ATORVASTATIN 10 MG FILM-COATED TABLETS

Main information

  • Trade name:
  • ATORVASTATIN 10 MG FILM-COATED TABLETS
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATORVASTATIN 10 MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/093/001
  • Authorization date:
  • 27-08-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atorvastatin10mgFilm -coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm -coatedtabletcontains10mgofatorvastatin(asatorvastatincalcium).

Excipients

Each10mgfilm -coatedtabletcontains60.84mgoflactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film -coatedtablet

Whitetooff -white,capsule-shaped,film-coatedtablet,debossedwith"93"ononesideand"7310"ontheotherside

ofthetablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolaemia

Atorvastatinisindicatedasanadjuncttodietforreductionofelevatedtotalcholesterol(total-C),LDL -cholesterol

(LDL-C),apolipoproteinBandtriglyceridesinadults,adolescentsandchildrenaged10yearsandolderwithprimary

hypercholesterolaemiaincludingfamilialhypercholesterolaemia(heterozygousvariant)orcombined(mixed)

hyperlipidaemia(correspondingtoTypesIIaandIIboftheFredricksonclassification)whenresponsetodietandother

-pharmacologicalmeasuresisinadequate.

Atorvastatinisalsoindicatedtoreducetotal -CandLDL-Cinadultswithhomozygousfamilialhypercholesterolaemia

asanadjuncttootherlipid -loweringtreatments(e.g.LDLapheresis)orifsuchtreatmentsareunavailable.

Preventionofcardiovasculardisease

Preventionofcardiovasculareventsinpatientsestimatedtohaveahighriskforafirstcardiovascularevent(seesection

5.1),asanadjuncttocorrectionofotherriskfactors.

4.2Posologyandmethodofadministration

Posology

Thepatientshouldbeplacedonastandardcholesterol -loweringdietbeforereceivingatorvastatinandshouldcontinue

onthisdietduringtreatmentwithatorvastatin.

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Theusualstartingdoseis10mgonceaday.Adjustmentofdoseshouldbemadeatintervalsof4weeksormore.The

maximumdoseis80mgonceaday.

Primaryhypercholesterolaemiaandcombined(mixed)hyperlipidaemia

Themajorityofpatientsarecontrolledwithatorvastatin10mgonceaday.Atherapeuticresponseisevidentwithin2

weeks,andthemaximumtherapeuticresponseisusuallyachievedwithin4weeks.Theresponseismaintainedduring

chronictherapy.

Heterozygousfamilialhypercholesterolaemia

Patientsshouldbestartedwithatorvastatin10mgdaily.Dosesshouldbeindividualisedandadjustedevery4weeksto

40mgdaily.Thereafter,eitherthedosemaybeincreasedtoamaximumof80mgdailyorabileacidsequestrantmay

becombinedwith40mgatorvastatinoncedaily.

Homozygousfamilialhypercholesterolaemia

Onlylimiteddataareavailable(seesection5.1).

Thedoseofatorvastatininpatientswithhomozygousfamilialhypercholesterolaemiais10to80mgdaily(seesection

5.1).Atorvastatinshouldbeusedasanadjuncttootherlipid -loweringtreatments(e.g.LDLapheresis)inthesepatients

orifsuchtreatmentsareunavailable.

Preventionofcardiovasculardisease

Intheprimarypreventiontrialsthedosewas10mg/day.Higherdosesmaybenecessaryinordertoattain(LDL -)

cholesterollevelsaccordingtocurrentguidelines.

Renalimpairment

Noadjustmentofdoseisrequired(seesection4.4).

Hepaticimpairment

Atorvastatinshouldbeusedwithcautioninpatientswithhepaticimpairment(seesections4.4and5.2).Atorvastatinis

contraindicatedinpatientswithactiveliverdisease(seesection4.3).

Useintheelderly

Efficacyandsafetyinpatientsolderthan70usingrecommendeddosesissimilartothoseseeninthegeneral

population.

Paediatricuse

Hypercholesterolaemia

Paediatricuseshouldonlybecarriedoutbyphysiciansexperiencedinthetreatmentofpaediatrichyperlipidaemiaand

patientsshouldbere-evaluatedonaregularbasistoassessprogress.

Forpatientsaged10yearsandabove,therecommendedstartingdoseofatorvastatinis10mgperdaywithtitrationup

to20mgperday.Titrationshouldbeconductedaccordingtotheindividualresponseandtolerabilityinpaediatric

patients.Safetyinformationforpaediatricpatientstreatedwithdosesabove20mg,correspondingtoabout0.5mg/kg,

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Thereislimitedexperienceinchildrenbetween6-10yearsofage(seesection5.1).Atorvastatinisnotindicatedinthe

treatmentofpatientsbelowtheageof10years.

Otherpharmaceuticalforms/strengthsmaybemoreappropriateforthispopulation.

Methodofadministration

Atorvastatinisfororaladministration.Eachdailydoseofatorvastatinisgivenallatonceandmaybegivenatanytime

ofdaywithorwithoutfood.

4.3Contraindications

Atorvastatiniscontraindicatedinpatients:

withhypersensitivitytotheactivesubstanceortoanyoftheexcipientsofthismedicinalproduct

withactiveliverdiseaseorunexplainedpersistentelevationsofserumtransaminasesexceeding3timesthe

upperlimitofnormal

duringpregnancy,whilebreast -feedingandinwomenofchild-bearingpotentialnotusingappropriate

contraceptivemeasures(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Livereffects

Liverfunctiontestsshouldbeperformedbeforetheinitiationoftreatmentandperiodicallythereafter.Patientswho

developanysignsorsymptomssuggestiveofliverinjuryshouldhaveliverfunctiontestsperformed.Patientswho

developincreasedtransaminaselevelsshouldbemonitoreduntiltheabnormality(ies)resolve.Shouldanincreasein

transaminasesofgreaterthan3timestheupperlimitofnormal(ULN)persist,reductionofdoseorwithdrawalof

atorvastatinisrecommended(seesection4.8).

Atorvastatinshouldbeusedwithcautioninpatientswhoconsumesubstantialquantitiesofalcoholand/orhavea

historyofliverdisease.

StrokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)

Inapost -hocanalysisofstrokesubtypesinpatientswithoutcoronaryheartdisease(CHD)whohadarecentstrokeor

transientischaemicattack(TIA)therewasahigherincidenceofhaemorrhagicstrokeinpatientsinitiatedon

atorvastatin80mgcomparedtoplacebo.Theincreasedriskwasparticularlynotedinpatientswithpriorhaemorrhagic

strokeorlacunarinfarctatstudyentry.Forpatientswithpriorhaemorrhagicstrokeorlacunarinfarct,thebalanceof

risksandbenefitsofatorvastatin80mgisuncertainandthepotentialriskofhaemorrhagicstrokeshouldbecarefully

consideredbeforeinitiatingtreatment(seesection5.1).

Skeletalmuscleeffects

Atorvastatin,likeotherHMG-CoAreductaseinhibitors,mayonrareoccasionsaffecttheskeletalmuscleandcause

myalgia,myositis,andmyopathythatmayprogresstorhabdomyolysis,apotentiallylife -threateningcondition

characterisedbymarkedlyelevatedcreatinekinase(CK)levels(>10timesULN),myoglobinaemiaandmyoglobinuria

whichmayleadtorenalfailure.

Beforethetreatment

Atorvastatinshouldbeprescribedwithcautioninpatientswithpre -disposingfactorsforrhabdomyolysis.ACKlevel

shouldbemeasuredbeforestartingstatintreatmentinthefollowingsituations:

Renalimpairment

Hypothyroidism

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Previoushistoryofmusculartoxicitywithastatinorfibrate

Previoushistoryofliverdiseaseand/orwheresubstantialquantitiesofalcoholareconsumed

Intheelderly(age>70years),thenecessityofsuchmeasurementshouldbeconsidered,accordingtothe

presenceofotherpre -disposingfactorsforrhabdomyolysis.

Situationswhereanincreaseinplasmalevelsmayoccur,suchasinteractions(seesection4.5)andspecial

populationsincludinggeneticsub-populations(seesection5.2).

Insuchsituations,theriskoftreatmentshouldbeconsideredinrelationtopossiblebenefit,andclinicalmonitoringis

recommended.

IfCKlevelsaresignificantlyelevated(>5timesULN)atbaseline,treatmentshouldnotbestarted.

Creatinekinasemeasurement

Creatinekinase(CK)shouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofanyplausible

alternativecauseofCKincreaseasthismakesvalueinterpretationdifficult.IfCKlevelsaresignificantlyelevatedat

baseline(>5timesULN),levelsshouldbere -measuredwithin5to7dayslatertoconfirmtheresults.

Whilstontreatment

Patientsmustbeaskedtopromptlyreportmusclepain,cramps,orweaknessespeciallyifaccompaniedby

malaiseorfever.

Ifsuchsymptomsoccurwhilstapatientisreceivingtreatmentwithatorvastatin,theirCKlevelsshouldbe

measured.Iftheselevelsarefoundtobesignificantlyelevated(>5timesULN),treatmentshouldbestopped.

Ifmuscularsymptomsaresevereandcausedailydiscomfort,eveniftheCKlevelsareelevatedto 5xULN,

treatmentdiscontinuationshouldbeconsidered.

IfsymptomsresolveandCKlevelsreturntonormal,thenre -introductionofatorvastatinorintroductionofan

alternativestatinmaybeconsideredatthelowestdoseandwithclosemonitoring.

AtorvastatinmustbediscontinuedifclinicallysignificantelevationofCKlevels(>10xULN)occur,orif

rhabdomyolysisisdiagnosedorsuspected.

Concomitanttreatmentwithothermedicinalproducts

Theriskofrhabdomyolysisisincreasedwhenatorvastatinisadministeredconcomitantlywithcertainmedicinal

productsthatmayincreasetheplasmaconcentrationofatorvastatinsuchaspotentinhibitorsofCYP3A4ortransport

proteins(e.g.ciclosporin,telithromycin,clarithromycin,delavirdine,stiripentol,ketoconazole,voriconazole,

itraconazole,posaconazoleandHIVproteaseinhibitorsincludingritonavir,lopinavir,atazanavir,indinavir,darunavir,

etc.).Theriskofmyopathymayalsobeincreasedwiththeconcomitantuseofgemfibrozilandotherfibricacid

derivatives,erythromycin,niacinandezetimibe.Ifpossible,alternative(non-interacting)therapiesshouldbe

consideredinsteadofthesemedicinalproducts.

Incaseswhereco -administrationofthesemedicinalproductswithatorvastatinisnecessary,thebenefitandtheriskof

concurrenttreatmentshouldbecarefullyconsidered.Whenpatientsarereceivingmedicinalproductsthatincreasethe

plasmaconcentrationofatorvastatin,alowermaximumdoseofatorvastatinisrecommended.Inaddition,inthecaseof

potentCYP3A4inhibitors,alowerstartingdoseofatorvastatinshouldbeconsideredandappropriateclinical

monitoringofthesepatientsisrecommended(seesection4.5).

Theconcurrentuseofatorvastatinandfusidicacidisnotrecommended,thereforetemporarysuspensionofatorvastatin

maybeconsideredduringfusidicacidtherapy(seesection4.5).

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,non -productivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

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Paediatricuse

Developmentalsafetyinthepaediatricpopulationhasnotbeenestablished(seesection4.8).

Excipients

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose -galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Effectofco -administeredmedicinalproductsonatorvastatin

AtorvastatinismetabolisedbycytochromeP4503A4(CYP3A4)andisasubstratetotransportproteinse.g.thehepatic

uptaketransporterOATP1B1.ConcomitantadministrationofmedicinalproductsthatareinhibitorsofCYP3A4or

transportproteinsmayleadtoincreasedplasmaconcentrationsofatorvastatinandanincreasedriskofmyopathy.The

riskmightalsobeincreasedbyconcomitantadministrationofatorvastatinwithothermedicinalproductsthathavea

potentialtoinducemyopathy,suchasfibricacidderivativesandezetimibe(seesection4.4).

CYP3A4inhibitors

PotentCYP3A4inhibitorshavebeenshowntoleadtomarkedlyincreasedconcentrationsofatorvastatin(seeTable1

andspecificinformationbelow).Co -administrationofpotentCYP3A4inhibitors(e.g.ciclosporin,telithromycin,

clarithromycin,delavirdine,stiripentol,ketoconazole,voriconazole,itraconazole,posaconazoleandHIVprotease

inhibitorsincludingritonavir,lopinavir,atazanavir,indinavir,darunavir,etc.)shouldbeavoidedifpossible.Incases

whereco -administrationofthesemedicinalproductswithatorvastatincannotbeavoided,lowerstartingandmaximum

dosesofatorvastatinshouldbeconsideredandappropriateclinicalmonitoringofthepatientisrecommended(see

Table1).

ModerateCYP3A4inhibitors(e.g.erythromycin,diltiazem,verapamilandfluconazole)mayincreaseplasma

concentrationsofatorvastatin(seeTable1).Anincreasedriskofmyopathyhasbeenobservedwiththeuseof

erythromycinincombinationwithstatins.Interactionstudiesevaluatingtheeffectsofamiodaroneorverapamilon

atorvastatinhavenotbeenconducted.BothamiodaroneandverapamilareknowntoinhibitCYP3A4activityand

-administrationwithatorvastatinmayresultinincreasedexposuretoatorvastatin.Therefore,alowermaximumdose

ofatorvastatinshouldbeconsideredandappropriateclinicalmonitoringofthepatientisrecommendedwhen

concomitantlyusedwithmoderateCYP3A4inhibitors.Appropriateclinicalmonitoringisrecommendedafterinitiation

orfollowingdoseadjustmentsoftheinhibitor.

CYP3A4inducers

ConcomitantadministrationofatorvastatinwithinducersofcytochromeP4503A(e.g.efavirenz,rifampicin,St.John's

Wort)canleadtovariablereductionsinplasmaconcentrationsofatorvastatinDuetothedualinteractionmechanismof

rifampicin(cytochromeP4503AinductionandinhibitionofhepaticuptaketransporterOATP1B1),simultaneous

-administrationofatorvastatinwithrifampicinisrecommended,asdelayedadministrationofatorvastatinafter

administrationofrifampicinhasbeenassociatedwithasignificantreductioninatorvastatinplasmaconcentrations.The

effectofrifampicinonatorvastatinconcentrationsinhepatocytesis,however,unknownandifconcomitant

administrationcannotbeavoided,patientsshouldbecarefullymonitoredforefficacy.

Transporterproteininhibitors

Inhibitorsoftransportproteins(e.g.ciclosporin)canincreasethesystemicexposureofatorvastatin(seeTable1).The

effectofinhibitionofhepaticuptaketransportersonatorvastatinconcentrationsinhepatocytesisunknown.If

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Gemfibrozil/fibricacidderivatives

Theuseoffibratesaloneisoccasionallyassociatedwithmuscle-relatedevents,includingrhabdomyolysis.Theriskof

theseeventsmaybeincreasedwiththeconcomitantuseoffibricacidderivativesandatorvastatin.Ifconcomitant

administrationcannotbeavoided,thelowestdoseofatorvastatintoachievethetherapeuticobjectiveshouldbeused

andthepatientsshouldbeappropriatelymonitored(seesection4.4).

Ezetimibe

Theuseofezetimibealoneisassociatedwithmuscle-relatedevents,includingrhabdomyolysis.Theriskoftheseevents

maythereforebeincreasedwithconcomitantuseofezetimibeandatorvastatin.Appropriateclinicalmonitoringof

thesepatientsisrecommended.

Colestipol

Plasmaconcentrationsofatorvastatinanditsactivemetaboliteswerelower(byapprox.25%)whencolestipolwas

-administeredwithatorvastatin.However,lipideffectsweregreaterwhenatorvastatinandcolestipolwere

-administeredthanwheneithermedicinalproductwasgivenalone.

Fusidicacid

Interactionstudieswithatorvastatinandfusidicacidhavenotbeenconducted.Aswithotherstatins,muscle-related

events,includingrhabdomyolysis,havebeenreportedinpost-marketingexperiencewithatorvastatinandfusidicacid

givenconcurrently.Themechanismofthisinteractionisnotknown.Patientsshouldbecloselymonitoredand

temporarysuspensionofatorvastatintreatmentmaybeappropriate.

Effectofatorvastatinonco -administeredmedicinalproducts

Digoxin

Whenmultipledosesofdigoxinand10mgatorvastatinwereco -administered,steady-statedigoxinconcentrations

increasedslightly.Patientstakingdigoxinshouldbemonitoredappropriately.

Oralcontraceptives

-administrationofatorvastatinwithanoralcontraceptiveproducedincreasesinplasmaconcentrationsof

norethindroneandethinyloestradiol.

Warfarin

Inaclinicalstudyinpatientsreceivingchronicwarfarintherapy,co -administrationofatorvastatin80mgdailywith

warfarincausedasmalldecreaseofabout1.7secondsinprothrombintimeduringthefirst4daysofdosingwhich

returnedtonormalwithin15daysofatorvastatintreatment.Althoughonlyveryrarecasesofclinicallysignificant

anticoagulantinteractionshavebeenreported,prothrombintimeshouldbedeterminedbeforestartingatorvastatinin

patientstakingcoumarinanticoagulantsandfrequentlyenoughduringearlytherapytoensurethatnosignificant

alterationofprothrombintimeoccurs.Onceastableprothrombintimehasbeendocumented,prothrombintimescanbe

monitoredattheintervalsusuallyrecommendedforpatientsoncoumarinanticoagulants.Ifthedoseofatorvastatinis

changedordiscontinued,thesameprocedureshouldberepeated.Atorvastatintherapyhasnotbeenassociatedwith

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Table1:Effectofco -administeredmedicinalproductsonthepharmacokineticsofatorvastatin

-administeredmedicinal

productanddosingregimen Atorvastatin

Dose(mg) Changein

& Clinicalrecommendation #

Tipranavir500mgBID/ritonavir

200mgBID,8days(days14to

40mgonday1,

10mgonday20 9.4 -fold

Incaseswhereco -administration

withatorvastatinisnecessary,do

notexceed10mgatorvastatin

daily.Clinicalmonitoringofthese

patientsisrecommended. Ciclosporin5.2mg/kg/day,stable

dose 10mgODfor28

days 8.7 -fold

Lopinavir400mgBID/ritonavir

100mgBID,14days 20mgODfor4

days 5.9 -fold

Incaseswereco -administration

withatorvastatinisnecessary,

lowermaintenancedosesof

atorvastatinarerecommended.At

atorvastatindosesexceeding

20mg,clinicalmonitoringofthese

patientsisrecommended. Clarithromycin500mgBID,9

days 80mgODfor8

days 4.4 -fold

Saquinavir400mgBID/ritonavir

(300mgBIDfromdays5-7,

increasedto400mgBIDonday

8),days5-18,30minafter

atorvastatindosing 40mgODfor4

days 3.9 -fold

Incaseswhereco -administration

withatorvastatinisnecessary,

lowermaintenancedosesof

atorvastatinarerecommended.At

atorvastatindosesexceeding

40mg,clinicalmonitoringofthese

patientsisrecommended. Darunavir300mgBID/ritonavir

100mgBID,9days 10mgODfor4

days 3.3 -fold

Itraconazole200mgOD,4days 40mgSD 3.3 -fold

Fosamprenavir700mg

BID/ritonavir100mgBID,14

days 10mgODfor4

days 2.5 -fold

Fosamprenavir1,400mgBID,14

days 10mgODfor4

days 2.3 -fold

Nelfinavir1,250mgBID,14days 10mgODfor28

days 1.7 -fold ^ Nospecificrecommendation

Grapefruitjuice,240ml,OD * 40mg,SD 37% Concomitantintakeoflarge

quantitiesofgrapefruitjuiceand

atorvastatinisnotrecommended.

Diltiazem240mgOD,28days 40mg,SD 51% Afterinitiationorfollowingdose

adjustmentsofdiltiazem,

appropriateclinicalmonitoringof

thesepatientsisrecommended.

Erythromycin500mgQID,7days 10mg,SD

Lowermaximumdoseandclinical

monitoringofthesepatientsis

recommended.

Amlodipine10mg,singledose 80mg,SD 18% Nospecificrecommendation

Cimetidine300mgQID,2weeks 10mgODfor4

weeks lessthan

Nospecificrecommendation

Antacidsuspensionofmagnesium

andaluminiumhydroxides,30ml

QID,2weeks 10mgODfor4

weeks 35% ^ Nospecificrecommendation

Efavirenz600mgOD,14days 10mgfor3days 41% Nospecificrecommendation

Rifampicin600mgOD,7days

-administered) 40mgSD 30% Ifco -administrationcannotbe

avoided,simultaneous

-administrationofatorvastatin

withrifampicinisrecommended,

withclinicalmonitoring. Rifampicin600mgOD,5days

(dosesseparated) 40mgSD 80%

Gemfibrozil600mgBID,7days 40mgSD 35% Lowerstartingdoseandclinical

monitoringofthesepatientsis

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&

Datagivenasx -foldchangerepresentasimpleratiobetweenco-administrationandatorvastatinalone(i.e.,1-fold=no

change).Datagivenas%changerepresent%differencerelativetoatorvastatinalone(i.e.,0%=nochange).

Seesections4.4and4.5forclinicalsignificance.

ContainsoneormorecomponentsthatinhibitCYP3A4andcanincreaseplasmaconcentrationsofmedicinalproducts

metabolisedbyCYP3A4.Intakeofone240mlglassofgrapefruitjuicealsoresultedinadecreasedAUCof20.4%forthe

activeorthohydroxymetabolite.Largequantitiesofgrapefruitjuice(over1.2ldailyfor5days)increasedAUCof

atorvastatin2.5 -foldandAUCofactive(atorvastatinandmetabolites).

Totalatorvastatin -equivalentactivity

Increaseisindicatedas"",decreaseas"".

OD=oncedaily;SD=singledose;BID=twicedaily;QID=fourtimesdaily

Table2:Effectofatorvastatinonthepharmacokineticsofco -administeredmedicinalproducts

&

Datagivenas%changerepresent%differencerelativetoatorvastatinalone(i.e.,0%=nochange).

-administrationofmultipledosesofatorvastatinandphenazoneshowedlittleornodetectableeffectintheclearanceof

phenazone.

Increaseisindicatedas"",decreaseas"".

OD=oncedaily;SD=singledose

Paediatricpopulation

Drug-druginteractionstudieshaveonlybeenperformedinadults.Theextentofinteractionsinthepaediatric

populationisnotknown.Theabove-mentionedinteractionsforadultsandthewarningsinsection4.4shouldbetaken

intoaccountforthepaediatricpopulation.

4.6Fertility,pregnancyandlactation

Womenofchild-bearingpotential

Womenofchild -bearingpotentialshoulduseappropriatecontraceptivemeasuresduringtreatment(seesection4.3).

Pregnancy

Atorvastatiniscontraindicatedduringpregnancy(seesection4.3).Safetyinpregnantwomenhasnotbeenestablished.

Nocontrolledclinicaltrialswithatorvastatinhavebeenconductedinpregnantwomen.Rarereportsofcongenital

anomaliesfollowingintra -uterineexposuretoHMG-CoAreductaseinhibitorshavebeenreceived.Animalstudies

Fenofibrate160mgOD,7days 40mgSD 3% Lowerstartingdoseandclinical

monitoringofthesepatientsis

recommended.

Atorvastatinand

dosingregimen Co -administeredmedicinalproduct

Medicinalproduct/dose(mg) Changein

& Clinicalrecommendation

80mgODfor10

days Digoxin0.25mgOD,20days 15% Patientstakingdigoxinshouldbe

monitoredappropriately.

40mgODfor22

days OralcontraceptiveOD,2months

norethindrone1mg

ethinyloestradiol35µg 28%

Nospecificrecommendation

80mgODfor15

days *

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Maternaltreatmentwithatorvastatinmayreducethefetallevelsofmevalonatewhichisaprecursorofcholesterol

biosynthesis.Atherosclerosisisachronicprocess,andordinarilydiscontinuationoflipid-loweringmedicinalproducts

duringpregnancyshouldhavelittleimpactonthelong-termriskassociatedwithprimaryhypercholesterolaemia.

Forthesereasons,atorvastatinshouldnotbeusedinwomenwhoarepregnant,tryingtobecomepregnantorsuspect

theyarepregnant.Treatmentwithatorvastatinshouldbesuspendedforthedurationofpregnancyoruntilithasbeen

determinedthatthewomanisnotpregnant(seesection4.3).

Breast -feeding

Itisnotknownwhetheratorvastatinoritsmetabolitesareexcretedinhumanmilk.Inrats,plasmaconcentrationsof

atorvastatinanditsactivemetabolitesaresimilartothoseinmilk(seesection5.3).Becauseofthepotentialforserious

adversereactions,womentakingatorvastatinshouldnotbreast -feedtheirinfants(seesection4.3).Atorvastatinis

contraindicatedduringbreast -feeding(seesection4.3).

Fertility

Inanimalstudiesatorvastatinhadnoeffectonmaleorfemalefertility(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

Atorvastatinhasnegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Intheatorvastatinplacebo-controlledclinicaltrialdatabaseof16,066(8,755atorvastatinvs.7,311placebo)patients

treatedforameanperiodof53weeks,5.2%ofpatientsonatorvastatindiscontinuedduetoadversereactionscompared

to4.0%ofthepatientsonplacebo.

Basedondatafromclinicalstudiesandextensivepost -marketingexperience,thefollowingtablepresentstheadverse

reactionprofileforatorvastatin.

Estimatedfrequenciesofreactionsarerankedaccordingtothefollowingconvention:common(1/100to<1/10);

uncommon(1/1,000to<1/100);rare(1/10,000to<1/1,000);veryrare(<1/10,000).

Infectionsandinfestations

Common: nasopharyngitis

Bloodandlymphaticsystemdisorders

Rare: thrombocytopenia

Immunesystemdisorders

Common: allergicreactions

Veryrare: anaphylaxis

Metabolismandnutritiondisorders

Common: hyperglycaemia

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Psychiatricdisorders

Uncommon: nightmares,insomnia

Nervoussystemdisorders

Common: headache

Uncommon: dizziness,paraesthesia,hypoaesthesia,dysgeusia,amnesia

Veryrare: peripheralneuropathy

Eyedisorders

Uncommon: visionblurred

Rare: visualdisturbance

Earandlabyrinthdisorders

Uncommon: tinnitus

Veryrare: hearingloss

Respiratory,thoracicandmediastinaldisorders

Common: pharyngolaryngealpain,epistaxis

Gastrointestinaldisorders

Common: constipation,flatulence,dyspepsia,nausea,diarrhoea

Uncommon: vomiting,abdominalpainupperandlower,eructation,pancreatitis

Hepatobiliarydisorders

Uncommon: hepatitis

Rare: cholestasis

Veryrare: hepaticfailure

Skinandsubcutaneoustissuedisorders

Uncommon: urticaria,skinrash,pruritus,alopecia

Rare: angioneuroticoedema,dermatitisbullousincludingerythemamultiforme,Stevens -Johnson

syndromeandtoxicepidermalnecrolysis

Musculoskeletalandconnectivetissuedisorders

Common: myalgia,arthralgia,paininextremity,musclespasms,jointswelling,backpain

Uncommon: neckpain,musclefatigue

Rare: myopathy,myositis,rhabdomyolysis,tendonopathysometimescomplicatedbyrupture

Reproductivesystemandbreastdisorders

Veryrare: gynaecomastia

Generaldisordersandadministrationsiteconditions

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Investigations

Common: liverfunctiontestabnormal,bloodcreatinekinaseincreased

Uncommon: whitebloodcellsurinepositive

AswithotherHMG -CoAreductaseinhibitorselevatedserumtransaminaseshavebeenreportedinpatientsreceiving

atorvastatin.Thesechangeswereusuallymild,transient,anddidnotrequireinterruptionoftreatment.Clinically

important(>3timesuppernormallimit)elevationsinserumtransaminasesoccurredin0.8%patientsonatorvastatin.

Theseelevationsweredose -relatedandwerereversibleinallpatients.

Elevatedserumcreatinekinase(CK)levelsgreaterthan3timesupperlimitofnormaloccurredin2.5%ofpatientson

atorvastatin,similartootherHMG -CoAreductaseinhibitorsinclinicaltrials.Levelsabove10timesthenormalupper

rangeoccurredin0.4%atorvastatin -treatedpatients(seesection4.4).

Thefollowingadverseeventshavebeenreportedwithsomestatins:

sexualdysfunction

depression

exceptionalcasesofinterstitiallungdisease,especiallywithlong -termtherapy(seesection4.4).

Paediatricpopulation

Theclinicalsafetydatabaseincludessafetydatafor249paediatricpatientswhoreceivedatorvastatin,amongwhich7

patientswere<6yearsold,14patientswereintheagerangeof6to9,and228patientswereintheagerangeof10to

Nervoussystemdisorders

Common: headache

Gastrointestinaldisorders

Common: abdominalpain

Investigations

Common: alanineaminotransferaseincreased,bloodcreatinephosphokinaseincreased

Basedonthedataavailable,frequency,typeandseverityofadversereactionsinchildrenareexpectedtobethesameas

inadults.Thereiscurrentlylimitedexperiencewithrespecttolong-termsafetyinthepaediatricpopulation.

4.9Overdose

Specifictreatmentisnotavailableforatorvastatinoverdose.Shouldanoverdoseoccur,thepatientshouldbetreated

symptomaticallyandsupportivemeasuresinstituted,asrequired.Liverfunctiontestsshouldbeperformedandserum

CPKlevelsshouldbemonitored.Duetoextensiveatorvastatinbindingtoplasmaproteins,haemodialysisisnot

expectedtosignificantlyenhanceatorvastatinclearance.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Lipid-modifyingagents,HMG -CoAreductaseinhibitors

ATCcode:C10AA05

Atorvastatinisaselective,competitiveinhibitorofHMG -CoAreductase,therate-limitingenzymeresponsibleforthe

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Triglyceridesandcholesterolintheliverareincorporatedintoverylow -densitylipoproteins(VLDL)andreleasedinto

theplasmafordeliverytoperipheraltissues.Low -densitylipoprotein(LDL)isformedfromVLDLandiscatabolised

primarilythroughthereceptorwithhighaffinitytoLDL(LDLreceptor).

AtorvastatinlowersplasmacholesterolandlipoproteinserumconcentrationsbyinhibitingHMG -CoAreductaseand

subsequentlycholesterolbiosynthesisintheliverandincreasesthenumberofhepaticLDLreceptorsonthecellsurface

forenhanceduptakeandcatabolismofLDL.

AtorvastatinreducesLDLproductionandthenumberofLDLparticles.Atorvastatinproducesaprofoundandsustained

increaseinLDLreceptoractivitycoupledwithabeneficialchangeinthequalityofcirculatingLDLparticles.

AtorvastatiniseffectiveinreducingLDL -Cinpatientswithhomozygousfamilialhypercholesterolaemia,apopulation

thathasnotusuallyrespondedtolipid -loweringmedicinalproducts.

Atorvastatinhasbeenshowntoreduceconcentrationsoftotal -C(30%-46%),LDL-C(41%-61%),apolipoprotein

B(34% -50%),andtriglycerides(14%-33%)whileproducingvariableincreasesinHDL-CandapolipoproteinA1

inadose -responsestudy.Theseresultsareconsistentinpatientswithheterozygousfamilialhypercholesterolaemia,

-familialformsofhypercholesterolaemia,andmixedhyperlipidaemia,includingpatientswith

-insulin-dependentdiabetesmellitus.

Reductionsintotal -C,LDL-C,andapolipoproteinBhavebeenproventoreduceriskforcardiovasculareventsand

cardiovascularmortality.

Homozygousfamilialhypercholesterolaemia

Inamulticentre8 -weekopen-labelcompassionate-usestudywithanoptionalextensionphaseofvariablelength,335

patientswereenrolled,89ofwhichwereidentifiedashomozygousfamilialhypercholesterolaemiapatient.Fromthese

89patients,themeanpercentreductioninLDL -Cwasapproximately20%.Atorvastatinwasadministeredatdosesup

to80mg/day.

Atherosclerosis

IntheReversingAtherosclerosiswithAggressiveLipid -LoweringStudy(REVERSAL),theeffectofintensive

lipid -loweringwithatorvastatin80mgandstandarddegreeoflipid-loweringpravastatin40mgoncoronary

atherosclerosiswasassessedbyintravascularultrasound(IVUS),duringangiography,inpatientswithcoronaryheart

disease.Inthisrandomised,double -blind,multicentre,controlledclinicaltrial,IVUSwasperformedatbaselineandat

18monthsin502patients.Intheatorvastatingroup(n=253),therewasnoprogressionofatherosclerosis.

Themedianpercentchangefrombaselineintotalatheromavolume(theprimarystudycriterion)was -0.4%(p=0.98)

intheatorvastatingroupand+2.7%(p=0.001)inthepravastatingroup(n=249).Whencomparedtopravastatinthe

effectsofatorvastatinwerestatisticallysignificant(p=0.02).Theeffectofintensivelipid-loweringoncardiovascular

endpoints(e.g.needforrevascularisation,non-fatalmyocardialinfarction,coronarydeath)wasnotinvestigatedinthis

study.

Intheatorvastatingroup,LDL-Cwasreducedtoameanof2.04mmol/l±0.8(78.9mg/dl±30)frombaseline

3.89mmol/l±0.7(150mg/dl±28)andinthepravastatingroup,LDL-Cwasreducedtoameanof2.85mmol/l±0.7

(110mg/dl±26)frombaseline3.89mmol/l±0.7(150mg/dl±26)(p<0.0001).Atorvastatinalsosignificantly

reducedmeanTCby34.1%(pravastatin:-18.4%,p<0.0001),meanTGlevelsby20%(pravastatin:-6.8%,

p<0.0009),andmeanapolipoproteinBby39.1%(pravastatin:-22.0%,p<0.0001).Atorvastatinincreasedmean

HDL-Cby2.9%(pravastatin:+5.6%,p=NS).Therewasa36.4%meanreductioninCRPintheatorvastatingroup

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Studyresultswereobtainedwiththe80mgdosestrength.Therefore,theycannotbeextrapolatedtothelowerdose

strengths.

Thesafetyandtolerabilityprofilesofthetwotreatmentgroupswerecomparable.

Theeffectofintensivelipidloweringonmajorcardiovascularendpointswasnotinvestigatedinthisstudy.Therefore,

theclinicalsignificanceoftheseimagingresultswithregardtotheprimaryandsecondarypreventionofcardiovascular

eventsisunknown.

Acutecoronarysyndrome

IntheMIRACLstudy,atorvastatin80mghasbeenevaluatedin3,086patients(atorvastatinn=1,538;placebon=1,548)

withanacutecoronarysyndrome(nonQ-waveMIorunstableangina).Treatmentwasinitiatedduringtheacutephase

afterhospitaladmissionandlastedforaperiodof16weeks.Treatmentwithatorvastatin80mg/dayincreasedthetime

tooccurrenceofthecombinedprimaryendpoint,definedasdeathfromanycause,non -fatalMI,resuscitatedcardiac

arrest,oranginapectoriswithevidenceofmyocardialischaemiarequiringhospitalisation,indicatingariskreduction

by16%(p=0.048).Thiswasmainlyduetoa26%reductioninre -hospitalisationforanginapectoriswithevidenceof

myocardialischaemia(p=0.018).Theothersecondaryendpointsdidnotreachstatisticalsignificanceontheirown

(overall:placebo:22.2%,atorvastatin:22.4%).

ThesafetyprofileofatorvastatinintheMIRACLstudywasconsistentwithwhatisdescribedinsection4.8.

Preventionofcardiovasculardisease

Theeffectofatorvastatinonfatalandnon -fatalcoronaryheartdiseasewasassessedinarandomised,double-blind,

placebo -controlledstudy,theAnglo-ScandinavianCardiacOutcomesTrialLipidLoweringArm(ASCOT-LLA).

Patientswerehypertensive,40 -79yearsofage,withnopreviousmyocardialinfarctionortreatmentforangina,and

withTClevels6.5mmol/L(251mg/dl).Allpatientshadatleast3ofthepredefinedcardiovascularriskfactors:male

gender,age55years,smoking,diabetes,historyofCHDinafirst -degreerelative,TC:HDL-C>6,peripheral

vasculardisease,leftventricularhypertrophy,priorcerebrovascularevent,specificECGabnormality,

proteinuria/albuminuria.Notallincludedpatientswereestimatedtohaveahighriskforafirstcardiovascularevent.

Patientsweretreatedwithantihypertensivetherapy(eitheramlodipineoratenolol -basedregimen)andeither

atorvastatin10mgdaily(n=5,168)orplacebo(n=5,137).

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Totalmortalityandcardiovascularmortalitywerenotsignificantlyreduced(185vs.212events,p=0.17and74vs.82

events,p=0.51).Inthesubgroupanalysesbygender(81%males,19%females),abeneficialeffectofatorvastatinwas

Event Relativerisk

reduction(%) No.ofevents

(atorvastatinvs

placebo) Absoluterisk

reduction 1

(%) Pvalue

FatalCHDplusnon -fatalMI36% 100vs.154 1.1% 0.0005

Totalcardiovascularevents

andrevascularisation

procedures 20% 389vs.483 1.9% 0.0008

Totalcoronaryevents 29% 178vs247 1.4% 0.0006

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow -upof3.3years.

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Overallandcardiovascularmortalitywerenumericallyhigherinthefemalepatients(38vs.30and17vs.12),butthis

wasnotstatisticallysignificant.Therewassignificanttreatmentinteractionbyantihypertensivebaselinetherapy.The

primaryendpoint(fatalCHDplusnon -fatalMI)wassignificantlyreducedbyatorvastatininpatientstreatedwith

amlodipine(HR0.47(0.32 -0.69),p=0.00008),butnotinthosetreatedwithatenolol(HR0.83(0.59-1.17),p=0.287).

Theeffectofatorvastatinonfatalandnon -fatalcardiovasculardiseasewasalsoassessedinarandomised,

double -blind,multicentre,placebo-controlledtrial,theCollaborativeAtorvastatinDiabetesStudy(CARDS)in

patientswithtype2diabetes,40 -75yearsofage,withoutpriorhistoryofcardiovasculardisease,andwithLDL-C

4.14mmol/l(160mg/dl)andTG6.78mmol/l(600mg/dl).Allpatientshadatleast1ofthefollowingriskfactors:

hypertension,currentsmoking,retinopathy,microalbuminuriaormacroalbuminuria.

Patientsweretreatedwitheitheratorvastatin10mgdaily(n=1,428)orplacebo(n=1,410)foramedianfollow -upof

3.9years.

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Therewasnoevidenceofadifferenceinthetreatmenteffectbypatient’sgender,age,orbaselineLDL -Clevel.A

favourabletrendwasobservedregardingthemortalityrate(82deathsintheplacebogroupvs.61deathsinthe

atorvastatingroup,p=0.0592).

Recurrentstroke

IntheStrokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)study,theeffectofatorvastatin

80mgdailyorplaceboonstrokewasevaluatedin4,731patientswhohadastrokeortransientischaemicattack(TIA)

withinthepreceding6monthsandnohistoryofcoronaryheartdisease(CHD).Patientswere60%male,21-92yearsof

age(averageage63years)andhadanaveragebaselineLDLof133mg/dl(3.4mmol/l).ThemeanLDL-Cwas

73mg/dl(1.9mmol/l)duringtreatmentwithatorvastatinand129mg/dl(3.3mmol/l)duringtreatmentwithplacebo.

Medianfollow-upwas4.9years.

Atorvastatin80mgreducedtheriskoftheprimaryendpointoffatalornon-fatalstrokeby15%(HR0.85;95%CI,

0.72-1.00;p=0.05or0.84;95%CI,0.71-0.99;p=0.03afteradjustmentforbaselinefactors)comparedtoplacebo.

-causemortalitywas9.1%(216/2,365)foratorvastatinversus8.9%(211/2,366)forplacebo.

Inapost-hocanalysis,atorvastatin80mgreducedtheincidenceofischaemicstroke(218/2,365,9.2%vs.274/2,366,

11.6%,p=0.01)andincreasedtheincidenceofhaemorrhagicstroke(55/2,365,2.3%vs.33/2,366,1.4%,p=0.02)

Event Relativerisk

reduction(%) No.ofevents

(atorvastatinvs

placebo) Absoluterisk

reduction 1

(%) Pvalue

Majorcardiovascularevents

(fatalandnon -fatalAMI,

silentMI,acuteCHDdeath,

unstableangina,CABG,

PTCA,revascularisation,

stroke) 37% 83vs.127 3.2% 0.0010

MI(fatalandnon -fatalAMI,

silentMI) 42% 38vs.64 1.9% 0.0070

Strokes(fatalandnon -fatal) 48% 21vs.39 1.3% 0.0163

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow -upof3.9years.

AMI=acutemyocardialinfarction;CABG=coronaryarterybypassgraft;CHD=coronaryheart

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Theriskofhaemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorhaemorrhagicstroke(7/45

foratorvastatinversus2/48forplacebo;HR4.06;95%CI,0.84-19.57)andtheriskofischaemicstrokewassimilar

betweengroups(3/45foratorvastatinversus2/48forplacebo;HR1.64;95%CI,0.27-9.82).

Theriskofhaemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorlacunarinfarct(20/708for

atorvastatinversus4/701forplacebo;HR4.99;95%CI,1.71-14.61),buttheriskofischaemicstrokewasalso

decreasedinthesepatients(79/708foratorvastatinversus102/701forplacebo;HR0.76;95%CI,0.57-1.02).Itis

possiblethatthenetriskofstrokeisincreasedinpatientswithpriorlacunarinfarctwhoreceiveatorvastatin80mg/day.

-causemortalitywas15.6%(7/45)foratorvastatinversus10.4%(5/48)inthesubgroupofpatientswithprior

haemorrhagicstroke.All -causemortalitywas10.9%(77/708)foratorvastatinversus9.1%(64/701)forplacebointhe

subgroupofpatientswithpriorlacunarinfarct.

Paediatricpopulation

Heterozygousfamilialhypercholesterolaemiainpaediatricpatientsaged6-17years

An8 -week,open-labelstudytoevaluatepharmacokinetics,pharmacodynamics,andsafetyandtolerabilityof

atorvastatinwasconductedinchildrenandadolescentswithgeneticallyconfirmedheterozygousfamilial

hypercholesterolemiaandbaselineLDL-C4mmol/l.Atotalof39childrenandadolescents,6to17yearsofage,were

enrolled.CohortAincluded15children,6to12yearsofageandatTannerStage1.CohortBincluded24children,10

to17yearsofageandatTannerStage2.

Theinitialdoseofatorvastatinwas5mgdailyofachewabletabletinCohortAand10mgdailyofatabletformulation

inCohortB.TheatorvastatindosewaspermittedtobedoubledifasubjecthadnotattainedtargetLDL-Cof

<3.35mmol/latWeek4andifatorvastatinwaswelltolerated.

MeanvaluesforLDL-C,TC,VLDL-C,andApoBdecreasedbyWeek2amongallsubjects.Forsubjectswhosedose

wasdoubled,additionaldecreaseswereobservedasearlyas2weeks,atthefirstassessment,afterdoseescalation.The

meanpercentdecreasesinlipidparametersweresimilarforbothcohorts,regardlessofwhethersubjectsremainedat

theirinitialdoseordoubledtheirinitialdose.AtWeek8,onaverage,thepercentchangefrombaselineinLDL-Cand

TCwasapproximately40%and30%,respectively,overtherangeofexposures.

Heterozygousfamilialhypercholesterolaemiainpaediatricpatientsaged10-17yearsold

Inadouble -blind,placebo-controlledstudyfollowedbyanopen-labelphase,187boysandpostmenarchalgirls10-17

yearsofage(meanage14.1years)withheterozygousfamilialhypercholesterolaemia(FH)orsevere

hypercholesterolaemiawererandomisedtoatorvastatin(n=140)orplacebo(n=47)for26weeksandthenallreceived

atorvastatinfor26weeks.Thedosageofatorvastatin(oncedaily)was10mgforthefirst4weeksandup -titratedto20

mgiftheLDL-Clevelwas>3.36mmol/l.Atorvastatinsignificantlydecreasedplasmalevelsoftotal-C,LDL-C,

triglycerides,andapolipoproteinBduringthe26weekdouble-blindphase.ThemeanachievedLDL-Cvaluewas

3.38mmol/l(range:1.81-6.26mmol/l)intheatorvastatingroupcomparedto5.91mmol/l(range:3.93-9.96mmol/l)in

theplacebogroupduringthe26 -weekdouble-blindphase.

Anadditionalpaediatricstudyofatorvastatinversuscolestipolinpatientswithhypercholesterolaemiaaged10-18years

demonstratedthatatorvastatin(N=25)causedasignificantreductioninLDL-Catweek26(p<0.05)comparedwith

colestipol(N=31).

Acompassionateusestudyinpatientswithseverehypercholesterolaemia(includinghomozygous

hypercholesterolaemia)included46paediatricpatientstreatedwithatorvastatintitratedaccordingtoresponse(some

subjectsreceived80mgatorvastatinperday).Thestudylasted3years:LDL -cholesterolwasloweredby36%.

Thelong-termefficacyofatorvastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthoodhasnot

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TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithatorvastatininchildren

aged0tolessthan6yearsinthetreatmentofheterozygoushypercholesterolaemiaandinchildrenaged0tolessthan

18yearsinthetreatmentofhomozygousfamilialhypercholesterolaemia,combined(mixed)hypercholesterolaemia,

primaryhypercholesterolaemiaandinthepreventionofcardiovascularevents(seesection4.2forinformationon

paediatricuse).

5.2Pharmacokineticproperties

Absorption

Atorvastatinisrapidlyabsorbedafteroraladministration;maximumplasmaconcentrations(C

)occurwithin1to2

hours.Extentofabsorptionincreasesinproportiontoatorvastatindose.Afteroraladministration,atorvastatin

film -coatedtabletsare95%to99%bioavailablecomparedtotheoralsolution.Theabsolutebioavailabilityof

atorvastatinisapproximately12%andthesystemicavailabilityofHMG -CoAreductaseinhibitoryactivityis

approximately30%.Thelowsystemicavailabilityisattributedtopresystemicclearanceingastrointestinalmucosa

and/orhepaticfirst -passmetabolism.

Distribution

Meanvolumeofdistributionofatorvastatinisapproximately381l.Atorvastatinis 98%boundtoplasmaproteins.

Biotransformation

AtorvastatinismetabolisedbycytochromeP4503A4toortho -andparahydroxylatedderivativesandvarious

beta -oxidationproducts.Apartfromotherpathwaystheseproductsarefurthermetabolisedviaglucuronidation.In

vitro,inhibitionofHMG -CoAreductasebyortho-andparahydroxylatedmetabolitesisequivalenttothatof

atorvastatin.Approximately70%ofcirculatinginhibitoryactivityforHMG -CoAreductaseisattributedtoactive

metabolites.

Excretion

Atorvastatiniseliminatedprimarilyinbilefollowinghepaticand/orextrahepaticmetabolism.However,atorvastatin

doesnotappeartoundergosignificantenterohepaticrecirculation.Meanplasmaeliminationhalf -lifeofatorvastatinin

humansisapproximately14hours.Thehalf -lifeofinhibitoryactivityforHMG-CoAreductaseisapproximately20to

30hoursduetothecontributionofactivemetabolites.

Specialpopulations

Elderly:Plasmaconcentrationsofatorvastatinanditsactivemetabolitesarehigherinhealthyelderlysubjects

thaninyoungadultswhilethelipideffectswerecomparabletothoseseeninyoungerpatientpopulations.

Paediatric:Inanopen -label,8-weekstudy,TannerStage1(N=15)andTannerStage2(N=24)paediatric

patients(ages6-17years)withheterozygousfamilialhypercholesterolemiaandbaselineLDL-C4mmol/lwere

treatedwith5or10mgofchewableor10or20mgoffilm -coatedatorvastatintabletsoncedaily,respectively.

BodyweightwastheonlysignificantcovariateinatorvastatinpopulationPKmodel.Apparentoralclearanceof

atorvastatininpaediatricsubjectsappearedsimilartoadultswhenscaledallometricallybybodyweight.

ConsistentdecreasesinLDL-CandTCwereobservedovertherangeofatorvastatinando-hydroxyatorvastatin

exposures.

Gender:Concentrationsofatorvastatinanditsactivemetabolitesinwomendifferfromthoseinmen(women:

approximately20%higherforC

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Thesedifferenceswereofnoclinicalsignificance,resultinginnoclinicallysignificantdifferencesinlipideffects

amongmenandwomen.

Renalinsufficiency:Renaldiseasehasnoinfluenceontheplasmaconcentrationsorlipideffectsofatorvastatin

anditsactivemetabolites.

Hepaticinsufficiency:Plasmaconcentrationsofatorvastatinanditsactivemetabolitesaremarkedlyincreased

(approximately16 -foldinC

andapproximately11 -foldinAUC)inpatientswithchronicalcoholicliver

disease(Child -PughB).

SLCO1B1polymorphism:HepaticuptakeofallHMG -CoAreductaseinhibitorsincludingatorvastatininvolves

theOATP1B1transporter.InpatientswithSLCO1B1polymorphismthereisariskofincreasedexposureof

atorvastatin,whichmayleadtoanincreasedriskofrhabdomyolysis(seesection4.4).Polymorphisminthegene

encodingOATP1B1(SLCO1B1c.521CC)isassociatedwitha2.4 -foldhigheratorvastatinexposure(AUC)than

inindividualswithoutthisgenotypevariant(c.521TT).Ageneticallyimpairedhepaticuptakeofatorvastatinis

alsopossibleinthesepatients.Possibleconsequencesfortheefficacyareunknown.

5.3Preclinicalsafetydata

Atorvastatinwasnegativeformutagenicandclastogenicpotentialinabatteryof4invitrotestsand1invivoassay.

Atorvastatinwasnotfoundtobecarcinogenicinrats,buthighdosesinmice(resultingin6-11 -foldtheAUC

0-24h

reachedinhumansatthehighestrecommendeddose)showedhepatocellularadenomasinmalesandhepatocellular

carcinomasinfemales

ThereisevidencefromanimalexperimentalstudiesthatHMG -CoAreductaseinhibitorsmayaffectthedevelopment

ofembryosorfetuses.Inrats,rabbitsanddogs,atorvastatinhadnoeffectonfertilityandwasnotteratogenic,however,

atmaternallytoxicdosesfetaltoxicitywasobservedinratsandrabbits.Thedevelopmentoftheratoffspringwas

delayedandpost-natalsurvivalreducedduringexposureofthedamstohighdosesofatorvastatin.Inrats,thereis

evidenceofplacentaltransfer.Inrats,plasmaconcentrationsofatorvastatinaresimilartothoseinmilk.Itisnotknown

whetheratorvastatinoritsmetabolitesareexcretedinhumanmilk.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Cores:

Lactosemonohydrate

Crospovidone

Magnesiumcarbonate,light

Colloidalanhydroussilica

Magnesiumstearate

Film-coating:

OpadryIIOY-GM-28900whitecontaining:

Polydextrose(E1200)

Titaniumdioxide(E171)

Hypromellose15cP(E464)

Macrogol4000

6.2Incompatibilities

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6.3Shelflife

1year

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

Shelflifeafterfirstopeningofthebottle:30days.

6.5Natureandcontentsofcontainer

Bottles

WhiteHDPEbottlewithpolypropylene(PP)closure,silicageldesiccantandoxygenabsorbercanisters.

Packsizes:1,4,7,10,14,15,20,28,30film-coatedtablets

Thedessicantandoxygenabsorbercanistersshouldbekeptinthebottleduringuse.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/93/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27August2010

10DATEOFREVISIONOFTHETEXT

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