BENETOR 40 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
OLMESARTAN MEDOXOMIL
Available from:
B & S Healthcare
ATC code:
C09CA08
INN (International Name):
OLMESARTAN MEDOXOMIL
Dosage:
40 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Angiotensin II antagonists, plain
Authorization status:
Authorised
Authorization number:
PPA1328/151/003
Authorization date:
2011-07-15

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Benetor10mgFilm-coatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each40mgtabletcontains40mgofolmesartanmedoxomil

Excipients:Alsocontainslactosemonohydrate(seesection4.4)

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablets.

ProductimportedfromFrance:

White,circular,film-coatedtabletswithC15embossedononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension.

4.2Posologyandmethodofadministration

Adults

Therecommendedstartingdoseofolmesartanmedoxomilis10mgoncedaily.Inpatientswhosebloodpressureisnot

adequatelycontrolledatthisdose,thedoseofolmesartanmedoxomilmaybeincreasedto20mgoncedailyasthe

optimaldose.Ifadditionalbloodpressurereductionisrequired,olmesartanmedoxomildosemaybeincreasedtoa

maximumof40mgdailyorhydrochlorothiazidetherapymaybeadded.

Theantihypertensiveeffectofolmesartanmedoxomilissubstantiallypresentwithin2weeksofinitiatingtherapyandis

maximalbyabout8weeksafterinitiatingtherapy.Thisshouldbeborneinmindwhenconsideringchangingthedose

regimenforanypatient.

Inordertoassistcompliance,itisrecommendedthatBenetortabletsbetakenataboutthesametimeeachday,withor

withoutfood,forexampleatbreakfasttime.

Elderly

Noadjustmentofdosageisgenerallyrequiredinelderlypatients(seebelowfordoserecommendationsinpatientswith

renalimpairment).Ifup-titrationtothemaximumdoseof40mgdailyisrequired,bloodpressureshouldbeclosely

monitored.

Renalimpairment

Themaximumdoseinpatientswithmildtomoderaterenalimpairment(creatinineclearanceof20–60mL/min)is20

mgolmesartanmedoxomiloncedaily,owingtolimitedexperienceofhigherdosagesinthispatientgroup.Theuseof

olmesartanmedoxomilinpatientswithsevererenalimpairment(creatinineclearance<20mL/min)isnot

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Hepaticimpairment

Noadjustmentofdosagerecommendationsisrequiredforpatientswithmildhepaticimpairment.Inpatientswith

moderatehepaticimpairment,aninitialdoseof10mgolmesartanmedoxomiloncedailyisrecommendedandthe

maximumdoseshouldnotexceed20mgoncedaily.Closemonitoringofbloodpressureandrenalfunctionisadvised

inhepatically-impairedpatientswhoarealreadyreceivingdiureticsand/orotherantihypertensiveagents.Thereisno

experienceofolmesartanmedoxomilinpatientswithseverehepaticimpairment,thereforeuseisnotrecommendedin

thispatientgroup(seesections4.4and5.2).Olmesartanmedoxomilshouldnotbeusedinpatientswithbiliary

obstruction(seesection4.3).

Childrenandadolescents

Benetorisnotrecommendedforuseinchildrenbelow18yearsduetoalackofdataonsafetyandefficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1).

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Biliaryobstruction(seesection5.2).

4.4Specialwarningsandprecautionsforuse

Intravascularvolumedepletion:

Symptomatichypotension,especiallyafterthefirstdose,mayoccurinpatientswhoarevolumeand/orsodiumdepleted

byvigorousdiuretictherapy,dietarysaltrestriction,diarrhoeaorvomiting.Suchconditionsshouldbecorrectedbefore

theadministrationofolmesartanmedoxomil.

Otherconditionswithstimulationoftherenin-angiotensin-aldosteronesystem:

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithotherdrugsthataffectthissystemhasbeenassociatedwithacutehypotension,azotaemia,

oliguriaor,rarely,acuterenalfailure.ThepossibilityofsimilareffectscannotbeexcludedwithangiotensinIIreceptor

antagonists.

Renovascularhypertension:

Thereisanincreasedriskofseverehypotensionandrenalinsufficiencywhenpatientswithbilateralrenalartery

stenosisorstenosisofthearterytoasinglefunctioningkidneyaretreatedwithmedicinalproductsthataffecttherenin-

angiotensin-aldosteronesystem.

Renalimpairmentandkidneytransplantation:

Whenolmesartanmedoxomilisusedinpatientswithimpairedrenalfunction,periodicmonitoringofserumpotassium

andcreatininelevelsisrecommended.Useofolmesartanmedoxomilisnotrecommendedinpatientswithsevererenal

impairment(creatinineclearance<20mL/min)(seesections4.2,5.2).Thereisnoexperienceoftheadministrationof

olmesartanmedoxomilinpatientswitharecentkidneytransplantorinpatientswithend-stagerenalimpairment(ie

creatinineclearance<12mL/min).

Hepaticimpairment:

Thereisnoexperienceinpatientswithseverehepaticimpairmentandthereforeuseofolmesartanmedoxomilinthis

patientgroupisnotrecommended(seesection4.2fordosagerecommendationsinpatientswithmildormoderate

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Hyperkalaemia:

Theuseofmedicinalproductsthataffecttherenin-angiotensin-aldosteronesystemmaycausehyperkalaemia.

Therisk,thatmaybefatal,isincreasedinelderly,inpatientswithrenalinsufficiencyandindiabeticpatients,in

patientsconcomitantlytreatedwithothermedicinalproductsthatmayincreasepotassiumlevels,and/orinpatientswith

intercurrentevents.

Beforeconsideringtheconcomitantuseofmedicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,the

benefitriskratioshouldbeevaluatedandotheralternativesconsidered.

Themainriskfactorsforhyperkalaemiatobeconsideredare:

Diabetes,renalimpairment,age(>70years)

Combinationwithoneormoreothermedicinalproductsthataffecttherenin-angiotensin-aldosteronesystem

and/orpotassiumsupplements.Somemedicinalproductsortherapeuticclassofmedicinalproductsmayprovokea

hyperkalaemia:saltsubstitutescontainingpotassium,potassium-sparingdiuretics,ACEinhibitors,angiotensinII

receptorsantagonists,nonsteroidalanti-inflammatorydrugs(includingselectiveCOX-2inhibitors),heparin,

immunosuppressorasciclosporinortacrolimus,trimethoprim.

Intercurrentevents,inparticulardehydration,acutecardiacdecompensation,metabolicacidosis,worseningof

renalfunction,suddenworseningoftherenalcondition(e.g.infectiousdiseases),cellularlysis(e.g,acutelimb

ischemia,rhabdomyolysis,extendedtrauma).

Close-monitoringofserumpotassiuminatriskpatientsisrecommended(seesection4.5).

Lithium:

Aswithotherangiotensin-IIreceptorantagonists,thecombinationoflithiumandolmesartanmedoxomilisnot

recommended(seesection4.5).

Aorticormitralvalvestenosis;obstructivehypertrophiccardiomyopathy:

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralvalvestenosis,or

obstructivehypertrophiccardiomyopathy.

Primaryaldosteronism:

Patientswithprimaryaldosteronismgenerallywillnotrespondtoantihypertensivedrugsactingthroughinhibitionof

therenin-angiotensinsystem.Therefore,theuseofolmesartanmedoxomilisnotrecommendedinsuchpatients.

Ethnicdifferences:

AswithallotherangiotensinIIantagonists,thebloodpressureloweringeffectofolmesartanmedoxomilissomewhat

lessinblackpatientsthaninnon-blackpatients,possiblybecauseofahigherprevalenceoflow-reninstatusinthe

blackhypertensivepopulation.

Pregnancy:

AngiotensinIIantagonistsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedangiotensinIIantagonists

therapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensive

treatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwith

angiotensinIIantagonistsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted(see

sections4.3and4.6).

Other:

Aswithanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswithischaemicheartdiseaseor

ischaemiccerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp-

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

Effectsofothermedicinalproductsonolmesartanmedoxomil:

Potassiumsupplementsandpotassiumsparingdiuretics:

Basedonexperiencewiththeuseofotherdrugsthataffecttherenin-angiotensinsystem,concomitantuseofpotassium-

sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassiumorotherdrugsthatmayincreaseserum

potassiumlevels(egheparin)mayleadtoincreasesinserumpotassium(seesection4.4).Suchconcomitantuseis

thereforenotrecommended.

Otherantihypertensivemedications:

Thebloodpressureloweringeffectofolmesartanmedoxomilcanbeincreasedbyconcomitantuseofother

antihypertensivemedications.

Non-steroidalanti-inflammatorydrugs(NSAIDs):

NSAIDs(includingacetylsalicylicacidatdoses>3g/dayandalsoCOX-2inhibitors)andangiotensin-IIreceptor

antagonistsmayactsynergisticallybydecreasingglomerularfiltration.TheriskoftheconcomitantuseofNSAIDsand

angiotensinIIantagonistsistheoccurrenceofacuterenalfailure.Monitoringofrenalfunctionatthebeginningof

treatmentshouldberecommendedaswellasregularhydrationofthepatient.

Additionally,concomitanttreatmentcanreducetheantihypertensiveeffectofangiotensinIIreceptorantagonists,

leadingtotheirpartiallossofefficacy.

Othercompounds:

Aftertreatmentwithantacid(aluminiummagnesiumhydroxide),amodestreductioninbioavailabilityofolmesartan

wasobserved.Coadministrationofwarfarinanddigoxinhadnoeffectonthepharmacokineticsofolmesartan.

Effectsofolmesartanmedoxomilonothermedicinalproducts:

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithangiotensinconvertingenzymeinhibitorsandangiotensinIIantagonists.Thereforeuse

ofolmesartanmedoxomilandlithiumincombinationisnotrecommended(seesection4.4).Ifuseofthecombination

provesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

Othercompounds:

Compoundswhichhavebeeninvestigatedinspecificclinicalstudiesinhealthyvolunteersincludewarfarin,digoxin,an

antacid(magnesiumaluminiumhydroxide),hydrochlorothiazideandpravastatin.Noclinicallyrelevantinteractions

wereobservedandinparticularolmesartanmedoxomilhadnosignificanteffectonthepharmacokineticsor

pharmacodynamicsofwarfarinorthepharmacokineticsofdigoxin.

OlmesartanhadnoclinicallyrelevantinhibitoryeffectsoninvitrohumancytochromeP450enzymes1A1/2,2A6,

2C8/9,2C19,2D6,2E1and3A4,andhadnoorminimalinducingeffectsonratcytochromeP450activities.Therefore

invivointeractionstudieswithknowncytochromeP450enzymeinhibitorsandinducerswerenotconducted,andno

clinicallyrelevantinteractionsbetweenolmesartananddrugsmetabolisedbytheabovecytochromeP450enzymesare

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4.6Fertility,pregnancyandlactation

Pregnancy

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithangiotensinIIantagonists,similarrisksmayexistforthisclassof

drugs.Unlesscontinuedangiotensinreceptorblockertherapyisconsideredessential,patientsplanningpregnancy

shouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforusein

pregnancy.Whenpregnancyisdiagnosed,treatmentwithangiotensinIIantagonistsshouldbestoppedimmediately,

and,ifappropriate,alternativetherapyshouldbestarted.

AngiotensinIIantagoniststherapyexposureduringthesecondandthirdtrimestersisknowntoinducehuman

fetotoxicity(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renal

failure,hypotension,hyperkalaemia).(Seealso5.3"PreclinicalSafetyData").

ShouldexposuretoangiotensinIIantagonistshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheck

ofrenalfunctionandskullisrecommended.

InfantswhosemothershavetakenangiotensinIIantagonistsshouldbecloselyobservedforhypotension(seealso

sections4.3and4.4).

Lactation

Olmesartanisexcretedinthemilkoflactatingratsbutitisnotknownwhetherolmesartanisexcretedinhumanmilk.

BecausenoinformationisavailableregardingtheuseofBenetorduringbreast-feeding,Benetorisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectontheabilitytodriveandusemachineshavebeenperformed.

Withrespecttodrivingvehiclesoroperatingmachines,itshouldbetakenintoaccountthatoccasionallydizzinessor

fatiguemayoccurinpatientstakingantihypertensivetherapy.

4.8Undesirableeffects

Marketexperience

Thefollowingadversereactionshavebeenreportedinpost-marketingexperience.

TheyarelistedbySystemOrganClassandrankedunderheadingsoffrequencyusingthefollowingconvention:very

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

TheuseofangiotensinIIantagonistsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).The

useofangiotensinIIantagonistsiscontraindicatedduringthesecondandthirdtrimesterofpregnancy(seesections

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SinglecasesofrhabdomyolysishavebeenreportedintemporalassociationwiththeintakeofangiotensinIIreceptor

blockers.Acausalrelationship,however,hasnotbeenestablished.

Clinicaltrials

Indouble-blind,placebo-controlledmonotherapystudies,theoverallincidenceoftreatment-emergentadverseevents

was42.4%onolmesartanmedoxomiland40.9%onplacebo.

Inplacebo-controlledmonotherapystudies,theonlyadversedrugreactionthatwasunequivocallyrelatedtotreatment

wasdizziness(2.5%incidenceonolmesartanmedoxomiland0.9%onplacebo).

Inlong-term(2-year)treatment,theincidenceofwithdrawalsduetoadverseeventsonolmesartanmedoxomil10-20

mgoncedailywas3.7%.

Thefollowingadverseeventshavebeenreportedacrossallclinicaltrialswitholmesartanmedoxomil(includingtrials

withactiveaswellasplacebocontrol),irrespectiveofcausalityorincidencerelativetoplacebo.Theyarelistedby

bodysystemandrankedunderheadingsoffrequencyusingtheconventionsdescribedabove:

Centralnervoussystemdisorders:

Common:Dizziness

Uncommon:Vertigo

Cardiovasculardisorders:

Rare:Hypotension

SystemOrganClass Veryrare

Bloodandlymphaticsystemdisorders Thrombocytopenia

Metabolismandnutritiondisorders Hyperkalaemia

Nervoussystemdisorders Dizziness,headache

Respiratory,thoracicandmediastinaldisorders Cough

Gastrointestinaldisorders Abdominalpain,nausea,vomiting

Skinandsubcutaneoustissuedisorders Pruritus,exanthem,rash

Allergicconditionssuchasangioneurotic

oedema,dermatitisallergic,faceoedemaand

urticaria

MusculoskeletalandconnectivetissuedisordersMusclecramp,myalgia

Renalandurinarydisorders Acuterenalfailureandrenalinsufficiency

(SeealsounderInvestigations)

Generaldisordersandadministrationsite

conditions Asthenicconditionssuchasasthenia,fatigue,

lethargy,malaise

Investigations Abnormalrenalfunctiontestssuchasblood

creatinineincreasedandbloodureaincreased

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Respiratorysystemdisorders:

Common:Bronchitis,cough,pharyngitis,rhinitis

Gastro-intestinaldisorders:

Common:Abdominalpain,diarrhoea,dyspepsia,gastroenteritis,nausea

Skinandappendagesdisorders:

Uncommon:Rash

Musculoskeletaldisorders:

Common:Arthritis,backpain,skeletalpain

Urinarysystemdisorders:

Common:Haematuria,urinarytractinfection

Generaldisorders:

Common:Chestpain,fatigue,influenza-likesymptoms,peripheraloedema,pain

Laboratoryparameters

Inplacebo-controlledmonotherapystudiestheincidencewassomewhathigheronolmesartanmedoxomilcompared

withplaceboforhypertriglyceridaemia(2.0%versus1.1%)andforraisedcreatinephosphokinase(1.3%versus0.7%).

Laboratoryadverseeventsreportedacrossallclinicaltrialswitholmesartanmedoxomil(includingtrialswithouta

placebocontrol),irrespectiveofcausalityorincidencerelativetoplacebo,included:

Metabolicandnutritionaldisorders:

Common:Increasedcreatinephosphokinase,hypertriglyceridaemia,hyperuricaemia.

Rare:Hyperkalaemia

Liverandbiliarydisorders:

Common:Liverenzymeelevations.

Additionalinformationonspecialpopulations

Inelderlypatientsthefrequencyofhypotensionisslightlyincreasedfromraretouncommon.

4.9Overdose

Onlylimitedinformationisavailableregardingoverdosageinhumans.Themostlikelyeffectofoverdosageis

hypotension.Intheeventofoverdosage,thepatientshouldbecarefullymonitoredandtreatmentshouldbe

symptomaticandsupportive.

Noinformationisavailableregardingthedialysabilityofolmesartan.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:

AngiotensinIIantagonists,ATCcode:C09CA08.

Olmesartanmedoxomilisapotent,orallyactive,selectiveangiotensinIIreceptor(typeAT

)antagonist.Itisexpected

toblockallactionsofangiotensinIImediatedbytheAT

receptor,regardlessofthesourceorrouteofsynthesisof

angiotensinII.TheselectiveantagonismoftheangiotensinII(AT

)receptorsresultsinincreasesinplasmarenin

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AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysasignificant

roleinthepathophysiologyofhypertensionviathetype1(AT

)receptor.

Inhypertension,olmesartanmedoxomilcausesadose-dependent,long-lastingreductioninarterialbloodpressure.

Therehasbeennoevidenceoffirst-dosehypotension,oftachyphylaxisduringlong-termtreatment,orofrebound

hypertensionaftercessationoftherapy.

Oncedailydosingwitholmesartanmedoxomilprovidesaneffectiveandsmoothreductioninbloodpressureoverthe

24hourdoseinterval.Oncedailydosingproducedsimilardecreasesinbloodpressureastwicedailydosingatthe

sametotaldailydose.

Withcontinuoustreatment,maximumreductionsinbloodpressureareachievedby8weeksaftertheinitiationof

therapy,althoughasubstantialproportionofthebloodpressureloweringeffectisalreadyobservedafter2weeksof

treatment.Whenusedtogetherwithhydrochlorothiazide,thereductioninbloodpressureisadditiveand

coadministrationiswelltolerated.

Theeffectofolmesartanonmortalityandmorbidityisnotyetknown.

5.2Pharmacokineticproperties

Absorptionanddistribution

Olmesartanmedoxomilisaprodrug.Itisrapidlyconvertedtothepharmacologicallyactivemetabolite,olmesartan,by

esterasesinthegutmucosaandinportalbloodduringabsorptionfromthegastrointestinaltract.

Nointactolmesartanmedoxomilorintactsidechainmedoxomilmoietyhavebeendetectedinplasmaorexcreta.The

meanabsolutebioavailabilityofolmesartanfromatabletformulationwas25.6%.

Themeanpeakplasmaconcentration(C

)ofolmesartanisreachedwithinabout2hoursafteroraldosingwith

olmesartanmedoxomil,andolmesartanplasmaconcentrationsincreaseapproximatelylinearlywithincreasingsingle

oraldosesuptoabout80mg.

Foodhadminimaleffectonthebioavailabilityofolmesartanandthereforeolmesartanmedoxomilmaybeadministered

withorwithoutfood.

Noclinicallyrelevantgender-relateddifferencesinthepharmacokineticsofolmesartanhavebeenobserved.

Olmesartanishighlyboundtoplasmaprotein(99.7%),butthepotentialforclinicallysignificantproteinbinding

displacementinteractionsbetweenolmesartanandotherhighlyboundcoadministereddrugsislow(asconfirmedbythe

lackofaclinicallysignificantinteractionbetweenolmesartanmedoxomilandwarfarin).Thebindingofolmesartanto

bloodcellsisnegligible.Themeanvolumeofdistributionafterintravenousdosingislow(16–29L).

Metabolismandelimination

Totalplasmaclearancewastypically1.3L/h(CV,19%)andwasrelativelyslowcomparedtohepaticbloodflow(ca90

L/h).Followingasingleoraldoseof 14

C-labelledolmesartanmedoxomil,10-16%oftheadministeredradioactivity

wasexcretedintheurine(thevastmajoritywithin24hoursofdoseadministration)andtheremainderoftherecovered

radioactivitywasexcretedinthefaeces.Basedonthesystemicavailabilityof25.6%,itcanbecalculatedthatabsorbed

olmesartanisclearedbybothrenalexcretion(ca40%)andhepato-biliaryexcretion(ca60%).Allrecovered

radioactivitywasidentifiedasolmesartan.Noothersignificantmetabolitewasdetected.Enterohepaticrecyclingof

olmesartanisminimal.Sincealargeproportionofolmesartanisexcretedviathebiliaryroute,useinpatientswith

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Theterminaleliminationhalflifeofolmesartanvariedbetween10and15hoursaftermultipleoraldosing.Steadystate

wasreachedafterthefirstfewdosesandnofurtheraccumulationwasevidentafter14daysofrepeateddosing.Renal

clearancewasapproximately0.5–0.7L/handwasindependentofdose.

Pharmacokineticsinspecialpopulations

Elderly:

Inhypertensivepatients,theAUCatsteadystatewasincreasedbyca35%inelderlypatients(65–75yearsold)andby

ca44%inveryelderlypatients(75yearsold)comparedwiththeyoungeragegroup.Thismaybeatleastinpart

relatedtoameandecreaseinrenalfunctioninthisgroupofpatients.

Renalimpairment:

Inrenallyimpairedpatients,theAUCatsteadystateincreasedby62%,82%and179%inpatientswithmild,moderate

andsevererenalimpairment,respectively,comparedtohealthycontrols(seesections4.2,4.4).

Hepaticimpairment:

Aftersingleoraladministration,olmesartanAUCvalueswere6%and65%higherinmildlyandmoderatelyhepatically

impairedpatients,respectively,thanintheircorrespondingmatchedhealthycontrols.Theunboundfractionof

olmesartanat2hourspost-doseinhealthysubjects,inpatientswithmildhepaticimpairmentandinpatientswith

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

moderatehepaticimpairment,olmesartanmeanAUCwasagainabout65%higherthaninmatchedhealthycontrols.

OlmesartanmeanC

valuesweresimilarinhepatically-impairedandhealthysubjects.Olmesartanmedoxomilhas

notbeenevaluatedinpatientswithseverehepaticimpairment(seesections4.2,4.4).

5.3Preclinicalsafetydata

Inchronictoxicitystudiesinratsanddogs,olmesartanmedoxomilshowedsimilareffectstootherAT

receptor

antagonistsandACEinhibitors:raisedbloodurea(BUN)andcreatinine(throughfunctionalchangestothekidneys

causedbyblockingAT

receptors);reductioninheartweight;areductionofredcellparameters(erythrocytes,

haemoglobin,haematocrit);histologicalindicationsofrenaldamage(regenerativelesionsoftherenalepithelium,

thickeningofthebasalmembrane,dilatationofthetubules).Theseadverseeffectscausedbythepharmacological

actionofolmesartanmedoxomilhavealsooccurredinpreclinicaltrialsonotherAT

receptorantagonistsandACE

inhibitorsandcanbereducedbysimultaneousoraladministrationofsodiumchloride.

Inbothspecies,increasedplasmareninactivityandhypertrophy/hyperplasiaofthejuxtaglomerularcellsofthekidney

wereobserved.Thesechanges,whichareatypicaleffectoftheclassofACEinhibitorsandotherAT

receptor

antagonists,wouldappeartohavenoclinicalrelevance.

LikeotherAT

receptorantagonistsolmesartanmedoxomilwasfoundtoincreasetheincidenceofchromosomebreaks

incellculturesinvitro.Norelevanteffectswereobservedinseveralinvivostudiesusingolmesartanmedoxomilat

veryhighoraldosesofupto2000mg/kg.Theoveralldataofacomprehensivegenotoxicitytestingsuggestthat

olmesartanisveryunlikelytoexertgenotoxiceffectsunderconditionsofclinicaluse.

Olmesartanmedoxomilwasnotcarcinogenic,neitherinratsina2yearstudynorinmicewhentestedintwo6month

carcinogenicitystudiesusingtransgenicmodels.

Inreproductivestudiesinrats,olmesartanmedoxomildidnotaffectfertilityandtherewasnoevidenceofateratogenic

effect.IncommonwithotherangiotensinIIantagonists,survivalofoffspringwasreducedfollowingexposureto

olmesartanmedoxomilandpelvicdilatationofthekidneywasseenafterexposureofthedamsinlatepregnancyand

lactation.Incommonwithotherantihypertensiveagents,olmesartanmedoxomilwasshowntobemoretoxicto

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Cellulose,microcrystalline

Lactosemonohydrate

Hydroxypropylcellulose

Lowsubstitutedhydroxypropylcellulose

Magnesiumstearate

Tabletcoat:

Titaniumdioxide(E171)

Talc

Hypromellose

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Aluminiumblisterpack.Packsof30film-coatedtablets.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4,BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/151/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

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10DATEOFREVISIONOFTHETEXT Irish Medicines Board

______________________________________________________________________________________________________________________

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