BELLPRAV

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0967/007/001
  • Authorization date:
  • 14-09-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BellPrav10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgpravastatinsodium.

Alsoincludeslactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Darkyellowtoyellowcolouredmottled,circular,biconvextabletsdebossedwith“P1”ononesideandplainonthe

otherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypercholesterolemia

Treatmentofprimaryhypercholesterolemiaormixeddyslipidaemia,asanadjuncttodiet,whenresponsetodietand

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

Primaryprevention

Reductionofcardiovascularmortalityandmorbidityinpatientswithmoderateorseverehypercholesterolemiaandat

highriskofafirstcardiovascularevent,asanadjuncttodiet(seesection5.1).

Secondaryprevention

Reductionofcardiovascularmortalityandmorbidityinpatientswithahistoryofmyocardialinfarctionorunstable

anginapectorisandwitheithernormalorincreasedcholesterollevels,asanadjuncttocorrectionofotherriskfactors

(seesection5.1).

Posttransplantation

Reductionofposttransplantationhyperlipidaemiainpatientsreceivingimmunosupressivetherapyfollowingsolid

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

4.2Posologyandmethodofadministration

PriortoinitiatingPravastatinTablets1,secondarycausesofhypercholesterolaemiashouldbeexcludedandpatients

shouldbeplacedonastandardlipid-loweringdietwhichshouldbecontinuedduringtreatment.

PravastatinTablets1isadministeredorallyoncedailypreferablyintheeveningwithorwithoutfood.

Hypercholesterolemia

Therecommendeddoserangeis10-40mgoncedaily.Thetherapeuticresponseisseenwithinaweekandthefull

effectofagivendoseoccurswithinfourweeks,thereforeperiodiclipiddeterminationsshouldbeperformedandthe

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Cardiovascularprevention

Inallpreventivemorbidityandmortalitytrials,theonlystudiedstartingandmaintenancedosewas40mgdaily.

Dosageaftertransplantation

Followingorgantransplantationastartingdoseof20mgperdayisrecommendedinpatientsreceiving

immunosuppressivetherapy(seesection4.5).Dependingontheresponseofthelipidparameters,thedosemaybe

adjustedupto40mgunderclosemedicalsupervision(seesection4.5).

Childrenandadolescents(8-18yearsofage)withheterozygousfamilialhypercholesterolaemia: The

recommendeddoserangeis10-20mgoncedailybetween8and13yearsofage,asdosesgreaterthan20mghavenot

beenstudiedinthispopulation,and10-40mgdailybetween14and18yearsofage(forchildrenandadolescentfemales

ofchildbearingpotential,seesection4.6;forresultsofthestudyseesection5.1)

Pravastatinisnotrecommendedforuseinchildrenbelow8yearsduetoinsufficientdataonsafetyandefficacy.

Elderlypatients

Thereisnodoseadjustmentnecessaryinthesepatientsunlesstherearepredisposingriskfactors(seesection4.4).

Renalorhepaticimpairment

Astartingdoseof10mgperdayisrecommendedinpatientswithmoderateorsevererenalimpairmentorsignificant

hepaticimpairment.Thedosageshouldbeadjustedaccordingtotheresponseoflipidparametersandundermedical

supervision.

Concomitanttherapy

ThelipidloweringeffectsofpravastatinontotalcholesterolandLDL-cholesterolareenhancedwhencombinedwitha

bileacid-bindingresin(e.g.cholestyramine,colestipol).PravastatinTablets1shouldbegiveneitheronehourbeforeor

atleastfourhoursaftertheresin(seesection4.5).

Forpatientstakingcyclosporinwithorwithoutotherimmunosuppressivemedicinalproducts,treatmentshouldbegin

with20mgoncedailyandtitrationto40mgshouldbeperformedwithcaution(seesection4.5).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Activeliverdiseaseincludingunexplainedpersistentelevationsofserumtransaminaseelevationexceeding3x

theupperlimitofnormal(ULN)(seesection4.4).

Pregnancyandlactation(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Pravastatinhasnotbeenevaluatedinpatientswithhomozygousfamilialhypercholesterolaemia.Therapyisnotsuitable

whenhypercholesterolaemiaisduetoelevatedHDL-Cholesterol.

AsforothersHMG-CoAreductaseinhibitors,combinationofpravastatinwith

fibratesisnotrecommended.

Inchildrenbeforepuberty,thebenefit/riskofthetreatmentshouldbecarefullyevaluatedbyphysiciansbefore

treatmentinitiation.

Hepaticdisorders

Aswithotherlipid-loweringagents,moderateincreasesinlivertransaminaselevelshavebeenobserved.Inthe

majorityofcases,livertransaminaselevelshavereturnedtotheirbaselinevaluewithouttheneedfortreatment

discontinuation.Specialattentionshouldbegiventopatientswhodevelopincreasedtransaminaselevelsandtherapy

shouldbediscontinuedifincreasesinalanineaminotransferase(ALT)andaspartateaminotransferase(AST)exceed

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Cautionshouldbeexercisedwhenpravastatinisadministeredtopatientswithahistoryofliverdiseaseorheavy

alcoholingestion.

Muscledisorders

AswithothersHMG-CoAReductaseinhibitors(statins),pravastatinhasbeenassociatedwiththeonsetofmyalgia,

myopathyandveryrarely,rhabdomyolysis.Myopathymustbeconsideredinanypatientunderstatintherapy

presentingwithunexplainedmusclesymptomssuchaspainortenderness,muscleweakness,ormusclecramps.Insuch

casescreatinekinase(CK)levelsshouldbemeasured(seebelow).Statintherapyshouldbetemporarilyinterrupted

whenCKlevelsare>5xULNorwhentherearesevereclinicalsymptoms.Veryrarely(inabout1caseover

100000patient-years),rhabdomyolysisoccurs,withorwithoutsecondaryrenalinsufficiency.Rhabdomyolysisisan

acutepotentiallyfatalconditionofskeletalmusclewhichmaydevelopatanytimeduringtreatmentandischaracterised

bymassivemuscledestructionassociatedwithmajorincreaseinCK(usually>30or40xULN)leadingto

myoglobinuria.

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),CKlevelsshouldberemeasuredabout5to7dayslater

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

hereditarymusculardiseaseissuspectedinsuchpatient,restartingstatintherapyisnotrecommended.

Interstitiallungdisease

Exceptionalcasesofinterstitiallungdiseasehavebeenreportedwithsomestatins,especiallywithlongtermtherapy

(seesection4.8).

Presentingfeaturescanincludedyspnoea,non-productivecoughanddeteriorationingeneralhealth(fatigue,weight

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Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Fibrates

Theuseoffibratesaloneisoccasionallyassociatedwithmyopathy.Anincreasedriskofmusclerelatedadverseevents,

includingrhabdomyolysis,havebeenreportedwhenfibratesareco-administeredwithotherstatins.Theseadverse

eventswithpravastatincannotbeexcluded;thereforethecombineduseofpravastatinandfibrates(e.g.gemfibrozil,

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

andCKmonitoringofpatientsonsuchregimenisrequired.

Cholestyramine/Colestipol

Concomitantadministrationresultedinapproximately40to50%decreaseinthebioavailabilityofpravastatin.There

wasnoclinicallysignificantdecreaseinbioavailabilityortherapeuticeffectwhenpravastatinwasadministeredone

hourbeforeorfourhoursaftercholestyramineoronehourbeforecolestipol(seesection4.2).

Cyclosporin

Concomitantadministrationofpravastatinandcyclosporinleadstoanapproximately4-foldincreaseinpravastatin

systemicexposure.Insomepatients,however,theincreaseinpravastatinexposuremaybelarger.Clinicaland

biochemicalmonitoringofpatientsreceivingthiscombinationisrecommended(seesection4.2).

Warfarinandotheroralanticoagulants

Bioavailabilityparametersatsteadystateforpravastatinwerenotalteredfollowingadministrationwithwarfarin.

Chronicdosingofthetwoproductsdidnotproduceanychangesintheanticoagulantactionofwarfarin.

ProductsmetabolisedbycytochromeP450

PravastatinisnotmetabolisedtoaclinicallysignificantextentbythecytochromeP450system.Thisiswhyproducts

thataremetabolisedby,orinhibitorsof,thecytochromeP450systemcanbeaddedtoastableregimenofpravastatin

withoutcausingsignificantchangesintheplasmalevelsofpravastatin,ashavebeenseenwithotherstatins.The

absenceofasignificantpharmacokineticinteractionwithpravastatinhasbeenspecificallydemonstratedforseveral

products,particularlythosethataresubstrates/inhibitorsofCYP3A4e.g.diltiazem,verapamil,itraconazole,

ketoconazole,proteaseinhibitors,grapefruitjuiceandCYP2C9inhibitors(e.g.fluconazole).

Inoneoftwointeractionsstudieswithpravastatinanderythromycinastatisticallysignificantincreaseinpravastatin

AUC(70%)andCmax(121%)wasobserved.Inasimilarstudywithclarithromycinastatisticallysignificantincrease

inAUC(110%)andCmax(127%)wasobserved.Althoughthesechangeswereminor,cautionshouldbeexercised

whenassociatingpravastatinwitherythromycinorclarithromycin.

Otherproducts

Ininteractionstudies,nostatisticallysignificantdifferencesinbioavailabilitywereobservedwhenpravastatinwas

administeredwithacetylsalicylicacid,antacids(whengivenonehourpriortopravastatin),nicotinicacidorprobucol.

4.6Fertility,pregnancyandlactation

Pregnancy

Pravastatiniscontraindicatedduringpregnancyandshouldbeadministeredtowomenofchildbearingpotentialonly

whenthesepatientsareunlikelytoconceiveandhavebeeninformedofthepotentialrisk.Specialcautionis

recommendedinadolescentfemalesofchildbearingpotentialtoensureproperunderstandingofthepotentialrisk

associatedwithpravastatintherapyduringpregnancy.Ifapatientplanstobecomepregnantorbecomespregnant,the

doctorhastobeinformedimmediatelyandpravastatinshouldbediscontinuedbecauseofthepotentialrisktothe

foetus.

Lactation

Asmallamountofpravastatinisexcretedinhumanbreastmilk,thereforepravastatiniscontraindicatedduring

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4.7Effectsonabilitytodriveandusemachines

Pravastatinhasnoornegligibleinfluenceontheabilitytodriveandusemachines.However,whendrivingvehiclesor

operatingmachines,itshouldbetakingintoaccountthatdizzinessandvisualdisturbancesmayoccurduringtreatment.

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),includingisolated

reports.

Clinicaltrials

Pravastatinhasbeenstudiedat40mginsevenrandomizeddouble-blindplacebo-controlledtrialsinvolvingover

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

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

Thefollowingadversedrugreactionswerereported;noneofthemoccurredatarateinexcessof0.3%inpravastatin

groupcomparedtotheplacebogroup.

Nervoussystemdisorders:

Uncommon:dizziness,headache,sleepdisturbance,insomnia.

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:

Uncommon:sexualdysfunction.

Generaldisorders:

Uncommon:fatigue.

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,WOSCOPandLIPIDwassimilartoplacebo(1.6%pravastatinvs1.6%placeboand1.0%

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

Livereffects:elevationsofserumtransaminaseshavebeenreported.Inthethreelong-term,placebo-controlledclinical

trialsCARE,WOSCOPandLIPID,markedabnormalitiesofALTandAST(>3xULN)occurredatsimilarfrequency

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Postmarketing

Inadditiontotheabovethefollowingadverseeventshavebeenreportedduringpostmarketingexperienceof

pravastatin:

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,sometimecomplicatedbyrupture.

Thefollowingadverseeventshavebeenreportedwithsomestatins:

Memoryloss

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,pravastatininhibitsLDLproductionbyinhibitingthehepaticsynthesisofVLDLcholesterol,theLDL-

cholesterolprecursor.

Inbothhealthysubjectsandpatientswithhypercholesterolaemia,pravastatinsodiumlowersthefollowinglipidvalues:

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

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Clinicalefficacy:

Childrenandadolescents(8-18yearsofage):

Adoubleblindplacebocontrolledstudyin214paediatricpatientswithheterozygousfamilialhypercholesterolaemia

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

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

Inclusioninthestudyrequiredoneparentwitheitheraclinicalormoleculardiagnosisoffamilial

hypercholesterolaemia.ThemeanbaselineLDL-Cvaluewas239mg/dland237mg/dlinthepravastatin(range151-

405mg/dl)andplacebo(range154-375mg/dl)groups,respectively.Therewasasignificantmeanpercentreductionin

LDL-Cof–22.9%andalsointotalcholesterol(-17.2%)fromthepooleddataanalysisinbothchildrenandadolescents,

similartodemonstratedefficacyinadultson20mgofpravastatin.

Theeffectsofpravastatintreatmentinthetwoagegroupswassimilar.ThemeanachievedLDL-Cwas186mg/dl

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

Insubjectsreceivingpravastatin,therewerenodifferencesseeninanyofthemonitoredendocrineparameters[ACTH,

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

developmentdifferences,testicularvolumechangesorTannerscoredifferencesobservedrelativetoplacebo.The

powerofthisstudytodetectadifferencebetweenthetwogroupsoftreatmentwaslow.

Thelongtermefficacyofpravastatintherapyinchildhoodtoreducemorbidityandmortalityinadulthoodhasnotbeen

established

Primaryprevention

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

trialamong6,595malepatientsagedfrom45to64yearswithmoderatetoseverehypercholesterolaemia(LDL-C:155

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

witheithera40mgdailydoseofpravastatinorplaceboasanadjuncttodiet.Inpravastatin-treatedpatients,results

showed:

adecreaseintheriskofmortalityfromcoronarydiseaseandofnon-lethalmyocardialinfarction(relativerisk

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

pravastatintreatedpatients);theeffectsonthesecumulativecardiovasculareventsratesbeingevidentasearly

as6monthsoftreatment;

adecreaseinthetotalnumberofdeathsfromacardiovascularevent(RRR32%;p=0.03);

whenriskfactorsweretakenintoaccount,aRRRof24%(p=0.039)intotalmortalitywasalsoobserved

amongpatientstreatedwithpravastatin;

adecreaseintherelativeriskforundergoingmyocardialrevascularisationprocedures(coronaryarterybypass

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

Thebenefitofthetreatmentonthecriteriaindicatedaboveisnotknowninpatientsovertheageof65years,whocould

notbeincludedinthestudy.

Intheabsenceofdatainpatientswithhypercholesterolaemiaassociatedwithatriglyceridelevelofmorethan

6mmol/L(5.3g/L)afteradietfor8weeks,inthisstudy,thebenefitofpravastatintreatmenthasnotbeenestablished

inthistypeofpatients.

Secondaryprevention

The"Long-TermInterventionwithPravastatininIschemicDisease(LIPID)"wasamulti-center,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.TreatmentwithpravastatinsignificantlyreducedtherelativeriskofCHD

deathby24%(p=0.0004,withanabsoluteriskof6.4%intheplacebogroup,and5.3%inpravastatintreatedpatients),

therelativeriskofcoronaryevents(eitherCHDdeathornonfatalMI)by24%(p<0.0001)andtherelativeriskoffatal

ornonfatalmyocardialinfarctionby29%(p<0.0001).Inpravastatin-treatedpatients,resultsshowed:

areductionintherelativeriskoftotalmortalityby23%(p<0.0001)andcardiovascularmortalityby25%

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areductionintherelativeriskofundergoingmyocardialrevascularisationprocedures(coronaryarterybypass

graftingorpercutaneoustransluminalcoronaryangioplasty)by20%(p<0.0001);

areductionintherelativeriskofstrokeby19%(p=0.048).

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

comparing,theeffectsofpravastatin(40mgOD)oncoronaryheartdiseasedeathandnonfatalmyocardialinfarction

foranaverageof4.9yearsin4,159patientsaged21to75years,withnormaltotalcholesterollevels(baselinemean

totalcholesterol<240mg/dl),whohadexperiencedamyocardialinfarctioninthepreceding3to20months.

Treatmentwithpravastatinsignificantlyreduced:

therateofarecurrentcoronaryevent(eithercoronaryheartdiseasedeathornonfatalMI)by24%(p=0.003,

placebo13.3%,pravastatin10.4%);

therelativeriskofundergoingrevascularisationprocedures(coronaryarterybypassgraftingorpercutaneous

transluminalcoronaryangioplasty)by27%(p<0.001).

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

combinedby27%(p=0.02).

Thebenefitofthetreatmentontheabovecriteriaisnotknowninpatientsovertheageof75years,whocouldnotbe

includedintheCAREandLIPIDstudies.

Intheabsenceofdatainpatientswithhypercholesterolaemiaassociatedwithatriglyceridelevelofmorethan

4mmol/L(3.5g/Lormorethan5mmol/L(4.45g/L)afterfollowingadietfor4or8weeks,intheCAREandLIPID

studies,respectively,thebenefitoftreatmentwithpravastatinhasnotbeenestablishedinthistypeofpatients.

IntheCAREandLIPIDstudies,about80%ofpatientshadreceivedASAaspartoftheirregimen.

Heartandkidneytransplantation

Theefficacyofpravastatininpatientsreceivinganimmunosuppressanttreatmentfollowing:

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

concurrentlywitheitherpravastatin(20-40mg)ornot,andastandardimmunosuppressiveregimenof

cyclosporin,prednisoneandaziathioprine.Treatmentwithpravastatinsignificantlyreducedtherateofcardiac

rejectionwithhaemodynamiccompromiseatoneyear,improvedone-yearsurvival(p=0.025),andloweredthe

riskofcoronaryvasculopathyinthetransplantasdeterminedbyangiographyandautopsy(p=0.049).

Renaltransplantwasassessedinoneprospectivenotcontrolled,notrandomisedstudy(n=48)of4months

duration.Patientsweretreatedconcurrentlywitheitherpravastatin(20mg)ornot,andastandard

immunosuppressiveregimenofcyclosporin,andprednisone.Inpatientsfollowingkidneytransplantation,

pravastatinsignificantlyreducedboththeincidenceofmultiplerejectionepisodesandtheincidenceofbiopsy-

provedacuterejectionepisodes,andtheuseofpulseinjectionsofbothprednisoloneandMuromonab-CD3.

5.2Pharmacokineticproperties

Absorption:

Pravastatinisadministeredorallyintheactiveform.Itisrapidlyabsorbed;peakserumlevelsareachieved1to

1.5hoursafteringestion.Onaverage,34%oftheorallyadministereddoseisabsorbed,withanabsolutebioavailability

of17%.

Thepresenceoffoodinthegastrointestinaltractleadstoareductioninthebioavailability,butthecholesterol-lowering

effectofpravastatinisidenticalwhethertakenwithorwithoutfood.

Afterabsorption,66%ofpravastatinundergoesafirst-passextractionthroughtheliver,whichistheprimarysiteofits

actionandtheprimarysiteofcholesterolsynthesisandclearanceofLDL-cholesterol.Invitrostudiesdemonstratedthat

pravastatinistransportedintohepatocytesandwithsubstantiallylessintakeinothercells.

Inviewofthissubstantialfirstpassthroughtheliver,plasmaconcentrationsofpravastatinhaveonlyalimitedvaluein

predictingthelipid-loweringeffect.

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Distribution:

About50%ofcirculatingpravastatinisboundtoplasmaproteins.

Thevolumeofdistributionisabout0.5l/kg.

Asmallquantityofpravastatinpassesintothehumanbreastmilk.

Metabolismandelimination:

PravastatinisnotsignificantlymetabolisedbycytochromeP450nordoesitappeartobeasubstrateoraninhibitorof

P-glycoproteinbutratherasubstrateofothertransportproteins.

Followingoraladministration,20%oftheinitialdoseiseliminatedintheurineand70%inthefaeces.Plasma

eliminationhalf-lifeoforalpravastatinis1.5to2hours.

Afterintravenousadministration,47%ofthedoseiseliminatedbytherenalexcretionand53%bybiliaryexcretionand

biotransformation.Themajordegradationproductofpravastatinisthe3--hydroxyisomericmetabolite.This

metabolitehasone-tenthtoone-fortieththeHMG-CoAreductaseinhibitoractivityoftheparentcompound.

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

Populationsatrisk:

Paediatricsubject:meanpravastatinCmaxandAUCvaluesforpaediatricsubjectspooledacrossageandgenderwere

similartothosevaluesobservedinadultsaftera20mgoraldose

Hepaticfailure:systemicexposuretopravastatinandmetabolitesinpatientswithalcoholiccirrhosisisenhancedby

about50%comparativelytopatientwithnormalliverfunction.

Renalimpairment:nosignificantmodificationswereobservedinpatientswithmildrenalimpairment.Howeversevere

andmoderaterenalinsufficiencymayleadtoatwofoldincreaseofthesystemicexposuretopravastatinand

metabolites.

5.3Preclinicalsafetydata

Basedonconventionalstudiesofsafetypharmacology,repeateddosetoxicityandtoxicityonreproduction,thereareno

otherrisksforthepatientthanthoseexpectedduetothepharmacologicalmechanismofaction.

Repeateddosestudiesindicatethatpravastatinmayinducevaryingdegreesofhepatotoxicityandmyopathy;ingeneral,

substantiveeffectsonthesetissueswereonlyevidentatdoses50ormoretimesthemaximumhumanmg/kgdose.

Invitroandinvivogenetictoxicologystudieshaveshownnoevidenceofmutagenicpotential.

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

themaximumhumanmg/kgdose),astatisticallysignificantincreasesintheincidenceofhepatocellularcarcinomasin

malesandfemales,andlungadenomasinfemalesonly.Inratsa2-yearcarcinogenicitystudydemonstratesatadoseof

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

hepatocellularcarcinomasinmalesonly.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose,anhydrous

Sodiumstearylfumarate

Ferricoxideyellow(E172).

6.2Incompatibilities

Notapplicable.

6.3Shelflife

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6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Blisterpackscomprisingofcoldformblisterlaminate(structurefromoutertoinnerside:orientedpolyamide/

aluminiumfoil/hardpolyvinylchloridefilm)withabackingofaluminiumfoilcoatedwithheatseallacquer.The

blisterstripsareenclosedinacardboardcarton.

Cartonswith10,14,20,28,30,50,60,98or100tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Ranbaxy(UK)Limited

20BaldertonStreet

LondonW1K6TL

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA967/7/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation14thSeptember2007.

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 05/08/2011 CRN 2089811 page number: 10