ENTRYDIL S.R. 90 MG PROLONGED-RELEASE, FILM-COATED

Main information

  • Trade name:
  • ENTRYDIL S.R. 90 MG PROLONGED-RELEASE, FILM-COATED
  • Dosage:
  • 90 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ENTRYDIL S.R. 90 MG PROLONGED-RELEASE, FILM-COATED
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1327/004/002
  • Authorization date:
  • 30-06-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EntrydilS.R.90mgProlonged-releaseFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolonged-releasefilm-coatedtabletcontains90mgdiltiazemhydrochloride.

Excipients:

Eachprolonged-releasefilm-coatedtabletcontains85.5mglactoseaslactosemonohydrate

Eachprolonged-releasefilm-coatedtabletcontains0.6mgsucrose

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-release,film-coatedtablet.

Whiteoralmostwhite,capsule-shapedfilm-coatedtabletwithcode“DL/90”markedononesideandascoreline

onbothsides.Thescorelineisforidentificationofthetablet,thetabletsshouldbeswallowedwhole.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AnginaPectorisincludingPrinzmetal’sangina

Mildtomoderatehypertension

4.2Posologyandmethodofadministration

Fororaladministration.

Thetabletsshouldbeswallowedwholeandnotchewed.

Adultsonly:

Theusualstartingdoseis90mgtwicedailyor60mgthreetimesdaily(correspondingto180mgofdiltiazem

hydrochloride).

Dependinguponclinicalresponsethepatient’sdosagemaybeincreasedto180mgtwicedailyor120mgthree

timesdailyifrequired.

Elderly(over65years)andthosewithrenalandhepaticimpairment

Dosageshouldcommenceatthelowerlevelof60mgtwicedailyandbeincreasedslowly.Donotincreasethedose

iftheheartratefallsbelow50beatsperminute.

Children(below18yearsofage):

Therearenodataavailableonuseofdiltiazeminchildrenbelowtheageof18years,anddiltiazemisnot

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4.3Contraindications

SicksinussyndromeorevidenceofsecondorthirddegreeAVblockexceptinthepresenceofa

functioningpacemaker

Hypotension(systolicbloodpressurelessthan90mmHg)

Severebradycardia(restingpulserateoflessthan40beatsperminute)

Atrialfibrillation/flutterandsimultaneouspresenceofWPW(Wolff-Parkinson-White)syndrome

(increasedriskoftriggeringaventriculartachycardia)

Decompensatedcardiacinsufficiency

Acutecomplicatedmyocardialinfarction(withbradycardia,severehypotension,leftheartinsufficiency)

Cardiogenicshock,leftventricularfailurewithstasis,pulmonarycongestion

Digitalisintoxication

Pregnancyorlactation(Pleaseseesection4.6)

Useinwomenofchildbearingpotential(Pleaseseesection4.6Fertility,pregnancyandlactation)

Knownhypersensitivitytodiltiazemhydrochlorideortoanyoftheexcipients(Pleaseseesection6.1)

Concomitantadministrationofdantroleneinfusionduetotheriskofventricularfibrillation(seesection

4.5).

4.4Specialwarningsandprecautionsforuse

1.Theuseofdiltiazemhydrochlorideindiabeticpatientswithimpairedrenalfunctionorpatientswithrenalor

hepaticimpairmentmayrequireadjustmentoftheircontrol.

2.Theproductshouldbeusedwithcautioninpatientswithhepaticdysfunction.Abnormalitiesofliverfunction

mayappearduringtherapy.Veryoccasionalreportsofabnormalliverfunctionhavebeenreceived.Thesereactions

havebeenreversibleupondiscontinuationoftherapy.

3.Priortogeneralanaesthesia,theanaesethistmustbeinformedofongoingdiltiazemtreatment.Depressionofcardiac

contractility,conductivityandautomaticity,aswellasthevasculardilatationassociatedwithanaestheticssuchas

enflurane,halothaneandisoflurane,maybepotentiatedbycalciumchannelblockers.

4.Theriskofraisedcreatinekinease,myopathyandrhabdomyolisisduetostatins(metabolisedbyCYP3A4)maybe

increasedincaseofaconcomitantuseofdiltiazem.Closermonitoringforsignsandsymptomsiswarrantedinsuch

case.

5.Calciumchannelblockingagents,suchasdiltiazem,maybeassociatedwithmoodchanges,including

depression.

6.Likeothercalciumchannelantagonists,diltiazemhasaninhibitoryeffectonintestinalmotility.Thereforeitshould

beusedwithcautioninpatientsatrisktodevelopanintestinalobstruction.

7.Theclearanceofdiltiazemcanbedecreasedinpatientswithimpairedhepaticorrenalfunctionandinelderly

patients.Suchpatientsshouldbetreatedcautiously.

8.Sincediltiazemhasshownprophyrogenicpropertiesininvitroandanimalstudies,cautionshouldbeexercised

inthetreatmentofpatientswithacuteporphyria.

9.Patientswithimpairedventricularfunction,bradycardia,firstdegreeAVblock,prolongedPQinterval,aortic

stenosis,andthosetreatedwithbeta-blockersorothermedicamentsthatimpaircardiacconductionorcontractility

mustbetreatedcautiously.DiltiazemprolongsAVnoderefractoryperiodswithoutsignificantlyprolongingsinus

noderecoverytime,exceptinpatientswithsicksinussyndrome.Thiseffectmayrarelyresultinabnormallyslow

heartrates(particularlyinpatientswithsicksinussyndrome)orsecond-orthird-degreeAVblock.(Pleasesee

section4.5)

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deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

11.Thismedicinecontainssucrose.Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactose

malabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

12.Thismedicinecontainscastoroil.Thismaycausestomachupsetanddiarrhoea.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Diltiazemmayincreasetheefficacyofotheranti-hypertensivedrugsanddiureticsifusedconcomitantly.Inallthe

patientstreatedwithcalciumantagonists,theprescriptionofnitratederivativesshouldonlybecarriedoutat

graduallyincreasingdoses.Ithasdecreasednifedipineclearancebyover50%andincreasedplasmalevelsof

propranololandmetoprolol.Thecombinationofdiltiazemwithanalpha-antagonistshouldbeconsideredonly

withthestrictmonitoringofthebloodpressure.

Dantrolene(infusion)alethalventricularfibrillationisregularlyobservedinanimalswhenintravenousverapamil

anddantroleneareadministeredconcomitantly.Thecombinationofcalciumantagonistanddantroleneis

thereforepotentiallydangerous(seesection4.3Contraindications).

Duetothepotentialforadditiveeffects,cautionandcarefultitrationarenecessaryinpatientsreceivingdiltiazem

concomitantlywithotheragentsknowntoaffectcardiaccontractilityand/orconduction.Concomitantusewith

beta-blockers,amiodarone,digoxin,halothaneandrelatedanaesthetics,orothermedicamentsthatimpaircardiac

conductionincreasestheriskofAVconductiondisturbances(pronouncedbradycardia,sinusarrest),sino-atrial

andatrio-ventricularconductiondisturbancesandheartfailure(synergisticeffect).Concomitantadministration

shouldbeusedwithcautionandmustonlybeusedundercloseclinicalandECGmonitoring,particularlyatthe

beginningoftreatment.Intravenousadministrationofbeta-blockersshouldbediscontinuedduringtherapywith

diltiazem.

Diltiazemwillnotprotectagainsteffectsofwithdrawalof-adrenoceptorblockingagents,northereboundeffects

seenwithvariousantihypertensives.Combinationwith-adrenoceptorblockershavingasignificant“firstpass”

losse.g.propranololmayrequireadecreaseintheirdoseandmayleadtobradycardia.Theremaybeanadditive

effectwhenusedwithdrugs,whichmayinducebradycardia,orwithotherantihypertensives.Sincediltiazemhas

antiarrhythmicproperties,itsconcomitantprescriptionwithotherantiarrhythmicagentsisnotrecommended

(additiveriskofincreasedcardiacadverseeffects).Thiscombinationshouldonlybeusedundercloseclinicaland

ECGmonitoring.

Pharmacokineticinteractions

Effectofotherdrugsondiltiazem

DiltiazemismainlymetabolisedbyCYP3A4.AgentsthatinhibitCYP3A4(suchasmacrolideantibiotics,azole

antifungals,fluoxetine,tamoxifen,nifedipine,cimetidine,HIVproteaseinhibitors)mayincreasetheconcentration

ofdiltiazem,whichcancausetoxiceffects.

AgentsthatinduceCYP3A4(suchascarbamazepine,phenobarbital,moricizine,rifampicin,phenytoin)may

decreasetheconcentrationofdiltiazem,whichcandecreasetheclinicaleffect.Thepatientshouldbecarefully

monitoredwheninitiatingordiscontinuingrifampicintreatment.

Diazepamhasdecreaseddiltiazemplasmalevelsby20%

ConcomitantH

antagonist(cimetidine,ranitidine)therapymayincreasediltiazembloodlevels.Patientscurrently

receivingdiltiazemtherapyshouldbecarefullymonitoredwheninitiatingordiscontinuingtherapywithanti-H

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Effectofdiltiazemonotherdrugs

DiltiazemanditsmetabolitesinhibittheactivityofCYP3A4,whichmayincreasetheconcentrationofdrugs

metabolisedbythatenzyme.

Clearanceofsimvastatin,atorvastatinandlovastatinisinhibitedbydiltiazem,whichmaycausesignificantly

increasedplasmalevelsofthosedrugs.Iftakenconcomitantly,asmalldoseofstatinmustbeusedandsymptoms

ofrhabdomyolysisandhepaticdamagemustbecloselymonitored.Whenpossible,anonCYP3A4-metabolised

statinshouldbeusedtogetherwithdiltiazem,otherwiseclosemonitoringforsignsandsymptomsofapotential

statintoxicityisrequired.

Theserumconcentrationand/orsignsoftoxicityofcarbamazepine,phenytoin,ciclosporin,sirolimus,tacrolimus,

digoxin,methylprednisolone,andtheophyllineshouldbemonitorediftheyareusedconcomitantlywithdiltiazem

andafteritsdiscontinuation.Ifnecessarythelevelsshouldbedeterminedandthedoseofcarbamazepine,

theophylline,ciclosporinA,ordigoxinbereducedifnecessary.Diltiazemhasincreasedtheplasmalevelsand

kidneytoxicityofciclosporin,thecombinationshouldbeusedwithcaution.Inonestudydiltiazemhasdecreased

theophyllineclearanceby25%,butonlyinmalesmokers.Diltiazemhasincreasedplasmalevelsandkidney

toxicityoftacrolimusinkidneyandlivertransplantrecipients.

ClearanceofotherdrugsmetabolisedbyCYP3A4(suchasnifedipine,quinidine,moricizine,imipramine,

nortriptyline,sildenafil,buspirone,midazolam,triazolam,alprazolam,alfentanil,andcisapride)maybeinhibited

bydiltiazem,andtheirplasmalevelsmaybeincreased.Thepossibleinteractionshouldbetakenintoaccount.

Specialcareshouldbetakenwhenprescribingshort-actingbenzodiazepinesmetabolizedbytheCYP3A4pathway

inpatientsusingdiltiazem.

Lithiumneurotoxicitymayoccurwhenusedconcomitantlywithdiltiazem.Thereforeserumconcentrationsof

lithiumshouldbemonitored.

Therehavebeenreportsintheliteratureofdiltiazeminteractionswithwarfarin.

4.6Fertility,pregnancyandlactation

Thereisverylimiteddatafromtheuseofdiltiazeminpregnantpatients.Highdiltiazemdoseshavebeenobservedto

induceincreasedfetalmortalityandmalformations.Diltiazemisthereforenotrecommendedduringpregnancy,aswell

asinwomenofchild-bearingpotientalnotusingeffectivecontraception.Noeffectsonfemalefertilityhavebeen

observed.

Diltiazemisexcretedinbreastmilk.Womenshouldnotbreast-feedwhileondiltiazemtreatment.Ifuseofdiltiazemis

consideredmedicallyessential,analternativemethodofinfantfeedingshouldbeinstituted.

4.7Effectsonabilitytodriveandusemachines

Atthebeginningoftreatmentwithdiltiazemthedecreaseinbloodpressuremayinducedizzinessespeciallywhen

standingup.Ifthisoccurs,thepatientshouldrefrainfromdrivingandusingmachines.Thepatient’sreactionto

diltiazemshouldbeknownbeforeshe/heisallowedtodriveorusemachinery.Wellbalancedtreatmentwith

diltiazemisnotknowntoaffectthepatient’sabilitytodriveoroperatemachines.However,nostudieshavebeen

performed.

4.8Undesirableeffects

ThefollowingCIOMSfrequencyratingisused,whenapplicable:Verycommon(1/10);common(1/100to<1/10);

uncommon(1/1,000to1/100);rare(1/10,000to1/1,000);veryrare(1/10,000);notknown(cannotbe

estimatedfromtheavailabledata).Withineachfrequencygrouping,adverseeventsarepresentedinorderof

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Very

Common Common Uncommon Rare NotKnown

Bloodand

lymphaticsystem

disorders Thrombocytopenia

Psychiatric

disorders nervousness,

insomnia Moodchanges

(including

depression)

Nervoussystem

disorders headache,

dizziness Extrapyramidal

syndrome

Cardiac

disorders atrioventricular

block(maybe

offirst,second

orthirddegree;

bundlebranch

blockmay

occur),

palpitations bradycardia Sinotrialblock,

congestiveheart

failure,syncope

Vascular

disorders flushing orthostatic

hypotension Vasculitis

(including

leukocytoclastic

vasculitis)

Gastrointestinal

disorders constipation,

dyspepsia,

gastricpain,

nausea vomiting,

diarrhoea drymouth Gingival

hyperplasia

Hepatobiliary

disorders hepatic

enzymes

increase

(AST,

ALT,LDH,

ALPincrease) Hepatitis

Musculoskeletal

andconnective

tissuedisorders Arthralgia

Skinand

subcutaneous

tissuedisorders erythema urticaria Photosensitivity

(including

lichenoidkeratosis

atsunexposedskin

areas),

angioneurotic

oedema,erythema

multiforme

(includingSteven-

Johnson's

syndromeandtoxic

epidermal

necrolysis),

sweating,

exfoliative

dermatitis,acute

generalized

exanthematous

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Aswithsomeothercalciumchannelblockers,exceptionalcasesofextrapyramidalsymptomsandgynaecomastiahave

beenreported,reversibleafterdiscontinuationofcalciumantagonists.Raisedcreatinekinase,myopathyand

rhabdomyolisisduetostatinsmetabolisedbytheCYP3A4systemwhentakenconcomitantlywithdiltiazem,see

section4.5,InteractionswithOtherMedicinalProductsandOtherFormsofInteraction.

4.9Overdose

Experienceofoverdosageinmanislimitedbutcasesofspontaneousrecoveryhavebeenreported.However,itis

recommendedthatpatientswithsuspectedoverdoseshouldbeplacedunderobservationinacoronarycareunit

withfacilitiesavailablefortreatmentofanypossiblehypotensionandconductiondisturbancesthatmayoccur.

Overdosageofdiltiazemmayleadtohypotensionanddisturbancesofelectricconductivityoftheheartwith

bradycardia.Mostpatientssufferingfromoverdosageofdiltiazembecomehypotensivewithin8hoursof

ingestion.Thesymptomsofoverdoseincludetiredness,irritability,somnolence,sinusbradycardia,firsttothird

degreeAVblocks,cardiacarrest,hypotension,collapse,hypothermia,hyperglycaemiaandnausea.

Thereisnospecificantidotefordiltiazem.Theeliminationhalf-lifeofdiltiazemafteroverdosageisestimatedto

beabout5.5–10.2hours.Absorptionshouldbepreventedbyuseofgastriclavageandadministrationofactivated

charcoalifthepatientpresentsearlyafteroverdose.

Suchpatientsshouldbetakencareofatintensivecareunitswithcardiac(ECG)monitoring.Theeffectof

diltiazemcanbeantagonisedbyi.v.calciumgluconateorcalciumchloridetorestorestablesinusactivity.

Hypotensionshouldbecorrectedwithplasmaexpanders,andintravenousinotropicagents(dopamine,dobutamine,

isoprenaline).SymptomaticbradycardiaandhighgradeAVblockmayrespondtoatropine,isoprenalineor

occasionallycardiacpacing.Otherwisetreatmentissymptomatic.

Theformulationisamodifiedreleasesystemthatwillcontinuetoreleasediltiazemforsomehours.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCodeC08DB01–Benzothiazepinederivatives.

Diltiazemisabenzothiazepinederivativethateffectivelyblockstheslowcalciumchannels(Lchannels)of

vascularsmoothmuscleandcardiacmusclecells.Slowcalciumchannelsplayanimportantroleespeciallyinthe

regulationofsinoatrialandatrioventricularnodefunctioninthecardiacmusclecells.

Diltiazempossessesbothperipheralandcoronaryvasodilatorproperties.However,diltiazem-inducedfallinblood

pressureisnotcommonlyfollowedbyreflectorytachycardiawhichisprobablyduetothedepressiveeffectofthe

drugonthestimulationofsinoatrialnodefunction.Diltiazemslowsatrioventricularconduction.Italsohasaweak

negativeinotropiceffectontheheart.Diltiazemimprovesrelaxationofthecardiacmuscleanddiastolicfunction

occasionally

desquamative

erythemawithor

withoutfever

Reproductive

systemand

breastdisorders Gynecomastia

General

disordersand

administration

siteconditions lowerlimb

oedema

(peripheral

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totalflowinhealthycoronaryarteriesdoesnotusuallychange,butsomeimprovementinthecirculationof

contractedarterieshasbeenobserved.Diltiazemrelaxessmoothmusclealsoelsewhereinthebody,eg.thelower

oesophagealsphinctermuscle.Diltiazemhasnotbeenshowntohaveaneffectonelectrolyte-,lipid-orglucose

balanceinhealthyordiabeticpersons.

5.2Pharmacokineticproperties

Diltiazemiscompletelyabsorbedafteroraladministration,butowingtoitsfirst-passmetabolismintheliver,the

absolutebioavailabilityofdiltiazemhydrochlorideisonlyabout40%(withinterindividualvariabilityrangingfrom

24to74%).Thebioavailabilityisindependentofformulationortherapeuticdose.Adietrichinfatandprotein

slightlyincreasesthebioavailabilityofasustained-releasecapsuleformulation,butthishasnoclinical

significance.Thereleaseofthedrughasbeenprolongedinthecontrolled-releaseformulationbyspecial

pharmaceuticaltechnology.Thepeakplasmaconcentrationsarereached2-3hoursafterdosing.Thehighpeak

concentrationsoftheabsorptionphasehavebeeneliminated.ThisallowstheEntrydilS.R.90mgtabletstobe

administeredtwiceeachday.

About80%ofdiltiazemisboundtoproteins,about40%ofthistoplasmaalbumin.Proteinbindingdoesnot

appeartobeinfluencedbyphenylbutazone,warfarin,propranolol,salicylicacidordigoxin.Diltiazemiswidely

distributedtovarioustissues.Theapparentvolumeofdistributionis5l/kgandthevolumeofcentralcompartment

is0.9l/kg.Intheblood,diltiazemisevenlydistributedtotheplasmaandbloodcells.Steadystateisreachedwithin

3dayswiththedosageofone60mgtablet3timesdaily.

Diltiazemisextensivelymetabolisedintheliver,andlessthan4%isexcretedunchangedintheurine.Thetotal

clearanceofdiltiazemisbetween0.7and1.3l/kg/h.Fiveunconjugatedmetaboliteshavebeenfoundintheurine,two

ofthemalsoinconjugatedforms.Diltiazemismetabolisedthroughdeacetylation,N-demethylation,andO-

demethylation.Deacetyldiltiazemisanactivemetabolite(40-50%oftheactivityofdiltiazem)withconcentrationsof

about15to35%ofthoseofdiltiazem.Thepharmacodynamicsignificanceofthismetaboliteisminor.Diltiazemis

metabolisedmainlybyCYP3A4andtoalesserextentbyCYP2D6.DiltiazemanditsN-demethylatedmetabolitesalso

actasinhibitorsofCYP3A4enzyme.Inliverfunctiondisordersdelayedmetabolismintheliverislikely.These

metabolitesareconvertedtoconjugates,generallytheglucuronideorthesulphate.

Accordingto3-compartmentmodel,thehalf-lifeofdiltiazemrangesfromabout0.1hoursinthefirstphaseto2.1

hoursinthemiddleand9.8hoursintheterminalphase.Theeliminationhalf-lifevariesbetween4and7hours.

Thepharmacokineticsofdiltiazemhasnotbeenobservedtochangeafterrepeatedadministrations.Thedrugisnot

accumulatedanditdoesnotinduceitsownmetabolism.Studieswithrenalinsufficiencyandanginapectoris

patientsdidnotshowdifferenceinthepharmacokineticprofileofdiltiazemascomparedwithstudiesonhealthy

volunteers.

Decreasedfirst-passmetabolismintheelderlytendstoresultinincreasedplasmaconcentrationsofcalcium

antagonistsbutnomajorchangeshavebeenfoundwithdiltiazem.Renalimpairmentdidnotcausesignificant

changesindiltiazempharmacokinetics.Plasmaconcentrationsofdiltiazemalsotendtobehigherinhepatic

cirrhosisduetoimpairedoxidativemetabolism.

5.3Preclinicalsafetydata

Intoxicitystudiesperformedinrodentstheacutetoxicityofdiltiazemhydrochloridewaslow(LD

>500mg/kg).

Somehearttoxicity(reversibleECGchanges)hasbeenfound.

Inreproductivestudiesdiltiazemhydrochloridehasbeenfoundtobetoxictothefoetus.Alsoteratogeniceffects

havebeenfound,butnoeffectsonfertility.

Chronictoxicitystudiesinratsrevealednoremarkablechangesatoraldosesupto125mg/kg/dayalthoughthere

was60%mortalityatthisdose.Indogschronicallytreatedwithoraldosesof20mg/kg/day,transientrisesinSGPT

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Embryotoxicityhasbeenreportedinmice,ratsandrabbitsfollowingi.p.administrationofdiltiazem.Maintypes

ofmalformationsincludedlimbandtaildefectswithasmallnumberofvertebralandribdeformities.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore:

Lactosemonohydrate

CastorOil,hydrogenated

Driedaluminiumhydroxidegel

Polyacrylatedispersion30percent

Talc

Magnesiumstearate

FilmCoating:

Hypromellose

Sucrose

Glycerol(85percent)

TitaniumDioxide(E171)

Magnesiumstearate

Polysorbate80

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keepthecontainertightlyclosed.

6.5Natureandcontentsofcontainer

Packsizes: 30&100tablets

Container: HDPEbottlepackedinanoutercardboardcarton.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

OrionCorporation

Orionintie1

FIN-02200Espoo

Finland

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8MARKETINGAUTHORISATIONNUMBER

PA1327/4/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:09July1996

Dateoflastrenewal:09July2006

10DATEOFREVISIONOFTHETEXT

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