Adcirca

Main information

  • Trade name:
  • Adcirca 20 mg Film coated tablet
  • Dosage:
  • 20 mg
  • Pharmaceutical form:
  • Film coated tablet
  • Units in package:
  • Blister pack, PVC/PE/Aclar/Al, starter pack, 14 tablets
  • Class:
  • Prescription
  • Prescription type:
  • Prescription
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug
  • Manufactured by:
  • Evonik Corporation

Documents

Localization

  • Available in:
  • Adcirca 20 mg Film coated tablet
    New Zealand
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • ADCIRCA is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.

Other information

Status

  • Source:
  • Medsafe - Medicines Safety Authority - New Zealand
  • Authorization number:
  • 15164
  • Authorization date:
  • 07-09-2011
  • Last update:
  • 27-09-2017

Summary of Product characteristics: dosage,interactions,side effects

DATA SHEET

ADCIRCA

(tadalafil)

NAMEOFTHEMEDICINE

ADCIRCA ® (tadalafil).

Chemically,tadalafilispyrazino[1’,2’:1,6]pyrido[3,4-b]indole-1,4-dione,6-(1,3-

benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-,(6R,12aR)-.Tadalafilhasthe

empiricalformulaC

representingamolecularweightof389.41.Tadalafilisa

crystallinesolidthatispracticallyinsolubleinwaterandveryslightlysolubleinethanol.The

CASnumberfortadalafilis171596-29-5.

Tadalafilhasthefollowingstructuralformula:

DESCRIPTION

ADCIRCA20mgtabletsareorange,almondshapedtablets,fororaladministration,marked

"4467"ononeside.TheactiveingredientinADCIRCAtabletsistadalafil.ADCIRCAtablets

alsocontainthefollowingexcipients:croscarmellosesodium,hydroxypropylcellulose,

hypromellose,lactose,magnesiumstearate,cellulose-microcrystalline,sodiumlauryl

sulfate,talc-purified,titaniumdioxide,glyceroltriacetate,ironoxideyellowandironoxide

red.

PHARMACOLOGY

PharmacodynamicsTadalafilisareversibleinhibitorofcyclicguanosinemonophosphate

(cGMP)–specificphosphodiesterasetype5(PDE5).Pulmonaryarterialhypertensionis

associatedwithimpairedreleaseofnitricoxidebythevascularendotheliumandconsequent

reductionofcGMPconcentrationswithinthepulmonaryvascularsmoothmuscle.PDE5isthe

predominantphosphodiesteraseinthepulmonaryvasculature.InhibitionofPDE5bytadalafil

increasestheconcentrationsofcGMPresultinginrelaxationofthepulmonaryvascular

smoothmusclecellandvasodilationofthepulmonaryvascularbed.

Studies invitrohaveshownthattadalafilinhibitsPDE5morepotentlythanotherPDEs.

PDE5isanenzymefoundinthecorpuscavernosumsmoothmuscle,vascularandvisceral

smoothmuscle,skeletalmuscle,platelets,kidney,lungandcerebellum.

Tadalafilis>10,000-foldmorepotentforPDE5thanforPDE1,PDE2,PDE4,andPDE7

enzymeswhicharefoundintheheart,brain,bloodvessels,liver,leukocytes,skeletal

muscleandotherorgans.Tadalafilis>10,000-foldmorepotentforPDE5thanforPDE3,an

enzymefoundintheheartandbloodvessels.ThisselectivityforPDE5overPDE3is

importantbecausePDE3isanenzymeinvolvedincardiaccontractility.Additionally,tadalafil

isapproximately700-foldmorepotentforPDE5thanforPDE6,anenzymewhichisfoundin

theretinaandisresponsibleforphototransduction.Tadalafilisalso>9,000-foldmore

potentforPDE5thanforPDE8,9and10and14-foldmorepotentforPDE5thanforPDE11.

ThetissuedistributionandphysiologicaleffectsoftheinhibitionofPDE8throughPDE11

havenotbeenelucidated.

Inastudytoassesstheeffectsoftadalafilonvision,noimpairmentofcolourdiscrimination

(blue/green)wasdetectedusingtheFarnsworth-Munsell100-huetest.Thisfindingis

consistentwiththelowaffinityoftadalafilforPDE6comparedtoPDE5.Inaddition,no

effectswereobservedonvisualacuity,electroretinograms,intraocularpressureor

pupillometry.Acrossallclinicalstudies,reportsofchangesincolourvisionwererare(see

ADVERSEEFFECTS).

Tadalafiladministeredtohealthysubjectsproducednosignificantdifferencecomparedto

placeboinsupinesystolicanddiastolicbloodpressure(meanmaximaldecreaseof1.6/0.8

mmHg,respectively),instandingsystolicanddiastolicbloodpressure(meanmaximal

decreaseof0.2/4.6mmHg,respectively)andnosignificantchangeinheartrate.Larger

effectswererecordedamongsubjectsreceivingconcomitantnitrates(see

CONTRAINDICATIONS).

Threestudieswereconductedinmentoassessthepotentialeffectonspermatogenesisof

tadalafil10mg(one6-monthstudy)and20mg(one6-monthandone9-monthstudy)

administereddaily.Therewerenoadverseeffectsonspermmorphologyorspermmotility

inanyofthethreestudies.Inthestudyof10mgtadalafilfor6monthsandthestudyof20

mgtadalafilfor9months,resultsshowedadecreaseinmeanspermconcentrationsrelative

toplacebo.Thiseffectwasnotseeninthestudyof20mgtadalafiltakenfor6months.In

all3studiestherewerenostatisticallysignificantdifferencesbetweentheplaceboand

tadalafilgroupsformeantotalspermcounts.Inadditiontherewasnoadverseeffecton

meanconcentrationsofreproductivehormones,testosterone,luteinisinghormoneorfollicle

stimulatinghormonewitheither10or20mgoftadalafilcomparedtoplacebo.

Pharmacokinetics

Absorption

Tadalafilisrapidlyabsorbedafteroraladministrationandthemeanmaximumobserved

plasmaconcentration(C

)isachievedatamediantimeof4hoursafterdosing.Thereis

noclinicallyrelevanteffectoffoodontherateandextentofabsorptionoftadalafil,thus

tadalafilmaybetakenwithorwithoutfood.Thetimeofdosing(morningversusevening

afterasingle10mgadministration)hasnoclinicallyrelevanteffectsontherateandextent

ofabsorption.Theabsolutebioavailabilityoforaltadalafilhasnotbeenestablished.The

meanbioavailabilityofthetadalafil20mgtablethasbeenestimatedtobe88%relativeto

anoralsuspensiondosageform.

Distribution

Themeanvolumeofdistributionafteroraldosingisapproximately77Latsteadystate.At

therapeuticconcentrations,94%oftadalafilinplasmaisboundtoproteins.Proteinbinding

isnotaffectedbyimpairedrenalfunction.Lessthan0.0005%oftheadministereddose

appearsinthesemenofhealthysubjects.

Metabolism

Tadalafilismetabolisedmainly(>80%)bythecytochromeP450(CYP)3A4isoform,with

minorcontributionsbyCYPs2C8,2C9,2C19and2D6(<20%collectively).Themajor

circulatingmetaboliteisthemethylcatecholglucuronide.Thismetaboliteisatleast13,000-

foldlesspotentthantadalafilforPDE5.Consequently,itisnotexpectedtobeclinically

activeatobservedmetaboliteconcentrations.

Elimination

Themeanoralclearancefortadalafilis3.4L/hratsteadystateandthemeanterminalhalf-

lifeis16hoursinhealthysubjects.Tadalafilisexcretedpredominantlyasinactive

metabolites,mainlyinthefaeces(approximately61%ofthedose)andtoalesserextentin

theurine(approximately36%ofthedose).

Linearity/non-linearity

Overadoserangeof2.5to20mg,tadalafilexposure(AUC)increasesproportionallywith

doseinhealthysubjects.Between20mgto40mg,alessthanproportionalincreasein

exposureisobserved.Duringtadalafil20mgand40mgoncedailydosing,steady-state

plasmaconcentrationsareattainedwithin5days,andexposureisapproximately1.5foldof

thatafterasingledose.

Populationpharmacokinetics

Inpatientswithpulmonaryhypertensionnotreceivingconcomitantbosentan,theaverage

tadalafilexposureatsteady-statefollowing40mgwas26%higherwhencomparedtothose

ofhealthyvolunteers.TherewerenoclinicallyrelevantdifferencesinC

comparedto

healthyvolunteers.Theresultssuggestalowerclearanceoftadalafilinpatientswith

pulmonaryhypertensioncomparedtohealthyvolunteers

SpecialPopulations

Elderly

Healthyelderlysubjects(65yearsorover)hadalowerclearanceoftadalafil,resultingina

halflifeof22hoursand25%higherexposure(AUC),relativetohealthysubjectsaged19

to45yearsaftera10mgdose(halflifeof16-17hours).Thiseffectdoesnotappearto

warrantadoseadjustment(seeDOSAGEANDADMINISTRATION–ElderlyPatients).The

half-lifeoftadalafilintheelderlyincreasestheperiodafterthelastdoseofADCIRCAduring

whichnitratesshouldbeavoided(seeCONTRAINDICATIONS).

RenalImpairment

Inclinicalpharmacologystudiesusingsingle-dosetadalafil(5-20mg),tadalafilexposure

(AUC)approximatelydoubledinsubjectswithmild(creatinineclearance51to80ml/min)or

moderate(creatinineclearance31to50ml/min)renalimpairmentandinsubjectswithend-

stagerenaldiseaseondialysis.Inhaemodialysispatientsinthesestudies,C

was41%

higherthanthatobservedinhealthysubjects.Haemodialysiscontributednegligiblyto

tadalafilelimination.

Duetoincreasedtadalafilexposure(AUC),limitedclinicalexperience,andthelackofability

toinfluenceclearancebydialysis,tadalafilisnotrecommendedinpatientswithsevererenal

impairment.

HepaticImpairment

Aclinicalpharmacologystudywasconductedusingasingle10-mgdoseoftadalafilto

investigatetheeffectofhepaticimpairmentonthepharmacokineticsoftadalafilinsubjects

withhepaticdysfunctionasdefinedbytheChild-Pughclassification.Tadalafilexposure

(AUC)insubjectswithmildandmoderatehepaticimpairment(Child-PughClassAandB)

wascomparabletoexposureinhealthysubjectsaftera10-mgdose.Therearenoavailable

dataabouttheadministrationofdoseshigherthan10mgoftadalafiltopatientswith

hepaticimpairment.Nocontrolleddataareavailableinpatientswithseverehepatic

impairment(Child-PughClassC)andthereforedosingoftadalafilinthesepatientsisnot

recommended.Iftadalafilisprescribed,acarefulindividualbenefit/riskevaluationshouldbe

undertakenbytheprescribingphysician.

PatientswithDiabetes

Tadalafilexposure(AUC)inpatientswithdiabeteswasapproximately19%lowerthanthe

AUCvalueforhealthysubjectsaftera10mgdose.Thisdifferenceinexposuredoesnot

warrantadoseadjustment.

Race

Pharmacokineticstudieshaveincludedsubjectsandpatientsfromdifferentethnicgroups,

andnodifferencesinthetypicalexposuretotadalafilhavebeenidentified.Nodose

adjustmentiswarranted.

Gender

Inhealthyfemaleandmalesubjectsfollowingsingleandmultiple-dosesoftadalafil,no

clinicallyrelevantdifferencesinexposurewereobserved.Nodoseadjustmentiswarranted.

CLINICALTRIALS

Arandomized,double-blind,16weekplacebo-controlledstudywasconductedin405

patientswithpulmonaryarterialhypertension,definedasarestingmeanpulmonaryartery

pressure(mPAP)≥25mmHg,pulmonarycapillarywedgepressure(PCWP)≤15mmHg,

andpulmonaryvascularresistance(PVR)≥3Woodunitsviarightheartcatheterization.

Allowedbackgroundtherapyincludedbosentan(maintenancedosingupto125mgtwice

daily)andchronicanticoagulation.Theuseofprostacyclinoranalogue,L-arginine,

phosphodiesteraseinhibitor,orotherchronicPAHmedicationswerenotpermitted.

Subjectswererandomlyassignedto1of5treatmentgroups(tadalafil2.5,10,20,40mg,or

placebo)ina1:1:1:1:1ratio.Subjectshadtobeatleast12yearsofageandhada

diagnosisofPAHthatwasidiopathic,relatedtocollagenvasculardisease,anorexigenuse,

humanimmunodeficiencyvirus(HIV)infection,associatedwithanatrial-septaldefect,or

associatedwithsurgicalrepairofacongenitalsystemic-to-pulmonaryshuntofleast1yearin

duration(forexample,ventricularseptaldefect,patentductusarteriosus).Patientswitha

historyofleft-sidedheartdisease,severerenalinsufficiency,orpulmonaryhypertension

relatedtoconditionsotherthanspecifiedintheinclusioncriteriawerenoteligiblefor

enrollment.

Themeanageofallsubjectswas54years(range14-90years)withthemajorityof

subjectsbeingCaucasian(81%)andfemale(78%).PAHetiologieswerepredominantly

idiopathicPAH(61%)andrelatedtocollagenvasculardisease(23%).Morethanhalf(53%)

ofthesubjectsinthestudywerereceivingconcomitantbosentantherapy.Themajorityof

subjectshadaWorldHealthOrganization(WHO)FunctionalClassIII(65%)orII(32%).

Themeanbaseline6-minutewalkdistance(6-MWD)was344meters.Ofthe405subjects,

341completedthestudy.

Theprimaryefficacyendpointwasthechangefrombaselineatweek16in6-MWD( see

Figure1,Table1).IntheADCIRCA40mgtreatmentgroup,theplacebo-adjustedmean

changeincreasein6-MWDwas33meters(95%C.I.15-50meters;p=0.0004).The

improvementin6-MWDwasapparentat8weeksoftreatmentandthenmaintainedatweek

12andweek16(p<0.05).

Figure1:6-MinuteWalkDistance(metres)MeanChangefromBaseline,with95%

ConfidenceIntervals

Table1–6-MinuteWalkDistance(metres)Mean ChangefromBaselineto Endpoint

Placebo

(N=82) Tadalafil

10mg

(N=80) Tadalafil

20mg

(N=82) Tadalafil

40mg

(N=79)

Mean(SD) 9.21(59.96) 28.60(62.17) 36.23(47.53) 41.14(49.39)

Treatment

difference a 19.9 27.5 32.8

95%C.I. a 0.9,38.8 10.6,44.3 15.2,50.3

Weeks 0 4 8 12 16 M ean C h an g e fr o m B asel in e (M et er s)

Placebo (N=82)

ADCIRCA40 mg (N=79)

*p=0.0152

**p=0.0084

***p=0.0004 * ** ***

ANCOVAmodelwithType IIsumofsquares including the centeredbaseline of6-MWdistance(cont.), PAH

etiology,andbosentanuse.Treatmentdifferenceisthe Active LeastSquare meansubtractPlaceboLeastSquare

mean.

PermutationteststratifiedbyPAHetiology,bosentanuse,and baseline6-minutewalkdistance(<=325mand

>325m) onrankcomparedto placebo.

Placebo-adjustedchangesin6-MWDat16weekswereevaluatedinsubgroups( seeFigure

2),althoughthestudywasnotpoweredtodemonstratestatisticalsignificancewithin

subgroups.InpatientstakingonlyADCIRCA40mg(i.e.,withoutconcomitantbosentan),the

placebo-adjustedmeanchangein6-MWDwas44meters(p<0.01).Inpatientstaking

ADCIRCA40mgandconcomitantbosentantherapy,theplaceboadjustedmeanchangein

6-MWDwas23meters(p>0.05).

Figure2:Placebo-adjusted MeanChangein6-MinuteWalkDistance(metres)ofADCIRCA

40 mg,with95%ConfidenceIntervals

Thesecondaryendpointsweretestedinasequentialorderspecifiedintheprotocol,whichis

theorderlistedinTable2,withnofurtherinferentialtestingonceastatisticallynon-

significantresultwasreached.InferentialtestingdidnotproceedbeyondWHOfunctional

Classsincethiscomparisonwasstatisticallynon-significant

Table2-SecondaryEndpoints(ChangefromBaselinetoEndofTreatment–Week16)

Placebo

(N=82) Tadalafil

10mg

(N=80) Tadalafil

20mg

(N=82) Tadalafil

40mg

(N=79)

ChangeinWHOFunctionalClassNo.(%)

Improved 17(20.7) 19(23.8) 30(36.6) 18(22.8)

NoChange 52(63.4) 50(62.5) 37(45.1) 53(67.1)

Worsen 13(15.9) 11(13.75) 15(18.3) 8(10.1)

P-value 0.5758 0.1694 0.3630

ClinicalWorsening a

ProbabilityofNoClinical

WorseningatWeek16(95%C.I.) 0.84

(0.74,0.90) 0.91

(0.82,0.95) 0.90

(0.80,0.95) 0.94

(0.85,0.98)

No.ofpatients(%)withClinical

Worsening 13(15.9) 7(8.8) 8(9.8) 4(5.1)

ChangeinBorgDyspnea b Score

Mean(SD) 0.41(1.89)-0.36(1.92)-0.29(2.08)-0.70(1.75)

Clinicalworseningwasdefinedasdeath,lungtransplantation,atrialseptostomy,hospitalizationduetoworseningPAH,

initiationofnewPAHtherapy,andworseningWHOfunctionalclass.

b ApositivechangeinBorg-Dyspneascorerepresentsaworseningofpatientperceivedbreathlessnessduringthe6minute

walk.

Astatisticallysignificant(p<0.05)increaseinqualityoflife,comparedtoplacebo,was

demonstratedinthetadalafil40mggroupin6ofthe8SF36domains(physicalfunctioning,

rolephysical,bodilypain,generalhealth,vitalityandsocialfunctioning)andinallquestions

ofEuroQoL.

Long-termtreatment

357patientsfromtheplacebo-controlledstudyenteredalong-termextensionstudy.Of

these,311patientshadbeentreatedwithtadalafilforatleast6monthsand293for1year

(medianexposure365days;range2daysto415days).Forthosepatientsforwhichthere

aredata,thesurvivalrateat1yearis96.4%.Additionally,6minutewalkdistanceandWHO

functionalclassstatusappearedtobestableinthosetreatedwithtadalafilfor1year.

INDICATIONS

ADCIRCAisindicatedinadultsforthetreatmentofpulmonaryarterialhypertension(PAH)

classifiedasWHOfunctionalclassIIandIII,toimproveexercisecapacity.Efficacyhasbeen

showninidiopathicPAH(IPAH)andinPAHrelatedtocollagenvasculardisease.

CONTRAINDICATIONS

Nitratesandtadalafilmustnotbeusedconcomitantly.Co-administrationoftadalafilwith

nitricoxidedonors,organicnitratesororganicnitritesinanyformeitherregularlyor

intermittentlyiscontraindicated.Drugswhichmustnotbeusedconcomitantlyinclude,but

arenotlimitedto,glyceryltrinitrate(injection,tablets,spraysorpatches),isosorbidesalts,

sodiumnitroprusside,amylnitrite,nicorandilororganicnitratesinanyform.Inclinical

studies,tadalafilwasshowntopotentiatethehypotensiveeffectsofbothacuteandchronic

nitrateadministration.Thisisthoughttoresultfromthecombinedeffectsofnitratesand

tadalafilonthenitricoxide/cGMPpathway.

Administrationoftadalafiltopatientswhoareusinganyformoforganicnitrateis

contraindicated.InapatientprescribedADCIRCAwherenitrateadministrationisdeemed

medicallynecessaryinalife-threateningsituation,atleast48hoursinmostpatientsand4-

5daysintheelderly(approximately4-5halflives)shouldhaveelapsedafterthelastdose

ofADCIRCAbeforenitrateadministrationisconsidered.Insuchcircumstances,nitrates

shouldonlybeadministeredunderclosemedicalsupervisionwithappropriate

haemodynamicmonitoring(seePRECAUTIONS-InteractionswithOtherDrugs).

Tadalafiliscontraindicatedinpatientswhohavelossofvisioninoneeyebecauseofnon-

arteriticanteriorischaemicopticneuropathy(NAION),regardlessofwhetherthisepisode

wasinconnectionornotwithpreviousPDE5inhibitorexposure(seePRECAUTIONS).

Thefollowinggroupsofpatientswithcardiovasculardiseasewerenotincludedinclinical

trialsandtheuseoftadalafilisthereforecontraindicated:

- patientswithacutemyocardialinfarctionwithinthelast90days.

- patientswithseverehypotension(<90/50mmHg)

- patientswithunstableangina

- patientswithuncontrolledarrhythmias

- patientswithuncontrolledhypertension

- patientswithastrokewithinthelast6months.

Tadalafilshouldnotbeusedinpatientswithaknownhypersensitivitytotadalafilortoany

ingredientofthetablet.

PRECAUTIONS

ThefollowinggroupsofpatientswithcardiovasculardiseasewerenotincludedinPAH

clinicaltrials:

-Patientswithclinicallysignificantaorticandmitralvalvedisease

-Patientswithpericardialconstriction

-Patientswithrestrictiveorcongestivecardiomyopathy

-Patientswithsignificantleftventriculardysfunction

-Patientswithlife-threateningarrhythmias

-Patientswithsymptomaticcoronaryarterydisease

Sincetherearenoclinicaldataonthesafetyoftadalafilinthesepatients,theuseof

tadalafilisnotrecommended.

Pulmonaryvasodilatorsmaysignificantlyworsenthecardiovascularstatusofpatientswith

pulmonaryveno-occlusivedisease(PVOD).Sincetherearenoclinicaldataonadministration

oftadalafiltopatientswithveno-occlusivedisease,administrationoftadalafiltosuch

patientsisnotrecommended.Shouldsignsofpulmonaryoedemaoccurwhentadalafilis

administered,thepossibilityofassociatedPVODshouldbeconsidered.

AswithotherPDE5inhibitors,tadalafilhassystemicvasodilatorypropertiesthatmayresult

inmildandtransientdecreasesinbloodpressure.PriortoprescribingADCIRCA,physicians

shouldcarefullyconsiderwhethertheirpatientswithunderlyingconditions,suchassevere

leftventricularoutflowobstruction,fluiddepletion,autonomichypotensionorpatientswith

restinghypotension,couldbeadverselyaffectedbyvasodilatoryeffects.

Tadalafilpotentiatesthehypotensiveeffectofnitrates.Therefore,coadministrationof

ADCIRCAandnitratesiscontraindicated(seeCONTRAINDICATIONS).Tadalafilalso

potentiatestheeffectofsomeclassesofantihypertensivemedications,andthismaybe

clinicallyimportantinsomeindividuals.Wheninitiatingdailytreatmentwithtadalafil,

appropriateclinicalconsiderationsshouldbegiventoapossibledoseadjustmentofthe

antihypertensivetherapy.(seePRECAUTIONS–PotentialforADCIRCAtoAffectOther

Drugs–AntihypertensiveAgents).

PhysiciansshouldadvisepatientstostoptakingPDE5inhibitors,includingADCIRCA,and

seekpromptmedicalattentionintheeventofsuddendecreaseorlossofhearing.These

events,whichmaybeaccompaniedbytinnitusanddizziness,havebeenreportedin

temporalassociationtotheintakeofPDE5inhibitors,includingADCIRCA.Itisnotpossible

todeterminewhethertheseeventsarerelateddirectlytotheuseofPDE5inhibitorsorto

otherfactors(seeADVERSEEFFECTS).

CautionshouldbeexercisedwhenprescribingADCIRCAtopatientswhoaretakingalpha[1]

blockers,suchasdoxazosin,assimultaneousadministrationmayleadtosymptomatic

hypotensioninsomepatients(SeePRECAUTIONS–PotentialforADCIRCAtoAffectOther

Drugs).

Patientswithseverehepaticcirrhosis(Child-PughClassC)havenotbeenstudiedand

thereforedosingofADCIRCAisnotrecommended.

Duetoincreasedtadalafilexposure(AUC),limitedclinicalexperience,andthelackofability

toinfluenceclearancebydialysis,tadalafilisnotrecommendedinpatientswithsevererenal

impairment.

ForpatientschronicallytakingpotentinducersofCYP3A4,suchasrifampicin,theuseof

tadalafilisnotrecommended(seePRECAUTIONS–InteractionswithOtherMedicines).

ForpatientstakingconcomitantpotentinhibitorsofCYP3A4,suchasketoconazoleor

ritonavir,theuseoftadalafilisnotrecommended(seePRECAUTIONS–Interactionswith

OtherMedicines).

Theefficacyandsafetyoftadalafilco-administeredwithprostacyclinoritsanalogueshas

notbeenstudiedincontrolledclinicaltrials.Therefore,cautionisrecommendedincaseof

co-administration.

Theefficacyoftadalafilinpatientsalreadyonbosentantherapyhasnotbeenconclusively

demonstrated(seePRECAUTIONS–InteractionswithOtherMedicinesandCLINICAL

TRIALS).

ThesafetyandefficacyofcombinationsofADCIRCAandotherPDE5inhibitorsorother

treatmentsforerectiledysfunctionhavenotbeenstudied.Thereforepatientsshouldbe

informednottotakeADCIRCAwiththesemedications.

PriapismhasbeenreportedwithPDE5inhibitors,includingtadalafil.Patientswho

experienceerectionslasting4hoursormoreshouldbeinstructedtoseekimmediate

medicalassistance.Ifpriapismisnottreatedimmediately,peniletissuedamageand

permanentlossofpotencymayresult.

Tadalafilshouldbeusedwithcautioninpatientswhohaveconditionsthatmightpredispose

themtopriapism(suchassicklecellanaemia,multiplemyeloma,orleukaemia),orin

patientswithanatomicaldeformationofthepenis(suchasangulation,cavernosalfibrosisor

Peyronie’sdisease).

PhysiciansshouldadvisepatientstostopuseofallPDE5inhibitors,includingADCIRCA,and

seekmedicalattentionintheeventofanysuddenvisualdefectincludinglossofvisionin

oneorbotheyes(seeCONTRAINDICATIONS).Suchaneventmaybeasignofnon-arteritic

anteriorischaemicopticneuropathy(NAION),acauseofdecreasedvision,including

permanentlossofvisionthathasbeenreportedrarelypostmarketingintemporal

associationwiththeuseofallPDE5inhibitors.Itisnotpossibletodeterminewhetherthese

eventsarerelateddirectlytotheuseofPDE5inhibitorsortootherfactors.Patientswith

knownhereditarydegenerativeretinaldisorders,includingretinitispigmentosa,werenot

includedintheclinicaltrials,anduseinthesepatientsisnotrecommended.

ADCIRCAtabletscontainlactose.

EffectsonFertility

Therewerenoeffectsonfertility,reproductiveperformanceorreproductiveorgan

morphologyinmaleorfemaleratsgivenoraldosesoftadalafilupto400mg/kg/day(adose

producingAUCsforunboundtadalafilof7–foldformalesor18–foldforfemalesthe

exposuresattherecommendedhumandoseof40mg).However,regressionofthe

seminiferoustubularepitheliumofthetestesresultinginoligospermiaoraspermiainthe

epididymideswasobservedindogstreatedfor3,6or12monthswithoraltadalafildoses≥

10mg/kg/day.AUC-basedexposureapproximately0.3to3-foldtheexposureatthe

recommendedhumandoseof40mg).Ano-effectlevelfortheseeffectsindogswasnot

establishedSimilarfindingswerenotobservedinmiceinacarcinogenicitystudyatAUC-

basedexposuressimilartoexposureattherecommendedhumandoseof40mg.The

potentialrelevanceofthemalereproductive-toxicityfindingstohumanstreatedchronically

withtadalafilisunkown.

UseinPregnancy

PregnancycategoryB1.

Studiesinratshaveshownthattadalafiland/oritsmetabolitescrosstheplacentaand

distributetothefetus.Noevidenceofembryofetaltoxicityorteratogenicitywasobservedin

pregnantratsormicegivenoraldosesoftadalafilupto1000mg/kg/day.Thesedoseswere

associatedwithsystemicexposuretotadalafil ca7-8-foldthatexpectedatthe

recommendeddoseof40mgtakenoncedaily,basedonAUCforunbounddrugatsteady

state.Increasedpostnatalpupmortalitywasobservedinratsafteroraltreatmentwith

tadalafildoses≥60mg/kg/dayduringgestationandlactation.Theno-effectdoseof30

mg/kg/daywasassociatedwithsystemicexposure ca5-foldthatexpectedinhumansatthe

recommendeddoseof40mgtadalafiltakenoncedaily,basedonAUCforunbounddrugat

steadystate.Therearenostudiesoftadalafilinpregnantwomen.Becauseanimal

reproductionstudiesarenotalwayspredictiveofhumanresponse,tadalafilshouldbeused

duringpregnancyonlyifclearlyneeded

UseinLactation

Tadalafiland/oritsmetabolitesareexcretedinthemilkoflactatingratsatconcentrations

upto2.4-foldhigherthanthemaximalmaternalplasmaconcentration.Increasedpostnatal

pupmortalitywasobservedinratsaftertreatmentwithoraltadalafildoses≥60mg/kg/day

duringgestationandlactation(seeUseinPregnancy).

Therearenohumandataontheexcretionoftadalafilintobreastmilkoronthesafetyof

tadalafilexposureininfants.Becausemanydrugsareexcretedinhumanmilk,caution

shouldbeexercisedwhenADCIRCAisadministeredtoanursingwoman.

Carcinogenicity

Oraladministrationoftadalafilatdosesof400mg/kg/dayforuptotwoyearsinmice

resultedinincreaseddevelopmentofhepatocellularadenomasinmalesbutnotinfemales.

Tadalafilalsocausedhepatocellularmicrosomalenzymeinductioninrodentsanditis

possiblethatthiscouldleadtoanincreasedincidenceofhepatocellularneoplasms.

However,hepaticmicrosomalenzymeinductionisacommonnon-genotoxicbiologiceffect

associatedwithhepatocellulartumourformationinrodentsandisnotconsideredrelevant

tohumancancerrisk.Thenoeffectdoseof60mg/kg/daywasassociatedwithsystemic

exposuretotadalafilapproximately2to3-foldthatexpectedinhumanstakingthe

recommendeddoseof40mgdaily,basedonunbounddrugconcentrations.

Genotoxicity

Tadalafilwasnotmutagenicorgenotoxicin invitrobacterialandmammaliancellassays,

andin invitrohumanlymphocytesandinvivoratmicronucleusassays.

InteractionswithOtherMedicines

Tadalafilisnotexpectedtocauseclinicallysignificantinhibitionorinductionoftheclearance

ofdrugsmetabolisedbyCYP450isoforms.Studieshaveconfirmedthattadalafildoesnot

inhibitorinduceCYP450isoforms,includingCYP1A2,CYP3A4,CYP2C9,CYP2C19,CYP2D6

andCYP2E1.

PotentialforOtherDrugstoAffectADCIRCA

CytochromeP450Inhibitors

AzoleAntifungals(e.g.ketoconazole)

TadalafilisprincipallymetabolisedbyCYP3A4.AselectiveinhibitorofCYP3A4,ketoconazole

(400mgdaily),increasedtadalafil(20mg)single-doseexposure(AUC)by312%andC

by22%,andketaconazole(200mgdaily),increasedtadalafil(10mg)single-doseexposure

(AUC)by107%,andC

by15%relativetotheAUCandC

values.

Proteaseinhibitors(e.g.ritonavir)

Ritonavir(200mgtwicedaily),aninhibitorofCYP3A4,2C9,2C19,and2D6,increased

tadalafil(20mg)single-doseexposure(AUC)by124%withnochangeinC

.Ritonavir

(500mgor600mgtwicedaily)increasedtadalafil(20mg)single-doseexposure(AUC)by

32%anddecreasedC

max by30%.Althoughspecificinteractionshavenotbeenstudied,

otherHIVproteaseinhibitorssuchassaquinavir,andotherCYP3A4inhibitors,suchas

erythromycin,clarithromycin,itraconazoleandgrapefruitjuiceshouldbeco-administered

withcautionbecausetheywouldbeexpectedtoincreaseplasmaconcentrationsoftadalafil.

CytochromeP450Inducers

Endothelin-1receptorantagonists(e.g.bosentan)

Bosentan(125mgtwicedaily),asubstrateofCYP2C9andCYP3A4andamoderateinducer

ofCYP3A4,CYP2C9andpossiblyCYP2C19,reducedtadalafil(40mgonceperday)systemic

exposureby42%andC

by27%followingmultipledoseco-administration.Theefficacy

oftadalafilinpatientsalreadyonbosentantherapyhasnotbeenconclusivelydemonstrated

(seePRECAUTIONSandCLINICALTRIALS).Tadalafildidnotaffecttheexposure(AUCand

)ofbosentanoritsmetabolites.ThesafetyandefficacyofcombinationsofADCIRCA

andotherendothelin-1receptorantagonistshavenotbeenstudied.

Antimicrobialagents(e.g.rifampicin)

AselectiveCYP3A4inducer,rifampicin(600mgdaily),reducedtadalafilsingle-dose

exposure(AUC)by88%,andC

by46%relativetotheAUCandC

max valuesfortadalafil

(10mg) alone.Thisreducedexposurecanbeanticipatedtodecreasetheefficacyofonce-a-

day-dosedtadalafil;themagnitudeofdecreasedefficacyisunknown.Itcanbeexpected

thatconcomitantadministrationofotherCYP3A4inducerssuchasphenobarbitone,

phenytoinandcarbamazepinewouldalsodecreaseplasmaconcentrationsoftadalafil.

CytochromeP450Substrates

StudieswiththeCYP3A4probesubstratesmidazolamwithtadalafil10mgandlovastatin

withtadalafil20mgshowedlittlealterationinthekineticssuggestingthattadalafilis

unlikelytohaveinteractionswithCYP3A4substrates.

Antacids(magnesiumhydroxide/aluminiumhydroxide)

Simultaneousadministrationofanantacid(magnesiumhydroxide/aluminiumhydroxide)

andtadalafilreducedtheapparentrateofabsorptionoftadalafilwithoutalteringexposure

(AUC)totadalafil(10mg).

antagonists

AnincreaseingastricpHresultingfromadministrationofnizatidinehadnosignificanteffect

ontadalafil(10mg)pharmacokinetics.

PotentialforADCIRCAtoAffectOtherDrugs

Nitrates

Inclinicalpharmacologystudies,tadalafil10mgwasshowntopotentiatethehypotensive

effectsofnitrates.Therefore,administrationoftadalafiltopatientswhoareusinganyform

oforganicnitrateiscontraindicated.Aplacebo-controlledstudywasconductedtoassess

thedegreeofinteractionbetweennitroglycerineandtadalafil.Onehundredandfifty

subjectsreceiveddailydosesoftadalafil20mgfor7days.Onthe7 th day,0.4mg

sublingualnitroglycerinewasgivenatvarioustimesfollowingthedailydoseoftadalafil.

Thisinteractionlastedformorethan24hoursandwasnolongerdetectablewhen48hours

hadelapsed(seeCONTRAINDICATIONS)

RecreationalDrugscalled“poppers”or“amyl”

Duetotheknowninteractionbetweentadalafilandnitratesorothernitricoxidedonorson

nitrogenmonoxide/cGMPmetabolism,patientsmustbeexpresslyinformedthattheyshould

neveruserecreationaldrugscalled“poppers”or“amyl”,typicallytakenthroughinhalation.

Thesedrugsrepresentvariousalkylnitritesincludingamylnitrite,butylnitriteandisobutyl

nitrite.

Antihypertensiveagents

Tadalafilhassystemicvasodilatorypropertiesandmayaugmentthebloodpressure

loweringeffectsofantihypertensiveagents.Patientsshouldbeadvisedofthispossibility.In

aclinicalpharmacologystudymeasuringambulatorybloodpressure,whentadalafil(20mg)

wasadministeredto17hypertensivepatientstreatedwithangiotensinIIreceptorblockers,

ambulatorysystolicbloodpressurefellby30mmHgormorein9(53%)subjectson

tadalafiltreatmentandin5(29%)subjectsonplacebotreatment,withamaximumfallof

57mmHgfollowingtadalafilcomparedto37mmHgfollowingplacebo.Noneofthe

decreaseswereassociatedwithanyhypotensivesymptoms.Additionally,inpatientstaking

multipleantihypertensiveagentswhosehypertensionwasnotwellcontrolledcomparedto

subjectswhosebloodpressurewaswellcontrolled,greaterreductionsinbloodpressure

wereobserved.Thesereductionswerenotassociatedwithhypotensivesymptomsinthe

vastmajorityofpatients.Appropriateclinicaladviceshouldbegiventopatientswhenthey

aretreatedwithantihypertensivemedicationsandADCIRCA.

Wheninitiatingdailytreatmentwithtadalafil,appropriateclinicalconsiderationsshouldbe

giventoapossibledoseadjustmentoftheantihypertensivetherapy.

Inotherclinicalpharmacologystudies,tadalafil10mgwasaddedtoangiotensinconverting

enzyme(ACE)inhibitors(enalapril),betablockers(metoprolol)orthiazidediuretics

(bendrofluazide).Tadalafil10mgand20mgwasaddedtocalciumchannelblockers

(amlodipine)oralpha-blockers(tamsulosin).Inallthesestudies,tadalafildidnotproducea

significantadditionalreductioninmeansystolicordiastolicbloodpressure.However,

potentiallysignificantbloodpressurereductionsoccurredinsomeindividuals.Analysisof

phase3clinicaltrialdatashowednodifferenceintheoverallincidenceofadverseeventsin

patientstakingtadalafilwithorwithouthypertensivemedications.

Intwoclinicalpharmacologystudies,nosignificantdecreasesinbloodpressurewere

observedwhentadalafilwasco-administeredtohealthysubjectstakingtheselective

alpha[1A]-adrenergicblocker,tamsulosin.

Inthreeclinicalpharmacologystudieswhentadalafilwasco-administeredtohealthy

subjectstakingdoxazosin(4-8mgdaily),analpha[1]-adrenergicblocker,therewasan

augmentationoftheblood-pressure-loweringeffectofdoxazosin.Thenumberofpatients

withpotentiallyclinicallysignificantstanding-blood-pressuredecreaseswasgreaterforthe

combination.Intheseclinicalpharmacologystudiesthereweresymptomsassociatedwith

thedecreaseinbloodpressureincludingsyncope.

CautionisadvisedwhenPDE5inhibitorsarecoadministeredwithnonselectivealpha(α1)-

blockers.PDE5inhibitors,includingADCIRCA,andalpha-adrenergicblockingagentsareboth

vasodilatorswithblood-pressure-loweringeffects.Whenvasodilatorsareusedin

combination,anadditiveeffectonbloodpressuremaybeanticipated.Insomepatients,

concomitantuseofthesetwodrugclassescanlowerbloodpressuresignificantly,whichmay

leadtosymptomatichypotension(e.g.,fainting).Considerationshouldbegiventothe

following;

-Patientsshouldbestableonalpha-blockertherapypriortoinitiatingaPDE5

inhibitor.Patientswhodemonstratehemodynamicinstabilityonalpha-blocker

therapyaloneareatincreasedriskofsymptomatichypotensionwithconcomitantuse

ofPDE5inhibitors.

-Inthosepatientswhoarestableonalpha-blockertherapy,PDE5inhibitorsshould

beinitiatedatthelowestrecommendeddose.

-InthosepatientsalreadytakinganoptimizeddoseofPDE5inhibitor,alpha-blocker

therapyshouldbeinitiatedatthelowestdose.Stepwiseincreaseinalpha-blocker

dosemaybeassociatedwithfurtherloweringofbloodpressurewhentakingaPDE5

inhibitor.

-SafetyofcombineduseofPDE5inhibitorsandalpha-blockersmaybeaffectedby

othervariables,includingintravascularvolumedepletionandotheranti-hypertensive

drugs.

HumanplateletscontainthePDE5enzymesystem.Tadalafil,inlimitedstudies,didnot

affectplateletfunctioninvivo.Ininvitrostudiestadalafilwasshowntopotentiatethe

antiaggregatoryeffectofsodiumnitroprusside(anitricoxidedonor).

Alcohol

Tadalafildidnotaffectalcoholconcentrations,andalcoholdidnotaffecttadalafil

concentrations.Athighdosesofalcohol(0.7g/kg),theadditionoftadalafil20mgdidnot

inducestatisticallysignificantmeanbloodpressuredecreases.Insomesubjects,postural

dizzinessandorthostatichypotensionwereobserved.Whentadalafilwasadministeredwith

lowerdosesofalcohol(0.6g/kg),hypotensionwasnotobservedanddizzinessoccurred

withsimilarfrequencytoalcoholalone.

Aspirin

Whenadministeredincombinationwithaspirin,tadalafil20mgdidnotprolongbleeding

time,relativetoaspirinalone.ADCIRCAhasnotbeenadministeredtopatientswith

bleedingdisordersorsignificantactivepepticulceration.AlthoughADCIRCAhasnotbeen

showntoincreasebleedingtimesinhealthysubjects,useinpatientswithbleeding

disordersorsignificantactivepepticulcerationshouldbebaseduponacarefulrisk-benefit

assessment.

P-glycoproteinsubstrates(e.g.digoxin)

Tadalafil(40mgonceperday)hadnoclinicallysignificanteffectonthepharmacokineticsof

digoxin.

CYP2C9substrates(e.g.R-warfarin)

Inacrossoverstudy,12healthyvolunteersreceivedasingledoseofwarfarin25mgafter

takingtadalafil10mgorplacebooncedailyfor6days.Tadalafilreducedtheexposure

(AUC)toR-andS-warfarinby11%and13%,respectivelybutdidnotaltertheeffectof

warfarinonprothrombintime(PT).Theclinicalimplicationsofthesefindingsareunclear.

ThepossibilityofanincreaseordecreaseinPTand/orinternationalnormalisedratio(INR)

shouldbeconsideredwhenpatientsbegintakingorceasetakingtadalafil.

OralContraceptivePill

Atsteady-state,tadalafil(40mgonceperday)increasedethinylestradiolexposure(AUC)by

26%andC

by70%relativetooralcontraceptiveadministeredwithplacebo.Therewas

nostatisticallysignificanteffectoftadalafilonlevonorgestrelwhichsuggeststheeffectof

ethinylestradiolisduetoinhibitionofgutsulphationbytadalafil.Theclinicalrelevanceof

thisfindingisuncertain.

CYP1A2substrates(e.g.theophylline)

Tadalafil(10mg)hadnoclinicallysignificanteffectonthepharmacokineticsor

pharmacodynamicsoftheophylline(CYP1A2substrate).Theonlypharmadynamiceffectwas

asmall(3.5bpm)increaseinheartrate.

Terbutaline

AsimilarincreaseinAUCandC

seenwithethinylestradiolmaybeexpectedwithoral

administrationofterbutaline,probablyduetoinhibitionofgutsulphationbytadalafil.The

clinicalrelevanceofthisfindingisuncertain

OtherPDE5inhibitors

ThesafetyandefficacyofcombinationsofADCIRCAandotherPDE5inhibitorshavenot

beenstudied.Therefore,theuseofsuchcombinationsisnotrecommended.

EffectsonAbilitytoDriveandOperateMachinery

Althoughthefrequencyofreportsofdizzinessinplaceboandtadalafilarmsinclinicaltrials

wassimilar,patientsshouldbeawareofhowtheyreacttotadalafilbeforedrivingor

operatingmachinery.

EffectsonLaboratoryTests

Therearenodataavailablethatshowsthattadalafilhasaneffectonlaboratorytests.

ADVERSEEFFECTS

Inthepivotalplacebo-controlledstudyofADCIRCAforthetreatmentofPAH,atotalof323

patientsweretreatedwithADCIRCAatdosesrangingfrom2.5mgto40mgoncedailyand

82patientsweretreatedwithplacebo.Thedurationoftreatmentwas16weeks.Theoverall

frequencyofdiscontinuationduetoadverseeventswaslow(ADCIRCA11%,placebo16%).

Threehundredandfiftyseven(357)subjectswhocompletedthepivotalstudyentereda

long-termextensionstudy.Dosesstudiedwere20mgand40mgoncedaily.

Table3belowliststheadverseeventsreportedingreaterthanorequalto4%ofpatients

takingADCIRCA40mgduringtheplacebo-controlledclinicaltrial.Pleasenotethatsomeof

theseadverseeventsoccurredmoreofteninpatientsreceivingplaceboandmaynot

necessarilybecausallyrelatedtoADCIRCAuse.

Table3.TreatmentEmergentAdverseEventsReportedby≥4%ofPatientsReceiving

ADCIRCA 40mg

ADVERSEEVENT Placebo(%)

(N=82) Tadalafil40mg

(%)

(N=79)

InfectionsandInfestations

Nasopharyngitis 7 13

RespiratoryTractInfection(UpperandLower) 6 13

Bronchitis 0 5

UrinaryTractInfection 0 4

Psychiatricdisorders

Insomnia 2 4

NervousSystemDisorders

Headache 15 42

Dizziness 9 8

Vasculardisorders

Flushing 2 13

HotFlush 2 4

RespiratoryTract,ThoracicandMediastrinalDisorders

Cough 9 9

NasalCongestion(includingsinuscongestion) 1 9

Pulmonaryhypertension 9 8

Dyspnoea 4 6

UpperRespiratoryTractInfection 4 6

Respiratorytractinfection 3 5

Epistaxis 4 4

GastrointestinalDisorders

Diarrhoea 10 11

Nausea 6 11

Dyspepsia 2 10

Vomiting 1 6

GastroesophagealRefluxDisease 4 5

Constipation 1 4

Skinandsubcutaneoustissuedisorders

Rash 3 5

MusculoskeletalandConnectiveTissueDisorders

Myalgia 4 14

PaininExtremity 2 11

BackPain 6 10

MusculoskeletalStiffness 0 4

Reproductivesystemandbreastdisorders

Menorrhagia(includingincreaseduterine

bleeding a) 0 4

GeneralDisordersandAdministrationSiteConditions

Oedemaperipheral 9 6

Fatigue 4 6

ChestPain 1 6

Oedema 1 5

Non-CardiacChestPain 0 4

Therapeuticresponseunexpected 0 4

Thetable4belowliststheadversereactionsreportedduringtheplacebo-controlledclinical

trialinpatientswithPAHtreatedwithADCIRCA.Theseadversereactionshavebeenfound

tooccurmoreofteninpatientsreceivingADCIRCAcomparedtoplaceboandareconsidered

tobecausallyrelatedtoADCIRCAuse.Theadversereactionsreportedweretransient,and

generallymildormoderate.Atthebeginningoftherapyheadachemayoccur;and

decreasesovertimeeveniftreatmentiscontinued.Adversereactiondataarelimitedin

patientsover75yearsofage.Alsoincludedinthetablearesomeadverseevents/reactions

whichhavebeenreportedinclinicaltrialsand/orpostmarketingwithtadalafilinthe

treatmentofmaleerectiledysfunction.

Themostfrequentlynotedadversereactionsinthepivotalstudywereheadache,nausea,

backpain,paininextremity,dyspepsia,flushing,myalgiaandnasopharyngitis

Adversereactions

Frequencyestimate:Verycommon(≥1/10),Common(≥1/100to<1/10),Uncommon

(≥1/1000to<1/100),Rare(≥1/10,000to<1/1000),VeryRare(<1/10,000)andNot

known.

Table4.TreatmentEmergentAdverseReactionsReportedbyPatientsReceiving

ADCIRCA 40mg

Verycommon

(≥1/10) Common

(≥1/100to

<1/10) Uncommon

(≥1/1000to

<1/100) Rare

(≥1/10,000to

<1/1000)

NervousSystemdisorders

Headache

Eyedisorders

Blurredvision

Vasculardisorders

Flushing Hypotension

Respiratory,thoracicandmediastinaldisorders

Nasopharyngitis

(includingnasal

congestion,sinus

congestionand

rhinitis) Epistaxis

Gastrointestinaldisorders

Nausea,

Dyspepsia

(including

abdominal

pain/discomfort 1 ) Vomiting

Musculoskeletal,connectivetissueandbonedisorders

Myalgia,

Backpain

Paininextremity

(includinglimb

discomfort)

Reproductivesystemandbreastdisorders

Increased

uterine

Bleeding 2

ActualMedDRAtermsincludedareabdominaldiscomfort,abdominalpain,abdominalpainlower,abdominalpainupper,and

stomachdiscomfort.

Clinicalnon-MedDRAtermtoincludereportsofabnormal/excessivemenstrualbleeding

conditionssuchasmenorrhagia,metrorrhagia,menometrorrhagia,orvaginalhemorrhage.

Adversereactionsidentifiedfromspontaneouspostmarketingsurveillance

Thefollowingadversereactionshavebeenidentifiedduringpostapprovaluseoftadalafil,in

whichtadalafilwasauthorizedforthetreatmentoferectiledysfunction.Theseeventshave

beenchosenforinclusioneitherduetotheirseriousness,reportingfrequency,lackofclear

alternativecausation,oracombinationofthesefactors.Becausethesereactionsare

reportedvoluntarilyfromapopulationofuncertainsize,itisnotalwayspossibletoreliably

estimatetheirfrequencyorestablishacausalrelationshiptodrugexposure.

Bodyasawhole:hypersensitivityreactionsincludingrash,urticaria,andfacialedema.

Cardiovascularandcerebrovascular:seriouscardiovascularevents,including

myocardialinfarction,suddencardiacdeath,stroke,chestpain,palpitations,and

tachycardia,havebeenreportedpostmarketingintemporalassociationwiththeuseof

tadalafil.Mostofthepatientsinwhomtheseeventshavebeenreportedhadpre-existing

cardiovascularriskfactors.However,itisnotpossibletodefinitivelydeterminewhether

theseeventsarerelateddirectlytotheseriskfactors,totadalafil,tosexualactivity,ortoa

combinationoftheseorotherfactors.

Hypotension(morecommonlyreportedwhentadalafilisgiventopatientswhoarealready

takingantihypertensiveagents),hypertension,andsyncope

Earandlabyrinthdisorders:suddenhearingloss

Skinandsubcutaneoustissues:hyperhidrosis(sweating),Stevens-Johnsonsyndrome,

andexfoliativedermatitis.

Nervoussystem:migraineseizureandtransientamnesia

Respiratorysystem:epistaxis

Specialsenses:blurredvision,retinalveinocclusion,visualfielddefect,non-arteritic

anteriorischemicopticneuropathy.

Non-arteriticanteriorischemicopticneuropathy,acauseofdecreasedvisionincluding

permanentlossofvision,hasbeenreportedrarelypostmarketingintemporalassociation

withtheuseofphosphodiesterasetype5(PDE5)inhibitors,includingCIALIS.Most,but,not

all,ofthesepatientshadunderlyinganatomicorvascularriskfactorsfordevelopmentof

NAION,includingbutnotnecessarilylimitedto:lowcuptodiscratio(“crowdeddisc”),age

over50,diabetes,hypertension,coronaryarterydisease,hyperlipidemia,andsmoking.Itis

notpossibletodeterminewhethertheseeventsarerelateddirectlytotheuseofPDE5

inhibitors,tothepatient’sunderlyingvascularriskfactorsoranatomicaldefects,toa

combinationofthesefactors,ortootherfactors.

Urogenital:priapismandprolongederection

DOSAGEANDADMINISTRATION

Treatmentshouldonlybeinitiatedandmonitoredbyaphysicianexperiencedinthe

treatmentofPAH.

Therecommendeddoseis40mg(2x20mg)takenoncedailywithorwithoutfood.

Useinpatientswithrenalimpairment:

Inpatientswithmildtomoderaterenalimpairmentastartingdoseof20mgonceperdayis

recommended

basedondatafromclinicalpharmacologystudies.Althoughclinical

pharmacologystudiesinpatientswithrenalimpairmenthavenotbeenperformedwith40mg

thedosemaybeincreasedto40mgonceperday,basedonindividualefficacyand

tolerability.InpatientswithsevererenalimpairmenttheuseofADCIRCAisnot

recommendedduetolimitedclinicalexperienceinthesepatients.(SeePrecautionsand

Pharmacokinetics).

Useinpatientswithhepaticimpairment:

Basedondataobtainedinaclinicalpharmacologystudyperformedusingsingledosesof10

mginpatientswithmildtomoderatehepaticcirrhosis(Child-PughClassAandB),astarting

doseof20mgonceperdaymaybeconsidered.Iftadalafilisprescribed,acarefulindividual

benefit/riskevaluationshouldbeundertakenbytheprescribingphysician.Patientswith

severehepaticcirrhosis(Child-PughClassC)havenotbeenstudiedandthereforedosingof

tadalafilisnotrecommended.(SeePrecautionsandPharmacokinetics).

Useinchildrenandadolescents

ADCIRCAshouldnotbeusedinindividualsbelow18yearsofage.

ElderlyPatients

Dosageadjustmentsarenotrequiredinelderlypatients.

OVERDOSAGE

Singledosesofupto500mgoftadalafilhavebeengiventohealthysubjectsandmultiple

dailydosesofupto100mghavebeengiventomalepatientswitherectiledysfunction.

Adverseeventsweresimilartothoseseenatlowerdoses.Incasesofoverdose,standard

supportivemeasuresshouldbeadoptedasrequired.Haemodialysiscontributesnegligibly

totadalafilelimination.Incaseofoverdose,immediatelycontactthePoisonsInformation

Centre(inAustralia,call131126;inNewZealandcall0800764766)foradvice.

PRESENTATION ANDSTORAGECONDITIONS

ADCIRCA20mgtabletsarepresentedinblisterpacksof14*,28**and56tabletsper

carton.

*onlyavailableasastarterpack

**notcurrently available

Storebelow25°C.Storeintheoriginalpackage.

NAMEANDADDRESSOFTHESPONSOR

Eli LillyandCompany(NZ)Limited

Level3,Dimension DataHouse,

414-422 KhyberPassRoad

Newmarket

POBox109 197

Newmarket,Auckland

NEWZEALAND

Telephone(09)523 9300

MEDICINECLASSIFICATION

PrescriptionMedicine

DATEOFPREPARATION

09December2011

Document Outline

17-1-2019

Safety and efficacy of 8‐mercapto‐p‐menthan‐3‐one and p‐menth‐1‐ene‐8‐thiol belonging to chemical group 20 when used as flavourings for all animal species

Safety and efficacy of 8‐mercapto‐p‐menthan‐3‐one and p‐menth‐1‐ene‐8‐thiol belonging to chemical group 20 when used as flavourings for all animal species

Published on: Wed, 16 Jan 2019 Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of two compounds belonging to chemical group 20 (aliphatic and aromatic mono‐ and di‐thiols and mono‐, di‐, tri‐, and polysulfides with or without additional oxygenated functional groups). 8‐Mercapto‐p‐menthan‐3‐one [12.038] and p‐menth‐1‐ene‐8‐thiol [12.085] are currently ...

Europe - EFSA - European Food Safety Authority EFSA Journal

16-1-2019

Safety and efficacy of Deccox® (decoquinate) for chickens for fattening

Safety and efficacy of Deccox® (decoquinate) for chickens for fattening

Published on: Mon, 14 Jan 2019 Deccox®, containing decoquinate as the active substance, is a feed additive intended to be used for the prevention of coccidiosis in chickens for fattening at a dose range of 20–40 mg/kg complete feed. Decoquinate from Deccox® is safe for chickens for fattening at the highest applied concentration in complete feed of 40 mg/kg. No practically relevant interactions with other additives or veterinary drugs exist except with bentonite. Decoquinate does not have antibacterial a...

Europe - EFSA - European Food Safety Authority EFSA Journal

8-1-2019

Happy Together, Inc. Issues Voluntary Nationwide Recall of Product Due to Presence of Undeclared Sildenafil and Tadalafil

Happy Together, Inc. Issues Voluntary Nationwide Recall of Product Due to Presence of Undeclared Sildenafil and Tadalafil

Happy Together, Inc. Boynton Beach, FL is voluntarily recalling all lots within expiry of the Rhino 5k capsules to the consumer level. FDA analysis founds these products to be tainted with sildenafil and Tadalafil. Sildenafil/Tadalafil is an FDA approved drug for the treatment of erectile dysfunction, the presence of sildenafil in the Rhino 5k products renders them unapproved drugs for which safety and efficacy have not been established, therefor subject to recall.

FDA - U.S. Food and Drug Administration

8-1-2019

Sun Pharmaceutical Industries, Inc. Issues Voluntary Nationwide Recall of Vecuronium Bromide for Injection Due to the Presence of Particulate Matter Identified as Glass

Sun Pharmaceutical Industries, Inc. Issues Voluntary Nationwide Recall of Vecuronium Bromide for Injection Due to the Presence of Particulate Matter Identified as Glass

Sun Pharmaceutical Industries, Inc. (SPII), a wholly owned subsidiary of Sun Pharmaceutical Industries, Ltd. is voluntarily recalling three lots of Vecuronium Bromide for Injection, 10 mg (lyophilized powder), and one lot of Vecuronium Bromide for Injection, 20 mg (lyophilized powder) to the hospital level. The Vecuronium Bromide for Injection has been found to contain particulate matter identified as glass.

FDA - U.S. Food and Drug Administration

21-12-2018

Peer review of the pesticide risk assessment of the active substance propanil

Peer review of the pesticide risk assessment of the active substance propanil

Published on: Thu, 20 Dec 2018 The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State Italy for the pesticide active substance propanil and the assessment of applications for maximum residue levels (MRLs) are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions were reached on the basis of the evaluation of t...

Europe - EFSA - European Food Safety Authority EFSA Journal

21-12-2018

Avian influenza overview August – November 2018

Avian influenza overview August – November 2018

Published on: Thu, 20 Dec 2018 Between 16 August and 15 November 2018, 14 highly pathogenic avian influenza (HPAI) A(H5N8) outbreaks in poultry establishments in Bulgaria and seven HPAI A(H5N6) outbreaks, one in captive birds in Germany and six in wild birds in Denmark and the Netherlands were reported in the European Union (EU). No human infection due to HPAI A(H5N8) and A(H5N6) viruses have been reported in Europe so far. Seroconversion of people exposed during outbreaks in Russia has been reported in...

Europe - EFSA - European Food Safety Authority EFSA Journal

18-12-2018

Enovachem Pharmaceuticals Issues Voluntary Nationwide Recall of Dyural-40 and Dyural-80 Convenience Kits Containing Recalled Sodium Chloride Injection, USP, 0.9% Due to Latex Hazard

Enovachem Pharmaceuticals Issues Voluntary Nationwide Recall of Dyural-40 and Dyural-80 Convenience Kits Containing Recalled Sodium Chloride Injection, USP, 0.9% Due to Latex Hazard

Torrance, CA, Asclemed USA Inc is voluntarily recalling 20 lots of Dyural-40 and 61 lots of Dyural-80, to the user level. The products include recalled Sodium Chloride, USP, 0.9% manufactured by Fresenius Kabi, which has been recalled due to product labeling incorrectly stating stoppers do not contain latex.

FDA - U.S. Food and Drug Administration

17-12-2018


Draft cabozantinib tablet 20 mg, 40 mg and 60 mg, capsule 20 4 mg and 80 mg product-specific bioequivalence guidance

Draft cabozantinib tablet 20 mg, 40 mg and 60 mg, capsule 20 4 mg and 80 mg product-specific bioequivalence guidance

Draft cabozantinib tablet 20 mg, 40 mg and 60 mg, capsule 20 4 mg and 80 mg product-specific bioequivalence guidance

Europe - EMA - European Medicines Agency

14-12-2018

Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food

Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food

Published on: Thu, 13 Dec 2018 The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in food. Regarding PFOS and PFOA occurrence, the final data set available for dietary exposure assessment contained a total of 20,019 analytical results (PFOS n = 10,191 and PFOA n = 9,828). There were large differences between upper and lower bound exposure due to analytical methods with i...

Europe - EFSA - European Food Safety Authority Publications

14-12-2018

Analysis of hunting statistics collection frameworks for wild boar across Europe and proposals for improving the harmonisation of data collection

Analysis of hunting statistics collection frameworks for wild boar across Europe and proposals for improving the harmonisation of data collection

Published on: Thu, 13 Dec 2018 Heterogeneities in the wild boar data collection frameworks across Europe were analysed using questionnaires to explore comparability of hunting data in the short term and propose a common framework for future collection. Fifty‐seven respondents representing 32 countries covering more than 95% of European territory participated to the questionnaire. The most frequently recorded information in the official statistics included the quantity of animals shot per hunting ground ...

Europe - EFSA - European Food Safety Authority Publications

11-12-2018


The new EudraVigilance system and the electronic reporting of individual case safety reports in the ISO/ICH E2B(R3) format: Hands-on training course, Madrid, Spain, from 20/05/2019 to 22/05/2019

The new EudraVigilance system and the electronic reporting of individual case safety reports in the ISO/ICH E2B(R3) format: Hands-on training course, Madrid, Spain, from 20/05/2019 to 22/05/2019

The new EudraVigilance system and the electronic reporting of individual case safety reports in the ISO/ICH E2B(R3) format: Hands-on training course, Madrid, Spain, from 20/05/2019 to 22/05/2019

Europe - EMA - European Medicines Agency

11-12-2018


The new EudraVigilance system and the electronic reporting of individual case safety reports in the ISO/ICH E2B(R3) format: Hands-on training course, London, United Kingdom, from 11/02/2019 to 20/02/2019

The new EudraVigilance system and the electronic reporting of individual case safety reports in the ISO/ICH E2B(R3) format: Hands-on training course, London, United Kingdom, from 11/02/2019 to 20/02/2019

The new EudraVigilance system and the electronic reporting of individual case safety reports in the ISO/ICH E2B(R3) format: Hands-on training course, London, United Kingdom, from 11/02/2019 to 20/02/2019

Europe - EMA - European Medicines Agency

21-11-2018

Fresenius Kabi Issues Voluntary Nationwide Recall of Sodium Chloride Injection, USP, 0.9% Due to Product Labeling Incorrectly Stating Stoppers Do Not Contain Latex

Fresenius Kabi Issues Voluntary Nationwide Recall of Sodium Chloride Injection, USP, 0.9% Due to Product Labeling Incorrectly Stating Stoppers Do Not Contain Latex

Fresenius Kabi USA is voluntarily recalling 163 lots of Sodium Chloride Injection, USP, 0.9%, 10 mL fill in a 10 mL vial and Sodium Chloride Injection, USP, 0.9%, 20 mL fill in a 20 mL vial to the user level. The product insert states that stoppers for both the 10mL and the 20mL vials do not contain natural rubber latex; the tray label for the two vial sizes and the vial label for the 20mL vial also state that the stoppers do not contain latex. The product is being recalled because the stoppers contain n...

FDA - U.S. Food and Drug Administration

21-11-2018

Enforcement Report for the Week of November 21, 2018

Enforcement Report for the Week of November 21, 2018

Recently Updated Records for the Week of November 21, 2018 Last Modified Date: Tuesday, November 20, 2018

FDA - U.S. Food and Drug Administration

21-11-2018

Implementation and verification of PBPK modelling codes of TCDD in rats and humans into Berkeley Madonna

Implementation and verification of PBPK modelling codes of TCDD in rats and humans into Berkeley Madonna

Published on: Tue, 20 Nov 2018 The goal of the current work was to implement and verify previously published rat and human PBPK modelling codes for TCDD into Berkeley Madonna. The US‐EPA has used these PBPK models in the reassessment of TCDD. A procurement contract has been set up to explore the possibilities to adequately run the models and reproduce previously published results. The implementation of the available codes in Berkeley Madonna was carried out at RIKILT‐WUR under the framework agreement wi...

Europe - EFSA - European Food Safety Authority Publications

21-11-2018

Extensive Literature Search, Selection for Relevance and Data Extraction of Studies Related to the Toxicity of PCDD/Fs and DL‐PCBs in Experimental Animals

Extensive Literature Search, Selection for Relevance and Data Extraction of Studies Related to the Toxicity of PCDD/Fs and DL‐PCBs in Experimental Animals

Published on: Tue, 20 Nov 2018 Polychlorinated dibenzodioxins (PCDD), polychlorinated dibenzofurans (PCDFs) and dioxin‐like polychlorinated biphenyls (DL‐PCBs) are detected ubiquitously in the environment, diet and human tissues. The European Food Safety Authority (EFSA) CONTAM Panel received a mandate from the European Commission for a scientific opinion on the risks for human and animal health related to the presence of dioxins and DL‐PCBs in food and feed. To support preparatory work for the hazard i...

Europe - EFSA - European Food Safety Authority Publications

21-11-2018

Safety and efficacy of Monteban® G100 (narasin) for chickens for fattening

Safety and efficacy of Monteban® G100 (narasin) for chickens for fattening

Published on: Tue, 20 Nov 2018 The feed additive Monteban® G100, containing the active substance narasin, an ionophore anticoccidial, is intended to control coccidiosis in chickens for fattening at a dose of 60–70 mg/kg complete feed. Narasin is produced by fermentation. Limited data on the taxonomic identification of the production strain did not allow the proper identification of strain NRRL 8092 as Streptomyces aureofaciens. The FEEDAP Panel cannot conclude on the absence of genetic determinants for ...

Europe - EFSA - European Food Safety Authority Publications

21-11-2018

Extensive literature search, selection for relevance and data extraction of studies related to the toxicity of PCDD/Fs and DL‐PCBs in humans

Extensive literature search, selection for relevance and data extraction of studies related to the toxicity of PCDD/Fs and DL‐PCBs in humans

Published on: Tue, 20 Nov 2018 To enable the hazard identification and characterisation in the risk assessment for humans related to the seventeen 2,3,7,8‐substituted dioxins (PCCDs) and furans (PCDFs) and the twelve dioxin‐like polychlorinated biphenyls (DL‐PCBs), EFSA outsourced an extensive literature search (ELS), followed by selection for relevance and extraction of relevant data for consideration in the risk assessment. Two tailored search strategies for Web of Science (WoS) and PubMed for identif...

Europe - EFSA - European Food Safety Authority Publications

21-11-2018

Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food

Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food

Published on: Tue, 20 Nov 2018 The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL‐PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre‐ and postnatal exposure. The critical s...

Europe - EFSA - European Food Safety Authority Publications

21-11-2018

Setting of an import tolerance for mandipropamid in cocoa beans

Setting of an import tolerance for mandipropamid in cocoa beans

Published on: Tue, 20 Nov 2018 In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Syngenta Agro GmbH submitted a request to the competent national authority in Austria to set a maximum residue level (MRL) for the active substance mandipropamid in cocoa beans imported from Nigeria and Cameroon. The data submitted in support of the request were found to be sufficient to derive a MRL proposal of 0.06 mg/kg. Adequate analytical methods for enforcement are available to control the res...

Europe - EFSA - European Food Safety Authority Publications

20-11-2018

November 20, 2018: Rochester Man Pleads Guilty to Smuggling Counterfeit Cialis and Viagra into the United States

November 20, 2018: Rochester Man Pleads Guilty to Smuggling Counterfeit Cialis and Viagra into the United States

November 20, 2018: Rochester Man Pleads Guilty to Smuggling Counterfeit Cialis and Viagra into the United States

FDA - U.S. Food and Drug Administration

20-11-2018

Vijf winnaars van energieneutrale sportprojecten kunnen aan de slag

Vijf winnaars van energieneutrale sportprojecten kunnen aan de slag

Op 20 november zijn de vijf winnaars van de Innovation Challenge Energieneutrale Sportaccommodaties, vanuit het programma Sportinnovator, bekendgemaakt. De innovatieve ideeën voor energiebesparing bij sportaccommodaties hebben groen licht gekregen. Ze ontvangen hiervoor steun van het ministerie van Volksgezondheid, Welzijn en Sport om innovatie in de sport te bevorderen. Onderstaande initiatieven krijgen 100.000 euro om het idee in de praktijk door te voeren.

Netherlands - Ministerie van Volksgezondheid, Welzijn en Sport

15-11-2018

Safety and efficacy of Monimax® (monensin sodium and nicarbazin) for chickens for fattening and chickens reared for laying

Safety and efficacy of Monimax® (monensin sodium and nicarbazin) for chickens for fattening and chickens reared for laying

Published on: Wed, 14 Nov 2018 The coccidiostat Monimax® (monensin sodium and nicarbazin) is considered safe for chickens for fattening and chickens reared for laying at the highest use level of 50 mg monensin and 50 mg nicarbazin/kg complete feed. This conclusion is extended to chickens reared for laying. For both active substances, the metabolic pathways in the chicken are similar to those in the turkey and rat. Nicarbazin, when ingested, is rapidly split in its two components dinitrocarbanilide (DNC)...

Europe - EFSA - European Food Safety Authority Publications

8-11-2018

Theme event on big data and medicine

Theme event on big data and medicine

The U.S. Food and Drug Administration, FDA, The European Medicines Agency, EMA, and Novo Nordisk are among the speakers when The Danish Medicines Agency on 20 November 2018 puts focus on big data and medicine under the event heading “From Big Data to Real World Evidence”.

Danish Medicines Agency

29-10-2018

Statement from FDA Commissioner Scott Gottlieb, M.D., on the FDA’s new consideration of labeling for sesame allergies

Statement from FDA Commissioner Scott Gottlieb, M.D., on the FDA’s new consideration of labeling for sesame allergies

Food allergies have touched the lives of most of us. Thousands of Americans experience life-threatening, food-related reactions each year, and an estimated 20 people die from them annually. In some cases, such reactions occur despite a careful reading of packaged food labels by conscientious consumers. To me, that’s unacceptable. The FDA is committed to advancing our efforts to help ensure that Americans have access to the information they need about common allergens in packaged foods.

FDA - U.S. Food and Drug Administration

24-10-2018

G & C Raw, LLC is Expanding Recall to Include All Product Lots Manufactured from February 27, 2018 Through July 20, 2018, Because of Possible Listeria Monocytogenes Health Risk

G & C Raw, LLC is Expanding Recall to Include All Product Lots Manufactured from February 27, 2018 Through July 20, 2018, Because of Possible Listeria Monocytogenes Health Risk

G & C Raw, of Versailles, OH is recalling all products lots manufactured from February 27, 2018 through July 20, 2018, as a precaution because they have the potential to be contaminated with Listeria monocytogenes

FDA - U.S. Food and Drug Administration

4-10-2018

Nederland organiseert wereldwijde conferentie tegen antibioticaresistentie

Nederland organiseert wereldwijde conferentie tegen antibioticaresistentie

Samen met de Wereldgezondheidorganisatie (WHO) zal Nederland in april 2019 een wereldwijde ministeriële conferentie organiseren over de strijd tegen antibioticaresistentie. Dat heeft minister Bruno Bruins (Medische Zorg) bekend gemaakt tijdens de G20-bijeenkomst in Argentinië. Bij deze bijeenkomst maakte Bruins afspraken met zijn collega’s uit de grootste 20 economieën van de wereld over een gezamenlijke aanpak van gezondheidsvraagstukken. Mede door jarenlange inzet van Nederland, staat antibioticaresist...

Netherlands - Ministerie van Volksgezondheid, Welzijn en Sport

21-9-2018

Pending EC decision:  Buvidal, buprenorphine, Opinion date: 20-Sep-2018

Pending EC decision: Buvidal, buprenorphine, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Emgality, galcanezumab, Opinion date: 20-Sep-2018

Pending EC decision: Emgality, galcanezumab, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  RoActemra, tocilizumab, Opinion date: 20-Sep-2018

Pending EC decision: RoActemra, tocilizumab, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Venclyxto, venetoclax, Opinion date: 20-Sep-2018

Pending EC decision: Venclyxto, venetoclax, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Jivi, damoctocog alfa pegol, Opinion date: 20-Sep-2018

Pending EC decision: Jivi, damoctocog alfa pegol, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Gilenya, fingolimod, Opinion date: 20-Sep-2018

Pending EC decision: Gilenya, fingolimod, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Apealea, paclitaxel, Opinion date: 20-Sep-2018

Pending EC decision: Apealea, paclitaxel, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Alunbrig, brigatinib, Opinion date: 20-Sep-2018

Pending EC decision: Alunbrig, brigatinib, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Cabometyx , cabozantinib, Opinion date: 20-Sep-2018

Pending EC decision: Cabometyx , cabozantinib, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Luxturna, voretigene neparvovec, Opinion date: 20-Sep-2018

Pending EC decision: Luxturna, voretigene neparvovec, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Fulphila, pegfilgrastim, Opinion date: 20-Sep-2018

Pending EC decision: Fulphila, pegfilgrastim, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Pelmeg, pegfilgrastim, Opinion date: 20-Sep-2018

Pending EC decision: Pelmeg, pegfilgrastim, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Ziextenzo, pegfilgrastim, Opinion date: 20-Sep-2018

Pending EC decision: Ziextenzo, pegfilgrastim, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Poteligeo, mogamulizumab, Opinion date: 20-Sep-2018

Pending EC decision: Poteligeo, mogamulizumab, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Pending EC decision:  Pifeltro, doravirine, Opinion date: 20-Sep-2018

Pending EC decision: Pifeltro, doravirine, Opinion date: 20-Sep-2018

Europe - EMA - European Medicines Agency

21-9-2018

Outcome of the consultation with Member States, the applicant and EFSA on the pesticide risk assessment for sulfoxaflor in light of confirmatory data

Outcome of the consultation with Member States, the applicant and EFSA on the pesticide risk assessment for sulfoxaflor in light of confirmatory data

Published on: Thu, 20 Sep 2018 00:00:00 +0200 The European Food Safety Authority (EFSA) was asked by the European Commission to provide scientific assistance with respect to the risk assessment for an active substance in light of confirmatory data requested following approval in accordance with Article 6(1) of Directive 91/414/EEC and Article 6(f) of Regulation (EC) No 1107/2009. In this context EFSA's scientific views on the specific points raised during the commenting phase conducted with Member State...

Europe - EFSA - European Food Safety Authority Publications

21-9-2018

Modification of the existing maximum residue level for clothianidin in potatoes

Modification of the existing maximum residue level for clothianidin in potatoes

Published on: Thu, 20 Sep 2018 00:00:00 +0200 In accordance with Article 6 of Regulation (EC) No 396/2005, the applicant Bayer CropScience AG submitted a request to the competent national authority in Germany to modify the existing maximum residue level (MRL) for the active substance clothianidin to accommodate the use on potatoes imported from Canada. The data submitted in support of the request were found to be sufficient to derive a MRL proposal. Adequate analytical methods for enforcement are availa...

Europe - EFSA - European Food Safety Authority Publications

20-9-2018

Pending EC decision:  Xtandi, enzalutamide, Opinion date: 20-Sep-2019

Pending EC decision: Xtandi, enzalutamide, Opinion date: 20-Sep-2019

Europe - EMA - European Medicines Agency

24-12-2018

ACCM meeting statement, Meeting 20, 16 November 2018

ACCM meeting statement, Meeting 20, 16 November 2018

ACCM meeting statement for 16 November 2018 published

Therapeutic Goods Administration - Australia

21-12-2018

Consultation: Fees and charges proposal 2019-20

Consultation: Fees and charges proposal 2019-20

The TGA is seeking comments from interested parties on the proposed changes in fees and charges for 2019-2020. Closing date: 8 February 2018

Therapeutic Goods Administration - Australia

20-12-2018

Namuscla (Lupin Europe GmbH)

Namuscla (Lupin Europe GmbH)

Namuscla (Active substance: Mexiletine) - New authorisation - Commission Decision (2018)9133 of Thu, 20 Dec 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4584

Europe -DG Health and Food Safety

20-12-2018

Bevespi Aerosphere (AstraZeneca AB)

Bevespi Aerosphere (AstraZeneca AB)

Bevespi Aerosphere (Active substance: glycopyrronium bromide / formoterol) - New authorisation - Commission Decision (2018)9127 of Thu, 20 Dec 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4245

Europe -DG Health and Food Safety

18-12-2018


Human medicines European public assessment report (EPAR): Vabomere, meropenem / vaborbactam, Urinary Tract Infections,Bacteremia,Bacterial Infections,Respiratory Tract Infections,Pneumonia,Pneumonia, Ventilator-Associated, Date of authorisation: 20/11/20

Human medicines European public assessment report (EPAR): Vabomere, meropenem / vaborbactam, Urinary Tract Infections,Bacteremia,Bacterial Infections,Respiratory Tract Infections,Pneumonia,Pneumonia, Ventilator-Associated, Date of authorisation: 20/11/20

Human medicines European public assessment report (EPAR): Vabomere, meropenem / vaborbactam, Urinary Tract Infections,Bacteremia,Bacterial Infections,Respiratory Tract Infections,Pneumonia,Pneumonia, Ventilator-Associated, Date of authorisation: 20/11/2018, Status: Authorised

Europe - EMA - European Medicines Agency

18-12-2018


Human medicines European public assessment report (EPAR): Buvidal, buprenorphine, Opioid-Related Disorders, Date of authorisation: 20/11/2018, Status: Authorised

Human medicines European public assessment report (EPAR): Buvidal, buprenorphine, Opioid-Related Disorders, Date of authorisation: 20/11/2018, Status: Authorised

Human medicines European public assessment report (EPAR): Buvidal, buprenorphine, Opioid-Related Disorders, Date of authorisation: 20/11/2018, Status: Authorised

Europe - EMA - European Medicines Agency

12-12-2018


Human medicines European public assessment report (EPAR): Exondys, eteplirsen, Muscular Dystrophy, Duchenne, Date of refusal: 20/09/2018, Status: Refused

Human medicines European public assessment report (EPAR): Exondys, eteplirsen, Muscular Dystrophy, Duchenne, Date of refusal: 20/09/2018, Status: Refused

Human medicines European public assessment report (EPAR): Exondys, eteplirsen, Muscular Dystrophy, Duchenne, Date of refusal: 20/09/2018, Status: Refused

Europe - EMA - European Medicines Agency

5-12-2018

TGA presentation: Webinar: Advertising therapeutic goods in 2019: The Code basics – 20 November

TGA presentation: Webinar: Advertising therapeutic goods in 2019: The Code basics – 20 November

The slides from TGA's webinar on Advertising Code Basics have been published

Therapeutic Goods Administration - Australia

28-11-2018

PHEBURANE (Eurocept International BV)

PHEBURANE (Eurocept International BV)

PHEBURANE (Active substance: Sodium Phenylbutyrate) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)8043 of Wed, 28 Nov 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2500/T/20

Europe -DG Health and Food Safety

26-11-2018

Data show that nearly 20% of current 510(k)s are cleared based on a predicate that’s more than 10 years old. That doesn’t mean the products are unsafe. But it does mean that some devices may not be continually improving, which is the hallmark of health te

Data show that nearly 20% of current 510(k)s are cleared based on a predicate that’s more than 10 years old. That doesn’t mean the products are unsafe. But it does mean that some devices may not be continually improving, which is the hallmark of health te

Data show that nearly 20% of current 510(k)s are cleared based on a predicate that’s more than 10 years old. That doesn’t mean the products are unsafe. But it does mean that some devices may not be continually improving, which is the hallmark of health technologies.

FDA - U.S. Food and Drug Administration

16-11-2018

Latuda (Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. S.p.A.)

Latuda (Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. S.p.A.)

Latuda (Active substance: lurasidone) - Centralised - Renewal - Commission Decision (2018)7674 of Fri, 16 Nov 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2713/R/20

Europe -DG Health and Food Safety

14-11-2018

Jinarc (Otsuka Pharmaceutical Netherlands B.V.)

Jinarc (Otsuka Pharmaceutical Netherlands B.V.)

Jinarc (Active substance: tolvaptan) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)7604 of Wed, 14 Nov 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2788/T/20

Europe -DG Health and Food Safety

1-10-2018

EU/3/05/328 (Celgene Europe B.V.)

EU/3/05/328 (Celgene Europe B.V.)

EU/3/05/328 (Active substance: (E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23- tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone) - Transfer of orphan designation - Commission Decision (2018)6434 of Mon, 01 Oct 2018 European Medicines Agency (EMA) procedure number: EMA/OD/056/05/T/03

Europe -DG Health and Food Safety

1-10-2018

EU/3/05/279 (Celgene Europe B.V.)

EU/3/05/279 (Celgene Europe B.V.)

EU/3/05/279 (Active substance: (E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23- tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone) - Transfer of orphan designation - Commission Decision (2018)6433 of Mon, 01 Oct 2018 European Medicines Agency (EMA) procedure number: EMA/OD/001/05/T/03

Europe -DG Health and Food Safety

17-9-2018

Agenda:  Agenda - CHMP agenda of the 17-20 September 2018 meeting

Agenda: Agenda - CHMP agenda of the 17-20 September 2018 meeting

Europe - EMA - European Medicines Agency