CENTER FOR DRUG EVALUATION AND
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`A RESEARCH
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`APPLICATION NUMBER: 18-936/S-060/S-062/S-063
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`FINAL PRINTED LABELING
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`SARAFEMTM
`FLUo-XETINE HYDROCHLORIDE -
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`SAR'AFENIT“ (fluoxetin'e‘ hydrochloride) is a selective Serotonin reuptake
`inhibitor (SSRI) Iororal administration; fluoxetine:was=initiallydeveloped and :
`marketed as an antidepressant (Prozac’. _flonetine hydrochloride) ItIs
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`N _designated(t)——N——methyl-3:phenyi-I-3Ken-gt(1--triflu ro—p—tonIIOIcylpropylamInei-
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`molecular.-‘wei'ght-us-345
`The structuraltormuIaI‘
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`FIuoxetine IhydrochloIride- Is a white to ott-whit {crystalline solid with a
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`solubility of 14mglmLIn water.
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`e.equivalentto.-10- mg (32.3 urnol).or 20 mg (64.I7 pmol)IofI
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`Ilu etinej, The _Pulyule
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`Themechanismofwhenof-Ifluo'xetln
`premenstrual.dysphoI'rioIdisorder (PMDD)IsIunl‘crIiown.:butIsIpresUmed
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`tobe- linked to its inhibition of CNSneuronal uptak
`
`have.”demonstratedthattluoxetine,bloaksthe Up
`eroto‘nlninto human:--pl'a‘téI‘e_ts-. StudiesIn animals-also
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`I potent up'tak inhibitor of serotoninthan of nore inephrine'.
`Suggest thatfluoxetihe-'Is'amuoh-
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`--Antagonism of muscarin
`is minergic,'and on
`renergic receptorshas-been hypothesized to be associated
`with various anticholine'rgic, sedative, and cardiova aular.effects ofcertain psychoactiIVedrugsi Fiuoxetine has
`little‘atfinity for these receptors
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`I Absorption Distribution;Metabolism,and.-
`sin l_e oral 4O-mgIdose, peak plasma concentrations of
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`'-"tyof.fluoxetine althoughit- may delay its absorption I
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`important (see.PRECAUTIONS)
`uoxetin‘e-enant merIs. In animal
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`IantiomerIsIelim natedmoreIslowIlIyan s-_thepredominan enantiorIIIeIr
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`ike It at of a number of other compoun s-including'TGAs and other SSRls,
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`involves the P450HDG-system: concomitant therapy with drugs also metabolized-by this enzyme system (such as
`the TCAs) may lead to‘ drug interactions (see Drug Interactions under PRECAUTIONS).
`'
`ACcumuIati'on and Slow Elimination—The relatively. slow eliminatipn of fluoxetine (elimination half-life of 1 to 3
`days after acute administration and 4 to 6 days atten‘ch‘ron'ic administration) and'its active metabolite, norfluoxetine
`(elimination half-life of 4' to 16 days after acute and chronic- administration), leads to significant accumulation of '
`these active species in chronic use and delayed attainment of steady state-even 'when‘ a fixed .dose is usedfi-Nt'er
`30 days of dosing at 40'mg/day. plasma 7concentrations ot-tluoxetine» in the range of 91 to 302"ng/mL‘ and
`norfluoxetine'in the'range of 72 to 2585riglmL haVe been observed. Plasma concentrations of fluoxetine-Were
`higher than those predicted by single—dose'studies, because fluoxetine's metabolism is- not proportion’alto dose.
`No’rtluoxe'tine, however; appears to have linear "pharmacokinetics. Its mean. terminal half-life after a single dose
`was 3.6 daysand afterrnultiple- dosing was 9,; days. SIeady—statelevels afteLprolonged. dosing-are‘similar to
`levels seen at'4 to 5 Weeks.
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`The lang- elimination halHive‘s of'lluoxetine an'dn'orfluo’xetine assure that, even when dosing is stopped, active
`drug sUbstance will persist in the body for weeks (primarily depending on individual patient--characteristics,
`previous dosing regimen, and length'of previous therapy at discontinuation). This is of potential consequence
`when drug discontinuation is: required or when drugs are prescribed that might interact with fluoxetine and
`norfluoxetihe folloWingrthe discontinuation 'of SAHAFEM.
`Liver Disease—As might be predicted from its primary site of metabolism; liver impairment can affect the
`elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a
`mean or 7.6' days compared toI‘the range of 2 to. 3 days seen in subjects without liver diseaseynorlluoxe‘tine
`_ elimination was"alsoi'delayed.’with2a meanidUration' of 12 days for cirrhotic patients compared to the range of-7 to
`93‘da'ys in normal-subjects-This' suggests that the. use 'of fluoxetine in patients with-liver disease'must'. be
`approached with caution. If ft'uoxetine is. administered to patients with liver diseaSe,~ a lower or less frequent dose
`should be used' (see Use in Patients with concomitant- Illness under PRECAUTIONS a‘n'd DOSAGEL- AND
`ADMINISTRATION)‘.V
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`Renal'Disease—l'n depressed patients on dialysis (N=12),. fluoxetine administered as 20 mg.once daily for 2
`months prOdU'cedI Steady-state fluoxetine-and no'rlluoxetine plasma‘concentraticins comparable to those seen in
`patients with normal=rehal fuhction.—Whil‘e-the possibility exists that re'rially'excr‘eted metabblites‘ of flu'o‘xetine’ may
`a'ccumu'late'ito higher levels inpatients With‘seve're-r'ena'l dysfunction, use ofa lower’br less" frequent dose is not
`routinelynece'ssary -’i_n
`renally imp-aired- patients (see Use in Patients-with” Concomitant
`Illness under
`‘#
`PRECAUTIONS and DOSAGE AND ADMINISTRATION).
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`Premenstrual Dysghoric Disarder-(PMDDl—The effectiveness of;SAFtAFEM-.for-‘»the treatment-of PMDD Was
`
`
`,Iished in me placebo—commuted?trials. Patients- in these trials met Diagnosticand'StatisticalManual-Sm
`
`edition-revised.(DS’MeIHR) criteria forEateé-Lu'tealuPha'se-Dy'
`or‘ic-Disbi'def-(LLPDD), the'clin'
`l‘ ehtityjnow
`gno’stic and'Stati'
`referredvto'ia's Premenstrua Dyé‘phoric Disorderi(PMDD) in th'
`‘ Dia
`‘lManual—4lh'e'dition (DSM-IV).
`Patients-on’ora'l-‘contrac
`s-were excluded-:fromthese‘triais'; therefore, the=effic y of fluoxetine- in Combination
`.
`withI’Oral'cohtraceptives‘fbr‘th‘e‘treatment'o‘f_'lI?MDD‘-is Unknown;
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`In thejtirst doublet-blind; parallel-group stridy of 6'mont'hs duration involving N=320 patiel‘hs, fixed‘ doses of '
`tluoxetine-_20 and SGE‘mglday 'given cohtihuditSly throughout theimens‘tr'ual'. cycle were show'nto be significantly
`more.
`ftective than placebo 'a's-r‘neas'u'red‘by. a Visual-Analogue scale (VA'S) total score (including-mood and
`
`
`re‘d'ecréa's'éde’lo on placebo treatment-..36%'ori-2IO mg; and 39%
`on.
`_
`the
`‘rrig and ”GO-mg 5dose§=—Was“fnot statistically significantfl'he
`fOIIOWIng table" sh'o
`fzpatlents meetin'gfc'riteria for-either moderate or marked improvement on
`
`the'VAStbtafscore;
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`Percentage-9t?
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`y an Markedly Improved (>50.% and 75% reduction, I
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`-"" respectir?eiy,fr'orn=bas_ in'etutealPhase‘VAStota‘f‘soore)"
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`Improvement
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`Fluox 60 mg
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`393%,?“Qg'
`37%2'511-
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`ouble.—blind,.cross-overi study, patients (N=1 9).were treated withtluoxetine 20. to .66.mg/day (mean
`
`3/6337) and placebocoritinuously throughoutjthe..menstrual,.cycl_e.for,.a_ periodot' 3' months each.
`isignificantly more'effectiveIthan.placebo':as.n'ieasured by within cycle. follicular to Iuteal.phase'
`_
`
`changes Iinthe VAS .total score (mood_,I physical, and socialimpairment symptoms). The average VAS total score
`
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`(-follipitlar‘to lgeal hIase' increase) waszafltimes higher. duringplacebq treatment than what was observed during
`
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`,ILLEDD (Nam). were treated with fluoiretine 20 mg/day,
`
`glday. or placebo to 2 month'SLNe‘
`.Tfludxetine nor bupropion was shown. 10 be-superior to
`
`
`(nary endpoint, i.e.,
`
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`. espouse _. teIdetiIned as'a rating of :1 (very much improved) or 2 (much .
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`GI], possibly/due to' sample-size.
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`INDICATIONS .AND, USAGE '
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`dicated forthe u’eatrhent of.premenstmal dysphoric disorder (PMDD).
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`fticacy of flooxetineinthe treatment attempt) was estaolished in .tw,'o placebof—controlled';
`trials (IseeClinical I
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`' underCLlNICAjL P ARMACQLIJ
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`
`
`PV32.81AMP
`
`Q
`
`lSAI-RAFEJMTM
`
`FLUOXETINE{HYDROCHLORIDE
`
`
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`SARAFEMT” (Fluoxetine Hydrocthride)
`b—n.‘
`Altered Appetite and Weight—1n a placebo--controlIed trial of Iluoxetine in PMDD, 4% of patients on SA-FIAFEM
`20 mg (the recommended dose) 13% on SAFIAFEM 60 mg and 3% of placebo patients reported anorexia. In two
`
`pIacebo-controlled trials _(onIy one of which included a _dos'e of 60 mgIday) potentially clinically significant weight
`
`gain (>' 7%) occurred"In 8% of patients on SAFIAFEM 0 mg 6% of patients on‘-SARAFEM60mg, and 1% of_
`patients (in plaCebo; Potentially? clinicaIIy=SIgnIfcant weightloss (> 7%) oc‘curredI'In-7% of patients on SARAFEM
`
`20 mg, 12%’of patients onSARAFEM 60 mg, and 3% otxpatients on. pIaCebo'. In US- placebo—centroIIed‘cIinic‘aI
`
`
`trials of tIuoxetin t »ether approved indications, changes in appetite and weight have also keen reported .(see
`Table 2andOther ventsObserv 37in: US Clinical Trials,under ADVERSE REACTIONS)“
`
`
`Activation of ManIa/Hypomania. No patients
`eated ith SARAFEM in threePMDD c-Iinicai trials (N=2_4_3)
`
`
`linicaltrials for conditidns other than PMDD 0.7% of 10.7B2 ,
`' reported mania/hypomania. In all US tluox'etin'e
`
`patients reported mania/hypomania; Activation of manialhypomania may occur with medications used to treat
`depression, especially.inpatients predisposed to Bipolar Atfec‘tive Disorder.
`
`
`Sei'zures—
`ati nts treated with SAR‘AFEMIn threePMDD clinical trials (N=243) reportedseizures. In all US
`iluoxetine-clinicaltrials'for c'onditio'n other than PMDD 0.2% at 10,782 patients reported Seizures. Antidepressant
`
`medication should be introduced with careiti-patients
`th. a historyof seizures.
`
`s__uicide—No patients.treated with SABAFEMin three PMDDcIinical trials (N=243) attempted suicide. The -
`
`
`
`possibility of a Suicid ‘
`ttemptI's
`t.‘Inmood disorders andmay persist until significant remission occurs. In
`’ PMDD patients WI
`
`
`sIgnIt'cant mood disturbance, close supervision should accompany drug therapy. In high-
`riskpatients, pres'
`
`for antidepressa tmedication should be written for the smallest quantityof medication
`I‘de}toreducethe riskcf-overdose.
`-
`consistent With= good
`
`
`
`Half-Lit/e of FI'uoxetine andIts Metabolites—Because of the longelimination haIt-lives ot
`.
`. he Long Elim‘inat
`
`e_parentdrug and its major active metabolite. changesIn dose will not be IuIIy retlected'In plasma for several
`
`
`
`weeks- affecting both strategies for titration to _final dose and withdrawal. trom treatment- (see CLINICAL
`PHARMACOLOGY and DOSAGE AND ADMINISTRATION)
`-
`
`Use in Patients With Cogmitant llIness—Clinical experience with tIuoxetine in patients with concomitant
`
`systemic illnessIs limited Cad ' nisadvisableInusing_fluoxetineIn patientswith diseases onconditions that could
`
`affe‘ct- metabolism or hemo’dynamic.‘responses.
`-
`' ecenthistory pt '
`
`
`
`Iy excluded froI-n.
`ith hese diagnoses were sys‘t
`.
`
`cII _caI-"situdies' duringth .prodtic
`er, the' electrocardiograms of 312 p
`
`, received Iluoxetine in doublerblind,trials for a condItioI'I .oth‘
`than PMDDwere retrospectively eva 'ated; no
`
`
`conduction abnorrn itIe
`that. resulte
`
`in heart blockWere obs rvedt The. mea
`ewas reduced by
`appro irnately 3beats]
`.
`
`In subjects with cirrhOSIs of. theliver the 7
`
`
`
`substances (see
`erDisease under CLINICAL
`atients with I'rrhosis (see DOSAGE AND.
`
`
`t.reveal excessIve.
`
`
`AHMACQLOGY)
`
`
`
`
`
`.
`ali drugs mepotentialfor- interactionby a variety of mechanisms.
`-'
`‘
`IsapossIbIIIty (see
`fmulatiqn a‘nd
`
`

`

`
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`
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`.
`
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`
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`nt. etc.) is a possibility ‘(see Accum
`ulation afid-
`'nhibition or enhanceme
`netic defect that leads
`harrfiacokine'tic drug
`'
`AL PHARMACOLOGY).
`n. has a ge
`ph'arrriacodynarnic. p
`Slow
`of the normal populatio
`have been referred to
`Elimination under CLINIC
`Dru s Metabo
`lized b ' P450HDG—Approxim'ately 7%
`.,
`_' he cytochrome P450 isoenzyme P450tlDB. Such individuals
`'
`‘
`'
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`' drugs.
`as “poor metabolizers" of dru
`gs such 'as. debrisoq‘uim dextromethorphan. and TCAs. Many
`d by this isoenzyme; thus. both the
`'
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`uptake inhibitors.:ot serotonin. are metabolize
`omparable
`fluoxetine and other selective
`erties and relative propor
`'
`.
`V
`concentrations of the four active enantiorners IS 0
`_
`_
`'
`pharmacokinetic prop
`_ )
`.
`" '
`' d its metabolite. th
`ive metabolizers (see Variability in Metabolism un er
`' HAEMACOLOGY)
`the activity of this isoenzyme. and. thus
`betWeeh poor and extens
`thatrare metabolized by P4501106.-inhibits
`rs resemble “poor metabolizers." Therapy with medications that are predominantly
`Fluoxetine. like other'agents,
`system and that have a relatively narrow therapeutic index (see listbelow). should
`'
`tly or has taken it in the
`make normal metabolize
`'
`may
`is receiving f
`_
`metabolized by the P4501106
`Osing requirements resem
`' If fluoxetine-is.added to
`nd of the dose range if- a patient
`be initiated at- the low e
`ks.‘l’hus.- her d
`ble those of “poor in tabolizers.’
`P4501106. the need-tor decreased
`previous 5 wee
`atient» already receiving a drug me
`‘dered._Drugs wtth arnarrow therapeutic l
`the treatment regimen of'a p
`ine should not be
`' al medication should beconsr
`.
`.
`.
`dose of the origin)
`fleca‘inide'. vinblastin'erand TCAs).'Due5to the risk of serious ventricu _,
`_
`_
`_
`.
`levels of thtbridazine. ~thioridaz
`sociated with elevated plasma
`_
`greatest concern (eg...
`eeks after fluoxetine has been discontinued (see
`Sudden death potentially as
`or within a minimum of 5 w
`WARNINGS).
`administered -with ‘Ilubxetine
`ng co»administration of;
`lasma terfenadine
`Viva interaction study involvi
`CONTRAINDICATIONS and
`Drugs Metabolized by Cfiochrome P4501ttA4——ln an in
`tluoxetine withsingle doses of tedenadine (a cytochrome P450I11A4 substrate). no increase in p
`'
`'tro studies have shown ketoconazole. a
`e or norfluoxetine as an
`‘ ant fluoXetine. In addition.
`in v:
`e. and midazolam.
`' 0 times more potent than Iluoxetin
`concentrations. occurred with concomrt
`
`inhibitor of-the' metabolism 0
`'
`’
`'
`zyme. including astemizole, cisaprid
`I<ely to be of
`otent inhibitor of P45_OIIIA4 activity, to
`oxeline‘s’ extent oilinhibition of cytochrome P45011IA4. activity is not Ii
`These 'data'iridicate that flu
`'
`'
`8 active drugs {has not been
`
`cliniCaI Significance.
`.
`n of fluoxetine and such
`ne'in-combination with other CN
`risk‘ of using fl'uoxeti
`ower initial doses of. the
`CNS Active Drug's—The‘
`advised it the‘ concomitant administratio
`
`nical status (see‘
`stema'tically 'eval
`sy
`uated. Nonetheless. caution is
`
`dividual cases. consideration should be given to using .1
`Inevaluating in
`drugs. using conservative titration schedules. and monitoring of cli
`drugs is required;
`
`concomitantly, administered
`CLINICAL PHARMACOLOGY).
`_
`Slow'Etimination under
`nts on stabledeses'ot phen'ytorn'f
`d"’ca‘rba'mazepine have developed elevated plasma
`Accumulation and
`
`‘ons and clinical anticonvulsant toxicity following initiation of concomitant tluoxetine
`Anticonvulsants~Patie
`Ior pharmacoldn'etic
`anticonvulsant concentratt
`
`treatment.
`7' possible pharmacodynamic and ‘
`_
`SSRls) andantipsydhotics. Elevation of blood-levels
`s'——*Some clinical data suggestsa
`' Antipsychotic
`
`ritic reuptake inhibitois' (
`" '
`comitar‘flluo
`",_e. A singlecase
`tine leading 0
`"interaction between serotonin spec
`d ctozapine has been‘observe'dgin"patientsre'ceivmg con
`
`of haloperidol an
`ssible additive effects. ofpimozide and tluoxe
`report has suggested po,TRAINDICATIONS andWARNINGS.
`diazepam may be prolonged in some patients
`..
`.
`.-
`thioridazine. see CON
`
`'
`‘
`’
`'Under'GLINICAL PHARMACOLOGY). Co-administration of.
`e halt-lite of concurrently. administered
`_
`Benzodiazepines—Th
`ed_.alprazol’am. plasma concentrations and. in turther
`‘
`v reas
`
`-(se'e' Accumulation an
`
`'
`amlevels.
`'
`'
`_,
`,
`.
`d ’lithium'ley‘els whenlttthium'
`
`P
`.
`-
`
`
`
`Lithium—.-Ther.e have
`
`.. c6n¢omitantlywith fluoxetine.
`
`be monitored'w 'en
`,
`
`'L_ithi‘um’levels should
`intestinal distress.
`
`uptopban—Five patients receiving fluoxet
`
`
`
`. NPICAIIQNSI .
`uding agitation, restlessness. and
`I 'or it'ttiprarniné 'a'nd desiprarnine' hatié
`,
`,
`
`See
`"
`' ase'tn
`is
`
`'bl'e plasma levels
`‘hNd"'studi s. ‘p
`‘
`
`fh'as‘been=administered in combination.This influence may
`
`old whe
`
`"Antidepressantsiéln
`
`e dose of TCA may need to be reduce
`
`increased greater than 2- to 10-t
`dxetine is (Jo-administered.
`
`_
`__
`er attertluoxetinei
`
`
`persist for 3 jugeeks or ten
`_
`tirins'mayrn'e‘eg to be men _,
`
`
`.
`_
`.
`0
`6
`
`. ("'ee__' Acc‘tsimuiati
`y: ‘- discontinue
`c .
`ti
`
`GY.V
`and _D_i‘u_gs Meta
`
`
`
`¢
`.
`re ,avebee rare_
`an SSFII- (e.g., fluoxetine. ttuvoxamm
`
`
`ate obse
`
`
`atment with sumatriptan and.
`Nation of the-patient is advised.
`_
`.
`to.-Plasma Proteins—Because iluoxetine is tightly
`
`nically warranted. appropti
`citalopram) is cli
`
`Ti ht! Bound
`another drug» that is tightly bound to
`
`f 00- dministration of,
`
`Po en ial Effects 0
`
`
`
`-
`1
`s potentially resulting in an adverse
`
`tein. the administm'ti
`.
`bound to plasma pro
`
`f'p‘otern—‘bound fluoxetine by other tightly-bound
`‘
`digitoxin) may caus
`
`
`
`
` ffects inay resu ' s‘pl’acement o
`
`
`protein (e.g.. warfann.
`
`' MACOLOQYI‘
`'.
`'
`' "
`'
`
`
`
`
`effect..Conversely. adverse e
`
`
`
`‘ have been-rep
`when fludxetine is
`liminatib'n, amderQLiNlCAL PH
`nd'Siew’
`drugs (see Accumulation;
`ttects. incl - ding. ii; teased bleedin
`I'd receive careful coagulation monitoring
`
`'
`rfarin therapy shou
`yam-Altered anti-co gu
`th warfarin. Patients receiving wa
`
`co—administered Wi
`of the‘cqmbined use ofECT'
`era ——The're are no clinicalstudies
`
`establishing the benefit
`- when fluoxetine is initiated or stopped.
`n fluoxetine receivingECT
`have beenrare reports of prolonge
`d seizures in patients 0
`_ Electroconvulsive
`
`and ttuoxetine. There
`esis,-Irr'rpairment of'Fenility—Thereis no evidence of carcinogenicity. mutagenicity. or
`treatrnent.’ .
`
`es of up'to tOfand'
`., Carcinogenesis, Mutag'en
`ration}of fluoietine to rats and mice for 2 years at dos
`mmendedhuman
`impairment of fertility with fluoxetine.
`dietary administ
`.
`.
`..
`
`Carcinogenicinghe,
`12 and-0.7 times. respectively. the maximum reco
`'
`eds baSedhorr' the
`no evidence of carcinogenicity.
`-
`.
`_-
`.
`
`12'mglkg'lday. respectively (approXimately
`
`
`
`g on a mg/mz'basis). produced
`_
`d nor-fluoxetine have been shown .to have no genotoxrcvetf
`dose.{MRHD] of 80 m
`'
`I’mpho aassay.
`
`
`
`
`n assay,;DNA repair assayincuttured rat hepatocytes in
`
`. Mut'agenicig—Fluoxetine an
`''' cterialmutatio
`
`
`
`
`
`
`
`‘
`-
`hinese hamster-bone.marrow<celts.. " "
`
`"
`'
`‘
`'
`"
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`-
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`-",
`" :_'
`scenductedm
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`

`

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`i‘mg'airrBEni’B’t FE'fi'iiiIQSTV:rigfififiyfsfiéaé'; .‘E'S'SEJEtEETWTartE-C'S?:E‘ég‘s’v‘égflp 'to: 7.5-».ana 1 2:5? rng/kg/day
`(approximately 0.9 and'ifis time‘s the-MRHD on' a mg/m2 basis) indicam'd mat'ftuoxetine had no adverse effects
`on lertility.
`.
`-
`.
`.
`Pregnancy—Pregnancy Category C:tln embryo-fetal development studies in rats and rabbits. there was no .
`evidence of Vteratog'enicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times,
`respectively, theMRHD of 80 mg' on a mgImZ basis), throughout organogenesis. However,' in rat reproduction
`studies. anjncrease in stillborn pups. a decrease in pup weight. and an increase in pup deaths during the first
`7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MFtHD on’a rng/m2
`basis) during gestation or 7.5 mg/kglday (0.9 times the MRHD' on a mg/m2 basis) during gestation and lactation.
`There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day
`during gestation. The no-effect dose for rat pup mortality was 5 mg/kglday (0.6 times the-MRHD on a m'glmz
`basis). Fluoxetine .should be used during pregnancy only if. the potential benefit justifies the potential risk to the
`fetus-
`. v
`'
`-
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`..
`_
`.
`_
`,
`.
`.
`,.
`.
`.
`»
`Labor and Delivery—The effect of- fluoxetine on labor and delivery in humans is unknown. However,'_because
`fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the
`newborn. tluoxetine should Vbe’used duringzlabor and delivery only if the potential'benefit justifies lhe‘potential risk‘
`to the fetus.
`.
`,
`.
`.="Nursing. Mothers—"Because fluoxetine is‘ excreted in human milk, nursing while on tluoxetine is not
`recommended. ln.one breast milk sampleirthe concentration-of ll'uoxetine.plus=n‘orfiuoxetine was”-7_0:4'nglmL. The
`concentration in-the mother's plasma was 295.0 nglmL. No adverse effects on the infant were reported. ln another
`case, anintant nursed by amother on fluoxetinerdeveloped crying, sleep disturbance, vomiting, and watery. stools.
`The infant‘s plasma drug levels were 340'ng/mL of fluoxetine-and 208 'ng/ml. of norfluoxetine on the second day
`
`
`offeeding.
`._
`_
`'_
`..
`'
`;'
`.
`_ .(‘f-f‘
`,
`
`Pediatric Use—Safety and effectiveness in pediatric" p‘ati
`_'_ts have not been established.
`.
`.'
`Geriatric Us'e. The-dieig‘nbsisot PMDD is notapplicaole o .postmenopa‘
`'
`"
`'
`'-
`
`
`, Hyponalrer'riiaéseveral' Cases of hyponatrem‘ia (some'With'semm’s'Odiu
`
`
`
`reported. The'hyppn
`appeared to bereyersiblewhen fluoxetine was discontinued. Although these cases
`
`
`Were ,co'm'p‘lex" ‘th'
`ping” o‘ssible: "tiologie ,
`'
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`'
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`_
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`'
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`
`
`313 fludxetine' patients a
`'
`.
`"
`
`'.range; thisdifte'rence was-no , _ . _ __
`
`
`
`
`
`
`obServed decreases were not clinically si‘gni cant.
`.
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`Function—There have been; ,
`arts-of alts
`lat etifu,
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`_
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`_
`_:
`'
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`.
`'.
`patientsltaking'tiuoxetin'e, it’is..Un'clear' whether lluokeft‘ne had-'a causative role.
`‘
`
`,
`
`
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`
`
`
`
`
`
`
`
`PV 3231 AMP ’5
`
`
`_
`emerge
`- 20 mg and greater
`
`
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`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SARA'FEMTM (FluoXetine Hydrochioride)
`.
`-
`.
`TABLE 1
`.
`‘
`MOST COMMON TREATMENT—EMERGENT
`=EBO-CONTROLLED CLINICAL TRIAL ’
`
`ADVERSE; EVENTS: INCIDENCEJN A PMDD PLAC
`e of patients reporting eVent
`’ Placebo
`'
`i“
`' Percentag
`
`
`
`'SARAFEM 20 mg
`
`Body system]
`'
`
`Adverse Event’
`’ Body as aWh‘ole
`
`. Headache
`_ Aéthenia
`
`
`
`
`
` ‘ lnleclion » ’1...
`
`
`Digestive System -.
`' Nausea
`
`Nervpus System
`
`'
`lnsomnia
`Dizziness
`
`Nervousness
`
`
`- Thinking abnormali‘
`
`
`
`Respiratbry System
`
`
` finnngitts ”——0 mg. except the lollow'lngzejvents. which hadian incidence onv
`
`
`
`
`'lnclud'tedare events reported by at least 5% ql patients taking SARAFE'M 2_
`
`placebo? SARAFEM 20 mg: diarrhea and flu' syndrome.
`TThinlging abnormal is the CQSTART term that captures concentration difficulties.
`
`. Vlinical Trials (Manny data-tram.
`_
`.
`,
`7- Incidence in US Depression, 0.00,. and Bulimia
`~lnéideriee 125;. than 0.5%.
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`ent adverse events associated with
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`the uSe'ol- tluoxetine up-to 80 mg'(incidence ol at least 2% for tluoxetine and.greater than placebo) in female
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`patients ages 18- to 45 years lrom US placebo-controlled clinical trials in the treat
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`TREATMENT—EMERGENT ADVERSE. eveur§;:- ..
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`Associated with Discontinuation ina PIace‘ldeontrol/edPMDD Clinical Trial—The most Common adverse event
`
`(incidence at least 2% for SARAFEM 20 mg and greater than placebo) associated with discontinuation in a PMDD
`placeboLcontrolled trial was nauséav(3% for SARAFEM 20 mg, N=1_04 andr1% for placebo. N=108). in this clinical
`
`trial, more than one event may have been'reco‘rded as the cause of discontinuation.
`_
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`'Assdciated'with Discontinuation in US Depression, OCD,' and Bulimia PlaCebo—Controlled Clinical .Trials
`
`(exclijding'data from extensions of trials)”—-l‘n» female patients age 18- to 45 years in US depression. 000, and .
`
`bulimia placebo—oontro'lied'clinical trials combined-which collected a single primary event associated with
`distontinuation (incidenceat-Ieast 1% for lluoxetine and at least twice thatfor placebo), insomnia (1%, N=561)
`
`,was, the only event*i"eported.--'
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`"FemaleSexu'al Dysfunction 'with SSRIs+AithoUgh changes in sexual desire, sexual performance, and sexual
`
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`satisfaction often'»_occur as manifestations’ot’a moodirelated disorder, th‘ey'may ”also be-a consequence of
`
`pharmacologic treatment, in particular, ome, evidence suggests that SSFils can muse such- untowardtsexual
`
`experien '
`vReliabie estimates-cf the incidence and 'sevefity of 'untowar'd 'eXpe‘ri nces involvings'exual desire,
`p'eit'orm'a
`,and-satisfaction-are difficult to obtain, however. in 'part‘because‘patientsfand physiciansf may be
`reluctant
`to discuss ‘thern. Accordingly, estimates of
`the incidence of untoward seanF experience and
`
`performance, cited in product labeling, are likely to underestimate their actual incidence. For example, in women
`
`(age-1‘8 to 45) receiving fluoxetine for indicatio'n'sother' than PMDD, decreased libido Was seen at an incidence of
`4% for fluoXetine Compared to 1% for placebo. There have been spontaneous reports ini'women (age ’18-t'o» 45),
`
`taldrigtluox‘etine fo'r indications other than- PMDD ol‘-Orgas‘micdysfunction, including-a'norgasmia.
`'
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`
`There are no adequate and well-controlied studies‘eXamining‘sexual dysfunction withiflu’o‘xetinetreatment,
`