orlistat label.pdf

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XENICAL - orlistat capsule

RochePharmaceuticals

XENICAL®

(orlistat)

CAPSULES

DESCRIPTION

XENICAL(orlistat)isalipaseinhibitorforobesitymanagementthatactsbyinhibitingtheabsorptionofdietaryfats.

Orlistatis(S)-2-formylamino-4-methyl-pentanoicacid(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecylester.Itsempirica

formulaisC29H53NO5,anditsmolecularweightis495.7.Itisasinglediastereomericmoleculethatcontainsfourchiralcenters,with

anegativeopticalrotationinethanolat529nm.Thestructureis:

Orlistatisawhitetooff-whitecrystallinepowder.Orlistatispracticallyinsolubleinwater,freelysolubleinchloroform,andvery

solubleinmethanolandethanol.OrlistathasnopK awithinthephysiologicalpHrange.

XENICALisavailablefororaladministrationindark-blue,hard-gelatincapsules,withlight-blueimprinting.Eachcapsulecontains120mgoftheactiveingredient,orlistat.Thecapsulesalsocontaintheinactiveingredientsmicrocrystallinecellulose,sodiumstarch

glycolate,sodiumlaurylsulfate,povidone,andtalc.Eachcapsuleshellcontainsgelatin,titaniumdioxide,andFD&CBlueNo.1,with

printingofpharmaceuticalglazeNF,titaniumdioxide,andFD&CBlueNo.1aluminumlake.

CLINICAL PHARMACOLOGY

Mechanism of Action

Orlistatisareversibleinhibitoroflipases.Itexertsitstherapeuticactivityinthelumenofthestomachandsmallintestinebyforming

acovalentbondwiththeactiveserineresiduesiteofgastricandpancreaticlipases.Theinactivatedenzymesarethusunavailableto

hydrolyzedietaryfatintheformoftriglyceridesintoabsorbablefreefattyacidsandmonoglycerides.Asundigestedtriglyceridesare

notabsorbed,theresultingcaloricdeficitmayhaveapositiveeffectonweightcontrol.Systemicabsorptionofthedrugistherefore

notneededforactivity.Attherecommendedtherapeuticdoseof120mgthreetimesaday,orlistatinhibitsdietaryfatabsorptionby

approximately30%.

Pharmacokinetics

Absorption

Systemicexposuretoorlistatisminimal.Followingoraldosingwith360mg14C-orlistat,plasmaradioactivitypeakedat

approximately8hours;plasmaconcentrationsofintactorlistatwerenearthelimitsofdetection(


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life(approximately3hours)whereasthesecondarymetaboliteM3disappearedataslowerrate(half-lifeapproximately13.5hours).In

obesepatients,steady-stateplasmalevelsofM1,butnotM3,increasedinproportiontoorlistatdoses.

Elimination

Followingasingleoraldoseof360mg14C-orlistatinbothnormalweightandobesesubjects,fecalexcretionoftheunabsorbed

drugwasfoundtobethemajorrouteofelimination.OrlistatanditsM1andM3metaboliteswerealsosubjecttobiliaryexcretion.

Approximately97%oftheadministeredradioactivitywasexcretedinfeces;83%ofthatwasfoundtobeunchangedorlistat.The

cumulativerenalexcretionoftotalradioactivitywas


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DiastolicBloodPressure,mmHg -1.19 +0.46

Anthropometric:

WaistCircumference,cm -6.45 -4.04

HipCircumference,cm -5.31 -2.96

*TreatmentdesignatesXENICAL120mgthreetimesadayplusdietorplaceboplusdiet

†Intent-to-treatpopulationatweek52,observeddatabasedonpooleddatafrom5studies

Population With Abnormal Risk Factors at Randomization

Thechangesfromrandomizationfollowing1-yeartreatmentinthepopulationwithabnormallipidlevels(LDL≥ 130mg/dL,LDL/HDL≥ 3.5,HDL


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†Lastobservationcarriedforward

‡Allstudies,withtheexceptionof14161wereconductedatcentersspecializingintreatingobesityorcomplicationsofobesity.Study

14161wasconductedwithprimarycarephysicians.

Therelativechangesinriskfactorsassociatedwithobesityfollowing2yearsoftherapywerealsoassessedinthepopulationasa

wholeandthepopulationwithabnormalriskfactorsatrandomization.

Population as a Whole

TherelativedifferencesinriskfactorsbetweentreatmentwithXENICALandplaceboweresimilartotheresultsfollowing1yearof

therapyfortotalcholesterol,LDL-cholesterol,LDL/HDLratio,triglycerides,fastingglucose,fastinginsulin,diastolicbloodpressure,

waistcircumference,andhipcircumference.TherelativedifferencesbetweentreatmentgroupsforHDLcholesterolandsystolicblood

pressurewerelessthanthatobservedintheyearoneresults.

Population With Abnormal Risk Factors at Randomization

TherelativedifferencesinriskfactorsbetweentreatmentwithXENICALandplaceboweresimilartotheresultsfollowing1yearof

therapyforLDL- andHDL-cholesterol,triglycerides,fastinginsulin,diastolicbloodpressure,andwaistcircumference.Therelative

differencesbetweentreatmentgroupsforLDL/HDLratioandisolatedsystolicbloodpressurewerelessthanthatobservedintheyear

oneresults.

Four-year Results: Long-term Weight Control and Risk Factors

Inthe4-yeardouble-blind,placebo-controlledXENDOSstudy,theeffectsoforlistatindelayingtheonsetoftype2diabetesand

onbodyweightwerecomparedtoplaceboin3304obesepatientswhohadeithernormalorimpairedglucosetoleranceatbaseline.

Thirty-fourpercentofthe1655patientswhowererandomizedtotheplacebogroupand52%ofthe1649patientswhowere

randomizedtotheorlistatgroupcompletedthe4-yearstudy.

Attheendofthestudy,themeanpercentweightlossintheplacebogroupwas-2.75%comparedwith-5.17%intheorlistatgroup

(p


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patientswhohadimpairedglucosetoleranceatbaseline(Table6andFigure2).Orlistatdidnotreducetheriskforthedevelopmentof

diabetesinpatientswithnormalglucosetoleranceatbaseline.

TheeffectofXENICALtodelaytheonsetoftype2diabetesinobesepatientswithIGTispresumablyduetoweightloss,andnotto

anyindependenteffectsofthedrugonglucoseorinsulinmetabolism.Theeffectoforlistatonweightlossisadjunctivetodietand

exercise.

Table6IncidenceRateofDiabetesatYear4byOGTTStatusatBaseline*

OGTT at baseline Normal Impaired All

Treatment Placebo Orlistat Placebo Orlistat Placebo Orlistat

Numberofpatients* 1148 1235 324 337 1472 1572

#ptsdevelopingdiabetes 16 21 62 48 78 69

Lifetablerate† 2.1% 1.7% 27.2% 18.7% 8.3% 5.5%

Observedpercent 1.4% 1.7% 19.1% 14.2% 5.3% 4.4%

Absoluteriskreduction

Lifetable 0.4% 8.5% 2.8%

Observed -0.3% 4.9% 0.9%

Relativeriskreduction‡ 8% 42% 34%

p-value 0.79


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†Lastobservationcarriedforward

INDICATIONS AND USAGE

XENICALisindicatedforobesitymanagementincludingweightlossandweightmaintenancewhenusedinconjunctionwith

areduced-caloriediet.XENICALisalsoindicatedtoreducetheriskforweightregainafterpriorweightloss.XENICALis

indicatedforobesepatientswithaninitialbodymassindex(BMI)≥ 30kg/m2or≥ 27kg/m2inthepresenceofotherriskfactors(eg,

hypertension,diabetes,dyslipidemia).

Table8illustratesbodymassindex(BMI)accordingtoavarietyofweightsandheights.TheBMIiscalculatedbydividingweightin

kilogramsbyheightinmeterssquared.Forexample,apersonwhoweighs180lbsandis5'5"wouldhaveaBMIof30.

Table8BodyMassIndex(BMI),kg/m2*

WEIGHT (lb)

120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320

4'10" 25 27 29 31 34 36 38 40 42 44 46 48 50 52 54 57 59 61 63 65 67

4'11" 24 26 28 30 32 34 36 38 40 43 45 47 49 51 53 55 57 59 61 63 65

5'0" 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63

5'1" 23 25 27 28 30 32 34 36 38 40 42 44 45 47 49 51 53 55 57 59 61

5'2" 22 24 26 27 29 31 33 35 37 38 40 42 44 46 48 49 51 53 55 57 59

5'3" 21 23 25 27 28 30 32 34 36 37 39 41 43 44 46 48 50 51 53 55 57

5'4" 21 22 24 26 28 29 31 33 34 36 38 40 41 43 45 46 48 50 52 53 55

5'5" 20 22 23 25 27 28 30 32 33 35 37 38 40 42 43 45 47 48 50 52 53

5'6" 19 21 23 24 26 27 29 31 32 34 36 37 39 40 42 44 45 47 49 50 52

5'7" 19 20 22 24 25 27 28 30 31 33 35 36 38 39 41 42 44 46 47 49 50

5'8" 18 20 21 23 24 26 27 29 30 32 34 35 37 38 40 41 43 44 46 47 49

5'9" 18 19 21 22 24 25 27 28 30 31 33 34 36 37 38 40 41 43 44 46 47

5'10" 17 19 20 22 23 24 26 27 29 30 32 33 35 36 37 39 40 42 43 45 46

5'11" 17 18 20 21 22 24 25 27 28 29 31 32 34 35 36 38 39 41 42 43 45

6'0" 16 18 19 20 22 23 24 26 27 29 30 31 33 34 35 37 38 39 41 42 43

6'1" 16 17 19 20 21 22 24 25 26 28 29 30 32 33 34 36 37 38 40 41 42

6'2" 15 17 18 19 21 22 23 24 26 27 28 30 31 32 33 35 36 37 39 40 41

HEIGHT

(ft/in)

*ConversionFactors:

Weightinlbs÷2.2=weightinkilograms(kg)

Heightininches×0.0254=heightinmeters(m)

1foot=12inches

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CONTRAINDICATIONS

XENICALiscontraindicatedinpatientswithchronicmalabsorptionsyndromeorcholestasis,andinpatientswithknown

hypersensitivitytoXENICALortoanycomponentofthisproduct.

WARNINGS

Miscellaneous

Organiccausesofobesity(eg,hypothyroidism)shouldbeexcludedbeforeprescribingXENICAL.

PreliminarydatafromaXENICALandcyclosporinedruginteractionstudyindicateareductionincyclosporineplasmalevelswhen

XENICALwascoadministeredwithcyclosporine.Therefore,XENICALandcyclosporineshouldnotbecoadministered.Toreduce

thechanceofadrug-druginteraction,cyclosporineshouldbetakenatleast2hoursbeforeorafterXENICALinpatientstakingboth

drugs.Inaddition,inthosepatientswhosecyclosporinelevelsarebeingmeasured,morefrequentmonitoringshouldbeconsidered.

PRECAUTIONS

General

Patientsshouldbeadvisedtoadheretodietaryguidelines(seeDOSAGEANDADMINISTRATION).Gastrointestinalevents

(seeADVERSEREACTIONS)mayincreasewhenXENICAListakenwithadiethighinfat(>30%totaldailycaloriesfromfat).

Thedailyintakeoffatshouldbedistributedoverthreemainmeals.IfXENICAListakenwithanyonemealveryhighinfat,the

possibilityofgastrointestinaleffectsincreases.

Patientsshouldbestronglyencouragedtotakeamultivitaminsupplementthatcontainsfat-solublevitaminstoensureadequate

nutritionbecauseXENICALhasbeenshowntoreducetheabsorptionofsomefat-solublevitaminsandbeta-carotene(seeDOSAGE

ANDADMINISTRATION).Inaddition,thelevelsofvitaminDandbeta-carotenemaybelowinobesepatientscomparedwithnon-

obesesubjects.Thesupplementshouldbetakenonceadayatleast2hoursbeforeoraftertheadministrationofXENICAL,suchasat

bedtime.

Table9illustratesthepercentageofadultpatientsonXENICALandplacebowhodevelopedalowvitaminlevelontwoormore

consecutivevisitsduring1and2yearsoftherapyinstudiesinwhichpatientswerenotpreviouslyreceivingvitaminsupplementation.

Table9IncidenceofLowVitaminValuesonTwoorMoreConsecutiveVisits(NonsupplementedAdultPatientsWithNormal

BaselineValues- FirstandSecondYear)

Placebo* XENICAL*

VitaminA 1.0% 2.2%

VitaminD 6.6% 12.0%

VitaminE 1.0% 5.8%

Beta-carotene 1.7% 6.1%*TreatmentdesignatesplaceboplusdietorXENICALplusdiet

Table10illustratesthepercentageofadolescentpatientsonXENICALandplacebowhodevelopedalowvitaminlevelontwoor

moreconsecutivevisitsduringthe1-yearstudy.

Table10IncidenceofLowVitaminValuesonTwoorMoreConsecutiveVisits(PediatricPatientsWithNormalBaselineValues*)

Placebo†

XENICAL†

VitaminA 0.0% 0.0%

VitaminD 0.7% 1.4%

VitaminE 0.0% 0.0%

Beta-carotene 0.8% 1.5%

*Allpatientsweretreatedwithvitaminsupplementationthroughoutthecourseofthestudy

†TreatmentdesignatesplaceboplusdietorXENICALplusdiet

SomepatientsmaydevelopincreasedlevelsofurinaryoxalatefollowingtreatmentwithXENICAL.Cautionshouldbeexercised

whenprescribingXENICALtopatientswithahistoryofhyperoxaluriaorcalciumoxalatenephrolithiasis.

Weight-lossinductionbyXENICALmaybeaccompaniedbyimprovedmetaboliccontrolindiabetics,whichmightrequirea

reductionindoseoforalhypoglycemicmedication(eg,sulfonylureas,metformin)orinsulin(seeCLINICALSTUDIES).

Substantialweightlosscanincreasetheriskofcholelithiasis.InaclinicaltrialofXENICALforthepreventionoftype2diabetes,

theratesofcholelithiasisasanadverseeventwere2.9%(47/1649)forpatientsrandomizedtoXENICALand1.8%(30/1655)for

patientsrandomizedtoplacebo.Inthistrial,theincidenceofcholelithiasiswassimilarforXENICALandplaceboatsimilaramounts

ofweightloss.AnincreaseincholelithiasiswithXENICALwasnotseenintrialsthatwerenotevaluatingthepreventionoftype2

diabetes.

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Misuse Potential

Aswithanyweight-lossagent,thepotentialexistsformisuseofXENICALininappropriatepatientpopulations(eg,patientswith

anorexianervosaorbulimia).SeeINDICATIONSANDUSAGEforrecommendedprescribingguidelines.

Information for Patients

PatientsshouldreadthePatientInformationbeforestartingtreatmentwithXENICALandeachtimetheirprescriptionisrenewed.

Drug Interactions

Alcohol

Inamultiple-dosestudyin30normal-weightsubjects,coadministrationofXENICALand40gramsofalcohol(eg,approximately3 glassesofwine)didnotresultinalterationofalcoholpharmacokinetics,orlistatpharmacodynamics(fecalfatexcretion),orsystemic

exposuretoorlistat.

Cyclosporine


XENICALwascoadministeredwithcyclosporine(seeWARNINGS).

Digoxin

In12normal-weightsubjectsreceivingXENICAL120mgthreetimesadayfor6days,XENICALdidnotalterthepharmacokinetics

ofasingledoseofdigoxin.

Fat-solubleVitaminSupplementsandAnalogues

Apharmacokineticinteractionstudyshoweda30%reductioninbeta-carotenesupplementabsorptionwhenconcomitantly administeredwithXENICAL.XENICALinhibitedabsorptionofavitaminEacetatesupplementbyapproximately60%.Theeffectof

orlistatontheabsorptionofsupplementalvitaminD,vitaminA,andnutritionally-derivedvitaminKisnotknownatthistime.

Glyburide

In12normal-weightsubjectsreceivingorlistat80mgthreetimesadayfor5days,orlistatdidnotalterthepharmacokineticsor

pharmacodynamics(bloodglucose-lowering)ofglyburide.

Levothyroxine

Hypothyroidismhasbeenreportedinpatientstreatedconcomitantlywithorlistatandlevothyroxinepostmarketing(seeADVERSE

REACTIONS: Other Clinical Studies or Postmarketing Surveillance).Patientstreatedconcomitantlywithorlistatand

levothyroxineshouldbemonitoredforchangesinthyroidfunction.Administerlevothyroxineandorlistatatleast4hoursapart.

Nifedipine(extended-releasetablets) In17normal-weightsubjectsreceivingXENICAL120mgthreetimesadayfor6days,XENICALdidnotalterthebioavailabilityof

nifedipine(extended-releasetablets).

OralContraceptives

In20normal-weightfemalesubjects,thetreatmentofXENICAL120mgthreetimesadayfor23daysresultedinnochangesinthe

ovulation-suppressingactionoforalcontraceptives.

Phenytoin

In12normal-weightsubjectsreceivingXENICAL120mgthreetimesadayfor7days,XENICALdidnotalterthepharmacokinetics

ofasingle300-mgdoseofphenytoin.

Pravastatin

Ina2-waycrossoverstudyof24normal-weight,mildlyhypercholesterolemicpatientsreceivingXENICAL120mgthreetimesaday

for6days,XENICALdidnotaffectthepharmacokineticsofpravastatin.

Warfarin

In12normal-weightsubjects,administrationofXENICAL120mgthreetimesadayfor16daysdidnotresultinanychangeineither

warfarinpharmacokinetics(bothR- andS-enantiomers)orpharmacodynamics(prothrombintimeandserumFactorVII).Although

undercarboxylatedosteocalcin,amarkerofvitaminKnutritionalstatus,wasunalteredwithXENICALadministration,vitaminK

levelstendedtodeclineinsubjectstakingXENICAL.Therefore,asvitaminKabsorptionmaybedecreasedwithXENICAL,patients

onchronicstabledosesofwarfarinwhoareprescribedXENICALshouldbemonitoredcloselyforchangesincoagulationparameters.

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FlatuswithDischarge 23.9 1.4 2.1 0.2

FecalUrgency 22.1 6.7 2.8 1.7

Fatty/OilyStool 20.0 2.9 5.5 0.6

OilyEvacuation 11.9 0.8 2.3 0.2

IncreasedDefecation 10.8 4.1 2.6 0.8

FecalIncontinence 7.7 0.9 1.8 0.2

*TreatmentdesignatesXENICALthreetimesadayplusdietorplaceboplusdiet

Theseandothercommonlyobservedadversereactionsweregenerallymildandtransient,andtheydecreasedduringthesecondyearoftreatment.Ingeneral,thefirstoccurrenceoftheseeventswaswithin3monthsofstartingtherapy.Overall,approximately50%of

allepisodesofGIadverseeventsassociatedwithorlistattreatmentlastedforlessthan1week,andamajoritylastedfornomorethan

4weeks.However,GIadverseeventsmayoccurinsomeindividualsoveraperiodof6monthsorlonger.

Discontinuation of Treatment

Incontrolledclinicaltrials,8.8%ofpatientstreatedwithXENICALdiscontinuedtreatmentduetoadverseevents,comparedwith

5.0%ofplacebo-treatedpatients.ForXENICAL,themostcommonadverseeventsresultingindiscontinuationoftreatmentwere

gastrointestinal.

Incidence in Controlled Clinical Trials

Thefollowingtablelistsothertreatment-emergentadverseeventsfromsevenmulticenter,double-blind,placebo-controlledclinical

trialsthatoccurredatafrequencyof≥ 2%amongpatientstreatedwithXENICAL120mgthreetimesadayandwithanincidencetha

wasgreaterthanplaceboduringyear1andyear2,regardlessofrelationshiptostudymedication.

Table12OtherTreatment-EmergentAdverseEventsFromSevenPlacebo-ControlledClinicalTrials

Body System/Adverse Event

Year 1 Year 2

XENICAL*

% Patients

(N=1913)

Placebo*

% Patients

(N=1466)

XENICAL*

% Patients

(N=613)

Placebo*

% Patients

(N=524)

Gastrointestinal System

AbdominalPain/Discomfort 25.5 21.4 – –

Nausea 8.1 7.3 3.6 2.7

InfectiousDiarrhea 5.3 4.4 – –

RectalPain/Discomfort 5.2 4.0 3.3 1.9ToothDisorder 4.3 3.1 2.9 2.3

GingivalDisorder 4.1 2.9 2.0 1.5

Vomiting 3.8 3.5 – –

Respiratory System

Influenza 39.7 36.2 – –

UpperRespiratoryInfection 38.1 32.8 26.1 25.8

LowerRespiratoryInfection 7.8 6.6 – –

Ear,Nose&ThroatSymptoms 2.0 1.6 – –

Musculoskeletal System

BackPain 13.9 12.1 – –

PainLowerExtremities – – 10.8 10.3

Arthritis 5.4 4.8 – –

Myalgia 4.2 3.3 – –

JointDisorder 2.3 2.2 – –

Tendonitis – – 2.0 1.9

Central Nervous System

Headache

Dizziness

30.6

5.2

27.6

5.0

–

–

–

–

Body as a Whole

Fatigue 7.2 6.4 3.1 1.7

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SleepDisorder 3.9 3.3 – –

Skin & Appendages

Rash

DrySkin

4.3

2.1

4.0

1.4

–

–

–

–

Reproductive, Female

MenstrualIrregularity

Vaginitis

9.8

3.8

7.5

3.6

–

2.6

–

1.9

Urinary System

UrinaryTractInfection 7.5 7.3 5.9 4.8

Psychiatric Disorder

PsychiatricAnxiety

Depression

4.7

–

2.9

–

2.8

3.4

2.1

2.5

Hearing & Vestibular Disorders

Otitis 4.3 3.4 2.9 2.5

Cardiovascular Disorders

PedalEdema – – 2.8 1.9

–Nonereportedatafrequency≥ 2%andgreaterthanplacebo


Inthe4-yearXENDOSstudy,thegeneralpatternofadverseeventswassimilartothatreportedforthe1- and2-yearstudieswiththe

totalincidenceofgastrointestinal-relatedadverseeventsoccurringinyear1decreasingeachyearoverthe4-yearperiod.

Other Clinical Studies or Postmarketing Surveillance

RarecasesofhypersensitivityhavebeenreportedwiththeuseofXENICAL.Signsandsymptomshaveincludedpruritus,rash,

urticaria,angioedema,bronchospasmandanaphylaxis.Veryrarecasesofbullouseruption,increaseintransaminasesandinalkaline

phosphatase,andexceptionalcasesofhepatitisthatmaybeserioushavebeenreported.Nocausalrelationshiporphysiopathological

mechanismbetweenhepatitisandorlistattherapyhasbeenestablished.Reportsofdecreasedprothrombin,increasedINRand

unbalancedanticoagulanttreatmentresultinginchangeofhemostaticparametershavebeenreportedinpatientstreatedconcomitantly

withorlistatandanticoagulants.Hypothyroidismhasbeenreportedinpatientstreatedconcomitantlywithorlistatandlevothyroxine.

PancreatitishasbeenreportedwiththeuseofXENICALinpostmarketingsurveillance.Nocausalrelationshiporphysiopathological

mechanismbetweenpancreatitisandobesitytherapyhasbeendefinitivelyestablished.

Inclinicaltrialsinobesediabeticpatients,hypoglycemiaandabdominaldistensionwerealsoobserved.


XENICALwascoadministeredwithcyclosporine(seeWARNINGS).

Pediatric Patients

InclinicaltrialswithXENICALinadolescentpatientsages12to16years,theprofileofadversereactionswasgenerallysimilarto

thatobservedinadults.

OVERDOSAGE

Singledosesof800mgXENICALandmultipledosesofupto400mgthreetimesadayfor15dayshavebeenstudiedinnormal

weightandobesesubjectswithoutsignificantadversefindings.

ShouldasignificantoverdoseofXENICALoccur,itisrecommendedthatthepatientbeobservedfor24hours.Basedonhumanand

animalstudies,systemiceffectsattributabletothelipase-inhibitingpropertiesoforlistatshouldberapidlyreversible.

DOSAGE AND ADMINISTRATIONTherecommendeddoseofXENICALisone120-mgcapsulethreetimesadaywitheachmainmealcontainingfat(duringorupto1

hourafterthemeal).

Thepatientshouldbeonanutritionallybalanced,reduced-caloriedietthatcontainsapproximately30%ofcaloriesfromfat.Thedaily

intakeoffat,carbohydrate,andproteinshouldbedistributedoverthreemainmeals.Ifamealisoccasionallymissedorcontainsno

fat,thedoseofXENICALcanbeomitted.

BecauseXENICALhasbeenshowntoreducetheabsorptionofsomefat-solublevitaminsandbeta-carotene,patientsshouldbe

counseledtotakeamultivitamincontainingfat-solublevitaminstoensureadequatenutrition(seePRECAUTIONS:General).The

supplementshouldbetakenatleast2hoursbeforeoraftertheadministrationofXENICAL,suchasatbedtime.

Forpatientsreceivingbothorlistatandlevothyroxinetherapy,administerlevothyroxineandorlistatatleast4hoursapart.

Dosesabove120mgthreetimesadayhavenotbeenshowntoprovideadditionalbenefit.

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Basedonfecalfatmeasurements,theeffectofXENICALisseenassoonas24to48hoursafterdosing.Upondiscontinuationof

therapy,fecalfatcontentusuallyreturnstopretreatmentlevelswithin48to72hours.

ThesafetyandeffectivenessofXENICALbeyond4yearshavenotbeendeterminedatthistime.

HOW SUPPLIED

XENICALisadark-blue,hard-gelatincapsulecontainingpelletsofpowder.

XENICAL120mgCapsules:Dark-blue,two-piece,No.1opaquehard-gelatincapsuleimprintedwithRocheandXENICAL120in

light-blueink—bottleof90(NDC0004-0256-52).

Storage Conditions

Storeat25°C(77°F);excursionspermittedto15°to30°C(59°to86°F)[seeUSPControlledRoomTemperature].Keepbottletightly

closed.

XENICALshouldnotbeusedafterthegivenexpirationdate.

PIRevised:July2008

IMPORTANT PATIENT INFORMATION

Patient Information about XENICAL® (orlistat) Capsules

XENICAL (zen' i-cal)

Generic Name: orlistat

PleasereadthisinformationbeforeyoustarttakingXENICALandeachtimeyourenewyourprescription.Thisimportantinformation

mayhelpyousuccessfullyloseweightandmaintainyourweightlosswhiletakingXENICAL.Thispatientinformationisasummary

andisnotintendedtotaketheplaceofdiscussionswithyourdoctor.ItdoesnotlistallbenefitsandrisksofXENICAL.The

medicationdescribedherecanonlybeprescribedanddispensedbyalicensedhealthcareprofessional,whohasinformationabout

yourmedicalconditionandmoreinformationaboutthedrug,includinghowtotakeit,whattoexpect,andpotentialsideeffects.Ifyou

haveanyquestionsaboutXENICAL,talkwithyourdoctor.

What is XENICAL?

XENICALisanoralprescriptionweightlossmedicationusedtohelpobesepeopleloseweightandkeepthisweightoff.XENICAL

worksinyourintestines,whereitblockssomeofthefatyoueatfrombeingabsorbed.Thisundigestedfatistheneliminatedinyour

bowelmovements.XENICALshouldbeusedtogetherwithareduced-caloriedietthatyourdoctorwillrecommend.

Excessweighthasbeenproventocontributetoanincreasedriskofdevelopingmanymedicalproblems,includinghighblood

pressure,highcholesterol,heartdisease,anddiabetes.Theconsumptionofexcessfattyfoodandcaloriesplaysasignificantrolein

thedevelopmentofexcessweight.Whilefatisanimportantcomponentofabalanceddiet,theconsumptionofexcessfatcontributes

toexcessbodyweight,sincefatprovidestwicethenumberofcaloriespergramofweightascarbohydratesandprotein.Reductionof

dietaryfatintakeisonepotentialwayoflosingweight.

How does XENICAL work?

Ifyoueatanexcessamountoffatorcalories,theexcessisstoredasfatbythebodyresultinginweightgain.Whenyoueatfat,yourbodybreaksitdownintoitssimplestcomponentssothatitcanbeabsorbed.Enzymesinyourintestinaltract,calledlipases,help

digest(orbreakdown)fat.WhenyoutakeXENICALwithmeals,XENICALattachestothelipasesandblocksthemfrombreaking

downsomeofthefatyouhaveeaten.Theundigestedfatcannotbeabsorbedandiseliminatedinyourbowelmovements.Byworking

thisway,XENICALhelpsblockabout30%ofthefateateninfoodfrombeingabsorbedbyyourbody.

Information for adult obese patients

Followingoneyearoftreatment,XENICALincombinationwithdietwasshowntobemoreeffectiveinreducingweightthandiet

alone.Inmostcases,weightlosswasgradual.PatientstreatedwithXENICALandareduced-caloriedietforoneyearlostanaverage

of13.4poundswhilethoseonareduced-caloriedietalonelost5.8pounds.

Information for adolescent obese patients

Followingoneyearoftreatment,XENICALincombinationwithdietwasshowntobemoreeffectiveinreducingBodyMassIndex

(BMI)thandietalone.AreductioninBodyMassIndexisabetterindicatorofweightlossinchildrenbecauseittakesintoaccount

changesinweightrelatedtogrowingchildren.

Who should use XENICAL?Aweightlossprogramthatincludesareduced-caloriedietandappropriatephysicalactivitymaybeadequateinsomepatients.You

shoulddiscusswithyourdoctororotherhealthcareproviderwhetherXENICALshouldbeaddedtosuchaprogram.

XENICALmayberightforyouifyouareconsiderablyoverweight(atleast30%aboveidealweightorabodymassindexof30or

greater).XENICALmayalsoberightforyouifyouareoverweight(atleast20%aboveidealweightorabodymassindexof27or

greater)andalsohaveotherriskfactorssuchashighbloodpressure,highcholesterol,heartdisease,ordiabetes.

Howtodetermineyourbodymassindex(BMI):

ThechartbelowillustratesBMIaccordingtoavarietyofweightsandheights.TheBMIiscalculatedbydividingyourweightin

kilogramsbyyourheightinmeterssquared.Tousethischart:

• Findtheheightclosesttoyourheightintheleft-handcolumn.

• Thenmoveacrossthetoprowtofindtheweightclosesttoyourweight.

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1600 53

1800 60

2000 67

Should I take a multivitamin with XENICAL?

XENICALinterfereswithyourbody’sabsorptionofsomefat-solublevitamins.Therefore,whenyouuseXENICAL,itishighly

recommendedthatyoutakeadailymultivitaminsupplementcontainingvitaminsD,E,K,andbeta-carotene.Takeyourmultivitamin

onceadayatleast2hoursbeforeoraftertakingXENICAL,suchasatbedtime.

Can I take XENICAL while taking other medications?

Besuretodiscusswithyourdoctorallmedications(includingherbalproducts)youarecurrentlytaking,includingmedicinesyou

cangetwithoutaprescription(over-the-counter),todetermineifXENICALcanbetakeninadditiontothesemedications.Ifyou

aretakingcyclosporine,XENICALandcyclosporineshouldbetakenatleast2hoursapart.Ifyourcyclosporinelevelsarebeing

measured,morefrequentmonitoringmaybenecessary.Ifyouaretakinglevothyroxine,XENICALandlevothyroxineshouldbetaken

atleast4hoursapart.

How long should I use XENICAL?

TheuseofXENICALformorethan4yearshasnotbeenstudied.Youandyourdoctorshoulddiscusshowlongyoushoulduse

XENICAL.

What are the most common side effects of XENICAL?

BecauseXENICALworksbyblockingtheabsorptionofdietaryfat,itislikelythatyouwillexperiencesomechangesinbowelhabits

Thesegenerallyoccurduringthefirstweeksoftreatment;however,theymaycontinuethroughoutyouruseofXENICAL.These

changesmayincludeoilyspotting,gaswithdischarge,urgentneedtogotothebathroom,oilyorfattystools,anoilydischarge, increasednumberofbowelmovements,andinabilitytocontrolbowelmovements.Duetothepresenceofundigestedfat,theoilseen

inabowelmovementmaybeclearorhaveacolorationsuchasorangeorbrown.

ThesebowelchangesareanaturaleffectofblockingthefatfrombeingabsorbedandindicatethatXENICALisworking.They

generallyoccurearlyintreatment,particularlyaftermealscontaininghigheramountsoffatthanarerecommended.Thesesymptoms

areoftentemporaryandmaylessenordisappearasyoucontinuetreatmentandkeeptoyourrecommendeddietofmealscontainingno

morethanabout30%fat.However,thesesideeffectsmayoccurinsomeindividualsoveraperiodof6monthsorlonger.

InobeseadolescentpatientstreatedwithXENICAL,thesideeffectsreportedweresimilartothoseobservedinadults.

If you are concerned about these or any other side effects you experience while taking XENICAL, talk to your doctor or

pharmacist.

What lifestyle changes should I consider when taking XENICAL?

You must use XENICAL with a recommended mildly reduced-calorie diet. Youshouldalsofollowaprogramofregularphysical

activity,suchaswalking.However, before you undertake any activity or exercise program, be sure to speak with your doctor or

health care professional.How can I reduce dietary fat?

Tohelpyougetstartedonreducingthefatinyourdiettoaround30%,readthelabelsonallthefoodsyoubuy.Youshouldavoid

foodsthatcontainmorethan30%fatwhileyouaretakingXENICAL.

• Wheneatingmeat,poultryorfish,limityourportionto2or3ounces(roughlythesizeofadeckofcards).Chooseleancutsof

meatandremovetheskinfrompoultry.Fillupyourmealplatebyincludingmoregrains,fruits,andvegetables.

• Replacewhole-milkproductswithnonfator1%milkandnonfat,reduced-fat,orlow-fatdairyitems.

• Cookwithlessfat.Usevegetableoilspraywhencooking.Saladdressings,manybakeditems,andprepackaged,processed,and

fastfoodsareusuallyhighinfat.Usethelow- ornon-fatversionsand/orcutbackonservingsizes.

• Whendiningout,askhowfoodsarepreparedandrequestthattheybepreparedwithlittleornoaddedfat.

Please visit www.xenical.com to help you succeed with your weight loss goals.

PPIRevised:January2009

Distributedby:

RocheLaboratories,Inc.

340KingslandStreet

Nutley,NJ07110–1199

27899513

27899661

Copyright©1999-2009byRocheLaboratoriesInc.Allrightsreserved.

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