MEDIKINET MR 20 MG MODIFIED-RELEASE CAPSULES

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SUMMARYOF PRODUCT CHARACTERISTICS

1 NAME OFTHEMEDICINALPRODUCT

MedikinetMR20mgmodified-releasecapsules

MedikinetMR 30mgmodified-releasecapsules

MedikinetMR 40mgmodified-releasecapsules

2 QUALITATIVEANDQUANTITATIVE COMPOSITION

EachMedikinetMR 20mgcapsulecontains 20 mgmethylphenidate

hydrochloride, correspondingto 17.30 mgmethylphenidate.

Excipients:114.65 mg–131.13 mgsucrose/capsule

EachMedikinetMR 30mgcapsulecontains 30 mgmethylphenidate

hydrochloride, correspondingto 26.10 mgmethylphenidate.

Excipients:69.6 mg–79.61 mgsucrose/capsule

EachMedikinetMR 40mgcapsulecontains 40 mgmethylphenidate

hydrochloride, correspondingto 34.80 mgmethylphenidate.

Excipients:92.8 mg–106.14 mgsucrose/capsule

For afulllistofexcipients,see section6.1.

3 PHARMACEUTICALFORM

MedikinetMR 20mg:modified-releasecapsule,hard.

Mauve capsulescontainingwhiteand bluepellets.

MedikinetMR 30mg:modified-releasecapsule,hard.

Darkvioletopaquecapanda lightgreyopaquebodycontainingwhiteand blue

pellets.

MedikinetMR 40mg:modified-releasecapsule,hard.

Darkvioletopaquecapanda greyopaquebodycontainingwhiteand bluepellets.

4 CLINICALPARTICULARS

4.1 Therapeuticindications

MedikinetMRis indicatedaspartofacomprehensivetreatmentprogramme for

attention-deficit/hyperactivitydisorder(ADHD)inchildren over6 years ofage when

remedialmeasuresalone prove insufficient.Treatmentmustbe underthe supervision

ofa specialistin childhoodbehaviouraldisorders. Diagnosis should be made

accordingto DSM-IVcriteria orthe guidelinesin ICD-10.

Additionalinformation onthe safe use ofthe medicinalproduct:

Thespecific aetiologyofthis syndrome isunknown, and thereis no single diagnostic

test. Adequate diagnosisrequiresthe useofmedicaland specialpsychological,

educational, andsocialresources.

Acomprehensivetreatmentprogramme typicallyincludespsychological, educational

and socialmeasuresand isaimed atstabilizingchildren witha behaviouralsyndrome

characterized bysymptomswhich mayinclude chronichistoryofshortattentionspan,

distractibility, emotionallability, impulsivity, moderate to severe hyperactivity, minor

neurologicalsigns andabnormalEEG. Learningmayormaynotbe impaired.

MedikinetMRtreatmentisnotindicatedin allchildrenwiththis syndrome andthe

decisiontousethesemedicinalproductmustbe basedon a verythorough assessment

ofthe severityofthechild’s symptoms.

4.2 Posology andmethodofadministration

MedikinetMRis takenin the morningwith orafterbreakfastin orderto obtain

sufficientlyprolonged action and to avoid high plasma peaks. Methylphenidateis

absorbed much fasterfromMedikinetMRwhenthe medicinalproductis taken onan

emptystomach.In this case, release maynotbe adequatelysustained.

MedikinetMRconsistsofan immediatereleasecomponent(50%ofthedose)anda

modifiedrelease component(50%ofthe dose).HenceMedikinetMR10 mgyields

an immediate-release doseof5 mgand an extendedreleasedoseof5 mg

methylphenidate hydrochloride.Theextended-releaseportion ofeach doseis

designedto maintaina treatmentresponsethrough theafternoon withoutthe needfor

a middaydose. Itis designed to delivertherapeuticplasma levels fora period of

approximately8 hours, which isconsistentwiththe schooldayratherthanthe whole

day(seesection 5.2 “Pharmacokinetic properties”). Forexample, 20 mgofMedikinet

MRisintended totake theplace of10mgatbreakfastand 10mgatlunchtime of

immediaterelease methylphenidatehydrochloride.

Adults:Notapplicable.

Elderly: Notapplicable.

Children(over6 years)andadolescents.

Dosetitration:

Carefuldosetitrationis necessaryatthe startoftreatmentwith methylphenidate.This

is normallyachieved usingan immediate releaseformulationtaken in divided doses.

Therecommended startingdailydoseis 5mgoncedailyortwicedaily(e.g. at

breakfastand lunch), increasingifnecessarybyweekly increments of5-10mgin the

dailydoseaccordingtotolerabilityand degreeofefficacyobserved. MedikinetMR

10mgoncedailymaybe used in placeofimmediatereleasemethylphenidate

hydrochloride 5mgtwicedailyfromthe beginningoftreatmentwherethe treating

physician considers thattwicedailydosingis appropriate fromthe outsetand twice

dailytreatmentadministration isimpracticable.

For dosesnotrealisable/practicable withthis strength,otherstrengths ofthis

medicinalproductandothermethylphenidate containingproducts are available.

Patients CurrentlyUsingMethylphenidate:Patients establishedon animmediate

release methylphenidate hydrochlorideformulation maybe switchedto the milligram

equivalentdailydoseofMedikinetMR.

Ifthe effectofthe medicinalproductwears offtoo earlyin thelate afternoon or

evening, disturbed behaviourand/orinabilityto go tosleep mayrecur. Asmalldose

ofanimmediate-release methylphenidate hydrochloride tabletlate inthedaymay

helpto solve this problem. Theregimen thatachievessatisfactorysymptomcontrol

withthelowesttotaldailydoseshouldbe employed.

Themaximumdailydoseofmethylphenidate hydrochloride is 60mg.

MedikinetMRshould notbe usedinchildren lessthan6 years due toa lackofdata

on safetyandefficacy.

MedikinetMRshould be given in themorningwith orafterbreakfast.

Thecapsulesmaybe swallowed wholewith the aid ofliquids,oralternatively, the

capsule maybe openedandthe capsulecontents sprinkled onto asmallamount

(tablespoon)ofapplesauceand given immediately, andnotstoredforfutureuse.

Drinkingsome fluids, e.g.water, shouldfollowtheintake ofthe sprinkles with

applesauce.The capsulesand thecapsule contents mustnotbecrushedorchewed.

Maintenance/Extendedtreatment:

Thelongtermuseofmethylphenidate hasnotbeen systematicallyevaluated in

controlledtrials.The physician who electsto use MedikinetMRforextended periods

in patients with ADHDshould periodicallyre-evaluatethelongtermusefulnessofthe

drugfortheindividualpatientwithtrialperiods offmedicationto assess the patient’s

functioningwithoutpharmacotherapy. Improvementmaybe sustained whenthe drug

is eithertemporarilyorpermanentlydiscontinued.

Note:Ifimprovementofsymptoms is notobserved afterappropriatedosage

adjustmentoveraone-month period, the treatmentshould bediscontinued.

Methylphenidate shouldbediscontinued periodicallytoassessthechild’s condition.

Medicinalproducttreatmentisusuallydiscontinuedduringorafterpuberty.

4.3 Contraindications

MedikinetMRis contra-indicated:

- in patients known to behypersensitiveto methylphenidate orto anyofthe

excipients.

- in patients withmarked anxiety, agitation ortension asthe useofMedikinet

MRmayaggravate thesesymptoms

- in patients with glaucoma

- in patients with hyperthyroidism

- in patients with thyrotoxicosis

- in patients with severe angina pectoris

- in patients with cardiacarrhythmia,

- in patients with severe hypertension

- in patients with heartfailure

- in patients with myocardialinfarction

- in patients who currentlyexhibitsevere depression, psychotic symptoms,

psychopathologicalpersonalitystructure, historyofaggression orsuicidal

tendency, sincemethylphenidate mightworsentheseconditions

- in patients with known drugdependence oralcoholism

- in combinationwith non-selective, irreversiblemonoamine oxydase

inhibitors, andalso within aminimumof14 days followingdiscontinuationof

a non-selective irreversibleMAOinhibitor(hypertensive crisesand

hyperthermia mayresult)(seeSection 4.5).

- in patients with motortics,tics insiblings, orafamilyhistoryordiagnosis of

Tourette's syndrome.

- -duringpregnancy(see Section4.6 and 5.3).

- a historyofpronounced anacidityofthe stomach with apHvalue above 5.5,

in therapywith H

-receptorblockers orin antacidtherapy,

4.4 Specialwarnings andprecautionsforuse

Warnings:MedikinetMRshould notbe used inchildren less than 6 years ofage due

to alackofdata on safetyand efficacy.

MedikinetMRshould notbe usedtotreatsevereexogenous orendogenous

depression.

Clinicalexperiencesuggests thatMedikinetMRmayexacerbate symptoms of

behaviouraldisturbance and thoughtdisorderin psychotic children.

MedikinetMRshould be administered withcaution topatients with severe depression

orwith suicidalthoughts oractionsbecausethereisa riskofaggravation ofthis

condition.

Available clinicalevidencesuggests thattreatmentwith methylphenidateduring

childhooddoesnotincreasethelikelihoodofaddictionin laterlife,though this should

always becarefullymonitoredin eachindividualcase.

Chronic abuseofmethylphenidatecanlead to markedtoleranceand psychological

dependence withvaryingdegrees ofabnormalbehaviour. Frankpsychotic episodes

can occur,especiallyin responseto parenteralabuse.

Thechoicebetweentreatmentwith eitherMedikinetMRoran immediate release

methylphenidateformulation should bedetermined onan individualbasis with

particularconsideration ofthe requirementforsymptomcontrolin thelatterpartof

the day(seealso section 4.2).

Methylphenidate shouldnotbe usedforthepreventionortreatmentofnormalfatigue

states.

Precautions:Treatmentwith methylphenidateis notindicatedin allcases ofADHD,

and should be considered onlyafterdetailed historytakingand evaluation.The

decisiontoprescribe methylphenidate depend on anassessmentofthe severityof

symptoms and theirappropriatenesstothechild’s ageand notsimplyon the presence

ofoneormore abnormalbehaviouralcharacteristics.Where thesesymptoms are

associated withacute stressreactions,treatmentwithmethylphenidateis usuallynot

indicated.

Reduced weightgain and slightgrowthretardationhave beenreported withthelong

termuseofstimulants in children. Carefulmonitoringofgrowthis recommended

duringextended treatmentwith methylphenidate. Patients who are notgrowingor

gainingweightasexpectedshould have theirtreatmentinterrupted temporarily.

Blood pressureshould bemonitoredatappropriate intervals inallpatients taking

methylphenidate,especiallythose with hypertension.

ExacerbationofmotorandphonicticsandTourette’ssyndrome hasbeenreported.

Therefore, clinicalevaluation forticsandTourette’ssyndrome should precede use of

stimulantmedications (seeSection 4.3 Contraindications).

Due tothe potentialdecreased appetiteassociated withmethylphenidate use, caution

is advisedin the presenceofanorexia nervosa.

Caution is called forin emotionallyunstablepatients, such asthosewith ahistoryof

drugdependenceoralcoholism, because such patientsmayincreasethe dosage on

theirowninitiative.

Thereissome clinicalevidencethatmethylphenidatemaylowerthe convulsive

threshold in patients with priorhistoryofseizures, inpatients with priorEEG

abnormalitiesin absence ofseizures, and, veryrarely, in absenceofhistoryof

seizures andno priorEEGevidenceofseizures. In thepresenceofseizures,the drug

should be discontinued.

Thelongtermsafetyand efficacyprofilesofmethylphenidatearenotfullyknown.

Patients requiringlongtermtherapyshouldthereforebe carefullymonitored and

complete and differentialblood countsand aplateletcountperformed periodically.

Carefulsupervision isrequired duringdrugwithdrawal, since thismayunmask

depression as wellas chronic over-activity. Some patients mayrequire long-term

followup.

Thereis no experience withthe useofMedikinetMRin patients withrenal

insufficiencyorhepatic insufficiency.

Women ofchildbearingpotentialshould useeffective contraceptive measures(see

Section 4.3, Section 4.6and Section5.3).

This medicinalproductcontains sucrose. Patients withrare hereditaryproblems of

fructose intolerance, glucosegalactosemalabsorption orsucrase-isomaltase

insufficiencyshould nottake this medicine.

Sport:This medicinalproductcontains methylphenidate which couldresultina

positive resultduringdrugtesting.

4.5 Interaction with othermedicinal products andotherforms ofinteraction

Because ofpossible hypertensive crisisMedikinetMRis contraindicatedin patients

beingtreated(currentlyorwithin the preceding2 weeks)with non-selective,

irreversible MAO-inhibitors (seeSection 4.3).

Because ofpossibleincreasesinblood pressure,MedikinetMRshould be used

cautiouslywith vasopressoragents.

Itis notknown howmethylphenidate mayaffectplasma concentrations of

concomitantlyadministereddrugs. Cautionisrecommended atcombination of

methylphenidate with otherdrugs, especiallythose with a narrowtherapeutic

window. Case reports have indicatedthatmethylphenidate mayinhibitthe

metabolismofcoumarin anticoagulants,anticonvulsants(eg, phenobarbital,

phenytoin,primidone),andsome antidepressants (tricyclicsand selective serotonin

reuptake inhibitors). Downward dose adjustmentofthese drugs maybe required

when given concomitantlywith methylphenidate. Itmaybe necessaryto adjustthe

dosage and monitorplasma drugconcentrations (or, inthe caseofcoumarin,

coagulationtimes), when initiatingordiscontinuingconcomitantmethylphenidate.

Serious adverseevents,includingsudden death, have been reportedinconcomitant

usewith clonidine, although no causalityforthe combinationhasbeenestablished.

Thesafetyofusingmethylphenidate incombination withclonidine orothercentrally

actingalpha-2 agonists hasnotbeen systematicallyevaluated. Possible interactions

with antipsychotics (haloperidoland thioridazine)have alsobeenreported.

Methylphenidate mayalsodecrease the antihypertensive effectofguanethidine.

MedikinetMRmustnotbetaken togetherwith H

receptorblockers orantacids,as

this couldleadtoa fasterrelease ofthe totalamountofactive substance.

Alcoholmayexacerbatethe CNS adversereactionsofpsychoactive drugs including

methylphenidate. Itisthereforeadvisableforpatientsto abstain fromalcoholduring

treatment.

Halogenated anaesthetics:Thereisa riskofsudden blood pressureincreaseduring

surgery. Ifsurgeryis planned, methylphenidate treatmentshould notbe used on the

dayofsurgery.

4.6 Pregnancy andlactation

Experience onthe useofmethylphenidatein pregnantwomen is limited.

Studiesin animals have shown reproductive toxicityofmethylphenidate(see Section

5.3).The potentialriskforhumansis unknown.

Methylphenidate is contraindicatedduringpregnancy(seeSection 4.3 and 4.4).

Itis notknown whethermethylphenidate oritsmetabolitespassinto breastmilk;but

forsafetyreasonsa decision should be madewhetherto discontinue breastfeedingor

discontinuethetreatmenttakinginto accountthe importance ofthemedicinalproduct

to breastfeedingmothers.

4.7 Effects on ability to driveandusemachines

MedikinetMRmaycausedizziness and drowsiness. Ithasa majorinfluenceon the

abilityto drive and usemachines. Itis therefore advisableto exercise caution when

driving, operatingmachineryorengagingin otherpotentiallyhazardousactivities.

4.8 Undesirable effects

Side-effectassessmentis based on the followingfrequencydata:

Verycommon (

1/10)

Common (

1/100to <1/10)

Occasional(

1/1.000to<1/100)

Rare(

1/10.000 to <1/1.000)

Veryrare(<1/10.000)

Nervousness andinsomniaare verycommon adversereactions occurringatthe

beginningoftreatmentbutcan usuallybe controlled byreducingthe dosage.

Decreasedappetiteisalso common butusuallytransient.

Blood and lymphatic systemdisorders

Veryrare: Anaemia,leucopenia,thrombocytopenia, thrombocytopenic

purpura.

Cardiacdisorders

Common: Arrhythmia, palpitations, tachycardia.

Rare: Angina pectoris.

Veryrare: Cardiacarrest.

Congenital, familialand genetic disorders:

Veryrare: Tourette’ssyndrome.

Eye disorders:

Rare: Difficultiesin visualaccommodation, blurred vision.

Gastrointestinaldisorders

Common: Abdominalpain, nausea and vomiting. Theseusuallyoccuratthe

beginningoftreatmentandmaybe alleviatedbyconcomitantfood

intake. Drymouth.

Generaldisorders and administration siteconditions

Rare: Growthretardation duringprolonged usein children.

Veryrare: Sudden death.

Hepatobiliarydisorders

Veryrare: Abnormalliverfunction,rangingfromtransaminase elevationto

hepaticcoma.

Investigations

Common: Changesin bloodpressureand heartrate(usuallyan increase).

Metabolismand nutrition disorders

Common: Decreasedappetite,reduced weightgain duringprolonged use in

children.

Musculoskeletaland connective tissuedisorders

Common: Arthralgia.

Veryrare: Musclespasms.

Nervous systemdisorders

Common: Dizziness, drowsiness,dyskinesia,headaches, hyperactivity.

Veryrare: Convulsions, choreo-athetoid movements.

Veryrarereportsofpoorlydocumented neuroleptic malignant

syndrome(NMS)have been received. Inmostofthesereports

patients were alsoreceivingothermedications. Itis uncertain what

rolemethylphenidate played inthese cases.

Psychiatric disorders

Verycommon: Insomnia, nervousness

Common: Abnormalbehaviour, aggression, agitation, anorexia, anxiety,

depression,

irritability

Veryrare: Hallucinations,psychotic disorder, suicidalbehaviour(including

completedsuicide),ticsorexacerbation ofpre-existingtics,

transient

depressed mood

Skin and subcutaneoustissue disorders

Common: Alopecia,pruritus,rash, urticaria.

Veryrare: Erythemamultiforme thromobocytopenic purpura, exfoliative

dermatitis,fixed drugeruption.

Vasculardisorders

Veryrare: Cerebralarteritis and/orocclusion

4.9 Overdose

Themodifiedrelease ofmethylphenidatefromMedikinetMRshould be considered

when treatingpatientswithoverdose.

Signs and symptoms

Acute overdose, mainlydue to overstimulation ofthecentralandsympatheticnervous

systems, mayresultin vomiting, agitation,tremors, hyperreflexia, muscle twitching,

convulsions(maybe followed bycoma), euphoria,confusion, hallucinations,

delirium, sweating, flushing, headache,hyperpyrexia,tachycardia, palpitations,

cardiacarrhythmias, hypertension, mydriasisand dryness ofmucousmembranes.

Treatment

Thereis no specific antidote toMedikinetMRL overdose.

Managementconsists ofappropriatesupportive measures, preventingselfinjuryand

protectingthepatientfromexternalstimulithatwouldaggravate over-stimulation

alreadypresent. Ifthe signs and symptoms are nottoosevere and the patientis

conscious, gastriccontentsmaybe evacuatedbyinduction ofvomitingorgastric

lavage.In the presenceofsevere intoxication, acarefullytitrated doseofashort-

actingbarbiturate should begiven beforeperforminggastriclavage.

Intensive caremustbe providedto maintainadequate circulation andrespiratory

exchange;externalcoolingproceduresmaybe requiredforhyperpyrexia.

Efficacyofperitonealdialysis orextracorporealhaemodialysis foroverdoseof

methylphenidate hasnotbeen established.

5 PHARMACOLOGICALPROPERTIES

5.1 Pharmacodynamicproperties

Pharmacotherapeutic group:psychostimulants, agentsusedforADHDand

nootropics;centrallyactingsympathomimetics

ATCCode:N06BA04

Mechanismofaction:MedikinetMRis amild CNS stimulantwithmore prominent

effects on mentalthan on motoractivities. Its mode ofactionin man is notcompletely

understood butits effects are thoughtto be dueto corticalstimulation andpossiblyto

stimulationofthereticularactivatingsystem.

ThemechanismbywhichMedikinetMRexerts its mentaland behaviouraleffects in

children is notclearlyestablished, noristhere conclusive evidence showinghow

these effectsrelateto thecondition ofthe centralnervous system. Itis thoughtto

blockthere-uptake ofnorepinephrine and dopamine into the presynapticneuroneand

increase the releaseofthesemonoaminesintotheextraneuronalspace. MedikinetMR

is aracemic mixture ofthed-and lthreo enantiomers ofmethylphenidate.The d-

enantiomeris more pharmacologicallyactivethanthel-enantiomer.

5.2 Pharmacokineticproperties

Absorption:

MedikinetMRhasa plasma profile showingtwo phasesofactive substancerelease,

with asharp,initial,upward slope similarto a methylphenidateimmediate-release

tablet,anda secondrisingportion approximatelythreehourslater, followed bya

gradualdecline.

Whentaken byadultsinthe morningafterbreakfast,the immediate-release portion of

the hardcapsuledissolvesrapidlyand resultsin aintialpeakplasma concentration.

Afterpassingthrough the stomach and into the smallintestine, the sustained-release

portion ofthe hardcapsulereleasesits methylphenidate. Thisresultsintheformation

ofa 3-4 hourplateauphaseduringwhich concentrations do notsinkbelow75%of

the peakplasma concentration. The amountofmethylphenidateabsorbed when

administered once dailyiscomparable withconventionalimmediate-release

formulations administeredtwicedaily.

MedikinetMRcombinesthe advantagesofafastonsetofaction withthe build-up of

an extended-duration plateau phase.

Thefollowingpharmacokinetic parameters were measured followinga single daily

doseofMedikinetMR20mgadministeredafterbreakfast:

cmax = 6.4 ng/ml, tmax = 2.75 h, AUCinf= 48.9ng.h.ml-1 and t½ = 3.2h

Theareaundertheplasma concentrationcurve (AUC), aswellas the peakplasma

concentration,is proportionalto the dose.

Food Effects:

Ingestion togetherwithfood witha high fatcontentdelays its absorption (T

)by

approximately1.5 hour.Thereis nodifferencein bioevailabilityofMedikinetMR

given eithera normalorhigh calorie breakfast.The plasma curvesshow similar

exposureregardingrate andextend ofabsorption.

Itis necessaryto take MedikinetMRwith orafterbreakfast.Thefoodinfluence takes

effectandshows asignificantandrelevantretardation.Thisjustifies theposologyto

be taken withfood. Arecommendation inrelation oftype offoodisnotnecessary.

Sprinkle Administration:

TheC

T

and AUCofthe sprinkled contentsofthe MedikinetMRcapsuleare

similar(bioequivalent)tothe intactcapsule. MedikinetMRmay, therefore, be

administered eitheras anintactcapsule, orthecapsulemaybe opened and the

contentsswallowed, withoutchewing, immediatelyaftersprinklingonto applesauce

orothersimilarsoftfood.

Age:

ThePharmacokineticsofMedikinetMRhave notbeenstudiedin children younger

than 6 years ofage.

Availability, systemic:

Owingto extensive first-passmetabolismitssystemicavailabilityamountsto

approximately30%(11-51%)ofthe dose.

Distribution:

In the blood, methylphenidateand its metabolites become distributedin the plasma

(57%)and the erythrocytes(43%).Methylphenidate and its metaboliteshave alow

plasma protein-binding(10-33%).The volume ofdistributionaftera single

intravenousdoseis2.2 l/kg (2.65±1.1l/kgford-methylphenidateand 1.8±0.9 L/kg

forl-methylphenidate).

Elimination:

Methylphenidate is eliminatedfromthe plasma withan average half-life of

approximately2 hours.Themean clearance afteranintravenoussingle doseis 0.565

l/h/kg(0.40±0.12 l/h/kgford-methylphenidateand 0.73±0.28 l/h/kgforl-

methylphenidate). Afteroraladministration, approximately78-97 %ofthedoseis

excreted within48 to 96 hvia the urine and 1 to 3%via the faecesin the formof

metabolites.Onlysmallamounts(< 1%)ofunchanged methylphenidate appearin the

urine. A large proportion ofanintravenousdose(89%)iseliminated intheurine

within 16 hours, presumablyregardless ofthepHvalue, asritalinic acid.

Thereisapparentlyno difference inthepharmacokineticsofmethylphenidate

between children withhyperkinetic disorders/ADHDand healthyadulttestsubjects.

Pharmacokinetic propertiesofmethylphenidate have notbeen studiedin children

below6 years ofage orin elderlyabove 65 years.

Therenalelimination ofritalinicacid maydecrease inthe caseofimpairedrenal

function.

Thebulkofthedoseisexcretedinthe urine as 2-phenyl-2-piperidylacetic acid

(PPAA, 60-86%).

Characteristicsin patients:

Thereareno apparentdifferencesin the pharmacokineticbehaviourof

methylphenidatein hyperactive childrenand healthyadultvolunteers.

Elimination data frompatients with normalrenalfunction suggestthatrenalexcretion

ofthe unchanged methylphenidate would hardlybe diminished atallinthe presence

ofimpaired renalfunction.However, renalexcretion ofPPAAmaybe reduced.

5.3 Preclinical safety data

Thereisevidence thatmethylphenidate maybe ateratogen in two species.Spina

bifidaand limb malformations have been reportedinrabbits whilstin the rat,

equivocalevidenceofinduction ofabnormalities ofthe vertebraewasfound.

Methylphenidate did notaffectreproductive performance orfertilityatlowmultiples

(2-5 times)ofthe clinicaldose.

In life-time ratand mousecarcinogenicitystudies,increasednumbers ofmalignant

livertumours were notedinmale miceonly. The significanceofthisfindingto

humansis unknown.

Theweightofevidencefromthe genotoxicitystudiesreveals nospecialhazard for

humans.

6 PHARMACEUTICALPARTICULARS

6.1 List ofexcipients

Sucrose

Gelatin

Maize starch

Methacrylicacid-ethylacrylate-copolymer(1:1)(Ph. Eur.)

Talc

Triethylcitrate

Titaniumdioxide(E 171)

Poly(vinylalcohol)

Macrogol3350

Polysorbate 80

Sodiumhydroxide

Sodiumlaurilsulfate

Simeticoneemulsion

Silicacolloidalanhydrous

Indigo carmine,lacquer

Erythrosine(E 127)

Methylcellulose

Sorbic acid(Ph. Eur.)

Purified water

MedikinetMR 20mg:PatentblueV(E 131)

MedikinetMR 30mg&40 mg:BlackIron oxide (E172)

6.2 Incompatibilities

Notapplicable.

6.3 Shelflife

3 years.

6.4 Specialprecautionsforstorage

Do notstoreabove25°C.

Storeintheoriginalpackage in orderto protectfrommoisture.

6.5 Natureandcontents ofcontainer

Boxesof 28, 30,50 modified-release capsules, hardinPVC/PVdCblistersheat

sealedto aluminumfoil.

Notallpackage sizesmaybe marketed.

6.6 Specialprecautionsfordisposal

No specialrequirements.

7 MARKETINGAUTHORISATIONHOLDER

MediceArzneimittelPütterGmbH&Co.KG

Kuhloweg37

58638 Iserlohn

Germany

LicenseHolder:MedilineLTD., CityGate, 22 G'BenGurion St., Herzlia