ATORVASTATIN BIOKANOL 80 MG FILM-COATED TABLETS

Main information

  • Trade name:
  • ATORVASTATIN BIOKANOL 80 MG FILM-COATED TABLETS
  • Dosage:
  • 80 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATORVASTATIN BIOKANOL 80 MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1304/004/004
  • Authorization date:
  • 20-05-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AtorvastatinBiokanol80mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains80mgatorvastatin(equivalentto82,90mgatorvastatincalcium).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Atorvastatin80mgfilm-coatedtabletsarewhitetooff-white,elliptic,biconvex,scoredononesideandembossedwith

“80”ontheotherside.Thetabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolaemia

Atorvastatinisindicatedasanadjuncttodietforreductionofelevatedtotalcholesterol(total-C),LDL-cholesterol

(LDL-C),apolipoproteinB,andtriglyceridesininadults,adolescentsandchildrenaged10yearsorolderwithprimary

hypercholesterolaemiaincludingfamilialhypercholesterolaemia(heterozygousvariant)orcombined(mixed)

hyperlipidaemia(CorrespondingtoTypesIIaandIIboftheFredricksonclassification)whenresponsetodietandother

nonpharmacologicalmeasuresisinadequate.

Atorvastatinisalsoindicatedtoreducetotal-CandLDL-Cinadultswithhomozygousfamilialhypercholesterolaemia

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

Preventionofcardiovasculardisease

Preventionofcardiovasculareventsinpatientsestimatedtohaveahighriskforafirstcardiovascularevent(seesection

5.1),asanadjuncttocorrectionofotherriskfactors.

4.2Posologyandmethodofadministration

Posology

Thepatientshouldbeplacedonastandardcholesterol-loweringdietbeforereceivingatorvastatinandshouldcontinue

onthisdietduringtreatmentwithatorvastatin.

ThedoseshouldbeindividualisedaccordingtobaselineLDL-Clevels,thegoaloftherapy,andpatientresponse.

Theusualstartingdoseis10mgonceaday.Adjustmentofdoseshouldbemadeatintervalsof4weeksormore.The

maximumdoseis80mgonceaday.

Primaryhypercholesterolaemiaandcombined(mixed)hyperlipidaemia

Themajorityofpatientsarecontrolledwithatorvastatin10mgonceaday.Atherapeuticresponseisevidentwithin2

weeks,andthemaximumtherapeuticresponseisusuallyachievedwithin4weeks.Theresponseismaintainedduring

chronictherapy.

Heterozygousfamilialhypercholesterolaemia

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40mgdaily.Thereafter,eitherthedosemaybeincreasedtoamaximumof80mgdailyorabileacidsequestrantmay

becombinedwith40mgatorvastatinoncedaily.

Homozygousfamilialhypercholesterolaemia

Onlylimiteddataareavailable(seesection5.1).

Thedoseofatorvastatininpatientswithhomozygousfamilialhypercholesterolemiais10to80mgdaily(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

Efficacyandsafetyinpatientsolderthan70usingrecommendeddosesaresimilartothoseseeninthegeneral

population.

Paediatricuse

Hypercholesterolaemia

Paediatricuseshouldonlybecarriedoutbyphysiciansexperiencedinthetreatmentofpaediatrichyperlipidaemiaand

patientsshouldbere-evaluatedonaregularbasistoassessprogress.

Forpatientsaged10yearsandabove,therecommendedstartingdoseofatorvastatinis10mgperdaywithtitrationup

to20mgperday.Titrationshouldbeconductedaccordingtotheindividualresponseandtolerabilityinpaediatric

patients.Safetyinformationforpaediatricpatientstreatedwithdosesabove20mg,correspondingtoabout0.5mg/kg,

islimited.

Thereislimitedexperienceinchildrenbetween6-10yearsofage(seesection5.1).Atorvastatinisnotindicatedinthe

treatmentofpatientsbelowtheageof10years.

Otherpharmaceuticalforms/strengthsmaybemoreappropriateforthispopulation.

Methodofadministration

Atorvastatinisfororaladministration.Eachdailydoseofatorvastatinisgivenallatonceandmaybegivenatanytime

ofdaywithorwithoutfood.

4.3Contraindications

Atorvastatiniscontraindicatedinpatients:

-withhypersensitivitytotheactivesubstanceortoanyoftheexcipientsofthismedicinalproduct.

-withactiveliverdiseaseorunexplainedpersistentelevationsofserumtransaminasesexceeding3timestheupperlimit

ofnormal.

-duringpregnancy,whilebreast-feedingandinwomenofchild-bearingpotentialnotusingappropriatecontraceptive

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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

transientischemicattack(TIA)therewasahigherincidenceofhemorrhagicstrokeinpatientsinitiatedonatorvastatin

80mgcomparedtoplacebo.Theincreasedriskwasparticularlynotedinpatientswithpriorhemorrhagicstrokeor

lacunarinfarctatstudyentry.Forpatientswithpriorhemorrhagicstrokeorlacunarinfarct,thebalanceofrisksand

benefitsofatorvastatin80mgisuncertain,andthepotentialriskofhemorrhagicstrokeshouldbecarefullyconsidered

beforeinitiatingtreatment(seesection5.1).

Skeletalmuscleeffects

Atorvastatin,likeotherHMG-CoAreductaseinhibitors,mayinrareoccasionsaffecttheskeletalmuscleandcause

myalgia,myositis,andmyopathythatmayprogresstorhabdomyolysis,apotentiallylife-threateningcondition

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

whichmayleadtorenalfailure.

Beforethetreatment

Atorvastatinshouldbeprescribedwithcautioninpatientswithpre-disposingfactorsforrhabdomyolysis.ACKlevel

shouldbemeasuredbeforestartingstatintreatmentinthefollowingsituations:

Renalimpairment

Hypothyroidism

Personalorfamilialhistoryofhereditarymusculardisorders

Previoushistoryofmusculartoxicitywithastatinorfibrate

Previoushistoryofliverdiseaseand/orwheresubstantialquantitiesofalcoholareconsumed

Inelderly(age>70years),thenecessityofsuchmeasurementshouldbeconsidered,accordingtothepresenceof

otherpredisposingfactorsforrhabdomyolysis

Situationswhereanincreaseinplasmalevelsmayoccur,suchasinteractions(seesection4.5)andspecial

populationsincludinggeneticsubpopulations(seesection5.2)

Insuchsituations,theriskoftreatmentshouldbeconsideredinrelationtopossiblebenefit,andclinicalmonitoringis

recommended.

IfCKlevelsaresignificantlyelevated(>5timesULN)atbaseline,treatmentshouldnotbestarted.

Creatinekinasemeasurement

Creatinekinase(CK)shouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofanyplausible

alternativecauseofCKincreaseasthismakesvalueinterpretationdifficult.IfCKlevelsaresignificantlyelevatedat

baseline(>5timesULN),levelsshouldberemeasuredwithin5to7dayslatertoconfirmtheresults.

Whilstontreatment

Patientsmustbeaskedtopromptlyreportmusclepain,cramps,orweaknessespeciallyifaccompaniedbymalaise

orfever.

Ifsuchsymptomsoccurwhilstapatientisreceivingtreatmentwithatorvastatin,theirCKlevelsshouldbe

measured.Iftheselevelsarefoundtobesignificantlyelevated(>5timesULN),treatmentshouldbestopped.

Ifmuscularsymptomsaresevereandcausedailydiscomfort,eveniftheCKlevelsareelevatedtod5xULN,

treatmentdiscontinuationshouldbeconsidered.

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alternativestatinmaybeconsideredatthelowestdoseandwithclosemonitoring.

AtorvastatinmustbediscontinuedifclinicallysignificantelevationofCKlevels(>10xULN)occur,orif

rhabdomyolysisisdiagnosedorsuspected.

Concomitanttreatmentwithothermedicinalproducts

Riskofrhabdomyolysisisincreasedwhenatorvastatinisadministeredconcomitantlywithcertainmedicinalproducts

thatmayincreasetheplasmaconcentrationofatorvastatinsuchaspotentinhibitorsofCYP3A4ortransportproteins

(e.g.ciclosporine,telithromycin,clarithromycin,delavirdine,stiripentol,ketoconazole,voriconazole,itraconazole,

posaconazoleandHIVproteaseinhibitorsincludingritonavir,lopinavir,atazanavir,indinavir,darunavir,etc).Therisk

ofmyopathymayalsobeincreasedwiththeconcomitantuseofgemfibrozilandotherfibricacidderivates,

erythromycin,niacinandezetimibe.Ifpossible,alternative(non-interacting)therapiesshouldbeconsideredinsteadof

thesemedicinalproducts.

Incaseswhereco-administrationofthesemedicinalproductswithatorvastatinisnecessary,thebenefitandtheriskof

concurrenttreatmentshouldbecarefullyconsidered.Whenpatientsarereceivingmedicinalproductsthatincreasethe

plasmaconcentrationofatorvastatin,alowermaximumdoseofatorvastatinisrecommended.Inaddition,inthecaseof

potentCYP3A4inhibitors,alowerstartingdoseofatorvastatinshouldbeconsideredandappropriateclinical

monitoringofthesepatientsisrecommended(seesection4.5).

Theconcurrentuseofatorvastatinandfusidicacidisnotrecommended,therefore,temporarysuspensionofatorvastatin

maybeconsideredduringfusidicacidtherapy(seesection4.5).

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

Paediatricuse

Developmentalsafetyinthepaediatricpopulationhasnotbeenestablished(seesection4.8).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Effectofco-administeredmedicinalproductsonatorvastatin

AtorvastatinismetabolizedbycytochromeP4503A4(CYP3A4)andisasubstratetotransportproteinse.g.thehepatic

uptaketransporterOATP1B1.ConcomitantadministrationofmedicinalproductsthatareinhibitorsofCYP3A4or

transportproteinsmayleadtoincreasedplasmaconcentrationsofatorvastatinandanincreasedriskofmyopathy.The

riskmightalsobeincreasedatconcomitantadministrationofatorvastatinwithothermedicinalproductsthathavea

potentialtoinducemyopathy,suchasfibricacidderivatesandezetimibe(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-administrationofthesemedicinalproductswithatorvastatincannotbeavoidedlowerstartingandmaximum

dosesofatorvastatinshouldbeconsideredandappropriateclinicalmonitoringofthepatientisrecommended(see

Table1).

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

concentrationsofatorvastatin(seeTable1).Anincreasedriskofmyopathyhasbeenobservedwiththeuseof

erythromycinincombinationwithstatins.Interactionstudiesevaluatingtheeffectsofamiodaroneorverapamilon

atorvastatinhavenotbeenconducted.BothamiodaroneandverapamilareknowntoinhibitCYP3A4activityandco-

administrationwithatorvastatinmayresultinincreasedexposuretoatorvastatin.Therefore,alowermaximumdoseof

atorvastatinshouldbeconsideredandappropriateclinicalmonitoringofthepatientisrecommendedwhen

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orfollowingdoseadjustmentsoftheinhibitor.

CYP3A4inducers

ConcomitantadministrationofatorvastatinwithinducersofcytochromeP4503A(e.g.efavirenz,rifampin,St.John’s

Wort)canleadtovariablereductionsinplasmaconcentrationsofatorvastatin.Duetothedualinteractionmechanism

ofrifampin,(cytochromeP4503AinductionandinhibitionofhepatocyteuptaketransporterOATP1B1),simultaneous

co-administrationofatorvastatinwithrifampinisrecommended,asdelayedadministrationofatorvastatinafter

administrationofrifampinhasbeenassociatedwithasignificantreductioninatorvastatinplasmaconcentrations.The

effectofrifampinonatorvastatinconcentrationsinhepatocytesis,however,unknownandifconcomitant

administrationcannotbeavoided,patientsshouldbecarefullymonitoredforefficacy.

Transportproteininhibitors

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

effectofinhibitionofhepaticuptaketransportersonatorvastatinconcentrationsinhepatocytesisunknown.If

concomitantadministrationcannotbeavoided,adosereductionandclinicalmonitoringforefficacyisrecommended

(seeTable1).

Gemfibrozil/fibricacidderivatives

Theuseoffibratesaloneisoccasionallyassociatedwithmusclerelatedevents,includingrhabdomyolysis.Theriskof

theseeventsmaybeincreasedwiththeconcomitantuseoffibricacidderivativesandatorvastatin.Ifconcomitant

administrationcannotbeavoided,thelowestdoseofatorvastatintoachievethetherapeuticobjectiveshouldbeused

andthepatientsshouldbeappropriatelymonitored(seesection4.4).

Ezetimibe

Theuseofezetimibealoneisassociatedwithmusclerelatedevents,includingrhabdomyolysis.Theriskoftheseevents

maythereforebeincreasedwithconcomitantuseofezetimibeandatorvastatin.Appropriateclinicalmonitoringof

thesepatientsisrecommended.

Colestipol

Plasmaconcentrationsofatorvastatinanditsactivemetaboliteswerelower(byapprox.25%)whencolestipolwasco-

administeredwithatorvastatin.However,lipideffectsweregreaterwhenatorvastatinandcolestipolwereco-

administeredthanwheneithermedicinalproductwasgivenalone.

Fusidicacid

Interactionstudieswithatorvastatinandfusidicacidhavenotbeenconducted.Aswithotherstatins,musclerelated

events,includingrhabdomyolysis,havebeenreportedinpost-marketingexperiencewithatorvastatinandfusidicacid

givenconcurrently.Themechanismofthisinteractionisnotknown.Patientsshouldbecloselymonitoredand

temporarysuspensionofatorvastatintreatmentmaybeappropriate.

Effectofatorvastatinonco-administeredmedicinalproducts

Digoxin

Whenmultipledosesofdigoxinand10mgatorvastatinwereco-administered,steady-statedigoxinconcentrations

increasedslightly.Patientstakingdigoxinshouldbemonitoredappropriately.

Oralcontraceptives

Co-administrationofatorvastatinwithanoralcontraceptiveproducedincreasesinplasmaconcentrationsof

norethindroneandethinyloestradiol.

Warfarin

Inaclinicalstudyinpatientsreceivingchronicwarfarintherapy,coadministrationofatorvastatin80mgdailywith

warfarincausedasmalldecreaseofabout1.7secondsinprothrombintimeduringthefirst4daysofdosingwhich

returnedtonormalwithin15daysofatorvastatintreatment.Althoughonlyveryrarecasesofclinicallysignificant

anticoagulantinteractionshavebeenreported,prothrombintimeshouldbedeterminedbeforestartingatorvastatinin

patientstakingcoumarinanticoagulantsandfrequentlyenoughduringearlytherapytoensurethatnosignificant

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monitoredattheintervalsusuallyrecommendedforpatientsoncoumarinanticoagulants.Ifthedoseofatorvastatinis

changedordiscontinued,thesameprocedureshouldberepeated.Atorvastatintherapyhasnotbeenassociatedwith

bleedingorwithchangesinprothrombintimeinpatientsnottakinganticoagulants.

Table1:Effectofco-administeredmedicinalproductsonthepharmacokineticsofatorvastatin

Co-administeredmedicinal

product

anddosingregimen Atorvastatin

Dose(mg) Changein

& ClinicalRecommendation #

Tipranavir500mgBID/

Ritonavir200mgBID,8

days

(days14to21) 40mgonday1,

10mgonday20 9.4fold Incaseswherecoadministration

withatorvastatinisnecessary,do

notexceed10mgatorvastatin

daily.Clinicalmonitoringof

thesepatientsisrecommended Ciclosporin5.2mg/kg/day,

stabledose 10mgODfor28

days 8.7fold

Lopinavir400mgBID/

Ritonavir100mgBID,14

days 20mgODfor4

days 5.9fold Incaseswhereco-administration

withatorvastatinisnecessary,

lowermaintenancedosesof

atorvastatinarerecommended.At

atorvastatindosesexceeding

20mg,clinicalmonitoringof

thesepatientsisrecommended. Clarithromycin500mgBID,

days 80mgODfor8

days 4.4fold

Saquinavir400mgBID/

Ritonavir(300mgBIDfrom

days5-7,increasedto400

mgBIDonday8),days5-

18,30minafteratorvastatin

dosing 40mgODfor4

days 3.9fold Incaseswhereco-administration

withatorvastatinisnecessary,

lowermaintenancedosesof

atorvastatinarerecommended.At

atorvastatindosesexceeding

40mg,clinicalmonitoringof

thesepatientsisrecommended. Darunavir300mgBID/

Ritonavir100mgBID,9

days 10mgODfor4

days 3.3fold

Itraconazole200mgOD,4

days 40mgSD 3.3fold

Fosamprenavir700mgBID/

Ritonavir100mgBID,14

days 10mgODfor4

days 2.5fold

Fosamprenavir1400mg

BID,

14days 10mgODfor4

days 2.3fold

Nelfinavir1250mgBID,14

days 10mgODfor28

days 1.7

fold^ Nospecificrecommendation

GrapefruitJuice,240mLOD

40mg,SD 37% Concomitantintakeoflarge

quantitiesofgrapefruitjuiceand

atorvastatinisnotrecommended.

Diltiazem240mgOD,28

days 40mg,SD 51% Afterinitiationorfollowingdose

adjustmentsofdiltiazem,

appropriateclinicalmonitoringof

thesepatientsisrecommended.

Erythromycin500mgQID,7

days 10mg,SD 33%^ Lowermaximumdoseand

clinicalmonitoringofthese

patientsisrecommended.

Amlodipine10mg,single

dose 80mg,SD 18% Nospecificrecommendation.

Cimetidine300mgQID,2

weeks 10mgODfor4

weeks lessthan

Nospecificrecommendation.

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&

Datagivenasx-foldchangerepresentasimpleratiobetweenco-administrationandatorvastatinalone(i.e.,1-fold=

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

Seesections4.4and4.5forclinicalsignificance.

ContainsoneormorecomponentsthatinhibitCYP3A4andcanincreaseplasmaconcentrationsofmedicinal

productsmetabolizedbyCYP3A4.Intakeofone240mlglassofgrapefruitjuicealsoresultedinadecreasedAUC

of20.4%fortheactiveorthohydroxymetabolite.Largequantitiesofgrapefruitjuice(over1.2ldailyfor5days)

increasedAUCofatorvastatin2.5foldandAUCofactive(atorvastatinandmetabolites).

Totalatorvastatinequivalentactivity

Increaseisindicatedas“”,decreaseas“”

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

Table2:Effectofatorvastatinonthepharmacokineticsofco-administeredmedicinalproducts

&

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

Co-administrationofmultipledosesofatorvastatinandphenazoneshowedlittleornodetectableeffectinthe

clearanceofphenazone.

Increaseisindicatedas“”,decreaseas“”

OD=oncedaily;SD=singledose

Paediatricpopulation

Drug-druginteractionstudieshaveonlybeenperformedinadults.Theextentofinteractionsinthepaediatric

populationisnotknown.Theabovementionedinteractionsforadultsandthewarningsinsection4.4shouldbetaken

magnesiumandaluminium

hydroxides,30mLQID,2

weeks weeks

Efavirenz600mgOD,14

days 10mgfor3days 41% Nospecificrecommendation.

Rifampin600mgOD,7

days

(co-administered) 40mgSD 30% Ifco-administrationcannotbe

avoided,simultaneousco-

administrationofatorvastatin

withrifampinisrecommended,

withclinicalmonitoring. Rifampin600mgOD,5

days

(dosesseparated) 40mgSD 80%

Gemfibrozil600mgBID,7

days 40mgSD 35% Lowerstartingdoseandclinical

monitoringofthesepatientsis

recommended.

Fenofibrate160mgOD,7

days 40mgSD 3% Lowerstartingdoseandclinical

monitoringofthesepatientsis

recommended.

Atorvastatinand

dosingregimen Co-administeredmedicinalproduct

Medicinalproduct/Dose(mg) Changein

& ClinicalRecommendation

80mgODfor

10days Digoxin0.25mgOD,20days 15% Patientstakingdigoxinshouldbe

monitoredappropriately.

40mgODfor

22days OralcontraceptiveOD,2

months

-norethindrone1mg

-ethinylestradiol35µg 28%

Nospecificrecommendation.

80mgODfor

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4.6Fertility,pregnancyandlactation

Womenofchildbearingpotential

Womenofchild-bearingpotentialshoulduseappropriatecontraceptivemeasuresduringtreatment(seesection4.3).

Pregnancy

Atorvastatiniscontraindicatedduringpregnancy(seesection4.3).Safetyinpregnantwomenhasnotbeenestablished.

Nocontrolledclinicaltrialswithatorvastatinhavebeenconductedinpregnantwomen.Rarereportsofcongenital

anomaliesfollowingintrauterineexposuretoHMG-CoAreductaseinhibitorshavebeenreceived.Animalstudieshave

showntoxicitytoreproduction(seesection5.3).

Maternaltreatmentwithatorvastatinmayreducethefetallevelsofmevalonatewhichisaprecursorofcholesterol

biosynthesis.Atherosclerosisisachronicprocess,andordinarilydiscontinuationoflipid-loweringmedicinalproducts

duringpregnancyshouldhavelittleimpactonthelong-termriskassociatedwithprimaryhypercholesterolaemia.

Forthesereasons,atorvastatinshouldnotbeusedinwomenwhoarepregnant,tryingtobecomepregnantorsuspect

theyarepregnant.Treatmentwithatorvastatinshouldbesuspendedforthedurationofpregnancyoruntilithasbeen

determinedthatthewomanisnotpregnant(seesection4.3.).

Breastfeeding

Itisnotknownwhetheratorvastatinoritsmetabolitesareexcretedinhumanmilk.Inrats,plasmaconcentrationsof

atorvastatinanditsactivemetabolitesaresimilartothoseinmilk(seesection5.3).Becauseofthepotentialforserious

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

contraindicatedduringbreastfeeding(seesection4.3).

Fertility

Inanimalstudiesatorvastatinhadnoeffectonmaleorfemalefertility(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

Atorvastatinhasnegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Intheatorvastatinplacebo-controlledclinicaltrialdatabaseof16,066(8755Biokanolvs.7311placebo)patientstreated

forameanperiodof53weeks,5.2%ofpatientsonatorvastatindiscontinuedduetoadversereactionscomparedto

4.0%ofthepatientsonplacebo.

Basedondatafromclinicalstudiesandextensivepost-marketingexperience,thefollowingtablepresentstheadverse

reactionprofileforatorvastatin.

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

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

Infectionsandinfestations

Common:nasopharyngitis.

Bloodandlymphaticsystemdisorders

Rare:thrombocytopenia.

Immunesystemdisorders

Common:allergicreactions.

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Metabolismandnutritiondisorders

Common:hyperglycaemia.

Uncommon:hypoglycaemia,weightgain,anorexia.

Psychiatricdisorders

Uncommon:nightmare,insomnia.

Nervoussystemdisorders

Common:headache.

Uncommon:dizziness,paraesthesia,hypoesthesia,dysgeusia,amnesia.

Rare: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-Johnsonsyndromeandtoxic

epidermalnecrolysis.

Musculoskeletalandconnectivetissuedisorders

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

Uncommon:neckpain,musclefatigue.

Rare:myopathy,myositis,rhabdomyolysis,tendonopathy,sometimescomplicatedbyrupture.

Reproductivesystemandbreastdisorders

Veryrare:gynecomastia.

Generaldisordersandadministrationsiteconditions

Uncommon:malaise,asthenia,chestpain,peripheraloedema,fatigue,pyrexia.

Investigations

Common:liverfunctiontestabnormal,bloodcreatinekinaseincreased.

Uncommon:whitebloodcellsurinepositive.

AswithotherHMG-CoAreductaseinhibitorselevatedserumtransaminaseshavebeenreportedinpatientsreceiving

atorvastatin.Thesechangeswereusuallymild,transient,anddidnotrequireinterruptionoftreatment.Clinically

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

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Elevatedserumcreatinekinase(CK)levelsgreaterthan3timesupperlimitofnormaloccurredin2.5%ofpatientson

atorvastatin,similartootherHMG-CoAreductaseinhibitorsinclinicaltrials.

Levelsabove10timesthenormalupperrangeoccurredin0.4%atorvastatin-treatedpatients

(seesection4.4).

Thefollowingadverseeventshavebeenreportedwithsomestatins:

Sexualdysfunction.

Depression.

Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(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

CKlevelsshouldbemonitored.Duetoextensiveatorvastatinbindingtoplasmaproteins,haemodialysisisnotexpected

tosignificantlyenhanceatorvastatinclearance.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Lipidmodifyingagents,HMG-CoA-reductaseinhibitors,

ATCcode:C10AA05

Atorvastatinisaselective,competitiveinhibitorofHMG-CoAreductase,therate-limitingenzymeresponsibleforthe

conversionof3-hydroxy-3-methyl-glutaryl-coenzymeAtomevalonate,aprecursorofsterols,includingcholesterol.

Triglyceridesandcholesterolintheliverareincorporatedintoverylow-densitylipoproteins(VLDL)andreleasedinto

theplasmafordeliverytoperipheraltissues.Low-densitylipoprotein(LDL)isformedfromVLDLandiscatabolized

primarilythroughthereceptorwithhighaffinitytoLDL(LDLreceptor).

AtorvastatinlowersplasmacholesterolandlipoproteinserumconcentrationsbyinhibitingHMG-CoAreductaseand

subsequentlycholesterolbiosynthesisintheliverandincreasesthenumberofhepaticLDLreceptorsonthecellsurface

forenhanceduptakeandcatabolismofLDL.

AtorvastatinreducesLDLproductionandthenumberofLDLparticles.Atorvastatinproducesaprofoundandsustained

increaseinLDLreceptoractivitycoupledwithabeneficialchangeinthequalityofcirculatingLDLparticles.

AtorvastatiniseffectiveinreducingLDL-Cinpatientswithhomozygousfamilialhypercholesterolaemia,apopulation

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

(34%-50%),andtriglycerides(14%-33%)whileproducingvariableincreasesinHDL-CandapolipoproteinA1ina

doseresponsestudy.Theseresultsareconsistentinpatientswithheterozygousfamilialhypercholesterolaemia,

nonfamilialformsofhypercholesterolaemia,andmixedhyperlipidaemia,includingpatientswithnoninsulin-dependent

diabetesmellitus.

Reductionsintotal-C,LDL-C,andapolipoproteinBhavebeenproventoreduceriskforcardiovasculareventsand

cardiovascularmortality.

Homozygousfamilialhypercholesterolaemia

Inamulticenter8weekopen-labelcompassionate-usestudywithanoptionalextensionphaseofvariablelength,335

patientswereenrolled,89ofwhichwereidentifiedashomozygousfamilialhypercholesterolaemiapatients.Fromthese

89patients,themeanpercentreductioninLDL-Cwasapproximately20%.Atorvastatinwasadministeredatdosesup

to80mg/day.

Atherosclerosis

IntheReversingAtherosclerosiswithAggressiveLipid-LoweringStudy(REVERSAL),theeffectofintensivelipid

loweringwithatorvastatin80mgandstandarddegreeoflipidloweringwithpravastatin40mgoncoronary

atherosclerosiswasassessedbyintravascularultrasound(IVUS),duringangiography,inpatientswithcoronaryheart

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

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

Themedianpercentchange,frombaseline,intotalatheromavolume(theprimarystudycriteria)was-0.4%(p=0.98)in

theatorvastatingroupand+2.7%(p=0.001)inthepravastatingroup(n=249).Whencomparedtopravastatintheeffects

ofatorvastatinwerestatisticallysignificant(p=0.02).Theeffectofintensivelipidloweringoncardiovascularendpoints

(e.g.needforrevascularisation,nonfatalmyocardialinfarction,coronarydeath)wasnotinvestigatedinthisstudy.

Intheatorvastatingroup,LDL-Cwasreducedtoameanof2.04mmol/L±0.8(78.9mg/dl±30)frombaseline3.89

mmol/l±0.7(150mg/dl±28)andinthepravastatingroup,LDL-Cwasreducedtoameanof2.85mmol/l±0.7(110

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

meanTCby34.1%(pravastatin:-18.4%,p<0.0001),meanTGlevelsby20%(pravastatin:-6.8%,p<0.0009),andmean

apolipoproteinBby39.1%(pravastatin:-22.0%,p<0.0001).AtorvastatinincreasedmeanHDL-Cby2.9%(pravastatin:

+5.6%,p=NS).Therewasa36.4%meanreductioninCRPintheatorvastatingroupcomparedtoa5.2%reductionin

thepravastatingroup(p<0.0001).

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,nonfatalMI,resuscitatedcardiac

arrest,oranginapectoriswithevidenceofmyocardialischaemiarequiringhospitalization,indicatingariskreduction

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

myocardialischaemia(p=0.018).Theothersecondaryendpointsdidnotreachstatisticalsignificanceontheirown

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

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Preventionofcardiovasculardisease

Theeffectofatorvastatinonfatalandnon-fatalcoronaryheartdiseasewasassessedinarandomized,double-blind,

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

Patientswerehypertensive,40-79yearsofage,withnopreviousmyocardialinfarctionortreatmentforangina,and

withTClevels6.5mmol/l(251mg/dl).Allpatientshadatleast3ofthepre-definedcardiovascularriskfactors:male

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

disease,leftventricularhypertrophy,priorcerebrovascularevent,specificECGabnormality,proteinuria/albuminuria.

Notallincludedpatientswereestimatedtohaveahighriskforafirstcardiovascularevent.

Patientsweretreatedwithanti-hypertensivetherapy(eitheramlodipineoratenolol-basedregimen)andeither

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

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.3years.

CHD=coronaryheartdisease;MI=myocardialinfarction.

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

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

seeninmalesbutcouldnotbeestablishedinfemalespossiblyduetotheloweventrateinthefemalesubgroup.Overall

andcardiovascularmortalitywerenumericallyhigherinthefemalepatients(38vs.30and17vs.12),butthiswasnot

statisticallysignificant.Therewassignificanttreatmentinteractionbyantihypertensivebaselinetherapy.Theprimary

endpoint(fatalCHDplusnon-fatalMI)wassignificantlyreducedbyatorvastatininpatientstreatedwithamlodipine

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

Theeffectofatorvastatinonfatalandnon-fatalcardiovasculardiseasewasalsoassessedinarandomized,double-blind,

multicenter,placebo-controlledtrial,theCollaborativeAtorvastatinDiabetesStudy(CARDS)inpatientswithtype2

diabetes,40-75yearsofage,withoutpriorhistoryofcardiovasculardisease,andwithLDL-C4.14mmol/l(160

mg/dl)andTG6.78mmol/l(600mg/dl).Allpatientshadatleast1ofthefollowingriskfactors:hypertension,current

smoking,retinopathy,microalbuminuriaormacroalbuminuria.

Patientsweretreatedwitheitheratorvastatin10mgdaily(n=1,428)orplacebo(n=1,410)foramedianfollow-upof3.9

years.

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.9years.

Event Relativerisk

reduction(%) No.ofevents

(atorvastatinvs

placebo) Absoluterisk

reduction 1

(%) Pvalue

FatalCHDplusnon-fatalMI 36% 100vs.154 1.1% 0.0005

Totalcardiovasculareventsand

revascularisationprocedures 20% 389vs.483 1.9% 0.0008

Totalcoronaryevents 29% 178vs247 1.4% 0.0006

Event Relativerisk

reduction(%) No.ofevents

(atorvastatin

vsplacebo) Absoluterisk

reduction 1

(%) Pvalue

Majorcardiovascularevents(fataland

-fatalAMI,silentMI,acuteCHD

death,unstableangina,CABG,PTCA,

revascularisation,stroke) 37% 83vs.127 3.2% 0.0010

MI(fatalandnon -fatalAMI,silent

38vs.64 1.9% 0.0070

Strokes(fatalandnon -fatal)

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myocardialinfarction;PTCA=percutaneoustransluminalcoronaryangioplasty.

Therewasnoevidenceofadifferenceinthetreatmenteffectbypatient’sgender,age,orbaselineLDL-Clevel.A

favourabletrendwasobservedregardingthemortalityrate(82deathsintheplacebogroupvs.61deathsinthe

atorvastatingroup,p=0.0592).

Recurrentstroke

IntheStrokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)study,theeffectofatorvastatin80

mgdailyorplaceboonstrokewasevaluatedin4731patientswhohadastrokeortransientischemicattack(TIA)

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

age(averageage63years),andhadanaveragebaselineLDLof133mg/dL(3.4mmol/L).ThemeanLDL-Cwas73

mg/dL(1.9mmol/L)duringtreatmentwith

atorvastatinand129mg/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.All

causemortalitywas9.1%(216/2365)foratorvastatinversus8.9%(211/2366)forplacebo.

Inapost-hocanalysis,atorvastatin80mgreducedtheincidenceofischemicstroke(218/2365,9.2%vs.274/2366,

11.6%,p=0.01)andincreasedtheincidenceofhemorrhagicstroke(55/2365,2.3%vs.33/2366,1.4%,p=0.02)

comparedtoplacebo.

Theriskofhemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorhemorrhagicstroke

(7/45foratorvastatinversus2/48forplacebo;HR4.06;95%CI,0.84-19.57),andtheriskofischemicstrokewas

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

Theriskofhemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorlacunarinfarct

(20/708foratorvastatinversus4/701forplacebo;HR4.99;95%CI,1.71-14.61),buttheriskofischemicstroke

wasalsodecreasedinthesepatients(79/708foratorvastatinversus102/701forplacebo;HR0.76;95%CI,0.57-

1.02).Itispossiblethatthenetriskofstrokeisincreasedinpatientswithpriorlacunarinfarctwhoreceive

atorvastatin80mg/day.

Allcausemortalitywas15.6%(7/45)foratorvastatinversus10.4%(5/48)inthesubgroupofpatientswithprior

hemorrhagicstroke.Allcausemortalitywas10.9%(77/708)foratorvastatinversus9.1%(64/701)forplacebointhe

subgroupofpatientswithpriorlacunarinfarct.

PaediatricPopulation

HeterozygousFamilialHypercholesterolaemiainPaediatricPatientsaged6-17yearsold

An8-week,open-labelstudytoevaluatepharmacokinetics,pharmacodynamics,andsafetyandtolerabilityof

atorvastatinwasconductedinchildrenandadolescentswithgeneticallyconfirmedheterozygousfamilial

hypercholesterolemiaandbaselineLDL-C 4mmol/L.Atotalof39childrenandadolescents,6to17yearsofage,

wereenrolled.CohortAincluded15children,6to12yearsofageandatTannerStage1.CohortBincluded24

children,10to17yearsofageandatTannerStage 2.

Theinitialdoseofatorvastatinwas5mgdailyofachewabletabletinCohortAand10mgdailyofatabletformulation

inCohortB.TheatorvastatindosewaspermittedtobedoubledifasubjecthadnotattainedtargetLDL-Cof<3.35

mmol/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

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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.ThemeanachievedLDLCvaluewas3.38

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

placebogroupduringthe26-weekdouble-blindphase.

Anadditionalpaediatricstudyofatorvastatinversuscolestipolinpatientswithhypercholesterolaemiaaged10-18years

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

colestipol(N=31).

Acompassionateusestudyinpatientswithseverehypercholesterolaemia(includinghomozygous

hypercholesterolaemia)included46paediatricpatientstreatedwithatorvastatintitratedaccordingtoresponse(some

subjectsreceived80mgatorvastatinperday).Thestudylasted3years:LDLcholesterolwasloweredby36%.

Thelong-termefficacyofatorvastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthoodhasnot

beenestablished.

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithatorvastatininchildren

aged0tolessthan6yearsinthetreatmentofheterozygoushypercholesterolaemiaandinchildrenaged0tolessthan

18yearsinthetreatmentofhomozygousfamilialhypercholesterolaemia,combined(mixed)hypercholesterolaemia,

primaryhypercholesterolaemiaandinthepreventionofcardiovascularevents(seesection4.2forinformationon

paediatricuse).

5.2Pharmacokineticproperties

Absorption

Atorvastatinisrapidlyabsorbedafteroraladministration;maximumplasmaconcentrations(C

)occurwithin1to2

hours.Extentofabsorptionincreasesinproportiontoatorvastatindose.Afteroraladministration,atorvastatinfilm-

coatedtabletsare95%to99%bioavailablecomparedtotheoralsolution.Theabsolutebioavailabilityofatorvastatinis

approximately12%andthesystemicavailabilityofHMG-CoAreductaseinhibitoryactivityisapproximately30%.

Thelowsystemicavailabilityisattributedtopresystemicclearanceingastrointestinalmucosaand/orhepaticfirst-pass

metabolism.

Distribution

Meanvolumeofdistributionofatorvastatinisapproximately381l.Atorvastatinis 98%boundtoplasmaproteins.

Biotransformation

AtorvastatinismetabolizedbycytochromeP4503A4toortho-andparahydroxylatedderivativesandvariousbeta-

oxidationproducts.Apartfromotherpathwaystheseproductsarefurthermetabolizedviaglucuronidation.Invitro,

inhibitionofHMG-CoAreductasebyortho-andparahydroxylatedmetabolitesisequivalenttothatofatorvastatin.

Approximately70%ofcirculatinginhibitoryactivityforHMG-CoAreductaseisattributedtoactivemetabolites.

Excretion

Atorvastatiniseliminatedprimarilyinbilefollowinghepaticand/orextrahepaticmetabolism.However,atorvastatin

doesnotappeartoundergosignificantenterohepaticrecirculation.Meanplasmaeliminationhalf-lifeofatorvastatinin

humansisapproximately14hours.Thehalf-lifeofinhibitoryactivityforHMG-CoAreductaseisapproximately20to

30hoursduetothecontributionofactivemetabolites.

Specialpopulations

Elderly:Plasmaconcentrationsofatorvastatinanditsactivemetabolitesarehigherinhealthyelderlysubjectsthanin

youngadultswhilethelipideffectswerecomparabletothoseseeninyoungerpatientpopulations.

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(ages6-17years)withheterozygousfamilialhypercholesterolemiaandbaselineLDL-C 4mmol/Lweretreatedwith

5or10mgofchewableor10or20mgoffilm-coatedatorvastatintabletsoncedaily,respectively.Bodyweightwas

theonlysignificantcovariateinatorvastatinpopulationPKmodel.Apparentoralclearanceofatorvastatininpaediatric

subjectsappearedsimilartoadultswhenscaledallometricallybybodyweight.ConsistentdecreasesinLDL-CandTC

wereobservedovertherangeofatorvastatinando-hydroxyatorvastatinexposures.

Gender:Concentrationsofatorvastatinanditsactivemetabolitesinwomendifferfromthoseinmen(Women:approx.

20%higherforC

andapprox.10%lowerforAUC).Thesedifferenceswereofnoclinicalsignificance,resultingin

noclinicallysignificantdifferencesinlipideffectsamongmenandwomen.

Renalinsufficiency:Renaldiseasehasnoinfluenceontheplasmaconcentrationsorlipideffectsofatorvastatinandits

activemetabolites.

Hepaticinsufficiency:Plasmaconcentrationsofatorvastatinanditsactivemetabolitesaremarkedlyincreased(approx.

16-foldinC

andapprox.11-foldinAUC)inpatientswithchronicalcoholicliverdisease(Child-PughB).

SLOC1B1polymorphism:HepaticuptakeofallHMG-CoAreductaseinhibitorsincludingatorvastatin,involvesthe

OATP1B1transporter.InpatientswithSLCO1B1polymorphismthereisariskofincreasedexposureofatorvastatin,

whichmayleadtoanincreasedriskofrhabdomyolysis(seesection4.4).Polymorphisminthegeneencoding

OATP1B1(SLCO1B1c.521CC)isassociatedwitha2.4-foldhigheratorvastatinexposure(AUC)thaninindividuals

withoutthisgenotypevariant(c.521TT).Ageneticallyimpairedhepaticuptakeofatorvastatinisalsopossibleinthese

patients.Possibleconsequencesfortheefficacyareunknown.

5.3Preclinicalsafetydata

Atorvastatinwasnegativeformutagenicandclastogenicpotentialinabatteryof4invitrotestsand1invivoassay.

Atorvastatinwasnotfoundtobecarcinogenicinrats,buthighdosesinmice(resultingin6-11foldtheAUC0-24h

reachedinhumansatthehighestrecommendeddose)showedhepatocellularadenomasinmalesandhepatocellular

carcinomasinfemales.

ThereisevidencefromanimalexperimentalstudiesthatHMG-CoAreductaseinhibitorsmayaffectthedevelopmentof

embryosorfetuses.Inrats,rabbitsanddogsatorvastatinhadnoeffectonfertilityandwasnotteratogenic,however,at

maternallytoxicdosesfetaltoxicitywasobservedinratsandrabbits.Thedevelopmentoftheratoffspringwasdelayed

andpost-natalsurvivalreducedduringexposureofthedamstohighdosesofatorvastatin.Inrats,thereisevidenceof

placentaltransfer.Inrats,plasmaconcentrationsofatorvastatinaresimilartothoseinmilk.Itisnotknownwhether

atorvastatinoritsmetabolitesareexcretedinhumanmilk.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Microcrystallinecellulose

Sodiumcarbonateanhydrous

Maltose

Croscarmellosesodium

Magnesiumstearate

Film-coating

Hypromellose(E464)

Hydroxypropylcellulose

Triethylcitrate(E1505)

Polysorbate80

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6.2Incompatibilities

Notapplicable

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PA/Al/PVC-Alblisters.

AtorvastatinBiokanolisavailableinpacksizesof14,20,28,30,50,56,60,84,90,100,112tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

BiokanolPharmaGmbH

KehlerStr.7

76437Rastatt

Germany

8MARKETINGAUTHORISATIONNUMBER

PA1304/4/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20thMay2011

10DATEOFREVISIONOFTHETEXT

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