CADUET ® 5/10

Caduet®Tablets,Israel, 29July2007

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CADUET ®

(amlodipine besylate/atorvastatin calcium)Tablets

DESCRIPTION

CADUET® (amlodipine besylate andatorvastatincalcium)tablets combinethe long-acting

calciumchannelblockeramlodipinebesylatewith the syntheticlipid-loweringagent

atorvastatin calcium.

Theamlodipine besylatecomponentofCADUETis chemicallydescribedas3-Ethyl-5-

methyl(±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl)-1,4-dihydro-6-methyl-3,5-

pyridinedicarboxylate, monobenzenesulphonate.Its empirical formulais

20 H

25 ClN

2 O

5 C

6 H

6 O

3 S.

The atorvastatincalcium component ofCADUET ischemicallydescribedas [R-(R*,R*)]-

2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-

1H-pyrrole-1-heptanoic acid,calcium salt (2:1) trihydrate.Itsempiricalformula is (C

Ca3H

O.

Thestructuralformulaefor amlodipinebesylateandatorvastatin calciumareshown below.

Amlodipinebesylate Atorvastatin calcium

CADUETcontainsamlodipinebesylate,a whiteto off-whitecrystallinepowder,and

atorvastatincalcium, alsoawhitetooff-whitecrystallinepowder. Amlodipinebesylate has

a molecularweightof567.1and atorvastatincalciumhasa molecularweightof1209.42.

Amlodipinebesylate isslightly soluble inwaterandsparinglysoluble inethanol.

Atorvastatincalciumisinsoluble inaqueoussolutionsof pH4and below. Atorvastatin

calciumisvery slightly solublein distilled water,pH 7.4phosphate buffer, andacetonitrile;

slightlysoluble inethanol, and freelysolubleinmethanol.

Caduet®Tablets,Israel, 29July2007

CADUETtabletsare formulatedfororaladministrationinthe followingstrength

combinations:

Table 1.CADUET TabletStrengths

5 mg/10

mg 5 mg/20

mg 5 mg/40

mg 5 mg/80

mg 10 mg/10

mg 10mg/

20mg 10 mg/

40 mg 10mg/

80mg

amlodipine

equivalent

(mg) 55551010 1010

atorvastatin

equivalent

(mg) 10204080 1020 4080

Each tabletalsocontainscalciumcarbonate, croscarmellosesodium,microcrystalline

cellulose,pregelatinizedstarch, polysorbate80, hydroxypropylcellulose, purifiedwater,

colloidalsilicondioxide (anhydrous),magnesiumstearate,Opadry® II White85F28751

(polyvinylalcohol,titaniumdioxide,PEG 3000andtalc)orOpadry® II Blue85F10919

(polyvinylalcohol,titaniumdioxide,PEG3000, talc andFD&C blue #2).Combinationsof

atorvastatinwith5 mgamlodipine are filmcoatedwhite,andcombinationsofatorvastatin

with10 mgamlodipinearefilmcoated blue.

CLINICALPHARMACOLOGY

MechanismofAction

CADUET

CADUET isacombinationoftwodrugs,adihydropyridinecalciumantagonist (calcium

ionantagonistor slow-channelblocker) amlodipine(antihypertensive/antianginal agent)

andanHMG-CoAreductaseinhibitor atorvastatin (cholesterolloweringagent).The

amlodipinecomponentofCADUETinhibitsthetransmembrane influxofcalciumionsinto

vascularsmoothmuscleand cardiacmuscle. TheatorvastatincomponentofCADUETisa

selective, competitiveinhibitor ofHMG-CoAreductase, the rate-limitingenzymethat

converts 3-hydroxy-3-methylglutaryl-coenzymeAtomevalonate,a precursor ofsterols,

includingcholesterol.

The Amlodipine ComponentofCADUET

Experimentaldatasuggestthatamlodipine bindstobothdihydropyridine and

nondihydropyridine bindingsites.Thecontractileprocessesof cardiac muscle andvascular

smoothmusclearedependentupon the movementofextracellularcalciumionsintothese

cellsthrough specificionchannels. Amlodipineinhibits calciumion influx across cell

membranesselectively, withagreatereffectonvascular smoothmusclecells than on

cardiac muscle cells.Negativeinotropiceffectscanbedetectedinvitrobutsucheffects

havenotbeenseeninintactanimals attherapeuticdoses. Serum calciumconcentrationis

not affectedbyamlodipine.

Caduet®Tablets,Israel, 29July2007

WithinthephysiologicpHrange, amlodipineis anionizedcompound (pKa=8.6), and its

kinetic interactionwiththe calciumchannel receptorischaracterizedbyagradualrateof

association anddissociationwith the receptor binding site, resulting inagradualonsetof

effect.

Amlodipineisaperipheral arterialvasodilator thatactsdirectly onvascularsmoothmuscle

tocausea reductioninperipheral vascularresistanceandreductioninbloodpressure.

The precise mechanismsbywhichamlodipine relievesanginahavenot beenfully

delineated, but arethoughttoinclude thefollowing:

ExertionalAngina:Inpatients withexertional angina,amlodipine reduces thetotal

peripheral resistance(afterload) against which the heartworksand reducestheratepressure

product,andthusmyocardialoxygendemand, atany givenlevel ofexercise.

VasospasticAngina:Amlodipinehasbeendemonstratedtoblock constrictionand restore

blood flowincoronaryarteriesand arteriolesinresponsetocalcium,potassium

epinephrine,serotonin, andthromboxaneA

analoginexperimental animalmodelsand in

humancoronaryvesselsinvitro. This inhibition ofcoronaryspasmisresponsibleforthe

effectiveness ofamlodipine in vasospastic (Prinzmetal’s orvariant)angina.

The Atorvastatin Component of CADUET

Cholesterolandtriglycerides circulatein thebloodstreamaspartoflipoprotein complexes.

Withultracentrifugation,thesecomplexesseparateinto HDL(high-densitylipoprotein),

IDL(intermediate-densitylipoprotein), LDL (low-densitylipoprotein),andVLDL(very-

low-densitylipoprotein)fractions.Triglycerides (TG)and cholesterol inthe liverare

incorporatedintoVLDLand releasedintothe plasmafor delivery to peripheral tissues.

LDLisformed fromVLDL and is catabolizedprimarilythroughthe high-affinityLDL

receptor.

Clinical andpathologic studies showthatelevated plasmalevelsof totalcholesterol(total-

C),LDL-cholesterol(LDL-C), andapolipoproteinB (apoB)promotehuman

atherosclerosis andarerisk factorsfor developingcardiovascular disease,whileincreased

levelsofHDL-Care associatedwithadecreasedcardiovascular risk.

Epidemiologicinvestigationshaveestablishedthat cardiovascularmorbidityand mortality

varydirectlywiththe leveloftotal-CandLDL-C,andinverselywiththe levelofHDL-C.

Inanimalmodels,atorvastatinlowers plasmacholesterolandlipoproteinlevelsby

inhibitingHMG-CoA reductase andcholesterolsynthesis inthe liverandby increasing the

numberofhepaticLDLreceptorsonthe cell-surfacetoenhance uptakeandcatabolismof

LDL; atorvastatinalsoreducesLDLproductionandthenumberofLDL particles.

Caduet®Tablets,Israel, 29July2007

Atorvastatinreduces total-C,LDL-C,and apoB inpatientswith homozygous and

heterozygousfamilialhypercholesterolemia(FH), nonfamilial forms of

hypercholesterolemia,andmixed dyslipidemia.Atorvastatinalsoreduces VLDL-CandTG

and producesvariableincreases in HDL-Candapolipoprotein A-1.Atorvastatinreduces

total-C,LDL-C, VLDL-C, apoB,TG,andnon-HDL-C,andincreasesHDL-Cinpatients

withisolatedhypertriglyceridemia.Atorvastatinreduces intermediate densitylipoprotein

cholesterol(IDL-C) inpatients withdysbetalipoproteinemia.

Like LDL,cholesterol-enrichedtriglyceride-richlipoproteins,includingVLDL,

intermediatedensitylipoprotein (IDL),and remnants,can alsopromoteatherosclerosis.

Elevatedplasma triglycerides are frequentlyfoundina triad with low HDL-C levelsand

smallLDLparticles,as wellas inassociation withnon-lipid metabolicriskfactorsfor

coronaryheartdisease. Assuch,total plasmaTGhas notconsistentlybeenshowntobean

independent riskfactor for CHD. Furthermore,theindependent effectofraisingHDL or

lowering TGontheriskofcoronaryand cardiovascular morbidity andmortalityhasnot

beendetermined.

PharmacokineticsandMetabolism

Absorption

Studieswithamlodipine:Afteroral administrationoftherapeuticdosesofamlodipine

alone, absorptionproduces peakplasmaconcentrationsbetween6and12hours.Absolute

bioavailabilityhas been estimated to bebetween64% and 90%.The bioavailability of

amlodipinewhenadministeredaloneis notalteredbythepresenceoffood.

Studies withatorvastatin:Afteroral administration alone,atorvastatinisrapidly absorbed;

maximumplasmaconcentrations occurwithin1to2 hours.Extentofabsorptionincreases

inproportionto atorvastatindose. The absolutebioavailabilityof atorvastatin(parentdrug)

is approximately14%and the systemicavailability ofHMG-CoA reductase inhibitory

activityis approximately30%. Thelow systemicavailabilityisattributedtopresystemic

clearancein gastrointestinalmucosa and/orhepatic first-passmetabolism. Althoughfood

decreasestherateandextentofdrugabsorptionbyapproximately25%and9%,

respectively,as assessedbyCmaxand AUC,LDL-Creduction is similarwhether

atorvastatinisgivenwithorwithoutfood.Plasmaatorvastatinconcentrationsare lower

(approximately 30%forCmaxand AUC)followingevening drug administration compared

withmorning.However,LDL-Creductionisthesameregardlessofthetimeofdayofdrug

administration(seeDOSAGE ANDADMINISTRATION).

Studies with CADUET:FollowingoraladministrationofCADUETpeakplasma

concentrationsofamlodipineandatorvastatinareseenat 6to12hoursand1to2hours

post dosing, respectively. The rate andextentofabsorption (bioavailability)ofamlodipine

and atorvastatinfromCADUETarenotsignificantlydifferent fromthebioavailabilityof

amlodipineand atorvastatinadministeredseparately (seeabove).

Caduet®Tablets,Israel, 29July2007

The bioavailabilityofamlodipine from CADUETwas notaffectedbyfood. Althoughfood

decreases the rateandextentofabsorptionofatorvastatinfrom CADUET by

approximately32%and 11%, respectively, as it does with atorvastatinwhengiven alone.

LDL-C reduction issimilar whether atorvastatinis givenwithorwithoutfood.

Distribution

Studieswithamlodipine:Ex vivostudieshave shownthatapproximately 93%ofthe

circulatingamlodipinedrugis boundtoplasmaproteinsinhypertensivepatients.

Steady-stateplasmalevelsofamlodipinearereached after 7to8 days ofconsecutivedaily

dosing.

Studies with atorvastatin:Meanvolumeofdistributionofatorvastatinisapproximately381

liters. Atorvastatinis ≥98% bound toplasmaproteins. A blood/plasma ratio of

approximately0.25indicatespoor drugpenetrationinto red bloodcells.Based on

observationsin rats,atorvastatincalciumislikelyto besecreted inhumanmilk (see

CONTRAINDICATIONS, Pregnancyand Lactation,andPRECAUTIONS,Nursing

Mothers).

Metabolism

Studieswithamlodipine:Amlodipineisextensively(about 90%)convertedtoinactive

metabolites via hepaticmetabolism.

Studies withatorvastatin:Atorvastatinis extensivelymetabolized toortho- and

parahydroxylatedderivativesandvarious beta-oxidationproducts.In vitroinhibitionof

HMG-CoA reductasebyortho- and parahydroxylatedmetabolites isequivalent to thatof

atorvastatin.Approximately70%ofcirculating inhibitoryactivityforHMG-CoAreductase

isattributedtoactivemetabolites.Invitrostudiessuggesttheimportanceof atorvastatin

metabolismbycytochromeP450 3A4, consistentwith increased plasmaconcentrationsof

atorvastatinin humans followingcoadministrationwitherythromycin,aknowninhibitorof

thisisozyme(seePRECAUTIONS, DrugInteractions).Inanimals,the ortho-hydroxy

metaboliteundergoesfurther glucuronidation.

Excretion

Studieswithamlodipine:Eliminationfromtheplasmaisbiphasicwithaterminal

elimination half-lifeofabout30-50hours. Tenpercent oftheparent amlodipine compound

and 60% ofthemetabolites ofamlodipineareexcretedintheurine.

Studies withatorvastatin:Atorvastatinand its metabolites are eliminatedprimarilyin bile

following hepaticand/or extra-hepaticmetabolism;however,the drugdoesnotappearto

undergo enterohepaticrecirculation.Meanplasmaeliminationhalf-lifeofatorvastatinin

humansis approximately14hours, butthehalf-life ofinhibitoryactivity forHMG-CoA

Caduet®Tablets,Israel, 29July2007

reductase is20 to 30hoursduetothecontribution ofactivemetabolites.Lessthan2%ofa

doseofatorvastatinisrecoveredinurine followingoral administration.

SpecialPopulations

Geriatric

Studieswithamlodipine:Elderly patients havedecreasedclearanceofamlodipine witha

resulting increaseinAUC ofapproximately40-60%, anda lower initialdose ofamlodipine

mayberequired.

Studies with atorvastatin:Plasmaconcentrationsofatorvastatinarehigher(approximately

40%forCmaxand30% for AUC) inhealthy elderly subjects(age ≥65years) thaninyoung

adults. Clinical data suggesta greaterdegreeofLDL-lowering atany dose ofatorvastatin

inthe elderlypopulationcomparedtoyoungeradults (seePRECAUTIONSsection,

Geriatric Use).

Pediatric

Studieswithamlodipine: Sixty-twohypertensive patientsaged6to17yearsreceiveddoses

ofamlodipinebetween1.25mgand20mg. Weight-adjustedclearanceand volumeof

distributionwere similartovaluesinadults.

Studies withatorvastatin:Pharmacokinetic datain thepediatricpopulationare not

available.

Gender

Studies withatorvastatin:Plasmaconcentrationsofatorvastatinin womendifferfromthose

inmen (approximately20% higherforCmaxand10% lower for AUC); however,thereis

noclinicallysignificantdifference inLDL-Creductionwithatorvastatinbetweenmen and

women.

Renal Insufficiency

Studieswithamlodipine:Thepharmacokineticsofamlodipinearenot significantly

influencedbyrenal impairment. Patientswith renalfailuremay thereforereceivetheusual

initial amlodipine dose.

Caduet®Tablets,Israel, 29July2007

Studies withatorvastatin:Renal disease has noinfluenceontheplasmaconcentrationsor

LDL-C reductionofatorvastatin;thus, doseadjustmentofatorvastatin inpatientswith

renal dysfunction is notnecessary(seeDOSAGE ANDADMINISTRATION).

Hemodialysis

While studieshavenotbeenconductedinpatientswithend-stagerenal disease,

hemodialysisisnot expectedtosignificantlyenhanceclearance ofatorvastatin and/or

amlodipinesince bothdrugsare extensivelyboundtoplasmaproteins.

Hepatic Insufficiency

Studieswithamlodipine:Elderly patients and patientswithhepaticinsufficiencyhave

decreased clearanceofamlodipinewitharesultingincrease inAUC ofapproximately

40-60%, anda lowerinitial dosemayberequired.

Studies withatorvastatin:Inpatientswithchronic alcoholicliverdisease, plasma

concentrationsofatorvastatinaremarkedly increased.Cmax andAUCareeach4-fold

greaterinpatientswith Childs-Pugh Adisease.CmaxandAUCofatorvastatinare

approximately16-foldand11-foldincreased, respectively,inpatients with Childs-PughB

disease(seeCONTRAINDICATIONS).

Heart Failure

Studieswithamlodipine:Inpatients withmoderateto severeheartfailure, theincreasein

AUCfor amlodipinewas similar tothatseeninthe elderlyandinpatients withhepatic

insufficiency.

Pharmacodynamics

HemodynamicEffects of Amlodipine:Followingadministrationoftherapeuticdosesto

patients withhypertension,amlodipineproduces vasodilationresultinginareductionof

supineand standingblood pressures.Thesedecreases in blood pressurearenot

accompaniedbya significant changeinheartrateorplasmacatecholamine levelswith

chronicdosing.Althoughtheacuteintravenousadministrationofamlodipinedecreases

arterialblood pressureandincreasesheart rateinhemodynamicstudiesof patients with

chronicstable angina,chronicadministration oforalamlodipineinclinicaltrialsdid not

lead toclinicallysignificant changes inheartrate orbloodpressures in normotensive

patients withangina.

Caduet®Tablets,Israel, 29July2007

Withchronic oncedaily oraladministration ofamlodipine,antihypertensiveeffectiveness

ismaintainedforatleast24hours. Plasmaconcentrationscorrelate witheffectinboth

youngandelderlypatients. The magnitudeofreductioninbloodpressurewithamlodipine

is alsocorrelatedwith theheightofpretreatment elevation; thus, individualswithmoderate

hypertension(diastolicpressure105-114 mmHg)hadabout a 50% greaterresponsethan

patients withmildhypertension (diastolic pressure 90-104mmHg).Normotensivesubjects

experiencednoclinically significantchangein blood pressures(+1/–2mmHg).

In hypertensivepatientswithnormalrenalfunction,therapeutic doses ofamlodipine

resultedina decreaseinrenal vascularresistanceandanincreaseinglomerularfiltration

rateandeffectiverenal plasmaflowwithoutchangein filtrationfractionorproteinuria.

Aswith other calciumchannel blockers, hemodynamicmeasurementsof cardiacfunction

atrestandduringexercise (or pacing) inpatientswithnormalventricular functiontreated

withamlodipinehavegenerallydemonstratedasmall increaseincardiacindex without

significantinfluenceondP/dt or onleftventricularenddiastolicpressureorvolume.In

hemodynamicstudies,amlodipinehasnotbeenassociatedwith anegativeinotropiceffect

whenadministeredinthetherapeutic doserangetointactanimalsandman,evenwhen

co-administeredwithbeta-blockers toman.Similar findings,however,havebeenobserved

innormals orwell-compensatedpatients with heartfailure withagentspossessing

significantnegativeinotropic effects.

ElectrophysiologicEffects of Amlodipine:Amlodipinedoes not changesinoatrial nodal

functionoratrioventricularconductioninintactanimals orman.Inpatients withchronic

stable angina,intravenousadministrationof10mgdidnot significantlyalterA-H andH-V

conductionandsinus node recoverytimeafter pacing.Similar results wereobtainedin

patientsreceivingamlodipineandconcomitant betablockers. Inclinical studiesinwhich

amlodipinewasadministeredincombinationwithbeta-blockers topatients witheither

hypertension or angina,no adverseeffects on electrocardiographicparameterswere

observed.Inclinicaltrialswith anginapatientsalone, amlodipinetherapydidnot alter

electrocardiographicintervals orproduce higherdegrees ofAVblocks.

LDL-C Reduction withAtorvastatin:Atorvastatin aswellassomeof itsmetabolitesare

pharmacologicallyactiveinhumans.Theliveris the primarysiteofactionand the

principal siteofcholesterolsynthesisandLDLclearance.Drugdosage ratherthansystemic

drugconcentrationcorrelates betterwithLDL-C reduction.Individualization ofdrug

dosage shouldbebasedontherapeutic response (seeDOSAGEAND

ADMINISTRATION).

Caduet®Tablets,Israel, 29July2007

ClinicalStudies

ClinicalStudies with Amlodipine

AmlodipineEffects in Hypertension

Adult Patients:The antihypertensive efficacyofamlodipine hasbeendemonstratedina

totalof15double-blind,placebo-controlled,randomizedstudiesinvolving800patientson

amlodipineand538onplacebo.Oncedailyadministrationproducedstatisticallysignificant

placebo-correctedreductions insupineandstandingbloodpressuresat 24hourspostdose,

averaging about 12/6mmHginthestandingpositionand 13/7mmHgin the supine position

in patientswithmild tomoderatehypertension.Maintenance ofthebloodpressureeffect

overthe 24-hour dosingintervalwas observed,withlittledifferenceinpeakandtrough

effect. Tolerancewas notdemonstrated inpatients studiedforup to 1 year. The 3parallel,

fixeddoses, doseresponsestudiesshowedthatthe reductioninsupineandstandingblood

pressureswasdose-relatedwithintherecommendeddosingrange.Effects on diastolic

pressure were similar inyoungandolderpatients. The effectonsystolic pressurewas

greaterinolderpatients,perhaps becauseofgreaterbaselinesystolicpressure.Effectswere

similarinblack patientsand in whitepatients.

Pediatric Patients:Two-hundredsixty-eighthypertensivepatientsaged6to17years were

randomizedfirsttoamlodipine2.5 or5mgoncedailyfor 4weeks and thenrandomized

againto thesamedoseor to placebofor another 4weeks.Patientsreceiving5mg

amlodipineat theendof8weekshad lowerbloodpressurethanthosesecondarily

randomizedtoplacebo.The magnitudeofthe treatmenteffectis difficultto interpret, but it

isprobably lessthan5mmHgsystoliconthe5mgdose. Adverse eventsweresimilar to

thoseseeninadults.

AmlodipineEffects inChronicStable Angina:The effectivenessof5-10mg/dayof

amlodipine inexercise-inducedanginahas beenevaluatedin 8placebo-controlled,

double-blind clinicaltrialsofupto 6weeksdurationinvolving 1038patients

(684amlodipine, 354placebo) withchronicstable angina.In5 ofthe8studies,significant

increasesinexercise time (bicycleortreadmill)wereseenwiththe10mgdose. Increases

in symptom-limited exercisetimeaveraged12.8% (63 sec)foramlodipine10 mg,and

averaged7.9%(38sec)for amlodipine 5 mg.Amlodipine10mgalsoincreasedtimeto

1mmSTsegment deviationin several studiesand decreasedangina attackrate.The

sustainedefficacyofamlodipineinanginapatientshas beendemonstratedoverlong-term

dosing.Inpatientswithangina,there werenoclinicallysignificantreductionsinblood

pressures(4/1 mmHg) orchangesinheart rate(+0.3 bpm).

Caduet®Tablets,Israel, 29July2007

AmlodipineEffects inVasospasticAngina:Ina double-blind,placebo-controlledclinical

trialof4weeks durationin50patients,amlodipinetherapydecreasedattacksby

approximately4/weekcomparedwithaplacebo decreaseof approximately 1/week

(p<0.01).Two of 23amlodipineand7 of27placebopatients discontinuedfromthe study

due to lackofclinicalimprovement.

AmlodipineEffects inPatientswithCongestiveHeartFailure:Amlodipinehas been

comparedto placeboin four8-12 week studiesofpatientswithNYHAclassII/IIIheart

failure,involving atotalof697patients. Inthesestudies,there wasnoevidenceof

worsenedheartfailurebased onmeasuresofexercisetolerance,NYHAclassification,

symptoms, orLVEF. Inalong-term(follow-upat least6months, mean13.8months)

placebo-controlledmortality/morbiditystudy ofamlodipine5-10mgin1153patients with

NYHAclassesIII(n=931) orIV(n=222)heartfailureonstable doses ofdiuretics,digoxin,

andACE inhibitors,amlodipinehadnoeffect onthe primaryendpointofthe studywhich

wasthecombinedendpointofall-causemortalityandcardiacmorbidity(asdefinedby

life-threateningarrhythmia, acutemyocardialinfarction,or hospitalization for worsened

heartfailure), oronNYHAclassification,orsymptoms ofheartfailure.Totalcombined

all-causemortality andcardiac morbidity events were222/571(39%) for patientson

amlodipine and246/583(42%)forpatients on placebo; thecardiacmorbidevents

representedabout25%ofthe endpoints inthestudy.

Another study (PRAISE-2)randomizedpatientswithNYHAclass III (80%) or IV (20%)

heartfailurewithoutclinicalsymptomsorobjectiveevidence ofunderlyingischemic

disease,onstabledosesof ACEinhibitor (99%),digitalis(99%)anddiuretics (99%), to

placebo (n=827) oramlodipine(n=827) andfollowedthemfor a meanof33months.

There wasno statisticallysignificantdifferencebetweenamlodipineand placebointhe

primaryendpointofallcausemortality(95%confidencelimits from8%reductionto 29%

increaseonamlodipine). Withamlodipinetherewere morereportsofpulmonaryedema.

ClinicalStudies with Atorvastatin

Preventionof Cardiovascular Disease:IntheAnglo-ScandinavianCardiacOutcomesTrial

(ASCOT),theeffect ofatorvastatinonfataland non-fatalcoronaryheartdiseasewas

assessed in10,305hypertensivepatients 40-80years ofage(meanof63years),withouta

previousmyocardial infarctionand with TClevels≤251mg/dl(6.5mmol/l).Additionally

allpatientshad atleast3ofthefollowing cardiovascularriskfactors: malegender

(81.1%),age>55years(84.5%),smoking(33.2%),diabetes(24.3%),historyofCHD ina

first-degree relative(26%), TC:HDL >6(14.3%),peripheralvasculardisease (5.1%),left

ventricularhypertrophy(14.4%),priorcerebrovascularevent(9.8%),specificECG

abnormality(14.3%),proteinuria/albuminuria(62.4%)]. Inthis double-blind,placebo-

controlledstudy patientsweretreatedwithanti-hypertensivetherapy(Goal BP<140/90

mmHg for non-diabeticpatients,<130/80mm Hgfordiabeticpatients) andallocatedto

eitheratorvastatin 10mgdaily (n=5168) orplacebo(n=5137), usinga covariateadaptive

method which tookinto accountthedistributionofnine baselinecharacteristicsofpatients

Caduet®Tablets,Israel, 29July2007

alreadyenrolledandminimizedtheimbalanceof those characteristics acrossthegroups.

Patients werefollowedforamediandurationof3.3years.

Theeffect of10mg/dayofatorvastatin onlipidlevels was similartothatseenin previous

clinical trials.

Atorvastatinsignificantly reducedtherateofcoronaryevents[either fatalcoronaryheart

disease(46 eventsin theplacebo group vs40 eventsin the atorvastatingroup)ornonfatal

MI(108eventsintheplacebogroup vs60eventsintheatorvastatingroup)]witha relative

riskreduction of36%[(based onincidencesof1.9% foratorvastatin vs3.0%for placebo),

p=0.0005(see Figure1)]. The riskreductionwasconsistentregardless ofage,smoking

status,obesityor presenceofrenal dysfunction. Theeffect of atorvastatinwas seen

regardless ofbaseline LDL levels.Due tothe small numberofevents,resultsfor women

were inconclusive.

Figure1:EffectofAtorvastatin10 mg/dayonCumulativeIncidenceofNonfatal

Myocardial InfarctionorCoronaryHeart DiseaseDeath (inASCOT-LLA)

Atorvastatinalsosignificantlydecreasedthe relativeriskforrevascularizationprocedures

by 42%Althoughthereductionoffatal and non-fatal strokes didnotreachapre-defined

significance level(p 0.01), a favorable trend was observed witha 26%relativerisk

reduction(incidences of1.7%for atorvastatinand 2.3% forplacebo).There was no

significant differencebetweenthe treatmentgroupsfor death due tocardiovascular causes

(p=0.51)ornoncardiovascularcauses(p=0.17).

AtorvastatinStudiesinHypercholesterolemia(Heterozygous Familial andNonfamilial)

and MixedDyslipidemia(FredricksonTypes IIaandIIb):Atorvastatin reduces total-C,

LDL-C, VLDL-C, apoB,andTG, andincreasesHDL-Cin patientswith

hypercholesterolemiaand mixeddyslipidemia. Therapeuticresponseis seen within2

weeks,and maximumresponseisusuallyachievedwithin 4 weeks and maintainedduring

chronic therapy.

Caduet®Tablets,Israel, 29July2007

Atorvastatin is effectiveina widevarietyofpatient populationswithhypercholesterolemia,

withandwithout hypertriglyceridemia,inmen and women, andintheelderly.

In twomulticenter,placebo-controlled,dose-response studies inpatients with

hypercholesterolemia,atorvastatingiven asasingledoseover6weeks significantly

reducedtotal-C,LDL-C,apoB,and TG(pooledresultsareprovidedin Table 2).

Table 2.Dose-Response in PatientsWithPrimary Hypercholesterolemia (Adjusted

MeanPercent ChangeFromBaseline) a

DOSE N TC LDL-C ApoB TG HDL-CNon-HDL-C/HDL-C

Placebo 21 4 4 3 10 -3 7

10 mg22 -29 -39 -32 -19 6 -34

20 mg20 -33 -43 -35 -26 9 -41

40 mg21 -37 -50 -42 -29 6 -45

80 mg23 -45 -60 -50 -37 5 -53

Resultsarepooled from2dose-responsestudies.

Inpatients withFredricksonTypes IIaandIIbhyperlipoproteinemia pooledfrom24

controlledtrials,themedian(25 th and75 th percentile)percentchanges from baselinein

HDL-Cfor atorvastatin10,20,40,and80mgwere6.4(-1.4,14),8.7(0,17),7.8 (0,16),

and 5.1 (-2.7,15), respectively. Additionally,analysis ofthe pooleddatademonstrated

consistent and significantdecreases in total-C,LDL-C,TG,total-C/HDL-C,andLDL-

C/HDL-C.

Inthree multicenter,double-blindstudiesinpatients withhypercholesterolemia,

atorvastatinwas comparedto other HMG-CoA reductaseinhibitors.Afterrandomization,

patients weretreatedfor 16weeks with eitheratorvastatin 10mgper day or afixeddoseof

thecomparativeagent(Table3).

Caduet®Tablets,Israel, 29July2007

Table 3.MeanPercent ChangeFromBaseline atEndpoint

(Double-Blind, Randomized,Active-Controlled Trials)

Treatment

(Daily Dose)

N

Total-C

LDL-C

Apo B

TG

HDL-C Non-HDL-C/

HDL-C

Study1

Atorvastatin10mg 707 -27 a -36 a -28 a -17 a +7 -37 a

Lovastatin 20 mg191 -19 -27 -20 - 6 +7 -28

95%CIfor Diff 1 -9.2, -6.5 -10.7, -7.1 -10.0,-6.5-15.2,-7.1 -1.7, 2.0-11.1, -7.1

Study2

Atorvastatin10mg 222 -25 b -35 b -27 b -17 b +6 -36 b

Pravastatin 20mg 77 -17 -23 -17 -9 +8 -28

95%CIfor Diff 1 -10.8, -6.1 -14.5, -8.2 -13.4,-7.4-14.1,-0.7 -4.9, 1.6-11.5, -4.1

Study3

Atorvastatin10mg 132 -29 c -37 c -34 c -23 c +7 -39 c

Simvastatin 10 mg 45-24-30-30-15 +7-33

95%CIfor Diff 1 -8.7, -2.7 -10.1, -2.6 -8.0,-1.1-15.1,-0.7 -4.3, 3.9 -9.6,-1.9

Anegative valuefor the95% CI forthe difference between treatmentsfavorsatorvastatin for allexcept

HDL-C, for which a positivevaluefavors atorvastatin. Ifthe rangedoes not include 0,this indicates a

statisticallysignificantdifference.

Significantly differentfromlovastatin, ANCOVA, p ≤0.05

Significantlydifferentfrompravastatin, ANCOVA, p ≤0.05

Significantly differentfromsimvastatin, ANCOVA, p ≤0.05

The impactonclinical outcomes ofthedifferences inlipid-alteringeffectsbetween

treatmentsshownin Table3 isnotknown. Table3doesnot containdata comparing the

effects ofatorvastatin10mgand higherdosesoflovastatin, pravastatin,andsimvastatin.

Thedrugscomparedinthestudiessummarizedinthetablearenot necessarily

interchangeable.

AtorvastatinEffects inHypertriglyceridemia(FredricksonTypeIV):Theresponseto

atorvastatinin64patients withisolatedhypertriglyceridemiatreatedacrossseveralclinical

trialsisshowninthetable below. Forthe atorvastatin-treatedpatients, median(min,max)

baselineTG levelwas 565(267-1502).

Caduet®Tablets,Israel, 29July2007

Table 4.Combined PatientsWith IsolatedElevated TG:

Median(min,max) Percent Changes FromBaseline

Placebo

(N=12) Atorvastatin 10mg

(N=37) Atorvastatin20mg

(N=13) Atorvastatin 80mg

(N=14)

Triglycerides -12.4(-36.6, 82.7) -41.0(-76.2, 49.4) -38.7(-62.7, 29.5) -51.8(-82.8,41.3)

Total-C -2.3 (-15.5,24.4) -28.2 (-44.9,-6.8) -34.9(-49.6, -15.2) -44.4 (-63.5,-3.8)

LDL-C 3.6 (-31.3,31.6) -26.5 (-57.7,9.8) -30.4(-53.9, 0.3) -40.5(-60.6, -13.8)

HDL-C 3.8(-18.6, 13.4) 13.8(-9.7, 61.5) 11.0(-3.2,25.2) 7.5(-10.8,37.2)

VLDL-C -1.0 (-31.9,53.2) -48.8 (-85.8,57.3) -44.6(-62.2, -10.8) -62.0 (-88.2,37.6)

non-HDL-C -2.8 (-17.6,30.0) -33.0 (-52.1, -13.3) -42.7(-53.7, -17.4) -51.5 (-72.9,-4.3)

Atorvastatin EffectsinDysbetalipoproteinemia(FredricksonType III):The resultsofan

open-labelcrossoverstudyof atorvastatinin 16patients (genotypes: 14apoE2/E2 and 2

apoE3/E2)withdysbetalipoproteinemia (FredricksonTypeIII) areshowninthe table

below.

Table 5.Open-Label Crossover Studyof16 Patients

WithDysbetalipoproteinemia(FredricksonTypeIII)

Median% Change(min, max)

Median (min, max) at

Baseline (mg/dL) Atorvastatin10mg Atorvastatin 80mg

Total-C 442 (225,1320) -37 (-85, 17) -58(-90,-31)

Triglycerides 678 (273,5990) -39 (-92, -8) -53(-95,-30)

IDL-C+ VLDL-C 215 (111,613) -32 (-76, 9) -63(-90, -8)

non-HDL-C 411 (218,1272) -43 (-87, -19) -64(-92,-36)

AtorvastatinEffectsinHomozygous FamilialHypercholesterolemia:Inastudywithouta

concurrentcontrol group,29patients ages 6to37years withhomozygousFHreceived

maximumdailydosesof20to80mgofatorvastatin. ThemeanLDL-Creductioninthis

studywas18%. Twenty-fivepatients witha reductioninLDL-C hadamean responseof

20% (rangeof7%to53%, medianof24%);theremaining4patients had7%to24%

increases inLDL-C. Fiveof the29patients had absentLDL-receptorfunction.Ofthese,2

patientsalsohad a portacaval shunt and hadno significantreduction inLDL-C. The

remaining 3 receptor-negativepatients had a meanLDL-Creductionof22%.

AtorvastatinEffects inHeterozygousFamilialHypercholesterolemicPediatricPatients:In

adouble-blind, placebo-controlledstudyfollowedbyanopen-label phase,187boysand

postmenarchal girls 10-17years ofage(meanage14.1years)with heterozygousFHor

severe hypercholesterolemia were randomizedtoatorvastatin(n=140) orplacebo (n=47)

for26weeks andthenall receivedatorvastatinfor 26weeks.Inclusioninthe study

required1) abaseline LDL-C level ≥190mg/dL or2)abaselineLDL-C≥160mg/dL and

positivefamilyhistoryofFHor documentedprematurecardiovasculardisease in afirst- or

second-degree relative.The meanbaselineLDL-C valuewas218.6mg/dL(range: 138.5-

385.0mg/dL)intheatorvastatingroupcomparedto230.0 mg/dL(range: 160.0-324.5

mg/dL) inplacebogroup.The dosage ofatorvastatin(once daily)was 10 mgforthe first4

weeks and up-titratedto20mgifthe LDL-Clevelwas> 130mg/dL.The number of

Caduet®Tablets,Israel, 29July2007

atorvastatin-treatedpatients whorequiredup-titrationto20mgafterWeek4duringthe

double-blindphase was80(57.1%).

Atorvastatinsignificantlydecreasedplasmalevelsoftotal-C,LDL-C,triglycerides,and

apolipoproteinB duringthe 26weekdouble-blindphase(seeTable 6).

Table 6.Lipid-alteringEffectsofAtorvastatin in AdolescentBoys and Girlswith

Heterozygous FamilialHypercholesterolemiaorSevereHypercholesterolemia

(MeanPercent Change from BaselineatEndpoint in Intention-to-TreatPopulation)

DOSAGEN Total-CLDL-CHDL-C TG Apolipoprotein B

Placebo47 -1.5-0.4 -1.9 1.0 0.7

Atorvastatin 140-31.4 -39.6 2.8-12.0-34.0

ThemeanachievedLDL-Cvaluewas 130.7mg/dL (range:70.0-242.0mg/dL) inthe

atorvastatingroupcomparedto228.5mg/dL (range:152.0-385.0mg/dL) intheplacebo

groupduringthe26weekdouble-blindphase.

The safetyandefficacyofatorvastatindoses above20mghavenotbeenstudiedin

controlledtrialsinchildren. Thelong-termefficacyofatorvastatintherapyinchildhoodto

reduce morbidityandmortality inadulthood hasnot beenestablished.

RecurrentStroke

In the StrokePreventionby AggressiveReduction in CholesterolLevels(SPARCL)study,

the effectofatorvastatin80mgdailyorplaceboonstrokewasevaluatedin4731patients

who hada strokeortransientischemic attack(TIA) withinthe preceding6monthsandno

history ofcoronaryheart disease(CHD). Patients were60%male, 21-92yearsofage

(average age63years),and had anaveragebaselineLDLof133 mg/dL (3.4mmol/L).The

meanLDL-C was73mg/dL(1.9mmol/L)duringtreatmentwithatorvastatin and129

mg/dL (3.3mmol/L) duringtreatment withplacebo.Medianfollow-upwas4.9 years.

Atorvastatin80mgreduced theriskof theprimaryendpoint offatal ornon-fatalstroke by

15%(HR0.85; 95%CI, 0.72-1.00; p=0.05or0.84; 95%CI, 0.71-0.99; p=0.03after

adjustmentforbaselinefactors) comparedtoplacebo.Atorvastatin80mgsignificantly

reducedthe riskofmajorcoronaryevents (HR 0.67; 95%CI,0.51-0.89;p=0.006),any

CHD event(HR0.60; 95%CI, 0.48-0.74; p<0.001), andrevascularizationprocedures(HR

0.57; 95%CI, 0.44-0.74; p<0.001).

Ina post-hocanalysis,atorvastatin80mgreducedtheincidenceofischemicstroke

(218/2365,9.2%vs. 274/2366,11.6%, p=0.01) andincreasedthe incidence ofhemorrhagic

stroke(55/2365,2.3%vs.33/2366, 1.4%, p=0.02) comparedtoplacebo.Theincidenceof

fatalhemorrhagic strokewas similar between groups (17atorvastatinvs.18placebo).

Reductionin theriskof

cardiovascular events withatorvastatin80 mgwasdemonstratedin allpatientgroups

exceptinpatients whoenteredthestudy with ahemorrhagicstrokeand hadarecurrent

hemorrhagicstroke(7atorvastatinvs2 placebo),where the numberofeventswastoosmall

to discernrisk orbenefit.

Caduet®Tablets,Israel, 29July2007

Inpatientstreatedwith atorvastatin80 mgtherewerefewer strokesofany type(265

atorvastatin vs311placebo) andfewerCHDevents(123atorvastatinvs204placebo).

Overallmortality was similaracrosstreatmentgroups (216 atorvastatinvs211 placebo).

Theoverall incidenceofadverseevents andserious adverseeventswassimilarbetween

treatment groups.

ClinicalStudyofCombinedAmlodipine and AtorvastatininPatients withHypertension

and Dyslipidemia

Ina double-blind, placebo-controlledstudy,atotalof1660patients withco-morbid

hypertension anddyslipidemia receivedoncedailytreatmentwitheight dosecombinations

ofamlodipineandatorvastatin(5/10,10/10,5/20,10/20,5/40,10/40,5/80, or10/80mg),

amlodipinealone(5mgor 10mg), atorvastatinalone(10mg,20mg,40mg, or80mg) or

placebo.Inadditiontoconcomitant hypertensionanddyslipidemia,15% ofthepatients had

diabetesmellitus, 22%weresmokersand 14% hadapositive familyhistoryof

cardiovascular disease.Ateightweeks,all eightcombination-treatment groups of

amlodipineand atorvastatindemonstratedstatistically significantdose-relatedreductionsin

systolic blood pressure(SBP), diastolic bloodpressure(DBP)andLDL-Ccomparedto

placebo,withnooverall modificationofeffectofeithercomponent onSBP,DBP and

LDL-C (Table7).

Table7.EfficacyinTerms ofReduction inBloodPressureand LDL-C

EfficacyoftheCombined Treatmentsin Reducing SystolicBP

Parameter/ Analysis ATO 0 mg ATO 10 mg ATO 20mg ATO 40 mg ATO 80 mg

Mean change

(mmHg) -3.0 -4.5-6.2 -6.2 -6.4

AML0 mg

Difference versus

placebo (mmHg) - -1.5-3.2 -3.2 -3.4

Mean change

(mmHg) -12.8 -13.7-15.3 -12.7 -12.2

AML5 mg

Difference versus

placebo (mmHg) -9.8 -10.7-12.3-9.7-9.2

Mean change

(mmHg) -16.2 -15.9-16.1 -16.3 -17.6

AML10 mg

Difference versus

placebo (mmHg) -13.2 -12.9-13.1 -13.3 -14.6

Caduet®Tablets,Israel, 29July2007

EfficacyoftheCombined Treatmentsin Reducing DiastolicBP

Parameter/ Analysis ATO 0 mg ATO 10 mg ATO 20mg ATO 40 mg ATO 80 mg

Mean change

(mmHg) -3.3 -4.1-3.9 -5.1 -4.1

AML0 mg

Difference versus

placebo (mmHg) - -0.8-0.6 -1.8 -0.8

Mean change

(mmHg) -7.6 -8.2-9.4 -7.3 -8.4

AML5 mg

Difference versus

placebo (mmHg) -4.3 -4.9-6.1 -4.0 -5.1

Mean change

(mmHg) -10.4-9.1 -10.6-9.8 -11.1

AML10 mg

Difference versus

placebo (mmHg) -7.1 -5.8-7.3 -6.5 -7.8

EfficacyoftheCombined Treatmentsin Reducing LDL-C (%change)

Parameter/ Analysis ATO 0 mg ATO10 mg ATO 20 mg ATO 40 mg ATO 80 mg

Mean % change -1.1-33.4 -39.5 -43.1 -47.2 AML 0 mg

Mean % change -0.1-38.7 -42.3 -44.9 -48.4 AML 5 mg

Mean % change -2.5-36.6 -38.6 -43.2 -49.1 AML 10 mg

INDICATIONS ANDUSAGE

CADUET (amlodipineand atorvastatin)is indicated inpatients forwhomtreatment with

bothamlodipineand atorvastatinis appropriate.

Amlodipine

1.Hypertension:Amlodipineisindicatedfor the treatmentofhypertension.Itmaybe

usedalone orincombinationwithother antihypertensiveagents;

2.Chronic Stable Angina:Amlodipineis indicated forthetreatment ofchronic stable

angina.Amlodipinemay beusedaloneorin combination withother antianginalor

antihypertensive agents;

3. VasospasticAngina(Prinzmetal’sorVariantAngina):Amlodipineisindicatedfor

the treatment ofconfirmedor suspectedvasospastic angina.Amlodipinemaybeused

as monotherapyorin combination with otherantianginal drugs.

AND

Atorvastatin

1. Prevention ofCardiovascularDisease:Inadult patients withoutclinicallyevident

coronaryheartdisease, butwithmultipleriskfactors forcoronaryheartdiseasesuch

as age≥55years,smoking,hypertension,lowHDL-C,orafamilyhistoryofearly

coronaryheartdisease, atorvastatinis indicated to:

Caduet®Tablets,Israel, 29July2007

- Reduce theriskofmyocardialinfarction

- Reduce theriskforrevascularizationproceduresandangina

2. Heterozygous Familialand Nonfamilial Hypercholesterolemia:Atorvastatinis

indicatedasanadjuncttodiettoreduceelevatedtotal-C, LDL-C, apoB, andTG

levels andtoincrease HDL-C inpatientswithprimaryhypercholesterolemia

(heterozygousfamilialandnonfamilial)andmixeddyslipidemia(FredricksonTypes

IIaand IIb);

3. ElevatedSerumTGLevels:Atorvastatin isindicatedasanadjunct todietfor the

treatmentofpatients withelevatedserumTGlevels(FredricksonTypeIV);

4.Primary Dysbetalipoproteinemia:Atorvastatinisindicatedforthetreatmentof

patientswithprimary dysbetalipoproteinemia(FredricksonType III)who donot

respondadequately todiet;

5.Homozygous Familial Hypercholesterolemia:Atorvastatinis indicatedtoreduce

total-CandLDL-Cinpatientswithhomozygousfamilialhypercholesterolemiaasan

adjunct toother lipid-lowering treatments(e.g.,LDL apheresis) orifsuchtreatments

are unavailable;

6.Pediatric Patients:Atorvastatinisindicated asanadjuncttodietto reduce total-C,

LDL-C, andapo B levels in boysand postmenarchal girls, 10to17years of age,with

heterozygous familialhypercholesterolemiaifafteranadequatetrialofdiettherapy

thefollowingfindingsarepresent:

a.LDL-Cremains ≥190mg/dL or

b.LDL-Cremains ≥160mg/dL and:

there isa positivefamilyhistoryof prematurecardiovasculardiseaseor

two ormoreother CVD riskfactors are presentinthe pediatricpatients.

Therapy with lipid-altering agentsshouldbeacomponentofmultiple-risk-factor

intervention in individualsatincreasedriskfor atherosclerotic vascular diseasedueto

hypercholesterolemia.Lipid-alteringagentsshouldbeused, in additiontoa dietrestricted

in saturated fat and cholesterol,onlywhenthe responsetodietandother

nonpharmacologicalmeasureshas beeninadequate(seeNational CholesterolEducation

Program (NCEP) Guidelines,summarizedin Table8).

Caduet®Tablets,Israel, 29July2007

Table 8. NCEPTreatment Guidelines: LDL-C Goalsand Cutpoints for Therapeutic

Lifestyle ChangesandDrugTherapyinDifferentRiskCategories

Risk Category

LDL-CGoal

(mg/dL) LDL-CLevelatWhich to

InitiateTherapeutic

Lifestyle Changes

(mg/dL)

LDL-CLevelatWhich to

Consider

Drug

Therapy(mg/dL)

CHD a or CHD risk

equivalents

(10-yearrisk >20%)

<100

≥100

≥130

(100-129: drugoptional) b

2+RiskFactors

(10-yearrisk ≤20%) <130 ≥130 10-year risk 10%-20%: ≥130

10-yearrisk<10%: ≥160

0-1 RiskFactor c <160 ≥160 ≥190

(160-189: LDL-lowering

drugoptional)

CHD,coronary heartdisease

Someauthorities recommend use ofLDL-loweringdrugsinthis category ifan LDL-C levelof<100mg/dL

cannotbe achievedbytherapeutic lifestylechanges. Otherspreferuseofdrugs that primarilymodify

triglyceridesand HDL-C,e.g.,nicotinic acidorfibrate. Clinical judgmentalsomaycall fordeferringdrug

therapyinthis subcategory.

Almostall people with0-1 riskfactor have10-yearrisk <10%;thus, 10-yearriskassessmentinpeoplewith

0-1riskfactoris notnecessary.

After the LDL-C goal has beenachieved,iftheTGisstill>200mg/dL, non-HDL-C (total-

C minusHDL-C) becomesa secondarytargetoftherapy. Non-HDL-C goalsareset30

mg/dLhigher thanLDL-Cgoals foreachriskcategory.

Priorto initiatingtherapywithatorvastatin, secondary causesforhypercholesterolemia

(e.g., poorly controlled diabetesmellitus, hypothyroidism,nephrotic syndrome,

dysproteinemias,obstructiveliverdisease, other drugtherapy, andalcoholism)shouldbe

excluded,and alipidprofileperformedtomeasure total-C, LDL-C,HDL-C,and TG.For

patientswith TG<400mg/dL(<4.5 mmol/L),LDL-Ccanbe estimatedusing the following

equation: LDL-C= total-C- (0.20x[TG]+ HDL-C). For TGlevels >400mg/dL(>4.5

mmol/L),this equationisless accurateandLDL-Cconcentrationsshouldbedeterminedby

ultracentrifugation.

Theantidyslipidemiccomponent ofCADUEThas not beenstudied inconditions where the

majorlipoprotein abnormalityiselevationofchylomicrons(FredricksonTypesI andV).

The NCEPclassificationofcholesterollevelsinpediatricpatientswithafamilial historyof

hypercholesterolemiaor premature cardiovasculardiseaseissummarizedbelow:

Table 9.NCEPClassification of Cholesterol LevelsinPediatric Patients

Category Total-C (mg/dL) LDL-C (mg/dL)

Acceptable

Borderline

High <170

170-199

≥200 <110

110-129

≥130

Caduet®Tablets,Israel, 29July2007

CONTRAINDICATIONS

CADUET containsatorvastatinandis thereforecontraindicatedinpatientswithactiveliver

diseaseorunexplainedpersistentelevationsofserumtransaminases.

CADUETiscontraindicated in patients withknown hypersensitivitytoany componentof

thismedication.

Pregnancy andLactation

Atherosclerosisis achronicprocessand discontinuation oflipid-lowering drugsduring

pregnancyshould have littleimpactonthe outcome oflong-termtherapyofprimary

hypercholesterolemia.Cholesterol andother productsofcholesterol biosynthesisare

essential components for fetaldevelopment (including synthesis ofsteroidsandcell

membranes). Since HMG-CoAreductaseinhibitorsdecrease cholesterolsynthesis and

possibly the synthesisof otherbiologicallyactivesubstancesderivedfromcholesterol, they

maycause fetalharmwhenadministeredtopregnant women.Therefore,HMG-CoA

reductaseinhibitorsare contraindicatedduringpregnancyandinnursingmothers.

CADUET,WHICHINCLUDESATORVASTATIN, SHOULDBE ADMINISTEREDTO

WOMENOF CHILDBEARINGAGEONLYWHENSUCHPATIENTSARE HIGHLY

UNLIKELYTOCONCEIVE AND HAVE BEENINFORMEDOF THEPOTENTIAL

HAZARDS.Ifthepatientbecomes pregnantwhiletakingthisdrug,therapyshouldbe

discontinuedand the patient apprisedofthepotential hazard tothefetus.

WARNINGS

IncreasedAnginaand/orMyocardialInfarction

Rarely, patients,particularlythose withsevereobstructive coronaryarterydisease,have

developeddocumentedincreased frequency,duration and/orseverityofanginaor acute

myocardialinfarction onstartingcalciumchannelblocker therapy oratthetimeofdosage

increase. The mechanismofthiseffecthasnotbeenelucidated.

Liver Dysfunction

HMG-CoA reductaseinhibitors,likesomeother lipid-loweringtherapies,have been

associatedwithbiochemicalabnormalitiesofliverfunction.Persistent elevations(>3

timestheupper limit ofnormal[ULN] occurring on 2ormoreoccasions) inserum

transaminasesoccurred in0.7%ofpatientswhoreceivedatorvastatin in clinical

trials. Theincidence of theseabnormalitieswas 0.2%,0.2%,0.6%,and2.3%for10,

20,40,and 80mg, respectively.

In clinicaltrials inpatients takingatorvastatinthefollowinghasbeenobserved. Onepatient

inclinicaltrialsdevelopedjaundice.Increasesinliverfunctiontests(LFT)inotherpatients

werenot associatedwith jaundiceorotherclinical signsor symptoms. Upondose

reduction,drug interruption,or discontinuation, transaminaselevelsreturnedto or near

Caduet®Tablets,Israel, 29July2007

pretreatmentlevelswithoutsequelae. Eighteenof30 patients,with persistentLFT

elevationscontinued treatmentwithareduceddose ofatorvastatin.

Itisrecommended thatliverfunctiontestsbe performed priortoandat12weeks

followingboththe initiationof therapyandany elevation of dose,andperiodically

(e.g., semiannually) thereafter. Liverenzymechanges generally occur inthe first 3

monthsoftreatmentwith atorvastatin.Patientswhodevelop increasedtransaminaselevels

shouldbemonitored untilthe abnormalitiesresolve. ShouldanincreaseinALTorASTof

>3timesULNpersist,reduction ofdoseorwithdrawalofCADUETis recommended.

CADUETshould beused withcaution inpatients who consumesubstantialquantitiesof

alcohol and/orhaveahistoryofliver disease.Activeliver disease or unexplainedpersistent

transaminaseelevations arecontraindications to the useofCADUET (see

CONTRAINDICATIONS).

SkeletalMuscle

Rarecases of rhabdomyolysiswithacuterenal failure secondarytomyoglobinuria

havebeenreportedwiththeatorvastatin componentofCADUETand with other

drugs intheHMG-CoAreductase inhibitor class.

Uncomplicatedmyalgiahas beenreportedinatorvastatin-treatedpatients(seeADVERSE

REACTIONS). Myopathy,definedasmuscleaches ormuscleweakness inconjunction

withincreases increatinephosphokinase (CPK) values>10timesULN,shouldbe

consideredinanypatientwith diffuse myalgias, muscletenderness orweakness, and/or

marked elevation ofCPK.Patientsshould beadvisedtoreportpromptlyunexplained

muscle pain,tenderness or weakness,particularlyifaccompaniedbymalaiseorfever.

CADUET therapy shouldbediscontinuedifmarkedlyelevatedCPK levelsoccuror

myopathyisdiagnosedor suspected.

The riskofmyopathyduringtreatment withdrugsintheHMG-CoA reductase inhibitor

classis increasedwithconcurrentadministration ofcyclosporine, fibricacidderivatives,

erythromycin, lipid-modifyingdosesof niacin,orazoleantifungals.Physiciansconsidering

combinedtherapy withCADUET andfibricacidderivatives, erythromycin,

immunosuppressive drugs,azoleantifungals, orlipid-loweringdoses ofniacinshould

carefullyweighthe potential benefits andrisks andshouldcarefullymonitor patientsfor

anysignsorsymptomsofmuscle pain, tenderness, or weakness,particularlyduringthe

initial months oftherapyand duringanyperiodsofupward dosagetitration ofeither drug.

Therefore, lowerstartingandmaintenance doses oftheatorvastatincomponentshould also be

consideredwhen taken concomitantlywith the aforementioneddrugs. (Seesection4.5Interaction

with other medicinal productsand otherformsofinteraction) . Periodiccreatine

phosphokinase (CPK) determinationsmaybeconsideredinsuchsituations,but there isno

assurancethatsuchmonitoringwillprevent the occurrenceofseveremyopathy.

Inpatients taking CADUET, therapyshouldbe temporarilywithheld or discontinued

in any patient with anacute,serious conditionsuggestiveofa myopathyor havinga

riskfactorpredisposingtothedevelopmentofrenal failure secondary to

Caduet®Tablets,Israel, 29July2007

rhabdomyolysis (e.g., severeacuteinfection, hypotension, majorsurgery,trauma,

severemetabolic,endocrineandelectrolyte disorders,anduncontrolled seizures).

PRECAUTIONS

General

Sincethevasodilation inducedbytheamlodipine component ofCADUETis gradualin

onset,acute hypotensionhas rarelybeenreported after oraladministrationofamlodipine.

Nonetheless, cautionshouldbeexercisedwhenadministering CADUET as withanyother

peripheral vasodilator particularlyinpatientswith severeaorticstenosis.

Beforeinstituting therapy withCADUET,an attemptshouldbe made to control

hypercholesterolemiawithappropriate diet,exercise, and weightreductioninobese

patients,and to treat otherunderlyingmedical problems(seeINDICATIONSAND

USAGE).

Use in PatientswithCongestive HeartFailure

In general,calciumchannelblockersshouldbe usedwithcaution inpatients withheart

failure.TheamlodipinecomponentofCADUET(5-10 mgperday)hasbeenstudiedina

placebo-controlledtrialof1153patients withNYHA ClassIIIorIVheart failure (see

CLINICALPHARMACOLOGY)onstabledoses ofACE inhibitor, digoxin,and

diuretics.Follow-up wasatleast6 months, withameanofabout14months.Therewasno

overalladverseeffect onsurvivalor cardiacmorbidity (as defined bylife-threatening

arrhythmia, acutemyocardialinfarction,orhospitalization forworsenedheartfailure).

Amlodipinehasbeencomparedto placeboin four8-12weekstudies ofpatientswith

NYHAclassII/III heartfailure,involvinga totalof697 patients.Inthesestudies,therewas

noevidenceofworsenedheartfailurebasedon measures ofexercisetolerance, NYHA

classification,symptoms, orLVEF.

Beta-Blocker Withdrawal

The amlodipinecomponentofCADUETisnotabeta-blockerand thereforegivesno

protectionagainst the dangersofabruptbeta-blockerwithdrawal;anysuchwithdrawal

shouldbebygradual reduction ofthedoseofbeta-blocker.

Endocrine Function

HMG-CoAreductaseinhibitors,suchasthe atorvastatincomponentofCADUETinterfere

withcholesterolsynthesis andtheoreticallymightbluntadrenaland/orgonadalsteroid

production.Clinicalstudieshave shown thatatorvastatindoes notreducebasalplasma

cortisol concentrationorimpair adrenal reserve.TheeffectsofHMG-CoA reductase

inhibitorsonmalefertilityhave notbeenstudiedinadequatenumbersofpatients. The

effects,ifany,onthe pituitary-gonadalaxis inpremenopausalwomenare unknown.

Caution shouldbe exercised ifan HMG-CoAreductase inhibitor isadministered

Caduet®Tablets,Israel, 29July2007

concomitantlywithdrugsthatmaydecreasethe levels oractivityofendogenoussteroid

hormones,suchasketoconazole,spironolactone,andcimetidine.

CNS Toxicity

Studies withatorvastatin:Brain hemorrhagewasseeninafemaledog treated with

atorvastatincalciumfor 3monthsatadoseequivalentto 120mgatorvastatin/kg/day. Brain

hemorrhage andopticnerve vacuolationwere seeninanother femaledogthatwas

sacrificedinmoribundconditionafter 11weeksof escalatingdosesofatorvastatincalcium

equivalent to upto280mgatorvastatin/kg/day.The120 mg/kg doseofatorvastatin

resultedina systemicexposure approximately16timesthe humanplasmaarea-under-the-

curve(AUC, 0-24hours)basedonthemaximumhumandoseof80 mg/day.A singletonic

convulsionwasseenineachof2 maledogs (onetreatedwithatorvastatincalciumat adose

equivalent to 10mgatorvastatin/kg/dayandoneatadoseequivalentto 120mg

atorvastatin/kg/day)ina 2-yearstudy.NoCNS lesions havebeenobservedinmice after

chronic treatment for upto 2 yearsat dosesof atorvastatincalciumequivalenttoup to400

mgatorvastatin/kg/dayorinrats atdosesequivalenttoupto100 mgatorvastatin/kg/day.

These doseswere6to11times (mouse)and8to16times(rat)the humanAUC(0-24)

basedonthemaximumrecommendedhumandoseof80mgatorvastatin/day.

CNSvascularlesions, characterized byperivascularhemorrhages, edema, andmononuclear

cell infiltrationof perivascularspaces,havebeenobservedindogs treatedwithother

members ofthe HMG-CoAreductaseclass.Achemicallysimilar drug inthisclass

producedopticnerve degeneration(Walleriandegenerationof retinogeniculate fibers)in

clinically normaldogsina dose-dependentfashionatadosethatproducedplasmadrug

levelsabout30times higherthanthemeandruglevelinhumanstakingthe highest

recommended dose.

Hemorrhagic Stroke

- A post-hocanalysis ofaclinicalstudyin4,731patientswithout

CHD whohadastrokeorTIAwithinthepreceding6monthsandwereinitiatedon

atorvastatin80mg,revealedahigherincidenceof hemorrhagicstroke inthe atorvastatin80

mggroup comparedtoplacebo (55 atorvastatinvs33placebo).Patientswithhemorrhagic

strokeonentryappeared tobeatincreasedriskfor recurrenthemorrhagicstroke(7

atorvastatinvs2 placebo). However,in patientstreated withatorvastatin 80mgtherewere

fewerstrokesofanytype(265 vs 311)andfewer CHDevents(123vs204).(See

CLINICAL PHARMACOLOGY, ClinicalStudies,Clinical StudieswithAtorvastatin,,

RecurrentStroke)

Information forPatients

DuetotheriskofmyopathywithdrugsoftheHMG-CoA reductase class, towhichthe

atorvastatincomponentofCADUET belongs,patients shouldbeadvised toreportpromptly

unexplainedmusclepain, tenderness,orweakness,particularlyif accompaniedbymalaise

orfever.

Caduet®Tablets,Israel, 29July2007

DrugInteractions

Data fromadrug-druginteractionstudyinvolving10mgofamlodipineand80mgof

atorvastatininhealthysubjectsindicatethatthepharmacokineticsofamlodipinearenot

alteredwhenthedrugsare coadministered. Theeffectofamlodipineonthe

pharmacokineticsofatorvastatinshowednoeffectonthe Cmax:91%(90%confidence

interval: 80to103%),buttheAUCofatorvastatinincreasedby18%(90%confidence

interval: 109to127%)inthe presenceofamlodipine.

Nodruginteraction studieshavebeenconductedwithCADUETandother drugs,although

studies havebeenconductedintheindividualamlodipineandatorvastatincomponents,as

described below:

Studies withAmlodipine:

Invitrodatain humanplasmaindicatethat amlodipinehasnoeffecton theproteinbinding

ofdrugstested(digoxin,phenytoin,warfarin,andindomethacin).

Cimetidine:Co-administrationofamlodipinewith cimetidinedidnotalterthe

pharmacokineticsofamlodipine.

Maalox®(antacid):Co-administrationofthe antacidMaalox witha singledoseof

amlodipinehadnosignificanteffectonthepharmacokineticsofamlodipine.

Sildenafil:Asingle 100mgdoseofsildenafil(Viagra®) insubjects withessential

hypertension hadno effectonthe pharmacokinetic parametersof amlodipine.When

amlodipineandsildenafilwere usedincombination,eachagent independentlyexertedits

own blood pressureloweringeffect.

Digoxin:Co-administrationof amlodipinewithdigoxin didnotchangeserumdigoxin

levelsordigoxin renalclearanceinnormal volunteers.

Ethanol(alcohol):Singleand multiple10mgdoses ofamlodipinehad nosignificant effect

onthe pharmacokineticsofethanol.

Warfarin:Co-administrationofamlodipine withwarfarindidnot change thewarfarin

prothrombinresponsetime.

Inclinicaltrials,amlodipine hasbeensafelyadministeredwiththiazidediuretics,

beta-blockers, angiotensin-converting enzymeinhibitors, long-actingnitrates,sublingual

nitroglycerin,digoxin, warfarin,non-steroidalanti-inflammatory drugs,antibiotics,and

oralhypoglycemicdrugs.

Caduet®Tablets,Israel, 29July2007

Studies withAtorvastatin:

The riskofmyopathyduringtreatment withHMG-CoA reductase inhibitor isincreased

withconcurrentadministrationofcyclosporine,fibric acid derivatives, lipid-modifying doses

of niacinor cytochromeP4503A4inhibitors(egerythromycin(seebelow)andazole

antifungals),(see alsosection 4.4Specialwarnings and precautions foruse:Skeletal

MuscleEffects).

Inhibitorsof cytochromeP4503A4

2 :AtorvastatinismetabolizedbycytochromeP450 3A4.

Concomitantadministration ofatorvastatinwithinhibitors of cytochromeP4503A4canlead to

increasesinplasmaconcentrationsofatorvastatin. The extentofinteraction andpotentiationof

effects depends onthevariabilityofeffectoncytochrome P450 3A4.

Transporter Inhibitors:Atorvastatinand atorvastatin-metabolitesare substratesofthe OATP1B1

transporter. Inhibitors oftheOATP1B1(e.g.cyclosporine)canincrease the bioavailabilityof

atorvastatin. Concomitantadministration ofatorvastatin10mgand cyclosporine5.2mg/kg/day

resultedin a7.7 foldincreaseinexposureto atorvastatin. (Seealsosection4.2Posologyand

methodofadministration-Use inCombination with OtherMedicinalCompounds)

Erythromycin/Clarithromycin:Co-administrationofatorvastatinanderythromycin

(500mgfourtimes daily),orclarithromycin (500mgtwicedaily)knowninhibitors of

cytochrome P4503A4,wasassociatedwithhigherplasmaconcentrationsofatorvastatin

(see WARNINGS, Skeletal Muscle ).

Proteaseinhibitors:Co-administrationofatorvastatinandprotease inhibitors,known

inhibitorsofcytochrome P4503A4,wasassociatedwithincreasedplasmaconcentrations

ofatorvastatin.

Diltiazem hydrochloride

2 : Co-administration ofatorvastatin (40mg)withdiltiazem

(240mg)wasassociatedwithhigherplasmaconcentrationsofatorvastatin.

Cimetidine:Anatorvastatininteraction studywithcimetidine wasconducted, and no

clinicallysignificantinteractions wereseen.

Itraconazole:Concomitantadministrationofatorvastatin(20to40mg)and itraconazole(200mg)

wasassociatedwith an increase in atorvastatinAUC.

Grapefruit juice:Containsoneor morecomponents thatinhibit CYP3A4andcanincreaseplasma

concentrationsofdrugsmetabolisedbyCYP3A4. Intakeofone240mlglassofgrapefruitjuice

resultedin anincrease in atorvastatinAUCof37%andadecreasedAUC of20.4%forthe active

orthohydroxymetabolite. However, large quantitiesofgrapefruitjuice(over 1.2Ldailyfor 5days)

increased AUCofatorvastatin 2.5fold andAUC of active (atorvastatinandmetabolites) HMG-

CoA reductaseinhibitors 1.3 fold. Concomitant intakeoflarge quantities ofgrapefruitjuiceand

atorvastatinistherefore not recommended.

Inducers ofcytochromeP4503A

2 :Concomitant administrationofatorvastatin withinducers of

cytochromeP4503A4(egefavirenz, rifampin) canleadtovariablereductionsinplasma

concentrationsofatorvastatin.Due tothedualinteractionmechanismofrifampin, (cytochrome

Caduet®Tablets,Israel, 29July2007

P4503A4 inductionand inhibition ofhepatocyte uptake transporter OATP1B1),simultaneous

coadministrationofatorvastatin with rifampinis recommended, asdelayed administration of

atorvastatinafter administrationofrifampin has been associated with asignificant reductionin

atorvastatinplasmaconcentrations.

Antacid:WhenatorvastatinandMaaloxTCsuspensionwerecoadministered, plasma

concentrationsofatorvastatindecreasedapproximately 35%.However,LDL-C reduction

was not altered.

Antipyrine:Because atorvastatindoes notaffectthepharmacokinetics ofantipyrine,

interactionswithotherdrugs metabolizedviathe same cytochromeisozymes arenot

expected.

Colestipol:Plasmaconcentrationsofatorvastatindecreasedapproximately 25% when

colestipolandatorvastatinwere coadministered.However,LDL-C reduction was greater

whenatorvastatinandcolestipol werecoadministeredthanwheneitherdrug was given

alone.

Digoxin:Whenmultipledosesofatorvastatin anddigoxinwere coadministered,steady-

stateplasmadigoxinconcentrationsincreasedbyapproximately20%.Patientstaking

digoxinshouldbe monitoredappropriately.

Azithromycin:Co– administrationofatorvastatin(10mgoncedaily) and azithromycin

(500mgoncedaily)didnot alter the plasmaconcentrationsofatorvastatin.

OralContraceptives:Coadministrationofatorvastatinand anoral contraceptiveincreased

AUCvaluesfornorethindroneandethinylestradiol byapproximately30%and 20%. These

increasesshouldbeconsideredwhenselectinganoralcontraceptivefora womantaking

CADUET.

Warfarin:Atorvastatinhadnoclinicallysignificanteffect onprothrombin timewhen

administered topatients receiving chronicwarfarin treatment.

Drug/LaboratoryTestInteractions

None known.

Carcinogenesis, Mutagenesis, ImpairmentofFertility

Studieswithamlodipine:Rats andmicetreatedwithamlodipinemaleateinthedietfor up

to twoyears,atconcentrationscalculatedto provide dailydosage levelsof0.5, 1.25, and

2.5mgamlodipine/kg/day,showednoevidenceof a carcinogenic effectof thedrug. For

themouse,the highestdose was, onamg/m 2 basis,similartothemaximumrecommended

humandose of10mgamlodipine/day*.For therat,the highestdose levelwas, ona mg/m 2

basis,abouttwicethemaximumrecommendedhumandose*.

Mutagenicitystudiesconductedwithamlodipinemaleaterevealednodrugrelatedeffects at

either thegeneor chromosomelevels.

Caduet®Tablets,Israel, 29July2007

There wasno effectonthefertility ofrats treated orallywith amlodipine maleate (malesfor

64 daysand females for 14daysprior tomating)at dosesupto 10mgamlodipine/kg/day

(8times*themaximumrecommendedhumandoseof10mg/dayona mg/m 2 basis).

Studies withatorvastatin:Ina 2-yearcarcinogenicitystudywithatorvastatincalciuminrats

at doselevels equivalentto 10,30,and 100mgatorvastatin/kg/day,2raretumorswere

foundinmuscle inhigh-dosefemales:inone, there was a rhabdomyosarcomaand,in

another,there was a fibrosarcoma.Thisdose representsaplasmaAUC(0-24)valueof

approximately16times themeanhumanplasmadrugexposureafteran80mgoral dose.

A 2-yearcarcinogenicitystudyinmicegivenatorvastatin calciumatdoselevelsequivalent

to 100,200,and400mgatorvastatin/kg/dayresultedin a significant increaseinliver

adenomasin high-dosemales andliver carcinomasin high-dose females. Thesefindings

occurredatplasmaAUC(0-24)valuesofapproximately6 timesthe mean human plasma

drugexposureafteran80mgoraldose.

Invitro, atorvastatinwasnotmutagenicorclastogenicinthefollowingtestswithand

withoutmetabolicactivation: the Ames testwithSalmonellatyphimuriumandEscherichia

coli, theHGPRTforwardmutationassayinChinese hamster lungcells,andthe

chromosomal aberrationassay inChinesehamster lungcells. Atorvastatinwasnegativein

theinvivomousemicronucleus test.

There werenoeffectson fertility whenrats weregivenatorvastatincalciumatdoses

equivalent to upto175mgatorvastatin/kg/day(15times thehumanexposure).There was

aplasiaand aspermia in theepididymidesof 2of10ratstreatedwithatorvastatincalciumat

adoseequivalent to100 mgatorvastatin/kg/dayfor 3months(16times thehumanAUCat

the80 mgdose);testis weightsweresignificantlylower at30and 100mg/kg/dayand

epididymalweightwaslower at100mg/kg/day.Male rats giventhe equivalent of100 mg

atorvastatin/kg/dayfor 11weeks priorto mating haddecreased spermmotility, spermatid

headconcentration,and increasedabnormal sperm.Atorvastatincausedno adverseeffects

onsemenparameters, orreproductiveorganhistopathologyindogsgivendosesof

atorvastatincalciumequivalentto 10,40,or120 mgatorvastatin/kg/dayfor twoyears.

Pregnancy

Pregnancy CategoryX

(see CONTRAINDICATIONS)

Safetyinpregnantwomenhasnot beenestablished with CADUET. CADUETshould be

administeredtowomenofchild-bearing potential onlywhensuchpatientsarehighly

unlikely toconceiveandhavebeeninformedofthepotentialhazards.Ifthewoman

becomespregnantwhile takingCADUET, itshouldbediscontinuedandthe patient

advisedagainasto thepotential hazardstothefetus.

Studieswithamlodipine:Noevidenceofteratogenicityorother embryo/fetal toxicitywas

foundwhenpregnantratsand rabbitsweretreated orallywithamlodipinemaleateat doses

upto10mgamlodipine/kg/day(respectively8times*and 23times*themaximum

recommended human doseof10mg/dayonamg/m 2 basis)duringtheir respectiveperiods

ofmajororganogenesis.However, litter sizewas significantlydecreased (by about50%)

Caduet®Tablets,Israel, 29July2007

and thenumberofintrauterinedeathswassignificantly increased (about5-fold) inrats

receivingamlodipine maleateat 10mgamlodipine/kg/dayfor14days before mating and

throughout matingand gestation.Amlodipinemaleatehas beenshowntoprolongboththe

gestationperiodandtheduration oflaborin ratsatthisdose.There arenoadequate and

well-controlledstudiesinpregnant women.

*Basedonpatientweightof50kg.

Studies withatorvastatin:Atorvastatincrossestheratplacentaandreaches a level infetal

liverequivalenttothatofmaternal plasma.Atorvastatinwasnot teratogenicinrats atdoses

ofatorvastatincalciumequivalenttoupto300 mgatorvastatin/kg/dayorinrabbits atdoses

ofatorvastatincalciumequivalentto upto100mgatorvastatin/kg/day. Thesedoses

resultedinmultiplesofabout 30times (rat) or 20times(rabbit)the humanexposure based

on surfacearea(mg/m 2 ).

Inastudyinratsgiven atorvastatin calciumat dosesequivalentto20,100,or225mg

atorvastatin/kg/day,from gestationday7throughtolactationday21(weaning), therewas

decreasedpupsurvivalatbirth,neonate,weaning,andmaturityfor pupsof mothersdosed

with225mg/kg/day. Bodyweightwasdecreasedondays 4and21for pupsofmothers

dosedat 100mg/kg/day; pupbodyweight was decreasedatbirth andatdays4,21,and 91

at 225 mg/kg/day. Pupdevelopment was delayed(rotorodperformanceat100mg/kg/day

andacousticstartleat225mg/kg/day;pinnae detachmentandeyeopeningat 225

mg/kg/day).These dosesofatorvastatincorrespondto6times (100mg/kg)and22times

(225mg/kg)the humanAUCat 80mg/day.

Rarereportsofcongenital anomalieshavebeenreceivedfollowing intrauterineexposureto

HMG-CoA reductaseinhibitors.There has beenonereport ofsevere congenital bony

deformity,tracheo-esophagealfistula,and analatresia (VATERassociation) ina babyborn

to awomanwhotook lovastatin with dextroamphetamine sulfate duringthefirsttrimester

ofpregnancy.

Labor andDelivery

No studieshavebeenconductedin pregnant women ontheeffectofCADUET,amlodipine

oratorvastatinon the mother or the fetusduringlaboror delivery,oron the durationof

labor ordelivery.Amlodipinehas beenshowntoprolongthe durationoflaborinrats.

NursingMothers

Itis notknownwhether theamlodipinecomponentofCADUET is excretedin humanmilk.

Nursingrat pups takingatorvastatinhadplasmaandliverdruglevelsof50% and40%,

respectively, of thatintheir mother’s milk.Because ofthepotentialfor adversereactionsin

nursinginfants,womentakingCADUETshould notbreast-feed(see

CONTRAINDICATIONS).

Caduet®Tablets,Israel, 29July2007

Pediatric Use

Therehavebeennostudies conductedtodeterminethe safety oreffectiveness ofCADUET

inpediatricpopulations.

Studies with amlodipine:Theeffect ofamlodipineonblood pressureinpatients lessthan6

years ofageis notknown.

Studies withatorvastatin:Safetyandeffectivenessinpatients 10-17yearsofagewith

heterozygousfamilialhypercholesterolemiahavebeenevaluated incontrolledclinical trials

of6monthsdurationinadolescent boysandpostmenarchalgirls.Patientstreatedwith

atorvastatinhadanadverseexperienceprofile generallysimilartothatofpatientstreated

withplacebo,themostcommonadverseexperiencesobservedinbothgroups, regardlessof

causalityassessment, were infections.Dosesgreater than20mg have not beenstudied

inthis patient population.Inthislimitedcontrolledstudy,there wasnodetectableeffect

on growth orsexualmaturationinboys oronmenstrualcyclelength ingirls. See

CLINICALPHARMACOLOGY,Clinical Studiessection;ADVERSE REACTIONS,

Pediatric Patients;andDOSAGE ANDADMINISTRATION,Pediatric Patients(10-17

yearsofage) withHeterozygousFamilialHypercholesterolemia.Adolescentfemales

shouldbecounseledonappropriatecontraceptive methodswhileonatorvastatintherapy

(seeCONTRAINDICATIONSandPRECAUTIONS,Pregnancy).Atorvastatin has

notbeen studied in controlledclinicaltrials involving pre-pubertalpatientsor

patientsyoungerthan 10years of age.

Clinicalefficacywithdoses ofatorvastatin upto80 mg/dayfor 1 year havebeenevaluated

in anuncontrolledstudy ofpatientswithhomozygousFHincluding 8 pediatricpatients.

SeeCLINICALPHARMACOLOGY,Clinical Studies,AtorvastatinEffectsin

HomozygousFamilialHypercholesterolemia.

Geriatric Use

Therehavebeennostudies conductedtodeterminethe safety oreffectiveness ofCADUET

ingeriatric populations.

Instudieswithamlodipine:Clinicalstudies ofamlodipine did not include sufficient

numbersofsubjectsaged65andovertodetermine whether theyresponddifferentlyfrom

youngersubjects.Other reportedclinicalexperiencehas not identifieddifferencesin

responsesbetween theelderlyand younger patients.Ingeneral,dose selectionofthe

amlodipinecomponentofCADUETfor anelderlypatientshouldbecautious,usually

startingatthe low endofthedosingrange,reflecting the greaterfrequencyofdecreased

hepatic,renal,orcardiacfunction,andofconcomitantdiseaseorotherdrugtherapy.

Elderly patientshave decreasedclearanceofamlodipinewitha resulting increaseofAUC

ofapproximately40-60%,and alowerinitialdosemayberequired(seeDOSAGE AND

ADMINISTRATION).

Caduet®Tablets,Israel, 29July2007

Instudieswith atorvastatin:Thesafetyandefficacyofatorvastatin(10-80mg)inthe

geriatricpopulation(>65yearsof age)wasevaluatedinthe ACCESSstudy. Inthis54-

weekopen-labeltrial 1,958 patientsinitiated therapywithatorvastatincalcium10mg.Of

these,835wereelderly (>65years)and1,123 were non-elderly.Themeanchangein LDL-

C frombaselineafter 6weeksof treatment withatorvastatincalcium10mgwas–38.2%in

the elderlypatientsversus–34.6%inthe non-elderlygroup.

Therates ofdiscontinuation inpatientsonatorvastatin due to adverseeventsweresimilar

betweenthe twoagegroups. Therewerenodifferencesinclinicallyrelevantlaboratory

abnormalities between the agegroups.

ADVERSE REACTIONS

CADUET

CADUET(amlodipinebesylate/atorvastatincalcium)has beenevaluated forsafetyin 1092

patientsindouble-blindplacebocontrolledstudiestreatedfor co-morbidhypertensionand

dyslipidemia.Ingeneral,treatmentwithCADUET was welltolerated. Forthe mostpart,

adverseexperienceshavebeenmild ormoderateinseverity. In clinicaltrialswith

CADUET, noadverse experiencespeculiartothiscombinationhave beenobserved.

Adverseexperiencesaresimilar intermsofnature,severity,andfrequencytothose

reportedpreviouslywithamlodipineandatorvastatin.

The followinginformationisbasedon the clinical experiencewith amlodipineand

atorvastatin.

The Amlodipine ComponentofCADUET

Amlodipinehas beenevaluatedforsafetyinmorethan11,000 patients inU.S. andforeign

clinical trials. Ingeneral,treatment withamlodipinewaswelltoleratedatdoses upto

10mgdaily.Mostadversereactionsreportedduringtherapywithamlodipinewereofmild

ormoderateseverity.Incontrolled clinicaltrialsdirectly comparing amlodipine(N=1730)

indosesupto10mgtoplacebo(N=1250), discontinuationofamlodipineduetoadverse

reactions wasrequiredinonlyabout 1.5% ofpatientsandwasnot significantly different

fromplacebo(about1%). Themostcommonsideeffects areheadacheandedema.The

incidence(%)ofsideeffects whichoccurredinadoserelatedmannerareasfollows:

Adverse Event amlodipine

2.5mg 5.0mg 10.0mg Placebo

N=275 N=296 N=268 N=520

Edema 1.8 3.0 10.8 0.6

Dizziness 1.1 3.4 3.4 1.5

Flushing 0.7 1.4 2.6 0.0

Palpitations 0.7 1.4 4.5 0.6

Caduet®Tablets,Israel, 29July2007

Otheradverseexperienceswhichwere notclearly doserelatedbut which were reported

withanincidence greaterthan1.0%inplacebo-controlledclinicaltrials include the

following:

Placebo-ControlledStudies

Adverse Event amlodipine(%) Placebo(%)

(N=1730) (N=1250)

Headache 7.3 7.8

Fatigue 4.5 2.8

Nausea 2.9 1.9

AbdominalPain 1.6 0.3

Somnolence 1.4 0.6

For severaladverseexperiencesthat appeartobedruganddose related,therewasa greater

incidenceinwomen thanmen associatedwithamlodipinetreatment asshown inthe

following table:

Adverse Event amlodipine Placebo

M=% F=% M=% F=%

(N=1218) (N=512) (N=914)(N=336)

Edema 5.6 14.6 1.4 5.1

Flushing 1.5 4.5 0.3 0.9

Palpitations 1.4 3.3 0.9 0.9

Somnolence 1.3 1.6 0.8 0.3

The followingeventsoccurredin1% but >0.1% ofpatientstreatedwith amlodipinein

controlledclinicaltrials orunderconditions of open trialsormarketing experience where a

causalrelationshipisuncertain;they arelistedtoalertthephysiciantoapossible

relationship:

Cardiovascular:arrhythmia (includingventriculartachycardiaandatrialfibrillation),

bradycardia,chest pain,hypotension,peripheralischemia, syncope,tachycardia,postural

dizziness, posturalhypotension, vasculitis.

Central andPeripheralNervous System:hypoesthesia, neuropathyperipheral,

paresthesia, tremor,vertigo.

Gastrointestinal:anorexia,constipation,dyspepsia,**dysphagia,diarrhea,flatulence,

pancreatitis, vomiting,gingival hyperplasia.

General:allergicreaction,asthenia,** backpain,hot flushes,malaise,pain, rigors, weight

gain, weightdecrease.

Caduet®Tablets,Israel, 29July2007

MusculoskeletalSystem:arthralgia, arthrosis,musclecramps,**myalgia.

Psychiatric:sexualdysfunction(male** and female),insomnia,nervousness,depression,

abnormaldreams,anxiety, depersonalization.

Respiratory System:dyspnea,**epistaxis.

SkinandAppendages:angioedema,erythemamultiforme, pruritus,**rash,** rash

erythematous,rashmaculopapular.

**Theseeventsoccurredin lessthan1%inplacebo-controlled trials, buttheincidenceof

thesesideeffectswas between1%and2%inall multipledosestudies.

SpecialSenses:abnormal vision, conjunctivitis,diplopia,eyepain,tinnitus.

Urinary System:micturitionfrequency,micturition disorder,nocturia.

Autonomic Nervous System:dry mouth, sweatingincreased.

Metabolic and Nutritional:hyperglycemia, thirst.

Hemopoietic:leukopenia, purpura,thrombocytopenia.

Thefollowingeventsoccurredin<0.1% ofpatientstreatedwithamlodipinein controlled

clinical trialsor underconditionsofopentrials ormarketingexperience: cardiac failure,

pulse irregularity,extrasystoles,skindiscoloration,urticaria,skindryness,alopecia,

dermatitis,muscleweakness, twitching,ataxia, hypertonia,migraine, coldandclammy

skin,apathy, agitation, amnesia,gastritis,increased appetite,loose stools,coughing,

rhinitis,dysuria,polyuria,parosmia, tasteperversion,abnormal visualaccommodation,and

xerophthalmia.

Otherreactionsoccurredsporadicallyandcannotbedistinguishedfrommedicationsor

concurrent diseasestatessuchas myocardialinfarction and angina.

Amlodipinetherapy hasnot beenassociatedwithclinicallysignificant changes inroutine

laboratorytests.Noclinicallyrelevantchangeswerenotedinserumpotassium,serum

glucose,total triglycerides, totalcholesterol,HDL cholesterol,uric acid,bloodurea

nitrogen,orcreatinine.

Thefollowingpostmarketingevent has beenreportedinfrequentlywithamlodipine

treatment where acausalrelationshipisuncertain:gynecomastia.Inpostmarketing

experience, jaundice andhepaticenzyme elevations(mostlyconsistentwithcholestasisor

hepatitis) insome cases severeenoughtorequirehospitalization havebeenreported in

association withuseofamlodipine.

Caduet®Tablets,Israel, 29July2007

Amlodipinehasbeenusedsafely inpatients withchronic obstructive pulmonarydisease,

well-compensatedcongestiveheart failure, peripheral vasculardisease, diabetes mellitus,

andabnormal lipidprofiles.

TheAtorvastatin Component ofCADUET

Atorvastatinis generallywell-tolerated. Adversereactions haveusually beenmildand

transient. Incontrolledclinicalstudiesof2502patients,<2% ofpatients werediscontinued

duetoadverseexperiences attributabletoatorvastatincalcium. The most frequent adverse

eventsthoughttoberelatedto atorvastatin calciumwereconstipation,flatulence,

dyspepsia,and abdominalpain.

ClinicalAdverseExperiences

Adverseexperiences reportedin ≥2%ofpatients inplacebo-controlledclinicalstudies of

atorvastatin,regardlessofcausalityassessment, areshowninTable 10.

Table10.AdverseEvents inPlacebo-Controlled Studies

(%ofPatients)

atorvastatin

Body System/ Placebo 10 mg 20 mg 40 mg 80mg

AdverseEvent N=270 N=863 N=36 N=79 N=94

BODY ASA WHOLE

Infection 10.0 10.3 2.8 10.1 7.4

Headache 7.0 5.4 16.7 2.5 6.4

Accidental Injury 3.7 4.2 0.0 1.3 3.2

Flu Syndrome 1.9 2.2 0.0 2.5 3.2

AbdominalPain 0.7 2.8 0.0 3.8 2.1

Back Pain 3.0 2.8 0.0 3.8 1.1

Allergic Reaction 2.6 0.9 2.8 1.3 0.0

Asthenia 1.9 2.2 0.0 3.8 0.0

DIGESTIVE SYSTEM

Constipation 1.8 2.1 0.0 2.5 1.1

Diarrhea 1.5 2.7 0.0 3.8 5.3

Dyspepsia 4.1 2.3 2.8 1.3 2.1

Flatulence 3.3 2.1 2.8 1.3 1.1

RESPIRATORY SYSTEM

Sinusitis 2.6 2.8 0.0 2.5 6.4

Pharyngitis 1.5 2.5 0.0 1.3 2.1

SKINANDAPPENDAGES

Rash 0.7 3.9 2.8 3.8 1.1

Caduet®Tablets,Israel, 29July2007

MUSCULOSKELETALSYSTEM

Arthralgia 1.5 2.0 0.0 5.1 0.0

Myalgia 1.1 3.2 5.6 1.3 0.0

Anglo-ScandinavianCardiac OutcomesTrial (ASCOT)

In ASCOT(seeCLINICAL PHARMACOLOGY,ClinicalStudies,ClinicalStudies

withAtorvastatin) involving10,305participantstreated with atorvastatin 10mgdaily

(n=5,168)or placebo (n=5,137),thesafetyandtolerability profile ofthe group treated with

atorvastatinwas comparable tothatofthe grouptreatedwith placeboduringa medianof

3.3 yearsoffollow-up.

Thefollowingadverse eventswere reported,regardlessofcausalityassessment, in patients

treatedwithatorvastatininclinicaltrials. The eventsinitalicsoccurredin ≥2%ofpatients

and theeventsinplain typeoccurredin<2% ofpatients.

Body asaWhole:Chestpain, faceedema,fever,neckrigidity, malaise, photosensitivity

reaction,generalizededema.

DigestiveSystem:Nausea,gastroenteritis, liverfunctiontestsabnormal, colitis,vomiting,

gastritis, drymouth,rectalhemorrhage,esophagitis,eructation, glossitis, mouth ulceration,

anorexia, increased appetite,stomatitis,biliarypain, cheilitis, duodenal ulcer,dysphagia,

enteritis,melena, gumhemorrhage, stomach ulcer,tenesmus,ulcerativestomatitis,

hepatitis,pancreatitis,cholestaticjaundice.

Respiratory System:Bronchitis,rhinitis, pneumonia, dyspnea,asthma, epistaxis.

Nervous System:Insomnia,dizziness, paresthesia, somnolence, amnesia,abnormal

dreams,libidodecreased, emotionallability,incoordination, peripheral neuropathy,

torticollis, facialparalysis,hyperkinesia,depression,hypesthesia, hypertonia.

MusculoskeletalSystem:Arthritis,leg cramps, bursitis, tenosynovitis,myasthenia,

tendinous contracture, myositis.

SkinandAppendages:Pruritus, contactdermatitis, alopecia, dryskin, sweating, acne,

urticaria, eczema, seborrhea,skinulcer.

Urogenital System:Urinary tractinfection,urinaryfrequency, cystitis, hematuria,

impotence, dysuria, kidneycalculus,nocturia,epididymitis, fibrocystic breast, vaginal

hemorrhage, albuminuria, breast enlargement,metrorrhagia, nephritis, urinary

incontinence,urinaryretention,urinaryurgency,abnormalejaculation,uterine hemorrhage.

SpecialSenses:Amblyopia, tinnitus,dryeyes,refraction disorder, eyehemorrhage,

deafness,glaucoma, parosmia, tasteloss, tasteperversion.

Caduet®Tablets,Israel, 29July2007

CardiovascularSystem:Palpitation,vasodilatation, syncope,migraine,postural

hypotension, phlebitis, arrhythmia,anginapectoris,hypertension.

Metabolic and Nutritional Disorders:Peripheraledema, hyperglycemia,creatine

phosphokinaseincreased,gout,weight gain,hypoglycemia.

Hemic andLymphaticSystem: Ecchymosis,anemia, lymphadenopathy,

thrombocytopenia, petechia.

Postintroduction Reports withAtorvastatin

Adverseevents associatedwithatorvastatintherapyreportedsincemarketintroduction,

thatarenotlistedabove,regardlessof causalityassessment,include the following:

anaphylaxis,angioneurotic edema, bullousrashes(includingerythemamultiforme,

Stevens-Johnson syndrome,andtoxicepidermal necrolysis),rhabdomyolysis, dysgeusia

, poisoningandproceduralcomplications:tendonrupture

Inpost-marketingexperience, thefollowingadditionalundesirableeffects have been reported

withatorvastatin: Blood andlymphatic systemdisorders:thrombocytopenia,Immunesystem

disorders:allergicreactions(includinganaphylaxis), Injury, poisoningandprocedural

complications:tendonrupture

2 , Metabolism andnutrition disorders:weight gain,Nervous

system disorders:hypoesthesia, amnesia,dizziness, dysgeusia

2 , Ear and labyrinth disorders:

tinnitus,Skinandsubcutaneous tissuedisorders:stevens-johnson syndrome,toxicepidermal

necrolysis, erythemamultiforme,bullous rashes, urticaria,Musculoskeletal andconnective

tissuedisorders:rhabdomyolysis,arthralgia, back pain,Generaldisorders andadministration

site conditions:chest pain,peripheraledema,malaise,fatigue.

PediatricPatients (ages 10-17 years)

Ina 26-weekcontrolledstudyinboysandpostmenarchalgirls(n=140),thesafetyand

tolerabilityprofileofatorvastatin10to20 mgdaily was generallysimilar tothat ofplacebo

(seeCLINICALPHARMACOLOGY,Clinical StudiessectionandPRECAUTIONS,

Pediatric Use).

OVERDOSAGE

There isnoinformationonoverdosage withCADUETinhumans.

Information onAmlodipine

Singleoral doses ofamlodipine maleateequivalentto40mgamlodipine/kgand100 mg

amlodipine/kginmiceandrats, respectively, causeddeaths.Singleoralamlodipinemaleate

dosesequivalent to4 or more mgamlodipine/kgindogs(11 ormoretimesthe maximum

recommendedclinicaldoseona mg/m 2 basis)causedamarkedperipheralvasodilationand

hypotension.

Caduet®Tablets,Israel, 29July2007

Overdosage might beexpectedtocause excessiveperipheral vasodilationwithmarked

hypotensionandpossiblyareflextachycardia.Inhumans, experiencewithintentional

overdosageofamlodipineislimited.Reportsof intentionaloverdosageinclude apatient

whoingested250mgand wasasymptomatic and wasnot hospitalized; another (120mg)

was hospitalized,underwent gastric lavageand remainednormotensive; thethird(105mg)

washospitalizedandhad hypotension(90/50mmHg)which normalizedfollowingplasma

expansion.A patient whotook70mgamlodipineandanunknownquantityof

benzodiazepineinasuicide attemptdeveloped shockwhichwas refractorytotreatmentand

diedthe following daywithabnormallyhighbenzodiazepine plasmaconcentration. A case

ofaccidentaldrugoverdosehasbeendocumentedin a19-month-oldmalewho ingested

30mgamlodipine(about2mg/kg).Duringtheemergency roompresentation, vital signs

werestablewithnoevidenceofhypotension, butaheartrate of180bpm. Ipecacwas

administered3.5hours after ingestionand onsubsequent observation(overnight) no

sequelae were noted.

Ifmassiveoverdoseshouldoccur,active cardiacand respiratorymonitoringshouldbe

instituted.Frequentbloodpressuremeasurements are essential.Shouldhypotensionoccur,

cardiovascularsupportincludingelevationoftheextremities andthejudicious

administrationoffluidsshouldbeinitiated.If hypotensionremains unresponsive tothese

conservativemeasures,administration ofvasopressors (suchasphenylephrine) should be

consideredwithattention to circulating volumeand urineoutput.Intravenouscalcium

gluconatemayhelptoreversetheeffectsofcalciumentryblockade.Asamlodipineis

highlyprotein bound, hemodialysisis notlikely tobe ofbenefit.

Information onAtorvastatin

Thereisnospecifictreatmentfor atorvastatinoverdosage. Intheevent ofanoverdose,the

patientshouldbetreatedsymptomatically,andsupportivemeasures institutedas required.

Duetoextensivedrugbindingto plasmaproteins, hemodialysisisnotexpectedto

significantly enhanceatorvastatinclearance.

DOSAGE ANDADMINISTRATION

Dosage ofCADUETmust be individualizedonthe basisofbotheffectivenessand

tolerancefor eachindividualcomponent in the treatmentofhypertension/angina and

hyperlipidemia.

Amlodipine(Hypertension or angina)

Adults:Theusual initialantihypertensiveoraldoseofamlodipineis 5 mgoncedailywith

amaximumdose of10mgoncedaily.Small, fragile,orelderly individuals,orpatients

withhepaticinsufficiencymaybe startedon2.5mgoncedailyand thisdosemaybeused

whenaddingamlodipinetoother antihypertensive therapy.

Dosageshouldbeadjustedaccordingtoeachpatient’s need. Ingeneral,titrationshould

proceedover7to14days sothatthephysiciancanfullyassess thepatient’sresponse to

Caduet®Tablets,Israel, 29July2007

each doselevel.Titration mayproceedmorerapidly,however, ifclinically warranted,

providedthe patientisassessedfrequently.

Therecommendeddoseofamlodipine forchronicstableor vasospasticanginais 5-10mg,

withthelowerdosesuggestedinthe elderlyandinpatients withhepaticinsufficiency.

Most patients willrequire 10mgfor adequateeffect.SeeADVERSE REACTIONS

sectionfor informationrelatedtodosageand sideeffects.

Children:Theeffectiveantihypertensiveoraldoseof amlodipineinpediatricpatients ages

6-17yearsis2.5mgto 5 mgoncedaily.Doses inexcessof 5 mgdailyhavenot been

studiedin pediatricpatients.SeeCLINICAL PHARMACOLOGY.

Atorvastatin (Hyperlipidemia)

Thepatientshouldbeplacedonastandardcholesterol-loweringdietbeforereceiving

atorvastatinandshouldcontinueonthisdietduringtreatmentwithatorvastatin.

Hypercholesterolemia(Heterozygous Familialand Nonfamilial) and Mixed

Dyslipidemia(FredricksonTypesIIa and IIb)

Therecommendedstartingdose ofatorvastatinis10or 20mgonce daily.Patients who

requirealargereduction inLDL-C(more than45%) maybestartedat40mgoncedaily.

The dosagerangeofatorvastatinis10 to 80mgoncedaily.Atorvastatin canbe

administeredas asingle dose atanytimeofthe day,withorwithoutfood. Thestarting

doseandmaintenance dosesofatorvastatinshouldbeindividualizedaccordingto patient

characteristicssuchas goaloftherapyandresponse(seeNCEPGuidelines,summarizedin

Table8). Afterinitiationand/orupon titrationofatorvastatin,lipid levelsshouldbe

analyzedwithin2to4weeksanddosageadjusted accordingly.

Sincethe goal oftreatmentistolowerLDL-C,theNCEP recommendsthat LDL-C levels

beused to initiateand assesstreatment response. OnlyifLDL-Clevels arenotavailable,

should total-C beusedtomonitor therapy.

Heterozygous FamilialHypercholesterolemiain PediatricPatients (10-17 yearsofage)

The recommendedstartingdoseofatorvastatinis 10mg/day;themaximumrecommended

doseis 20mg/day(dosesgreater than20 mghavenot beenstudiedinthis patient

population).Dosesshould beindividualizedaccordingtotherecommended goaloftherapy

(seeNCEPPediatricPanel Guidelines 1 ,CLINICALPHARMACOLOGY, and

INDICATIONS ANDUSAGE). Adjustments shouldbe madeatintervalsof4weeksor

more.

HomozygousFamilialHypercholesterolemia

The dosageofatorvastatin inpatientswith homozygousFHis10to80mgdaily.

Atorvastatinshouldbeused asanadjuncttootherlipid-loweringtreatments (e.g.,LDL

apheresis) inthesepatients orif suchtreatmentsareunavailable. Note: a 2.5/80mg

NationalCholesterol Education Program(NCEP): Highlightsofthe Report oftheExpert Panel onBlood

CholesterolLevels inChildren Adolescents.Pediatrics.89(3):495-501.1992.

Caduet®Tablets,Israel, 29July2007

CADUETtabletisnotavailable. Managementofpatients needing a2.5/80mgcombination

requiresindividual assessments ofdyslipidemiaandtherapy with the individual

components asa2.5/80mgCADUETtabletis notavailable.

Concomitant Therapy

Atorvastatinmaybe usedincombinationwitha bileacidbindingresinfor additive effect.

The combinationofHMG-CoAreductaseinhibitorsandfibrates shouldgenerallybe

avoided (seeWARNINGS, SkeletalMuscle, andPRECAUTIONS, DrugInteractions

for other drug-druginteractions).

Dosage inPatients WithRenal Insufficiency

Renaldiseasedoesnot affecttheplasmaconcentrations norLDL-C reductionof

atorvastatin;thus, dosage adjustmentinpatients with renaldysfunctionis notnecessary

(seeCLINICALPHARMACOLOGY,Pharmacokinetics).

Use inCombinationwithOther MedicinalCompounds

Studies withatorvastatin:

Incases where co-administrationofatorvastatinwithcyclosporineis necessary,the dose of

atorvastatinshould notexceed10mg(seesection4.4Specialwarningsandprecautionsforuse–

SkeletalMuscleEffectsandsection4.5Interaction withothermedicinalproductsandother

formsofinteraction-In Studies withAtorvastatin:TransporterInhibitors).

CADUET

CADUET maybesubstitutedforits individually titrated components. Patients maybe

giventheequivalentdoseofCADUETora doseof CADUETwithincreasedamounts of

amlodipine,atorvastatinor bothforadditionalantianginaleffects,blood pressurelowering,

orlipid loweringeffect.

CADUET maybeusedtoprovideadditional therapy forpatientsalreadyononeofits

components.As initialtherapy foroneindicationand continuationoftreatment ofthe

other,the recommendedstarting doseofCADUETshouldbe selectedbasedonthe

continuationofthecomponent being usedandtherecommendedstarting dose for the

addedmonotherapy.

CADUET maybeused toinitiatetreatmentinpatientswithhyperlipidemia andeither

hypertension or angina.The recommended startingdose ofCADUETshouldbebasedon

theappropriatecombinationofrecommendationsfor themonotherapies.The maximum

doseoftheamlodipinecomponent ofCADUET is 10 mgoncedaily.The maximumdose

ofthe atorvastatin component ofCADUETis 80mgoncedaily.

See abovefor detailedinformationrelatedtothedosingandadministrationofamlodipine

and atorvastatin.

Caduet®Tablets,Israel, 29July2007

HOW SUPPLIED

CADUET® tabletscontainamlodipinebesylateand atorvastatin calciumequivalent to

amlodipineandatorvastatinin thedosestrengthsdescribed below.

CADUETtablets are differentiatedbytabletcolor/sizeandareengravedwith“Pfizer”on

onesideandauniquenumberontheotherside.CADUET tablets are supplied for oral

administrationin thefollowing strengths andpackageconfigurations:

Storeat25°C; excursionspermitted to15-30°C

Manufacturer: PfizerInc., Brooklyn,USA

For:PfizerPharmaceuticalsIsraelLtd.,9 Shenkar St,HertzliyaPituach46725

Last revisiondate:29July2007