AMARYL

Main information

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

Documents

Localization

  • Available in:
  • AMARYL Tablets 4 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/048/002
  • Authorization date:
  • 13-10-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1328/048/002

CaseNo:2052901

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Amaryl4mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom31/03/2009until12/10/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 31/03/2009 CRN 2052901 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Amaryl4mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains4mgglimepiride.

Excipient:Lactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromPortugalandSpain:

Lightblue,oblongtabletswith‘NMO’,alogoandabreaklineonbothsides.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Amarylisindicatedforthetreatmentoftype2diabetesmellitus,whendiet,physicalexerciseandweightreduction

alonearenotadequate.

4.2Posologyandmethodofadministration

Thebasisforsuccessfultreatmentofdiabetesisagooddiet,regularphysicalactivity,aswellasroutinechecksof

bloodandurine.Tabletsorinsulincannotcompensateifthepatientdoesnotkeeptotherecommendeddiet.

Dosageisdeterminedbytheresultsofbloodandurinaryglucosedeterminations.

Thestartingdoseis1mgglimepirideperday.Ifgoodcontrolisachievedthisdosageshouldbeusedformaintenance

therapy.

Ifcontrolisunsatisfactorythedosageshouldbeincreased,basedontheglycaemiccontrol,inastepwisemannerwith

anintervalofabout1to2weeksbetweeneachstep,to2,3or4mgglimepirideperday.

Adosageofmorethan4mgglimepirideperdaygivesbetterresultsonlyinexceptionalcases.Themaximum

recommendeddoseis6mgglimepirideperday.

Inpatientsnotadequatelycontrolledwiththemaximumdailydoseofmetformin,concomitantglimepiridetherapycan

beinitiated.

Whilemaintainingthemetformindose,theglimepiridetherapyisstartedwithalowdose,andisthentitratedup

dependingonthedesiredlevelofmetaboliccontroluptothemaximumdailydose.Thecombinationtherapyshouldbe

initiatedunderclosemedicalsupervision.

InpatientsnotadequatelycontrolledwiththemaximumdailydoseofAmaryl,concomitantinsulintherapycanbe

initiatedifnecessary.Whilemaintainingtheglimepiridedose,insulintreatmentisstartedatlowdoseandtitratedup

dependingonthedesiredlevelofmetaboliccontrol.Thecombinationtherapyshouldbeinitiatedunderclosemedical

supervision.

Normallyasingledailydoseofglimepirideissufficient.Itisrecommendedthatthisdosebetakenshortlybeforeor

duringasubstantialbreakfastor-ifnoneistaken-shortlybeforeorduringthefirstmainmeal.

Ifadoseisforgotten,thisshouldnotbecorrectedbyincreasingthenextdose.

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Ifapatienthasahypoglycaemicreactionon1mgglimepiridedaily,thisindicatesthattheycanbecontrolledbydiet

alone.

Inthecourseoftreatment,asanimprovementincontrolofdiabetesisassociatedwithhigherinsulinsensitivity,

glimepiriderequirementsmayfall.Toavoidhypoglycaemiatimelydosereductionorcessationoftherapymust

thereforebeconsidered.Changeindosagemayalsobenecessary,iftherearechangesinweightorlifestyleofthe

patient,orotherfactorsthatincreasetheriskofhypo-orhyperglycaemia.

SwitchoverfromotheroralhypoglycaemicagentstoAmaryl

AswitchoverfromotheroralhypoglycaemicagentstoAmarylcangenerallybedone.FortheswitchovertoAmaryl

thestrengthandthehalf-lifeofthepreviousmedicationhastobetakenintoaccount.Insomecases,especiallyin

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

minimisetheriskofhypoglycaemicreactionsduetotheadditiveeffect.

Therecommendedstartingdoseis1mgglimepirideperday.Basedontheresponsetheglimepiridedosagemaybe

increasedstepwise,asindicatedearlier.

SwitchoverfromInsulintoAmaryl

Inexceptionalcases,wheretype2diabeticpatientsareregulatedoninsulin,achangeovertoAmarylmaybeindicated.

Thechangeovershouldbeundertakenunderclosemedicalsupervision.

Useinrenalorhepaticimpairment

Seesection4.3Contraindications.

4.3Contraindications

Amarylshouldnotbeusedinthefollowingcases:

insulindependentdiabetes,diabeticcoma,ketoacidosis,severerenalorhepaticfunctiondisorders,hypersensitivityto

glimepiride,othersulphonylureasorsulphonamidesorexcipientsinthetablet.

Incaseofsevererenalorhepaticfunctiondisorders,achangeovertoinsulinisrequired.

Amaryliscontra-indicatedinpregnancyandlactation.

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.

Itisknownfromothersulphonylureasthat,despiteinitiallysuccessfulcountermeasures,hypoglycaemiamayrecur.

Severehypoglycaemiaorprolongedhypoglycaemia,onlytemporarilycontrolledbytheusualamountsofsugar,require

immediatemedicaltreatmentandoccasionallyhospitalisation.

Factorsfavouringhypoglycaemiainclude:

-unwillingnessor(morecommonlyinolderpatients)incapacityofthepatienttocooperate,

-undernutrition,irregularmealtimesormissedmealsorperiodsoffasting,

-alterationsindiet,

-imbalancebetweenphysicalexertionandcarbohydrateintake,

-consumptionofalcohol,especiallyincombinationwithskippedmeals,

-impairedrenalfunction,

-seriousliverdysfunction,

-overdosagewithAmaryl,

-certainuncompensateddisordersoftheendocrinesystemaffectingcarbohydratemetabolismorcounterregulationof

hypoglycaemia(asforexampleincertaindisordersofthyroidfunctionandinanteriorpituitaryoradrenocortical

insufficiency),

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TreatmentwithAmarylrequiresregularmonitoringofglucoselevelsinbloodandurine.Inadditiondeterminationof

theproportionofglycosylatedhaemoglobinisrecommended.

Regularhepaticandhaematologicalmonitoring(especiallyleucocytesandthrombocytes)arerequiredduringtreatment

withAmaryl.

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

indicated.

NoexperiencehasbeengainedconcerningtheuseofAmarylinpatientswithsevereimpairmentofliverfunctionor

dialysispatients.Inpatientswithsevereimpairmentofrenalorliverfunctionchangeovertoinsulinisindicated.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.TreatmentofpatientswithG6PD-deficiencywithsulfonylureaagentscan

leadtohaemolyticanaemia.Sinceglimepiridebelongtotheclassofsulfonylureaagents,cautionshouldbeusedin

patientswithG6PD-definciencyandanon-sulfonylureaalternativeshouldbeconsidered.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

IfAmarylistakensimultaneouslywithcertainothermedicines,bothundesiredincreasesanddecreasesinthe

hypoglycaemicactionofglimepiridecanoccur.Forthisreason,othermedicinesshouldonlybetakenwiththe

knowledge(orattheprescription)ofthedoctor.

GlimepirideismetabolisedbycytochromeP4502C9(CYP2C9).Itsmetabolismisknowntobeinfluencedby

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

ResultsfromavivointeractionstudyreportedinliteratureshowthatglimepirideAUCisincreasedapproximately2-

foldbyfluconazole,oneofthemostpotentCYP2C9inhibitors.

BasedontheexperiencewithAmarylandwithothersulphonylureasthefollowinginteractionshavetobementioned.

Potentiationoftheblood-glucose-loweringeffectand,thus,insomeinstanceshypoglycaemiamayoccurwhenoneof

thefollowingdrugsistaken,forexample:

phenylbutazone,azapropazonand

oxyfenbutazone,

insulinandoralantidiabeticproducts,

metformin,

salicylatesandp-amino-salicylicacid,

anabolicsteroidsandmalesexhormones,

chloramphenicol,

coumarinanticoagulants,

fenfluramine,

fibrates,

ACEinhibitors,

fluoxetine,

allopurinol,

sympatholytics,

sulphinpyrazone,

certainlongactingsulphonamides,

tetracyclines,

MAO-inhibitors,

quinoloneantibiotics,

probenecid,

miconazol,

pentoxifylline(highdoseparenteral),

tritoqualine,

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Weakeningoftheblood-glucose-loweringeffectand,thusraisedbloodglucoselevelsmayoccurwhenoneofthe

followingdrugsistaken,forexample:

oestrogensandprogestagens,

saluretics,thiazidediuretics,

thyroidstimulatingagents,glucocorticoids,

phenothiazinederivatives,chlorpromazine,

adrenalineandsympathicomimetics,

nicotinicacid(highdosages)andnicotinicacidderivatives,

laxatives(longtermuse),

phenytoin,diazoxide,

glucagon,barbituratesandrifampicin,

acetozolamide.

antagonists,betablockers,clonidineandreserpinemayleadtoeitherpotentiationorweakeningofthebloodglucose

loweringeffect.

Undertheinfluenceofsympatholyticdrugssuchasbetablockers,clonidine,guanethidineandreserpine,thesignsof

adrenergiccounterregulationtohypoglycaemiamaybereducedorabsent.

Alcoholintakemaypotentiateorweakenthehypoglycaemicactionofglimepirideinanunpredictablefashion.

Glimepiridemayeitherpotentiateorweakentheeffectsofcoumarinderivatives.

4.6Pregnancyandlactation

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

Thepatient'sabilitytoconcentrateandreactmaybeimpairedasaresultofhypoglycaemiaorhyperglycaemiaor,for

example,asaresultofvisualimpairment.Thismayconstituteariskinsituationswheretheseabilitiesareofspecial

importance(e.g.drivingacaroroperatingmachinery).

Patientsshouldbeadvisedtotakeprecautionstoavoidhypoglycaemiawhilstdriving.Thisisparticularlyimportantin

thosewhohavereducedorabsentawarenessofthewarningsymptomsofhypoglycaemiaorhavefrequentepisodesof

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4.8Undesirableeffects

ThefollowingundesirableeffectsarebasedonexperiencewithAmarylandwithothersulphonylureas.

Bloodandlymphaticsystemdisorders

Rare:moderatetoseverethrombocytopenia,leucopenia,erythrocytopenia,granulocytopenia,agranulocytosis,

erythrocytopenia,haemolyticanaemiaandpancytopeniawhichareingeneralreversibleupondiscontinuationof

medication.

Immunesystemdisorders

Veryrare:allergicvasculitis,mildhypersensitivityreactionsthatmaydevelopintoseriousreactionswithdysponea,fall

inbloodpressureandsometimesshock.

Cross-allergenicitywithsulphonylureas,sulphonamidesorrelatedsubstancesispossible.

Metabolismandnutritiondisorders

Rare:hypoglycaemicreactionswhichmostlyoccurimmediately,maybesevereandarenotalwayseasytocorrect.The

occurrenceofsuchreactionsdepends,aswithotherhypoglycaemictherapies,onindividualfactorssuchasdietary

habitsanddosage(seefurtherunder"Specialwarningsandspecialprecautionsforuse").

Eyedisorders

Transientvisualdisturbancesmayoccurespeciallyoninitiationoftreatment,duetochangesinbloodglucoselevels.

Gastrointestinaldisorders

Veryrare:nausea,vomiting,diarrhoea,pressureorafeelingoffullnessinthestomachandabdominalpainwhich

seldomleadtodiscontinuationoftherapy.

Hepato-biliarydisorders

Elevationofliverenzymesmayoccur.

Veryrare:impairmentofliverfunction(e.g.withcholestasisandjaundice),hepatitiswhichmayprogresstoliver

failure.

Skinandsubcutaneoustissuedisorders

Hypersensitivityreactionsoftheskinmayoccurasitching,rashandurticaria.

Veryrare:hypersensitivitytolight.

Investigations

Veryrare:Serumsodiumdecrease.

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:Oralbloodglucoseloweringdrugs:Sulfonamides,ureaderivatives.ATCCode:A10B

B12.

Glimepirideisanorallyactivehypoglycaemicsubstancebelongingtothesulphonylureagroup.

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Glimepirideactsmainlybystimulatinginsulinreleasefrompancreaticbetacells.

Aswithothersulphonylureasthiseffectisbasedonanincreaseofresponsivenessofthepancreaticbetacellstothe

physiologicalglucosestimulus.Inaddition,glimepirideseemstohavepronouncedextrapancreaticeffectsalso

postulatedforothersulphonylureas.

Insulinrelease

SulphonylureasregulateinsulinsecretionbyclosingtheATP-sensitivepotassiumchannelinthebetacellmembrane.

Closingthepotassiumchannelinducesdepolarisationofthebetacellandresults-byopeningofcalciumchannels-in

anincreasedinfluxofcalciumintothecell.

Thisleadstoinsulinreleasethroughexocytosis.

GlimepiridebindswithahighexchangeratetoabetacellmembraneproteinwhichisassociatedwiththeATP-

sensitivepotassiumchannelbutwhichisdifferentfromtheusualsulphonylureabindingsite.

Extrapancreaticactivity

Theextrapancreaticeffectsareforexampleanimprovementofthesensitivityoftheperipheraltissueforinsulinanda

decreaseoftheinsulinuptakebytheliver.

Theuptakeofglucosefrombloodintoperipheralmuscleandfattissuesoccursviaspecialtransportproteins,locatedin

thecellsmembrane.Thetransportofglucoseinthesetissuesistheratelimitingstepintheuseofglucose.Glimepiride

increasesveryrapidlythenumberofactiveglucosetransportmoleculesintheplasmamembranesofmuscleandfat

cells,resultinginstimulatedglucoseuptake.

Glimepirideincreasestheactivityoftheglycosyl-phosphatidylinositol-specificphospholipaseCwhichmaybe

correlatedwiththedrug-inducedlipogenesisandglycogenesisinisolatedfatandmusclecells.

Glimepirideinhibitstheglucoseproductionintheliverbyincreasingtheintracellularconcentrationoffructose-2,6-

bisphosphate,whichinitsturninhibitsthegluconeogenesis.

General

Inhealthypersons,theminimumeffectiveoraldoseisapproximately0.6mg.Theeffectofglimepirideisdose-

dependentandreproducible.Thephysiologicalresponsetoacutephysicalexercise,reductionofinsulinsecretion,is

stillpresentunderglimepiride.

Therewasnosignificantdifferenceineffectregardlessofwhetherthedrugwasgiven30minutesorimmediately

beforeameal.Indiabeticpatients,goodmetaboliccontrolover24hourscanbeachievedwithasingledailydose.

Althoughthehydroxymetaboliteofglimepiridecausedasmallbutsignificantdecreaseinserumglucoseinhealthy

persons,itaccountsforonlyaminorpartofthetotaldrugeffect.

Combinationtherapywithmetformin

Improvedmetaboliccontrolforconcomitantglimepiridetherapycomparedtometforminaloneinpatientsnot

adequatelycontrolledwiththemaximumdosageofmetforminhasbeenshowninonestudy.

Combinationtherapywithinsulin

Dataforcombinationtherapywithinsulinarelimited.Inpatientsnotadequatelycontrolledwiththemaximumdosage

ofglimepiride,concomitantinsulintherapycanbeinitiated.Intwostudies,thecombinationachievedthesame

improvementinmetaboliccontrolasinsulinalone;however,aloweraveragedoseofinsulinwasrequiredin

combinationtherapy.

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)whichisroughlyequaltothe

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

Inanimals,glimepirideisexcretedinmilk.Glimepirideistransferredtotheplacenta.Passageofthebloodbrainbarrier

islow.

Biotransformationandelimination:Meandominantserumhalf-life,whichisofrelevancefortheserum

concentrationsundermultiple-doseconditions,isabout5to8hours.Afterhighdoses,slightlylongerhalf-liveswere

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Afterasingledoseofradiolabelledglimepiride,58%oftheradioactivitywasrecoveredintheurine,and35%inthe

faeces.Nounchangedsubstancewasdetectedintheurine.Twometabolites-mostprobablyresultingfromhepatic

metabolism-wereidentifiedbothinurineandfaeces:thehydroxyderivativeandthecarboxyderivative.Afteroral

administrationofglimepiride,theterminalhalf-livesofthesemetaboliteswere3to6and5to6hoursrespectively.

Comparisonofsingleandmultipleonce-dailydosingrevealednosignificantdifferencesinpharmacokinetics,andthe

intraindividualvariabilitywasverylow.Therewasnorelevantaccumulation.

Pharmacokineticsweresimilarinmalesandfemales,aswellasinyoungandelderly(above65years)patients.In

patientswithlowcreatinineclearance,therewasatendencyforglimepirideclearancetoincreaseandforaverageserum

concentrationstodecrease,mostprobablyresultingfromamorerapideliminationbecauseoflowerproteinbinding.

Renaleliminationofthetwometaboliteswasimpaired.Overallnoadditionalriskofaccumulationistobeassumedin

suchpatients.

Pharmacokineticsinfivenon-diabeticpatientsafterbileductsurgeryweresimilartothoseinhealthypersons.

5.3Preclinicalsafetydata

Preclinicaleffectsobservedoccurredatexposuressufficientlyinexcessofthemaximumhumanexposureastoindicate

littlerelevancetoclinicaluse,orwereduetothepharmacodynamicaction(hypoglycaemia)ofthecompound.This

findingisbasedonconventionalsafetypharmacology,repeateddosetoxicity,genotoxicity,carcinogenicity,and

reproductiontoxicitystudies.Inthelatter(coveringembryotoxicity,teratogenicityanddevelopmentaltoxicity),

adverseeffectsobservedwereconsideredtobesecondarytothehypoglycaemiceffectsinducedbythecompoundin

damsandinoffspring.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose

Sodiumstarchglycolate

Magnesiumstearate

Microcrystallinecellulose

Povidone25000

Indigo-carminealuminiumlake(E132)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8ParallelProductAuthorisationNumber

PPA1328/48/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:13thOctober2006

10DATEOFREVISIONOFTHETEXT

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