Cymbalta

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Duloxetine hydrochloride 67.3 mg equivalent to duloxetine base 60 mg
Available from:
Eli Lilly and Company (NZ) Limited
INN (International Name):
Duloxetine hydrochloride 67.3 mg (equivalent to duloxetine base 60 mg)
Dosage:
60 mg
Pharmaceutical form:
Modified release capsule
Composition:
Active: Duloxetine hydrochloride 67.3 mg equivalent to duloxetine base 60 mg Excipient: Ammonia solution Colour Mixture White DDB8257W Gelatin Hypromellose Hypromellose acetate succinate Indigo carmine Ink Iron oxide yellow Purified talc Sodium laurilsulfate Sucrose Sugar spheres Titanium dioxide Triethyl citrate
Units in package:
Blister pack, PVC/PE/Aclar x 7 caps. sample, 7 capsules
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Evonik Corporation
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PE/Aclar x 7 caps. sample - 7 capsules - 36 months from date of manufacture stored at or below 30°C - Blister pack, PVC/PE/Aclar x 28 capsules - 28 capsules - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-7105a
Authorization date:
2003-07-31

Cymbalta NZDatasheet

Data Sheet

CYMBALTA ®

Duloxetine capsules,30mgand60mg.

Presentation

CYMBALTA30mgcapsuleshave opaquewhite bodiesand opaquebluecaps.

CYMBALTA60mgcapsuleshave opaquegreenbodiesand opaquebluecaps.

CYMBALTAisa delayed-releaseformulationfororaladministration.CYMBALTA30mg and

60 mg capsulescontainsenteric-coated pelletsofduloxetine hydrochloride equivalentto 30

mgand60mgofduloxetine,respectively. Entericcoatingpreventsdegradation ofthe

medicine within the acidicenvironmentofthestomach.

Uses

Actions

Pharmacotherapeuticgroup:medicinesusedforthe treatmentofdepression,anxietyand

neuropathicpain.

Duloxetine isa combined serotonin (5-HT)and noradrenaline (NA)reuptakeinhibitor.It

weaklyinhibitsdopaminereuptake with nosignificantaffinityforhistaminergic,

dopaminergic,cholinergicand adrenergicreceptors. Duloxetine dose-dependently

increased extracellularlevelsofserotonin andnoradrenaline in variousbrain areasof

animals.

Pharmacodynamics

Neurochemicalandbehaviouralstudiesin laboratoryanimalsshowed an enhancementof

both serotoninand noradrenaline neurotransmission in theCNS.Duloxetine also

normalised painthresholdsin severalpreclinicalmodelsofneuropathicand inflammatory

pain and attenuatedpainbehaviourin amodelofpersistentpain.Thepresumed

mechanismofaction ofduloxetine in the treatmentofdepression isthoughtto bedueto its

inhibition ofneuronaluptakeofserotonin andnoradrenaline,and aresultantincrease in

serotonergicandnoradrenergicneurotransmission in theCNS.Thepaininhibitoryaction of

duloxetine isbelieved tobe aresultofpotentiation ofdescendinginhibitorypain pathways

within the centralnervoussystem.

ClinicalTrials

Acute treatmentofdepression:

TheefficacyofCYMBALTAwasestablished in sixdouble-blind,placebo-controlled acute

Phase 3 studiesin 1978adultoutpatients(18to83 years)meeting theDSM-IVcriteriafor

majordepression atdosesof40mg to120mgdaily.Infourofthesestudies,CYMBALTA

wassignificantlysuperiortoplacebo asmeasuredbythemeanchange inthe 17-item

Hamilton DepressionRatingScale(HAMD-17)totalscorefrombaseline toendpoint.The

remainingtwo studiesshowed numericallysuperiormean changecomparedwith placebo.

In both oftheselatterstudies,theactive comparatorparoxetine also did notseparate

significantlyfromplacebo onthe primaryoutcome measure. Response( ≥50%reductionin

HAMD-17totalscore)and remission (HAMD-17 totalscore ≤7)werealsosignificantly

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higherwith CYMBALTAcomparedwithplacebo andfive outofsixand three outofsixacute

studies,respectively.

Whileresultswere positive forimprovementinthe HAMD-17 ata doseof40mg dailyin one

oftwo studies,thisdosedid notdemonstrate statisticalsuperiorityon anyothermeasure

includingresponse orremission.

In additiontotheHAMD-17 totalscore,severalothermeasureswereincluded in the

evaluation ofefficacyofCYMBALTA. HAMD-17Depressed Mood Item(Item1),theAnxiety

Subfactorofthe HAMD-17,the PatientGlobalImpressions(PGI)ImprovementScore,bodily

pain asmeasuredbyVisualAnalogScale(VAS),and theQualityofLifeinDepression rating

scaleswere also examined.Inthefourstudieswhere CYMBALTAdemonstrated statistical

superiorityoverplaceboasmeasuredbyimprovementin theHAMD-17 totalscore,results

were also positive fortheadditionalmeasuresatdosesof60mg to120mg perday.

Measurementsofpainand otherbodilysymptomswere incorporatedintothe studiesto

assessduloxetine’seffectsonpainfulphysicalsymptomsthatoftenaccompanyMajor

DepressiveDisorder(MDD).AsuperioreffectofCYMBALTAcomparedwith placebo on

mean changeofHAMD-17 Item13(ameasure ofsomaticsymptomsincludingpain)was

observed.Improvementofpainfulphysicalsymptomsassociatedwith MDD(VASoverall

pain)wasconsistentwith otherresults,especiallyatthe duloxetine 60mgonce-dailydose.

In eachstudyand in pooled data,the effectivenessofCYMBALTAwassimilarregardlessof

age,genderorracialorigin.

Prevention ofdepression relapse

Patientsrespondingto 12 weeksofacutetreatmentwith open-labelduloxetine ata dose of

60mg once dailywere randomlyassignedtoeitherCYMBALTA60mgonce dailyorplacebo

forafurther6months(continuation phase)andtimetorelapse in eachgroup was

compared.Theestimated probabilityofdepressive relapse at6monthsforplacebo was

38.3 andforCYMBALTA60mgoncedailywas19.7(p=0.004).Duringthe 6-month

continuationtherapyphase ofthisstudy,17.4%ofCYMBALTA-treatedpatientsmetthea

priori-definedcriteriaforrelapse comparedwith 28.5%on placebo(p=0.042).

Of88 patientswho relapsed duringthecontinuation phase,87received double blind rescue

therapy.Patientsrelapsing on placebowere treated with CYMBALTAatadose of60mg

once daily,and thoserelapsingonCYMBALTA60mg once dailywere treated with

CYMBALTA 60mgtwicedaily. Ofthosepatientsrelapsing on placebo and treatedwith

CYMBALTA 60mgoncedaily,response(50%reduction in HAMD-17 totalscore)occurred

in 77%andremission(HAMD-17 totalscore ≤7)occurredin57%attheendof12further

weeksoftreatment.Ofthose patientswho relapsed on CYMBALTA60mg once dailyand

whowere treated with anincreaseddose of60mg twice daily,62%metresponse criteria

and38%metremissioncriteria.

Use in elderlypatientswith depression:

The efficacyand safetyofduloxetine60mgonce daily(n=207)and placebo (n=104)have been

comparedintheacutetreatment(studyduration8weeks)ofelderlypatientswithMDD(>65

yearsofage,meanage72.9 years). Duloxetinetreated patientsexperienced improvementin

depressive symptoms,asassessedbytheGeriatricDepression Scale,fromweek1,with least-

squaresmean changesfrombaseline to endpointof-1.34 forplacebo-treated patientsand

-4.07forduloxetine-treatedpatients(p<0.001).OntheHamiltonDepressionRatingScale,

leastsquaresmeanchangesfrombaselineto endpointfortotalHAMDscore were-3.72for

placebo-treatedpatientsand-6.49 forduloxetine-treatedpatients(p<0.001).Duloxetine-treated

patientsalsoexperienced agreaterimprovementin compositecognitivescore than the

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placebo-treated patients. The least-squaresmeanchangefrombaselinetoendpointforthe

compositecognitive score was0.76 in placebo-treated patientsand1.95forduloxetine-treated

patients(p=0.013).

DiabeticPeripheralNeuropathicPain

The efficacyofCymbaltaforthemanagementofneuropathicpain associated with

diabeticperipheralneuropathy(DPN)wasestablishedin 2randomized,12-week,

double-blind,placebo-controlled,fixed-dosestudiesin adultpatientshavingdiabetic

peripheralneuropathyforatleast6 months.

The two studiesenrolled atotalof792 PatientswhomhadType IorIIdiabetes

mellituswith adiagnosisofpainfuldistalsymmetricalsensorimotorpolyneuropathy

foratleast6months.The patientshada baselinepainscore of ≥4onan11-point

scale rangingfrom0 (no pain)to10 (worstpossible pain).

The weeklymeanofthe 24-houraverage pain severitywasthe primaryefficacy

measureforthe assessmentofduloxetine’seffectivenessinthetreatmentofDPNP.

Evidence ofefficacyfromtheprimaryefficacymeasure isconfirmed by

comprehensive resultsfromthesecondarypain and DPNPsymptommeasures.The

secondaryefficacymeasuresthatsupported the use ofCYMBALTAin thetreatment

ofDPNPwere: weeklymeansofnightpainand 24-hourworstpainfromthedaily

diary,BriefPainInventorySeverityand Interference (BPISeverityand Interference),

ClinicalGlobalImpressionsofSeverity(CGI-Severity),PatientGlobalImpression of

Improvement(PGI-Improvement)scale,andSensoryportion oftheShort-form

McGillpain questionnaire.In addition,measuresofmood were employed in both

placebo-controlled studiestodemonstrate changesofpainuncontaminatedby

duloxetine’seffectonmood

Atotalof792 patientswereenrolled in bothstudies,which compared Cymbalta 60

mgoncedailyor60mgtwice dailywith placebo,with one studyadditionally

comparingCymbalta 20 mgwith placeboDuloxetine 60mgQDand duloxetine

60mgBID werebothstatisticallysignificantlybetterthanplacebo intheprimary

efficacyendpoint,24-hourpain severity.

Treatmentwith Cymbalta 60mgoneortwo timesa daystatisticallysignificantly

improved the endpointmean pain scoresfrombaseline and increased the proportion

ofpatientswithatleasta 50%reductionin pain scorefrombaseline.

Forvariousdegreesofimprovementin painfrombaseline to studyendpoint,Figures

1 and 2showthefraction ofpatientsachievingthatdegree ofimprovement.The

figuresare cumulative,so thatpatientswhosechangefrombaselineis,forexample,

50%,are alsoincludedateverylevelofimprovementbelow50%.Patientswho did

notcompletethe studywere assigned 0%improvement.Some patientsexperienced

a decrease in pain asearlyasWeek1,which persisted throughoutthe study.

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GeneralisedAnxietyDisorder

TheefficacyofCymbaltahasbeenestablished in5 Phase 3clinicaltrials.Fourofthe

studieswere acute placebo-controlled studiesand thefifth wasarelapseprevention study.

Ofthefourplacebocontrolled studiesone wasafixed dose studywhile the otherthreewere

flexible dose studies.

Study1 (fixed dose)wasa randomised double blindtrialdesigned to assesswhether

duloxetine120mgonce daily(QD)wassuperiorto placebo in thetreatmentofGAD

asmeasured bythemean change in Hamilton AnxietyDepressionRatingScale

(HAMA)duringthe 9-week,double-blind,acute therapyphase.Akeysecondary

objective wasto assesswhetherduloxetine 60mgQDwassuperiorto placebo in the

treatmentofGADduringthe9-week,doubleblind acutetherapyphase

Studies2,3 and4 were Phase3 (flexible dose) randomiseddouble-blind placebo-

controlledstudiesthatusedthesameprimaryobjective:to assesswhether

duloxetine flexiblydosed from60 mgto120mgQDwassuperiortoplacebo inthe

treatmentofGADasmeasured bymean change in HAMAtotalscoreover10 weeks

Venlafaxine 25mgto225mgQDwasusedasanactive comparatorin studies3and

4 and datafromthesetrialswascombined (designeda priori)to have sufficient

powerfornon-inferioritycomparisonofduloxetine with venlafaxine.Forall3 studies

doseswere increasedatspecified visitsiftheCGI-Improvementscore remainedat3

orbeloworminimallyimproved.

In all4 acuteplacebo controlled studiesthemean decreasein HAMAtotalscorewas

significantlygreaterforduloxetine-treatedpatientscomparedwith placebo treatedpatients

Pharmacokinetics

Duloxetine iswellabsorbed afteroraladministration with a Cmaxoccurring 6 hourspost

dose.Food delaysthetimetoreachthepeakconcentrationfrom6to10hoursandit

marginallydecreasestheextentofabsorption (approximately11%). Duloxetine ishighly

protein bound(>90%),primarilyto albumin andalpha1 acidglycoprotein,butprotein binding

isnotaffectedbyrenalorhepaticimpairment.Duloxetine isextensivelymetabolised andthe

metabolitesareexcretedprincipallyin urine. Both cytochromesP450-CYP2D6 and

P450-CYP1A2catalysethe formationofthe twomajormetabolitesglucuronide conjugate of

4-hydroxyduloxetine and sulphateconjugate of5-hydroxy,6-methoxyduloxetine. Based

upon in vitro studies,thecirculating metabolitesofduloxetine are considered

pharmacologicallyinactive.The elimination half-life ofduloxetine rangesfrom8.1to 17.4

hours(meanof12.1 hours).Apparentplasmaclearance ofduloxetine rangesfrom33to261

L/hr(mean of101L/hr).

Gender

Althoughpharmacokineticdifferenceshave been identified betweenmalesandfemales

(apparentplasmaclearance lowerinfemales),the magnitudeofchangeisnotsufficientto

justifyanadjustmenttothe dose based upongender.

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Age

Pharmacokineticdifferenceshave been identifiedbetween youngerandelderlyfemales

(greaterthanorequalto65 years)(AUCishigherand half-life islongerinthe elderly),

althoughthemagnitudeofthesechangesisnotsufficienttojustifyadjustmentstothedose.

RenalImpairment

End stagerenaldisease(ESRD)patientsreceiving dialysishad a 2-fold higherduloxetine

Cmaxand AUCvaluescomparedtohealthysubjects.Therefore,alowerdose should be

consideredforpatientswith clinicallysignificantrenalimpairment(seeDosageand

Administrationsection).

HepaticImpairment

Patientswith cirrhosisofthe liverhad asimilarCmax,butthe half-life ofduloxetinewas34

hourslonger,while clearance wasapproximately15%ofthatforhealthysubjects.

CYMBALTAiscontraindicated in patientswith hepaticimpairment(see Contraindications).

Indications

CYMBALTAisindicatedforthetreatmentofmajordepressive disorder.

Amajordepressive episode (DSM-IV)impliesaprominentand relativelypersistent(nearly

everydayforatleast2 weeks)depressedordysphoricmoodthatusuallyinterfereswith

dailyfunctioning,and includesatleast5ofthefollowing9symptoms:depressedmood,loss

ofinterestin usualactivities,significantchangein weightand/orappetite,insomnia or

hypersomnia,psychomotoragitation orretardation,increasedfatigue,feelingsofguiltor

worthlessness,slowed thinking orimpairedconcentration,orasuicide attemptorsuicidal

ideation.

CYMBALTAisindicatedforthetreatmentofdiabeticperipheralneuropathicpain (DPNP).

CYMBALTAisindicatedforthetreatmentofgeneralisedanxietydisorder(GAD).

DosageandAdministration

MajorDepressive Disorder

CYMBALTAshould be initiated ata dose of60mgonce dailywithoutregardtomeals.

There isno adequate evidence suggestingthatpatientsnotresponding to60mg once daily

willbenefitfromhavingtheirdose increased.

DiabeticPeripheralNeuropathicPain

Duloxetineshouldbeadministeredatadoseof60mgoncedailywithoutregardtomeals.

Some patientsmaybenefitfromdosagesabovethe recommended 60mg once dailyup to a

maximumdose of120mgperday.Dosesabove 120 mghave notbeen systematically

evaluated

Generalised AnxietyDisorder

Therecommended starting dose ofCYMBALTAin patientswithgeneralizedanxietydisorder

is30mgoncedailywith orwithoutfood.Thedailydose should be increased in 30mg

incrementsuntiltheminimumeffective dose isachieved. Themaximumdose is120mg per

day,given as120mgonce daily. Dosesabove 120 mg have notbeen systematically

evaluated.

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Initial Tolerability

Forpatientsin whominitialtolerabilitymaybeaconcern,such astreatment-naïvepatients

orthose with a historyofadverse eventswith othermedications,use ofa lowerstartingdose

suchas30mgoncedailyforoneweekbeforeincreasingthedoseto60mgoncedaily

should be considered.Adose of30mgoncedailyshould be used inpatientswith end

stagerenaldisease(seebelow).Inaddition,clinicalstudieshaveshownthattaking

CYMBALTAwith foodmayimprove initialtolerability.

ElderlyPatients

No dosage adjustmentisrecommendedforelderlypatientssolelyon thebasisofage.

Children

Thesafetyand efficacyofduloxetine in patientsunderthe ageof18 yearshave notbeen

studied.

Patients withRenalImpairment

Initialdosage shouldbe30 mg once dailyin patientswith end stagerenaldisease (ESRD)

(creatinine clearance<30 mL/min).(SeeWarningsand Precautionssection).

Patients withHepaticImpairment

CYMBALTAiscontraindicated inpatientswith liverdiseaseresultinginhepaticimpairment

(see Contraindications).

Discontinuation oftreatment

When discontinuingCYMBALTAaftermorethanone weekoftherapyitisgenerally

recommendedthatthe dose betaperedtominimise theriskofdiscontinuation symptoms.

Asageneralrecommendation,the dose ofCYMBALTAshouldbereduced byhalfor

administeredon alternate daysduringaperiod ofnotlessthantwo weeks.The precise

regimenfollowed should take intoaccounttheindividualcircumstancesofthe patient,such

asduration oftreatment,dose atdiscontinuation,etc.

Contraindications

CYMBALTAiscontraindicated in patientsknown to be hypersensitive toduloxetine ortoany

oftheexcipients.

CYMBALTAshould notbe used incombinationwithmonoamineoxidase inhibitors(MAOIs),

orwithin atleast14daysofdiscontinuingtreatmentwith an MAOI. Basedon thehalf-life of

duloxetine,atleast5daysshould beallowed afterstoppingCYMBALTAbeforestartingan

MAOI.

CYMBALTAiscontraindicated inpatientswith liverdiseaseresultinginhepaticimpairment

(see Pharmacokinetics)

CYMBALTAshould notbe used in combination with potentCYP1A2 inhibitors(seeDrug

Interactions).

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WarningsandPrecautions

ClinicalWorsening and SuicideRisk

Thepossibilityofa suicide attemptisinherentin depression andmaypersistuntilsignificant

remissionoccurs.Close supervision ofhigh-riskpatientsshouldaccompanytreatment.

Patientswith depressionmayexperience worseningoftheirdepressive symptomsand/or

the emergenceofsuicidalideation and behaviours(suicidality)whetherornottheyare

taking antidepressantmedications,andthisriskmaypersistuntilsignificantremission

occurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreoftreatment,

patientsshould becloselymonitoredforclinicalworsening andsuicidality,especiallyatthe

beginning ofacourseoftreatment,oratthetimeofdosechanges,eitherincreasesor

decreases.Consideration should begiven tochangingthetherapeuticregimen,including

possiblydiscontinuingthe medication,in patientswhose depression ispersistentlyworse or

whose emergentsuicidalityissevere,abruptin onset,orwasnotpartofthe patient’s

presentingsymptoms. Patients(andcaregiversofpatients)should bealerted aboutthe

need tomonitorforanyworseningoftheircondition and/orthe emergence ofsuicidal

ideation/behaviourorthoughtsofharmingthemselvesand to seekmedicaladvice

immediatelyifthese symptomspresent.Patientswithco-morbid depression associatedwith

otherpsychiatricdisordersbeingtreatedwith antidepressantsshouldbe similarlyobserved

forclinicalworseningand suicidality.

Pooled analysesof24short-term(4to16 weeks),placebo-controlled trialsofnine

antidepressantmedicines(SSRIsand others)in4400 children andadolescentswith major

depressive disorder(16trials),obsessive compulsive disorder(4trials)orotherpsychiatric

disorders(4trials)have revealed a greaterriskofadverse eventsrepresenting suicidal

behaviourorthinking(suicidality)duringthe firstfewmonthsoftreatmentin thosereceiving

antidepressants.Theaverageriskofsucheventsin patientstreated with an antidepressant

was4%compared with 2%ofpatientsgiven placebo.Therewasconsiderable variation in

riskamongthe antidepressants,buttherewasa tendencytowardsan increaseforalmostall

antidepressantsstudied.Theriskofsuicidalitywasmostconsistentlyobserved in themajor

depressive disordertrials,buttherewere signalsofriskarisingfromtrialsin otherpsychiatric

indications(obsessivecompulsive disorderandsocialanxietydisorder)aswell. No suicides

occurredinthesetrials.Itisunknown whetherthe suicidalityriskin children and adolescent

patientsextendstousebeyond severalmonths.Thenine antidepressantmedicationsinthe

pooledanalysesincluded fiveSSRIs(citalopram,fluoxetine,fluvoxamine,paroxetine,

sertraline)andfournon-SSRIs(bupropion,mirtazapine,nefazodone,venlafaxine).

Symptomsofanxiety,agitation,panicattacks,insomnia,irritability,hostility

(aggressiveness),impulsivity,akathisia (psychomotorrestlessness),hypomania andmania

have been reported inadults,adolescentsand childrenbeing treatedwithantidepressants

formajordepressive disorderaswellasforotherindications,bothpsychiatricand

nonpsychiatric.Although a causallinkbetween the emergence ofsuchsymptomsand either

worseningofdepressionand/oremergenceofsuicidalimpulseshasnotbeen established,

thereisconcernthatsuch symptomsmaybeprecursorsofemergingsuicidality.

Familiesand caregiversofchildrenand adolescentsbeingtreatedwith antidepressantsfor

majordepressive disorderorforanyothercondition (psychiatricornonpsychiatric)should be

informedaboutthe needtomonitorthese patientsforthe emergence ofagitation,irritability,

unusualchangesinbehaviourand othersymptomsdescribed above,aswellasthe

emergenceofsuicidality,andtoreportsuchsymptomsimmediatelyto healthcareproviders.

Itisparticularlyimportantthatmonitoring be undertakenduring the initialfewmonthsof

antidepressanttreatmentorattimesofdoseincrease ordecrease.

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PrescriptionsforCYMBALTAshould be writtenforthesmallestquantityoftabletsconsistent

withgood patientmanagement,in ordertoreduce theriskofoverdose.

Hepatotoxicity

CYMBALTAshouldordinarilynotbe prescribedto patientswithevidence ofchronicliver

disease asitispossible thatduloxetine mayaggravate pre existingliverdisease(see

Contraindications).

CYMBALTAincreasestheriskofelevationofserumtransaminaselevels.Liver

transaminase elevationsresulted in the discontinuation of0.3%(82/27,229)ofCYMBALTA-

treated patients.In these patients,the median time to detection ofthe transaminase

elevationwasabouttwomonths. Inplacebo controlled trialsin anyindication,elevationsof

alaninetransaminase(ALT)to>3timestheupperlimitofnormaloccurredin1.1%(85/7632)

ofCYMBALTA-treatedpatientsandin0.2%(13/5578)ofplacebotreatedpatients.Inthe full

cohortofplacebo-controlledtrialsinanyindication,elevationofALT>3timestheupperlimit

ofnormaloccurredin1%(39/3732)ofCYMBALTA-treatedpatientscomparedto0.2%

(6/2568)ofplacebo-treated patients.In placebo-controlled studiesusingafixed dose design,

there wasevidence ofadose-response relationship forALTand ASTelevation of>3 times

the upperlimitofnormaland >5timesthe upperlimitofnormal,respectively.Postmarketing

reportshave described casesofhepatitiswith abdominalpain,hepatomegalyand elevation

oftransaminaselevelstomorethantwentytimestheupperlimitofnormalwithorwithout

jaundice,reflectinga mixed orhepatocellularpattern ofliverinjury.Casesofcholestatic

jaundice with minimalelevation oftransaminaselevelshave also been reported.Isolated

casesofliverfailure,includingfatalcases,have been reported.Amajorityofthese cases

have beenreported in patientswith pastorcurrentriskfactorsforliverinjury,including

alcoholabuse,hepatitisorexposuretodrugswithknown adverse effectson theliver.

The combination oftransaminase elevationsand elevated bilirubin,withoutevidence of

obstruction,isgenerallyrecognisedasanimportantpredictorofsevereliverinjury.Inclinical

trials,three CYMBALTApatientshad elevationsoftransaminasesand bilirubin,but also had

elevation ofalkaline phosphatase,suggestingan obstructive process;in these patients,

therewasevidenceofheavyalcoholuseandthismayhavecontributedtotheabnormalities

seen.

Postmarketingreportsindicate thatelevated transaminases,bilirubin and alkaline

phosphatasehave occurred in patientswith chronicliverdisease orcirrhosis.

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Alcohol

Use ofCYMBALTAwith substantialalcoholconsumption maybeassociatedwith severe

liverinjury.Isolatedcasesofliverfailure,includingfatalcases,have beenreported(see

Warningsand Precautions–Hepatotoxicity). CYMBALTAshouldonlybeused in

exceptionalcircumstanceswith extreme caution in patientswho consume substantial

amountsofalcohol.

Mania, seizures

In placebo-controlledtrialsin patientswith majordepressive disorder,activation of

hypomania ormania occurred in 0.1%ofduloxetinetreated patientsand 0.1%ofplacebo

treated patients.Activation ofmania/hypomaniahasbeenreported ina smallproportion of

patientswithmood disorderswho were treatedwith othermarketed drugseffective in the

treatmentofmajordepressive disorder.Aswith similarCNSactive medicines,duloxetine

should be usedwith cautionin patientswith a historyofmania oradiagnosisofbipolar

disorder,and/orseizures.

Mydriasis

Mydriasishasbeen reportedin associationwith duloxetine,therefore,caution should be

used when prescribingduloxetine in patientswith raised intraocularpressure,orthoseatrisk

ofacute narrow-angle glaucoma.

Hyponatraemia

Hyponatraemiahasbeenreportedveryrarely,predominantlyintheelderly,when

administeringCYMBALTA.Caution isrequired in patientsatincreasedriskfor

hyponatraemia;such aselderly,cirrhotic,ordehydrated patientsorpatientstreated with

diuretics.Hyponatraemiamaybe dueto a syndrome ofinappropriate anti-diuretichormone

secretion(SIADH).

Use in PatientswithConcomitantIllness

Clinicalexperiencewithduloxetinein patientswith concomitantsystemicillnessesislimited.

Caution isadvisable in usingduloxetine in patientswith diseasesorconditionsthatproduce

alteredmetabolismorhaemodynamicresponses.

Duloxetine hasnotbeen systematicallyevaluated in patientswith a recenthistoryof

myocardialinfarction orunstable heartdisease.Patientswiththesediagnoseswere

generallyexcludedfromclinicalstudiesduringtheproduct’spremarketingtesting.However,

evaluation ofelectrocardiograms(ECGs)of321 patientswho received duloxetine in

placebo-controlled clinicaltrialsindicated thatduloxetineisnotassociated with the

developmentofclinicallysignificantECGabnormalities(seeWarningsand Precautions-

Electrocardiograms).

Increasedplasmaconcentrationsofduloxetine occurin patientswith end stage renal

disease (ESRD)andin patientswithmoderate hepaticimpairment(see Pharmacokinetics).

Use inpatients withrenalimpairment

Increasedplasmaconcentrationsofduloxetine occurin patientswith severe renal

impairment(creatinine clearance<30mL/min).Alowerstarting doseshould be used in

such patientsifclinicallyrelevant(seeDosage and Administration andPharmacokinetics

sections)Population pharmacokineticanalysessuggestthatmild renaldysfunctionhasno

significanteffectonapparentplasmaclearanceofduloxetine.

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Increasein blood pressure

Duloxetine isassociatedwithan increase inbloodpressure insomepatients.Inclinical

trials,duloxetine treatmentwasassociatedwith increasesin blood pressure,averaging 2

mmHgsystolicand0.5mmHgdiastoliccompared toplacebo(seeAdverse Effects).Large,

potentiallyclinicallysignificant,elevationsin bloodpressure donotappearto bemore

commonwith duloxetine than with placebo.Inpatientswithknown hypertension and/orother

cardiacdisease,blood pressuremonitoring isrecommendedasappropriate.CYMBALTA

should be usedwith cautionin patientswhose conditionscould becompromisedbyan

increased heartrate orbyan increase in bloodpressure.

OrthostaticHypotension and Syncope

Orthostatichypotensionandsyncopehavebeenreportedwiththerapeuticdosesof

duloxetine.Syncope andhypotension tend to occurwithinthe firstweekoftherapybutcan

occuratanytime during duloxetine treatment,particularlyafterdose increases.The riskof

blood pressure decreasesmaybe greaterin patientstakingconcomitantmedicationsthat

induce orthostatichypotension (such asantihypertensives)orare potentCYP1A2 inhibitors

and in patientstaking dosesabove 60mgdaily. Consideration should begiven to

discontinuingCYMBALTAinpatientswhoexperiencesymptomaticorthostatichypotension

and/orsyncope duringtherapy.

Electrocardiograms

Electrocardiogramswere obtainedfrom321 duloxetine-treatedpatientswith MDDand 169

placebo-treated patientsin clinicaltrialslastingupto8 weeks.Therate-corrected QT(QTc)

intervalin duloxetine-treated patientsdid notdifferfromthatseenin placebo-treated

patients.No clinicallysignificantdifferenceswere observedforQT,PR,and QRSintervals

between duloxetine-treated and placebo-treatedpatients.

Discontinuing Treatment

Aswithothermedicineseffectiveinthetreatmentofmajordepressivedisorder,when

discontinuingCYMBALTAaftermorethan1weekoftherapy,itisgenerallyrecommended

thatthe dose be taperedto minimise the riskofdiscontinuation symptoms(see Dosage and

Administration).Themostcommonlyreportedsymptomsfollowingabruptdiscontinuationof

duloxetine in clinicaltrialshave included dizziness,nausea,headache,paraesthesia,

vomiting,irritability,nightmares,insomnia,diarrhoea,anxiety,hyperhidrosisand vertigo.

SerotoninSyndrome

Inrarecasesserotonin syndrome hasbeenreported in patientsusingSSRIs(e.g.

paroxetine,fluoxetine)concomitantlywith serotonergicmedicinalproducts.Caution is

advisable ifCYMBALTAisused concomitantlywith serotonergicantidepressantslikeSSRIs,

tricyclicslikeclomipramine oramitriptyline,StJohn’sWort(Hypericumperforatum),

venlafaxine ortriptans,tramadol,pethidine andtryptophan.

DrugDependence

While duloxetinehasnotbeensystematicallystudiedinhumansforitspotentialforabuse,

there wasnoindication ofdrug-seeking behaviourintheclinicaltrials.However,itisnot

possible to predictonthebasisofpremarketing experiencethe extentto which a CNSactive

drugwillbe misused,diverted,and/orabused oncemarketed.Consequently,physiciansshould

carefullyevaluatepatientsforahistoryofdrugabuse andfollowsuch patientsclosely,

observingthemforsignsofmisuseorabuseofduloxetine(e.g.developmentoftolerance,

incrementation ofdose,drug-seeking behaviour).

WeightChanges

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Weightchangesdo notappearto be clinicallysignificantoutcomesoftreatmentwith

duloxetine. In placebo-controlled clinicaltrials,patientstreated with duloxetine forupto9-

weeksexperiencedameanweightlossofapproximately0.5kg,comparedwith a mean

weightgain ofapproximately0.2kg in placebo-treated patients.

Carcinogenicity,Mutagenesis,ImpairmentofFertility

Duloxetinewasnotgenotoxicin a standardbatteryoftestsand producedno teratogenic

effectsinratsorrabbits.Duloxetine did notcausean increase inthe incidence of

neoplasmsinrats. Female micereceivingduloxetinefor2yearshadan increased incidence

ofhepatocellularadenomasandcarcinomasatthe highdoseonly(144mg/kg/day),but

these were consideredto be secondarytohepaticenzyme induction with associated

centrilobularhypertrophyand vacuolation.Therelevance ofthismousedatato humansis

unknown.Reproductive performancewasnotaffected inmaleratsreceiving duloxetine (45

mg/kg/day). Female ratsreceivingduloxetine (45mg/kg/day),had adecrease inmaternal

food consumptionand bodyweight,oestrouscycle disruption,depressionsin live birth

indicesand progenysurvival,and progenygrowth retardation.The no-observed-effectlevel

(NOEL)formaternaltoxicity,reproductive toxicity,anddevelopmentaltoxicityin thefemale

fertilitystudywas10 mg/kg/day.

Pregnancyand Lactation

The safetyofduloxetine foruse in humanpregnancyhasnotbeen established,therefore

CYMBALTAshould be used in pregnantwomenonlyiftheexpectedbenefitjustifiesthe

potentialrisktothefoetus.Womenshould be advised to notifytheirphysician ifthey

become pregnant,orintend tobecomepregnantduring therapy.Therewasno evidence of

teratogenicityin animalstudies.

Duloxetine isexcreted intothemilkoflactating women.Theestimateddailyinfantdoseona

mg/kg basisisapproximately0.14%ofthematernaldose.AdministrationofCYMBALTAto

nursing mothersisnotrecommended.

Effects onAbility toDrive andUse Machinery

Althoughin controlled studiesduloxetine hasnotbeen shown to impairpsychomotor

performance,cognitive function,ormemory,itmaybeassociatedwithsedation. Therefore,

patientsshould becautioned abouttheirabilitytodrive a caroroperate hazardous

machinery.

AdverseEffects

Thefollowinginformationon adverse effectsisbased on adverseeventreportingand

laboratoryinvestigationsfromclinicaltrialsofduloxetine in 9445 patientswith depression or

otherindications.Verycommoneventsare definedasthoseoccurringin ≥10%ofpatients,

commoneventsare defined asthoseoccurringin ≥1%and<10%ofpatients,uncommon

eventsare defined asthose occurringin ≥0.1%and<1%ofpatientsandrareeventsare

defined asthoseoccurring in <0.1%ofpatients.

CardiacDisorders:

Common:PalpitationsUncommon:tachycardia.

Earand LabyrinthDisorders:

Uncommon:vertigo,earpain,tinnitus

Endocrine Disorders

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Rare:hypothyroidism.

Eye Disorders:

Common:Vision blurredUncommon:mydriasis,visualdisturbance.

GastrointestinalDisorders:

VeryCommon:Nausea,drymouth,diarrhoea,constipation,Common:abdominalpain,

vomiting,dyspepsia,loose stools.Uncommon:eructation,gastroenteritis,stomatitis,

halitosis,gastritis.

GeneralDisordersand Administration Site Conditions:

Verycommon:Fatigue.Common:Asthenia,pyrexia.Uncommon:feeling abnormal,feeling

cold,feelinghot,malaise,thirst;Rare:gaitdisturbance.

InfectionsandInfestations

Common:Nasopharyngitis.Uncommon:laryngitis

Investigations:

Common:Weightincreased,weightdecreased.Uncommon:bloodpressure increased

(includingblood pressure systolicincreasedandblood pressure diastolicincreased),hepatic

lab relatedfindings(includingalanine aminotransferase increased,hepaticenzyme

increased,aspartateaminotransferaseincreased,liverfunctiontestabnormal,gamma-

glutamyltransferaseincreased,bloodalkaline phosphatase increased,blood bilirubin

increased),weightincreased,bloodcholesterolincreased.

Metabolismand NutritionDisorders:

Common:Decreased appetite,anorexia.Uncommon:dehydration

Musculoskeletaland Connective TissueDisorders:

Common:Muscle cramp,myalgia,musculoskeletalpain,muscle spasms.Uncommon:

muscle tightness,muscletwitching.

NervousSystemDisorders:

VeryCommon:Dizziness,somnolence,headache.Common:Tremor,parasthesia,

dysgeusia.Uncommondisturbancein attention,dyskinesia,poorqualitysleep;Rare:

myoclonus.

PsychiatricDisorders:

Common:Insomnia,agitation (includingfeelingjittery,nervousness,restlessness,tension,

psychomotoragitation),anxiety,libido decreased (including lossoflibido),orgasmabnormal

(includinganorgasmia),abnormaldreams(includingnightmares).Uncommon: bruxism,

disorientation (includingconfusionalstate),apathy.

Renaland UrinaryDisorders:

Uncommon:nocturia,urinaryhesitation,urinaryretention,dysuria,polyuria;Rare:urine

odourabnormal,urineflowdecreased.

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Duloxetine isin a classofmedicinesknown toaffecturethralresistance.In placebo-

controlled clinicaltrialsinpatientswith majordepressive disorder,urinaryhesitation was

reportedrarely(<1%)inmale patientsonly.Ifsymptomsofurinaryhesitation develop during

treatmentwith duloxetine,consideration should begiven tothe possibilitythattheymightbe

medicine-related.

Reproductive Systemand BreastDisorders:

Common:Erectile dysfunction,ejaculationdelayed,ejaculation disorder.Uncommon:

ejaculation delayed,menopausalsymptoms,erectile dysfunction,sexualdysfunction.

Respiratory,Thoracicand MediastinalDisorders:

Common:yawning,cough,pharyngolaryngealpain.Uncommon:throattightness

Skin andSubcutaneousTissueDisorders:

Common:Hyperhidrosis,rash,pruritis.Uncommon:nightsweats,photosensitivityreaction,

cold sweat,dermatitiscontact.

VascularDisorders:

Common:Hot flush.Uncommon:peripheralcoldness,orthostatichypotension

Discontinuation symptoms

Dizziness,nauseaand headache (greaterthan orequalto5%)were alsoreportedas

commonadverse eventsupon duloxetine discontinuation.Discontinuationsymptomshave

been reportedwhen stoppingduloxetine.Symptomsmayinclude dizziness,nausea,

headache,paraesthesia,vomiting,irritability,insomnia,diarrhoea,anxiety,hyperhidrosis,

vertigo andnightmares(seeWarningsandPrecautions).

ECGAbnormalities

Electrocardiogramswere obtained from321duloxetine-treatedpatientsinplacebo-controlled

clinicaltrials.Thedataindicate thatduloxetine isnotassociated with thedevelopmentof

clinicallysignificantECGabnormalities(seeWarningsandPrecautions).

Blood Pressure

In placebo-controlled clinicaltrialsofupto9 weeksduration,duloxetinetreatmentwas

associated with a smallincrease inheartrateofabout2beatsperminuteand increasesin

blood pressure averaging 2mmHgsystolicand0.5mmHgdiastoliccompared with placebo.

Blood Glucose

Inthreeclinicaltrialsofduloxetine forthetreatmentofdiabeticneuropathicpain,themean

duration ofdiabeteswasapproximately12 years,themeanbaselinefasting bloodglucose

was176 mg/dL,andthemean baseline haemoglobin HbA1cwas7.81%.Inthe12 week

acutetreatmentphase ofthesestudies,smallincreasesinfasting bloodglucose were

observed in duloxetine-treated patients.HbA1cwasstable in bothduloxetine-treatedand

placebo-treated patients.Inthe extension phaseofthesestudies,which lasted upto52

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weeks,therewasan increase in HbA1cin boththe duloxetine and theroutinecaregroups,

butthemean increase was0.3%greaterintheduloxetine-treatedgroup. Therewasalsoa

smallincreaseinfastingblood glucoseand intotalcholesterolinduloxetine-treatedpatients

while those laboratorytestsshowed a slightdecrease in theroutine caregroup.

SpontaneousData

Thefollowinglistofadverse drugreactionsisbased on postmarketingspontaneousreports,

and correspondingreporting rateshave beenprovided.Rareeventsare defined asthose

occurringinlessthan 1/1000 patients;veryrare eventsarethoseoccurring in lessthan

1/10,000patients.

Endocrine disorders

Veryrare:SIADH

Cardiacdisorders

Veryrare:supraventriculartachycardia

Earand Labyrinthdisorders

Veryrare:Tinnitusupon treatmentdiscontinuation

Eye disorders

Veryrare:glaucoma

Hepatobiliarydisorders

Veryrare:alanine aminotransferaseincreased,alkaline phosphataseincreased,aspartate

aminotransferase increased,bilirubin increased,hepatitis,jaundice

Isolatedcasesofliverfailure,includingfatalcases,have beenreported.Amajorityofthese

caseshave beenreported in patientswithpastorcurrentriskfactorsforliverinjury,including

alcoholabuse,hepatitisorexposure to drugswith known adverse effectson the liver. (see

WarningsandPrecautions)

Immune systemdisorders

Veryrare:anaphylacticreaction,hypersensitivity

Metabolismand nutrition disorders

Veryrare:hyponatraemia,hypoglycaemia(reported especiallyin diabeticpatients)

Musculoskeletaland connective tissue disorders

Veryrare:trismus,muscle spasm

Nervoussystemdisorders

Veryrare:extrapyramidaldisorder,serotoninsyndrome,seizures

Psychiatricdisorders

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Rare:hallucinations;Veryrare:mania,aggression and anger(particularlyearlyin treatment

oraftertreatmentdiscontinuations)

Renaland urinarydisorders

Rare:urinaryretention

Skin andsubcutaneoustissue disorders

Rare: rash;Veryrare:angioneuroticoedema,contusion,ecchymosis,Stevens-Johnson

Syndrome,urticaria

Vasculardisorders

Veryrare:orthostatichypotension (especiallyatthe initiation oftreatment),syncope

(especiallyatinitiation oftreatment),hypertensive crisis

Interactions

Duloxetineisa SNRIwith itsprimaryeffectonthe CNS. Caution should be used when itis

administered in combination with othercentrallyactingdrugsand substances,especially

those with a similarmechanismofaction,includingalcohol. Concurrentuse with otherdrugs

with serotonergicactivity(egSNRIs,SSRIs,triptansortramadol)mayresultin serotonin

syndrome (seeWarningsand Precautions).

Althoughduloxetine doesnotincreasethe impairmentofmentalandmotorskillscaused by

alcohol,use ofCYMBALTAwith substantialalcoholconsumptionmaybe associated with

severeliverinjury.Isolatedcasesofliverfailure,includingfatalcases,havebeenreported

(seeWarningsandPrecautions–Hepatotoxicity). CYMBALTAshould onlybe used in

exceptionalcircumstanceswith extreme caution in patientswho consume substantial

amountsofalcohol.

Medicinesmetabolisedby CYP1A2:ina clinicalstudy,thepharmacokineticsof

theophylline,a CYP1A2 substrate,were notsignificantlyaffectedbyco-administration with

duloxetine (60 mg twice daily).Theseresultssuggestthatduloxetine isunlikelyto have a

clinicallysignificanteffectonthemetabolismofCYP1A2 substrates.

InhibitorsofCYP1A2:because CYP1A2 isinvolved in duloxetine metabolism,concomitant

use ofduloxetine with potentinhibitorsofCYP1A2 willlikelyresultin higherconcentrations

ofduloxetine.Fluvoxamine (100mg oncedaily),a potentinhibitorofCYP1A2,decreased

the apparentplasmaconcentration ofduloxetinebyabout77%.CYMBALTAshould notbe

used in combination with potentinhibitorsofCYP1A2 (e.g.,fluvoxamine)(see

Contraindications).

Medicinesmetabolisedby CYP2D6:duloxetineisamoderate inhibitorofCYP2D6.When

duloxetinewasadministered atadose of60mgtwice dailywith a single dose of

desipramine,a CYP2D6substrate,the AUCofdesipramine increased 3-fold.The co-

administration ofduloxetine (40mg twice daily)increasessteadystateAUCoftolterodine (2

mgtwice daily)by71%butdoesnotaffectthe pharmacokineticsofits5-hydroxylmetabolite.

Therefore,cautionshould be usedifduloxetine isco-administeredwith medicationsthatare

predominantlymetabolised byCYP2D6 and which have a narrowtherapeuticindex(e.g.

tricyclicantidepressantssuch asnortriptylineand imipramine,phenothiazines,flecainide,

propafenone).Becauseoftheriskofseriousventriculararrhythmiasand sudden death

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potentiallyassociated with elevated plasmaconcentrationsofthioridazine,CYMBALTAand

thioridazine should notbe coadministered..

InhibitorsofCYP2D6:because CYP2D6 isinvolved in duloxetine metabolism,concomitant

use ofduloxetine with potentinhibitorsofCYP2D6 mayresultin higherconcentrationsof

duloxetine. Paroxetine (20 mg once daily)decreased theapparentplasma clearanceof

duloxetine byabout37%.Caution isadvisedifadministeringduloxetinewith inhibitorsof

CYP2D6(e.g.,SSRIs).

CNSmedicines:cautionisadvised when duloxetine istaken in combination with other

centrallyactingmedicinesorsubstances,especiallythose with a similarmechanismof

action,andincluding alcohol. Concomitantuseofotheragentswith serotonergicactivity

(e.g.,SNRIs,SSRIs,triptansortramadol)mayresultinserotonin syndrome.

Monoamine Oxidase Inhibitors (MAOI)-Because duloxetine isan inhibitorofboth

serotonin andnoradrenaline reuptake,itisrecommendedthatduloxetine notbeused in

combination with an MAOI(seeContraindications)

Antacids andH2 antagonists:co-administrationofduloxetinewith aluminium-and

magnesium-containingantacidsorduloxetine withfamotidine hadno significanteffectonthe

rateorextentofduloxetine absorption afteradministrationofa 40mg oraldose.

StJohn’s Wort-In common with otherantidepressants,concomitantadministration of

duloxetine and the herbalremedyStJohn'sWort(Hypericumperforatum)isnot

recommended.

Warfarin and INR–Increasesin INRhavebeen reported when duloxetinewasco-

administeredwith warfarin.

Lorazepam:understeady-state conditions,duloxetine had noeffectonlorazepamkinetics

and lorazepamhadno effecton duloxetinekinetics.The combinationofduloxetine and

lorazepamresultedin increased sedation compared with lorazepamalone.

Oralcontraceptivesand othersteroidalagents:resultsofin vitro studiesdemonstrate

thatduloxetinedoesnotinhibitorinducethecatalyticactivityofCYP3A. No increaseor

decrease inthemetabolismofCYP3Asubstrates(e.g.oralcontraceptivesand other

steroidalagents)isanticipated.

Overdosage

There islimitedclinicalexperience with duloxetine overdose in humans.In pre-marketing

clinicaltrials,casesofacute ingestionupto 1400mg,alone orin combination with other

drugs,were reportedwith none beingfatal.Postmarketing experience includesreportsof

overdoses,alone orincombination with otherdrugs,with duloxetine dosesofalmost

2000mg.Fatalitieshave been veryrarelyreported,primarilywith mixed overdoses,butalso

with duloxetine alone ata dose ofapproximately1000mg.Signsand symptomsof

overdose (mostwith mixed drugs)included serotonin syndrome,somnolence,vomiting,and

seizures.

In animalstudies,themajorsignsofoverdosetoxicityarerelatedtothecentralnervousand

gastrointestinalsystems.Theseinclude centralnervoussystemeffectssuch astremors,

clonicconvulsions,ataxia,emesis,and decreased appetite.

No specificantidote isknown,butifserotonin syndromeensues,specifictreatment(suchas

with cyproheptadine and/ortemperature control)maybe considered.Anairwayshould be

established.Monitoringofcardiacandvitalsignsisrecommended,alongwith appropriate

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symptomaticandsupportive measures.Gastriclavage maybeindicated ifperformedsoon

afteringestionorin symptomaticpatients.Activated charcoalmaybe usefulin limiting

absorption. Duloxetine hasa largevolumeofdistributionandforced diuresis,

haemoperfusion,and exchangeperfusion are unlikelyto bebeneficial.

PharmaceuticalPrecautions

Storage

Store below25°Cin the originalpackage.

Shelf Life

2 years.

InstructionsforUseand Handling

No specialrequirements.

MajorIncompatibilities

Notapplicable.

Medicine Classification

PrescriptionMedicine.

Package Quantities

CYMBALTAcapsulesare blisterpackagedandare available in cartonscontaining7or28

capsules.

FurtherInformation

Excipients

Gelatin,hydroxypropylmethylcellulose,hydroxypropylmethylcelluloseacetate succinate,

sodiumlaurylsulphate,sucrose,sugarspheres,talc,titaniumdioxide,andtriethylcitrate,

indigo carmine.The60mgcapsulesalsocontain iron oxide yellow.

Nameand Address

EliLillyand Company(NZ)Limited

Level3,Axon House,414-422 KhyberPassRoad

POBox109197

Newmarket,Auckland

NEWZEALAND.

Telephone(09)523 9300

DateofPreparation

May2011

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