Pizaccord

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Active ingredient:
Pioglitazone hydrochloride 33.07 mg equivalent to Pioglitazone 30 mg;  
Available from:
Douglas Pharmaceuticals Limited
INN (International Name):
Pioglitazone hydrochloride 33.07 mg (equivalent to Pioglitazone 30 mg)
Dosage:
30 mg
Pharmaceutical form:
Tablet
Composition:
Active: Pioglitazone hydrochloride 33.07 mg equivalent to Pioglitazone 30 mg   Excipient: Carmellose calcium Hyprolose Lactose monohydrate Magnesium stearate
Units in package:
Aluminium foil, Alu/Alu 28 tablets, 28 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Biocon Limited
Product summary:
Package - Contents - Shelf Life: Aluminium foil, Alu/Alu 28 tablets - 28 tablets - 36 months from date of manufacture stored at or below 25°C protect from light and moisture
Authorization number:
TT50-7697a
Authorization date:
2006-06-22

DATASHEET

PIZACCORD

15mg,30mgand45mgTablets

TheactiveingredientinPIZACCORDtabletsispioglitazoneaspioglitazone

hydrochloride.Chemically,pioglitazonehydrochlorideis[(±)-5-[[4-[2-(5-ethyl-2-

pyridinyl)ethoxy]phenyl]methyl]-2,4-]thiazolidinedionehydrochloride.Theempirical

formulaisC

SHClwhichcorrespondstoamolecularweightof392.90

daltons.

TheCASnumberforpioglitazoneHClis112529-15-4.TheCASnumberfor

pioglitazonefreebaseis111025-46-8.

Description

Pioglitazoneisanodourless,whitecrystallinepowderthatissolubleinN,N-

dimethylformamide,slightlysolubleinanhydrousethanol,veryslightlysolublein

acetoneandacetonitrile,practicallyinsolubleinwaterandinsolubleinether.

Eachtabletcontains15,30or45mgofpioglitazone(aspioglitazonehydrochloride).

Thetabletsalsocontainhydroxypropylcellulose,carmellosecalcium,lactose

monohydrateandmagnesiumstearate.

PIZACCORD15mgtabletsareround,white,biconvex,uncoatedtabletsembossed

with‘PIO’ononesideand‘15’ontheotherside.PIZACCORD30mgtabletsare

round,white,flat,uncoatedtabletsembossedwith‘PIO’ononesideand‘30’onthe

otherside.PIZACCORD45mgtabletsareround,white,flat,uncoatedtablets

embossedwith‘PIO’ononesideand‘45’ontheotherside.

Donothalvethetablets.Doseequivalencewhenatabletisdividedhasnotbeen

established

Pharmacology

Pioglitazoneisanoralantidiabeticagentthatactsprimarilybydecreasinginsulin

resistance.Pharmacologicalstudiesindicatethatpioglitazoneimprovessensitivityto

insulininmuscleandadiposetissueandinhibitshepaticgluconeogenesis.

Pioglitazoneimprovesglycaemiccontrolwhilereducingcirculatinginsulinlevels.

Fastingandpostprandialglycaemiccontrolareimprovedinpatientswithtype2

diabetesmellitus.Thedecreasedinsulinresistanceproducedbypioglitazoneresultsin

lowerbloodglucoseconcentrations,lowerplasmainsulinlevelsandlowerHbA

values.

ModeofAction

Pioglitazoneisathiazolidinedioneantidiabeticagentthatdependsonthepresenceof

insulinforitsuniquemechanismofaction.Pioglitazonedecreasesinsulinresistance

intheperipheryandintheliverresultinginincreasedinsulin-dependentglucose

disposalanddecreasedhepaticglucoseoutput.Unlikesulfonylureas,pioglitazoneis

notaninsulinsecretagogue.Pioglitazoneisapotentandhighlyselectiveagonistfor

peroxisomeproliferator-activatedreceptor-gamma(PPARγ).PPARreceptorsare

foundintissuesimportantforinsulinactionsuchasadiposetissue,skeletalmuscle

andliver.ActivationofPPARγnuclearreceptorsmodulatesthetranscriptionofa

numberofinsulinresponsivegenesinvolvedinthecontrolofglucoseandlipid

metabolism.

Inanimalmodelsofdiabetes,pioglitazonereducesthehyperglycaemia,

hyperinsulinaemiaandhypertriglyceridaemiacharacteristicofinsulin-resistantstates

suchastype2diabetes.Themetabolic changesproducedbypioglitazoneresultin

increasedresponsivenessofinsulin-dependenttissuesandareobservedinnumerous

animalmodelsofinsulinresistance.

Sincepioglitazoneenhancestheeffectsofcirculatinginsulin(bydecreasinginsulin

resistance),itdoesnotlowerbloodglucoseinanimalmodelsthatlackendogenous

insulin.

Pharmacokinetics

Absorption:Followingoraladministration,inthefastingstate,pioglitazoneisfirst

measurableinserumwithin30minutes,withpeakconcentrationsobservedwithin2

hours.Steadystateisachievedafter4-7daysofdosing.Foodslightlydelaysthetime

topeakserumconcentrationto3to4hours,butdoesnotaltertheextentof

absorption.Theabsolutebioavailabilityfollowingoraladministrationis

approximately83%.

Distribution:Themeanapparentvolumeofdistribution(Vd/F)ofpioglitazone

followingintravenousadministrationis0.25L/kgofbodyweight.

ProteinBinding:Pioglitazoneisextensivelyboundtoplasmaprotein(>99%),

principallytoserumalbumin.Thefreefractionislessthan2%andindependentof

concentrationintherangeof34-2000ng/mL(whichincludesthetherapeutic

concentrationrange).

Metabolism:Pioglitazoneundergoesextensivehepaticmetabolismbyhydroxylation

ofaliphaticmethylenegroups.ThisispredominantlyviacytochromeP4502C8and

3A4.Threeofthesixmetabolitesformedareactive.Themajorcirculatingmetabolite

isM-IV(1-hydroxyethylpioglitazone),whichaccountsformostofthedrug-related

materialinhumanplasmaandprobablyaccountsformuchofthetherapeuticefficacy.

PioglitazonedidnotinhibitP450activitywhenincubatedwithhumanP450liver

microsomes.

Elimination:Followingoraladministrationofradiolabelledpioglitazonetohumans,

recoveredlabelwasmainlyinfaeces(55%)andalesseramountinurine(45%).In

animals,onlyasmallamountofunchangedpioglitazonecanbedetectedineither

urineorfaeces.Themeanplasmaeliminationhalf-lifeofunchangedpioglitazonein

manis5-6hoursandforitstotalactivemetabolites16-23hours.

SpecialPopulations

Renalinsufficiency:Inpatientswithrenalimpairment,plasmaconcentrationsof

pioglitazoneanditsmetabolitesarelowerthanthoseseeninsubjectswithnormal

renalfunction,butwithsimilaroralclearanceofparentdrug.Thusfree(unbound)

pioglitazoneconcentrationremainsunchanged.Doseadjustmentinpatientswithrenal

dysfunctionisnotrecommended(seeDosageandAdministration).Noinformationis

availableforpatientsondialysisthereforePIZACCORDshouldnotbeusedinsuch

patients.

Hepaticinsufficiency:Insubjectswithimpairedhepaticfunction,totalplasma

concentrationofpioglitazoneisunchanged,butwithanincreasedvolumeof

distribution.Intrinsicclearanceisthereforereduced,coupledwithahigherunbound

fractionofpioglitazone.PIZACCORDtherapyshouldnotbeinitiatedinpatientswith

increasedbaselineliverenzymelevels(ALT>2.5timestheupperlimitofnormal).

Elderly:Noclinicallysignificantdifferencesbetweenelderlyandyoungsubjects

wereobserved.

Paediatric:Pharmacokineticdatainthepaediatricpopulationisnotavailable.

Gender:ThemeanC

andAUCvalueswereincreased20%to60%infemales.As

monotherapyandincombinationwithsulfonylurea,metforminorinsulin,

pioglitazoneimprovedglycaemiccontrolinbothmalesandfemales.Incontrolled

clinicaltrials,haemoglobinA

(HbA

)decreasesfrombaselineweregenerally

greaterforfemalesthanformales(averagemeandifferenceinHbA

0.5%).Since

therapyshouldbeindividualisedforeachpatienttoachieveglycaemiccontrol,dose

adjustmentisnotrecommendedbasedongenderalone.

ClinicalTrials

Clinicalstudiesdemonstratethatpioglitazoneimprovesinsulinsensitivityininsulin-

resistantpatients.Pioglitazoneenhancescellularresponsivenesstoinsulin,increases

insulin-dependentglucosedisposal,improveshepaticsensitivitytoglucoseandthus

improvesdysfunctionalglucosehomeostasis.

Monotherapy

Threerandomised,doubleblind,placebo-controlledtrialsof16to26weekswere

conductedtostudytheuseofpioglitazoneasmonotherapyinpatientswithtype2

diabetes.Thesestudiesexaminedpioglitazonedosesfrom7.5to45mg/dayin865

patients.

Ina26-weekdose-rangingstudy,408patientswithtype2diabeteswererandomised

toreceive7.5,15,30or45mgofpioglitazone,orplacebo.Comparedwithplacebo,

treatmentwith15to45mgofpioglitazoneresultedinsignificantimprovementsin

andfastingbloodglucose(FBG)(seeFigure1).

Figure1MeanChangefromBaselineforFBGandHbA

1c ina26-WeekPlacebo-

ControlledDose-RangingStudy

Thestudypopulationincludedpatientsnotpreviouslytreatedwithantidiabetic

medication(naive;31%)andpatientswhowerereceivingantidiabeticmedicationat

thetimeofstudyenrolment(previouslytreated;69%).Thedataforthenaiveand

previouslytreatedpatientsubsetsareshowninTable1.Thisrun-inperiodwas

associatedwithlittlechangeinHbA

andFBGvaluesfromscreeningtobaselinefor

thenaivepatients.However,forthepreviously-treatedgroup,washoutfromprevious

antidiabeticmedicationresultedindeteriorationofglycaemiccontrolandincreasesin

andFBG.Withpioglitazone,whilemostpatientsinthepreviously-treated

grouphadadecreasefrombaselineinHbA

andFBGinmanycasesthevaluesdid

notreturntoscreeninglevelsbytheendofthestudy.Thestudydesigndidnotpermit

theevaluationofpatientswhoswitcheddirectlytopioglitazonefromanother

antidiabeticagent.

Table1GlycaemicParametersina26-WeekPlacebo-ControlledDose-RangingStudy

Placeb

o PIOGLITAZONE

15mg

OnceDaily PIOGLITAZONE

30mg

OnceDaily PIOGLITAZONE

45mg

OnceDaily

NaivetoTherapy

HbA

1c (%) N=25 N=26 N=26 N=21

Screening(mean) 9.3 10.0 9.5 9.8

Baseline(mean) 9.0 9.9 9.3 10.0

Changefrombaseline

(adjustedmean + ) 0.6 -0.8 -0.6 -1.9

Differencefromplacebo

(adjustedmean + ) -1.4 -1.3 -2.6

FBG(mmol/L)

N=25

N=26

N=26

N=21

Screening(mean) 12.39 13.61 13.28 13.28

Table1GlycaemicParametersina26-WeekPlacebo-ControlledDose-RangingStudy

Placeb

o PIOGLITAZONE

15mg

OnceDaily PIOGLITAZONE

30mg

OnceDaily PIOGLITAZONE

45mg

OnceDaily

Baseline(mean) 12.72 13.94 12.5 13.06

Changefrombaseline

(adjustedmean + ) 0.89 -2.06 -2.28 -3.56

Differencefromplacebo

(adjustedmean + ) -2.89 -3.11 -4.44

PreviouslyTreated

HbA

1c (%) N=54 N=53 N=59 N=55

Screening(mean) 9.3 9.0 9.1 9.0

Baseline(mean) 10.9 10.4 10.4 10.6

Changefrombaseline

(adjustedmean + ) 0.8 -.01 -0.0 -0.6

Differencefromplacebo

(adjustedmean +

) -1.0 -0.9 -1.4

FBG(mmol/L)

N=54

N=53

N=58

N=56

Screening(mean) 12.33 11.61 12.78 11.94

Baseline(mean) 15.83 15.28 15.89 16.22

Changefrombaseline

(adjustedmean +

) 0.22 -1.78 -1.50 -3.06

Differencefromplacebo

(adjustedmean + ) -2.00 -1.72 -3.28

Adjustedforbaseline,pooledcentre

Pioglitazonehasbeenshowntoreducetotalplasmatriglyceridesandfreefattyacids

andtoincreaseHDL-cholesterollevels.LDL-cholesterollevelsremainunchanged.In

a26-week,placebo-controlled,dose-rangingstudy,meantriglyceridelevelsdecreased

inthe15mg,30mgand45mgpioglitazonedosegroupscomparedtoamean

increaseintheplacebogroup.MeanHDLlevelsincreasedtoagreaterextentinthe

pioglitazone-treatedpatientsthanintheplacebo-treatedpatients.Therewereno

consistentdifferencesforLDLandtotalcholesterolinpioglitazone-treatedpatients

comparedwithplacebo(Table2).

Table2Lipidsina26-WeekPlacebo-ControlledDose-RangingStudy

Placeb

o PIOGLITAZONE

15mg

OnceDaily PIOGLITAZONE

30mg

OnceDaily PIOGLITAZONE

45mg

OnceDaily

Triglycerides(mmol/L)N=79 N=79 N=84 N=77

Baseline(mean) 2.97 3.20 2.95 2.93

Percentchangefrom

baseline(mean) 4.8% -9.0% -9.6% -9.3%

HDLCholesterol

(mmol/L) N=79 N=79 N=83 N=77

Baseline(mean) 1.08 1.04 1.06 1.05

Table2Lipidsina26-WeekPlacebo-ControlledDose-RangingStudy

Placeb

o PIOGLITAZONE

15mg

OnceDaily PIOGLITAZONE

30mg

OnceDaily PIOGLITAZONE

45mg

OnceDaily

Percentchangefrom

baseline(mean) 8.1% 14.1% 12.2% 19.1%

LDLCholesterol

(mmol/L) N=65 N=63 N=74 N=62

Baseline(mean) 3.59 3.41 3.51 3.28

Percentchangefrom

baseline(mean) 4.8% 7.2% 5.2% 6.0%

TotalCholesterol

(mmol/L) N=79 N=79 N=84 N=77

Baseline(mean) 5.81 5.69 5.76 5.53

Percentchangefrom

baseline(mean) 4.4% 4.6% 3.3% 6.4%

Inaseparate24-weekstudy,260patientswithtype2diabeteswererandomisedto

oneoftwoforced-titrationpioglitazonetreatmentarms(finaldoses30or45mg),ora

mocktitrationplaceboarm.Inonepioglitazonetreatmentgroup,patientsreceivedan

initialdoseof7.5mgoncedaily.Afterfourweeks,thedosewasincreasedto15mg

oncedailyandafteranotherfourweeksthedosewasincreasedto30mgoncedaily

fortheremainderofthestudy(16weeks).Inthesecondpioglitazonetreatmentgroup,

patientsreceivedaninitialdoseof15mgoncedailyandweretitratedto30mgonce

dailyand45mgoncedailyinasimilarmanner.Treatmentwithpioglitazone,as

described,producedstatisticallysignificantimprovementsinHbA

andFBGat

endpointcomparedwithplacebo(seeTable3).

Table3GlycaemicParametersina24-WeekPlacebo-ControlledForced-TitrationStudy

Placeb

o PIOGLITAZONE

30mg +

OnceDaily PIOGLITAZONE

45mg +

OnceDaily

TotalPopulation

HbA

1c (%) N=83 N=85 N=85

Baseline(mean) 10.8 10.3 10.8

Changefrombaseline(adjustedmean ++ ) 0.9 -0.6 -0.6

Differencefromplacebo(adjusted

mean ++ ) -1.5* -1.5*

FBG(mmol/L) N=78 N=82 N=85

Baseline(mean) 15.50 14.89 15.61

Changefrombaseline(adjustedmean ++ ) 1.00 -2.44 -2.77

Differencefromplacebo(adjusted

mean ++ ) -3.44* -3.77*

Finaldoseinforcedtitration

Adjustedforbaseline,pooledcentre,andpooledcentrebytreatmentinteraction

*p<0.05vs.placebo

Forpatientswhohadnotbeenpreviouslytreatedwithantidiabeticmedication(24%),

meanvaluesatscreeningwere10.1%forHbA

and13.22mmol/LforFBG.At

baseline,meanHbA

was10.2%andmeanFBGwas13.5mmol/L.Comparedwith

placebo,treatmentwithpioglitazonetitratedtoafinaldoseof30mgand45mg

resultedinreductionsfrombaselineinmeanHbA

of2.3%and2.6%andmeanFBG

of3.5mmol/Land5.28mmol/L,respectively.Forpatientswhohadbeenpreviously

treatedwithantidiabeticmedication(76%),thismedicationwasdiscontinuedat

screening.Meanvaluesatscreeningwere9.4%forHbA

and12mmol/LforFBG.

Atbaseline,meanHbA

was10.7%andmeanFBGwas16.11mmol/L.Compared

withplacebo,treatmentwithpioglitazonetitratedtoafinaldoseof30mgand45mg

resultedinreductionsfrombaselineinmeanHbA

of1.3%and1.4%andmeanFBG

of3.06mmol/Land3.33mmol/L,respectively.Formanypreviously-treatedpatients,

andFBGhadnotreturnedtoscreeninglevelsbytheendofthestudy.

Ina16weekstudy,197patientswithtype2diabeteswererandomisedtotreatment

with30mgpioglitazoneorplacebooncedaily.Comparedwithplacebo,treatment

withpioglitazoneresultedinsignificantreductionsinHbA

andFBG(seeTable4).

Table4GlycaemicParametersina16-WeekPlacebo-ControlledStudy

Placeb

o PIOGLITAZONE

30mg

OnceDaily

TotalPopulation

HbA

(%) N=93 N=100

Baseline(mean) 10.3 10.5

Changefrombaseline(adjustedmean + ) 0.8 -0.6

Differencefromplacebo(adjustedmean + ) -1.4*

FBG(mmol/L) N=91 N=99

Baseline(mean) 15.00 15.17

Changefrombaseline(adjustedmean + ) 0.44 -2.78

Differencefromplacebo(adjustedmean + ) -3.22*

Adjustedforbaseline,pooledcentre,andpooledcentrebytreatmentinteraction

*p<0.05vs.placebo

Forpatientswhohadnotbeenpreviouslytreatedwithantidiabeticmedication(40%),

meanvaluesatscreeningwere10.3%forHbA

and13.33mmol/LforFBG.At

baseline,meanHbA

was10.4%andmeanFBGwas14.11mmol/L.Comparedwith

placebo,treatmentwithpioglitazone30mgresultedinreductionsfrombaselinein

meanHbA

of1.0%andmeanFBGof3.44mmol/L.Forpatientswhohadbeen

previouslytreatedwithantidiabeticmedication(60%),thismedicationwas

discontinuedatscreening.Meanvaluesatscreeningwere9.4%forHbA

and12

mmol/LforFBG.Atbaseline,meanHbA

was10.6%andmeanFBGwas15.94

mmol/L.Comparedwithplacebo,treatmentwithpioglitazone30mgresultedin

reductionsfrombaselineinmeanHbA

of1.3%andmeanFBGof2.56mmol/L.For

manypreviously-treatedpatients,HbA

andFBGhadnotreturnedtoscreeninglevels

bytheendofthestudy.

Combinationtherapy

Three16-week,randomised,double-blind,placebo-controlledclinicalstudieswere

conductedtoevaluatetheeffectsofpioglitazoneonglycaemiccontrolinpatientswith

type2diabeteswhowereinadequatelycontrolled(HbA

greaterthanorequalto8%)

despitesulfonylurea,metforminorinsulintherapy.Previousdiabetestreatmentmay

havebeenmonotherapyorcombinationtherapy.

Inonecombinationstudy,560patientsonasulfonylureaeitheraloneorcombined

withanotherantidiabeticagent,wererandomisedtoreceivepioglitazone15mg,

pioglitazone30mgorplaceboinadditiontotheirsulfonylurearegimen.Anyother

antidiabeticagentwaswithdrawn.Comparedwithplacebo,theadditionof

pioglitazonetothesulfonylureasignificantlyreducedthemeanHbA

0.9%and1.3%

forthe15and30mgdoses,respectively.Inaddition,comparedwithplacebo,

pioglitazonedecreasedFBGby2.17mmol/L(15mgdose)and3.22mmol/L(30mg

dose).Thetherapeuticeffectofpioglitazoneincombinationwithasulfonylureawas

observedinpatientsregardlessofwhetherthepatientswerereceivinglow,medium,

orhighdosesofsulfonylurea(<50%,50%,or>50%oftherecommendedmaximum

dailydose).

Inasecondcombinationstudy,328patientswithtype2diabetesonmetformineither

aloneorcombinedwithanotherantidiabeticagent,wererandomisedtoreceiveeither

pioglitazone30mgorplaceboinadditiontotheirmetformin.Anyotherantidiabetic

agentwaswithdrawn.Comparedwithplacebo,theadditionofpioglitazoneto

metforminsignificantlyreducedthemeanHbA

0.8%andFBG2.11mmol/L.The

therapeuticeffectofpioglitazoneincombinationwithmetforminwasobservedin

patientsregardlessofwhetherthepatientswerereceivinglowerorhigherdosesof

metformin(<2000mgperdayorgreaterthanorequalto2000mgperday).

Inathirdcombinationstudy,566patientswithtype2diabetesreceivingamedianof

60.5units/dayinsulin,eitheraloneorcombinedwithanotherantidiabeticagent,were

randomisedtoreceiveeitherpioglitazone15mg,pioglitazone30mgorplaceboin

additiontotheirinsulin.Anyotherantidiabeticagentwasdiscontinued.Compared

withtreatmentwithplacebo,treatmentwithpioglitazoneinadditiontoinsulin

significantlyreducedbothHbA

0.7%(15mgdose)and1.00%(30mgdose)and

FBG1.94mmol/L(15mgdose)and2.72mmol/L(30mgdose).Thetherapeutic

effectofpioglitazoneincombinationwithinsulinwasobservedinpatientsregardless

ofwhetherthepatientswerereceivinglowerorhigherdosesofinsulin(<60.5units

perdayorgreaterthanorequalto60.5unitsperday).

Indications

PIZACCORDisindicatedforthetreatmentoftype2diabetesmellitusinadequately

controlledbydiet.PIZACCORDiseffectiveasasingleagentandmayalsobeusedin

combinationwithsulfonylureas,metforminorinsulinwhendietplusthesingleagent

doesnotresultinadequateglycaemiccontrol.

Contraindications

PIZACCORDiscontraindicatedinpatientswithknownhypersensitivityorallergyto

PIZACCORDoranyofitsexcipients.

Pizaccordisnotrecommendedinpatientswithsymptomaticheartfailure.Initiationof

Pizaccord(likeotherthiazolidinediones)iscontraindicatedinpatientswithNYHA

ClassII,IIIorIVheartfailure(seeprecautions).

Becauseofitsmechanismofaction,Pizaccordisonlyactiveinthepresenceof

insulin.Therefore,PizaccordshouldnotbeusedintypeIdiabetesorforthetreatment

ofdiabeticketoacidosis.

Precautions

Hypoglycaemia

PatientsreceivingPIZACCORDincombinationwithinsulinororalhypoglycaemic

agentsmaybeatriskforhypoglycaemia.Areductioninthedoseoftheconcomitant

agentmaybenecessary.

Cardiac

PIZACCORD,likeotherthiazolidinediones,cancauseorexacerbatecongestiveheart

failure(CHF)insomepatients.Inpost-marketingexperiencewithpioglitazone,CHF

hasbeenreportedinpatientsbothwithandwithoutpre-existingcardiacdisease.After

initiationofPIZACCORD,andafterdoseincreases,observepatientscarefullyfor

signsandsymptomsofheartfailure(includingexcessive,rapidweightgain,

dyspnoea,and/oroedema).Ifthesesignsandsymptomsdevelop,PIZACCORD

shouldbediscontinued.Thepatient'sheartfailureshouldbeevaluatedandmanaged

accordingtothecurrentstandardsofcare.

PatientswithNewYorkHeartAssociation(NYHA)ClassIIIandIVcardiacstatus

wereexcludedfrominitialclinicaltrials.Therefore,PIZACCORDisnotindicatedin

patientswithNYHAClassIIIorIVcardiacstatus.

Inone16-weekU.S.double-blind,placebo-controlledclinicaltrialinvolving566

patientswithtype2diabetes,pioglitazoneatdosesof15mgand30mgin

combinationwithinsulinwerecomparedtoinsulintherapyalone.Thistrialincluded

patientswithlong-standingdiabetesandahighprevalenceofpre-existingmedical

conditionsasfollows:arterialhypertension(57.2%),peripheralneuropathy(22.6%),

coronaryheartdisease(19.6%),retinopathy(13.1%),myocardialinfarction(8.8%),

vasculardisease(6.4%),anginapectoris(4.4%),strokeand/ortransientischaemic

attack(4.1%),andcongestiveheartfailure(2.3%).

Inthisstudytwoofthe191patientsreceiving15mgpioglitazoneplusinsulin(1.1%)

andtwoofthe188patientsreceiving30mgpioglitazoneplusinsulin(1.1%)

developedcongestiveheartfailurecomparedwithnoneofthe187patientsoninsulin

therapyalone.Allfourofthesepatientshadprevioushistoriesofcardiovascular

conditionsincludingcoronaryarterydisease,previousCABGprocedures,and

myocardialinfarction.Analysisofdatafromthisstudydidnotidentifyspecific

factorsthatpredictincreasedriskofcongestiveheartfailureoncombinationtherapy

withinsulin.

A24-weekpost-marketingstudywasperformedtocomparepioglitazone(n=262)to

glyburide(n-256)inuncontrolleddiabeticpatients(meanHbA1C8.8%atbaseline)

withNYHAClassIIandIIIheartfailureandejectionfractionlessthan40%(mean

EF30%atbaseline).Overnighthospitalisationforcongestiveheartfailurewas

reportedin9.9%ofpatientsonpioglitazonecomparedto4.7%ofpatientson

glyburidewithatreatmentdifferenceobservedfrom6weeks.Thisadverseevent

associatedwithpioglitazonewasmoremarkedinpatientsusinginsulinatbaseline

andinpatientsover64yearsofage.Nodifferenceincardiovascularmortality

betweenthetreatmentgroupswasobserved.

Acardiovascularoutcomestudyofpioglitazonehasbeenperformedinpatientswith

type2diabetesmellitusandpre-existingmajormacrovasculardisease(PROactive).

Pioglitazoneorplacebowasaddedtoexistingantidiabeticandcardiovasculartherapy

forupto3.5years.Thisstudyshowedanincreaseinreportsofheartfailure;however

thisdidnotleadtoanincreaseinmortalityinthisstudy.

Oedema

Asthiazolidinedionescancausefluidretention,PIZACCORDshouldbeusedwith

cautioninpatientswithoedema.Inplacebocontrolledclinicaltrialsoedemawas

reportedmorefrequentlyinpatientstreatedwithpioglitazonethaninplacebotreated

patients.

WeightGain

Doserelatedweightgainwasseenwithpioglitazonealoneandincombinationwith

otherhypoglycaemicagents(Table5).Themechanismofweightgainisunclearbut

probablyinvolvesacombinationoffluidretentionandfataccumulation.

Table5:WeightChanges(kg)fromBaselineduringDouble-BlindClinicalTrialswith

PIOGLITAZONE

Control

Group

(Placebo) PIOGLITAZON

E15mg PIOGLITAZON

E30mg PIOGLITAZON

E45mg

Median

(25 th /75 th

percentile

) Median

(25 th /75 th

percentile) Median

(25 th /75 th

percentile) Median

(25 th /75 th

percentile)

Monotherapy -1.4(-

2.7/0.0)

n=256 a,b,c 0.9(-0.5/3.4)

n=79 a 1.0(-0.9/3.4)

n=188 a,c 2.6(0.2/5.4)

n=79 c

Control

Group

(Placebo) PIOGLITAZON

E15mg PIOGLITAZON

E30mg PIOGLITAZON

E45mg

Median

(25 th /75 th

percentile

) Median

(25 th /75 th

percentile) Median

(25 th /75 th

percentile) Median

(25 th /75 th

percentile)

Sulphonylurea

-0.5(-

1.8/0.7)

n=187

2.0(0.2/3.2)

3.0n=183

2.7(1.1/4.5)

n=186

N/A

Metformin e -1.4(-

3.2/0.3)

n=160 N/A 1.4(-0.9/3.0)

n=167 N/A Combinatio

nTherapy

Insulin f

0.2(-

1.4/1.4)

n=182 2.3(0.5/4.3)

n=190 3.6(1.4/5.9)

n=188 N/A

StudyPNFP-001 d

StudyPNFP-010

StudyPNFP-012 e StudyPNFP-027

StudyPNFP-026 f

StudyPNFP-014

HepaticImpairment

Inclinicaltrialsworldwide,over4500patientshavebeentreatedwithpioglitazone.

Therewasnoevidenceofdrug-inducedhepatotoxicity.

Therapyshouldnotbeinitiatedifthepatientexhibitsclinicalevidenceofactiveliver

diseaseorincreasedtransaminaselevels(ALT>2.5timestheupperlimitofnormal)

atthestartoftherapy.

Liverfunctiontestsshouldbeperformedatbaselineandeverytwomonthsforthe

firsttwelvemonthsandperiodicallythereafter,andifapatientdevelopssymptoms

suggestiveofhepaticdysfunction,liverenzymelevelsshouldbechecked.

BoneFracture

Anincreasedincidenceinbonefracturesinwomenwasseeninapooledanalysisof

adverseeventreportsofbonefracturefromrandomised,controlled,doubleblind

clinicaltrialsinover8100pioglitazoneand7400comparator(excluding

thiazolidinediones)treatedpatients,ontreatmentforupto3.5years.Fractureswere

observedin2.6%ofwomentakingpioglitazonecomparedto1.7%ofwomentreated

withacomparator.Noincreaseinfracturerateswasobservedinmentreatedwith

pioglitazone(1.3%)versuscomparator(1.5%).Thefractureincidencecalculatedwas

1.9fracturesper100patientyearsinwomentreatedwithpioglitazoneand1.1

fracturesper100patientyearsinwomentreatedwithacomparator.Theobserved

excessriskoffracturesforwomeninthisdatasetonpioglitazoneistherefore0.8

fracturesper100patientyearsofuse.

Inthe3.5yearcardiovascularriskPROactivestudy,44/870(5.1%;1.0fracturesper

100patientyears)ofpioglitazone-treatedfemalepatientsexperiencedfractures

comparedto23/905(2.5%;0.5fracturesper100patientyears)offemalepatients

treatedwithcomparator.Thisdifferencewasnotedafterthefirstyearoftreatmentand

remainedduringthecourseofthestudy.Noincreaseinfracturerateswasobservedin

mentreatedwithpioglitazone(1.7%)versuscomparator(2.1%).

Theriskoffracturesshouldbeconsideredinthelongtermcareofwomentreated

withpioglitazone.

Ovulation

Inpremenopausalanovulatorypatientswithinsulinresistance,treatmentwith

thiazolidinediones,includingPIZACCORD,mayresultinresumptionofovulation.

Thesepatientsmaybeatriskofpregnancy.

BladderCancer

Pioglitazoneshouldbeavoidedinpatientswithactivebladdercancerorahistoryof

bladdercancer.

Availableepidemiologicaldatahavesuggestedapossibleassociationbetween

pioglitazoneuseandanincreasedriskofbladdercancer.Afive-yearinterimreport,

fromanongoing10-yearobservationalcohortstudy,foundanon-significantincrease

intheriskforbladdercancerinsubjectseverexposedtopioglitazone,comparedto

subjectsneverexposedtopioglitazone(HR1.2;95%CI0.9-1.5).Durationoftherapy

longerthan24monthswasassociatedwithastatisticallysignificantincreaseinrisk

(HR1.4;95%CI1.03-2.0).

Riskfactorsforbladdercancershouldbeassessedbeforeinitiatingpioglitazone

treatment(including:age,smokinghistory,exposuretooccupationalchemicals,or

chemotherapeuticagentsandradiationtreatmentinthepelvicregion.Any

macroscopichaematuriashouldbeinvestigatedbeforestatingpioglitazonetherapy.

Patientsshouldbeadvisedtopromptlyseekmedicalattentionifmacroscopic

haematuriaorothersymptomssuchasdysuriaorurinaryurgencydevelopduring

treatment.

Carcinogenicity,MutagenicityandImpairmentofFertility

Atwo-yearcarcinogenicitystudyinmiceshowednodrug-relatedincreasesintumour

incidencesatoraldosesupto91mg/kg/day.Ratsdosedorallywithpioglitazoneat

0.9-57mg/kg/dayfortwoyearsshowedincreasedincidencesofsubcutaneousbenign

adiposetissuetumours(lipomas)andurinarybladdertransitionalcelltumours.

Systemicexposure(plasmaAUC

0-24h )tototalactivecompoundsatthehighestdosein

bothstudieswas8timesgreaterthanthatinhumansatthemaximumrecommended

dose.Theno-effectdoseswerenotestablishedforeithertumoursite.Subcutaneous

benignadiposetissuetumours(lipomas)havebeenobservedinratstreatedwithother

thiazolidinedionedrugs,andareprobablyrelatedtothepharmacodynamicactivityof

thisdrugclass.Urinarybladdertumourswereprobablysecondarytoformationof

urinarycalculi,andareunlikelytoposeacarcinogenicriskinhumans.

Pioglitazonewasnotmutagenicinabatteryoftestsforgenemutationinbacteriaand

mammaliancellsinvitro,inassaysforchromosomaldamageinvitroandinvivo,and

inanassayforDNAdamage(unscheduledDNAsynthesisinrathepatocytesinvitro).

Noadverseeffectsonfertilitywereobservedinmaleandfemaleratsatoraldosesup

to40mg/kg/day.Systemicexposure(plasmaAUC

0-24h )tototalactivecompoundsat

thehighestdosewasabout7timesgreaterthanthatinhumansatthemaximum

recommendeddose.

UseinPregnancy-PregnancyCategoryB3

Astudyinpregnantratsshowedthatpioglitazoneanditsmetabolitescrossthe

placenta.Pioglitazonewasnotteratogenicinratsorrabbitsatoraldosesupto80and

160mg/kg/dayrespectively.Systemicexposure(plasmaAUC

0-24h )tototalactive

compoundsatthehighestdosewasabout12times(rats)and7times(rabbits)greater

thanthatinhumansatthemaximumrecommendeddose.Embryotoxicity(increased

post-implantationloss)wasobservedinbothanimalspecies,andfoetotoxiceffects

(reducedfoetalweightandretardeddevelopment)wereseeninrats.Administrationof

pioglitazoneduringtheperiodoforganogenesisalsocausedsuppressionofpostnatal

growthinrats.Administrationofpioglitazonetoratsthroughoutgestationand

lactationcausedretardationinpostnatalgrowthanddevelopment,andimpaired

fertilityoftheoffspring.Theno-effectdoseforretardationofpostnatalgrowthand

developmentinratswas3mg/kg/dayandsystemicexposuretototalactive

compoundsatthisdosewassimilartothatinhumans.Therearenoadequateandwell

controlledstudiesinpregnantwomen.PIZACCORDshouldbeusedduring

pregnancyonlyifthepotentialbenefitsjustifythepotentialrisktothefoetus.

UseinLactation

Pioglitazoneissecretedinthemilkoflactatingrats.Itisnotknownwhether

pioglitazoneissecretedinhumanmilk.Inreproductivestudiesinrats,oral

administrationofpioglitazoneduringlategestationandlactationcausedadverse

effectsonpostnatalsurvival,growth,developmentandfertilityoftheoffspring.The

no-effectdoseonretardationofpostnatalgrowthanddevelopmentwas3mg/kg/day

andsystemicexposuretototalactivecompoundsatthisdosewassimilartothatin

humans.PIZACCORDshouldnotbeadministeredtolactatingwomen.

EffectsontheAbilitytoDriveandUseMachines

Theeffectofpioglitazoneontheabilitytodriveandusemachineryhasnotbeen

studiedbutbasedonitspharmacodynamicproperties,PIZACCORDmonotherapyis

unlikelytoaffectthisability.Whendrivingvehiclesoroperatingmachineryitshould

betakenintoaccountthatthehypoglycaemiceffectsofsulphonylureasandinsulin

maybeexacerbateduponcombinationtherapywithPIZACCORD.

PaediatricUse

Safetyandeffectivenessinpaediatricpatientshavenotbeenestablished.

ElderlyUse

Approximately500patientsinplacebo-controlledclinicaltrialsofpioglitazonewere

65andover.Nosignificantdifferencesinsafetyandefficacywereobservedbetween

thesepatientsandyoungerpatients.

InteractionswithotherDrugs

ThecytochromeP450isoformsCYP2C8andCYP3A4arepartiallyresponsiblefor

themetabolismofpioglitazone.Interactionswithsubstancesmetabolisedbythese

enzymese.g.oralcontraceptives,cyclosporine,calciumchannelblockers,andHMG

CoAreductaseinhibitorsarenottobeexpected.InhibitorsofCYP2C8(suchas

gemfibrozil)mayincreasetheAUCofpioglitazone,adecreaseintheAUCof

pioglitazonemayoccurwhenadministeredincombinationwithCYP2C8inducers

(suchasrifampicin).

Gemfibrozil:Coadministrationofpioglitazoneandgemfibrozilisreportedtoresultin

a3-foldincreaseintheAUCofpioglitazone.Sincethereisapotentialfordose-

relatedadverseeventswithpioglitazone,adecreaseinthedoseofpioglitazonemay

beneededwhengemfibrozilisconcomitantlyadministered.

Rifampicin:Coadministrationofpioglitazoneandrifampicinisreportedtoresultina

54%decreaseintheAUCofpioglitazone.ThedoseofPIZACCORDmayneedtobe

increasedbasedonclinicalresponsewhenrifampicinisconcomitantlyadministered.

OralContraceptives:Administrationofasimilarthiazolidinedionewithanoral

contraceptivecontainingethinyloestradiolandnorethindronereducedtheplasma

concentrationsofbothhormonesbyapproximately30%.Thiscouldresultinlossof

contraception.Therefore,ahigherdoseoforalcontraceptiveoranalternativemethod

ofcontraceptionshouldbeconsidered.

Glipizide:Coadministrationofpioglitazoneandglipizidedoesnotalterthesteady

statepharmacokineticsofglipizide.

Digoxin:Coadministrationofpioglitazonewithdigoxindoesnotalterthesteady-state

pharmacokineticsofdigoxin.

Warfarin:Coadministrationofpioglitazonewithwarfarindoesnotalterthesteady-

statepharmacokineticsofwarfarin.Inaddition,pioglitazonehasnoclinically

significanteffectonprothrombintimewhenadministeredtopatientsreceiving

chronicwarfarintherapy.

Metformin:Coadministrationofpioglitazonewithmetformindoesnotalterthe

steady-statepharmacokineticsofmetformin.

AdverseReactions

AdverseEventsidentifiedfromClinicalTrials:

Theoverallincidenceandtypesofadverseeventsreportedinplacebocontrolled

clinicaltrialsofpioglitazonemonotherapyareshowninTable6.Inpooled,double

blind,placebocontrolledtrialsin862patientstakingpioglitazoneand431patients

takingplacebo,withdrawalduetoadverseeventsoccurredin3.6%ofpioglitazone

patientsandin4.6%ofpatientsonplacebo.Table6showsthe12weekcumulative

incidenceat>2%ofpatientswithpioglitazonewhenthiswasinexcessofplacebo.

Table6:12weekcumulativeincidenceofAdverseEventsat>2%ofpioglitazone

-treatedpatients

Placebo(N=431)Pioglitazone(N=862)

Upperrespiratorytractinfection 7.2 8.7

Headache 6.5 7.0

Sinusitis 2.9 3.6

Myalgia 2.3 3.2

Oedema 0.6 3.2

Backpain 2.3 3.1

Urinarytractinfection 1.6 2.7

Pharyngitis 0.3 2.7

Toothdisorder 1.5 2.6

Fatigue 2.4 2.5

Accidentalinjury 1.5 2.2

Crampslegs 1.1 2.1

Visionabnormal 1.4 2.1

Althoughpioglitazonedoesnotchangethesafetyprofileofsulfonylureasandinsulin,

thecombinationmayincreasetheriskofdevelopinghypoglycaemicsymptoms.In

combinationtherapystudies,oedemawasreportedfor7.2%ofpatientstreatedwith

pioglitazoneandsulfonylureascomparedto2.1%ofpatientsonsulfonylureasalone.

Incombinationtherapystudieswithmetformin,oedemawasreportedin6.0%of

patientsoncombinationtherapycomparedto2.5%ofpatientsonmetforminalone.In

combinationtherapystudieswithinsulin,oedemawasreportedin15.3%ofpatients

oncombinationtherapycomparedto7.0%ofpatientsoninsulinalone(see

Precautions,Oedema).Mostoftheseeventswereconsideredmildormoderatein

intensity.

Inallclinicaltrials,weightincreasedproportionatelyastheHbA

decreased

suggestingthatweightgainwasassociatedwithimprovedglycaemiccontrol.

Occasionaltransientincreasesincreatininephosphokinasewerenoticedinpatients

takingpioglitazone.

Bone Fracture

Apooledanalysiswasconductedofadverseeventreportsofbonefracturesfrom

randomised,comparatorcontrolled(excludingthiazolidinediones),doubleblind

clinicaltrialsinover8100patientsinthepioglitazone-treatedgroupsand7400inthe

comparator-treatedgroupsofupto3.5yearsduration.Ahigherrateoffractureswas

observedinwomentakingpioglitazone(2.6%)versuscomparator(1.7%).No

increaseinfracturerateswasobservedinmentreatedwithpioglitazone(1.3%)versus

comparator(1.5%)(seePRECAUTIONS,BoneFracture).

Inthe3.5yearPROactivestudy,44/870(5.1%)ofpioglitazone-treatedfemale

patientsexperiencedfracturescomparedto23/905(2.5%)offemalepatientstreated

withcomparator.Noincreaseinfracturerateswasobservedinmentreatedwith

pioglitazone(1.7%)versuscomparator(2.1%).

CardiovascularSystem

Ininsulincombinationstudiesasmallnumberofpatientswithpreviouslyexisting

cardiacdiseasedevelopedcongestiveheartfailurewhentreatedwithpioglitazone.

Theincidenceofcongestiveheartfailureisincreasedinpatientswithuncontrolled

diabetes,NYHAClassIIorIIIcardiacstatusandejectionfractionlessthan40%

whentreatedwithpioglitazone(seePrecautions,Cardiac).

InthePROactivestudy,whichinvolvedahighriskpopulationofpatientswithpre-

existingmacrovasculardisease,treatmentemergentadverseeventsthatoccurredmore

ofteninthepioglitazonegroupcomparedtoplacebogroupwereoedema(26.4%and

15.1%respectively),hypoglycaemia(27.2%and18.8%respectively)andheartfailure

(7.8%and6.0%respectively).Therateofseriousheartfailurewashigherforpatients

treatedwithpioglitazone(5.7%)thanforpatientstreatedwithplacebo(4.1%)andthe

incidenceofdeathsubsequenttoareportofseriousheartfailurewas1.5%inpatients

treatedwithpioglitazoneand1.4%inplacebo-treatedpatients.Inpatientstreatedwith

aninsulin-containingregimenatbaseline,theincidenceofseriousheartfailurewas

6.3%withpioglitazoneand5.2%withplacebo.Forthosepatientstreatedwitha

sulfonylurea-containingregimenatbaseline,theincidenceofseriousheartfailurewas

5.8%withpioglitazoneand4.4%withplacebo.

Inone16-weekclinicaltrialofinsulinpluspioglitazonecombinationtherapy,more

patientsdevelopedcongestiveheartfailureoncombinationtherapy(1.1%)compared

tononeoninsulinalone(seePRECAUTIONS,Cardiac).

AdverseEventsidentifiedfromSpontaneousPost-marketingSurveillance:

CardiovascularSystem

Cardiacfailure :Inpost-marketingexperiencewithpioglitazone,congestiveheart

failurehasbeenreportedveryrarely(0.9/10000patientyears)inpatientsbothwith

andwithoutpre-existingcardiacdisease.Inclinicaltrials,heartfailurewasreported

morefrequentlywhenpioglitazonewasusedincombinationwithinsulinorin

patientswithahistoryofcardiacfailure(seeCONTRAINDICATIONSand

PRECAUTIONS,Cardiac).

DigestiveSystem

Hepatocellulardysfunction :Inpost-marketingexperiencewithpioglitazone,reportsof

hepatitisandhepaticenzymeelevationsto3ormoretimestheupperlimitofnormal

havebeenreceived.Veryrarely,thesehaveinvolvedhepaticfailurewithandwithout

fataloutcome,althoughcausalityhasnotbeenestablished.

EyeDisorders

Varyrarely,postmarketingreportsofnewonsetorworsening(diabetic)macular

oedemawithdecreasedvisualacuityhavebeenreportedwiththeuseof

thiazolidinediones,includingpioglitazone.Itisunknownwhetherornotthereisa

causalrelationshipbetweenpioglitazoneandmacularoedema.Physiciansshould

considerthepossibilityofmacularoedemaifapatientreportsdecreasedvisualacuity.

LaboratoryTestAbnormalities

Haematologic :Pioglitazonemaycausedecreasesinhaemoglobinandhaematocrit.

Acrossallclinicalstudies,meanhaemoglobinvaluesdeclinedby2%to4%in

patientstreatedwithpioglitazone.Thesechangesgenerallyoccurredwithinthefirst4

to12weeksoftherapyandremainedrelativelystablethereafter.Thesechangesmay

berelatedtoincreasedplasmavolumeassociatedwithpioglitazonetherapyandhave

notbeenassociatedwithanysignificanthaematologicclinicaleffects.

SerumTransaminaseLevels :Duringplacebo-controlledclinicaltrialsintheU.S.,atotal

of4of1526(0.26%)patientstreatedwithpioglitazoneand2of793(0.25%)placebo-

treatedpatientshadALTvaluesgreaterthanorequalto3timestheupperlimitof

normal.DuringallclinicalstudiesintheU.S.,11of2561(0.43%)patientstreated

withpioglitazonehadALTvaluesgreaterthanorequalto3timestheupperlimitof

normal.Allpatientswithfollow-upvalueshadreversibleelevationsinALT.Inthe

populationofpatientstreatedwithpioglitazone,meanvaluesforbilirubin,AST,ALT,

alkalinephosphatase,andGGTweredecreasedatthefinalvisitcomparedwith

baseline.Fewerthan0.12%ofpatientstreatedwithpioglitazonewerewithdrawn

fromclinicaltrialsintheU.S.duetoabnormalliverfunctiontests.Inpre-approval

clinicaltrials,therewerenocasesofidiosyncraticdrugreactionsleadingtohepatic

failure(seePrecautions,HepaticImpairment).

CPKLevels :Duringrequiredlaboratorytestinginclinicaltrials,sporadic,transient

elevationsincreatinephosphokinaselevels(CPK)wereobserved.Asingle,isolated

elevationtogreaterthan10timestheupperlimitofnormal(valuesof2150to8610

IU/L)wasnotedin7patients.Fiveofthesepatientscontinuedtoreceivepioglitazone

andtheothertwopatientshadcompletedreceivingstudymedicationatthetimeofthe

elevatedvalue.Theseelevationsresolvedwithoutanyapparentclinicalsequelae.The

relationshipoftheseeventstopioglitazonetherapyisunknown.

DosageandAdministration

PIZACCORDshouldbetakenoncedailywithorwithoutfood.Donothalvethe

tablets.Doseequivalencewhenatabletisdividedhasnotbeenestablished

AfterinitiationofPIZACCORDorwithdoseincrease,patientsshouldbecarefully

monitoredforadverseeventsrelatedtofluidretention(seePRECAUTIONS).

Monotherapy

TherecommendeddosageofPIZACCORDis15mgor30mgoncedaily,increasing

afterfourweeks,ifgreatertherapeuticeffectisneeded,to45mgoncedaily.

CombinationTherapy

TherecommendeddoseofPIZACCORDis30mgoncedailyincombinationwith

sulfonylureas,insulinormetformin.Itmaybepossibletoachievemetaboliccontrolat

areduceddoseofthesulfonylurea,insulinormetformin.Ifthereisaparticularriskof

hypoglycaemia,PIZACCORDcanbeintroducedatadoseof15mg.Forpatients

alreadyoninsulin,PIZACCORDshouldbeintroducedatadoseof15mgoncedaily.

Dosagecanthenbeincreasedcautiously.

MaximumRecommendedDose

Thedoseshouldnotexceed45mg/daysincedoseshigherthan45mg/dayhavenot

beenstudiedinclinicaltrials.

PatientswithRenalInsufficiency

Doseadjustmentinpatientswithrenalinsufficiencyisnotrecommended(see

PHARMACOLOGY,Pharmacokinetics).Noinformationisavailableforpatientson

dialysisthereforePIZACCORDshouldnotbeusedinsuchpatients.

PatientswithHepaticImpairment

Theintrinsicclearanceofpioglitazonemaybereducedinpatientswithhepatic

disease.Dosageshouldstartat15mgandbeincreasedcautiously.PIZACCORD

therapyshouldnotbeinitiatedinpatientswithincreasedbaselineliverenzymelevels

(ALT>2.5timestheupperlimitofnormal).

Overdosage

Duringclinicaltrials,onecaseofoverdosewithpioglitazonewasreported.Apatient

took120mg/dayforfourdays,then180mg/dayforsevendays.Thepatientdidnot

reportanyclinicalsymptoms.

Hypoglycaemiawouldnotbeexpectedwithpioglitazonealonebutmayoccurin

combinationwithsulfonylureasorinsulin.Symptomaticandgeneralsupportive

measuresshouldbetakenincaseofoverdose.

PharmaceuticalPrecautions

PIZACCORDtabletshave36monthshelflifewhenstoredbelow25°C.

Incompatibilities

NotApplicable.

MedicineClassification

PrescriptionMedicine.

PackageQuantities

Blisterpackscontaining28tablets

NameandAddress

DistributedinNewZealandby:

DouglasPharmaceuticalsLimited

POBox45027

Auckland0651

NewZealand

TollFree:0800DOUGLAS(0800368452)

DateofPreparation

06October2011

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