CRESTOR

Main information

  • Trade name:
  • CRESTOR Film Coated Tablet 20 Milligram
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CRESTOR Film Coated Tablet 20 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/002/001
  • Authorization date:
  • 08-05-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Crestor20mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains20mgofrosuvastatin(asrosuvastatincalcium).

Excipients:Lactosemonohydrate

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-CoatedTablet

ProductimportedfromtheUK,SpainandItaly.

Round,Pink,BiconvexTabletwith‘ZD4522’and‘20’ononesideandplainonthereverse

4CLINICALPARTICULARS

4.1TherapeuticIndications

Primaryhypercholesterolaemia(typeIIaincludingheterozygousfamilialhypercholesterolaemia)ormixed

dyslipidaemia(typeIIb)asanadjuncttodietwhenresponsetodietandothernon-pharmacologicaltreatments(e.g.

exercise,weightreduction)isinadequate.

Homozygousfamilialhypercholesterolaemiaasanadjuncttodietandotherlipidloweringtreatments(e.g.LDL

apheresis)orifsuchtreatmentsarenotappropriate.

4.2Posologyandmethodofadministration

Beforetreatmentinitiationthepatientshouldbeplacedonastandardcholesterol-loweringdietthatshouldcontinue

duringtreatment.Thedoseshouldbeindividualisedaccordingtothegoaloftherapyandpatientresponse,usingcurrent

consensusguidelines.

Therecommendedstartdoseis5mgor10mgorallyoncedailyinbothstatinnaïveorpatientsswitchedfromanother

HMGCoAreductaseinhibitor.Thechoiceofstartdoseshouldtakeintoaccounttheindividualpatient'scholesterol

levelandfuturecardiovascularriskaswellasthepotentialriskforadversereactions(seebelow).Adoseadjustmentto

thenextdoselevelcanbemadeafter4weeks,ifnecessary(seeSection5.1).Inlightoftheincreasedreportingrateof

adversereactionswiththe40mgdosecomparedtolowerdoses(seeSection4.8),afinaltitrationtothemaximumdose

of40mgshouldonlybeconsideredinpatientswithseverehypercholesterolaemiaathighcardiovascularrisk(in

particularthosewithfamilialhypercholesterolaemia),whodonotachievetheirtreatmentgoalon20mg,andinwhom

routinefollow-upwillbeperformed(seeSection4.4).Specialistsupervisionisrecommendedwhenthe40mgdoseis

initiated.

Crestormaybegivenatanytimeofday,withorwithoutfood.

Paediatricuse

Safetyandefficacyhavenotbeenestablishedinchildren.Paediatricexperienceislimitedtoasmallnumberofchildren

(aged8yearsorabove)withhomozygousfamilialhypercholesterolaemia.Therefore,Crestorisnotrecommendedfor

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 1

Useintheelderly

Astartdoseof5mgisrecommendedinpatients>70years(seeSection4.4).Nootherdoseadjustmentisnecessaryin

relationtoage.

Dosageinpatientswithrenalinsufficiency

Nodoseadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment.Therecommendedstartdoseis5

mginpatientswithmoderaterenalimpairment(creatinineclearanceof<60ml/min).The40mgdoseiscontraindicated

inpatientswithmoderaterenalimpairment.TheuseofCrestorinpatientswithsevererenalimpairmentis

contraindicatedforalldoses(SeeSection4.3andSection5.2).

Dosageinpatientswithhepaticimpairment

TherewasnoincreaseinsystemicexposuretorosuvastatininsubjectswithChild-Pughscoresof7orbelow.However,

increasedsystemicexposurehasbeenobservedinsubjectswithChild-Pughscoresof8and9(seeSection5.2).Inthese

patientsanassessmentofrenalfunctionshouldbeconsidered(seeSection4.4).Thereisnoexperienceinsubjectswith

Child-Pughscoresabove9.Crestoriscontraindicatedinpatientswithactiveliverdisease(seeSection4.3).

Race

IncreasedsystemicexposurehasbeenseeninAsiansubjects(seeSection4.4andSection5.2).Therecommendedstart

doseis5mgforpatientsofAsianancestry.The40mgdoseiscontraindicatedinthesepatients.

Dosageinpatientswithpre-disposingfactorstomyopathy

Therecommendedstartdoseis5mginpatientswithpredisposingfactorstomyopathy(seeSection4.4).The40mg

doseiscontraindicatedinsomeofthesepatients(seeSection4.3).

4.3Contraindications

Crestoriscontraindicated:

-inpatientswithhypersensitivitytorosuvastatinortoanyoftheexcipients.

-inpatientswithactiveliverdiseaseincludingunexplained,persistentelevationsofserumtransaminasesandany

serumtransaminaseelevationexceeding3xtheupperlimitofnormal(ULN).

-inpatientswithsevererenalimpairment(creatinineclearance<30ml/min).

-inpatientswithmyopathy.

-inpatientsreceivingconcomitantciclosporin.

-duringpregnancyandlactationandinwomenofchildbearingpotentialnotusingappropriatecontraceptivemeasures.

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).

Thereportingrateforseriousrenaleventsinpost-marketinguseishigheratthe40mgdose.Anassessmentofrenal

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 2

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

personalorfamilyhistoryofhereditarymusculardisorders

previoushistoryofmusculartoxicitywithanotherHMG-CoAreductaseinhibitororfibrate

alcoholabuse

age>70years

situationswhereanincreaseinplasmalevelsmayoccur(seeSection5.2)

concomitantuseoffibrates.

Insuchpatientstheriskoftreatmentshouldbeconsideredinrelationtopossiblebenefitandclinicalmonitoringis

recommended.IfCKlevelsaresignificantlyelevatedatbaseline(>5xULN)treatmentshouldnotbestarted.

WhilstonTreatment

Patientsshouldbeaskedtoreportinexplicablemusclepain,weaknessorcrampsimmediately,particularlyifassociated

withmalaiseorfever.CKlevelsshouldbemeasuredinthesepatients.TherapyshouldbediscontinuedifCKlevelsare

markedlyelevated(>5xULN)orifmuscularsymptomsaresevereandcausedailydiscomfort(evenifCKlevelsare5x

ULN).IfsymptomsresolveandCKlevelsreturntonormal,thenconsiderationshouldbegiventore-introducing

CrestororanalternativeHMG-CoAreductaseinhibitoratthelowestdosewithclosemonitoring.Routinemonitoring

ofCKlevelsinasymptomaticpatientsisnotwarranted.

Inclinicaltrialstherewasnoevidenceofincreasedskeletalmuscleeffectsinthesmallnumberofpatientsdosedwith

Crestorandconcomitanttherapy.However,anincreaseintheincidenceofmyositisandmyopathyhasbeenseenin

patientsreceivingotherHMG-CoAreductaseinhibitorstogetherwithfibricacidderivativesincludinggemfibrozil,

cilosporin,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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 3

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

Patientswithrarehereditaryproblemsofglactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

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

increaseinrosuvastatinCmaxandAUC(seeSection4.4).

Basedondatafromspecificinteractionstudiesnopharmacokineticrelevantinteractionwithfenofibrateisexpected,

howeverapharmacodynamicinteractionmayoccur.Gemfibrozil,fenofibrate,otherfibratesandlipidloweringdoses

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

CoAreductaseinhibitors,probablybecausetheycanproducemyopathywhengivenalone.The40mgdoseis

contraindicatedwithconcomitantuseofafibrate(seeSection4.3andSection4.4).Thesepatientsshouldalsostart

withthe5mgdose.

Proteaseinhibitors:Althoughtheexactmechanismofinteractionisunknown,concomitantproteaseinhibitorusemay

stronglyincreaserosuvastatinexposure.Inapharmacokineticstudy,co-administrationof20mgrosuvastatinanda

combinationproductoftwoproteaseinhibitors(400mglopinavir/100mgritonavir)inhealthyvolunteerswas

associatedwithanapproximatelytwo-foldandfive-foldincreaseinrosuvastatinsteady-stateAUC(0-24)andCmax

respectively.Therefore,concomitantuseofrosuvastatininHIVpatientsreceivingproteaseinhibitorsisnot

recommended(seealsoSection4.4).

Antacid:ThesimultaneousdosingofCrestorwithanantacidsuspensioncontainingaluminiumandmagnesium

hydroxideresultedinadecreaseinrosuvastatinplasmaconcentrationofapproximately50%.Thiseffectwasmitigated

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 4

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

decreaseinCmaxofrosuvastatin.Thisinteractionmaybecausedbytheincreaseingutmotilitycausedby

erythromycin.

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(seeSection

4.3).

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

Nervoussystemdisorders

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 5

Gastrointestinaldisorders

Common:constipation,nausea,abdominalpain

Rare:pancreatitis

Skinandsubcutaneoustissuedisorders

Uncommon:pruritus,rashandurticaria

Musculoskeletal,connectivetissueandbonedisorders

Common:myalgia

Rare:myopathy(includingmyositis)andrhabdomyolysis

Generaldisorders

Common:asthenia

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:

Gastrointestinaldisorders:Notknown:diarrhoea.

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

Musculoskeletaldisorders:Veryrare:arthralgia.

Nervoussystemdisorders:Veryrare:polyneuropathy,memoryloss.

Renaldisorders:Veryrare:haematuria.

Skinandsubcutaneoustissuedisorders:Notknown:Stevens-Johnsonsyndrome.

Thereportingratesforrhabdomyolysis,seriousrenaleventsandserioushepaticevents(consistingmainlyofincreased

hepatictransaminases)ishigheratthe40mgdose.

4.9Overdose

Thereisnospecifictreatmentintheeventofoverdose.Intheeventofoverdose,thepatientshouldbetreated

symptomaticallyandsupportivemeasuresinstitutedasrequired.LiverfunctionandCKlevelsshouldbemonitored.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 6

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.

Table1Doseresponseinpatientswithprimaryhypercholesterolaemia(typeIIaandIIb)(adjustedmean

percentchangefrombaseline)

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(<3

mmol/l).

Inalargestudy,435patientswithheterozygousfamilialhypercholesterolaemiaweregivenCrestorfrom20mgto80

mginaforce-titrationdesign.Alldosesshowedabeneficialeffectonlipidparametersandtreatmenttotargetgoals.

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).

Rosuvastatinhasnotbeenproventopreventtheassociatedcomplicationsoflipidabnormalities,suchascoronaryheart

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

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 7

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

ageandatlowriskforcoronaryheartdisease(definedasFraminghamrisk<10%over10years),withmeanLDL-Cor

4.0mmol/l(154.5mg/dL),butwithsubclinicalatherosclerosis(detectedbyCarotidIntimaMediaThickness)were

randomisedto40mgrosuvastatinoncedailyorplacebofor2years.Rosuvastatinsignificantlyslowedtherateof

progressionofthemaximumCIMTforthe12carotidarterysitescomparedtoplaceboby-0.0145mm/year[95%

confidenceinterval0.0196,-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

directcorrelationbetweenCIMTdecreaseandreductionoftheriskofcardiovasculareventshasyetbeendemonstrated.

ThepopulationstudiedinMETEORislowriskfortheriskofcardiovasculareeventshasyetbeendemonstrated.The

populationstudiedinMETEORislowriskforcoronaryheartdiseaseanddoesnotrepresentthetargetpopulationof

Crestor40mg.The40mgdoseshouldonlybeprescribedinpatientswithseverehypercholesterolaemiaathigh

cardiovascularrisk(seeSection4.2).

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:Therewasnoclinicallyrelevanteffectofageorsexonthepharmacokineticsofrosuvastatin.

Race:Pharmacokineticstudiesshowanapproximate2-foldelevationinmedianAUCandCmaxinAsiansubjects

(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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 8

However,twosubjectswithChild-Pughscoresof8and9showedanincreaseinsystemicexposureofatleast2-fold

comparedtosubjectswithlowerChild-Pughscores.ThereisnoexperienceinsubjectswithChild-Pughscoresabove

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(E171)

RedIronoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storebelow30°C

Storeintheoriginalpackage

6.5Natureandcontentsofcontainer

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 9

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/2/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization:8 th

May2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/10/2010 CRN 2090418 page number: 10