ATORVASTATIN PHARMATHEN 80 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
ATORVASTATIN CALCIUM
Available from:
Pharmathen S.A.
ATC code:
C10AA05
INN (International Name):
ATORVASTATIN CALCIUM
Dosage:
80 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
HMG CoA reductase inhibitors
Authorization status:
Authorised
Authorization number:
PA1368/013/004
Authorization date:
2011-06-03

PACKAGE LEAFLET:INFORMATIONFOR THE USER

Atorvastatin Pharmathen 10 mgfilm-coatedtablets

Atorvastatin Pharmathen 20 mg film-coated tablets

Atorvastatin Pharmathen 40 mg film-coated tablets

Atorvastatin Pharmathen 80 mg film-coated tablets

Atorvastatin

Read all of these leaflet carefully before you start

taking this medicinebecause it contains important

information for you.

-Keepthisleaflet.Youmayneedtoreaditagain.

-Ifyouhaveanyfurtherquestions,askyourdoctor,

pharmacistornurse.

-Thismedicinehasbeenprescribedforyouonly.Donot

passitontoothers.Itmayharmthem,eveniftheirsigns

ofillnessarethesameasyours.

-Ifyougetanysideeffectstalktoyourdoctor,pharmacist

ornurse.Thisincludesanypossiblesideeffectsnotlisted

inthisleaflet.Seesection4.

Whatis inthis leaflet:

1.WhatAtorvastatinPharmathenisandwhatitisusedfor

2.WhatyouneedtoknowbeforeyoutakeAtorvastatin

Pharmathen

3.HowtotakeAtorvastatinPharmathen

4.Possiblesideeffects

5.HowtostoreAtorvastatinPharmathen

6.Contentsofthepackandotherinformation

1.WhatAtorvastatin Pharmathenis and whatitis

used for

Atorvastatin,belongstoagroupofmedicinesknownas

statins,whicharelipid(fat)regulatingmedicines.

AtorvastatinPharmathenisusedtolowerlipidsknownas

cholesterolandtriglyceridesinthebloodwhenalowfatdiet

andlifestylechangesontheirownhavefailed.Ifyouareat

anincreasedriskofheartdisease,AtorvastatinPharmathen

canalsobeusedtoreducesuchriskevenifyourcholesterol

levelsarenormal.Youshouldmaintainastandardcholesterol

loweringdietduringtreatment.

2.Whatyou need to know before you take

Atorvastatin Pharmathen

Do nottake Atorvastatin Pharmathen:

ifyouarehypersensitivetoAtorvastatin,ortoanysimilar

medicinesusedtolowerbloodlipids,ortoanyoftheother

ingredientsofthemedicinelistedinsection6.

ifyouhaveorhaveeverhadadiseasewhichaffectstheliver

ifyouhavehadanyunexplainedabnormalbloodtestsfor

liverfunction.

ifyouareawomanabletohavechildrenandnotusinga

reliablecontraception.

ifyouarepregnant,ortryingtobecomepregnant.

Ifyouarebreast-feeding.

Warnings and precautionsAtorvastatin Pharmathen

Talktoyourdoctor,pharmacistornursebeforetaking

AtorvastatinPharmathen

ifyouhavehadapreviousstrokewithbleedingintothe

brain,orhavesmallpocketsoffluidinthebrainfrom

previousstrokes

ifyou havekidneyproblems

ifyouhaveanunder-activethyroidgland(hypothyroidism)

ifyouhavehadrepeatedorunexplainedmuscleachesor

pains,personalhistoryorfamilyhistoryofmuscleproblems

ifyouhavehadpreviousmuscularproblemsduring

treatmentwithotherlipid-loweringmedicines(e.g.other

‘-statin’or‘-fibrate’medicines)

Ifyouaretakingorhavetakeninthelast7daysamedicine

calledfusidicacid,(amedicineforbacterialinfection)

orallyorbyinjection.Thecombinationoffusidicacid

andAtorvastatinPharmathencanleadtoseriousmuscle

problems(rhabdomyolysis).

ifyouregularlydrinkalargeamountofalcohol

ifyouhaveahistoryofliverdisease

ifyouareolderthan70years

Checkwith your doctor or pharmacist before taking

Atorvastatin Pharmathen if you:

Havesevererespiratoryfailure

Ifanyoftheseapplytoyou,yourdoctorwillneedtocarry

outbloodtestsbeforeandpossiblyduringyourAtorvastatin

Pharmathentreatmenttopredictyourriskofmusclerelated

sideeffects.Theriskofmusclerelatedsideeffectse.g

rhabdomyolysisisknowntoincreasewhencertainmedicines

aretakenatthesametime(seesection2‘‘Othermedicines

andAtorvastatinPharmathen’’).

Alsotellyourdoctororpharmacistifyouhaveamuscle

weaknessthatisconstant.Additionaltestsandmedicines

maybeneededtodiagnoseandtreatthis.

Whileyouareonthismedicineyourdoctorwillmonitor

youcloselyifyouhavediabetesorareatriskofdeveloping

diabetes.Youarelikelytobeatriskofdevelopingdiabetes

ifyouhavehighlevelsofsugarsandfatsinyourblood,are

overweightandhavehighbloodpressure.

Other medicines and Atorvastatin Pharmathen

Tellyourdoctororpharmacistifyouaretaking,haverecently

takenormighttakeanyothermedicines.

Ifyouneedtotakeoralfusidicacidtotreata

bacterialinfectionyouwillneedtotemporarilystop

itissafetorestartAtorvastatinPharmathen.Taking

AtorvastatinPharmathenwithfusidicacidmay

rarelyleadtomuscleweakness,tendernessorpain

(rhabdomyolysis).Seemoreinformationregarding

rhabdomyolysis in section 4.

Therearesomemedicinesthatmaychangetheeffectof

AtorvastatinPharmathen,ortheireffectmaybechanged

byAtorvastatinPharmathen.Thistypeofinteraction

couldmakeoneorbothofthemedicineslesseffective.

Alternativelyitcouldincreasetheriskorseverityofside-

effects,includingtheimportantmusclewastingcondition

knownasrhabdomyolysisdescribedinsection4:

Medicinesusedtoalterthewayyourimmunesystem

works,e.g.ciclosporin.

Certainantibioticsorantifungalmedicines,e.g.

erythromycin,clarithromycintelithromycin,ketoconazole,

itraconazole,voriconazole,fluconazoleposaconazole

rifampin,fusidicacid.

Othermedicinestoregulatelipidlevels,e.g.gemfibrozil,

otherfibrates,colestipol.

Somecalciumchannelblockersusedforanginaorhighblood

pressure,e.g.amlodipine,diltiazem,;medicinestoregulate

yourheartrhythme.g.digoxinverapamil,amiodarone.

MedicinesusedinthetreatmentofHIVe.g.ritonavir,

lopinavir,atazanavir,indinavir,darunavir,thecombination

oftipranavir/ritonaviretc.

SomemedicinesusedinthetreatmentofhepatitisCe.g.

telaprevir.

OthermedicinesknowntointeractwithAtorvastatin

Pharmathenincludeezetimibe(whichlowerscholesterol)

,warfarin(whichreducesbloodclotting),oral

contraceptives,stiripentol(ananti-convulsantforepilepsy),

cimetidine(usedforheartburnandpepticulcers),

phenazone(apainkiller),colchicine(usedtotreatgout),

antacids(indigestionproductscontainingaluminiumor

magnesium)andboceprevir(usedtotreatliverdisease

suchashepatitisC).

Medicinesobtainedwithoutaprescription:StJohn’sWort.

Taking Atorvastatin Pharmathen with food and drink

SeeSection3forinstructionsonhowtotakeAtorvastatin

Pharmathen.Pleasenotethefollowing:

Grapefruitjuice

Donottakemorethanoneortwosmallglassesofgrapefruit

juiceperdaybecauselargequantitiesofgrapefruitjuicecan

changetheeffectsofAtorvastatinPharmathen.

Alcohol

Avoiddrinkingtoomuchalcoholwhiletakingthismedicine.

SeeSection2‘‘Warningsandprecautions”fordetails.

Pregnancy and breast-feeding

DonottakeAtorvastatinPharmathenifyouarepregnant,

orifyouaretryingtobecomepregnant.

DonottakeAtorvastatinPharmathenifyouareabletobecome

pregnantunlessyouusereliablecontraceptivemeasures.

DonottakeAtorvastatinPharmathenifyouarebreast-

feeding.

ThesafetyofAtorvastatinPharmathenduringpregnancy

andbreast-feedinghasnotyetbeenproven.

Askyourdoctororpharmacistforadvicebeforetakingany

medicine.

Driving and using machines

Normallythismedicinedoesnotaffectyourabilityto

driveoroperatemachines.However,donotdriveifthis

medicineaffectsyourabilitytodrive.Donotuseanytools

ormachinesifyourabilitytousethemisaffectedbythis

medicine.

Atorvastatin Pharmathen contains lactose

Ifyouhavebeentoldbyyourdoctorthatyouhavean

intolerancetosomesugars,contactyourdoctorbefore

takingthismedicine.

3.How to takeAtorvastatin Pharmathen

Alwaystakethismedicineexactlyasyourdoctororpharmacisthas

toldyou.Checkwithyourdoctororpharmacistifyouarenotsure.

Beforestartingtreatment,yourdoctorwillplaceyouona

low-cholesteroldiet,whichyoushouldmaintainalsoduring

therapywithAtorvastatinPharmathen.

TherecommendedstartingdoseofAtorvastatin

Pharmathenis10mgonceadayinadultsandchildren

aged10yearsorolder.Thismaybeincreasedifnecessary

byyourdoctoruntilyouaretakingtheamountyouneed.

Yourdoctorwilladaptthedoseatintervalsof4weeksor

more.Themaximumdoseis80mgoncedailyforadults

and20mgoncedailyforchildren.

AtorvastatinPharmathentabletsshouldbeswallowedwhole

withadrinkofwater,andcanbetakenatanytimeofday,

withorwithoutfood.However,trytotakeyourtabletatthe

sametimeeveryday.

AtorvastatinPharmathen Thedurationoftreatmentwith

AtorvastatinPharmathenisdeterminedbyyourdoctor.

Pleaseaskyourdoctorifyouthinkthattheeffectof

AtorvastatinPharmathenistoostrongortooweak,

IfyoutakemoreAtorvastatinPharmathenthanyou

should:

IfyouaccidentallytaketoomanyAtorvastatinPharmathen

tablets(morethanyourusualdailydose),contactyour

doctororthenearesthospitalforadvice.

If you forget to take Atorvastatin Pharmathen:

Ifyouforgettotakeadose,justtakeyournextscheduled

doseatthecorrecttime.Donottakeadoubledosetomake

upforaforgottendose.

If you stop taking Atorvastatin Pharmathen:

Ifyouhaveanyfurtherquestionsontheuseofthismedicine

orwishtostopyourtreatment,askyourdoctororpharmacist.

4.Possible side effects

Likeallmedicines,thismedicineAtorvastatinPharmathen

maycausesideeffects,althoughnoteverybodygetsthem.

If you experience any of the following serious side

effects,stop taking your tablets and tell your doctor

immediately or go to the nearesthospital accident

and emergency department.

Raremayaffect1in1000people

Seriousallergicreactionwhichcausesswellingofthe

face,tongueandthroatthatcancausegreatdifficultyin

breathing.

Seriousillnesswithseverepeelingandswellingoftheskin,

blisteringoftheskin,mouth,eyesgenitalsandfever.Skin

rashwithpink-redblotchesespeciallyonpalmsofhandsor

solesoffeetwhichmay blister.

Muscleweakness,tendernessorpainandparticularly,ifat

thesametime,youfeelunwellorhaveahightemperature

itmaybecausedbyanabnormalmusclebreakdown.The

abnormalmusclebreakdowndoesnotalwaysgoaway,

evenafteryouhavestoppedtakingatorvastatin,anditcan

belife-threateningandleadtokidneyproblems.

Very rare (mayaffectupto1in10,000people)

Ifyouexperienceproblemswithunexpectedorunusual

bleedingorbruising,thismaybesuggestiveofaliver

complaint.Youshouldconsultyourdoctorassoonaspossible.

Other possible side effects with Atorvastatin

Pharmathen:

Common(mayaffectupto1in10people)

inflammationofthenasalpassages,paininthethroat,nosebleed

allergicreactions

increasesinbloodsugarlevels(ifyouhavediabetes

continuecarefulmonitoringofyourbloodsugarlevels),

increaseinbloodcreatinekinase

headache

Nausea,constipation,wind,indigestion,diarrhoea

jointpain,,musclepain,backpain

bloodtestresultsthatshowyourliverfunctioncan

becomeabnormal

Uncommon(mayaffectupto1in100people)

Anorexia(lossofappetite),weightgain,decreasesinblood

sugarlevels(Ifyouhavediabetesyoushouldcontinue

carefulmonitoring ofyourbloodsugarlevels)

havingnightmares,insomnia

dizziness,numbnessortinglinginthefingersandtoes,

reductionsofsensationtopainortouch,changeinsense

oftaste,lossofmemory

blurredvision

ringingintheearsand/orhead

vomiting,belching,abdominalpainupperandlower,

pancreatitis(inflammationofpancreasleadingtostomach

pain)

hepatitis(liverinflammation)

rash,skinrashanditching,hives,hairloss

neckpain,musclefatigue

fatigue,feelingunwell,weakness,chestpain,swelling

especiallyintheankles(oedema),raisedtemperature

urineteststhatarepositiveforwhitebloodcells

Rare(mayaffectupto1in1,000people)

visualdisturbance

unexpectedbleedingorbruising

cholestasis(yellowingoftheskinandwhitesoftheeyes)

tendoninjury.

Very rare(mayaffectupto1in10,000people)

anallergicreaction–symptomsmayincludesudden

wheezingandchestpainortightness,swellingofthe

eyelids,face,lips,mouth,tongueorthroat,difficulty

breathing,collapse

hearingloss

gynecomastia(breastenlargementinmen).

Side effects of unknown frequency:Muscleweakness

thatisconstant

The following adverse reactions have been reported

with other statins:

Possiblesideeffectsreportedwithsomestatins(medicines

ofthesametype):

Sexualdifficulties

Depression

Breathingproblems includingpersistentcoughand/or

shortnessofbreathorfever

Diabetes. Thisismorelikelyifyouhavehighlevelsof

sugarsandfatsinyourblood,areoverweightandhave

highbloodpressure.Yourdoctorwillmonitoryouwhile

youaretakingthismedicine.

Reporting of side effects

Ifyougetanysideeffects,talktoyourdoctor,pharmacist

ornurse. Thisincludesanypossiblesideeffectsnotlisted

inthisleaflet.Youcanalsoreportsideeffectsdirectlyvia

HPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin

2,Tel:+35316764971,Fax:+35316762517,Website:

www.hpra.ie,e-mail:medsafety@hpra.ie.Byreportingside

effectsyoucanhelpprovidemoreinformationonthesafety

5.How to store Atorvastatin Pharmathen

Keepoutofreachandsightofchildren.

Storebelow30°C.

DonotuseAtorvastatinPharmathenaftertheexpirydate

whichisstatedonthecontainerandouterpackagingafter

(EXP).Theexpirydatereferstothelastdayofthatmonth.

Askyourpharmacisthowtothrowawaymedicinesyou

nolongeruse.Thesemeasureswillhelptoprotectthe

environment.

6.Contents of the packand other information

WhatAtorvastatin Pharmathen contains

-Theactivesubstanceisatorvastatin.

oEachAtorvastatinPharmathen10mgfilm-coatedtablet

contains10mgatorvastatin(asatorvastatincalcium).

oEachAtorvastatinPharmathen20mgfilm-coatedtablet

contains20mgatorvastatin(asatorvastatincalcium).

oEachAtorvastatinPharmathen40mgfilm-coatedtablet

contains40mgatorvastatin(asatorvastatincalcium).

oEachAtorvastatinPharmathen80mgfilm-coatedtablet

contains80mgatorvastatin(asatorvastatincalcium).

-TheotheringredientsofAtorvastatinPharmathenare:

oTabletcore:Activatedattapulgite,lactosemonohydrate,

cellulosemicrocrystalline,starchmaizepregelatinised,

hydroxypropylcellulose,magnesiumstearateandsilica

colloidalanhydrous.

oTFilm-coating:Titaniumdioxide(E171),lactose

monohydrate,macrogol/PEG4000,hypromellose15

cP(E464),hypromellose3cP(E464)andhypromellose

50cP(E464)..

WhatAtorvastatin Pharmathen looks like and

contents of the pack

10mgfilm-coatedtablets:

White,oval,biconvex tablets,withdimensions10.1±0.1mm

x5.6±0.1mmand3.7±0.2mminthickness

20mgfilm-coatedtablets:

White,ovalbiconvextablets,withbreaklineinonesideand

dimensions12.7±0.1mmx6.7±0.1mmand4.6±0.2mmin

thickness

40mgfilm-coatedtablets:

White,oblong,biconvextabletswithdimensions

19.4±0.1mmx7.8±0.1mmand4.7±0.2mminthickness

80mgfilm-coatedtablets:

White,oblong,biconvextabletswithbreaklineinone

sideanddimensions22.8±0.1mm,10.9±0.1mmand

5.7±0.2mminthickness

Thebreaklineisonlytofacilitatebreakingforeaseof

swallowingand nottodivideintoequaldoses.

AtorvastatinPharmathenissuppliedinPA/ALL/PVC–

Aluminium foilblisterpacks.

Thepacksizesarethefollowing:

10,14,28,30,50,60,84,90,96,98,100

Notallpacksizesmaybemarketed.

Marketing Authorisation Holder and Manufacturer

MarketingAuthorisationHolder:

PHARMATHENS.A.,Dervenakion6,Pallini15351,Attiki

Greece

Manufacturer:

PHARMATHENS.A.,Dervenakion6,Pallini15351,Attiki

Greece

Or

PHARMATHENINTERNATIONALS.A,IndustrialParkSapes,

RodopiPrefecture,Block No5,Rodopi69300,Greece

McDermottLaboratoriest/aGerardLaboratories,35/36

BaldoyleIndustrialEstate,GrangeRoad,Dublin13,Ireland

Or

Generics[UK]Limited,StationClose,PottersBar,

Hertfordshire,EN61TL,UnitedKingdom

Or

SUPROBIONSpólkazograniczonaodpowiedzialnoscia

Spólkakomandytowa,ul.Kiełczowska2,Mirków,55-095,

Poland(for10mg,20mg,40mgonly)

This medicinal productis authorized in the Member

States of the EEA under the following names:

Denmark:AtorvastatinGenerics

Netherlands:Atorvastatine10A,filmomhuldetabletten

10mg,Atorvastatine20A,filmomhuldetabletten20

mg,Atorvastatine40A,filmomhuldetabletten40mg,

Atorvastatine80A,filmomhuldetabletten80mg

Cyprus,Poland:Lambrinex

Germany:AtorvastatinMylan10mg,20mg,40mg,80mg

Filmtablette

Spain:AtorvastatinaAmneal10mg,20mg,40mg,80mg

ComprimidorecubiertoconpelículaEFG

France:AtorvastatinMylanPharma10mg,20mg,40mg,

80mgComprimépelliculé

Ireland:AtorvastatinPharmathen10mg,20mg,40mg,80

mgFilm-coatedtablet

UK:Atorvastatin10mg,20mg,40mg, 80mgfilm-coated

tablet

Greece:Lambrinex10mg,20mg,40mg,80mg

This leafletwas lastapproved in

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AtorvastatinPharmathen80mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains80mgatorvastatin(asatorvastatincalcium).

Excipients:

Each80mgfilm-coatedtabletcontains331.32-349.08mgoflactosemonohydrate.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet

White,oblong,biconvextabletswithbreaklineinonesideanddimensions22.8±0.1mm,10.9±0.1mmand5.7±0.2mm

inthickness.

Thebreaklineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolaemia:

AtorvastatinPharmathenisindicatedasanadjuncttodietforreductionofelevatedtotalcholesterol(total-C),

LDLcholesterol(LDL-C),apolipoproteinB,andtriglyceridesinadults,adolescentsandchildrenaged10yearsorolder

withprimaryhypercholesterolaemia,includingfamilialhypercholesterolaemia(heterozygousvariant)orcombined

(mixed)hyperlipidaemia(correspondingtoTypesIIaandIIboftheFredricksonclassification)whenresponsetodiet

andothernon-pharmacologicalmeasuresisinadequate.

AtorvastatinPharmathenisalsoindicatedtoreducetotal-CandLDL-Cinadultswithhomozygousfamilial

hypercholesterolaemiaasanadjuncttootherlipid-loweringtreatment(e.g.LDLapheresis)orifsuchtreatmentsare

unavailable.

Preventionofcardiovasculardisease:

Preventionofcardiovasculareventsinadultpatientsestimatedtohaveahighriskforafirstcardiovascularevent(see

section5.1)asanadjuncttocorrectionofotherriskfactors.

4.2Posologyandmethodofadministration

Posology

Thepatientshouldbeplacedonastandardcholesterol-loweringdietbeforereceivingAtorvastatinPharmathenand

shouldcontinueonthisdietduringtreatmentwithAtorvastatinPharmathen.

ThedoseshouldbeindividualisedaccordingtobaselineLDL -Clevels,thegoaloftherapy,andpatientresponse.

Theusualstartingdosein10mgonceaday.Adjustmentofdoseshouldbemadeatintervalsof4weeksormore.The

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Primaryhypercholesterolaemiaandcombined(mixed)hyperlipidaemia

ThemajorityofpatientsarecontrolledwithAtorvastatinPharmathen10mgonceaday.Atherapeuticresponseis

evidentwithin2weeks,andthemaximumtherapeuticresponseisusuallyachievedwithin4weeks.Theresponseis

maintainedduringchronictherapy.

Heterozygousfamilialhypercholesterolaemia

PatientsshouldbestartedwithAtorvastatinPharmathen10mgdaily.Dosesshouldbeindividualisedandadjusted

every4weeksto40mgdaily.Thereafter,eitherthedosemaybeincreasedtoamaximumof80mgdailyorabileacid

sequestrantmaybecombinedwith40mgatorvastatinoncedaily.

Homozygousfamilialhypercholesterolaemia

Onlylimiteddataareavailable(seesection5.1).

Thedoseofatorvastatininpatientswithhomozygousfamilialhypercholesterolaemiais10to80mgdaily(seesection

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

orifsuchtreatmentsareunavailable.

Preventionofcardiovasculardisease

Intheprimarypreventiontrials,thedosewas10mg/day.Higherdosesmaybenecessaryinordertoattain(LDL-)

cholesterollevelsaccordingtocurrentguidelines.

Patientswithrenalimpairement

Noadjustmentofdoseisrequired(seesection4.4).

Patientswithhepaticimpairment

AtorvastatinPharmathenshouldbeusedwithcautioninpatientswithhepaticimpairment(seesections4.4and5.2).

AtorvastatinPharmatheniscontraindicatedinpatientswithactiveliverdisease(seesection4.3).

Useintheelderly

Efficacyandsafetyinpatientsolderthan70usingrecommendeddosesaresimilartothatseeninthegeneral

population.

Paediatricuse

Hypercholesterolaemia:

Paediatricuseshouldonlybecarriedoutbyphysiciansexperiencedinthetreatmentofpaediatrichyperlipidaemiaand

patientsshouldbere-evaluatedonaregularbasistoassessprogress.

Forpatientsaged10yearsandabove,therecommendedstartingdoseofatorvastatinis10mgperdaywithtitrationup

to20mgperday.Titrationshouldbeconductedaccordingtotheindividualresponseandtolerabilityinpaediatric

patients.Safetyinformationforpaediatricpatientstreatedwithdosesabove20mg,correspondingtoabout0.5mg/kg,

islimited.

Thereislimitedexperienceinchildrenbetween6-10yearsofage(seesection5.1).Atorvastatinisnotindicatedinthe

treatmentofpatientsbelowtheageof10years.

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Methodofadministration

AtorvastatinPharmathenisfororaladministration.Eachdailydoseofatorvastatinisgivenallatonceandmaybe

givenatanytimeoftheday,withorwithoutfood.

4.3Contraindications

AtorvastatinPharmatheniscontraindicatedinpatients:

withhypersensitivitytotheactivesubstanceortoanyoftheexcipientsofthismedicinalproductlistedinsection

6.1.

withactiveliverdiseaseorunexplainedpersistentelevationsofserumtransaminasesexceeding3timestheupper

limitofnormal

duringpregnancy,whilebreast-feeding,andinwomenofchild-bearingpotentialnotusingappropriate

contraceptivemeasures(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Livereffects

Liverfunctiontestsshouldbeperformedbeforetheinitiationoftreatmentandperiodicallythereafter.Patientswho

developanysignsorsymptomssuggestiveofliverinjuryshouldhaveliverfunctiontestsperformed.Patientswho

developincreasedtransaminaselevelsshouldbemonitoreduntiltheabnormality(ies)resolve.Shouldanincreasein

transaminasesofgreaterthan3timestheupperlimitofnormal(ULN)persist,reductionofdoseorwithdrawalof

AtorvastatinPharmathenisrecommended(seesection4.8).

AtorvastatinPharmathenshouldbeusedwithcautioninpatientswhoconsumesubstantialquantitiesofalcoholand/or

haveahistoryofliverdisease.

StrokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)

Inapost-hocanalysisofstrokesubtypesinpatientswithoutcoronaryheartdisease(CHD)whohadarecentstrokeor

transientischemicattack(TIA)therewasahigherincidenceofhemorrhagicstrokeinpatientsinitiatedonatorvastatin

80mgcomparedtoplacebo.Theincreasedriskwasparticularlynotedinpatientswithpriorhemorrhagicstrokeor

lacunarinfarctatstudyentry.Forpatientswithpriorhemorrhagicstrokeorlacunarinfarct,thebalanceofrisksand

benefitsofatorvastatin80mgisuncertainandthepotentialriskofhemorrhagicstrokeshouldbecarefullyconsidered

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

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otherpredisposingfactorsforrhabdomyolysis

Situationswhereanincreaseinplasmalevelsmayoccur,suchasinteractions(seesection4.5)andspecial

populationsincludinggeneticsubpopulations(seesection5.2)

Insuchsituations,theriskoftreatmentshouldbeconsideredinrelationtopossiblebenefitandclinicalmonitoringis

recommended.

IfCKlevelsaresignificantlyelevated(>5timesULN)atbaseline,treatmentshouldnotbestarted.

Creatinekinasemeasurement

Creatinekinase(CK)shouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofanyplausible

alternativecauseofCKincreaseasthismakesvalueinterpretationdifficult.IfCKlevelsaresignificantlyelevatedat

baseline(>5timesULN),levelsshouldbere-measuredwithin5to7dayslatertoconfirmtheresults.

Whilstontreatment

Patientsmustbeaskedtopromptlyreportmusclepain,crampsorweaknessespeciallyifaccompaniedbymalaise

orfever.

Ifsuchsymptomsoccurwhilstapatientisreceivingtreatmentwithatorvastatin,theirCKlevelsshouldbe

measured.Iftheselevelsarefoundtobesignificantlyelevated(>5timesULN),treatmentshouldbestopped.

Ifmuscularsymptomsaresevereandcausedailydiscomfort,eveniftheCKlevelsareelevatedto 5xULN,

treatmentdiscontinuationshouldbeconsidered.

IfsymptomsresolveandCKlevelsreturntonormal,thenre-introductionofatorvastatinorintroductionofan

alternativestatinmaybeconsideredatthelowestdoseandwithclosemonitoring.

AtorvastatinmustbediscontinuedifclinicallysignificantelevationofCKlevels(>10xULN)occur,orif

rhabdomyolysisisdiagnosedorsuspected.

Concomitanttreatmentwithothermedicinalproducts

Riskofrhabdomyolysisisincreasedwhenatorvastatinisadministeredconcomitantlywithcertainmedicinalproducts

thatmayincreasetheplasmaconcentrationofatorvastatinsuchaspotentinhibitorsofCYP3A4ortransportproteins

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

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

ofmyopathymayalsobeincreasedwiththeconcomitantuseofgemfibrozilandotherfibricacidderivates,boceprevir,

erythromycin,niacin,ezetimibe,telaprevir,orthecombinationoftipranavir/ritonavir.Ifpossible,alternative(non-

interacting)therapiesshouldbeconsideredinsteadofthesemedicinalproducts.

Incaseswhereco-administrationofthesemedicinalproductswithatorvastatinisnecessary,thebenefitandtheriskof

concurrenttreatmentshouldbecarefullyconsidered.Whenpatientsarereceivingmedicinalproductsthatincreasethe

plasmaconcentrationofatorvastatin.,alowermaximumdoseofatorvastatinisrecommended.Inaddition,inthecase

ofpotentCYP3A4inhibitors,alowerstartingdoseofatorvastatinshouldbeconsideredandappropriateclinical

monitoringofthesepatientsisrecommended(seesection4.5).

Atorvastatinmustnotbeco-administeredwithsystemicformulationsoffusidicacidorwithin7daysofstopping

fusidicacidtreatment.Inpatientswheretheuseofsystemicfusidicacidisconsideredessential,statintreatmentshould

bediscontinuedthroughoutthedurationoffusidicacidtreatment.Therehavebeenreportsofrhabdomyolysis

(includingsomefatalities)inpatientsreceivingfusidicacidandstatinsincombination(seesection4.5).Thepatient

shouldbeadvisedtoseekmedicaladviceimmediatelyiftheyexperienceanysymptomsofmuscleweakness,painor

tenderness.

Statintherapymaybere-introducedsevendaysafterthelastdoseoffusidicacid.

Inexceptionalcircumstances,whereprolongedsystemicfusidicacidisneeded,e.g.,forthetreatmentofsevere

infections,theneedforco-administrationofAtorvastatinandfusidicacidshouldonlybeconsideredonacasebycase

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Paediatricuse

Developmentalsafetyinthepaediatricpopulationhasnotbeenestablished(seesection4.8).

DiabetesMellitus

Someevidencesuggeststhatstatinsasaclassraisebloodglucoseandinsomepatients,athighriskoffuturediabetes,

mayproducealevelofhyperglycaemiawhereformaldiabetescareisappropriate.Thisrisk,however,isoutweighedby

thereductioninvascularriskwithstatinsandthereforeshouldnotbeareasonforstoppingstatintreatment.Patientsat

risk(fastingglucose5.6to6.9mmol/L,BMI>30kg/m 2

,raisedtriglycerides,hypertension)shouldbemonitoredboth

clinicallyandbiochemicallyaccordingtonationalguidelines.

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,nonproductivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

Immune-mediatednecrotizingmyopathy(IMNM)

Therehavebeenveryrarereportsofanimmune-mediatednecrotizingmyopathy(IMNM)duringoraftertreatment

withsomestatins.IMNMisclinicallycharacterizedbypersistentproximalmuscleweaknessandelevatedserum

creatinekinase,whichpersistdespitediscontinuationofstatintreatment.

Excipients

AtorvastatinPharmathencontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,Lapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

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

concomitantlyusedwithmoderateCYP3A4inhibitors.Appropriateclinicalmonitoringisrecommendedafterinitiation

orfollowingdoseadjustmentsoftheinhibitor.

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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,includingrhabdomyolysisTheriskof

theseeventsmaybeincreasedwiththeconcomitantuseoffibricacidderivativesandatorvastatin.Ifconcomitant

administrationcannotbeavoided,thelowestdoseofatorvastatintoachievethetherapeuticobjectiveshouldbeused

andthepatientsshouldbeappropriatelymonitored(seesection4.4).

Ezetimibe

Theuseofezetimibealoneisassociatedwithmusclerelatedevents,includingrhabdomyolysis.Theriskoftheseevents

maythereforebeincreasedwithconcomitantuseofezetimibeandatorvastatin.Appropriateclinicalmonitoringof

thesepatientsisrecommended.

Colestipol

Plasmaconcentrationsofatorvastatinanditsactivemetaboliteswerelower((byapprox.25%)whencolestipolwasco-

administeredwithAtorvastatinPharmathen.However,lipideffectsweregreaterwhenAtorvastatinPharmathenand

colestipolwereco-administeredthanwheneithermedicinalproductwasgivenalone.

Fusidicacid

Theriskofmyopathyincludingrhabdomyolysismaybeincreasedbytheconcomitantadministrationofsystemic

fusidicacidwithstatins.Themechanismofthisinteraction(whetheritispharmacodynamicorpharmacokinetic,or

both)isyetunknown.Therehavebeenreportsofrhabdomyolysis(includingsomefatalities)inpatientsreceivingthis

combination.

Iftreatmentwithsystemicfusidicacidisnecessary,atorvastatintreatmentshouldbediscontinuedthroughoutthe

durationofthefusidicacidtreatment.Alsoseesection4.4

Colchicine

Althoughinteractionstudieswithatorvastatinandcolchicinehavenotbeenconducted,casesofmyopathyhavebeen

reportedwithatorvastatinco-administeredwithcolchicine,andcautionshouldbeexercisedwhenprescribing

atorvastatinwithcolchicine.

Effectofatorvastatinonco-administeredmedicinalproducts

Digoxin

Whenmultipledosesofdigoxinand10mgatorvastatinwereco-administered,steady-statedigoxinconcentrations

increasedslightly.Patientstakingdigoxinshouldbemonitoredappropriately.

Oralcontraceptives

Co-administrationofAtorvastatinPharmathenwithanoralcontraceptiveproducedincreasesinplasmaconcentrations

ofnorethindroneandethinyloestradiol.

Warfarin

Inaclinicalstudyinpatientsreceivingchronicwarfarintherapy,co-administrationofatorvastatin80mgdailywith

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returnedtonormalwithin15daysofatorvastatintreatment.Althoughonlyveryrarecasesofclinicallysignificant

anticoagulantinteractionshavebeenreported,prothrombintimeshouldbedeterminedbeforestartingatorvastatinin

patientstakingcoumarinanticoagulantsandfrequentlyenoughduringearlytherapytoensurethatnosignificant

alterationofprothrombintimeoccurs.Onceastableprothrombintimehasbeendocumented,prothrombintimescanbe

monitoredattheintervalsusuallyrecommendedforpatientsoncoumarinanticoagulants.Ifthedoseofatorvastatinis

changedordiscontinued,thesameprocedureshouldberepeated.Atorvastatintherapyhasnotbeenassociatedwith

bleedingorwithchangesinprothrombintimeinpatientsnottakinganticoagulants.

Table1:Effectofco-administeredmedicinalproductsonthepharmacokineticsofatorvastatin

Co-administeredmedicinal

product

anddosingregimen Atorvastatin

Dose(mg) ChangeinAUC& Clinical

Recommendation#

Telaprevir750mgq8h,10days 20mg,SD 7.9fold Incaseswhere

coadministrationwith

atorvastatinis

necessary,donot

exceed10mg

atorvastatindaily.

Clinicalmonitoring

ofthesepatientsis

recommended Tipranavir500mgBID/

Ritonavir200mgBID,8days

(days14to21) 40mgonday1,10

mgonday20 9.4fold

Ciclosporin5.2mg/kg/day,stable

dose 10mgODfor28

days 8.7fold

Lopinavir400mgBID/Ritonavir

100mgBID,14days 20mgODfor4

days 5.9fold Incaseswhereco-

administrationwith

atorvastatinis

necessary,lower

maintenancedosesof

atorvastatinare

recommended.At

atorvastatindoses

exceeding20mg,

clinicalmonitoringof

thesepatientsis

recommended. Clarithromycin500mgBID,9

days 80mgODfor8

days 4.4fold

Saquinavir400mgBID/

Ritonavir(300mgBIDfrom

days5-7,increasedto400mg

BIDonday8),days5-18,30min

afteratorvastatindosing 40mgODfor4

days 3.9fold Incaseswhereco-

administrationwith

atorvastatinis

necessary,lower

maintenancedosesof

atorvastatinare

recommended.At

atorvastatindoses

exceeding40mg,

clinicalmonitoringof

thesepatientsis

recommended. Darunavir300mgBID/

Ritonavir100mgBID,9days 10mgODfor4

days 3.3fold

Itraconazole200mgOD,4days 40mgSD 3.3fold

Fosamprenavir700mgBID/

Ritonavir100mgBID,14days 10mgODfor4

days 2.5fold

Fosamprenavir1400mgBID,14

days 10mgODfor4

days 2.3fold

Nelfinavir1250mgBID,14days 10mgODfor28

days 1.7fold^ Nospecific

recommendation

GrapefruitJuice,240mLOD* 40mg,SD 37% Concomitantintake

oflargequantitiesof

grapefruitjuiceand

atorvastatinisnot

recommended.

Diltiazem240mgOD,28days 40mg,SD 51% Afterinitiationor

followingdose

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

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

Seesections4.4and4.5forclinicalsignificance.

ContainsoneormorecomponentsthatinhibitCYP3A4andcanincreaseplasmaconcentrationsof

medicinalproductsmetabolizedbyCYP3A4.Intakeofone240mlglassofgrapefruitjuicealsoresulted

inadecreasedAUCof20.4%fortheactiveorthohydroxymetabolite.Largequantitiesofgrapefruitjuice

(over1.2ldailyfor5days)increasedAUCofatorvastatin2.5foldandAUCofactive(atorvastatinand

metabolites).

diltiazem,appropriate

clinicalmonitoringof

thesepatientsis

recommended.

Erythromycin500mgQID,7

days 10mg,SD 33%^ Lowermaximum

doseandclinical

monitoringofthese

patientsis

recommended.

Amlodipine10mg,singledose 80mg,SD 18% Nospecific

recommendation.

Cimetidine300mgQID,2weeks 10mgODfor2

weeks lessthan1%^ Nospecific

recommendation.

Antacidsuspensionof

magnesiumandaluminium

hydroxides,30mLQID,2weeks 10mgODfor4

weeks 35%^ Nospecific

recommendation.

Efavirenz600mgOD,14days 10mgfor3days 41% Nospecific

recommendation.

Rifampin600mgOD,7days

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

cannotbeavoided,

simultaneousco-

administrationof

atorvastatinwith

rifampinis

recommended,with

clinicalmonitoring. Rifampin600mgOD,5days

(dosesseparated) 40mgSD 80%

Gemfibrozil600mgBID,7days 40mgSD 35% Lowerstartingdose

andclinical

monitoringofthese

patientsis

recommended.

Fenofibrate160mgOD,7days 40mgSD 3% Lowerstartingdose

andclinical

monitoringofthese

patientsis

recommended.

Boceprevir800mgTID,7days 40mgSD 2.3fold Lowerstartingdose

andclinical

monitoringofthese

patientsis

recommended.The

doseofatorvastatin

shouldnotexceeda

dailydoseof20mg

duringco-

administrationwith

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Increaseisindicatedas“”,decreaseas“”

OD=oncedaily;SD=singledose;BID=twicedaily;TID=threetimesdaily;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

intoaccountforthepaediatricpopulation.

4.6Fertility,pregnancyandlactation

Womenofchildbearingpotential

Womenofchild-bearingpotentialshoulduseappropriatecontraceptivemeasuresduringtreatment(seesection4.3).

Pregnancy

AtorvastatinPharmatheniscontraindicatedduringpregnancy(seesection4.3).Safetyinpregnantwomenhasnotbeen

establishedNocontrolledclinicaltrialswithatorvastatinhavebeenconductedinpregnantwomen.Rarereportsof

congenitalanomaliesfollowingintrauterineexposuretoHMG-CoAreductaseinhibitorshavebeenreceived.Animal

studieshaveshowntoxicitytoreproduction(seesection5.3).

Atorvastatin and dosing

regimen Co-administeredmedicinalproduct

Medicinal

product/Dose(mg) ChangeinAUC& Clinical

Recommendation

80mgODfor10days Digoxin 0.25 mg

OD,20days 15% Patients taking

digoxinshouldbe

monitored

appropriately.

40mgODfor22days Oral contraceptive

OD,2months

norethindrone 1

-ethinylestradiol35

specific

recommendation.

80mgODfor15days *Phenazone,600

mgSD 3% No specific

recommendation

10mg,SD Tipranavir500mg

BID/ritonavir200

mgBID,7days Nochange Nospecific

recommendation

10mg,ODfor4days Fosamprenavir1400

mgBID,14days 27% Nospecific

recommendation

10mgODfor4days Fosamprenavir700

mgBID/ritonavir

100mgBID,14

days Nochange Nospecific

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biosynthesis.Atherosclerosisisachronicprocess,andordinarilydiscontinuationoflipid-loweringmedicinalproducts

duringpregnancyshouldhavelittleimpactonthelong-termriskassociatedwithprimaryhypercholesterolaemia.

Forthesereasons,AtorvastatinPharmathenshouldnotbeusedinwomenwhoarepregnant,tryingtobecomepregnant

orsuspecttheyarepregnant.TreatmentwithAtorvastatinPharmathenshouldbesuspendedforthedurationof

pregnancyoruntilithasbeendeterminedthatthewomanisnotpregnant(seesection4.3.)

Breastfeeding

Itisnotknownwhetheratorvastatinoritsmetabolitesareexcretedinhumanmilk.Inrats,plasmaconcentrationsof

atorvastatinanditsactivemetabolitesaresimilartothoseinmilk(seesection5.3).

Becauseofthepotentialforseriousadversereactions,womentakingAtorvastatinPharmathenshouldnotbreast-feed

theirinfants(seesection4.3).Atorvastatiniscontraindicatedduringbreastfeeding(seesection4.3).

Fertility

Inanimalstudiesatorvastatinhadnoeffectonmaleorfemalefertility(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

AtorvastatinPharmathenhasnegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

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

forameanperiodof53weeks,5.2%ofpatientsonatorvastatindiscontinuedduetoadversereactionscomparedto

4.0%ofthepatientsonplacebo.

Basedondatafromclinicalstudiesandextensivepost-marketingexperience,thefollowingtablepresenttheadverse

reactionprofileforAtorvastatinPharmathen.Estimatedfrequenciesofreactionsarerankedaccordingtothefollowing

convention:common(1/100to<1/10);uncommon(1/1,000to<1/100);rare(1/10,000to<1/1,000);veryrare

(<1/10,000)andnotknown(cannotbeestimatedfromtheavailabledata).

Infectionsandinfestations:

Common:nasopharyngitis.

Bloodandlymphaticsystemdisorders

Rare:thrombocytopenia.

Immunesystemdisorders

Common:allergicreactions

Veryrare:anaphylaxis

Metabolismandnutritiondisorders

Common:hyperglycaemia

Uncommon:hypoglycaemia,weightgain,anorexia

Psychiatricdisorders

Uncommon:nightmare,insomnia.

Nervoussystemdisorders

Common:headache

Uncommon:dizziness,paraesthesia,hypoesthesia,dysgeusia,amnesia

Rare:peripheralneuropathy

Eyedisorders

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Rare:visualdisturbance.

Earandlabyrinthdisorders

Uncommon:tinnitus.

Veryrare:hearingloss.

Respiratory,thoracicandmediastinaldisorders:

Common:pharyngolaryngealpain,epistaxis.

Gastrointestinaldisorders

Common:constipation,flatulence,dyspepsia,nausea,diarrhoea

Uncommon:vomiting,abdominalpain,upperandlower,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,tendinopathy,sometimescomplicatedbyrupture.

Notknown:immune-mediatednecrotizingmyopathy(seesection4.4)

Reproductivesystemandbreastdisorders

Veryrare:gynecomastia.

Generaldisordersandadministrationsiteconditions

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

ClassEffects

Sexualdysfunction

Depression

Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seesection4.4)

DiabetesMellitus:Frequencywilldependonthepresenceorabsenceofriskfactors(fastingbloodglucose 5.6

mmol/L,BMI>30kg/m 2

,raisedtriglycerides,historyofhypertension).

Investigations

Common:liverfunctiontestabnormal,bloodcreatinekinaseincreased.

Uncommon:whitebloodcellsurinepositive.

AswithotherHMG-CoAreductaseinhibitorselevatedserumtransaminaseshavebeenreportedinpatientsreceiving

AtorvastatinPharmathen.Thesechangeswereusuallymild,transient,anddidnotrequireinterruptionoftreatment.

Clinicallyimportant(>3timesuppernormallimit)elevationsinserumtransaminasesoccurredin0.8%patients

onAtorvastatinPharmathen.Theseelevationsweredose-relatedandwerereversibleinallpatients.

Elevatedserumcreatinekinase(CK)levelsgreaterthan3timesupperlimitofnormaloccurredin2.5%ofpatientson

AtorvastatinPharmathen,similartootherHMG-CoAreductaseinhibitorsinclinicaltrials..Levelsabove10timesthe

normalupperrangeoccurredin0.4%AtorvastatinPharmathentreatedpatients(seesection4.4).

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Theclinicalsafetydatabaseincludessafetydatafor249paediatricpatientswhoreceivedatorvastatin,amongwhich7

patientswere<6yearsold,14patientswereintheagerangeof6to9,and228patientswereintheagerangeof10to

Nervoussystemdisorders

Common:Headache

Gastrointestinaldisorders

Common:Abdominalpain

Investigations

Common:Alanineaminotransferaseincreased,bloodcreatinephosphokinaseincreased

Basedonthedataavailable,frequency,typeandseverityofadversereactionsinchildrenareexpectedtobethesameas

inadults.Thereiscurrentlylimitedexperiencewithrespecttolong-termsafetyinthepaediatricpopulation.

Reportingofsuspectedadversereactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportany

suspectedadversereactionsviaHPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin2;Tel:+35316764971;

Fax:+35316762517.Website:www.hpra.ie;E-mail:medsafety@hpra.ie.

4.9Overdose

SpecifictreatmentisnotavailableforAtorvastatinPharmathenoverdose.Shouldanoverdoseoccur,thepatientshould

betreatedsymptomaticallyandsupportivemeasuresinstituted,asrequired.Liverfunctiontestsshouldbeperformed

andserumCKlevelsshouldbemonitored.Duetoextensiveatorvastatinbindingtoplasmaproteins,haemodialysisis

notexpectedtosignificantlyenhanceatorvastatinclearance.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Lipidmodifyingagents,HMG-CoAreductaseinhibitors,ATCcode:

C10AA05

Atorvastatinisaselective,competitiveinhibitorofHMG -CoAreductase,therate-limitingenzymeresponsibleforthe

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

Triglyceridesandcholesterolintheliverareincorporatedintoverylow-densitylipoptoteins(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%),apolipoproteinB

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doseresponsestudy.Theseresultsareconsistentinpatientswithheterozygousfamilialhypercholesterolaemia,

nonfamilialformsofhypercholesterolaemia,andmixedhyperlipidaemia,includingpatientswithnoninsulin-dependent

diabetesmellitus.

Reductionsintotal-C,LDL-CandapolipoproteinBhavebeenproventoreduceriskforcardiovasculareventsand

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%).

ThesafetyprofileofatorvastatinintheMIRACLstudywasconsistentwithwhatisdescribedinsection4.8.

Preventionofcardiovasculardisease

Theeffectofatorvastatinonfatalandnon-fatalcoronaryheartdiseasewasassessedinarandomised,double-blind,

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

Patientswerehypertensive,40-79yearsofage,withnopreviousmyocardialinfarctionortreatmentforangina,and

withTClevels 6.5mmol/L(251mg/dL).Allpatientshadatleast3ofthepre-definedcardiovascularriskfactors:

malegender,age 55years,smoking,diabetes,historyofCHDinafirst-degreerelative,TC:HDL-C>6,peripheral

vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality,

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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

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-fatalcardiovasculardiseasewasalsoassessedinarandomised,double-blind,

multicentre,placebo-controlledtrial,theCollaborativeAtorvastatinDiabetesStudy(CARDS)inpatientswithtype2

diabetes,40-75yearsofage,withoutpriorhistoryofcardiovasculardisease,andwithLDL-C 4.14mmol/L(160

mg/dL)andTG 6.78mmol/L(600mg/dL).Allpatientshadatleast1ofthefollowingriskfactors:hypertension,

currentsmoking,retinopathy,microalbuminuriaormacroalbuminuria.

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

years.

Event Relative

Risk

Reduction

(%) No.ofevents

(atorvastatinvs

placebo) Absolute

Risk

Reduction 1

(%) P-value

FatalCHDplusnon-

fatalMI 36% 100vs.154 1.1% 0.0005

Totalcardiovascular

eventsand

revascularisation

procudures 20% 389vs.483 1.9% 0.0008

Totalcoronary

events 29% 178vs.247 1.4% 0.0006

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.9years.

CHD=coronaryheartdisease;MI=myocardialinfarction

Event Relativerisk

reduction

(%) No.ofevents

(atorvastatinvs.

placebo) Absoluterisk

reduction 1

(%) Pvalue

Majorcardiovascularevents

(fatalandnon-fatalAMI,silent

MI,acuteCHDdeath,unstable

angina,CABG,PTCA,

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

MI(fatalandnon-fatalAMI,

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Therewasnoevidenceofadifferenceinthetreatmenteffectbypatient’sgender,ageorbaselineLDL-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)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.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)andincreasedtheincidenceofhaemorrhagicstroke(55/2365,2.3%vs.33/2366,1.4%,p=0.02)

comparedtoplacebo.

Theriskofhaemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorhaemorrhagicstroke

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

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

Theriskofhaemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorlacunarinfarct

(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

haemorrhagicstroke.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

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

Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.9years.

AMI=acutemyocardialinfarction;CABG=coronaryarterybypassgraft;CHD=

coronaryheartdisease;MI=myocardialinfarction;PTCA=percutaneoustransluminal

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

Forsubjectswhosedosewasdoubled,additionaldecreaseswereobservedasearlyas2weeks,atthefirstassessment,

afterdoseescalation.Themeanpercentdecreasesinlipidparametersweresimilarforbothcohorts,regardlessof

whethersubjectsremainedattheirinitialdoseordoubledtheirinitialdose.AtWeek8,onaverage,thepercentchange

frombaselineinLDL-CandTCwasapproximately40%and30%,respectively,overtherangeofexposures.

HeterozygousFamilialHypercholesterolaemiainPaediatricPatientsaged10-17yearsold

Inadouble-blind,placebocontrolledstudyfollowedbyanopen-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-Cvaluewas3.38

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).

compassionate use study in patients with severe hypercholesterolaemia (including homozygous

hypercholesterolaemia)included46paediatricpatientstreatedwithatorvastatintitratedaccordingtoresponse(some

subjectsreceived80mgatorvastatinperday).Thestudylasted3years:LDL-cholesterolwasloweredby36%.

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%.The

lowsystemicavailabilityisattributedtopresystemicclearanceingastrointestinalmucosaand/orhepaticfirst-pass

metabolism.

Distribution

Meanvolumeofdistributionofatorvastatinisapproximately381L.Atorvastatinis98%boundtoplasmaproteins.

Biotransformation

AtorvastatinismetabolisedbycytochromeP4503A4toortho-andparahydroxylatedderivativesandvariousbeta-

oxidationproducts.Apartfromotherpathwaystheseproductsarefurthermetabolisedviaglucuronidation.Invitro,

inhibitionofHMG-CoAreductasebyortho-andparahydroxylatedmetabolitesisequivalenttothatofatorvastatin.

Approximately70%ofcirculatinginhibitoryactivityforHMG-CoAreductaseisattributedtoactivemetabolites.

Elimination

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doesnotappeartoundergosignificantenterohepaticrecirculation.Meanplasmaeliminationhalf-lifeofatorvastatinin

humansisapproximately14hours.Thehalf-lifeofinhibitoryactivityforHMG-CoAreductaseisapproximately20to

30hoursduetothecontributionofactivemetabolites.

SpecialPopulations

Elderly

Plasmaconcentrationsofatorvastatinanditsactivemetabolitesarehigherinhealthyelderlysubjectsthaninyoung

adultswhilethelipideffectswerecomparabletothoseseeninyoungerpatientpopulations.

Paediatric

Inanopenlabel,8-weekstudy,TannerStage1(N=15)andTannerStage2(N=24)paediatricpatients(ages6-17

years)withheterozygousfamilialhypercholesterolemiaandbaselineLDL-C4mmol/Lweretreatedwith5or10mg

ofchewableor10or20mgoffilm-coatedatorvastatintabletsoncedaily,respectively.Bodyweightwastheonly

significantcovariateinatorvastatinpopulationPKmodel.Apparentoralclearanceofatorvastatininpaediatricsubjects

appearedsimilartoadultswhenscaledallometricallybybodyweight.ConsistentdecreasesinLDL-CandTCwere

observedovertherangeofatorvastatinando-hydroxyatorvastatinexposures.

Gender

Concentrationsofatorvastatinanditsactivemetabolitesinwomendifferfromthoseinmen(women:approx.20%

higherforC

andapprox.10%lowerforAUC).Thesedifferenceswereofnoclinicalsignificance,resultinginno

clinicallysignificantdifferencesinlipideffectsamongmenandwomen.

Patientswithrenalinsufficiency

Renaldiseasehasnoinfluenceontheplasmaconcentrationsorlipideffectsofatorvastatinanditsactivemetabolites.

PatientswithhepaticInsufficiency

Plasmaconcentrationsofatorvastatinanditsactivemetabolitesaremarkedlyincreased(approx.16-foldinCmaxand

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

SLOC1B1polymorphism

HepaticuptakeofallHMG-CoAreductaseinhibitorsincludingatorvastatin,involvestheOATP1B1transporter.In

patientswithSLCO1B1polymorphismthereisariskofincreasedexposureofatorvastatin,whichmayleadtoan

increasedriskofrhabdomyolysis(seesection4.4).PolymorphisminthegeneencodingOATP1B1(SLCO1B1

c.521CC)isassociatedwitha2.4-foldhigheratorvastatinexposure(AUC)thaninindividualswithoutthisgenotype

variant(c.521TT).Ageneticallyimpairedhepaticuptakeofatorvastatinisalsopossibleinthesepatients.Possible

consequencesfortheefficacyareunknown.

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

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Activatedattapulgite

Lactosemonohydrate

Cellulosemicrocrystalline

Starchmaizepregelatinised(Starch1500)

Hydroxypropylcellulose(HPC-L)

Magnesiumstearate

SilicaColloidalanhydrous

Film-coating

Titaniumdioxide(E171)

Lactosemonohydrate

Macrogol/PEG4000

Hypromellose15cP(E464)

Hypromellose3cP(E464)

Hypromellose50cP(E464)

6.2Incompatibilities

Notapplicable

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Storebelow30°C.

6.5Natureandcontentsofcontainer

listersofPA/ALL/PVC-Aluminiumfoil

AtorvastatinPharmathenissuppliedinthefollowingpacksizes:10,14,28,30,50,60,84,90,96,98,100

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

PharmathenS.A.

6Dervenakionstr.

15351Pallini

Attiki

Greece

8MARKETINGAUTHORISATIONNUMBER

PA1368/013/004

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

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Dateoflastrenewal:6thNovember2015

10DATEOFREVISIONOFTHETEXT

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Date Printed 21/07/2016 CRN 2173433 page number: 19

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