ATORVASTATIN ACTAVIS

Main information

  • Trade name:
  • ATORVASTATIN ACTAVIS
  • Dosage:
  • 40 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATORVASTATIN ACTAVIS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/023/003
  • Authorization date:
  • 11-09-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AtorvastatinActavis40mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains:40mgofatorvastatinasatorvastatinmagnesiumtrihydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,oval,biconvexfilm-coatedtabletsmarkedwith“40”ononesideand“A”ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolaemia

AtorvastatinActavisisusedasasupplementtoachangeindietforreductionofelevatedtotalcholesterol,

LDL-cholesterol,apolipoproteinB,ortriglyceridesinpatientswithprimaryhypercholesterolaemiaincluding

heterozygousfamilialhypercholesterolaemiaorcombined(mixed)hyperlipidaemia(suchasFrederickson'stypesIIa

andIIb),whensatisfactoryresultshavenotbeenobtainedbyaspecialdietormeasuresotherthanmedicaltreatment.

AtorvastatinActavisisalsoindicatedtoreducetotal-cholesterolandLDL-cholesterolinpatientswithhomozygous

familialhypercholesterolaemiaasanadjuncttootherlipid-loweringtreatments(e.g.LDLapheresis)orifsuch

treatmentsareunavailable.

Preventionofcardiovasculardisease

Preventionofcardiovasculareventsinpatientsestimatedtohaveahighriskforafirstcardiovascularevent(seesection

5.1),asanadjuncttocorrectionofotherriskfactors.

4.2Posologyandmethodofadministration

Fororaladministration.

Thepatientshouldbeplacedonastandardcholesterol-loweringdietbeforereceivingAtorvastatinActavisandshould

continueonthisdietduringtreatmentwithAtorvastatinActavis.Dosesshouldbedeterminedindividuallyaccordingto

thebaselineLDL-cholesterolvalue,treatmentobjectiveandpatientresponse.

Theusualstartingdoseis10mgonceaday.Adjustmentofdosesshouldbemadeatintervalsof4weeksormore.The

maximumdoseis80mgonceaday.Dosesabove20mg/dayhavenotbeeninvestigatedinpatientsaged<18years.

Thedailydoseshouldbeadministeredallatonceandcanbetakenatanytimeoftheday,withorwithoutfood.

Currentconsensusguidelinesshouldbeconsultedtoestablishtreatmentgoalsforindividualpatients.

Primaryhypercholesterolaemiaandcombined(mixed)hyperlipidaemia

Anappropriatedoseformostpatientsis10mgAtorvastatinActavisaday.Aresponseisevidentwithin2weeksand

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Heterozygousfamilialhypercholesterolaemia

Initialdoseis10mgAtorvastatinActavisaday.Dosesshouldbedeterminedforeachpatientandadjustedat4week

intervalsupto40mgaday.Thenthedosecanbeincreasedtoeitheramaximumof80mgadayoradminister40mg

ofatorvastatinonceadayincombinationwithabileacidsequestrant.

Homozygousfamilialhypercholesterolaemia

Inacompassionate-usestudyof64patientstherewere46patientsforwhomconfirmedLDLreceptorinformationwas

available.Fromthese46patients,themeanpercentreductioninLDL-Cwasapproximately21%.Atorvastatinwas

administeredatdosesupto80mg/day.

Thedoseforpatientswithhomozygousfamilialhypercholesterolaemiais10-80mgdaily,inadditiontootherlipid

lowering-treatment(e.g.LDLapheresis)orifsuchtreatmentsareunavailable.

Preventionofcardiovasculardisease

Intheprimarypreventiontrialsthedosewas10mg/day.Higherdosesmaybenecessaryinordertoattain

LDL-cholesterollevelsaccordingtocurrentguidelines.

Patientswithimpairedrenalfunction

Renaldiseasesneitheraffectplasmaconcentrationnortheeffectsofatorvastatinonbloodlipidsandthereforenodose

adjustmentisrequired.

Patientswithimpairedhepaticfunction

AtorvastatinActavisshouldbeusedwithcautioninpatientswithhepaticimpairment(seesections4.4and5.2).

AtorvastatinActavisiscontraindicatedinpatientswithactiveliverdisease(seesection4.3).

Elderly

Efficacyandsafetyoftheuseofrecommendeddosesforpatientsover70yearsoldaresimilarasforotheradults.

Childrenandadolescents

Theuseinchildrenshouldbesupervisedbyaspecialist.Theexperienceinchildrenislimitedandrestrictedtoasmall

groupofpatients(aged4-17years)withserioushyperlipidaemiasuchashomozygousfamilialhypercholesterolaemia

(seesection5.1).Developmentalsafetydatainthispopulationhavenotbeenevaluated.Therecommendedinitialdose

forthisgroupis10mgatorvastatinaday.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Activeliverdiseaseorunexplainedpersistentelevationofserumtransaminaselevelswheretheelevationis

exceedingthreetimesthemeanupperlimits.

Myopathy.

Pregnantandbreastfeedingwomenandwomenofchildbearingpotentialnotusingcontraceptives(see

section4.6).

4.4Specialwarningsandprecautionsforuse

Livereffects

Itisrecommendedthatliverfunctiontestsbeperformedbeforetheinitiationoftreatment,at12weeksafterinitiationof

therapyorelevationofdoseandperiodically(e.g.sixmonths)thereafter.Liverfunctiontestsshouldbeperformedif

signsorsymptomsofpossibleliverdamageareobserved.Patientswhodevelopincreasedtransaminaselevelsshould

bemonitoreduntiltheabnormality(ies)resolve.Incaseofanelevationoftransaminaselevelsexceedingthreetimesthe

meanupperlimit,dosereductionisrecommendedordiscontinuationoftreatmentwithAtorvastatinActavis(see

section4.8).

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historyofliverdisease.

Previousstroke

Apost-hocanalysisofsubtypesofstrokeinpatientswithoutcoronaryheartdisease,whonewlyhadastrokeorTIA,

demonstratedhigherincidenceofhemorrhagicstrokeinpatientstreatedwith80mgatorvastatincomparedwith

placebo.Theincreasedriskwasseenespeciallyinpatientswithahistoryofhemorrhagicstrokeorlacunarinfarctatthe

startofthetrial.Benefit/riskratioforatorvastatin80mghasnotbeenestablishedforpatientswithhistoryof

hemorrhagicstrokeorlacunarinfarct.Thepotentialriskofhemorrhagicstrokeshouldbecarefullyconsideredbefore

thestartofthetreatment(seesection5.1).

Skeletalmuscleeffects

Atorvastatin,asotherHMG-CoAreductaseinhibitorscanrarelyinfluenceskeletalmusclesandcausemyalgia,myositis

andmyopathywhichcandevolveintorhabdomyolysis,whichisapotentiallyfatalconditionandischaracterizedbyan

elevatedCPKvalue(exceedingtentimesmeasuredupperlimits),myoglobinaemiaandmyoglobinuria,whichcan

causerenalfailure.

Priortotreatmentinitiation

Atorvastatinshouldbeusedwithcautioninpatientspredisposedforrhabdomyolysis.Creatinephosphokinase(CPK)

levelsshouldbemeasuredpriortoinitiatingtreatmentwithstatinsincaseof:

Renalimpairment

Hypothyroidism

Personalorfamilialhistoryofhereditarymusculardisorders

Previoushistoryofmusculartoxicitywithastatinorfibrate

Previoushistoryofliverdiseaseand/orwheresubstantialquantitiesofalcoholareconsumed

Inelderly(age>70years),thenecessityofsuchmeasurementshouldbeconsidered,accordingtothepresenceof

otherpredisposingfactorsforrhabdomyolysis

Inthesesituations,theriskoftreatmentshouldbeconsideredcarefullywithrespecttothepossiblebenefitsandclinical

monitoringisrecommended.IftheCPKvaluesaresignificantlyelevated,exceedingfivetimesmeasuredupperlimits,

treatmentshallnotbestarted.

Creatinephosphokinase(CPK)measurements

CPKshouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofanyplausiblealternativecauseofCPK

increase,sincethatmakesinterpretationdifficult.IftheCPKvalueissignificantlyhigh(fivetimesmeasuredupper

limits),themeasurementshouldberepeatedafter5-7daysforconfirmation.

Duringtreatment

Theimportanceofimmediatereportingofmyalgia,crampsorfatigue,especiallyfollowedbymalaiseandfever,

mustbeexplainedtothepatients.

IfthesesymptomsemergeduringtreatmentwithatorvastatinCPKvaluesshouldbemeasuredandincaseof

elevationexceedingfivetimesmeasuredupperlimits,treatmentshouldbediscontinued.

Ifsymptomsfrommusclesaresevereorcausedailydiscomfort,discontinuationoftreatmentshouldbe

considered,eventhoughCPKvaluesarenotoverfivetimesmeasuredupperlimits.

IfsymptomsresolveandCPKvaluesbecomenormal,treatmentwithatorvastatinoranotherstatincanbe

considered,withminimumdoseandclosemonitoring.

IfsignificantelevationofCPKvalues(exceedingtentimesmeasuredupperlimits)orrhabdomyolysisemergeor

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Theriskofrhabdomyolysisisincreasedbyconcurrentuseofatorvastatinandcertainothermedicinalproductswhich

canincreaseatorvastatinplasmaconcentrationsuchasciclosporin,erythromycin,clarithromycin,itraconazole,

ketoconazole,nefazodone,niacin,gemfibrozile,otherfibratesandHIV-proteaseinhibitors.Theriskofmyopathycan

alsobeincreasedduringconcurrentadministrationofatorvastatinandezetimibe.Differenttreatment(thatdoesnot

interact)shouldbeconsidered,ifpossible.Whenconcomitanttreatmentofthesesubstancesandatorvastatinis

necessary,thebenefitandtheriskofthetreatmentshouldbecarefullyconsidered.Alowerstartingdoseofatorvastatin

isrecommendedforpatientsduringconcomitantuseofproductsthatincreaseatorvastatinplasmaconcentration,

Duringconcurrentuseofciclosporin,clarithromycinoritraconazol,alowermaximaldoseofatorvastatinis

recommendedandthesepatientsshouldbeclinicallymonitoredasappropriate(seesection4.5).

Childrenandadolescents

Inpatientsaged<18yearsefficacyandsafetyhavenotbeenstudiedfortreatmentperiods>52weeks'durationand

effectsonlong-termcardiovascularoutcomesareunknown.

Theeffectsofatorvastatininchildrenaged<10yearsandpremenarchalgirlshavenotbeeninvestigated.

Longtermeffectsoncognitivedevelopment,growthandpubertalmaturationareunknown.

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,nonproductivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

TheriskofmyopathyduringuseofHMG-CoAreductaseinhibitorsisincreasedwithco-administrationofciclosporin,

fibrates,macrolideantibiotics,includingerythromycin,azoleantifungals,HIV-proteaseinhibitorsorniacinandhas

rarelyledtorhabdomyolysisandrenalinsufficiencycausedbymyoglobinuria.Therefore,possiblebenefitsandtherisk

involvedwithconcurrenttreatmentmustbeconsideredcarefully.Whenconcomitantadministrationofthesesubstances

andatorvastatinisnecessary,thebenefitandtheriskofthetreatmentshouldbeconsideredcarefully.Alowerstarting

doseofatorvastatinisrecommendedforpatientsduringco-administrationofmedicinalproductsthatincrease

atorvastatinplasmaconcentration.Duringadministrationofciclosporin,chlarithromycinoritraconazole,alower

maximaldoseofatorvastatinisrecommendedandthesepatientsshouldbemonitoredclinicallyasappropriate(see

section4.4).

CytochromeP4503A4inhibitor

AtorvastatinismetabolisedbycytochromeP4503A4.Interactionscanoccurduringconcurrentadministrationof

atorvastatinandacytochromeP4503A4inhibitor(e.g.ciclosporin,macrolideantibiotics,includingerythromycinand

clarithromycin,nefazodone,azoleantifungals,includingitraconazoleandHIVproteaseinhibitors).Specialprecaution

isthereforerequiredduringconcurrentadministrationofatorvastatinandthesemedicinalproductsbecauseitcanresult

inelevatedplasmaconcentrationofatorvastatin(seealsosection4.4).

Transportproteininhibitors

AtorvastatinanditsmetabolitesaresubstratesofOATP1B1transporters.Concomitantuseof10mgatorvastatinand

5.2mg/kg/dayofciclosporinresultedin7.7-foldincreasinginatorvastatinexposure.Whenconcurrentadministration

ofatorvastatinandciclosporinisnecessary,theatorvastatindoseshouldnotbehigherthan10mg.

Erythromycin,clarithromycin

ErythromycinandclarithromycinareknowninhibitorsoftheenzymesystemcytochromeP4503A4.Concurrent

administrationof80mgatorvastatinonceadayanderythromycin(500mgfourtimesaday)resultedin33%increase

inexposureofatorvastatintotalactivity.Concurrentadministrationof10mgatorvastatindailyandclarithromycin

(500mgtwiceaday)resultedin3.4-foldincreaseinexposureofatorvastatin.Whenconcurrentadministrationof

atorvastatinandclarithromycinisnecessary,lowermaintainancedosesarerecommendedforatorvastatin.Atdoses

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Itraconazole

Concomitantadministrationofatorvastatin40mganditraconazole200mgdailyresultedina2.5-3.3foldincreasein

exposuretoatorvastatin.Incaseswhereco-administrationofitraconazolewithatorvastatinisnecessary,the

maintenancedoseofatorvastatinshouldnotexceed40mgdaily.Patientswhonormallyrequire80mgofatorvastatin

shouldeitherreducetheirdosesduringconcomitantitraconazoletreatment,oralternatively(forshortcoursesofthis

antifungalmedicinalproduct)wherenotpractical,atemporarysuspensionoftreatmentwithatorvastatinmaybe

considered.

Proteaseinhibitors

Co-administrationofatorvastatinandproteaseinhibitors,knowninhibitorsofcytocromeP4503A4,wasassociated

withanapproximatelytwofoldincreaseinplasmaconcentrationofatorvastatin.Lipidlevelsshouldbemonitoredto

ensurethatthelowestdosenecessaryofatorvastatinisused.

Diltiazemhydrochloride

Concurrentadministrationof40mgatorvastatinand240mgdiltiazemresultedin51%increaseinexposureof

atorvastatin.Appropriateclinicalmonitoringisrecommendedforthesepatientsafterinitiationofdiltiazemandafter

doseadjustments.

Ezetimibe

Theuseofezetimibeasmonotherapyisassociatedwithmyopathy.Theriskofmyopathycanthereforebeincreased

withconcurrentadministrationofezetimibeandatorvastatin.

Grapefruitjuice

GrapefruitjuicecontainsoneormoreCYP3A4inhibitorsandcancauseelevationinplasmaconcentrationofmedicinal

productsmetabolisedbyCYP3A4.AUCforatorvastatinincreasedby37%andAUCoftheactiveorthohydroxy

metabolitedecreasedby20.4%followingintakeof1glass(240ml)ofgrapefruitjuice.Alargeamountofgrapefruit

juice(exceeding1.2ladayforfivedays)howevercausesa2.5-foldincreaseintheAUCforatorvastatinanda1.3-fold

increaseinAUCfortheactivesubstances(atorvastatinandmetabolites).Drinkinglargeamountsofgrapefruitjuiceis

thereforenotrecommendedduringatorvastatintreatment.

CytochromeP4503A4inducers

ConcurrentadministrationofatorvastatinandcytochromeP4503A4inducers(e.g.efavirenz,rifampinorSt.John’s

Wort)canresultinvariousdecreaseofplasmaconcentrationofatorvastatin.Duetothedoubleinteractionmechanism

ofrifampin(cytochromeP4503AinductionandblockingofthetransportproteinOATP1B1inthehepatocyts),itis

recommendedtoadministeratorvastatinandrifampinatthesametimesincetheadministrationofatorvastatinafter

administrationofrifampinhasbeenconnectedwithsignificantreductionofplasmaconcentrationofatorvastatin.

Verapamilandamiodarone

Interactionstudieswithatorvastatinandverapamilandaminodaronehavenotbeenconducted.Bothverapamiland

amiodaroneinhibitCYP3A4activityandco-administrationwithatorvastatinmayresultinincreasedexposureto

atorvastatin.Lipidlevelsshouldbemonitoredtoensurethatthelowestdosenecessaryofatorvastatinisused.

Concurrentuseofothermedicinalproducts

Gemfibrozil/fibrates

Theadministrationoffibratesasmonotherapyisassociatedwithmyopathy.Riskofatorvastatininducedmyopathycan

beincreasedduringconcurrentadministrationoffibrates(seesection4.4).Concomitantadministrationof600mg

gemfibroziltwicedailyresultedin24%increaseintheexposureofatorvastatin.

Digoxin

Repeatedadministrationofdigoxinandatorvastatin10mgatthesametimedidnotinfluencethesteadystateplasma

concentrationofdigoxin.Digoxinconcentrationhoweverincreasedbyca.20%duringconcurrentuseofdigoxinand

atorvastatin80mgaday.ThisinteractioncanbeexplainedbyinhibitionoftheP-glycoprotein(membranetransferring

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Oralcontraceptives

Concurrentuseofatorvastatinandoralcontraceptivesincreasedtheplasmaconcentrationofnorethisteroneandethinyl

oestradiol.Thisshouldbeconsideredwhenselectingoralcontraceptivedoses.

Colestipol

Plasmaconcentrationofatorvastatinanditsactivemetabolitesdecreased(approx.25%)whencolestipolwas

administeredwithatorvastatin.However,lipideffectsweregreaterwhenatorvastatinandcolestipolwereadministered

togetherthanwheneithermedicinalproductwasadministeredalone.

Antacids

Concurrentadministrationofatorvastatinandoralantacidliquidformulationscontainingmagnesiumandaluminium

hydroxidesdecreasedplasmaconcentrationofatorvastatinanditsactivemetabolitesbyapprox.35%;reductionof

LDL-cholesterolwashowevernotaltered.

Warfarin

Concurrentuseofatorvastatinandwarfarincausedaminordecreaseinprothrombintimeduringthefirstdaysof

treatment,butreturnedtonormalwithin15days.Neverthelesspatientsreceivingwarfarinshouldbecloselymonitored

whenatorvastatinisaddedtotheirtreatment.

Phenazone

Concurrentuseofrepeateddosesofatorvastatinandphenazoneresultedinlittleornovisibleeffectontheclearanceof

phenazone.

Cimetidine

Intheonestudyavailableofinteractionsbetweencimetidineandatorvastatinnointeractionwasseen.

Amlodipine

Aninteractionstudyonhealthyvoluntarysubjectsshowedthatconcomitantadministrationofatorvastatin80mgand

amlodipine10mgresultedin18%increaseintheexposureofatorvastatin.

Otherinteractions

Inclinicalstudiesnoclinicallysignificantinteractionswereobservedwhenatorvastatinwasadministeredtogetherwith

antihypertensivesorhypoglycemicagents.

4.6Fertility,pregnancyandlactation

AtorvastatinActavisiscontraindicatedinpregnancyandwhilebreast-feeding.Womenofchildbearingpotentialmust

useeffectivecontraceptivemeasuresduringtreatment.Safetyofatorvastatinuseduringpregnancyandlactationhasnot

beenestablished(seesection4.3).

AnimalstudiesindicatethatHMG-CoAreductaseinhibitorscaninfluencetheembryonicandfoetaldevelopment.

Maturationofratoffspringwasdelayedandpost-natalsurvivalwasreducedafteradministeringatorvastatintothe

motherindoseshigherthan20mg/kg/day(clinicalsystemicexposure).

Inratstheconcentrationofatorvastatinanditsactivemetabolitesissimilarinplasmaandmilk.Itisnotknownwhether

atorvastatinoritsmetabolitesareexcretedintobreastmilkinhumans.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Themostfrequentadverseeventsthatcanbeexpectedaresymptomsfromthegastrointestinalsystem,including

constipation,flatulence,dyspepsia,abdominalpain,usuallyresolvingduringcontinuedtreatment.Lessthan2%of

patientswerediscontinuedfromclinicaltrialsduetosideeffectsrelatedtoatorvastatin.

Thefollowinglistofadverseeventsisbasedonresultsfromclinicalstudiesandpostmarketingreports.

Estimatedfrequencyofeventsisasfollows:Common( ≥1/100to<1/10);uncommon(≥1/1,000to<1/100);rare(≥

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

Bloodandlymphaticsystemdisorders

Uncommon:Thrombocytopenia.

Nervoussystemdisorders

Common:Headache,dizziness,paraesthesia,hypoesthesia.

Uncommon:Peripheralneuropathy.

Veryrare:Tastedisturbances.

Eyedisorders

Veryrare:Sightdisturbances.

Earandlabyrinthdisorders

Uncommon:Tinnitus.

Veryrare:Impairedhearing.

Respiratory,thoracicandmediastinaldisorders

Frequencynotknown:Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seesection4.4).

Gastrointestinaldisorders

Common:Abdominalpain,constipation,flatulence,dyspepsia,nausea,diarrhea.

Uncommon:Anorexia,vomiting.

Skinandsubcutaneoustissuedisorders

Common:Rash,pruritus.

Uncommon:Urticaria.

Veryrare:Angioedema,bullouseruptions(includingerythemamultiforme,Steven-Johnsonssyndromeandtoxic

epidermalnecrolysis).

Musculoskeletalandconnectivetissuedisorders

Common:Myalgia,arthralgia,backpain.

Uncommon:Myopathy,musclespasms.

Rare:Myositis,rhabdomyolysis.

Veryrare:Ruptureoftendons.

Endocrinedisorders

Uncommon:Alopecia,hyper-orhypoglycaemia,pancreatitis.

Generaldisordersandadministrationsiteconditions

Common:Asthenia,chestpain,peripheraloedema,fatigue.

Uncommon:Malaise,weightgain.

Immunesystemdisorders

Common:Allergicreactions.

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Hepatobilarydisorders

Rare:Hepatitis,cholestaticjaundice.

Veryrare:Liverfailure.

Reproductivesystemandbreastdisorders

Uncommon:Impotence.

Veryrare:Gynecomastia.

Frequencynotknown:Sexualdysfunction.

Psychiatricdisorders

Common:Insomnia.

Uncommon:Amnesia.

Frequencynotknown:Depression,sleepdisturbances,includingnightmares

Investigations

ElevationofserumtransaminaseshasbeenreportedinpatientsreceivingatorvastatinaswithotherHMG-CoA

reductaseinhibitors.Thesealterationsweremostoftenmildandtransientanddiscontinuationoftreatmentwasnot

necessary.Elevationofserumtransaminasesofclinicalsignificance(exceedingthreetimesmeanvaluesofupper

limits)wasobservedin0.8%ofpatientsreceivingatorvastatin.Theseelevationsweredosedependentandresolvedin

allpatients.

Inclinicalstudiesincreaseinserumcreatinephosphokinase(CPK)wasobserved(exceedingthreetimesmeanvalues

ofupperlimits)in2.5%ofpatientsreceivingatorvastatinwhichissimilaraswithotherHMG-CoAreductase

inhibitors.Valuesexceedingtentimestheuppermeanvalueswereobservedin0.4%ofpatientsreceivingatorvastatin

(seesection4.4).

4.9Overdose

NospecifictreatmentforAtorvastatinActavisoverdoseisavailable.Incaseofanoverdosethepatientshouldbe

treatedsymptomaticallyandsupportivemeasuresinstitutedifrequired.Liverfunctionshouldbemonitoredandserum

CPK-values.Duetoextensivebindingtoplasmaproteins,haemodilaysisisnotexpectedtoenhancesignificantly

atorvastatinclearance.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:HMG-CoAreductaseinhibitors,ATCcode:C10AA05

Atorvastatinisaselective,competitiveinhibitorofHMG-CoAreductase,therate-limitingenzymeresponsibleforthe

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

TriglyceridesandcholesterolintheliverareincorporatedintoVLDL(verylowdensitylipoproteins)andreleasedinto

thebloodfordeliverytoperipheraltissues.Low-densitylipoprotein(LDL)isformedfromVLDLandiscatabolised

primarilythroughthehighaffinityLDLreceptor.

AtorvastatinlowersplasmacholesterolandlipoproteinlevelsbyinhibitingHMG-CoAreductaseandcholesterol

synthesisintheliver.AtorvastatinalsoincreasesthenumberofhepaticLDLreceptorsonthecellsurfaceintheliver,

whichresultsinenhanceduptakeandcatabolismofLDL.

AtorvastatinreducesLDLproductionandthenumberofLDL-particles.Atorvastatinproducesaprofoundand

sustainedincreaseinLDLreceptoractivitycoupledwithabeneficialchangeinthequalityofcirculatingLDL-particles.

AtorvastatiniseffectiveinreducingLDL-Cinpatientswithhomozygousfamilialhypercholesterolemia,apopulation

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Atorvastatinhasbeenshowntoreducetotalcholesterol(30-46%),LDL-cholesterol(41-61%),apolipoproteinB

(34-50%)andtriglycerides(14-33%),buttocausevariableincreasesinHDLcholesterolandapolipolipoproteinA1in

doserelatedstudies.Theseresultsapplytopatientswithheterozygousfamilialhypercholesterolaemia,nonfamilial

hypercholesterolaemiaandmixedhyperlipidaemia,includingpatientswithnon-insulindependentdiabetesmellitus.

Reductionsintotal-cholesterol,LDL-cholesterolandapolipoproteinBhavebeenprovedtoreduceriskfor

cardiovasculareventsandcardiovascularmortality.Mortalityandmorbiditystudieswithatorvastatinhavenotyet

completed.

Atherosclerosis

IntheREVERSAL(ReversingAtherosclerosiswithAggressiveLipid-LoweringStudy),theeffectofaggressivelipid

loweringwithatorvastatin80mgandlipidloweringtostandardlevelswithpravastatin40mgoncoronary

atherosclerosiswasassessedbyintravascularultrasound(IVUS),duringangiography,inpatientswithcoronaryheart

disease.

Inthisrandomized,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).Whencomparedtopravastatin,the

effectsofatorvastatinwerestatisticallysignificant(p=0.02).

Theeffectofintensivelipidreductiononcardiovalscularend-points(e.g.theneedforrevascularisation,non-fatal

myocardialinfarction,coronarydeath)wasnotinvestigatedinthisstudy.

Intheatorvastatingroup,LDL-cholesterolwasreducedtoameanvalueof2.04mmol/l ±

0.8(78.9mg/dl ±

30)from

baselinevalue3.98mmol/l ±

0.7.

Inthepravastatingroup,LDL-cholesterolwasreducedtoameanvalueof2.85mmol/l ±

0.7(110mg/dl ±

26)from

baselinevalue3.89mmol/l ±

0.7(150mg/dl ±

26)(p<0.0001).AtorvastatinalsosignificantlyreducedmeanTCby

34.1%(pravastatin:-18.4%,p<0.0001),meanTGlevelsby20%(pravastatin:-6.8%,p<0.0009,andmean

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

AtorvastatinincreasedmeanHDL-cholesterolby2.9%(pravastatin:+5.6%,p=NS).

Therewasa36.4%meanreductioninc-reactiveprotein(CRP)intheatorvastatingroupcomparedtoa5.2%reduction

inthepravastatingroup(p<0.0001).

Thestudyresultswereobtainedwith80mgdosesofatorvastatinandcanthereforenotbeextrapolatedtolowerdoses.

Thesafetyandtolerabilityprofilesofthetwotreatmentgroupswerecomparable.

Theeffectofintensivelipidloweringwithatorvastatinoncardiovascularmortalityandmorbiditywasnotinvestigated

inthisstudy.Therefore,theclinicalsignificanceoftheseimagingresultswithregardtotheprimaryandsecondary

preventionofcardiovasculareventsisunknown.

Heterozygousfamilialhypercholesterolaemiainpaediatricpatients

Inadouble-blind,placebocontrolledstudyfollowedbyanopen-labelphase,187boysandpostmenarchalgirls

10-17yearsofage(meanage14.1years)withheterozygousfamilialhypercholesterolaemia(FH)orsevere

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

atorvastatinfor26weeks.Inclusioninthestudyrequired1)abaselineLDL-Clevel4.91mmol/lor2)abaseline

LDL-C4.14mmol/landpositivefamilyhistoryofFHordocumentedprematurecardiovasculardiseaseinafirst-or

seconddegreerelative.ThemeanbaselineLDL-Cvaluewas5.65mmol/l(range:3.58-9.96mmol/l)intheatorvastatin

groupcomparedto5.95mmol/l(range:4.14-8.39mmol/l)inplacebogroup.Thedoseofatorvastatin(oncedaily)was

10mgforthefirst4weeksandup-titratedto20mgiftheLDL-Clevelwas>3.36mmol/l.Thenumberofatorvastatin-

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Atorvastatinsignificantlydecreasedplasmalevelsoftotal-C,LDL-C,triglycerides,andapolipoproteinBduringthe

26weekdouble-blindphase(seeTable1).

ThemeanachievedLDL-Cvaluewas3.38mmol/l(range:1.816.26mmol/l)intheatorvastatingroupcomparedto

5.91mmol/l(range:3.939.96mmol/l)intheplacebogroupduringthe26-weekdouble-blindphase.

Inthislimitedcontrolledstudy,therewasnodetectableeffectongrowthorsexualmaturationinboysoronmenstrual

lengthingirls.Atorvastatinhasnotbeenstudiedincontrolledclinicaltrialsinvolvingpre-pubertalpatientsorpatients

youngerthan10yearsofage.Thesafetyandefficacyofdosesabove20mghavenotbeenstudiedincontrolledtrialsin

children.Thelong-termefficacyofatorvastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthood

hasnotbeenestablished.

Preventionofcardiovasculardisease

Theeffectofatorvastatinonfatalandnon-fatalcoronaryheartdiseasewasassessedinarandomized,double-blind,

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

Patientswerehypertensive,40-79yearsofage,withnopreviousmyocardialinfarctionortreatmentforangina,and

withTClevels ≤6.5mmol/l(251mg/dl).Allpatientshadatleast3ofthepre-definedcardiovascularriskfactors:male

gender,age ≥55years,smoking,diabetes,historyofCHDinafirst-degreerelative,TC:HDL-C>6,peripheralvascular

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

Notallincludedpatientswereestimatedtohaveahighriskforafirstcardiovascularevent.

Patientsweretreatedwithanti-hypertensivetherapy(eitheramlodipineoratenolol-basedregimen)andeither

atorvastatin10mgdaily(n=5168)orplacebo(n=5137).

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.3years.

CHD=coronaryheartdisease;MI=myocardialinfarction.

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

82events,p=0.51).Inthesubgroupanalysesbygender(81%males,19%females),abeneficialeffectofatorvastatin

wasseeninmalesbutcouldnotbeestablishedinfemalespossiblyduetotheloweventrateinthefemalesubgroup.

Totalmortalityandcardiovascularmortalitywerenumericallyhigherinthefemalepatients(38vs.30and17vs.12),

butthiswasnotstatisticallysignificant.Therewassignificanttreatmentinteractionbyantihypertensivebaseline

therapy.Theprimaryendpoint(fatalCHDandnon-fatalMI)wassignificantlyreducedbyatorvastatininpatients

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

TABLE1.LipidLoweringeffectsofatorvastatininadolescentboysandgirlswith

heterozygousfamilialhypercholesterolaemiaorseverehypocholesterolaemia(meanpercent

changefrombaselineatendpointinintention-to-treat-population

DOSES N Total-C LDL-C HDL-C TG ApoB

Placebo 47 -1.5 -0.4 -1.9 1.0 0.7

Atorvastatin 140 -31.4 -39.6 2.8 -12.0 -34.0

Events Relativerisk

reduction

No.ofevents

(atorvastatinvs.

placebo) Absoluterisk

reduction 1

p-value

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

Totalcardiovasculareventsand

revascularisationprocedures 20% 389vs.483 1.9% 0.0008

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Theeffectofatorvastatinonfatalandnon-fatalcardiovasculardiseasewasalsoassessedinarandomized,double-blind,

multicenter,placebo-controlledtrial,theCollaborativeAtorvastatinDiabetesStudy(CARDS)inpatientswithtype2

diabetes,40-75yearsofage,withoutpriorhistoryofcardiovasculardisease,andwithLDL-cholesterol ≤4.14mmol/l

(160mg/dl)andTG ≤6.78mmol/l(600mg/dl).Allpatientshadatleast1ofthefollowingriskfactors:hypertension,

currentsmoking,retinopathy,microalbuminuriaormacroalbuminuria.

Patientsweretreatedwitheitheratorvastatin10mgdaily(n=1428)orplacebo(n=1410)foramedianfollow-upof

3.9years.

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.9years.

AMI=acutemyocardialinfarction;CABG=coronaryarterybypassgraft;CHD=coronaryheartdisease;MI=

myocardialinfarction;PTCA=percutaneoustransluminalcoronaryangioplasty.

Therewasnoevidenceofadifferenceinthetreatmenteffectbypatient'sgender,age,orbaselineLDL-cholesterol

level.

Afavourabletrendwasobservedregardingthemortalityrate(82deathsintheplacebogroupvs.61deathsinthe

atorvastatingroup,p=0.0592).

Previousstroke

Inthestudy“strokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)”,theeffectofatorvastatin

80mgdailyonstrokein4731patientswithnoknowncoronaryheartdisease(CHD)whohavehadastrokeoran

ischemicattack(TIA)withinthelast6monthswasevaluatedandcomparedwithplacebo.Ofthepatientgroup60%

weremales,21-92yearsold(mean63years)withameanLDL-cholesterollevel3.4mmol/l(133mg/dl)atthe

initiationofthetreatment.ThemeanLDL-cholesterollevelwas1.9mmol/l(73mg/dl)fortheatorvastatingroupand

3.3mmol/l(129mg/dl)fortheplacebogroup.Themeanoffollow-upwas4.9years.

Areductionseenforatorvastatin80mgintheprimaryendpointforfatalornon-fatalstrokewas15%(HR0.85;95%

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

placebo.Totalmortality(allcauses)was9.1%(216/2365)foratorvastatincomparedto8.9%(211/2366)forplacebo.

Apost-hocanalysisforatorvastatin80mgshowedareducedincidenceofischemicstroke(218/2365,9.2%versus

274/2366,11,6%,p=0.01)andincreasedincidenceofhaemorrhagicstroke(55/2365,2,3%versus33/2366,1,4%,

p=0.02)comparedtoplacebo.

Theriskofhaemorrhagicstrokewasincreasedinpatientswithahistoryofhaemorrhagicstrokewhenjoining

thestudy(7/45foratorvastatincomparedwith2/48forplacebo;HR4.06;95%CI,0.84-19.57)andtheriskfor

ischemicstrokewassimilarforbothgroups(3/45foratorvastatincomparedwith2/48forplacebo;HR1.64;

Events Relativerisk

reduction

No.ofevents

(atorvastatinvs.

placebo) Absoluterisk

reduction 1

p-value

Majorcardiovascularevents

(fatalandnon-fatalAMI,silent

MI,acuteCHDdeath,unstable

angina,CABG,PTCA,

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

MI(fatalandnon-fatal,AMI,

silentMI) 42% 38vs.64 1.9% 0.0070

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Theriskofhaemorrhagicstrokewasincreasedinpatientswhojoinedthestudywithahistoryofalacunar

infarct(20/708foratorvastatincomparedto4/701forplacebo;HR4.99;95%CI,1.17-14.61)buttheriskfor

ischemicstrokereducedalsointhesepatients(79/708foratorvastatincomparedto102/701forplacebo;HR

0.76;95%CI;0.57-1.02).Itispossiblethatthetotalriskforastrokeisincreasedinpatientwithahistoryof

lacunarinfarcttakingatorvastatin80mgdaily.

Thetotalmortality(allcauses)was15.6%(7/45)foratorvastatincomparedto10.4%(5/48)fortheplacebogroupfor

patientswithahistoryofahemorrhagicstroke.Thetotalmortalitywas10.9%(77/708)foratorvastatincomparedto

9.1%(64/701)forplaceboinasubgroupofpatientswithahistoryoflacunarinfarct.

5.2Pharmacokineticproperties

Absorption

Atorvastatinisrapidlyabsorbedfollowingoraladministration;maximumplasmaconcentration(C

)isobtained

within1-2hours.Extentofabsorptionincreasesinproportiontotheatorvastatindose.Bioavailabilityofatorvastatin

followingintakeoffilm-coatedtabletsis95-99%comparedtothebioavailabilityofatorvastatinsolutions.Absolute

bioavailabilityisabout12%andsystemicavailabilityoftheactiveHMG-CoAreductaseinhibitorisabout30%.The

lowsystemicavailabilityisduetopresystemicclearanceingastrointestinalmucosaand/orhepaticfirstpass

metabolism.

Distribution

Meanvolumeofdistributionofatorvastatinisapproximately381l.Atorvastatinis ≥98%boundtoplasmaproteins.

Metabolism

AtorvastatinismetabolisedbycytochromeP4503A4toortho-andparahydroxylatedderivativesandvarious

beta-oxidationproducts.Apartfromotherpathwaysthesecompoundsarefurthermetabolisedbyglucuronisation.

InvitroinhibitionofHMG-CoAreductasebyortho-andparahydroxylatedmetabolitesisequivalenttothatof

atorvastatin.Approx.70%ofinhibitoryactivityforHMG-CoAreductaseisattributedtoactivemetabolites.

Excretion

Atorvastatinisexcretedprimarilyinbilefollowinghepaticand/orextrahepaticmetabolism.Themedicinalproduct

doeshowevernotappeartoundergosignificantenterohepaticrecirculation.Meanplasmametabolismhalf-lifeof

atorvastatininhumansisapprox.14hours.Duetotheactivemetabolitesthehalf-lifeofinhibitoryactivityfor

HMG-CoAreductaseisapproximately20-30hours.

Specialpatientgroups

Elderly:Concentrationofatorvastatinanditsactivemetabolitesinplasmaishigherinhealthyelderlyindividuals

thaninthosewhoareyounger,butthebloodlipideffectsaresimilarinbothagegroups.

Childrenandadolescents:Pharmacokineticdataforchildrenbelow18yearsisnotavailable.

Gender:Concentrationsofatorvastatinanditsactivemetabolitesdifferinwomen(maximumplasmaconcentration

isabout20%higherandAUCabout10%lower)fromthoseinmen.Thisdifferenceisnotofclinicalrelevance,and

thedifferenceineffectsonbloodlipidsbetweenmenandwomenisnotsignificant.

Renalimpairment:Renaldiseasesneitheraffectplasmaconcentrationnorbloodlipideffectsofatorvastatinandits

activemetabolites.

Hepaticimpairment:Plasmaconcentrationofatorvastatinanditsactivemetabolitesincreasessignificantly(C

approx.16-foldandAUC11-fold)inpatientswithchronicalcoholicliverdisease(Childs-PughB).

5.3Preclinicalsafetydata

Atorvastatinwasnotcarcinogenicinrats.Themaximumdoseusedwas63-foldhigherthanthehighesthumandose

(80mg/day)onamg/kgbody-weightbasisand8to16-foldhigherbasedonAUC

(0-24) valuesasdeterminedbytotal

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Ina2-yearstudyinmice,incidencesofhepatocellularadenomainmalesandhepatocellularcarcinomasinfemales

wereincreasedatthemaximumdoseused,andthemaximumdoseusedwas250-foldhigherthanthehighesthuman

doseusedonamg/kgbody-weightbasis.Systemicexposurewas6to11-foldhigherbasedonAUC

(0-24) .

Atorvastatindidnotdemonstratemutagenicorclastogenicpotentialin4invitrotestswithorwithoutmetabolic

activationand1invivoassay.

Inanimalstudiesatorvastatinhadnoeffectonmaleorfemalefertilityatdosesofupto175mg/kgand225mg/kg/day,

respectively,andwasnotteratogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Mannitol

Microcrystallinecellulose

Crospovidone

Sodiumcarbonateanydrous

PovidoneK29-32

Magnesiumstearate

Coating:

Hypromellose

Titaniumdioxide(E171)

Macrogol6000

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Aluminium/Aluminiumblisters.

Whitetabletcontainer(HDPE)withsilicageldesiccant,closedwithsnap-oncap(LDPE)withatamperevidentring.

Packsizes:

Blisters:10,20,28,30,50,98and100film-coatedtablets.

Tabletcontainer:30,100,250and500film-coatedtablets.

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalandotherhandling

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7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/23/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11thSeptember2009

10DATEOFREVISIONOFTHETEXT

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