ENTRYDIL S.R. 120MG PROLONGED RELEASE FILM-COATED

Main information

  • Trade name:
  • ENTRYDIL S.R. 120MG PROLONGED RELEASE FILM-COATED
  • Dosage:
  • 120 mg Milligram
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ENTRYDIL S.R. 120MG PROLONGED RELEASE FILM-COATED
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1327/004/003
  • Authorization date:
  • 30-06-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EntrydilS.R.120mgProlonged-releaseFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolonged-releasefilm-coatedtabletcontains120mgdiltiazemhydrochloride.

Excipients

EachProlongedReleasetabletcontains114mglactoseaslactosemonohydrate

EachProlongedReleasetabletcontains0.8mgsucrose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-release,film-coatedtablets.

Whiteoralmostwhite,capsule-shapedfilm-coatedtablets,marked“DL/120”,withascorelineonbothsides.The

tabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AnginapectorisincludingPrinzmetal’sangina

Mildtomoderatehypertension

4.2Posologyandmethodofadministration

Fororaladministration.

Adultsonly:

Theusualstartingdoseis90mgtwicedailyor60mgthreetimesdaily(correspondingto180mgofdiltiazem

hydrochloride).

Dependinguponclinicalresponsethepatient’sdosagemaybeincreasedto180mgtwicedailyor120mgthreetimes

dailyifrequired.

Elderlyandthosewithrenalandhepaticimpairment:

Dosageshouldcommenceatthelowerlevelof60mgtwicedailyandbeincreasedslowly.Donotincreasethedoseif

theheartratefallsbelow50beatsperminute.

Children(below18yearsofage):

Therearenodataavailableonuseofdiltiazeminchildrenbelowtheageof18years,anddiltiazemisnot

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4.3Contraindications

SicksinussyndromeorevidenceofsecondorthirddegreeAVblockexceptinthepresenceofafunctioning

pacemaker

Hypotension(systolicbloodpressurelessthan90mmHg)

Severebradycardia(restingpulserateoflessthan40beatsperminute)

Atrialfibrillation/flutterandsimultaneouspresenceofWPW(Wolff-Parkinson-White)syndrome(increasedriskof

triggeringaventriculartachycardia)

Decompensatedcardiacinsufficiency

Acutecomplicatedmyocardialinfarction(withbradycardia,severehypotension,leftheartinsufficiency)

Cardiogenicshock,leftventricularfailurewithstasis,pulmonarycongestion

Digitalisintoxication

Pregnancyorlactation(Pleaseseesection4.6)

Useinwomenofchildbearingpotential(Pleaseseesection4.6Fertility,pregnancyandlactation)

Knownhypersensitivitytodiltiazemhydrochlorideortoanyoftheexcipients(Pleaseseesection6.1)

Concomitantadministrationofdantroleneinfusionduetotheriskofventricularfibrillation(seesection4.5)

4.4Specialwarningsandprecautionsforuse

1.Theuseofdiltiazemhydrochlorideindiabeticpatientswithimpairedrenalfunctionorpatientswithrenalorhepatic

impairmentmayrequireadjustmentoftheircontrol.

2.Theproductshouldbeusedwithcautioninpatientswithhepaticdysfunction.Abnormalitiesofliverfunctionmay

appearduringtherapy.Veryoccasionalreportsofabnormalliverfunctionhavebeenreceived.Thesereactionshave

beenreversibleupondiscontinuationoftherapy.

3.Priortogeneralanaesthesia,theanaesethistmustbeinformedofongoingdiltiazemtreatment.Depressionofcardiac

contractility,conductivityandautomaticity,aswellasthevasculardilatationassociatedwithanaestheticssuchas

enflurane,halothaneandisoflurane,maybepotentiatedbycalciumchannelblockers.

4.Theriskofraisedcreatinekinease,myopathyandrhabdomyolisisduetostatins(metabolisedbyCYP3A4)maybe

increasedincaseofaconcomitantuseofdiltiazem.Closermonitoringforsignsandsymptomsiswarrantedinsuch

case.

5.Calciumchannelblockingagents,suchasdiltiazem,maybeassociatedwithmoodchanges,includingdepression

6.Likeothercalciumchannelantagonists,diltiazemhasaninhibitoryeffectonintestinalmotility.Thereforeitshould

beusedwithcautioninpatientsatrisktodevelopanintestinalobstruction.

7.Clearanceofdiltiazemcanbedecreasedinpatientswithimpairedhepaticorrenalfunctionandinelderlypatients.

Suchpatientsshouldbetreatedcautiously.

8.Sincediltiazemhasshownporphyrogeniccharacteristicsininvitroandanimalstudies,cautionshouldbeexercised

inthetreatmentofpatientswithacuteporphyria.

9.Patientswithimpairedventricularfunction,bradycardia,firstdegreeAVblock,prolongedPQinterval,aortic

stenosis,andthosetreatedwithbeta-blockersorothermedicamentsthatimpaircardiacconductionorcontractilitymust

betreatedcautiously.DiltiazemprolongsAVnoderefractoryperiodswithoutsignificantlyprolongingsinusnode

recoverytime,exceptinpatientswithsicksinussyndrome.Thiseffectmayrarelyresultinabnormallyslowheartrates

(particularlyinpatientswithsicksinussyndrome)orsecond-orthird-degreeAVblock.(Pleaseseesection4.5)

10.Thismedicinecontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

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malabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

12.Thismedicinecontainscastoroil.Thismaycausestomachupsetanddiarrhoea.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Diltiazemmayincreasetheefficacyofotheranti-hypertensivedrugsanddiureticsifusedconcomitantly.Inallthe

patientstreatedwithcalciumantagonists,theprescriptionofnitratederivativesshouldonlybecarriedoutat

graduallyincreasingdoses.Ithasdecreasednifedipineclearancebyover50%andincreasedplasmalevelsof

propranololandmetoprolol.Thecombinationofdiltiazemwithanalpha-antagonistshouldbeconsideredonlywith

thestrictmonitoringofthebloodpressure.

Dantrolene(infusion)alethalventricularfibrillationisregularlyobservedinanimalswhenintravenousverapamil

anddantroleneareadministeredconcomitantly.Thecombinationofcalciumantagonistanddantroleneistherefore

potentiallydangerous(seesection4.3Contraindications).

Duetothepotentialforadditiveeffects,cautionandcarefultitrationarenecessaryinpatientsreceivingdiltiazem

concomitantlywithotheragentsknowntoaffectcardiaccontractilityand/orconduction.Concomitantusewith

beta-blockers,amiodarone,digoxin,halothaneandrelatedanaesthetics,orothermedicamentsthatimpaircardiac

conductionincreasestheriskofAVconductiondisturbances(pronouncedbradycardia,sinusarrest),sino-atrialand

atrio-ventricularconductiondisturbancesandheartfailure(synergisticeffect).Concomitantadministrationshould

beusedwithcaution.AndmustonlybeusedundercloseclinicalandECGmonitoring,particularlyatthebeginning

oftreatment.Intravenousadministrationofbeta-blockersshouldbediscontinuedduringtherapywithdiltiazem.

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

agents.Anadjustmentindiltiazemdailydosemaybenecessary.

Effectofdiltiazemonotherdrugs

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metabolisedbythatenzyme.

Clearanceofsimvastatin,atorvastatinandlovastatinisinhibitedbydiltiazem,whichmaycausesignificantly

increasedplasmalevelsofthosedrugs.Iftakenconcomitantly,asmalldoseofstatinmustbeusedandsymptomsof

rhabdomyolysisandhepaticdamagemustbecloselymonitored.Whenpossible,anonCYP3A4-metabolisedstatin

shouldbeusedtogetherwithdiltiazem,otherwiseclosemonitoringforsignsandsymptomsofapotentialstatin

toxicityisrequired.

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)maybeinhibitedby

diltiazem,andtheirplasmalevelsmaybeincreased.Thepossibleinteractionshouldbetakenintoaccount.Special

careshouldbetakenwhenprescribingshort-actingbenzodiazepinesmetabolizedbytheCYP3A4pathwayin

patientsusingdiltiazem.

Lithiumneurotoxicitymayoccurwhenusedconcomitantlywithdiltiazem.Thereforeserumconcentrationsof

lithiumshouldbemonitored.

Therehavebeenreportsintheliteratureofdiltiazeminteractionswithwarfarin.

4.6Fertility,pregnancyandlactation

Thereisverylimiteddatafromtheuseofdiltiazeminpregnantpatients.Highdiltiazemdoseshavebeenobservedto

induceincreasedfetalmortalityandmalformations.Diltiazemisthereforenotrecommendedduringpregnancy,aswell

asinwomenofchild-bearingpotentialnotusingeffectivecontraception.Noeffectsonfemalefertilityhavebeen

observed.

Diltiazemisexcretedinbreastmilk.Womenshouldnotbreast-feedwhileondiltiazemtreatment.Ifuseofdiltiazemis

consideredmedicallyessential,analternativemethodofinfantfeedingshouldbeinstituted.

4.7Effectsonabilitytodriveandusemachines

Atthebeginningoftreatmentwithdiltiazemthedecreaseinbloodpressuremayinducedizzinessespeciallywhen

standingup.Ifthisoccurs,thepatientshouldrefrainfromdrivingandusingmachines.Thepatient’sreactionto

diltiazemshouldbeknownbeforeshe/heisallowedtodriveorusemachinery.Wellbalancedtreatmentwithdiltiazem

isnotknowntoaffectthepatient’sabilitytodriveoroperatemachines.However,nostudieshavebeenperformed.

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

decreasingseriousness

Very

Common Common Uncommon Rare NotKnown

Bloodand

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disorders

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 dry

mouth Gingival

hyperplasia

Hepatobiliary

disorders hepatic

enzymes

increase

(AST,

ALT,LDH,

increase) Hepatitis

Musculoskeletal

andconnective

tissuedisorders Arthralgia

Skinand

subcutaneous

tissuedisorders erythema urticaria Photosensitivity

(including

lichenoidkeratosis

atsunexposed

skin

areas),

angioneurotic

oedema,erythema

multiforme

(includingSteven-

Johnson's

syndromeand

toxicepidermal

necrolysis),

sweating,

exfoliative

dermatitis,acute

generalized

exanthematous

pustulosis,

occasionally

desquamative

erythemawithor

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Aswithsomeothercalciumchannelblockers,exceptionalcasesofextrapyramidalsymptomsandgynaecomastiahave

beenreported,reversibleafterdiscontinuationofcalciumantagonists.Raisedcreatinekinase,myopathyand

rhabdomyolisisduetostatinsmetabolisedbytheCYP3A4systemwhentakenconcomitantlywithdiltiazem,see

section4.5,InteractionswithOtherMedicinalProductsandOtherFormsofInteraction.

4.9Overdose

Experienceofoverdosageinmanislimitedbutcasesofspontaneousrecoveryhavebeenreported.However,itis

recommendedthatpatientswithsuspectedoverdoseshouldbeplacedunderobservationinacoronarycareunitwith

facilitiesavailablefortreatmentofanypossiblehypotensionandconductiondisturbancesthatmayoccur.

Mostpatientssufferingfromoverdosageofdiltiazembecomehypotensivewithin8hoursofingestion.Thesymptoms

ofoverdoseincludetiredness,irritability,somnolence,sinusbradycardia,firsttothirddegreeAVblocks,cardiacarrest,

hypotension,collapse,hypothermia,hyperglycaemiaandnausea.

Thereisnospecificantidotefordiltiazem.Theeliminationhalf-lifeofdiltiazemafteroverdosageisestimatedtobe

about5.5–10.2hours.Absorptionshouldbepreventedbyuseofgastriclavageandadministrationofactivated

charcoalifthepatientpresentsearlyafteroverdose.

Suchpatientsshouldbetakencareofatintensivecareunitswithcardiac(ECG)monitoring.Theeffectofdiltiazemcan

beantagonisedbyi.v.calciumgluconateorcalciumchloridetorestorestablesinusactivity.Hypotensionshouldbe

correctedwithplasmaexpanders,andintravenousinotropicagents(dopamine,dobutamine,isoprenaline).Symptomatic

bradycardiaandhighgradeAVblockmayrespondtoatropine,isoprenalineoroccasionallycardiacpacing.Otherwise

treatmentissymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCodeC08DB01–Benzothiazepinederivatives.

Diltiazemisabenzothiazepinederivativethateffectivelyblockstheslowcalciumchannels(Lchannels)ofvascular

smoothmuscleandcardiacmusclecells.Slowcalciumchannelsplayanimportantroleespeciallyintheregulationof

sinoatrialandatrioventricularnodefunctioninthecardiacmusclecells.

Diltiazempossessesbothperipheralandcoronaryvasodilatorproperties.However,diltiazem-inducedfallinblood

pressureisnotcommonlyfollowedbyreflectorytachycardiawhichisprobablyduetothedepressiveeffectofthedrug

onthestimulationofsinoatrialnodefunction.Diltiazemslowsatrioventricularconduction.Italsohasaweaknegative

inotropiceffectontheheart.Diltiazemimprovesrelaxationofthecardiacmuscleanddiastolicfunctionwhichtogether

withdecreasedafterloadimprovestheleftventricularfunction.Inspiteofcoronarydilatationthetotalflowinhealthy

coronaryarteriesdoesnotusuallychange,butsomeimprovementinthecirculationofcontractedarterieshasbeen

observed.Diltiazemrelaxessmoothmusclealsoelsewhereinthebody,eg.theloweroesophagealsphinctermuscle.

Diltiazemhasnotbeenshowntohaveaneffectonelectrolyte-,lipid-orglucosebalanceinhealthyordiabeticpersons.

5.2Pharmacokineticproperties

Reproductive

systemand

breastdisorders Gynecomastia

General

disordersand

administration

siteconditions lowerlimb

oedema

(peripheral

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absolutebioavailabilityofdiltiazemhydrochlorideisonlyabout40%(withinterindividualvariabilityrangingfrom24

to74%).Thebioavailabilityisindependentofformulationortherapeuticdose.Adietrichinfatandproteinslightly

increasesthebioavailabilityofasustained-releasecapsuleformulation,butthishasnoclinicalsignificance.Therelease

ofthedrughasbeenprolongedinthecontrolled-releaseformulationbyspecialpharmaceuticaltechnology.Thepeak

plasmaconcentrationsarereached2-3hoursafterdosing.Thehighpeakconcentrationsoftheabsorptionphasehave

beeneliminated.ThisallowstheEntrydilS.R.90mgtabletstobeadministeredtwiceeachday.

About80%ofdiltiazemisboundtoproteins,about40%ofthistoplasmaalbumin.Proteinbindingdoesnotappearto

beinfluencedbyphenylbutazone,warfarin,propranolol,salicylicacidordigoxin.Diltiazemiswidelydistributedto

varioustissues.Theapparentvolumeofdistributionis5l/kgandthevolumeofcentralcompartmentis0.9l/kg.Inthe

blood,diltiazemisevenlydistributedtotheplasmaandbloodcells.Steadystateisreachedwithin3dayswiththe

dosageofone60mgtablet3timesdaily.

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-lifeofdiltiazemrangesfromabout0.1hoursinthefirstphaseto2.1hours

inthemiddleand9.8hoursintheterminalphase.Theeliminationhalf-lifevariesbetween4and7hours.

Thepharmacokineticsofdiltiazemhasnotbeenobservedtochangeafterrepeatedadministrations.Thedrugisnot

accumulatedanditdoesnotinduceitsownmetabolism.Studieswithrenalinsufficiencyandanginapectorispatients

didnotshowdifferenceinthepharmacokineticprofileofdiltiazemascomparedwithstudiesonhealthyvolunteers.

Decreasedfirst-passmetabolismintheelderlytendstoresultinincreasedplasmaconcentrationsofcalciumantagonists

butnomajorchangeshavebeenfoundwithdiltiazem.Renalimpairmentdidnotcausesignificantchangesindiltiazem

pharmacokinetics.Plasmaconcentrationsofdiltiazemalsotendtobehigherinhepaticcirrhosisduetoimpaired

oxidativemetabolism.

5.3Preclinicalsafetydata

Theacutetoxicityofdiltiazemwaslow(oralLD50>500mg/kg)intoxicitystudiesonrodents.Thetoxicityofdiltiazem

wasmainlydirectedtotheheart(transientECGchanges).Interatogenicitystudies,diltiazeminducedfoetalmortality

andmalformations.

Chronictoxicitystudiesinratsrevealednoremarkablechangesatoraldosesupto125mg/kg/dayalthoughtherewas

60%mortalityatthisdose.Indogschronicallytreatedwithoraldosesof20mg/kg/day,transientrisesinSGPTwere

observed.

Embryotoxicityhasbeenreportedinmice,ratsandrabbitsfollowingi.p.administrationofdiltiazem.Maintypesof

malformationsincludedlimbandtaildefectswithasmallnumberofvertebralandribdeformities.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Castoroil,hydrogenated

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Polyacrylatedispersion30percent

Talc

Magnesiumstearate

Film-coating:

Hypromellose

Sucrose

Glycerol(85percent)

Titaniumdioxide(E171)

Magnesiumstearate

Polysorbate80

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Packsizes: 30&100tablets

Container: AbrownamberPh.Eur.TypeIIIglasscontainerclosedwithapilfer-proofclosurelinedwithexpanded

polyethylene,aluminiumandMelinexandpackedinanoutercardboardcarton.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

OrionCorporation

Orionintie1

FIN-02200Espoo

Finland

8MARKETINGAUTHORISATIONNUMBER

PA1327/4/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:30May1988

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10DATEOFREVISIONOFTHETEXT

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