GERFORMIN 850

Main information

  • Trade name:
  • GERFORMIN 850
  • Dosage:
  • 850 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GERFORMIN 850
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/039/002
  • Authorization date:
  • 23-02-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gerformin850mgFilm-coatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onefilm-coatedtabletcontains850mgmetforminhydrochloridecorrespondingto662.9mgmetforminbase.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

White,circularconvextablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentoftype2diabetesmellitus,particularlyinoverweightpatients,whendietarymanagementandexercisealone

doesnotresultinadequateglycaemiccontrol.

Inadults,Gerformin850mgfilm-coatedtabletsmaybeusedasmonotherapyorincombinationwithotheroral

anti-diabeticagentsorwithinsulin.

Inchildrenfrom10yearsofageandadolescents,Gerformin850mgfilm-coatedtabletsmaybeusedas

monotherapyorincombinationwithinsulin.

Areductionofdiabeticcomplicationshasbeenshowninoverweighttype2diabeticadultpatientstreatedwith

metforminhydrochlorideasfirst-linetherapyafterdietfailure(seesection5.1,Pharmacodynamicproperties).

4.2Posologyandmethodofadministration

Adults:

Monotherapyandcombinationwithotheroralantidiabeticagents:

Theusualstartingdoseisonetablet2or3timesdailygivenduringoraftermeals.

After10to15daysthedoseshouldbeadjustedonthebasisofbloodglucosemeasurements.Aslowincreaseofdose

mayimprovegastrointestinaltolerability.Themaximumrecommendeddoseofmetforminhydrochlorideis3gdaily,

takenas3divideddoses.

Iftransferfromanotheroralantidiabeticagentisintended:discontinuetheotheragentandinitiatemetformin

hydrochlorideatthedoseindicatedabove.

Combinationwithinsulin:

Metforminhydrochlorideandinsulinmaybeusedincombinationtherapytoachievebetterbloodglucosecontrol.

Metforminhydrochlorideisgivenattheusualstartingdoseofonetablet2or3timesdaily,whileinsulindosageis

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Elderly:

Duetothepotentialfordecreasedrenalfunctioninelderlysubjects,themetforminhydrochloridedosageshouldbe

adjustedbasedonrenalfunction.Regularassessmentofrenalfunctionisnecessary(seesection4.4,Specialwarnings

andprecautionsforuse).

Childrenandadolescents:

Monotherapyandcombinationwithinsulin

Gerformin850mgfilm-coatedtabletscanbeusedinchildrenfrom10yearsofageandadolescents.

Theusualstartingdoseis500mgor850mgmetforminhydrochlorideoncedaily,givenduringoraftermeals.

After10to15daysthedoseshouldbeadjustedonthebasisofbloodglucosemeasurements.Aslowincreaseofdose

mayimprovegastrointestinaltolerability.Themaximumrecommendeddoseofmetforminhydrochlorideis2gdaily,

takenas2or3divideddoses.

4.3Contraindications

Hypersensitivitytometforminhydrochlorideortoanyoftheexcipients.

Diabeticketoacidosis,diabeticpre-coma.

Renalfailureorrenaldysfunction(creatinineclearance<60ml/min).

Acuteconditionswiththepotentialtoalterrenalfunctionsuchas:dehydration,severeinfection,shock,

intravascularadministrationofiodinatedcontrastagents(seesection4.4,Specialwarningsandprecautionsfor

use).

Acuteorchronicdiseasewhichmaycausetissuehypoxiasuchas:cardiacorrespiratoryfailure,recent

myocardialinfarction,shock.

Hepaticinsufficiency,acutealcoholintoxication,alcoholism.

Lactation.

4.4Specialwarningsandprecautionsforuse

Lacticacidosis:

Lacticacidosisisarare,butserious(highmortalityintheabsenceofprompttreatment),metaboliccomplicationthat

canoccurduetometforminhydrochlorideaccumulation.Reportedcasesoflacticacidosisinpatientsonmetformin

hydrochloridehaveoccurredprimarilyindiabeticpatientswithsignificantrenalfailure.Theincidenceoflacticacidosis

canandshouldbereducedbyassessingalsootherassociatedriskfactorssuchascontrolleddiabetes,ketosis,prolonged

fasting,excessivealcoholintake,hepaticinsufficiencyandanyconditionassociatedwithhypoxia.

Diagnosis:

Theriskoflacticacidosismustbeconsideredintheeventofnon-specificsignssuchasmusclecrampswithdigestive

disordersasabdominalpainandsevereasthenia.

Lacticacidosisischaracterisedbyacidoticdyspnea,abdominalpainandhypothermiafollowedbycoma.Diagnostic

laboratoryfindingsaredecreasedbloodpH,plasmalactatelevelsabove5mmol/l,andanincreasedaniongapand

lactate/pyruvateratio.Ifmetabolicacidosisissuspected,metforminhydrochlorideshouldbediscontinuedandthe

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Renalfunction:

Asmetforminhydrochlorideisexcretedbythekidney,serumcreatininelevelsshouldbedeterminedbeforeinitiating

treatmentandregularlythereafter:

atleastannuallyinpatientswithnormalrenalfunction,

atleasttwotofourtimesayearinpatientswithserumcreatininelevelsattheupperlimitofnormalandinelderly

subjects.

Decreasedrenalfunctioninelderlysubjectsisfrequentandasymptomatic.Specialcautionshouldbeexercisedin

situationswhererenalfunctionmaybecomeimpaired,forexamplewheninitiatingantihypertensivetherapyordiuretic

therapyandwhenstartingtherapywithanon-steroidalanti-inflammatorydrug.

Administrationofiodinatedcontrastagent:

Astheintravascularadministrationofiodinatedcontrastmaterialsinradiologicstudiescanleadtorenalfailure,

metforminhydrochloridemustbediscontinuedpriorto,oratthetimeofthetestandnotbereinstituteduntil48hours

afterwards,andonlyafterrenalfunctionhasbeenre-evaluatedandfoundtobenormal(seesection4.5,Interactionwith

othermedicinalproductsandotherformsofinteraction).

Surgery:

Metforminhydrochloridemustbediscontinued48hoursbeforeelectivesurgeryundergeneral,spinalorperi-dural

anaesthesia.Therapymayberestartednoearlierthan48hoursfollowingsurgeryorresumptionoforalnutritionand

onlyifnormalrenalfunctionhasbeenestablished.

Childrenandadolescents:

Thediagnosisoftype2diabetesmellitusshouldbeconfirmedbeforetreatmentwithmetforminhydrochlorideis

initiated.

Noeffectofmetforminhydrochlorideongrowthandpubertyhasbeendetectedduringcontrolledclinicalstudiesof

one-yeardurationbutnolong-termdataonthesespecificpointsareavailable.Therefore,acarefulfollow-upofthe

effectofmetforminhydrochlorideontheseparametersinmetforminhydrochloride-treatedchildren,especiallypre-

pubescentchildren,isrecommended.

Childrenagedbetween10and12years:

Only15subjectsagedbetween10and12yearswereincludedinthecontrolledclinicalstudiesconductedinchildren

andadolescents.Althoughefficacyandsafetyofmetforminhydrochlorideinthesechildrendidnotdifferfromefficacy

andsafetyinolderchildrenandadolescents,particularcautionisrecommendedwhenprescribingtochildrenaged

between10and12years.

Otherprecautions:

Allpatientsshouldcontinuetheirdietwitharegulardistributionofcarbohydrateintakeduringtheday.Overweight

patientsshouldcontinuetheirenergy-restricteddiet.

Theusuallaboratorytestsfordiabetesmonitoringshouldbeperformedregularly.

Metforminhydrochloridealonedoesnotcausehypoglycaemia,butcautionisadvisedwhenitisusedincombination

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantusenotrecommended:

Alcohol:

Increasedriskoflacticacidosisinacutealcoholintoxication,particularlyincaseof:

fastingormalnutrition,hepaticinsufficiency.

Avoidconsumptionofalcoholandalcohol-containingmedicinalproduct.

Iodinatedcontrastagents(seesection4.4,Specialwarningsandprecautionsforuse):

Intravascularadministrationofiodinatedcontrastagentsmayleadtorenalfailure,resultinginmetforminhydrochloride

accumulationandanincreasedriskoflacticacidosis.

Metforminhydrochloridemustbediscontinuedpriorto,oratthetimeofthetestandnotbereinstituteduntil48hours

afterwards,andonlyafterrenalfunctionhasbeenre-evaluatedandfoundtobenormal.

Combinationsrequiringprecautionsforuse:

Glucocorticoids(systemicandlocalroutes),beta-2-agonists,anddiuretics:

haveintrinsichyperglycaemicactivity.Informthepatientandperformmorefrequentbloodglucosemonitoring,

especiallyatthebeginningoftreatment.Ifnecessary,adjustthedosageoftheantidiabeticmedicinalproductduring

therapywiththeothermedicinalproductanduponitsdiscontinuation.

ACE-inhibitors:

maydecreasethebloodglucoselevels.Therefore,doseadjustmentofmetforminhydrochloridemaybenecessary

duringandafteradditionordiscontinuationofsuchmedicinalproducts.

4.6Pregnancyandlactation

Todate,norelevantepidemiologicaldataareavailable.Animalstudiesdonotindicateharmfuleffectswithrespectto

pregnancy,embryonalorfoetaldevelopment,parturitionorpostnataldevelopment(seesection5.3,Preclinicalsafety

data).

Whenthepatientplanstobecomepregnantandduringpregnancy,diabetesshouldnotbetreatedwithmetformin

hydrochloridebutinsulinshouldbeusedtomaintainbloodglucoselevelsasclosetonormalaspossibleinorderto

lowertheriskoffoetalmalformationsassociatedwithabnormalbloodglucoselevels.

Metforminhydrochlorideisexcretedintomilkinlactatingrats.Similardataarenotavailableinhumansandadecision

shouldbemadewhethertodiscontinuebreast-feedingortodiscontinuemetforminhydrochloride,takingintoaccount

theimportanceofthemedicinalproducttothemother.

4.7Effectsonabilitytodriveandusemachines

Metforminhydrochloridemonotherapydoesnotcausehypoglycaemiaandthereforehasnoeffectontheabilitytodrive

ortousemachines.

However,patientsshouldbealertedtotheriskofhypoglycaemiawhenmetforminhydrochlorideisusedin

combinationwithotherantidiabeticagents(sulfonylureas,insulin,repaglinide).

4.8Undesirableeffects

Thefollowingundesirableeffectsmayoccurundertreatmentwithmetforminhydrochloride.Frequenciesaredefinedas

follows:verycommon:1/10;common>1/100,<1/10;uncommon>1/1,000,<1/100;rare>1/10,000,<1/1,000;very

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Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Nervoussystemdisorders:

Common:Tastedisturbance

Gastrointestinaldisorders:

Verycommon:Gastrointestinaldisorderssuchasnausea,vomiting,diarrhoea,abdominalpainandlossofappetite.

Theseundesirableeffectsoccurmostfrequentlyduringinitiationoftherapyandresolvespontaneouslyinmostcases.

Topreventthem,itisrecommendedthatmetforminhydrochloridebetakenin2or3dailydosesduringoraftermeals.

Aslowincreaseofthedosemayalsoimprovegastrointestinaltolerability .

Skinandsubcutaneoustissuedisorders:

Veryrare:Skinreactionssuchaserythema,pruritus,urticaria

Metabolismandnutritiondisorders:

Veryrare:Lacticacidosis(seesection4.4,Specialwarningsandprecautionsforuse).

DecreaseofvitaminB12absorptionwithdecreaseofserumlevelsduringlong-termuseofmetforminhydrochloride.

Considerationofsuchaetiologyisrecommendedifapatientpresentswithmegaloblasticanaemia.

Hepatobiliarydisorders:

Notknown:Isolatedreportsofliverfunctiontestsabnormalitiesorhepatitisresolvinguponmetforminhydrochloride

discontinuation.

Inpublishedandpostmarketingdataandincontrolledclinicalstudiesinalimitedpaediatricpopulationaged10-16

yearstreatedduring1year,adverseeventreportingwassimilarinnatureandseveritytotharreportedinadults.

4.9Overdose

Hypoglycaemiahasnotbeenseenwithmetforminhydrochloridedosesofupto85g,althoughlacticacidosishas

occurredinsuchcircumstances.Highoverdoseofmetforminhydrochlorideorconcomitantrisksmayleadtolactic

acidosis.Lacticacidosisisamedicalemergencyandmustbetreatedinhospital.Themosteffectivemethodtoremove

lactateandmetforminhydrochlorideishaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Bloodglucoseloweringdrugs.Biguanides;

ATCcode:A10BA02

Metforminhydrochlorideisabiguanidewithantihyperglycaemiceffects,loweringbothbasalandpostprandialplasma

glucose.Itdoesnotstimulateinsulinsecretionandthereforedoesnotproducehypoglycaemia.

Metforminhydrochloridemayactvia3mechanisms:

Reductionofhepaticglucoseproductionbyinhibitinggluconeogenesisandglycogenolysis.

Inmuscle,byincreasinginsulinsensitivity,improvingperipheralglucoseuptakeandutilization.

Anddelayofintestinalglucoseabsorption.

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Metforminhydrochlorideincreasesthetransportcapacityofalltypesofmembraneglucosetransporters(GLUTs)

knowntodate.

Inhumans,independentlyofitsactiononglycaemia,metforminhydrochloridehasfavourableeffectsonlipid

metabolism.Thishasbeenshownattherapeuticdosesincontrolled,medium-termorlong-termclinicalstudies:

metforminhydrochloridereducestotalcholesterol,LDLcholesterolandtriglyceridelevels.

Clinicalefficacy:

Theprospectiverandomisedstudy(UKPDS)hasestablishedthelong-termbenefitofintensivebloodglucosecontrolin

adultpatientswithtype2diabetes.

Analysisoftheresultsforoverweightpatientstreatedwithmetforminhydrochlorideafterfailureofdietaloneshowed:

asignificantreductionoftheabsoluteriskofanydiabetes-relatedcomplicationinthemetforminhydrochloride

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

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

asignificantreductionoftheabsoluteriskofdiabetes-relatedmortality:metforminhydrochloride7.5

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

asignificantreductionoftheabsoluteriskofoverallmortality:metforminhydrochloride13.5events/1000

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

andinsulinmonotherapygroups18.9events/1000patient-years(p=0.021);

asignificantreductionintheabsoluteriskofmyocardialinfarction:metforminhydrochloride11events/1000

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

Benefitregardingclinicaloutcomehasnotbeenshownformetforminhydrochlorideusedassecond-linetherapy,in

combinationwithasulfonylurea.

Intype1diabetes,thecombinationofmetforminhydrochlorideandinsulinhasbeenusedinselectedpatients,butthe

clinicalbenefitofthiscombinationhasnotbeenformallyestablished.

Controlledclinicalstudiesinalimitedpaediatricpopulationaged10-16yearstreatedduring1yeardemonstrateda

similarresponseinglycaemiccontroltothatseeninadults.

5.2Pharmacokineticproperties

Absorption:

Afteranoraldoseofmetforminhydrochloride,T

isreachedin2.5hours.Absolutebioavailabilityofa500mgor

850mgmetforminhydrochloridetabletisapproximately50-60%inhealthysubjects.Afteranoraldose,thenon-

absorbedfractionrecoveredinfaeceswas20-30%.

Afteroraladministration,metforminhydrochlorideabsorptionissaturableandincomplete.Itisassumedthatthe

pharmacokineticsofmetforminhydrochlorideabsorptionisnon-linear.

Attherecommendedmetforminhydrochloridedosesanddosingschedules,steadystateplasmaconcentrationsare

reachedwithin24to48hoursandaregenerallylessthan1microgram/ml.Incontrolledclinicaltrials,maximum

metforminhydrochlorideplasmalevels(C

)didnotexceed4microgram/ml,evenatmaximumdoses.

Fooddecreasestheextentandslightlydelaystheabsorptionofmetforminhydrochloride.Followingadministrationofa

doseof850mg,a40%lowerplasmapeakconcentration,a25%decreaseinAUC(areaunderthecurve)anda35

minuteprolongationofthetimetopeakplasmaconcentrationwereobserved.Theclinicalrelevanceofthesefindingsis

unknown.

Distribution:

Plasmaproteinbindingisnegligible.Metforminhydrochloridepartitionsintoerythrocytes.Thebloodpeakislower

thantheplasmapeakandappearsatapproximatelythesametime.Theredbloodcellsmostlikelyrepresenta

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Metabolism:

Metforminhydrochlorideisexcretedunchangedintheurine.Nometaboliteshavebeenidentifiedinhumans .

Elimination:

Renalclearanceofmetforminhydrochlorideis>400ml/min,indicatingthatmetforminhydrochlorideiseliminatedby

glomerularfiltrationandtubularsecretion.Followinganoraldose,theapparentterminaleliminationhalf-lifeis

approximately6.5hours.

Whenrenalfunctionisimpaired,renalclearanceisdecreasedinproportiontothatofcreatinineandthusthe

eliminationhalf-lifeisprolonged,leadingtoincreasedlevelsofmetforminhydrochlorideinplasma.

Childrenandadolescents:

Singledosestudy:Aftersingledosesofmetforminhydrochloride500mgpaediatricpatientshaveshownsimilar

pharmacokineticprofiletothatobservedinhealthyadults.

Multipledosestudy:Dataarerestrictedtoonestudy.Afterrepeateddosesof500mgtwicedailyfor7daysin

paediatricpatientsthepeakplasmaconcentration(C

)andsystemicexposure(AUC0-t)werereducedby

approximately33%and40%,respectivelycomparedtodiabeticadultswhoreceivedrepeateddosesof500mgtwice

dailyfor14days.Asthedoseisindividuallytitratedbasedonglycaemiccontrol,thisisoflimitedclinicalrelevance.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesonsafety,pharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotentialandreproductivetoxicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core

Povidone

Magnesiumstearate

Coating

Hypromellose

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

1(x100),8,9,10,14,20,21,30,40,50,56,60,84,90,100,120,300,600or1000tabletsinblisterpacks(PVC-

aluminium)

30,60,200,300or600tabletsinplasticbottles(high-densitypolyethylene)withcaps(polypropylene).

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLimited(t/aGerardLaboratories),

35-36BaldoyleIndustrialEstate,

GrangeRoad,

Dublin13.

8MARKETINGAUTHORISATIONNUMBER

PA0577/039/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 23February2001

Dateoflastrenewal: 23February2006

10DATEOFREVISIONOFTHETEXT

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