ATORVASTATIN 20 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
ATORVASTATIN CALCIUM TRIHYDRATE
Available from:
Ranbaxy Ireland Limited
ATC code:
C10AA05
INN (International Name):
ATORVASTATIN CALCIUM TRIHYDRATE
Dosage:
20 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:
Transfer Pending
Authorization number:
PA0408/090/002
Authorization date:
2012-09-07

Package leaflet: Informationfor the patient

Atorvastatin10 mg Film-coatedTablets

Atorvastatin20 mg Film-coatedTablets

Atorvastatin40 mg Film-coatedTablets

Atorvastatin80 mg Film-coatedTablets

Atorvastatin

Readall ofthisleafletcarefullybefore youstarttakingthismedicine because it

containsimportantinformationforyou.

Keepthisleaflet.Youmayneedtoreaditagain.

Ifyou haveanyfurtherquestions, askyourdoctororpharmacist.

Thismedicinehasbeen prescribedforyouonly. Donotpassiton to others.Itmay

harm them,eveniftheirsignsofillnessare the same asyours.

Ifyougetanysideeffects, talk toyourdoctororpharmacist. Thisincludesany

possiblesideeffectsnot listedinthisleaflet.See section4.

Whatisinthisleaflet

1. WhatAtorvastatin isand whatitisused for

2. Whatyou need to knowbeforeyou takeAtorvastatin

3. HowtotakeAtorvastatin

4. Possible side effects

5. Howto storeAtorvastatin

6. Contentsofthepack andotherinformation.

1. WhatAtorvastatinisandwhatitisusedfor

Atorvastatin belongsto agroup ofmedicinesknown asstatins, whicharelipid (fat)

regulatingmedicines.

Atorvastatin isused tolowerlipidsknown ascholesteroland triglyceridesin theblood

when alowfatdietandlife style changesontheirownhavefailed.Ifyouare atan

increased risk ofheartdisease, Atorvastatin can also beused to reducesuch risk even if

yourcholesterollevelsarenormal. You should maintain astandard cholesterollowering

diet duringtreatment.

2. Whatyouneedto knowbeforeyoutakeAtorvastatin

Do nottakeAtorvastatin:

ifyouare allergic toatorvastatinortoanysimilarmedicinesusedtolowerblood

lipidsortoanyoftheotheringredientsofthismedicine–(listed in section 6).

ifyouhave orhave everhada disease whichaffectsthe liver

ifyou havehadanyunexplained abnormalblood testsforliverfunction

ifyou areawoman ableto havechildrenand notusingreliablecontraception

ifyou arepregnant, ortryingto becomepregnant

ifyouare breast-feeding.

Warningsand precautions

Talk toyourdoctororpharmacistbeforetakingAtorvastatin

ThefollowingarereasonswhyAtorvastatinmaynotbesuitableforyou.

ifyou havehad apreviousstrokewithbleedinginto thebrain, orhavesmall

pocketsoffluid in thebrain frompreviousstrokes

ifyou havekidneyproblems

ifyou havean under-activethyroid gland (hypothyroidism)

ifyou havehad repeated orunexplained muscleachesorpains, apersonalhistory

orfamilyhistoryofmuscleproblems.

ifyou havehad previousmuscularproblemsduring treatmentwith otherlipid-

loweringmedicines(e.g.other‘-statin’or‘-fibrate’medicines)

ifyou regularlydrinkalargeamountofalcohol

ifyou haveahistoryofliverdisease

ifyou areolderthan 70years.

Checkwithyourdoctororpharmacistbeforetaking Atorvastatin

ifyouhave severerespiratoryfailure.

Ifanyoftheseapplytoyou,yourdoctorwillneed tocarryoutablood testbeforeand

possiblyduringyourAtorvastatintreatment topredictyourriskofmusclerelatedside

effects. Therisk ofmusclerelated sideeffectse.g. rhabdomyolysisisknowntoincrease

whencertainmedicinesare takenatthe same time (seesection 2 “Othermedicinesand

Atorvastatin”).

Whileyou areon thismedicineyour doctor willmonitor you closelyifyou havediabetesor

areatrisk ofdevelopingdiabetes. You arelikelytobeatrisk ofdevelopingdiabetesifyou

havehigh levelsofsugarsand fatsin your blood, areoverweightand havehigh blood

pressure.

OthermedicinesandAtorvastatin

There are some medicinesthatmaychange the effectofAtorvastatinortheireffectmay

bechanged byAtorvastatin. Thistypeofinteraction could makeoneorboth ofthe

medicineslesseffective.Alternativelyit couldincreasetheriskorseverityofside-

effects, includingtheimportantmusclewastingcondition knownasrhabdomyolysis

described insection 4“Possible side effects”.

Medicinesusedtoalterthe wayyourimmunesystemworks, e.g. ciclosporin

Certain antibioticsorantifungalmedicines, e.g. erythromycin, clarithromycin,

telithromycin, ketoconazole, itraconazole,voriconazole, fluconazole,

posaconazole, rifampin, fusidicacid

Othermedicinestoregulatelipid levels, e.g.gemfibrozil, otherfibrates, colestipol

Somecalciumchannelblockersused foranginaorhigh blood pressure, e.g.

amlodipine,diltiazem;medicinestoregulateyourheartrhythme.g.digoxin,

verapamil, amiodarone

Medicinesused in thetreatmentofHIVe.g. ritonavir, lopinavir, atazanavir,

indinavir, darunavir,thecombination oftipranavir/ritonaviretc.

Somemedicinesusedinthetreatment ofhepatitisCe.g.telaprevir

Othermedicinesknowntointeract withAtorvastatinincludeezetimibe(which

lowerscholesterol), warfarin (whichreducesblood clotting), oralcontraceptives,

stiripentol (ananti-convulsantforepilepsy), cimetidine(used forheartburn and

pepticulcers), phenazone(apainkiller), colchicine(used to treatgout),antacids

(indigestionproductscontainingaluminium ormagnesium)andboceprevir(for

treatment ofliverdiseaseashepatitisC).

Medicinesobtained withoutaprescription:StJohn’sWort

Tellyourdoctororpharmacistifyouare taking,have recentlytakenormighttakeany

othermedicines.

Atorvastatinwithfood,drinkandalcohol

Seesection3 forinstructionson howto takeAtorvastatin.

Pleasenotethefollowing:

Grapefruit juice

Do nottakemorethan oneortwo smallglassesofgrapefruitjuiceperdaybecause large

quantitiesofgrapefruitjuicecanchange the effectsofAtorvastatin.

Alcohol

Avoid drinkingtoo much alcoholwhiletakingthismedicine.Seesection 2.“Warnings

and precautions”fordetails.

Pregnancy andbreast-feeding

Do nottakeAtorvastatinifyou arepregnant, orifyou aretryingto becomepregnant.

Do nottakeAtorvastatinifyou areableto becomepregnantunlessyou usereliable

contraceptive measures.

Do nottakeAtorvastatinifyou arebreast-feeding.

The safetyofAtorvastatin duringpregnancyand breast-feedinghasnotyetbeen proven.

Askyourdoctororpharmacistforadvicebeforetakinganymedicine

Drivingand usingmachines

Normallythismedicinedoesnot affectyourabilitytodriveoroperatemachines.

However, do notdriveifthismedicineaffectsyourabilityto drive. Do notuseanytools

ormachinesifyourabilitytousethem isaffectedbythismedicine.

Atorvastatincontainslactose

Ifyou havebeen told byyourdoctorthatyou haveintoleranceto somesugars, contact

yourdoctorbeforetaking thismedicine

Atorvastatin containslessthan1mmol sodium (23mg)pertablet,i.e.essentially

‘sodium-free’.

3. Howto takeAtorvastatin

Beforestartingtreatment,yourdoctorwill placeyou on alow-cholesteroldiet, whichyou

should maintain also duringtherapywithAtorvastatin.

TherecommendedstartingdoseofAtorvastatinis10 mgonceadayin adultsand

children aged 10yearsorolder.

Thismaybe increasedifnecessarybyyourdoctoruntilyouaretakingtheamountyou

need. Yourdoctorwilladaptthedoseatintervalsof4 weeksormore.

ThemaximumdoseofAtorvastatin is80 mgoncedailyforadultsand 20mgoncedaily

forchildren.

Atorvastatin should beswallowed wholewith adrink ofwater,and canbetakenatany

timeofday, with orwithoutfood. However, trytotakeyourtabletatthesametimeevery

day.

Alwaystakethismedicineexactlyasyourdoctororpharmacisthastoldyou.Checkwith

yourdoctororpharmacistifyou arenotsure.

ThedurationoftreatmentwithAtorvastatinisdeterminedby yourdoctor.

Pleaseaskyourdoctorifyou think thattheeffectofAtorvastatin istoo strongortoo

weak.

IfyoutakemoreAtorvastatinthanyoushould

Ifyou accidentlytaketoomanyAtorvastatin tablets(morethanyourusualdailydose),

contactyourdoctorornearesthospitalforadvice

Ifyouforgetto takeAtorvastatin

Ifyou forgetto takeadose, justtakeyournextscheduled doseatthecorrecttime. Do not

takeadoubledoseto makeup foraforgotten dose.

Ifyoustoptaking Atorvastatin

Ifyou haveanyfurtherquestionson theuseofthismedicine, orwish to stopyour

treatment, askyourdoctororpharmacist.

4. Possible side effects

Like allmedicines,thismedicine cancause sideeffects,althoughnoteverybodygets

them.

Ifyouexperience anyofthe followingseriousside effects,stoptakingyour tablets

andtellyourdoctorimmediately orgo tothenearesthospitalaccidentand

emergencydepartment.

Rare(mayaffect1to 10patientsin 10,000)

Seriousallergicreactionwhichcausesswelling offace, tongueand throatthatcan

causegreatdifficultyinbreathing.

Seriousillnesswithseverepeelingandswellingoftheskin,blisteringoftheskin,

mouth,eyes,genitalsandfever. Skinrashwith pink-redblotchesespeciallyonpalms

ofhandsorsolesoffeetwhich mayblister.

Muscleweakness,tendernessorpainandparticularly,ifatthesametime,youfeel

unwellorhaveahightemperatureitmaybe causedbyanabnormalmuscle

breakdown.Theabnormalmusclebreakdowndoesnotalwaysgo awayeven after

youhavestoppedtakingatorvastatinand itcanbe life-threateningand lead to kidney

problems.

Veryrare (mayaffectupto1 in 10,000patients)

Ifyouexperienceproblemswith unexpected orunusualbleeding orbruising, this

maybesuggestiveofalivercomplaint.You shouldconsultyourdoctorassoon as

possible.

Other possible side effectswithAtorvastatin:

Common side effects(mayaffect1 to 10 patientsin 100)include

inflammation ofthenasalpassages, pain in thethroat, nosebleed

allergic reactions

increasesin blood sugarlevels(ifyou havediabetescontinuecarefulmonitoring

ofyourblood sugarlevels),increasein blood creatinekinase

headache

nausea, constipation, wind, indigestion, diarrhoea

jointpain, musclepain and back pain

blood testresultsthatshowyourliverfunction canbecomeabnormal

Uncommonside effects(mayaffect1 to 10 patientsin 1,000)include

anorexia(lossofappetite), weightgain, decreasesin blood sugarlevels(ifyou

havediabetesyou shouldcontinuecarefulmonitoringofyourblood sugarlevels)

havingnightmares, insomnia

dizziness, numbnessortinglingin thefingersandtoes, reductionsofsensation to

pain ortouch, changeinsenseoftaste, lossofmemory

blurred vision

ringingin theearsand/orhead

vomiting, belching, abdominalpain upperand lower, pancreatitis(inflammation

ofthepancreasleadingto stomach pain)

hepatitis(liverinflammation)

rash, skin rash and itching, hives, hairloss

neck pain, musclefatigue

fatigue,feelingunwell,weakness,chestpain,swellingespeciallyinthe ankles

(oedema),raisedtemperature

urineteststhat arepositiveforwhiteblood cells

Rare side effects(mayaffect1 to 10 patientsin 10,000)include

visualdisturbance

unexpected bleedingorbruising

cholestasis(yellowingoftheskin and whitesoftheeyes)

tendon injury

Veryrare sideeffects(mayaffectup to 1 in 10,000 patients)include

anallergicreaction-symptomsmayincludesudden wheezingand chestpain or

tightness, swellingoftheeyelids, face, lips, mouth, tongueorthroat, difficulty

breathing,collapse

hearingloss

gynaecomastia (breastenlargementinmen).

Possible side effectsreportedwithsome statins(medicinesofthe same type)

Sexual difficulties

Depression

Breathingproblemsincludingpersistentcoughand/orshortnessofbreath orfever.

Diabetes.Thisismorelikelyifyou havehigh levelsofsugarsandfatsinyour

blood, areoverweightand havehigh blood pressure. Yourdoctorwillmonitor

youwhileyouaretakingthismedicine.

Reportingofside effects

Ifyougetanysideeffects, talk toyourdoctor, pharmacistornurse. Thisincludesany

possiblesideeffectsnot listedinthisleaflet.Youcanalsoreport sideeffectsdirectlyvia

HPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin 2;Tel:+353 1 6764971;Fax:

+353 1 6762517. Website: wwwhpra.ie ; e-mail: medsafety@hpra.ie

Byreportingsideeffectsyou can help providemoreinformation on thesafetyofthis

medicine.

5. Howto storeAtorvastatin

Keepthismedicineoutofthesightandreachofchildren.

Storebelow25 ˚

C.Do notusethismedicineafterthe expirydatewhichisstatedonthe

carton and blisterafterEXP. Theexpirydaterefersto thelastdayofthatmonth.

Donotthrowawayanymedicinesviawastewaterorhousehold waste.Askyour

pharmacisthowtothrowawaymedicinesyouno longeruse.These measureswillhelp

protecttheenvironment.

6. Contentsofthepackandotherinformation

WhatAtorvastatin10mg, 20mg, 40mg, 80mg contain:

Theactive substanceinAtorvastatinfilm-coatedtabletsisatorvastatinasatorvastatin

calcium trihydrate.Eachfilm-coated tabletcontains10 mg, 20 mg, 40 mgor80 mg

atorvastatin.

Theother ingredientsare:

Tabletcore: Microcrystallinecellulose(E460),Lactosemonohydrate, Colloidal

anhydroussilica, Croscarmellosesodium(E468),Sodiumhydrogen carbonate,Sodium

carbonate, anhydrous,Hyproxypropylcellulose(E463),Magnesiumstearate(E470b),

Butylhydroxyanisole,Butylhydroxytoluene

Filmcoating:OpadryWhiteYS-1-7040 (Hypromellose(E464), macrogol8000, titanium

dioxide(E171), talc(E553b).

WhatAtorvastatin10 mg, 20 mg, 40 mg, 80 mg looklikeandcontentsofthepack

Atorvastatin10 mg:

Whitetooffwhite,film-coated ovaltabletsabout6.1 mmwideand about8.6 mm

long,debossedwith ‘A30’on onesideandplainon otherside

Atorvastatin20 mg:

Whitetooffwhite,film-coated ovaltabletsabout6.6 mmwideand about12.1 mm

long,debossedwith ‘A31’on onesideand plainon otherside

Atorvastatin40mg:

Whitetooffwhite,film-coatedovaltabletsabout8.1 mmwideand about16.9 mm

long,debossedwith ‘A32’on onesideand plainon otherside

Atorvastatin80mg:

Whitetooffwhite,film-coated ovaltabletsabout10.8 mmwideand about21.7

mmlong,debossedwith‘A33’on onesideand plain on otherside

Atorvastatin issupplied in thepack of:

Coldform blisterlaminate(structure: orientedpolyamide/aluminium foil/PVC)withthe

backingofhard tempered, aluminiumfoilcoated with heatseallacqueroninnerside

Packsof10, 14, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100 film-coatedtabletseach

(Notallpacksize maybemarketed)

MarketingAuthorisationHolder

RanbaxyIrelandLtd., Spafield, Cork Road, Cashel, Co. Tipperary,Ireland

Manufacturer

RanbaxyIrelandLtd., Spafield, Cork Road, Cashel, Co. Tipperary,Ireland

BasicsGmbH,HemmelratherWeg201, D-51377 Leverkusen, Germany

TerapiaS.A., 124FabricciStreet, 400 632 ClujNapoca, Romania

Cemelog-BRSLtd., 2040 Budaörs,Vasútu. 13,Hungary

Thismedicinalproductisauthorised in theMemberStatesofthe EEAunderthe

following names:

Austria: Atorvastatin Basics10/20/40/80 mgFilmtabletten

Bulgaria: ATORVISTATK10/20/40/80 mg филмиранитаблетки

Czech: SpatizalexNeo 10/20/40/80 mgpotahované tablety

Finland: AtorvastatinOrion10/20/40/80 mgtabletti, kalvopäällysteinen

France: ATORVASTATINERANBAXY 10/20/40/80 mg, comprimépelliculé

Greece: AtorvastatinRanbaxyIreland 10/20/40/80 mgεπικαλυμμένο με λεπτό

υμένιο δισκίο

Hungary: Atorvastatin Ranbaxy10/20/40/80mgfilmtabletta

Ireland: Atorvastatin 10/20/40/80 mgfilm-coatedtablets

Latvia: AtorvastatinRanbaxy 10/20/40/80mgapvalkotāstabletes

Lithuania: Atorvastatin Ranbaxy10/20/40/80 mgplėveledengtostabletės

Poland: StorvasCRT

Portugal: AtorvastatinaTovat(10/20/40/80 mgComprimidosrevestidospor

película)

Romania: Atorvastatin Ranbaxy10/20/40/80mgcomprimatefilmate

Slovak: SpatizalexNeo10/20/40/80 mgfilmomobalenétablety

Spain: ATORVASTATINA RANBAXYGEN 10-20-40-80mgCOMPRIMIDOS

RECUBIERTOSCONPELÍCULAEFG

United Kingdom:Atorvastatin10/20/40/80 mgFilm-coatedTablets

ThisleafletwaslastrevisedinNovember2014

Document Outline

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atorvastatin20mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains20mgofatorvastatinasatorvastatincalciumtrihydrate.

Excipientwithknowneffect:

Contains76.7mglactosemonohydrate,5.6mgsodium.

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitetooffwhite,film-coatedovaltabletsabout6.6mmwideandabout12.1mmlong,embossedwith‘A31’onone

sideandplainonotherside

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolaemia:

Atorvastatinisindicatedasanadjuncttodietforreductionofelevatedtotalcholesterol(total-C),LDL-cholesterol

(LDL-C),apolipoproteinB,andtriglyceridesinadults,adolescentsandchildrenaged10yearsorolderwithprimary

hypercholesterolaemiaincludingfamilialhypercholesterolaemia(heterozygousvariant)orcombined(mixed)

hyperlipidaemia(CorrespondingtoTypesIIaandIIboftheFredricksonclassification)whenresponsetodietandother

nonpharmacologicalmeasuresisinadequate.

Atorvastatinisalsoindicatedtoreducetotal-CandLDL-Cinadultswithhomozygousfamilialhypercholesterolaemia

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

Preventionofcardiovasculardisease

Preventionofcardiovasculareventsinadultpatientsestimatedtohaveahighriskforafirstcardiovascularevent(see

section5.1),asanadjuncttocorrectionofotherriskfactors.

4.2Posologyandmethodofadministration

Posology

Thepatientshouldbeplacedonastandardcholesterol-loweringdietbeforereceivingatorvastatinandshouldcontinue

onthisdietduringtreatmentwithatorvastatin.

ThedoseshouldbeindividualisedaccordingtobaselineLDL-Clevels,thegoaloftherapy,andpatientresponse.

Theusualstartingdoseis10mgonceaday.Adjustmentofdoseshouldbemadeatintervalsof4weeksormore.The

maximumdoseis80mgonceaday.

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Themajorityofpatientsarecontrolledwith10mgatorvastatinonceaday.Atherapeuticresponseisevidentwithin2

weeks,andthemaximumtherapeuticresponseisusuallyachievedwithin4weeks.Theresponseismaintainedduring

chronictherapy.

HeterozygousFamilialHypercholesterolaemia

Patientsshouldbestartedwithatorvastatin10mg daily.Dosesshouldbeindividualisedandadjustedevery4weeksto

40mgdaily.Thereafter,eitherthedosemay beincreasedtoamaximumof80mgdailyorabileacidsequestrant

maybecombinedwith40mgatorvastatinoncedaily.

HomozygousFamilialHypercholesterolaemia

Onlylimiteddataareavailable(seesection5.1).

Thedoseofatorvastatininpatientswithhomozygousfamilialhypercholesterolemiais10to80mgdaily(seesection

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

orifsuchtreatmentsareunavailable.

PreventionofCardiovasculardisease

Intheprimary preventiontrials,thedosewas10mg/dayHigherdosesmaybenecessaryinordertoattain(LDL-)

cholesterollevelsaccordingtocurrentguidelines.

Renalimpairment

Noadjustmentofdoseisrequired(seesection4.4).

Hepaticimpairment

Atorvastatinshouldbeusedwithcautioninpatientswithhepaticimpairment(seesections4.4and5.2).Atorvastatinis

contraindicatedinpatientswithactiveliverdisease(seesection4.3).

Olderpeople

Efficacyandsafetyinpatientsolderthan70usingrecommendeddosesaresimilartothoseseeninthegeneral

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

Atorvastatinisfororaladministration.Eachdailydoseofatorvastatinisgivenallatonceandmaybegivenatanytime

ofdaywithorwithoutfood.

4.3Contraindications

Atorvastatiniscontraindicatedinpatients:

−withhypersensitivitytotheactivesubstanceortoanyoftheexcipientsaslistedinsection6.1

−withactiveliverdiseaseorunexplainedpersistentelevationsofserumtransaminasesexceeding3timestheupper

limitofnormal

−duringpregnancy,whilebreast-feedingandinwomenofchild-bearingpotentialnotusingappropriatecontraceptive

measures(seesection4.6).

4.4Specialwarningsandprecautionsforuse

LiverEffects

Liverfunctiontestsshouldbeperformedbeforetheinitiationoftreatmentandperiodicallythereafter.Patientswho

developanysignsorsymptomssuggestiveofliverinjuryshouldhaveliverfunctiontestsperformed. Patientswho

developincreasedtransaminaselevelsshouldbemonitoreduntiltheabnormality(ies)resolve.

Shouldanincreaseintransaminasesofgreaterthan3timestheupperlimitofnormal(ULN)persist,reductionof

doseorwithdrawalofatorvastatinisrecommended(seesection4.8).

Atorvastatinshould beused withcautioninpatientswhoconsumesubstantialquantitiesofalcoholand/orhavea

history ofliverdisease.

StrokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)

Inapost-hocanalysisofstrokesubtypesinpatientswithoutcoronaryheartdisease(CHD)whohadarecentstrokeor

transientischemicattack(TIA)therewasahigherincidenceofhaemorrhagicstrokeinpatientsinitiatedonatorvastatin

80mg comparedtoplacebo.Theincreasedriskwasparticularlynotedinpatientswithpriorhaemorrhagicstrokeor

lacunarinfarctatstudyentry. Forpatientswithpriorhaemorrhagicstrokeorlacunarinfarct,thebalanceofrisksand

benefitsofatorvastatin80mgisuncertainandthepotentialriskofhaemorrhagicstrokeshouldbecarefully

consideredbeforeinitiatingtreatment(see Section5.1).

Skeletalmuscleeffects

Atorvastatin,likeotherHMG-CoAreductaseinhibitors,mayinrareoccasionsaffecttheskeletalmuscleandcause

myalgia,myositis,andmyopathythatmayprogresstorhabdomyolysis,apotentiallylife-threateningcondition

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

whichmayleadtorenalfailure.

Beforethetreatment

Atorvastatinshouldbeprescribedwithcautioninpatientswithpre-disposingfactorsforrhabdomyolysis.ACKlevel

shouldbemeasuredbeforestartingstatintreatmentinthefollowingsituations:

−Renalimpairment

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−Personalorfamilialhistoryofhereditarymusculardisorders

−Previoushistoryofmusculartoxicitywithastatinorfibrate

−Previoushistoryofliverdiseaseand/orwheresubstantialquantitiesofalcoholareconsumed

−Inelderly(age>70years),thenecessityofsuchmeasurementshouldbeconsidered,accordingtothepresenceof

otherpredisposingfactorsforrhabdomyolysis

−Situationswhereanincreaseinplasmalevelsmayoccur,suchasinteractions(seesection4.5)andspecial

populationsincludinggeneticsubpopulations(seesection5.2)

Insuchsituations,theriskoftreatmentshouldbeconsideredinrelationtopossiblebenefit,andclinicalmonitoringis

recommended.

IfCKlevelsaresignificantlyelevated(>5timesULN)atbaseline,treatmentshouldnotbestarted.

Creatinekinasemeasurement

Creatinekinase(CK)shouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofanyplausible

alternativecauseofCKincreaseasthismakesvalueinterpretationdifficult.IfCKlevelsaresignificantlyelevatedat

baseline(>5timesULN),levelsshouldberemeasuredwithin5to7dayslatertoconfirmtheresults.

Whilstontreatment

−Patientsmustbeaskedtopromptlyreportmusclepain,cramps,orweaknessespeciallyifaccompaniedbymalaiseor

fever.

−Ifsuchsymptomsoccurwhilstapatientisreceivingtreatmentwithatorvastatin,theirCKlevelsshouldbemeasured.

Iftheselevelsarefoundtobesignificantlyelevated(>5timesULN),treatmentshouldbestopped.

−Ifmuscularsymptomsaresevereandcausedailydiscomfort,eveniftheCKlevelsareelevatedto 5xULN,

treatmentdiscontinuationshouldbeconsidered.

−IfsymptomsresolveandCKlevelsreturntonormal,thenre-introductionofatorvastatinorintroductionofan

alternativestatinmaybeconsideredatthelowestdoseandwithclosemonitoring.

−AtorvastatinmustbediscontinuedifclinicallysignificantelevationofCKlevels(>10xULN)occur,orif

rhabdomyolysisisdiagnosedorsuspected.

Concomitanttreatmentwithothermedicinalproducts

Riskofrhabdomyolysisisincreasedwhenatorvastatinisadministeredconcomitantlywithcertainmedicinalproducts

thatmayincreasetheplasmaconcentrationofatorvastatinsuchaspotentinhibitorsofCYP3A4ortransportproteins

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

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

ofmyopathymayalsobeincreasedwiththeconcomitantuseofgemfibrozilandotherfibricacidderivates,boceprevir,

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

interacting)therapiesshouldbeconsideredinsteadofthesemedicinalproducts.

Therehavebeenveryrarereportsofimmune-mediatednecrotizingmyopathy(IMNM),duringoraftertreatmentwith

somestatins.IMNMisclinicallycharacterizedbypersistentproximalmuscleweaknessandelevatedserumcreatinine

kinase,whichperistdespitediscontinuationofstatintreatment.

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concurrenttreatmentshouldbecarefullyconsidered.Whenpatientsarereceivingmedicinalproductsthatincreasethe

plasmaconcentrationofatorvastatin,alowermaximumdoseofatorvastatinisrecommended.Inaddition,inthecaseof

potentCYP3A4inhibitors,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

basisandunderclosemedicalsupervision.

Paediatricuse

Developmentalsafetyinthepaediatricpopulationhasnotbeenestablished(seesection4.8).

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

DiabetesMellitus

Someevidencesuggeststhatstatinsasaclassraisebloodglucoseandinsomepatients,athighriskoffuturediabetes,

mayproducealevelofhyperglycaemiawhereformaldiabetescareisappropriate.Thisrisk,however,isoutweighedby

thereductioninvascularriskwithstatinsandthereforeshouldnotbeareasonforstoppingstatintreatment.Patientsat

risk(fastingglucose5.6to6.9mmol/L,BMI>30kg/m2,raisedtriglycerides,hypertension)shouldbemonitoredboth

clinicallyandbiochemicallyaccordingtonationalguidelines.

Excipients

Atorvastatincontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,Lapplactasedeficiency

orglucose-galactosemalabsorptionshouldnottakethismedicine.

Atorvastatincontainslessthan1mmolsodium(23mg)pertablet,i.e.essentially‘sodium-free’.

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

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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.

CYP3A4inducers

ConcomitantadministrationofatorvastatinwithinducersofcytochromeP4503A4(e.g.efavirenz,rifampin,St.John's

Wort)canleadtovariablereductionsinplasmaconcentrationsofatorvastatin.Duetothedualinteractionmechanism

ofrifampin,(cytochromeP4503A4inductionandinhibitionofhepatocyteuptaketransporterOATP1B1),

simultaneousco-administrationofatorvastatinwithrifampinisrecommended,asdelayedadministrationofatorvastatin

afteradministrationofrifampinhasbeenassociatedwithasignificantreductioninatorvastatinplasmaconcentrations.

Theeffectofrifampinonatorvastatinconcentrationsinhepatocytesis,however,unknownandifconcomitant

administrationcannotbeavoided,patientsshouldbecarefullymonitoredforefficacy.

Transportproteininhibitors

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

effectofinhibitionofhepaticuptaketransportersonatorvastatinconcentrationsinhepatocytesisunknown.If

concomitantadministrationcannotbeavoided,adosereductionandclinicalmonitoringforefficacyisrecommended

(seeTable1).

Gemfibrozil/fibricacidderivatives

Theuseoffibratesaloneisoccasionallyassociatedwithmusclerelatedevents,includingrhabdomyolysis.Theriskof

theseeventsmaybeincreasedwiththeconcomitantuseoffibricacidderivativesandatorvastatin.Ifconcomitant

administrationcannotbeavoided,thelowestdoseofatorvastatintoachievethetherapeuticobjectiveshouldbeused

andthepatientsshouldbeappropriatelymonitored(seesection4.4).

Ezetimibe

Theuseofezetimibealoneisassociatedwithmusclerelatedevents,includingrhabdomyolysis.Theriskoftheseevents

maythereforebeincreasedwithconcomitantuseofezetimibeandatorvastatin.Appropriateclinicalmonitoringof

thesepatientsisrecommended.

Colestipol

Plasmaconcentrationsofatorvastatinanditsactivemetaboliteswerelower(byapprox.25%)whencolestipolwasco-

administeredwithatorvastatin.However,lipideffectsweregreaterwhenatorvastatinandcolestipolwereco-

administeredthanwheneithermedicinalproductwasgivenalone.

Fusidicacid

Theriskofmyopathyincludingrhabdomyolisismaybeincreasedbytheconcomitantadministrationofsystemic

fusidicacidwithstatins.Themechanismofthisinteraction(whetheritispharmacodynamicorpharmacokinetic,or

both)isyetunknown.Therehavebeenreportsofrhabdomyolysis(includingsomefatalities)inpatientsreceivingthis

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Iftreatmentwithsystemicfusidicacidisnecessary,atorvastatintreatmentshouldbediscontinuedthroughoutthe

durationofthefusidicacidtreatment.Seealsosection4.4.

Colchicine

Althoughinteractionstudieswithatorvastatinandcolchicinehavenotbeenconducted,casesofmyopathyhavebeen

reportedwithatorvastatinco-administeredwithcolchicine,andcautionshouldbeexercisedwhenprescribing

atorvastatinwithcolchicine.

Effectofatorvastatinonco-administeredmedicinalproducts

Digoxin

Whenmultipledosesofdigoxinand10mgatorvastatinwereco-administered,steady-statedigoxinconcentrations

increasedslightly.Patientstakingdigoxinshouldbemonitoredappropriately.

Oralcontraceptives

Co-administrationofatorvastatinwithanoralcontraceptiveproducedincreasesinplasmaconcentrationsof

norethindroneandethinyloestradiol.

Warfarin

Inaclinicalstudyinpatientsreceivingchronicwarfarintherapy,coadministrationofatorvastatin80mgdailywith

warfarincausedasmalldecreaseofabout1.7secondsinprothrombintimeduringthefirst4daysofdosingwhich

returnedtonormalwithin15daysofatorvastatintreatment.Althoughonlyveryrarecasesofclinicallysignificant

anticoagulantinteractionshavebeenreported,prothrombintimeshouldbedeterminedbeforestartingatorvastatinin

patientstakingcoumarinanticoagulantsandfrequentlyenoughduringearlytherapytoensurethatnosignificant

alterationofprothrombintimeoccurs.

Onceastableprothrombintimehasbeendocumented,prothrombintimescanbemonitoredattheintervalsusually

recommendedforpatientsoncoumarinanticoagulants.Ifthedoseofatorvastatinischangedordiscontinued,thesame

procedureshouldberepeated.Atorvastatintherapyhasnotbeenassociatedwithbleedingorwithchangesin

prothrombintimeinpatientsnottakinganticoagulants.

Paediatricpopulation

Drug-druginteractionstudieshaveonlybeenperformedinadults.Theextentofinteractionsinthepaediatric

populationisnotknown.Theabovementionedinteractionsforadultsandthewarningsinsection4.4shouldbetaken

intoaccountforthepaediatricpopulation.

Table1:Effectofco-administeredmedicinalproductsonthepharmacokineticsofatorvastatin

Co-administeredmedicinalproductand

dosingregimen Atorvastatin

Dose(mg) Change

inAUC & ClinicalRecommendation #

Tipranavir500mgBID/Ritonavir200mgBID,

8days(days14to21) 40mgonday1,10

mgonday20 9.4foldIncaseswhere

coadministrationwith

atorvastatinisnecessary,do

notexceed10mg

atorvastatindaily.Clinical

monitoringofthesepatients

isrecommended Telaprevir750mgq8h,10days 20mgSD 7.9fold

Ciclosporin5.2mg/kg/day,stabledose 10mgODfor28

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Lopinavir400mgBID/Ritonavir100mgBID,

14days 20mgODfor4

days 5.9foldIncaseswhereco-

administrationwith

atorvastatinisnecessary,

lowermaintenancedosesof

atorvastatinare

recommended.At

atorvastatindosesexceeding

20mg,clinicalmonitoringof

thesepatientsis

recommended. Clarithromycin500mgBID,9days 80mgODfor8

days 4.4fold

Saquinavir400mgBID/Ritonavir(300mgBID

fromdays5-7,increasedto400mgBIDonday

8),days4-18,30minafteratorvastatindosing 40mgODfor4

days 3.9foldIncaseswhereco-

administrationwith

atorvastatinisnecessary,

lowermaintenancedosesof

atorvastatinare

recommended.At

atorvastatindosesexceeding

40mg,clinicalmonitoringof

thesepatientsis

recommended. Darunavir300mgBID/Ritonavir100mgBID,9

days 10mgODfor4

days 3.3fold

Itraconazole200mgOD,4days 40mgSD 3.3fold

Fosamprenavir700mgBID/Ritonavir100mg

BID,14days 10mgODfor4

days 2.5fold

Fosamprenavir1400mgBID,14days 10mgODfor4

days 2.3fold

Nelfinavir1250mgBID,14days 10mgODfor28

days 1.7

fold^ Nospecificrecommendation

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

quantitiesofgrapefruitjuice

andatorvastatinisnot

recommended.

Diltiazem240mgOD,28days 40mg,SD 51% Afterinitiationorfollowing

doseadjustmentsof

diltiazem,appropriateclinical

monitoringofthesepatients

isrecommended.

Erythromycin500mgQID,7days 10mg,SD 33%^ Lowermaximumdoseand

clinicalmonitoringofthese

patientsisrecommended.

Amlodipine10mg,singledose 80mg,SD 18% Nospecificrecommendation.

Cimetidine300mgQID,2weeks 10mgODfor2

weeks less

than1%^ Nospecificrecommendation.

Antacidsuspensionofmagnesiumand

aluminiumhydroxides,30mLQID,2weeks 10mgODfor4

weeks 35%^ Nospecificrecommendation.

Efavirenz600mgOD,14days 10mgfor3days 41% Nospecificrecommendation.

Rifampin600mgOD,7days(co-administered) 40mgSD 30% Ifco-administrationcannot

beavoided,simultaneousco-

administrationofatorvastatin

withrifampinis

recommended,withclinical

monitoring. Rifampin600mgOD,5days(dosesseparated) 40mgSD 80%

Gemfibrozil600mgBID,7days 40mgSD 35% Lowerstartingdoseand

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&

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

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

Seesections4.4and4.5forclinicalsignificance.

*ContainsoneormorecomponentsthatinhibitCYP3A4andcanincreaseplasmaconcentrationsofmedicinalproducts

metabolizedbyCYP3A4.Intakeofone240mlglassofgrapefruitjuicealsoresultedinadecreasedAUCof20.4%for

theactiveorthohydroxymetabolite.Largequantitiesofgrapefruitjuice(over1.2ldailyfor5days)increasedAUCof

atorvastatin2.5foldandAUCofactive(atorvastatinandmetabolites).

^Totalatorvastatinequivalentactivity

Increaseisindicatedas“”,decreaseas“ ”

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

Table2:Effectofatorvastatinonthepharmacokineticsofco-administeredmedicinalproducts

&

patientsisrecommended.

Fenofibrate160mgOD,7days 40mgSD 3% Lowerstartingdoseand

clinicalmonitoringofthese

patientsisrecommended.

Boceprevir800mgTID,7days 40mgSD 2.3foldLowerstartingdoseand

clinicalmonitoringofthese

patientsisrecommended.

Thedoseofatorvastatin

shouldnotexceedadaily

doseof

20mgduringco-administra-

tionwithboceprevir.

Atorvastatinand

dosingregimen Co-administeredmedicinalproduct

Medicinalproduct/Dose(mg) Changein

AUC & Clinical

Recommendation

80mgODfor10

days Digoxin0.25mgOD,20days 15% Patientstakingdigoxin

shouldbemonitored

appropriately.

40mgODfor22

days OralcontraceptiveOD,2months

-norethindrone1mg

-ethinylestradiol35µg 28%

Nospecific

recommendation.

80mgODfor15

days *Phenazone,600mgSD 3% Nospecific

recommendation

10mg,SD Tipranavir500mgBID/ritonavir200mgBID,7

days Nochange Nospecific

recommendation.

10mg,ODfor4daysFosamprenavir1400mgBID,14

days 27% Nospecific

recommendation.

10mgODfor4days Fosamprenavir700mg

BID/ritonavir100mgBID,14days Nochange Nospecific

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*Co-administrationofmultipledosesofatorvastatinandphenazoneshowedlittleornodetectableeffectinthe

clearanceofphenazone.

Increaseisindicatedas“”,decreaseas“ ”

OD=oncedaily;SD=singledose

4.6Fertility,pregnancyandlactation

Womenofchildbearingpotential

Womenofchild-bearingpotentialshoulduseappropriatecontraceptivemeasuresduringtreatment(seesection4.3).

Pregnancy

Atorvastatiniscontraindicatedduringpregnancy(seesection4.3).Safetyinpregnantwomenhasnotbeenestablished.

Nocontrolledclinicaltrialswithatorvastatinhavebeenconductedinpregnantwomen.Rarereportsofcongenital

anomaliesfollowingintrauterineexposuretoHMG-CoAreductaseinhibitorshavebeenreceived.Animalstudieshave

showntoxicitytoreproduction(seesection5.3).

Maternaltreatmentwithatorvastatinmayreducethefetallevelsofmevalonatewhichisaprecursorofcholesterol

biosynthesis.Atherosclerosisisachronicprocess,andordinarilydiscontinuationoflipid-loweringmedicinalproducts

duringpregnancyshouldhavelittleimpactonthelong-termriskassociatedwithprimaryhypercholesterolaemia.

Forthesereasons,atorvastatinshouldnotbeusedinwomenwhoarepregnant,tryingtobecomepregnantorsuspect

theyarepregnant.Treatmentwithatorvastatinshouldbesuspendedforthedurationofpregnancyoruntilithasbeen

determinedthatthewomanisnotpregnant(seesection4.3.)

Breast-feeding

Itisnotknownwhetheratorvastatinoritsmetabolitesareexcretedinhumanmilk.Inrats,plasmaconcentrationsof

atorvastatinanditsactivemetabolitesaresimilartothoseinmilk(seesection5.3).Becauseofthepotentialforserious

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

contraindicatedduringbreastfeeding(seesection4.3).

Fertility

Inanimalstudiesatorvastatinhadnoeffectonmaleorfemalefertility(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

Atorvastatinhasnegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Intheatorvastatinplacebo-controlledclinicaltrialdatabaseof16,066(8755atorvastatinvs.7311placebo)patients

treatedforamedianperiodof53weeks,5.2%ofpatientsonatorvastatindiscontinuedduetoadversereactions

comparedto4.0%ofthepatientsonplacebo.

Basedondatafromclinicalstudiesandextensivepost-marketingexperience,thefollowingtablepresentstheadverse

reactionprofileforatorvastatin.

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

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

estimatedfromtheavailabledata)

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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

Uncommon:visionblurred.

Rare:visualdisturbance.

Earandlabyrinthdisorders

Uncommon:tinnitus

Veryrare:hearingloss.

Respiratory,thoracicandmediastinaldisorders:

Common:pharyngolaryngealpain,epistaxis.

Gastrointestinaldisorders

Common:constipation,flatulence,dyspepsia,nausea,diarrhoea.

Uncommon:vomiting,abdominalpainupperandlower,eructation,pancreatitis.

Hepatobiliarydisorders

Uncommon:hepatitis.

Rare:cholestasis.

Veryrare:hepaticfailure.

Skinandsubcutaneoustissuedisorders

Uncommon:urticaria,skinrash,pruritus,alopecia.

Rare:angioneuroticoedema,dermatitisbullousincludingerythemamultiforme,Stevens-Johnsonsyndromeandtoxic

epidermalnecrolysis.

Musculoskeletalandconnectivetissuedisorders

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

Uncommon:neckpain,musclefatigue.

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

Notknown:immune-mediatednecrotizingmyopathy(seesection4.4)

Reproductivesystemandbreastdisorders

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4.9Overdose

Specifictreatmentisnotavailableforatorvastatinoverdosage.Shouldanoverdoseoccur,thepatientshouldbetreated

symptomaticallyandsupportivemeasuresinstituted,asrequired.LiverfunctiontestsandserumCKlevelsshouldbe

monitored.Duetoextensiveatorvastatinbindingtoplasmaproteins,haemodialysisisnotexpectedtosignificantly

enhanceatorvastatinclearance.

5PHARMACOLOGICALPROPERTIES

Generaldisordersandadministrationsiteconditions

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

Investigations

Common:liverfunctiontestabnormal,bloodcreatinekinaseincreased.

Uncommon:whitebloodcellsurinepositive.

AswithotherHMG-CoAreductaseinhibitorselevatedserumtransaminaseshavebeenreportedinpatientsreceiving

atorvastatin.Thesechangeswereusuallymild,transient,anddidnotrequireinterruptionoftreatment.Clinically

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

Theseelevationsweredoserelatedandwerereversibleinallpatients.

Elevatedserumcreatinekinase(CK)levelsgreaterthan3timesupperlimitofnormaloccurredin2.5%ofpatientson

atorvastatin,similartootherHMG-CoAreductaseinhibitorsinclinicaltrials.Levelsabove10timesthenormalupper

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

PaediatricPopulation

Theclinicalsafetydatabaseincludessafetydatafor249paediatricpatientswhoreceivedatorvastatin,amongwhich7

patientswere<6yearsold,14patientswereintheagerangeof6to9,and228patientswereintheagerangeof10to

Nervoussystemdisorders

Common:Headache

Gastrointestinaldisorders

Common:Abdominalpain

Investigations

Common:Alanineaminotransferaseincreased,bloodcreatinephosphokinaseincreased

Basedonthedataavailable,frequency,typeandseverityofadversereactionsinchildrenareexpectedtobethesame

asinadults.Thereiscurrentlylimitedexperiencewithrespecttolong-termsafetyinthepaediatricpopulation.

ClassEffects

Sexualdysfunction.

Depression.

Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seesection4).

DiabetesMellitus:Frequencywilldependonthepresenceorabsenceofriskfactors(fastingbloodglucose

5.6mmol/L,BMI>30kg/m2,raisedtriglycerides,historyofhypertension).

Reportingofsuspectedadversereactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportany

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

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Pharmacotherapeuticgroup:Lipidmodifyingagents,HMG-CoA-reductaseinhibitors,ATCcode:C10AA05

Atorvastatinisaselective, competitiveinhibitorofHMG-CoAreductase,therate-limitingenzymeresponsiblefor

theconversionof3-hydroxy-3-methyl-glutaryl-coenzymeAtomevalonate,a precursorofsterols,including

cholesterol.Triglyceridesand cholesterolintheliverareincorporatedintoverylow-densitylipoproteins(VLDL)and

releasedintotheplasmafordeliverytoperipheraltissues.Low-densitylipoprotein(LDL)isformedfromVLDLand

iscatabolisedprimarilythroughthehighaffinitytoLDL(LDLreceptor).

Atorvastatinlowersplasma cholesterolandlipoproteinserumconcentrationsbyinhibitingHMG-CoAreductase

andsubsequentlycholesterolbiosynthesisintheliverandincreasesthenumberofhepaticLDLreceptorsonthe

cellsurfaceforenhanceduptakeandcatabolismofLDL.

AtorvastatinreducesLDLproductionandthenumberofLDL particles.Atorvastatinproducesaprofoundandsustained

increaseinLDL receptoractivitycoupledwithabeneficialchangeinthequalityofcirculatingLDLparticles.

AtorvastatiniseffectiveinreducingLDL-Cinpatientswithhomozygousfamilialhypercholesterolaemia,apopulation

thathasnotusuallyrespondedtolipid-loweringmedicinalproducts.

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

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

doseresponsestudy.Theseresultsareconsistentinpatientswithheterozygousfamilialhypercholesterolaemia,

nonfamilialformsofhypercholesterolaemia,andmixedhyperlipidaemia,includingpatientswithnoninsulin-dependent

diabetesmellitus.

Reductionsintotal-C,LDL-C,andapolipoproteinBhavebeenproventoreduceriskforcardiovasculareventsand

cardiovascularmortality.

Homozygousfamilialhypercholesterolaemia

Inamulticenter8weekopen-labelcompassionate-usestudywithanoptionalextensionphaseofvariablelength,335

patientswereenrolled,89ofwhichwereidentifiedashomozygousfamilialhypercholesterolaemiapatients.Fromthese

89patients,themeanpercentreductioninLDL-Cwasapproximately20%.Atorvastatinwasadministeredatdosesup

to80mg/day.

Atherosclerosis

IntheReversingAtherosclerosiswithAggressiveLipid-LoweringStudy(REVERSAL),theeffectofintensivelipid

loweringwithatorvastatin80mgandstandarddegreeoflipidloweringwithpravastatin40mgoncoronary

atherosclerosiswasassessedbyintravascularultrasound(IVUS),duringangiography,inpatientswithcoronaryheart

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

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

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

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

ofatorvastatinwerestatisticallysignificant(p=0.02).Theeffectofintensivelipidloweringoncardiovascularendpoints

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

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

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

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

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

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

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

thepravastatingroup(p<0.0001).

Studyresultswereobtainedwiththe80mgdosestrength.Therefore,theycannotbeextrapolatedtothelowerdose

strengths.

Thesafetyandtolerabilityprofilesofthetwotreatmentgroupswerecomparable.

Theeffectofintensivelipidloweringonmajorcardiovascularendpointswasnotinvestigatedinthisstudy.Therefore,

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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-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,peripheral

vasculardisease,leftventricularhypertrophy,priorcerebrovascularevent,specificECGabnormality,

proteinuria/albuminuria.Notallincludedpatientswereestimatedtohaveahighriskforafirstcardiovascularevent.

Patientsweretreatedwithanti-hypertensivetherapy(eitheramlodipineoratenolol-basedregimen)andeither

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

Theabsoluteandrelativeriskreductioneffectofatorvastatinwasasfollows:

BasedondifferenceincrudeeventsPatientsweretreatedwitheitheratorvastatin10mgdaily(n=1,428)orplacebo

(n=1,410)foramedianfolratesoccurringoveramedianfollow-upof3.3years.

CHD=coronaryheartdisease;MI=myocardialinfarction.

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

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

seeninmalesbutcouldnotbeestablishedinfemalespossiblyduetotheloweventrateinthefemalesubgroup.Overall

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

statisticallysignificant.Therewassignificanttreatmentinteractionbyantihypertensivebaselinetherapy.Theprimary

endpoint(fatalCHDplusnon-fatalMI)wassignificantlyreducedbyatorvastatininpatientstreatedwithamlodipine

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

Theeffectofatorvastatinonfatalandnon-fatalcardiovasculardiseasewasalsoassessedinarandomized,double-blind,

multicenter,placebo-controlledtrial,theCollaborativeAtorvastatinDiabetesStudy(CARDS)inpatientswithtype2

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

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

smoking,retinopathy,microalbuminuriaormacroalbuminuria.

low-upof3.9years.

Event RelativeRisk

Reduction(%) No.ofEvents

(Atorvastatin

vsPlacebo) AbsoluteRisk

Reduction 1

(%) p-value

FatalCHDplusnon-fatalMI

Totalcardiovasculareventsand

revascularizationprocedures

Totalcoronaryevents 36%

100vs.154

389vs.483

178vs247 1.1%

1.9%

1.4% 0.0005

0.0008

0.0006

Event RelativeRisk

Reduction(%) No.ofEvents

(Atorvastatinvs

Placebo) AbsoluteRisk

Reduction 1

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Basedondifferenceincrudeeventsratesoccurringoveramedianfollow-upof3.9years.

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

myocardialinfarction;PTCA=percutaneoustransluminalcoronaryangioplasty.

Therewasnoevidenceofadifferenceinthetreatmenteffectbypatient'sgender,age,orbaselineLDL-Clevel.A

favourabletrendwasobservedregardingthemortalityrate(82deathsintheplacebogroupvs.61deathsinthe

atorvastatingroup,p=0.0592).

Recurrentstroke

IntheStrokePreventionbyAggressiveReductioninCholesterolLevels(SPARCL)study,theeffectofatorvastatin80

mgdailyorplaceboonstrokewasevaluatedin4731patientswhohadastrokeortransientischemicattack(TIA)

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

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

mg/dL(1.9mmol/L)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)andincreasedtheincidenceofhemorrhagicstroke(55/2365,2.3%vs.33/2366,1.4%,p=0.02)

comparedtoplacebo.

Theriskofhemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorhemorrhagicstroke(7/45

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

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

Theriskofhemorrhagicstrokewasincreasedinpatientswhoenteredthestudywithpriorlacunarinfarct(20/708for

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

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

thenetriskofstrokeisincreasedinpatientswithpriorlacunarinfarctwhoreceiveatorvastatin80mg/day.

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

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

subgroupofpatientswithpriorlacunarinfarct.

PaediatricPopulation

HeterozygousFamilialHypercholesterolaemiainPaediatricPatientsaged6-17yearsold

An8-week,open-labelstudytoevaluatepharmacokinetics,pharmacodynamics,andsafetyandtolerabilityof

atorvastatinwasconductedinchildrenandadolescentswithgeneticallyconfirmedheterozygousfamilial

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

wereenrolled.CohortAincluded15children,6to12yearsofageandatTannerStage1.CohortBincluded24

children,10to17yearsofageandatTannerStage 2.

Theinitialdoseofatorvastatinwas5mgdailyofachewabletabletinCohortAand10mgdailyofatabletformulation

inCohortB.TheatorvastatindosewaspermittedtobedoubledifasubjecthadnotattainedtargetLDL-Cof<3.35

mmol/LatWeek4andifatorvastatinwaswelltolerated.

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

wasdoubled,additionaldecreaseswereobservedasearlyas2weeks,atthefirstassessment,afterdoseescalation.The

Majorcardiovascularevents(fatalandnon-

fatalAMI,silentMI,acuteCHDdeath,

unstableangina,CABG,PTCA,

revascularization,stroke)

MI(fatalandnon-fatalAMI,silentMI)

Strokes(Fatalandnon-fatal) 37%

83vs.127

38vs64

3.2%

1.9%

0.0010

0.0070

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theirinitialdoseordoubledtheirinitialdose.AtWeek8,onaverage,thepercentchangefrombaselineinLDL-Cand

TCwasapproximately40%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).

Acompassionateusestudyinpatientswithseverehypercholesterolaemia(includinghomozygous

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.Apartfromotherpathwaystheseproductsarefurthermetabolizedviaglucuronidation.Invitro,

inhibitionofHMG-CoAreductasebyortho-andparahydroxylatedmetabolitesisequivalenttothatofatorvastatin.

Approximately70%ofcirculatinginhibitoryactivityforHMG-CoAreductaseisattributedtoactivemetabolites.

Elimination:

Atorvastatiniseliminatedprimarilyinbilefollowinghepaticand/orextrahepaticmetabolism.However,the

atorvastatindoesnotappeartoundergosignificantenterohepaticrecirculation.Meanplasmaeliminationhalf-lifeof

atorvastatininhumansisapproximately14hours.Thehalf-lifeofinhibitoryactivityforHMGCoAreductaseis

approximately20to30hoursduetothecontributionofactivemetabolites.

SpecialPopulations

Elderly:Plasmaconcentrationsofatorvastatinanditsactivemetabolotesarehigherinhealthyelderlysubjectsthanin

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Paediatric:Inanopen-label,8-weekstudy,TannerStage1(N=15)andTannerStage 2(N=24)paediatricpatients

(ages6-17years)withheterozygousfamilialhyper-cholesterolemiaandbaselineLDL-C4mmol/Lweretreatedwith

5or10mgofchewableor10or20mgoffilm-coatedatorvastatintabletsoncedaily,respectively.Bodyweightwas

theonlysignificantcovariateinatorvastatinpopulationPKmodel.Apparentoralclearanceofatorvastatininpaediatric

subjectsappearedsimilartoadultswhenscaledallometricallybybodyweight.ConsistentdecreasesinLDL-CandTC

wereobservedovertherangeofatorvastatinando-hydroxyatorvastatinexposures.

Gender:Concentrationsofatorvastatinanditsactivemetabolitesinwomendifferfromthoseinmen(women:

approximately20%higherforCmaxand10%lowerforAUC).Thesedifferenceswereofnoclinicalsignificance,

resultinginnoclinicallysignificantdifferencesinlipideffectsamongmenandwomen.

RenalInsufficiency:Renaldiseasehasnoinfluenceontheplasmaconcentrationsorlipideffectsofatorvastatinandits

activemetabolites.

HepaticInsufficiency:Plasmaconcentrationsofatorvastatinanditsactivemetabolitesaremarkedlyincreased

(approximately16-foldinCmaxandapprox.11foldinAUC)inpatientswithchronicalcoholicliverdisease(Child

PughB).

SLOC1B1polymorphism:HepaticuptakeofallHMG-CoAreductaseinhibitorsincludingatorvastatin,involvesthe

OATP1B1transporter.InpatientswithSLCO1B1polymorphismthereisariskofincreasedexposureofatorvastatin,

whichmayleadtoanincreasedriskofrhabdomyolysis(seesection4.4).Polymorphisminthegeneencoding

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

withoutthisgenotypevariant(c.521TT).Ageneticallyimpairedhepaticuptakeofatorvastatinisalsopossibleinthese

patients.Possibleconsequencesfortheefficacyareunknown.

5.3Preclinicalsafetydata

Atorvastatinwasnegativeformutagenicandclastogenicpotentialinabatteryof4invitrotestsand1invivoassay.

Atorvastatinwasnotfoundtobecarcinogenicinrats,buthighdosesinmice(resultingin6-11foldtheAUC0-24h

reachedinhumansatthehighestrecommendeddose)showedhepatocellularadenomasinmalesandhepatocellular

carcinomasinfemales.

ThereisevidencefromanimalexperimentalstudiesthatHMG-CoAreductaseinhibitorsmayaffectthedevelopmentof

embryosorfetuses.Inrats,rabbitsanddogsatorvastatinhadnoeffectonfertilityandwasnotteratogenic;however,at

maternallytoxicdosesfetaltoxicitywasobservedinratsandrabbits.Thedevelopmentoftheratoffspringwasdelayed

andpost-natalsurvivalreducedduringexposureofthedamstohighdosesofatorvastatin.Inrats,thereisevidenceof

placentaltransfer.Inrats,plasmaconcentrationsofatorvastatinaresimilartothoseinmilk.Itisnotknownwhether

atorvastatinoritsmetabolitesareexcretedinhumanmilk.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Lactosemonohydrate

Colloidalanhydroussilica

Croscarmellosesodium

Sodiumhydrogencarbonate

Sodiumcarbonate,anhydrous

Hyproxypropylcellulose

Magnesiumstearate

Butylhydroxyanisole

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Tabletcoating:

OpadryYS-1-7040white

Hypromellose

Macrogol8000

Titaniumdioxide(E171)

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

24months

6.4Specialprecautionsforstorage

Storebelow25°C

6.5Natureandcontentsofcontainer

Coldformblisterlaminate(structure:orientedpolyamide/aluminiumfoil/PVC)withthebackingofhardtempered,

aluminiumfoilcoatedwithheatseallacqueroninnerside

Packsof10,14,20,28,30,50,56,60,84,90,98,100film-coatedtabletseach

(Notallpacksizemaybemarketed)

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLimited

Spafield

CorkRoad

Cashel

Co.Tipperary

8MARKETINGAUTHORISATIONNUMBER

PA408/90/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:7 th

September2012

10DATEOFREVISIONOFTHETEXT

Health Products Regulatory Authority

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Date Printed 11/10/2016 CRN 2181193 page number: 18

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