GERFORMIN

Main information

  • Trade name:
  • GERFORMIN 1000 Milligram
  • Dosage:
  • 1000 Milligram
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GERFORMIN  1000 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/112/003
  • Authorization date:
  • 05-06-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gerformin1000mgDispersibleTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Metformin1000mgdispersibletablets:Eachtabletcontains1000mgMetformin,asMetforminhydrochloride

correspondingto780mgmetforminbase.

Excipients:sulphurousanhydride(E220),maltodextrin

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Dispersibletablet

Awhite,marbledandoblongdispersibletabletswith2lines.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentoftype2diabetesmellitus,particularlyinoverweightpatients,whendietarymanagementandexercisealone

doesnotresultinadequateglycaemiccontrol.

Inadults,GERFORMIN1000mgdispersibletabletmaybeusedasmonotherapyorincombinationwith

otheroralanti-diabeticagentsorwithinsulin.

Inchildrenfrom10yearsofageandadolescents,GERFORMIN1000mgdispersibletabletmaybeused

asmonotherapyorincombinationwithinsulin.

Areductionofdiabeticcomplicationshasbeenshowninoverweighttype2diabeticadultpatientstreatedwith

metforminhydrochlorideasfirst-linetherapyafterdietfailure(seesection5.1).

4.2Posologyandmethodofadministration

Posology

Adults:

Monotherapyandcombinationwithotheroralantidiabeticagents:

TheusualstartingdoseisonetabletofGERFORMIN500mgor850mg,dispersibletablet2or3timesdailygiven

duringoraftermeals

After10to15daysthedoseshouldbeadjustedonthebasisofbloodglucosemeasurements.Aslowincreaseofdose

mayimprovegastrointestinal

tolerability.Themaximumrecommendeddoseofmetforminhydrochlorideis3gdailytakenas3divideddoses

Iftransferfromanotheroralantidiabeticagentisintended:discontinuetheotheragentandinitiatemetformin

hydrochlorideatthedoseindicatedabove.

Combinationwithinsulin:

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MetforminhydrochlorideisgivenattheusualstartingdoseofGERFORMIN500mgor,850mgdispersibletablet2or

3timesdaily,whileinsulindosageisadjustedonthebasisofbloodglucosemeasurements.

Elderly:

Duetothepotentialfordecreasedrenalfunctioninelderlysubjects,themetforminhydrochloridedosageshouldbe

adjustedbasedonrenalfunction.Regularassessmentofrenalfunctionisnecessary(seesection4.4).

Childrenandadolescents:

Monotherapyorincombinationwithinsulin:

GERFORMIN1000mgdispersibletabletcanbeusedinchildrenfrom10yearsofageandadolescents.

TheusualstartingdoseisGERFORMIN500mgor850mgdispersibletabletoncedaily,givenduringmealsorafter

meals.

After10to15daysthedoseshouldbeadjustedonthebasisofbloodglucosemeasurements.Aslowincreaseofdose

mayimprovegastrointestinaltolerability.Themaximumrecommendeddoseofmetforminhydrochlorideis2gdaily,

takenas2or3divideddoses.

Inpatientsreceivingahighmetformindose(2to3gramsperday),itispossibletoreplacetwoGERFORMIN500mg

dispersibletabletswithoneGERFORMIN1000mgdispersibletablet.

Methodofadministration:

Oraluse.

Thetabletshouldbeswallowedwithwater.Alternatively,inpatientsexperiencingdifficultyswallowing,especiallyin

childrenandelderly,thetabletcouldbedispersedinwaterpriortoingestion.

4.3Contraindications

Hypersensitivitytometforminhydrochlorideortoanyoftheexcipients.

Diabeticketoacidosis,diabeticpre-coma.

Renalfailureorrenaldysfunction(creatinineclearance<60mL/min).

Acuteconditionswiththepotentialtoalterrenalfunctionsuchas:

dehydration,

severeinfection,

shock,

Acuteorchronicdiseasewhichmaycausetissuehypoxiasuchas:

cardiacorrespiratoryfailure,

recentmyocardialinfarction,

shock.

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4.4Specialwarningsandprecautionsforuse

Lacticacidosis:

Lacticacidosisisarare,butserious(highmortalityintheabsenceofprompttreatment),metaboliccomplicationthat

canoccurduetometforminhydrochlorideaccumulation.Reportedcasesoflacticacidosisinpatientsonmetformin

hydrochloridehaveoccurredprimarilyindiabeticpatientswithsignificantrenalfailure.Theincidenceoflactic

acidosiscanandshouldbereducedbyassessingalsootherassociatedriskfactorssuchaspoorlycontrolleddiabetes,

ketosis,prolongedfasting,excessivealcoholintake,hepaticinsufficiencyandanyconditionassociatedwithhypoxia.

Diagnosis:

Theriskoflacticacidosismustbeconsideredintheeventofnon-specificsignssuchasmusclecrampswithdigestive

disordersasabdominalpainandsevereasthenia.

Thiscanbefollowedbyacidoticdyspnea,abdominalpainandhypothermiaandcoma.Diagnosticlaboratoryfindings

aredecreasedbloodpH,plasmalactatelevelsabove5mmol/l,andanincreasedaniongapandlactate/pyruvateratio.

Ifmetabolicacidosisissuspected,metforminhydrochlorideshouldbediscontinuedandthepatientshouldbe

hospitalisedimmediately(seesection4.9).

Renalfunction:

Asmetforminhydrochlorideisexcretedbythekidney,creatinineclearance(thiscanbeestimatedfromserum

creatininelevelsbyusingtheCockcroft-Gaultformula)shouldbedeterminedbeforeinitiatingtreatmentandregularly

thereafter:

atleastannuallyinpatientswithnormalrenalfunction,

atleasttwotofourtimesayearinpatientswithcreatinineclearancelevelatthelowerlimitofnormalandinelderly

subjects.

Decreasedrenalfunctioninelderlysubjectsisfrequentandasymptomatic.Specialcautionshouldbeexercisedin

situationswhererenalfunctionmaybecomeimpaired,forexamplewheninitiatingantihypertensivetherapyordiuretic

therapyandwhenstartingtherapywithanon-steroidalanti-inflammatorydrug(NSAID).

Administrationofiodinatedcontrastmedia:

Theintravascularadministrationofiodinatedcontrastmediainradiologicstudiescanleadtorenalfailure.Thismay

inducemetforminaccumulationandmayexposetolacticacidosis.Metforminhydrochlorideshouldbediscontinued

priorto,oratthetimeofthetestandnotreinstituteduntil48hoursafterwards,andonlyafterrenalfunctionhasbeen

re-evaluatedandfoundtobenormal(seesection4.5).

Surgery:

Metforminhydrochloridemustbediscontinued48hoursbeforeelectivesurgeryundergeneral,spinalorperidural

anaesthesia.Therapymayberestartednoearlierthan48hoursfollowingsurgeryorresumptionoforalnutritionand

onlyifnormalrenalfunctionhasbeenestablished.

Childrenandadolescents:

Thediagnosisoftype2diabetesmellitusshouldbeconfirmedbeforetreatmentwithmetforminhydrochlorideis

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Noeffectofmetforminhydrochlorideongrowthandpubertyhasbeendetectedduringcontrolledclinicalstudiesof

one-yeardurationbutnolong-termdataonthesespecificpointsareavailable.Therefore,acarefulfollow-upofthe

effectofmetforminhydrochlorideontheseparametersinmetforminhydrochloride-treatedchildren,especiallypre-

pubescentchildren,isrecommended.

Childrenagedbetween10and12years:

Only15subjectsagedbetween10and12yearswereincludedinthecontrolledclinicalstudiesconductedinchildren

andadolescents.Althoughmetforminhydrochlorideefficacyandsafetyinchildrenbelow12didnotdifferfrom

efficacyandsafetyinolderchildren,particularcautionisrecommendedwhenprescribingtochildrenagedbetween10

and12years.

Otherprecautions:

Allpatientsshouldcontinuetheirdietwitharegulardistributionofcarbohydrateintakeduringtheday.Overweight

patientsshouldcontinuetheirenergy-restricteddiet.

Theusuallaboratorytestsfordiabetesmonitoringshouldbeperformedregularly.

Metforminhydrochloridealonedoesnotcausehypoglycaemia,althoughcautionisadvisedwhenitisusedin

combinationwithinsulinororalantidiabetics(e.g.sulfonylureasormeglitinides).

Excipients:becauseofmaltodextrin(sourceofglucose),patientswithraremalabsorptionoftheglucose/galactose

shouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantusenotrecommended:

Alcohol:

Increasedriskoflacticacidosisinacutealcoholintoxication,particularlyincaseof:

fastingormalnutrition,

hepaticinsufficiency.

Avoidconsumptionofalcoholandalcohol-containingmedicinalproduct.

Iodinatedcontrastmedia

Intravascularadministrationofiodinatedcontrastmediamayleadtorenalfailure,resultinginmetforminhydrochloride

accumulationandanincreasedriskoflacticacidosis.

Metforminhydrochlorideshouldbediscontinuedpriorto,oratthetimeofthetestandnotreinstituteduntil48hours

afterwards,andonlyafterrenalfunctionhasbeenre-evaluatedandfoundtobenormal(seesection4.4).

Combinationsrequiringprecautionsforuse:

Medicinalproductswithintrinsichyperglycaemicactivityasglucocorticoids(systemicorbylocalroute)and

sympathomimetics.Morefrequentbloodglucosemonitoringmayberequired,especiallyatthebeginningof

treatment.Ifnecessary,adjustthemetformindosageduringthetherapywiththerespectivemedicinalproducts.

Diureticsespeciallyloopdiuretics,mayincreasetheriskoflacticacidosisduetotheirpotentialtodecreaserenal

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4.6Fertility,pregnancyandlactation

Pregnancy

Uncontrolleddiabetesduringpregnancy(gestationalorpermanent)isassociatedwithincreasedriskofcongenital

abnormalitiesandperinatalmortality.

Alimitedamountofdatafromtheuseofmetforminhydrochlorideinpregnantwomendoesnotindicateanincreased

riskofcongenitalabnormalities.Animalstudiesdonotindicateharmfuleffectswithrespecttopregnancy,embryonal

orfœtaldevelopment,parturitionorpostnataldevelopment(seesection5.3).

Whenthepatientplanstobecomepregnantandduringpregnancy,itisrecommendedthatdiabetesisnottreatedwith

metformin,butinsulinbeusedtomaintainbloodglucoselevelsasclosetonormalaspossible,toreducetheriskof

malformationsofthefoetus.

Lactation

Metforminhydrochlorideisexcretedintohumanbreastmilk.Noadverseeffectswereobservedinbreastfednewborns/

infants.However,asonlylimiteddataareavailable,breastfeedingisnotrecommendedduringmetformin

hydrochloridetreatment.Adecisiononwhethertodiscontinuebreast-feedingshouldbemade,takenintoaccountthe

benefitofbreast-feedingandthepotentialrisktoadverseeffectsonthechild.

Fertility

Fertilityofmaleorfemaleratswasunaffectedbymetforminwhenadministeredatdosesashighas600mg/kg/day,

whichisapproximatelythreetimesthemaximumrecommendedhumandailydosebasedonbodysurfacearea

comparisons.

4.7Effectsonabilitytodriveandusemachines

Gerformin1000mgdispersibletabletmonotherapydoesnotcausehypoglycaemiaandthereforehasnoeffectonthe

abilitytodriveortousemachines.

However,patientsshouldbealertedtotheriskofhypoglycaemiawhenmetforminhydrochlorideisusedin

combinationwithotherantidiabeticagents(sulfonylureas,insulin,meglitinides).

4.8Undesirableeffects

Duringtreatmentinitiation,themostcommonadversereactionsarenausea,vomiting,diarrhoea,abdominalpainand

lossofappetitewhichresolvespontaneouslyinmostcases.Topreventthem,itisrecommendedtotakemetforminin2

or3dailydosesandtoincreaseslowlythedoses.

Thefollowingadversereactionsmayoccurundertreatmentwithmetformin.Frequenciesaredefinedasfollows:very

common:1/10;common>1/100,<1/10;uncommon>1/1,000,<1/100;rare>1/10,000,<1/1,000;veryrare<1/10,000.

Withineachfrequencygrouping,adversereactionsarepresentedinorderofdecreasingseriousness.

Metabolismandnutritiondisorders:

veryrare:

Lacticacidosis(seesection4.4).

DecreaseofvitaminB12absorptionwithdecreaseofserumlevelsduringlong-termuseofmetformin.Considerationof

suchaetiologyisrecommendedifapatientpresentswithmegaloblasticanaemia.

Nervoussystemdisorders:

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Gastrointestinaldisorders:

verycommon:Gastrointestinaldisorderssuchasnausea,vomiting,diarrhoea,abdominalpainandlossofappetite.

Theseundesirableeffectsoccurmostfrequentlyduringinitiationoftherapyandresolvespontaneouslyinmostcases.

Topreventthem,itisrecommendedthatmetforminbetakenin2or3dailydosesduringoraftermeals.Aslow

increaseofthedosemayalsoimprovegastrointestinaltolerability.

Hepatobiliarydisorders:

veryrare:Isolatedreportsofliverfunctiontestsabnormalitiesorhepatitisresolvinguponmetformindiscontinuation.

Skinandsubcutaneoustissuedisorders:

veryrare:Skinreactionssuchaserythema,pruritus,urticaria

Paediatricpopulation

Inpublishedandpostmarketingdataandincontrolledclinicalstudiesinalimitedpaediatricpopulationaged10-

16yearstreatedduring1year,adverseeventreportingwassimilarinnatureandseveritytothatreportedinadults.

Excipients:

Sulphurousanhydridemaycausehypersensitivityreactions,includinganaphylacticreactionsandbronchospasms .

4.9Overdose

Hypoglycaemiahasnotbeenseenwithmetforminhydrochloridedosesofupto85g,althoughlacticacidosishas

occurredinsuchcircumstances.Highoverdoseofmetforminhydrochlorideorconcomitantrisksmayleadtolactic

acidosis.Lacticacidosisisamedicalemergencyandmustbetreatedinhospital.Themosteffectivemethodtoremove

lactateandmetforminhydrochlorideishaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ORALANTI-DIABETICS,ATCcode:A10BA02

Metforminhydrochlorideisabiguanidewithantihyperglycaemiceffects,loweringbothbasalandpostprandialplasma

glucose.Itdoesnotstimulateinsulinsecretionandthereforedoesnotproducehypoglycaemia.

Metforminhydrochloridemayactvia3mechanisms:

(1)reductionofhepaticglucoseproductionbyinhibitinggluconeogenesisandglycogenolysis.

(2)inmuscle,byincreasinginsulinsensitivity,improvingperipheralglucoseuptakeandutilization.

(3)anddelayofintestinalglucoseabsorption.

Metforminhydrochloridestimulatesintracellularglycogensynthesisbyactingonglycogensynthase.

Metforminhydrochlorideincreasesthetransportcapacityofalltypesofmembraneglucosetransporters(GLUT).

Inclinicalstudies,useofmetforminwasassociatedwitheitherastablebodyweightormodestweightloss.

Inhumans,independentlyofitsactiononglycaemia,metforminhydrochloridehasfavourableeffectsonlipid

metabolism.Thishasbeenshownattherapeuticdosesincontrolled,medium-termorlong-termclinicalstudies:

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Clinicalefficacy:

TheprospectiverandomisedUKPDSstudyhasestablishedthelong-termbenefitofintensivebloodglucosecontrolin

adultpatientswithtype2diabetes.

Analysisoftheresultsforoverweightpatientstreatedwithmetforminhydrochlorideafterfailureofdietaloneshowed:

asignificantreductionoftheabsoluteriskofanydiabetes-relatedcomplicationinthemetforminhydrochloride

group(29.8events/1000patient-years)versusdietalone(43.3events/1000patient-years),p=0.0023,andversusthe

combinedsulfonylureaandinsulinmonotherapygroups(40.1events/1000patient-years),p=0.0034;

asignificantreductionoftheabsoluteriskofdiabetes-relatedmortality:metforminhydrochloride

7.5events/1000patient-years,dietalone12.7events/1000patient-years,p=0.017;

asignificantreductionoftheabsoluteriskofoverallmortality:metforminhydrochloride13.5events/1000patient-

yearsversusdietalone20.6events/1000patient-years(p=0.011),andversusthecombinedsulfonylureaandinsulin

monotherapygroups18.9events/1000patient-years(p=0.021);

significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride

11events/1000patient-years,dietalone18events/1000patient-years(p=0.01).

Formetforminhydrochlorideusedassecond-linetherapy,incombinationwithasulfonylurea,benefitregarding

clinicaloutcomehasnotbeenshown.

Intype1diabetes,thecombinationofmetforminhydrochlorideandinsulinhasbeenusedinselectedpatients,butthe

clinicalbenefitofthiscombinationhasnotbeenformallyestablished.

Paediatricpopulation

Controlledclinicalstudiesinalimitedpaediatricpopulationaged10-16yearstreatedduring1yeardemonstrateda

similarresponseinglycaemiccontroltothatseeninadults.

5.2Pharmacokineticproperties

Absorption:

Afteranoraldoseofmetforminhydrochloride,maximumplasmaconcentration(

Cmax )isreachedinapproximately

2.5hours(t

Absolutebioavailabilityofa500mgor850mgmetforminhydrochloridetabletisapproximately50-60%inhealthy

subjects.Afteranoraldose,thenon-absorbedfractionrecoveredinfaeceswas20-30%.

Afteroraladministration,metforminhydrochlorideabsorptionissaturableandincomplete.Itisassumedthatthe

pharmacokineticsofmetforminhydrochlorideabsorptionisnon-linear.

Attheusualmetforminhydrochloridedosesanddosingschedules,steadystateplasmaconcentrationsarereached

within24to48hoursandaregenerallylessthan1microgram/ml.Incontrolledclinicaltrials,maximummetformin

hydrochlorideplasmalevels(C

)didnotexceed4microgram/ml,evenatmaximumdoses.

Fooddecreasestheextentandslightlydelaystheabsorptionofmetforminhydrochloride.Followingadministrationofa

doseof850mg,a40%lowerplasmapeakconcentration,a25%decreaseinAUC(areaunderthecurve)anda

35minuteprolongationoftimetopeakplasmaconcentrationwereobserved.Theclinicalrelevanceofthesedecreases

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Distribution:

Plasmaproteinbindingisnegligible.Metforminhydrochloridepartitionsintoerythrocytes.Thebloodpeakislower

thantheplasmapeakandappearsatapproximatelythesametime.Theredbloodcellsmostlikelyrepresenta

secondarycompartmentofdistribution.Themeanvolumeofdistribution(Vd)rangedbetween63and2761.

Metabolism:

Metforminhydrochlorideisexcretedunchangedintheurine.Nometabolitehasbeenidentifiedinhumans.

Elimination:

Renalclearanceofmetforminhydrochlorideis>400ml/min,indicatingthatmetforminhydrochlorideiseliminatedby

glomerularfiltrationandtubularsecretion.Followinganoraldose,theapparentterminaleliminationhalf-lifeis

approximately6.5hours.

Whenrenalfunctionisimpaired,renalclearanceisdecreasedinproportiontothatofcreatinineandthusthe

eliminationhalf-lifeisprolonged,leadingtoincreasedlevelsofmetforminhydrochlorideinplasma.

Paediatricpopulation:

Singledosestudy:Aftersingledosesofmetforminhydrochloride500mgpaediatricpatientshaveshownsimilar

pharmacokineticprofiletothatobservedinhealthyadults.

Multipledosestudy:Dataarerestrictedtoonestudy.Afterrepeateddosesof500mgBIDfor7daysinpaediatric

patientsthepeakplasmaconcentration(C

)andsystemicexposure(AUC0-t)werereducedbyapproximately33%

and40%,respectivelycomparedtodiabeticadultswhoreceivedrepeateddosesof500mgBIDfor14days.Asthe

doseisindividuallytitratedbasedonglycaemiccontrol,thisisoflimitedclinicalrelevance.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesonsafety,pharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotential,toxicityreproduction.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

PovidoneK30,microcrystallinecellulose,saccharinsodium,sodiumbenzoate,pregelatinisedmaizestarch,lemon

flavour(alpha-pinene,beta-pinene,myrcene,limonene,gamma-terpinene,neral,geranial,maltodextrin,acacia,

butylhydroxyanisole,sulphurousanhydride(E220)).

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

20,30,50,60,90,100,150,180or270tabletsinblisterpacks(PVC/PVDC/Aluminium)or(Aluminium/Aluminium)

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialsshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtd|

t/aGerardLaboratories

35/36BalydoyleIndustrialEstate

GrangeRoad

Dublin13

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA577/112/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5June2009

10DATEOFREVISIONOFTHETEXT

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