CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER: 18-936/S—054
`
`FINAL PRINTED LABEL
`
`
`
`

`

`
`
`SOIHO'IHDOHOAHENLLEXOH'H
`
`@OVZOHd
`
`
`
`ddClll€8Ad
`
`PV 3311 DPP
`
`PROZAC®
`FLUOXETINE HYDROCHLORIDE
`DESCRIPTION
`Prozac° (Fluoxetine Hydrochloride) is an antidepressant tor oral admmistration it is chemically unrelated to
`tricyclic tetracyclic, or other available antidepressant agents It is designated (:)—N:methy1-3—phenyl-3-[(oga.a-
`e structural formula is
`weight is 345 79
`tnlluoro-p-tolylloxy‘lrpropylamine hydrochloride and has
`e empirical tormula ol CnHwFaNO-HCI Its molecular
`
`FJC
`
`o — CH CHZCH2 NH CH3 . HCl
`
`Fluoxetme hydrochlonde is a white to ell-white crystalline solid wrth e solubility at 14 rug/ml. in water
`Each Pulvule‘ contains flucnretine hydrochloride equlvalent to 10mg (323.”urnol), 20
`(64 7 urnol). or
`40 mg (129 3 pmoDollluoxetine The Pulvulesalsocontainstarch. gelatin. silicone, titamurn
`ide iron mode
`andolhermactrveingredientsThe lOn'igandZOrngPulvulesalsocoritain FDliCBlue No 1 andthewma
`PulvulealsocontatnsFDatCBlueNo 1 andFDaiCYelleos.
`EachmuetcuimhismmxemhydmmeqummtowmgtfiapniwdmmThetabletsalso
`contain nucroaystalline cellulose, magnesium steamte. Whydroxypropyt
`lulcse,tttanlurn
`ditmde, polyethytene glycol, andyellcwrron oxide lnadd‘montolheabove mgredientsthe 1 mgtabletcontalns
`F D & C Blue No 1 alumrrium lake, and polysorbate 80
`The oral solution contains lluoxetine hydrochloride equivalent to 20 rug/5 mL (64 7 umol) of fluoxetine It also
`contains alcohol 0 23%. benzotc acid, flavoring agent, glycerin. purified water, and sucrose
`CLINICAL PHARMACOLOGY
`
`Pnarrnacodynamlcs
`The antldepressant, antiobsessrve—compulsive, and antlbulimic cottons ot fluoxetine are presumed to be
`linkadtoltslnhibitionotCNSneuronaluptakeolseiotoninSlidesatclmmllyrelevantdosesmmnhave
`demonstrated that lluoxetine blocks the uptake of serotonin into human platelets Studies tneanimals also
`ntagonism ot muscannic, histamine to, and aradrenergic receptors has been hypothesrzed to be
`suggest that lluoxetine is a much more potent uptake Inhibitor ol serotonin than at norepinephrin
`associated wrth various anticholinergic,s
`tive and cardiovascular eflects ol classical tricycfic antldepressant
`to
`rugs
`drug: chydluoxetin: binds to these and other membrane receptors from brain tissue much less potentty in vltro than
`Absorpaon. Drsmbution, Mambo/ism. and Excretron
`lluoxetrnefrom15t055
`LateobservedaerGtoahours
`W—lnmanJoflmtgasmgleoralwmgdose, peakplasmaconcentmtlonsot
`ThePulvule.tablet.
`oralsoluhmdosagelomisolfluoxebnearemfioddoesmt
`to
`aflectmesystermcbioavanabitnyotflumehnomtsalthoughnmaydetay W,
`—
`concentratron
`«H.000
`app
`"BMW Overthe wither
`rangetrorrizoo
`ngImL mudniatatyst.s%otlltmtlne
`isbmuidhvihomhuniansenunprotensincludingalbwnmand a1—glycoproteln'lhe hteractlonbetween
`mmmmmpmmmhasmmmwa'mmmmmmmme
`Precautions).
`m—Hmeammmtmwmmmmsmmmm
`mmemmmmmmmmimm
`mmwmmsmmmeummmmwam
`enantrmnerpremmrnplasmaatsteadystate.
`unidentified metabolitesnieonly
`active membolite. norlluoxetlne, lslbrmed
`Metamhsn——Fluouretineis
`MWMMWWMWWIWOIMJ
`actrvityessentiallyequlvelentto
`uoxeunefinorfluoxetineis gilllcanttylass
`or
`flmnelnmmwgmbammmxmzmdm
`“and
`drugmlhelnhlbitionyolsemnnuptalte‘lheprlmaryrouteolelimuiahonappearstobehepetlc
`bmlo
` ; -,. ,. W;- .A. c||1m|l|flI|—mmp‘exnyduw metabollsmottluoxefinehas
`
`inactivemetabolitesexcreted
`several consequences thatrnaypotanhallyatledfluomtme'hsdlmcaluse
`olthedrig‘wmetabollzlng
`—Asr.ibset(abom7%)olthepoputationhasrcduceda
`dezctrornethorptian,
`antidepmants na
`PMIDSammWhare
`to'as smdylnvolvlnglabegdendmlabelelg
`debrlsoquh.
`enarmontersedmlnlfieredesaracernatemiese Wmmbomdsmmammmm
`werelowar
`metabolisrnotR-Ilimtinenthese
`metabolizers
`normalWhencornparedwlth
`mummfiasdsmmmmmmdmmmsmdym
`nanialnieiabdzemttietotalwmatsteadystated
`gyneconcentra
`otthe4ectlveenentlomerswas
`notsgmfimnttyyeaterarmpoormetabouzersnms,
`netpharmecodynamlcadlvltleswere
`the
`sameAltematrvenonsatu
`EWmoMIDQalsocmflmetuthemetabofismdmmtineThs
`Because uoxetine‘s
`that
`anum
`otheroompoundsmctudmgmcyeuc
`«tier
`houtluoxatiiaeachievesastea mtfikgoncengialronrathéganhcrewm Mthwtllrnit
`and
`selecnveserutonmantidepmants, irivolvesIriePtsollesystem concornltanttherapywlthdrugselso
`membofizedbythisenzymesysterMstmaslhetrwclicantidepressants)mayleadtodmghteraalons(see
`
`iim u—Therelafivelysloweflnuneuonotflmunehlmunmhafl—fleott to
`adaysetteracuteadmlmstrauonand4m6daysalterchronicedrnlmstration)andttsacuverrietabolite,
`norfluaxetme (elimination hall—lite of 4 to 16 days after acute and chronic adrnlntstrnoon).
`leads to slgrilflcent
`ammflahmdflwseacuvespeaeslndtmmcuseanddehyedaflmmwntdsteadystateevenwhenetbred
`doseisused Atter30daysoldosingat4o
`dayplasmaconcentrationsotlluoxetmelntherangeotm to
`302 ngImL and norfluoxetme in the ra
`cl 7 to 258 nglmL have been observed Plasma concentrations at
`fluoxeline were higher than those pr
`ed by srngle~dose studies, because l'luoxetine's metabolism is not
`proportional to dose Nortluoxetine, however, appears to have linear pharmacokinetics Its mean temiinal hall-
`lrle alter a Single dose was 6 6 days and after muluple dosmg was 9 3 days Steady state levels alter prolonged
`dosmg are Similar to levels seen at 4-5 weeks W- .
`. -a 1- -
`The long elirnination halt-lives at fluoxetine and norfluoxetme assure that even when dosing is stopped active
`pre'VIous dosmg regimen and lengt oprevious therapy at discontinuation) This is 01 potential consequence
`drug substance wrll perstst in theh
`for weeks (primarily depending on indiViduaI patient characteristics,
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`actiwty essentially equwalent to F?- or S-IluoxetinerFt-norfluoxetme is Significantly less potent than the parent
`drug in the inhibition ol serotonin uptake The primary route at elimination appears to be hepatic metabolism to
`inactive metabolites excreted by the kidney
`Ii
`—The compleitity of the metabolism ol fluoxetrne has
`several consequences that may potentially allect fluoxetine‘s clinical use
`Ii —Asubset(about7%)olthepopulationhasreduceda
`olthedmgmetabollzmg
`enzyme cytochrome PASOIIDG Such indivtduals are relerred to as 'poor meta
`izers' ol drugs such as
`debrisoquin, dextromethorphan. and the tricyclic antidepressants In a study mvolvmg labeled and unlabeled
`enantiomers admmistered as a racemate, these individuals metabolized S-lluoxetine at a slower rate and thus
`achieved h
`or concentrations of S-Iluoxettne Consequently, concentrations 01 Snorfluoxetine at steady state
`nonhalmetabolizeithetotalsumatsteadystateol
`concentrationsoltl'ie4activeanaritiomerswas
`werelcwver
`metabdsmdflflummhmlggmmembduersappearsmmalWhenoompamdwm
`notsignificanttygreater
`poormetabolizerst'hus.
`netphannacodynamicactrvrtieswereessen
`the
`same. Alternative, nonsatu
`pathways (non-IIDG) abo contribute to the metabolism 01 lluoxetine. This
`Because fluoxetine‘s me
`Ism, like that of a number 01 char compounds including tricyclic and other
`how lluoxetine achieves a am-state concentration rather than increasing without limn.
`selective serotonin antidepressants. Involves the P450IIDG system. concomitant therapy with dnigs also
`metabolized by this enzyme system (such as the tncyclic antidepressants) may lead to drug interactions (see
`Drug Interactions under Precautions)
`minimum—The relatively slow elimination ot lluoxetina (elimination halt-lite cl 1 to
`3 days aher acute adininlstration and 4 to 8 days alter chronic adrninistration) and its active rnetabottte.
`norfluoxetine (elimination hall—lite cl 4 to 16 days alter acute and chronic administration),
`leads to significant
`accumulation oltheseactivespeaesmchmnicuseariddelayedattammemotsteadystate.evenmnaflxed
`doseisused Alter30daysoldosingat40
`day,plasrnaconcentrahonsottluoxatmelntherangeot91to
`fluoxetina were higher than those pr
`ted by Single-dose studies. because fluoxetme's metabolism is not
`302ng/mLandnorfluoxetineintharaéggol
`toe
`nglmLhavebeenobserved Plasmaconcentratlonsol
`proportional to dose Norfluoxatine, however, appears to have linear pharmacokinetim Its mean terminal hall-
`lile alter a single dose was 8 6 days and alter multiple dosing was 9 3 days Steady state levels alter prolonged
`dosing are stmrlar to levels seen at 4-5 weeks
`The long elimmation hall-lives ol tliioxetine and nortluoxetine assure that, even when dosing is stopped. active
`drug substance wtll persist In the
`tor weeks (primanty depending on inndtual patient characteristics.
`prowous dostng regimen. and length
`prevrous therapy at discontinuation) This is at potential consequence
`when drug dmontinuation is requrred or when drugs are prescribed that might interact wrth fluoxetina and
`norltuoxetine lollowmg the discontinuation ol Prozac.
`'
`—
`W—As
`tbepredictedtroinits
`rysitaolrnetabolisrnJi’verimpaimieMcanaltectlhe
`eliminationotlluoaietine
`eelimtnation hall—lileot
`mprolongedinamidyolcmhotic patientswllh
`ameanot76dayscomparedtotherangeot2toadaysseenin
`withomliverdiseasemorfluoxetine
`elirninationwasalsodelayed,wlthameandurationollz
`brci
`oticpahents
`aredtotherangeot
`7co9dayslnnonnalsuects‘lhissuggeststhattheuse
`lluoiteiinelnpatientswilh
`diseasemustbe
`approachedwithcaution
`I’IuoxetineisadministeredtopaoentswithIlverdisease,alowerorlesslrequentdcse
`should be used (see Precautions and Dosage and Admlnistration)
`Begum—In depressed patients on dialysis (N=12), lluomtine administered as 20 mg once daily tor
`two months produced steady-state tluoxetine and norltuoxetina plasma concentrations comparable to those
`seen in patients wrth normal renal lunctim While the possbillty must: that renally excreted metabolites ot
`ltuoxetina may accumulate to higher levels in patients with severe renal dysfunction. use at a lower or less
`frequent dose is not routinely necessary in renalty impaired patients (see Use in Patients with Concomitant
`Illness unde/ Precautions and Dosage and Admrnistration)
`Age—The disposmon ol Single doses at fluoxetine In healthy elderly subjects (greater than 65 years at age)
`did not dittei Significantly lrorn that In younger normal subgects However. given the long halt-lite and nonlinear
`dlsposmon ol the drug. a Single-dose study is not adequate to mle out the possrbility ol altered pharmacokinelics
`in the elderly, particularly it they have systemic Illness or are recon/mg multiple drugs for concomrtant diseases
`The ellects at age upon the metabolism of fluoxetine have been Investigated in 260 elderly but otherwise healthy
`depressed patients (2 60 years at age) who received 20 mg ftuoxetine lor 6 weeks Combined tluoxetine plus
`norfluoxetine plasma concentrations were 209 3 2 65 7 nglmt. at the end ol 6 weeks No unusual age-assomated
`pattern at adverse events was observed in those elderly patients
`Clinical Trials
`Depression—The elficacy ol Prozac lor the treatment of patients with depresSIOn (2 18 years ol age) has
`been studied in 5- and 6-week placebocontrolled tnals Prozac was shown to be Significantly more ellective than
`placebo as measured by the Hamilton Depression Rating Scale (HAM-D) Prozac was also Signrlicantly more
`ellective than placebo on the HAM-D subscores tor depressed mood, sleep disturbance, and the aniuety
`Simlactor
`
`effedrve in the treatment of elderly patients (2 60 years at age) with depressm In these
`es,
`rozac
`Two 6-weekcontmlledstudiec comparing Prozac,20rng. andplmebohavashownProzac. msmdaiptobe
`prodwedasgnmcandyhigherrateolmspmseandmmasdefimdmwecm byaSO‘tsdecreaselnthe
`HAMD score and a total endpomt HAM—D score of s 7 Prozac was well toleiat
`and the rate of treatment
`discontinuations due to adverse events did not ditler between Prozac (12%) and placebo (9%)
`A study was conducted invoMng depressed outpatients who had re
`(modified HAND-17 score ol 3 7
`bytheendolanmitiallZJweekopen treatmentphaseoanzacmmglday
`patients(N=298) were
`during each at the last 3 weeks at open—label treatment and absence mayor down by DSM~IIl—R criteria)
`randomized to continuation on doubleMnd Prozac 20 rnglday or placebo At 38 weeks (50 weeks total), a
`statistically signilicantly lower relapse rate (defined as symptoms sulfident to meet a dagnosis ot mayor
`nlor2weeksorarnodified HAMD-l7woreol214lor3weeks)msobservedlorpatientstakng
`Prozac compared to those on placebo
`WWWI—Memdemummmmme
`cusorder (000) was demonstrated in two 13-week, rnultiwnter, parallel group studies (Studies 1 and 2) or adult
`outpatients who received fixed Prozac doses at 20. 40, orso
`day (on a once a dayschadule, in the morning)
`or placebo Patients In both studies had moderate to severe
`D (DSM~IIl-R), with mean baseline ratings on
`the Yale-Brown Obsessive Compulsive Scale (YBOCS. total wore) rang
`from 22 to 26 In Study 1, patients
`Prozacexpenenoedmeanreductionsolappmmatety4m unhsontheYBOCStotalscore.
`compared to a Hinit reduction lor placebo patients. In Study 2, potions iaceivtng Prozac experienced mean
`reductionsolapproxnriately4toQunitsonlheYBOCStotalscore.comparedtoal-unitreductionlor
`patients Whiletherewasnomdicationotadosereqaonsarelatiorishpbreflactivenessmsmdyt,adose
`The lollowtng table prowdes the outcome classification by treatment group on the Clinical
`lobal Impresston
`relationship was observed in Study 2. with nurnencalty better responses in the 2 higher dose
`
`(CGI) improvement scale tor studies 1 and 2 combined
`Outcome Classd‘mtron at.) on Get I
`merit Scale tor
`Cornpleters in
`ol Two
`0 Studies
`
`
`
`Emmwamsvagemmreflwbmmddmmamdnmmudm
`onthebasisotageoisex.
`mmm—mmamummammmmhmm
`andonetmhmwhounermamndmshflmdwuhamnsnmtngDSM-IIl-Rmbrmm
`Patientsintheawveekstuifiesraceivedeitherzoniyihyoreo
`olProzncor
`Inthemorning.
`PatientsmthelG-weekstudyreceivedafixedProzacdosedGOnigl
`(onceaday orplaceboPaiientsin
`thesaastudieshadmodaratetoseverebutimlawithinedian
`andvornltingtrequenclesianglnglrom
`7to10perweekand5to§perweehmspectrvelyInthase3studes,szac,60mg.butnot20mg.was
`mmwmwwmmummmmmdmwmmmpu
`study
`iuzac
`persistedthroughout
`appea
`weekThestatistlcally
`sulgerloretlactolGOmgvsplwebowaspresentmeadyasweektand
`otbasellnedeprasslonasassessedbydeHamflton
`Deprm
`.Ineachottheseastud‘iesthe
`baselinemlrequencyolbulimicbehathorsatandpoint.
`from b2episodesperweeklor
`ueaomaflea.asmawrwbyddbmwesbeMeumnc.wm¥.aMphcebommedanreamm
`and2to4episodesperweeklorvomitmg‘l'hesizeotthe
`wasielatedtobaselinetrequency.
`geater
`reductionsseenin patiemswittihigherbaseline frequencies
`tsachieved lreedomtrom
`binge-eanngandpurgingasaresultoltreatrnermlorthempnty
`bene wasapartialreductiontnthe
`hequencyolbmge—eatingandpurging
`INDICATIONS AND USAGE
`PmmcbwfmtedbrmueammddepressimTheelflcacydezacmseskbfismdm
`tolheDSM-IlHairrenlly DSM-IV) categoryo maprdepressivecisordeusee Clinical
`rialsunderdtnical
`5-end6—weekuulswnhdepmssedwmafientsleayearsctage)wlwifiagnoses
`rnoactosely
`Pharma
`)
`Amapr
`esstveeptsodeDSM
`prmwientandrelatrvely
`rststentnearty
`brat
`WZMWdemegpmmaammm»wmm1ywu
`(.andmmtleast
`smmHmemmmmmm,mdmmmmmfimmmmW
`and/orappetite.insomniaor
`psychomotoragltaoonorretardauonnncreasedlattguefieellngsot
`wnmmmhssrmfibwedMHngmmimdmmuomambdeMmamdalmm
`mmdemessanawondemhlnspnmueddemessedpamsmmbemademmtaym
`TtieetficacyolProzaclnmamtalningananddepressamresponselor
`toaaweekslollaimg 12weeksot
`open-labelaoutetreatment(50weekstoml)wasdernonstratedina
`triaI.Theusel'Iilnessol
`the dru in patients recemng Prozac tor extended periods should be reevaluated periodically (see Clinical Trials
`under
`Iinical Pharmacology)
`ObsessrveCompuls/ve Disorder—Prozac is indicated tor the treatment at obsessions and compulsions in
`patients with obsesswe-cornpulswe disorder (0CD). as defined “1 the DSM-Ill-R, Ie.
`the obsessiions or
`compulsions cause marked distress. are time~oonsuming_ or Slgfllfitfiam mJedere wwifioqal or occupational
`lunctioning
`‘
`The efficacy ol Prozac was established in tsweek trials wrth obsesswe—compulsive outpatients whose
`diagnoses corresponded most closely to the DSM-III-Ft category at obsessrvecompulsive disorder (see Clinical
`Trials under Clinical Pharmacology)
`
`

`

`ectwe than
`depress-on (z ta years on .9” .,..
`real TnaIS'
`shown to be srgmflcahs also srgmtroantty more
`tor the treatment at pattents wrth
`trofledtnals Prozac wasto (HM-+0) Prozac wa
`The etflcacy o! Prozac
`eep drsturbame. and the annety
`to 5— and eweek
`as measured by the Hamrtton Depressbn Rattng St»
`on the HAM—D subscores tor depressed mood.
`
`
`
`on the bass 0! age 01 sex
`Bulrmra Nemsa—The euecttveness ot Prozac tor
`mcenter. para|tel group studies 0! adult wtpatrents mee
`rthefzomgldayor mgldayotProzacorpla
`day (woe a day) or placebo
`treq
`ranging from
`ta
`k studies r
`e
`wed a hxed Prozac dos
`
`vslsied throng sswn as 3559
`treatment em 5 measured by drtterenc
`some
`ot bullmtc behawors at endpomt.
`The sue otthee ectwas relatedto
`per week tor vommng
`h
`er baselrne trequencnas
`reductions
`a mu“ 0! treatment. tor the mapnty.
`bwm and purgtng as
`trequenq 0t bingo-eating and purgmg
`PrOzac rs mdroated bf the
`atmem
`ents (z 18 years 01 age)
`pr
`serve dtsorder see Ch
`5— and 6—week tnals wrth depreDsM-IV) category 01 me
`to the DSM—Ill (currentty
`Pharmacology)
`(DSM-IV) miles a ptusualty Interteves
`ressrvo eprsode
`mayo!
`or dysphonc mood tha
`
`trams achmat reduotron tn the
`
`newnmg
`
`the d
`lsiva
`mar—Prozac ts muted tor the treatment 01 obsesstons
`dtsorder 000). as defined tn the DSM—Itl'R. re. the W5 or
`mt
`meantty untertere wrlh 5068‘ 0' WW
`unggrnrcal managing
`The attrcacy ot Prozac was estabhshed m tameek trtals with obsessive
`nosescorreSpondedmosoglctoselytotheDSM—III—Rcategory01obsessive-compulsivedtsordef
`rrent and persrstent rdeas. thoughts. Wm
`09V)
`elul. and Intentional behavrors
`repetitive. purpos
`of
`Tnats under Clrnrcal Pharma
`uI
`disorder ts characterized by men
`Obsesslwm stve
`Images (absessrons) that are ego-dystomc
`that are recognued by the person as excessive or unr
`term use. to, tor more than 13 weekS. has not
`who elects to use Prozac tor extemled
`mdeual patent (see Dosage and
`
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`ddOLL88Ad
`
`PROZACo (Fluoxetine Hydrochloride)
`and/or at higher doses [see Accumulation and Slow Elirnination under Clinical Phannaoologyl) should be
`allowed after stopping Prozac belore starting an MAOlWARNINGS
`Rash and Possr
`Allergic Events—In US lluoxatine clmical trials. 7% at 10.782 patients developed varlous
`types at rashes a
`or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials,
`almost a third were Withdrawn trom treatment because of the rash and/or systemic Signs or symptoms assocrated
`with the rash Clinical findings reported in association with rash include lever, leukocytosis. arthralgias. edema,
`carpal tunnel syndrome, respiratory distress, lymphadenopathy. proteinuna, and mild transamtnase elevation
`Most patients improved promptly wrth discontinuation of lluoxetine and/or adiunctive treatment wrth antihistamines
`or stemids. and all patients experiencing these events were reported to recover completely
`In prernarketing clinical trials. 2 patients are known to have developed a serious cutaneous systemic Illness
`In neither patient was there an unequwocal diagnosis. but I was conSidered to have a leukocytoctastic vasculitis,
`and the other, a severe desquamating syndrome that was consrdered variously to be a vasculitis or erythema
`multitorme Other patients have had systemic syndromes suggestive ol semm sickness
`Since the mtroduction of Prozac, systemic events. possibly related to vasculitis, have developed in patients
`With rash Although these events are rare, they may be serious. IfWOMI'lg the lung, kidney. or liver Death has
`been re
`rted to occur in association with these systemic events
`been report
`edord events, including bronchospasm, angioadema, and urtimna alone and in combination. have
`Pulmonary events. including inflammatory processes of varying histopathology and/or fibrosis have been
`reported rarely These events have occurred with dyspnea as the only preceding symptom
`Whether these systernic events and rash have a common unde
`ng cause or are due to ditlerent etiologies
`has not been identified Upon the appearance at rash or of other possi y allergic phenomena lor which an
`or pathogenic processes is not known Furthermore. a spacrfic
`
`rlyinologng‘immunologic baSIS lor these events
`altamatrve ecology cannot be identified, Prozac should be discontinued
`PFIECAU l IONS
`General
`Wnusmbocmwleddmmbrdemm tnmtsfihotpatrentstreated
`anSpIacebo—controlladclinicaltrialslorobsasslva-corimulslve doorder,rrisornnawasreportedm28%ol
`mmmnmmdmmmmmmmmmmmmomma
`pauentstremodwithProzacaridmmapauentstreatedwithplaceboArmetywasreportedmtfiotpatlents
`treatedwrthProzacandeotpatientstraatedwmiplacebo
`In US placebocontrolled clinicaltrialslorbulin-rlanervose.lrisorririiawasreportadin 33%otpatients treated
`with Prozac. 60 mg. and 13% of patients treated wlth placebo Anxrety and nervousness were reported
`Marespectivecalmly in 15% and11% otpatients treated with Prozac. 60mg. and in 9%arid 5% or patients treated wrtti
`AmongMunstcmnmonadverseeventsassoclatadmmascmmmmonancidanceetleasttwicethattor
`placebo and at
`least 1% tor Prozac in clinical
`trials collecting only a primary event associated with
`dlscontinuatlon) In US placebocontrolled fluoxotlne clinical trialswera anxiety (2% in 000), insomnia (1% in
`combined indications and2%inbulimia), andnervousness(l°/-mdapressron)(see1’able3. below)
`maybeanundesuableresuttoltreatmamwithmzac
`WW—Significant weightless especiallyinunderweight depressedorbulimic patients
`InUSWpIacebo—coritrolt.edclmrceltiialslordepressi0n11%olpatiantstreatedwithProzacand2'ltotpaflants
`traatadwith
`and 05%otanentsweatedeplacebonnwenomymrelyhmpahentsdiscammed
`madmmmwnedamraxra((dacrewedeppetlta) Welghtloaswasreportedin 14%otpetlents
`treatmentwithProzacbecaumolanoreidaor
`loss
`
`treated
`plecaboreportad anorexra(daoreasad appetite Onepatientdmontinuad treatmentwithProcec
`lnusg‘aoabo-cormolladclmlcalmalsloroc 1mg tlamstreatedwithProzacendImSolpatiants
`becausedanoreada.
`In US placabocontrolledctiniceltrlalslorbutlmla nervosa.8%otpatrentstreatedwrthProzac. 60
`.and4%
`"19-0"
`otpatlentstreatedwlthplecebo WWWariorexra (decreased appetite) Patients treatedwnhProzac
`averagelosto'45kgoompered
`galnolOtGkgbypatlantstraatedwrthplacebolnthelG—weekdouble
`
`
`~.
`.A
`r:
`n
`placebo-corny
`trials
`depressionion.rnanlalhypomania
`blind
`_
`:_should_bernorli’istoreddurlng
`clinical
`ior
`was
`InotxotpatientstraatadwmiProzacandonsotpabantsueatedwlm
`Actrvetlonol
`hasabobeonmponedhasnanwopomondpaflensmhMaiaMecweDsomrmted
`wrthotharmarlieted
`wMIszacandmpabentsneatedMMptaceboNopabansmpmedmamaAiypanama
`USplacabo-
`Inusuacebocmmbdcfinwmbrocomwmmammpmwnofidp‘amtsm
`controfladctlnlcgu'lalabrbulumalnalUSszacdlnicaltriaIs 07%oI10782patleritsraportad
`havrngbeensaizures)werereportadinot%otpatientstreetedwlthProzacandozfisol
`tstreatad
`m—lnuswambownudbddmmbrdemmbn,wmbm(mmdescnbaduposm
`SPromc
`modeOJBZpammmpMedmnvumThepemwmgaappearsmmmlmm
`BlaceboNo
`bentsreponedcorwulslorismUSplacebo-oontrofladdmrcalmalstorelmer
`Dorbiifimlalnall
`ory
`selzures.
`maseoociatadwnhotharmanretedantideprassamsProzacshouldbeintroducedvnthcereinpatientswitha
`sinus—me possibllityotasuicida atternptislnharentmdepresslonand maypersrst until
`Prozacstiouldbewntten
`thasmallestquarmyotcapsules
`witfi
`" patiammanagement,lri
`remusronowursCloeesummsronolhighigl'inskpatrentsshould
`inmald
`therapy Prescnptionstor
`ordertoreduoatherlskotoverdosa
`WMMWWWMOCDMWMMMWWJB
`mmmmmmmmmmmmmmmmuwpam
`with 000 or bulimla.
`
`it
`=
`=*
`a.
`~ w .olthelongelirmriatlorihall—lives
`
`oltl'ieparantdruqendltsrriaroractiverrietabolitachanges
`willnotbetuoyreflectedinptasrnatorseveral
`mammbommwgesummmwmmmmimmm(mw
`
`—
`—C1iriicel experience with Prozac In patiams wrth concorrutant
`Pharmacologyand Dosa : and Adriiiiiistration)
`ernicillnesslsmmed CaubomsadvisablemusrnngmcmpabemswmicflseasesucondmmtcuM
`a
`metabolism or hemodyriarnic responses
`Hucxemahasnotbeenevaluatedmusadtoarvapmadaflaexterflhpabentswmiarecanthistoryor
`tlnlarction or unstable heart disem Patients with these diagnoses were 5ystematical
`excluded
`tromctlnicetstudiesd
`ttmprodudsprenwkettesmgHowavermealacuocardiogmmsot32peflents
`who received Prozac in
`trials were retrospectively evaluated; no conductim abnomialities that
`resulted in heart block were observed The mean heart rate was reduced by approiomately 3 beats/min
`In subrects With arrhosrs ol the liver the clearances 01 lluoxetine and its active metabolite. norfluoxetine were
`decreased thus increasrng the elimrnation halllives of these substances A lower or less Irequent dose should
`be used in patients wrtti cirrhosis
`Studies in depressed patients on dialyss did not reveal excessrve accumulation at fluoxetine or norfluoxetine
`in plasma (see Renal Disease under Clinical Pharmacology) Useol a lower‘or less lmqtr’erit dose tor renally
`impaired patients is not routinely necessary (see Dosage and Admmistration)
`In patients wrth diabetes Prozac may alter glycemic control Hypoglycemia has occurred during therapy with
`-r._-.a.t..._ L._ ._r _- .__.
`Prozac and hyperglycemia has developed lollowrng discontinuation ol the drug As is true wrth many other types
`
`

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`In all US Prozac clinical
`lnals. 0 7% of 10.782 patients reported
`trials lor bulimia
`controlled clinical
`mania/hypomania
`Mums—In US placebocontrolled clinical trials tor depressm. convulsrons (or events described as
`haying been seizures) were reported in o 1% at patients treated with Prozac and 0 2% 01
`Item treated with
`BtaceboNo
`bentsrepmtedcomulsmanSplaceboconoolladdinicalmalsbreither
`orbidirmalnal
`S Prozac
`inicaltnals.02%ot 10.782patientsreportedconvulsions Theperoentageappearslobesimilarto
`history 0 seizures
`that associated wrth other marketed antidepressants Prozac should be introduced wrth care in patients wnh a
`m—Mpossibifuyolasiwdealtemptismherentmdepreesmandinaypersislmfilsrgnificant
`remissron occurs Close supervrsmn ot high risk patients should mnpany initial drug therapy Prescriptions tor
`Prozac shouldbewnttenlorthesmallestquarmtyolwpswescorisrstemmgoodpaoentmanagementin
`order to reduce the risk oi overdose
`Because 01 well-established
`between both OCD and depression and bulimia and depression. the
`same precautions observed when treating patients With depressmn should be observed when treating patients
`
`li-
`.-
`.
`“als-
`,
`22mins
`-: useotthelongetiminatlonhall-lives
`ollheparentdmganditsmatoracuvemembdne.dtangesrndosewiflmtbelullyreflededmplasmalorseveral
`weeks. affecting both strategies tor titration to final dose and Withdrawal from treatment (586 Clinical
`Pharmacology andDosa
`and Administration)
`—Clinical experience with Prozac in patients with concomrtant
`emic illness is limited Caution is adVisabla in usmg Prozac in patients with diseases or conditions that could
`metabolism or hemodynamrc responses
`Fluoxetirie has not been evaluated or used to any appreciable extent in patients with a recent history at
`myocardial inlaictiori or unstable heart disease Patients witti trim diagnoses were systematically excluded
`from clinical studies dun
`the product's premaikct testing However. the e
`ms of 312 patients
`who received Prozac in
`uble-blind trials were rett
`evaluated, no conduction abnormalities that
`resulted In heart block were observed The mean heart rate was reduced by approxnnately 3 beats/mm
`In subjects with cirrhosis of the liver, the clearances 01 lluoxetine and its active metabolite, norfluoxeline. were
`decreased, thus increasmg the elimination hall-lives 0! these substances A lower or less frequent dose should
`be used in patients with cirrhosis
`Studies in depressed patients on die
`is did not reveal excessrva accumulation of tluoxetirie or nortluoxetine
`in plasma (see Renal Disease under
`inical Pharmacology) Use of a lower or less frequent dose for renally
`trad patients is not routinely necessary (see Dosage and Mrriinistration)
`n patients with diabetes. Prozac may alter glycernic control
`hascccurred during therapy with
`Prozac. andhyperglycerniahasdevelopedlolkmngdiscontinuation
`thedmg Asistruewithmanyothertypes
`olmedicationwhentakenconcurren
`bypationlswithdiabeies, insulinand/oroialhypoglycernicdosagemay
`need to be adjusted when therapy
`Prozac is instituted or discoritlmied
`
`i
`z
`'
`‘
`t
`=
`A
`'
`a: mm: m:
`'
`psychoactive drug may impair pudgment. thinking.
`or motor skills. and patients shou be cautioned about opemtlng hazardous machinery. including automobiles.
`until they are reasonably certain that the drug treatment does not allect them adversely
`prescri
`rozac'
`Inmbegoo for Pallents—Physicians are advtsed to discuss the lollowing ssues With patients tor whom they
`Because Prozac may impair judgment. thinking, or motor skills. patients should be mm to avotd drivtrig
`a car or operating hazardous machinery until they are reasonably certain that their performance is not
`affected
`Patients should be advised to intorm their physician it they are taking or plan to take any prescription or
`overvlhe~counter drugs. or alcohol
`Patients should be advrsed to notify their physiCIan it they become pregnant or Intend to become pregnant
`during therapy
`Patients should be advrsed to notify their physrman it they are breast leading an infant
`Patients should be adVIsed to notily their physman it they develop a rash or hives
`Laboratory Tests-There are no specmc laboratory tests recommended
`Drug Interactions—As With all drugs.
`the potential
`tor interaction by a variety ol mechanisms (eg,
`pharmacodynamic. pharmacokinetic drug inhibition or enhancement. etc) is a possibility (see Accumulation and
`Slow Elimination under Clinical Pharmacology)
`Woiflpproxrmately 7% ol the normal population has a genetic detect that leads
`to reduced levels 0! actwity ol the cytochrome P450 isoenzyme P450IIDG Such indivrduals have been relerred
`to as 'poor metabolizers' 01 drugs such as debnsoquin, dextrornethorphan. and tricyclic antidepressants Many
`drugs. such as most antidepressants. including lluoxetine and other selective uptake inhibitors ol serotonin. are
`metabolized by this isoenzyme. thus. both the pharmacokinetic properties and relative proportion ol metabolites
`are altered in poor metabolizers However. tor lluoxetine and its metabolite the sum 01 the plasma concentrations
`oi
`the 4 active enantiomers is comparable between poor and extensive metabolizers (see Variability in
`Metabolism under Clinical Pharmacology)
`Fluoxetine, like other agents that are metabolized by P450ll06. inhizirts the actrwty oi this isoenzyrne, and thus
`may make normal metabolizers resemble 'poor metabolizers ' Therapy wrth medications that are predommantly
`metabolized by the P450l|D$ system and that have a relatively narrow therapeutic indent (see list below). should
`be initiated at the low end at the dose range it a patient is receivmg fluoxetine concurrently or hastaken it in the
`preiiious 5 weeks Thus, his/her dosing requrrements resemble those of 'poor metabolizers ' It lluoxetine is
`added to the treatment regimen ol 8 patient alre
`receivrng a dnig metabolized by P450ll06. the need tor
`decreased dose at the onng medication shou
`be conselered Drugs with a narrow therapeutic index
`represent the realest concern (e9. flecainide. vmblastine. and tricyclic an
`)
`—In an in vrvo interaction
`involvrng co-adinmistiation cl
`humane with single doses at terlenadine (a cytochrome P450IllM Wale). no increase in plasma
`immmmmmmmmmmmmmwmmmmmm
`ketoconazole. apotentinhibitorolP450lllM actMty.tobeatleast100tiinesmorepotemthanllumnetineor
`nomioxetine as an inhibitor ol the metabolism oi several substrates for this enzyme. including astermzole.
`. and midazolam These data indicate that fluoxetine's extent of inhibition of cytochrome P450lllM
`is notlikelytobeotdinical significance
`—ThenskotusmgProzacrncombmatnnwrthotherCNSectrve
`hasnotbeen
`syaematical
`evaluated Nonetheless. caution is advised it the concomitant adrriinistration ol
`rozac and such
`dnigs is requ red in evaluating individual cases. consrdeiation should be given to using lower initial doses ol the
`concomnantly administered drugs, us
`conservative titration schedules. and monitoring ot clinical status (see
`Accumulation and Slow Elimmation u
`rClinical Pharmacology)
`plasma antioonvulsant concentrations and clinical anticonvulsant torricity lollowmg initiation
`concomitant
`Antietam—Patients on stable doses ol phenytoin and carbamazepino have dove?“ elevated
`Mum—Some clinical
`ta suggests a
`or plumes
`lluoxetine treatment
`da
`and/
`( Rls)andan
`inte