ALIPZA

Main information

  • Trade name:
  • ALIPZA Film Coated Tablet 4 Base Milligrams
  • Dosage:
  • 4 Base Milligrams
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALIPZA Film Coated Tablet 4 Base Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1532/002/002
  • Authorization date:
  • 05-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Alipza4mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilmcoatedtabletcontainspitavastatincalciumequivalentto4mgpitavastatin.

Excipient(s)include252.34mgLactosemonohydrate.

ForafulllistofexcipientsseeSection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Roundwhitefilm-coatedtabletsembossed‘KC’ononefaceand‘4’onthereverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Alipzaisindicatedforthereductionofelevatedtotalcholesterol(TC)andLDL-C,inadultpatientswithprimary

hypercholesterolaemia,includingheterozygousfamilialhypercholesterolaemia,andcombined(mixed)dyslipidaemia,

whenresponsetodietandothernon-pharmacologicalmeasuresisinadequate.

4.2Posologyandmethodofadministration

Fororaluseonlyandshouldbeswallowedwhole.Alipzacanbetakenatanytimeofthedaywithorwithoutfood.Itis

desirablethatthepatienttakesthetabletatthesametimeeachday.Statintherapyisgenerallymoreeffectiveinthe

eveningduetothecircadianrhythmoflipidmetabolism.Patientsshouldbeonacholesterolloweringdietbefore

treatment.Itisimportantthatpatientscontinuedietarycontrolduringtreatment.

Adults: Theusualstartingdoseis1mgoncedaily.

Adjustmentofdoseshouldbemadeatintervals

of4weeksormore.Dosesshouldbe

individualizedaccordingtoLDL-CLevels,the

goaloftherapyandpatientresponse.Most

Patientswillrequirea2mgdose(seeSection

5.1).TheMaximumdailydoseis4mg.

Elderly: Nodosageadjustmentisrequired(seeSections

5.1and5.2).

Paediatricuse: Pitavastatinshouldnotbeusedinchildrenaged

below18yearsbecausesafetyandefficacyhas

notbeenestablished.Nodataarecurrently

available.

Patientswith

impairedrenal Nodosageadjustmentisrequiredinmildrenal

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4.3Contraindications

Alipzaiscontraindicated:

inpatientswithknownhypersensitivitytopitavastatinortoanyoftheexcipientsorotherstatins

inpatientswithseverehepaticimpairment,activeliverdiseaseorunexplainedpersistentelevationsinserum

transaminases(exceeding3timestheupperlimitofnormal[ULN])

inpatientswithmyopathy

inpatientsreceivingconcomitantciclosporin

duringpregnancy,whilebreastfeedingandinwomenofchildbearingpotentialnottakingappropriate

contraceptiveprecautions

4.4Specialwarningsandprecautionsforuse

MuscleEffects

IncommonwithotherHMG-CoAreductaseinhibitors(statins),thereisthepotentialformyalgia,myopathyand,

rarely,rhabdomyolysistodevelop.Patientsshouldbeaskedtoreportanymusclesymptoms.Creatinekinase(CK)

levelsshouldbemeasuredinanypatientreportingmusclepain,muscletendernessorweaknessespeciallyif

accompaniedbymalaiseorfever.

Creatinekinaseshouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofanyotherplausiblecauseof

CKincreasewhichmayconfoundinterpretationoftheresult.WhenelevatedCKconcentrations(>5xULN)arenoted,

aconfirmatorytestshouldbeperformedwithin5to7days.

BeforeTreatment

Incommonwithotherstatins,Alipzashouldbeprescribedwithcautioninpatientswithpre-disposingfactorsfor

rhabdomyolysis.Acreatininekinaselevelshouldbemeasured,toestablishareferencebaseline,inthefollowing

situations:

renalimpairment,

hypothyroidism,

personalorfamilyhistoryofhereditarymusculardisorders,

previoushistoryofmusculartoxicitywithafibrateoranotherstatin,

historyofliverdiseaseoralcoholabuse,

elderlypatients(over70years)withotherpredisposingriskfactorsforrhabdomyolysis,

Insuchsituations,clinicalmonitoringisrecommendedandtheriskoftreatmentshouldbeconsideredinrelationtothe

possiblebenefit.TreatmentwithAlipzashouldnotbestartedifCKvaluesare>5xULN.

DuringTreatment

function: caution.Datawith4mgdosearelimitedinall

gradesofimpairedrenalfunction.Therefore

4mgdoseshouldONLYbeusedwithclose

monitoringaftergradeddosetitration.Inthose

withsevererenalimpairment4mgdoseisnot

recommended(seeSections4.4and5.2).

Patientswith

mildtomoderate

impairedhepaticfunction: The4mgdoseisnotrecommendedinpatients

withmildtomoderateimpairedhepatic

function.Amaximumdailydoseof2mgmay

begivenwithclosemonitoring(seeSections

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measuredandtreatmentstoppedifCKlevelsareelevated(>5xULN).Stoppingtreatmentshouldbeconsideredif

muscularsymptomsaresevereevenifCKlevelsare ≤5xULN.IfsymptomsresolveandCKlevelsreturntonormal,

thenre-introductionofAlipzamaybeconsideredatadoseof1mgandwithclosemonitoring.

LiverEffects

Incommonwithotherstatins,Alipzashouldbeusedwithcautioninpatientswithahistoryofliverdiseaseorwho

regularlyconsumeexcessivequantitiesofalcohol.Liverfunctiontestsshouldbeperformedpriortoinitiating

treatmentwithAlipzaandthenperiodicallyduringtreatment.Alipzatreatmentshouldbediscontinuedinpatientswho

haveapersistentincreaseinserumtransaminases(ALTandAST)exceeding3xULN.

RenalEffects

Alipzashouldbeusedwithcautioninpatientswithmoderateorsevererenalimpairment.Doseincrementsshouldbe

institutedonlywithclosemonitoring.Inthosewithsevererenalimpairment,4mgdoseisnotrecommended(see

Section4.2).

InterstitialLungDisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seeSection4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

Othereffects

AtemporarysuspensionofAlipzaisrecommendedforthedurationoftreatmentwitherythromycin,othermacrolide

antibioticsorfusidicacid(seeSection4.5).Alipzashouldbeusedwithcautioninpatientstakingdrugsknowntocause

myopathy(e.g.fibratesorniacinseeSection4.5).

Thetabletscontainlactose.Patientswiththerarehereditaryproblemsofgalactoseintolerance,Lapplactasedeficiency

orglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pitavastatinisactivelytransportedintohumanhepatocytesbymultiplehepatictransporters(includingorganicanion

transportingpolypeptide,OATP),whichmaybeinvolvedinsomeofthefollowinginteractions.

Ciclosporin:Co-administrationofasingledoseofciclosporinwithAlipzaatsteadystateresultedina4.6-fold

increaseinpitavastatinAUC.TheeffectofsteadystateciclosporinonsteadystateAlipzaisnotknown.Alipzais

contraindicatedinpatientsbeingtreatedwithciclosporin(seesection4.3).

Erythromycin:Co-administrationwithAlipzaresultedina2.8-foldincreaseinpitavastatinAUC.Atemporary

suspensionofAlipzaisrecommendedforthedurationoftreatmentwitherythromycinorothermacrolideantibiotics.

Gemfibrozilandotherfibrates:Theuseoffibratesaloneisoccasionallyassociatedwithmyopathy.Co-

administrationoffibrateswithstatinshasbeenassociatedwithincreasedmyopathyandrhabdomyolysis.Alipzashould

beadministeredwithcautionwhenusedconcomitantlywithfibrates(seeSection4.4).InPharmacokineticstudiesco-

administrationofAlipzawithGemfibrozilresultedina1.4-foldincreaseinpitavastatinAUCwithFenofibrateAUC

increased1.2-fold.

Niacin:InteractionstudieswithAlipzaandniacinhavenotbeenconducted.Theuseofniacinalonehasbeen

associatedwithmyopathyandrhabdomyolysiswhenusedasamonotherapy.

ThusAlipzashouldbeadministeredwithcautionwhenusedconcomitantlywithniacin.

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betweenfusidicacidandstatins.AtemporarysuspensionofAlipzaisrecommendedforthedurationoftreatmentwith

fusidicacid(seesection4.4).

Rifampicin:Co-administrationwithAlipzaatthesametimeresultedina1.3-foldincreaseinpitavastatinAUCdueto

reducedhepaticuptake

Proteaseinhibitors:Co-administrationwithAlipzaatthesametimemayresultinminorchangesinpitavastatinAUC.

Ezetimibeanditsglucuronidemetaboliteinhibittheabsorptionofdietaryandbiliarycholesterol.Co-administrationof

Alipzahadnoeffectonplasmaezetimibeortheglucuronidemetaboliteconcentrationsandezetimibehadnoimpacton

pitavastatinplasmaconcentrations.

InhibitorsofCYP3A4:Interactionstudieswithitraconazoleandgrapefruitjuice,knowninhibitorsofCYP3A4,had

noclinicallysignificanteffectontheplasmaconcentrationsofpitavastatin.

Digoxin,aknownP-gpsubstrate,didnotinteractwithAlipza.Duringco-administrationtherewasnosignificant

changeineitherpitavastatinordigoxinconcentrations.

Warfarin:Thesteady-statepharmacokineticsandpharmacodynamics(INRandPT)ofwarfarininhealthyvolunteers

wasunaffectedbytheco-administrationofAlipza4mgdaily.However,asforotherstatins,patientsreceivingwarfarin

shouldhavetheirprothrombintimeorINRmonitoredwhenAlipzaisaddedtotheirtherapy.

4.6Fertility,pregnancyandlactation

Pregnancy

Alipzaiscontraindicatedduringpregnancy(seeSection4.3).Womenofchildbearingpotentialmusttakeappropriate

contraceptiveprecautionsduringtreatmentwithAlipza.Sincecholesterolandotherproductsofcholesterol

biosynthesisareessentialforthedevelopmentofthefetus,thepotentialriskforinhibitionofHMG-CoAreductase

outweighstheadvantageoftreatmentduringpregnancy.Animalstudiesshowevidenceofreproductivetoxicity,butno

teratogenicpotential(seeSection5.3).Ifthepatientisplanningtobecomepregnant,treatmentshouldbestoppedat

leastonemonthpriortoconception.IfapatientbecomespregnantduringuseofAlipza,treatmentmustbe

discontinuedimmediately.

Lactation

Alipzaiscontraindicatedduringlactation(seeSection4.3).Pitavastatinisexcretedinratmilk.Itisnotknownwhether

itisexcretedinhumanmilk.

4.7Effectsonabilitytodriveandusemachines

ThereisnopatternofadverseeventsthatsuggeststhatpatientstakingAlipzawillhaveanyimpairmentofabilityto

driveandusehazardousmachinery,butitshouldbetakenintoaccountthattherehavebeenreportsofdizzinessand

somnolenceduringtreatmentwithAlipza.

4.8Undesirableeffects

Summaryofthesafetyprofile

Incontrolledclinicaltrials,attherecommendeddoses,lessthan4%ofAlipzatreatedpatientswerewithdrawndueto

adverseevents.Themostcommonlyreportedpitavastatinrelatedadversereactionincontrolledclinicaltrialswas

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Summaryofadversereactions

Adversereactionsandfrequenciesobservedinworldwidecontrolledclinicaltrialsandextensionstudies,atthe

recommendeddoses,arelistedbelowbysystemorganclass.Frequenciesaredefinedas:verycommon( ≥1/10),

common( ≥1/100,to<1/10),uncommon(≥1/1,000to<1/100),rare(≥1/10,000to<1/1,000)veryrare(<1/10,000)and

notknown.

Bloodandthelymphaticsystemdisorders

Uncommon:Anaemia

Metabolismandnutritiondisorders

Uncommon:Anorexia

Psychiatricdisorders

Uncommon:Insomnia

Nervoussystemdisorders

Common:Headache

Uncommon:Dizziness,Dysgeusia,Somnolence

Eyedisorders

Rare:Visualacuityreduced

Earandlabyrinthdisorders

Uncommon:Tinnitus

Gastrointestinaldisorders

Common:Constipation,Diarrhoea,Dyspepsia,Nausea

Uncommon:AbdominalPain,DryMouth,Vomiting

Rare:Glossodynia,pancreatitisacute

Hepato-biliarydisorders

Uncommon:Transaminases(aspartateaminotransferase,alanineaminotransferase)increased

Rare:Jaundicecholestatic

Skinandsubcutaneoustissuedisorders

Uncommon:Pruritus,Rash

Rare:Urticaria,Erythema

Musculoskeletal,connectivetissueandbonedisorders

Common:Myalgia,Arthralgia

Uncommon:Musclespasms

Renalandurinarydisorders

Uncommon:Pollakiuria

Generaldisordersandadministrationsiteconditions

Uncommon:Asthenia,Malaise,Fatigue,PeripheralOedema

Elevatedbloodcreatininekinaseof>3timestheupperlimitofnormal(ULN)occurredin49outof2800(1.8%)

patientsreceivingAlipzainthecontrolledclinicaltrials.Levelsof ≥10timesULNwithconcurrentmusclesymptoms

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PostMarketingExperience

Atwoyearprospectivepost-marketingsurveillancestudywasconductedinnearly20,000patientsinJapan.

Theoverwhelmingmajorityofthe20,000patientsinthestudyweretreatedwith1mgor2mgpitavastatinandnot

4mg.10.4%ofpatientsreportedadverseeventsforwhichacausalrelationshiptopitavastatincouldnotberuledout

and7.4%ofpatientswithdrewfromtherapyduetoadverseevents.Themyalgiaratewas1.08%.Themajorityof

adverseeventsweremild.Adverseeventrateswerehigherover2yearsinpatientswithahistoryofdrugallergy

(20.4%),orhepaticorrenaldisease(13.5%).

Adversereactionsandfrequenciesobservedintheprospectivepost-marketingsurveillancestudybutnotinworldwide

controlledclinicaltrials,attherecommendeddosesarelistedbelow.

Hepato-biliarydisorders

Rare:Hepaticfunctionabnormal,Liverdisorder

Musculoskeletal,connectivetissuedisorders

Rare:Myopathy,Rhabdomyolysis

Inthepost-marketingsurveillancestudythereweretworeportsofrhabdomyolysisrequiringhospitalisation(0.01%of

patients).

Inadditionthereareunsolicitedpost-marketingreportsofskeletalmuscleeffectsincludingmyalgiaandmyopathyin

Alipzatreatedpatientsatallrecommendeddoses.Reportsofrhabdomyolysis,withandwithoutacuterenalfailure,

includingfatalrhabdomyolysishavealsobeenreceived.

Statinclasseffects

Thefollowingadverseeventshavebeenreportedwithsomestatins:

Sleepdisturbances,includingnightmares

Memoryloss

Sexualdysfunction

Depression

Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seeSection4.4)

4.9Overdose

Thereisnospecifictreatmentintheeventofoverdose.Thepatientshouldbetreatedsymptomaticallyandsupportive

measuresinstitutedasrequired.LiverfunctionandCKlevelsshouldbemonitored.Haemodialysisisunlikelytobeof

benefit.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:HMG-CoAreductaseinhibitors

ATCCode:C10AA08

MechanismofAction

PitavastatincompetitivelyinhibitsHMG-CoAreductase,therate-limitingenzymeinthebiosynthesisofcholesterol,

andinhibitscholesterolsynthesisintheliver.AsaresulttheexpressionofLDLreceptorsintheliverisincreased,

promotingtheuptakeofcirculatingLDLfromtheblood,decreasingtotalcholesterol(TC)andLDL-cholesterol(LDL-

C)concentrationsintheblood.ItssustainedinhibitionofhepaticcholesterolsynthesisreducesVLDLsecretionintothe

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PharmacodynamicEffects

AlipzareduceselevatedLDL-C,totalcholesterolandtriglyceridesandincreasesHDL-cholesterol(HDL-C).

ItreducesApo-B,andproducesvariableincreasesinApo-A1(seeTable1).Italsoreducesnon-HDL-Candelevated

TC/HDL-C,andApo-B/Apo-A1ratios.

Clinicalefficacy

Incontrolledclinicalstudieswhichenrolledatotalof1687patientswithprimaryhypercholesterolaemiaandmixed

dyslipidaemia,including1239patientstreatedatthetherapeuticdoses(meanbaselineLDL-Cabout4.8

mmol/L),AlipzaconsistentlyreducedLDL-C,TC,non-HDL-C,TGandApo-BconcentrationsandelevatedHDL-C

andApo-A1concentrations.TC/HDL-CandApo-B/Apo-A1ratioswerereduced.LDL-Cwasreducedby38to39%

withAlipza2mgand44to45%withAlipza4mg.Themajorityofpatientstaking2mgachievedtheEuropean

AtherosclerosisSociety(EAS)treatmenttargetforLDL-C(<3mmol/L).

Inacontrolledclinicaltrialin942patientsaged ≥65years(434treatedwithAlipza1mg,2mgor4mg)withprimary

hypercholesterolaemiaandmixeddyslipidaemia(meanbaselineLDL-Cabout4.2mmol/L),LDL-Cvalueswere

reducedby31%,39.0%and44.3%,respectively,andabout90%ofpatientsreachedtheEAStreatmenttarget.More

than80%ofthepatientsweretakingconcomitantmedications,buttheincidenceofadverseeventswassimilarinall

treatmentgroupsandfewerthan5%ofpatientswithdrewfromthestudyduetoadverseevents.Safetyandefficacy

findingsweresimilarinpatientsinthedifferentagesubgroups(65-69,70-74,and ≥75years).

Incontrolledclinicaltrialswhichenrolledatotalof761patients(507treatedwithAlipza4mg)whohadprimary

hypercholesterolaemiaormixeddyslipidaemia,with2ormorecardiovascularriskfactors(meanbaselineLDL-Cabout

4.1mmol/L),ormixeddyslipidaemiawithtype2diabetes(meanbaselineLDL-Cabout3.6mmol/L),approximately

80%achievedtherelevantEAStarget(either3or2.5mmol/L,dependingonrisk).LDL-Cwasreducedby44%and

41%,respectively,inthepatientgroups.

Inlongtermstudiesofupto60weeksdurationinprimaryhypercholesterolaemiaandmixeddyslipidaemia,EAStarget

attainmenthasbeenmaintainedbypersistentandstablereductionsofLDL-C,andHDL-Cconcentrationshave

continuedtoincrease.Inastudyin1346patientswhohadcompleted12weeksofstatintherapy(LDL-Creduction

42.3%,EAStargetattainment69%,HDL-Celevation5.6%),valuesafterafurther52weeksoftreatmentwith

pitavastatin4mgwereLDL-Creduction42.9%,EAStargetattainment74%,HDL-Celevation14.3%.

Abeneficialeffectofpitavastatinoncardiovascularmorbidityandmortalityhasnotbeendemonstratedasnooutcome

studieswereincludedintheclinicalprogramme.

5.2Pharmacokineticproperties

Absorption:Pitavastatinisrapidlyabsorbedfromtheuppergastrointestinaltractandpeakplasmaconcentrationsare

achievedwithinonehourafteroraladministration.Absorptionisnotaffectedbyfood.Unchangeddrugundergoes

enterohepaticcirculationandiswellabsorbedfromthejejunumandileum.Theabsolutebioavailabilityofpitavastatin

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Distribution:Pitavastatinismorethan99%proteinboundinhumanplasma,mainlytoalbuminandalpha1-acid

glycoprotein,andthemeanvolumeofdistributionisapproximately133L.Pitavastatinisactivelytransportedinto

hepatocytes,thesiteofactionandmetabolism,bymultiplehepatictransportersincludingOATP1B1andOATP1B3.

PlasmaAUCisvariablewithanapproximately4-foldrangebetweenthehighestandlowestvalues.Studieswith

SLCO1B1(thegenewhichencodesOATP1B1)suggeststhatpolymorphismofthisgenecouldaccountformuchofthe

variabilityinAUC.Pitavastatinisnotasubstrateforp-glycoprotein.

Metabolism:Unchangedpitavastatinisthepredominantdrugmoietyinplasma.Theprincipalmetaboliteisthe

inactivelactonewhichisformedviaanester-typepitavastatinglucuronideconjugatebyUDPglucuronosyltransferase

(UGT1A3and2B7).Invitrostudies,using13humancytochromeP450(CYP)isoforms,indicatethatthemetabolism

ofpitavastatinbyCYPisminimal;CYP2C9(andtoalesserextentCYP2C8)isresponsibleforthemetabolismof

pitavastatintominormetabolites.

Excretion:Unchangedpitavastatinisrapidlyclearedfromtheliverinthebile,butundergoesenterohepatic

recirculation,contributingtoitsdurationofaction.Lessthan5%ofpitavastatinisexcretedintheurine.Theplasma

eliminationhalf-liferangesfrom5.7hours(singledose)to8.9hours(steadystate)andtheapparentgeometricmean

oralclearanceis43.4L/haftersingledose.

Effectoffood:Themaximumplasmaconcentrationofpitavastatinwasreducedby43%whenitwastakenwitha

high-fatmeal,butAUCwasunchanged.

Specialpopulations

Elderly:Inapharmacokineticstudywhichcomparedhealthyyoungandelderly( ≥65years)volunteers,pitavastatin

AUCwas1.3-foldhigherinelderlysubjects.ThishasnoeffectonthesafetyorefficacyofAlipzainelderlypatientsin

clinicaltrials.

Gender:Inapharmacokineticstudywhichcomparedhealthymaleandfemalevolunteers,pitavastatinAUCwas

increased1.6-foldinwomen.ThishasnoeffectonthesafetyorefficacyofAlipzainwomeninclinicaltrials.

Race:TherewasnodifferenceinthepharmacokineticprofileofpitavastatinbetweenJapaneseandCaucasianhealthy

volunteerswhenageandbodyweightwastakenintoaccount.

Paediatric:Pharmacokineticdatainthepaediatricpopulationarenotavailable.

Renalinsufficiency:ForpatientswithmoderaterenaldiseaseandthoseonhaemodialysisincreasesinAUCvalues

were1.8-foldand1.7-foldrespectively(seeSection4.2).

Hepaticinsufficiency:Forpatientswithmild(Child-PughA)hepaticimpairmentAUCwas1.6timesthatinhealthy

subjects,whileforpatientswithmoderate(Child-PughB)hepaticimpairmentAUCwas3.9-foldhigher.Dose

restrictionsarerecommendedinpatientswithmildandmoderatehepaticimpairment(seeSection4.2).Alipzais

contraindicatedinpatientswithseverehepaticimpairment.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonresultsfromconventionalstudiesofsafety

pharmacology,repeateddosetoxicity,genotoxicityandcarcinogenicpotential.Indicationsofrenaltoxicitywereseen

inmonkeysatexposuresgreaterthanthosereachedinadulthumansadministeredthemaximumdailydoseof4mgand

urinaryexcretionplaysafargreaterroleinthemonkeythaninotheranimalspecies.Invitrostudieswithliver

microsomesindicatethatamonkey-specificmetabolitemaybeimplicated.Therenaleffectsobservedinmonkeysare

unlikelytohaveclinicalrelevanceforhumans,howeverthepotentialforrenaladversereactionscannotbecompletely

excluded.

Pitavastatinhadnoeffectonfertilityorreproductiveperformanceandtherewasnoevidenceofteratogenicpotential.

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Astudyinratsindicatedmaternalmortalityatorneartermaccompaniedbyfetalandneonataldeathsatdosesof

1mg/kg/day(approximately4foldgreaterthanthehighestdoseinhumansonanAUCbasis).Nostudieshavebeen

conductedinjuvenileanimals.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Lactosemonohydrate

Lowsubstitutedhydroxypropylcellulose

Hypromellose(E464)

MagnesiumAluminometasilicate

Magnesiumstearate

Filmcoating

Hypromellose(E464)

Titaniumdioxide(E171)

Triethylcitrate(E1505)

Colloidalanhydroussilica

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25ºC.

Toprotectfromlightkeepblisterintheoutercarton.

6.5Natureandcontentsofcontainer

WhitePVdCcoatedPVC/ALblistersincartonsof7,28or30tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Toprotecttheenvironment,donotdisposeofviawastewaterorhouseholdwaste.

7MARKETINGAUTHORISATIONHOLDER

KowaPharmaceuticalEuropeCo.Ltd.,

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8MARKETINGAUTHORISATIONNUMBER

PA1532/2/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5thNovember2010

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