BENETOR PLUS

Main information

  • Trade name:
  • BENETOR PLUS
  • Dosage:
  • 20/ 25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BENETOR PLUS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/152/002
  • Authorization date:
  • 29-07-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BenetorPlus20mg/25mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

BenetorPlus20mg/25mgfilmcoatedtablets:Eachfilm-coatedtabletcontains20mgolmesartanmedoxomiland25

mghydrochlorothiazide.

Excipients:

BenetorPlus20mg/25mgfilmcoatedtablets:Eachfilm-coatedtabletcontainslactosemonohydrate(98.2mg),

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablets

ProductimportedfromFrance:

Pinkishroundfilm-coatedtabletwith‘C24’debossedononeside

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension.

BenetorPlusfixeddosecombinationisindicatedinpatientswhosebloodpressureisnotadequatelycontrolledon

olmesartanmedoxomilalone.

4.2Posologyandmethodofadministration

Adults

BenetorPlusisnotforuseasinitialtherapy,butinpatientswhosebloodpressureisnotadequatelycontrolledby20mg

olmesartanmedoxomilalone.BenetorPlusisadministeredoncedaily,withorwithoutfood.

Whenclinicallyappropriate,directchangefrommonotherapywith20mgolmesartanmedoxomiltothefixed

combinationmaybeconsidered,takingintoaccountthattheantihypertensiveeffectofolmesartanmedoxomilis

maximalbyabout8weeksafterinitiatingtherapy(seesection5.1).Dosetitrationoftheindividualcomponentsis

recommended:

20mgolmesartanmedoxomil/12.5mghydrochlorothiazidemaybeadministeredinpatientswhosebloodpressureis

notadequatelycontrolledbytheoptimalmonotherapyolmesartanmedoxomil20mgalone.

20mgolmesartanmedoxomil/25mghydrochlorothiazidemaybeadministeredinpatientswhosebloodpressureisnot

adequatelycontrolledby20mgolmesartanmedoxomil/12.5mghydrochlorothiazide.

Amaximumdailydoseof20mgolmesartanmedoxomiland25mghydrochlorothiazideincombinationshouldnotbe

exceeded.

Elderly

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Renalimpairment

WhenBenetorPlusisusedinpatientswithmildtomoderaterenalimpairment(creatinineclearanceof30–60ml/min)

periodicmonitoringofrenalfunctionisadvised(seesection4.4).BenetorPlusiscontraindicatedinpatientswith

severerenalimpairment(creatinineclearance<30mL/min)(seesection4.3).

Hepaticimpairment

BenetorPlusshouldbeusedwithcautioninpatientswithmildtomoderatehepaticimpairment(seesections4.4,5.2).

Inpatientswithmoderatehepaticimpairment,aninitialdoseof10mgolmesartanmedoxomiloncedailyis

recommendedandthemaximumdoseshouldnotexceed20mgoncedaily.Closemonitoringofbloodpressureand

renalfunctionisadvisedinhepatically-impairedpatientswhoarereceivingdiureticsand/orotherantihypertensive

agents.Thereisnoexperienceofolmesartanmedoxomilinpatientswithseverehepaticimpairment.

BenetorPlusshouldnotbeusedinpatientswithseverehepaticimpairment(seesections4.3,5.2),cholestasisand

biliaryobstruction(seesection4.3).

Childrenandadolescents

BenetorPlusisnotrecommendedforuseinchildrenbelow18yearsduetoalackofdataonsafetyandefficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstances,toanyoftheexcipients(seesection6.1)ortoothersulfonamide-derived

substances(sincehydrochlorothiazideisasulfonamide-derivedmedicinalproduct).

Severerenalimpairment(creatinineclearance<30mL/min).

Refractoryhypokalaemia,hypercalcaemia,hyponatraemiaandsymptomatichyperuricaemia.

Severehepaticimpairment,cholestasisandbiliaryobstructivedisorders.

2ndand3rdtrimesterofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

Intravascularvolumedepletion:

Symptomatichypotension,especiallyafterthefirstdose,mayoccurinpatientswhoarevolumeand/orsodiumdepleted

byvigorousdiuretictherapy,dietarysaltrestriction,diarrhoeaorvomiting.Suchconditionsshouldbecorrectedbefore

theadministrationofBenetorPlus.

Otherconditionswithstimulationoftherenin-angiotensin-aldosteronesystem:

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithmedicinalproductsthataffectthissystemhasbeenassociatedwithacutehypotension,

azotaemia,oliguriaor,rarely,acuterenalfailure.

Renovascularhypertension:

Thereisanincreasedriskofseverehypotensionandrenalinsufficiencywhenpatientswithbilateralrenalartery

stenosisorstenosisofthearterytoasinglefunctioningkidneyaretreatedwithmedicinalproductsthataffecttherenin-

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Renalimpairmentandkidneytransplantation:

BenetorPlusshouldnotbeusedinpatientswithsevererenalimpairment(creatinineclearance<30ml/min)(see

section4.3).Nodosageadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment(creatinine

clearanceis 30ml/min,<60mL/min).However,insuchpatientsBenetorPlusshouldbeadministeredwithcaution

andperiodicmonitoringofserumpotassium,creatinineanduricacidlevelsisrecommended.Thiazidediuretic-

associatedazotaemiamayoccurinpatientswithimpairedrenalfunction.Ifprogressiverenalimpairmentbecomes

evident,carefulreappraisaloftherapyisnecessary,withconsiderationgiventodiscontinuingdiuretictherapy.Thereis

noexperienceoftheadministrationofBenetorPlusinpatientswitharecentkidneytransplantation.

Hepaticimpairment:

Thereiscurrentlynoexperienceofolmesartanmedoxomilinpatientswithseverehepaticimpairment.Furthermore,

minoralterationsoffluidandelectrolytebalanceduringthiazidetherapymayprecipitatehepaticcomainpatientswith

impairedhepaticfunctionorprogressiveliverdisease.Thereforecareshouldbetakeninpatientswithmildto

moderatehepaticimpairment(seesection4.2).UseofBenetorPlusinpatientswithseverehepaticimpairment,

cholestasisandbiliaryobstructioniscontraindicated(seesections4.3,5.2).

Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyopathy:

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,orobstructive

hypertrophiccardiomyopathy.

Primaryaldosteronism:

Patientswithprimaryaldosteronismgenerallywillnotrespondtoanti-hypertensivemedicinalproductsactingthrough

inhibitionoftherenin-angiotensinsystem.Therefore,theuseofBenetorPlusisnotrecommendedinsuchpatients.

Metabolicandendocrineeffects:

Thiazidetherapymayimpairglucosetolerance. Indiabeticpatientsdosageadjustmentsofinsulinororal

hypoglycaemicagentsmayberequired(seesection4.5).Latentdiabetesmellitusmaybecomemanifestduring

thiazidetherapy.

Increasesincholesterolandtriglyceridelevelsareundesirableeffectsknowntobeassociatedwiththiazidediuretic

therapy.

Hyperuricaemiamayoccurorfrankgoutmaybeprecipitatedinsomepatientsreceivingthiazidetherapy.

Electrolyteimbalance:

Asforanypatientreceivingdiuretictherapy,periodicdeterminationofserumelectrolytesshouldbeperformedat

appropriateintervals.

Thiazides,includinghydrochlorothiazide,cancausefluidorelectrolyteimbalance(includinghypokalaemia,

hyponatraemiaandhypochloraemicalkalosis).Warningsignsoffluidorelectrolyteimbalancearedrynessofthe

mouth,thirst,weakness,lethargy,drowsiness,restlessness,musclepainorcramps,muscularfatigue,hypotension,

oliguria,tachycardia,andgastrointestinaldisturbancessuchasnauseaorvomiting(seesection4.8).

Theriskofhypokalaemiaisgreatestinpatientswithcirrhosisoftheliver,inpatientsexperiencingbriskdiuresis,in

patientswhoarereceivinginadequateoralintakeofelectrolytesandinpatientsreceivingconcomitanttherapywith

corticosteroidsorACTH(seesection4.5).

Conversely,duetoantagonismattheangiotensin-IIreceptors(AT1)throughtheolmesartanmedoxomilcomponentof

BenetorPlushyperkalaemiamayoccur,especiallyinthepresenceofrenalimpairmentand/orheartfailure,and

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Potassium-sparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutesandothermedicinal

productsthatmayincreaseserumpotassiumlevels(e.g.heparin)shouldbeco-administeredcautiouslywithBenetor

Plus(seesection4.5).

Thereisnoevidencethatolmesartanmedoxomilwouldreduceorpreventdiuretic-inducedhyponatraemia.Chloride

deficitisgenerallymildandusuallydoesnotrequiretreatment.

Thiazidesmaydecreaseurinarycalciumexcretionandcauseanintermittentandslightelevationofserumcalciumin

theabsenceofknowndisordersofcalciummetabolism.Hypercalcaemiamaybeevidenceofhidden

hyperparathyroidism.Thiazidesshouldbediscontinuedbeforecarryingouttestsforparathyroidfunction.

Thiazideshavebeenshowntoincreasetheurinaryexcretionofmagnesium,whichmayresultinhypomagnesaemia.

Dilutionalhyponatraemiamayoccurinoedematouspatientsinhotweather.

Lithium:

AswithothermedicinalproductscontainingangiotensinIIreceptorantagonistsandthiazideincombination,the

coadministrationofBenetorPlusandlithiumisnotrecommended(seesection4.5).

Ethnicdifferences:

AswithallotherangiotensinIIantagonists,thebloodpressureloweringeffectofolmesartanmedoxomilissomewhat

lessinblackpatientsthaninnon-blackpatients,possiblybecauseofahigherprevalenceoflow-reninstatusinthe

blackhypertensivepopulation.

Anti-dopingtest:

Hydrochlorothiazidecontainedinthismedicinalproductcouldproduceapositiveanalyticresultinananti-dopingtest.

Pregnancy:

AngiotensinIIantagonistsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedangiotensinIIantagonists

therapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensive

treatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwith

angiotensinIIantagonistsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted(see

sections4.3and4.6).

Other:

Ingeneralarteriosclerosis,inpatientswithischaemicheartdiseaseorischaemiccerebrovasculardisease,thereis

alwaysariskthatexcessivebloodpressuredecreasecouldresultinamyocardialinfarctionorstroke.

Hypersensitivityreactionstohydrochlorothiazidemayoccurinpatientswithorwithoutahistoryofallergyor

bronchialasthma,butaremorelikelyinpatientswithsuchahistory.

Exacerbationoractivationofsystemiclupuserythematosushasbeenreportedwiththeuseofthiazidediuretics.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp-

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Potentialinteractionsrelatedtobotholmesartanmedoxomilandhydrochloro-thiazide:

Concomitantusenotrecommended

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithangiotensinconvertingenzymeinhibitorsand,rarely,withangiotensinIIantagonists.In

addition,renalclearanceoflithiumisreducedbythiazidesandconsequentlytheriskoflithiumtoxicitymaybe

increased.ThereforeuseofBenetorPlusandlithiumincombinationisnotrecommended(seesection4.4).Ifuseof

thecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

Concomitantuserequiringcaution

Baclofen:

Potentiationofantihypertensiveeffectmayoccur.

Non-steroidalanti-inflammatorymedicinalproducts:

NSAIDs(i.e.acetylsalicylicacid(>3g/day),COX-2inhibitorsandnon-selectiveNSAIDs)mayreducethe

antihypertensiveeffectofthiazidediureticsandangiotensinIIantagonists.

Insomepatientswithcompromisedrenalfunction(e.g.dehydratedpatientsorelderlypatientswithcompromisedrenal

function)theco-administrationofangiotensinIIantagonistsandagentsthatinhibitcyclo-oxygenasemayresultin

furtherdeteriorationofrenalfunction,includingpossibleacuterenalfailure,whichisusuallyreversible.Therefore,the

combinationshouldbeadministeredwithcaution,especiallyintheelderly.Patientsshouldbeadequatelyhydratedand

considerationshouldbegiventomonitoringofrenalfunctionafterinitiationofconcomitanttherapyandperiodically

thereafter.

Concomitantusetobetakenintoaccount

Amifostine:

Potentiationofantihypertensiveeffectmayoccur.

Otherantihypertensiveagents:

ThebloodpressureloweringeffectofBenetorPluscanbeincreasedbyconcomitantuseofotherantihypertensive

medicinalproducts.

Alcohol,barbiturates,narcoticsorantidepressants:

Potentiationoforthostatichypotensionmayoccur.

Potentialinteractionsrelatedtoolmesartanmedoxomil:

Concomitantusenotrecommended

Medicinalproductsaffectingpotassiumlevels:

Basedonexperiencewiththeuseofothermedicinalproductsthataffecttherenninangiotensinsystem,concomitant

useofpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassiumorothermedicinal

productsthatmayincreaseserumpotassiumlevels(e.g.heparin,ACEinhibitors)mayleadtoincreasesinserum

potassium(seesection4.4).Ifmedicinalproductwhichaffectpotassiumlevelsaretobeprescribedincombination

withBenetorPlus,monitoringofpotassiumplasmalevelsisadvised.

Additionalinformation

Aftertreatmentwithantacid(aluminiummagnesiumhydroxide),amodestreductioninbioavailabilityofolmesartan

wasobserved.

Olmesartanmedoxomilhadnosignificanteffectonthepharmacokineticsorpharmacodynamicsofwarfarinorthe

pharmacokineticsofdigoxin.

Coadministrationofolmesartanmedoxomilwithpravastatinhadnoclinicallyrelevanteffectsonthepharmacokinetics

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OlmesartanhadnoclinicallyrelevantinhibitoryeffectsonhumancytochromeP450enzymes1A1/2,2A6,2C8/9,

2C19,2D6,2E1and3A4invitro,andhadnoorminimalinducingeffectsonratcytochromeP450activities.No

clinicallyrelevantinteractionsbetweenolmesartanandmedicinalproductsmetabolisedbytheabovecytochromeP450

enzymesareexpected.

Potentialinteractionsrelatedtohydrochlorothiazide:

Concomitantusenotrecommended

Medicinalproductsaffectingpotassiumlevels:

Thepotassium-depletingeffectofhydrochlorothiazide(seesection4.4)maybepotentiatedbythecoadministrationof

othermedicinalproductsassociatedwithpotassiumlossandhypokalaemia(e.g.otherkaliureticdiuretics,laxatives,

corticosteroids,ACTH,amphotericin,carbenoxolone,penicillinGsodiumorsalicylicacidderivatives).Such

concomitantuseisthereforenotrecommended.

Concomitantuserequiringcaution

Calciumsalts:

Thiazidediureticsmayincreaseserumcalciumlevelsduetodecreasedexcretion.Ifcalciumsupplementsmustbe

prescribed,serumcalciumlevelsshouldbemonitoredandcalciumdosageadjustedaccordingly.

Cholestyramineandcolestipolresins:

Absorptionofhydrochlorothiazideisimpairedinthepresenceofanionicexchangeresins.

Digitalisglycosides:

Thiazide-inducedhypokalaemiaorhypomagnesaemiamayfavourtheonsetofdigitalisinducedcardiacarrhythmias.

Medicinalproductsaffectedbyserumpotassiumdisturbances:

PeriodicmonitoringofserumpotassiumandECGisrecommendedwhenBenetorPlusisadministeredwithmedicinal

productsaffectedbyserumpotassiumdisturbances(e.g.digitalisglycosidesandantiarrhythmics)andwiththe

followingtorsadesdepointes(ventriculartachycardia)-inducingmedicinalproducts(includingsomeantiarrhythmics),

hypokalaemiabeingapredisposingfactortotorsadesdepointes(ventriculartachycardia):

ClassIaantiarrythmics(e.g.quinidine,hydroquinidine,disopyramide).

ClassIIIantiarrythmics(e.g.amiodarone,sotalol,dofetilide,ibutilide).

Someantipsychotics(e.g.thioridazine,chlorpromazine,levomepromazine,trifluoperazine,cyamemazine,

sulpiride,sultopride,amisulpride,tiapride,pimozide,haloperidol,droperidol).

Others(e.g.bepridil,cisapride,diphemanil,erythromycinIV,halofantrin,mizolastin,pentamidine,

sparfloxacin,terfenadine,vincamineIV).

Non-depolarizingskeletalmusclerelaxants(e.g.tubocurarine):

Theeffectofnondepolarizingskeletalmusclerelaxantsmaybepotentiatedbyhydrochlorothiazide.

Anticholinergicagents(e.g.atropine,biperiden):

Increaseofthebioavailabilityofthiazide-typediureticsbydecreasinggastrointestinalmotilityandstomachemptying

rate.

Antidiabeticmedicinalproducts(oralagentsandinsulin):

Thetreatmentwithathiazidemayinfluencetheglucosetolerance.Dosageadjustmentoftheantidiabeticmedicinal

productmayberequired(seesection4.4).

Metformin:

Metforminshouldbeusedwithcautionbecauseoftheriskoflacticacidosisinducedbypossiblefunctionalrenal

failurelinkedtohydrochlorothiazide.

Beta-blockersanddiazoxide:

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Pressoramines(e.g.noradrenaline):

Theeffectofpressoraminesmaybedecreased.

Medicinalproductsusedinthetreatmentofgout(probenecid,sulfinpyrazoneandallopurinol):

Dosageadjustmentofuricosuricmedicinalproductsmaybenecessarysincehydrochlorothiazidemayraisethelevelof

serumuricacid.Increaseindosageofprobenecidorsulfinpyrazonemaybenecessary.Coadministrationofathiazide

mayincreasetheincidenceofhypersensitivityreactionstoallopurinol.

Amantadine:

Thiazidesmayincreasetheriskofadverseeffectscausedbyamantadine.

Cytotoxicagents(e.g.cyclophosphamide,methotrexate):

Thiazidesmayreducetherenalexcretionofcytotoxicmedicinalproductsandpotentiatetheirmyelosuppressiveeffects.

Salicylates:

Incaseofhighdosagesofsalicylateshydrochlorothiazidemayenhancethetoxiceffectofthesalicylatesonthecentral

nervoussystem.

Methyldopa:

Therehavebeenisolatedreportsofhaemolyticanaemiaoccurringwithconcomitantuseofhydrochlorothiazideand

methyldopa.

Cyclosporin:

Concomitanttreatmentwithcyclosporinmayincreasetheriskofhyperuricaemiaandgouttypecomplications.

Tetracyclines:

Concomitantadministrationoftetracyclinesandthiazidesincreasestheriskoftetracycline-inducedincreaseinurea.

Thisinteractionisprobablynotapplicabletodoxycycline.

4.6Fertility,pregnancyandlactation

Pregnancy(seesection4.3):

Giventheeffectsoftheindividualcomponentsinthiscombinationproductonpregnancy,theuseofBenetorPlusisnot

recommendedduringthefirsttrimesterofpregnancy(seesection4.4).TheuseofBenetorPlusiscontra-indicated

duringthe2 nd

and3 rd

trimesterofpregnancy(seesections4.3and4.4).

TheuseofantiotensinIIantagonistsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).The

useofangiotensinIIantagonistsiscontra-indicatedduringthe2 nd

and3 rd

trimesterofpregnancy(seesections4.3and

4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereis

nocontrolledepidemiologicaldataontheriskwithangiotensinIIantagonists,similarrisksmayexistforthisclassof

drugs.Unlesscontinuedangiotensinreceptorblockertherapyisconsideredessential,patientsplanningpregnancy

shouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforusein

pregnancy.Whenpregnancyisdiagnosed,treatmentwithangiotensinIIantagonistsshouldbestoppedimmediately,

and,ifappropriate,alternativetherapyshouldbestarted.

AngiotensinIIantagoniststherapyexposureduringthe2 nd

and3 rd

trimestersisknowntoinducehumanfetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia).(Seealso5.3“Preclinicalsafetydata”.)

ShouldexposuretoangiotensinIIantagonistshaveoccurredfromthe2 nd

trimesterofpregnancy,ultrasoundcheckof

renalfunctionandskullisrecommended.

InfantswhosemothershavetakenangiotensinIIantagonistsshouldbecloselyobservedforhypotension(seealso

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Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.

Hydrochlorothiazidecrossestheplacenta.Basedonthepharmacologicalmechanismofactionofhydrochlorothiazide

itsuseduringthe2 nd

and3 rd

trimestermaycompromisefoeto-placentalperfusionandmaycausefoetalandneonatal

effectslikeicterus,disturbanceoftheelectrolytebalanceandthrombocytopenia.

Hydrochlorothiazideshouldnotbeusedforgestationaloedema,gestationalhypertensionorpreeclampsiaduetothe

riskofdecreasedplasmavolumeandplacentalhypoperfusion,withoutabeneficialeffectonthecourseofthedisease.

Hydrochlorothiazideshouldnotbeusedforessentialhypertensioninpregnantwomenexceptinraresituationswhere

noothertreatmentcouldbeused

Lactation:

Olmesartanisexcretedintothemilkoflactatingrats.However,itisnotknownwhetherolmesartanpassesintohuman

milk.Thiazidespassintohumanmilkandmayinhibitlactation.Becausenoinformationisavailableregardingtheuse

ofBenetorPlusduringbreast-feeding,BenetorPlusisnotrecommendedandalternativetreatmentswithbetter

establishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,itshouldbebornein

mindthatdizzinessorfatiguemayoccasionallyoccurinpatientstakingantihypertensivetherapy.

4.8Undesirableeffects

Fixeddosecombination:

Inclinicaltrialsinvolving1155patientstreatedwitholmesartanmedoxomil/hydrochlorothiazidecombinationsat

dosagesof20/12.5mgor20/25mgand466patientstreatedwithplaceboforperiodsofupto21months,theoverall

frequencyofadverseeventsonolmesartanmedoxomil/hydrochlorothiazidecombinationtherapywassimilartothaton

placebo.Discontinuationsduetoadverseeventswerealsosimilarforolmesartanmedoxomil/hydrochlorothiazide

20/12.5mg - 20/25mg (2%) and placebo (3%). The frequency of adverse events on olmesartan

medoxomil/hydrochlorothiazideoverallrelativetoplaceboappearedtobeunrelatedtoage(<65yearsversus 65

years),genderorracealthoughthefrequencyofdizzinesswassomewhatincreasedinpatientsaged>75years.

Themostfrequentadverseeventonolmesartanmedoxomil/hydrochlorothiazide20/12.5mg–20/25mg,andtheonly

adverseeventforwhichthefrequencyexceededthatonplacebobyatleast1%,wasdizziness(2.6%onolmesartan

medoxomil/hydrochlorothiazide20/12.5mg-20/25mgand1.3%onplacebo).

AdverseeventsofpotentialclinicalrelevancearelistedbelowbySystemOrganClass.Frequenciesaredefinedas:

common(1/100<1/10);uncommon(1/1,000<1/100);rare(1/10,000<1/1,000);veryrare(<1/10000).

Adversedrugreactionsadditionallyreportedfrompostmarketingexperiencearealsolisted.Foralltheadversedrug

reactionsreportedfrompostmarketingexperienceonly,itisnotpossibletoassignfrequencyandthereforetheyare

mentionedwitha“notknown”frequency(cannotbeestimatedfromtheavailabledata).

Common

(1/100<1/10) Uncommon

(1/1,000<1/100) Rare

(1/10,000<1/1,000) Veryrare

(<1/10,000) Notknown

(cannotbeestimated

fromtheavailable

data)

SystemOrganClass:Metabolismandnutritiondisorders

Hyperuricaemia

Hypertriglyceridaemia

SystemOrganClass:Nervoussystemdisorders

Dizziness Syncope Headache

Disturbancesin

consciousness(such

aslossof

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Additionalinformationontheindividualcomponents:

Adversereactionspreviouslyreportedwitheitheroftheindividualcomponentsmaybepotentialadversereactionswith

BenetorPlus,evenifnotobservedinpostmarketingexperienceandclinicaltrialswiththisproduct.

Olmesartanmedoxomil:

Furtheradverseeventsreportedinclinicaltrialswitholmesartanmedoxomilmonotherapyinhypertensionarelistedby

bodysystemandrankedunderheadingsoffrequency.

Adversedrugreactionsadditionallyreportedfrompostmarketingexperiencearealsolisted.Foralltheadversedrug

reactionsreportedfrompostmarketingexperienceonly,itisnotpossibletoassignfrequencyandthereforetheyare

SystemOrganClass:Cardiacdisorders

Palpitations

SystemOrganClass:Vasculardisorders

Hypotension

Orthostatichypotension

SystemOrganClass:Respiratory,thoracicandmediastinaldisorders

Cough

SystemOrganClass:Gastrointestinaldisorders

Abdominalpain

Nausea

Vomiting

Diarrhoea

SystemOrganClass:Skinandsubcutaneoustissuedisorders

Rash

Eczema Allergicconditions

(suchas

angioneurotic

oedema,and

urticaria)

SystemOrganClass:Musculoskeletalandconnectivetissuedisorders

Myalgia

Musclespasm

SystemOrganClass:Renalandurinarydisorders

Acuterenalfailure

SystemOrganClass:Generaldisordersandadministrationsiteconditions

Fatigue Weakness Asthenicconditions

(suchasasthenia,

malaise)

SystemOrganClass:Investigations

Bloodpotassiumdecreased

Bloodpotassiumincreased

Bloodcalcium

increased

Bloodureaincreased

Bloodlipidsincreased Abnormalrenal

functiontests

SystemOrganClass:LaboratoryFindings

Minorincreasesin

meanuricacid

Minorincreasesin

nitrogenand

creatininevalues

Minordecreasesin

meanhaemoglobin

andhaematocrit

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SinglecasesofrhabdomyolysishavebeenreportedintemporalassociationwiththeintakeofangiotensinIIreceptor

blockers.Acausalrelationship,however,hasnotbeenestablished.

Hydrochlorothiazide:

Hydrochlorothiazidemaycauseorexacerbatevolumedepletionwhichmayleadtoelectrolyteimbalance(seesection

4.4).

Common

(1/100<1/10) Uncommon

(1/1,000<1/100) Rare

(1/10,000<1/1,000) Veryrare

(<1/10,000) Notknown

(cannotbeestimated

fromtheavailable

data)

SystemOrganClass:Bloodandlymphaticsystemdisorders:

Thrombocytopenia

SystemOrganClass:Metabolismandnutritiondisorders

Increasedcreatine

phosphokinase

SystemOrganClass:Nervoussystemdisorders

Vertigo

SystemOrganClass:Cardiacdisorders

Anginapectoris

SystemOrganClass:Respiratory,thoracicandmediastinaldisorders

BronchitisPharyngitis

Rhinitis

SystemOrganClass:Gastrointestinaldisorders

Dyspepsia

Gastroenteritis

SystemOrganClass:Skinandsubcutaneoustissuedisorders

Pruritus

Exanthem

Allergicconditions

suchasdermatitis

allergicandface

oedema

SystemOrganClass:Musculoskeletalandconnectivetissuedisorders

Arthritis

Backpain

Skeletalpain

SystemOrganClass:Renalandurinarydisorders

Haematuria

Urinarytractinfection Renalinsufficiency

SystemOrganClass:Generaldisordersandadministrationsiteconditions

Chestpain

Influenza-like

symptoms

Peripheraloedema

Pain Lethargy

Common

(1/100<1/10) Uncommon

(1/1,000<1/100) Rare

(1/10,000<1/1,000) Veryrare

(<1/10,000) Notknown

(cannotbe

estimatedfromthe

availabledata)

SystemOrganClass:Infectionsandinfestations

Sialadenitis

SystemOrganClass:Bloodandlymphaticsystemdisorders

Leukopenia

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Thrombocytopenia

Aplasticanaemia

Haemolyticanaemia

Bonemarrowdepression

SystemOrganClass:Metabolismandnutritiondisorders

Hyperglycaemia

Glykosuria

Electrolyteimbalance

(including

hyponatraemia,

hypomagnesaemia,

hypochloraemia) Anorexia

SystemOrganClass:Psychiatricdisorders

Restlessness

Depression

Sleepdisturbances

Apathy

SystemOrganClass:Nervoussystemdisorders

Light-headedness

Confusionalstate Lossofappetite Paraesthesia

Convulsions

SystemOrganClass:Eyedisorders

Xanthopsia

Transientblurredvision

Lacrimationdecreased

SystemOrganClass:Earandlabyrinthdisorders

Vertigo

SystemOrganClass:Cardiacdisorders

Cardiacarrhythmias

SystemOrganClass:Vasculardisorders

Necrotisingangiitis(vasculitis,

cutaneousvasculitis)

Thrombosis

Embolism

SystemOrganClass:Respiratory,thoracicandmediastinaldisorders

Dispnoea(includinginterstitial

pneumoniaandpulmonary

oedema)

SystemOrganClass:Gastrointestinaldisorders

Gastricirritation

Constipationand

meteorism Pancreatitis Paralyticileus

SystemOrganClass:Hepatobiliarydisorders

Jaundice(intrahepatic

cholestaticicterus)

Acutecholecystitis

SystemOrganClass:Skinandsubcutaneoustissuedisorders

Photosensitivity

reactions Cutaneouslupus

erythematosus-likereactions,

Reactivationofcutaneouslupus

erythematosus,

Anaphylacticreactions,

Toxicepidermalnecrolysis

SystemOrganClass:Musculoskeletalandconnectivetissuedisorders

Muscleweakness

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4.9Overdose

NospecificinformationisavailableontheeffectsortreatmentofBenetorPlusoverdose.Thepatientshouldbeclosely

monitored,andthetreatmentshouldbesymptomaticandsupportive.Managementdependsuponthetimesince

ingestionandtheseverityofthesymptoms.Suggestedmeasuresincludeinductionofemesisand/orgastriclavage.

Activatedcharcoalmaybeusefulinthetreatmentofoverdose.Serumelectrolytesandcreatinineshouldbemonitored

frequently.Ifhypotensionoccurs,thepatientshouldbeplacedinasupineposition,withsaltandvolumereplacements

givenquickly.

Themostlikelymanifestationsofolmesartanoverdoseareexpectedtobehypotensionandtachycardia;bradycardia

mightalsooccur.Overdosewithhydrochlorothiazideisassociatedwithelectrolytedepletion(hypokalaemia,

hypochloraemia)anddehydrationresultingfromexcessivediuresis.Themostcommonsignsandsymptomsof

overdosearenauseaandsomnolence.Hypokalaemiamayresultinmusclespasmand/oraccentuatecardiac

arrhythmiasassociatedwiththeconcomitantuseofdigitalisglycosidesorcertainanti-arrhythmicmedicinalproducts.

Noinformationisavailableregardingthedialysabilityofolmesartanorhydrochlorothiazide.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:AngiotensinIIantagonistsanddiuretics,ATCcode:C09DA08.

BenetorPlusisacombinationofanangiotensinIIreceptorantagonist,olmesartanmedoxomil,andathiazidediuretic,

hydrochlorothiazide.Thecombinationoftheseingredientshasanadditiveantihypertensiveeffect,reducingblood

pressuretoagreaterdegreethaneithercomponentalone.

OncedailydosingwithBenetorPlusprovidesaneffectiveandsmoothreductioninbloodpressureoverthe24hour

doseinterval.

Olmesartanmedoxomilisanorallyactive,selectiveangiotensinIIreceptor(typeAT1)antagonist.AngiotensinIIis

theprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysasignificantroleinthe

pathophysiologyofhypertension.TheeffectsofangiotensinIIincludevasoconstriction,stimulationofthesynthesis

andreleaseofaldosterone,cardiacstimulationandrenalreabsorptionofsodium. Olmesartanblocksthe

vasoconstrictorandaldosterone-secretingeffectsofangiotensinIIbyblockingitsbindingtotheAT1receptorintissues

includingvascularsmoothmuscleandtheadrenalgland.Theactionofolmesartanisindependentofthesourceor

routeofsynthesisofangiotensinII.TheselectiveantagonismoftheangiotensinII(AT1)receptorsbyolmesartan

resultsinincreasesinplasmareninlevelsandangiotensinIandIIconcentrations,andsomedecreaseinplasma

aldosteroneconcentrations.

Inhypertension,olmesartanmedoxomilcausesadose-dependent,long-lastingreductioninarterialbloodpressure.

Therehasbeennoevidenceoffirst-dosehypotension,oftachyphylaxisduringlong-termtreatment,orofrebound

hypertensionafterabruptcessationoftherapy.

Oncedailydosingwitholmesartanmedoxomilprovidesaneffectiveandsmoothreductioninbloodpressureoverthe

24hourdoseinterval.Oncedailydosingproducedsimilardecreasesinbloodpressureastwicedailydosingatthe

sametotaldailydose.

Withcontinuoustreatment,maximumreductionsinbloodpressureareachievedby8weeksaftertheinitiationof

therapy,althoughasubstantialproportionofthebloodpressureloweringeffectisalreadyobservedafter2weeksof

SystemOrganClass:Renalandurinarydisorders

Renaldysfunction

Interstitialnephritis

SystemOrganClass:ReproductiveSymptomsandBreastdisorders

Erectiledysfunction

SystemOrganClass:Generaldisordersandadministrationsiteconditions

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Theeffectofolmesartanmedoxomilonmortalityandmorbidityisnotyetknown.

Hydrochlorothiazideisathiazidediuretic.Themechanismoftheantihypertensiveeffectofthiazidediureticsisnot

fullyknown.Thiazidesaffecttherenaltubularmechanismsofelectrolytereabsorption,directlyincreasingexcretionof

sodiumandchlorideinapproximatelyequivalentamounts.Thediureticactionofhydrochlorothiazidereducesplasma

volume,increasesplasmareninactivityandincreasesaldosteronesecretion,withconsequentincreasesinurinary

potassiumandbicarbonateloss,anddecreasesinserumpotassium.Therenin-aldosteronelinkismediatedby

angiotensinIIandthereforecoadministrationofanangiotensinIIreceptorantagonisttendstoreversethepotassium

lossassociatedwiththiazidediuretics.Withhydrochlorothiazide,onsetofdiuresisoccursatabout2hoursandpeak

effectoccursatabout4hourspost-dose,whilsttheactionpersistsforapproximately6-12hours.

Epidemiologicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidemonotherapyreducestherisk

ofcardiovascularmortalityandmorbidity.

Thecombinationofolmesartanmedoxomilandhydrochlorothiazideproducesadditivereductionsinbloodpressure

whichgenerallyincreasewiththedoseofeachcomponent.Inpooledplacebo-controlledstudies,administrationofthe

20/12.5mgand20/25mgcombinationsofolmesartanmedoxomil/hydrochlorothiazideresultedinmeanplacebo-

subtractedsystolic/diastolicbloodpressurereductionsattroughof12/7mmHgand16/9mmHg,respectively.Age

andgenderhadnoclinicallyrelevanteffectonresponsetotreatmentwitholmesartanmedoxomil/hydrochlorothiazide

combinationtherapy.

Administrationof12.5mgand25mghydrochlorothiazideinpatientsinsufficientlycontrolledbyolmesartan

medoxomil20mgmonotherapygaveadditionalreductionsin24-hoursystolic/diastolicbloodpressuresmeasuredby

ambulatorybloodpressuremonitoringof7/5mmHgand12/7mmHg,respectively,comparedwitholmesartan

medoxomilmonotherapybaseline.Theadditionalmeansystolic/diastolicbloodpressurereductionsattrough

comparedwithbaseline,measuredconventionally,were11/10mmHgand16/11mmHg,respectively.

Theeffectivenessofolmesartanmedoxomil/hydrochlorothiazidecombinationtherapywasmaintainedoverlong-term

(one-year)treatment.Withdrawalofolmesartanmedoxomiltherapy,withorwithoutconcomitanthydrochlorothiazide

therapy,didnotresultinreboundhypertension.

Theeffectsoffixeddosecombinationofolmesartanmedoxomil/hydrochlorothiazideonmortalityandcardiovascular

morbidityarecurrentlyunknown.

5.2Pharmacokineticproperties

Absorptionanddistribution

Olmesartanmedoxomil:

Olmesartanmedoxomilisaprodrug.Itisrapidlyconvertedtothepharmacologicallyactivemetabolite,olmesartan,by

esterasesinthegutmucosaandinportalbloodduringabsorptionfromthegastrointestinaltract.Nointactolmesartan

medoxomilorintactsidechainmedoxomilmoietyhavebeendetectedinplasmaorexcreta.Themeanabsolute

bioavailabilityofolmesartanfromatabletformulationwas25.6%.

Themeanpeakplasmaconcentration(C

)ofolmesartanisreachedwithinabout2hoursafteroraldosingwith

olmesartanmedoxomil,andolmesartanplasmaconcentrationsincreaseapproximatelylinearlywithincreasingsingle

oraldosesuptoabout80mg.

Foodhadminimaleffectonthebioavailabilityofolmesartanandthereforeolmesartanmedoxomilmaybeadministered

withorwithoutfood.

Noclinicallyrelevantgender-relateddifferencesinthepharmacokineticsofolmesartanhavebeenobserved.

Olmesartanishighlyboundtoplasmaprotein(99.7%),butthepotentialforclinicallysignificantproteinbinding

displacementinteractionsbetweenolmesartanandotherhighlyboundcoadministeredactivesubstancesislow(as

confirmedbythelackofaclinicallysignificantinteractionbetweenolmesartanmedoxomilandwarfarin).Thebinding

ofolmesartantobloodcellsisnegligible.Themeanvolumeofdistributionafterintravenousdosingislow(16–29L).

Hydrochlorothiazide:

Followingoraladministrationofolmesartanmedoxomilandhydrochlorothiazideincombination,themediantimeto

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Hydrochlorothiazideis68%proteinboundintheplasmaanditsapparentvolumeofdistributionis0.83–1.14L/kg.

Metabolismandelimination

Olmesartanmedoxomil:

Totalplasmaclearanceofolmesartanwastypically1.3L/h(CV,19%)andwasrelativelyslowcomparedtohepatic

bloodflow(ca90L/h).Followingasingleoraldoseof14C-labelledolmesartanmedoxomil,10-16%ofthe

administeredradioactivitywasexcretedintheurine(thevastmajoritywithin24hoursofdoseadministration)andthe

remainderoftherecoveredradioactivitywasexcretedinthefaeces.Basedonthesystemicavailabilityof25.6%,itcan

becalculatedthatabsorbedolmesartanisclearedbybothrenalexcretion(ca40%)andhepato-biliaryexcretion(ca

60%).Allrecoveredradioactivitywasidentifiedasolmesartan.Noothersignificantmetabolitewasdetected.

Enterohepaticrecyclingofolmesartanisminimal.Sincealargeproportionofolmesartanisexcretedviathebiliary

route,useinpatientswithbiliaryobstructioniscontraindicated(seesection4.3).

Theterminaleliminationhalflifeofolmesartanvariedbetween10and15hoursaftermultipleoraldosing.Steadystate

wasreachedafterthefirstfewdosesandnofurtheraccumulationwasevidentafter14daysofrepeateddosing.Renal

clearancewasapproximately0.5–0.7L/handwasindependentofdose.

Hydrochlorothiazide:

Hydrochlorothiazideisnotmetabolisedinmanandisexcretedalmostentirelyasunchangedactivesubstanceinurine.

About60%oftheoraldoseiseliminatedasunchangedactivesubstancewithin48hours.Renalclearanceisabout250

–300mL/min.Theterminaleliminationhalf-lifeofhydrochlorothiazideis10–15hours.

BenetorPlus

Thesystemicavailabilityofhydrochlorothiazideisreducedbyabout20%whenco-administeredwitholmesartan

medoxomil,butthismodestdecreaseisnotofanyclinicalrelevance.Thekineticsofolmesartanareunaffectedbythe

co-administrationofhydrochlorothiazide.

Pharmacokineticsinspecialpopulations

Elderly:

Inhypertensivepatients,theolmesartanAUCatsteadystatewasincreasedbyca35%inelderlypatients(65–75years

old)andbyca44%inveryelderlypatients(75yearsold)comparedwiththeyoungeragegroup(seesection4.2).

Limiteddatasuggestthatthesystemicclearanceofhydrochlorothiazideisreducedinbothhealthyandhypertensive

elderlypatientscomparedtoyounghealthyvolunteers.

Renalimpairment:

Inrenallyimpairedpatients,theolmesartanAUCatsteadystateincreasedby62%,82%and179%inpatientswith

mild,moderateandsevererenalimpairment,respectively,comparedtohealthycontrols(seesections4.2,4.4).

Thehalf-lifeofhydrochlorothiazideisprolongedinpatientswithimpairedrenalfunction.

Hepaticimpairment:

Aftersingleoraladministration,olmesartanAUCvalueswere6%and65%higherinmildlyandmoderatelyhepatically

impairedpatients,respectively,thanintheircorrespondingmatchedhealthycontrols.Theunboundfractionof

olmesartanat2hourspost-doseinhealthysubjects,inpatientswithmildhepaticimpairmentandinpatientswith

moderatehepaticimpairmentwas0.26%,0.34%and0.41%,respectively.Followingrepeateddosinginpatientswith

moderatehepaticimpairment,olmesartanmeanAUCwasagainabout65%higherthaninmatchedhealthycontrols.

OlmesartanmeanCmaxvaluesweresimilarinhepatically-impairedandhealthysubjects.Olmesartanmedoxomilhas

notbeenevaluatedinpatientswithseverehepaticimpairment(seesections4.2,4.4).

Hepaticimpairmentdoesnotsignificantlyinfluencethepharmacokineticsofhydrochlorothiazide.

5.3Preclinicalsafetydata

Thetoxicpotentialofolmesartanmedoxomil/hydrochlorothiazidecombinationswasevaluatedinrepeateddoseoral

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Asforeachoftheindividualsubstancesandothermedicinalproductsinthisclass,themaintoxicologicaltargetorgan

ofthecombinationwasthekidney.Thecombinationofolmesartanmedoxomil/hydrochlorothiazideinducedfunctional

renalchanges(increasesinserumureanitrogenandinserumcreatinine).Highdosagescausedtubulardegeneration

andregenerationinthekidneysofratsanddogs,probablyviaachangeinrenalhaemodynamics(reducedrenal

perfusionresultingfromhypotensionwithtubularhypoxiaandtubularcelldegeneration).Inadditiontheolmesartan

medoxomil/hydrochlorothiazidecombinationcausedadecreaseinredbloodcellparameters(erythrocytes,

haemoglobinandhaematocrit)andareductioninheartweightinrats.

TheseeffectshavealsobeenobservedforotherAT1receptorantagonistsandforACEinhibitorsandtheyseemtohave

beeninducedbythepharmacologicalactionofhighdosagesofolmesartanmedoxomilandseemtobenotrelevantto

humansattherecommendedtherapeuticdoses.

Genotoxicitystudiesusingcombinedolmesartanmedoxomilandhydrochlorothiazideaswellastheindividual

componentshavenotshownanysignsofaclinicallyrelevantgenotoxicactivity.

Thecarcinogenicpotentialofacombinationofolmesartanmedoxomilandhydrochlorothiazidewasnotinvestigatedas

therewasnoevidenceofrelevantcarcinogeniceffectsforthetwoindividualcomponentsunderconditionsofclinical

use.

Therewasnoevidenceofteratogenicityinmiceorratstreatedwitholmesartanmedoxomil/hydrochlorothiazide

combinations.Asexpectedfromthisclassofmedicinalproduct,fetaltoxicitywasobservedinrats,asevidencedby

significantlyreducedfetalbodyweights,whentreatedwitholmesartanmedoxomil/hydrochlorothiazidecombinations

duringgestation(seesections4.3,4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Microcrystallinecellulose

Lactosemonohydrate

Lowsubstitutedhydroxypropylcellulose

Hydroxypropylcellulose

Magnesiumstearate

Tabletcoat

Talc

Hypromellose

Titaniumdioxide(E171)

Iron(III)oxideyellow(E172)

Iron(III)oxidered(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

Over-labelledaluminiumblisterstripsinover-labelledcarton.Packsof30film-coatedtablets.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4,BradfieldRoad

Ruislip

Middlesex

HA40NU

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/152/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29 th

July2011

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