ACTELSAR

Main information

  • Trade name:
  • ACTELSAR Tablets 40 Milligram
  • Dosage:
  • 40 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTELSAR Tablets 40 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/121/002
  • Authorization date:
  • 17-06-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Actelsar40mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each40mgtabletcontains40mgoftelmisartan

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

40mgtabletsarewhite,oval,biconvex,withabreaklineandlogoTononeside.Thetabletcanbedividedintoequal

halves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

Treatmentofessentialhypertensioninadults.

Cardiovascularprevention

Reductionofcardiovascularmorbidityinpatientswith:

i)manifestatherothromboticcardiovasculardisease(historyofcoronaryheartdisease,stroke,orperipheralarterial

disease)or

ii)type2diabetesmellituswithdocumentedtargetorgandamage.

4.2Posologyandmethodofadministration

Treatmentofessentialhypertension:

Theusuallyeffectivedoseis40mgoncedaily.Somepatientsmayalreadybenefitatadailydoseof20mg.Incases

wherethetargetbloodpressureisnotachieved,thedoseoftelmisartancanbeincreasedtoamaximumof80mgonce

daily.Alternatively,telmisartanmaybeusedincombinationwiththiazide-typediureticssuchashydrochlorothiazide

whichhasbeenshowntohaveanadditivebloodpressureloweringeffectwithtelmisartan.Whenconsideringraising

thedose,itmustbeborneinmindthatthemaximumantihypertensiveeffectisgenerallyattainedfourtoeightweeks

afterthestartoftreatment(seesection5.1).

Cardiovascularprevention:

Therecommendeddoseis80mgoncedaily.Itisnotknownwhetherdoseslowerthan80mgoftelmisartanare

effectiveinreducingcardiovascularmorbidity.

Wheninitiatingtelmisartantherapyforthereductionofcardiovascularmorbidity,closemonitoringofbloodpressureis

recommended,andifappropriateadjustmentofmedicationsthatlowerbloodpressuremaybenecessary.

Telmisartanmaybetakenwithorwithoutfood.

Specialpatientpopulations:

Renalimpairment:Noposologyadjustmentisrequiredforpatientswithmildtomoderaterenalimpairment.Limited

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Alowerstartingdoseof20mgisrecommendedinthesepatients(seesection4.4).

Hepaticimpairment:Inpatientswithmildtomoderatehepaticimpairment,theposologyshouldnotexceed40mgonce

daily(seesection4.4).

Elderly

Nodoseadjustmentisnecessaryforelderlypatients.

Paediatricpatients

Actelsarisnotrecommendedforuseinchildrenbelow18yearsduetoalackofdataonsafetyandefficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1)

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

Biliaryobstructivedisorders

Severehepaticimpairment

4.4Specialwarningsandprecautionsforuse

Pregnancy:

AngiotensinIIreceptorantagonistsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedangiotensinIIreceptor

antagonisttherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

anti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithangiotensinIIreceptorantagonistsshouldbestoppedimmediately,and,ifappropriate,

alternativetherapyshouldbestarted(seesections4.3and4.6).

Hepaticimpairment:

Actelsarisnottobegiventopatientswithcholestasis,biliaryobstructivedisordersorseverehepaticimpairment(see

section4.3)sincetelmisartanismostlyeliminatedwiththebile.Thesepatientscanbeexpectedtohavereducedhepatic

clearancefortelmisartan.Actelsarshouldbeusedonlywithcautioninpatientswithmildtomoderatehepatic

impairment.

Renovascularhypertension:

Thereisanincreasedriskofseverehypotensionandrenalinsufficiencywhenpatientswithbilateralrenalartery

stenosisorstenosisofthearterytoasinglefunctioningkidneyaretreatedwithmedicinalproductsthataffecttherenin-

angiotensin-aldosteronesystem.

Renalimpairmentandkidneytransplantation:

WhenActelsarisusedinpatientswithimpairedrenalfunction,periodicmonitoringofpotassiumandcreatinineserum

levelsisrecommended.ThereisnoexperienceregardingtheadministrationofActelsarinpatientswithrecentkidney

transplantation.

Intravascularhypovolaemia:

Symptomatichypotension,especiallyafterthefirstdoseofActelsar,mayoccurinpatientswhoarevolumeand/or

sodiumdepletedbyvigorousdiuretictherapy,dietarysaltrestriction,diarrhoea,orvomiting.Suchconditionsshouldbe

correctedbeforetheadministrationofActelsar.Volumeand/orsodiumdepletionshouldbecorrectedpriorto

administrationofActelsar.

Dualblockadeoftherenin-angiotensin-aldosteronesystem:

Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,hypotension,syncope,hyperkalaemia,and

changesinrenalfunction(includingacuterenalfailure)havebeenreportedinsusceptibleindividuals,especiallyif

combiningmedicinalproductsthataffectthissystem.Dualblockadeoftherenin-angiotensin-aldosteronesystem(e.g.

byaddinganACE-inhibitortoanangiotensinIIreceptorantagonist)isthereforenotrecommendedinpatientswith

alreadycontrolledbloodpressureandshouldbelimitedtoindividuallydefinedcaseswithclosemonitoringofrenal

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Otherconditionswithstimulationoftherenin-angiotensin-aldosteronesystem:

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithmedicinalproductsthataffectthissystemsuchastelmisartanhasbeenassociatedwithacute

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.Medicinalproductsortherapeuticclassesofmedicinalproductsthatmayprovoke

hyperkalaemiaaresaltsubstitutescontainingpotassium,potassium-sparingdiuretics,ACEinhibitors,angiotensinII

receptorsantagonists,nonsteroidalanti-inflammatorymedicinalproducts(NSAIDs,includingselectiveCOX-2

inhibitors),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).Theriskmayincreaseincaseoftreatmentcombinationwithothermedicinalproducts

thatmayalsoprovokehyperkalaemia(saltsubstitutescontainingpotassium,potassium-sparingdiuretics,ACE

inhibitors,angiotensinIIreceptorantagonists,nonsteroidalanti-inflammatorymedicinalproducts(NSAIDs,including

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Theoccurrenceofhyperkalaemiadependsonassociatedriskfactors.Theriskisincreasedincaseoftheabove-

mentionedtreatmentcombinations.Theriskisparticularlyhighincombinationwithpotassiumsparing-diuretics,and

whencombinedwithsaltsubstitutescontainingpotassium.

AcombinationwithACEinhibitorsorNSAIDs,forexample,presentsalesserriskprovidedthatprecautionsforuse

arestrictlyfollowed.

Concomitantusenotrecommended

Potassiumsparingdiureticsorpotassiumsupplements:

AngiotensinIIreceptorantagonistssuchastelmisartan,attenuatediureticinducedpotassiumloss.Potassiumsparing

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

saltsubstitutesmayleadtoasignificantincreaseinserumpotassium.Ifconcomitantuseisindicatedbecauseof

documentedhypokalaemia,theyshouldbeusedwithcautionandwithfrequentmonitoringofserumpotassium.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithangiotensinconvertingenzymeinhibitors,andwithangiotensinIIreceptorantagonists,

includingtelmisartan.Ifuseofthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsis

recommended.

Concomitantuserequiringcaution

Non-steroidalanti-inflammatorymedicinalproducts:

NSAIDs(i.e.acetylsalicylicacidatanti-inflammatorydosageregimens,COX-2inhibitorsandnonselective

NSAIDs)mayreducetheantihypertensiveeffectofangiotensinIIreceptorantagonists.

Insomepatientswithcompromisedrenalfunction(e.g.dehydratedpatientsorelderlypatientswithcompromisedrenal

function),theco-administrationofangiotensinIIreceptorantagonistsandagentsthatinhibitcyclo-oxygenasemay

resultinfurtherdeteriorationofrenalfunction,includingpossibleacuterenalfailure,whichisusuallyreversible.

Therefore,thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patientsshouldbe

adequatelyhydratedandconsiderationshouldbegiventomonitoringofrenalfunctionafterinitiationofconcomitant

therapyandperiodicallythereafter.

Inonestudytheco-administrationoftelmisartanandramiprilledtoanincreaseofupto2.5foldintheAUC

0-24 and

oframiprilandramiprilat.Theclinicalrelevanceofthisobservationisnotknown.

Diuretics(thiazideorloopdiuretics):

Priortreatmentwithhighdosediureticssuchasfurosemide(loopdiuretic)andhydrochlorothiazide(thiazidediuretic)

mayresultinvolumedepletion,andinariskofhypotensionwheninitiatingtherapywithtelmisartan.

Tobetakenintoaccountwithconcomitantuse

Otherantihypertensiveagents:

Thebloodpressureloweringeffectoftelmisartancanbeincreasedbyconcomitantuseofotherantihypertensive

medicinalproducts.

Basedontheirpharmacologicalpropertiesitcanbeexpectedthatthefollowingmedicinalproductsmaypotentiatethe

hypotensiveeffectsofallantihypertensivesincludingtelmisartan:Baclofen,amifostine.

Furthermore,orthostatichypotensionmaybeaggravatedbyalcohol,barbiturates,narcotics,orantidepressants.

Corticosteroids(systemicroute):

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4.6Fertility,pregnancyandlactation

Pregnancy:

TheuseofangiotensinIIreceptorantagonistsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection

4.4).TheuseofangiotensinIIreceptorantagonistsiscontraindicatedduringthesecondandthirdtrimestersof

pregnancy(seesections4.3and4.4).

Therearenoadequatedatafromtheuseoftelmisartaninpregnantwomen.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithangiotensinIIreceptorantagonists,similarrisksmayexistforthis

classofdrugs.UnlesscontinuedangiotensinIIreceptorantagonisttherapyisconsideredessential,patientsplanning

pregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofilefor

useinpregnancy.

Whenpregnancyisdiagnosed,treatmentwithangiotensinIIreceptorantagonistsshouldbestoppedimmediately,and,

ifappropriate,alternativetherapyshouldbestarted.

ExposuretoangiotensinIIreceptorantagonisttherapyduringthesecondandthirdtrimestersisknowntoinducehuman

fetotoxicity(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renal

failure,hypotension,hyperkalaemia).(Seesection5.3).

ShouldexposuretoangiotensinIIreceptorantagonistshaveoccurredfromthesecondtrimesterofpregnancy,

ultrasoundcheckofrenalfunctionandskullisrecommended.

InfantswhosemothershavetakenangiotensinIIreceptorantagonistsshouldbecloselyobservedforhypotension(see

sections4.3and4.4).

Lactation

Becausenoinformationisavailableregardingtheuseoftelmisartanduringbreast-feeding,telmisartanisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreastfeedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachineryitshouldbetakenintoaccountthatdizzinessordrowsinessmayoccasionallyoccur

whentakingantihypertensivetherapy.

4.8Undesirableeffects

Theoverallincidenceofadverseeventsreportedwithtelmisartan(41.4%)wasusuallycomparabletoplacebo(43.9%)

incontrolledtrialsinpatientstreatedforhypertension.Theincidenceofadverseeventswasnotdoserelatedand

showednocorrelationwithgender,ageorraceofthepatients.Thesafetyprofileoftelmisartaninpatientstreatedfor

thereductionofcardiovascularmorbiditywasconsistentwiththatobtainedinhypertensivepatients.

Theadversedrugreactionslistedbelowhavebeenaccumulatedfromcontrolledclinicaltrialsinpatientstreatedfor

hypertensionandfrompost-marketingreports.Thelistingalsotakesintoaccountseriousadverseeventsandadverse

eventsleadingtodiscontinuationreportedinthreeclinicallongtermstudiesincluding21642patientstreatedwith

telmisartanforthereductionofcardiovascularmorbidityforuptosixyears.

Adversereactionshavebeenrankedunderheadingsoffrequencyusingthefollowingconvention:

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

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Withineachfrequencygrouping,adversereactionsarepresentedinorderofdecreasingseriousness.

Infectionsandinfestations

Uncommon: Upperrespiratorytractinfectionincluding

pharyngitisandsinusitis,urinarytractinfection

includingcystitis

Notknown:

Sepsisincludingfataloutcome 1

Bloodandthelymphaticsystemdisorders

Uncommon: Anaemia

Rare: Thrombocytopenia

Notknown: Eosinophilia

Immunesystemdisorders

Rare: Hypersensitivity

Notknown: Anaphylacticreaction

Metabolismandnutritiondisorders

Uncommon: Hyperkalaemia

Psychiatricdisorders

Uncommon: Depression,insomnia

Rare: Anxiety

Nervoussystemdisorders

Uncommon: Syncope

Eyedisorders:

Rare: Visualdisturbance

Earandlabyrinthdisorders:

Uncommon: Vertigo

Cardiacdisorders

Uncommon Bradycardia

Rare: Tachycardia

Vasculardisorders

Uncommon: Hypotension 2

,orthostatichypotension

Respiratory,thoracicandmediastinaldisorders

Uncommon: Dyspnoea

Gastrointestinaldisorders

Uncommon: Abdominalpain,diarrhoea,dyspepsia,

flatulence,vomiting

Rare: Stomachdiscomfort,drymouth

Hepato-biliarydisorders

Rare: Hepaticfunctionabnormal/liverdisorder

Skinandsubcutaneoustissuedisorders

Uncommon: Hyperhidrosis,pruritus,rash

Rare: Erythema,angioedema,drugeruption,toxic

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InthePRoFESStrial,anincreasedincidenceofsepsiswasobservedwithtelmisartancomparedwithplacebo.The

eventmaybeachancefindingorrelatedtoamechanismcurrentlynotknown(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,plain,ATCCode:C09CA07.

Mechanismofaction:

TelmisartanisanorallyactiveandspecificangiotensinIIreceptor(typeAT

Notknown: Urticaria

Muscoloskeletal and connective tissue

disorders

Uncommon: Myalgia,backpain(e.g.sciatica),muscle

spasms

Rare: Arthralgia,paininextremity

Notknown: Tendonpain(tendonitis-likesymptoms)

Renalandurinarydisorders

Uncommon: Renalimpairmentincludingacuterenalfailure

General disorders and administration site

conditions

Uncommon: Chestpain,asthenia(weakness)

Rare: Influenza-likeillness

Investigations

Uncommon: Bloodcreatinineincreased

Rare: Blooduricacidincreased,hepaticenzyme

increased,bloodcreatine

phosphokinaseincreased,haemoglobin

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TelmisartandisplacesangiotensinIIwithveryhighaffinityfromitsbindingsiteattheAT

receptorsubtype,whichis

responsiblefortheknownactionsofangiotensinII.Telmisartandoesnotexhibitanypartialagonistactivityatthe

receptor.TelmisartanselectivelybindstheAT

receptor.Thebindingislong-lasting.Telmisartandoesnotshow

affinityforotherreceptors,includingAT

andotherlesscharacterisedATreceptors.Thefunctionalroleofthese

receptorsisnotknown,noristheeffectoftheirpossibleoverstimulationbyangiotensinII,whoselevelsareincreased

bytelmisartan.

Plasmaaldosteronelevelsaredecreasedbytelmisartan.Telmisartandoesnotinhibithumanplasmareninorblockion

channels.Telmisartandoesnotinhibitangiotensinconvertingenzyme(kininaseII),theenzymewhichalsodegrades

bradykinin.Thereforeitisnotexpectedtopotentiatebradykinin-mediatedadverseeffects.

Inhuman,an80mgdoseoftelmisartanalmostcompletelyinhibitstheangiotensinIIevokedbloodpressureincrease.

Theinhibitoryeffectismaintainedover24hoursandstillmeasurableupto48hours.

Clinicalefficacyandsafety:

Treatmentofessentialhypertension

Afterthefirstdoseoftelmisartan,theantihypertensiveactivitygraduallybecomesevidentwithin3hours.The

maximumreductioninbloodpressureisgenerallyattained4to8weeksafterthestartoftreatmentandissustained

duringlong-termtherapy.

Theantihypertensiveeffectpersistsconstantlyover24hoursafterdosingandincludesthelast4hoursbeforethenext

doseasshownbyambulatorybloodpressuremeasurements.Thisisconfirmedbytroughtopeakratiosconsistently

above80%seenafterdosesof40and80mgoftelmisartaninplacebocontrolledclinicalstudies.

Thereisanapparenttrendtoadoserelationshiptoatimetorecoveryofbaselinesystolicbloodpressure(SBP).Inthis

respectdataconcerningdiastolicbloodpressure(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

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

macro-ormicroalbuminuria),whichisapopulationatriskforcardiovascularevents.

Patientswererandomizedtooneofthethreefollowingtreatmentgroups:telmisartan80mg(n=8542),ramipril10mg

(n=8576),orthecombinationoftelmisartan80mgplusramipril10mg(n=8502),andfollowedforamean

observationtimeof4.5years.

Telmisartanshowedasimilareffecttoramiprilinreducingtheprimarycompositeendpointofcardiovasculardeath,

non-fatalmyocardialinfarction,non-fatalstroke,orhospitalizationforcongestiveheartfailure.Theincidenceofthe

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

vs.ramiprilwas1.01(97.5%CI0.93-1.10,p(non-inferiority)=0.0019atamarginof1.13).Theall-causemortality

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Telmisartanwasfoundtobesimilarlyeffectivetoramiprilinthepre-specifiedsecondaryendpointofcardiovascular

death,non-fatalmyocardialinfarction,andnon-fatalstroke[0.99(97.5%CI0.90-1.08),p(non-inferiority)=0.0004],

theprimaryendpointinthereferencestudyHOPE(TheHeartOutcomesPreventionEvaluationStudy),whichhad

investigatedtheeffectoframiprilvs.placebo.

TRANSCENDrandomizedACE-IintolerantpatientswithotherwisesimilarinclusioncriteriaasONTARGETto

telmisartan80mg(n=2954)orplacebo(n=2972),bothgivenontopofstandardcare.Themeandurationoffollowup

was4yearsand8months.Nostatisticallysignificantdifferenceintheincidenceoftheprimarycompositeendpoint

(cardiovasculardeath,non-fatalmyocardialinfarction,non-fatalstroke,orhospitalizationforcongestiveheartfailure)

wasfound[15.7%inthetelmisartanand17.0%intheplacebogroupswithahazardratioof0.92(95%CI0.81-1.05,p

=0.22)].Therewasevidenceforabenefitoftelmisartancomparedtoplacebointhepre-specifiedsecondarycomposite

endpointofcardiovasculardeath,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.

Combiningtelmisartanwithramiprildidnotaddfurtherbenefitoverramiprilortelmisartanalone.CVmortalityandall

causemortalitywerenumericallyhigherwiththecombination.Inaddition,therewasasignificantlyhigherincidenceof

hyperkalaemia,renalfailure,hypotensionandsyncopeinthecombinationarm.Thereforetheuseofacombinationof

telmisartanandramiprilisnotrecommendedinthispopulation.

Inthe"PreventionRegimenForEffectivelyavoidingSecondStrokes"(PRoFESS)trialinpatients50yearsandolder,

whorecentlyexperiencedstroke,anincreasedincidenceofsepsiswasnotedfortelmisartancomparedwithplacebo,

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

patientstakingtelmisartan(0.33%)vs.patientstakingplacebo(0.16%)[RR2.07(95%confidenceinterval1.14-

3.76)].Theobservedincreasedoccurrencerateofsepsisassociatedwiththeuseoftelmisartanmaybeeitherachance

findingorrelatedtoamechanismnotcurrentlyknown.

5.2Pharmacokineticproperties

Absorption:

Absorptionoftelmisartanisrapidalthoughtheamountabsorbedvaries.Themeanabsolutebioavailabilityfor

telmisartanisabout50%.

Whentelmisartanistakenwithfood,thereductionintheareaundertheplasmaconcentration-timecurve(AUC

)of

telmisartanvariesfromapproximately6%(40mgdose)toapproximately19%(160mgdose).By3hoursafter

administration,plasmaconcentrationsaresimilarwhethertelmisartanistakenfastingorwithfood.

Linearity/non-linearity:

ThesmallreductioninAUCisnotexpectedtocauseareductioninthetherapeuticefficacy.

Thereisnolinearrelationshipbetweendosesandplasmalevels.C

andtoalesserextentAUCincrease

disproportionatelyatdosesabove40mg.

Distribution:

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

steadystateapparentvolumeofdistribution(V

)isapproximately500l.

Metabolism:

Telmisartanismetabolisedbyconjugationtotheglucuronideoftheparentcompound.Nopharmacologicalactivityhas

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Elimination:

Telmisartanischaracterisedbybiexponentialdecaypharmacokineticswithaterminaleliminationhalf-lifeof

>20hours.Themaximumplasmaconcentration(C

)and,toasmallerextent,theareaundertheplasma

concentration-timecurve(AUC)increasedisproportionatelywithdose.Thereisnoevidenceofclinicallyrelevant

accumulationoftelmisartantakenattherecommendeddose.Plasmaconcentrationswerehigherinfemalesthanin

males,withoutrelevantinfluenceonefficacy.

Afteroral(andintravenous)administration,telmisartanisnearlyexclusivelyexcretedwiththefaeces,mainlyas

unchangedcompound.Cumulativeurinaryexcretionis<1%ofdose.Totalplasmaclearance(Cl

)ishigh

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

SpecialPopulations

Gendereffects:

Differencesinplasmaconcentrationswereobserved,withC

andAUCbeingapproximately3-and2-foldhigher,

respectively,infemalescomparedtomales.

Elderlypatients:

Thepharmacokineticsoftelmisartandonotdifferbetweentheelderlyandthoseyoungerthan65years.

Patientswithrenalimpairment:

Inpatientswithmildtomoderateandsevererenalimpairment,doublingofplasmaconcentrationswasobserved.

However,lowerplasmaconcentrationswereobservedinpatientswithrenalinsufficiencyundergoingdialysis.

Telmisartanishighlyboundtoplasmaproteininrenal-insufficientpatientsandcannotberemovedbydialysis.The

eliminationhalf-lifeisnotchangedinpatientswithrenalimpairment.

Patientswithhepaticimpairment:

Pharmacokineticstudiesinpatientswithhepaticimpairmentshowedanincreaseinabsolutebioavailabilityuptonearly

100%.Theeliminationhalf-lifeisnotchangedinpatientswithhepaticimpairment.

5.3Preclinicalsafetydata

Inpreclinicalsafetystudies,dosesproducingexposurecomparabletothatintheclinicaltherapeuticrangecaused

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

receptorantagonists,donotappeartohaveclinicalsignificance.

Thereisnoevidenceofateratogeniceffect,butanimalstudiesindicatedsomehazardouspotentialoftelmisartantothe

postnataldevelopmentoftheoffspringsuchaslowerbodyweight,delayedeyeopening,andhighermortality.

Therewasnoevidenceofmutagenicityandrelevantclastogenicactivityininvitrostudiesandnoevidenceof

Irish Medicines Board

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Date Printed 17/06/2011 CRN 2101157 page number: 10

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Magnesiumstearate

Croscarmellosesodium

Mannitol(E421)

Povidone(K-29/32)

PotassiumHydroxide

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Al/Alblisters:

Storeintheoriginalpackageinordertoprotectfromlight.

HDPEtabletcontainerwithLDPElid:

Keepthecontainertightlyclosedinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Al/Alblisters:14,28,30,56,84,90,98,100tablets

HDPEcontainerwithLDPElidanddesiccant:30,250tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/121/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Irish Medicines Board

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Date Printed 17/06/2011 CRN 2101157 page number: 11

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 17/06/2011 CRN 2101157 page number: 12