BENEPRAV

Main information

  • Trade name:
  • BENEPRAV Tablets 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BENEPRAV Tablets 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1595/004/001
  • Authorization date:
  • 09-10-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Beneprav10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgpravastatinsodium.

Eachtabletcontains64.45mgoflactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Yellowbiconvexoblongtabletwithabreakingnotchonbothsidesandanimprint'10'ononeside.

Thetabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolaemia

Treatmentofprimaryhypercholesterolaemiaormixeddyslipidaemia,asanadjuncttodiet,whenresponsetodietand

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

Primaryprevention

Reductionofcardiovascularmortalityandmorbidityinpatientswithmoderateorseverehypercholesterolaemiaandat

highriskofafirstcardiovascularevent,asanadjuncttodiet(seesection5.1).

Secondaryprevention

Reductionofcardiovascularmortalityandmorbidityinpatientswithahistoryofmyocardialinfarctionorunstable

anginapectorisandwitheithernormalorincreasedcholesterollevels,asanadjuncttocorrectionofotherriskfactors

(seesection5.1).

Posttransplantation

Reductionofposttransplantationhyperlipidaemiainpatientsreceivingimmunosuppressivetherapyfollowingsolid

organtransplantation(seesections4.2,4.5and5.1).

4.2Posologyandmethodofadministration

PriortoinitiatingBenepravTablets,secondarycausesofhypercholesterolaemiashouldbeexcludedandpatientsshould

beplacedonastandardlipid-loweringdietwhichshouldbecontinuedduringtreatment.

BenepravTabletsareadministeredorallyoncedailypreferablyintheeveningwithorwithoutfood.

Hypercholesterolaemia:therecommendeddoserangeis10-40mgoncedaily.Thetherapeuticresponseisseenwithin

aweekandthefulleffectofagivendoseoccurswithinfourweeks,thereforeperiodiclipiddeterminationsshouldbe

performedandthedosageadjustedaccordingly.Themaximumdailydoseis40mg.

Cardiovascularprevention:inallpreventivemorbidityandmortalitytrials,theonlystudiedstartingandmaintenance

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Dosageaftertransplantation:followingorgantransplantationastartingdoseof20mgperdayisrecommendedin

patientsreceivingimmunosuppressivetherapy(seesection4.5).Dependingontheresponseofthelipidparameters,the

dosemaybeadjustedupto40mgunderclosemedicalsupervision(seesection4.5).

Childrenandadolescents(8-18yearsofage):Foradolescents(14-18yearsofage),therecommendeddoserangeis

10-40mgoncedaily.Inchildren(8-13yearsofage),therecommendeddoseis10-20mgoncedaily,asdosesgreater

than20mghavenotbeenstudiedinthispopulation(forchildrenandadolescentfemalesofchild-bearingpotential,see

alsosection4.6;forresultsofthestudyseesection5.1).

Thedocumentationonefficacyandsafetyinpatientslessthan8yearsoldislimited;therefore,theuseofPravastatin

SodiumTabletsisnotrecommendedinthesepatients.

Elderlypatients:thereisnodoseadjustmentnecessaryinthesepatientsunlesstherearepredisposingriskfactors(see

section4.4).

Renalorhepaticimpairment:astartingdoseof10mgadayisrecommendedinpatientswithmoderateorsevere

renalimpairmentorsignificanthepaticimpairment.Thedosageshouldbeadjustedaccordingtotheresponseoflipid

parametersandundermedicalsupervision.

Concomitanttherapy:thelipidloweringeffectsofBenepravTabletsontotalcholesterolandLDL-cholesterolare

enhancedwhencombinedwithabileacid-bindingresin(e.g.cholestyramine,colestipol).BenepravTabletsshouldbe

giveneitheronehourbeforeoratleastfourhoursaftertheresin(seesection4.5).

Forpatientstakingciclosporinwithorwithoutotherimmunosuppressivemedicinalproducts,treatmentshouldbegin

with20mgofpravastatinoncedailyandtitrationto40mgshouldbeperformedwithcaution(seesection4.5).

4.3Contraindications

-Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

-Activeliverdiseaseincludingunexplainedpersistentelevationsofserumtransaminaseexceeding3xtheupperlimit

ofnormal(ULN)(seesection4.4).

-Pregnancyandlactation(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Pravastatinhasnotbeenevaluatedinpatientswithhomozygousfamilialhypercholesterolaemia.Therapyisnotsuitable

whenhypercholesterolaemiaisduetoelevatedHDL-Cholesterol.

AsforotherHMG-CoAreductaseinhibitors,combinationofpravastatinwithfibratesisnotrecommended.

Inchildrenbeforepuberty,thebenefit/riskoftreatmentshouldbecarefullyevaluatedbyphysiciansbeforetreatment

initiation.

Hepaticdisorders:aswithotherlipid-loweringagents,moderateincreasesinlivertransaminaselevelshavebeen

observed.Inthemajorityofcases,livertransaminaselevelshavereturnedtotheirbaselinevaluewithouttheneedfor

treatmentdiscontinuation.Specialattentionshouldbegiventopatientswhodevelopincreasedtransaminaselevelsand

therapyshouldbediscontinuedifincreasesinalanineaminotransferase(ALT)andaspartateaminotransferase(AST)

exceedthreetimestheupperlimitofnormalandpersist.

Cautionshouldbeexercisedwhenpravastatinisadministeredtopatientswithahistoryofliverdiseaseorheavy

alcoholingestion.

Muscledisorders:aswithotherHMG-CoAreductaseinhibitors(statins),pravastatinhasbeenassociatedwiththe

onsetofmyalgia,myopathyandveryrarely,rhabdomyolysis.

Myopathymustbeconsideredinanypatientunderstatintherapypresentingwithunexplainedmusclesymptomssuch

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measured(seebelow).

StatintherapyshouldbetemporarilyinterruptedwhenCKlevelsare>5xULNorwhentherearesevereclinical

symptoms.Veryrarely(inabout1caseover100000patient-years),rhabdomyolysisoccurs,withorwithoutsecondary

renalinsufficiency.Rhabdomyolysisisanacutepotentiallyfatalconditionofskeletalmusclewhichmaydevelopatany

timeduringtreatmentandischaracterisedbymassivemuscledestructionassociatedwithmajorincreaseinCK(usually

>30or40xULN)leadingtomyoglobinuria.

Theriskofmyopathywithstatinsappearstobeexposure-dependentandthereforemayvarywithindividualdrugs(due

tolipophilicityandpharmacokineticdifferences),includingtheirdosageandpotentialfordruginteractions.Although

thereisnomuscularcontraindicationtotheprescriptionofastatin,certainpredisposingfactorsmayincreasetheriskof

musculartoxicityandthereforejustifyacarefulevaluationofthebenefit/riskandspecialclinicalmonitoring.CK

measurementisindicatedbeforestartingstatintherapyinthesepatients(seebelow).

Theriskandseverityofmusculardisordersduringstatintherapyisincreasedbytheco-administrationofinteracting

medicines.Theuseoffibratesaloneisoccasionallyassociatedwithmyopathy.Thecombineduseofastatinand

fibratesshouldgenerallybeavoided.Theco-administrationofstatinsandnicotinicacidshouldbeusedwithcaution.

Anincreaseintheincidenceofmyopathyhasalsobeendescribedinpatientsreceivingotherstatinsincombination

withinhibitorsofcytochromeP450metabolism.Thismayresultfrompharmacokineticinteractionsthathavenotbeen

documentedforpravastatin(seesection4.5).Whenassociatedwithstatintherapy,musclesymptomsusuallyresolve

followingdiscontinuationofstatintherapy.

Creatinekinasemeasurementandinterpretation:

Routinemonitoringofcreatinekinase(CK)orothermuscleenzymelevelsisnotrecommendedinasymptomatic

patientsonstatintherapy.However,measurementofCKisrecommendedbeforestartingstatintherapyinpatientswith

specialpredisposingfactors,andinpatientsdevelopingmuscularsymptomsduringstatintherapy,asdescribedbelow.

IfCKlevelsaresignificantlyelevatedatbaseline(>5xULN),CKlevelsshouldbere-measuredabout5to7dayslater

toconfirmtheresults.Whenmeasured,CKlevelsshouldbeinterpretedinthecontextofotherpotentialfactorsthatcan

causetransientmuscledamage,suchasstrenuousexerciseormuscletrauma.

Beforetreatmentinitiation:cautionshouldbeusedinpatientswithpredisposingfactorssuchasrenalimpairment,

hypothyroidism,previoushistoryofmusculartoxicitywithastatinorfibrate,personalorfamilialhistoryofhereditary

musculardisorders,oralcoholabuse.Inthesecases,CKlevelsshouldbemeasuredpriortoinitiationoftherapy.CK

measurementshouldalsobeconsideredbeforestartingtreatmentinpersonsover70yearsofageespeciallyinthe

presenceofotherpredisposingfactorsinthispopulation.IfCKlevelsaresignificantlyelevated(>5xULN)at

baseline,treatmentshouldnotbestartedandtheresultsshouldbere-measuredafter5-7days.ThebaselineCKlevels

mayalsobeusefulasareferenceintheeventofalaterincreaseduringstatintherapy.

Duringtreatment:patientsshouldbeadvisedtoreportpromptlyunexplainedmusclepain,tenderness,weaknessor

cramps.Inthesecases,CKlevelsshouldbemeasured.Ifamarkedlyelevated(>5xULN)CKlevelisdetected,statin

therapymustbeinterrupted.Treatmentdiscontinuationshouldalsobeconsideredifthemuscularsymptomsaresevere

andcausedailydiscomfort,eveniftheCKincreaseremains 5xULN.IfsymptomsresolveandCKlevelsreturnto

normal,thenreintroductionofstatintherapymaybeconsideredatthelowestdoseandwithclosemonitoring.Ifa

hereditarymusculardiseaseissuspectedinsuchpatients,restartingstatintherapyisnotrecommended.

Thisproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp-lactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth

(fatigue,weightlossandfever).Ifitissuspectedapatienthasdevelopedinterstitiallungdisease,statintherapyshould

bediscontinued.

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Fibrates:theuseoffibratesaloneisoccasionallyassociatedwithmyopathy.Anincreasedriskofmuscle-related

adverseevents,includingrhabdomyolysis,havebeenreportedwhenfibratesareco-administeredwithotherstatins.

Theseadverseeventswithpravastatincannotbeexcluded;thereforethecombineduseofpravastatinandfibrates(e.g.

gemfibrozil,fenofibrate)shouldgenerallybeavoided(seesection4.4).Ifthiscombinationisconsiderednecessary,

carefulclinicalandCKmonitoringofpatientsonsuchregimenisrequired.

Cholestyramine/Colestipol:concomitantadministrationresultedinapproximately40to50%decreaseinthe

bioavailabilityofpravastatin.Therewasnoclinicallysignificantdecreaseinbioavailabilityortherapeuticeffectwhen

pravastatinwasadministeredonehourbeforeorfourhoursaftercholestyramineoronehourbeforecolestipol(see

section4.2).

Ciclosporin:concomitantadministrationofpravastatinandciclosporinleadstoanapproximately4-foldincreasein

pravastatinsystemicexposure.Insomepatients,however,theincreaseinpravastatinexposuremaybelarger.Clinical

andbiochemicalmonitoringofpatientsreceivingthiscombinationisrecommended(seesection4.2).

Warfarinandotheroralanticoagulants:bioavailabilityparametersatsteadystateforpravastatinwerenotaltered

followingadministrationwithwarfarin.Chronicdosingofthetwoproductsdidnotproduceanychangesinthe

anticoagulantactionofwarfarin.

ProductsmetabolisedbycytochromeP450:pravastatinisnotmetabolisedtoaclinicallysignificantextentbythe

cytochromeP450system.Thisiswhyproductsthataremetabolisedby,orinhibitorsof,thecytochromeP450system

canbeaddedtoastableregimenofpravastatinwithoutcausingsignificantchangesintheplasmalevelsofpravastatin,

ashavebeenseenwithotherstatins.Theabsenceofasignificantpharmacokineticinteractionwithpravastatinhasbeen

specificallydemonstratedforseveralproducts,particularlythosethataresubstrates/inhibitorsofCYP3A4e.g.

diltiazem,verapamil,itraconazole,ketoconazole,proteaseinhibitors,grapefruitjuiceandCYP2C9inhibitors(e.g.

fluconazole).

Inoneoftwointeractionstudieswithpravastatinanderythromycinastatisticallysignificantincreaseinpravastatin

AUC(70%)andC

(121%)wasobserved.Inasimilarstudywithclarithromycinastatisticallysignificantincreasein

AUC(110%)andC

(127%)wasobserved.Althoughthesechangeswereminor,cautionshouldbeexercisedwhen

associatingpravastatinwitherythromycinorclarithromycin.

Otherproducts:ininteractionstudies,nostatisticallysignificantdifferencesinbioavailabilitywereobservedwhen

pravastatinwasadministeredwithacetylsalicylicacid,antacids(whengivenonehourpriortopravastatin),nicotinic

acidorprobucol.

4.6Fertility,pregnancyandlactation

Pregnancy:pravastatiniscontraindicatedduringpregnancyandshouldbeadministeredtowomenofchildbearing

potentialonlywhenthesepatientsareunlikelytoconceiveandhavebeeninformedofthepotentialhazards.Special

cautionisrecommendedinchildrenandadolescentfemalesofchild-bearingpotentialtoensureproperunderstandingof

thepotentialrisksassociatedwithpravastatintherapyduringpregnancyandtheuseofadequatecontraceptivemeasures

asappropriatewhileonpravastatintherapy.

Ifapatientplanstobecomepregnantorbecomespregnant,thedoctorhastobeinformedimmediatelyandpravastatin

shouldbediscontinuedbecauseofthepotentialrisktothefoetus.

Lactation:asmallamountofpravastatinisexcretedinhumanbreastmilk,thereforepravastatiniscontraindicated

duringbreastfeeding(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

Pravastatinhasnoornegligibleinfluenceontheabilitytodriveandusemachines.However,whendrivingvehiclesor

operatingmachines,itshouldbetakenintoaccountthatdizzinessmayoccurduringtreatment.

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Thefrequenciesofadverseeventsarerankedaccordingtothefollowing:verycommon(1/10);common(1/100,

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

Clinicaltrials:

BenepravTabletshasbeenstudiedat40mginsevenrandomizeddouble-blindplacebo-controlledtrialsinvolvingover

21,000patientstreatedwithpravastatin(N=10764)orplacebo(N=10719),representingover47,000patientyearsof

exposuretopravastatin.Over19,000patientswerefollowedforamedianof4.8-5.9years.

Thefollowingadversedrugreactionswerereported;noneofthemoccurredatarateinexcessof0.3%inpravastatin

groupcomparedtotheplacebogroup.

Eventsofspecialclinicalinterest

Skeletalmuscle:effectsontheskeletalmuscle,e.g.musculoskeletalpainincludingarthralgia,musclecramps,myalgia,

muscleweaknessandelevatedCKlevelshavebeenreportedinclinicaltrials.Therateofmyalgia(1.4%pravastatinvs

1.4%placebo)andmuscleweakness(0.1%pravastatinvs<0.1%placebo)andtheincidenceofCKlevel>3xULN

and>10xULNinCARE,WOSCOPSandLIPIDwassimilartoplacebo(1.6%pravastatinvs1.6%placeboand1.0%

pravastatinvs1.0%placebo,respectively)(seesection4.4).

Livereffects:elevationsofserumtransaminaseshavebeenreported.Inthethreelong-term,placebo-controlledclinical

trialsCARE,WOSCOPSandLIPID,markedabnormalitiesofALTandAST(>3xULN)occurredatsimilar

frequency(1.2%)inbothtreatmentgroups.

Postmarketing:

Inadditiontotheabovethefollowingadverseeventshavebeenreportedduringpostmarketingexperienceof

SystemOrganClass Uncommon

Nervoussystemdisorders Dizziness,headache,sleepdisturbance,

insomnia,nightmares

Eyedisorders Visiondisturbance(includingblurredvision

anddiplopia)

Gastrointestinaldisorders Dyspepsia/heartburn,abdominalpain,

nausea/vomiting,constipation,diarrhoea,

flatulence

Skinandsubcutaneoustissuedisorders Pruritus,rash,urticaria,scalp/hair

abnormality(includingalopecia)

Renalandurinarydisorders Abnormalurination(includingdysuria,

frequency,nocturia)

Reproductivesystemandbreastdisorders Sexualdysfunction

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Thefollowingadverseeventshavebeenreportedwithsomestatins:

Memoryloss

Sexualdysfunction

Depression

Exceptionalcasesofinterstitiallungdisease,especiallywithlongtermtherapy(seesection4.4)

4.9Overdose

Todatetherehasbeenlimitedexperiencewithoverdosageofpravastatin.Thereisnospecifictreatmentintheeventof

overdose.Intheeventofoverdose,thepatientshouldbetreatedsymptomaticallyandsupportivemeasuresinstitutedas

required.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:serumlipidreducingagents/cholesterolandtriglyceridereducers/HMG-CoAreductase

inhibitors,ATC-Code:C10AA03

Mechanismofaction:

Pravastatinisacompetitiveinhibitorof3-hydroxy-3-methylglutaryl-coenzymeA(HMGCoA)reductase,theenzyme

catalysingtheearlyrate-limitingstepincholesterolbiosynthesis,andproducesitslipid-loweringeffectintwoways.

Firstly,withthereversibleandspecificcompetitiveinhibitionofHMG-CoAreductase,iteffectsmodestreductionin

thesynthesisofintracellularcholesterol.ThisresultsinanincreaseinthenumberofLDL-receptorsoncellsurfaces

andenhancedreceptor-mediatedcatabolismandclearanceofcirculatingLDL-cholesterol.Secondly,pravastatin

inhibitsLDLproductionbyinhibitingthehepaticsynthesisofVLDL-cholesterol,theLDL-cholesterolprecursor.

Inbothhealthysubjectsandpatientswithhypercholesterolaemia,pravastatinsodiumlowersthefollowinglipidvalues:

totalcholesterol,LDL-cholesterol,apolipoproteinB,VLDL-cholesterolandtriglycerides;whileHDL-cholesteroland

apolipoproteinAareelevated.

Clinicalefficacy:

Primaryprevention

The"WestofScotlandCoronaryPreventionStudy(WOSCOPS)"wasarandomised,double-blind,placebo-controlled

trialamong6,595malepatientsagedfrom45to64yearswithmoderatetoseverehypercholesterolaemia(LDL-C:155-

232mg/dl[4.0-6.0mmol/l])andwithnohistoryofmyocardialinfarction,treatedforanaveragedurationof4.8years

SystemOrganClass Veryrare

Nervoussystemdisorders Peripheralpolyneuropathy,inparticularifusedforlongperiod

oftime,paresthesia

Immunesystemdisorders Hypersensitivityreactions:anaphylaxis,angioedema,lupus

erythematous-likesyndrome

Gastrointestinaldisorders Pancreatitis

Hepatobiliarydisorders Jaundice,hepatitis,fulminanthepaticnecrosis

Musculoskeletalandconnectivetissuedisorders Rhabdomyolysis,whichcanbeassociatedwithacuterenal

failuresecondarytomyoglobinuria,myopathy(seesection

4.4);myositisandpolymyositis

Isolatedcasesoftendondisorders,sometimescomplicatedby

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showed:

-adecreaseintheriskofmortalityfromcoronarydiseaseandofnon-lethalmyocardialinfarction(relativerisk

reductionRRRwas31%;p=0.0001withanabsoluteriskof7.9%intheplacebogroup,and5.5%inpravastatin

treatedpatients);theeffectsonthesecumulativecardiovasculareventsratesbeingevidentasearlyas6monthsof

treatment;

-adecreaseinthetotalnumberofdeathsfromacardiovascularevent(RRR32%;p=0.03);

-whenriskfactorsweretakenintoaccount,anRRRof24%(p=0.039)intotalmortalitywasalsoobservedamong

patientstreatedwithpravastatin;

-adecreaseintherelativeriskforundergoingmyocardialrevascularisationprocedures(coronaryarterybypassgraft

surgeryorcoronaryangioplasty)by37%(p=0.009)andcoronaryangiographyby31%(p=0.007).

Thebenefitofthetreatmentonthecriteriaindicatedaboveisnotknowninpatientsovertheageof65years,whocould

notbeincludedinthestudy.

Intheabsenceofdatainpatientswithhypercholesterolaemiaassociatedwithatriglyceridelevelofmorethan6mmol/l

(5.3g/l)afteradietfor8weeks,inthisstudy,thebenefitofpravastatintreatmenthasnotbeenestablishedinthistype

ofpatient.

Secondaryprevention

The"Long-TermInterventionwithPravastatininIschemicDisease(LIPID)"wasamulti-centre,randomised,double-

blind,placebo-controlledstudycomparingtheeffectsofpravastatin(40mgOD)withplaceboin9014patientsaged31

to75yearsforanaveragedurationof5.6yearswithnormaltoelevatedserumcholesterollevels(baselinetotal

cholesterol=155to271mg/dl[4.0-7.0mmol/l],meantotalcholesterol=219mg/dl[5.66mmol/l])andwithvariable

triglyceridelevelsofupto443mg/dl[5.0mmol/l]andwithahistoryofmyocardialinfarctionorunstableangina

pectorisinthepreceding3to36months.

TreatmentwithpravastatinsignificantlyreducedtherelativeriskofCHDdeathby24%(p=0.0004,withanabsolute

riskof6.4%intheplacebogroup,and5.3%inpravastatin-treatedpatients),therelativeriskofcoronaryevents(either

CHDdeathornonfatalMI)by24%(p<0.0001)andtherelativeriskoffatalornon-fatalmyocardialinfarctionby29%

(p<0.0001).Inpravastatin-treatedpatients,resultsshowed:

-areductionintherelativeriskoftotalmortalityby23%(p<0.0001)andcardiovascularmortalityby25%

(p<0.0001);

-areductionintherelativeriskofundergoingmyocardialrevascularisationprocedures(coronaryarterybypassgrafting

orpercutaneoustransluminalcoronaryangioplasty)by20%(p<0.0001);

-areductionintherelativeriskofstrokeby19%(p=0.048).

The"CholesterolandRecurrentEvents(CARE)"studywasarandomised,double-blind,placebo-controlledstudy

comparingtheeffectsofpravastatin(40mgOD)oncoronaryheartdiseasedeathandnon-fatalmyocardialinfarction

foranaverageof4.9yearsin4,159patientsaged21to75years,withnormaltotalcholesterollevels(baselinemean

totalcholesterol<240mg/dl),whohadexperiencedamyocardialinfarctioninthepreceding3to20months.

Treatmentwithpravastatinsignificantlyreduced:

-therateofarecurrentcoronaryevent(eithercoronaryheartdiseasedeathornon-fatalMI)by24%(p=0.003,placebo

13.3%,pravastatin10.4%);

-therelativeriskofundergoingrevascularisationprocedures(coronaryarterybypassgraftingorpercutaneous

transluminalcoronaryangioplasty)by27%(p<0.001).

Therelativeriskofstrokewasalsoreducedby32%(p=0.032),andstrokeortransientischaemicattack(TIA)

combinedby27%(p=0.02).

Thebenefitofthetreatmentontheabovecriteriaisnotknowninpatientsovertheageof75years,whocouldnotbe

includedintheCAREandLIPIDstudies.

Intheabsenceofdatainpatientswithhypercholesterolaemiaassociatedwithatriglyceridelevelofmorethan4mmol/l

(3.5g/l)ormorethan5mmol/l(4.45g/l)afterfollowingadietfor4or8weeks,intheCAREandLIPIDstudies,

respectively,thebenefitoftreatmentwithpravastatinhasnotbeenestablishedinthistypeofpatient.

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Heartandkidneytransplantation

Theefficacyofpravastatininpatientsreceivinganimmunosuppressanttreatmentfollowing:

-Hearttransplantwasassessedinoneprospective,randomised,controlledstudy(n=97).Patientsweretreated

concurrentlywitheitherpravastatin(20-40mg)ornot,andastandardimmunosuppressiveregimenofciclosporin,

prednisoneandazathioprine.Treatmentwithpravastatinsignificantlyreducedtherateofcardiacrejectionwith

haemodynamiccompromiseatoneyear,improvedone-yearsurvival(p=0.025),andloweredtheriskofcoronary

vasculopathyinthetransplantasdeterminedbyangiographyandautopsy(p=0.049).

-Renaltransplantwasassessedinoneprospectivenotcontrolled,notrandomisedstudy(n=48)of4monthsduration.

Patientsweretreatedconcurrentlywitheitherpravastatin(20mg)ornot,andastandardimmunosuppressiveregimen

ofciclosporin,andprednisone.Inpatientsfollowingkidneytransplantation,pravastatinsignificantlyreducedboththe

incidenceofmultiplerejectionepisodesandtheincidenceofbiopsy-provedacuterejectionepisodes,andtheuseof

pulseinjectionsofbothprednisoloneandMuromonab-CD3.

Childrenandadolescents(8-18yearsofage)

Adouble-blindplacebo-controlledstudyin214paediatricpatientswithheterozygousfamilialhypercholesterolaemia

wasconductedover2years.Children(8-13years)wererandomisedtoplacebo(n=63)or20mgofpravastatindaily

(n=65)andtheadolescents(14-18years)wererandomisedtoplacebo(n=45)or40mgofpravastatindaily(n=41).

InclusioninthestudyrequiredanLDL-Clevel>95thpercentileforageandsexandoneparentwitheitheraclinicalor

moleculardiagnosisoffamilialhypercholesterolaemia.ThemeanbaselineLDL-Cvaluewas239mg/dland237mg/dl

inthepravastatin(range:151-405mg/dl)andplacebo(range:154-375mg/dl)groups,respectively.

TherewasasignificantmeanpercentreductioninLDL-Cof-22.9%andalsointotalcholesterol(-17.2%)fromthe

pooleddataanalysisinbothchildrenandadolescents,similartodemonstratedefficacyinadultson20mgof

pravastatin.ReductionsinapolipoproteinBwerealsoobservedinbothchildrenandadolescents.

Theeffectofpravastatintreatmentinthetwoagegroupswassimilar.ThemeanachievedLDL-Cwas186mg/dl

(range:67-363mg/dl)inthepravastatingroupcomparedto236mg/dl(range:105-438mg/dl)intheplacebogroup.In

subjectsreceivingpravastatin,therewerenodifferencesseeninanyofthemonitoredendocrineparameters[ACTH,

cortisol,DHEAS,FSH,LH,TSH,estradiol(girls)ortestosterone(boys)]relativetoplacebo.Therewereno

developmentaldifferences,testicularvolumechanges,orTannerscoredifferencesobservedrelativetoplacebo.

Thelong-termefficacyofpravastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthoodhasnotbeen

established.

5.2Pharmacokineticproperties

Absorption:

Pravastatinisadministeredorallyintheactiveform.Itisrapidlyabsorbed;peakserumlevelsareachieved1to1.5

hoursafteringestion.Onaverage,34%oftheorallyadministereddoseisabsorbed,withanabsolutebioavailabilityof

17%.

Thepresenceoffoodinthegastrointestinaltractleadstoareductioninthebioavailability,butthecholesterol-lowering

effectofpravastatinisidenticalwhethertakenwithorwithoutfood.Afterabsorption,66%ofpravastatinundergoesa

first-passextractionthroughtheliver,whichistheprimarysiteofitsactionandtheprimarysiteofcholesterol

synthesisandclearanceofLDL-cholesterol.Invitrostudiesdemonstratedthatpravastatinistransportedinto

hepatocytesandwithsubstantiallylessintakeinothercells.

Inviewofthissubstantialfirstpassthroughtheliver,plasmaconcentrationsofpravastatinhaveonlyalimitedvaluein

predictingthelipid-loweringeffect.Theplasmaconcentrationsareproportionaltothedosesadministered.

Distribution:

About50%ofcirculatingpravastatinisboundtoplasmaproteins.Thevolumeofdistributionisabout0.5l/kg.Asmall

quantityofpravastatinpassesintothehumanbreastmilk.

Metabolismandelimination:

PravastatinisnotsignificantlymetabolisedbycytochromeP450nordoesitappeartobeasubstrateoraninhibitorof

P-glycoproteinbutratherasubstrateofothertransportproteins.Followingoraladministration,20%oftheinitialdose

iseliminatedintheurineand70%inthefaeces.Plasmaeliminationhalf-lifeoforalpravastatinis1.5to2hours.After

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biotransformation.Themajordegradationproductofpravastatinisthe3--hydroxyisomericmetabolite.

Thismetabolitehasone-tenthtoone-fortieththeHMG-CoAreductaseinhibitoractivityoftheparentcompound.

Thesystemicclearanceofpravastatinis0.81l/h/kgandtherenalclearanceis0.38l/h/kgindicatingtubularsecretion.

Populationsatrisk:

Paediatricsubjects:meanpravastatinC

andAUCvaluesforpaediatricsubjectspooledacrossageandgenderwere

similartothosevaluesobservedinadultsaftera20mgoraldose.

Hepaticfailure:systemicexposuretopravastatinandmetabolitesinpatientswithalcoholiccirrhosisisenhancedby

about50%comparativelytopatientswithnormalliverfunction.

Renalimpairment:nosignificantmodificationswereobservedinpatientswithmildrenalimpairment.Howeversevere

andmoderaterenalinsufficiencymayleadtoatwofoldincreaseofthesystemicexposuretopravastatinand

metabolites.

5.3Preclinicalsafetydata

Basedonconventionalstudiesofsafetypharmacology,repeateddosetoxicityandtoxicityonreproduction,thereareno

otherrisksforthepatientthanthoseexpectedduetothepharmacologicalmechanismofaction.

Repeateddosestudiesindicatethatpravastatinmayinducevaryingdegreesofhepatotoxicityandmyopathy;ingeneral,

substantiveeffectsonthesetissueswereonlyevidentatdoses50ormoretimesthemaximumhumanmg/kgdose.

Invitroandinvivogenetictoxicologystudieshaveshownnoevidenceofmutagenicpotential.

Inmice,a2-yearcarcinogenicitystudywithpravastatindemonstratesatdosesof250and500mg/kg/day(310times

themaximumhumanmg/kgdose),astatisticallysignificantincreaseintheincidenceofhepatocellularcarcinomasin

malesandfemales,andlungadenomasinfemalesonly.Inrats,a2-yearcarcinogenicitystudydemonstratesatadoseof

100mg/kg/day(125timesthemaximumhumanmg/kg/dose)astatisticallysignificantincreaseintheincidenceof

hepatocellularcarcinomasinmalesonly.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Croscarmellosesodium

Lactosemonohydrate

Magnesiumstearate

Heavymagnesiumoxide

Microcrystallinecellulose

Povidone

Yellowferricoxide

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

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Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Aluminium/aluminiumblisterpacks.

Packsof20,28,30,50,56,72,90,98,100,200(10x20),250(5x50)and500(25x20)tablets.

Packswithperforatedunitdoseblistersof20,30,50,100,200,250and500tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

DaiichiSankyoIrelandLimited

RiversideOne

SirJohnRogerson’sQuay

Dublin2

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA1595/004/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

29thSeptember2006

10DATEOFREVISIONOFTHETEXT

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