CRESTOR 20MG FILM-COATED TABLETS

Main information

  • Trade name:
  • CRESTOR 20MG FILM-COATED TABLETS
  • Dosage:
  • 20mg Milligram
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CRESTOR 20MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/140/002A
  • Authorization date:
  • 07-06-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Crestor20mgFilm-coatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains20mgofrosuvastatin(asrosuvastatincalcium).

Excipients:Lactosemonohydrate

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet(tablet)

ProductimportedfromItaly,Greece,UnitedKingdomandtheNetherlands:

Pinkcoloured,roundfilm-coatedtabletwith‘ZD4522’and‘20’engravedononesideandplainontheotherside.

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).

Adoseadjustmenttothenextlevelcanbemadeafter4weeks,ifnecessary(seeSection5.1Pharmacodynamic

properties).Inlightoftheincreasedreportingrateofadversereactionswiththe40mgdosecomparedtolowerdoses

(seeSection4.8Undesirableeffects),finaltitrationtothemaximumdoseto40mgshouldonlybeconsideredin

patientswithseverehypercholesterolaemiaathighcardiovascularrisk(inparticularthosewithfamilial

hypercholesterolaemia),whodonotachievetheirtreatmentgoalon20mg,andinwhomroutinefollow-upwillbe

performed(seeSection4.4Specialwarningsandprecautions).

Specialistsupervisionisrecommendedwhenthe40mgdoseisinitiated.

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Paediatricuse:

Safetyandefficacyhavenotbeenestablishedinchildren.

Paediatricexperienceislimitedtoasmallnumberofchildren(aged8yearsorabove)withhomozygousfamilial

hypercholesterolaemia.Therefore,Crestorisnotrecommendedforpaediatricuseatthistime.

Useintheelderly

Astartdoseof5mgisrecommendedinpatients>70years(seesection4.4Specialwarningsandprecautionsforuse).

Nootherdoseadjustmentisnecessaryinrelationtoage.

Dosageinpatientswithrenalinsufficiency

Nodoseadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment.TheuseofCrestorinpatientswith

severerenalimpairmentiscontraindicatedforalldoses.The40mgdoseisalsocontraindicatedinpatientswith

moderaterenalimpairment(creatinineclearance<60ml/min,seeSection4.3ContraindicationsandSection5.2

Pharmacokineticproperties).

Dosageinpatientswithhepaticimpairment

TherewasnoincreaseinsystemicexposuretorosuvastatininsubjectswithChild-Pughscoresof7orbelow.However,

increasedsystemicexposurehasbeenobservedinsubjectswithChild-Pughscoresof8and9(seeSection5.2

Pharmacokineticproperties).Inthesepatientsanassessmentofrenalfunctionshouldbeconsidered(seeSection4.4

Specialwarningsandspecialprecautionsforuse).ThereisnoexperienceinsubjectswithChild-Pughscoresabove9.

Crestoriscontraindicatedinpatientswithactiveliverdisease(seeSection4.3Contraindications).

Race

IncreasedsystemicexposurehasbeenseeninAsiansubjects(seesection4.4Specialwarningsandspecialprecautions

foruseandsection5.2Pharmacokineticproperties).Therecommendedstartdoseis5mgforpatientsofAsian

ancestry.The40mgdoseiscontraindicatedinthesepatients.

Dosageinpatientswithpre-disposingfactorstomyopathy

Therecommendedstartdoseis5mginpatientswithpredisposingfactorstomyopathy(seesection4.4Special

warningsandspecialprecautionsforuse).

The40mgdoseiscontraindicatedinsomeofthesepatients(seesection4.3Contraindications).

4.3Contraindications

Crestoriscontraindicated:

inpatientswithhypersensitivitytorosuvastatinortoanyoftheexcipients.

inpatientswithactiveliverdiseaseincludingunexplained,persistentelevationsofserumtransaminasesandany

serumtransaminaseelevationexceeding3xtheupperlimitofnormal(ULN).

inpatientswithsevererenalimpairment(creatinineclearance<30ml/min).

inpatientswithmyopathy.

inpatientsreceivingconcomitantcyclosporin.

duringpregnancyandlactationandinwomenofchildbearingpotentialnotusingappropriatecontraceptive

measures.

The40mgdoseiscontraindicatedinpatientswithpre-disposingfactorsformyopathy/rhabdomyolysis.Suchfactors

include:

moderaterenalimpairment(creatinineclearance<60ml/min)

hypothyroidism

personalorfamilyhistoryofhereditarymusculardisorders

previoushistoryofmusculartoxicitywithanotherHMG-CoAreductaseinhibitororfibrate

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situationswhereanincreaseinplasmalevelsmayoccur

Asianpatients

concomitantuseoffibrates.

(seesections4.4Specialwarningsandspecialprecautionsforuse,4.5Interactionwithothermedicinalproductsand

otherformsofinteractionand5.2Pharmacokineticproperties)

4.4Specialwarningsandprecautionsforuse

Lactoseintolerance

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine

RenalEffects

Proteinuria,detectedbydipsticktestingandmostlytubularinorigin,hasbeenobservedinpatientstreatedwithhigher

dosesofCrestor,inparticular40mg,whereitwastransientorintermittentinmostcases.Proteinuriahasnotbeen

showntobepredictiveofacuteorprogressiverenaldisease(seeSection4.8Undesirableeffects).Thereportingratefor

seriousrenaleventsinpost-marketinguseishigheratthe40mgdose.Anassessmentofrenalfunctionshouldbe

consideredduringroutinefollow-upofpatientstreatedwithadoseof40mg.

SkeletalMuscleEffects

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

patientswithalldosesandinparticularwithdoses>20mg.Veryrarecasesofrhabdomyolysishavebeenreported

withtheuseofezetimibeincombinationwithHMG-CoAreductaseinhibitors.Apharmacodynamicinteractioncannot

beexcluded(seesection4.5Interactionswithothermedicinalproductsandotherformsofinteractions)andcaution

shouldbeexercisedwiththeircombineduse.

CreatineKinaseMeasurement

CreatineKinase(CK)shouldnotbemeasuredfollowingstrenuousexerciseorinthepresenceofaplausiblealternative

causeofCKincreasewhichmayconfoundinterpretationoftheresult.IfCKlevelsaresignificantlyelevatedat

baseline>5xULN)aconfirmatorytestshouldbecarriedoutwithin5–7days.

IftherepeattestconfirmsabaselineCK>5xULN,treatmentshouldnotbestarted.

BeforeTreatment

Crestor,aswithotherHMG-CoAreductaseinhibitors,shouldbeprescribedwithcautioninpatientswithpre-disposing

factorsformyopathy/rhabdomyolysis.Suchfactorsinclude:

renalimpairment

hypothyroidism

personalorfamilyhistoryofhereditarymusculardisorders

previoushistoryofmusculartoxicitywithanotherHMG-CoAreductaseinhibitororfibrate

alcoholabuse

age>70years

situationswhereanincreaseinplasmalevelsmayoccur(seesection5.2Pharmacokineticproperties)

concomitantuseoffibrates.

Insuchpatientstheriskoftreatmentshouldbeconsideredinrelationtopossiblebenefitandclinicalmonitoringis

recommended.IfCKlevelsaresignificantlyelevatedatbaseline>5xULN)treatmentshouldnotbestarted.

WhilstonTreatment

Patientsshouldbeaskedtoreportinexplicablemusclepain,weaknessorcrampsimmediately,particularlyifassociated

withmalaiseorfever.CKlevelsshouldbemeasuredinthesepatients.TherapyshouldbediscontinuedifCKlevelsare

markedlyelevated>5xULN)orifmuscularsymptomsaresevereandcausedailydiscomfort(evenifCKlevelsare<

5xULN).IfsymptomsresolveandCKlevelsreturntonormal,thenconsiderationshouldbegiventore-introducing

CrestororanalternativeHMG-CoAreductaseinhibitoratthelowestdosewithclosemonitoring.

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Inclinicaltrialstherewasnoevidenceofincreasedskeletalmuscleeffectsinthesmallnumberofpatientsdosedwith

Crestorandconcomitanttherapy.However,anincreaseintheincidenceofmyositisandmyopathyhasbeenseenin

patientsreceivingotherHMG-CoAreductaseinhibitorstogetherwithfibricacidderivativesincludinggemfibrozil,

cyclosporin,nicotinicacid,azoleantifungals,proteaseinhibitorsandmacrolideantibiotics.Gemfibrozilincreasesthe

riskofmyopathywhengivenconcomitantlywithsomeHMG-CoAreductaseinhibitors.Therefore,thecombinationof

Crestorandgemfibrozilisnotrecommended.

ThebenefitoffurtheralterationsinlipidlevelsbythecombineduseofCrestorwithfibratesorniacinshouldbe

carefullyweighedagainstthepotentialrisksofsuchcombinations.The40mgdoseiscontraindicatedwithconcomitant

useofafibrate.

(SeeSection4.5InteractionwithothermedicinalproductsandotherformsofinteractionandSection4.8Undesirable

effects.)

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

PosologyandMethodofadministrationandsection5.2Pharmacokineticproperties).

Proteaseinhibitors

Theconcomitantusewithproteaseinhibitorsisnotrecommended(seesection4.5).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Cyclosporin:DuringconcomitanttreatmentwithCrestorandcyclosporin,rosuvastatinAUCvalueswereonaverage7

timeshigherthanthoseobservedinhealthyvolunteers(seeSection4.3Contraindications).

Concomitantadministrationdidnotaffectplasmaconcentrationsofcyclosporin.

VitaminKantagonists:AswithotherHMG-CoAreductaseinhibitors,theinitiationoftreatmentordosageup-

titrationofCrestorinpatientstreatedconcomitantlywithvitaminKantagonists(e.g.warfarin)mayresultinan

increaseinInternationalNormalisedRatio(INR).Discontinuationordown-titrationofCrestormayresultinadecrease

inINR.Insuchsituations,appropriatemonitoringofINRisdesirable.

Ezetimibe:ConcomitantuseofCrestorandezetimiberesultedinnochangetoAUCorC

foreitherdrug.

However,apharmacodynamicinteraction,intermsofadverseeffects,betweenCrestorandezetimibecannotberuled

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Gemfibrozilandotherlipid-loweringproducts:ConcomitantuseofCrestorandgemfibrozilresultedina2-fold

increaseinrosuvastatinC

andAUC(seeSection4.4Specialwarningsandspecialprecautionsforuse).

Basedondatafromspecificinteractionstudiesnopharmacokineticrelevantinteractionwithfenofibrateisexpected,

howeverapharmacodynamicinteractionmayoccur.Gemfibrozil,fenofibrate,otherfibratesandlipidloweringdoses>

orequalto1g/day)ofniacin(nicotinicacid)increasetheriskofmyopathywhengivenconcomitantlywithHMG-CoA

reductaseinhibitors,probablybecausetheycanproducemyopathywhengivenalone.The40mgdoseis

contraindicatedwithconcomitantuseofafibrate(seeSection4.3ContraindicationsandSection4.4Specialwarnings

andspecialprecautionsforuse).

Antacid:ThesimultaneousdosingofCrestorwithanantacidsuspensioncontainingaluminiumandmagnesium

hydroxideresultedinadecreaseinrosuvastatinplasmaconcentrationofapproximately50%.Thiseffectwasmitigated

whentheantacidwasdosed2hoursafterCrestor.Theclinicalrelevanceofthisinteractionhasnotbeenstudied.

Proteaseinhibitors:

Althoughtheexactmechanismofinteractionisunknown,concomitantproteaseinhibitorusemaystronglyincrease

rosuvastatinexposure.Inapharmacokineticstudy,co-administrationof20mgrosuvastatinandacombinationproduct

oftwoproteaseinhibitors(400mglopinavir/100mgritonavir)inhealthyvolunteerswasassociatedwithan

approximatelytwo-foldsandfive-foldincreaseinrosuvastatinsteady-stateAUC(0-24)andCmaxrespectively.

Therefore,concomitantuseofrosuvastatininHIVpatientsreceivingproteaseinhibitorsisnotrecommended(seealso

Section4.4).

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

decreaseinC

ofrosuvastatin.Thisinteractionmaybecausedbytheincreaseingutmotilitycausedby

erythromycin.

Oralcontraceptive/hormonereplacementtherapy(HRT):ConcomitantuseofCrestorandanoralcontraceptive

resultedinanincreaseinethinyloestradiolandnorgestrelAUCof26%and34%,respectively.Theseincreasedplasma

levelsshouldbeconsideredwhenselectingoralcontraceptivedoses.Therearenopharmacokineticdataavailablein

subjectstakingconcomitantCrestorandHRTandthereforeasimilareffectcannotbeexcluded.However,the

combinationhasbeenextensivelyusedinwomeninclinicaltrialsandwaswelltolerated.

Othermedicinalproducts:Basedondatafromspecificinteractionstudiesnoclinicallyrelevantinteractionswith

digoxinorfenofibrateareexpected.

CytochromeP450enzymes:Resultsfrominvitroandinvivostudiesshowthatrosuvastatinisneitheraninhibitornor

aninducerofcytochromeP450isoenzymes.Inaddition,rosuvastatinisapoorsubstratefortheseisoenzymes.No

clinicallyrelevantinteractionshavebeenobservedbetweenrosuvastatinandeitherfluconazole(aninhibitorof

CYP2C9andCYP3A4)orketoconazole(aninhibitorofCYP2A6andCYP3A4).Concomitantadministrationof

itraconazole(aninhibitorofCYP3A4)androsuvastatinresultedina28%increaseinAUCofrosuvastatin.Thissmall

increaseisnotconsideredclinicallysignificant.

Therefore,druginteractionsresultingfromcytochromeP450-mediatedmetabolismarenotexpected.

4.6Pregnancyandlactation

Crestoriscontraindicatedinpregnancyandlactation.

Womenofchildbearingpotentialshoulduseappropriatecontraceptivemeasures.

Sincecholesterolandotherproductsofcholesterolbiosynthesisareessentialforthedevelopmentofthefoetus,the

potentialriskfrominhibitionofHMG-CoAreductaseoutweighstheadvantageoftreatmentduringpregnancy.Animal

studiesprovidelimitedevidenceofreproductivetoxicity(seeSection5.3Preclinicalsafetydata).Ifapatientbecomes

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Rosuvastatinisexcretedinthemilkofrats.Therearenodatawithrespecttoexcretioninmilkinhumans.

(seeSection4.3Contraindications).

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).

Immunesystemdisorders

Rare:hypersensitivityreactionsincludingangioedema

Nervoussystemdisorders

Common:headache,dizziness

Gastrointestinaldisorders

Common:constipation,nausea,abdominalpain

Rare:pancreatitis

Skinandsubcutaneoustissuedisorders

Uncommon:pruritus,rashandurticaria

Musculoskeletal,connectivetissueandbonedisorders

Common:myalgia

Rare:myopathyincludingmyositisandrhabdomyolysis

Generaldisorders

Common:asthenia

AswithotherHMG-CoAreductaseinhibitors,theincidenceofadversedrugreactionstendstobedosedependent.

RenalEffects:Proteinuria,detectedbydipsticktestingandmostlytubularin origin,hasbeenobservedinpatients

treatedwithCrestor.Shiftsinurineproteinfromnoneortraceto++ormorewereseenin<1%ofpatientsatsometime

duringtreatmentwith10and20mg,andinapproximately3%ofpatientstreatedwith40mg.Aminorincreaseinshift

fromnoneortraceto+wasobservedwiththe20mgdose.Inmostcases,proteinuriadecreasesor

disappearsspontaneouslyoncontinuedtherapy.Reviewofdatafromclinicaltrialsandpost-marketingexperienceto

datahasnotidentifiedacasualassociationbetweenproteinuriaandacuteorprogressiverenaldisease.

HaematuriahasbeenobservedinpatientstreatedwithCrestorandclinicaltrialdatashowtheoccurrenceislow.

Skeletalmuscleeffects:Effectsonskeletalmusclee.g.myalgia,myopathyand,rarely,rhabdomyolysishavebeen

reportedinCrestor-treatedpatientswithalldosesandinparticularwithdoses>20mg.

Adose-relatedincreaseinCKlevelshasbeenobservedinpatientstakingrosuvastatin;themajorityofcasesweremild,

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

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LiverEffects:AswithotherHMG-CoAreductaseinhibitors,adose-relatedincreaseintransaminaseshasbeen

observedinasmallnumberofpatientstakingrosuvastatin;themajorityofcasesweremild,asymptomaticand

transient.

PostMarketingExperience:

Inadditiontotheabove,thefollowingadverseeventshavebeenreportedduringpost-marketingexperienceforCrestor:

Gastrointestinaldisorders:Notknown:diarrhoea

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

Musculoskeletaldisorders:Rare:arthralgia.

Nervoussystemdisorders:Veryrare:polyneuropathy.

Renaldisorders:Veryrare:haematuria.

Thereportingrateforrhabdomylosis,seriousrenaleventsandserioushepaticevents(consistingmainlyofincreased

hepatictransaminases)ishigheratthe40mgdose.

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.

Pharmacodynamiceffect

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)

(adjustedmeanpercentchangefrombaseline)

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

Placebo 13 -7 -53-3 -7 -3 0

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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(seeSection4.4Specialwarningsandspecialprecautionsforuse).

Rosuvastatinhasnotbeenproventopreventtheassociatedcomplicationsoflipidabnormalities,suchascoronaryheart

diseaseasmortalityandmorbiditystudieswithCrestorhavenotyetbeencompleted.

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

directcorrelationbetweenCIMTdecreaseandreductionoftheriskofcardiovasculareventshasyetbeendemonstrated.

ThepopulationstudiedinMETEORislowriskforcoronaryheartdiseaseanddoesnotrepresentthetargetpopulation

ofCrestor40mg.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

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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-foldelevationinmedianAUCandC

inAsiansubjects

(Japanese,Chinese,Filipino,VietnameseandKoreans)comparedwithCaucasiansAsian-Indiansshowanapproximate

1.3-foldelevationinmedianAUCandCmax.Apopulationpharmacokineticanalysisrevealednoclinicallyrelevant

differencesinpharmacokineticsbetweenCaucasianandBlackgroups.

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

Child-Pughscores.ThereisnoexperienceinsubjectswithChild-Pughscoresabove9.

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

Lactosemonohydrate

Microcrystallinecellulose

Calciumphosphate

Crospovidone

Magnesiumstearate

Hypromellose

TriacetinTitaniumdioxide(E171)

Irish Medicines Board

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Date Printed 22/05/2009 CRN 2066306 page number: 9

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeinoriginalpackage.

6.5Natureandcontentsofcontainer

Blisterpacksof28and30tabletscontainedinanoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

PCOManufacturingLimited

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8ParallelProductAuthorisationNumber

PPA0465/140/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoflastrenewal:07June2005

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 22/05/2009 CRN 2066306 page number: 10