AMARYL 4 MG TABLET

Main information

  • Trade name:
  • AMARYL 4 MG TABLET
  • Dosage:
  • 4.0mg Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AMARYL 4 MG TABLET
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0540/028/004
  • Authorization date:
  • 22-07-2000
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Amaryl4mgtablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains4mgglimepiride.

Excipients:alsocontains135.9mglactosemonohydratepertablet.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Thetabletsarelightblue,oblongandscoredonbothsides.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Amarylisindicatedforthetreatmentoftype2diabetesmellitus,whendiet,physicalexerciseandweightreduction

alonearenotadequate.

4.2Posologyandmethodofadministration

Fororaladministration

Thebasisforsuccessfultreatmentofdiabetesisagooddiet,regularphysicalactivity,aswellasroutinechecksof

bloodandurine.Tabletsorinsulincannotcompensateifthepatientdoesnotkeeptotherecommendeddiet.

Dosageisdeterminedbytheresultsofbloodandurinaryglucosedeterminations.

Thestartingdoseis1mgglimepirideperday.Ifgoodcontrolisachievedthisdosageshouldbeusedformaintenance

therapy.

Forthedifferentdosageregimensappropriatestrengthsareavailable.

Ifcontrolisunsatisfactorythedosageshouldbeincreased,basedontheglycaemiccontrol,inastepwisemannerwith

anintervalofabout1to2weeksbetweeneachstep,to2,3or4mgglimepirideperday.

Adosageofmorethan4mgglimepirideperdaygivesbetterresultsonlyinexceptionalcases.Themaximum

recommendeddoseis6mgglimepirideperday.

Inpatientsnotadequatelycontrolledwiththemaximumdailydoseofmetformin,concomitantglimepiridetherapycan

beinitiated.

Whilemaintainingthemetformindose,theglimepiridetherapyisstartedwithalowdose,andisthentitratedup

dependingonthedesiredlevelofmetaboliccontroluptothemaximumdailydose.Thecombinationtherapyshouldbe

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InpatientsnotadequatelycontrolledwiththemaximumdailydoseofAmaryl,concomitantinsulintherapycanbe

initiatedifnecessary.Whilemaintainingtheglimepiridedose,insulintreatmentisstartedatlowdoseandtitratedup

dependingonthedesiredlevelofmetaboliccontrol.Thecombinationtherapyshouldbeinitiatedunderclosemedical

supervision.

Normallyasingledailydoseofglimepirideissufficient.Itisrecommendedthatthisdosebetakenshortlybeforeor

duringasubstantialbreakfastor -ifnoneistaken-shortlybeforeorduringthefirstmainmeal.

Ifadoseisforgotten,thisshouldnotbecorrectedbyincreasingthenextdose.

Tabletsshouldbeswallowedwholewithsomeliquid.

Ifapatienthasahypoglycaemicreactionon1mgglimepiridedaily,thisindicatesthattheycanbecontrolledbydiet

alone.

Inthecourseoftreatment,asanimprovementincontrolofdiabetesisassociatedwithhigherinsulinsensitivity,

glimepiriderequirementsmayfall.Toavoidhypoglycaemiatimelydosereductionorcessationoftherapymust

thereforebeconsidered.Changeindosagemayalsobenecessary,iftherearechangesinweightorlifestyleofthe

patient,orotherfactorsthatincreasetheriskofhypo-orhyperglycaemia.

SwitchoverfromotheroralhypoglycaemicagentstoAmaryl

AswitchoverfromotheroralhypoglycaemicagentstoAmarylcangenerallybedone.FortheswitchovertoAmaryl

thestrengthandthehalf-lifeofthepreviousmedicinalproducthastobetakenintoaccount.Insomecases,especially

inantidiabeticswithalonghalf-life(e.g.chlorpropamide),awashoutperiodofafewdaysisadvisableinorderto

minimisetheriskofhypoglycaemicreactionsduetotheadditiveeffect.

Therecommendedstartingdoseis1mgglimepirideperday.Basedontheresponsetheglimepiridedosagemaybe

increasedstepwise,asindicatedearlier.

SwitchoverfromInsulintoAmaryl

Inexceptionalcases,wheretype2diabeticpatientsareregulatedoninsulin,achangeovertoAmarylmaybeindicated.

Thechangeovershouldbeundertakenunderclosemedicalsupervision.

SpecialPopulations

Patientswithrenalorhepaticimpairment:

Seesection4.3.

Childrenandadolescents:

Therearenodataavailableontheuseofglimepirideinpatientsunder8yearsofage.Forchildrenaged8to17years,

therearelimiteddataonglimepirideasmonotherapy(seesections5.1and5.2).

Theavailabledataonsafetyandefficacyareinsufficientinthepaediatricpopulationandthereforesuchuseisnot

recommended.

4.3Contraindications

Glimepirideiscontraindicatedinpatientswiththefollowingconditions:

hypersensitivitytoglimepiride,othersulfonylureasorsulfonamidesortoanyoftheexcipients

insulindependentdiabetes,

diabeticcoma,

ketoacidosis,

severerenalorhepaticfunctiondisorders.Incaseofsevererenalorhepaticfunctiondisorders,achangeoverto

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4.4Specialwarningsandprecautionsforuse

Amarylmustbetakenshortlybeforeorduringameal.

Whenmealsaretakenatirregularhoursorskippedaltogether,treatmentwithAmarylmayleadtohypoglycaemia.

Possiblesymptomsofhypoglycaemiainclude:headache,ravenoushunger,nausea,vomiting,lassitude,sleepiness,

disorderedsleep,restlessness,aggressiveness,impairedconcentration,alertnessandreactiontime,depression,

confusion,speechandvisualdisorders,aphasia,tremor,paresis,sensorydisturbances,dizziness,helplessness,lossof

self-control,delirium,cerebralconvulsions,somnolenceandlossofconsciousnessuptoandincludingcoma,shallow

respirationandbradycardia.Inaddition,signsofadrenergiccounter-regulationmaybepresentsuchassweating,

clammyskin,anxiety,tachycardia,hypertension,palpitations,anginapectorisandcardiacarrhythmias.

Theclinicalpictureofaseverehypoglycaemicattackmayresemblethatofastroke.

Symptomscanalmostalwaysbepromptlycontrolledbyimmediateintakecarbohydrates(sugar).Artificialsweeteners

havenoeffect.

Itisknownfromothersulfonylureasthat,despiteinitiallysuccessfulcountermeasures,hypoglycaemiamayrecur.

Severehypoglycaemiaorprolongedhypoglycaemia,onlytemporarilycontrolledbytheusualamountsofsugar,require

immediatemedicaltreatmentandoccasionallyhospitalisation.

Factorsfavouringhypoglycaemiainclude:

unwillingnessor(morecommonlyinolderpatients)incapacityofthepatienttocooperate,

undernutrition,irregularmealtimesormissedmealsorperiodsoffasting,

alterationsindiet,

imbalancebetweenphysicalexertionandcarbohydrateintake,

consumptionofalcohol,especiallyincombinationwithskippedmeals,

impairedrenalfunction,

seriousliverdysfunction,

overdosagewithAmaryl,

certainuncompensateddisordersoftheendocrinesystemaffectingcarbohydratemetabolismorcounter-

regulationofhypoglycaemia(asforexampleincertaindisordersofthyroidfunctionandinanteriorpituitaryor

adrenocorticalinsufficiency),

concurrentadministrationofcertainothermedicinalproducts(seesection4.5).

TreatmentwithAmarylrequiresregularmonitoringofglucoselevelsinbloodandurine.Inadditiondeterminationof

theproportionofglycosylatedhaemoglobinisrecommended.

Regularhepaticandhaematologicalmonitoring(especiallyleucocytesandthrombocytes)arerequiredduringtreatment

withAmaryl.

Instress-situations(e.g.accidents,acuteoperations,infectionswithfever,etc.)atemporaryswitchtoinsulinmaybe

indicated.

NoexperiencehasbeengainedconcerningtheuseofAmarylinpatientswithsevereimpairmentofliverfunctionor

dialysispatients.Inpatientswithsevereimpairmentofrenalorliverfunctionchangeovertoinsulinisindicated.

TreatmentofpatientswithG6PD-deficiencywithsulfonylureaagentscanleadtohemolyticanaemia.Sinceglimepiride

belongstotheclassofsulfonylureaagents,cautionshouldbeusedinpatientswithG6PD-deficiencyandanon-

sulfonylureaalternativeshouldbeconsidered.

Amarylcontainslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Ifglimepirideistakensimultaneouslywithcertainothermedicinalproducts,bothundesiredincreasesanddecreasesin

thehypoglycaemicactionofglimepiridecanoccur.Forthisreason,othermedicinalproductsshouldonlybetakenwith

theknowledge(orattheprescription)ofthedoctor.

GlimepirideismetabolizedbycytochromeP4502C9(CYP2C9).Itsmetabolismisknowntobeinfluencedby

concomitantadministrationofCYP2C9inducers(e.g.rifampicin)orinhibitors(e.g.fluconazole)

ResultsfromaninvivointeractionstudyreportedinliteratureshowthatglimepirideAUCisincreasedapproximately

2-foldbyfluconazole,oneofthemostpotentCYP2C9inhibitors.

Basedontheexperiencewithglimepirideandwithothersulfonylureasthefollowinginteractionshavetobementioned.

Potentiationoftheblood-glucose-loweringeffectand,thus,insomeinstanceshypoglycaemiamayoccurwhenoneof

thefollowingmedicinalproductsistaken,forexample:

-phenylbutazone,azapropazoneandoxyfenbutazone,

-insulinandoralantidiabeticproducts,suchasmetformin,

-salicylatesandp-amino-salicylicacid,

-anabolicsteroidsandmalesexhormones,

-chloramphenicol,certainlongactingsulfonamides,tetracyclines,quinoloneantibioticsand

clarithromycin,

-coumarinanticoagulants,

-fenfluramine,

-disopyramide,

-fibrates,

-ACEinhibitors,

-fluoxetine,MAO-inhibitors,

-allopurinol,probenecid,sulfinpyrazone,

-sympatholytics,

-cyclophosphamide,trophosphamideandiphosphamides,

-miconazole,fluconazole.

-pentoxifylline(highdoseparenteral),

-tritoqualine.

Weakeningoftheblood-glucose-loweringeffectand,thusraisedbloodglucoselevelsmayoccurwhenoneofthe

followingmedicinalproductsistaken,forexample:

-oestrogensandprogestogens,

-saluretics,thiazidediuretics,

-thyroidstimulatingagents,glucocorticoids,

-phenothiazinederivatives,chlorpromazine,

-adrenalineandsympathicomimetics,

-nicotinicacid(highdosages)andnicotinicacidderivatives,

-laxatives(longtermuse),

-phenytoin,diazoxide,

-glucagon,barbituratesandrifampicin,

-acetazolamide.

antagonists,beta-blockers,clonidineandreserpinemayleadtoeitherpotentiationorweakeningoftheblood

glucoseloweringeffect.

Undertheinfluenceofsympatholyticmedicinalproductssuchasbeta-blockers,clonidine,guanethidineandreserpine,

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Alcoholintakemaypotentiateorweakenthehypoglycaemicactionofglimepirideinanunpredictablefashion.

Glimepiridemayeitherpotentiateorweakentheeffectsofcoumarinderivatives.

4.6Fertility,pregnancyandlactation

Pregnancy

Riskrelatedtothediabetes

Abnormalbloodglucoselevelsduringpregnancyareassociatedwithahigherincidenceofcongenitalabnormalities

andperinatalmortality.Sothebloodglucoselevelmustbecloselymonitoredduringpregnancyinordertoavoidthe

teratogenicrisk.Theuseofinsulinisrequiredundersuchcircumstances.Patientswhoconsiderpregnancyshould

informtheirphysician.

Riskrelatedtoglimepiride

Therearenoadequatedatafromtheuseofglimepirideinpregnantwomen.Animalstudieshaveshownreproductive

toxicitywhichlikelywasrelatedtothepharmacologicaction(hypoglycaemia)ofglimepiride(seesection5.3).

Consequently,glimepirideshouldnotbeusedduringthewholepregnancy.

Incaseoftreatmentbyglimepiride,ifthepatientplanstobecomepregnantorifapregnancyisdiscovered,the

treatmentshouldbeswitchedassoonaspossibletoinsulintherapy.

Lactation

Theexcretioninhumanmilkisunknown.Glimepirideisexcretedinratmilk.Asothersulfonylureasareexcretedin

humanmilkandbecausethereisariskofhypoglycaemiainnursinginfants,breast-feedingisadvisedagainstduring

treatmentwithglimepiride.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

Thepatient'sabilitytoconcentrateandreactmaybeimpairedasaresultofhypoglycaemiaorhyperglycaemiaor,for

example,asaresultofvisualimpairment.Thismayconstituteariskinsituationswheretheseabilitiesareofspecial

importance(e.g.drivingacaroroperatingmachinery).

Patientsshouldbeadvisedtotakeprecautionstoavoidhypoglycaemiawhilstdriving.Thisisparticularlyimportantin

thosewhohavereducedorabsentawarenessofthewarningsymptomsofhypoglycaemiaorhavefrequentepisodesof

hypoglycaemia.Itshouldbeconsideredwhetheritisadvisabletodriveoroperatemachineryinthesecircumstances.

4.8Undesirableeffects

ThefollowingadversereactionsfromclinicalinvestigationswerebasedonexperiencewithAmarylandother

sulfonylureas,werelistedbelowbysystemorganclassandinorderofdecreasingincidence(verycommon: 1/10;

common:1/100to<1/10;uncommon: 1/1,000to<1/100;rare:1/10,000to<1/1,000;veryrare:<1/10,000),not

known(cannotbeestimatedfromtheavailabledata).

Bloodandlymphaticsystemdisorders

Rare:thrombocytopenia,leukopenia,granulocytopenia,agranulocytosis,erythropenia,haemolyticanaemiaand

pancytopenia,whichareingeneralreversibleupondiscontinuationofmedication.

Immunesystemdisorders

Veryrare:leukocytoclasticvasculitis,mildhypersensitivityreactionsthatmaydevelopintoseriousreactionswith

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Notknown:cross-allergenicitywithsulfonylureas,sulfonamidesorrelatedsubstancesispossible.

Metabolismandnutritiondisorders

Rare:hypoglycaemia.

Thesehypoglycaemicreactionsmostlyoccurimmediately,maybesevereandarenotalwayseasytocorrect.The

occurrenceofsuchreactionsdepends,aswithotherhypoglycaemictherapies,onindividualfactorssuchasdietary

habitsanddosage(seefurtherundersection4.4).

Eyedisorders

Notknown:visualdisturbances,transient,mayoccurespeciallyoninitiationoftreatment,duetochangesinblood

glucoselevels.

Gastrointestinaldisorders

Veryrare:nausea,vomiting,diarrhoea,abdominaldistension,abdominaldiscomfortandabdominalpain,which

seldomleadtodiscontinuationoftherapy.

Hepato-biliarydisorders

Notknown:hepaticenzymesincreased.

Veryrare:hepaticfunctionabnormal(e.g.withcholestasisandjaundice),hepatitisandhepaticfailure.

Skinandsubcutaneoustissuedisorders

Notknown:hypersensitivityreactionsoftheskinmayoccuraspruritus,rash,urticariaandphotosensitivity.

Investigations

Veryrare:bloodsodiumdecrease.

4.9Overdose

Afteringestionofanoverdosagehypoglycaemiamayoccur,lastingfrom12to72hours,andmayrecurafteraninitial

recovery.Symptomsmaynotbepresentforupto24hoursafteringestion.Ingeneralobservationinhospitalis

recommended.Nausea,vomitingandepigastricpainmayoccur.Thehypoglycaemiamayingeneralbeaccompanied

byneurologicalsymptomslikerestlessness,tremor,visualdisturbances,co-ordinationproblems,sleepiness,comaand

convulsions.

Treatmentprimarilyconsistsofpreventingabsorptionbyinducingvomitingandthendrinkingwaterorlemonadewith

activatedcharcoal(adsorbent)andsodium-sulphate(laxative).Iflargequantitieshavebeeningested,gastriclavageis

indicated,followedbyactivatedcharcoalandsodium-sulphate.Incaseof(severe)overdosagehospitalisationinan

intensivecaredepartmentisindicated.Starttheadministrationofglucoseassoonaspossible,ifnecessarybyabolus

intravenousinjectionof50mlofa50%solution,followedbyaninfusionofa10%solutionwithstrictmonitoringof

bloodglucose.Furthertreatmentshouldbesymptomatic.

InparticularwhentreatinghypoglycaemiaduetoaccidentalintakeofAmarylininfantsandyoungchildren,thedoseof

glucosegivenmustbecarefullycontrolledtoavoidthepossibilityofproducingdangeroushyperglycaemia.Blood

glucoseshouldbecloselymonitored.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Bloodglucoseloweringdrugs,excl.insulins:Sulfonamides,ureaderivatives.ATCCode:

A10BB12.

Glimepirideisanorallyactivehypoglycaemicsubstancebelongingtothesulfonylureagroup.Itmaybeusedinnon-

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Glimepirideactsmainlybystimulatinginsulinreleasefrompancreaticbetacells.

Aswithothersulfonylureasthiseffectisbasedonanincreaseofresponsivenessofthepancreaticbetacellstothe

physiologicalglucosestimulus.Inaddition,glimepirideseemstohavepronouncedextrapancreaticeffectsalso

postulatedforothersulfonylureas.

Insulinrelease

SulfonylureasregulateinsulinsecretionbyclosingtheATP-sensitivepotassiumchannelinthebetacellmembrane.

Closingthepotassiumchannelinducesdepolarisationofthebetacellandresults-byopeningofcalciumchannels-in

anincreasedinfluxofcalciumintothecell.

Thisleadstoinsulinreleasethroughexocytosis.

GlimepiridebindswithahighexchangeratetoabetacellmembraneproteinwhichisassociatedwiththeATP-

sensitivepotassiumchannelbutwhichisdifferentfromtheusualsulfonylureabindingsite.

Extrapancreaticactivity

Theextrapancreaticeffectsareforexampleanimprovementofthesensitivityoftheperipheraltissueforinsulinanda

decreaseoftheinsulinuptakebytheliver.

Theuptakeofglucosefrombloodintoperipheralmuscleandfattissuesoccursviaspecialtransportproteins,locatedin

thecellsmembrane.Thetransportofglucoseinthesetissuesistheratelimitingstepintheuseofglucose.Glimepiride

increasesveryrapidlythenumberofactiveglucosetransportmoleculesintheplasmamembranesofmuscleandfat

cells,resultinginstimulatedglucoseuptake.

Glimepirideincreasestheactivityoftheglycosyl-phosphatidylinositol-specificphospholipaseCwhichmaybe

correlatedwiththedrug-inducedlipogenesisandglycogenesisinisolatedfatandmusclecells.Glimepirideinhibitsthe

glucoseproductionintheliverbyincreasingtheintracellularconcentrationoffructose-2,6-bisphosphate,whichinits

turninhibitsthegluconeogenesis.

General

Inhealthypersons,theminimumeffectiveoraldoseisapproximately0.6mg.Theeffectofglimepirideisdose-

dependentandreproducible.Thephysiologicalresponsetoacutephysicalexercise,reductionofinsulinsecretion,is

stillpresentunderglimepiride.

Therewasnosignificantdifferenceineffectregardlessofwhetherthemedicinalproductwasgiven30minutesor

immediatelybeforeameal.Indiabeticpatients,goodmetaboliccontrolover24hourscanbeachievedwithasingle

dailydose.

Althoughthehydroxymetaboliteofglimepiridecausedasmallbutsignificantdecreaseinserumglucoseinhealthy

persons,itaccountsforonlyaminorpartofthetotaldrugeffect.

Combinationtherapywithmetformin

Improvedmetaboliccontrolforconcomitantglimepiridetherapycomparedtometforminaloneinpatientsnot

adequatelycontrolledwiththemaximumdosageofmetforminhasbeenshowninonestudy.

Combinationtherapywithinsulin

Dataforcombinationtherapywithinsulinarelimited.Inpatientsnotadequatelycontrolledwiththemaximumdosage

ofglimepiride,concomitantinsulintherapycanbeinitiated.Intwostudies,thecombinationachievedthesame

improvementinmetaboliccontrolasinsulinalone;however,alower

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Specialpopulations

Childrenandadolescents

Anactivecontrolledclinicaltrial(glimepirideupto8mgdailyormetforminupto2,000mgdaily)of24weeks

durationwasperformedin285children(8-17yearsofage)withtype2diabetes.

BothglimepirideandmetforminexhibitedasignificantdecreasefrombaselineinHbA

(glimepiride-0.95(se0.41);

metformin-1.39(se0.40)).However,glimepiridedidnotachievethecriteriaofnoninferioritytometformininmean

changefrombaselineofHbA

.Thedifferencebetweentreatmentswas0.44%infavourofmetformin.Theupperlimit

(1.05)ofthe95%confidenceintervalforthedifferencewasnotbelowthe0.3%non-inferioritymargin.

Followingglimepiridetreatment,therewerenonewsafetyconcernsnotedinchildrencomparedtoadultpatientswith

type2diabetesmellitus.Nolong-termefficacyandsafetydataareavailableinpaediatricpatients.

5.2Pharmacokineticproperties

Absorption:Thebioavailabilityofglimepirideafteroraladministrationiscomplete.Foodintakehasnorelevant

influenceonabsorption,onlyabsorptionrateisslightlydiminished.Maximumserumconcentrations(C

)are

reachedapprox.2.5hoursafteroralintake(mean0.3µg/mlduringmultipledosingof4mgdaily)andthereisalinear

relationshipbetweendoseandbothC

andAUC(areaunderthetime/concentrationcurve).

Distribution:Glimepiridehasaverylowdistributionvolume(approx.8.8litres)whichisroughlyequaltothealbumin

distributionspace,highproteinbinding(>99%),andalowclearance(approx.48ml/min).

Inanimals,glimepirideisexcretedinmilk.Glimepirideistransferredtotheplacenta.Passageofthebloodbrainbarrier

islow.

Biotransformationandelimination:Meandominantserumhalf-life,whichisofrelevancefortheserumconcentrations

undermultiple-doseconditions,isabout5to8hours.Afterhighdoses,slightlylongerhalf-liveswerenoted.

Afterasingledoseofradiolabelledglimepiride,58%oftheradioactivitywasrecoveredintheurine,and35%inthe

faeces.Nounchangedsubstancewasdetectedintheurine.Twometabolites -mostprobablyresultingfromhepatic

metabolism(majorenzymeisCYP2C9)-wereidentifiedbothinurineandfaeces:thehydroxyderivativeandthe

carboxyderivative.Afteroraladministrationofglimepiride,theterminalhalf-livesofthesemetaboliteswere3to6and

5to6hoursrespectively.

Comparisonofsingleandmultipleonce-dailydosingrevealednosignificantdifferencesinpharmacokinetics,andthe

intraindividualvariabilitywasverylow.Therewasnorelevantaccumulation.

Specialpopulations

Pharmacokineticsweresimilarinmalesandfemales,aswellasinyoungandelderly(above65years)patients.In

patientswithlowcreatinineclearance,therewasatendencyforglimepirideclearancetoincreaseandforaverageserum

concentrationstodecrease,mostprobablyresultingfromamorerapideliminationbecauseoflowerproteinbinding.

Renaleliminationofthetwometaboliteswasimpaired.Overallnoadditionalriskofaccumulationistobeassumedin

suchpatients.

Pharmacokineticsinfivenon-diabeticpatientsafterbileductsurgeryweresimilartothoseinhealthypersons.

Childrenandadolescents

Afedstudyinvestigatingthepharmacokinetics,safety,andtolerabilityofa1mgsingledoseofglimepiridein30

paediatricpatients(4childrenaged10-12yearsand26childrenaged12-17years)withtype2diabetesshowedmean

(0-last) ,Cmaxandt

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5.3Preclinicalsafetydata

Preclinicaleffectsobservedoccurredatexposuressufficientlyinexcessofthemaximumhumanexposureastoindicate

littlerelevancetoclinicaluse,orwereduetothepharmacodynamicaction(hypoglycaemia)ofthecompound.This

findingisbasedonconventionalsafetypharmacology,repeateddosetoxicity,genotoxicity,carcinogenicity,and

reproductiontoxicitystudies.Inthelatter(coveringembryotoxicity,teratogenicityanddevelopmentaltoxicity),adverse

effectsobservedwereconsideredtobesecondarytothehypoglycaemiceffectsinducedbythecompoundindamsand

inoffspring.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Sodiumstarchglycollate(typeA)

Magnesiumstearate

Microcrystallinecellulose

Povidone25000

Indigo-carminealuminiumlake(E132)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisters.

14,20,28,30,50,60,90,112,120,280and300tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

sanofi-aventisIrelandLimited

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization:29November1996

Dateoflastrenewal:20February2010

10DATEOFREVISIONOFTHETEXT

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