Lopid 300 mg Hard Capsules - (emc) - eMC

Each hard capsule contains 300 mg of gemfibrozil. ... Lopid is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight ... Skiptomaincontent Lopid300mgHardCapsules Backtotop PfizerLimitedcontactdetails Activeingredient gemfibrozil LegalCategory POM:Prescriptiononlymedicine ATCcode C10AB04 Findsimilarproducts ReportSideEffect RelatedMedicines Sameactiveingredients Samecompany Bookmark Email Lastupdatedonemc:22Apr2021 Viewchanges Print Showtableofcontents Hidetableofcontents 1.Nameofthemedicinalproduct2.Qualitativeandquantitativecomposition3.Pharmaceuticalform4.Clinicalparticulars4.1Therapeuticindications4.2Posologyandmethodofadministration4.3Contraindications4.4Specialwarningsandprecautionsforuse4.5Interactionwithothermedicinalproductsandotherformsofinteraction4.6Fertility,pregnancyandlactation4.7Effectsonabilitytodriveandusemachines4.8Undesirableeffects4.9Overdose5.Pharmacologicalproperties5.1Pharmacodynamicproperties5.2Pharmacokineticproperties5.3Preclinicalsafetydata6.Pharmaceuticalparticulars6.1Listofexcipients6.2Incompatibilities6.3Shelflife6.4Specialprecautionsforstorage6.5Natureandcontentsofcontainer6.6Specialprecautionsfordisposalandotherhandling7.Marketingauthorisationholder8.Marketingauthorisationnumber(s)9.Dateoffirstauthorisation/renewaloftheauthorisation10.Dateofrevisionofthetext Thisinformationisintendedforusebyhealthprofessionals 1.Nameofthemedicinalproduct Lopid300mgcapsules,hard 2.Qualitativeandquantitativecomposition Eachhardcapsulecontains300mgofgemfibrozil. Forthefulllistofexcipients,seesection6.1 3.Pharmaceuticalform Capsule,hard Description Lopid300mg:finewhitepowdercontainedinhardgelatinecapsulewithawhiteopaquebodyandamaroonopaquecapimprinted'Lopid300'oneachcapsulehalf 4.Clinicalparticulars 4.1Therapeuticindications Lopidisindicatedasanadjuncttodietandothernon-pharmacologicaltreatment(e.g.exercise,weightreduction)forthefollowing: -TreatmentofseverehypertriglyceridaemiawithorwithoutlowHDLcholesterol. -Mixedhyperlipidaemiawhenastatiniscontraindicatedornottolerated. -Primaryhypercholesterolaemiawhenastatiniscontraindicatedornottolerated. Primaryprevention Reductionofcardiovascularmorbidityinmaleswithincreasednon-HDLcholesterolandathighriskforafirstcardiovasculareventwhenastatiniscontraindicatedornottolerated(seesection5.1). 4.2Posologyandmethodofadministration Priortoinitiatinggemfibrozil,othermedicalproblemssuchashypothyroidismanddiabetesmellitusmustbecontrolledasbestaspossibleandpatientsshouldbeplacedonastandardlipid-loweringdiet,whichshouldbecontinuedduringtreatment.Lopidshouldbetakenorally. Posology Adult Thedoserangeis900mgto1200mgdaily. Theonlydosewithdocumentedeffectonmorbidityis1200mgdaily. SeeMethodofadministration. Elderly(over65yearsold) Asforadults Childrenandadolescents Gemfibroziltherapyhasnotbeeninvestigatedinchildren.DuetothelackofdatatheuseofLopidinchildrenisnotrecommended. Renalimpairment Inpatientswithmildtomoderaterenalimpairment(Glomerularfiltrationrate50-80and30-<50ml/min/1.73m2,respectively),starttreatmentat900mgdailyandassessrenalfunctionbeforeincreasingdose.Lopidshouldnotbeusedinpatientswithseverelyimpairedrenalfunction(seesection4.3). Hepaticimpairment Gemfibroziliscontraindicatedinhepaticimpairment(seesection4.3). Methodofadministration The1200mgdoseistakenas600mgtwicedaily,halfanhourbeforebreakfastandhalfanhourbeforetheeveningmeal. The900mgdoseistakenasasingledosehalfanhourbeforetheeveningmeal. 4.3Contraindications •Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1. •Hepaticimpairment •Severerenalimpairment •Historyof/orpre-existinggallbladderorbiliarytractdisease,includinggallstones •Concomitantuseofrepaglinide,dasabuvir,selexipag(seesection4.5),simvastatin,orrosuvastatinat40mg(seesections4.4and4.5) •Patientswithprevioushistoryofphotoallergyorphototoxicreactionduringtreatmentwithfibrates 4.4Specialwarningsandprecautionsforuse Muscledisorders(myopathy/rhabdomyolysis) Therehavebeenreportsofmyositis,myopathyandmarkedlyelevatedcreatinephosphokinaseassociatedwithgemfibrozil.Rhabdomyolysishasalsobeenreportedrarely. Muscledamagemustbeconsideredinanypatientpresentingwithdiffusemyalgia,muscletendernessand/ormarkedincreaseinmuscleCPKlevels(>5xULN);undertheseconditionstreatmentmustbediscontinued. ConcomitantHMGCoAreductaseinhibitors Theconcomitantadministrationofgemfibrozilwithsimvastatin,aswellaswithrosuvastatinat40mgiscontraindicated.Concomitanttherapyofgemfibrozilwithlowerdosesofrosuvastatinshouldbeusedonlywhenthebenefitoutweighstherisks.Therehavebeenreportsofseveremyositiswithmarkedlyelevatedcreatinekinaseandmyoglobinuria(rhabdomyolysis)whengemfibrozilandHMGCoAreductaseinhibitorswereusedconcomitantly(seesections4.3and4.5).Pharmacokineticinteractionsmayalsobepresent(seealsosection4.5)anddosageadjustmentsmaybenecessary. ThebenefitoffurtheralterationsinlipidlevelsbythecombineduseofgemfibrozilandHMG-CoAreductaseinhibitorsshouldbecarefullyweighedagainstthepotentialrisksofsuchcombinationsandclinicalmonitoringisrecommended. Acreatinephosphokinase(CPK)levelshouldbemeasuredbeforestartingsuchacombinationinpatientswithpre-disposingfactorsforrhabdomyolysisasfollows: •renalimpairment •hypothyroidism •alcoholabuse •age>70years •personalorfamilyhistoryofhereditarymusculardisorders •previoushistoryofmusculartoxicitywithanotherfibrateorHMG-CoAreductaseinhibitor Inmostsubjectswhohavehadanunsatisfactorylipidresponsetoeitherdrugalone,thepossiblebenefitsofcombinedtherapywithHMG-CoAreductaseinhibitorsandgemfibrozildoesnotoutweightherisksofseveremyopathy,rhabdomyolysisandacuterenalfailure. Useinpatientswithgallstoneformation Gemfibrozilmayincreasecholesterolexcretionintothebileraisingthepotentialforgallstoneformation.Casesofcholelithiasishavebeenreportedwithgemfibroziltherapy.Ifcholelithiasisissuspected,gallbladderstudiesareindicated.Gemfibroziltherapyshouldbediscontinuedifgallstonesarefound. Monitoringserumlipids Periodicdeterminationsofserumlipidsarenecessaryduringtreatmentwithgemfibrozil.Sometimesaparadoxicalincreaseof(totalandLDL)cholesterolcanoccurinpatientswithhypertriglyceridaemia.Iftheresponseisinsufficientafter3monthsoftherapyatrecommendeddosestreatmentshouldbediscontinuedandalternativetreatmentmethodsconsidered. Monitoringliverfunction ElevatedlevelsofALAT,ASAT,alkalinephosphatase,LDH,CKandbilirubinhavebeenreported.Theseareusuallyreversiblewhengemfibrozilisdiscontinued.Thereforeliverfunctiontestsshouldbeperformedperiodically.Gemfibroziltherapyshouldbeterminatedifabnormalitiespersist. Monitoringbloodcounts Periodicbloodcountdeterminationsarerecommendedduringthefirst12monthsofgemfibroziladministration.Anaemia,leucopenia,thrombocytopenia,eosinophiliaandbonemarrowhypoplasiahavebeenreportedrarely(seesection4.8). Interactionswithothermedicinalproducts(seealsosections4.3and4.5) ConcomitantusewithCYP2C8,CYP2C9,CYP2C19,CYP1A2,UGTA1,UGTA3andOATP1B1substrates Theinteractionprofileofgemfibroziliscomplexresultinginincreasedexposureofmanymedicinalproductsifadministeredconcomitantlywithgemfibrozil. GemfibrozilpotentlyinhibitsCYP2C8,CYP2C9,CYP2C19,CYP1A2,andUDPglucuronyltransferase(UGTA1andUGTA3)enzymesandalsoinhibitsorganicanion-transportingpolypeptide1B1(OATP1B1)(seesection4.5).Inaddition,gemfibrozilismetabolisedtogemfibrozil1-O-β-glucuronidewhichalsoinhibitsCYP2C8andOATP1B1. Concomitantusewithhypoglycaemicagents Therehavebeenreportsofhypoglycaemicreactionsafterconcomitantusewithgemfibrozilandhypoglycaemicagents(oralagentsandinsulin).Monitoringofglucoselevelsisrecommended. Concomitantanticoagulants GemfibrozilmaypotentiatetheeffectsofcoumarintypevitaminKantagonistanticoagulantssuchaswarfarin,acenocoumarol,orphenprocoumon.Theconcomitantadministrationofgemfibrozilwiththeseanticoagulantsnecessitatescarefulmonitoringofprothrombintime(INR-InternationalNormalisedRatio).CautionshouldbeexercisedwhensuchacoumarintypevitaminKantagonistanticoagulantisgivenconcomitantlywithgemfibrozil.Thedosageoftheanticoagulantmayneedtobereducedtomaintaindesiredprothrombintimelevels(seesection4.5). Dietarysodium Thismedicinalproductcontainslessthan1mmolsodium(23mg)pertablet.Patientsonlowsodiumdietsshouldbeinformedthatthismedicinalproductisessentially'sodium-free'. 4.5Interactionwithothermedicinalproductsandotherformsofinteraction Theinteractionprofileofgemfibroziliscomplex.Invivostudiesindicatethatgemfibrozilanditsmetabolitegemfibrozil1-O-β-glucuronidearepotentinhibitorsofCYP2C8(anenzymeimportantforthemetabolismofe.g.dabrafenib,enzalutamide,loperamide,montelukast,repaglinide,rosiglitazone,pioglitazone,dasabuvir,selexipagandpaclitaxel).Co-administrationofgemfibrozilwithrepaglinide,dasabuvirorselexipagiscontraindicated(seesection4.3).Inaddition,dosingreductionofdrugsthataremainlymetabolisedbyCYP2C8enzymemayberequiredwhengemfibrozilisusedconcomitantly.InvitrostudieshaveshownthatgemfibrozilisastronginhibitorofCYP2C9(anenzymeinvolvedinthemetabolismofe.g.warfarinandglimepiride),butalsoofCYP2C19,CYP1A2,OATP1B1andUGTA1andUGTA3(seesection4.4).Gemfibrozil1-O-β-glucuronidealsoinhibitsOATP1B1. Repaglinide Inhealthyvolunteers,co-administrationwithgemfibrozilincreasedtheAUCandCmaxofrepaglinideby8.1-foldand2.4-fold,respectively.Inthesamestudy,co-administrationwithgemfibrozilanditraconazoleincreasedtheAUCandCmaxofrepaglinideby19.4-foldand2.8-fold,respectively.Inaddition,co-administrationwithgemfibrozilorwithgemfibrozilanditraconazoleprolongeditshypoglycaemiceffects.Therefore,co-administrationofgemfibrozilandrepaglinideincreasestheriskforseverehypoglycaemiaandiscontraindicated(seesection4.3). Dasabuvir Co-administrationofgemfibrozilwithdasabuvirincreaseddasabuvirAUCandCmax(ratios:11.3and2.01,respectively)duetoCYP2C8inhibition.IncreaseddasabuvirexposuremayincreasetheriskofQTprolongation,therefore,co-administrationofgemfibrozilwithdasabuviriscontraindicated(seesection4.3). Selexipag Co-administrationofgemfibrozilwithselexipag,asubstrateforCYP2C8,doubledexposure(AUC)toselexipagandincreasedexposure(AUC)totheactivemetabolite,ACT-333679,byapproximately11-fold.Concomitantadministrationofgemfibrozilwithselexipagiscontraindicated(seesection4.3). Enzalutamide Inhealthyvolunteersgivenasingle160mgdoseofenzalutamideaftergemfibrozil600mgtwicedaily,theAUCofenzalutamideplusactivemetabolite(N-desmethylenzalutamide)wasincreasedby2.2-foldandcorrespondingCmaxwasdecreasedby16%.Increasedenzalutamideexposuremayincreasetheriskofseizures.Concomitanttreatmentofgemfibrozilandenzalutamideshouldbeavoided;ifco-administrationisconsiderednecessary,thedoseofenzalutamideshouldbereduced(seesection4.4). Rosiglitazone Thecombinationofgemfibrozilwithrosiglitazoneshouldbeapproachedwithcaution.Co-administrationwithrosiglitazonehasresultedin2.3-foldincreaseinrosiglitazonesystemicexposure,probablybyinhibitionoftheCYP2C8isozyme(seesection4.4). HMGCoAreductaseinhibitors Theconcomitantadministrationofgemfibrozilwithsimvastatin,aswellaswithrosuvastatinat40mgiscontraindicated(seesections4.3and4.4).Thecombineduseofgemfibrozilandastatinshouldgenerallybeavoided(seesection4.4).Theuseoffibratesaloneisoccasionallyassociatedwithmyopathy.Anincreasedriskofmusclerelatedadverseevents,includingrhabdomyolysis,hasbeenreportedwhenfibratesareco-administeredwithstatins. Gemfibrozilhasalsobeenreportedtoinfluencethepharmacokineticsofsimvastatin,lovastatin,pravastatin,rosuvastatinandatorvastatin.Gemfibrozilcausedanalmost3-foldincreasedinAUCofsimvastatinacidpossiblyduetoinhibitionofglucoronidationviaUGTA1andUGTA3,anda3-foldincreaseinpravastatinAUCwhichmaybeduetointerferencewithtransportproteins.Onestudyindicatedthattheco-administrationofasinglerosuvastatindoseof80mgtohealthyvolunteersongemfibrozil(600mgtwicedaily)resultedina2.2-foldincreaseinmeanCmaxanda1.9-foldincreaseinmeanAUCofrosuvastatin.Theco-administrationofasinglelovastatindoseof40mgwithgemfibrozil(600mgtwicedailyfor3days)inhealthyvolunteersresultedina2.8-foldincreaseofthemeanAUCandCmaxoflovastatinacid.Theco-administrationofasingleatorvastatindoseof40mgwithgemfibrozil(600mgtwicedailyfor7days)inhealthyvolunteersresultedina1.35-foldincreaseinmeanAUCandnoincreaseinmeanCmaxofatorvastatin. Anticoagulants GemfibrozilmaypotentiatetheeffectsofcoumarintypevitaminKantagonistanticoagulantssuchaswarfarin,acenocoumarol,orphenprocoumon.Theconcomitantadministrationofgemfibrozilwiththeseanticoagulantsnecessitatescarefulmonitoringofprothrombintime(INR)(seesection4.4). Bexarotene Concomitantadministrationofgemfibrozilwithbexaroteneisnotrecommended.ApopulationanalysisofplasmabexaroteneconcentrationsinpatientswithcutaneousT-celllymphoma(CTCL)indicatedthatconcomitantadministrationofgemfibrozilresultedinsubstantialincreasesinplasmaconcentrationsofbexarotene. Bileacid–bindingresins Reducedbioavailabilityofgemfibrozilmayresultwhengivensimultaneouslywithresin-granuledrugssuchascolestipol.Administrationoftheproductstwohoursormoreapartisrecommended. Colchicine Riskofmyopathyandrhabdomyolysismaybeincreasedwithconcomitantadministrationofcolchicineandgemfibrozil.Thisriskmaybeincreasedintheelderlyandinpatientswithhepaticorrenaldysfunction.Clinicalandbiologicalmonitoringarerecommended,especiallyatthestartofcombinedtreatment. Gemfibrozilishighlyboundtoplasmaproteinsandthereispotentialfordisplacementinteractionswithotherdrugs. 4.6Fertility,pregnancyandlactation Pregnancy TherearenoadequatedataonuseofLopidinpregnantwomen.Animalstudiesareinsufficientlycleartoallowconclusionstobedrawnonpregnancyandfoetaldevelopment(seesection5.3).Thepotentialriskforhumansisunknown.Lopidshouldnotbeusedduringpregnancyunlessitisclearlynecessary. Breast-feeding Therearenodataonexcretionofgemfibrozilinmilk.Lopidshouldnotbeusedwhenbreast-feeding. Fertility Reversibledecreasesinmalefertilityhavebeenobservedinreproductivetoxicitystudiesinrats(seesection5.3). 4.7Effectsonabilitytodriveandusemachines Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Inisolatedcasesdizzinessandvisualdisturbancescanoccurwhichmaynegativelyinfluencedriving. 4.8Undesirableeffects Mostcommonlyreportedadversereactionsareofgastrointestinalcharacterandareseeninapproximately7%ofthepatients.Theseadversereactionsdonotusuallyleadtodiscontinuationofthetreatment. Adversereactionsarerankedaccordingtofrequencyusingthefollowingconvention:Verycommon(≥1/10),Common(≥1/100to<1/10),Uncommon(≥1/1,000to<1/100),Rare(≥1/10,000to<1/1,000),Veryrare(<1/10,000),includingisolatedreports: SystemOrganClass Undesirableeffect Bloodandlymphaticsystemdisorders Rare Bonemarrowfailure,severeanaemia,thrombocytopenia,leukopenia,eosinophilia Psychiatricdisorders Rare Depression,decreasedlibido Nervoussystemdisorders Common Vertigo,headache Rare Neuropathyperipheral,paraesthesia,dizziness,somnolence Eyedisorders Rare Visionblurred Cardiacdisorders Uncommon Atrialfibrillation Respiratory,thoracicandmediastinaldisorders Rare Laryngealoedema Gastrointestinaldisorders Verycommon Dyspepsia Common Diarrhoea,vomiting,nausea,abdominalpainconstipation,flatulence Rare Pancreatitis,appendicitis Hepatobiliarydisorders Rare Jaundicecholestatic,hepatitis,cholelithiasis,cholecystitis,hepaticfunctionabnormal Skinandsubcutaneoustissuedisorders Common Eczema,rash Rare Angioedema,dermatitisexfoliative,urticaria,dermatitis,alopecia,photosensitivityreaction,pruritus Musculoskeletalandconnectivetissuedisorders Rare Rhabdomyolysis,myopathy,myositis,muscularweakness,synovitis,myalgia,arthralgia,paininextremity Reproductivesystemandbreastdisorder Rare Erectiledysfunction Generaldisordersandadministrationsiteconditions Common Fatigue Investigations Rare Haemoglobindecreased,haematocritdecreased,whitebloodcellcountdecreased,bloodcreatinephosphokinaseincreased Reportingofsuspectedadversereactions Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinuedmonitoringofthebenefit/riskbalanceofthemedicinalproduct.HealthcareprofessionalsareaskedtoreportanysuspectedadversereactionsviatheYellowCardSchemeatwww.mhra.gov.uk/yellowcardorsearchforMHRAYellowCardintheGooglePlayorAppleAppstore. 4.9Overdose Overdosehasbeenreported.Symptomsreportedwithoverdosagewereabdominalcramps,abnormalLFT's,diarrhea,increasedCPK,jointandmusclepain,nauseaandvomiting.Thepatientsfullyrecovered.Symptomaticsupportivemeasuresshouldbetakenifoverdoseoccurs. 5.Pharmacologicalproperties 5.1Pharmacodynamicproperties Pharmacotherapeuticgroup:Serum-lipidloweringagent Chemicalsubgroup:Fibrates ATCcode:C10AB04 Gemfibrozilisanon-halogenatedphenoxypentanoicacid.Gemfibrozilisalipidregulatingagentwhichregulateslipidfractions. Gemfibrozil'smechanismofactionhasnotbeendefinitivelyestablished.Inman,gemfibrozilstimulatestheperipherallipolysisoftriglyceriderichlipoproteinssuchasVLDLandcholymicrons(bystimulationofLPL).GemfibrozilalsoinhibitssynthesisofVLDLintheliver.GemfibrozilincreasestheHDL2andHDL3subfractionsaswellasapolipoproteinA-IandA-II. Animalstudiessuggestthattheturnoverandremovalofcholesterolfromtheliverisincreasedbygemfibrozil. Thereisevidencethattreatmentwithfibratesmayreducecoronaryheartdiseaseeventsbuttheyhavenotbeenshowntodecreaseallcausemortalityintheprimaryorsecondarypreventionofcardiovasculardisease. IntheHelsinkiHeartStudy,whichwasalargeplacebo-controlledstudywith4081malesubjects,40to55yearsofage,withprimarydyslipidaemia(predominantlyraisednon-HDLcholesterol+/-hypertriglyceridaemia),butnoprevioushistoryofcoronaryheartdisease,gemfibrozil600mgtwicedaily,producedasignificantreductionintotalplasmatriglycerides,totalandlowdensitylipoproteincholesterolandasignificantincreaseinhighdensitylipoproteincholesterol.Thecumulativerateofcardiacend-points(cardiacdeathandnon-fatalmyocardialinfarction)duringa5yearfollow-upwas27.3/1,000inthegemfibrozilgroup(56subjects)and41.4/1000intheplacebogroup(84subjects)showingarelativeriskreductionof34.0%(95%confidenceinterval8.2to52.6,p<0.02)andanabsoluteriskreductionof1.4%inthegemfibrozilgroupcomparedtoplacebo.Therewasa37%reductioninnon-fatalmyocardialinfarctionanda26%reductionincardiacdeaths.Thenumberofdeathsfromallcauseswas,however,notdifferent(44inthegemfibrozilgroupand43intheplacebogroup).Diabetespatientsandpatientswithseverelipidfractiondeviationsshoweda68%and71%reductionofCHDendpoints,respectively. TheVA-HITstudywasadouble-blindstudycomparinggemfibrozil(1200mgperday)withplaceboin2531menwithahistoryofcoronaryheartdisease,HDL-Clevelsof<40mg/dL(1.0mmol/L),andnormalLDLClevels.Afteroneyear,themeanHDL-Clevelwas6%higherandthemeantriglyceridelevelwas31%lowerinthegemfibrozilgroupthanintheplacebogroup.Theprimaryeventofnon-fatalmyocardialinfarctionorcardiacdeathoccurredin17.3%ofgemfibrozil-treatedand21.7%ofplacebo-treatedpatients(reductioninrelativerisk22%;95%CI,7to35%;P=0.006).Amongsecondaryoutcomes,patientstreatedwithgemfibrozilexperiencedrelativeriskreductionsof25%(95%CI–6-47%,p=0.10)forstroke,24%(95%CI11-36%,p<0.001)forthecombinedoutcomeofdeathfromCHD,non-fatalmyocardialinfarction,orconfirmedstroke,59%(95%CI33-75%,p<0.001)fortransientischaemicattack,and65%(95%CI37-80%,p<0.001)forcarotidendarterectomy. 5.2Pharmacokineticproperties Absorption Gemfibroziliswellabsorbedfromthegastro-intestinaltractafteroraladministrationwithabioavailabilitycloseto100%.Asthepresenceoffoodaltersthebioavailabilityslightlygemfibrozilshouldbetaken30minutesbeforeameal.Peakplasmalevelsoccurinonetotwohours.Afteradministrationof600mgtwicedailyaCmaxintherange15to25mg/Lisobtained. Distribution Volumeofdistributionatsteadystateis9-13L.Theplasmaproteinbindingofgemfibrozilanditsmainmetaboliteareatleast97%. Biotransformation Gemfibrozilundergoesoxidationofaringmethylgrouptoformsuccessivelyahydroxymethylandacarboxylmetabolite(themainmetabolite).Thismetabolitehasalowactivitycomparedtothemothercompoundgemfibrozilandaneliminationhalf-lifeofapproximately20hours.Glucuronidationtogemfibrozil1-O-β-glucuronideisanotherimportanteliminationpathwayforgemfibrozilinman. Theenzymesinvolvedinthemetabolismofgemfibrozilarenotknown.Theinteractionprofileofgemfibrozilanditsmetabolitesiscomplex(seesections4.3,4.4and4.5).InvitroandinvivostudieshaveshownthatgemfibrozilinhibitsCYP2C8,CYP2C9,CYP2C19,CYP1A2,UGTA1,UGTA3andOATP1B1.Gemfibrozil1-O-β-glucuronidealsoinhibitsCYP2C8andOATP1B1. Elimination Gemfibroziliseliminatedmainlybymetabolism.Approximately70%oftheadministeredhumandoseisexcretedintheurine,mainlyasconjugatesofgemfibrozilanditsmetabolites.Lessthan6%ofthedoseisexcretedunchangedintheurine.Sixpercentofthedoseisfoundinfaeces.Thetotalclearanceofgemfibrozilisintherange100to160ml/min,andtheeliminationhalf-lifeisintherange1.3to1.5hours.Thepharmacokineticsislinearwithinthetherapeuticdoserange. Specialpatientgroups Nopharmacokineticstudieshavebeenperformedinpatientswithimpairedhepaticfunction. Therearelimiteddataonpatientswithmild,moderateandnon-dialysedsevererenalimpairment.Thelimiteddatasupporttheuseofupto1200mgadayinpatientswithmildtomoderaterenalfailurenotreceivinganotherlipidloweringdrug. 5.3Preclinicalsafetydata Ina2-yearstudyofgemfibrozil,subcapsularbilateralcataractsoccurredin10%,andunilateralin6.3%,ofmaleratstreatedat10timesthehumandose. Inamousecarcinogenicitystudyatdosagescorrespondingto0.1and0.7timestheclinicalexposure(basedonAUC),therewerenosignificantdifferencesfromcontrolsintheincidenceoftumours.Inaratcarcinogenicitystudyatdosagescorrespondingto0.2and1.3timestheclinicalexposure(basedonAUC),theincidenceofbenignlivernodulesandlivercarcinomaswassignificantlyincreasedinhighdosemales,andtheincidenceoflivercarcinomasincreasedalsointhelowdosemales,butthisincreasewasnotstatisticallysignificant. Livertumoursinducedbygemfibrozilandotherfibratesinsmallrodentsaregenerallyconsideredtoberelatedtotheextensiveproliferationofperoxisomesinthesespeciesand,consequently,ofminorclinicalrelevance. Inthemalerat,gemfibrozilalsoinducedbenignLeydigcelltumours.Theclinicalrelevanceofthisfindingisminimal. Inreproductivetoxicitystudies,administrationofgemfibrozilatapproximately2timesthehumandose(basedonbodysurfacearea)tomaleratsfor10weeksresultedindecreasedfertility.Fertilitywasrestoredafteradrug-freeperiodof8weeks.Gemfibrozilwasnotteratogenicineitherratsorrabbits.Administrationof1and3timesthehumandose(basedonbodysurfacearea)ofgemfibroziltofemalerabbitsduringorganogenesiscausedadose-relateddecreaseinlittersize.Administrationof0.6and2timesthehumandose(basedonbodysurfacearea)ofgemfibroziltofemaleratsfromgestationDay15throughweaningcauseddose-relateddecreasesinbirthweightandsuppressionofpupgrowthduringlactation.Maternaltoxicitywasobservedinbothspeciesandtheclinicalrelevanceofdecreasesinrabbitlittersizeandratpupweightisuncertain. 6.Pharmaceuticalparticulars 6.1Listofexcipients Capsulecontent: Polysorbate(E433) Colloidalsilica Maizestarch CapsuleShell: Body: Gelatin Titaniumdioxide(E171) Cap: Gelatin TitaniumdioxideE171 IndigocarmineE132 ErythrosineE127 Printingink: Shellacglaze Ironoxideblack(E172) 6.2Incompatibilities Notapplicable. 6.3Shelflife 3years 6.4Specialprecautionsforstorage Storebelow25°Cintheoriginalpackageinordertoprotectfrommoisture. 6.5Natureandcontentsofcontainer Hardcapsules: PVC/Aluminiumblisterswith20,60,100and112capsules. Notallpacksizesmaybemarketed. 6.6Specialprecautionsfordisposalandotherhandling Nospecialrequirementsfordisposal. 7.Marketingauthorisationholder PfizerLimited RamsgateRoad Sandwich KentCT139NJ UnitedKingdom 8.Marketingauthorisationnumber(s) PL00057/0534 9.Dateoffirstauthorisation/renewaloftheauthorisation Renewalofauthorization:04April2010 10.Dateofrevisionofthetext 04/2021 Ref:LP18_1 ReportSideEffect RelatedMedicines Sameactiveingredients Samecompany Bookmark Email Lastupdatedonemc:22Apr2021 Viewchanges Print Companycontactdetails PfizerLimited Address RamsgateRoad,Sandwich,Kent,CT139NJ MedicalInformationDirectLine +44(0)1304616161 Telephone +44(0)1304616161 MedicalInformationWebsite www.pfizermedicalinformation.co.uk × Bookmarkthismedicine Tobookmarkamedicineyoumustsignupandlogin. SignUp LogIn Cancel × Emailthismedicine Toemailamedicineyoumustsignupandlogin. SignUp LogIn Cancel × Viewmedicinechanges Toviewthechangestoamedicineyoumustsignupandlogin. 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