ETHIRFIN

Main information

  • Trade name:
  • ETHIRFIN Tablet Prolonged Release 20 Milligram
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ETHIRFIN Tablet Prolonged Release 20 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0549/015/001
  • Authorization date:
  • 09-01-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PA0549/015/001

CaseNo:2038354

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

EthypharmSA

17-21rueSt.Mattieu,78550Houdan,France

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Ethirfin20MilligramTabletProlongedRelease

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/06/2007until08/01/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ETHIRFIN20mg,prolonged-releasecapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachhard,prolongedreleasecapsulecontainsmorphinesulphate20mg.

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasecapsule,hard

Capsulewithlight-blueopaquecapandwhiteopaquebodywith'20'printedinblackonthebody,containingoff-white

toyellowishsphericalmicrogranules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Severechronicstablepain.

Thismedicinalproductisnotsuitableforinitiatingtreatment,thereforetheuseshouldbelimitedtopatientsalready

controlledbyimmediatereleasemorphineorbyprolongedreleasemorphineintendedfortwicedailyadministration.

4.2Posologyandmethodofadministration

Adults

Thedosagedependsontheseverityofthepain,thepatient’sageandprevioushistoryofanalgesicrequirements.

Patientsshouldhavetheirdoserequirementofimmediatereleasemorphineorprolongedreleasemorphinecalculated

thenchangetoETHIRFINcapsuleoncedaily.

Adjustmentofthedosage

Anadjustmentofthedosageisjustifiedwhenpreviouslyprescribeddoses(thelastprescribedlevel)proveinsufficient.

Frequencyofevaluation

Whenadosagelevelprovestobeineffective,itshouldnotbemaintainedformorethan24to48hours.Thepatient

shouldthereforebeassessedatshortintervalsuntilthepainiscontrolled.Inpractice,atthestartoftreatment,daily

evaluationisrecommended.

Increaseofthedoses

Ifthepatient’spainisnotcontrolled,thedosesofmorphineshouldbeincreasedbyabout30to50%.Inthisdose

adjustmentprocess,thereisnoupperlimitaslongasundesirableeffectscanbecontrolled.

Decreaseofthedoses

Whenrequired,decreasesofdosesshouldbemadegraduallyinordertoavoidwithdrawalsyndrome.

Correspondencebetweendifferentroutesofadministration

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Incomparisonwiththeoralroute,theintravenousdosageshouldbereducedbytwothirdsandthesubcutaneous

dosagebyhalf.

Whenswitchingoverfromonerouteofadministrationtoanother,thesecoefficientsmustbetakenintoconsideration

inordertomaintainthesamequantityofbioavailablemorphine.

Similarly,inpatientspreviouslytreatedwithimmediatereleaseoralmorphine,thedailydosageofmorphinewill

remainunchanged.

Treatmentofbreakthroughpain

Incaseofbreakthroughpain,ashort-actingmorphinemaybeadministeredinadditiontotheprolonged-release

morphinemaintenancetreatment.

Children

TheuseofETHIRFINcapsulesinchildrenhasnotbeenevaluatedandisnotrecommended.

Specialpatientpopulation

Areductionindosagemaybeadvisableinelderlyandinpatientswithsignificantlyimpairedrenalorhepaticfunctions

(seesection4.4).Thetreatmentshouldbestartedatalowerdosageandthedosesandfrequencyofadministration

adaptedsubsequently,asforanypatient,totheclinicalcondition.

Methodofadministration

Oraluse.

Capsulesshouldbeadministeredat24-hourlyintervals.

Thecapsulesmaybeswallowedwhole.Thecapsulesandcontentsshouldnotbecrushedorchewed.Ifthecapsules

cannotbeswallowed,theircontentscanbeadministereddirectlyinsemi-solidfoodsuchasafruitorvegetablepurée,

jamoryoghurt,orthroughgastricorgastrostomytubeswithadiameterofatleast16FG(Frenchgauge)withanopen

distalendorlateralpores.30to50mlwaterissufficienttoflushthetube.

4.3Contraindications

Decompensaterespiratoryfailure,

acuteabdominalsyndromeofunknownorigin,

severehepaticinsufficiency,

uncontrolledconvulsivedisorders,

concomitantuseofmorphineagonist/antagonist(seesection4.5),

concomitantintakeofalcohol,

breast-feedingiflongtermtreatmentafterbirthisnecessary(seesection4.6),

hypersensitivitytomorphineortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Warnings

Sustained-releasedformsofmorphinearenotemergencytreatmentsofpain.Thisformulationisnotappropriatefor

treatingperi-operativepain.

Itshouldbeemphasisedthatpatients,oncetitratedtoaneffectivedoseofacertainopioiddrug,shouldnotbechanged

tootherprolonged-releasemorphineorothernarcoticanalgesicpreparationswithoutretitrationandclinical

assessment.Otherwiseacontinuinganalgesicactionisnotensured.

Anincreaseinthedosesforpainmanagement,eveniftherearehigh,doesnotgenerallyreflectadevelopmentof

tolerance.

Insistentandrepeateddemandsimposefrequentre-evaluationofthepatient’scondition.Inmostcases,theyreflecta

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Whenthecauseofpainistreatedsimultaneously:thedosesshouldbeadjustedaccordingtotheresultsofthe

treatmentadministered.

Suddendiscontinuationofprolongedtreatmentinducesawithdrawalsyndrome,characterisedbythefollowing

symptoms:anxiety,irritability,shivering,mydriasis,hotflushes,sudation,lacrimation,rhinorrhoea,nausea,vomiting,

abdominalcramps,diarrhoea,jointpain.Theoccurrenceofthiswithdrawalsyndromecanbepreventedbyreducing

thedosesgradually.

Morphineisanarcotic,whichmaybeusedforpurposesforwhichitisnotintended(misuse):inthiscontext,chronic

usemayleadtophysicalandmentaldependenceandtolerance.

Morphinecanneverthelessbeprescribedinpatientswithahistoryofdrugaddictionifmorphineisconsidered

absolutelynecessaryforthetreatmentofpain.

TheconcomitantintakeofalcoholduringtherapywithETHIRFINmustbeavoided,sincealcoholacceleratesthe

releaseofmorphinewhichmayleadtoincreasedbloodlevelsofmorphine.

Specialprecautionsforuse

Morphineshouldbeusedwithprecautioninthefollowingcases:

Disordersofconsciousness,convulsivedisorders,biliarytractdisorders,pancreatitis,prostatichypertrophy,

Respiratoryinsufficiency:

Respirationrateshouldbecloselymonitored.Drowsinessmaybeawarningofdecompensation.

Itisimportanttoreducethedosesofmorphinewhenotheranalgesictreatmentsareprescribedsimultaneously,assuch

combinationsenhancedtheriskofsuddenoccurrenceofrespiratoryfailure.

Elderly:

Becauseoftheparticularsensitivityofelderlysubjectstothecentraladverseeffects(confusion)orgastrointestinal

effects,andofthephysiologicalreductionoftheirrenalfunction,cautionshouldbeexercised.

Concomitantadministrationofothermedicinalproducts,andparticularlyoftricyclicantidepressants,furtherincreases

thelikelihoodofundesirableeffectssuchasconfusionandconstipation.

Urethro-prostaticdisease,whichisfrequentinthispopulation,enhancestheriskofurineretention.

Theseconsiderationsshouldneverthelessnotrestricttheuseofmorphineinelderlypatientsprovidedthese

precautionsarecompliedwith.

Impairedhepaticfunction:

Morphineshouldbeadministeredunderclosemedicalsupervision.

Impairedrenalfunction:

Asmorphineiseliminatedbythekidneysintheformofanactivemetabolite,reductionofdosagemaybeadvisable

(seesection4.2).

Chronicconstipationandintestinalmechanicaldisorders:

Opioidsinhibittheperistaltismofthelongitudinalfibresofsmoothmuscles;thereforeitisessentialtoensurethatno

occlusivesyndrome,inparticularileusexistsbeforeinitiatingthetreatment.

Constipationisacommonproblemduringtreatmentwithopioids.Aprophylactictreatmentshouldbeprescribed

concomitantlywithmorphine.

Intracranialhypertensionandheadinjury:

Inthepresenceofincreasedintracranialpressure,morphineshouldbeusedwithcautionsinceitmayinduceafurther

rise.Inpatientswithheadinjurymorphinemayobscurethediagnosisortheclinicalcourse.

Inthesepatients,morphineshouldbeusedonlyifthebenefitofthetreatmentclearlyoutweighstherisk.

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Morphinemayproduceapositivereactiontoanti-dopingtests.

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Thefactthatalotofmedicinalproductsorsubstancesmayaddtheirsedativeeffectsandleadtoadecreaseof

vigilanceshouldbetakenintoaccount.Thesemedicinalproductsaremorphinicderivatives(analgesics,cough

medicines,opiatedependencetreatments),neuroleptics,barbiturics,benzodiazepines,othertreatmentsofanxietythan

benzodiazepines(e.g.meprobamate),sedativeantidepressants(amitriptyline,doxepine,mianserine,mirtazapine,

trimipramide),sedativeH1antihistaminics,centralantihypertensivedrugs,baclofeneandthalidomide.

Monoamineoxidaseinhibitorshavebeenreportedtoreactwithnarcoticanalgesics,producingCNSexcitationor

depressionwithhyper-orhypotensivecrises.

Contraindicationofconcomitantuse(seesection4.3)

+Morphineagonists/antagonists(buprenorphine,nalbuphine,pentazocine):reductionoftheanalgesicorcougheffect

bycompetitiveblockingofthereceptors,withariskofoccurrenceofawithdrawalsyndrome.

+Alcoholintake:

TheconcomitantintakeofalcoholduringtherapywithETHIRFINmustbeavoided,sincealcoholacceleratesthe

releaseofmorphinewhichmayleadtoincreasedbloodlevelsofmorphine.

Alcoholincreasesthesedativeeffectofmorphineandmorphine-likeanalgesics.

Consumptionofalcoholicdrinksandmedicinalproductscontainingalcoholiscontraindicated.

Theimpairmentofvigilancemaymakeitdangeroustodrivevehiclesandoperatemachines.

Concomitantusenotrecommended

+Naltrexone:

riskofreductionoftheanalgesiceffect.Thedosesofthemorphinicderivativeshouldbeincreasedifneeded.

Precautionincludingdoseadjustment

+Rifampicine:

Riskofdecreaseoftheplasmaconcentrationsofmorphineanditsactivemetaboliteandthusefficacy.Clinicaleffect

ofmorphineshouldbemonitoredanddosesofmorphineadjustedduringandaftertreatmentwithrifampicine.

Concomitantusewhichneedstobetakenintoconsideration

+Othermorphinic-agonistanalgesics(alfentanil,codeine,dextromoramide,dextropropoxyphene,dihydrocodeine,

fentanyl,oxycodone,pethidine,phenoperidine,remifentanil,sufentanil,tramadol).

+Morphine-likecoughtreatments(dextrometorphane,noscapine,pholcodine,codeine,ethylmorphine).

+Barbiturics.

+Benzodiazepinesandbenzodiazepine-liketreatments.

Increasedriskofrespiratorydepression,thatcouldbefatalincaseofoverdose

4.6Pregnancyandlactation

Pregnancy

Animalstudiesindicateteratogeniceffects(seesection5.3).

Inhumans,dataonalargenumberofexposedpregnanciesindicatenoundesirableeffectofmorphinesulphate.

Highdosesadministeredattheendofpregnancy,evenforbriefperiodsoftreatment,cancauserespiratorydepression

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Chronicconsumptionofmorphinebythemotherduringthelastthreemonthsofpregnancy,regardlessofthedose,can

produceawithdrawalsyndromeinthenewborncharacterisedbyirritability,vomiting,convulsionsandincreased

lethality.

Intheeventofoccasionalconsumptionofhighdoses,chronictreatmentoraddictionattheendofpregnancy,neonatal

monitoringisrecommendedinordertopreventtherisksofrespiratorydepressionorwithdrawalsymptomsinthe

newborn.Administrationofanopioidantagonistshouldbeconsideredifnecessary.

Therefore,itisadvisednottousemorphineduringpregnancy,exceptwhennoalternativepaintreatmentsare

available,takingintoaccountthebenefitforthemotherandthepotentialriskforthefoetus.

Lactation

Morphineisexcretedinbreastmilkandreachesahigherconcentrationasintheplasmaofthemother.Therefore,

therapeuticrelevantconcentrationscanbereached.

Asingleadministrationappearswithoutriskforthenewborn,

ifrepeatedadministrationsforseveraldaysareneeded,breastfeedingshouldbetemporarilysuspended,

iflong-termtreatmentafterbirthisnecessary,breastfeedingiscontra-indicated(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

ETHIRFINhasmajorinfluenceontheabilitytodriveandusemachines.Thishastobeexpectedespeciallyatthe

beginningoftreatment,atanychangeofdosageaswellasinconnectionwithalcoholortranquilizers.Patients

stabilizedonaspecificdosagewillnotnecessarilyberestricted.Therefore,patientsshouldconsulttheirphysicianto

knowwhetherdrivingoruseofmachinesispermitted.

4.8Undesirableeffects

Atusualdoses,themostcommonundesirableeffectsofmorphinearenausea,vomiting,constipationanddrowsiness.

Ifnecessary,thecapsulescaneasilybecombinedwithananti-emetic.Constipationcanbetreatedwithasuitable

laxative.

Cardiovascularsystemdisorders:

Uncommon(>1/1000,<1/100):clinicalrelevantchangesofbloodpressure.

Rare(>1/10000,<1/1000):facialflushing,palpitations,severedecreaseinbloodpressure,bradycardia,tachycardia.

Centralandperipheralnervoussystemdisorders:

Verycommon(>1/10):dependingfromdosesedationandrespiratorydepression.

Common(>1/100,<1/10):headache,dizziness.

Rare(>1/10000,<1/1000):raisedintracranialpressure.

Veryrare(<1/10000)includingisolatedreports:tremor,muscularfasciculations,epileptiformconvulsions.

Especiallyunderhighdosagehyperalgesiaandallodyniawhichwillnotrespondtoahigherdoseofmorphine.

Psychiatricdisorders:

Verycommon(>1/10):moodalterations.

Common(>1/100,<1/10):Psychicside-effectsmayoccurfollowingadministrationofmorphinewhichvary

individuallyinintensityandnature(dependingonpersonalityanddurationofmedication).Theseincludechangesin

mood(usuallyelation,occasionallydysphoria),sleepdisturbance,changesinactivity(usuallysuppression,

occasionallyexcitation)andchangesincognitiveandsensorialcapacity(e.g.decisionbehaviour,perceptiondisorders,

hallucinations,nightmares,particularlyintheelderly).

Visiondisorders:

Common(>1/100,<1/10):miosis.

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Respiratorysystemdisorders:

Rare(>1/10000,<1/1000):bronchospasm.

Veryrare(<1/10000)includingisolatedreports:dyspnoea.

Gastrointestinaldisorders:

Verycommon:nausea,drymouth.

Common(>1/100,<1/10):vomiting,constipation,dyspepsia,lossofappetite.

Rare(>1/10000,<1/1000):pancreatitis.

Veryrare(<1/10000)includingisolatedreports:abdominalpain.

Skinandappendagesdisorders:

Common(>1/100,<1/10):sweating,hypersensitivityreactions,e.g.urticaria,pruritus.

Veryrare(<1/10000)includingisolatedreports:dermalreactions(e.g.exanthema,peripheraledema).

Musculo-Skeletalsystemdisorders:

Veryrare(<1/10000)includingisolatedreports:musclecramps.

Liverandbiliarysystemdisorders:

Rare(>1/10000,<1/1000):biliarycolic.

Veryrare(<1/10000)includingisolatedreports:increasedactivityofhepaticenzymes.

Urinarysystemdisorders:

Common(>1/100,<1/10):micturitiondisorders(difficultyinpassingurineandurinaryretention).

Rare(>1/10000,<1/1000):renalcolic.

Bodyasawhole:

Symptomsofwithdrawalreactions,similartothoseoccurringduringopiatewithdrawal,mayoccurasfollows:

agitation,anxiety,nervousness,insomnia,hyperkinesia,tremorandgastrointestinalsymptoms.

Theeffectofmorphinehasledtoitsabuse,anddependencemaydevelopwithregular,inappropriateuse.

4.9Overdose

Signsofmorphineintoxicationandoverdosearedrowsiness,severemiosis(pinpointpupils),respiratorydepression,

hypothermiaandhypotension.Circulatorycollapseandcomamayoccurinmoreseverecases.

Treatmentofmorphineoverdose:

Primaryattentionshouldbegiventoestablishingfreeairwaysandinitiatingassistedorcontrolledventilation.

Gastricemptyingmaybenecessaryinordertoremoveunabsorbeddrug,particularlywhenamodified-release

formulationhasbeentaken.

Intheeventofmassiveoverdose,administrationofnaloxone0.4-0.8mgintravenouslyisrecommended.The

administrationshouldberepeatedat2-3minuteintervals,asnecessary,oranaloxoneinfusionof2mgin500ml(0.004

mg/ml)insodiumchloridesolution9mg/ml(0.9%)oringlucosesolution5%shouldbeadministered.

Theinfusionshouldbegivenataraterelatedtothepreviousbolusdosesadministeredandshouldbeinaccordance

withthepatient’sresponse.However,becausetheeffectsofnaloxonearerelativelyshort-lived,thepatientmustbe

carefullymonitoreduntilspontaneousrespirationhasbeenreliablyrestored.Significantplasmaticconcentrationsof

morphinemaycontinueforupto24hoursafteradministrationandmorphineoverdosemanagementshouldbeadapted

accordingly.

Forlesssevereoverdose,administrationofnaloxone0.2mgintravenouslywillbefollowedbyincrementsof0.1mg

every2minutes,ifrequired.

Naloxoneshouldnotbeadministeredintheabsenceofclinicallysignificantrespiratoryorcirculatorydepression

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tobephysicallydependentonmorphine.Insuchcases,anabruptorcompletereversalofopioideffectsmayprecipitate

acutewithdrawalsyndrome.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Opioids;naturalopiumalkaloids.

ATCcode:N02AA01

MorphineactsasanagonistonopioidreceptorsintheCNS,particularlymuandtoalesserextentkappareceptors.

Actiononthecentralnervoussystem:

Morphineexertsadose-dependantanalgesicaction.Itcanaffectpsychomotorbehaviourandinduce,dependingonthe

doseandthepatientcondition,sedationorexcitation.

Atandabovetherapeuticdoselevels,morphinehasadepressanteffectontherespiratoryandcoughingcentres.The

respiratorydepressanteffectsofmorphinesubsidewithchronicadministration.Morphinehasvariableemetic

propertiesduetoitstripleactiononthevomitingcentre,possiblyonthecochleovestibularcentreandongastric

emptying(seebelow).

Finally,morphinecausesmiosisofcentralorigin.

Actiononsmoothmuscle:

Morphinereducesthetoneandperistaltismofthelongitudinalfibresandincreasesthetoneofthecircularfibres,thus

causingspasmofthesphincters(pylorus,ileocaecalvalve,analsphincter,sphincterofOddi,bladdersphincter).

5.2Pharmacokineticproperties

Absorption

Morphineiswellabsorbedfromcapsulesand,ingeneral,peakplasmaconcentrationsareachievedabout5hours

followingadministration.Astudyontheinfluenceoffoodshowedthatthisfactordoesnothaveaclinicallysignificant

influenceonthepharmacokineticprofileofETHIRFIN.

ETHIRFINcanthereforebegivenwithorwithoutmeals.Whengivenorally,morphinedisplayssignificantfirst-pass

metabolism,resultinginlowerbioavailabilityascomparedwithanequivalentintravenousorintramusculardose.

Distribution

30%ofthedrugisboundtoplasmaproteins.

Metabolism

Morphineismainlymetabolisedthroughglucuronidationtomorphine-3-glucuronideandmorphine-6-glucuronide,

whichthenundergorenalexcretion.Thesemetabolitesarealsopartiallyexcretedinbileandmaybesubjectto

hydrolysisandsubsequentreabsorption.

Elimination

Theglucuronidemetabolitesareeliminatedessentiallybytheurinaryroute,bybothglomerularfiltrationandtubular

secretion.Theamounteliminatedinthefaecesissmall(<10%).

Linearity

Thepharmacokineticsofmorphinearelinearacrossaverywidedoserange.

Becauseofthegreatinter-patientvariationsinmorphinepharmacokineticsandinpatients’analgesicrequirements,the

dailydosagemustbeindividuallytitratedtoachieveappropriatepainmanagement.

5.3Preclinicalsafetydata

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organism,whiledatainhumansdonotshowevidenceofmalformationsorfetotoxiceffectsofmorphine.

Experimentalstudieshaveshownthatmorphinesulphateinduceschromosomedamageinanimalsinsomaticandgerm

cellsandinhumansomaticcells.Agenotoxicpotentialforhumanscannotbeeliminated.

Therearenootherpreclinicaldataofrelevancetotheprescriber.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents:

Sugarspheres(containingsucroseandmaizestarch)

Hypromellose

Poly(ethylacrylate,methylmethacrylate,trimethylammonioethylmethacrylatechloride)1:2:0.1

Triethylcitrate

Talc

Hydrophobiccolloidalsilica

Capsuleshell:

Gelatin

Titaniumdioxide(E171)

BrilliantblueFCF(E133)

Blackink:

Shellac

Blackironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Blister(PVC/aluminium),packedincardboardboxes.

Packsizes:7,8,10,14,16,20,28,30,50,60,90,100,120or200capsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

ETHYPHARM

17/21rueSaint-Matthieu

78550Houdan

France

8MARKETINGAUTHORISATIONNUMBER

PA549/15/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

09January2006

10DATEOFREVISIONOFTHETEXT

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