EXEMESTANE HELM

Main information

  • Trade name:
  • EXEMESTANE HELM
  • Dosage:
  • 25 Milligram
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EXEMESTANE HELM
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1597/001/001
  • Authorization date:
  • 11-02-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ExemestaneHelm25mgCoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcoatedtabletcontains25mgexemestane.

Excipients:

Eachcoatedtabletcontains31.63mgofSucrose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Coatedtablet

Whitetooffwhite,round,biconvex,coatedtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

ExemestanHELMisindicatedfortheadjuvanttreatmentofpostmenopausalwomenwithoestrogenreceptorpositive

invasiveearlybreastcancer,following2–3yearsofinitialadjuvanttamoxifentherapy.

ExemestanHELMisindicatedforthetreatmentofadvancedbreastcancerinwomenwithnaturalorinduced

postmenopausalstatuswhosediseasehasprogressedfollowinganti-oestrogentherapy.Efficacyhasnotbeen

demonstratedinpatientswithoestrogenreceptornegativestatus.

4.2Posologyandmethodofadministration

Adultandelderlypatients

TherecommendeddoseofExemestanHELMisone25mgtablettobetakenoncedaily,afterameal.

Inpatientswithearlybreastcancer,treatmentwithExemestanHELMshouldcontinueuntilcompletionoffiveyearsof

combinedsequentialadjuvanthormonaltherapy(tamoxifenfollowedbyExemestanHELM),orearlieriftumour

relapseoccurs.

Inpatientswithadvancedbreastcancer,treatmentwithExemestanHELMshouldcontinueuntiltumourprogressionis

evident.

Hepaticorrenalimpairment

Nodoseadjustmentsarerequiredforpatientswithhepaticorrenalimpairment(seesection5.2).

Paediatricpopulation

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 1

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients

Pre-menopausalwomen

Pregnancy

Lactation

4.4Specialwarningsandprecautionsforuse

ExemestanHELMmustnotbeadministeredtowomenwithpre-menopausalendocrinestatus.Therefore,whenever

clinicallyappropriate,thepost-menopausalstatusshouldbeascertainedbyassessmentofLH,FSHandoestradiol

levels.

ExemestanHELMshouldbeusedwithcautioninpatientswithhepaticorrenalimpairment.

ExemestanHELMisapotentoestrogenloweringagent,andareductioninbonemineraldensityandanincreased

fractureratehasbeenobservedfollowingadministration(seesection5.1).DuringadjuvanttreatmentwithExemestan

HELM,womenwithosteoporosisoratriskofosteoporosisshouldhavetheirbonemineraldensityformallyassessed

bybonedensitometryatthecommencementoftreatment.Althoughadequatedatatoshowtheeffectsoftherapyinthe

treatmentofthebonemineraldensitylosscausedbyExemestanHELMarenotavailable,treatmentforosteoporosis

shouldbeinitiatedinatriskpatients.PatientstreatedwithExemestanHELMshouldbecarefullymonitored.

ExemestanHELMtabletscontainsucrose.Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-

galactosemalabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

ExemestanHELMtabletscontainmannitolwhichmayhaveamildlaxativeeffect.

Athletesmustbeawarethatthismedicinemaycauseapositivereactionto‘anti-doping’tests.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

InvitroevidenceshowedthatthemedicinalproductismetabolisedthroughcytochromeP450(CYP)3A4and

aldoketoreductases(seesection5.2)anddoesnotinhibitanyofthemajorCYPisoenzymes.Inaclinical

pharmacokineticstudy,thespecificinhibitionofCYP3A4byketoconazoleshowednosignificanteffectsonthe

pharmacokineticsofexemestane.

Inaninteractionstudywithrifampicin,apotentCYP450inducer,atadoseof600mgdailyandasingledoseof

exemestane25mg,theAUCofexemestanewasreducedby54%andC

by41%.Sincetheclinicalrelevanceofthis

interactionhasnotbeenevaluated,theco-administrationofdrugs,suchasrifampicin,anticonvulsants(e.g.phenytoin

andcarbamazepine)andherbalpreparationscontaininghypericumperforatum(StJohn'sWort)knowntoinduce

CYP3A4mayreducetheefficacyofExemestanHELM.

ExemestanHELMshouldbeusedcautiouslywithmedicinalproductsthataremetabolisedviaCYP3A4andhavea

narrowtherapeuticwindow.ThereisnoclinicalexperienceoftheconcomitantuseofExemestanHELMwithother

anticancermedicinalproducts.

ExemestanHELMshouldnotbeco-administeredwithoestrogen-containingmedicinesasthesewouldnegateits

pharmacologicalaction.

4.6Fertility,pregnancyandlactation

Forexemestanenoclinicaldataonexposedpregnanciesareavailable.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).ExemestanHELMisthereforecontraindicatedinpregnancy(seesection4.3).

Itisnotknownwhetherexemestaneisexcretedintohumanmilk.ExemestanHELMmustnotbeadministeredto

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 2

4.7Effectsonabilitytodriveandusemachines

ExemestanHELMhasminorormoderateinfluenceontheabilitytodriveandusemachines.Drowsiness,somnolence,

astheniaanddizzinesshavebeenreportedwiththeuseofthemedicinalproduct.Patientsshouldbeadvisedthat,if

theseeventsoccur,theirphysicaland/ormentalabilitiesrequiredforoperatingmachineryordrivingacarmaybe

impaired.

4.8Undesirableeffects

ExemestanHELMwasgenerallywelltoleratedacrossallclinicalstudiesconductedwithexemestaneatastandarddose

of25mg/day,andundesirableeffectswereusuallymildtomoderate.

Thewithdrawalrateduetoadverseeventswas7,4%inpatientswithearlybreastcancerreceivingadjuvanttreatment

withexemestanefollowinginitialadjuvanttamoxifentherapy.Themostcommonlyreportedadversereactionswerehot

flushes(22%),arthralgia(18%)andfatique(16%).

Thewithdrawalrateduetoadverseeventswas2,8%intheoverallpatientpopulationwithadvancedbreastcancer.The

mostcommonlyreportedadversereactionswerehotflushes(14%)andnausea(12%).

Mostadversereactionscanbeattributedtothenormalpharmacologicalconsequencesofoestrogendeprivation(e.g.hot

flushes).

Theevaluationofadversereactionsisbasedonthefollowingdefinitionoffrequency:

Verycommon( ≥1/10)

Common( ≥1/100to<1/10)

Uncommon( ≥1/1,000to<1/100)

Rare( ≥1/10,000to<1/1,000)

Veryrare(<1/10,000)

Notknown(cannotbeestimatedfromtheavailabledata)

Bloodandlymphaticsystemdisorders

Verycommon: Anoccasionaldecreaseinlymphocyteshasbeenobservedinapproximately20%ofthepatients

receivingexemestane,particularyinpatientsreceivingexemestanewithpre-existinglymphopenia;

however,meanlymphocytevaluesinthesepatientsdidnotchangesignificantlyovertimeandno

correspondingincreaseinviralinfectionswasobserved.Theseeffectshavenotbeenobservedin

patientstreatedinearlybreastcancerstudies.

Rare: Thrombocytopeniaandleucopenia(inpatientswithadvancedbreastcancer).

Nervoussystemdisorders

Verycommon: Headache

Common: Dizziness,carpaltunnelsyndrome

Uncommon: Somnolence

Gastrointestinaldisorders

VeryCommon: Nausea

Common: Abdominalpain,vomiting,constipation,dyspepsia,diarrhoea

Skinandsubcutaneoustissuedisorders

Verycommon: Increasedsweating

Common: Rash,alopecia

Musculoskeletalandconnectivetissuedisorders

Verycommon: Jointandmusculoskeletalpain(includes:arthralgia,andlessfrequentlypaininlimbs,

osteoarthritis,backpain,arthritis,myalgiaandjointstiffness)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 3

Metabolismandnutritiondisorders

Common: Anorexia

Vasculardisorders

Verycommon: Hotflushes

Generaldisordersandadministrationsiteconditions

Verycommon: Fatigue

Common: Pain,peripheraloedema

Uncommon: Asthenia

Hepatobiliarydisorders

Notknown: Elevationofliverfunctiontestparametersincludingenzymes,bilirubinandalkalinephosphatase

Psychiatricdisorders

Verycommon: Insomnia

Common: Depression

Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsandillnessesintheearlybreastcancerstudy

(IES),irrespectiveofcausality,reportedinpatientsreceivingtrialtherapyandupto30daysaftercessationoftrial

therapy.

IntheIESstudy,thefrequencyofischaemiccardiaceventsintheexemestaneandtamoxifentreatmentarmswas4.5%

versus4.2%,respectively.Nosignificantdifferencewasnotedforanyindividualcardiovasculareventincluding

hypertension(9.9%versus8.4%),myocardialinfarction(0.6%versus0.2%)andcardiacfailure(1.1%versus0.7%).

IntheIESstudy,gastriculcerwasobservedatahigherfrequencyintheexemestanearmcomparedtotamoxifen(0.7%

versus<0.1%).Themajorityofpatientsonexemestanewithgastriculcerreceivedconcomitanttreatmentwithnon-

steroidalanti-inflammatoryagentsand/orhadapriorhistory.

4.9Overdose

Nocaseofoverdosehasbeenreported.

Clinicaltrialshavebeenconductedwithexemestanegivenupto800mginasingledosetohealthyfemalevolunteers

andupto600mgdailytopostmenopausalwomenwithadvancedbreastcancer;thesedosageswerewelltolerated.The

Adverseeventsandillnesses Exemestane(N=2,249) Tamoxifen(N=2,279)

Hotflushes 491(21.8%) 457(20.1%)

Fatique 367(16.3%) 344(15.1%)

Headache 305(13.6%) 255(11.2%)

Insomnia 290(12.9%) 204(9.0%)

Sweatingincreased 270(12.0%) 242(10.6%)

Gynaecological 235(10.5%) 340(14.9%)

Dizziness 224(10.0%) 200(8.8%)

Nausea 200(8.9%) 208(9.1%)

Osteoporosis 116(5.2%) 66(2.9%)

Vaginalhaemorrhage 90(4.0%) 121(5.3%)

Otherprimarycancer 84(3.6%) 125(5.3%)

Vomiting 50(2.2%) 54(2.4%)

Visualdisturbance 45(2.0%) 53(2.3%)

Thromboembolism 16(0.7%) 42(1.8%)

Osteoporoticfracture 14(0.6%) 12(0.5%)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 4

Inratsanddogs,lethalitywasobservedaftersingleoraldosesequivalentrespectivelyto2000and4000timesthe

recommendedhumandoseonamg/m 2

basis.

Thereisnospecificantidotetooverdosageandtreatmentmustbesymptomatic.Generalsupportivecare,including

frequentmonitoringofvitalsignsandcloseobservationofthepatient,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Hormoneantagonistandrelatedagents,enzymeinhibitors,ATCcode:L02BG06

Exemestaneisanirreversible,steroidalaromataseinhibitor,structurallyrelatedtothenaturalsubstrate

androstenedione.Inpostmenopausalwomen,oestrogensareproducedprimarilyfromtheconversionofandrogensinto

oestrogensthroughthearomataseenzymeinperipheraltissues.Oestrogendeprivationthrougharomataseinhibitionis

aneffectiveandselectivetreatmentforhormonedependentbreastcancerinpostmenopausalwomen.In

postmenopausalwomen,oralexemestanesignificantlyloweredserumoestrogenconcentrationsstartingfroma5mg

dose,reachingmaximalsuppression(>90%)withadoseof10-25mg.Inpostmenopausalbreastcancerpatientstreated

withthe25mgdailydose,wholebodyaromatisationwasreducedby98%.

Exemestanedoesnotpossessanyprogestogenicoroestrogenicactivity.Aslightandrogenicactivity,probablydueto

the17-hydroderivative,hasbeenobservedmainlyathighdoses.Inmultipledailydosestrials,exemestanehadno

detectableeffectsonadrenalbiosynthesisofcortisoloraldosterone,measuredbeforeorafterACTHchallenge,thus

demonstratingitsselectivitywithregardtotheotherenzymesinvolvedinthesteroidogenicpathway.

Glucocorticoidormineralocorticoidreplacementsarethereforenotneeded.Anondose-dependentslightincreasein

serumLHandFSHlevelshasbeenobservedevenatlowdoses:thiseffectis,however,expectedforthe

pharmacologicalclassandisprobablytheresultoffeedbackatthepituitarylevelduetothereductioninoestrogen

levelsthatstimulatethepituitarysecretionofgonadotropinsalsoinpostmenopausalwomen.

AdjuvantTreatmentofEarlyBreastCancer

Inamulticentre,randomised,double-blindstudy,conductedin4,724postmenopausalpatientswithoestrogen-receptor-

positiveorunknownprimarybreastcancer,patientswhohadremaineddisease-freeafterreceivingadjuvanttamoxifen

therapyfor2to3yearswererandomisedtoreceive2to3yearsofexemestane(25mg/day)ortamoxifen(20or

30mg/day)tocompleteatotalof5yearsofhormonaltherapy.

Afteramediandurationoftherapyofabout30monthsandamedianfollow-upofabout52months,resultsshowedthat

sequentialtreatmentwithexemestanafter2to3yearsofadjuvanttamoxifentherapywasassociatedwithaclinically

andstatisticallysignificantimprovementindisease-freesurvival(DFS)comparedwithcontinuationoftamoxifen

therapy.Analysisshowedthatintheobservedstudyperiodexemestanereducedtheriskofbreastcancerrecurrenceby

24%comparedwithtamoxifen(hazardratio0.76;p=0.00015).Thebeneficialeffectofexemestaneovertamoxifen

withrespecttoDFSwasapparentregardlessofnodalstatusorpriorchemotherapy.

Exemestanealsosignificantlyreducedtheriskofcontralateralbreastcancer(hazardratio0.57,p=0.04158).Inthe

wholestudypopulation,atrendforimprovedoverallsurvivalwasobservedforexemestane(222deaths)comparedto

tamoxifen(262deaths)withahazardratio0.85(log-ranktest:p=0.07362),representinga15%reductionintheriskof

deathinfavourofexemestane.Astatisticallysignificant23%reductionintheriskofdying(hazardratioforoverall

survival0.77;Waldchisquaretest:p=0.0069)wasobservedforexemestanecomparedtotamoxifenwhenadjusting

fortheprespecifiedprognosticfactors(i.e.,ERstatus,nodalstatus,priorchemotherapy,useofHRTanduseof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 5

Mainefficacyresultsinallpatients(intentiontotreatpopulation)andoestrogenreceptorpositivepatientsare

summarisedinthetablebelow:

Log-ranktest;ER+patients=oestrogenreceptorpositivepatients

Disease-freesurvivalisdefinedasthefirstoccurrenceoflocalordistantrecurrence,contralateralbreastcancer,or

deathfromanycause;

Breastcancerfreesurvivalisdefinedasthefirstoccurrenceoflocalordistantrecurrence,contralateralbreastcancer

orbreastcancerdeath;

Distantrecurrencefreesurvivalisdefinedasthefirstoccurrenceofdistantrecurrenceorbreastcancerdeath;

Overallsurvivalisdefinedasoccurrenceofdeathfromanycause.

Intheadditionalanalysisforthesubsetofpatientswithoestrogenreceptorpositiveorunknownstatus,theunadjusted

overallsurvivalhazardratiowas0.83(log-ranktest:p=0.04250),representingaclinicallyandstatisticallysignificant

17%reductionintheriskofdying.

Resultsfromabonesubstudydemonstratedthatwomentreatedwithexemestanefollowing2to3yearsoftamoxifen

treatmentexperiencedmoderatereductioninbonemineraldensity.Intheoverallstudy,thetreatmentemergentfracture

incidenceevaluatedduringthe30monthstreatmentperiodwashigherinpatientstreatedwithexemestanecompared

Endpoint Exemstane Tamoxifen HazardRatio p-value

Population Events/N(%) Events/N(%) (95%CI)

Disease-free

survival a

Allpatients 354/2,352

(15.1%) 453/2,372

(19.1%) 0.76(0.67-0.88) 0.00015

ER+

patients 289/2,033

(14.3%) 370/2,021

(18.3%) 0.75(0.65-0.88) 0.00030

Contralateral

breastcancer

Allpatients 20/2,352(0.9%) 33/2,372(1.5%) 0.57(0.33-0.99) 0.04158

ER+

patients 18/2,023(0.9%) 33/2,021(1.6%) 0.54(0.30-0.95) 0.03048

Breastcancerfree

survival b

Allpatients 289/2,352

(12.3%) 373/2,021

(15.7%) 0.76(0.65-0.89) 0.00041

ER+

patients 232/2,023

(11.5%) 305/2,021

(15.1%) 0.73(0.62-0.87) 0.00038

Distantrecurrence

freesurvival c

Allpatients 248/2,352

(10.5%) 297/2,372

(12.5%) 0.83(0.70-0.98) 0.02621

ER+

patients 194/2,023(9.6%) 242/2,021

(12.0%) 0.78(0.65-0.95) 0.01123

Overallsurvival d

Allpatients 222/2,352(9.4%) 262/2,372

(11.0%) 0.85(0.71-1.02) 0.07362

ER+

patients 178/2,023(8.8%) 211/2,021

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 6

Resultsfromanendometrialsubstudyindicatethatafter2yearsoftreatmenttherewasamedian33%reductionof

endometrialthicknessintheexemestane-treatedpatientscomparedwithnonotablevariationinthetamoxifen-treated

patients.Endometrialthickening,reportedatthestartofstudytreatment,wasreversedtonormal(<5mm)for54%of

patientstreatedwithexemestane.

TreatmentofAdvancedBreastCancer

Inarandomisedpeerreviewedcontrolledclinicaltrial,exemestaneatthedailydoseof25mghasdemonstrated

statisticallysignificantprolongationofsurvival,TimetoProgression(TTP),TimetoTreatmentFailure(TTF)as

comparedtoastandardhormonaltreatmentwithmegestrolacetateinpostmenopausalpatientswithadvancedbreast

cancerthathadprogressedfollowing,orduring,treatmentwithtamoxifeneitherasadjuvanttherapyorasfirst-line

treatmentforadvanceddisease.

5.2Pharmacokineticproperties

Absorption

AfteroraladministrationofExemestanHELMtablets,exemestaneisabsorbedrapidly.Thefractionofthedose

absorbedfromthegastrointestinaltractishigh.Theabsolutebioavailabilityinhumansisunknown,althoughitis

anticipatedtobelimitedbyanextensivefirstpasseffect.Asimilareffectresultedinanabsolutebioavailabilityinrats

anddogsof5%.Afterasingledoseof25mg,maximumplasmalevelsof18ng/mlarereachedafter2hours.

Concomitantintakewithfoodincreasesthebioavailabilityby40%.

Distribution

Thevolumeofdistributionofexemestane,notcorrectedfortheoralbioavailability,isapprox.20,000l.Thekineticis

linearandtheterminaleliminationhalf-lifeis24h.Bindingtoplasmaproteinsis90%andisconcentration

independent.Exemestaneanditsmetabolitesdonotbindtoredbloodcells.

Exemestanedoesnotaccumulateinanunexpectedwayafterrepeateddosing.

Metabolismandexcretion

Exemestaneismetabolisedbyoxidationofthemethylenemoietyonthe6positionbyCYP3A4isoenzymeand/or

reductionofthe17-ketogroupbyaldoketoreductasefollowedbyconjugation.Theclearanceofexemestaneisapprox.

500l/h,notcorrectedfortheoralbioavailability.Themetabolitesareinactiveortheinhibitionofaromataseislessthan

theparentcompound.

Theamountexcretedunchangedinurineis1%ofthedose.Inurineandfaecesequalamounts(40%)of 14

C-labeled

exemestanewereeliminatedwithinaweek.

Specialpopulations

Age:Nosignificantcorrelationbetweenthesystemicexposureofexemestaneandtheageofsubjectshasbeen

observed.

Renalinsufficiency

Inpatientswithsevererenalimpairment(Clcr<30ml/min)thesystemicexposuretoexemestanewas2timeshigher

comparedwithhealthyvolunteers.

Giventhesafetyprofileofexemestane,nodoseadjustmentisconsideredtobenecessary.

Hepaticinsufficiency

Inpatientswithmoderateorseverehepaticimpairmenttheexposureofexemestaneis2-3foldhighercomparedwith

healthyvolunteers.Giventhesafetyprofileofexemestane,nodoseadjustmentisconsideredtobenecessary.

5.3Preclinicalsafetydata

Toxicologicalstudies

Findingsintherepeatdosetoxicologystudiesinratanddogweregenerallyattributabletothepharmacologicalactivity

ofexemestane,suchaseffectsonreproductiveandaccessoryorgans.Othertoxicologicaleffects(onliver,kidneyor

centralnervoussystem)wereobservedonlyatexposuresconsideredsufficientlyinexcessofthemaximumhuman

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 7

Mutagenicity

Exemestanewasnotgenotoxicinbacteria(Amestest),inV79Chinesehamstercells,inrathepatocytesorinthemouse

micronucleusassay.Althoughexemestanewasclastogenicinlymphocytesinvitro,itwasnotclastogenicintwoinvivo

studies.

Reproductivetoxicology

Exemestanewasembryotoxicinratsandrabbitsatsystemicexposurelevelssimilartothoseobtainedinhumansat

25mg/day.Therewasnoevidenceofteratogenicity.

Carcinogenicity

Inatwo-yearcarcinogenicitystudyinfemalerats,notreatment-relatedtumourswereobserved.Inmaleratsthestudy

wasterminatedonweek92,becauseofearlydeathbychronicnephropathy.Inatwo-yearcarcinogenicitystudyin

mice,anincreaseintheincidenceofhepaticneoplasmsinbothgenderswasobservedattheintermediateandhigh

doses(150and450mg/kg/day).Thisfindingisconsideredtoberelatedtotheinductionofhepaticmicrosomal

enzymes,aneffectobservedinmicebutnotinclinicalstudies.Anincreaseintheincidenceofrenaltubularadenomas

wasalsonotedinmalemiceatthehighdose(450mg/kg/day).Thischangeisconsideredtobespecies-andgender-

specificandoccurredatadosewhichrepresents63-foldgreaterexposurethanoccursatthehumantherapeuticdose.

Noneoftheseobservedeffectsisconsideredtobeclinicallyrelevanttothetreatmentofpatientswithexemestane

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Crospovidone

Polysorbate80

Mannitol(E421)

Colloidalanhydroussilica

Magnesiumstearate

Sucrose

Spray-driedAcacia

Purifiedtalc

Titaniumdioxide(E171)

Opaglos(Dehydratedethanol,Shellac,BeeswaxWhite,CarnaubaWaxYellow)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

30months

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialtemperaturestorageconditions.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 8

6.5Natureandcontentsofcontainer

Aluminium-PVDC/PVC-PVDCblisterpacks

Packsizes:10,15,30,90,105,100,20,120

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements

7MARKETINGAUTHORISATIONHOLDER

HelmPharmaceuticalsGmbH

Nordkanalstrasse28

20097Hamburg

Germany

8MARKETINGAUTHORISATIONNUMBER

PA1597/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11thFebruary2011

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 25/08/2011 CRN 2100271 page number: 9