COMTAN ®

עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי ב רבוטקוא 2010

COMTAN ®

(entacapone)

200 mg film-coated tablets

Prescribing Information

1 Name of the medicinal product

COMTAN ®

2 Qualitative and quantitative composition

Tabletcontaining 200mg entacapone.

For afull list of excipients, see section 6.1 Listofexcipients.

3 Pharmaceutical form

Film-coated tablet.

Brownish-orange, oval, biconvexfilm-coatedtablet with Comtan ® engraved on one side.

4 Clinical particulars

4.1 Therapeutic indications

Entacapone is indicatedas an adjunctto standardpreparations oflevodopa/benserazide or

levodopa/carbidopa for usein patientswithParkinson’s disease andend-of-dosemotor

fluctuations,who cannotbestabilized on thosecombinations.

4.2 Posology and method of administration

Entacapone shouldonlybe used incombinationwith levodopa/benserazideor

levodopa/carbidopa. Theprescribing information for these levodopapreparations isapplicable

to theirconcomitant usewith entacapone.

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Posology

One200mgtabletistaken witheachlevodopa/dopa decarboxylase inhibitor dose. The

maximumrecommendeddose is200mgtentimes daily,i.e. 2,000mgofentacapone.

Entacaponeenhancestheeffects of levodopa. Hence,toreduce levodopa-related

dopaminergicadverse reactions, e.g.dyskinesias,nausea, vomiting and hallucinations,itis

oftennecessaryto adjustlevodopa dosagewithinthe first daysto first weeks after initiating

entacapone treatment.The dailydose of levodopashould be reducedbyabout10 to30% by

extendingthedosing intervals and/or byreducingthe amount oflevodopa perdose, according

tothe clinical condition ofthepatient.

Entacaponeincreasesthe bioavailabilityoflevodopa fromstandard levodopa/benserazide

preparations slightlymore (5 to 10%) thanfromstandard levodopa/carbidopa preparations.

Hence, patients who aretaking standard levodopa/benserazide preparationsmayneeda larger

reductionoftheir levodopa dose when entacapone isinitiated.

If entacapone treatmentisdiscontinued, itis necessaryto adjustthe dosingof other

antiparkinsoniantreatments, especiallylevodopa,toachievea sufficientlevel ofcontrol of the

parkinsonian symptoms.

Renalinsufficiencydoes not affectthe pharmacokineticsof entacaponeand there is noneed

for doseadjustment. However, for patients whoarereceiving dialysis therapy,alongerdosing

intervalmaybeconsidered(seesection 5.2 Pharmacokinetic properties).

Elderly

Nodosageadjustmentof entacapone is required for elderlypatients.

Children

Comtanisnot recommended for use in childrenbelowage 18due tolack ofdata onsafety

and efficacy.

Methodof administration

Entacapone is administered orallyand simultaneouslywith each levodopa/carbidopaor

levodopa/benserazidedose.

Entacaponecan betakenwith or without food (seesection 5.2 Pharmacokinetic properties).

4.3 Contraindications

Liver impairment.

Patientswithpheochromocytoma duetotheincreased riskof hypertensivecrisis.

Aprevioushistoryofneurolepticmalignant syndrome(NMS) and/ornon-traumatic

rhabdomyolysis.

Concomitantuseofentacaponeandnon-selectivemonoamineoxidase(MAO-A andMAO-B)

inhibitors(e.g. phenelzine, tranylcypromine).

Concomitantuseofa selective MAO-Ainhibitorplus a selective MAO-Binhibitorand

entacapone (see section4.5 Interactionwithother medicinal productsand other forms of

interaction).

Known hypersensitivityto entacapone ortoanyoftheexcipients.

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4.4 Special warnings and precautions foruse

Rhabdomyolysis secondarytoseveredyskinesiasor neurolepticmalignantsyndrome(NMS)

has been observedrarelyin patients withParkinson’s disease.Isolatedcasesof

rhabdomyolysis havebeen reportedwith entacaponetreatment.

NMS,including rhabdomyolysis and hyperthermia, ischaracterized bymotorsymptoms

(rigidity, myoclonus, tremor),mentalstatuschanges(e.g. agitation, confusion,coma),

hyperthermia,autonomic dysfunction(tachycardia,labile blood pressure) andelevated serum

creatine phosphokinase(CPK).In individualcases, onlysomeof these symptomsand/or

findingsmaybe evident.

Isolatedcasesof NMS havebeen reported,especiallyfollowing abrupt reduction or

discontinuation of entacapone and other dopaminergicmedications. Whenconsidered

necessary, withdrawalofentacaponeand other dopaminergic treatment shouldproceed

slowly, and ifsigns and/or symptomsoccur despiteaslow withdrawal of entacapone,an

increasein levodopa dosagemaybenecessary.

Entacaponetherapyshould beadministered withcaution topatients withischaemicheart

disease.

Because of itsmechanismof action,entacapone mayinterferewiththemetabolismof

medicinal productscontainingacatecholgroup and potentiatetheir action.Thus, entacapone

should beadministeredcautiouslyto patients being treatedwithmedicinalproducts

metabolizedbycatechol-O-methyl transferase (COMT), e.g. rimiterol,isoprenaline,

adrenaline,noradrenaline, dopamine, dobutamine,alpha-methyldopa, and apomorphine (see

section 4.5 Interaction with othermedicinal productsand other forms of interaction).

Entacaponeis alwaysgivenas anadjuncttolevodopa treatment. Hence,the precautions valid

for levodopa treatmentshould also betaken intoaccount for entacaponetreatment.

Entacaponeincreasesthe bioavailabilityof levodopa fromstandard levodopa/benserazide

preparations 5 to 10%more thanfromstandardlevodopa/carbidopa preparations.

Consequently, undesirable dopaminergiceffectsmaybemorefrequentwhenentacaponeis

addedtolevodopa/benserazidetreatment(seesection 4.8 Undesirableeffects). To reduce

levodopa-related dopaminergic adverse reactions,itis often necessaryto adjustlevodopa

dosagewithin the first daysto first weeks after initiating entacaponetreatment,according to

theclinicalcondition of the patient (see section 4.2 Posologyandmethodof administration

and 4.8 Undesirableeffects).

Entacapone mayaggravate levodopa-inducedorthostatic hypotension. Entacapone should be

givencautiouslyto patients who aretaking othermedicinal productswhichmaycause

orthostatic hypotension.

In clinical studies, undesirable dopaminergiceffects,e.g. dyskinesia, weremorecommonin

patients who receivedentacaponeanddopamineagonists(such as bromocriptine), selegiline

or amantadinecomparedto those who receivedplacebo withthiscombination. Thedoses of

otherantiparkinsonianmedicationsmayneed to beadjusted whenentacapone treatment is

initiated.

Entacaponeused incombination with levodopahas beenassociated withsomnolence and

episodes ofsudden sleep onsetin patientswith Parkinson’s disease andcaution should

thereforebeexercised when drivingor operatingmachines (see section4.7 Effects onability

todrive and usemachines).

For patientsexperiencingdiarrhoea,afollow-up ofweightisrecommendedin order toavoid

potentialexcessiveweightdecrease. Prolonged orpersistentdiarrhoea suspectedto berelated

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toentacaponemaybeasignof colitis.Intheevent ofprolongedorpersistentdiarrhoea,

entacaponeshould be discontinuedand appropriatemedical therapyand investigations

considered.

For patientswhoexperienceprogressiveanorexia, astheniaandweight decrease withina

relativelyshort period oftime,a generalmedicalevaluationincluding liver functionshould be

considered .

Pathological gambling,increasedlibido and hypersexualityhavebeen reportedinParkinson’s

disease patients treated with dopamine agonistsand otherdopaminergictreatments suchas

entacaponein association with levodopa.

Comtan tablets containsucrose.Therefore, patientswith rarehereditaryproblems of fructose

intolerance, glucose-galactosemalabsorptionorsucrase-isomaltase insufficiencyshould not

takethismedicine.

4.5 Interaction with other medicinal products and other forms of

interaction

Nointeraction of entacapone withcarbidopahasbeenobserved withtherecommended

treatment schedule.Pharmacokinetic interactionwith benserazidehas notbeen studied.

In single-dosestudiesinhealthyvolunteers, nointeractionswere observed between

entacapone and imipramineorbetween entacapone andmoclobemide. Similarly,no

interactions between entacapone andselegiline were observedin repeated-dose studiesin

parkinsonianpatients. However, theexperienceoftheclinicaluse of entacapone with several

drugs, including MAO-A inhibitors, tricyclicantidepressants, noradrenaline reuptake

inhibitors suchas desipramine,maprotilineandvenlafaxine, andmedicinalproducts that are

metabolizedbyCOMT(e.g. catechol-structured compounds:rimiterole, isoprenaline,

adrenaline,noradrenaline, dopamine, dobutamine,alpha-methyldopa, apomorphine,and

paroxetine) isstill limited. Caution should beexercised whenthesemedicinal productsare

usedconcomitantlywith entacapone(seesections 4.3 Contraindications and 4.4 Special

warningsand precautions for use).

Entacaponemaybe usedwith selegiline (aselective MAO-B inhibitor), but the dailydose of

selegiline shouldnotexceed 10mg.

Entacaponemayformchelateswith ironin the gastrointestinaltract. Entacapone andiron

preparations should betakenatleast2 to 3 hours apart (see section 4.8 Undesirableeffects).

Entacaponebinds to humanalbumin binding siteII which also binds several othermedicinal

products,including diazepamandibuprofen.Clinical interaction studieswith diazepamand

non-steroidal anti-inflammatorydrugs havenot been carriedout. According toin vitrostudies,

significantdisplacement isnot anticipated at therapeutic concentrationsofthemedicinal

products.

Dueto its affinityto cytochromeP450 2C9in vitro(see section5.2 Pharmacokinetic

properties),entacapone maypotentiallyinterfere with drugswhosemetabolismis dependent

on thisisoenzyme, suchas S-warfarin. However, in aninteraction studyin healthyvolunteers,

entacaponedid notchangethe plasmalevels of S-warfarin,whilethe AUC for R-warfarin

increasedonaverage by18%[CI

11 to 26%]. The INR valuesincreasedon averageby13%

6 to19%]. Thus, control of INR is recommended whenentacapone treatment is initiated

for patientsreceiving warfarin.

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4.6 Pregnancy and lactation

Pregnancy

Noovertteratogenic orprimaryfetotoxiceffects were observed inanimal studies in whichthe

exposurelevelsof entacaponewere markedlyhigher than thetherapeuticexposurelevels. As

thereisno experience inpregnantwomen, entacapone should not be used during pregnancy.

Lactation

In animal studiesentacapone wasexcretedinmilk. The safetyofentacapone in infants is

unknown.Women should not breast-feed during treatmentwith entacapone.

4.7 Effects on ability todrive anduse machines

Comtan inassociationwith levodopamayhave majorinfluence on theabilityto driveand use

machines. Patients beingtreated withentacaponeinassociation with levodopaand presenting

with somnolenceand/orsudden sleep onsetepisodesmust beinstructedto refrain from

driving or engaginginactivitieswhere impairedalertnessmayput themselves or othersat risk

of serious injuryor death(e.g. operatingmachines) until such recurrentepisodes have

resolved (see section 4.4Special warnings and precautions for use).

Entacaponemay,together with levodopa,causedizzinessand symptomatic orthostatism.

Therefore,caution should beexercisedwhen driving or usingmachines.

4.8 Undesirable effects

Verycommon undesirableeffects found indouble-blind placebo controlled phaseIII studies

are dyskinesia, nausea,and abnormal urine (see below).

Commonundesirableeffects found in double-blind placebocontrolled phaseIII studiesare

diarrhoea,Parkinsonismaggravated,dizziness,abdominal pain, insomnia,drymouth,fatigue,

hallucinations, constipation, dystonia, increasedsweating,hyperkinesia, headache, leg

cramps, confusion,paroniria, fall, posturalhypotension, vertigo andtremor.

Most of theundesirableeffectscausedbyentacapone relateto theincreased dopaminergic

activityand occurmostcommonlyatthe beginningof treatment. Reductionof levodopa

dosagemaydecreasethe severityand frequencyofthese effects.Theothermajor classof

undesirableeffectsare gastrointestinal symptoms, includinge.g. nausea, vomiting,abdominal

pains,constipationand diarrhoea. Urinemaybediscoloured reddish-brown byentacapone,

but this isaharmless phenomenon.

Usuallyundesirableeffectscaused byentacapone are mildtomoderate.The mostcommon

undesirableeffects leading to discontinuation ofentacapone treatmenthave been

gastrointestinal symptoms(e.g. diarrhoea, 2.5%) and dopaminergic symptoms(e.g.

dyskinesias,1.7%).

Dyskinesias(27%), nausea(11%), diarrhoea (8%),abdominal pain(7%) and drymouth

(4.2%)were reported significantlymore often with entacaponethan withplacebo inclinical

studies.

Someof theadverse reactions, such asdyskinesia,nausea,andabdominalpain,maybemore

commonwith thehigher doses (1,400 to 2,000mgperday)than with the lower doses of

entacapone

.

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Slight decreases in haemoglobin,erythrocytecount andhaematocrithavebeen reported

during entacapone treatment. The underlyingmechanismmayinvolve decreasedabsorption of

iron fromthegastrointestinaltract.During long-termtreatment(6 months)withentacaponea

clinicallysignificant decreaseinhaemoglobin has been observed in 1.5%of patients.

Rare reportsof clinicallysignificantincreasesin liverenzymeshave beenreceived.

The following adverse drug reactions, listed belowin Table 1,havebeenaccumulatedboth

fromclinicalstudies withentacaponeandsincethe introduction of entacapone intothe

market.

Table 1

Adverse reactions are rankedunder headingsoffrequency,themost frequent first, using the

following convention:Verycommon( ≥1/10); common(≥1/100, <1/10); uncommon

≥1/1,000, <1/100); rare(≥1/10,000,<1/1,000); veryrare (<1/10,000), notknown (cannot be

estimated fromtheavailable data, since no validestimatecan bederived fromclinicaltrialsor

epidemiological studies).

Psychiatricdisorders

Common Insomnia,hallucinations,confusion,nightmares

Veryrare Agitation

Nervoussystemdisorders

Verycommon Dyskinesia

Common Parkinsonism aggravated,dizziness,dystonia,hyperkinesias

Cardiacdisorders

Common Ischaemic heartdiseaseeventsotherthanmyocardialinfarction*(e.g.anginapectoris)

Uncommon Myocardial infarction*

Gastrointestinal disorders

Verycommon Nausea

Common Diarrhoea,abdominal pain,drymouth,constipation, vomiting

Veryrare Anorexia,colitis

Hepato-biliarydisorders

Rare Hepaticfunctiontestsabnormal

Notknown Hepatitis withmainlycholestaticfeatures

Skinandsubcutaneoustissue disorders

RareErythematous ormaculopapularrash

Veryrare Urticaria

Notknown Skin, hair,beardand naildiscolourations

Renal andurinarydisorders

Verycommon Urinediscolouration

General disordersandadministrationsiteconditions

CommonFatigue, sweating increased, fall

Veryrare Weightdecrease

*The incidence ratesofmyocardialinfarctionandotherischaemicheart diseaseevents(0.43%and1.54%,

respectively)arederived fromananalysisof13double-blindstudiesinvolving2082patientswithend-of-dose

motor fluctuationsreceivingentacapone.

Entacaponeused incombination with levodopahas beenassociated withisolatedcases of

excessive daytime somnolenceand sudden sleeponsetepisodes(see section 4.7 Effects on

abilityto drive and usemachines).

Isolatedcasesof neurolepticmalignant syndrome (NMS) have been reportedespecially

following abrupt reduction ordiscontinuation ofentacaponeand other dopaminergic

medications.

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Isolatedcasesof rhabdomyolysis have been reported.

Parkinson’s diseasepatients treated with dopamineagonistsand other dopaminergic

treatments suchas entacapone inassociationwithlevodopa,especiallyathighdoses,have

been reported as exhibitingsigns ofpathologicalgambling,increased libidoand

hypersexuality,generallyreversible upon reduction of thedose or treatmentdiscontinuation.

4.9 Overdose

The post-marketing data includes isolatedcases ofoverdoseinwhich thereported highest

dailydose ofentacapone has been 16,000mg. Theacute symptomsand signs in thesecasesof

overdoseincluded confusion,decreasedactivity,somnolence,hypotonia,skin discolouration

and urticaria.

Managementof acuteoverdosingissymptomatic.

5 Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeuticgroup:catechol-O-methyltransferase inhibitor, ATC code:NO4BX02.

Entacapone belongs toa newtherapeutic class, catechol-O-methyl transferase (COMT)

inhibitors. It isa reversible, specific,andmainlyperipherallyactingCOMT inhibitor designed

forconcomitant administrationwith levodopapreparations. Entacapone decreases the

metabolic loss of levodopa to 3-O-methyldopa (3-OMD) byinhibitingthe COMT enzyme.

This leads toan increasein thebioavailabilityoflevodopaand an increasedamount of

levodopaavailableto the brain. Entacaponethusprolongs the clinical response tolevodopa.

EntacaponeinhibitstheCOMT enzymemainlyin peripheraltissues. COMTinhibition in red

blood cellscloselyfollowsthe plasmaconcentrationsof entacapone,thusclearlyindicating

the reversible nature ofCOMT inhibition.

Clinical studies

In two phase III double-blind studies inaltogether 376 patients withParkinson’sdisease and

end-of-dose motor fluctuations, entacaponeor placebo was given witheachlevodopa/dopa

decarboxylase inhibitor dose. The resultsare given in Table2. InstudyI,dailyON time

(hours)was measuredfromhome diaries andinstudyII, the proportion of dailyON time was

measured.

Table 2:

DailyON time (Mean ±SD)

StudyI:DailyONtime(h)

Entacapone(n=85) Placebo(n=86) Difference

Baseline9.3±2.2 9.2±2.5

Week8-24 10.7±2.2 9.4±2.6 1h20min

(8.3%)

45min,1 h56

StudyII:ProportionofdailyONtime(%)

Entacapone(n=103) Placebo(n=102) Difference

Baseline60.0±15.260.8±14.0

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Week8-24 66.8±14.5 62.8±16.80 4.5%(0 h 35min)

0.93%,7.97%

There werecorresponding decreasesinOFFtime.

In study1OFF-timewasreducedby24% comparedwith 0%inthe placebo group.

In study2OFF-timewasreducedby18% comparedwith 5%inthe placebo group.

5.2 Pharmacokinetic properties

a)Generalcharacteristics of the active substance

Absorption

There are largeintra- andinterindividual variationsinthe absorptionof entacapone.

The peakconcentration (C

) in plasmais usuallyreachedaboutonehourafter a 200mg

entacaponetablet. Thedrug is subject to extensive first-passmetabolism.The bioavailability

of entacapone isabout 35% afteranoraldose. Food doesnotaffecttheabsorptionof

entacaponeto anysignificantextent.

Distribution

After absorption fromthegastrointestinal tract,entacapone israpidlydistributedto the

peripheral tissues witha distributionvolumeatsteadystateof 20 L. Approximately92% of

the doseiseliminatedduring beta-phase,witha short eliminationhalf-lifeof 30minutes.The

totalclearance of entacapone isabout800mL/min.

Entacapone isextensivelyboundto plasmaproteins,mainlyto albumin.Inhuman plasmathe

unbound fraction is about 2.0%in thetherapeuticconcentration range. At therapeutic

concentrations, entacapone doesnotdisplace other extensivelybound drugs (e.g. warfarin,

salicylicacid, phenylbutazone, or diazepam),norisit displaced to anysignificantextentby

anyof thesedrugsat therapeutic or higher concentrations.

Metabolism

Asmall amount of entacapone, the (E)-isomer, is convertedto its (Z)-isomer. The (E)-isomer

accountsfor 95% oftheAUC of entacapone. The (Z)-isomerand traces ofothermetabolites

accountfor the remaining 5%.

Data frominvitro studies using human livermicrosomal preparationsindicate thatentacapone

inhibitscytochromeP4502C9 (IC50~ 4microM). Entacapone showed little or noinhibition

of other types of P450 isoenzymes(CYP1A2,CYP2A6, CYP2D6, CYP2E1, CYP3Aand

CYP2C19)(see section 4.5 Interaction with other medicinalproductsandother forms of

interaction).

Elimination

Theelimination of entacapone occursmainlybynon-renalmetabolic routes. It isestimated

that80-90% of the doseis excreted in faeces, although this hasnotbeenconfirmedinman.

Approximately10-20%is excreted in urine. Onlytraces ofentacapone are found unchanged

in urine.Themajor part (95%) ofthe productexcreted inurine isconjugatedwithglucuronic

acid. Of themetabolitesfoundinurine onlyabout 1% havebeen formedthrough oxidation.

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b) Characteristics inpatients

The pharmacokinetic properties of entacapone aresimilarinboth youngandelderlyadults.

Themetabolismof themedicinal productisslowed in patients withmildtomoderateliver

insufficiency(Child-Pugh Class Aand B), which leadstoanincreased plasmaconcentration

of entacapone bothin theabsorptionandelimination phases (seesection 4.3

Contraindications). Renalimpairment does notaffectthe pharmacokinetics of entacapone.

However, alongerdosing intervalmaybeconsidered for patientswho arereceiving dialysis

therapy.

5.3 Preclinical safety data

Preclinical data revealedno specialhazard for humans basedonconventional studiesof safety

pharmacology,repeated-dose toxicity, genotoxicity, and carcinogenicpotential. In repeated-

dose toxicitystudies, anaemiamostlikelydueto iron chelating propertiesof entacapone was

observed.Instudiesof reproductiontoxicity,decreasedfetal weight and a slightlydelayed

bone development werenoticedin rabbitsat systemic exposure levels inthetherapeutic range.

6. Pharmaceutical particulars

6.1 Listofexcipients

Tablet core:microcrystallinecellulose,mannitol,croscarmellose sodium, hydrogenated

vegetable oil,magnesium stearate.

Film-coating:hypromellose, polysorbate80, glycerol85%, sucrose, magnesiumstearate,

yellowironoxide (E 172), red iron oxide (E 172), titaniumdioxide (E 171).

6.2 Incompatibilities

Not applicable

6.3 Special precautions for storage

Nospecialprecaution for storage.

Comtanmust be keptout of the reachand sightofchildren.

6.5 Nature and contentofcontainer

Amber glassbottles(hydrolytic class III)withwhitetamper-resistant polypropyleneclosures

containing 30tablets.

6.6 Instructions for use and handling

Nospecial requirements.

Manufacturer:

OrionCorporation,Finland

for NovartisPharmaAG,Basel, Switzerland

License Holder:

Novartis PharmaServices AG, 36 ShachamSt.,Petach-Tikva