BELLFORMIN

Main information

  • Trade name:
  • BELLFORMIN Tablets 850 Milligram
  • Dosage:
  • 850 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BELLFORMIN Tablets 850 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1185/001/002
  • Authorization date:
  • 10-12-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bellformin850mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains:Metforminhydrochloride850mg.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Film-coatedtablets

Whitecoloured,round,biconvextablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Non-insulin-dependentdiabetes(NIDDM,typeII),whenadequatedietarytreatmenthasfailed.

Bellformin850mgtabletscanbegivenaloneasinitialtherapy,orcanbeadministeredincombinationwith

sulphonylureasaftercarefulassessmentofthecontraindications.

4.2Posologyandmethodofadministration

Dosage

Usualdosage:

Therequireddailydoserangesfrom0.5to3g.Therapyshouldbeinitiatedwithalowdoseofoneortwotabletsdaily.

Dependingonthemetabolicstatethedosecanbeincreasedstepwiseatintervalsofafewdaysuptotwoweeksuntil

thetherapeuticallyrequireddosehasbeenreached.Inordertominimisethegastro-intestinalside-effectsthedaily

doseshouldbedividedandtakenwithoraftermeals.Generally,dailydosesof1.5g(twotablets)aresufficient.If

diabeticcontrolisincompleteacautiousincreaseindosagetoamaximumof3gdailyisjustified.

Noadditionalbenefitcanusuallybeachievedbyuseofdosesexceeding3gdaily.Oncecontrolhasbeenachievedit

maybepossibletoreducethedailydose.

Incasesofmetabolicdecompensation:

Incasesofmetabolicdecompensation-thisshouldbestabilisedbeforetheadministrationofmetforminisconsidered.

Childrenandjuveniles:

Bellformin850mgtabletsarenotrecommendedforuseinchildren.

Bellformin850mgtabletsarenotindicatedforthetreatmentofinsulin-dependentdiabetes(IDDM,typeI)inchildren

andjuveniles.

TheuseofBellformin850mgtabletsisnotadvisedfortreatmentoftheveryrarelyoccurringinsulin-dependent

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ElderlyPatients:

Bellformin850mgtabletsmaybeindicatedintheelderly,butnotwhenrenalfunctionisimpaired.

Furtherdosageinformation

Combinationwithsulphonylureas:

Bellformin850mgtabletsmaybeusedincombinationwithsulphonylureasifmonotherapywithmetformindoesnot

leadtoasatisfactoryresponse.However,itshouldbenotedthatmetforminandsulphonylureashaveadifferentmode

ofactionandthereforeanadditiveorpotentiatingeffectofthesedrugsmightcausehypoglycaemia.

Substitutionforsulphonylureas:

Bellformin850mgtabletsmaybeusedinsteadofsulphonylureasinpatientswhoformerlyhavebeentreatedwith

sulphonylureas.

MethodofAdministration

Bellformin850mgtabletsshouldbetakenunchewedtogetherwithaglassofwaterduringoraftermeals.

Monitoringadvice

Seespecialwarningsandspecialprecautionsforuse.

4.3Contraindications

Duringpregnancyandlactation.

Inchildrenandveryoldpatients.

Inpatientswithinsulin-dependentdiabetes(IDDM,typeI).

Inpatientswithnon-insulin-dependentdiabetes(NIDDM,typeII),ifsulphonylureatherapyhascompletelyfailed.

Acidoticstatesduringmetaboliccompensation.

Precoma,hyperosmolaricorketo-acidoticcomadiabeticum.

Hypersensitivitytometformin.

Impairmentofliverand,inparticular,renalfunctions.

Respiratoryinsufficiency.

Severecardiovascularimpairment.

Cardiacfailureandrecentmyocardialinfarction.

Acuteseveredisorders,forexampleinfectionswithfever,pancreatitisortrauma.

Historyof,orstatesassociatedwith,lacticacidosissuchasshockorpulmonaryinsufficiency,alcoholism(acute

orchronic),andconditionsassociatedwithhypoxaemia.

Catabolicstates,e.g.intumourdiseases.

Surgerywithgeneralanaesthesia.Metformintherapyshouldbestoppedbefore,duringandaftersurgery.

Intravascularcontraststudieswithiodinatedmaterialscanleadtoacutealterationofrenalfunctionandhavebeen

associatedwithlacticacidosisinpatientsreceivingmetformin.Therefore,inpatientsinwhomanysuchstudies

areplanned,metforminshouldbediscontinuedatthetimeof,orpriorto,theprocedureandwithheldfor48hours

subsequenttotheprocedureandre-institutedonlyafterrenalfunctionhasbeenre-evaluatedandfoundtobe

normal.

Reduceddiet(<1000kcalor4200kJperday).

4.4Specialwarningsandprecautionsforuse

Warnings

Inpatientswithimpairedliverfunction,lactateclearancemayberestricted.

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requiresanormalrenalfunction,whichshouldberegularlyreviewed.

Duringconcomitanttherapywithsulphonylureasorinsulin,bloodglucoselevelsshouldbemonitoredbecause

combinedtherapymaycausehypoglycaemia.Stabilisationofdiabeticpatientswithmetforminandinsulinshould

becarriedoutinahospitaluntilthecorrectratioofthetwodrugshasbeenobtained.

PatientsreceivingcontinuousmetformintherapyshouldhaveanannualestimationofVitaminB

levelsbecause

ofreportsofdecreasedVitaminB

absorption.

Precautionforuse

Theuseofmetforminisnotadvisedinconditionswhichmaycausedehydrationorinpatientssufferingfrom

seriousinfectionsortrauma.

Patientswhosuddenlysufferfrommusclespasms,dyspepsia,abdominalpainandfatigueshouldconsulta

physicianimmediately,sincethesesymptomsmayindicatelacticacidosis.Lacticacidosisisaccompaniedby

acidoticdyspnoea,abdominalpain,hyperthermia,comatosestate,decreaseofbloodpHvalueandincreaseof

lactatevalue.

Serumcreatininelevelsshouldbedeterminedbeforeandfourweeksaftermetformintherapyhasbeenstarted.

Regularmeasurementsshouldtakeplaceonceortwiceayearunlessrequiredearlierduetointercurrentdisorders.

Intheelderly,creatinineclearanceisadvisedbeforetheonsetofmetformintherapy.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

DuringtreatmentwithBellformin850mgtabletsalcoholhastobestrictlyavoided.Acuteandchronicalcohol

abusemayincreasethebloodglucosedecreasingeffectandtheserumlactateincreasingeffectofmetforminto

unpredictableextents.

Intravascularcontraststudieswithiodinatedmaterialscanleadtoacutealterationofrenalfunctionandhavebeen

associatedwithlacticacidosisinpatientsreceivingmetformin.Therefore,inpatientsinwhomanysuchstudies

areplanned,metforminshouldbediscontinuedatthetimeof,orpriorto,theprocedureandwithheldfor48hours

subsequenttotheprocedureandre-institutedonlyafterrenalfunctionhasbeenre-evaluatedandfoundtobe

normal.

Metformintherapyshouldalsobestoppedtwodaysbeforeandtwodaysaftersurgerywithgeneralanaesthesia.

PrecautionsforUse

Anincreaseoftheantihyperglycaemiceffectofmetforminispossibleintheeventofconcomitantadministrationwith

medicinalproductsforthesameindication,forexample:

Insulin.

Oralantidiabeticdrugs,ofthesulphonylureaandacarbose.

Anincreaseoftheantihyperglycaemiceffectofmetforminisalsopossibleintheeventofconcomitantadministration

withmedicinalproductsforotherindicationswhichpossessbloodglucose-loweringeffectsoftheirown,forexample:

Nonsteroidalanti-inflammatorydrugs(NSAIDs),e.g.salicylatesorpyrazolones.

Monoamineoxidase(MAO)inhibitors.

Oxytetracycline.

Angiotensinconvertingenzyme(ACE)inhibitors.

Clofibratederivatives.

Cyclophosphamideanditsderivatives.

Thecombinationofmetforminandtheabovementioneddrugscaninducehypoglycaemia.

Moreover,duringpermanenttherapy,beta-blockersandantisympathotonicdrugs,suchasclonidine,reserpineor

guanethidine,maydecreasebloodglucoselevels.However,ofparticularclinicalrelevanceistheirreducingactionon

thehormonalandneuralcounterregulationduringhypoglycaemia,whichinturnmayimpairthesubjectiveperception

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Adecreaseoftheantihyperglycaemiceffectofmetforminincombinationwithoneofthefollowingdrugsmayoccur:

Glucocorticoids.

Estrogen-Gestagen-Combinations.

AdrenalineandotherSympathomimetics.

Glucagon.

Thyroidhormones.

Thiazidesandloopdiuretics.

Diazoxide.

Phenothiazines.

Nicotinicacidderivatives.

Tobetakenintoaccount

Duringmaintenancetherapytheonsetorterminationofanyotheradditionaltherapycandisturbthecontrolofdiabetes.

4.6Pregnancyandlactation

DuringpregnancytheadministrationofBellformin850mgtabletsarecontraindicated.TheuseofBellformin850mg

tabletsshouldbeavoidedinwomenwhoarebreast-feeding.Noinformationisavailableonwhethermetforminorits

metabolitesareexcretedinthebreastmilk.

4.7Effectsonabilitytodriveandusemachines

WhenBellformin850mgtabletsareusedasmonotherapy,hypoglycaemiaisnotusuallyaproblemanddoesnot

influencetheabilitytodriveoroperatemachinery.Incasesofcombinedtherapywithsulphonylureasorotherdrugs

withbloodglucoseloweringeffects,hypoglycaemiamayoccurand,hence,suchcombinationsmayproduceminoror

moderateadverseeffects.Patientsundergoingsuchcombinationtherapyshouldbeadvisedtotakeprecautionstoavoid

hypoglycaemiawhilstdrivingoroperatingmachinery.

4.8Undesirableeffects

Frequentlyarisingundesirableeffectsare:Gastro-intestinaldisturbances.

Bellformin850mgtabletsisnormallywelltolerated,butatthebeginningofmetformintherapygastro-intestinal

disturbances,suchasnausea,vomiting,abdominalpain,diarrhoea,anorexiaandmetallictasteoccurin5-20%of

patients.Thesegastro-intestinaldisturbancesaregenerallyofminorimportanceandrequirenoterminationof

metformintherapy.Thefrequencyandseverityofthesegastro-intestinaldisturbancescanbereducedmarkedlyby

startingwithlowandgraduallyincreasingmetformindosesandbyadministrationofmetforminwithorafter

meals.

About5%ofallpatientsdonottoleratemetformintherapy.

Veryrarelyarisingundesirableeffectsare:

Hypersensitivityandlacticacidosis.

Guar: Adecreaseoftheabsorptionofmetforminmayleadtoanattenuationofmetformineffects.

Cimetidine: Substanceswhichdelaytheeliminationofmetformin,e.g.cimetidine,mayincreasetheriskof

lacticacidosis.

Anticoagulants: Eliminationofanticoagulantse.g.coumarinsmaybeacceleratedduringmetformintherapy.

Thereforethebloodcoagulationinhibitingeffectmaybedecreasedandfrequentcontrolsofblood

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Lacticacidosis.

Withmetformintherapylacticacidosiswithcomaanddeathispossible.Lacticacidosisinducedbymetforminis

accompaniedbyimpairedhepaticlactateclearanceandincreasedmuscularlactaterelease.Althoughmetformin-

inducedlacticacidosisoccursveryrarely(untilnowonly100incidentsworld-wide)themortalityreaches50%.

Causesoflacticacidosis:

Thefollowingmaypredisposetolacticacidosis:Renalinsufficiency,impairedliverfunction,alcoholconsumption,

otherdiseaseswitheffectontheoxidativemetabolism,forexamplecardiacdecompensationorsevereinfectionsand

catbolicconditionsaswellasinteractionswithotherdrugs.

Symptomsoflacticacidosis:

Atfirstlacticacidosisresemblesthegastro-intestinalside-effectsofmetformin,forexamplenausea,vomiting,

diarrhoeaandabdominalpain.However,withinafewhoursthecompleteclinicalpictureoflacticacidosiswithmuscle

pains,hyperventilation,cloudingofconsciousnessandcomamaydevelop.Onsuspicionoflacticacidosismetformin

therapymustbeimmediatelystoppedandthepatientmustbetreatedatonceasanemergencyinahospital.

Reportedsinglecases:

InhibitionoftheabsorptionofVitaminB

orfolicacidmaycausemegaloblasticanaemia.Patientsreceiving

continuousmetformintherapyshouldhaveanannualestimationofVitaminB

levels.

Persistinggastro-intestinaldisturbancesrequiretheterminationofmetformintherapy.

4.9Overdose

Humanexperience

IntoxicationwithBellformin850mgtabletsdoesnotleadtohypoglycaemiabutlacticacidosismaydevelop.Usually,

thecauseisnotoverdosage,butaccumulationasaresultofimpairedrenalfunctionand,atthesametime,inadequate

doseadjustment.

HypoglycaemiacanoccurwhenBellformin850mgtabletsaregivenconcomitantlywithsulphonylureas,alcoholor

insulin.

Managementofoverdosageinman

Ifsignsoflacticacidosisorofmetforminoverdosage,forexampleinsuicidalintention,areshown,patientsmustbe

admittedtoahospitalasanemergency.Thediagnosisoflacticacidosisshouldbeconfirmedbydeterminationof

lactateandifpossiblemetforminconcentrations.Haemodialysisisthemosteffectivemeasuretoeliminatelactateand

metformin.Symptomatictreatmentincludescirculatorystabilisation,compensationofacidosisandeliminationof

hypoxia.Themetforminconcentrationinerythrocytesisagoodindicatorforaccumulationandcanbeusedtodecide

whetherrepeatedhaemodialysisisindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Metforminisabiguanideoralantihyperglycaemicagent(ATCCodeA10BA02)andreduceselevatedbloodglucose

levelsonlyinpatientswithnon-insulin-dependentdiabetes(NIDDM)(typeIIdiabetesmellitus),butdoesnotincrease

insulinsecretionanddoesnotcausehypoglycaemiaorincreasedweightgain.Itsmodeofactionismultifactorialand

notyetcompletelyunderstood.However,theaugmentationofglucoseuptakeintoperipheraltissuesmayinfluence

glucoseutilisation.Furthermore,theeffectsofmetforminincludereducedhepaticgluconeogenesisanddelayed

intestinalglucoseabsorptionwhichmayexplainthebloodglucose-loweringeffect.Theefficacyofmetforminis

dependentonaminimumconcentrationofinsulin.

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thepost-receptorpathwaysofinsulin-action.Apartfromtheglucose-loweringeffect,metforminreducestheserum

triglyceridelevelandpossessesantithromboticproperties.

5.2Pharmacokineticproperties

Afteroraladministrationmetforminisincompletelyabsorbedfromthegastro-intestinaltract.Theoralbioavailability

ofusualdosesis50-60%.Themaximumplasmaconcentrationisachievedafterabout2hours.Gastrointestinal

absorptioniscompletewithin6hoursofingestion.Thevolumeofdistributionliesbetween63and276litres.

Metforminisrapidlydistributedbutaslowtransfertoadeepcompartmentseemstooccur.Metformindoesnotbindto

plasmaproteinsbutaccumulatesinthesalivaryglands,duodenum,kidneysandliver.Nometabolitesorconjugatesof

metforminhavebeenidentified.Metforminiscompletelyeliminatedbyrenalexcretionandthemeanplasma

eliminationhalf-liferangesbetween1.5and4.5hours.

Aquantitativelyminorterminaleliminationphase,probablyoutofthedeepcompartment,withalongermeanhalf-life,

rangingfrom8.9to19hours,hasbeenobserved.Therenalclearanceofmetforminrangesbetween350and550ml/min

andcorrelateswiththecreatinineclearance,indicatingthatmetforminisexcretedbyactivetubularsecretion.In

patientswithimpairedrenalfunctionaccumulationofmetforminisprobable.

5.3Preclinicalsafetydata

Acutetoxicity:

Acutetoxicityafterdifferentroutesofadministrationandindifferentanimalswasinvestigated.Thedataindicatethe

highesttoxicityofmetforminhydrochlorideaftersubcutaneousadministrationtoguineapigsandrabbits(LD

=150

mg/kg)andintravenousadministrationtomice(LD

=180mg/kg).

Thetoxicityafteroralingestionofmetforminhydrochlorideseemstobeseveraltimeslower,rabbitsandguineapigs

350and500mg/kg,respectively)beingmoresensitivethanmiceorrats(LD

1450mg/kgand1000mg,

respectively).Hence,invariousanimalspeciesstudied,afterdifferentroutesofadministrationtheLD

valuesare

considerablyabovethetherapeuticdoserangeinhumans(maximumapproximately40mg/kg/day).

Chronictoxicity:

Studieswithrepeatedadministrationofmetformintorats(upto18months),dogs(upto18months)andmonkeys(up

to2years)revealednospecifictoxiceffects.

Mutagenicandcarcinogeniceffects:

Bacterialtestsformutagenicityofmetforminwerenegativebutchromosomalalterationswereobservedinvitroin

mammaliancells.Therelevanceoftheseeffectsremainsobscure.Long-termanimalstudiesfailedtodetectany

oncogenicpropertiesofmetformin.

Reproductivetoxicity:

Noteratogenicpropertiesofmetforminhavebeenfoundinrats.Thenoadverse-effectlevel(NOAEL)ofmetforminin

ratswasestimatedtobe300mg/kg/dayforembryotoxicityandfemalereproductionandupto600mg/kg/dayformale

fertility.Noteratogeniceffectswereobservedinrabbitswithdosesupto140mg/kg/day(p.o.).Inratsdosesupto600

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Sodiumstarchglycolate(TypeA)

Maizestarch

Povidone

Colloidalanhydroussilica

Magnesiumstearate

Film-coating:

Hypromellose

Titaniumdioxide(E171)

Propyleneglycol(E1520)

Macrogol6000

Talc

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25˚C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

BlisterstripsconsistingofPVC/PE/PVDC–Aluminiumfoilcontaining56film–coatedtabletsinanoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

BellPharmaLimited

FirstFloor

69St.Patrick’sRoad

Dalkey

CountyDublin

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10December1999

Dateoflastrenewal:10December2004

10DATEOFREVISIONOFTHETEXT

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