AMARYL

Main information

  • Trade name:
  • AMARYL Tablets 3 Milligram
  • Dosage:
  • 3 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AMARYL Tablets 3 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/104/003A
  • Authorization date:
  • 30-06-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Amaryl3mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains3mgglimepiride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromPortugalandtheNetherlands:

Cream,oblongtabletwith‘NMN’,alogoandabreaklineonbothfaces.

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,glimepiridetherapyisstartedwithalowdose,andisthentitratedupdepending

onthedesiredlevelofmetaboliccontroluptothemaximumdailydose.Thecombinationtherapyshouldbeinitiated

underclosemedicalsupervision.

InpatientsnotadequatelycontrolledwiththemaximumdailydoseofAmaryl,concomitantinsulintherapycanbe

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Whilemaintainingtheglimepiridedose,insulintreatmentisstartedatlowdoseandtitratedupdependingonthe

desiredlevelofmetaboliccontrol.Thecombinationtherapyshouldbeinitiatedunderclosemedicalsupervision.

Normallyasingledailydoseofglimepirideissufficient.Itisrecommendedthatthisdosebetakenshortlybeforeor

duringasubstantialbreakfastorifnoneistaken-shortlybeforeorduringthefirstmainmeal.

Ifadoseisforgotten,thisshouldnotbecorrectedbyincreasingthenextdose.

Tabletsshouldbeswallowedwholewithsomeliquid.

Ifapatienthasahypoglycaemicreactionon1mgglimepiridedaily,thisindicatesthattheycanbecontrolledbydiet

alone.

Inthecourseoftreatment,asanimprovementincontrolofdiabetesisassociatedwithhigherinsulinsensitivity,

glimepiriderequirementsmayfall.Toavoidhypoglycaemiatimelydosereductionorcessationoftherapymust

thereforebeconsidered.Changeindosagemayalsobenecessary,iftherearechangesinweightorlifestyleofthe

patient,orotherfactorsthatincreasetheriskofhypo-orhyperglycaemia.

SwitchoverfromotheroralhypoglycaemicagentstoAmaryl:

AswitchoverfromotheroralhypoglycaemicagentstoAmarylcangenerallybedone.FortheswitchovertoAmaryl

thestrengthandthehalflifeofthepreviousmedicationhastobetakenintoaccount.Insomecases,especiallyin

antidiabeticswithalonghalflife(e.g.chlorpropamide),awashoutperiodofafewdaysisadvisableinorderto

minimisetheriskofhypoglycaemicreactionsduetotheadditiveeffect.Therecommendedstartingdoseis1mg

glimepirideperday.

Basedontheresponsetheglimepiridedosagemaybeincreasedstepwise,asindicatedearlier.

SwitchoverfromInsulintoAmaryl:

Inexceptionalcases,wheretype2diabeticpatientsareregulatedoninsulin,achangeovertoAmarylmaybeindicated.

Thechangeovershouldbeundertakenunderclosemedicalsupervision.

Useinrenalorhepaticimpairment:

Seesection4.3Contraindications.

4.3Contraindications

Amarylshouldnotbeusedinthefollowingcases:insulindependentdiabetes,diabeticcoma,ketoacidosis,severerenal

orhepaticfunctiondisorders,hypersensitivitytoglimepiride,othersulphonylureasorsulphonamidesorexcipientsin

thetablet.

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

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Inaddition,signsofadrenergiccounter-regulationmaybepresentsuchassweating,clammyskin,anxiety,tachycardia,

hypertension,palpitations,anginapectorisandcardiacarrhythmias.

Theclinicalpictureofaseverehypoglycaemicattackmayresemblethatofastroke.

Symptomscanalmostalwaysbepromptlycontrolledbyimmediateintakeofcarbohydrates(sugar).Artificial

sweetenershavenoeffect.

Itisknownfromothersulphonylureasthat,despiteinitiallysuccessfulcountermeasures,hypoglycaemiamayrecur.

Severehypoglycaemiaorprolongedhypoglycaemia,onlytemporarilycontrolledbytheusualamountsofsugar,require

immediatemedicaltreatmentandoccasionallyhospitalisation.

Factorsfavouringhypoglycaemiainclude:

unwillingnessor(morecommonlyinolderpatients)incapacityofthepatienttocooperate,

undernutrition,irregularmealtimesormissedmealsorperiodsoffasting,

alterationsindiet,

imbalancebetweenphysicalexertionandcarbohydrateintake,

consumptionofalcohol,especiallyincombinationwithskippedmeals,

impairedrenalfunction,

seriousliverdysfunction,

overdosagewithAmaryl,

certainuncompensateddisordersoftheendocrinesystemaffectingcarbohydratemetabolismor

counterregulationofhypoglycaemia(asforexampleincertaindisordersofthyroidfunctionandinanterior

pituitaryoradrenocorticalinsufficiency),

concurrentadministrationofcertainothermedicines(see“Interactions”).

TreatmentwithAmarylrequiresregularmonitoringofglucoselevelsinbloodandurine.Inadditiondeterminationof

theproportionofglycosylatedhaemoglobinisrecommended.

Regularhepaticandhaematologicalmonitoring(especiallyleucocytesandthrombocytes)arerequiredduringtreatment

withAmaryl.

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

indicated.

NoexperiencehasbeengainedconcerningtheuseofAmarylinpatientswithsevereimpairmentofliverfunctionor

dialysispatients.Inpatientswithsevereimpairmentofrenalorliverfunctionchangeovertoinsulinisindicated.

TreatmentofpatientswithG6PD-deficiencywithsulfonylureaagentscanleadtohaemolyticanaemia.SinceAmaryl

belongstotheclassofsulfonylureaagents,cautionshouldbeusedinpatientswithG6PD-deficiencyandanon-

sulfonylureaalternativeshouldbeconsidered.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

IfAmarylistakensimultaneouslywithcertainothermedicines,bothundesiredincreasesanddecreasesinthe

hypoglycaemicactionofglimepiridecanoccur.Forthisreason,othermedicinesshouldonlybetakenwiththe

knowledge(orattheprescription)ofthedoctor.

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Potentiationoftheblood-glucose-loweringeffectand,thus,insomeinstanceshypoglycaemiamayoccurwhenoneof

thefollowingdrugsistaken,forexample:

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.

Phenylbutazone,azapropazonandoxyfenbutazone Sulphinpyrazone

Insulinandoralantidiabeticproducts Metformin

Certainlongactingsulphonamides Tetracyclines

Salicylatesandp-aminosalicylicacid MAOinhibitors

Anabolicsteroidsandmalesexhormones Quinoloneantibiotics

Chloramphenicol Probenecid

Coumarinanticoagulants Miconazol

Pentoxifylline(highdoseparenteral), Fenfluramine

Fibrates Tritoqualine

ACEinhibitors Fluoxetine,

Allopurinol Sympatholytics,

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4.6Pregnancyandlactation

Pregnancy:

Amaryliscontra-indicatedduringpregnancy.Theuseofinsulinisrequiredundersuchcircumstances.Patientswho

considerpregnancyshouldinformtheirphysician.

Lactation:

Becausesulphonylureaderivativeslikeglimepiridepassintothebreastmilk,Amarylmustnotbetakenbybreast-

feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Thepatient'sabilitytoconcentrateandreactmaybeimpairedasaresultofhypoglycaemiaorhyperglycaemiaor,for

example,asaresultofvisualimpairment.Thismayconstituteariskinsituationswheretheseabilitiesareofspecial

importance(e.g.drivingacaroroperatingmachinery).

Patientsshouldbeadvisedtotakeprecautionstoavoidhypoglycaemiawhilstdriving.Thisisparticularlyimportantin

thosewhohavereducedorabsentawarenessofthewarningsymptomsofhypoglycaemiaorhavefrequentepisodesof

hypoglycaemia.Itshouldbeconsideredwhetheritisadvisabletodriveoroperatemachineryinthesecircumstances.

4.8Undesirableeffects

BasedonexperiencewithAmarylandwithothersulphonylureasthefollowingsideeffectshavetobementioned.

Immunesystemdisorders

Inveryrarecasesmildhypersensitivityreactionsmaydevelopintoseriousreactionswithdyspnoea,fallinblood

pressureandsometimesshock.Allergicvasculitisispossibleinveryrarecases.

Crossallergenicitywithsulphonylureas,sulphonamidesorrelatedsubstancesispossible.

Bloodandlymphaticsystemdisorders

ChangesinhaematologyarerareduringAmaryltreatment.Moderatetoseverethrombocytopenia,leucopenia,

erythrocytopenia,granulocytopenia,agranulocytosis,haemolyticanaemiaandpancytopeniamayoccur.

Theseareingeneralreversibleupondiscontinuationofmedication.

Metabolismandnutritiondisorders

InrarecaseshypoglycaemicreactionshavebeenobservedafteradministrationofAmaryl.Thesereactionsmostly

occurimmediately,maybesevereandarenotalwayseasytocorrect.Theoccurrenceofsuchreactionsdepends,as

withotherhypoglycaemictherapies,onindividualfactorssuchasdietaryhabitsandthedosage(seefurtherunder

"Specialwarningsandspecialprecautionsforuse").

Eyedisorders

Transientvisualdisturbancesmayoccurespeciallyoninitiationoftreatment,duetochangesinbloodglucoselevels.

Gastrointestinaldisorders

Gastrointestinalcomplaintslikenausea,vomitinganddiarrhoea,pressureorafeelingoffullnessinthestomachand

abdominalpainareveryrareandseldomleadtodiscontinuationoftherapy.

Hepato-biliarydisorders

Elevationofliverenzymesmayoccur.Inveryrarecases,impairmentofliverfunction(e.g.withcholestasisand

jaundice)maydevelop,aswellashepatitiswhichmayprogresstoliverfailure.

Skinandsubcutaneoustissuedisorders

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Inveryrarecaseshypersensitivitytolightmayoccur.

Investigations

Inveryrarecases,adecreaseinthesodiumserumconcentrationsmayoccur.

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,gastriclavageisindicated,followedbyactivatedcharcoalandsodium-sulphate.

Incaseof(severe)overdosagehospitalisationinanintensivecaredepartmentisindicated.

Starttheadministrationofglucoseassoonaspossible,ifnecessarybyabolusintravenousinjectionof50mlofa50%

solution,followedbyaninfusionofa10%solutionwithstrictmonitoringofbloodglucose.Furthertreatmentshould

besymptomatic.

InparticularwhentreatinghypoglycaemiaduetoaccidentalintakeofAmarylininfantsandyoungchildren,thedoseof

glucosegivenmustbecarefullycontrolledtoavoidthepossibilityofproducingdangeroushyperglycaemia.Blood

glucoseshouldbecloselymonitored.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Oralbloodglucoseloweringdrugs:Sulfonamides,ureaderivatives.ATCCode:A10B

B12.

Glimepirideisanorallyactivehypoglycaemicsubstancebelongingtothesulphonylureagroup.Itmaybeusedinnon-

insulindependentdiabetesmellitus.

Glimepirideactsmainlybystimulatinginsulinreleasefrompancreaticbetacells.

Aswithothersulphonylureasthiseffectisbasedonanincreaseofresponsivenessofthepancreaticbetacellstothe

physiologicalglucosestimulus.Inaddition,glimepirideseemstohavepronouncedextrapancreaticeffectsalso

postulatedforothersulphonylureas.

Insulinrelease:

SulphonylureasregulateinsulinsecretionbyclosingtheATP-sensitivepotassiumchannelinthebetacellmembrane.

Closingthepotassiumchannelinducesdepolarisationofthebetacellandresults-byopeningofcalciumchannels-in

anincreasedinfluxofcalciumintothecell.

Thisleadstoinsulinreleasethroughexocytosis.

GlimepiridebindswithahighexchangeratetoabetacellmembraneproteinwhichisassociatedwiththeATP-

sensitivepotassiumchannelbutwhichisdifferentfromtheusualsulphonylureabindingsite.

Extrapancreaticactivity:

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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,isstillpresentunderglimepiride.

Therewasnosignificantdifferenceineffectregardlessofwhetherthedrugwasgiven30minutesorimmediately

beforeameal.Indiabeticpatients,goodmetaboliccontrolover24hourscanbeachievedwithasingledailydose.

Althoughthehydroxymetaboliteofglimepiridecausedasmallbutsignificantdecreaseinserumglucoseinhealthy

persons,itaccountsforonlyaminorpartofthetotaldrugeffect.

Combinationtherapywithmetformin

Improvedmetaboliccontrolforconcomitantglimepiridetherapycomparedtometforminaloneinpatientsnot

adequatelycontrolledwiththemaximumdailydosageofmetforminhasbeenshowninonestudy.

Combinationtherapywithinsulin

Dataforcombinationtherapywithinsulinarelimited.Inpatientsnotadequatelycontrolledwiththemaximumdosage

ofglimepiride,concomitantinsulintherapycanbeinitiated.Intwostudies,thecombinationachievedthesame

improvementinmetaboliccontrolasinsulinalone;however,aloweravaragedoseofinsulinwasrequiredin

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)whichisroughlyequaltothealbumin

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

Inanimals,glimepirideisexcretedinmilk.Glimepirideistransferredtotheplacenta.Passageofthebloodbrainbarrier

islow.

Biotransformationandelimination:Meandominantserumhalf-life,whichisofrelevancefortheserum

concentrationsundermultiple-doseconditions,isabout5to8hours.Afterhighdoses,slightlylongerhalf-liveswere

noted.

Afterasingledoseofradiolabelledglimepiride,58%oftheradioactivitywasrecoveredintheurine,and35%inthe

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Twometabolites-mostprobablyresultingfromhepaticmetabolism-wereidentifiedbothinurineandfaeces:the

hydroxyderivativeandthecarboxyderivative.Afteroraladministrationofglimepiride,theterminalhalf-livesofthese

metaboliteswere3to6and5to6hoursrespectively.

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

Cellulose

Povidone25000

Yellowironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateforthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

PCOManufacturingLimited

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8ParallelProductAuthorisationNumber

PPA0465/104/003

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:30June2003

Dateoflastrenewal:30June2008

10DATEOFREVISIONOFTHETEXT

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