlyatleastonceaweek.If the patient has more than one PROAIR HFA inhaler, the patient should wash each one separately to prevent at-taching the wrong canister to the wrong plastic actuator. In this way, the patient can be sure to always know the correct number of remaining doses. Never attach a canister of medication from any other inhaler to the PROAIR HFA actuator and never attach the PROAIR HFA canister to an actuator from any other inhaler. If the mouthpiecebecomesblocked,washingthemouthpiecewillremovetheblockage.Ifitisnecessarytousetheinhalerbeforeitiscompletelydry,shakeoffexcesswater,replacecanister, spray twice into theair away from face, and take theprescribeddose.After suchuse, themouthpieceshouldbe rewashedandallowed toairdrythoroughly.[see FDA-Approved Patient Labeling (17.9)].

Dose Counter:PROAIRHFAhasadosecounterattachedtotheactuator.Whenthepatientreceivestheinhaler,ablackdotwillappearintheviewingwindowuntilithasbeenprimed3times,atwhichpointthenumber200willbedisplayed.Thedosecounterwillcountdowneachtimeasprayisreleased.Whenthedosecounterreaches20, the colorof thenumberswill change to red to remind thepatient tocontact theirpharmacist for a refill ofmedicationor consult theirphysician for aprescriptionrefill.Whenthedosecounterreaches0,thebackgroundwillchangetosolidred.PROAIRHFAinhalershouldbediscardedwhenthedosecounterdisplays0oraftertheexpirationdateontheproduct,whichevercomesfirst.3 DOSAGE FORMS & STRENGTHS

PROAIRHFAisaninhalationaerosol.PROAIRHFAissuppliedasan8.5g/200actuations pressurized aluminumcanisterwith a red plastic actuatorwith a dosecounterandwhitedustcapeachinboxesofone.Eachactuationdelivers120mcgofalbuterolsulfatefromthecanistervalveand108mcgofalbuterolsulfatefromtheactuatormouthpiece(equivalentto90mcgofalbuterolbase).4 CONTRAINDICATIONS

PROAIRHFAInhalationAerosol iscontraindicatedinpatientswithahistoryofhypersensitivitytoalbuterolandanyotherPROAIRHFAInhalationAerosolcomponents.Rarecasesofhypersensitivityreactions,includingurticaria,angioedema,andrashhavebeenreportedaftertheuseofalbuterolsulfate[see Warnings and Precautions (5.6)].5 WARNINGS & PRECAUTIONS

5.1 Paradoxical Bronchospasm PROAIRHFAInhalationAerosolcanproduceparadoxicalbronchospasmthat

maybelifethreatening.Ifparadoxicalbronchospasmoccurs,PROAIRHFAInhala-tionAerosolshouldbediscontinuedimmediatelyandalternativetherapyinstituted.Itshouldberecognizedthatparadoxicalbronchospasm,whenassociatedwithinhaledformulations,frequentlyoccurswiththefirstuseofanewcanister.

5.2 Deterioration of AsthmaAsthmamay deteriorate acutely over a period of hours or chronically over

severaldaysorlonger.IfthepatientneedsmoredosesofPROAIRHFAInhalationAerosolthanusual,thismaybeamarkerofdestabilizationofasthmaandrequiresre-evaluationofthepatientandtreatmentregimen,givingspecialconsiderationtothepossibleneedforanti-inflammatorytreatment,e.g.,corticosteroids.

5.3 Use of Anti-inflammatory AgentsTheuseofbeta-adrenergic-agonistbronchodilatorsalonemaynotbeadequate

tocontrolasthmainmanypatients.Earlyconsiderationshouldbegiventoaddinganti-inflammatoryagents,e.g.,corticosteroids,tothetherapeuticregimen.

5.4 Cardiovascular EffectsPROAIRHFAInhalationAerosol,likeotherbeta-adrenergicagonists,canpro-

duceclinicallysignificantcardiovasculareffects insomepatientsasmeasuredbypulserate,bloodpressure,and/orsymptoms.Althoughsucheffectsareuncommon

after administrationofPROAIRHFA InhalationAerosol at recommendeddoses, iftheyoccur,thedrugmayneedtobediscontinued.Inaddition,beta-agonistshavebeenreportedtoproduceECGchanges,suchasflatteningoftheTwave,prolonga-tion of the QTc interval, and ST segment depression. The clinical significance ofthesefindingsisunknown.Therefore,PROAIRHFAInhalationAerosol,likeallsym-pathomimeticamines,shouldbeusedwithcautioninpatientswithcardiovasculardisorders,especiallycoronaryinsufficiency,cardiacarrhythmias,andhypertension.

5.5 Do Not Exceed Recommended DoseFatalitieshavebeenreportedinassociationwithexcessiveuseofinhaledsym-

pathomimeticdrugsinpatientswithasthma.Theexactcauseofdeathisunknown,butcardiacarrestfollowinganunexpecteddevelopmentofasevereacuteasthmaticcrisisandsubsequenthypoxiaissuspected.

5.6 Immediate Hypersensitivity ReactionsImmediatehypersensitivity reactionsmayoccur after administrationof albu-

terolsulfate,asdemonstratedby rarecasesofurticaria,angioedema, rash,bron-chospasm,anaphylaxis,andoropharyngealedema.ThepotentialforhypersensitivitymustbeconsideredintheclinicalevaluationofpatientswhoexperienceimmediatehypersensitivityreactionswhilereceivingPROAIRHFAInhalationAerosol.

5.7 Coexisting ConditionsPROAIR HFA Inhalation Aerosol, like all sympathomimetic amines, should

beusedwithcautioninpatientswithcardiovasculardisorders,especiallycoronaryinsufficiency, cardiac arrhythmias, and hypertension; in patients with convulsivedisorders,hyperthyroidism,ordiabetesmellitus;andinpatientswhoareunusuallyresponsivetosympathomimeticamines.Clinicallysignificantchangesinsystolicanddiastolicbloodpressurehavebeenseeninindividualpatientsandcouldbeexpectedto occur in some patients after use of any beta-adrenergic bronchodilator. Largedosesofintravenousalbuterolhavebeenreportedtoaggravatepreexistingdiabetesmellitusandketoacidosis.

5.8 HypokalemiaAswithotherbeta-agonists,PROAIRHFAInhalationAerosolmayproducesig-

nificanthypokalemiainsomepatients,possiblythroughintracellularshunting,whichhasthepotentialtoproduceadversecardiovasculareffects.Thedecreaseisusuallytransient,notrequiringsupplementation.6 ADVERSE REACTIONS

UseofPROAIRHFAmaybeassociatedwiththefollowing:• Paradoxicalbronchospasm[see Warnings and Precautions (5.1)]• CardiovascularEffects[see Warnings and Precautions (5.4)]• Immediatehypersensitivityreactions[see Warnings and Precautions (5.6)]• Hypokalemia[see Warnings and Precautions (5.8)]6.1 Clinical Trials ExperienceAtotalof1090subjectsweretreatedwithPROAIRHFAInhalationAerosol,or

withthesameformulationofalbuterolasinPROAIRHFAInhalationAerosol,duringtheworldwideclinicaldevelopmentprogram.

Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinpractice.

Adult and Adolescents 12 Years of Age and Older:Theadverse reaction in-formationpresentedinthetablebelowconcerningPROAIRHFAInhalationAerosolisderivedfroma6-week,blindedstudywhichcomparedPROAIRHFAInhalationAerosol(180mcg four times daily)with a double-blindedmatched placeboHFA-InhalationAerosolandanevaluator-blindedmarketedactivecomparatorHFA-134aalbuterolin-halerin172asthmaticpatients12to76yearsofage.Thetableliststheincidenceofalladverseevents(whetherconsideredbytheinvestigatordrugrelatedorunrelatedtodrug)fromthisstudywhichoccurredatarateof3%orgreaterinthePROAIRHFAInhalationAerosoltreatmentgroupandmorefrequentlyinthePROAIRHFAInhalationAerosoltreatmentgroupthaninthematchedplacebogroup.Overall,theincidenceandnatureoftheadverseeventsreportedforPROAIRHFAInhalationAerosolandthemarketedactivecomparatorHFA-134aalbuterolinhalerwerecomparable.

Adverse Experience Incidences (% of Patients) in a Six-Week Clinical Trial*

Body System/Adverse Event(as Preferred Term)

PROAIR HFAInhalation

Aerosol(N = 58)

Marketed activecomparatorHFA-134aalbuterol inhaler(N = 56)

Matched Placebo

HFA-134aInhalation

Aerosol(N = 58)

BodyasaWhole Headache 7 5 2

Cardiovascular Tachycardia 3 2 0

Musculoskeletal Pain 3 0 0

NervousSystem Dizziness 3 0 0

RespiratorySystem PharyngitisRhinitis

145

74

92

* Thistableincludesalladverseevents(whetherconsideredbytheinvestigatordrugrelatedorunrelatedtodrug)whichoccurredatanincidencerateofatleast3.0%inthePROAIRHFAInhalationAerosolgroupandmorefrequentlyinthePROAIRHFAInhalationAerosolgroupthanintheplaceboHFAInhalationAerosolgroup.

Adverseeventsreportedbylessthan3%ofthepatientsreceivingPROAIRHFAInhalationAerosolbutbyagreaterproportionofPROAIRHFA InhalationAerosol

FULL PRESCRIBING INFORMATION

patientsthanthematchedplacebopatients,whichhavethepotentialtoberelatedtoPROAIRHFAInhalationAerosol,includedchestpain,infection,diarrhea,glossi-tis,accidentalinjury(nervoussystem),anxiety,dyspnea,eardisorder,earpain,andurinarytractinfection.

Insmallcumulativedosestudies,tremor,nervousness,andheadachewerethemostfrequentlyoccurringadverseevents.

Pediatric Patients 4 to 11 Years of Age:Adverseeventsreportedina3-weekpediatricclinicaltrialcomparingthesameformulationofalbuterolasinPROAIRHFAInhalationAerosol(180mcgalbuterolfourtimesdaily)toamatchingplaceboHFAinhalationaerosoloccurredatalowincidencerate(nogreaterthan2%intheactivetreatmentgroup)andweresimilartothoseseeninadultandadolescenttrials.

6.2 Postmarketing ExperienceThefollowingadversereactionshavebeenidentifiedduringpostapprovaluse

ofPROAIRHFA.Becausethesereactionsarereportedvoluntarilyfromapopulationof uncertain size, it is not always possible to reliably estimate their frequency orestablishacausalrelationshiptodrugexposure.Reportshaveincludedrarecasesofaggravatedbronchospasm, lackofefficacy,asthmaexacerbation(reportedfatalinonecase),musclecramps,andvariousoropharyngealside-effectssuchasthroatirritation,alteredtaste,glossitis,tongueulceration,andgagging.

Thefollowingadverseeventshavebeenobservedinpostapprovaluseofin-haledalbuterol:urticaria,angioedema,rash,bronchospasm,hoarseness,oropharyngealedema,andarrhythmias(includingatrialfibrillation,supraventriculartachycardia,extra-systoles).Inaddition,albuterol,likeothersympathomimeticagents,cancauseadversereactionssuchas:angina,hypertensionorhypotension,palpitations,centralnervoussystemstimulation,insomnia,headache,nervousness,tremor,musclecramps,dryingorirritationoftheoropharynx,hypokalemia,hyperglycemia,andmetabolicacidosis.7 DRUG INTERACTIONS

Other short-actingsympathomimetic aerosolbronchodilators shouldnotbeused concomitantlywithPROAIRHFA InhalationAerosol. If additional adrenergicdrugsaretobeadministeredbyanyroute,theyshouldbeusedwithcautiontoavoiddeleteriouscardiovasculareffects.

7.1 Beta-BlockersBeta-adrenergic-receptorblockingagentsnotonlyblock thepulmonaryeffect

ofbeta-agonists,suchasPROAIRHFA InhalationAerosol,butmayproduceseverebronchospasminasthmaticpatients.Therefore,patientswithasthmashouldnotnor-mallybe treatedwithbeta-blockers.However,undercertaincircumstances,e.g., asprophylaxisaftermyocardialinfarction,theremaybenoacceptablealternativestotheuseofbeta-adrenergic-blockingagentsinpatientswithasthma.Inthissetting,con-sidercardioselectivebeta-blockers,althoughtheyshouldbeadministeredwithcaution.

7.2 DiureticsThe ECG changes and/or hypokalemiawhichmay result from the adminis-

trationofnon-potassiumsparingdiuretics(suchaslooporthiazidediuretics)canbeacutelyworsenedbybeta-agonists,especiallywhentherecommendeddoseofthebeta-agonist is exceeded.Although theclinical significanceof theseeffects isnot known, caution is advised in the coadministrationof beta-agonistswith non-potassiumsparingdiuretics.Considermonitoringpotassiumlevels.

7.3 DigoxinMeandecreasesof16%and22%inserumdigoxinlevelsweredemonstrated

after singledose intravenousandoral administrationof albuterol, respectively, tonormalvolunteerswhohadreceiveddigoxin for10days.Theclinicalsignificanceofthesefindingsforpatientswithobstructiveairwaydiseasewhoarereceivingal-buterolanddigoxinonachronicbasisisunclear.Nevertheless,itwouldbeprudenttocarefullyevaluatetheserumdigoxinlevelsinpatientswhoarecurrentlyreceivingdigoxinandPROAIRHFAInhalationAerosol.

7.4 Monoamine Oxidase Inhibitors or Tricyclic AntidepressantsPROAIRHFAInhalationAerosolshouldbeadministeredwithextremecautionto

patientsbeingtreatedwithmonoamineoxidaseinhibitorsortricyclicantidepressants,orwithin2weeksofdiscontinuationofsuchagents,becausetheactionofalbuterolonthecardiovascularsystemmaybepotentiated.ConsideralternativetherapyinpatientstakingMAOinhibitorsortricyclicantidepressants.8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyTeratogenicEffects:PregnancyCategoryC:Therearenoadequateandwell-controlledstudiesofPROAIRHFAInhalation

Aerosoloralbuterolsulfateinpregnantwomen.Duringworldwidemarketingexpe-rience,variouscongenitalanomalies, includingcleftpalateand limbdefects,havebeenreportedintheoffspringofpatientstreatedwithalbuterol.Someofthemothersweretakingmultiplemedicationsduringtheirpregnancies.Noconsistentpatternofdefectscanbediscerned,andarelationshipbetweenalbuteroluseandcongenitalanomalieshasnotbeenestablished.Animalreproductionstudiesinmiceandrabbitsrevealedevidenceofteratogenicity.PROAIRHFAInhalationAerosolshouldbeusedduringpregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.

In amouse reproduction study, subcutaneously administered albuterol sul-fateproducedcleftpalateformationin5of111(4.5%)fetusesatanexposureap-proximatelyeight-tenthsof themaximumrecommendedhumandose(MRHD)foradultsonamg/m2basisandin10of108(9.3%)fetusesatapproximately8timestheMRHD.Similareffectswerenotobservedatapproximatelyone-thirteenthoftheMRHD.Cleftpalatealsooccurredin22of72(30.5%)fetusesfromfemalestreatedsubcutaneouslywithisoproterenol(positivecontrol).

Ina rabbit reproductionstudy,orallyadministeredalbuterolsulfate inducedcranioschisisin7of19fetuses(37%)atapproximately630timestheMRHD.

Inaratreproductionstudy,analbuterolsulfate/HFA-134aformulationadmin-isteredbyinhalationdidnotproduceanyteratogeniceffectsatexposuresapproxi-mately65timestheMRHD[see Nonclinical Toxicology (13.2)].

8.2 Labor and DeliveryBecauseofthepotentialforbeta-agonistinterferencewithuterinecontractil-

ity,useofPROAIRHFAInhalationAerosolforreliefofbronchospasmduringlaborshould be restricted to those patients inwhom the benefits clearly outweigh therisk.PROAIRHFAInhalationAerosolhasnotbeenapprovedforthemanagementofpre-termlabor.Thebenefit:riskratiowhenalbuterolisadministeredfortocolysishasnotbeenestablished.Seriousadversereactions,includingpulmonaryedema,havebeenreportedduringorfollowingtreatmentofprematurelaborwithbeta2-agonists,includingalbuterol.

8.3 Nursing MothersPlasmalevelsofalbuterolsulfateandHFA-134aafterinhaledtherapeuticdos-

esareverylowinhumans,butitisnotknownwhetherthecomponentsofPROAIRHFAInhalationAerosolareexcretedinhumanmilk.

CautionshouldbeexercisedwhenPROAIRHFAInhalationAerosolisadmin-isteredtoanursingwoman.Becauseofthepotentialfortumorigenicityshownforalbuterol inanimal studiesand lackof experiencewith theuseofPROAIRHFAInhalationAerosolbynursingmothers,adecisionshouldbemadewhethertodis-continuenursingortodiscontinuethedrug,takingintoaccounttheimportanceofthedrugtothemother.

8.4 Pediatric UseThesafetyandeffectivenessofPROAIRHFAInhalationAerosolforthetreat-

ment or prevention of bronchospasm in children 12 years of age and olderwithreversibleobstructiveairwaydiseaseisbasedonone6-weekclinicaltrialin116pa-tients 12 years of age and olderwith asthma comparing doses of 180mcg fourtimesdailywithplacebo,andonesingle-dosecrossoverstudycomparingdosesof90,180,and270mcgwithplaceboin58patients[see Clinical Studies (14.1)].ThesafetyandeffectivenessofPROAIRHFAInhalationAerosolfortreatmentofexercise-inducedbronchospasminchildren12yearsofageandolderisbasedononesingle-dosecrossoverstudyin24adultsandadolescentswithexercise-inducedbroncho-spasmcomparingdosesof180mcgwithplacebo[see Clinical Studies (14.2)].

ThesafetyofPROAIRHFAInhalationAerosolinchildren4to11yearsofageisbasedonone3-weekclinicaltrialin50patients4to11yearsofagewithasthmausingthesameformulationofalbuterolasinPROAIRHFAInhalationAerosolcom-paringdosesof180mcgfourtimesdailywithplacebo.TheeffectivenessofPROAIRHFAInhalationAerosolinchildren4to11yearsofageisextrapolatedfromclinicaltrialsinpatients12yearsofageandolderwithasthmaandexercise-inducedbron-chospasm,basedondatafromasingle-dosestudycomparingthebronchodilatoryeffectofPROAIRHFA90mcgand180mcgwithplaceboin55patientswithasthmaanda3-weekclinicaltrialusingthesameformulationofalbuterolasinPROAIRHFAInhalationAerosolin95asthmaticchildren4to11yearsofagecomparingadoseof180mcgalbuterolfourtimesdailywithplacebo[see Clinical Studies (14.1)].

Thesafety andeffectivenessofPROAIRHFA InhalationAerosol inpediatricpatientsbelowtheageof4yearshavenotbeenestablished.

8.5 Geriatric UseClinicalstudiesofPROAIRHFA InhalationAerosoldidnot includesufficient

numbersofpatientsaged65andovertodeterminewhethertheyresponddifferentlyfromyoungerpatients.Otherreportedclinicalexperiencehasnot identifieddiffer-encesinresponsesbetweenelderlyandyoungerpatients.Ingeneral,doseselectionforanelderlypatientshouldbecautious,usuallystartingatthelowendofthedosingrange,reflectingthegreaterfrequencyofdecreasedhepatic,renal,orcardiacfunc-tion,andofconcomitantdiseaseorotherdrugtherapy [see Warnings and Precau-tions (5.4, 5.7)].

All beta2-adrenergicagonists, includingalbuterol, areknown tobesubstan-tiallyexcretedbythekidney,andtheriskoftoxicreactionsmaybegreaterinpatientswith impaired renal function.Becauseelderlypatientsaremore likely tohavede-creasedrenalfunction,careshouldbetakenindoseselection,anditmaybeusefultomonitorrenalfunction.10 OVERDOSAGE

Theexpectedsymptomswithoverdosagearethoseofexcessivebeta-adrenergicstimulationand/oroccurrenceorexaggerationofanyof thesymptomslistedunderADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachy-cardiawith ratesup to200beatsperminute,arrhythmias,nervousness,headache,tremor,drymouth,palpitation,nausea,dizziness,fatigue,malaise,andinsomnia.

Hypokalemiamayalsooccur.Aswithallsympathomimeticmedications,cardiacarrestandevendeathmaybeassociatedwithabuseofPROAIRHFAInhalationAerosol.

TreatmentconsistsofdiscontinuationofPROAIRHFAInhalationAerosolto-getherwithappropriatesymptomatictherapy.Thejudicioususeofacardioselectivebeta-receptorblockermaybeconsidered,bearinginmindthatsuchmedicationcanproducebronchospasm.Thereisinsufficientevidencetodetermineifdialysisisben-eficialforoverdosageofPROAIRHFAInhalationAerosol.

The oralmedian lethal dose of albuterol sulfate inmice is greater than2,000mg/kg(approximately6,800timesthemaximumrecommendeddailyinhala-tiondoseforadultsonamg/m2basisandapproximately3,200timesthemaximumrecommendeddailyinhalationdoseforchildrenonamg/m2basis).Inmaturerats,thesubcutaneousmedianlethaldoseofalbuterolsulfateisapproximately450mg/kg(ap-proximately3,000timesthemaximumrecommendeddailyinhalationdoseforadultson a mg/m2basisandapproximately1,400timesthemaximumrecommendeddailyin-halation dose for children on a mg/m2basis).Inyoungrats,thesubcutaneousmedianlethaldoseisapproximately2,000mg/kg(approximately14,000timesthemaximumrecommendeddaily inhalationdose foradultsonamg/m2basisandapproximately6,400timesthemaximumrecommendeddailyinhalationdoseforchildrenonamg/m2 basis).Theinhalationmedianlethaldosehasnotbeendeterminedinanimals.

11 DESCRIPTIONTheactiveingredientofPROAIRHFA(albuterolsulfate)InhalationAerosolis

albuterolsulfate,aracemicsalt,ofalbuterol.Albuterolsulfatehasthechemicalnamea1-[(tert-butylamino)methyl]-4-hydroxy-m-xylene-a,a'-diolsulfate(2:1)(salt),andhasthefollowingchemicalstructure:

Themolecularweightofalbuterolsulfateis576.7,andtheempiricalformulais (C13H21NO3)2•H2SO4. Albuterol sulfate is awhite to off-white crystalline powder.Itissolubleinwaterandslightlysolubleinethanol.AlbuterolsulfateistheofficialgenericnameintheUnitedStates,andsalbutamolsulfateistheWorldHealthOrgani-zationrecommendedgenericname.PROAIRHFAInhalationAerosolisapressurizedmetered-doseaerosolunitwithadosecounter.PROAIRHFA is fororal inhalationonly.ItcontainsamicrocrystallinesuspensionofalbuterolsulfateinpropellantHFA-134a(1,1,1,2-tetrafluoroethane)andethanol.

Primetheinhalerbeforeusingforthefirsttimeandincaseswheretheinhalerhasnotbeenusedformorethan2weeksbyreleasingthreespraysintotheair,awayfromtheface.Afterpriming,eachactuationdelivers108mcgalbuterolsulfate,fromtheactuatormouthpiece(equivalentto90mcgofalbuterolbase).Eachcanisterpro-vides200actuations(inhalations).

Thisproductdoesnotcontainchlorofluorocarbons(CFCs)asthepropellant.12 CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionAlbuterolsulfate isabeta2-adrenergicagonist.Thepharmacologiceffectsof

albuterolsulfateareattributabletoactivationofbeta2-adrenergicreceptorsonairwaysmoothmuscle.Activationofbeta2-adrenergicreceptors leads to theactivationofadenylcyclaseand toan increase in the intracellularconcentrationofcyclic-3’,5’- adenosinemonophosphate(cyclicAMP).ThisincreaseofcyclicAMPisassociatedwiththeactivationofproteinkinaseA,whichinturninhibitsthephosphorylationofmyosin and lowers intracellular ionic calcium concentrations, resulting inmusclerelaxation.Albuterolrelaxesthesmoothmuscleofallairways,fromthetracheatotheterminalbronchioles.Albuterolactsasafunctionalantagonisttorelaxtheairwayirrespectiveofthespasmogeninvolved,thusprotectingagainstallbronchoconstric-tor challenges. Increased cyclic AMP concentrations are also associatedwith theinhibitionofreleaseofmediatorsfrommastcellsintheairway.Whileitisrecognizedthat beta2-adrenergicreceptorsarethepredominantreceptorsonbronchialsmoothmuscle,dataindicatethattherearebeta-receptorsinthehumanheart,10%to50%ofwhicharecardiacbeta2-adrenergicreceptors.Theprecisefunctionoftheserecep-tors has not been established [see Warnings and Precautions (5.4)].

Albuterolhasbeenshowninmostcontrolledclinicaltrialstohavemoreeffecton the respiratory tract, in the formof bronchial smoothmuscle relaxation, thanisoproterenol at comparable doses while producing fewer cardiovascular effects.However,inhaledalbuterol,likeotherbeta-adrenergicagonistdrugs,canproduceasignificantcardiovasculareffectinsomepatients,asmeasuredbypulserate,bloodpressure,symptoms,and/orelectrocardiographicchanges[see Warnings and Pre-cautions (5.4)].

12.2 PharmacokineticsThe systemic levels of albuterol are low after inhalation of recommended

doses.Inacrossoverstudyconductedinhealthymaleandfemalevolunteers,highcumulativedosesofPROAIRHFAInhalationAerosol(1,080mcgofalbuterolbaseadministeredoveronehour)yieldedmeanpeakplasmaconcentrations(Cmax)andsystemic exposure (AUCinf) of approximately 4,100 pg/mL and 28,426 pg/mL*hr,respectivelycomparedtoapproximately3,900pg/mLand28,395pg/mL*hr,respec-tively following the same dose of an active HFA-134a albuterol inhaler compara-tor.The terminalplasmahalf-lifeofalbuteroldeliveredbyPROAIRHFA InhalationAerosolwasapproximately6hours.Comparisonofthepharmacokineticparametersdemonstratednodifferencesbetweentheproducts.

ThepharmacokineticprofileofPROAIRHFAInhalationAerosolwasevaluatedinatwo-waycross-overstudyin11healthypediatricvolunteers,4to11yearsofage.AsingledoseadministrationofPROAIRHFAInhalationAerosol(180mcgalbuterolbase)yieldedaleastsquaremean(SE)CmaxandAUC0-∞of1,100(1.18)pg/mLand5,120(1.15)pg/mL*hr,respectively.Theleastsquaremean(SE)terminalplasmahalf-lifeofalbuteroldeliveredbyPROAIRHFAInhalationAerosolwas166(7.8)minutes.

Metabolism and Elimination:Informationavailableinthepublishedliteraturesuggests that the primary enzyme responsible for themetabolismof albuterol inhumans isSULTIA3 (sulfotransferase).When racemic albuterolwas administeredeitherintravenouslyorviainhalationafteroralcharcoaladministration,therewasa3-to4-folddifferenceintheareaundertheconcentration-timecurvesbetweenthe(R)-and(S)-albuterolenantiomers,with(S)-albuterolconcentrationsbeingconsis-tentlyhigher.However,withoutcharcoalpretreatment,aftereitheroralorinhalationadministrationthedifferenceswere8-to24-fold,suggestingthatthe(R)-albuterolispreferentiallymetabolizedinthegastrointestinaltract,presumablybySULTIA3.

Theprimaryrouteofeliminationofalbuterolisthroughrenalexcretion(80%to100%)ofeithertheparentcompoundortheprimarymetabolite.Lessthan20%ofthedrugisdetectedinthefeces.Followingintravenousadministrationofracemicalbuterol,between25%and46%ofthe(R)-albuterolfractionofthedosewasex-cretedasunchanged(R)-albuterolintheurine.

Geriatric, Pediatric, Hepatic/Renal Impairment:Nopharmacokinetic stud-iesforPROAIRHFAInhalationAerosolhavebeenconductedinneonatesorelderlysubjects.

TheeffectofhepaticimpairmentonthepharmacokineticsofPROAIRHFAInhalationAerosolhasnotbeenevaluated.

Theeffectofrenalimpairmentonthepharmacokineticsofalbuterolwasevalu-atedin5subjectswithcreatinineclearanceof7to53mL/min,andtheresultswerecomparedwith those fromhealthyvolunteers.Renaldiseasehadnoeffecton thehalf-life,buttherewasa67%declineinalbuterolclearance.CautionshouldbeusedwhenadministeringhighdosesofPROAIRHFAInhalationAerosoltopatientswithrenalimpairment[see Use in Specific Populations (8.5)].13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityIna2-yearstudyinSprague-Dawleyrats,albuterolsulfatecausedadose-related

increaseintheincidenceofbenignleiomyomasofthemesovariumatandabovedi-etarydosesof2mg/kg(approximately15 times themaximumrecommendeddailyinhalationdoseforadultsonamg/m2basisandapproximately6timesthemaximumrecommendeddailyinhalationdoseforchildrenonamg/m2basis).Inanotherstudythiseffectwasblockedbythecoadministrationofpropranolol,anon-selectivebeta-adrenergicantagonist.Inan18-monthstudyinCD-1mice,albuterolsulfateshowedno evidence of tumorigenicity at dietary doses of up to 500mg/kg (approximately1,600timesthemaximumrecommendeddailyinhalationdoseforadultsonamg/m2 basisandapproximately740timesthemaximumrecommendeddailyinhalationdosefor children on a mg/m2basis).Ina22-monthstudyinGoldenHamsters,albuterolsulfateshowednoevidenceoftumorigenicityatdietarydosesofupto50mg/kg(ap-proximately210timesthemaximumrecommendeddailyinhalationdoseforadultson a mg/m2basisandapproximately100timesthemaximumrecommendeddailyinhalation dose for children on a mg/m2basis).

Albuterol sulfatewasnotmutagenic in theAmes test or amutation test inyeast.AlbuterolsulfatewasnotclastogenicinahumanperipherallymphocyteassayorinanAH1strainmousemicronucleusassay.

Reproductionstudiesinratsdemonstratednoevidenceofimpairedfertilityatoraldosesupto50mg/kg(approximately310timesthemaximumrecommendeddailyinhalationdoseforadultsonamg/m2basis).

13.2 Animal Toxicology and/or PharmacologyPreclinical: Intravenous studies in ratswith albuterol sulfate have demon-

stratedthatalbuterolcrossestheblood-brainbarrierandreachesbrainconcentra-tionsamounting toapproximately5%of theplasmaconcentrations. Instructuresoutsidetheblood-brainbarrier(pinealandpituitaryglands),albuterolconcentrationswerefoundtobe100timesthoseinthewholebrain.

Studiesinlaboratoryanimals(minipigs,rodents,anddogs)havedemonstrat-edtheoccurrenceofcardiacarrhythmiasandsuddendeath(withhistologicevidenceofmyocardial necrosis)whenb-agonists andmethylxanthineswere administeredconcurrently.Theclinicalsignificanceofthesefindingsisunknown.

PropellantHFA-134aisdevoidofpharmacologicalactivityexceptatveryhighdosesinanimals(380-1300timesthemaximumhumanexposurebasedoncom-parisonsofAUCvalues),primarilyproducingataxia,tremors,dyspnea,orsalivation.Thesearesimilartoeffectsproducedbythestructurallyrelatedchlorofluorocarbons(CFCs),whichhavebeenusedextensivelyinmetered-doseinhalers.

In animals and humans, propellant HFA-134a was found to be rapidly ab-sorbedandrapidlyeliminated,withaneliminationhalf-lifeof3-27minutesinani-malsand5-7minutesinhumans.Timetomaximumplasmaconcentration(Tmax)andmeanresidencetimearebothextremelyshortleadingtoatransientappearanceofHFA-134ainthebloodwithnoevidenceofaccumulation.

Reproductive Toxicology Studies: A study in CD-1mice given albuterolsulfatesubcutaneouslyshowedcleftpalateformationin5of111(4.5%)fetusesat0.25mg/kg(less than themaximumrecommendeddaily inhalationdose foradultsonamg/m2basis)andin10of108(9.3%)fetusesat2.5mg/kg(approxi-mately8timesthemaximumrecommendeddailyinhalationdoseforadultsonamg/m2 basis).Thedrugdidnotinducecleftpalateformationatadoseof0.025mg/kg(lessthanthemaximumrecommendeddailyinhalationdoseforadultsonamg/m2basis).Cleftpalatealsooccurredin22of72(30.5%)fetusesfromfemalestreatedsubcutane-ouslywith2.5mg/kgofisoproterenol(positivecontrol).

A reproduction study in StrideDutch rabbits revealed cranioschisis in 7 of19fetuses(37%)whenalbuterolsulfatewasadministeredorallyat50mg/kg(ap-proximately630timesthemaximumrecommendeddailyinhalationdoseforadultson a mg/m2basis).

InaninhalationreproductionstudyinSprague-Dawleyrats,thealbuterolsulfate/HFA-134adid not exhibit any teratogenic effects at 10.5mg/kg (approximately 65timesthemaximumrecommendeddailyinhalationdoseforadultsonamg/m2basis).

Astudyinwhichpregnantratsweredosedwithradiolabeledalbuterolsulfatedemonstratedthatdrug-relatedmaterialistransferredfromthematernalcirculationtothefetus.14 CLINICAL STUDIES

14.1 Bronchospasm Associated with AsthmaAdult and Adolescent Patients 12 Years of Age and Older:Ina6-week,ran-

domized,double-blind,placebo-controlledtrial,PROAIRHFAInhalationAerosol(58patients)wascomparedtoamatchedplaceboHFAinhalationaerosol(58patients)inasthmaticpatients12to76yearsofageatadoseof180mcgalbuterolfourtimesdaily.Anevaluator-blindmarketedactivecomparatorHFA-134aalbuterolinhalerarm(56patients)wasincluded.

Serial FEV1 measurements, shown below as percent change from test-daybaselineatDay1andatDay43,demonstratedthattwoinhalationsofPROAIRHFAInhalationAerosolproducedsignificantlygreaterimprovementinFEV1overthepre-treatmentvaluethanthematchedplacebo,aswellasacomparablebronchodilatoreffecttothemarketedactivecomparatorHFA-134aalbuterolinhaler.

FEV1 as Mean Percent Change from Test-Day Pre-Dosein a 6-Week Clinical Trial

Day 1

Day 43

Inthisstudy,31of58patientstreatedwithPROAIRHFAInhalationAerosolachieveda15%increase inFEV1within30minutespost-doseonDay1. In thesepatients,themediantimetoonset,mediantimetopeakeffect,andmediandurationofeffectwere8.2minutes,47minutes,andapproximately3hours,respectively.Insomepatients,thedurationofeffectwasaslongas6hours.

Inaplacebo-controlled,single-dose,crossoverstudy,PROAIRHFAInhalationAerosol,administeredatalbuteroldosesof90,180and270mcg,producedbroncho-dilatorresponsessignificantlygreaterthanthoseobservedwithamatchedplaceboHFA inhalationaerosolandcomparable toamarketedactivecomparatorHFA-134aalbuterolinhaler.

Pediatric Patients 4 to 11 Years of Age: Ina3-week, randomized,double-blind,placebo-controlledtrial,thesameformulationofalbuterolasinPROAIRHFAInhalationAerosol(50patients)wascomparedtoamatchedplaceboHFAinhalationaerosol(45patients)inasthmaticchildren4to11yearsofageatadoseof180mcgalbuterol four timesdaily.Serial FEV1measurements, expressedas themaximumpercentchangefromtest-daybaselineinpercentpredictedFEV1atDay1andatDay22observedwithintwohourspost-dose,demonstratedthattwoinhalationsofHFAalbuterolsulfateproducedsignificantlygreater improvement inFEV1over thepre-treatmentvaluethanthematchedplacebo.

In this study,21of50pediatricpatients treatedwith the same formulationofalbuterolasinPROAIRHFAInhalationAerosolachieveda15%increaseinFEV1 within30minutespost-doseonDay1.Inthesepatients,themediantimetoonset,mediantimetopeakeffectandmediandurationofeffectwere10minutes,31min-utes,andapproximately4hours,respectively.Insomepediatricpatients,thedura-tionofeffectwasaslongas6hours.

Inaplacebo-controlled,single-dose,crossoverstudyin55pediatricpatients4to11yearsofage,PROAIRHFAInhalationAerosol,administeredatalbuteroldosesof90and180mcg,wascomparedwithamatchedplaceboHFAinhalationaerosol.Serial FEV1 measurements, expressed as the baseline-adjusted percent predictedFEV1observedover6hourspost-dose,demonstratedthatoneandtwoinhalationsofPROAIRHFAInhalationAerosolproducedsignificantlygreaterbronchodilatorre-sponsesthanthematchedplacebo.

14.2 Exercise-Induced BronchospasmInarandomized,single-dose,crossoverstudy in24adultsandadolescents

withexercise-inducedbronchospasm(EIB), two inhalationsofPROAIRHFA taken30minutesbeforeexercisepreventedEIBforthehourfollowingexercise(definedasmaintenance of FEV1within80%ofpost-dose,pre-exercisebaselinevalues)in83%(20of24)ofpatientsascomparedto25%(6of24)ofpatientswhentheyreceivedplacebo.

Somepatientswhoparticipatedintheseclinicaltrialswereusingconcomitantsteroidtherapy.

16 HOW SUPPLIED/STORAGE & HANDLINGPROAIRHFA(albuterolsulfate)InhalationAerosolissuppliedasapressurized

aluminumcanisterwitharedplasticactuatorwithadosecounterandwhitedustcapeachinboxesofone.Eachcanistercontains8.5goftheformulationandprovides200actuations(NDC59310-579-22).Eachactuationdelivers120mcgofalbuterolsulfatefromthecanistervalveand108mcgofalbuterolsulfatefromtheactuatormouthpiece(equivalentto90mcgofalbuterolbase).

SHAKEWELLBEFOREUSE.Storebetween15°and25°C(59°and77°F).Con-tentsunderpressure.Donotpunctureorincinerate.Protectfromfreezingtempera-turesandprolongedexposure todirectsunlight.Exposure to temperaturesabove120°Fmaycausebursting.Forbestresults,canistershouldbeatroomtemperaturebeforeuse.Avoidsprayingineyes.Keepoutofreachofchildren.

SeeFDA-Approved Patient Labeling (17.9)forprimingandcleaninginstructions.The red actuator suppliedwith PROAIRHFA Inhalation Aerosol should not

beusedwiththecanisterfromanyotherinhalationaerosolproducts.ThePROAIRHFAInhalationAerosolcanistershouldnotbeusedwiththeactuatorfromanyotherinhalationaerosolproducts.

PROAIRHFAinhalerhasadosecounterattachedtotheactuator.Patientsshouldnevertrytoalterthenumbersforthedosecounterortamperwiththepinmechanisminsidetheactuator.DiscardthePROAIRHFAinhalerwhenthecounterdisplays0oraftertheexpirationdateontheproduct,whichevercomesfirst.Thelabeledamountofmedicationineachactuationcannotbeassuredafterthecounterdisplays0,eventhoughthecanisterisnotcompletelyemptyandwillcontinuetooperate.Neverim-mersethecanisterintowatertodeterminehowfullthecanisteris(“floattest”).

PROAIRHFAInhalationAerosoldoesnotcontainchlorofluorocarbons(CFCs)asthepropellant.17 PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling (17.9)Patientsshouldbegiventhefollowinginformation:

17.1 Frequency of UseTheactionofPROAIRHFA InhalationAerosol should last for4 to6hours.

Do not use PROAIRHFA Inhalation Aerosolmore frequently than recommended.Instruct patients to not increase the dose or frequency of doses of PROAIRHFAInhalationAerosolwithoutconsultingthephysician. Ifpatientsfindthat treatmentwithPROAIRHFAInhalationAerosolbecomeslesseffectiveforsymptomaticrelief,symptomsbecomeworse,and/ortheyneedtousetheproductmorefrequentlythanusual,theyshouldseekmedicalattentionimmediately.

17.2 Priming and CleaningPriming:Primingisessentialtoensureappropriatealbuterolcontentineach

actuation.Instructpatientstoprimetheinhalerbeforeusingforthefirsttimeandincaseswheretheinhalerhasnotbeenusedformorethan2weeksbyreleasingthreespraysintotheair,awayfromtheface.

Cleaning:Toensureproperdosingandpreventactuatororificeblockage,in-structpatients towashtheredplasticactuatormouthpieceanddry thoroughlyatleastonceaweek. Instructpatients that if theyhavemore thanonePROAIRHFAinhaler,theyshouldwasheachoneatseparatetimestopreventattachingthewrongcanistertothewrongplasticactuator.Inthisway,theycanbesuretheywillalwaysknowthecorrectnumberofremainingdoses.PatientsshouldbeinstructedtoneverattachacanisterofmedicinefromanyotherinhalertothePROAIRHFAactuatorandneverattachthePROAIRHFAcanistertoanactuatorfromanyotherinhaler.Patientsshouldnotremovethecanisterfromtheactuatorexceptduringcleaningbecausere-attachmentmayreleaseadoseintotheairandthedosecounterwillcountdowneachtimeasprayisreleased.DetailedcleaninginstructionsareincludedintheillustratedInformationforthePatientleaflet.

17.3 Dose CounterPatientsshouldbe informed thatPROAIRHFAhasadosecounterattached

totheactuator.Whenthepatientreceivestheinhaler,ablackdotwillappearintheviewingwindowuntilithasbeenprimed3times,atwhichpointthenumber200willbedisplayed.Thedosecounterwillcountdowneachtimeasprayisreleased.Thedose-counterwindowdisplaysthenumberofspraysleftintheinhalerinunitsoftwo(e.g.,200,198,196,etc).Whenthecounterdisplays20,thecolorofthenumberswill change to red to remind thepatient tocontact theirpharmacist for a refillofmedicationorconsulttheirphysicianforaprescriptionrefill.Whenthedosecounterreaches0,thebackgroundwillchangetosolidred.PatientsshouldbeinformedtodiscardPROAIRHFAinhalerwhenthedosecounterdisplays0oraftertheexpirationdateontheproduct,whichevercomesfirst.

17.4 Paradoxical BronchospasmInformpatientsthatPROAIRHFAInhalationAerosolcanproduceparadoxical

bronchospasm. Instructpatients todiscontinuePROAIRHFA InhalationAerosol ifparadoxicalbronchospasmoccurs.

17.5 Concomitant Drug UseWhilepatientsaretakingPROAIRHFAInhalationAerosol,otherinhaleddrugs

andasthmamedicationsshouldbetakenonlyasdirectedbyaphysician.17.6 Common Adverse EventsCommonadverseeffectsoftreatmentwith inhaledalbuterol includepalpita-

tions,chestpain,rapidheartrate,tremor,ornervousness.17.7 PregnancyPatientswhoarepregnantornursingshouldcontacttheirphysicianaboutthe

useofPROAIRHFAInhalationAerosol.17.8 General Information on UseEffectiveandsafeuseofPROAIRHFAInhalationAerosolincludesanunder-

standingofthewaythatitshouldbeadministered.Shakewellbeforeeachspray.

UsePROAIRHFAInhalationAerosolonlywiththeactuatorsuppliedwiththeproduct.DiscardthePROAIRHFAinhalerwhenthedosecounterdisplays0oraftertheexpirationdateontheproduct,whichevercomesfirst.Neverimmersethecanis-terinwatertodeterminehowfullthecanisteris(“floattest”).

In general, the technique for administeringPROAIRHFA InhalationAerosoltochildrenissimilartothatforadults.ChildrenshouldusePROAIRHFAInhalationAerosolunderadultsupervision,asinstructedbythepatient’sphysician.

17.9 FDA-Approved Patient LabelingSeetear-offillustratedInformationforthePatientleaflet.

Mktdby:TevaRespiratory,LLC Horsham,PA19044 Mfdby:IVAXPharmaceuticalsIreland Waterford,IrelandCopyright©2012,TevaRespiratory,LLCAllrightsreserved.PROAIR®isaregisteredtrademarkofTevaRespiratory,LLC

ManufacturedInIreland PE255705/2012

•GetmedicalhelprightawayifPROAIRHFAnolongerhelpsyoursymptoms.

•Getmedicalhelprightawayifyoursymptomsgetworseorifyouneedtouseyourinhalermoreoften.

•WhileyouareusingPROAIRHFA,do notuseotherinhaledres-cuemedicinesandasthmamedicinesunlessyourdoctortellsyoutodoso.

•Call yourdoctor if yourasthmasymptoms likewheezingandtroublebreathingbecomeworseoverafewhoursordays.Yourdoctormayneed togive you anothermedicine (for example,corticosteroids)totreatyoursymptoms.

What are the possible side effects of PROAIR HFA? PROAIR HFA may cause serious side effects, including: •worsening trouble breathing, coughing and wheezing (para-

doxical bronchospasm).IfthishappensstopusingPROAIRHFAandcallyourdoctororgetemergencyhelprightaway.Paradoxi-calbronchospasmismorelikelytohappenwithyourfirstuseofanewcanisterofmedicine.

•heart problems including faster heart rate and higher blood pressure

•possible death in people with asthma who use too much PROAIR HFA

•allergic reactions.Callyourdoctorrightawayifyouhavethefollowingsymptomsofanallergicreaction:

ºitchyskin ºswellingbeneathyourskinorinyourthroat º rash ºworseningtroublebreathing • low potassium levels in your blood •worsening of other medical problems in people who also use

PROAIR HFA including increases in blood sugar ThemostcommonsideeffectsofPROAIRHFAinclude: •yourheartfeelslikeitispoundingorracing(palpitations) •chestpain • fastheartrate •shakiness •nervousness •headache •dizziness •sorethroat • runnynoseTellyourdoctorifyouhaveanysideeffectthatbothersyouorthatdoesnotgoaway.Thesearenotallof thepossiblesideeffectsofPROAIRHFA.Formoreinformation,askyourdoctororpharmacist.Callyourdoctorformedicaladviceaboutsideeffects.Youmayre-portsideeffectstoFDAat1-800-FDA-1088.How should I store PROAIR HFA? •StorePROAIRHFAatroomtemperaturebetween59ºFand77ºF(15ºCand25ºC).

•Avoidexposuretoextremeheatandcold. •ShakethePROAIRHFAcanisterwellbeforeuse. •Do notpuncturethePROAIRHFAcanister. •Do not store the PROAIRHFA canister near heat or a flame.Temperaturesabove120°Fmaycausethecanistertoburst.

• Do notthrowthePROAIRHFAcanisterintoafireoranincinerator. •AvoidsprayingPROAIRHFAinyoureyes.Keep PROAIR HFA and all medicines out of the reach of children.General Information about the safe and effective use of PROAIR HFA MedicinesaresometimesprescribedforpurposesotherthanthoselistedinaMedicationGuide.DonotusePROAIRHFAforaconditionforwhichitwasnotprescribed.DonotgivePROAIRHFAtootherpeople,eveniftheyhavethesamesymptomsthatyouhave.Itmayharmthem.

Patient InformationPROAIR® HFA (pro´ar)

(albuterol sulfate) Inhalation Aerosol

ReadthisPatientInformationbeforeyoustartusingPROAIRHFAandeachtimeyougetarefill.Theremaybenewinformation.Thisinformationdoesnottaketheplaceoftalkingtoyourdoctoraboutyourmedicalconditionoryourtreatment.What is PROAIR HFA? PROAIRHFAisaprescriptionmedicineusedinpeople4yearsofage and older to: • treatorpreventbronchospasminpeoplewhohavereversibleobstructiveairwaydisease

•preventexerciseinducedbronchospasmItisnotknownifPROAIRHFAissafeandeffectiveinchildrenunder4yearsofage.Who should not use PROAIR HFA? Do not use PROAIR HFA if youareallergictoalbuterolsulfateoranyoftheingredientsinPROAIRHFA.SeetheendofthisleafletforacompletelistofingredientsinPROAIRHFA.What should I tell my doctor before I use PROAIR HFA? Before you use PROAIR HFA, tell your doctor if you: •haveheartproblems •havehighbloodpressure(hypertension) •haveconvulsions(seizures) •havethyroidproblems •havediabetes •havelowpotassiumlevelsinyourblood •are pregnant or plan to become pregnant. It is not known ifPROAIRHFAwillharmyourunbornbaby.Talktoyourdoctorifyouarepregnantorplantobecomepregnant.

•arebreastfeedingorplantobreastfeed.ItisnotknownifPROAIRHFApassesintoyourbreastmilk.TalktoyourdoctoraboutthebestwaytofeedyourbabyifyouareusingPROAIRHFA.

Tell your doctor about all the medicines you take,includingpre-scription and non-prescription medicines, vitamins, and herbalsupplements.PROAIRHFAandothermedicinesmayaffecteachotherandcausesideeffects.PROAIRHFAmayaffectthewayothermedicineswork,andothermedicinesmayaffectthewayPROAIRHFAworks.Especiallytellyourdoctorifyoutake: •otherinhaledmedicinesorasthmamedicines •betablockermedicines •diuretics •digoxin •monoamineoxidaseinhibitors • tricyclicantidepressantsAskyourdoctororpharmacistforalistofthesemedicinesifyouarenotsure.Knowthemedicinesyoutake.Keepalistofthemtoshowyourdoc-torandpharmacistwhenyougetanewmedicine.How should I use PROAIR HFA? •Fordetailedinstructions,see“Instructions for Use” at the end ofthisPatientInformation.

•UsePROAIRHFAexactlyasyourdoctortellsyoutouseit. • IfyourchildneedstousePROAIRHFA,watchyourchildcloselytomakesureyourchildusestheinhalercorrectly.YourdoctorwillshowyouhowyourchildshouldusePROAIRHFA.

•EachdoseofPROAIRHFAshouldlastupto4hoursto6hours. •Do notincreaseyourdoseortakeextradosesofPROAIRHFAwithoutfirsttalkingtoyourdoctor.

Attention Pharmacist:DetachPatient’sInstructionsforusefrompackageinsertanddispensewiththeproduct.

ThisPatientInformationsummarizesthemostimportantinforma-tionaboutPROAIRHFA. If youwould likemore information, talkwithyourdoctor.Youcanaskyourpharmacistordoctorforinfor-mationaboutPROAIRHFAthatiswrittenforhealthprofessionals.For more information, go to www.ProAirHFA.com or call 1-888-482-9522.What are the ingredients in PROAIR HFA? Activeingredient:albuterolsulfateInactiveingredients:propellantHFA-134aandethanol.

Instructions for UsePROAIR® HFA (pro´ar)

(albuterol sulfate)Inhalation Aerosol

ReadthisInstructionsforUsebeforeyoustartusingPROAIRHFAandeachtimeyougetarefill.Theremaybenewinformation.Thisinformationdoesnottaketheplaceoftalkingtoyourdoctoraboutyourmedicalconditionoryourtreatment.The Parts of Your PROAIR HFA Inhaler Device:Thereare2mainpartsofyourPROAIRHFAinhalerdeviceincludinga: • redplasticactuatorthatspraysthemedicinefromthecanister.SeeFigureA.

•protectivedustcapthatcoversthemouthpieceoftheactuator.SeeFigureA.

Thereisalsoametalcanisterthatholdsthemedicine.SeeFigureA.Thereisalsoadosecounterattachedtothebackoftheactuatorwithaviewingwindowthatshowsyouhowmanyspraysofmedicineyouhaveleft.SeeFigureB.Youwillseeablackdotintheviewingwindowontheactuatoruntilthedevicehasbeenprimed3 times.See FigureB and“Priming Your PROAIR HFA Device”below.

FigureA FigureB •Do notusethePROAIRHFAactuatorwithacanisterofmedicinefromanyotherinhaler.

•Do notuseaPROAIRHFAcanisterwithanactuatorfromanyotherinhaler,includinganotherPROAIRHFAinhaler.

Priming Your PROAIR HFA Device:YourPROAIRdevicemustbeprimedbeforeyouuseitforthefirsttimeorifyourdevicehasnotbeenusedformorethan14daysinarow.Do notprimeyourPROAIRHFAdeviceeveryday. •RemoveyourPROAIRHFAdevicefromitspackage. •Removetheprotectivedustcapfromthemouthpiece. •Shaketheinhalerwell,andsprayitintotheairawayfromyourface.SeeFigureC.

FigureC •Shake and spray the inhaler like this 2more times to finishprimingit.Thedosecounterontheactuatorshoulddisplaythenumber200afteryouprimetheactuatorforthefirsttime.SeeFigureD.

FigureDEach Time You Use Your PROAIR HFA Device: •Makesurethecanisterfitsfirmlyintheplasticactuator. •Look into themouthpiece tomake sure there are no foreignobjectsthere,especiallyifthecaphasnotbeenusedtocoverthemouthpiece.

Reading the Dose Counter on Your PROAIR HFA Actuator •Thedosecounterwillcountdowneachtimeasprayisreleased.Thedosecounterwindowshowsthenumberofspraysleftinyourinhalerinunitsof2sprays.Forexample,thereare190spraysleftifthearrowisexactlyoppositethenumber190,or189spraysleftifthearrowpointsbetween190and188.SeeFigureD.

•Whenthedosecounterreaches0,itwillcontinuetoshow0 and youshouldreplaceyourPROAIRHFAdevice.

•Thedosecountercannotberesetandispermanentlyattachedtotheactuator.Neverchangethenumbersforthedosecounterortouchthepininsidetheactuator.

•Do notremovethecanisterfromtheplasticactuatorexceptdur-ingcleaning.Reattaching thecanister to theactuatormayac-cidently release adoseofPROAIRHFA into the air. Thedosecounterwillcountdowneachtimeasprayisreleased.

Using Your PROAIR HFA Device: Step1.Shake the inhaler wellbeforeeachspray.Takethecapoff

themouthpieceoftheactuator.Step2.Holdtheinhalerwiththemouthpiecedown.SeeFigureE.

FigureEStep3.Breathe out through your mouthandpushasmuchairfrom

yourlungsasyoucan.Putthemouthpieceinyourmouthandcloseyourlipsaroundit.SeeFigureF.

Step4.Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth. SeeFigureF.

FigureFStep5.Rightafterthespraycomesout,takeyourfingeroffthecan-

ister.Afteryouhavebreathedinalltheway,taketheinhaleroutofyourmouthandcloseyourmouth.

Step6.Hold your breath as long as you can, up to10seconds,thenbreathenormally.

If your doctor has told you to use more sprays,wait1min-ute and shake the inhaler again. Repeat Steps 2 throughStep6.

Step7.Putthecapbackonthemouthpieceaftereverytimeyouusetheinhaler.Makesurethecapsnapsfirmlyintoplace.

Cleaning Your PROAIR HFA Device: It is very important to keep the plastic actuator clean so the medi-cine will not build-up and block the spray.SeeFigureGandFigureH.

FigureG FigureH •Do not try to clean the metal canister or let it get wet.Theinhalermaystopsprayingifitisnotcleanedcorrectly.

• Ifyouhavemorethan1PROAIRHFAinhaler,washeachdeviceatseparatetimestopreventputtingthewrongcanistertogetherwiththewrongplasticactuator.Thiswayyoucanbesureyouwill always know the correct number of remaining doses ofPROAIRHFA.

•Wash the actuatoratleast1timeeachweekasfollows: ºTakethecanisteroutoftheactuator,andtakethecapoffthe

mouthpiece. ºHoldtheactuatorunderthefaucetandrunwarmwaterthrough

itforabout30seconds.SeeFigureI.

FigureI ºTurntheactuatorupsidedownandrunwarmwaterthrough

themouthpieceforabout30seconds.SeeFigureJ.

FigureJ ºShakeoffasmuchwaterfromtheactuatorasyoucan.Look

intothemouthpiecetomakesureanymedicinebuild-uphasbeencompletelywashedaway.Ifthereisanybuild-up,repeatthewashinginstructions.

ºLet the actuator air-dry completely, such as overnight. SeeFigureK.

FigureK ºWhentheactuatorisdry,putthecanisterintheactuatorand

make sure it fits firmly. Shake the inhalerwell and spray ittwiceintotheairawayfromyourface.Putthecapbackonthemouthpiece.

If you need to use your inhaler before the actuator is completely dry: •Shakeasmuchwaterofftheactuatorasyoucan. •Putthecanisterintheactuatorandmakesureitfitsfirmly. •Shaketheinhalerwellandsprayittwiceintotheairawayfromyourface.

•TakeyourPROAIRHFAdoseasprescribed. •FollowtheCleaningInstructionsabove.Replacing Your PROAIR HFA Device •When the dose counter on the actuator says the number 20,thecolorofthenumberswillchangetored.TherednumbersaretoremindyoutorefillyourprescriptionoraskyourdoctorforanotherprescriptionforPROAIRHFA.Whenthedosecoun-ter reaches 0,thebackgroundcolorwillchangetosolidred.

•Throw the PROAIR HFA inhaler away as soon as the dose countersays0oraftertheexpirationdateonthePROAIRHFApackaging,whichevercomesfirst.Youshouldnotkeepusingtheinhalerafter200sprayseventhoughthecanistermaynotbecompletelyempty.Youcannotbesureyouwillreceiveanymedicineafterusing200sprays.

•Do not use the inhaleraftertheexpirationdateonthePROAIRHFApackaging.

This Patient Information and Instructions for Use has been ap-provedbytheU.S.FoodandDrugAdministration.MarketedbyTevaRespiratory,LLCHorsham,PA19044ManufacturedbyIVAXPharmaceuticalsIrelandWaterford,IrelandRevised05/12 PE2557

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