FLUVASTATIN TEVA

Main information

  • Trade name:
  • FLUVASTATIN TEVA
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUVASTATIN TEVA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/043/001
  • Authorization date:
  • 25-07-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0749/043/001

CaseNo:2076636

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

TevaPharmaB.V.

Computerweg10,3542DRUtrecht,Netherlands

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

FluvastatinTeva20mgCapsules

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom09/04/2010until24/07/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FluvastatinTeva20mgCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

One20mgcapsulecontains20mgfluvastatin(asfluvastatinsodium).

Excipient:99.6mglactosemonohydrate/capsule

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

The20mgcapsuleshaveanivoryopaquebodyandpinkopaquecapmarked93/7442,andarefilledwithanoff-white

toyellowishpowderwithsmallagglomerates.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Fluvastatinisindicatedasanadjuncttodietforthereductionofelevatedtotalcholesterol(total-C)andlow-density

lipoproteincholesterol(LDL-C),whenresponsetodietandothernon-pharmacologicaltreatments(e.g.exercise,

weightreduction)isinadequateinadultswithprimaryhypercholesterolaemia(heterozygousvariant)andmixed

dyslipidaemia(FredricksontypesIIaandIIb).

Fluvastatinisalsoindicatedforthesecondarypreventionofmajoradversecardiacevents(cardiacdeath,non-fatal

myocardialinfarctionandcoronaryrevascularisation)aftercoronarytranscathetertherapy).

4.2Posologyandmethodofadministration

Priortoinitiatingtreatmentwithfluvastatin,thepatientshouldbeplacedonastandardcholesterol-loweringdiet,which

shouldbecontinuedduringtreatment.

Therecommendedstartingdoseis20mgor40mgoncedaily.Adoseof20mgoncedailymaybeadequateinmild

cases.Mostpatientswillrequireadoseof20mgto40mgoncedailybutthedosemaybeincreasedto80mgdaily

(one40mgcapsuletwicedaily),individualisedaccordingtobaselineLDL-Clevelsandtherecommendedgoalof

therapytobeaccomplished.Themaximumrecommendeddailydoseis80mg.

Inpatientswithcoronaryheartdiseaseaftercoronarytranscathetertherapy,theappropriatedoseis80mgdaily.

Thecapsulesshouldbetakenintheeveningoratbedtimewithoutregardtomealsandshouldbeswallowedwholewith

aglassofwater.

Themaximumlipid-loweringeffectwithagivendoseofthesubstanceisachievedwithin4weeks.

Dosesshouldbeadjustedaccordingtothepatient'sresponseanddoseadjustmentmadeatintervalsof4weeksormore.

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Fluvastatinisefficientinmonotherapy.Dataexisttosupporttheefficacyandsafetyoffluvastatinincombinationwith

nicotinicacid,cholestyramineorfibrates(seesection4.5).

Whenfluvastatinisusedincombinationwithcholestyramineorotherresins,itshouldbeadministeredatleast4hours

aftertheresintoavoidasignificantinteractionduetobindingofthesubstancetotheresin.

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Priortoinitiatingtreatmentwithfluvastatininchildrenandadolescentsaged9yearsandolderwithheterozygous

familialhypercholesterolaemia,thepatientshouldbeplacedonastandardcholesterol-loweringdiet.Dietarytherapy

shouldbecontinuedduringtreatment.

Therecommendedstartingdoseis40mg(1capsulefluvastatin40mg)or80mg(1capsulefluvastatin40mgtwice

daily).Thedoseof20mgfluvastatin(1capsulefluvastatin20mg)maybeadequateinmildcases.Startingdoses

shouldbeindividualizedaccordingtobaselineLDL-Clevelsandtherecommendedgoaloftherapytobeaccomplished.

Theuseoffluvastatinincombinationwithnicotinicacid,cholestyramine,orfibratesinchildrenandadolescentshas

notbeeninvestigated.

Elderly

Thereisnoevidenceofreducedtolerabilityoraltereddosagerequirementsinelderlypatientsthus,nodoseadjustment

isrequiredinsuchpatients.

Impairedkidneyfunction

Fluvastatinisclearedbytheliver,withlessthan6%oftheadministereddoseexcretedintotheurine.The

pharmacokineticsoffluvastatinremainunchangedinpatientswithmildtosevererenalinsufficiency.Nodose

adjustmentsarethereforenecessaryinthesepatients.

However,sincefluvastatinhasnotbeenstudiedatdosesgreaterthan40mginpatientswithsevererenalimpairment,

cautionshouldbeexercisedwhentreatingsuchpatientsathigherdoses.

Impairedliverfunction

Fluvastatiniscontraindicatedinpatientswithactiveliverdisease,orunexplained,persistentelevationsinserum

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

4.3Contraindications

Fluvastatiniscontraindicated:

inpatientswithhypersensitivitytofluvastatinortoanyoftheexcipients.

inpatientswithactiveliverdisease,orunexplained,persistentelevationsinserumtransaminases(seesections

4.2,4.4and4.8).

inpatientswithmyopathy

duringpregnancyandlactation(seesection4.6)

4.4Specialwarningsandprecautionsforuse

Liverfunction

Aswithotherlipid-loweringagents,itisrecommendedthatliverfunctiontestsbeperformedbeforetheinitiationof

treatment,at12weeksfollowinginitiationoftreatmentorelevationindose,andperiodicallythereafterinallpatients.

Patientswhoselevelsincreaseinresponsetothesubstanceshouldbemonitoredparticularlyclosely,withimmediate

repetitionofthemeasurementfollowedbymorefrequentmeasurements.Shouldanincreaseinaspartate

aminotransferase(AST)oralanineaminotransferase(ALT)exceed3timestheupperlimitofnormal(ULN)and

persist,therapyshouldbediscontinued.Inveryrarecases,possiblysubstance-relatedhepatitiswasobservedthat

resolvedupondiscontinuationoftreatment.

Cautionshouldbeexercisedwhenfluvastatinisadministeredtopatientswithahistoryofliverdiseaseorheavyalcohol

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Skeletalmuscle

Withfluvastatin,myopathyhasrarelybeenreported,whereasmyositisandrhabdomyolysishavebeenreportedvery

rarely.Inpatientswithunexplaineddiffusemyalgias,muscletendernessormuscleweakness,and/ormarkedelevation

ofcreatinekinase(CK)values,myopathy,myositisorrhabdomyolysishavetobeconsidered.Patientsshouldtherefore

beadvisedtopromptlyreportunexplainedmusclepain,muscletendernessormuscleweakness,particularlyif

accompaniedbymalaiseorfever.

Creatinekinasemeasurement

Thereisnocurrentevidencetorequireroutinemonitoringofplasmatotalcreatinekinaseorothermuscleenzyme

levelsinasymptomaticpatientsonstatins.Ifcreatinekinasehastobemeasureditshouldnotbedonefollowing

strenuousexerciseorinthepresenceofanyplausiblealternativecauseofCKincreaseasthismakesthevalue

interpretationdifficult.

Beforethetreatment

Physiciansshouldprescribefluvastatinwithcautioninpatientswithpre-disposingfactorsforrhabdomyolysisandits

complications.Acreatinekinaselevelshouldbemeasuredbeforestartingfluvastatintreatmentinthefollowing

situations:

Renalimpairment;

Hypothyroidism;

Personalorfamilialhistoryofhereditarymusculardisorders;

Previoushistoryofmusculartoxicitywithastatinorfibrate;

Alcoholabuse;

Inelderly(age>70years),thenecessityofsuchmeasurementshouldbeconsidered,accordingtothepresence

ofotherpredisposingfactorsforrhabdomyolysis.

Insuchsituations,theriskoftreatmentshouldbeconsideredinrelationtothepossiblebenefitandclinicalmonitoring

isrecommended.IfCKlevelsaresignificantlyelevatedatbaselinetomorethan5timestheupperlimitofnormal

(ULN),levelsshouldbere-measuredwithin5to7dayslatertoconfirmtheresults.IfCKlevelsarestillsignificantly

elevated(>5xULN)atbaseline,treatmentshouldnotbestarted.

Whilstontreatment

Ifmuscularsymptomslikepain,weaknessorcrampsoccurinpatientsreceivingfluvastatin,theirCKlevelsshouldbe

measured.Treatmentshouldbestopped,iftheselevelsarefoundtobesignificantlyelevated(>5xULN).

Ifmuscularsymptomsaresevereandcausedailydiscomfort,evenifCKlevelsareelevatedto ≤5xULN,treatment

discontinuationshouldbeconsidered.

ShouldthesymptomsresolveandCKlevelsreturntonormal,thenre-introductionoffluvastatinoranotherstatinmay

beconsideredatthelowestdoseandunderclosemonitoring.

Theriskofmyopathyhasbeenreportedtobeincreasedinpatientsreceivingimmunosuppressiveagents(including

ciclosporin),fibrates,nicotinicacid,erythromycin,togetherwithotherHMG-CoAreductaseinhibitors.However,in

clinicaltrialsinpatientsreceivingfluvastatinincombinationwithnicotinicacid,fibratesorciclosporin,myopathyhas

notbeenobserved.Isolatedcasesofmyopathyhavebeenreportedpost-marketingforconcomitantadministrationof

fluvastatinwithciclosporinandfluvastatinwithcolchicine.Thebenefitsofthecombineduseoffluvastatinwith

fibrates,niacinorcolchicineshouldbecarefullyweighedagainstthepotentialrisksofthesecombinationsand

fluvastatinshouldbeusedwithcautioninpatientsreceivingsuchconcomitantmedication(seesection4.5).

Hyperlipoproteinaemia

Nodataareavailablefortheuseoffluvastatininpatientswithhyperlipoproteinaemiawithamajorincreasein

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Homozygousfamilialhypercholesterolaemia

Nodataareavailablefortheuseoffluvastatininpatientswitharareconditionknownashomozygousfamilial

hypercholesterolaemia.TheeffectisexpectedtobelowduetoLDL-receptordeficiencyinthesepatients.Thereforeuse

offluvastatinisnotrecommendedinthesepatients.

Patientswithrarehereditaryproblemsofgalactoseintolerance,thelapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Inpatientsaged<18years,efficacyandsafetyhavenotbeenstudiedfortreatmentperiodslongerthantwoyears.No

dataareavailableaboutthephysical,intellectualandsexualmaturationforprolongedtreatmentperiod.Thelong-term

efficacyoffluvastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthoodhasnotbeenestablished.

(seeSection5.1).

Fluvastatinhasonlybeeninvestigatedinchildrenof9yearsandolderwithheterozygousfamilial

hypercholesterolaemia(fordetailsseesection5.1Pharmacodynamicproperties).Inthecaseofpre-pubertalchildren,as

experienceisverylimitedinthisgroup,thepotentialrisksandbenefitsshouldbecarefullyevaluatedbeforethe

initiationoftreatment.

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,nonproductivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Foodinteractions

Therearenoapparentdifferencesinthelipid-loweringeffectsoffluvastatinwhenadministeredwiththeeveningmeal

or4hoursaftertheeveningmeal.BasedonthelackofinteractionoffluvastatinwithotherCYP3A4substrates,

fluvastatinisnotexpectedtointeractwithgrapefruitjuice.

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

fluvastatinwasadministeredtorenaltransplantpatientswhowereonstableciclosporinregimensshowedthat

fluvastatinexposure(AUC)andmaximumconcentration(C

)wereincreasedby2-foldcomparedtohistoricaldata

inhealthysubjects.Althoughtheseincreasesinfluvastatinlevelswerenotclinicallysignificant,thiscombination

shouldbeusedwithcaution.Startingandmaintainingfluvastatintherapyshouldbeinasdoseaslowaspossiblewhen

combinedwithciclosporin.

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Warfarinandothercoumarinderivatives

Inhealthyvolunteers,theuseoffluvastatinandwarfarin(singledose)didnotadverselyinfluencewarfarinplasma

levelsandprothrombintimescomparedtowarfarinalone.However,isolatedindidencesofbleedingepisodesand/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)diabetesmellitus(NIDDM),additionoffluvastatindoesnotleadtoclinicallysignificantchangesin

glycaemiccontrol.

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

increasedthemeanC

,AUCandt

ofglibenclamideapproximately50%,69%and121%,respectively.

Glibenclamide(5to20mgdaily)increasedthemeanC

andAUCoffluvastatinby44%and51%,respectively.In

thisstudytherewerenochangesinglucose,insulinandC-peptidelevels.However,patientsonconcomitanttherapy

withglibenclamide(glyburide)andfluvastatinshouldcontinuetobemonitoredappropriatelywhentheirfluvastatin

doseisincreasedto80mgperday.

Bileacidsequestrants

Fluvastatinshouldbeadministeredatleast4hoursaftertheresin(e.g.cholestyramine)toavoidasignificantinteraction

duetodrugbindingoftheresin.

Fluconazole

Administrationoffluvastatintohealthyvolunteerspre-treatedwithfluconazole(CYP2C9inhibitor)resultedinan

increaseintheexposureandmeanpeakconcentrationoffluvastatinbyabout84%and44%.Althoughtherewasno

clinicalevidencethatthesafetyprofileoffluvastatinwasalteredinpatientspre-treatedwithfluconazolefor4days,

cautionshouldbeexercisedwhenfluvastatinisadministeredconcomitantlywithfluconazole.

Itraconazoleanderythromycin

ConcomitantadministrationoffluvastatinwiththepotentcytochromeP450(CYP)3A4inhibitorsitraconazoleand

erythromycinhasminimaleffectsonthebioavailabilityoffluvastatin.Giventheminimalinvolvementofthisenzyme

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

unlikelytoaffectthebioavailabilityoffluvastatin.

HistamineH

2 -receptorantagonistsandprotonpumpinhibitors

Concomitantadministrationoffluvastatinwithcimetidine,ranitidineoromeprazoleresultsinanincreaseinthe

bioavailabilityoffluvastatin,which,however,isofnoclinicalrelevance.

Phenytoin

Theoverallmagnitudeofthechangesinphenytoinpharmacokineticsduringco-administrationwithfluvastatinis

relativelysmallandnotclinicallysignificant.Thus,routinemonitoringofphenytoinplasmalevelsissufficientduring

co-administrationwithfluvastatin.Theminimaleffectofphenytoinonfluvastatinpharmacokineticsindicatesthat

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Cardiovascularagents

Noclinicallysignificantpharmacokineticinteractionsoccurwhenfluvastatinisconcomitantlyadministeredwith

propranolol,digoxin,losartan,amlodipineorACEinhibitors.Basedonthepharmacokineticdata,nomonitoringor

dosageadjustmentsarerequiredwhenfluvastatinisconcomitantlyadministeredwiththeseagents.

4.6Pregnancyandlactation

Pregnancy

Fluvastatiniscontraindicatedduringpregnancy(seesection4.3).

Thereareinsufficientdataontheuseoffluvastatinduringpregnancy.SinceHMG-CoAreductaseinhibitorsdecrease

thesynthesisofcholesterolandpossiblyofotherbiologicallyactivesubstancesderivedfromcholesterol,theymay

causefetalharmwhenadministeredtopregnantwomen.

Atherosclerosisisachronicprocess,andordinarilydiscontinuationoflipid-loweringmedicinalproductsduring

pregnancyshouldhavelittleimpactonthelong-termriskassociatedwithprimaryhypercholesterolaemia.Forthese

reasons,fluvastatinmustnotbeusedinwomenwhoarepregnantorsuspecttheyarepregnantandinwomenofchild-

bearingpotentialnottakingadequatecontraceptiveprecautions.Treatmentwithfluvastatinmustbesuspendedforthe

durationofpregnancyoruntilithasbeendeterminedthatthewomanisnotpregnant(seesection4.3).

Lactation

Itisnotknownwhetherfluvastatinoritsmetabolitesareexcretedinhumanmilk.Becausemanymedicinalproductsare

excretedinhumanmilkandbecauseofthepotentialforseriousadversereactions,womentakingfluvastatinmustnot

breast-feedtheirinfants(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,basedonits

pharmacodynamicproperties,fluvastatinisunlikelytoaffectthisability.

Whendrivingvehiclesoroperatingmachines,itshouldbetakenintoaccountthatdizzinessmayoccurduring

treatment.

4.8Undesirableeffects

Adversereactionsarerankedunderheadingsoffrequency,themostfrequentfirst,usingthefollowingconvention:very

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

(<1/10,000),notknown(cannotbeestimatedfromavailabledata).Withineachfrequencygrouping,adversereactions

arerankedinorderofdecreasingseriousness.

Themostcommonlyreportedadversereactionsareminorgastrointestinalsymptoms,insomniaandheadache.

Bloodandlymphaticsystemdisorders

Veryrare: thrombocytopenia

Psychiatricdisorders

Common: insomnia

Nervoussystemdisorders

Common: headache,dizziness,fatigue

Veryrare: paraesthesia,dysaesthesia,hypoaesthesiaandperipheralneuropathyalsoknowntobeassociatedwith

underlyinghyperlipidaemicdisorders

Vasculardisorders

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Gastrointestinaldisorders

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

Veryrare: pancreatitis

Hepato-biliarydisorders

Veryrare: hepatitis

Skinandsubcutaneoustissuedisorders

Rare: hypersensitivityreactionssuchasrash,urticaria

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

Musculoskeletalandconnectivetissuedisorders

Common: arthralgia

Rare: myalgia,muscletenderness,muscleweaknessandmyopathy

Veryrare: myositis,rhabdomyolysis,lupuserythematosus-likereactions

BiochemicalabnormalitiesofliverfunctionhavebeenassociatedwithHMG-CoAreductaseinhibitorsandotherlipid-

loweringagents.Confirmedelevationsoftransaminaselevelstomorethan3timestheupperlimitofnormal(ULN)

developedin1to2%ofpatients.MarkedelevationsofCKlevelstomorethan5xULNdevelopedin0.3-1.0%of

patients.

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Thesafetyprofileoffluvastatininchildrenandadolescentswithheterozygousfamilialhypercholesterolemiaassessed

in114patientsaged9-17yearstreatedintwoopennon-comparativeclinicaltrialswassimilartotheoneobservedin

adults.Inbothclinicaltrialsnoeffectwasobservedongrowthandsexualmaturation.Theabilityofthetrialstodetect

anyeffectoftreatmentinthisareawashoweverlow.

Thefollowingadverseeventshavebeenreportedwithsomestatins:

Sleepdisturbances,includinginsomniaandnightmares

Memoryloss

Sexualdysfunction

Depression

Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seesection4.4)

4.9Overdose

Shouldanaccidentaloverdoseoccur,administrationofactivatedcharcoalisrecommendedandliverfunctionshouldbe

monitored.Inthecaseofveryrecentoralintakegastriclavagemaybeconsidered.Treatmentshouldbesymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:HMG-CoAreductaseinhibitors

ATCcode:C10AA04

Fluvastatin,afullysyntheticcholesterol-loweringagent,isacompetitiveinhibitorofHMG-CoAreductase,whichis

responsiblefortheconversionofHMG-CoAtomevalonate,aprecursorofsterols,includingcholesterol.Fluvastatin

exertsitsmaineffectintheliverandismainlyaracemateofthetwoerythroenantiomersofwhichoneexertsthe

pharmacologicalactivity.Theinhibitionofcholesterolbiosynthesisreducesthecholesterolinhepaticcells,which

stimulatesthesynthesisoflow-densitylipoprotein(LDL)receptorsandtherebyincreasestheuptakeofLDLparticles.

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Theoverallcholesterolprofileisimprovedwiththeprincipaleffectsbeingthereductionoftotal-CandLDL-C.

Fluvastatinalsoproducesamoderatereductionintriglycerides(TG)andamoderateincreaseinHDL-C.

Inapooledanalysisofallplacebo-controlledstudies,patientswithprimarymixeddyslipidaemia(TypeIIb)definedas

baselineTGlevels ≥200mg/dL,treatmentwithfluvastatinindailydosesrangingfrom20mgto80mg(40mgtwice

daily)demonstratedconsistentandsignificantdecreasesintotal-C,LDL-C,andapolipoproteinB,TG,andanincrease

inHDL-C.

IntheLIPSstudy,theeffectoffluvastatinonmajoradversecardiacevents(MACE)wasassessedinpatientswith

coronaryheartdiseasewhohadfirstsuccessfultranscathethertherapy(TCT).Thestudyincludedmaleandfemale

patients(18-80yearsold)andwithbaselinetotal-Clevelsrangingfrom3.5-7.0mmol/L.

Inthisrandomised,double-blind,placebo-controlledtrial,fluvastatin(N=844),givenas80mgdailyover4years.

significantlyreducedtheriskofthefirstMACEby22%(p=0.013)ascomparedtoplacebo(N=833).Thesebeneficial

effectswereparticularlynoteworthyindiabeticsandpatientswithmultivesseldisease.

Therapywithfluvastatinreducedtheriskofcardiacdeathand/ormyocardialinfarctionby31%(p=0.065).

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Thesafetyandefficacyoffluvastatininchildrenandadolescentpatientsaged9-16yearsofagewithheterozygous

familialhypercholesterolemiahasbeenevaluatedin2openlabel,uncontrolledclinicaltrialsof2years'duration.114

patients(66boysand48girls)weretreatedwithfluvastatinadministeredaseitherfluvastatincapsules20mg-40mg

bidorfluvastatin80mgextendedreleasetabletsusingadose-titrationregimenbaseduponLDL-Cresponse.

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

oneparentwithprimaryhypercholesterolemiaandeitherafamilyhistoryofprematureischemicheartdiseaseortendon

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

3.6–9.2mmol/L).Allpatientswerestartedonfluvastatincapsules20mgdailywithdoseadjustmentsevery6weeks

to40mgdailythen80mgdaily(40mgbid)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).Allpatientswerestartedonfluvastatincapsules20mgdailywithdoseadjustmentsevery6weeksto40mg

dailythen80mgdaily(fluvastatin80mgprolongedreleasetablet)toachieveanLDL-Cgoalof ≤130mg/dL(3.4

mmol/L).

Inthefirststudy,fluvastatin20to80mgdailydosesdecreasedplasmalevelsoftotal-CandLDL-Cby21%and27%,

respectively.ThemeanachievedLDL-Cwas161mg/dLequivalentto4.2mmol/L(range:74-336mg/dLequivalent

1.9–8.7mol/L).Inthesecondstudy,fluvastatin20to80mgdailydosesdecreasedplasmalevelsoftotal-CandLDL-

Cby22%and28%,respectively.ThemeanachievedLDL-Cwas159mg/dLequivalentto4.1mmol/L(range:90-

295mg/dLequivalentto2.3–7.6mmol/L).

Themajorityofpatientsinbothstudies(83%inthefirststudyand89%inthesecondstudy)weretitratedtothe

maximumdailydoseof80mg.Atstudyendpoint,26to30%ofpatientsinbothstudiesachievedatargetedLDL-C

goalof<130mg/dL(3.4mmol/L).

5.2Pharmacokineticproperties

Absorption

Fluvastatinisabsorbedrapidlyandcompletely(98%)afteroraladministrationtofastedvolunteers.Inthefedstate,the

substanceisabsorbedatareducedrate.NosignificantdifferenceinAUCwasobservedwhenfluvastatinwas

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Distribution

Absolutebioavailabilityisvariableandincreaseswithincreasingdoses.Theabsolutebioavailabilityoffluvastatin

followinga10mgdosewas24%(range:9-50%).Atdosesabove20mg,fluvastatinexhibitsnonlinearkinetics,atleast

inthefastingstate,resultingindosenormalizedAUCvalues20-40%higherthanexpectedforthe40mgdose.The

apparentvolumeofdistributionforthesubstanceis330L.Morethan98%ofthecirculatingsubstanceisboundto

plasmaproteins,andthisbindingisnotaffectedeitherbytheconcentrationoffluvastatin,orbywarfarin,salicylicacid,

andglyburide.

Metabolism

Fluvastatinismainlymetabolisedintheliver.Themajorcomponentscirculatinginthebloodarefluvastatinandthe

pharmacologicallyinactiveN-desisopropyl-propionicacidmetabolite.Thehydroxylatedmetaboliteshave

pharmacologicalactivitybutdonotcirculatesystemically.

Thehepaticmetabolicpathwaysoffluvastatininhumanshavebeencompletelyelucidated.Therearemultiple,

alternativecytochromeP450(CYP450)pathwaysforfluvastatinbiotransformationandthusfluvastatinmetabolismis

relativelyinsensitivetoCYP450inhibition,amajorcauseofadverseinteractionsinvolved.

SeveraldetailedinvitrostudieshaveaddressedtheinhibitorypotentialoffluvastatinoncommonCYPisoenzymes.

FluvastatininhibitedonlythemetabolismofcompoundsthataremetabolizedbyCYP2C9.Despitethepotentialthat

thereforeexistsforcompetitiveinteractionbetweenfluvastatinandcompoundsthatareCYP2C9substrates,suchas

diclofenac,phenytoin,tolbutamide,andwarfarin,clinicaldataindicatethatthisinteractionisunlikely.

Elimination

Followingadministrationof3H-fluvastatintohealthyvolunteers,excretionofradioactivityisabout6%intheurineand

93%inthefaeces,andfluvastatinaccountsforlessthan2%ofthetotalradioactivityexcreted.Theplasmaclearance

forfluvastatininmaniscalculatedtobe1.8±0.8L/min.Steady-stateplasmaconcentrationsshownoevidenceof

fluvastatinaccumulationfollowingadministrationof40mgdaily.Followingoraladministrationof40mgof

fluvastatin,theterminaldispositionhalf-lifeis2.3±0.9hours.

Characteristicsinpatients

Plasmaconcentrationsoffluvastatindonotvaryasafunctionofeitherageorgenderinthegeneralpopulation.

However,enhancedtreatmentresponsewasobservedinwomenandinelderlypeople.

Sincefluvastatiniseliminatedprimarilyviathebiliaryrouteandissubjecttosignificantpre-systemicmetabolism,the

potentialexistsforaccumulationinpatientswithhepaticinsufficiency(seesections4.3and4.4).

Childrenandadolescentswithheterozygousfamilialhypercholesterolemia

Nopharmacokineticdatainchildrenareavailable.

5.3Preclinicalsafetydata

RepeattoxicitystudieswithfluvastatinidentifiedavarietyofchangesthatarecommontoHMG-CoAreductase

inhibitors,viz.hyperplasiaandhyperkeratosisoftherodentnon-glandularstomach,cataractsindogs,myopathyin

rodents,mildliverchangesinmostlaboratoryanimalswithgallbladderchangesindog,monkeyandhamster,thyroid

weightincreasesintheratandtesticulardegenerationinthehamster.Fluvastatinisdevoidofthecentralnervous

system(CNS)vascularanddegenerativechangesrecordedindogswithothermembersofthisclassofcompound.

Carcinogenicitystudiesinratsandmicerevealedalowincidenceofforestomachsquamouspapillomasinmiceandrats

andonecarcinomainratsatthehighestdose(18mg/kgperdayescalatedto24mg/kgperdayafter1year).

Theforestomachneoplasmsreflectchronichyperplasiacausedbydirectcontactexposuretofluvastatinratherthana

genotoxiceffectofthesubstance.Inaddition,anincreasedincidenceofthyroidfollicularcellneoplasmsinmalerats

giventhehighestdoseoffluvastatinwasrecorded.Thisisconsistentwithspecies-specificfindingswithotherHMG-

CoAreductaseinhibitors.IncontrasttootherHMG-CoAreductaseinhibitors,notreatment-relatedincreasesinthe

incidenceofhepaticadenomasorcarcinomaswereobserved.

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Reproductivetoxicitystudiesindicatedthatfluvastatinhadnoadverseeffectsonfertilityorreproductiveperformance

inmalesorfemales,norwasitembryotoxicorteratogenic.Lategestationaleffectsathighdosesresultedinmaternal

mortalityandfetalandneonatallethalityattributabletoexaggeratedpharmacologicaleffectsoffluvastatinduring

pregnancy.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactosemonohydrate

Colloidalanhydroussilica

Crospovidone

Magnesiumstearate

Capandbody:

Redironoxide(E172)

YellowIronOxide(E172)

Titaniumdioxide(E171)

Gelatin

Printinginkcomposition:

Shellac

Propyleneglycol

Blackironoxide(E172)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Blisters:Donotstoreabove30°C.

Bottles:Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

Blisters:Aluminium–Aluminiumblisterpacks

Bottles:WhiteHDPEbottleswithwhitePPchild-resistantclosureandsilicagelasdesiccant.

Packsizes:

Blisters:1,14,15,28,30,50,50x2,56,60,84,90,98and100capsules.

Hospitalpacksinblisters:1,50and100capsules

Bottles:100,250and500capsules

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

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7MARKETINGAUTHORISATIONHOLDER

TEVAPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA0749/043/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:25thJuly2008

10DATEOFREVISIONOFTHETEXT

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