17/6/2014 Statins: Actions, side effects, and administration

http://www.uptodate.com/contents/statins-actions-side-effects-and-administration?topicKey=PC%2F4564&elapsedTimeMs=1&source=search_result&searc 1/19
OfficialreprintfromUpToDate
www.uptodate.com2014UpToDate
Author
RobertSRosenson,MD
SectionEditor
MasonWFreeman,MD
DeputyEditor
DavidMRind,MD
Statins:Actions,sideeffects,andadministration
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:May2014.|Thistopiclastupdated:Feb24,2014.
INTRODUCTIONLipidalteringagentsencompassseveralclassesofdrugsthatincludeHMGCoAreductase(hydroxymethylglutarylCoAreductase)
inhibitorsorstatins,fibricacidderivatives,bileacidsequestrants,cholesterolabsorptioninhibitors,andnicotinicacid.Thesedrugsdifferwithrespectto
mechanismofactionandtothedegreeandtypeoflipidlowering.Thus,theindicationsforaparticulardrugareinfluencedbytheunderlyinglipid
abnormality.Conventionaldosingregimensandcommonadversereactionsaredescribedinatable(table1)andtherangeofexpectedchangesinthe
lipidprofilearelistedinaseparatetable(table2).
Lipidlowering,atleastwithstatins,isbeneficialinpatientswithdyslipidemiasforbothprimaryandsecondarypreventionofcoronaryheartdisease.
(See"Clinicaltrialsofcholesterolloweringforprimarypreventionofcoronaryheartdisease"and"Clinicaltrialsofcholesterolloweringinpatientswith
cardiovasculardiseaseordiabetes".)
Themechanismsofbenefitseenwithlipidloweringareincompletelyunderstood.Regressionofatherosclerosisoccursinonlyaminorityofpatients
furthermore,clinicalbenefitsoflipidloweringareseeninaslittleassixmonths,beforesignificantregressioncouldoccur.Thus,otherfactorsmust
contributetheseincludeplaquestabilization,reversalofendothelialdysfunction,anddecreasedthrombogenicity.(See"Mechanismsofbenefitoflipid
loweringdrugsinpatientswithcoronaryheartdisease".)
Thecharacteristicsandefficacyofthestatinswillbereviewedhere(table3).Possiblenoncardiovascularbenefitsofstatinsarediscussedseparately.
(See"Statins:Possiblenoncardiovascularbenefits".)Theefficacyoffibrates,lipidloweringdrugsotherthanstatinsandfibrates,anddietanddietary
supplementsarealsodiscussedseparately.(See"Lipidloweringwithfibricacidderivatives"and"Lipidloweringwithdrugsotherthanstatinsand
fibrates"and"Lipidloweringwithdietordietarysupplements".)
Therapeuticdecisionmakinginpatientswithelevatedlipidlevels,includingindicationsforanddosingofstatins,isdiscussedindetailseparately:
MECHANISMOFACTIONCurrentlyavailablestatinsincludelovastatin,pravastatin,simvastatin,fluvastatin,atorvastatin,rosuvastatin,and,in
somecountries,pitavastatin(table3).TheseagentsarecompetitiveinhibitorsofHMGCoAreductase,theratelimitingstepincholesterolbiosynthesis
(figure1).TheyoccupyaportionofthebindingsiteofHMGCoA,blockingaccessofthissubstratetotheactivesiteontheenzyme[1].
AreductioninintrahepaticcholesterolleadstoanincreaseinLDLreceptorturnoverthatresultsfromanenhancedrateofhepaticLDLreceptorcycling
[2].StatinsalsoreduceVLDLproduction,viaaneffectmediatedbyhepaticapoBsecretion[3,4],anditisassociatedwithadiminishedrateof
recoveryofHMGCoAreductaseactivityafterdrugtreatment[5].
MostofthestatinshavemodestHDLcholesterol(HDLC)raisingproperties(about5percent),althoughrosuvastatinhasalargereffect(see'Effecton
HDL'below).Triglycerideconcentrationsfallbyanaverageof20to40percentdependinguponthestatinanddoseused(see'Effectontriglycerides'
below).ThereductioninplasmatriglyceridesisduetoadecreaseinVLDLsynthesisandtoclearanceofVLDLremnantparticlesbyapoB/E(LDL)
receptors.
Themechanismsbywhichstatinsmayaffectcardiovasculardiseasearediscussedseparately.(See"Mechanismsofbenefitoflipidloweringdrugsin
patientswithcoronaryheartdisease".)
EFFICACYThestatinsarecommonlyusedinthetreatmentofhypercholesterolemiaandmixedhyperlipidemia.
EffectonLDLcholesterol
PotencyThestatinsarethemostpowerfuldrugsforloweringLDLcholesterol(LDLC),withreductionsintherangeof30to63percent(table
3)[610].Whenswitchingbetweenstatindrugs,equipotentdoseswithregardtoLDLCreductioncanbefoundinthefigure(figure2).
Rosuvastatinissomewhatmorepotentthanatorvastatin[10,11],andboththeseagentsaresignificantlymorepotentthansimvastatin,lovastatin,
pravastatin,andfluvastatin[11,12].Atmaximalprescribeddoses,LDLCreductionisgreaterwithrosuvastatinandatorvastatinthanwiththeother
availablestatins(figure2).
Atdosesofupto40mg/day,fluvastatinistheleastpotentstatin(figure2).However,atdosesof80mg/day,fluvastatinisaseffectiveonlowering
LDLCasmoststatinsotherthanrosuvastatinandatorvastatin[13].Fluvastatinislesslikelytohavedruginteractionsorproducemuscletoxicitythan
someotherstatins.(See'Sideeffects'below.)
Althoughsimvastatin80mg/dayisamoderatelypotentdoseofstatin,givenhighratesofmyopathy[14]andtheavailabilityofrosuvastatinandgeneric
atorvastatin,wesuggestnottreatingpatientswithdosesofsimvastatinabove40mg/day.Additionally,cliniciansshouldstronglyconsiderswitching
evenpatientswhoarecurrentlytoleratingsimvastatin80mg/daytooneoftheseotherstatinoptions,sincefuturemedicationtherapyorillnesscould
increasetheriskfordevelopmentofmyopathyonhighdosesimvastatin.Highdosesimvastatinmaybeappropriateforasmallnumberofpatientswho
havetolerateditwellformanyyearsorwhoareintolerantofotherhighpotencystatinoptions.
Thereisanadditivehypolipidemiceffectwhenanyofthestatinsisusedincombinationwithabileacidsequestrant(figure3)[1517],orthecholesterol
absorptioninhibitorezetimibe.(See"Lipidloweringwithdrugsotherthanstatinsandfibrates",sectionon'Ezetimibe'.)
LDLsubfractionsStatinsarethemosteffectiveagentsforloweringtotalLDLparticleconcentration,howevertheyarenonselectiveforreducing
LDLsubclassestheyreducethepredominantsubclass[18].Amongpatientswiththeatherogenicdyslipidemiaprofile,thereductioninthepredominant
subclassofsmall,denseLDLparticlesresultsinashiftoftheLDLsubfractionstomorebuoyant,andpotentiallylessatherogenic,LDL[1921].(See

(See"Treatmentoflipids(includinghypercholesterolemia)inprimaryprevention".)
(See"Treatmentoflipids(includinghypercholesterolemia)insecondaryprevention".)
(See"Intensityoflipidloweringtherapyinsecondarypreventionofcardiovasculardisease".)
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"InheriteddisordersofLDLcholesterolmetabolism",sectionon'SmalldenseLDL(LDLphenotypeB)'and"Lipoproteinclassificationmetabolismand
roleinatherosclerosis",sectionon'Intermediatedensitylipoprotein(remnantlipoproteins)'and"Lipoproteinclassificationmetabolismandrolein
atherosclerosis",sectionon'Lowdensitylipoprotein'.)
EffectonHDLSimvastatin(40to80mg/day)appearstobemoreeffectivethanatorvastatin(20to40mg/day)forincreasingserumHDLCand
apolipoproteinAIconcentrations[22].However,rosuvastatinmaybeevenmoreeffective,raisingHDLCbyupto10percent[11].Inmetabolic
syndromepatients,rosuvastatin(10to20mg/day)wasmoreeffectivethanatorvastatin(10to20mg/day)inincreasinglargeHDLparticles[18].
Whetherthisisclinicallyimportantisuncertain.(See"HDLmetabolismandapproachtothepatientwithabnormalHDLcholesterollevels".)
EffectontriglyceridesAtorvastatinandrosuvastatinaremoreeffectiveatloweringtriglycerides(14to33percent)thanotherstatinsinpatientswith
hypercholesterolemia[11,2325].Themagnitudeoftriglycerideloweringwithstatinsmaybelargerinpatientswithhypertriglyceridemia.
Theeffectsofatorvastatinandrosuvastatinonserumtriglyceridesaredosedependent[11,23].Asanexample,inaseriesof56patientswithprimary
hypertriglyceridemiainwhomtheaveragetriglycerideconcentrationwas600mg/dLandLDLCconcentrationwas120mg/dL(3.1mmol/L),the
administrationofatorvastatinatdosesof5,20,or80mg/dayproducedreductionsintriglyceridesof27,32,and46percent,respectively,andinLDLC
of17,33,and41percent,respectively[23].
Genetic/ethniceffectsPartofthevariabilityintheresponsetoandsideeffectswithstatinsmayberelatedtogeneticdifferencesintherateofdrug
metabolism.Asanexample,CYP2D6isamemberofthecytochromeP450superfamilyofdrugoxidizingenzymes.CYP2D6isfunctionallyabsentin7
percentofCaucasiansandAfricanAmericans,whiledeficiencyisrareamongAsians.
TheCYP2D6phenotypeappearstobeimportantinpatientstreatedwithsimvastatin,asitcanaffectboththedegreeoflipidloweringandtolerability
[26].PolymorphismsinthegenecodingforHMGCoAreductasealsoappeartoaffecttheLDLCresponsetostatins,butnottheHDLCresponse[27].
ConcernshavebeenraisedthatAsiansmayhavegreaterresponsestolowdosesofstatinsthanCaucasians[28].Prescribinginformationfor
rosuvastatinrecommendsstartingtherapyatalowerinitialdoseinAsiansthaninothergroups,givenobserveddifferencesinpharmacokinetics[29].
Thereisnostrongevidencesupportingsuchanapproachwithotherstatins.
PreventionofcardiovasculardiseaseThemajoruseofstatinsisintheprimaryandsecondarypreventionofcardiovasculardisease.Thisuseis
discussedextensivelyelsewhere:
SIDEEFFECTSAdversereactionsoccurlessfrequentlywiththestatinsthanwithmostotherclassesoflipidloweringagents.Hepaticdysfunction
hasbeenasourceofconcernhowever,theactualriskappearstobeverysmall.Myopathyremainsanimportantsideeffect.
Therehavebeenconcernsthatthemorelipophilicstatins(simvastatin,lovastatin,atorvastatin,andfluvastatin)maybeassociatedwithmoreadverse
eventsthanthemorehydrophilicstatins(pravastatinandrosuvastatin)[30,31]however,fluvastatin(alipophilicstatin)appearstohavealowrateof
musclesideeffects[32].
Inrandomizedtrials,statintherapyappearstocauseonlyaslightincreasedriskofsideeffectscomparedwithplacebo,andnoincreasedriskof
discontinuationoftherapycomparedwithplacebo[33,34].However,experienceinclinicalpracticesuggeststhatmusclesideeffectsarerelatively
common,includingsideeffectsrequiringdiscontinuationofstatintherapy.Theexplanationforthisdifferenceisuncertain,butmayrelatetoselection
criteriainrandomizedtrialsthatlimittheabilitytogeneralizetheirresultstothesideeffectprofilesseeninabroaderpopulationofpatients.
Observationaldatasuggestthatwhilediscontinuationofstatintherapyforsideeffectsisrelativelycommon,manyofthesepatientstoleratethesame
statinoranotherstatinwhenrechallenged[35].
HepaticdysfunctionClinicalstudiesofstatinshavedemonstrateda0.5to3.0percentoccurrenceofpersistentelevationsinaminotransferasesin
patientsreceivingstatins.Thishasprimarilyoccurredduringthefirstthreemonthsoftherapyandisdosedependent.Rareepisodesofmoresevere
liverinjuryhavealsobeenseen,andonestudysuggestedthatthesepredominantlyoccurthreetofourmonthsafterinitiationofstatintherapy[36].
However,thesearesufficientlyuncommonthatoveralltheincidenceofhepaticfailureinpatientstakingstatinsappearstobenodifferentfromthe
incidenceinthegeneralpopulation[37].
Severalrandomizedtrialshavereportednosignificantdifferenceintheincidenceofpersistentlyelevatedaminotransferasesbetweenstatinandplacebo
therapy[3840].Asimilarfindingwasnotedinareviewofthreepravastatintrialswithover112,000patientyearsofexposure[41].Therewasno
differenceintheincidenceorseverityofserumaminotransferaseelevationswithpravastatinorplacebo,includingpatientswithaminotransferase
elevationsatstudyentry.Ametaanalysisof35randomizedtrialsfoundanexcessriskofaminotransferaseelevationwithstatintherapyversus
placeboof4.2casesper1000patients[33].
AlargecohortstudyfromEnglandandWalesfoundsimilarrisksofhepaticdysfunctionwithdifferentstatins,withtheexceptionofahigherriskwith
fluvastatin[42].
Areviewofoneyearofrecordsfor1014patientstakingstatinsinaprimarycarepracticefoundthat1percentofpatientshadtransaminaseelevations
morethanthreetimesnormal,and0.5percenthadtransaminaseelevationstwotothreetimesnormal[43].Noneoftheseelevationsappearedtobe
relatedtostatinuse.Similarly,areviewoffiveyearsofahealthmaintenanceorganization'scomputerizedrecordson23,000patientswhowere
receivingstatinsfoundthat17(0.1percent)hadanalanineaminotransferaselevelmorethan10timestheupperlimitofnormalthatappearedtobe
attributabletostatintherapy[44].Ofthese,allbutfourwereassociatedwithdruginteractions.
In2012,theUSFoodandDrugAdministrationreviseditslabelinginformationonstatinstoonlyrecommendliverfunctiontestingpriortoinitiationof
statintherapyandtoonlyrepeatsuchtestingforclinicalindications[45].Weandothersagreethatroutinemonitoringofliverfunctiontestsinpatients
(See"Treatmentoflipids(includinghypercholesterolemia)inprimaryprevention".)
(See"Treatmentoflipids(includinghypercholesterolemia)insecondaryprevention".)
(See"Intensityoflipidloweringtherapyinsecondarypreventionofcardiovasculardisease".)
(See"Clinicaltrialsofcholesterolloweringforprimarypreventionofcoronaryheartdisease".)
(See"Clinicaltrialsofcholesterolloweringinpatientswithcardiovasculardiseaseordiabetes".)
(See"Lowdensitylipoproteincholesterol(LDLC)loweringafteranacutecoronarysyndrome".)
(See"Mechanismsofbenefitoflipidloweringdrugsinpatientswithcoronaryheartdisease".)
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receivingstatintherapyisnotnecessary[40,44,46,47].
Werecommendchangingmedicationsorloweringthestatindoseinpatientswhoarefoundtohaveanalanineaminotransferase(ALT)levelmorethan
threetimestheupperlimitofnormalthatisconfirmedonasecondoccasion.
MuscleinjuryDevelopmentofmuscletoxicityremainsaconcernwiththeuseofthestatins[30,48,49].Myopathicsyndromesassociatedwith
statinsspanaspectrumofcomplaintsrangingfrommyalgiastomyositistoovertrhabdomyolysis,whichmaybeassociatedwithacuterenalfailure
frommyoglobinuria.Thisproblem,includingpredisposingdruginteractions,isdiscussedindetailelsewhere.(See"Statinmyopathy".)Summarized
briefly:
Hypothyroidismisapotentialcauseofdyslipidemia(see"Lipidabnormalitiesinthyroiddisease"),andhypothyroidismmaypredisposepatientsto
statininducedmyopathy[50,51].Assuch,wesuggestcheckingaTSHlevelpriortoinitiatingstatintherapy.
RenaldysfunctionStatinsappeartobeabletocauseproteinuriathroughtubularinhibitionofactivetransportofsmallmolecularweightproteins
[52,53].TherehavebeenanumberofreportstotheFDAaboutproteinuriawithstatins,particularlyinpatientsreceivingrosuvastatinorsimvastatin
[54].However,itisbelievedthatproteinuriawithstatinsisabenignfinding[55,56].(See"Statinsandchronickidneydisease",sectionon'Effecton
proteinexcretion'.)
Therehavealsobeenrareepisodesofrenalfailureinclinicaltrialsofpatientstreatedwith80mg/dayofrosuvastatin[11],ahigherdosethanis
available.However,itisunclearifrosuvastatinwasresponsiblefortherenalfailure,asthesepatientswereonotherpotentiallynephrotoxic
medications.AlthoughconcernshadbeenraisedabouthighratesofadverseeventreportstotheFDAregardingrosuvastatin[54],subsequent
informationsuggeststhatrenaladverseeventswithrosuvastatinarerareandaresimilartothoseseenwithotherstatins[5760].
BehavioralandcognitiveAlthoughconcernshavebeenraisedaboutincreasedsuicideinpatientstreatedwithsomelipidloweringtherapies,
statinsdonotappeartobeassociatedwithanincreasedriskofsuicideordepression[61].(See"Treatmentoflipids(includinghypercholesterolemia)in
secondaryprevention",sectionon'Safetyofcholesterollowering'.)
Therehavebeencasereportsofpatientsdevelopingsevereirritabilityandaggressionassociatedwiththeuseofstatins[62].Itisnotknownwhether
thestatinusecausedthesesymptoms,butveryrareidiosyncraticreactionsofthissortcouldbemissedincontrolledtrials.
Aretrospectivecohortstudyinelderlypatientsfoundanassociationbetweenperioperativestatinuseandpostoperativedelirium[63],howeveritis
difficulttotellwhetherthisassociationwascausal[64].Perioperativeadministrationofstatinsmayhaveimportantcardiovascularbenefits.(See
"Perioperativemedicationmanagement",sectionon'Statins'.)
Concernshavebeenraisedinthemediaandpopularpressaboutcognitivedysfunctionandmemorylossassociatedwithstatinuse[65,66].Areviewof
adverseeventsreportedtotheUSFoodandDrugAdministrationbetweenNovember1997andFebruary2002found60reportsofpatientswhohad
memorylossassociatedwithstatins[67].Fourteenof25patientshadimprovementwhenthestatinwasdiscontinued,andfourhadrecurrenceof
memorylossonrechallenge.Thestatinsinvolvedweresimvastatin(36patients),atorvastatin(23patients),andpravastatin(1patient).
Althoughthisanalysisofadverseeventreportsdoesnotshowthatstatinscausememoryloss,theapparentlyhighrateofreportswithlipophilicstatins
(simvastatinandatorvastatin)comparedwithhydrophilicstatins(pravastatin)doessuggestapossiblebiologiceffect.Randomizedtrialsoflovastatin
andsimvastatinhaveshownsomeevidenceofminordecrementsincognitivefunctionasmeasuredbyneuropsychologicaltesting[68,69].A
systematicreviewofrandomizedtrialsandobservationalstudiesfoundthatpublisheddatadonotsuggestthatstatinsharmcognitionhowever,the
qualityoftheevidencewasfelttobeonlylowtomoderate,particularlywithregardtohighintensitystatintherapy[70].
Intheabsenceofmoredefinitivedata,itmaybeappropriateforphysicianstodeterminewhetherstatintherapywasrecentlyinitiatedinpatientswho
developnewmemoryloss.Ifanindividualpatientappearstohavememorylossassociatedwithlipophilicstatintherapy(simvastatin,lovastatin,
atorvastatin,orfluvastatin)andhasastrongindicationforlipidloweringtherapy,itwouldbereasonabletoattempttreatmentwithamorehydrophilic
statin(pravastatinorrosuvastatin)[71].
Incontrasttotheaboveobservationssuggestingthatstatinsmayproducecognitiveimpairment,otherstudieshavesuggestedthatstatinsmayhavea
roleinthepreventionofdementia.(See"Preventionofdementia",sectionon'Statins'.)
CancerPreclinicalstudiesfoundthatveryhighdosestatintherapyincreasedtheriskoflivertumorsinrodents[72].
Asdiscussedelsewhere,metaanalysesofrandomizedtrialshaveshownnoeffectofstatinsoncancerincidenceorcancermortality[7375].(See
"Statins:Possiblenoncardiovascularbenefits",sectionon'Cancer'.)Apotentiallimitationofthemetaanalysesisrelativelyshortdurationoffollowup.
However,tenyearfollowupofthe4StrialandtheWestofScotlandCoronaryPreventionStudy(WOSCOPS)and11yearfollowupoftheHeart
ProtectionStudy(HPS)showednoincreasesincancerdeaths[7678].
Muscleinjuryisuncommonwithstatintherapyalone,withafrequencyof2to11percentformyalgias,0.5percentformyositis,andlessthan0.1
percentforrhabdomyolysis.

Patientscanexperiencestatininducedmyalgiaswithoutanelevationinserumcreatinekinase(CK)concentration.
Musclesymptomsusuallybeginwithinweekstomonthsafterstartingstatins.Myalgias,weakness,andserumCKconcentrationsusuallyreturn
tonormaloverdaystoweeksafterdrugdiscontinuation.

Pravastatinandfluvastatinappeartohavelessintrinsicmuscletoxicity.
Enhancedsusceptibilitytostatinassociatedmyopathyoccursinpatientswithacuteorchronicrenalfailure,obstructiveliverdisease,and
hypothyroidism.

Ifapatientrequiresastatinandexperiencesmuscletoxicity(otherthanrhabdomyolysis)withastatinotherthanpravastatinorfluvastatin,once
symptomshaveresolvedoffstatintherapy,itisreasonabletoconsideratrialofpravastatinorfluvastatinwithcarefulmonitoring.

ClinicaljudgmentisnecessaryininterpretingelevatedCKlevelsinpatientsonstatins.CKelevationscanberelatedtohypothyroidismortrauma
duringsports(running,divingforavolleyball,hockey),andpatientswhoengageinhighimpactsportsshouldbeadvisedtohaveaCKmeasured
beforeengaginginexercisethatday.Intheabsenceofclinicalsymptoms,aCKlevelmorethan10timestheupperlimitofnormalthatisfeltto
beduetoastatinisanindicationfordiscontinuingthemedication.Patientsshoulddrinklargequantitiesoffluidstofacilitaterenalexcretionof
myoglobin.AftertheCKand/ormyoglobinhavereturnedtobaseline,patientsmaybetriedonastatinlesslikelytocausemuscletoxicity(as
above)withcarefulmonitoring.

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Insummary,thereisnoconvincingevidencethatstatinsincreaseordecreasetheriskofcancer.
DiabetesmellitusStatinscouldhaveeffectsonglucosemetabolismthatmightinfluencethedevelopmentofdiabetesmellitusinnondiabeticsor
affectglycemiccontrolinpatientswithexistingdiabetes.Experimentalevidencehasbeenconflictingaboutwhetherstatinsasagroupimproveglucose
metabolismorwhethersomestatinsshowbeneficialeffectswhileothersshowharmfuleffects[7984].
Previously,someclinicaltrialsofstatinshadreportedconflictingresultsontheissueofglucosemetabolism[8588].However,a2010metaanalysisof
13trials(N=91,140)foundlittleevidenceofheterogeneityamonglargescalechronictreatmenttrials[89].Forinclusion,trialswererequiredtohave
morethan1000patientsandadurationoffollowupofmorethanoneyear.Thismetaanalysisfoundanoverallsmallincreasedriskfordiabetesin
patientstreatedwithstatins(oddsratio[OR]forincidentdiabetes1.09,95%CI1.021.17).Subgroupanalysesfoundverysimilardiabetesrisksintrials
ofhydrophilicorlipophilicstatins,andnocleardifferencesamongindividualstatins.TheresultswerealsosimilaraftertheexclusionoftheJUPITER
trial.SinceJUPITERhadraisedmuchoftheconcernaboutdiabetesandstatins[86],thestabilityoftheresultwithoutJUPITERlowersthelikelihood
thattheglucosefindingsinthemetaanalysiswereduetochance.
A2011metaanalysisoffiverandomizedtrials(N=32,752)alsofoundanincreasedriskofincidentdiabeteswithintensivestatintherapycompared
withmoderatestatintherapy(OR1.12,CI1.041.22)withlittleornoheterogeneityacrosstrials[90].Thistranslatesintoapproximatelyoneadditional
caseofdiabetesforevery500patientstreatedwithintensiveratherthanmoderatestatintherapy.Similarly,alargeobservationalstudyusing
administrativedatafoundahigherriskofdiabeteswithhighpotencystatins,anintermediateriskwithmoderatepotencystatins,andalowerriskwith
lowpotencystatins[91].
Itappearslikelythatstatintherapyconfersasmallincreasedriskofdevelopingdiabetes,andthattheriskisslightlygreaterwithintensivestatin
therapythanmoderatestatintherapy.Aswouldbeexpected,giventheevidencefromclinicaltrialsthatstatinsreduceCVeventsinpatientwith
diabetes(see"Clinicaltrialsofcholesterolloweringinpatientswithcardiovasculardiseaseordiabetes"),bothrandomizedtrialsandobservational
studiessuggestthatthebeneficialeffectsofstatinsonCVeventsandmortalityoutweighanyincreasedriskconferredbypromotingthedevelopment
ofdiabetes[92,93].
Other
RisksinpregnancyandbreastfeedingIntheUnitedStates,statinsareratedcategoryXinpregnancy(table4),andtherecommendationisto
discontinuetheirusepriortoconceptionifpossible.
Animalstudiesindicatethatatmaternallytoxicdosesstatinsareassociatedwithadversefetaloutcomes,butlimitedhumandatasuggestthatstatins
arenotmajorhumanteratogens[106].Althoughsomeauthorshaverecommendedthatpregnantwomencanbereassuredthatthefetalriskislowif
inadvertentexposureoccurs[106],ananalysisofanFDAsurveillancedatabasesuggestsapossibleincreaseincongenitalcentralnervoussystemand
limbabnormalitieswithexposuretolipophilicstatinsduringthefirsttrimester[107].
Theriskofstatinsinpregnancyremainsuncertain,howeveritappearsthatifstatinsareinfactharmful,theeffectislikelyrelativelysmall[108110].
Dataonstatinsafetyinbreastfeedingareverylimited.Intheabsenceofadequatesafetydata,useofstatinsbybreastfeedingmothersisdiscouraged.
ADMINISTRATION
TimingofadministrationThemajorityofcholesterolsynthesisappearstooccuratnight[111],presumablyreflectingtheeffectsofafastingstate.
Forthisreason,itistypicallyrecommendedthatthestatinswithshorterhalflivesbeadministeredintheeveningoratbedtime(table3).
Insupportofthis,trialshavefoundgreaterreductionsintotalandLDLcholesterolwhensimvastatin,whichhasarelativelyshorthalflife,is
administeredintheeveningratherthaninthemorning[112,113].Asmallstudyofatorvastatin,whichhasalonghalflife,foundnosignificant
differenceswhetheritwasadministeredinthemorningortheevening[114].
Whileitisunknownwhetherthetimingofstatinadministrationisimportantforclinicaloutcomes,wetypicallyadministerstatinsatthetime
recommendedbythemanufacturer(table3).Lovastatinabsorptionisincreasedbyfood,anditshouldbeadministeredwiththemorningandevening
meals.
AlternativedosingregimensEveryotherdaystatintherapyhasbeensuggestedasastrategytoimproveutilizationanddecreasecost.Small
studieshavecompareddailystatinusewithalternatedaydosing,andmeasuredeffectsonlipidparametersand,insomecases,attainmentof
CataractInpreclinicaltoxicitytesting,dogsdevelopedcataractswhengivendosesofstatinsmuchhigherthanhumandoses[94].Whilemost
largecasecontrolandcohortstudies[9597],aswellasasmallrandomizedtrial[98],havenotfoundanincreasedriskofcataract,largecohort
studiesfromEnglandandWalesandfromtheUnitedStatesmilitaryhealthsystemhavefoundthatstatinusewasassociatedwithanincreased
riskofcataract[42,99].
Inasubsetanalysis,onecohortstudyreportedanassociationbetweenstatinsandadecreasedriskofonetypeofcataract(nuclearcataract)
[97]however,additionalstudyisclearlyneededbeforeitcanbeconcludedthatstatinsactuallyhaveanysuchprotectiveeffect.

NeuropathyAnumberofcasereportshavesuggestedthatstatinusemaybeassociatedwiththedevelopmentofperipheralneuropathy.Ina
casecontrolstudythatincluded166patientswithafirsttimediagnosisofidiopathicpolyneuropathy(35definite,54probable,and77possible),
theoddsratioofdevelopingpolyneuropathywithstatinusewas3.7forallcases(95%CI1.87.6)and14.2fordefinitecases(95%CI5.338)
[100].Theoddsratioincreasedwithadurationofuseoftwoormoreyears.Forpatientsages50andolder,therewasoneexcesscaseof
idiopathicpolyneuropathyforevery2200personyearsofstatinuse.
Asubsequentcasecontrolstudyusingacomputerdatabasetoidentify272patientswithidiopathicpolyneuropathybasedondiagnosiscodesdid
notconfirmasignificantlyincreasedriskwithstatinuse,howevertheremayhavebeenproblemswithmisclassificationandtheconfidence
intervalswerewide(oddsratio1.30,95%CI0.32.1)[101].
Assuch,acausalassociationbetweenstatinuseandneuropathyremainspossiblebuthasnotbeenproven.

LupusTherehavebeencasereportsofdruginducedlupusinpatientsreceivingstatins.(See"Druginducedlupus".)
AndrogensynthesisSome[102,103],butnotall[104],studiessuggestthatstatinsmaylowerandrogenlevelsinmen,althoughitappears
unlikelythatthiseffectisclinicallysignificant[105].Statinsmayalsoreduceandrogenlevelsinwomen,includinginwomenwithandrogenexcess
[84].

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cholesterolgoalsoversixtotwelveweeks[115119].Everyotherdayregimens,andevenonceweeklyregimens,havealsobeenevaluatedas
strategiesforimprovingtolerability[120122].
Resultswithatorvastatin,fluvastatin,androsuvastatinsuggestthattoyieldsimilarLDLClowering,theeveryotherdaydoseneedstobeonaverage
nearlytwicethatofthedailydose[115,116,118,122].Therearefewdataonalternatedayregimensusingadosegreaterthan40mgoronhowpatient
adherenceisimpacted.
Majoroutcomestrialsofstatinshaveuseddailystatintherapy.Intheabsenceofdatafromlargerandomizedtrialsdemonstratingequivalenteffectson
clinicaloutcomeswithalternativedosingregimens,wesuggestdailydosinginpatientswhoaretreatedwithstatins.Wepreferothermeasuresforcost
control,suchaspricecomparisonamonggenericstatins[123].Clinicalexperiencesuggeststhatalternatedaydosingmayimprovethetolerabilityof
statinsinpatientsexperiencingmyalgias,andthisstrategycanreasonablybetriedinpatientsunabletotoleratedailystatintherapy.
InterchangeWhenswitchingbetweenstatindrugs,equipotentdoseswithregardtoLDLCreductioncanbefoundinthefigure(figure2).(See
'Potency'above.)
Simvastatinandatorvastatinmaybeassociatedwithmoreadverseeventsthanpravastatinorfluvastatin[32].(See'Sideeffects'above.)
DruginteractionsDruginteractions,includingwithotherlipidloweringagents,canpredisposetostatininducedmuscleinjury.Thesearediscussed
inmoredetailseparately.(See"Statinmyopathy".)Summarizedbriefly:
TheantiplateletagentclopidogrelisaprodrugthatisactivatedviametabolismbyCYP450.Basedoncurrentevidenceclopidogreltherapyneednot
affectthechoiceofstatin.(See"Clopidogrelresistanceandclopidogreltreatmentfailure",sectionon'Interactionwithotherdrugs'.)
MonitoringRoutinemonitoringofserumcreatinekinase(CK)levelsisnotrecommendedinpatientsonstatins,butitisusefultoobtainabaseline
CKlevelforreferencepurposespriortostartingstatintherapy.Patientstreatedwithstatinsshouldbealertedtoreportthenewonsetofmyalgiasor
weakness.(See"Statinmyopathy",sectionon'Monitoring'.)
Wecheckbaselineaminotransferaselevelspriortoinitiatingstatintherapywedonotroutinelymonitortheselevelsinpatientsonstatins.(See'Hepatic
dysfunction'above.)
Monitoringofthelipidresponsetostatintherapyisdiscussedseparately.(See"Treatmentoflipids(includinghypercholesterolemia)inprimary
prevention",sectionon'Sideeffectsandmonitoring'and"Treatmentoflipids(includinghypercholesterolemia)insecondaryprevention",sectionon
'Monitoringtherapy'.)
Specificpopulations
ChronickidneydiseaseChronickidneydiseasepresentsanadditionalchallengefortheselectionofastatin.Atorvastatinandfluvastatindonot
requiredoseadjustmentandarethestatinsofchoiceinpatientswithsevererenalimpairment[125,126].
Doseadjustmentiswarrantedwithotherstatinsinpatientswithseverekidneydisease(CrCllessthan30mL/min).Ifstatinsotherthanatorvastatinor
fluvastatinareused,pravastatinmaybesaferthanotherstatins.Asanexample,inasubsetanalysisof1711participantswithchronickidneydisease
(creatinineclearance75mL/min)fromtheCAREtrial,treatmentwithpravastatinforamedianof58.9monthssignificantlyimprovedoutcomes
comparedwithplacebowithoutanincreaseinsideeffects[127].
ChronicliverdiseaseInpatientswithchronicliverdiseasewhorequireastatinbecauseofhighcardiovascularrisk,wesuggestcomplete
abstinencefromalcoholandtheuseofpravastatinatalowdose.IftheLDLCremainselevated,combinedtherapywithabileacidsequestrantmay
allowsuchpatientstoachievetheirLDLCtarget.Statinsarecontraindicatedinpatientswithprogressiveliverdisease.
Patientswhosimplyhavebaselineelevationsinaminotransferasesdonotappeartobeatincreasedriskwhenprescribedastatin[37].Astudythat
lookedatpatientswithoutevidenceofalcoholabuse,hepatitisB,orhepatitisCcomparedacohortof342patients(manyofwhompresumablyhadfatty
liverornonalcoholicsteatohepatitis)withhyperlipidemiaandbaselineaminotransferaseelevation(AST>40IU/L[mean55IU/L]orALT>35IU/L[mean
43IU/L])whowereprescribedastatinwithacohortof2245patientswithbaselineaminotransferaseelevationwhowerenotprescribedastatin[128].
Therewasnosignificantdifferencebetweenthecohortsintheincidenceofmildtomoderateaminotransferaseelevations(4.7versus6.4percent)or
severeelevations(0.6versus0.4percent).Ratesofaminotransferaseelevationswerealsosimilarinacohortofhyperlipidemicpatientswithand
withouthepatitisCwhowereprescribedastatin[129].
A36weekrandomizedtrialcomparingpravastatin80mgdailyorplaceboin326patientswithwellcompensatednoncholestaticchronicliverdisease
(64percentwithnonalcoholicsteatohepatitis23percentwithhepatitisC)foundsimilarevidenceofsafety[130].Overthecourseofthetrial,ratesof
aminotransferaseelevationswerelowinthegroupreceivingpravastatinandnodifferentfromplacebo,andnoneofthepatientshadanexacerbationof
theirunderlyingliverdisease.Similarly,aposthocanalysisofarandomizedtrialofstatintherapy(mainlyatorvastatin,24mgdaily)foundnoevidence
ofincreasedhepaticriskinpatientswithmoderatelyabnormalliverfunctiontestsatbaselinewhoweretreatedwithastatin[131].
Inasmallstudyofpatientswithprimarybiliarycirrhosiswhoweretreatedwithatorvastatin,significanttransaminaseelevationswerecommon[132].
Moststatinsareultimatelyexcretedinthebile,andtoxiclevelscandevelopinpatientswithcholestasis[133].Additionally,thestandardcalculationof
LDLCdoesnotexcludelipoproteinX,whichcanaccumulateincholestasisbutisnotatherogenicandsonotatargetoftherapy.Whileitmaybe
TheriskissubstantiallyincreasedformoststatinsextensivelymetabolizedbycytochromeP4503A4(lovastatin,simvastatinandtoalesser
extentatorvastatin)withconcurrenttherapywithdrugsthatinterferewithCYP3A4(table5).Pravastatin,fluvastatin,rosuvastatin,andpitavastatin
arepreferredwhenconcurrenttherapywithastronginhibitorofCYP3A4cannotbeavoided.GrapefruitjuiceinhibitsCYP3A4,howeverdaily
consumptionofeightouncesorlessofgrapefruitjuice,oronehalfofagrapefruitorless,isunlikelytoincreasetheriskofanadverseinteraction
ormuscleinjury.(Seeindividualdrugmonographsformoredetailedinformationoninteractions).

DespitenotbeingsignificantlymetabolizedbyCYP3A4,rosuvastatinlevelsareincreasedbytheproteaseinhibitorcombinationslopinavir/ritonavir
andatazanavir/ritonavir[124].

Pravastatinisthestatinofchoiceinpatientsoncyclosporine.
Pravastatinorperhapsfluvastatinisthestatinofchoiceinpatientstreatedwithgemfibrozil(orotherfibricacidderivatives).However,itshouldbe
usedcautiouslyandonlyifthebenefitislikelytooutweighthelowriskofmuscletoxicity.Fenofibrateisthepreferredfibrateinpatientswho
requirecombinedtherapywithastatin.

Inpatientstakingamlodipine,thedoseofsimvastatinshouldbenomorethan20mgdaily.
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possibletousestatinssafelyinpatientswithmildcholestasiswhohaveanappropriateindicationfortherapy[134],weavoidstatintherapyinpatients
withsignificantcholestasisunlesstherearecompellingindicationssuchasestablishedatheroscleroticvasculardiseasethatisconsideredclinically
important.(See"Hypercholesterolemiaandatherosclerosisinprimarybiliarycirrhosis",sectionon'Cholesterolprofile'and"Hypercholesterolemiaand
atherosclerosisinprimarybiliarycirrhosis",sectionon'Drugtherapy'.)
TheuseofstatinsisbelievedtobesafeinpatientswithGilbertssyndrome.(See"Gilbertsyndromeandunconjugatedhyperbilirubinemiadueto
bilirubinoverproduction".)
STATININTOLERANCEAsdiscussedabove,whiledatafromclinicaltrialssuggestlowratesofstatinsideeffectsleadingtodiscontinuation,in
clinicalexperienceitisrelativelycommontofindpatientswhoareintolerantofoneormorestatinsbecauseofmyalgiasorothermuscularsymptoms
(see'Sideeffects'above).Lesscommonly,aminotransferaseelevationsrequiremakingchangesinthestatin,thestatindosage,orchangestoanother
classofcholesterolloweringtherapy.
Optionsformanagingstatininducedmuscleinjuryarediscussedindetailseparately.(See"Statinmyopathy",sectionon'Preventionand
management'.)
Optionsinpatientswithaminotransferaseelevations(morethanthreetimestheupperlimitofnormalconfirmedonrepeattesting)aresimilar,and
include(see'Hepaticdysfunction'above):
Despitethesemeasures,manypatientsdonottoleratestatintherapy.Theclinicalmanagementofpatientsunabletotakestatintherapyforprimaryor
secondarypreventionisdiscussedindetailseparately.(See"Treatmentoflipids(includinghypercholesterolemia)inprimaryprevention",sectionon
'Statinintolerance'and"Treatmentoflipids(includinghypercholesterolemia)insecondaryprevention",sectionon'Drugtherapy'.)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyondtheBasics.TheBasics
patienteducationpiecesarewritteninplainlanguage,atthe5 to6 gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatient
mighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.
BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10 to12 grade
readinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalso
locatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)
SUMMARYANDRECOMMENDATIONSStatinsarethemostpowerfuldrugsavailableforloweringLDLCandarethemosteffectivelipidlowering
drugsforimprovingclinicaloutcomeswhenusedforprimaryandsecondarypreventionofcardiovasculardisease.Thechoiceofstatindependsupona
numberoffactors,includingthedegreeofhyperlipidemia,pharmacokineticproperties,druginteractions,thepresenceofrenalimpairment,andcost.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
Adultdosing,sideeffects,anddruginteractionsoflipidloweringdrugs
Drugclass Dose Dosing Majorsideeffectsanddruginteractions
Statins(HMGCoAreductaseinhibitors)
Lovastatin 2080
mg/day
IRtakewithevening
meal.BIDwithmealsif
dose>20mg/day.XR
takeanytime.
Headachenauseasleepdisturbanceelevationsinhepatocellular
enzymesandalkalinephosphatase.Myositisandrhabdomyolysis,
primarilywhengivenwithgemfibrozilorcyclosporinemyositisisalso
seenwithsevererenalinsufficiency(CrCl<30mL/min).Lovastatin,
atorvastatin,rosuvastatin,andsimvastatinpotentiateeffectofwarfarin
thisinteractionisnotseenwithpravastatin,fluvastatin,orpitavastatin.
Moststatinscanalsoaffectdigoxinmetabolismandlevels.
Pravastatin 1080
mg/day

Simvastatin 540
mg/day
Takeintheevening
Fluvastatin 2080
mg/day
IRtakeintheevening
ifdose>40mg/day
takemorningand
evening.XRtakeany
time.
80mg
XR/day
Atorvastatin 1080
mg/day

Rosuvastatin 540
mg/day

Pitavastatin 14mg/day
Gemfibrozil 600mg
BID
30to60minbefore
meals
Potentiateswarfarinaction.Absorptionofgemfibrozildiminishedbybile
acidsequestrants.
Fenofibrate Nanocrystal
145
mg/day
Micronized
160200
mg/day
Micronizedtakenwith
meals.Uselowerdoses
withrenal
insufficiency.
Skinrash,gastrointestinal(nausea,bloating,cramping)myalgialowers
bloodcyclosporinelevelspotentiallynephrotoxicincyclosporinetreated
patients.AvoidinpatientswithCrCl<30mL/min.
Nicotinicacid 112g/day Givenwithmeals.
Startwith100mgBID
andtitrateto500mg
TID.Aftersixweeks,
checklipids,glucose,
liverfunction,anduric
acid.Increasedoseas
needed.
Prostaglandinmediatedcutaneousflushing,headache,warmsensation,
andpruritushyperpigmentation(particularlyinintertriginousregions)
acanthosisnigricansdryskinnauseavomitingdiarrheaandmyositis
Bileacidsequestrants
Cholestyramine 424g/day Takewithin30minof
ameal.Adoubledose
withdinnerproduces
samelipidlowering
effectasBIDdosing.
Nausea,bloating,cramping,andconstipationelevationsinhepatic
transaminasesandalkalinephosphatase.Impairedabsorptionoffat
solublevitamins,digoxin,warfarin,thiazides,blockers,thyroxine,and
phenobarbital.
Colestipol 530g/day
Colesevelam 3.75g/day TakewithmealsQDor
dividedBID
Similar
Cholesterolabsorptioninhibitors
Ezetimibe 10mg/day Increasedtransaminasesincombinationwithstatins
Neomycin 1gBID Ototoxicitynephrotoxicity
Probucol 500mg
BID
LoosestoolseosinophiliaQTprolongationangioneuroticedema
BID:twicedailyQD:dailyTID:threetimesdailyIR:immediatereleaseXR:extendedreleaseCrCl:creatinineclearance.
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Averageeffectsofdifferentclassesoflipidloweringdrugsonserumlipids
Drugclass SerumLDLcholesterol SerumHDLcholesterol Serumtriglycerides
Bileacidsequestrants 15to30percent 0toslightincrease Nochange*
Nicotinicacid 10to25percent 15to35percent 25to30percent
HMGCoAreductaseinhibitors 20to60percent 5to10percent 10to33percent
Gemfibrozil 10to15percent 5to20percent 35to50percent
Fenofibrate(micronizedform) 6to20percent 5to20percent 41to53percent
Cholesterolabsorptioninhibitors 17percent 1percent 7to8percent
Neomycin 20to25percent Nochange Nochange
Omega3fattyacids 4to49percent 5to9percent 23to45percent
:increase:decrease.
*Serumtriglyceridelevelsmayincreaseinpatientswithpreexistinghypertriglyceridemia.
Increasesof20percentareseeninpatientswithveryhightriglyceridesincreasesof5percentaremoretypicalwithfibratemonotherapy
inpatientswithlowertriglycerides.
Lovaza4gramsdailyor12to15gramsoflesspurifiedformofomega3fattyacids.
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Propertiesofstatins
Variable Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin
LDL
cholesterol
reductions
(doserange,
mg)
38to54
percent(10to
80)
17to33
percent(20to
80)
29to48
percent(20
to80)
31to41
percent(1to4)
19to40
percent(10to
40)
52to63percent
(10to40)
28to41
percent(10to
40)
Elimination
halflife,hours
15to30 0.5to2.3 2.9 12 1.3to2.8 19 2to3
Bioavailability,
percent
12 19to29 5 51 18 20 5
Protein
binding,
percent
80to90 >99 >95 99 43to55 88 94to98
Solubility Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Hydrophilic Lipophilic
Cytochrome
450
metabolism
andlsozyme
3A4 2C9 3A4 Limited2C9,
2C8
Limited2C9 3A4,3A5
Active
metabolites
Yes No Yes Yes No No Yes
Effectoffood
onabsorption
ofdrug
None Negligible Increased
absorption
Decreases Decreased
absorption
None None
Optimaltime
of
administration
Anytime IR:evening
(ormorning
andeveningif
takentwice
daily)
XR:anytime
IR:with
eveningmeal
(orwith
morningand
eveningmeal
iftakentwice
daily)
XR:anytime
Anytime Anytime Anytime Evening
Renal
excretionof
absorbed
dose,percent
2 <6 10 15 20 10 13
IR:immediatereleaseXR:extendedrelease.
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Statinsandcholesterolsynthesis
InhibitionofHMGCoAreductasereducesintracellularcholesterollevelsthis
activatesaprotease,whichinturncleavessterolregulatoryelementbinding
proteins(SREBP's)fromtheendoplasmicreticulum.TheSREBP'stranslocateto
thenucleuswheretheyupregulateexpressionoftheLDLreceptorgene.
EnhancedLDLreceptorexpressionincreasesreceptormediatedendocytosisof
LDLandthuslowersserumLDL.InhibitionofHMGCoAreductasealsoreduces
intracellularlevelsofisoprenoids,whichareintermediatesincholesterol
biosynthesis.
Reprintedwithpermissionfrom:Vaughan,CJ,Gotto,AM,Basson,CT.JAmCollCardiol
200035:1.Copyright2000AmericanCollegeofCardiology.
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Comparisonoftheefficacyofstatindrugs
Comparisonofthepercentreductioninserumlowdensitylipoprotein(LDL)
cholesterolwithvariousstatindrugs.
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Thecombinationofastatinandabileacidbinding
resinismoreeffectivethaneitheralone
Thereductioninlowdensitylipoprotein(LDL)cholesterol
concentrationandtheincreaseinhighdensitylipoprotein(HDL)
concentrationisgreaterwiththecombinationofastatinandabile
acidbindingresin,givenascholestyramine,whencomparedwith
therapywitheitherdrugalone.Theeffectsofbothdrugsdecline
exponentiallywithincreasingdoses.
DatafromThePrevastatinMulticenterStudyGroupII,ArchInternMed1993
153:1321.
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Drugratingsinpregnancy(USFood&DrugAdministration)
Category Interpretation
A Controlledhumanstudiesshownorisk
Controlledstudiesinpregnantwomenfailtodemonstratearisktothefetusinthefirsttrimesterwithnoevidenceof
riskinlatertrimesters.Thepossibilityoffetalharmappearsremote.
B Noevidenceofriskinstudies
Eitheranimalreproductionstudieshavenotdemonstratedafetalriskbuttherearenocontrolledstudiesinpregnant
women,oranimalreproductionstudieshaveshownanadverseeffect(otherthanadecreaseinfertility)thatwas
notconfirmedincontrolledstudiesinwomeninthefirsttrimesterandthereisnoevidenceofariskinlater
trimesters.
C Riskcannotberuledout
Eitherstudiesinanimalshaverevealedadverseeffectsonthefetus(teratogenicorembryocidaleffectsorother)and
therearenocontrolledstudiesinwomen,orstudiesinwomenandanimalsarenotavailable.Drugsshouldbegiven
onlyifthepotentialbenefitsjustifythepotentialrisktothefetus.
D Positiveevidenceofrisk
Thereispositiveevidenceofhumanfetalrisk,butthebenefitsfromuseinpregnantwomenmaybeacceptable
despitetherisk(eg,ifthedrugisneededinalifethreateningsituationorforaseriousdiseaseforwhichsaferdrugs
cannotbeusedorareineffective).
X Contraindicatedinpregnancy
Studiesinanimalsorhumanbeingshavedemonstratedfetalabnormalitiesorthereisevidenceoffetalriskbasedon
humanexperience,orboth,andtheriskoftheuseofthedruginpregnantwomenclearlyoutweighsanypossible
benefit.Thedrugiscontraindicatedinwomenwhoareormaybecomepregnant.
Reproducedwithpermissionfrom:LexicompOnline.Copyright19782014Lexicomp,Inc.AllRightsReserved.
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InhibitorsandinducersofcytochromeP4503A4(CYP3A4)*
Stronginhibitors
Atazanavir
Boceprevir
Chloramphenicol
Clarithromycin
Cobicistatcontaining
coformulations
Conivaptan
Darunavir
Delavirdine
Fosamprenavir
Indinavir
Itraconazole
Ketoconazole
Lopinavir
Nefazodone
Nelfinavir
Nicardipine
Posaconazole
Ritonavirandritonavir
containingcoformulations
Saquinavir
Telaprevir
Telithromycin
Voriconazole
Moderateinhibitors
Abiraterone
Amiodarone
Aprepitant
Bicalutamide
Cimetidine
Ciprofloxacin
Clotrimazole
Crizotinib
Cyclosporine
Desipramine
Diltiazem
Danazol
Dasatinib
Dronedarone
Efavirenz
Erythromycin
Fluconazole
Fosaprepitant
Grapefruitjuice
Haloperidol
Iloperidone
Imatinib
Lapatinib
Lomitapide
Metronidazole
Miconazole
Mifepristone
Norfloxacin
Quinupristindalfopristin
Sertraline
Sitaxsentan
Tamoxifen
Tetracycline
Verapamil
Zafirlukast
Stronginducers
Carbamazepine
Dexamethasone
Enzalutamide
Fosphenytoin
Mitotane
Nafcillin
Nevirapine
Oxcarbazepine
Pentobarbital
Phenobarbital
Phenytoin
Primidone
Rifabutin
Rifampin(rifampicin)
Rifapentine
St.John'swort
Moderateorweak
inducers
Aprepitant
Armodafinil
Artemether
Bexarotene
Bosentan
Calcitriol
Clobazam
Colchicine
Dabrafenib
Deferasirox
Desvenlafaxine
Dicloxacillin
Efavirenz
Eslicarbazepine
Estrogens
Etravirine
Exemestane
Felbamate
Fosaprepitant
Griseofulvin
Hydrocortisone
Medroxyprogesterone
Metyrapone
Modafinil
Paclitaxel
Perampanel
Pioglitazone
Prednisone
Ritonavir
Rufinamide
Terbinafine
Topiramate
Trametinib
Vemurafenib
NOTES:Dataareforsystemicdrugforms.Degreeofinhibitionorinductionmaybealteredbydoseandmethodof
administration.SpecificdruginteractionsandmanagementsuggestionsmaybedeterminedbyusingLexiInteract,thedrug
interactionsprogramincludedwithUpToDate.
*TheCYP3A4inhibitorsandinducerslistedinthistablearerelevantfordeterminingpotentialinteractionsofdrugsthatareCYP3Asubfamily
substrates.
LesspotenteffectonCYP3A4reportedinsomereferences.
Datafrom:
1. LexicompOnline.Copyright19782014Lexicomp,Inc.AllRightsReserved.
2. HanstenPD,HornJR.Top100druginteractions:guidetopatientmanagement,13thed,H&HPublications,2013.
3. InhibitorsandinducersofCYPenzymesandPglycoproteinTheMedicalLetter201355(1417):44.
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Disclosures:RobertSRosenson,MDGrant/Research/ClinicalTrialSupport:Amgen[Lipids(Evolocumab)]Sanofi[Lipids
(Alirocumab)]AstraZeneca[Lipids(Epanova)Peripheralarterydisease(Ticagrelor)].Speaker'sBureau:AstraZeneca[Lipids
(Diseasestatemanagement)].Consulant/AdvisoryBoards:Aegerion[Lipids(Limitapide)]Amgen[Lipids(Evolocumab)]Astra
Zeneca[Lipids(Epanova)]EliLilly[Lipids(Diseasestate)]Janssen[Diabetes(Canagliflozin)]Novartis[DMC(Hedgehoginhibitor)]
Regeneron[Lipids(Diseasestate)]Sanofi[Lipids(Alirocumab)].EquityOwnership/StockOptions:LipoScienceMedicinesCo
MesoblastTeva.MasonWFreeman,MDGrant/ResearchSupport/ClinicalTrialSupport:Sanofi[RxofLDLc(PCSK9Ab)].DavidM
Rind,MDEmployeeofUpToDate,Inc.EquityOwnership/StockOptions(Spouse):BonfireDevelopmentAdvisors[CBT(iCBT)].
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
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Disclosures