CRESTOR

Main information

  • Trade name:
  • CRESTOR Film Coated Tablet 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CRESTOR Film Coated Tablet 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/003/001
  • Authorization date:
  • 08-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PPA1659/003/001

CaseNo:2085239

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

IPSHealthcareLimited

SterlingHouse,501MiddletonRoad,Chadderton,Oldham,LancashireOL99LY,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Crestor10mgfilm-coatedtablets

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom08/10/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Crestor10mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgrosuvastatin(asrosuvastatincalcium).Eachtabletscontains91.3mglactosemonohydrate.

Forafulllistofexcipients,seeSection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromUnitedKingdom:

Round,pinkcolouredtablets,intag1iatedwith'ZD4S22'and'10'ononesideandplainonthereverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofhypercholesterolaemia

Adults,adolescentsandchildrenaged10yearsorolderwithprimaryhypercholesterolaemia(typeIIaincluding

heterozygousfamilialhypercholesterolaemia)ormixeddyslipidaemia(typeIIb)asanadjuncttodietwhenresponseto

dietandothernon-pharmacologicaltreatments(e.g.exercise,weightreduction)isinadequate.

Homozygousfamilialhypercholesterolaemiaasanadjuncttodietandotherlipidloweringtreatments(e.g.LDL

apheresis)orifsuchtreatmentsarenotappropriate.

PreventionofCardiovascularEvents

Preventionofmajorcardiovasculareventsinpatientswhoareestimatedtohaveahighriskforafirstcardiovascular

event(seeSection5.1),asanadjuncttocorrectionofotherriskfactors.

4.2Posologyandmethodofadministration

Beforetreatmentinitiationthepatientshouldbeplacedonastandardcholesterol-loweringdietthatshouldcontinue

duringtreatment.Thedoseshouldbeindividualisedaccordingtothegoaloftherapyandpatientresponse,usingcurrent

consensusguidelines.

Crestormaybegivenatanytimeofday,withorwithoutfood.

Treatmentofhypercholesterolaemia

Therecommendedstartdoseis5mgor10mgorallyoncedailyinbothstatinnaïveorpatientsswitchedfromanother

HMGCoAreductaseinhibitor.Thechoiceofstartdoseshouldtakeintoaccounttheindividualpatient’scholesterol

levelandfuturecardiovascularriskaswellasthepotentialriskforadversereactions(seebelow).Adoseadjustmentto

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Inlightoftheincreasedreportingrateofadversereactionswiththe40mgdosecomparedtolowerdoses(seeSection

4.8),afinaltitrationtothemaximumdoseof40mgshouldonlybeconsideredinpatientswithsevere

hypercholesterolaemiaathighcardiovascularrisk(inparticularthosewithfamilialhypercholesterolaemia),whodonot

achievetheirtreatmentgoalon20mg,andinwhomroutinefollow-upwillbeperformed(seeSection4.4).Specialist

supervisionisrecommendedwhenthe40mgdoseisinitiated.

PreventionofCardiovascularEvents

Inthecardiovasculareventsriskreductionstudy,thedoseusedwas20mgdaily(seeSection5.1).

Paediatricpopulation

Paediatricuseshouldonlybecarriedoutbyspecialists.

Childrenandadolescents10to17yearsofage(boysTannerStageIIandabove,andgirlswhoareatleast1yearpost-

menarche)

Inchildrenandadolescentswithheterozygousfamilialhypercholesterolaemiatheusualstartdoseis5mgdaily.The

usualdoserangeis5-20mgorallyoncedaily.Titrationshouldbeconductedaccordingtotheindividualresponseand

tolerabilityinpaediatricpatients,asrecommendedbythepaediatrictreatmentrecommendations(seeSection4.4).

Childrenandadolescentsshouldbeplacedonstandardcholesterol-loweringdietbeforerosuvastatintreatment

initiation;thisdietshouldbecontinuedduringrosuvastatintreatment.Safetyandefficacyofdosesgreaterthan20mg

havenotbeenstudiedinthispopulation.

The40mgtabletisnotsuitableforuseinpaediatricpatients.

Childrenyoungerthan10years

Experienceinchildrenyoungerthan10yearsislimitedtoasmallnumberofchildren(agedbetween8and10years)

withhomozygousfamilialhypercholesterolaemia.Therefore,Crestorisnotrecommendedforuseinchildrenyounger

than10years.

Useintheelderly

Astartdoseof5mgisrecommendedinpatients>70years(seeSection4.4Nootherdoseadjustmentisnecessaryin

relationtoage.

Dosageinpatientswithrenalinsufficiency

Nodoseadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment.Therecommendedstartdoseis

5mginpatientswithmoderaterenalimpairment(creatinineclearanceof<60ml/min).The40mgdoseis

contraindicatedinpatientswithmoderaterenalimpairmentTheuseofCrestorinpatientswithsevererenalimpairment

iscontraindicatedforalldoses.(SeeSection4.3andSection5.2).

Dosageinpatientswithhepaticimpairment

TherewasnoincreaseinsystemicexposuretorosuvastatininsubjectswithChild-Pughscoresof7orbelow.However,

increasedsystemicexposurehasbeenobservedinsubjectswithChild-Pughscoresof8and9(seeSection5.2).Inthese

patientsanassessmentofrenalfunctionshouldbeconsidered(seeSection4.4).Thereisnoexperienceinsubjects

withChild-Pughscoresabove9 . Crestoriscontraindicatedinpatientswithactiveliverdisease(seeSection4.3).

Race

IncreasedsystemicexposurehasbeenseeninAsiansubjects(seeSection4.4andSection5.2).Therecommendedstart

doseis5mgforpatientsofAsianancestry.The40mgdoseiscontraindicatedinthesepatients.

Dosageinpatientswithpre-disposingfactorstomyopathy

Therecommendedstartdoseis5mginpatientswithpredisposingfactorstomyopathy(seeSection4.4).

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4.3Contraindications

Crestoriscontraindicated:

inpatientswithhypersensitivitytorosuvastatinortoanyoftheexcipients.

inpatientswithactiveliverdiseaseincludingunexplained,persistentelevationsofserumtransaminasesand

anyserumtransaminaseelevationexceeding3xtheupperlimitofnormal(ULN).

inpatientswithsevererenalimpairment(creatinineclearance<30ml/min).

inpatientswithmyopathy.

inpatientsreceivingconcomitantciclosporin.

duringpregnancyandlactationandinwomenofchildbearingpotentialnotusingappropriatecontraceptive

measures.

The40mgdoseiscontraindicatedinpatientswithpre-disposingfactorsformyopathy/rhabdomyolysis.Suchfactors

include:

moderaterenalimpairment(creatinineclearance<60ml/min)

hypothyroidism

personalorfamilyhistoryofhereditarymusculardisorders

previoushistoryofmusculartoxicitywithanotherHMG-CoAreductaseinhibitororfibrate

alcoholabuse

situationswhereanincreaseinplasmalevelsmayoccur

Asianpatients

concomitantuseoffibrates.

(seeSections4.4,4.5and5.2)

4.4Specialwarningsandprecautionsforuse

RenalEffects

Proteinuria,detectedbydipsticktestingandmostlytubularinorigin,hasbeenobservedinpatientstreatedwithhigher

dosesofCrestor,inparticular40mg,whereitwastransientorintermittentinmostcases.Proteinuriahasnotbeen

showntobepredictiveofacuteorprogressiverenaldisease(seeSection4.8).Thereportingrateforseriousrenal

eventsinpost-marketinguseishigheratthe40mgdose.Anassessmentofrenalfunctionshouldbeconsideredduring

routinefollow-upofpatientstreatedwithadoseof40mg.

SkeletalMuscleEffects

Effectsonskeletalmusclee.g.myalgia,myopathyand,rarely,rhabdomyolysishavebeenreportedinCrestor-treated

patientswithalldosesandinparticularwithdoses>20mg.Veryrarecasesofrhabdomyolysishavebeenreported

withtheuseofezetimibeincombinationwithHMG-CoAreductaseinhibitors.Apharmacodynamicinteractioncannot

beexcluded(seeSection4.5)andcautionshouldbeexercisedwiththeircombineduse.

AswithotherHMG-CoAreductaseinhibitors,thereportingrateforrhabdomyolysisassociatedwithCrestorinpost-

marketinguseishigheratthe40mgdose.

CreatineKinaseMeasurement

CreatineKinase(CK)shouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofaplausiblealternative

causeofCKincreasewhichmayconfoundinterpretationoftheresult.IfCKlevelsaresignificantlyelevatedat

baseline(>5xULN)aconfirmatorytestshouldbecarriedoutwithin5–7days.Iftherepeattestconfirmsabaseline

CK>5xULN,treatmentshouldnotbestarted.

BeforeTreatment

Crestor,aswithotherHMG-CoAreductaseinhibitors,shouldbeprescribedwithcautioninpatientswithpre-disposing

factorsformyopathy/rhabdomyolysis.Suchfactorsinclude:

renalimpairment

hypothyroidism

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previoushistoryofmusculartoxicitywithanotherHMG-CoAreductaseinhibitororfibrate

alcoholabuse

age>70years

situationswhereanincreaseinplasmalevelsmayoccur(seeSection5.2)

concomitantuseoffibrates.

Insuchpatientstheriskoftreatmentshouldbeconsideredinrelationtopossiblebenefitandclinicalmonitoringis

recommended.IfCKlevelsaresignificantlyelevatedatbaseline(>5xULN)treatmentshouldnotbestarted.

WhilstonTreatment

Patientsshouldbeaskedtoreportinexplicablemusclepain,weaknessorcrampsimmediately,particularlyifassociated

withmalaiseorfever.CKlevelsshouldbemeasuredinthesepatients.TherapyshouldbediscontinuedifCKlevelsare

markedlyelevated(>5xULN)orifmuscularsymptomsaresevereandcausedailydiscomfort(evenifCKlevelsare

≤5xULN).IfsymptomsresolveandCKlevelsreturntonormal,thenconsiderationshouldbegiventore-introducing

CrestororanalternativeHMG-CoAreductaseinhibitoratthelowestdosewithclosemonitoring.Routinemonitoring

ofCKlevelsinasymptomaticpatientsisnotwarranted.

Inclinicaltrialstherewasnoevidenceofincreasedskeletalmuscleeffectsinthesmallnumberofpatientsdosedwith

Crestorandconcomitanttherapy.However,anincreaseintheincidenceofmyositisandmyopathyhasbeenseenin

patientsreceivingotherHMG-CoAreductaseinhibitorstogetherwithfibricacidderivativesincludinggemfibrozil,

ciclosporin,nicotinicacid,azoleantifungals,proteaseinhibitorsandmacrolideantibiotics.Gemfibrozilincreasesthe

riskofmyopathywhengivenconcomitantlywithsomeHMG-CoAreductaseinhibitors.Therefore,thecombinationof

Crestorandgemfibrozilisnotrecommended.Thebenefitoffurtheralterationsinlipidlevelsbythecombineduseof

Crestorwithfibratesorniacinshouldbecarefullyweighedagainstthepotentialrisksofsuchcombinations.The40mg

doseiscontraindicatedwithconcomitantuseofafibrate.

(SeeSection4.5andSection4.8)

Crestorshouldnotbeusedinanypatientwithanacute,seriousconditionsuggestiveofmyopathyorpredisposingto

thedevelopmentofrenalfailuresecondarytorhabdomyolysis(e.g.sepsis,hypotension,majorsurgery,trauma,severe

metabolic,endocrineandelectrolytedisorders;oruncontrolledseizures).

LiverEffects

AswithotherHMG-CoAreductaseinhibitors,Crestorshouldbeusedwithcautioninpatientswhoconsumeexcessive

quantitiesofalcoholand/orhaveahistoryofliverdisease.

Itisrecommendedthatliverfunctiontestsbecarriedoutpriorto,and3monthsfollowing,theinitiationoftreatment.

Crestorshouldbediscontinuedorthedosereducedifthelevelofserumtransaminasesisgreaterthan3timestheupper

limitofnormal.Thereportingrateforserioushepaticevents(consistingmainlyofincreasedhepatictransaminases)in

post-marketinguseishigheratthe40mgdose.

Inpatientswithsecondaryhypercholesterolaemiacausedbyhypothyroidismornephroticsyndrome,theunderlying

diseaseshouldbetreatedpriortoinitiatingtherapywithCrestor.

Race

PharmacokineticstudiesshowanincreaseinexposureinAsiansubjectscomparedwithCaucasians(seeSection4.2

andSection5.2)

Proteaseinhibitors

Theconcomitantusewithproteaseinhibitorsisnotrecommended(seeSection4.5).

Lactoseintolerance

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seeSection4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth

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Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshouldbediscontinued.

DiabetesMellitus

Inpatientswithfastingglucose5.6to6.9mmol/L,treatmentwithrosuvastatinhasbeenassociatedwithanincreased

riskofdiabetesmellitus(seeSection4.8).

Paediatricpopulation

Theevaluationoflineargrowth(height),weight,BMI(bodymassindex),andsecondarycharacteristicsofsexual

maturationbyTannerstaginginpaediatricpatients10to17yearsofagetakingrosuvastatinislimitedtoaone-year

period.After52weeksofstudytreatment,noeffectongrowth,weight,BMIorsexualmaturationwasdetected(see

Section5.1).Theclinicaltrialexperienceinchildrenandadolescentpatientsislimitedandthelong-termeffectsof

rosuvastatin(>1year)onpubertyareunknown.

Inaclinicaltrialofchildrenandadolescentsreceivingrosuvastatinfor52weeks,CKelevations>10xULNandmuscle

symptomsfollowingexerciseorincreasedphysicalactivitywereobservedmorefrequentlycomparedtoobservationsin

clinicaltrialsinadults(seeSection4.8).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Ciclosporin:DuringconcomitanttreatmentwithCrestorandciclosporin,rosuvastatinAUCvalueswereonaverage7

timeshigherthanthoseobservedinhealthyvolunteers(seeSection4.3).

Concomitantadministrationdidnotaffectplasmaconcentrationsofciclosporin.

VitaminKantagonists:AswithotherHMG-CoAreductaseinhibitors,theinitiationoftreatmentordosageup-

titrationofCrestorinpatientstreatedconcomitantlywithvitaminKantagonists(e.g.warfarinoranothercoumarin

anticoagulant)mayresultinanincreaseinInternationalNormalisedRatio(INR).Discontinuationordown-titrationof

CrestormayresultinadecreaseinINR.Insuchsituations,appropriatemonitoringofINRisdesirable.

Ezetimibe:ConcomitantuseofCrestorandezetimiberesultedinnochangetoAUCorCmaxforeitherdrug.

However,apharmacodynamicinteraction,intermsofadverseeffects,betweenCrestorandezetimibecannotberuled

out(seeSection4.4).

Gemfibrozilandotherlipid-loweringproducts:ConcomitantuseofCrestorandgemfibrozilresultedina2-fold

increaseinrosuvastatinC

andAUC(seeSection4.4).

Basedondatafromspecificinteractionstudiesnopharmacokineticrelevantinteractionwithfenofibrateisexpected,

howeverapharmacodynamicinteractionmayoccur.Gemfibrozil,fenofibrate,otherfibratesandlipidloweringdoses

(>orequalto1g/day)ofniacin(nicotinicacid)increasetheriskofmyopathywhengivenconcomitantlywithHMG-

CoAreductaseinhibitors,probablybecausetheycanproducemyopathywhengivenalone.The40mgdoseis

contraindicatedwithconcomitantuseofafibrate(seeSection4.3andSection4.4).Thesepatientsshouldalsostart

withthe5mgdose.

Proteaseinhibitors:Althoughtheexactmechanismofinteractionisunknown,concomitantproteaseinhibitoruse

maystronglyincreaserosuvastatinexposure.Inapharmacokineticstudy,co-administrationof20mgrosuvastatinand

acombinationproductoftwoproteaseinhibitors(400mglopinavir/100mgritonavir)inhealthyvolunteerswas

associatedwithanapproximatelytwo-foldandfive-foldincreaseinrosuvastatinsteady-stateAUC

(0-24) andCmax

respectively.Therefore,concomitantuseofrosuvastatininHIVpatientsreceivingproteaseinhibitorsisnot

recommended(seealsoSection4.4).

Antacid:ThesimultaneousdosingofCrestorwithanantacidsuspensioncontainingaluminiumandmagnesium

hydroxideresultedinadecreaseinrosuvastatinplasmaconcentrationofapproximately50%.Thiseffectwasmitigated

whentheantacidwasdosed2hoursafterCrestor.Theclinicalrelevanceofthisinteractionhasnotbeenstudied.

Erythromycin:ConcomitantuseofCrestoranderythromycinresultedina20%decreaseinAUC(0-t)anda30%

decreaseinC

ofrosuvastatin.Thisinteractionmaybecausedbytheincreaseingutmotilitycausedby

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Oralcontraceptive/hormonereplacementtherapy(HRT):ConcomitantuseofCrestorandanoralcontraceptive

resultedinanincreaseinethinylestradiolandnorgestrelAUCof26%and34%,respectively.Theseincreasedplasma

levelsshouldbeconsideredwhenselectingoralcontraceptivedoses.Therearenopharmacokineticdataavailablein

subjectstakingconcomitantCrestorandHRTandthereforeasimilareffectcannotbeexcluded.However,the

combinationhasbeenextensivelyusedinwomeninclinicaltrialsandwaswelltolerated.

Othermedicinalproducts:Basedondatafromspecificinteractionstudiesnoclinicallyrelevantinteractionwith

digoxinisexpected.

CytochromeP450enzymes:Resultsfrominvitroandinvivostudiesshowthatrosuvastatinisneitheraninhibitornor

aninducerofcytochromeP450isoenzymes.Inaddition,rosuvastatinisapoorsubstratefortheseisoenzymes.No

clinicallyrelevantinteractionshavebeenobservedbetweenrosuvastatinandeitherfluconazole(aninhibitorof

CYP2C9andCYP3A4)orketoconazole(aninhibitorofCYP2A6andCYP3A4).Concomitantadministrationof

itraconazole(aninhibitorofCYP3A4)androsuvastatinresultedina28%increaseinAUCofrosuvastatin.Thissmall

increaseisnotconsideredclinicallysignificant.Therefore,druginteractionsresultingfromcytochromeP450-mediated

metabolismarenotexpected.

4.6Pregnancyandlactation

Crestoriscontraindicatedinpregnancyandlactation.

Womenofchildbearingpotentialshoulduseappropriatecontraceptivemeasures.

Sincecholesterolandotherproductsofcholesterolbiosynthesisareessentialforthedevelopmentofthefoetus,the

potentialriskfrominhibitionofHMG-CoAreductaseoutweighstheadvantageoftreatmentduringpregnancy.Animal

studiesprovidelimitedevidenceofreproductivetoxicity(seeSection5.3).Ifapatientbecomespregnantduringuseof

thisproduct,treatmentshouldbediscontinuedimmediately.

Rosuvastatinisexcretedinthemilkofrats.Therearenodatawithrespecttoexcretioninmilkinhumans.

(seeSection4.3).

4.7Effectsonabilitytodriveandusemachines

StudiestodeterminetheeffectofCrestorontheabilitytodriveandusemachineshavenotbeenconducted.However,

basedonitspharmacodynamicproperties,Crestorisunlikelytoaffectthisability.Whendrivingvehiclesoroperating

machines,itshouldbetakenintoaccountthatdizzinessmayoccurduringtreatment.

4.8Undesirableeffects

TheadverseeventsseenwithCrestoraregenerallymildandtransient.Incontrolledclinicaltrials,lessthan4%of

Crestor-treatedpatientswerewithdrawnduetoadverseevents.

Thefrequenciesofadverseeventsarerankedaccordingtothefollowing:Common(>1/100,<1/10);Uncommon

(>1/1,000,<1/100);Rare(>1/10,000,<1/1000);Veryrare(<1/10,000);Notknown(cannotbeestimatedfromthe

availabledata).

Immunesystemdisorders

Rare:hypersensitivityreactionsincludingangioedema

Endocrinedisorders

Common:diabetesmellitus 1

Nervoussystemdisorders

Common:headache,dizziness

Gastrointestinaldisorders

Common:constipation,nausea,abdominalpain

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Skinandsubcutaneoustissuedisorders

Uncommon:pruritus,rashandurticaria

Musculoskeletal,connectivetissueandbonedisorders

Common:myalgia

Rare:myopathy(includingmyositis)andrhabdomyolysis

Generaldisorders

Common:asthenia

ObservedintheJUPITERstudy(reportedoverallfrequency2.8%inrosuvastatinand2.3%inplacebo)mostlyin

patientswithfastingglucose5.6to6.9mmol/L.

AswithotherHMG-CoAreductaseinhibitors,theincidenceofadversedrugreactionstendstobedosedependent.

RenalEffects:Proteinuria,detectedbydipsticktestingandmostlytubularinorigin,hasbeenobservedinpatients

treatedwithCrestor.Shiftsinurineproteinfromnoneortraceto++ormorewereseenin<1%ofpatientsatsometime

duringtreatmentwith10and20mg,andinapproximately3%ofpatientstreatedwith40mg.Aminorincreaseinshift

fromnoneortraceto+wasobservedwiththe20mgdose.Inmostcases,proteinuriadecreasesordisappears

spontaneouslyoncontinuedtherapy.Reviewofdatafromclinicaltrialsandpost-marketingexperiencetodatehasnot

identifiedacausalassociationbetweenproteinuriaandacuteorprogressiverenaldisease.

HaematuriahasbeenobservedinpatientstreatedwithCrestorandclinicaltrialdatashowthattheoccurrenceislow.

Skeletalmuscleeffects:Effectsonskeletalmusclee.g.myalgia,myopathy(includingmyositis)and,rarely,

rhabdomyolysiswithandwithoutacuterenalfailurehavebeenreportedinCrestor-treatedpatientswithalldosesandin

particularwithdoses>20mg.

Adose-relatedincreaseinCKlevelshasbeenobservedinpatientstakingrosuvastatin;themajorityofcasesweremild,

asymptomaticandtransient.IfCKlevelsareelevated(>5xULN),treatmentshouldbediscontinued(seeSection4.4).

LiverEffects:AswithotherHMG-CoAreductaseinhibitors,adose-relatedincreaseintransaminaseshasbeen

observedinasmallnumberofpatientstakingrosuvastatin;themajorityofcasesweremild,asymptomaticand

transient.

PostMarketingExperience:

Inadditiontotheabove,thefollowingadverseeventshavebeenreportedduringpostmarketingexperiencefor

CRESTOR:

Nervoussystemdisorders:Veryrare:polyneuropathy,memoryloss.

Respiratory,thoracicandmediastinaldisorders:Notknown:cough,dyspnoea.

Gastrointestinaldisorders:Notknown:diarrhoea.

Hepatobiliarydisorders:Veryrare:jaundice,hepatitis;rare:increasedtransaminases.

Skinandsubcutaneoustissuedisorders:Notknown:Stevens-Johnsonsyndrome.

Musculoskeletaldisorders:Veryrare:arthralgia.

Renaldisorders:Veryrare:haematuria.

Generaldisordersandadministrationsiteconditions:Notknown:oedema.

Thefollowingadverseeventshavebeenreportedwithsomestatins:

Depression.

Sleepdisturbances,includinginsomniaandnightmares.

Sexualdysfunction.

Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seeSection4.4).

Thereportingratesforrhabdomyolysis,seriousrenaleventsandserioushepaticevents(consistingmainlyofincreased

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Paediatricpopulation:Creatinekinaseelevations>10xULNandmusclesymptomsfollowingexerciseorincreased

physicalactivitywereobservedmorefrequentlyina52-weekclinicaltrialofchildrenandadolescentscomparedto

adults(seeSection4.4).Inotherrespects,thesafetyprofileofrosuvastatinwassimilarinchildrenandadolescents

comparedtoadults.

4.9Overdose

Thereisnospecifictreatmentintheeventofoverdose.Intheeventofoverdose,thepatientshouldbetreated

symptomaticallyandsupportivemeasuresinstitutedasrequired.LiverfunctionandCKlevelsshouldbemonitored.

Haemodialysisisunlikelytobeofbenefit.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:HMG-CoAreductaseinhibitors

ATCcode:C10AA07

Mechanismofaction

RosuvastatinisaselectiveandcompetitiveinhibitorofHMG-CoAreductase,therate-limitingenzymethatconverts3-

hydroxy-3-methylglutarylcoenzymeAtomevalonate,aprecursorforcholesterol.Theprimarysiteofactionof

rosuvastatinistheliver,thetargetorganforcholesterollowering.

RosuvastatinincreasesthenumberofhepaticLDLreceptorsonthecell-surface,enhancinguptakeandcatabolismof

LDLanditinhibitsthehepaticsynthesisofVLDL,therebyreducingthetotalnumberofVLDLandLDLparticles.

Pharmacodynamiceffects

CrestorreduceselevatedLDL-cholesterol,totalcholesterolandtriglyceridesandincreasesHDL-cholesterol.Italso

lowersApoB,nonHDL-C,VLDL-C,VLDL-TGandincreasesApoA-I(seeTable1).CrestoralsolowerstheLDL-

C/HDL-C,totalC/HDL-CandnonHDL-C/HDL-CandtheApoB/ApoA-Iratios.

Table1 Doseresponseinpatientswithprimaryhypercholesterolaemia(typeIIaandIIb)(adjustedmeanpercentchangefrom

baseline)

Atherapeuticeffectisobtainedwithin1weekfollowingtreatmentinitiationand90%ofmaximumresponseis

achievedin2weeks.Themaximumresponseisusuallyachievedby4weeksandismaintainedafterthat.

Clinicalefficacy

Crestoriseffectiveinadultswithhypercholesterolaemia,withandwithouthypertriglyceridaemia,regardlessofrace,

sex,orageandinspecialpopulationssuchasdiabetics,orpatientswithfamilialhypercholesterolaemia.

FrompooledphaseIIIdata,CrestorhasbeenshowntobeeffectiveattreatingthemajorityofpatientswithtypeIIaand

IIbhypercholesterolaemia(meanbaselineLDL-Cabout4.8mmol/l)torecognisedEuropeanAtherosclerosisSociety

(EAS;1998)guidelinetargets;about80%ofpatientstreatedwith10mgreachedtheEAStargetsforLDL-Clevels

(<3mmol/l).

Inalargestudy,435patientswithheterozygousfamilialhypercholesterolaemiaweregivenCrestorfrom20mgto80

Dose N LDL-C Total-C HDL-C TG nonHDL-C ApoB ApoA-I

Placebo 13 -7 -5 3 -3 -7 -3 0

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Followingtitrationtoadailydoseof40mg(12weeksoftreatment),LDL-Cwasreducedby53%.33%ofpatients

reachedEASguidelinesforLDL-Clevels(<3mmol/l).

Inaforce-titration,openlabeltrial,42patientswithhomozygousfamilialhypercholesterolaemiawereevaluatedfor

theirresponsetoCrestor20-40mg.Intheoverallpopulation,themeanLDL-Creductionwas22%.

Inclinicalstudieswithalimitednumberofpatients,Crestorhasbeenshowntohaveadditiveefficacyinlowering

triglycerideswhenusedincombinationwithfenofibrateandinincreasingHDL-Clevelswhenusedincombination

withniacin(seeSection4.4).

Inamulti-centre,double-blind,placebo-controlledclinicalstudy(METEOR),984patientsbetween45and70yearsof

ageandatlowriskforcoronaryheartdisease(definedasFraminghamrisk<10%over10years),withameanLDL-C

of4.0mmol/l(154.5mg/dL),butwithsubclinicalatherosclerosis(detectedbyCarotidIntimaMediaThickness)were

randomisedto40mgrosuvastatinoncedailyorplacebofor2years.Rosuvastatinsignificantlyslowedtherateof

progressionofthemaximumCIMTforthe12carotidarterysitescomparedtoplaceboby-0.0145mm/year[95%

confidenceinterval-0.0196,-0.0093;p<0.0001].Thechangefrombaselinewas-0.0014mm/year(-0.12%/year(non-

significant))forrosuvastatincomparedtoaprogressionof+0.0131mm/year(1.12%/year(p<0.0001))forplacebo.No

directcorrelationbetweenCIMTdecreaseandreductionoftheriskofcardiovasculareventshasyetbeen

demonstrated.ThepopulationstudiedinMETEORislowriskforcoronaryheartdiseaseanddoesnotrepresentthe

targetpopulationofCrestor40mg.The40mgdoseshouldonlybeprescribedinpatientswithsevere

hypercholesterolaemiaathighcardiovascularrisk(seeSection4.2).

IntheJustificationfortheUseofStatinsinPrimaryPrevention:AnInterventionTrialEvaluatingRosuvastatin

(JUPITER)study,theeffectofrosuvastatinontheoccurrenceofmajoratheroscleroticcardiovasculardiseaseevents

wasassessedin17,802men( ≥50years)andwomen(≥60years).

Studyparticipantswererandomlyassignedtoplacebo(n=8901)orrosuvastatin20mgoncedaily(n=8901)andwere

followedforameandurationof2years.

LDL-cholesterolconcentrationwasreducedby45%(p<0.001)intherosuvastatingroupcomparedtotheplacebo

group.

Inapost-hocanalysisofahigh-risksubgroupofsubjectswithabaselineFraminghamriskscore>20%(1558subjects)

therewasasignificantreductioninthecombinedend-pointofcardiovasculardeath,strokeandmyocardialinfarction

(p=0.028)onrosuvastatintreatmentversusplacebo.Theabsoluteriskreductionintheeventrateper1000patient-years

was8.8.Totalmortalitywasunchangedinthishighriskgroup(p=0.193).Inapost-hocanalysisofahigh-risk

subgroupofsubjects(9302subjectstotal)withabaselineSCORErisk ≥5%(extrapolatedtoincludesubjectsabove65

yrs)therewasasignificantreductioninthecombinedend-pointofcardiovasculardeath,strokeandmyocardial

infarction(p=0.0003)onrosuvastatintreatmentversusplacebo.Theabsoluteriskreductionintheeventratewas5.1

per1000patient-years.Totalmortalitywasunchangedinthishighriskgroup(p=0.076).

IntheJUPITERtrialtherewere6.6%ofrosuvastatinand6.2%ofplacebosubjectswhodiscontinueduseofstudy

medicationduetoanadverseevent.Themostcommonadverseeventsthatledtotreatmentdiscontinuationwere:

myalgia(0.3%rosuvastatin,0.2%placebo),abdominalpain(0.03%rosuvastatin,0.02%placebo)andrash(0.02%

rosuvastatin,0.03%placebo).Themostcommonadverseeventsatarategreaterthanorequaltoplacebowereurinary

tractinfection(8.7%rosuvastatin,8.6%placebo),nasopharyngitis(7.6%rosuvastatin,7.2%placebo),backpain(7.6%

rosuvastatin,6.9%placebo)andmyalgia(7.6%rosuvastatin,6.6%placebo).

Paediatricpopulation

Inadouble-blind,randomized,multi-centre,placebo-controlled,12-weekstudy(n=176,97maleand79female)

followedbya40-week(n=173,96maleand77female),open-label,rosuvastatindose-titrationphase,patients10-17

yearsofage(TannerstageII-V,femalesatleast1yearpost-menarche)withheterozygousfamilial

hypercholesterolaemiareceivedrosuvastatin5,10or20mgorplacebodailyfor12weeksandthenallreceived

rosuvastatindailyfor40weeks.Atstudyentry,approximately30%ofthepatientswere10-13yearsandapproximately

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LDL-Cwasreduced38.3%,44.6%,and50.0%byrosuvastatin5,10and20mg,respectively,comparedto0.7%for

placebo.

Attheendofthe40-week,open-label,titrationtogoal,dosinguptoamaximumof20mgoncedaily,70of173

patients(40.5%)hadachievedtheLDL-Cgoaloflessthan2.8mmol/l.

After52weeksofstudytreatment,noeffectongrowth,weight,BMIorsexualmaturationwasdetected(seeSection

4.4).Theclinicaltrialexperienceinchildrenandadolescentpatientsislimitedandthelong-termeffectsofrosuvastatin

(>1year)onpubertyareunknown.Thistrial(n=176)wasnotsuitedforcomparisonofrareadversedrugevents.

5.2Pharmacokineticproperties

Absorption:Maximumrosuvastatinplasmaconcentrationsareachievedapproximately5hoursafteroral

administration.Theabsolutebioavailabilityisapproximately20%.

Distribution:Rosuvastatinistakenupextensivelybytheliverwhichistheprimarysiteofcholesterolsynthesisand

LDL-Cclearance.Thevolumeofdistributionofrosuvastatinisapproximately134L.Approximately90%of

rosuvastatinisboundtoplasmaproteins,mainlytoalbumin.

Metabolism:Rosuvastatinundergoeslimitedmetabolism(approximately10%).Invitrometabolismstudiesusing

humanhepatocytesindicatethatrosuvastatinisapoorsubstrateforcytochromeP450-basedmetabolism.CYP2C9was

theprincipalisoenzymeinvolved,with2C19,3A4and2D6involvedtoalesserextent.Themainmetabolitesidentified

aretheN-desmethylandlactonemetabolites.TheN-desmethylmetaboliteisapproximately50%lessactivethan

rosuvastatinwhereasthelactoneformisconsideredclinicallyinactive.Rosuvastatinaccountsforgreaterthan90%of

thecirculatingHMG-CoAreductaseinhibitoractivity.

Excretion:Approximately90%oftherosuvastatindoseisexcretedunchangedinthefaeces(consistingofabsorbed

andnon-absorbedactivesubstance)andtheremainingpartisexcretedinurine.Approximately5%isexcreted

unchangedinurine.Theplasmaeliminationhalf-lifeisapproximately19hours.Theeliminationhalf-lifedoesnot

increaseathigherdoses.Thegeometricmeanplasmaclearanceisapproximately50litres/hour(coefficientofvariation

21.7%).AswithotherHMG-CoAreductaseinhibitors,thehepaticuptakeofrosuvastatininvolvesthemembrane

transporterOATP-C.Thistransporterisimportantinthehepaticeliminationofrosuvastatin.

Linearity:Systemicexposureofrosuvastatinincreasesinproportiontodose.Therearenochangesinpharmacokinetic

parametersfollowingmultipledailydoses.

Specialpopulations:

Ageandsex:Therewasnoclinicallyrelevanteffectofageorsexonthepharmacokineticsofrosuvastatininadults.

Thepharmacokineticsofrosuvastatininchildrenandadolescentswithheterozygousfamilialhypercholesterolaemia

wassimilartothatofadultvolunteers(see“Paediatricpopulation”below).

Race:Pharmacokineticstudiesshowanapproximate2-foldelevationinmedianAUCandC

inAsiansubjects

(Japanese,Chinese,Filipino,VietnameseandKoreans)comparedwithCaucasians;Asian-Indiansshowan

approximate1.3-foldelevationinmedianAUCandCmax.Apopulationpharmacokineticanalysisrevealedno

clinicallyrelevantdifferencesinpharmacokineticsbetweenCaucasianandBlackgroups.

Renalinsufficiency:Inastudyinsubjectswithvaryingdegreesofrenalimpairment,mildtomoderaterenaldisease

hadnoinfluenceonplasmaconcentrationofrosuvastatinortheN-desmethylmetabolite.Subjectswithsevere

impairment(CrCl<30ml/min)hada3-foldincreaseinplasmaconcentrationanda9-foldincreaseintheN-desmethyl

metaboliteconcentrationcomparedtohealthyvolunteers.Steady-stateplasmaconcentrationsofrosuvastatininsubjects

undergoinghaemodialysiswereapproximately50%greatercomparedtohealthyvolunteers.

Hepaticinsufficiency:Inastudywithsubjectswithvaryingdegreesofhepaticimpairmenttherewasnoevidenceof

increasedexposuretorosuvastatininsubjectswithChild-Pughscoresof7orbelow.However,twosubjectswithChild-

Pughscoresof8and9showedanincreaseinsystemicexposureofatleast2-foldcomparedtosubjectswithlower

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Paediatricpopulation:Thepharmacokineticparametersinpaediatricpatientswithheterozygousfamilial

hypercholesterolaemiaaged10to17yearshavenotbeenfullycharacterised.Asmallpharmacokineticstudywith

rosuvastatin(givenastablets)in18paediatricpatientsdemonstratedthatexposureinpaediatricpatientsappears

comparabletoexposureinadultpatients.Inaddition,theresultsindicatethatalargedeviationfromdose

proportionalityisnotexpected.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,

genotoxicityandcarcinogenicitypotential.SpecifictestsforeffectsonhERGhavenotbeenevaluated.Adverse

reactionsnotobservedinclinicalstudies,butseeninanimalsatexposurelevelssimilartoclinicalexposurelevelswere

asfollows:Inrepeated-dosetoxicitystudieshistopathologicliverchangeslikelyduetothepharmacologicactionof

rosuvastatinwereobservedinmouse,rat,andtoalesserextentwitheffectsinthegallbladderindogs,butnotin

monkeys.Inaddition,testiculartoxicitywasobservedinmonkeysanddogsathigherdosages.Reproductivetoxicity

wasevidentinrats,withreducedlittersizes,litterweightandpupsurvivalobservedatmaternallytoxicdoses,where

systemicexposureswereseveraltimesabovethetherapeuticexposurelevel.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Lactosemonohydrate

Microcrystallinecellulose

Calciumphosphate

Crospovidone

Magnesiumstearate

Tabletcoat

Lactosemonohydrate

Hypromellose

Triacetin

Titaniumdioxide(EI71)

Ferricoxide,red(EI72)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storebelow30°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

Oldham

Lancashire

OL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/3/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:8thOctober2010

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