Lopid (Gemfibrozil): Uses, Dosage, Side Effects, Interactions ...

LOPID is a lipid regulating agent which decreases serum triglycerides and very low density lipoprotein (VLDL) cholesterol, and increases high density ... Lopid GenericName:gemfibrozilBrandName:Lopid DrugClass:FibricAcidAgents LastupdatedonRxList:1/13/2021 home drugsa-zlist sideeffectsdrugcenterlopid(gemfibrozil)drug RelatedDrugs Crestor Juxtapid Kynamro Lipitor Livalo Nexlizet Niacor Niaspan Pradaxa Pravachol RosuvastatinCalcium Roszet Tricor Triglide Vytorin Welchol Zetia Zocor HealthResources Cholesterol(LoweringYourCholesterol) RelatedSupplements Alfalfa Artichoke Avocado Barley Beta-Sitosterol BlackPsyllium BlondPsyllium Calcium CodLiverOil EnglishWalnut FishOil Flaxseed GammaOryzanol Glucomannan GreenTea GuarGum InositolNicotinate Inulin Jiaogulan MacadamiaNut Magnesium Mesoglycan Oats Olive Pantethine Pectin RedYeast RiceBran Safflower Sitostanol Soy SoybeanOil SweetOrange XanthanGum Yogurt DrugComparison Lopidvs.Lipitor Lopidvs.Lovaza Lopidvs.Tricor,Trilipix Lopidvs.Zocor LopidUserReviews PROFESSIONAL CONSUMER SIDEEFFECTS DrugDescription Indications&Dosage SideEffects DrugInteractions Warnings Precautions Overdosage&Contraindications ClinicalPharmacology MedicationGuide DrugDescription FindLowestPriceson WhatIsLopidandhowisitused?Lopid(gemfibrozil)isalipidregulatingagentusedtotreatveryhighcholesterolandtriglyceridelevelsinpeoplewithpancreatitis,andisalsousedtolowertheriskofstroke,heartattack,orotherheartcomplicationsinpeoplewithhighcholesterolandtriglycerideswhohavenotbeenhelpedbyothertreatments.Lopidisavailableingenericform.WhataresideeffectsofLopid?CommonsideeffectsofLopidinclude:stomachupset,stomach/abdominalpain,nausea,vomiting,diarrhea,headache,dizziness,drowsiness,jointormusclepain,lossofinterestinsex,impotence,difficultyhavinganorgasm,numbnessortinglyfeeling,unusualtaste,orcoldsymptomssuchasstuffynose,sneezing,sorethroat.Lopidmayinfrequentlycausegallstonesandliverproblems.Tellyourdoctorifyounoticeanyofthefollowingunlikely,butserioussideeffectsofLopidincluding:severestomach/abdominalpain,persistentnauseaorvomiting,yellowingeyesorskin,anddarkurine.DESCRIPTIONLOPID®(gemfibroziltablets,USP)isalipidregulatingagent.Itisavailableastabletsfororaladministration.Eachtabletcontains600mggemfibrozil.Eachtabletalsocontainscalciumstearate,NF;candelillawax,FCC;microcrystallinecellulose,NF;hydroxypropylcellulose,NF;hypromellose,USP;methylparaben,NF;Opaspraywhite;polyethyleneglycol,NF;polysorbate80,NF;propylparaben,NF;colloidalsilicondioxide,NF;pregelatinizedstarch,NF.Thechemicalnameis5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoicacid,withthefollowingstructuralformula:TheempiricalformulaisC15H22O3andthemolecularweightis250.35;thesolubilityinwaterandacidis0.0019%andindilutebaseitisgreaterthan1%.Themeltingpointis58°–61°C.Gemfibrozilisawhitesolidwhichisstableunderordinaryconditions. Indications&Dosage INDICATIONSLOPID(gemfibroziltablets,USP)isindicatedasadjunctivetherapytodietfor:Treatmentofadultpatientswithveryhighelevationsofserumtriglyceridelevels(TypesIVandVhyperlipidemia)whopresentariskofpancreatitisandwhodonotrespondadequatelytoadetermineddietaryefforttocontrolthem.Patientswhopresentsuchrisktypicallyhaveserumtriglyceridesover2000mg/dLandhaveelevationsofVLDL-cholesterolaswellasfastingchylomicrons(TypeVhyperlipidemia).Subjectswhoconsistentlyhavetotalserumorplasmatriglyceridesbelow1000mg/dLareunlikelytopresentariskofpancreatitis.LOPIDtherapymaybeconsideredforthosesubjectswithtriglycerideelevationsbetween1000and2000mg/dLwhohaveahistoryofpancreatitisorofrecurrentabdominalpaintypicalofpancreatitis.ItisrecognizedthatsomeTypeIVpatientswithtriglyceridesunder1000mg/dLmay,throughdietaryoralcoholicindiscretion,converttoaTypeVpatternwithmassivetriglycerideelevationsaccompanyingfastingchylomicronemia,buttheinfluenceofLOPIDtherapyontheriskofpancreatitisinsuchsituationshasnotbeenadequatelystudied.DrugtherapyisnotindicatedforpatientswithTypeIhyperlipoproteinemia,whohaveelevationsofchylomicronsandplasmatriglycerides,butwhohavenormallevelsofverylowdensitylipoprotein(VLDL).Inspectionofplasmarefrigeratedfor14hoursishelpfulindistinguishingTypesI,IV,andVhyperlipoproteinemia.ReducingtheriskofdevelopingcoronaryheartdiseaseonlyinTypeIIbpatientswithouthistoryoforsymptomsofexistingcoronaryheartdiseasewhohavehadaninadequateresponsetoweightloss,dietarytherapy,exercise,andotherpharmacologicagents(suchasbileacidsequestrantsandnicotinicacid,knowntoreduceLDL-andraiseHDL-cholesterol)andwhohavethefollowingtriadoflipidabnormalities:lowHDL-cholesterollevelsinadditiontoelevatedLDL-cholesterolandelevatedtriglycerides(seeWARNINGS,PRECAUTIONS,andCLINICALPHARMACOLOGY).TheNationalCholesterolEducationProgramhasdefinedaserumHDL-cholesterolvaluethatisconsistentlybelow35mg/dLasconstitutinganindependentriskfactorforcoronaryheartdisease.Patientswithsignificantlyelevatedtriglyceridesshouldbecloselyobservedwhentreatedwithgemfibrozil.Insomepatientswithhightriglyceridelevels,treatmentwithgemfibrozilisassociatedwithasignificantincreaseinLDL-cholesterol.BECAUSEOFPOTENTIALTOXICITYSUCHASMALIGNANCY,GALLBLADDERDISEASE,ABDOMINALPAINLEADINGTOAPPENDECTOMYANDOTHERABDOMINALSURGERIES,ANINCREASEDINCIDENCEINNON-CORONARYMORTALITY,ANDTHE44%RELATIVEINCREASEDURINGTHETRIALPERIODINAGE-ADJUSTEDALL-CAUSEMORTALITYSEENWITHTHECHEMICALLYANDPHARMACOLOGICALLYRELATEDDRUG,CLOFIBRATE,THEPOTENTIALBENEFITOFGEMFIBROZILINTREATINGTYPEIIAPATIENTSWITHELEVATIONSOFLDL-CHOLESTEROLONLYISNOTLIKELYTOOUTWEIGHTHERISKS.LOPIDISALSONOTINDICATEDFORTHETREATMENTOFPATIENTSWITHLOWHDL-CHOLESTEROLASTHEIRONLYLIPIDABNORMALITY.InasubgroupanalysisofpatientsintheHelsinkiHeartStudywithabove-medianHDL-cholesterolvaluesatbaseline(greaterthan46.4mg/dL),theincidenceofseriouscoronaryeventswassimilarforgemfibrozilandplacebosubgroups(seeTableI).Theinitialtreatmentfordyslipidemiaisdietarytherapyspecificforthetypeoflipoproteinabnormality.Excessbodyweightandexcessalcoholintakemaybeimportantfactorsinhypertriglyceridemiaandshouldbemanagedpriortoanydrugtherapy.Physicalexercisecanbeanimportantancillarymeasure,andhasbeenassociatedwithrisesinHDL-cholesterol.Diseasescontributorytohyperlipidemiasuchashypothyroidismordiabetesmellitusshouldbelookedforandadequatelytreated.Estrogentherapyissometimesassociatedwithmassiverisesinplasmatriglycerides,especiallyinsubjectswithfamilialhypertriglyceridemia.Insuchcases,discontinuationofestrogentherapymayobviatetheneedforspecificdrugtherapyofhypertriglyceridemia.Theuseofdrugsshouldbeconsideredonlywhenreasonableattemptshavebeenmadetoobtainsatisfactoryresultswithnondrugmethods.Ifthedecisionismadetousedrugs,thepatientshouldbeinstructedthatthisdoesnotreducetheimportanceofadheringtodiet.DOSAGEANDADMINISTRATIONTherecommendeddoseforadultsis1200mgadministeredintwodivideddoses30minutesbeforethemorningandeveningmeals(seeCLINICALPHARMACOLOGY).HOWSUPPLIEDLOPID(Tablet737),white,elliptical,film-coated,scoredtablets,eachcontaining600mggemfibrozil,areavailableasfollows:NDC0071-0737-20:Bottlesof60NDC0071-0737-30:Bottlesof500Storeatcontrolledroomtemperature20°–25°C(68°–77°F)[seeUSP].Protectfromlightandhumidity.DistributedbyParke-DavisDivisionofPfizerInc,NY,NY10017.Revised:Dec2020 SLIDESHOW HowtoLowerYourCholesterol&SaveYourHeart SeeSlideshow SideEffects SIDEEFFECTSInthedouble-blindcontrolledphaseoftheprimarypreventioncomponentoftheHelsinkiHeartStudy,2046patientsreceivedLOPIDforuptofiveyears.Inthatstudy,thefollowingadversereactionswerestatisticallymorefrequentinsubjectsintheLOPIDgroup:LOPID(N=2046)PLACEBO(N=2035)FrequencyinpercentofsubjectsGastrointestinalreactions34.223.8  Dyspepsia19.611.9  Abdominalpain9.85.6  Acuteappendicitis1.20.6  (histologicallyconfirmedinmostcaseswheredatawereavailable)Atrialfibrillation0.70.1Adverseeventsreportedbymorethan1%ofsubjects,butwithoutasignificantdifferencebetweengroups:Diarrhea7.26.5Fatigue3.83.5Nausea/Vomiting2.52.1Eczema1.91.2Rash1.71.3Vertigo1.51.3Constipation1.41.3Headache1.21.1Gallbladdersurgerywasperformedin0.9%ofLOPIDand0.5%ofplacebosubjectsintheprimarypreventioncomponent,a64%excess,whichisnotstatisticallydifferentfromtheexcessofgallbladdersurgeryobservedintheclofibrategroupcomparedtotheplacebogroupoftheWHOstudy.GallbladdersurgerywasalsoperformedmorefrequentlyintheLOPIDgroupcomparedtotheplacebogroup(1.9%versus0.3%,p=0.07)inthesecondarypreventioncomponent.Astatisticallysignificantincreaseinappendectomyinthegemfibrozilgroupwasseenalsointhesecondarypreventioncomponent(6ongemfibrozilversus0onplacebo,p=0.014).NervoussystemandspecialsensesadversereactionsweremorecommonintheLOPIDgroup.Theseincludedhypesthesia,paresthesias,andtasteperversion.OtheradversereactionsthatweremorecommonamongLOPIDtreatmentgroupsubjectsbutwhereacausalrelationshipwasnotestablishedincludecataracts,peripheralvasculardisease,andintracerebralhemorrhage.FromotherstudiesitseemsprobablethatLOPIDiscausallyrelatedtotheoccurrenceofMUSCULOSKELETALSYMPTOMS(seeWARNINGS),andtoABNORMALLIVERFUNCTIONTESTSandHEMATOLOGICCHANGES(seePRECAUTIONS).Reportsofviralandbacterialinfections(commoncold,cough,urinarytractinfections)weremorecommoningemfibroziltreatedpatientsinothercontrolledclinicaltrialsof805patients.Additionaladversereactionsthathavebeenreportedforgemfibrozilarelistedbelowbysystem.ThesearecategorizedaccordingtowhetheracausalrelationshiptotreatmentwithLOPIDisprobableornotestablished:CAUSALRELATIONSHIPPROBABLECAUSALRELATIONSHIPNOTESTABLISHEDGeneral:weightlossCardiac:extrasystolesGastrointestinal:cholestaticjaundicepancreatitishepatomacolitisCentralNervousSystem:dizzinessconfusionsomnolenceconvulsionsparesthesiasyncopeperipheralneuritisdecreasedlibidodepressionheadacheEye:blurredvisionretinaledemaGenitourinary:impotencedecreasedmalefertilityrenaldysfunctionMusculoskeletal:myopathymyastheniamyalgiapainfulextremitiesarthralgiasynovitisrhabdomyolysis(seeWARNINGSandDRUGINTERACTIONSunderPRECAUTIONS)ClinicalLaboratory:increasedcreatinephosphokinasepositiveantinuclearantibodyincreasedbilirubinincreasedlivertransaminases(AST,ALT)increasedalkalinephosphataseHematopoietic:anemiathrombocytopenialeukopeniabonemarrowhypoplasiaeosinophiliaImmunologic:angioedemaanaphylaxislaryngealedemaLupus-likesyndromeurticariavasculitisIntegumentary:exfoliativedermatitisalopeciarashphotosensitivitydermatitispruritusAdditionaladversereactionsthathavebeenreportedincludecholecystitisandcholelithiasis(seeWARNINGS). DrugInteractions DRUGINTERACTIONSHMG-CoAReductaseInhibitorsTheconcomitantadministrationofLOPIDwithsimvastatiniscontraindicated(seeCONTRAINDICATIONSandWARNINGS).AvoidconcomitantuseofLOPIDwithrosuvastatin.Ifconcomitantusecannotbeavoided,initiaterosuvastatinat5mgoncedaily.Thedoseofrosuvastatinshouldnotexceed10mgoncedaily.TheriskofmyopathyandrhabdomyolysisisincreasedwithcombinedgemfibrozilandHMG-CoAreductaseinhibitortherapy.Myopathyorrhabdomyolysiswithorwithoutacuterenalfailurehavebeenreportedasearlyasthreeweeksafterinitiationofcombinedtherapyorafterseveralmonths(seeWARNINGS).Thereisnoassurancethatperiodicmonitoringofcreatinekinasewillpreventtheoccurrenceofseveremyopathyandkidneydamage.AnticoagulantsCAUTIONSHOULDBEEXERCISEDWHENWARFARINISGIVENINCONJUNCTIONWITHLOPID.THEDOSAGEOFWARFARINSHOULDBEREDUCEDTOMAINTAINTHEPROTHROMBINTIMEATTHEDESIREDLEVELTOPREVENTBLEEDINGCOMPLICATIONS.FREQUENTPROTHROMBINDETERMINATIONSAREADVISABLEUNTILITHASBEENDEFINITELYDETERMINEDTHATTHEPROTHROMBINLEVELHASSTABILIZED.CYP2C8SubstratesGemfibrozilisastronginhibitorofCYP2C8andmayincreaseexposureofdrugsmainlymetabolizedbyCYP2C8(e.g.,dabrafenib,enzalutamide,loperamide,montelukast,paclitaxel,pioglitazone,rosiglitazone).Therefore,dosingreductionofdrugsthataremainlymetabolizedbyCYP2C8enzymemayberequiredwhengemfibrozilisusedconcomitantly(seeWARNINGS).RepaglinideInhealthyvolunteers,co-administrationwithgemfibrozil(600mgtwicedailyfor3days)resultedinan8.1-fold(range5.5-to15.0-fold)higherrepaglinideAUCanda28.6-fold(range18.5-to80.1-fold)higherrepaglinideplasmaconcentration7hoursafterthedose.Inthesamestudy,gemfibrozil(600mgtwicedailyfor3days)+itraconazole(200mginthemorningand100mgintheeveningatDay1,then100mgtwicedailyatDay2-3)resultedina19.4-(range12.9-to24.7-fold)higherrepaglinideAUCanda70.4-fold(range42.9-to119.2-fold)higherrepaglinideplasmaconcentration7hoursafterthedose.Inaddition,gemfibrozilaloneorgemfibrozil+itraconazoleprolongedthehypoglycemiceffectsofrepaglinide.Co-administrationofgemfibrozilandrepaglinideincreasestheriskofseverehypoglycemiaandiscontraindicated(seeCONTRAINDICATIONS).DasabuvirCo-administrationofgemfibrozilwithdasabuvirincreaseddasabuvirAUCandCmax(ratios:11.3and2.01,respectively)duetoCYP2C8inhibition.IncreaseddasabuvirexposuremayincreasetheriskofQTprolongation,therefore,co-administrationofgemfibrozilwithdasabuviriscontraindicated(seeCONTRAINDICATIONS).SelexipagCo-administrationofgemfibrozilwithselexipagdoubledexposuretoselexipagandincreasedexposuretotheactivemetabolitebyapproximately11-fold.Concomitantadministrationofgemfibrozilwithselexipagiscontraindicated(seeCONTRAINDICATIONS).EnzalutamideInhealthyvolunteersgivenasingle160mgdoseofenzalutamideaftergemfibrozil600mgtwicedaily,theAUCofenzalutamideplusactivemetabolite(N-desmethylenzalutamide)wasincreasedby2.2foldandcorrespondingCmaxwasdecreasedby16%.Increasedenzalutamideexposuremayincreasetheriskofseizures.Ifco-administrationisconsiderednecessary,thedoseofenzalutamideshouldbereduced(seeWARNINGS).OATP1B1SubstratesGemfibrozilisaninhibitorofOATP1B1transporterandmayincreaseexposureofdrugsthataresubstratesofOATP1B1(e.g.,atrasentan,atorvastatin,bosentan,ezetimibe,fluvastatin,glyburide,SN-38[activemetaboliteofirinotecan],rosuvastatin,pitavastatin,pravastatin,rifampin,valsartan,olmesartan).Therefore,dosingreductionsofdrugsthataresubstratesofOATP1B1mayberequiredwhengemfibrozilisusedconcomitantly(seeWARNINGS).Combinationtherapyofgemfibrozilwithsimvastatinorwithrepaglinide,whichareOATP1B1substrates,iscontraindicated(seeCONTRAINDICATIONS).InVitroStudiesOfCYPEnzymes,UGTAEnzymesAndOATP1B1TransporterInvitrostudieshaveshownthatgemfibrozilisaninhibitorofCYP1A2,CYP2C8,CYP2C9,CYP2C19,OATP1B1,andUDP-glucuronosyltransferase(UGT)1A1and1A3(seeWARNINGS).BileAcid-BindingResinsGemfibrozilAUCwasreducedby30%whengemfibrozilwasgiven(600mg)simultaneouslywithresin-granuledrugssuchascolestipol(5g).Administrationofthedrugstwohoursormoreapartisrecommendedbecausegemfibrozilexposurewasnotsignificantlyaffectedwhenitwasadministeredtwohoursapartfromcolestipol.ColchicineMyopathy,includingrhabdomyolysis,hasbeenreportedwithchronicadministrationofcolchicineattherapeuticdoses.ConcomitantuseofLOPIDmaypotentiatethedevelopmentofmyopathy.Patientswithrenaldysfunctionandelderlypatientsareatincreasedrisk.CautionshouldbeexercisedwhenprescribingLOPIDwithcolchicine,especiallyinelderlypatientsorpatientswithrenaldysfunction. Warnings WARNINGSBecauseofthemorelimitedsizeoftheHelsinkiHeartStudy,theobserveddifferenceinmortalityfromanycausebetweentheLOPIDandplacebogroupsisnotstatisticallysignificantlydifferentfromthe29%excessmortalityreportedintheclofibrategroupintheseparateWHOstudyatthenineyearfollow-up(seeCLINICALPHARMACOLOGY).NoncoronaryheartdiseaserelatedmortalityshowedanexcessinthegrouporiginallyrandomizedtoLOPIDprimarilyduetocancerdeathsobservedduringtheopen-labelextension.DuringthefiveyearprimarypreventioncomponentoftheHelsinkiHeartStudy,mortalityfromanycausewas44(2.2%)intheLOPIDgroupand43(2.1%)intheplacebogroup;includingthe3.5yearfollow-upperiodsincethetrialwascompleted,cumulativemortalityfromanycausewas101(4.9%)intheLOPIDgroupand83(4.1%)inthegrouporiginallyrandomizedtoplacebo(hazardratio1:20infavorofplacebo).BecauseofthemorelimitedsizeoftheHelsinkiHeartStudy,theobserveddifferenceinmortalityfromanycausebetweentheLOPIDandplacebogroupsatYear-5oratYear-8.5isnotstatisticallysignificantlydifferentfromthe29%excessmortalityreportedintheclofibrategroupintheseparateWHOstudyatthenineyearfollow-up.NoncoronaryheartdiseaserelatedmortalityshowedanexcessinthegrouporiginallyrandomizedtoLOPIDatthe8.5yearfollow-up(65LOPIDversus45placebononcoronarydeaths).Theincidenceofcancer(excludingbasalcellcarcinoma)discoveredduringthetrialandinthe3.5yearsafterthetrialwascompletedwas51(2.5%)inbothoriginallyrandomizedgroups.Inaddition,therewere16basalcellcarcinomasinthegrouporiginallyrandomizedtoLOPIDand9inthegrouporiginallyrandomizedtoplacebo(p=0.22).Therewere30(1.5%)deathsattributedtocancerinthegrouporiginallyrandomizedtoLOPIDand18(0.9%)inthegrouporiginallyrandomizedtoplacebo(p=0.11).Adverseoutcomes,includingcoronaryevents,werehigheringemfibrozilpatientsinacorrespondingstudyinmenwithahistoryofknownorsuspectedcoronaryheartdiseaseinthesecondarypreventioncomponentoftheHelsinkiHeartStudy(seeCLINICALPHARMACOLOGY).Acomparativecarcinogenicitystudywasalsodoneinratscomparingthreedrugsinthisclass:fenofibrate(10and60mg/kg;0.3and1.6timesthehumandose,respectively),clofibrate(400mg/kg;1.6timesthehumandose),andgemfibrozil(250mg/kg;1.7timesthehumandose).Pancreaticacinaradenomaswereincreasedinmalesandfemalesonfenofibrate;hepatocellularcarcinomaandpancreaticacinaradenomaswereincreasedinmalesandhepaticneoplasticnodulesinfemalestreatedwithclofibrate;hepaticneoplasticnoduleswereincreasedinmalesandfemalestreatedwithclofibrate;hepaticneoplasticnoduleswereincreasedinmalesandfemalestreatedwithgemfibrozilwhiletesticularinterstitialcell(Leydigcell)tumorswereincreasedinmalesonallthreedrugs.Becauseofchemical,pharmacological,andclinicalsimilaritiesbetweengemfibrozilandclofibrate,theadversefindingswithclofibrateintwolargeclinicalstudiesmayalsoapplytogemfibrozil.Inthefirstofthosestudies,theCoronaryDrugProject,1000subjectswithpreviousmyocardialinfarctionweretreatedforfiveyearswithclofibrate.Therewasnodifferenceinmortalitybetweentheclofibrate-treatedsubjectsand3000placebo-treatedsubjects,buttwiceasmanyclofibrate-treatedsubjectsdevelopedcholelithiasisandcholecystitisrequiringsurgery.Intheotherstudy,conductedbytheWorldHealthOrganization(WHO),5000subjectswithoutknowncoronaryheartdiseaseweretreatedwithclofibrateforfiveyearsandfollowedoneyearbeyond.Therewasastatisticallysignificant(44%)higherage-adjustedtotalmortalityintheclofibrate-treatedgroupthaninacomparableplacebo-treatedcontrolgroupduringthetrialperiod.Theexcessmortalitywasduetoa33%increaseinnon-cardiovascularcauses,includingmalignancy,post-cholecystectomycomplications,andpancreatitis.Thehigherriskofclofibrate-treatedsubjectsforgallbladderdiseasewasconfirmed.Agallstoneprevalencesubstudyof450HelsinkiHeartStudyparticipantsshowedatrendtowardagreaterprevalenceofgallstonesduringthestudywithintheLOPIDtreatmentgroup(7.5%versus4.9%fortheplacebogroup,a55%excessforthegemfibrozilgroup).AtrendtowardagreaterincidenceofgallbladdersurgerywasobservedfortheLOPIDgroup(17versus11subjects,a54%excess).ThisresultdidnotdifferstatisticallyfromtheincreasedincidenceofcholecystectomyobservedintheWHOstudyinthegrouptreatedwithclofibrate.Bothclofibrateandgemfibrozilmayincreasecholesterolexcretionintothebile,leadingtocholelithiasis.Ifcholelithiasisissuspected,gallbladderstudiesareindicated.LOPIDtherapyshouldbediscontinuedifgallstonesarefound.Casesofcholelithiasishavebeenreportedwithgemfibroziltherapy.Sinceareductionofmortalityfromcoronaryheartdiseasehasnotbeendemonstratedandbecauseliverandinterstitialcelltesticulartumorswereincreasedinrats,LOPIDshouldbeadministeredonlytothosepatientsdescribedintheINDICATIONSsection.Ifasignificantserumlipidresponseisnotobtained,LOPIDshouldbediscontinued.ConcomitantAnticoagulants–CautionshouldbeexercisedwhenwarfarinisgiveninconjunctionwithLOPID.Thedosageofwarfarinshouldbereducedtomaintaintheprothrombintimeatthedesiredleveltopreventbleedingcomplications.Frequentprothrombindeterminationsareadvisableuntilithasbeendefinitelydeterminedthattheprothrombinlevelhasstabilized.TheconcomitantadministrationofLOPIDwithsimvastatiniscontraindicated(seeCONTRAINDICATIONSandPRECAUTIONS).ConcomitanttherapywithLOPIDandanHMG-CoAreductaseinhibitorisassociatedwithanincreasedriskofskeletalmuscletoxicitymanifestedasrhabdomyolysis,markedlyelevatedcreatinekinase(CPK)levels,andmyoglobinuria,leadinginahighproportionofcasestoacuterenalfailureanddeath.INPATIENTSWHOHAVEHADANUNSATISFACTORYLIPIDRESPONSETOEITHERDRUGALONE,THEBENEFITOFCOMBINEDTHERAPYWITHLOPIDANDanHMG-CoAREDUCTASEINHIBITORDOESNOTOUTWEIGHTHERISKSOFSEVEREMYOPATHY,RHABDOMYOLYSIS,ANDACUTERENALFAILURE(seePRECAUTIONS,DRUGINTERACTIONS).Theuseoffibratesalone,includingLOPID,mayoccasionallybeassociatedwithmyositis.PatientsreceivingLOPIDandcomplainingofmusclepain,tenderness,orweaknessshouldhavepromptmedicalevaluationformyositis,includingserumcreatine–kinaseleveldetermination.Ifmyositisissuspectedordiagnosed,LOPIDtherapyshouldbewithdrawn.Cataracts–Subcapsularbilateralcataractsoccurredin10%,andunilateralin6.3%,ofmaleratstreatedwithgemfibrozilat10timesthehumandose.CYP2C8substrates-Gemfibrozil,astronginhibitorofCYP2C8,mayincreaseexposureofCYP2C8substrateswhenadministeredconcomitantly(seePRECAUTIONS,DRUGINTERACTIONS).OATP1B1substrates–Gemfibrozilisaninhibitoroforganicanion-transporterpolyprotein(OATP)1B1andmayincreaseexposureofdrugsthataresubstratesofOATP1B1(e.g.,atrasentan,atorvastatin,bosentan,ezetimibe,fluvastatin,glyburide,SN-38[activemetaboliteofirinotecan],rosuvastatin,pitavastatin,pravastatin,rifampin,valsartan,olmesartan).Therefore,dosingreductionsofdrugsthataresubstratesofOATP1B1mayberequiredwhengemfibrozilisusedconcomitantly(seePRECAUTIONS,DRUGINTERACTIONS).Combinationtherapyofgemfibrozilwithsimvastatinorwithrepaglinide,whichareOATP1B1substrates,iscontraindicated(seeCONTRAINDICATIONS). Precautions PRECAUTIONSInitialTherapyLaboratorystudiesshouldbedonetoascertainthatthelipidlevelsareconsistentlyabnormal.BeforeinstitutingLOPIDtherapy,everyattemptshouldbemadetocontrolserumlipidswithappropriatediet,exercise,weightlossinobesepatients,andcontrolofanymedicalproblemssuchasdiabetesmellitusandhypothyroidismthatarecontributingtothelipidabnormalities.ContinuedTherapyPeriodicdeterminationofserumlipidsshouldbeobtained,andthedrugwithdrawniflipidresponseisinadequateafterthreemonthsoftherapy.Carcinogenesis,Mutagenesis,ImpairmentOfFertilityLong-termstudieshavebeenconductedinratsat0.2and1.3timesthehumanexposure(basedonAUC).Theincidenceofbenignlivernodulesandlivercarcinomaswassignificantlyincreasedinhighdosemalerats.Theincidenceoflivercarcinomasincreasedalsoinlowdosemales,butthisincreasewasnotstatisticallysignificant(p=0.1).Maleratshadadose-relatedandstatisticallysignificantincreaseofbenignLeydigcelltumors.Thehigherdosefemaleratshadasignificantincreaseinthecombinedincidenceofbenignandmalignantliverneoplasms.Long-termstudieshavebeenconductedinmiceat0.1and0.7timesthehumanexposure(basedonAUC).Therewerenostatisticallysignificantdifferencesfromcontrolsintheincidenceoflivertumors,butthedosestestedwerelowerthanthoseshowntobecarcinogenicwithotherfibrates.ElectronmicroscopystudieshavedemonstratedafloridhepaticperoxisomeproliferationfollowingLOPIDadministrationtothemalerat.Anadequatestudytotestforperoxisomeproliferationhasnotbeendoneinhumansbutchangesinperoxisomemorphologyhavebeenobserved.Peroxisomeproliferationhasbeenshowntooccurinhumanswitheitheroftwootherdrugsofthefibrateclasswhenliverbiopsieswerecomparedbeforeandaftertreatmentinthesameindividual.Administrationofapproximately2timesthehumandose(basedonsurfacearea)tomaleratsfor10weeksresultedinadose-relateddecreaseoffertility.Subsequentstudiesdemonstratedthatthiseffectwasreversedafteradrug-freeperiodofabouteightweeks,anditwasnottransmittedtotheoffspring.PregnancyLOPIDhasbeenshowntoproduceadverseeffectsinratsandrabbitsatdosesbetween0.5and3timesthehumandose(basedonsurfacearea).Therearenoadequateandwell-controlledstudiesinpregnantwomen.LOPIDshouldbeusedduringpregnancyonlyifthepotentialbenefitjustifiesthepotentialrisktothefetus.AdministrationofLOPIDtofemaleratsat2timesthehumandose(basedonsurfacearea)beforeandthroughoutgestationcausedadose-relateddecreaseinconceptionrate,anincreaseinstillborns,andaslightreductioninpupweightduringlactation.Therewerealsodose-relatedincreasedskeletalvariations.Anophthalmiaoccurred,butrarely.Administrationof0.6and2timesthehumandose(basedonsurfacearea)ofLOPIDtofemaleratsfromgestationday15throughweaningcauseddose-relateddecreasesinbirthweightandsuppressionsofpupgrowthduringlactation.Administrationof1and3timesthehumandose(basedonsurfacearea)ofLOPIDtofemalerabbitsduringorganogenesiscausedadose-relateddecreaseinlittersizeand,atthehighdose,anincreasedincidenceofparietalbonevariations.NursingMothersItisnotknownwhetherthisdrugisexcretedinhumanmilk.BecausemanydrugsareexcretedinhumanmilkandbecauseofthepotentialfortumorigenicityshownforLOPIDinanimalstudies,adecisionshouldbemadewhethertodiscontinuenursingortodiscontinuethedrug,takingintoaccounttheimportanceofthedrugtothemother.HematologicChangesMildhemoglobin,hematocrit,andwhitebloodcelldecreaseshavebeenobservedinoccasionalpatientsfollowinginitiationofLOPIDtherapy.However,theselevelsstabilizeduringlong-termadministration.Rarely,severeanemia,leukopenia,thrombocytopenia,andbonemarrowhypoplasiahavebeenreported.Therefore,periodicbloodcountsarerecommendedduringthefirst12monthsofLOPIDadministration.LiverFunctionAbnormalliverfunctiontestshavebeenobservedoccasionallyduringLOPIDadministration,includingelevationsofAST,ALT,LDH,bilirubin,andalkalinephosphatase.TheseareusuallyreversiblewhenLOPIDisdiscontinued.Therefore,periodicliverfunctionstudiesarerecommendedandLOPIDtherapyshouldbeterminatedifabnormalitiespersist.KidneyFunctionTherehavebeenreportsofworseningrenalinsufficiencyupontheadditionofLOPIDtherapyinindividualswithbaselineplasmacreatinine>2.0mg/dL.Insuchpatients,theuseofalternativetherapyshouldbeconsideredagainsttherisksandbenefitsofalowerdoseofLOPID.PediatricUseSafetyandefficacyinpediatricpatientshavenotbeenestablished. Overdosage&Contraindications OVERDOSETherehavebeenreportedcasesofoverdosagewithLOPID.Inonecase,a7-year-oldchildrecoveredafteringestingupto9gramsofLOPID.Symptomsreportedwithoverdosagewereabdominalcramps,abnormalliverfunctiontests,diarrhea,increasedCPK,jointandmusclepain,nauseaandvomiting.Symptomaticsupportivemeasuresshouldbetaken,shouldanoverdoseoccur.CONTRAINDICATIONSHepaticorsevererenaldysfunction,includingprimarybiliarycirrhosis.Preexistinggallbladderdisease(seeWARNINGS).Hypersensitivitytogemfibrozil.Combinationtherapyofgemfibrozilwithsimvastatin(seeWARNINGSandPRECAUTIONS).Combinationtherapyofgemfibrozilwithrepaglinide(seePRECAUTIONS).Combinationtherapyofgemfibrozilwithdasabuvir(seePRECAUTIONS).Combinationtherapyofgemfibrozilwithselexipag(seePRECAUTIONS). ClinicalPharmacology CLINICALPHARMACOLOGYLOPIDisalipidregulatingagentwhichdecreasesserumtriglyceridesandverylowdensitylipoprotein(VLDL)cholesterol,andincreaseshighdensitylipoprotein(HDL)cholesterol.Whilemodestdecreasesintotalandlowdensitylipoprotein(LDL)cholesterolmaybeobservedwithLOPIDtherapy,treatmentofpatientswithelevatedtriglyceridesduetoTypeIVhyperlipoproteinemiaoftenresultsinariseinLDL-cholesterol.LDL-cholesterollevelsinTypeIIbpatientswithelevationsofbothserumLDL-cholesterolandtriglyceridesare,ingeneral,minimallyaffectedbyLOPIDtreatment;however,LOPIDusuallyraisesHDL-cholesterolsignificantlyinthisgroup.LOPIDincreaseslevelsofhighdensitylipoprotein(HDL)subfractionsHDL2andHDL3,aswellasapolipoproteinsAIandAII.EpidemiologicalstudieshaveshownthatbothlowHDL-cholesterolandhighLDL-cholesterolareindependentriskfactorsforcoronaryheartdisease.IntheprimarypreventioncomponentoftheHelsinkiHeartStudy,inwhich4081malepatientsbetweentheagesof40and55werestudiedinarandomized,double-blind,placebo-controlledfashion,LOPIDtherapywasassociatedwithsignificantreductionsintotalplasmatriglyceridesandasignificantincreaseinhighdensitylipoproteincholesterol.ModeratereductionsintotalplasmacholesterolandlowdensitylipoproteincholesterolwereobservedfortheLOPIDtreatmentgroupasawhole,butthelipidresponsewasheterogeneous,especiallyamongdifferentFredricksontypes.Thestudyinvolvedsubjectswithserumnon-HDL-cholesterolofover200mg/dLandnoprevioushistoryofcoronaryheartdisease.Overthefive-yearstudyperiod,theLOPIDgroupexperienceda1.4%absolute(34%relative)reductionintherateofseriouscoronaryevents(suddencardiacdeathsplusfatalandnonfatalmyocardialinfarctions)comparedtoplacebo,p=0.04(seeTableI).Therewasa37%relativereductionintherateofnonfatalmyocardialinfarctioncomparedtoplacebo,equivalenttoatreatment-relateddifferenceof13.1eventsperthousandpersons.Deathsfromanycauseduringthedouble-blindportionofthestudytotaled44(2.2%)intheLOPIDrandomizationgroupand43(2.1%)intheplacebogroup.TableIReductioninCHDRates(eventsper1000patients)byBaselineLipids1intheHelsinkiHeartStudy,Years0–52AllPatientsLDL-C>175;HDL-C>46.4LDL-C>175;TG>177LDL-C>175;TG>200;HDL-C<35PLDif3PLDifPLDifPLDifIncidenceofEvents44127143229371442714964851lipidvaluesinmg/dLatbaseline2P=placebogroup;L=LOPIDgroup3differenceinratesbetweenplaceboandLOPIDgroups4fatalandnonfatalmyocardialinfarctionsplussuddencardiacdeaths(eventsper1000patientsover5years)AmongFredricksontypes,duringthe5-yeardouble-blindportionoftheprimarypreventioncomponentoftheHelsinkiHeartStudy,thegreatestreductionintheincidenceofseriouscoronaryeventsoccurredinTypeIIbpatientswhohadelevationsofbothLDL-cholesterolandtotalplasmatriglycerides.ThissubgroupofTypeIIbgemfibrozilgrouppatientshadalowermeanHDL-cholesterollevelatbaselinethantheTypeIIasubgroupthathadelevationsofLDL-cholesterolandnormalplasmatriglycerides.ThemeanincreaseinHDL-cholesterolamongtheTypeIIbpatientsinthisstudywas12.6%comparedtoplacebo.ThemeanchangeinLDL-cholesterolamongTypeIIbpatientswas–4.1%withLOPIDcomparedtoariseof3.9%intheplacebosubgroup.TheTypeIIbsubjectsintheHelsinkiHeartStudyhad26fewercoronaryeventsperthousandpersonsoverfiveyearsinthegemfibrozilgroupcomparedtoplacebo.ThedifferenceincoronaryeventswassubstantiallygreaterbetweenLOPIDandplaceboforthatsubgroupofpatientswiththetriadofLDL-cholesterol>175mg/dL(>4.5mmol),triglycerides>200mg/dL(>2.2mmol),andHDL-cholesterol<35mg/dL(<0.90mmol)(seeTableI).Furtherinformationisavailablefroma3.5year(8.5yearcumulative)follow-upofallsubjectswhohadparticipatedintheHelsinkiHeartStudy.AtthecompletionoftheHelsinkiHeartStudy,subjectscouldchoosetostart,stop,orcontinuetoreceiveLOPID;withoutknowledgeoftheirownlipidvaluesordouble-blindtreatment,60%ofpatientsoriginallyrandomizedtoplacebobegantherapywithLOPIDand60%ofpatientsoriginallyrandomizedtoLOPIDcontinuedmedication.Afterapproximately6.5yearsfollowingrandomization,allpatientswereinformedoftheiroriginaltreatmentgroupandlipidvaluesduringthefiveyearsofthedouble-blindtreatment.AfterfurtherelectivechangesinLOPIDtreatmentstatus,61%ofpatientsinthegrouporiginallyrandomizedtoLOPIDweretakingdrug;inthegrouporiginallyrandomizedtoplacebo,65%weretakingLOPID.Theeventrateper1000occurringduringtheopen-labelfollow-upperiodisdetailedinTableII.TableIICardiacEventsandAll-CauseMortality(eventsper1000patients)OccurringDuringthe3.5YearOpen-LabelFollow-uptotheHelsinkiHeartStudy1Group:PDropN=215PNN=494PLN=1283LDropN=221LNN=574LLN=1207CardiacEvents38.822.922.537.228.325.4All-CauseMortality41.922.315.672.319.224.91Thesixopen-labelgroupsaredesignatedfirstbytheoriginalrandomization(P=placebo,L=LOPID)andthenbythedrugtakeninthefollow-upperiod(N=Attendclinicbuttooknodrug,L=LOPID,Drop=Noattendanceatclinicduringopen-label).Cumulativemortalitythrough8.5yearsshoweda20%relativeexcessofdeathsinthegrouporiginallyrandomizedtoLOPIDversustheoriginallyrandomizedplacebogroupanda20%relativedecreaseincardiaceventsinthegrouporiginallyrandomizedtoLOPIDversustheoriginallyrandomizedplacebogroup(seeTableIII).Thisanalysisoftheoriginallyrandomized“intent-to-treat’’populationneglectsthepossiblecomplicatingeffectsoftreatmentswitchingduringtheopen-labelphase.Adjustmentofhazardratios,takingintoaccountopen-labeltreatmentstatusfromyears6.5to8.5,couldchangethereportedhazardratiosformortalitytowardunity.TableIIICardiacEvents,CardiacDeaths,Non-CardiacDeaths,andAll-CauseMortalityintheHelsinkiHeartStudy,Years0–8.51EventLOPIDatStudyStartPlaceboatStudyStartLOPID:PlaceboHazardRatio2ClHazardRatio3CardiacEvents41101310.800.62–1.03CardiacDeaths36380.980.63–1.54Non-CardiacDeaths65451.400.95–2.05All-CauseMortality101831.200.90–1.611Intention-to-TreatAnalysisoforiginallyrandomizedpatientsneglectingtheopen-labeltreatmentswitchesandexposuretostudyconditions.2HazardratioforriskeventinthegrouporiginallyrandomizedtoLOPIDcomparedtothegrouporiginallyrandomizedtoplaceboneglectingopen-labeltreatmentswitchandexposuretostudyconditions.395%confidenceintervalsofLOPID:placebogrouphazardratio4Fatalandnon-fatalmyocardialinfarctionsplussuddencardiacdeathsoverthe8.5yearperiod.ItisnotcleartowhatextentthefindingsoftheprimarypreventioncomponentoftheHelsinkiHeartStudycanbeextrapolatedtoothersegmentsofthedyslipidemicpopulationnotstudied(suchaswomen,youngeroroldermales,orthosewithlipidabnormalitieslimitedsolelytoHDL-cholesterol)ortootherlipid-alteringdrugs.ThesecondarypreventioncomponentoftheHelsinkiHeartStudywasconductedoverfiveyearsinparallelandatthesamecentersinFinlandin628middle-agedmalesexcludedfromtheprimarypreventioncomponentoftheHelsinkiHeartStudybecauseofahistoryofangina,myocardialinfarction,orunexplainedECGchanges.Theprimaryefficacyendpointofthestudywascardiacevents(thesumoffatalandnon-fatalmyocardialinfarctionsandsuddencardiacdeaths).Thehazardratio(LOPID:placebo)forcardiaceventswas1.47(95%confidencelimits0.88–2.48,p=0.14).Ofthe35patientsintheLOPIDgroupwhoexperiencedcardiacevents,12patientssufferedeventsafterdiscontinuationfromthestudy.Ofthe24patientsintheplacebogroupwithcardiacevents,4patientssufferedeventsafterdiscontinuationfromthestudy.Therewere17cardiacdeathsintheLOPIDgroupand8intheplacebogroup(hazardratio2.18;95%confidencelimits0.94–5.05,p=0.06).TenofthesedeathsintheLOPIDgroupand3intheplacebogroupoccurredafterdiscontinuationfromtherapy.Inthisstudyofpatientswithknownorsuspectedcoronaryheartdisease,nobenefitfromLOPIDtreatmentwasobservedinreducingcardiaceventsorcardiacdeaths.Thus,LOPIDhasshownbenefitonlyinselecteddyslipidemicpatientswithoutsuspectedorestablishedcoronaryheartdisease.EveninpatientswithcoronaryheartdiseaseandthetriadofelevatedLDL-cholesterol,elevatedtriglycerides,pluslowHDL-cholesterol,thepossibleeffectofLOPIDoncoronaryeventshasnotbeenadequatelystudied.NoefficacyinthepatientswithestablishedcoronaryheartdiseasewasobservedduringtheCoronaryDrugProjectwiththechemicallyandpharmacologicallyrelateddrug,clofibrate.TheCoronaryDrugProjectwasa6-yearrandomized,double-blindstudyinvolving1000clofibrate,1000nicotinicacid,and3000placebopatientswithknowncoronaryheartdisease.Aclinicallyandstatisticallysignificantreductioninmyocardialinfarctionswasseenintheconcurrentnicotinicacidgroupcomparedtoplacebo;noreductionwasseenwithclofibrate.Themechanismofactionofgemfibrozilhasnotbeendefinitelyestablished.Inman,LOPIDhasbeenshowntoinhibitperipherallipolysisandtodecreasethehepaticextractionoffreefattyacids,thusreducinghepatictriglycerideproduction.LOPIDinhibitssynthesisandincreasesclearanceofVLDLcarrierapolipoproteinB,leadingtoadecreaseinVLDLproduction.Animalstudiessuggestthatgemfibrozilmay,inadditiontoelevatingHDL-cholesterol,reduceincorporationoflong-chainfattyacidsintonewlyformedtriglycerides,accelerateturnoverandremovalofcholesterolfromtheliver,andincreaseexcretionofcholesterolinthefeces.LOPIDiswellabsorbedfromthegastrointestinaltractafteroraladministration.Peakplasmalevelsoccurin1to2hourswithaplasmahalf-lifeof1.5hoursfollowingmultipledoses.GemfibroziliscompletelyabsorbedafteroraladministrationofLOPIDtablets,reachingpeakplasmaconcentrations1to2hoursafterdosing.Gemfibrozilpharmacokineticsareaffectedbythetimingofmealsrelativetotimeofdosing.Inonestudy(ref.4),boththerateandextentofabsorptionofthedrugweresignificantlyincreasedwhenadministered0.5hourbeforemeals.AverageAUCwasreducedby14–44%whenLOPIDwasadministeredaftermealscomparedto0.5hourbeforemeals.Inasubsequentstudy,rateofabsorptionofLOPIDwasmaximumwhenadministered0.5hourbeforemealswiththeCmax50–60%greaterthanwhengiveneitherwithmealsorfasting.Inthisstudy,therewerenosignificanteffectsonAUCoftimingofdoserelativetomeals(seeDOSAGEANDADMINISTRATION).LOPIDmainlyundergoesoxidationofaringmethylgrouptosuccessivelyformahydroxymethylandacarboxylmetabolite.Approximatelyseventypercentoftheadministeredhumandoseisexcretedintheurine,mostlyastheglucuronideconjugate,withlessthan2%excretedasunchangedgemfibrozil.Sixpercentofthedoseisaccountedforinthefeces.Gemfibrozilishighlyboundtoplasmaproteinsandthereispotentialfordisplacementinteractionswithotherdrugs(seePRECAUTIONS). MedicationGuide PATIENTINFORMATIONNoinformationprovided.PleaserefertotheWARNINGSandPRECAUTIONSsections. From CholesterolResources LivingWithHighCholesterol FeaturedCenters WhatAretheBestPsATreatmentsforYou?UnderstandingBiologics 10ThingsPeopleWithDepressionWishYouKnew HealthSolutionsFromOurSponsors Shot-FreeMSTreatment YourChildandCOVID-19 ReportProblemstotheFoodandDrugAdministration YouareencouragedtoreportnegativesideeffectsofprescriptiondrugstotheFDA.VisittheFDAMedWatchwebsiteorcall1-800-FDA-1088. HealthSolutionsFromOurSponsors PenisCurvedWhenErect CouldIhaveCAD? TreatBentFingers TreatHR+,HER2-MBC TiredofDandruff? LifewithCancer PillIdentifierToolQuick,Easy,PillIdentification DrugInteractionToolCheckPotentialDrugInteractions PharmacyLocatorToolIncluding24Hour,Pharmacies LopidDrugImprint 000710737_PB elliptical,white,imprintedwithLopid,P-D737 000930670_PB oval,white,imprintedwith93670 001439130_PB capsule,white,imprintedwith225,IG 167140101_PB oval,white,imprintedwithN111 246580260_PB oval,white,imprintedwithB260 317220225_PB capsule,white,imprintedwith225,IG 433530090_PB oval,white,imprintedwithIG,225 433530772_PB oval,white,imprintedwithB260 604290081_PB oval,white,imprintedwithS741 605050034_PB oval,white,imprintedwithAPO034,600 762820225_PB capsule,white,imprintedwithIG,225 Gemfibrozil600mg-TEV oval,white,imprintedwith93670 Gemfibrozil600mg-WAT oval,orange,imprintedwith454,WATSON Gemfibrozil600mg-WC elliptical,white,imprintedwithWC,084 Lopid600mg elliptical,white,imprintedwithLopid,P-D737