BYSTAT

Main information

  • Trade name:
  • BYSTAT Tablets 20 Milligram
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BYSTAT Tablets 20 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0915/032/002
  • Authorization date:
  • 14-08-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bystat20mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains20mgofpravastatinsodium.

Excipients:Eachtabletcontains105.46mglactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Lightyellow,round,shallowconvextablet,withtheinscription“93”ononesideand“7201”ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolemia

Treatmentofprimaryhypercholesterolemiaormixeddyslipidaemia,asanadjuncttodiet,whenresponseto

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

Primaryprevention

Reduction of cardiovascular mortality and morbidity in patients with moderate or severe

hypercholesterolemiaandathighriskofafirstcardiovascularevent,asanadjuncttodiet(seesection5.1).

Secondaryprevention

Reductionofcardiovascularmortalityandmorbidityinpatientswithahistoryofmyocardialinfarctionor

unstableanginapectorisandwitheithernormalorincreasedcholesterollevels,asanadjuncttocorrection

ofotherriskfactors(seesection5.1).

Posttransplantation

Reductionofposttransplantationhyperlipidaemiainpatientsreceivingimmunosuppressivetherapy

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

4.2Posologyandmethodofadministration

PriortoinitiatingBystatTablets,secondarycausesofhypercholesterolaemiashouldbeexcludedand

patientsshouldbeplacedonastandardlipid-loweringdietwhichshouldbecontinuedduringtreatment.

Pravastatinisadministeredorallyoncedailypreferablyintheeveningwithorwithoutfood.

Hypercholesterolaemia

Therecommendeddoserangeis10-40mgoncedaily.Thetherapeuticresponseisseenwithinaweekand

thefulleffectofagivendoseoccurswithinfourweeks,thereforeperiodiclipiddeterminationsshouldbe

performedandthedosageadjustedaccordingly.Themaximumdailydoseis40mg.

Cardiovascularprevention

Inallpreventivemorbidityandmortalitytrials,theonlystudiedstartingandmaintenancedosewas40mg

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Dosageaftertransplantation

Followingorgantransplantationastartingdoseof20mgperdayisrecommendedinpatientsreceiving

immunosuppressivetherapy(seesection4.5).Dependingontheresponseofthelipidparameters,thedose

maybeadjustedupto40mgunderclosemedicalsupervision(seesection4.5).

Childrenandadolescent(8–18yearsofage)withheterozygousfamilialhypercholesterolaemia

Therecommendeddoserangeis10-20mgoncedailybetween8and13yearsofageasdosesgreaterthan

20mghavenotbeenstudiedinthispopulationand10-40mgdailybetween14and18yearsofage(for

childrenandadolescentfemalesofchild-bearingpotential,seesection4.6;forresultsofthestudysee

section5.1).

Elderlypatients

Thereisnodoseadjustmentnecessaryinthesepatientsunlesstherearepredisposingriskfactors(see

section4.4).

Renalorhepaticimpairment

Astartingdoseof10mgadayisrecommendedinpatientswithmoderateorsevererenalimpairmentor

significanthepaticimpairment.Thedosageshouldbeadjustedaccordingtotheresponseoflipidparameters

andundermedicalsupervision.

Concomitanttherapy

Thelipid-loweringeffectsofpravastatinontotalcholesterolandLDL-cholesterolareenhancedwhen

combinedwithabileacid-bindingresin(e.g.cholestyramine,colestipol).Pravastatinshouldbegiveneither

onehourbeforeoratleastfourhoursaftertheresin(seesection4.5).

Forpatientstakingcyclosporinwithorwithoutotherimmunosuppressivemedicinalproducts,treatment

shouldbeginwith20mgofpravastatinsodiumoncedailyandtitrationto40mgshouldbeperformedwith

caution(seesection4.5).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Activeliverdiseaseincludingunexplainedpersistentelevationsofserumtransaminase,elevation

exceeding3xtheupperlimitofnormal(ULN)(seesection4.4).

Pregnancyandlactation(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Pravastatinhasnotbeenevaluatedinpatientswithhomozygousfamilialhypercholesterolaemia.Therapyis

notsuitablewhenhypercholesterolaemiaisduetoelevatedHDL-Cholesterol.

AsforotherHMG-CoAreductaseinhibitors,combinationofpravastatinwithfibratesisnotrecommended.

Inchildrenbeforepuberty,thebenefit/riskoftreatmentshouldbecarefullyevaluatedbyphysiciansbefore

treatmentinitiation.

Hepaticdisorders

Aswithotherlipid-loweringagents,moderateincreasesinlivertransaminaselevelshavebeenobserved.In

themajorityofcases,livertransaminaselevelshavereturnedtotheirbaselinevaluewithouttheneedfor

treatmentdiscontinuation.

Specialattentionshouldbegiventopatientswhodevelopincreasedtransaminaselevelsandtherapyshould

bediscontinuedifincreasesinalanineaminotransferase(ALT)andaspartateaminotransferase(AST)

exceedthreetimestheupperlimitofnormalandpersist.Cautionshouldbeexercisedwhenpravastatinis

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Muscledisorders

AswithotherHMG-CoAreductaseinhibitors(statins),pravastatinhasbeenassociatedwiththeonsetof

myalgia,myopathyandveryrarely,rhabdomyolysis.

Myopathymustbeconsideredinanypatientunderstatintherapypresentingwithunexplainedmuscle

symptomssuchaspainortenderness,muscleweakness,ormusclecramps.Insuchcasescreatinekinase

(CK)levelsshouldbemeasured(seebelow).StatintherapyshouldbetemporarilyinterruptedwhenCK

levelsare>5xULNorwhentherearesevereclinicalsymptoms.Veryrarely(inabout1caseover100,000

patient-years),rhabdomyolysisoccurs,withorwithoutsecondaryrenalinsufficiency.Rhabdomyolysisisan

acutepotentiallyfatalconditionofskeletalmusclewhichmaydevelopatanytimeduringtreatmentandis

characterisedbymassivemuscledestructionassociatedwithmajorincreaseinCK(usually>30or40x

ULN)leadingtomyoglobinuria.Theriskofmyopathywithstatinsappearstobeexposure-dependentand

thereforemayvarywithindividualmedicinalproducts(duetolipophilicityandpharmacokinetic

differences),includingtheirdosageandpotentialforinteractions.Althoughthereisnomuscular

contraindicationtotheprescriptionofastatin,certainpredisposingfactorsmayincreasetheriskof

musculartoxicityandthereforejustifyacarefulevaluationofthebenefit/riskandspecialclinical

monitoring.CKmeasurementisindicatedbeforestartingstatintherapyinthesepatients(seebelow).The

riskandseverityofmusculardisordersduringstatintherapyisincreasedbythecoadministrationof

interactingmedicinalproducts.Theuseoffibratesaloneisoccasionallyassociatedwithmyopathy.The

combineduseofastatinandfibratesshouldgenerallybeavoided.Theco-administrationofstatinsand

nicotinicacidshouldbeusedwithcaution.Anincreaseintheincidenceofmyopathyhasalsobeen

describedinpatientsreceivingotherstatinsincombinationwithinhibitorsofcytochromeP450metabolism.

Thismayresultfrompharmacokineticinteractionsthathavenotbeendocumentedforpravastatin(see

section4.5)Whenassociatedwithstatintherapy,musclesymptomsusuallyresolvefollowing

discontinuationofstatintherapy.

Creatinekinasemeasurementandinterpretation

Routinemonitoringofcreatinekinase(CK)orothermuscleenzymelevelsisnotrecommendedin

asymptomaticpatientsonstatintherapy.However,measurementofCKisrecommendedbeforestarting

statintherapyinpatientswithspecialpredisposingfactors,andinpatientsdevelopingmuscularsymptoms

duringstatintherapy,asdescribedbelow.IfCKlevelsaresignificantlyelevatedatbaseline(>5xULN),

CKlevelsshouldbere-measuredabout5to7dayslatertoconfirmtheresults.Whenmeasured,CKlevels

shouldbeinterpretedinthecontextofotherpotentialfactorsthatcancausetransientmuscledamage,such

asstrenuousexerciseormuscletrauma.

Beforetreatmentinitiation:cautionshouldbeusedinpatientswithpredisposingfactorssuchasrenal

impairment,hypothyroidism,previoushistoryofmusculartoxicitywithastatinorfibrate,personalor

familialhistoryofhereditarymusculardisorders,oralcoholabuse.Inthesecases,CKlevelsshouldbe

measuredpriortoinitiationoftherapy.CKmeasurementshouldalsobeconsideredbeforestarting

treatmentinpersonsover70yearsofageespeciallyinthepresenceofotherpredisposingfactorsinthis

population.IfCKlevelsaresignificantlyelevated(>5xULN)atbaseline,treatmentshouldnotbestarted

andtheresultsshouldberemeasuredafter5-7days.ThebaselineCKlevelsmayalsobeusefulasa

referenceintheeventofalaterincreaseduringstatintherapy.

Duringtreatment:patientsshouldbeadvisedtoreportpromptlyunexplainedmusclepain,tenderness,

weaknessorcramps.Inthesecases,CKlevelsshouldbemeasured.Ifamarkedlyelevated(>5xULN)CK

levelisdetected,statintherapymustbeinterrupted.

Treatmentdiscontinuationshouldalsobeconsideredifthemuscularsymptomsaresevereandcausedaily

discomfort,eveniftheCKincreaseremains 5xULN.IfsymptomsresolveandCKlevelsreturnto

normal,thenreintroductionofstatintherapymaybeconsideredatthelowestdoseandwithclose

monitoring.Ifahereditarymusculardiseaseissuspectedinsuchpatients,restartingstatintherapyisnot

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Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlong-

termtherapy(seesection4.8).Presentingfeaturescanincludedyspnoea,non-productivecoughand

deteriorationingeneralhealth(fatigue,weightlossandfever).Ifitissuspectedapatienthasdeveloped

interstitiallungdisease,statintherapyshouldbediscontinued.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-

galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Fibrates

Theuseoffibratesaloneisoccasionallyassociatedwithmyopathy.Anincreasedriskofmusclerelated

adverseevents,includingrhabdomyolysis,havebeenreportedwhenfibratesareco-administeredwithother

statins.Theseadverseeventswithpravastatincannotbeexcluded;thereforethecombineduseof

pravastatinandfibrates(e.g.gemfibrozil,fenofibrate)shouldgenerallybeavoided(seesection4.4).Ifthis

combinationisconsiderednecessary,carefulclinicalandCKmonitoringofpatientsonsuchregimenis

required.

Cholestyramine/Colestipol

Concomitantadministrationresultedinapproximately40to50%decreaseinthebioavailabilityof

pravastatin.Therewasnoclinicallysignificantdecreaseinbioavailabilityortherapeuticeffectwhen

pravastatinwasadministeredonehourbeforeorfourhoursaftercholestyramineoronehourbefore

colestipol(seesection4.2).

Cyclosporin

Concomitantadministrationofpravastatinandcyclosporinleadstoanapproximately4-foldincreasein

pravastatinsystemicexposure.Insomepatients,however,theincreaseinpravastatinexposuremaybe

larger.Clinicalandbiochemicalmonitoringofpatientsreceivingthiscombinationisrecommended(see

section4.2).

Warfarinandotheroralanticoagulants

Bioavailabilityparametersatsteadystateforpravastatinwerenotalteredfollowingadministrationwith

warfarin.Chronicdosingofthetwoproductsdidnotproduceanychangesintheanticoagulantactionof

warfarin.

ProductsmetabolisedbycytochromeP450

PravastatinisnotmetabolisedtoaclinicallysignificantextentbythecytochromeP450system.Thisiswhy

productsthataremetabolisedby,orinhibitorsof,thecytochromeP450systemcanbeaddedtoastable

regimenofpravastatinwithoutcausingsignificantchangesintheplasmalevelsofpravastatin,ashavebeen

seenwithotherstatins.Theabsenceofasignificantpharmacokineticinteractionwithpravastatinhasbeen

specificallydemonstratedforseveralproducts,particularlythosethataresubstrates/inhibitorsofCYP3A4

e.g.diltiazem,verapamil,itraconazole,ketoconazole,proteaseinhibitors,grapefruitjuiceandCYP2C9

inhibitors(e.g.fluconazole).

Inoneoftwointeractionstudieswithpravastatinanderythromycinastatisticallysignificantincreasein

pravastatinAUC(70%)andC (121%)wasobserved.Inasimilarstudywithclarithromycina

statisticallysignificantincreaseinAUC(110%)andC (127%)wasobserved.Althoughthesechanges

wereminor,cautionshouldbeexercisedwhenassociatingpravastatinwitherythromycinorclarithromycin. max

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Otherproducts

Ininteractionstudies,nostatisticallysignificantdifferencesinbioavailabilitywereobservedwhen

pravastatinwasadministeredwithacetylsalicylicacid,antacids(whengivenonehourpriortopravastatin),

nicotinicacidorprobucol.

4.6Fertility,pregnancyandlactation

Pregnancy

Pravastatiniscontraindicatedduringpregnancyandshouldbeadministeredtowomenofchildbearing

potentialonlywhenthesepatientsareunlikelytoconceiveandhavebeeninformedofthepotentialrisk.

Specialcautionisrecommendedinadolescentfemalesofchildbearingpotentialtoensureproper

understandingofthepotentialriskassociatedwithpravastatintherapyduringpregnancy.Ifapatientplans

tobecomepregnantorbecomespregnant,thedoctorhastobeinformedimmediatelyandpravastatinmust

bediscontinuedbecauseofthepotentialrisktothefoetus.

Lactation

Asmallamountofpravastatinisexcretedinhumanbreastmilk,thereforepravastatiniscontraindicated

duringbreastfeeding(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

Pravastatinhasnoornegligibleinfluenceontheabilitytodriveandusemachines.However,whendriving

vehiclesoroperatingmachines,itshouldbetakenintoaccountthatdizzinessmayoccurduringtreatment.

4.8Undesirableeffects

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

Pravastatinhasbeenstudiedat40mginsevenrandomizeddoubleblindplacebo-controlledtrialsinvolving

over21,000patientstreatedwithpravastatin(N=10,764)orplacebo(N=10,719),representingover

47,000patientsyearsofexposuretopravastatin.Over19,000patientswerefollowedforamedianof4.8-

5.9years.Thefollowingadversereactionswerereported;noneofthemoccurredatarateinexcessof0.3%

inpravastatingroupcomparedtotheplacebogroup.

Nervoussystemdisorders:

Uncommon:dizziness,headache,sleepdisturbance,insomniaandnightmares

Eyedisorders:

Uncommon:visiondisturbance(includingblurredvisionanddiplopia)

Gastrointestinaldisorders:

Uncommon:dyspepsia/heartburn,abdominalpain,nausea/vomiting,constipation,diarrhoea,flatulence

Skinandsubcutaneoustissuedisorders:

Uncommon:pruritus,rash,urticaria,scalp/hairabnormality(includingalopecia)

Renalandurinarydisorders:

Uncommon:abnormalurination(includingdysuria,frequency,nocturia)

Reproductivesystemandbreastdisorders:

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Generaldisorders:

Uncommon:fatigue

Eventsofspecialclinicalinterest

Skeletalmuscle:

Effectsontheskeletalmuscle,e.g.musculoskeletalpainincludingarthralgia,musclecramps,myalgia,

muscleweaknessandelevatedCKlevelshavebeenreportedinclinicaltrials.Therateofmyalgia(1.4%

pravastatinvs1.4%placebo)andmuscleweakness(0.1%pravastatinvs<0.1%placebo)andtheincidence

ofCKlevel>3xULNand>10xULNinCARE,WOSCOPSandLIPIDwassimilartoplacebo(1.6%

Pravastatinvs1.6%placeboand1.0%Pravastatinvs1.0%placebo,respectively)(seesection4.4).

Livereffects:

Elevationsofserumtransaminaseshavebeenreported.Inthethreelong-term,placebo-controlledclinical

trialsCARE,WOSCOPSandLIPID,markedabnormalitiesofALTandAST(>3xULN)occurredat

similarfrequency(1.2%)inbothtreatmentgroups.

Postmarketing

Inadditiontotheabovethefollowingadverseeventshavebeenreportedduringpostmarketingexperience

ofpravastatin:

Nervoussystemdisorders:

Veryrare:peripheralpolyneuropathy,inparticularifusedforlongperiodoftime,paresthesia

Immunesystemdisorders:

Veryrare:hypersensitivityreactions:anaphylaxis,angioedema,lupuserythematous-likesyndrome

Gastrointestinaldisorders:

Veryrare:pancreatitis

Hepatobiliarydisorders:

Veryrare:jaundice,hepatitis,fulminanthepaticnecrosis

Musculoskeletalandconnectivetissuedisorders:

Veryrare:rhabdomyolysis,whichcanbeassociatedwithacuterenalfailuresecondarytomyoglobinuria,

myopathy(seesection4.4)

Isolatedcasesoftendondisorders,sometimescomplicatedbyrupture.

Thefollowingadverseeventshavebeenreportedwithsomestatins:memoryloss,depressionand

exceptionalcasesofinterstitiallungdisease,especiallywithlong-termtherapy(seesection4.4).

4.9Overdose

Todatetherehasbeenlimitedexperiencewithoverdosageofpravastatin.Thereisnospecifictreatmentin

theeventofoverdose.Intheeventofoverdose,thepatientshouldbetreatedsymptomaticallyand

supportivemeasuresinstitutedasrequired.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup

Serumlipidreducingagents/cholesterolandtriglyceridereducers/3-hydroxy-3-methylglutaryl-coenzyme

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ATCCode:C10AA03

Mechanismofaction

Pravastatinisacompetitiveinhibitorof3-hydroxy-3-methylglutaryl-coenzymeA(HMG-CoA)reductase,

theenzymecatalysingtheearlyrate-limitingstepincholesterolbiosynthesis,andproducesitslipid-

loweringeffectintwoways.Firstly,withthereversibleandspecificcompetitiveinhibitionofHMG-CoA

reductase,iteffectsmodestreductioninthesynthesisofintracellularcholesterol.Thisresultsinanincrease

inthenumberoflowdensitylipoprotein(LDL)-receptorsoncellsurfacesandenhancedreceptor-mediated

catabolismandclearanceofcirculatingLDL-cholesterol.Secondly,pravastatininhibitsLDLproductionby

inhibitingthehepaticsynthesisofverylowdensitylipoprotein(VLDL)cholesterol,theLDL-cholesterol

precursor.

Inbothhealthysubjectsandpatientswithhypercholesterolaemia,pravastatinsodiumlowersthefollowing

lipidvalues:totalcholesterol,LDLcholesterol,apolipoproteinB,VLDL-cholesterolandtriglycerides,

whilehighdensitylipoprotein(HDL)cholesterolandapolipoproteinAareelevated.

Clinicalefficacy

Primaryprevention

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

placebo-controlledtrialamong6,595malepatientsagedfrom45to64yearswithmoderatetosevere

hypercholesterolaemia(LDL-cholesterol:155-232mg/dl[4.0-6.0mmol/l])andwithnohistoryof

myocardialinfarction,treatedforanaveragedurationof4.8yearswitheithera40mgdailydoseof

pravastatinsodiumorplaceboasanadjuncttodiet.Inpravastatin-treatedpatients,resultsshowed:

adecreaseintheriskofmortalityfromcoronarydiseaseandofnon-lethalmyocardialinfarction

(relativeriskreductionRRRwas31%;p=0.0001withanabsoluteriskof7.9%intheplacebogroup,

and5.5%inpravastatin-treatedpatients);theeffectsonthesecumulativecardiovasculareventsrates

beingevidentasearlyas6monthsoftreatment;

adecreaseinthetotalnumberofdeathsfromacardiovascularevent(RRR32%;p=0.03);

whenriskfactorsweretakenintoaccount,aRRRof24%(p=0.039)intotalmortalitywasalso

observedamongpatientstreatedwithpravastatin;

adecreaseintherelativeriskforundergoingmyocardialrevascularisationprocedures(coronary

arterybypassgraftsurgeryorcoronaryangioplasty)by37%(p=0.009)andcoronaryangiographyby

31%(p=0.007).

Thebenefitofthetreatmentonthecriteriaindicatedaboveisnotknowninpatientsovertheageof65

years,whocouldnotbeincludedinthestudy.

Intheabsenceofdatainpatientswithhypercholesterolaemiaassociatedwithatriglyceridelevelofmore

than6mmol/l(5.3g/l)afteradietfor8weeks,inthisstudy,thebenefitofpravastatintreatmenthasnot

beenestablishedinthistypeofpatients.

Secondaryprevention

The"Long-TermInterventionwithPravastatininIschemicDisease(LIPID)"wasamulticenter,

randomised,double-blind,placebo-controlledstudycomparingtheeffectsofpravastatinsodium(40mg

OD)withplaceboin9,014patientsaged31to75yearsforanaveragedurationof5.6yearswithnormalto

elevatedserumcholesterollevels(baselinetotalcholesterol=155to271mg/dl[4.0-7.0mmol/l],meantotal

cholesterol=219mg/dl[5.66mmol/l])andwithvariabletriglyceridelevelsofupto443mg/dl

[5.0mmol/l]andwithahistoryofmyocardialinfarctionorunstableanginapectorisinthepreceding3to36

months.

Treatmentwithpravastatinsignificantlyreducedtherelativeriskofcoronaryheartdisease(CHD)deathby

24%(p=0.0004,withanabsoluteriskof6.4%intheplacebogroup,and5.3%inpravastatin-treated

patients),therelativeriskofcoronaryevents(eitherCHDdeathornonfatalmyocardialinfarction(MI))by

24%(p<0.0001)andtherelativeriskoffatalornonfatalMIby29%(p<0.0001).Inpravastatin-treated

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areductionintherelativeriskoftotalmortalityby23%(p<0.0001)andcardiovascular

mortalityby25%(p<0.0001);

areductionintherelativeriskofundergoingmyocardialrevascularisationprocedures(coronary

arterybypassgraftingorpercutaneoustransluminalcoronaryangioplasty)by20%(p<0.0001);

areductionintherelativeriskofstrokeby19%(p=0.048).

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

studycomparing,theeffectsofpravastatinsodium(40mgOD)oncoronaryheartdiseasedeathandnon-

fatalMIforanaverageof4.9yearsin4,159patientsaged21to75years,withnormaltotalcholesterol

levels(baselinemeantotalcholesterol<240mg/dl),whohadexperiencedamyocardialinfarctioninthe

preceding3to20months.Treatmentwithpravastatinsignificantlyreduced:

therateofarecurrentcoronaryevent(eithercoronaryheartdiseasedeathornon-fatalMI)by24%

(p=0.003,placebo13.3%,Pravastatin10.4%);

therelativeriskofundergoingrevascularisationprocedures(coronaryarterybypassgraftingor

percutaneoustransluminalcoronaryangioplasty)by27%(p<0.001).

Therelativeriskofstrokewasalsoreducedby32%(p=0.032),andstrokeortransientischaemicattack

(TIA)combinedby27%(p=0.02).

Thebenefitofthetreatmentontheabovecriteriaisnotknowninpatientsovertheageof75years,who

couldnotbeincludedintheCAREandLIPIDstudies.

Intheabsenceofdatainpatientswithhypercholesterolaemiaassociatedwithatriglyceridelevelofmore

than4mmol/l(3.5g/l)ormorethan5mmol/l(4.45g/l)afterfollowingadietfor4or8weeks,inthe

CAREandLIPIDstudies,respectively,thebenefitoftreatmentwithPravastatinhasnotbeenestablishedin

thistypeofpatients.

IntheCAREandLIPIDstudies,about80%ofpatientshadreceivedacetylsalicylicacidaspartoftheir

regimen.

Heartandkidneytransplantation

Theefficacyofpravastatininpatientsreceivinganimmunosuppressanttreatmentfollowing:

Hearttransplantwasassessedinoneprospective,randomised,controlledstudy(n=97).Patients

weretreatedconcurrentlywitheitherpravastatin(20-40mg)ornot,andastandard

immunosuppressiveregimenofcyclosporin,prednisoneandazathioprine.Treatmentwithpravastatin

significantlyreducedtherateofcardiacrejectionwithhaemodynamiccompromiseatoneyear,

improvedone-yearsurvival(p=0.025),andloweredtheriskofcoronaryvasculopathyinthe

transplantasdeterminedbyangiographyandautopsy(p=0.049).

Renaltransplantwasassessedinoneprospectivenotcontrolled,notrandomisedstudy(n=48)of4

monthsduration.Patientsweretreatedconcurrentlywitheitherpravastatin(20mg)ornot,anda

standardimmunosuppressiveregimenofcyclosporin,andprednisone.Inpatientsfollowingkidney

transplantation,pravastatinsignificantlyreducedboththeincidenceofmultiplerejectionepisodesand

theincidenceofbiopsyprovedacuterejectionepisodes,andtheuseofpulseinjectionsofboth

prednisoloneandMuromonab-CD3.

Childrenandadolescents(8–18yearsofage)

Adouble-blindplacebo-controlledstudyin214paediatricpatientswithheterozygousfamilial

hypercholesterolaemiawasconductedover2years.Children(8-13years)wererandomisedtoplacebo(n=

63)or20mgofpravastatindaily(n=65)andtheadolescents(aged14-18years)wererandomisedto

placebo(n=45)or40mgpravastatindaily(n=41).

Inclusioninthisstudyrequiredoneparentwitheitheraclinicalormoleculardiagnosisoffamilial

hypercholesterolaemia.ThemeanbaselineLDL-Cvaluewas239mg/dl(6.2mmol/l)and237mg/dlinthe

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

fromthepooleddataanalysisinbothchildrenandadolescents,similartodemonstratedefficacyinadultson

20mgofpravastatin.

Theeffectsofpravastatintreatmentinthetwoagegroupswassimilar.ThemeanachievedLDL-Cwas186

mg/dl(4.8mmol/l)(range:67-363mg/dl[1.7-9.4mmol/l]inthepravastatingroupcomparedto236mg/dl

(6.1mmol/l)(range:105-438mg/dl[2.7-11.3mmol/l]intheplacebogroup.Insubjectsreceiving

pravastatin,therewerenodifferencesseeninanyofthemonitoredendocrineparameters[ACTH,cortisol,

DHES,FSH,LH,TSH,estradiol(girls)ortestosterone(boys)]relativetoplacebo.

Therewerenodevelopmentaldifferences,testicularvolumechangesorTannerscoredifferencesobserved

relativetoplacebo.Thepowerofthisstudytodetectadifferencebetweenthetwogroupsoftreatmentwas

low.

Thelong-termefficacyofpravastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthood

hasnotbeenestablished.

5.2Pharmacokineticproperties

Absorption

Pravastatinisadministeredorallyintheactiveform.Itisrapidlyabsorbed;peakplasmalevelsareachieved

1to1.5hoursafteringestion.Onaverage,34%oftheorallyadministereddoseisabsorbed,withan

absolutebioavailabilityof17%.Thepresenceoffoodinthegastrointestinaltractleadstoareductioninthe

bioavailability,butthecholesterol-loweringeffectofpravastatinisidenticalwhethertakenwithorwithout

food.Afterabsorption,66%ofpravastatinundergoesfirst-passextractionthroughtheliver,whichisthe

primarysiteofitsactionandtheprimarysiteofcholesterolsynthesisandclearanceofLDL-cholesterol.In

vitrostudiesdemonstratedthatpravastatinistransportedintohepatocytesandwithsubstantiallylessintake

inothercells.Inviewofthissubstantialfirstpassthroughtheliver,plasmaconcentrationsofpravastatin

haveonlyalimitedvalueinpredictingthelipid-loweringeffect.Theplasmaconcentrationsare

proportionaltothedosesadministered.

Distribution

About50%ofcirculatingpravastatinisboundtoplasmaproteins.Thevolumeofdistributionisabout0.5

l/kg.Asmallquantityofpravastatinpassesintohumanbreastmilk.

Metabolismandelimination

PravastatinisnotsignificantlymetabolisedbycytochromeP450nordoesitappeartobeasubstrateoran

inhibitorofP-glycoproteinbutratherasubstrateofothertransportproteins.

Followingoraladministration,20%oftheinitialdoseiseliminatedintheurineand70%inthefaeces.

Plasmaeliminationhalf-lifeoforalpravastatinis1.5to2hours.Afterintravenousadministration,47%of

thedoseiseliminatedbyrenalexcretionand53%bybiliaryexcretionandbiotransformation.Themajor

degradationproductofpravastatinisthe3--hydroxyisomericmetabolite.Thismetabolitehasone-tenthto

one-fortieththeHMG-CoAreductaseinhibitoractivityoftheparentcompound.

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

secretion.

Populationsatrisk

Paediatricsubject:

MeanpravastatinC andAUCvaluesforpaediatricsubjectspooledacrossageandgenderweresimilar

tothosevaluesobservedinadultsaftera20mgoraldose.

Hepaticfailure:

Systemicexposuretopravastatinandmetabolitesinpatientswithalcoholiccirrhosisisenhancedbyabout

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Renalimpairment:

Nosignificantmodificationswereobservedinpatientswithmildrenalimpairment.Howeversevereand

moderaterenalinsufficiencymayleadtoatwo-foldincreaseofthesystemicexposuretopravastatinand

metabolites.

5.3Preclinicalsafetydata

Basedonconventionalstudiesofsafetypharmacology,repeateddosetoxicityandtoxicityonreproduction,

therearenootherrisksforthepatientthanthoseexpectedduetothepharmacologicalmechanismofaction.

Repeateddosestudiesindicatethatpravastatinmayinducevaryingdegreesofhepatotoxicityand

myopathy;ingeneral,substantiveeffectsonthesetissueswereonlyevidentatdoses50ormoretimesthe

maximumhumanmg/kgdose.

Invitroandinvivogenetictoxicologystudieshaveshownnoevidenceofmutagenicpotential.

Inmice,a2-yearcarcinogenicitystudywithpravastatindemonstratesatdosesof250and500mg/kg/day

(310timesthemaximumhumanmg/kgdose),statisticallysignificantincreasesintheincidenceof

hepatocellularcarcinomasinmalesandfemales,andlungadenomasinfemalesonly.Inratsa2-year

carcinogenicitystudydemonstratesatadoseof100mg/kg/day(125timesthemaximumhuman

mg/kg/dose)astatisticallysignificantincreaseintheincidenceofhepatocellularcarcinomasinmalesonly.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactoseanhydrous

Povidone(PVPK-30)

Crospovidone

Calciumhydrogenphosphate,anhydrous(E341)

Yellowironoxide(E172)

Sodiumstearylfumarate

Cellulosemicrocrystalline(E460)

Croscarmellosesodium(E466)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

TransparentPVC-PE-PVdC/Alublisters:10,20,28,30,50,56,84,98,100,200tablets.

Hospitalpacksof50x1unitdosetablets.

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HelsinnBirexTherapeuticsLimited

Damastown

Mulhuddart

Dublin15

8MARKETINGAUTHORISATIONNUMBER

PA0915/032/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24 th

March2005

Dateoflastrenewal:30 th

November2008

10DATEOFREVISIONOFTHETEXT

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