ESTRADIOL

Main information

  • Trade name:
  • ESTRADIOL Implant 25 Milligram
  • Dosage:
  • 25 Milligram
  • Pharmaceutical form:
  • Implant
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESTRADIOL Implant 25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0061/015/001
  • Authorization date:
  • 01-04-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EstradiolImplant25mg

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachimplantcontains25mgestradiol(ashemihydrate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Implant

Whitetopalebrownopaqueortranslucentcylinder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)forestrogendeficiencysymptomsinpostmenopausalwomen.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

4.2Posologyandmethodofadministration

Frequencyofreplacementdependsonthedurationofactivityoftheimplantsadministeredandtheseverityofthe

symptoms.Patientsrequireafurtherimplantwhensymptomsreturn,usuallyevery4to8months.

Estradiolimplantsshouldbeinsertedsubcutaneouslyunderlocalanestheticeitherbymeansofatrocarandcannulaor

inthewoundatthetimeoflaparotomy,intoanareawherethereislittlemovement,suchastheupperouterpartofthe

buttockorthelowerabdominalwall.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsoSection4.4)shouldbeused.

BecauseofthesustainedabsorptionofEstradiol,theendometriumofpost-menopausalorovariectomizedwomenis

liabletoprogressivehypertrophy.Therefore,inwomenwithanintactuterus,additionaladministrationofa

progestogenisessential,for12–14dayseverymonth,topreventendometrialhyperplasia.Literaturedatasuggeststhat

co-administrationofprogestogenswithEstradiolimplantsdoespreventendometrialhyperplasia.Onlyprogestogens

approvedforadditiontoestrogentreatmentarerecommended.Unlessthereisapreviousdiagnosisofendometriosis,it

isnotrecommendedtoaddaprogestogeninhysterectomizedwomen.

Whenthepatientnolongerrequiresorseeksre-implantationwithEstradiolimplants,itisrecommendedthat,inthose

womenwithanintactuterus,cyclicaladministrationofanoralprogestogenshouldbecontinueduntilthereisa

cessationofthewithdrawalbleeding,inordertothepreventthepossibilityofcontinuedendometrialstimulation.

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SincetheimplantsconsistentirelyofEstradiolwithoutanyauxiliaryingredients,theyarebiodegradableandno

removalprocedureisrequired.Intherareeventthatremovaloftheimplantshouldbenecessary,theimplantmaybe

locatedbypalpationorifnotsuccessfulbyMagneticResonanceImagingtechnique.Thistechniquecanidentifythe

implantbyitssizeandstructureandtheimplantcanexactlybelocalizedbyinsertionofalocalizerwirewiththetip

endingattheimplant.Afterlocalization,theimplantcanberemovedafterasmallincisionunderlocalanesthetic.

4.3Contraindications

Known,pastorsuspectedbreastcancer.

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer).

Undiagnosedgenitalbleeding

Untreatedendometrialhyperplasia

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism).

Activeorrecentarterialthromboembolicdisease(egangina,myocardialinfarction).

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal.

KnownhypersensitivitytoEstradiol.

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindications(section4.3)and

warningsforuse(section4.4).Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnature

adaptedtotheindividualwoman.Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheir

doctorornurse(see“Breastcancerbelow).Investigations,includingmammography,shouldbecarriedoutin

accordancewithcurrentlyacceptedscreeningpractices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithEstradiolimplantsinparticular:

Leiomyoma(uterinefibroids)orendometriosis

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow).

Riskfactorsforestrogendependenttumours,e.g.1 st

degreehereditaryforbreastcancer.

Hypertension.

Liverdisorders(e.g.liveradenoma).

Diabetesmellituswithorwithoutvascularinvolvement.

Cholelithiasis.

Migraineor(severe)headache.

Systemiclupuserythematosis.

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy.

Asthma.

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Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenestrogenareadministeredaloneforprolonged

periods(seeSection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-hysterectomizedwomen

greatlyreducestherisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Unopposedestrogenstimulationmayleadtopre-malignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestogenstoestrogenreplacementshouldbeconsideredinwomenwho

haveundergonehysterectomybecauseofendometriosis,iftheyareknowtohaveresidualendometriosis.

Breastcancer

Arandomisedplacebo-controlledtrial,theWomen’sHealthInitiativestudy(WHI),andepidemiologicalstudies,

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

estrogens,estrogen-progestogencombinationsortiboloneforHRTforseveralyears(seeSection4.8).ForallHRT,an

excessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturnstobaseline

withinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineestrogen(CEE)orEstradiol(E

)wasgreater

whenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.IntheWHIstudy,thecontinuous

combinedconjugatedequineestrogenandmedroxyprogesteroneacetate(CEE+MPA)productusedwasassociated

withbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocallymphnodemetastasescomparedto

placebo.

HRT,especiallyestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimages,whichmay

adverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosis

orpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfounda2-3foldhigherriskfor

userscomparedwithnon-users.Fornon-usersitisestimatedthatthenumberofcasesofVTEthatwilloccurovera5

yearperiodisabout3per1000womenaged50-59yearsand8per1000womenaged60-69years.Itisestimatedthat

inhealthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5yearperiodwillbe

between2and6(bestestimate=4)per1000womenaged50-59yearsandbetween5and15(bestestimate=9)per

1000womenaged60-69years.

TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistoryandsevereobesity(BodyMass

Index>30kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricose

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PatientswithahistoryofVTEorknownthrombophillicstateshaveanincreasedriskofVTE.HRTmayaddtothis

risk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbeinvestigated

inordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilicfactorshasbeenmade

oranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedascontraindicated.Thosewomen

alreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.Asin

allpostoperativepatientsscrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTEfollowing

surgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalororthopaedic

surgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT,ifpossible.Treatmentshould

notberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapythedrugshouldbediscontinuedand/oradequateanticoagulanttreatment

shouldbegiven.Patientsshouldbetoldtocontacttheirdoctorsimmediatelywhentheyareawareofapotential

thromboembolicsymptom(egpainfulswellingofaleg,suddenpaininthechest,dyspnea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

estrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERSi.e.Heartand

Estrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyear

ofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomisedcontrolledtrials

examiningeffectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthesefindingsalsoextend

tootherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedestrogenandMPA.Forwomenwhodonotuse

HRT,itisestimatedthatthenumberofcasesofstrokethatwilloccuroverafiveyearperiodisabout3per1000

womenaged50-59yearsand11per1000womenaged60-69years.Itisestimatedthatforwomenwhouseconjugated

estrogenandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000

usersaged50-59yearsandbetween1and9(bestestimate=4)per1000usersaged60-69years.Itisunknown

whethertheincreasedriskalsoextendstootherHRTproducts.

Ovariancancer

Long-term(atleast5-10years)useofestrogen-onlyHRTproductsinhysterectomisedwomenhasbeenassociatedwith

anincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseofcombined

HRTconfersadifferentthanestrogen-onlyproducts.

Otherconditions

Estrogenmaycausefluidretentionandthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevelof

circulatingactiveingredientsinEstradiolimplantsisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogenreplacementorhormone

replacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeen

reportedwithestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,asmeasured

byprotein-boundiodine(PBI),T4levels(bycolumnorbyradio-immunoassay)orT3levels(byradio-immunoassay).

T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsareunaltered.Other

bindingproteinsmaybeelevatedinserum,i.e.corticoidbindingglobulin(CBG),sex-hormone-bindingglobulin

(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.Freeorbiologicalactive

hormoneconcentrationsareunchanged.Otherplasmaproteinsmaybeincreased(angiotensinogen/reninsubstrate,

alpha-I-antitrysin,ceruloplasmin).

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increasedriskofprobabledementiainwomenwhostartusingcontinuouscombineCEEandMPAaftertheageof65.

Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRTproducts.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

SinceEstradiolimplantsareadministeredparentally,thefirst-passeffectintheliverisavoidedand,thus,parentally

administeredestrogensmightbelessaffectedthanoralhormonesbyenzymeinducers.Themetabolismofestrogensin

generalmaybeincreasedbyconcomitantuseofsubstancesknowntoinducedrug-metabolisingenzymes,specifically

cytochromeP450enzymes,suchasanticonvulsants(e.g.Phenobarbital,phenytonin,carbamezapine)andanti-infectives

(e.g.rifampicin,ritabutin,nevirapine,efavirenz).

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.HerbalpreparationcontainingStJohn’swort(HyperticumPerforatum)may

inducethemetabolismofestrogens.

Clinically,anincreasedmetabolismofestrogensandprogestagensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

4.6Pregnancyandlactation

Notapplicable,becauseestradiolimplantsareonlyindicatedinwomenwithoutaUterus.

4.7Effectsonabilitytodriveandusemachines

AsfarasknownEstradiolimplantshavenoeffectonalertnessorconcentration.

4.8Undesirableeffects

NorecentclinicaltrialshavebeenconductedwithEstradiolimplantsthatwouldallowareliableestimationofthe

percentageofthepatientsexpectedtoexperienceadversereactions.Fromliteratureandfrommonitoringduring

marketusetheprevalenceappearstolessthan1%.Thefollowingundesirableeffectshavebeenreportedinassociation

withestrogen-progestogentreatment.

Breast: Tenderness,pain,swelling,secretion.

General: Fluidretention,weightgain.

Skin: Transienterythema,chloasma,rash,vascularpurpura

CentralNervousSystem: Headache,migraine,fatigue,nervousnessandchangesinmood,probabledementia(see

Section4.4).

Digestivetractandliver: Nausea,bloating,cholelithiasis,cholestaticicterus,changesinserumliverenzyme

levels.

Urogenitalarea: Aggravationofendometriosis,

Cardiovascularsystem: Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonary

embolism,ismorefrequentamongHRTusersthanamongnon-users.Forfurther

informationseeSection4.3and4.4

Myocardialinfarctionandstroke

Eyes:discomfortwhencontactlensesareused

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below).

Withimplants,occasionallysubdermalhematomamayoccurattheimplantationsite.

BreastCancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTusein

currentorrecentHRTusers.

Forestrogen-onlyHRT,estimatesofrelativerisk(RR)fromareanalysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenStudy

(MWS)aresimilarat1.35(95%CI:1.21–1.49)and1.30(95%CI:1.21–1.40),respectively.

Forestrogen-progestogencombinedHRT,severalepidemiologicalstudieshavereportedandoverallhigherriskfor

breastcanerthanwithestrogen’salone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofestrogen-progestogencombinedHRTwas

associatedwithahigherriskofbreastcancer(RR=2.00,95%CI:1.88–2.12)thanuseofestrogensalone(RR=1.30,

95%CI:1.21–1.40)oruseoftibolone(RR=1.45;95%CI:1.25–1.68)

TheWHItrialreportedariskestimateof1.24(95%CI:1.01–1.54)after5.6yearsofestrogen-progestogencombined

HRT(CEE+MPA)inalluserscomparedwithplacebo.TheabsoluteriskscalculatedfromtheMWSandtheWHItrial

arepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweentheagesof

50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwillbe:

Forusersofestrogen-onlyreplacementtherapy,between0and3(bestestimate=1.5)for5years’usebetween3

and7(bestestimate=5)for10years’use.

Forusersofestrogen-progestogencombinedHRT,between5and7(bestestimate=6)for5years’usebetween18

and20(bestestimate=19)for10years’use.

TheWHITrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50to79years,andadditional

8casesofinvasivebreastcancerwouldbeduetoestrogen-progestogencombinedHRT(CEE+MPA)per10,000

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,

About16casesofinvasivebreastcancerwouldbediagnosedin5years.

For1000womenwhousedestrogen-progestogencombinedHRT(CEE+MPA),thenumberofadditionalcases

wouldbe,

Between0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

irrespectiveofageatstartofuse(betweentheagesof45-65)(seeSection4.4).

Endometrialcancer

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durationofuseofunopposedestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftheriskis

thatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetweenthe

agesof50and65.Dependingonthedurationoftreatmentandestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestogentoestrogen-onlytherapygreatlyreducesthisincreasedrisk.

4.9Overdose

Generally,estrogensarewelltoleratedeveninmassivedoses.Possiblesymptomsofoverdosageincludethoselisted

underundesirableeffects(Section4.8).Treatmentissymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:G03CA03

Theactiveingredient,synthetic17-estradiolischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms.

Estrogenpreventbonelossfollowingmenopauseorovariectomy.

Clinicaltrialinformation.

Reliefofestrogen-deficiencysymptom.Reliefofmenopausalsymptomswasachievedusuallyduringthefirstweekof

treatment.

Preventionofosteoporosis

Estrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.The

effectofestrogenonbonemineraldensityisdose-dependent.Protectionappearstobeeffectiveforaslongas

treatmentiscontinued.AfterdiscontinuationofHRT,bonemassislostataratesimilartothatinuntreatedwomen.

EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombinationwitha

progestogen-giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andotherosteoporotic

fractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablishedosteoporosis,butthe

evidenceforthatislimited.

StudieshavereportedsignificantincreasesinbonemineraldensityatspineandhipaftertreatmentwithEstradiol

implants(25-100mgevery6months)for1to15.5years.

5.2Pharmacokineticproperties

Afterinsertionofa25mgimplantintothesubcutaneousfattheEstradiolplasmalevelreachesitsmaximumofabout

400pmol/1inafewdaysandshowsaslowandgradualdeclinetoabout150pmol/1atsixmonths.Aswithother

estrogensandprogestagens,therearelargeinter-individualdifferencesinhormonelevels,butintra-individual

variabilityappearstobesmall.

AfterrepeatedimplantationEstradiollevelsreachhighervaluesthanaftertheinitialimplantation,buttheyremainwell

withinthemidfollicularrangeasfoundinpremenopausalwomen.Withtwoimplantsatatimeand/orimplantation

intervalsshorterthan6months,occasionallyhigherEstradiollevelsmayoccur.Subcutaneousadministrationof

Estradiolbypassesthegastrointestinaltract,whereorallyadministeredEstradiolisconvertedintoestrone.

Inaddition,thefirst-passeffectoftheliverisavoided.Therefore,moreunconjugatedEstradiolisavailableandamore

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5.3Preclinicalsafetydata

Thereisnopreclinicaldataofrelevancetotheprescriberwhichisadditionaltothatincludedinothersectionsofthe

SPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

None.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Thesterileimplantissuppliedinasealedglasstube.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Fullaseptic“notouch”techniqueshouldbeused.

7MARKETINGAUTHORISATIONHOLDER

Organon(Ireland)Limited

P.O.Box2857

DrynamRoad

Swords

Co.Dublin

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0061/015/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateofthefirstauthorisation:01April1979

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10DATEOFREVISIONOFTHETEXT

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