FLUVAT

Main information

  • Trade name:
  • FLUVAT Tablet Prolonged Release 80 Milligram
  • Dosage:
  • 80 Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUVAT Tablet Prolonged Release 80 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/117/003
  • Authorization date:
  • 30-05-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fluvat80mgprolonged-releasetablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Oneprolongedreleasetabletcontainsfluvastatinsodiumequivalentto80mgfluvastatin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolongedreleasetablet

Yellowcoloured,film-coated,roundshaped,biconvextabletwithbevelededges.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Dyslipidaemia

Treatmentofadultswithprimaryhypercholesterolaemiaormixeddyslipidaemia,asanadjuncttodiet,whenresponse

todietandothernonpharmacologicaltreatments(e.g.exercise,weightreduction)isinadequate.

Secondarypreventionincoronaryheartdisease

Secondarypreventionofmajoradversecardiaceventsinadultswithcoronaryheartdiseaseafterpercutaneouscoronary

interventions(seesection5.1).

4.2Posologyandmethodofadministration

Adults

Dyslipidaemia

Priortoinitiatingtreatmentwithfluvastatin,patientsshouldbeplacedonastandardcholesterol-loweringdiet,which

shouldbecontinuedduringtreatment.

StartingandmaintenancedosesshouldbeindividualizedaccordingtothebaselineLDL-Clevelsandthetreatmentgoal

tobeaccomplished.

Therecommendeddosingrangeis20to80mg/day.ForpatientsrequiringLDL-Creductiontoagoalof<25%a

startingdoseof20mgmaybeusedasone20mgcapsuleintheevening.ForpatientsrequiringLDL-Creductiontoa

goalof ≥25%,therecommendedstartingdoseis40mgasone40mgcapsuleintheevening.Thedosemaybe

uptitratedto80mgdaily,administeredasasingledose(oneprolonged-releasetabletfluvastatin80mg)atanytimeof

thedayorasone40mgcapsulegiventwicedaily(oneinthemorningandoneintheevening).

Themaximumlipid-loweringeffectwithagivendoseisachievedwithin4weeks.Doseadjustmentsshouldbemadeat

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Secondarypreventionincoronaryheartdisease

Inpatientswithcoronaryheartdiseaseafterpercutaneouscoronaryinterventionstheappropriatedailydoseis80mg.

Fluvastatinisefficaciousinmonotherapy.Whenfluvastatinisusedincombinationwithcholestyramineorotherresins,

itshouldbeadministeredatleast4hoursaftertheresintoavoidsignificantinteractionduetobindingofthedrugtothe

resin.Incaseswherecoadministrationwithafibrateorniacinisnecessary,thebenefitandtheriskofconcurrent

treatmentshouldbecarefullyconsidered(forusewithfibratesorniacinseesection4.5).

Paediatricpopulation

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Priortoinitiatingtreatmentwithfluvastatininchildrenandadolescentsaged9yearsandolderwithheterozygous

familialhypercholesterolaemia,thepatientshouldbeplacedonastandardcholesterol-loweringdiet,andcontinued

duringtreatment.

Therecommendedstartingdoseisone20mgcapsule.Doseadjustmentsshouldbemadeat6-weekintervals.Doses

shouldbeindividualisedaccordingtobaselineLDL-Clevelsandtherecommendedgoaloftherapytobeaccomplished.

Themaximumdailydoseadministeredis80mgeitherasimmediate-releasecapsules40mgtwicedailyorasone

prolonged-releasetablet80mgoncedaily.

Theuseoffluvastatinincombinationwithnicotinicacid,cholestyramine,orfibratesinchildrenandadolescentshas

notbeeninvestigated.

Fluvastatinhasonlybeeninvestigatedinchildrenof9yearsandolderwithheterozygousfamilial

hypercholesterolaemia.

Renalimpairment

Fluvastatinisclearedbytheliver,withlessthan6%oftheadministereddoseexcretedintotheurine.The

pharmacokineticsoffluvastatinremainunchangedinpatientswithmildtosevererenalinsufficiency.Nodose

adjustmentsarethereforenecessaryinthesepatients,however,duetolimitedexperiencewithdoses>40mg/dayincase

ofsevererenalimpairment(CrCL<0.5mL/secor30mL/min),thesedosesshouldbeinitiatedwithcaution.

Hepaticimpairment

Fluvastatiniscontraindicatedinpatientswithactiveliverdisease,orunexplained,persistentelevationsinserum

transaminases(seesections4.3,4.4and5.2).

Elderlypopulation

Nodoseadjustmentsarenecessaryinthispopulation.

Methodofadministration

Fluvat80mgprolonged-releasetabletscanbetakenwithorwithoutmealsandshouldbeswallowedaswholewitha

glassofwater.

4.3Contraindications

Fluvastatiniscontraindicated:

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-inpatientswithactiveliverdisease,orunexplained,persistentelevationsinserumtransaminases(seesection4.2,4.4

and4.8).

-duringpregnancyandlactation(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Liverfunction

Aswithotherlipid-loweringagents,itisrecommendedthatliverfunctiontestsbeperformedbeforetheinitiationof

treatmentandat12weeksfollowinginitiationoftreatmentorelevationindoseandperiodicallythereafterinall

patients.Shouldanincreaseinaspartateaminotransferase(AST)oralanineaminotransferase(ALT)exceed3timesthe

upperlimitofnormalandpersist,therapyshouldbediscontinued.Inveryrarecases,possiblydrug-relatedhepatitis

wasobservedthatresolvedupondiscontinuationoftreatment.

Cautionshouldbeexercisedwhenfluvastatinisadministeredtopatientswithahistoryofliverdiseaseorheavyalcohol

ingestion.

Skeletalmuscle

Myopathyhasrarelybeenreportedwithfluvastatin.Myositisandrhabdomyolysishavebeenreportedveryrarely.In

patientswithunexplaineddiffusemyalgias,muscletendernessormuscleweakness,and/ormarkedelevationofcreatine

kinase(CK)values,myopathy,myositisorrhabdomyolysishavetobeconsidered.Patientsshouldthereforebeadvised

topromptlyreportunexplainedmusclepain,muscletendernessormuscleweakness,particularlyifaccompaniedby

malaiseorfever.

Creatinekinasemeasurement

ThereisnocurrentevidencetorequireroutinemonitoringofplasmatotalCKorothermuscleenzymelevelsin

asymptomaticpatientsonstatins.IfCKhastobemeasureditshouldnotbedonefollowingstrenuousexerciseorinthe

presenceofanyplausiblealternativecauseofCK-increaseasthismakesthevalueinterpretationdifficult.

Beforethetreatment

Aswithallotherstatinsphysiciansshouldprescribefluvastatinwithcautioninpatientswithpre-disposingfactorsfor

rhabdomyolysisanditscomplications.Acreatinekinaselevelshouldbemeasuredbeforestartingfluvastatintreatment

inthefollowingsituations:

Renalimpairment.

Hypothyroidism.

Personalorfamilialhistoryofhereditarymusculardisorders.

Previoushistoryofmusculartoxicitywithastatinorfibrate.

Alcoholabuse.

Inelderly(age>70years),thenecessityofsuchmeasurementshouldbeconsidered,accordingtothepresence

ofotherpredisposingfactorsforrhabdomyolysis.

Insuchsituations,theriskoftreatmentshouldbeconsideredinrelationtothepossiblebenefitandclinicalmonitoring

isrecommended.IfCKlevelsaresignificantlyelevatedatbaselinetomorethan5timestheupperlimitofnormal

(ULN),levelsshouldbere-measuredwithin5to7dayslatertoconfirmtheresults.IfCKlevelsarestillsignificantly

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Whilstontreatment

Ifmuscularsymptomslikepain,weaknessorcrampsoccurinpatientsreceivingfluvastatin,theirCKlevelsshouldbe

measured.Treatmentshouldbestopped,iftheselevelsarefoundtobesignificantlyelevated(>5xULN).

Ifmuscularsymptomsaresevereandcausedailydiscomfort,evenifCKlevelsareelevatedto ≤5xULN,treatment

discontinuationshouldbeconsidered.

ShouldthesymptomsresolveandCKlevelsreturntonormal,thenre-introductionoffluvastatinoranotherstatinmay

beconsideredatthelowestdoseandunderclosemonitoring.

Theriskofmyopathyhasbeenreportedtobeincreasedinpatientsreceivingimmunosuppressiveagents(including

ciclosporin),fibrates,nicotinicacidorerythromycintogetherwithotherHMG-CoAreductaseinhibitors.Isolatedcases

ofmyopathyhavebeenreportedpost-marketingforconcomitantadministrationoffluvastatinwithciclosporinand

fluvastatinwithcolchicine.Fluvastatinshouldbeusedwithcautioninpatientsreceivingsuchconcomitantmedication

(seesection4.5).

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

Paediatricpopulation

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Inpatientsaged<18years,efficacyandsafetyhavenotbeenstudiedfortreatmentperiodslongerthantwoyears.No

dataareavailableaboutthephysical,intellectualandsexualmaturationforprolongedtreatmentperiod.Thelong-term

efficacyoffluvastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthoodhasnotbeenestablished

(seesection5.1).

Fluvastatinhasonlybeeninvestigatedinchildrenof9yearsandolderwithheterozygousfamilial

hypercholesterolaemia(fordetailsseesection5.1).Inthecaseofpre-pubertalchildren,asexperienceisverylimitedin

thisgroup,thepotentialrisksandbenefitsshouldbecarefullyevaluatedbeforetheinitiationoftreatment.

Homozygousfamilialhypercholesterolemia

Nodataareavailablefortheuseoffluvastatininpatientswiththeveryrareconditionofhomozygousfamilial

hypercholesterolemia.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Foodinteractions

BasedonthelackofinteractionoffluvastatinwithotherCYP3A4substrates,fluvastatinisnotexpectedtointeractwith

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Druginteractions

Fibricacidderivatives(fibrates)andniacin(nicotinicacid)

Concomitantadministrationoffluvastatinwithbezafibrate,gemfibrozil,ciprofibrateorniacin(nicotinicacid)hasno

clinicallyrelevanteffectonthebioavailabilityoffluvastatinortheotherlipid-loweringagent.Anincreasedriskof

myopathyand/orrhabdomyolysishasbeenobservedinpatientsreceivingotherHMG-CoAreductaseinhibitors

togetherwithanyofthesemolecules,probablybecausetheycanproducemyopathywhengivenalone.Therefore,the

benefitandtheriskofconcurrenttreatmentshouldbecarefullyweighedandthesecombinationsshouldonlybeused

withcaution(seesection4.4).

Colchicines

Myotoxicity,includingmusclepainandweaknessandrhabdomyolysis,havebeenreportedinisolatedcaseswith

concomitantadministrationofcolchicine.Thebenefitandtheriskofconcurrenttreatmentshouldbecarefullyweighed

andthesecombinationsshouldonlybeusedwithcaution(seesection4.4)

Ciclosporin

Studiesinrenaltransplantpatientsindicatethatthebioavailabilityoffluvastatin(upto40mg/day)isnotelevatedtoa

clinicallysignificantextentinpatientsonstableregimensofciclosporin.Theresultsfromanotherstudywherein80mg

fluvastatinwasadministeredtorenaltransplantpatientswhowereonstableciclosporinregimenshowedthat

fluvastatinexposure(AUC)andmaximumconcentration(Cmax)wereincreasedby2foldcomparedtohistoricaldata

inhealthysubjects.Althoughtheseincreasesinfluvastatinlevelswerenotclinicallysignificant,thiscombination

shouldbeusedwithcaution.Startingandmaintainingfluvastatintherapyshouldbeinadoseaslowaspossiblewhen

combinedwithciclosporin.

Fluvastatin(40mgand80mg)hadnoeffectonciclosporinbioavailabilitywhenco-administered.

Warfarinandothercoumarinderivatives

Inhealthyvolunteers,theuseoffluvastatinandwarfarin(singledose)didnotadverselyinfluencewarfarinplasma

levelsandprothrombintimescomparedtowarfarinalone.However,isolatedincidencesofbleedingepisodesand/or

increasedprothrombintimeshavebeenreportedveryrarelyinpatientsonfluvastatinreceivingconcomitantwarfarinor

othercoumarinderivatives.Itisrecommendedthatprothrombintimesaremonitoredwhenfluvastatintreatmentis

initiated,discontinued,orthedosagechangedinpatientsreceivingwarfarinorothercoumarinderivatives.

Rifampicin(rifampin)

Administrationoffluvastatintohealthyvolunteerspre-treatedwithrifampicin(rifampin)resultedinareductionofthe

bioavailabilityoffluvastatinbyabout50%.Althoughatpresentthereisnoclinicalevidencethatfluvastatinefficacyin

loweringlipidlevelsisaltered,forpatientsundertakinglong-termrifampicintherapy(e.g.treatmentoftuberculosis),

appropriateadjustmentoffluvastatindosagemaybewarrantedtoensureasatisfactoryreductioninlipidlevels.

Oralantidiabeticagents

Forpatientsreceivingoralsulfonylureas(glibenclamide[glyburide],tolbutamide)forthetreatmentofnon-insulin-

dependent(type2)diabetesmellutis(NIDDM),additionoffluvastatindoesnotleadtoclinicallysignificantchangesin

glycemiccontrol.

Inglibenclamide-treatedNIDDMpatients(n=32),administrationoffluvastatin(40mgtwicedailyfor14days)

increasedthemeanCmax,AUC,andt1/2ofglibenclamideapproximately50%,69%and121%,respectively.

Glibenclamide(5to20mgdaily)increasedthemeanCmaxandAUCoffluvastatinby44%and51%,respectively.In

thisstudytherewerenochangesinglucose,insulinandC-peptidelevels.

However,patientsonconcomitanttherapywithglibenclamide(glyburide)andfluvastatinshouldcontinuetobe

monitoredappropriatelywhentheirfluvastatindoseisincreasedto80mgperday.

Bileacidsequestrants

Fluvastatinshouldbeadministeredatleast4hoursaftertheresin(e.g.cholestyramine)toavoidasignificantinteraction

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Fluconazole

Administrationoffluvastatintohealthyvolunteerspre-treatedwithfluconazole(CYP2C9inhibitor)resultedinan

increaseintheexposureandpeakconcentrationoffluvastatinbyabout84%and44%.

Althoughtherewasnoclinicalevidencethatthesafetyprofileoffluvastatinwasalteredinpatientspre-treatedwith

fluconazolefor4days,cautionshouldbeexercisedwhenfluvastatinisadministeredconcomitantlywithfluconazole.

Itraconazoleanderythromycin

ConcomitantadministrationoffluvastatinwiththepotentcytochromeP450(CYP)3A4inhibitorsitraconazoleand

erythromycinhasminimaleffectsonthebioavailabilityoffluvastatin.Giventheminimalinvolvementofthisenzyme

inthemetabolismoffluvastatin,itisexpectedthatotherCYP3A4inhibitors(e.g.ketoconazole,ciclosporin)are

unlikelytoaffectthebioavailabilityoffluvastatin.

HistamineH2-receptorantagonistsandprotonpumpinhibitors

Concomitantadministrationoffluvastatinwithcimetidine,ranitidine,oromeprazoleresultsinanincreaseinthe

bioavailabilityoffluvastatin,which,however,isofnoclinicalrelevance.

Phenytoin

Theoverallmagnitudeofthechangesinphenytoinpharmacokineticsduringco-administrationwithfluvastatinare

relativelysmallandnotclinicallysignificant.Thus,routinemonitoringofphenytoinplasmalevelsissufficientduring

co-administrationwithfluvastatin.Theminimaleffectofphenytoinonfluvastatinpharmacokineticsindicatesthat

dosageadjustmentoffluvastatinisnotwarrantedwhenco-administeredwithphenytoin.

Cardiovascularagents

Noclinicallysignificantpharmacokineticinteractionsoccurwhenfluvastatinisconcomitantlyadministeredwith

propranolol,digoxin,losartan,amlodipineorACE-inhibitors.Basedonthepharmacokineticdata,nomonitoringor

dosageadjustmentsarerequiredwhenfluvastatinisconcomitantlyadministeredwiththeseagents.

4.6Fertility,pregnancyandlactation

Pregnancy

Thereisinsufficientdataontheuseoffluvastatinduringpregnancy.

SinceHMG-CoAreductaseinhibitorsdecreasethesynthesisofcholesterolandpossiblyofotherbiologicallyactive

substancesderivedfromcholesterol,theymaycausefoetalharmwhenadministeredtopregnantwomen.Therefore,

fluvastatiniscontraindicatedduringpregnancy(seesection4.3).

Womenofchildbearingpotentialhavetouseeffectivecontraception.

Ifapatientbecomespregnantwhiletakingfluvastatin,therapyshouldbediscontinued.

Lactation

Basedonpreclinicaldata,itisexpectedthatfluvastatinisexcretedintohumanmilk.Thereisinsufficientinformation

ontheeffectsoffluvastatininnewborns/infants.

Fluvastatiniscontraindicatedinbreastfeedingwomen.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactionsaremildgastrointestinalsymptoms,insomniaandheadache.

Adversereactionsarerankedunderheadingoffrequency,themostfrequentfirst,usingthefollowingconvention:very

common( ≥1/10);common(≥1/100to<1/10);uncommon(≥1/1,000to<1/100);rare(≥1/10,000to<1/1,000)very

rare(<1/10,000),includingisolatedreports.

Bloodandlymphaticsystemdisorders

Veryrare:Thrombocytopenia

Immunesystemdisorders

Veryrare:Anaphylacticreaction

Psychiatricdisorders

Common:Insomnia

Nervoussystemdisorders

Common:Headache

Veryrare:Paraesthesia,dysaesthesia,hypoaesthesiaalsoknowntobeassociatedwiththeunderlyinghyperlipidemic

disorders

Vasculardisorders

Veryrare:Vasculitis

Gastrointestinaldisorders

Common:Dyspepsia,abdominalpain,nausea

Veryrare:Pancreatitis

Hepatobiliarydisorders

Veryrare:Hepatitis

Skinandsubcutaneoustissuedisorders

Rare:Hypersensitivityreactionssuchasrash,urticaria

Veryrare:Otherskinreactions(e.g.eczema,dermatitis,bullousexanthema),faceoedema,angioedema

Musculoskeletalandconnectivetissuedisorders

Rare:Myalgia,muscleweakness,myopathy

Veryrare:Rhabdomyolysis,myositis,lupuserythematosus-likereactions

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Sleepdisturbances,includinginsomniaandnightmares

Memoryloss

Sexualdysfunction

Depression

Exceptionalcasesofinterstitiallungdisease,especiallywithlong-termtherapy(seesection4.4)

Paediatricpopulation

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Thesafetyprofileoffluvastatininchildrenandadolescentswithheterozygousfamilialhypercholesterolemiaassessed

in114patientsaged9-17yearstreatedintwoopennon-comparativeclinicaltrialswassimilartotheoneobservedin

adults.Inbothclinicaltrialsnoeffectwasobservedongrowthandsexualmaturation.Theabilityofthetrialstodetect

anyeffectoftreatmentinthisareawashoweverlow.

Laboratoryfindings

BiochemicalabnormalitiesofliverfunctionhavebeenassociatedwithHMG-CoAreductaseinhibitorsandotherlipid-

loweringagents.Basedonpooledanalysesofcontrolledclinicaltrialsconfirmedelevationsofalanineaminotransferase

oraspartateaminotranferaselevelstomorethan3timestheupperlimitofnormal(ULN)occurredin0.2%on

fluvastatincapsules20mg/day,1.5%to1.8%onfluvastatincapsules40mg/day,1.9%onfluvastatintablets80mg/day

andin2.7%to4.9%ontwicedailyfluvastatincapsules40mg.Themajorityofpatientswiththeseabnormal

biochemicalfindingswereasymptomatic.MarkedelevationsofCKlevelstomorethan5xULNdevelopedinavery

smallnumberofpatients(0.3to1.0%).

4.9Overdose

Shouldanaccidentaloverdosageoccur,administrationofactivatedcharcoalisrecommendedandtheliverfunction

shouldbemonitored.Inthecaseofaveryrecentoralintakegastriclavagemaybeconsidered.Treatmentshouldbe

symptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:HMG-CoAreductaseinhibitors

ATCCode:C10AA04

Fluvastatin,afullysyntheticcholesterol-loweringagent,isacompetitiveinhibitorofHMG-CoAreductase,whichis

responsiblefortheconversionofHMG-CoAtomevalonate,aprecursorofsterols,includingcholesterol.Fluvastatin

exertsitsmaineffectintheliverandismainlyaracemateofthetwoerythroenantiomersofwhichoneexertsthe

pharmacologicalactivity.Theinhibitionofcholesterolbiosynthesisreducesthecholesterolinhepaticcells,which

stimulatesthesynthesisofLDLreceptorsandtherebyincreasestheuptakeofLDLparticles.Theultimateresultof

thesemechanismsisareductionintheplasmacholesterolconcentration.

Fluvastatinreducestotal-C,LDL-C,ApoB,andtriglycerides,andincreasesHDL-Cinpatientswith

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In12placebo-controlledstudiesinpatientswithTypeIIaorIIbhyperlipoproteinaemia,fluvastatinalonewas

administeredto1,621patientsindailydoseregimensof20mg,40mgand80mg(40mgtwicedaily)foratleast6

weeksduration.Ina24-weekanalysis,dailydosesof20mg,40mgand80mgproduceddose-relatedreductionsin

total-C,LDL-C,ApoBandintriglyceridesandincreasesinHDL-C(seeTable1).

Fluvastatin80mgprolonged-releasetablets(LescolXL)wereadministeredtoover800patientsinthreepivotaltrials

of24weeksactivetreatmentdurationandcomparedtofluvastatin(Lescol)40mgonceortwicedaily.Givenasa

singledailydoseof80mg,fluvastatinsignificantlyreducedtotal-C,LDL-C,triglycerides(TG)andApoB(seeTable

Therapeuticresponseiswellestablishedwithintwoweeks,andamaximumresponseisachievedwithinfourweeks.

Afterfourweeksoftherapy,themediandecreaseinLDL-Cwas38%andatweek24(endpoint)themedianLDL-C

decreasewas35%.SignificantincreasesinHDL-Cwerealsoobserved.

Table1Medianpercentchangeinlipidparametersfrombaselinetoweek24Placebo-controlledstudies

(fluvastatinimmediate-releasecapsules,Lescol)andactive-controlledtrials(fluvastatinprolonged-release

capsules,LescolXL)

DataforLescolfrom12placebo-controlledtrials

DataforLescolXL80mgtabletfromthree24-weekcontrolledtrials

IntheLipoproteinandCoronaryAtherosclerosisStudy(LCAS),theeffectoffluvastatinoncoronaryatherosclerosis

wasassessedbyquantitativecoronaryangiographyinmaleandfemalepatients(35to75yearsold)withcoronary

arterydiseaseandbaselineLDL-Clevelsof3.0to4.9mmol/l(115to190mg/dl).Inthisrandomised,double-blind,

controlledclinicalstudy,429patientsweretreatedwitheitherfluvastatin40mg/dayorplacebo.Quantitativecoronary

angiogramswereevaluatedatbaselineandafter2.5yearsoftreatmentandwereevaluablein340outof429patients.

Fluvastatintreatmentslowedtheprogressionofcoronaryatherosclerosislesionsby0.072mm(95%confidence

intervalsfortreatmentdifferencefrom−0.1222to−0.022mm)over2.5yearsasmeasuredbychangeinminimum

lumendiameter(fluvastatin−0.028mmvs.placebo−0.100mm).Nodirectcorrelationbetweentheangiographic

Total-C TG LDL-C ApoB HDL-C

Dose N % N % N % N % N %

Allpatients

Lescol20mg 1 747-17747-12 747 -22 114 -19 747 +3

Lescol40mg 1 748-19748-14 748 -25 125 -18 748 +4

Lescol40mgtwice

daily 1 257-27257-18 257 -36 232 -28 257 +6

LescolXL80mg 2 750-25750-19 748 -35 745 -27 750 +7

BaselineTG200

mg/dl

Lescol20mg 1 148-16148-17 148 -22 23 -19 148 +6

Lescol40mg 1 179-18179-20 179 -24 47 -18179 +7

Lescol40mgtwice

daily 1 76 -27 76 -23 76 -35 69 -28 76 +9

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IntheLescolInterventionPreventionStudy(LIPS),theeffectoffluvastatinonmajoradversecardiacevents(MACE;

i.e.cardiacdeath,non-fatalmyocardialinfarctionandcoronaryrevascularisation)wasassessedinpatientswith

coronaryheartdiseasewhohadfirstsuccessfulpercutaneouscoronaryintervention.Thestudyincludedmaleand

femalepatients(18-80yearsold)andwithbaselinetotalcholesterollevelsrangingfrom3.5-7.0mmol/l(135to270

mg/dl).

Inthisrandomised,double-blind,placebo-controlledtrialfluvastatin(n=844),givenas80mgdailyover4years,

significantlyreducedtheriskofthefirstMACEby22%(p=0.013)ascomparedtoplacebo(n=833).Theprimary

endpointofMACEoccurredin21.4%ofpatientstreatedwithfluvastatinvs26.7%ofpatientstreatedwithplacebo

(absoluteriskdifference:5.2%;95%CI:1.1to9.3).

Thesebeneficialeffectswereparticularlynoteworthyinpatientswithdiabetesmellitusandinpatientswithmultivessel

disease.

Paediatricpopulation

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Thesafetyandefficacyoffluvastatininchildrenandadolescentpatientsaged9-16yearsofagewithheterozygous

familialhypercholesterolemiahasbeenevaluatedin2openlabel,uncontrolledclinicaltrialsof2years'duration.114

patients(66boysand48girls)weretreatedwithfluvastatinadministeredaseitherfluvastatin20mg/dayto40mg

twicedailyorfluvastatin80mgprolonged-releasetabletsoncedailyusingadose-titrationregimenbaseduponLDL-C

response.

Thefirststudyenrolled29pre-pubertalboys,9-12yearsofage,whohadanLDL-Clevel>90thpercentileforageand

oneparentwithprimaryhypercholesterolemiaandeitherafamilyhistoryofprematureischemicheartdiseaseortendon

xanthomas.ThemeanbaselineLDL-Cwas226mg/dLequivalentto5.8mmol/L(range:137-354mg/dLequivalentto

3.6–9.2mmol/L).Allpatientswerestartedonfluvastatin20mgdailywithdoseadjustmentsevery6weeksto40mg

dailythen80mgdaily(40mgtwicedaily)toachieveanLDL-Cgoalof96.7to123.7mg/dL(2.5mmol/Lto3.2

mmol/L).

Thesecondstudyenrolled85maleandfemalepatients,10to16yearsofage,whohadanLDL-C>190mg/dL

(equivalentto4.9mmol/L)orLDL-C>160mg/dL(equivalentto4.1mmol/L)andoneormoreriskfactorsfor

coronaryheartdisease,orLDL-C>160mg/dL(equivalentto4.1mmol/L)andaprovenLDL-receptordefect.The

meanbaselineLDL-Cwas225mg/dLequivalentto5.8mmol/L(range:148-343mg/dLequivalentto3.8–8.9

mmol/L).Allpatientswerestartedonfluvastatin20mgdailywithdoseadjustmentsevery6weeksto40mgdailythen

80mgdailytoachieveanLDL-Cgoalof<130mg/dL(3.4mmol/L).70patientswerepubertalorpostpubertal(n=69

evaluatedforefficacy).

Inthefirststudy(inprepubertalboys),fluvastatin20to80mgdailydosesdecreasedplasmalevelsoftotal-CandLDL-

Cby21%and27%,respectively.ThemeanachievedLDL-Cwas161mg/dLequivalentto4.2mmol/L(range:74-

336mg/dLequivalent1.9–8.7mmol/L).Inthesecondstudy(inpubertalandpostpubertalgirlsandboys),fluvastatin

20to80mgdailydosesdecreasedplasmalevelsoftotal-CandLDL-Cby22%and28%,respectively.Themean

achievedLDL-Cwas159mg/dLequivalentto4.1mmol/L(range:90-295mg/dLequivalentto2.3–7.6mmol/L).

Themajorityofpatientsinbothstudies(83%inthefirststudyand89%inthesecondstudy)weretitratedtothe

maximumdailydoseof80mg.Atstudyendpoint,26to30%ofpatientsinbothstudiesachievedatargetedLDL-C

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5.2Pharmacokineticproperties

Absorption

Fluvastatinisabsorbedrapidlyandcompletely(98%)afteroraladministrationofasolutiontofastedvolunteers.After

oraladministrationoffluvastatin80mgprolongedreleasetablets,andincomparisonwiththeimmediate-release

capsules,theabsorptionrateoffluvastatinisalmost60%slowerwhilethemeanresidencetimeoffluvastatinis

increasedbyapproximately4hours.Inafedstate,thedrugisabsorbedatareducedrate.

Distribution

Fluvastatinexertsitsmaineffectintheliver,whichisalsothemainorganforitsmetabolism.Theabsolute

bioavailabilityassessedfromsystemicbloodconcentrationsis24%.Theapparentvolumeofdistribution(Vz/f)forthe

drugis330litres.Morethan98%ofthecirculatingdrugisboundtoplasmaproteins,andthisbindingisnotaffected

eitherbytheconcentrationoffluvastatin,orbywarfarin,salicylicacid,orglyburide.

BiotransformationFluvastatinismainlymetabolizedintheliver.Themajorcomponentscirculatinginthebloodare

fluvastatinandthepharmacologicallyinactiveN-desisopropyl-propionicacidmetabolite.Thehydroxylatedmetabolites

havepharmacologicalactivitybutdonotcirculatesystemically.Therearemultiple,alternativecytochromeP450

(CYP450)pathwaysforfluvastatinbiotransformationandthusfluvastatinmetabolismisrelativelyinsensitiveto

CYP450inhibition.

FluvastatininhibitedonlythemetabolismofcompoundsthataremetabolizedbyCYP2C9.Despitethepotentialthat

thereforeexistsforcompetitiveinteractionbetweenfluvastatinandcompoundsthatareCYP2C9substrates,suchas

diclofenac,phenytoin,tolbutamide,andwarfarin,clinicaldataindicatethatthisinteractionisunlikely.

Elimination

Followingadministrationof 3

H-fluvastatintohealthyvolunteers,excretionofradioactivityisabout6%intheurineand

93%inthefaeces,andfluvastatinaccountsforlessthan2%ofthetotalradioactivityexcreted.Theplasmaclearance

(CL/f)forfluvastatininmaniscalculatedtobe1.8±0.8L/min.Steady-stateplasmaconcentrationsshownoevidence

offluvastatinaccumulationfollowingadministrationof80mgdaily.Followingoraladministrationof40mg

fluvastatin,theterminaldispositionhalf-lifeforfluvastatinis2.3±0.9hours.

Characteristicsinpatients

Plasmaconcentrationsoffluvastatindonotvaryasafunctionofeitherageorgenderinthegeneralpopulation.

However,enhancedtreatmentresponsewasobservedinwomenandinelderlypeople.

Sincefluvastatiniseliminatedprimarilyviathebiliaryrouteandissubjecttosignificantpre-systemicmetabolism,the

potentialexistsfordrugaccumulationinpatientswithhepaticinsufficiency(seesections4.3and4.4)

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

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5.3Preclinicalsafetydata

Theconventionalstudies,includingsafetypharmacology,genotoxicity,repeateddosetoxicity,carcinogenicityand

toxicityonreproductionstudiesdidnotindicateotherrisksforthepatientthanthoseexpectedduetothe

pharmacologicalmechanismofaction.Avarietyofchangeswereidentifiedintoxicitystudiesthatarecommonto

HMG-CoAreductaseinhibitors.Basedonclinicalobservations,liverfunctiontestsarealreadyrecommended(see

section4.4).Furthertoxicityseeninanimalswaseithernotrelevantforhumanuseoroccurredatexposurelevels

sufficientlyinexcessofthemaximumhumanexposureindicatinglittlerelevancetoclinicaluse.Despitethetheoretical

considerationsconcerningtheroleofcholesterolinembryodevelopment,animalstudiesdidnotsuggestan

embryotoxicandteratogenicpotentialoffluvastatin.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Cellulose,microcrystalline

Hypromellose

Hyprolose(Hydroxypropylcellulose)

Potassiumhydrogencarbonate

PovidoneK-30

Magnesiumstearate

Film-coating:

Hypromellose

Ironoxideyellow(E172)

Titaniumdioxide(E171)

Macrogol8000

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

In-useshelflifeforHDPEbottleafterfirstopeningofthebottle:4months

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

OPA/Aluminium/PVC//Aluminiumblister:7,10,14,20,28,30,50,84,90,100,490

HDPEbottlewithPPscrewcap:14,20,28,30,49,50,56,60,100

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

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Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry

Co.Cork

8MARKETINGAUTHORISATIONNUMBER

PA711/117/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:30thMay2007

Dateoflastrenewal:30thApril2010

10DATEOFREVISIONOFTHETEXT

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