DINORTES 80MG TABLETS

Main information

  • Trade name:
  • DINORTES 80MG TABLETS
  • Dosage:
  • 80 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DINORTES 80MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1239/016/003
  • Authorization date:
  • 26-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dinortes80mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains80mgoftelmisartan

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablet

White,oblongtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Treatmentofessentialhypertensioninadults

Cardiovascularprevention:

Reductionofcardiovascularmorbidityinpatientswith:

i)manifestatherothromboticcardiovasculardisease(historyofcoronaryheartdisease,stroke,orperipheralarterial

disease)or

ii)type2diabetesmellituswithdocumentedtargetorgandamage.

4.2Posologyandmethodofadministration

Treatmentofessentialhypertension:

Theusuallyeffectivedoseis40mgoncedaily.Somepatientsmayalreadybenefitatadailydoseof20mg.Incases

wherethetargetbloodpressureisnotachieved,telmisartandosecanbeincreasedtoamaximumof80mgoncedaily.

Alternatively,telmisartanmaybeusedincombinationwiththiazidetypediureticssuchashydrochlorothiazidewhich

hasbeenshowntohaveanadditivebloodpressureloweringeffectwithtelmisartan.Whenconsideringraisingthedose,

itmustbeborneinmindthatthemaximumantihypertensiveeffectisgenerallyattainedfourtoeightweeksafterthe

startoftreatment(seesection5.1).

Cardiovascularprevention:

Therecommendeddoseis80mgoncedaily.Itisknownwhetherdoseslowerthan80mgoftelmisartanareeffectivein

reducingcardiovascularmorbidity.

Wheninitiatingtelmisartantherapyforthereductionofcardiovascularmobidity,closemonitoringofbloodpressureis

recommended,andifappropriateadjustmentofmedicationsthatlowerbloodpressuremaybenecessary.

Dinortesmaybetakenwithorwithoutfood.

Renalimpairment:noposologyadjustmentisrequiredforpatientswithmildtomoderaterenalimpairment.Limited

experienceisavailableinpatientswithsevererenalimpairmentorhaemodialysis.

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Hepaticimpairment:inpatientswithmildtomoderatehepaticimpairmenttheposologyshouldnotexceed40mg

oncedaily(seesection4.4).

Elderly

Nodosingadjustmentisnecessaryforelderlypatients.

Paediatricpatients

Dinortesisnotrecommendedforuseinchildrenbelow18yearsduetoalackofdataonsafetyandefficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1)

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

Biliaryobstructivedisorders

Severehepaticimpairment

4.4Specialwarningsandprecautionsforuse

Pregnancy:

AngiotensinIIreceptorantagonistsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedangiotensinIIreceptor

antagonisttherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithangiotensinIIreceptorantagonistsshouldbestoppedimmediately,and,ifappropriate,alternative

therapyshouldbestarted(seesections4.3and4.6).

Hepaticimpairment:

Dinortesisnotbegiventopatientswithcholestasis,biliaryobstructivedisordersorseverehepaticimpairment(see

section4.3)sincetelmisartanismostlyeliminatedwiththebile.Thesepatientscanbeexpectedtohavereducedhepatic

clearancefortelmisartan.Dinortesshouldbeusedonlywithcautioninpatientswithmildtomoderatehepatic

impairment.

Renovascularhypertension:

Thereisanincreasedriskofseverehypotensionandrenalinsufficiencywhenpatientswithbilateralrenalartery

stenosisorstenosisofthearterytoasinglefunctioningkidneyaretreatedwithmedicinalproductsthataffecttherenin-

angiotensin-aldosteronesystem.

Renalimpairmentandkidneytransplant:

WhenDinortesisusedinpatientswithimpairedrenalfunction,periodicmonitoringofpotassiumandcreatinineserum

levelsisrecommended.ThereisnoexperienceregardingtheadministrationofDinortesinpatientswithrecentkidney

transplantation.

Intravascularhypovolaemia:

Symptomatichypotension,especiallyafterthefirstdoseofDinortes,mayoccurinpatientswhoarevolumeand/or

sodiumdepletedbyvigorousdiuretictherapy,dietarysaltrestriction,diarrhoeaorvomiting.Suchconditionsshouldbe

correctedbeforetheadministrationofDinortes.Volumeand/orsodiumdepletionshouldbecorrectedpriorto

administrationofDinortes.

Dualblockadeoftherenin-angiotensin-aldosteronesystem:Asaconsequenceofinhibitingthereninangiotensin-

aldosteronesystem,hypotensionandchangesinrenalfunction(includingacuterenalfailure)havebeenreportedin

susceptibleindividuals,especiallyifcombiningmedicinalproductsthataffectthissystem.

Dualblockadeoftherenin-angiotensin-aldosteronesystem(e.g.byaddinganACEinhibitortoanangiotensinII

receptorantagonist)isthereforenotrecommendedinpatientswithalreadycontrolledbloodpressureandshouldbe

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Otherconditionswithstimulationoftherenin-angiotensin-aldosteronesystem:

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityofthereninangiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithmedicinalproductsthataffectthissystemsuchastelmisartan,hasbeenassociatedwithacute

hypotension,hyperazotaemia,oliguria,orrarelyacuterenalfailure(seesection4.8).

Primaryaldosteronism:

Patientswithprimaryaldosteronismgenerallywillnotrespondtoantihypertensivemedicinalproductsactingthrough

inhibitionoftherenin-angiotensinsystem.Therefore,theuseoftelmisartanisnotrecommended.

Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyopathy:

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,orobstructive

hypertrophiccardiomyopathy.

Hyperkalaemia:

Theuseofmedicinalproductsthataffecttherenin-angiotensin-aldosteronesystemmaycausehyperkalaemia.

Intheelderly,inpatientswithrenalinsufficiency,indiabeticpatients,inpatientsconcomitantlytreatedwithother

medicinalproductsthatmayincreasepotassiumlevels,and/orinpatientswithintercurrentevents,hyperkalaemiamay

befatal.

Beforeconsideringtheconcomitantuseofmedicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,the

benefitriskratioshouldbeevaluated.

Themainriskfactorsforhyperkalaemiatobeconsideredare:

-Diabetesmellitus,renalimpairment,age(>70years)

-Combinationwithoneormoreothermedicinalproductsthataffecttherenin-angiotensin-aldosteronesystemand/or

potassiumsupplements.Medicinalproductsortherapeuticclassofmedicinalproductsthatmayprovokehyperkalaemia

aresaltsubstitutescontainingpotassium,potassium-sparingdiuretics,ACEinhibitors,angiotensinIIreceptors

antagonists,nonsteroidalanti-inflammatorymedicinalproducts(NSAIDs,includingselectiveCOX-2inhibitors),

heparin,immunosuppressives(cyclosporinortacrolimus)andtrimethoprim.

-Intercurrentevents,inparticulardehydratation,acutecardiacdecompensation,metabolicacidosis,worseningofrenal

function,suddenworseningoftherenalcondition(e.g.infectiousdiseases),cellularlysis(e.g.acutelimbischemia,

rhabdomyolysis,extendtrauma).

Close-monitoringofserumpotassiuminatriskpatientsisrecommended(seesection4.5).

Ethnicdifferences:

Asobservedforangiotensinconvertingenzymeinhibitors,telmisartanandtheotherangiotensinIIreceptorantagonists

areapparentlylesseffectiveinloweringbloodpressureinblackpeoplethaninnon-blacks,possiblybecauseofhigher

prevalenceoflow-reninstatesintheblackhypertensivepopulation.

Other:

Aswithanyantihypertensiveagent,excessivereductionofbloodpressureinpatientswithischaemiccardiopathyor

ischaemiccardiovasculardiseasecouldresultinamyocardialinfarctionorstroke.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

Aswithothermedicinalproductsactingontherenin-angiotensin-aldosteronesystem,telmisartanmayprovoke

hyperkalaemia(seesection4.4).

Theriskmayincreaseincaseoftreatmentcombinationwithothermedicinalproductsthatmayalsoprovoke

hyperkalaemia(saltsubstitutescontainingpotassium,potassium-sparingdiuretics,ACEinhibitors,angiotensinII

receptorantagonists,nonsteroidalanti-inflammatorymedicinalproducts(NSAIDs,includingselectiveCOX-2

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Theoccurrenceofhyperkalaemiadependsonassociatedriskfactors.Theriskisincreasedincaseoftheabove-

mentionedtreatmentcombinations.

Theriskisparticularlyhighincombinationwithpotassiumsparing-diureticsandwhencombinedwithsaltsubstitutes

containingpotassium.AcombinationwithACEinhibitorsorNSAIDS,forexample,presentsalesserriskprovidedthat

precautionsforusearestrictlyfollowed.

Concomitantusenotrecommended

Potassiumsparingdiureticsorpotassiumsupplements:

AngiotensinIIreceptorantagonistssuchastelmisartanattenuatediureticinducedpotassiumloss.Potassiumsparing

diureticse.g.spirinolactone,eplerenone,triamterene,oramiloride,potassiumsupplements,orpotassium-containing

saltsubstitutesmayleadtosignificantincreaseinserumpotassium.Ifconcomitantuseisindicatedbecauseof

documentedhypokalaemiatheyshouldbeusedwithcautionandwithfrequentmonitoringofserumpotassium.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithangiotensinconvertingenzymeinhibitors,and,withangiotensinIIantagonists,including

telmisartan.Ifuseofthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

Concomitantuserequiringcaution

Non-steroidalanti-inflammatorymedicinalproducts:

NSAIDs(i.e.acetylsalicylicacidatanti-inflammatorydosageregimens,COX-2inhibitorsandnonselectiveNSAIDs)

mayreducetheantihypertensiveeffectofangiotensinIIantagonists.

Insomepatientswithcompromisedrenalfunction(e.g.dehydratedpatientsorelderlypatientswithcompromisedrenal

function)theco-administrationofangiotensinIIreceptorantagonistsandagentsthatinhibitcyclo-oxygenasemay

resultinfurtherdeteriorationofrenalfunction,includingpossibleacuterenalfailure,whichisusuallyreversible.

Therefore,thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patientsshouldbe

adequatelyhydratedandconsiderationshouldbegiventomonitoringofrenalfunctionafterinitiationofconcomitant

therapyandperiodicallythereafter.

Inonestudytheco-administrationoftelmisartanandramiprilledtoanincreaseofupto2.5foldintheAUC0-24and

Cmaxoframiprilandramiprilat.Theclinicalrelevanceofthisobservationisnotknown.

Diuretics(thiazideorloopdiuretics):

Priortreatmentwithhighdosediureticssuchasfurosemide(loopdiuretic)andhydrochlorothiazide(thiazidediuretic)

mayresultinvolumedepletion,andinariskofhypotensionwheninitiatingtherapywithtelmisartan.

Tobetakenintoaccountwithconcomitantuse

Otherantihypertensiveagents

Thebloodpressureloweringeffectoftelmisartancanbeincreasedbyconcomitantuseofotherantihypertensive

medicinalproducts.

Basedontheirpharmacologicalpropertiesitcanbeexpectedthatthefollowingmedicinalproductsmaypotentiatethe

hypotensiveeffectsofallantihypertensivesincludingtelmisartan:Baclofen,amifostine.Furthermore,orthostatic

hypotensionmaybeaggravatedbyalcohol,barbiturates,narcoticsorantidepressants.

Corticosteroïds(systemicroute):

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4.6Fertility,pregnancyandlactation

Pregnancy(seesection4.3and4.4):

TherearenoadequatedatafromtheuseofMicardisinpregnantwomen.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithangiotensinIIreceptorantagonists,similarrisksmayexistforthis

classofdrugs.UnlesscontinuedangiotensinIIreceptorantagonisttherapyisconsideredessential,patientsplanning

pregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofilefor

useinpregnancy.

Whenpregnancyisdiagnosed,treatmentwithangiotensinIIreceptorantagonistsshouldbestoppedimmediately,and,

ifappropriate,alternativetherapyshouldbestarted.

AngiotensinIIreceptorantagonisttherapyexposureduringthesecondandthirdtrimestersisknowntoinducehuman

fetotoxicity(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renal

failure,hypotension,hyperkalaemia).(Seealsosection5.3).

ShouldexposuretoangiotensinIIreceptorantagonistshaveoccurredfromthesecondtrimesterofpregnancy,

ultrasoundcheckofrenalfunctionandskullisrecommended.

InfantswhosemothershavetakenangiotensinIIreceptorantagonistsshouldbecloselyobservedforhypotension(see

alsosections4.3and4.4).

Lactation(seesection4.3):

BecausenoinformationisavailableregardingtheuseofTelmisartanduringbreast-feeding,Telmisartanisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachineryitmustbeborneinmindthatdizzinessordrowsinessmayoccasionallyoccurwhen

takingantihypertensivetherapy.

4.8Undesirableeffects

Theoverallincidenceofadverseeventsreportedwithtelmisartan(41.4%)wasusuallycomparabletoplacebo(43.9%)

inplacebocontrolledtrials.Theincidenceofadverseeventswasnotdoserelatedandshowednocorrelationwith

gender,ageorraceofthepatients.Thesafetyprofileoftelmisartaninpatientstreatedforthereductionof

cardiovascularmorbiditywasconsistentwiththatobtainedinhypertensivepatients.

Theadversedrugreactionslistedbelowhavebeenaccumulatedfromallclinicaltrialsinpatientstreatedfor

hypertensionandfrompostmarketingreports.Thelistingalsotakesintoaccountseriousadverseeventsandadverse

eventsleadingtodiscontinuationreportedinthreeclinicallong-termstudiesincluding21642patientstreatedwith

telmisartanforthereductionofcardiovascularmorbidityforuptosixyears

Adversereactionshavebeenrankedunderheadingsoffrequencyusingthefollowingconvention:verycommon( ≥

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

notknown(cannotbeestimatedfromtheavailabledata).

Withineachfrequencygrouping,adversereactionsarepresentedinorderofdecreasingseriousness.

TheuseofangiotensinIIreceptorantagonistsisnotrecommendedduringthefirsttrimesterof

pregnancy(seesection4.4).TheuseofangiotensinIIreceptorantagonistsiscontraindicated

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Uncommon( ≥1/1,000to<1/100):Upperrespiratorytractinfectionincludingpharyngitisandsinusitis,urinarytract

infectionincludingcystitis

Notknown(cannotbeestimatedfromtheavailabledata):Sepsisincludingfataloutcome 1

Bloodandthelymphaticsystemdisorders

Uncommon( ≥1/1,000to<1/100):Anaemia

Rare( ≥1/10,000to<1/1,000):Thrombocytopenia

Notknown(cannotbeestimatedfromtheavailabledata):Eosinophilia

Immunesystemdisorders

Rare( ≥1/10,000to<1/1,000:Hypersensitivity

Notknown(cannotbeestimatedfromtheavailabledata):Anaphylacticreaction

Metabolismandnutritiondisorders

Uncommon( ≥1/1,000to<1/100):Hyperkalaemia

Psychiatricdisorders:

Uncommon( ≥1/1,000to<1/100):Depression,insomnia

Rare( ≥1/10,000to<1/1,000:Anxiety.

Nervoussystemdisorders

Uncommon( ≥1/1,000to<1/100):Syncope.

Eyedisorders:

Rare( ≥1/10,000to<1/1,000):Abnormalvision

Earandlabyrinthdisorders:

Uncommon( ≥1/1,000to<1/100):Vertigo

Cardiacdisorders

Uncommon( ≥1/1,000to<1/100):Bradycardia

Rare( ≥1/10,000to<1/1,000):Tachycardia

Vasculardisorders

Uncommon( ≥1/1,000to<1/100):Hypotension 2

,orthostatichypotension

Respiratory,thoracicandmediastinaldisorders

Uncommon( ≥1/1,000to<1/100):Dyspnoea

Gastrointestinaldisorders:

Uncommon( ≥1/1,000to<1/100):Abdominalpain,diarrhoea,dyspepsia,flatulence,vomiting

Rare( ≥1/10,000to<1/1,000):Stomachupset,drymouth

Hepato-biliarydisorders

Rare( ≥1/10,000to<1/1,000):Hepaticfunctionabnormal/liverdisorder

Skinandsubcutaneoustissuedisorders:

Uncommon( ≥1/1,000to<1/100):Hyperhidrosis,pruritus,rash.

Rare( ≥1/10,000to<1/1,000):Erythema,angioedema,,drugeruption,toxicskineruption,eczema.

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Musculoskeletalandconnectivetissuedisorders:

Uncommon( ≥1/1,000to<1/100):Myalgia,backpain(e.g.sciatica),musclecramps

Rare( ≥1/10,000to<1/1,000):Arthralgia,,paininextremity.

Notknown(cannotbeestimatedfromtheavailabledata):Tendonitis

Renalandurinarydisorders

Uncommon( ≥1/1,000to<1/100):Renalimpairmentincludingacuterenalfailure

Generaldisordersandadministrationsiteconditions

Uncommon( ≥1/1,000to<1/100):Chestpain,asthenia(weakness).

Rare( ≥1/10,000to<1/1,000):Influenza-likeillness

Investigations

Uncommon( ≥1/1,000to<1/100):Bloodcreatinineincreased.

Rare( ≥1/10,000to<1/1,000):Blooduricacidincreased,hepaticenzymeincreased,bloodcreatinephosphokinase

increased,haemoglobindecreased.

InthePRoFEESStrial,anincreasedincidenceofsepsiswasobservedwithtelmisartancomparedwithplacebo.The

eventmaybeachancefindingorrelatedtoamechanismcurrentlynotknow(seesection5.1).

Reportedascommoninpatientswithcontrolledbloodpressurewhoweretreatedwithtelmisartanforthereductionof

cardiovascularmorbidityontopofstandardcare.

4.9Overdose

Thereislimitedinformationavailablewithregardtooverdoseinhumans.

Symptoms:Themostprominentmanifestationsoftelmisartanoverdosewerehypotensionandtachycardia;bradycardia

dizziness,increaseinserumcreatinine,andacuterenalfailurehavealsobeenreported.

Treatment:Telmisartanisnotremovedbyhaemodialysis.Thepatientshouldbecloselymonitored,andthetreatment

shouldbesymptomaticandsupportive.Managementdependsonthetimesinceingestionandtheseverityofthe

symptoms.Suggestedmeasuresincludeinductionofemesisand/orgastriclavage.Activatedcharcoalmaybeusefulin

thetreatmentofoverdosage.Serumelectrolytesandcreatinineshouldbemonitoredfrequently.Ifhypotensionoccurs,

thepatientshouldbeplacedinasupineposition,withsaltandvolumereplacementgivenquickly.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

PharmacotherapeuticGroup:AngiotensinIIAntagonists,ATCCode:C09CA07.

Mechanismofaction:

TelmisartanisanorallyactiveandspecificangiotensinIIreceptor(typeAT1)antagonist.

TelmisartandisplacesangiotensinIIwithveryhighaffinityfromitsbindingsiteattheAT1receptorsubtype,whichis

responsiblefortheknownactionsofangiotensinII.TelmisartandoesnotexhibitanypartialagonistactivityattheAT1

receptor.TelmisartanselectivelybindstheAT1receptor.Thebindingislong-lasting.Telmisartandoesnotshow

affinityforotherreceptors,includingAT2andotherlesscharacterisedATreceptors.Thefunctionalroleofthese

receptorsisnotknown,noristheeffectoftheirpossibleoverstimulationbyangiotensinII,whoselevelsareincreased

bytelmisartan.Plasmaaldosteronelevelsaredecreasedbytelmisartan.Telmisartandoesnotinhibithumanplasma

reninorblockionchannels.Telmisartandoesnotinhibitangiotensinconvertingenzyme(kininaseII),theenzyme

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Inhuman,an80mgdoseoftelmisartanalmostcompletelyinhibitstheangiotensinIIevokedbloodpressureincrease.

Theinhibitoryeffectismaintainedover24hoursandstillmeasurableupto48hours.

Clinicalefficacyandsafety:

Treatmentofessentialhyertension:

Afterthefirstdoseoftelmisartan,theantihypertensiveactivitygraduallybecomesevidentwithin3hours.The

maximumreductioninbloodpressureisgenerallyattained4-8weeksafterthestartoftreatmentandissustainedduring

long-termtherapy.

Theantihypertensiveeffectpersistsconstantlyover24hoursafterdosingandincludesthelast4hoursbeforethenext

doseasshownbyambulatorybloodpressuremeasurements.

Thisisconfirmedbytroughtopeakratiosconsistentlyabove80%seenafterdosesof40and80mgoftelmisartanin

placebocontrolledclinicalstudies.Thereisanapparenttrendtoadoserelationshiptoatimetorecoveryofbaseline

systolicbloodpressure(SBP).Inthisrespectdataconcerningdiastolicbloodpressure(DBP)areinconsistent.

Inpatientswithhypertensiontelmisartanreducesbothsystolicanddiastolicbloodpressurewithoutaffectingpulserate.

Thecontributionofthemedicinalproduct’sdiureticandnatriureticeffecttoitshypotensiveactivityhasstilltobe

defined.Theantihypertensiveefficacyoftelmisartaniscomparabletothatofagentsrepresentativeofotherclassesof

antihypertensivemedicinalproducts(demonstratedinclinicaltrialscomparingtelmisartantoamlodipine,atenolol,

enalapril,hydrochlorothiazide,andlisinopril).

Uponabruptcessationoftreatmentwithtelmisartan,bloodpressuregraduallyreturnstopre-treatmentvaluesovera

periodofseveraldayswithoutevidenceofreboundhypertension.

Theincidenceofdrycoughwassignificantlylowerinpatientstreatedwithtelmisartanthaninthosegivenangiotensin

convertingenzymeinhibitorsinclinicaltrialsdirectlycomparingthetwoantihypertensivetreatments.

Cardiovascularprevention:

ONTARGET(OngoingTelmisartanAloneandinCombinationwithRamiprilGlobalEndpointTrial)comparedthe

effectsoftelmisartan,ramiprilandthecombinationoftelmisartanandramipriloncardiovascularoutcomesin25620

patientsaged55yearsorolderwithahistoryofcoronaryarterydisease,stroke,TIA,peripheralarterialdisease,ortype

2diabetesmellitysaccompaniedbyevidenceofend-organdamage(e.g.retinopathy,leftventricularhypertrophy,

macro-ormicroalbuminuria),whichisapopulationatriskforcardiovascularevents.

Patientswererandomizedtooneofthethreefollowingtreatmentgroups:telmisartan80mg(n=8542),ramipril10mg

(n=8576),orthecomibinationoftemisartan80mgplusramipril10mg(n=8502),andfollowedforameanobservation

timeof4.5years.

Telmisartanshowecasimilareffecttoramiprilinreducingtheprimarycompositeendpointofcardiovasculardeath,

non-fatalmyocardialinfarction,non-fatalstroke,or,hospitalizationforcongestiveheartfailure.Theincidenceofthe

primaryendpointwassimilarinthetelmisartan(16.7%)andramipril(16.5%)groups.Thehazardratiofortemisartan

vs.ramiprilwas1.01(97.5%Cl0.93–1.10,p(non-inferiority)=0.0019atamarginof1.13).Theall-causemortality

ratewas11.6%and11.8%amongtelmisartanandramipriltreatedpatients,respectively.

Telmisartanwasfoundtobesimilarlyeffectivetoramiprilinthepre-specifiedsecondaryendpointofcardiovascular

death,non-fatal,myocardialinfarction,andnon-fatalstroke[0.99(97.5%CI0.90–1.08),p(non–inferiority)

=0.0004],theprimaryendpointinthereferencestudyHOPE(TheHeartOutcomesPreventionEvaluationStudy),

whichhadinvestigatedtheeffectorramiprilvs.placebo.

TRANSCENDrandomizedACE-IintolerantpatientswithotherwisesimilarinclusioncriteriaasONTARGETto

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Themeandurationoffollowupwas4yearsand8months.Nostatisticallysignificantdifferenceintheincidenceorthe

primarycompositeendpoint(cardiovasculardeath)non-fatalmyocardialinfarction,non-fatalstroke,orhospitalization

forcongestiveheartfailure)wasfound[15.7%inthetelmisartanand17.0%intheplacebogroupswithahazardration

of0.92(95%CI0.81-1.05,p=0.22)].

Therewasevidenceforabenefitoftelmisartancomparedtoplacebointhepre-specifiedsecondarycompositeendpoint

ofcardiovasculardeath,non-fatalmyocardialinfarction,andnon-fatalstroke]0.87(95%CI0.76–1.00,p=0.048)].

Therewasnoevidenceforbenefitoncardiovascularmortality(hazardratio1.03,95%CI0.85–1.24).

Coughandangioedemawerelessfrequentlyreportedinpatientstreatedwithtelmisartanthaninpatientstreatedwith

ramipril,whereashypotensionwasmorefrequentlyreportedwithtelmisartan.

Combiningtelmisartanwithramiprildidnotaddfurtherbenefitoverramipirlortelmisartanalone.CVmortalityandall

causemortalitywerenumericallyhigherwiththecombination.

Inaddition,therewasasignificantlyhigherincidenceorhyperkalaemia,renalfailure,hypotensionandsyncopeinthe

combinationarm.Thereforetheuseofacombinationoftelmisartanandramiprilisnotrecommendedinthis

population.

Inthe“PreventionRegimenForEffectivelyavoidingSecondStrokes”(PRoFESS)trialinpatients50yearandolder,

whorecentlyexperiencestroke,anincreasedincidenceofsepsiswasnotedfortelmisartancomparedwithplacebo,

0.70%vs.0.49%[RR1.43(95%confidenceinterval1.00-2.06];theincidenceoffatalsepsiscaseswasincreasedfor

patientstakingtelmisartan(0.33%)vs.patientsrakingplacebo(0.16%)[RR2.07(95%confidenceinterval1.14-3.76].

Theobservedincreasedoccurrencerateofsepsisassociatedwiththeuseoftelmisartanmaybeeitherachancefinding

orrelatedtoamechanismnotcurrentlyknown.

Beneficialeffectsoftelmisartanonmortalityandcardiovascularmorbidityarecurrentlyunknown.

5.2Pharmacokineticproperties

Absorption:

Absorptionoftelmisartanisrapidalthoughtheamountabsorbedvaries.Themeanabsolutebioavailabilityfor

telmisartanisabout50%.Whentelmisartanistakenwithfood,thereductionintheareaundertheplasma

concentration-timecurve(AUC0- ∞)oftelmisartanvariesfromapproximately6%(40mgdose)toapproximately19%

(160mgdose).By3hoursafteradministrationplasmaconcentrationsaresimilarwhethertelmisartanistakenfastingor

withfood.

Linearity/non-linearity:

ThesmallreductioninAUCisnotexpectedtocauseareductioninthetherapeuticefficacy.Thereisnolinear

relationshipbetweendosesandplasmalevels.CmaxandtoalesserextentAUCincreasedisproportionatelyatdoses

above40mg.

Distribution:

Telmisartanislargelyboundtoplasmaprotein(>99.5%),mainlyalbuminandalpha-1acidglycoprotein.Themean

steadystateapparentvolumeofdistribution(Vdss)isapproximately500l.

Metabolism:

Telmisartanismetabolisedbyconjugationtotheglucuronideoftheparentcompound.Nopharmacologicalactivityhas

beenshownfortheconjugate.

Elimination:

Telmisartanischaracterisedbybiexponentialdecaypharmacokineticswithaterminaleliminationhalf-lifeof>20

hours.Themaximumplasmaconcentration(Cmax)and,toasmallerextent,theareaundertheplasmaconcentration-

timecurve(AUC),increasedisproportionatelywithdose.Thereisnoevidenceofclinicallyrelevantaccumulationof

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Plasmaconcentrationswerehigherinfemalesthaninmales,withoutrelevantinfluenceonefficacy.

Afteroral(andintravenous)administrationtelmisartanisnearlyexclusivelyexcretedwiththefaeces,mainlyas

unchangedcompound.Cumulativeurinaryexcretionis<1%ofdose.Totalplasmaclearance(Cltot)ishigh

(approximately1,000ml/min)comparedwithhepaticbloodflow(about1,500ml/min).

SpecialPopulations

Gendereffects:

Differencesinplasmaconcentrationswereobserved,withCmaxandAUCbeingapproximately3-and2-foldhigher,

respectively,infemalescomparedtomales.

Elderlypatients:

Thepharmacokineticsoftelmisartandonotdifferinyoungandelderlypatients.

Patientswithrenalimpairment:

Inpatientswithmildtomoderateandsevererenalimpairmentpatientsdoublingofplasmaconcentrationswas

observed.However,lowerplasmaconcentrationswereobservedinpatientswithrenalinsufficiencyundergoing

dialysis.Telmisartanishighlyboundtoplasmaproteininrenal-insufficientpatientsandcannotberemovedbydialysis.

Theeliminationhalf-lifeisnotchangedinpatientswithrenalimpairment.

Patientswithhepaticimpairment:

Pharmacokineticstudiesinpatientswithhepaticimpairmentshowedanincreaseinabsolutebioavailabilityuptonearly

100%.Theeliminationhalf-lifeisnotchangedinpatientswithhepaticimpairment.

5.3Preclinicalsafetydata

Inpreclinicalsafetystudiesdosesproducingexposurecomparabletothatintheclinicaltherapeuticrangecaused

reducedredcellparameters(erythrocytes,haemoglobin,haematocrit),changesinrenalhaemodynamics(increased

bloodureanitrogenandcreatinine),aswellasincreasedserumpotassiuminnormotensiveanimals.Indogsrenal

tubulardilationandatrophywereobserved.Gastricmucosalinjury(erosion,ulcersorinflammation)alsowasnotedin

ratsanddogs.Thesepharmacologically-mediatedundesirableeffects,knownfrompreclinicalstudieswithboth

angiotensinconvertingenzymeinhibitorsandangiotensinIIreceptorantagonists,werepreventedbyoralsaline

supplementation.

Inbothspecies,increasedplasmareninactivityandhypertrophy/hyperplasiaoftherenaljuxtaglomerularcellswere

observed.Thesechanges,alsoaclasseffectofangiotensinconvertingenzymeinhibitorsandotherangiotensinII

antagonists,donotappeartohaveclinicalsignificance.

Thereisnoevidenceofteratogeniceffectbutanimalstudiesindicatedsomehazardouspotentialoftelmisartantothe

postnataldevelopmentoftheoffspring:lowerbodyweight,delayedeyeopening,highermortality.

Therewasnoevidenceofmutagenicityandrelevantclastogenicactivityininvitrostudiesandnoevidenceof

carcinogenicityinratsandmice.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Povidone

Meglumine

Sodiumhydroxide

Mannitol

Magnesiumstearate

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6.2Incompatibilities

Notapplicable

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Aluminium/aluminiumblisters:

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Theoutercontainersarecartonboxes.

Dinortes20/40/80mgtabletsaresuppliedinblisters(Aluminium/Aluminium)containing14,28,30,56,84,90,98

tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

LaboratoriosLiconsaSA

GranViaCarlosIII,98,7 th

Floor

Barcelona08028

Spain

8MARKETINGAUTHORISATIONNUMBER

PA1239/16/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26thNovember2010

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