BYMOT DISPERSIBLE TABLETS

Main information

  • Trade name:
  • BYMOT DISPERSIBLE TABLETS
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BYMOT DISPERSIBLE TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0966/016/004
  • Authorization date:
  • 25-08-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0966/016/004

CaseNo:2054755

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ErghaHealthcareLtd

Damastown,Mulhuddart,Dublin15

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Bymot50mgDispersibleTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom17/02/2009until24/08/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bymot50mgDispersibleTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachdispersibletabletcontains50mglamotrigine.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Dispersibletablet

Whitetooffwhite,roundtablet,debossedwiththenumber“50”ononesideand“DLT”ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epilepsy

Adultsandadolescentsaged13yearsandabove

Adjunctiveormonotherapytreatmentofpartialseizuresandgeneralisedseizures,includingtonic-clonic

seizures.

SeizuresassociatedwithLennox-Gastautsyndrome.Lamotrigineisgivenasadjunctivetherapybutmaybethe

initialantiepilepticdrug(AED)tostartwithinLennox-Gastautsyndrome.

Childrenandadolescentsaged2to12years

Adjunctivetreatmentofpartialseizuresandgeneralisedseizures,includingtonic-clonicseizuresandthe

seizuresassociatedwithLennox-Gastautsyndrome.

Monotherapyoftypicalabsenceseizures.

4.2Posologyandmethodofadministration

Lamotriginedispersible/chewabletabletsmaybechewed,dispersedinasmallvolumeofwater(atleastenoughto

coverthewholetablet)orswallowedwholewithalittlewater.

Restartingtherapy

Prescribersshouldassesstheneedforescalationtomaintenancedosewhenrestartinglamotrigineinpatientswhohave

discontinuedlamotrigineforanyreason,sincetheriskofseriousrashisassociatedwithhighinitialdosesand

exceedingtherecommendeddoseescalationforlamotrigine(seesection4.4).Thegreatertheintervaloftimesincethe

previousdose,themoreconsiderationshouldbegiventoescalationtothemaintenancedose.Whentheintervalsince

discontinuinglamotrigineexceedsfivehalf-lives(seesection5.2),lamotrigineshouldgenerallybeescalatedtothe

maintenancedoseaccordingtotheappropriateschedule.

Epilepsy

Therecommendeddoseescalationandmaintenancedosesforadultsandadolescentsaged13yearsandabove(Table1)

andforchildrenandadolescentsaged2to12years(Table2)aregivenbelow.Becauseofariskofrashtheinitialdose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 2

WhenconcomitantAEDsarewithdrawnorotherAEDs/medicinalproductsareaddedontotreatmentregimes

containinglamotrigine,considerationshouldbegiventotheeffectthismayhaveonlamotriginepharmacokinetics(see

section4.5).

Table1:Adultsandadolescentsaged13yearsandabove–recommendedtreatmentregimeninepilepsy

Treatment

Regimen Weeks1+2 Weeks3+4 Usualmaintenancedose

Monotherapy: 25mg/day

(onceaday) 50mg/day

(onceaday) 100−200mg/day(oncea

dayortwodivideddoses)

Toachievemaintenance,

dosesmaybeincreasedby

maximumof50-100mg

everyonetotwoweeks

untiloptimalresponseis

achieved

500mg/dayhasbeen

requiredbysomepatientsto

achievedesiredresponse

AdjunctivetherapyWITHvalproate(inhibitoroflamotrigine

glucuronidation–seesection4.5):

Thisdosage 12.5mg/day 25mg/day 100−200mg/day

regimenshould

beusedwith

valproate

regardlessofany (givenas25

mgon

alternatedays) (onceaday) (onceadayortwodivided

doses)

concomitant

medicinal

products Toachievemaintenance,

dosesmaybeincreasedby

maximumof25-50mg

everyonetotwoweeks

untiloptimalresponseis

achieved

AdjunctivetherapyWITHOUTvalproateandWITHinducersof

lamotrigineglucuronidation(seesection4.5):

Thisdosage 50mg/day 100mg/day 200−400mg/day

regimenshould

beusedwithout

valproatebut (onceaday)

(twodivided

doses) (twodivideddoses)To

achievemaintenance,doses

with: maybeincreasedby

maximum

phenytoin of100mgeveryonetotwo

weeksuntiloptimal

response

carbamazepine isachieved

phenobarbitone

primidone 700mg/dayhasbeen

required

rifampicin bysomepatientstoachieve

desiredresponse

lopinavir/ritonavir

AdjunctivetherapyWITHOUTvalproateandWITHOUTinducers

oflamotrigineglucuronidation(seesection4.5):

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 3

Table2:Childrenandadolescentsaged2to12years-recommendedtreatmentregimeninepilepsy(totaldailydosein

regimenshould

beusedwith

othermedicinal

productsthatdo

notsignificantly

inhibitorinduce

lamotrigine

glucuronidation (onceaday) (onceaday) dayortwodivideddoses)

Toachievemaintenance,

dosesmaybeincreasedby

maximumof50-100mg

everyonetotwoweeks

untiloptimalresponseis

achieved

Inpatientstakingmedicinalproductswherethepharmacokinetic

interactionwithlamotrigineiscurrentlynotknown(seesection4.5),the

treatmentregimenasrecommendedforlamotriginewithconcurrent

valproateshouldbeused.

Treatment

regimen Weeks1+2 Weeks3+4 Usualmaintenancedose

Monotherapy

of 0.3mg/kg/day 0.6

mg/kg/day 1–10mg/kg/day,

although

typicalabsence (onceadayor (onceadayor somepatientshave

required

seizures: twodivided

doses) twodivided

doses) higherdoses(upto15

mg/kg/day)toachieve

desiredresponse(oncea

dayortwodivideddoses)

Toachievemaintenance,

dosesmaybeincreasedby

maximumof0.6

mg/kg/dayeveryoneto

twoweeksuntiloptimal

responseisachieved

AdjunctivetherapyWITHvalproate(inhibitoroflamotrigine

glucuronidation–seesection4.5):

Thisdosage 0.15

mg/kg/day* 0.3

mg/kg/day 1−5mg/kg/day

regimenshould

beusedwith

valproate (onceaday) (onceaday)

(onceadayortwodivided

doses)

regardlessofany

other

concomitant

medicinal

products Toachievemaintenance,

dosesmaybeincreasedby

maximumof0.3mg/kg

everyonetotwoweeks

untiloptimalresponseis

achieved,withamaximum

maintenancedoseof200

mg/day

AdjunctivetherapyWITHOUTvalproateandWITHinducersof

lamotrigineglucuronidation(seesection4.5):

Thisdosage 0.6mg/kg/day 1.2

mg/kg/day 5−15mg/kg/day

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 4

Toensureatherapeuticdoseismaintainedtheweightofachildmustbemonitoredandthedosereviewedasweight

changesoccur.Itislikelythatpatientsagedtwotosixyearswillrequireamaintenancedoseatthehigherendofthe

recommendedrange.

Ifepilepticcontrolisachievedwithadjunctivetreatment,concomitantAEDsmaybewithdrawnandpatientscontinued

beusedwithout

valproatebut doses) doses) (onceadayortwodivided

doses)

with:

phenytoin Toachievemaintenance,

doses

carbamazepine maybeincreasedby

maximumof1.2mg/kg

everyonetotwo

phenobarbitone weeksuntiloptimal

response

primidone isachieved,witha

maximummaintenance

doseof

rifampicin 400mg/day

lopinavir/ritonavir

AdjunctivetherapyWITHOUTvalproateandWITHOUTinducers

oflamotrigineglucuronidation(seesection4.5):

Thisdosage 0.3mg/kg/day 0.6

mg/kg/day 1−10mg/kg/day

regimenshould

beusedwith

othermedicinal (onceadayor

twodivided

doses) (onceadayor

twodivided

doses) (onceadayortwodivided

doses)

productsthatdo

notsignificantly

inhibitorinduce

lamotrigine

glucuronidation Toachievemaintenance,

dosesmaybeincreasedby

maximumof0.6mg/kg

everyonetotwoweeks

untiloptimalresponseis

achieved,withamaximum

ofmaintenancedoseof

200mg/day

Inpatientstakingmedicinalproductswherethepharmacokinetic

interactionwithlamotrigineiscurrentlynotknown(seesection4.5),the

treatmentregimenasrecommendedforlamotriginewithconcurrent

valproateshouldbeused.

2mgdispersible/chewabletablets-wherethisisthelowestmarketed

strength:<*Ifthecalculateddailydoseinpatientstakingvalproateis1

mgormorebutlessthan2mg,thenlamotrigine2mg

dispersible/chewabletabletsmaybetakenonalternatedaysforthefirst

twoweeks.Ifthecalculateddailydoseinpatientstakingvalproateisless

than1mg,thenlamotrigineshouldnotbeadministered.>

5mgdispersible/chewabletablets-where2mgdispersible/chewable

tabletsarenotmarketedandlamotrigine5mgdispersible/chewabletablets

arethelowestmarketedstrength:<*Ifthecalculateddailydosein

patientstakingvalproateis2.5mgormorebutlessthan5mg,then

lamotrigine5mgdispersible/chewabletabletsmaybetakenonalternate

daysforthefirsttwoweeks.Ifthecalculateddailydoseinpatientstaking

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 5

5mgdispersible/chewabletablets–where2mgdispersible/chewabletabletsarenotmarketedand5mg

dispersible/chewabletabletsarethelowestmarketedstrength:

Itshouldbenotedthatwiththecurrentlyavailablelamotrigine5mgdispersible/chewabletabletstrength,itisnot

possibletoaccuratelyinitiatelamotriginetherapyusingtherecommendeddosingguidelinesinpaediatricpatients

weighinglessthan17kg.

Childrenbelow2years

Therearelimiteddataontheefficacyandsafetyoflamotrigineforadjunctivetherapyofpartialseizuresinchildren

aged1monthto2years(seesection4.4).Therearenodatainchildrenbelow1monthofage.Thuslamotrigineisnot

recommendedforuseinchildrenbelow2yearsofage.If,basedonclinicalneed,adecisiontotreatisnevertheless

taken,seesections4.4,5.1and5.2.

Generaldosingrecommendationsforlamotrigineinspecialpatientpopulations

Womentakinghormonalcontraceptives

Theuseofanethinyloestradiol/levonorgestrel(30µg/150µg)combinationincreasestheclearanceoflamotrigineby

approximatelytwo-fold,resultingindecreasedlamotriginelevels.Followingtitration,highermaintenancedosesof

lamotrigine(byasmuchastwo-fold)maybeneededtoattainamaximaltherapeuticresponse.Duringthepill-free

week,atwo-foldincreaseinlamotriginelevelshasbeenobserved.Dose-relatedadverseeventscannotbeexcluded.

Therefore,considerationshouldbegiventousingcontraceptionwithoutapill-freeweek,asfirst-linetherapy(for

example,continuoushormonalcontraceptivesornon-hormonalmethods;seesections4.4and4.5).

StartinghormonalcontraceptivesinpatientsalreadytakingmaintenancedosesoflamotrigineandNOTtaking

inducersoflamotrigineglucuronidation

Themaintenancedoseoflamotriginewillinmostcasesneedtobeincreasedbyasmuchastwo-fold(seesections4.4

and4.5).Itisrecommendedthatfromthetimethatthehormonalcontraceptiveisstarted,thelamotriginedoseis

increasedby50to100mg/dayeveryweek,accordingtotheindividualclinicalresponse.Doseincreasesshouldnot

exceedthisrate,unlesstheclinicalresponsesupportslargerincreases.Measurementofserumlamotrigine

concentrationsbeforeandafterstartinghormonalcontraceptivesmaybeconsidered,asconfirmationthatthebaseline

concentrationoflamotrigineisbeingmaintained.Ifnecessary,thedoseshouldbeadapted.Inwomentakinga

hormonalcontraceptivethatincludesoneweekofinactivetreatment("pill-freeweek"),serumlamotriginelevel

monitoringshouldbeconductedduringweek3ofactivetreatment,i.e.ondays15to21ofthepillcycle.Therefore,

considerationshouldbegiventousingcontraceptionwithoutapill-freeweek,asfirst-linetherapy(forexample,

continuoushormonalcontraceptivesornon-hormonalmethods;seesections4.4and4.5).

StoppinghormonalcontraceptivesinpatientsalreadytakingmaintenancedosesoflamotrigineandNOTtaking

inducersoflamotrigineglucuronidation

Themaintenancedoseoflamotriginewillinmostcasesneedtobedecreasedbyasmuchas50%(seesections4.4and

4.5).Itisrecommendedtograduallydecreasethedailydoseoflamotrigineby50-100mgeachweek(ataratenot

exceeding25%ofthetotaldailydoseperweek)overaperiodof3weeks,unlesstheclinicalresponseindicates

otherwise.Measurementofserumlamotrigineconcentrationsbeforeandafterstoppinghormonalcontraceptivesmay

beconsidered,asconfirmationthatthebaselineconcentrationoflamotrigineisbeingmaintained.Inwomenwhowish

tostoptakingahormonalcontraceptivethatincludesoneweekofinactivetreatment("pill-freeweek"),serum

lamotriginelevelmonitoringshouldbeconductedduringweek3ofactivetreatment,i.e.ondays15to21ofthepill

cycle.Samplesforassessmentoflamotriginelevelsafterpermanentlystoppingthecontraceptivepillshouldnotbe

collectedduringthefirstweekafterstoppingthepill.

Startinglamotrigineinpatientsalreadytakinghormonalcontraceptives

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 6

Startingandstoppinghormonalcontraceptivesinpatientsalreadytakingmaintenancedosesoflamotrigineand

TAKINGinducersoflamotrigineglucuronidation

Adjustmenttotherecommendedmaintenancedoseoflamotriginemaynotberequired.

Elderly(above65years)

Nodosageadjustmentfromtherecommendedscheduleisrequired.Thepharmacokineticsoflamotrigineinthisage

groupdonotdiffersignificantlyfromanon-elderlyadultpopulation(seesection5.2).

Renalimpairment

Cautionshouldbeexercisedwhenadministeringlamotriginetopatientswithrenalfailure.Forpatientswithend-stage

renalfailure,initialdosesoflamotrigineshouldbebasedonpatients'concomitantmedicinalproducts;reduced

maintenancedosesmaybeeffectiveforpatientswithsignificantrenalfunctionalimpairment(seesections4.4and5.2).

Hepaticimpairment

Initial,escalationandmaintenancedosesshouldgenerallybereducedbyapproximately50%inpatientswithmoderate

(Child-PughgradeB)and75%insevere(Child-PughgradeC)hepaticimpairment.Escalationandmaintenancedoses

shouldbeadjustedaccordingtoclinicalresponse(seesection5.2).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Skinrash

Therehavebeenreportsofadverseskinreactions,whichhavegenerallyoccurredwithinthefirsteightweeksafter

initiationoflamotriginetreatment.Themajorityofrashesaremildandself-limiting,howeverseriousrashesrequiring

hospitalisationanddiscontinuationoflamotriginehavealsobeenreported.Thesehaveincludedpotentiallylife-

threateningrashessuchasStevens–Johnsonsyndromeandtoxicepidermalnecrolysis(seesection4.8).

Inadultsenrolledinstudiesutilizingthecurrentlamotriginedosingrecommendationstheincidenceofseriousskin

rashesisapproximately1in500inepilepsypatients.ApproximatelyhalfofthesecaseshavebeenreportedasStevens–

Johnsonsyndrome(1in1000).

Theriskofseriousskinrashesinchildrenishigherthaninadults.Availabledatafromanumberofstudiessuggestthe

incidenceofrashesassociatedwithhospitalisationinepilepticchildrenisfrom1in300to1in100.

Inchildren,theinitialpresentationofarashcanbemistakenforaninfection,physiciansshouldconsiderthepossibility

ofareactiontolamotriginetreatmentinchildrenthatdevelopsymptomsofrashandfeverduringthefirsteightweeks

oftherapy.

Additionallytheoverallriskofrashappearstobestronglyassociatedwith:

highinitialdosesoflamotrigineandexceedingtherecommendeddoseescalationoflamotriginetherapy(see

section4.2)

concomitantuseofvalproate(seesection4.2).

CautionisalsorequiredwhentreatingpatientswithahistoryofallergyorrashtootherAEDsasthefrequencyofnon-

seriousrashaftertreatmentwithlamotriginewasapproximatelythreetimeshigherinthesepatientsthaninthose

withoutsuchhistory.

Allpatients(adultsandchildren)whodeveloparashshouldbepromptlyevaluatedandlamotriginewithdrawn

immediatelyunlesstherashisclearlynotrelatedtolamotriginetreatment.Itisrecommendedthatlamotriginenotbe

restartedinpatientswhohavediscontinuedduetorashassociatedwithpriortreatmentwithlamotrigineunlessthe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 7

Rashhasalsobeenreportedaspartofahypersensitivitysyndromeassociatedwithavariablepatternofsystemic

symptomsincludingfever,lymphadenopathy,facialoedemaandabnormalitiesofthebloodandliver(seesection4.8).

Thesyndromeshowsawidespectrumofclinicalseverityandmay,rarely,leadtodisseminatedintravascular

coagulationandmultiorganfailure.Itisimportanttonotethatearlymanifestationsofhypersensitivity(forexample

fever,lymphadenopathy)maybepresenteventhoughrashisnotevident.Ifsuchsignsandsymptomsarepresentthe

patientshouldbeevaluatedimmediatelyandlamotriginediscontinuedifanalternativeaetiologycannotbeestablished.

Clinicalworseningandsuiciderisk

SuicidalideationandbehaviourhavebeenreportedinpatientstreatedwithAEDsinseveralindications.Ameta-

analysisofrandomisedplacebo-controlledtrialsofAEDshasalsoshownasmallincreasedriskofsuicidalideationand

behaviour.Themechanismofthisriskisnotknownandtheavailabledatadonotexcludethepossibilityofan

increasedriskforlamotrigine.

Thereforepatientsshouldbemonitoredforsignsofsuicidalideationandbehavioursandappropriatetreatmentshould

beconsidered.Patients(andcaregiversofpatients)shouldbeadvisedtoseekmedicaladviceshouldsignsofsuicidal

ideationorbehaviouremerge.

Hormonalcontraceptives

Effectsofhormonalcontraceptivesonlamotrigineefficacy

Theuseofanethinyloestradiol/levonorgestrel(30µg/150µg)combinationincreasestheclearanceoflamotrigineby

approximatelytwo-foldresultingindecreasedlamotriginelevels(seesection4.5).Adecreaseinlamotriginelevelshas

beenassociatedwithlossofseizurecontrol.Followingtitration,highermaintenancedosesoflamotrigine(byasmuch

astwo-fold)willbeneededinmostcasestoattainamaximaltherapeuticresponse.Whenstoppinghormonal

contraceptives,theclearanceoflamotriginemaybehalved.Increasesinlamotrigineconcentrationsmaybeassociated

withdose-relatedadverseevents.Patientsshouldbemonitoredwithrespecttothis.

Inwomennotalreadytakinganinduceroflamotrigineglucuronidationandtakingahormonalcontraceptivethat

includesoneweekofinactivetreatment(forexample"pill-freeweek"),gradualtransientincreasesinlamotriginelevels

willoccurduringtheweekofinactivetreatment(seesection4.2).Variationsinlamotriginelevelsofthisordermaybe

associatedwithadverseeffects.Therefore,considerationshouldbegiventousingcontraceptionwithoutapill-free

week,asfirst-linetherapy(forexample,continuoushormonalcontraceptivesornon-hormonalmethods).

TheinteractionbetweenotheroralcontraceptiveorHRTtreatmentsandlamotriginehavenotbeenstudied,thoughthey

maysimilarlyaffectlamotriginepharmacokineticparameters.

Effectsoflamotrigineonhormonalcontraceptiveefficacy

Aninteractionstudyin16healthyvolunteershasshownthatwhenlamotrigineandahormonalcontraceptive

(ethinyloestradiol/levonorgestrelcombination)areadministeredincombination,thereisamodestincreasein

levonorgestrelclearanceandchangesinserumFSHandLH(seesection4.5).Theimpactofthesechangesonovarian

ovulatoryactivityisunknown.However,thepossibilityofthesechangesresultingindecreasedcontraceptiveefficacy

insomepatientstakinghormonalpreparationswithlamotriginecannotbeexcluded.Thereforepatientsshouldbe

instructedtopromptlyreportchangesintheirmenstrualpattern,i.e.breakthroughbleeding.

Dihydrofolatereductase

Lamotriginehasaslightinhibitoryeffectondihydrofolicacidreductase,hencethereisapossibilityofinterference

withfolatemetabolismduringlong-termtherapy(seesection4.6).However,duringprolongedhumandosing,

lamotriginedidnotinducesignificantchangesinthehaemoglobinconcentration,meancorpuscularvolume,orserum

orredbloodcellfolateconcentrationsupto1yearorredbloodcellfolateconcentrationsforupto5years.

Renalfailure

Insingledosestudiesinsubjectswithendstagerenalfailure,plasmaconcentrationsoflamotriginewerenot

significantlyaltered.However,accumulationoftheglucuronidemetaboliteistobeexpected;cautionshouldtherefore

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 8

Patientstakingotherpreparationscontaininglamotrigine

lamotrigineshouldnotbeadministeredtopatientscurrentlybeingtreatedwithanyotherpreparationcontaining

lamotriginewithoutconsultingadoctor.

Developmentinchildren

Therearenodataontheeffectoflamotrigineongrowth,sexualmaturationandcognitive,emotionalandbehavioural

developmentsinchildren.

Precautionsrelatingtoepilepsy

AswithotherAEDs,abruptwithdrawaloflamotriginemayprovokereboundseizures.Unlesssafetyconcerns(for

examplerash)requireanabruptwithdrawal,thedoseoflamotrigineshouldbegraduallydecreasedoveraperiodoftwo

weeks.

Therearereportsintheliteraturethatsevereconvulsiveseizuresincludingstatusepilepticusmayleadto

rhabdomyolysis,multiorgandysfunctionanddisseminatedintravascularcoagulation,sometimeswithfataloutcome.

Similarcaseshaveoccurredinassociationwiththeuseoflamotrigine.

Aclinicallysignificantworseningofseizurefrequencyinsteadofanimprovementmaybeobserved.Inpatientswith

morethanoneseizuretype,theobservedbenefitofcontrolforoneseizuretypeshouldbeweighedagainstany

observedworseninginanotherseizuretype.

Myoclonicseizuresmaybeworsenedbylamotrigine.

Thereisasuggestioninthedatathatresponsesincombinationwithenzymeinducersislessthanincombinationwith

non-enzymeinducingantiepilepticagents.Thereasonisunclear.

Inchildrentakinglamotrigineforthetreatmentoftypicalabsenceseizures,efficacymaynotbemaintainedinall

patients.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

UDP-glucuronyltransferaseshavebeenidentifiedastheenzymesresponsibleformetabolismoflamotrigine.Thereis

noevidencethatlamotriginecausesclinicallysignificantinductionorinhibitionofhepaticoxidativedrug-metabolising

enzymes,andinteractionsbetweenlamotrigineandmedicinalproductsmetabolisedbycytochromeP450enzymesare

unlikelytooccur.Lamotriginemayinduceitsownmetabolismbuttheeffectismodestandunlikelytohavesignificant

clinicalconsequences.

Table3:Effectsofothermedicinalproductsonglucuronidationoflamotrigine

Medicinalproductsthat

significantlyinhibit

glucuronidationof

lamotrigine Medicinalproductsthat

significantlyinduce

glucuronidationof

lamotrigine Medicinalproductsthatdo

notsignificantlyinhibitor

induceglucuronidationof

lamotrigine

Valproate Phenytoin Oxcarbazepine

Carbamazepine Felbamate

Phenobarbitone Gabapentin

Primidone Levetiracetam

Rifampicin Pregabalin

Lopinavir/ritonavir Topiramate

Ethinyloestradiol/

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 9

*OtheroralcontraceptiveandHRTtreatmentshavenotbeenstudied,thoughtheymaysimilarlyaffectlamotrigine

pharmacokineticparameters(seesections4.2and4.4).

Interactionsinvolvingantiepilepticdrugs

Valproate,whichinhibitstheglucuronidationoflamotrigine,reducesthemetabolismoflamotrigineandincreasesthe

meanhalf-lifeoflamotriginenearlytwo-fold.Inpatientsreceivingconcomitanttherapywithvalproate,theappropriate

treatmentregimenshouldbeused(seesection4.2).

CertainAEDs(suchasphenytoin,carbamazepine,phenobarbitoneandprimidone)whichinducehepaticdrug-

metabolisingenzymesinducetheglucuronidationoflamotrigineandenhancethemetabolismoflamotrigine.In

patientsreceivingconcomitanttherapywithphenytoin,carbamazepine,phenobarbitoneorprimidone,theappropriate

treatmentregimenshouldbeused(seesection4.2).

Therehavebeenreportsofcentralnervoussystemeventsincludingdizziness,ataxia,diplopia,blurredvisionand

nauseainpatientstakingcarbamazepinefollowingtheintroductionoflamotrigine.Theseeventsusuallyresolvewhen

thedoseofcarbamazepineisreduced.Asimilareffectwasseenduringastudyoflamotrigineandoxcarbazepinein

healthyadultvolunteers,butdosereductionwasnotinvestigated.

Therearereportsintheliteratureofdecreasedlamotriginelevelswhenlamotriginewasgivenincombinationwith

oxcarbazepine.However,inaprospectivestudyinhealthyadultvolunteersusingdosesof200mglamotrigineand

1200mgoxcarbazepine,oxcarbazepinedidnotalterthemetabolismoflamotrigineandlamotriginedidnotalterthe

metabolismofoxcarbazepine.Thereforeinpatientsreceivingconcomitanttherapywithoxcarbazepine,thetreatment

regimenforlamotrigineadjunctivetherapywithoutvalproateandwithoutinducersoflamotrigineglucuronidation

shouldbeused(seesection4.2).

Inastudyofhealthyvolunteers,coadministrationoffelbamate(1200mgtwicedaily)withlamotrigine(100mgtwice

dailyfor10days)appearedtohavenoclinicallyrelevanteffectsonthepharmacokineticsoflamotrigine.

Basedonaretrospectiveanalysisofplasmalevelsinpatientswhoreceivedlamotriginebothwithandwithout

gabapentin,gabapentindoesnotappeartochangetheapparentclearanceoflamotrigine.

Potentialinteractionsbetweenlevetiracetamandlamotriginewereassessedbyevaluatingserumconcentrationsofboth

agentsduringplacebo-controlledclinicaltrials.Thesedataindicatethatlamotriginedoesnotinfluencethe

pharmacokineticsoflevetiracetamandthatlevetiracetamdoesnotinfluencethepharmacokineticsoflamotrigine.

Steady-statetroughplasmaconcentrationsoflamotriginewerenotaffectedbyconcomitantpregabalin(200mg,3times

daily)administration.Therearenopharmacokineticinteractionsbetweenlamotrigineandpregabalin.

Topiramateresultedinnochangeinplasmaconcentrationsoflamotrigine.Administrationoflamotrigineresultedina

15%increaseintopiramateconcentrations.

Inastudyofpatientswithepilepsy,coadministrationofzonisamide(200to400mg/day)withlamotrigine(150to500

mg/day)for35dayshadnosignificanteffectonthepharmacokineticsoflamotrigine.

AlthoughchangesintheplasmaconcentrationsofotherAEDshavebeenreported,controlledstudieshaveshownno

evidencethatlamotrigineaffectstheplasmaconcentrationsofconcomitantAEDs.Evidencefrominvitrostudies

indicatesthatlamotriginedoesnotdisplaceotherAEDsfromproteinbindingsites.

Interactionsinvolvingotherpsychoactiveagents

Thepharmacokineticsoflithiumafter2gofanhydrouslithiumgluconategiventwicedailyforsixdaysto20healthy

Lithium

Buproprion

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 10

Multipleoraldosesofbupropionhadnostatisticallysignificanteffectsonthesingledosepharmacokineticsof

lamotriginein12subjectsandhadonlyaslightincreaseintheAUCoflamotrigineglucuronide.

Inastudyinhealthyadultvolunteers,15mgolanzapinereducedtheAUCandCmaxoflamotriginebyanaverageof

24%and20%,respectively.Aneffectofthismagnitudeisnotgenerallyexpectedtobeclinicallyrelevant.Lamotrigine

at200mgdidnotaffectthepharmacokineticsofolanzapine.

Multipleoraldosesoflamotrigine400mgdailyhadnoclinicallysignificanteffectonthesingledosepharmacokinetics

of2mgrisperidonein14healthyadultvolunteers.Followingtheco-administrationofrisperidone2mgwith

lamotrigine,12outofthe14volunteersreportedsomnolencecomparedto1outof20whenrisperidonewasgiven

alone,andnonewhenlamotriginewasadministeredalone.

Invitroexperimentsindicatedthattheformationoflamotrigine'sprimarymetabolite,the2-N-glucuronide,was

minimallyinhibitedbyco-incubationwithamitriptyline,bupropion,clonazepam,haloperidolorlorazepam.These

experimentsalsosuggestedthatmetabolismoflamotriginewasunlikelytobeinhibitedbyclozapine,fluoxetine,

phenelzine,risperidone,sertralineortrazodone.Inaddition,astudyofbufuralolmetabolismusinghumanliver

microsomepreparationssuggestedthatlamotriginewouldnotreducetheclearanceofmedicinalproductsmetabolised

predominantlybyCYP2D6.

Interactionsinvolvinghormonalcontraceptives

Effectofhormonalcontraceptivesonlamotriginepharmacokinetics

Inastudyof16femalevolunteers,dosingwith30µgethinyloestradiol/150µglevonorgestrelinacombinedoral

contraceptivepillcausedanapproximatelytwo-foldincreaseinlamotrigineoralclearance,resultinginanaverage52%

and39%reductioninlamotrigineAUCandCmax,respectively.Serumlamotrigineconcentrationsincreasedduringthe

courseoftheweekofinactivetreatment(includingthe"pill-free"week),withpre-doseconcentrationsattheendofthe

weekofinactivetreatmentbeing,onaverage,approximatelytwo-foldhigherthanduringco-therapy(seesection4.4).

Noadjustmentstotherecommendeddoseescalationguidelinesforlamotrigineshouldbenecessarysolelybasedonthe

useofhormonalcontraceptives,butthemaintenancedoseoflamotriginewillneedtobeincreasedordecreasedinmost

caseswhenstartingorstoppinghormonalcontraceptives(seesection4.2).

Effectoflamotrigineonhormonalcontraceptivepharmacokinetics

Inastudyof16femalevolunteers,asteadystatedoseof300mglamotriginehadnoeffectonthepharmacokineticsof

theethinyloestradiolcomponentofacombinedoralcontraceptivepill.Amodestincreaseinoralclearanceofthe

levonorgestrelcomponentwasobserved,resultinginanaverage19%and12%reductioninlevonorgestrelAUCand

Cmax,respectively.MeasurementofserumFSH,LHandoestradiolduringthestudyindicatedsomelossof

suppressionofovarianhormonalactivityinsomewomen,althoughmeasurementofserumprogesteroneindicatedthat

therewasnohormonalevidenceofovulationinanyofthe16subjects.Theimpactofthemodestincreasein

levonorgestrelclearance,andthechangesinserumFSHandLH,onovarianovulatoryactivityisunknown(seesection

4.4).Theeffectsofdosesoflamotrigineotherthan300mg/dayhavenotbeenstudiedandstudieswithotherfemale

hormonalpreparationshavenotbeenconducted.

Interactionsinvolvingothermedicinalproducts

Inastudyin10malevolunteers,rifampicinincreasedlamotrigineclearanceanddecreasedlamotriginehalf-lifedueto

inductionofthehepaticenzymesresponsibleforglucuronidation.Inpatientsreceivingconcomitanttherapywith

rifampicin,theappropriatetreatmentregimenshouldbeused(seesection4.2).

Inastudyinhealthyvolunteers,lopinavir/ritonavirapproximatelyhalvedtheplasmaconcentrationsoflamotrigine,

probablybyinductionofglucuronidation.Inpatientsreceivingconcomitanttherapywithlopinavir/ritonavir,the

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 11

4.6Pregnancyandlactation

Riskrelatedtoantiepilepticdrugsingeneral

Specialistadviceshouldbegiventowomenwhoareofchildbearingpotential.TheneedfortreatmentwithAEDs

shouldbereviewedwhenawomanisplanningtobecomepregnant.Inwomenbeingtreatedforepilepsy,sudden

discontinuationofAEDtherapyshouldbeavoidedasthismayleadtobreakthroughseizuresthatcouldhaveserious

consequencesforthewomanandtheunbornchild.

Theriskofcongenitalmalformationsisincreasedbyafactorof2to3intheoffspringofmotherstreatedwithAEDs

comparedwiththeexpectedincidenceinthegeneralpopulationofapproximately3%.Themostfrequentlyreported

defectsarecleftlip,cardiovascularmalformationsandneuraltubedefects.TherapywithmultipleAEDsisassociated

withahigherriskofcongenitalmalformationsthanmonotherapyandthereforemonotherapyshouldbeusedwhenever

possible.

Riskrelatedtolamotrigine

Pregnancy

Epidemiologicalstudiesinvolvingintotalapproximately2000womenexposedtolamotriginemonotherapyduring

pregnancycannotexcludeanincreasedriskforcongenitalmalformations.Oneregistryhasreportedanincreased

incidenceoffacialclefts.Otherdatasetshavenotconfirmedthisfinding.Animalstudieshaveshowndevelopmental

toxicity(seesection5.3).

Iftherapywithlamotrigineisconsiderednecessaryduringpregnancy,thelowestpossibletherapeuticdoseis

recommended.

Lamotriginehasaslightinhibitoryeffectondihydrofolicacidreductaseandcouldthereforetheoreticallyleadtoan

increasedriskofembryofoetaldamagebyreducingfolicacidlevels(seesection4.4).Intakeoffolicacidwhen

planningpregnancyandduringearlypregnancymaybeconsidered.

Physiologicalchangesduringpregnancymayaffectlamotriginelevelsand/ortherapeuticeffect.Therehavebeen

reportsofdecreasedlamotrigineplasmalevelsduringpregnancywithapotentialriskoflossofseizurecontrol.After

birthlamotriginelevelsmayincreaserapidlywithariskofdose-relatedadverseevents.Thereforelamotrigineserum

concentrationsshouldbemonitoredbefore,duringandafterpregnancy,aswellasshortlyafterbirth.Ifnecessary,the

doseshouldbeadaptedtomaintainthelamotrigineserumconcentrationatthesamelevelasbeforepregnancy,or

adaptedaccordingtoclinicalresponse.Inaddition,dose-relatedundesirableeffectsshouldbemonitoredafterbirth.

Lactation

Dataindicatethatlamotriginepassesintobreastmilk.Insomebreast-fedinfants,theserumconcentrationsof

lamotriginereachedlevelsatwhichpharmacologicaleffectsmayoccur.

Thepotentialbenefitsofbreast-feedingshouldbeweighedagainstthepotentialriskofadverseeffectsoccurringinthe

infant.Shouldawomandecidetobreast-feedwhileontherapywithlamotrigine,theinfantshouldbemonitoredfor

adverseeffects.

Fertility

Animalexperimentsdidnotrevealimpairmentoffertilitybylamotrigine(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

AsthereisindividualvariationinresponsetoallAEDtherapy,patientstakinglamotriginetotreatepilepsyshould

consulttheirphysicianonthespecificissuesofdrivingandepilepsy.

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Twovolunteerstudieshave

demonstratedthattheeffectoflamotrigineonfinevisualmotorco-ordination,eyemovements,bodyswayand

subjectivesedativeeffectsdidnotdifferfromplacebo.Inclinicaltrialswithlamotrigineadversereactionsofa

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 12

Therefore,patientsshouldseehowlamotriginetherapyaffectsthembeforedrivingoroperatingmachinery.

4.8Undesirableeffects

Theundesirableeffectshavebeendividedintosectionsbasedonthedatacurrentlyavailable.

Thefollowingconventionhasbeenutilisedfortheclassificationofundesirableeffects:

Verycommon(>1/10),

Common(>1/100,<1/10),

Uncommon(>1/1000,<1/100),

Rare(>1/10,000,<1/1000),

Veryrare(<1/10,000).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Epilepsy

Bloodandlymphaticsystemdisorders

Veryrare: haematologicalabnormalitiesincludingneutropenia,leucopenia,anaemia,thrombocytopenia,

pancytopenia,aplasticanaemia,agranulocytosis.

Haematologicalabnormalitiesmayormaynotbeassociatedwiththehypersensitivitysyndrome(seeImmunesystem

disorders**).

Immunesystemdisorders

Veryrare: hypersensitivitysyndrome**(includingsuchsymptomsas,fever,lymphadenopathy,facial

oedema,abnormalitiesofthebloodandliver,disseminatedintravascularcoagulation,multi-

organfailure).

**Rashhasalsobeenreportedaspartofahypersensitivitysyndromeassociatedwithavariablepatternofsystemic

symptomsincludingfever,lymphadenopathy,facialoedemaandabnormalitiesofthebloodandliver.Thesyndrome

showsawidespectrumofclinicalseverityandmay,rarely,leadtodisseminatedintravascularcoagulationand

multiorganfailure.Itisimportanttonotethatearlymanifestationsofhypersensitivity(forexamplefever,

lymphadenopathy)maybepresenteventhoughrashisnotevident.Ifsuchsignsandsymptomsarepresent,thepatient

shouldbeevaluatedimmediatelyandlamotriginediscontinuedifanalternativeaetiologycannotbeestablished.

Psychiatricdisorders

Common: aggression,irritability.

Veryrare: confusion,hallucinations,tics.

Nervoussystemdisorders

Duringmonotherapyclinicaltrials:

Verycommon: headache.

Common: somnolence,dizziness,tremor,insomnia.

Uncommon: ataxia.

Rare: nystagmus.

Duringotherclinicalexperience:

Verycommon: somnolence,ataxia,dizziness,headache.

Common: nystagmus,tremor,insomnia.

Veryrare: agitation,unsteadiness,movementdisorders,worseningofParkinson'sdisease,extrapyramidal

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 13

Therehavebeenreportsthatlamotriginemayworsenparkinsoniansymptomsinpatientswithpre-existingParkinson’s

disease,andisolatedreportsofextrapyramidaleffectsandchoreoathetosisinpatientswithoutthisunderlyingcondition.

Eyedisorders

Duringmonotherapyclinicaltrials:

Uncommon: diplopia,blurredvision.

Duringotherclinicalexperience:

Verycommon: diplopia,blurredvision.

Rare: conjunctivitis.

Gastrointestinaldisorders

Duringmonotherapyclinicaltrials:

Common: nausea,vomiting,diarrhoea.

Duringotherclinicalexperience:

Verycommon: nausea,vomiting.

Common: diarrhoea.

Hepato-biliarydisorders

Veryrare: hepaticfailure,hepaticdysfunction,increasedliverfunctiontests.

Hepaticdysfunctionusuallyoccursinassociationwithhypersensitivityreactionsbutisolatedcaseshavebeenreported

withoutovertsignsofhypersensitivity.

Skinandsubcutaneoustissuedisorders

Verycommon: skinrash.

Rare: Stevens–JohnsonSyndrome.

Veryrare: toxicepidermalnecrolysis.

Indouble-blind,adjunctiveclinicaltrialsinadults,skinrashesoccurredinupto10%ofpatientstakinglamotrigineand

in5%ofpatientstakingplacebo.Theskinrashesledtothewithdrawaloflamotriginetreatmentin2%ofpatients.The

rash,usuallymaculopapularinappearance,generallyappearswithineightweeksofstartingtreatmentandresolveson

withdrawaloflamotrigine(seesection4.4).

Seriouspotentiallylife-threateningskinrashes,includingStevens–Johnsonsyndromeandtoxicepidermalnecrolysis

(Lyell’sSyndrome)havebeenreported.Althoughthemajorityrecoveronwithdrawaloflamotriginetreatment,some

patientsexperienceirreversiblescarringandtherehavebeenrarecasesofassociateddeath(seesection4.4).

Theoverallriskofrashappearstobestronglyassociatedwith:

highinitialdosesoflamotrigineandexceedingtherecommendeddoseescalationoflamotriginetherapy(see

section4.2)

concomitantuseofvalproate(seesection4.2).

Rashhasalsobeenreportedaspartofahypersensitivitysyndromeassociatedwithavariablepatternofsystemic

symptoms(seeImmunesystemdisorders**).

Musculoskeletalandconnectivetissuedisorders

Veryrare: lupus-likereactions.

Generaldisordersandadministrationsiteconditions

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 14

4.9Overdose

Symptomsandsigns

Acuteingestionofdosesinexcessof10to20timesthemaximumtherapeuticdosehasbeenreported.Overdosehas

resultedinsymptomsincludingnystagmus,ataxia,impairedconsciousnessandcoma.

Treatment

Intheeventofoverdosage,thepatientshouldbeadmittedtohospitalandgivenappropriatesupportivetherapy.

Therapyaimedatdecreasingabsorption(activatedcharcoal,laxativeorgastriclavage)shouldbeperformedif

indicated.Thereisnoexperiencewithhaemodialysisastreatmentofoverdose.Insixvolunteerswithkidneyfailure,

20%ofthelamotriginewasremovedfromthebodyduringa4-hourhaemodialysissession(seesection5.2).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:otherantiepileptics,

ATCcode:N03AX09.

Mechanismofaction

Theresultsofpharmacologicalstudiessuggestthatlamotrigineisause-andvoltage-dependentblockerofvoltage

gatedsodiumchannels.Itinhibitssustainedrepetitivefiringofneuronesandinhibitsreleaseofglutamate(the

neurotransmitterwhichplaysakeyroleinthegenerationofepilepticseizures).Theseeffectsarelikelytocontributeto

theanticonvulsantpropertiesoflamotrigine.

Pharmacodynamiceffects

Intestsdesignedtoevaluatethecentralnervoussystemeffectsofmedicinalproducts,theresultsobtainedusingdoses

of240mglamotrigineadministeredtohealthyvolunteersdidnotdifferfromplacebo,whereasboth1000mgphenytoin

and10mgdiazepameachsignificantlyimpairedfinevisualmotorco-ordinationandeyemovements,increasedbody

swayandproducedsubjectivesedativeeffects.

Inanotherstudy,singleoraldosesof600mgcarbamazepinesignificantlyimpairedfinevisualmotorco-ordinationand

eyemovements,whileincreasingbothbodyswayandheartrate,whereasresultswithlamotrigineatdosesof150mg

and300mgdidnotdifferfromplacebo.

Clinicalefficacyandsafetyinchildrenaged1to24months

Theefficacyandsafetyofadjunctivetherapyinpartialseizuresinpatientsaged1to24monthshasbeenevaluatedina

smalldouble-blindplacebo-controlledwithdrawalstudy.Treatmentwasinitiatedin177subjects,withadosetitration

schedulesimilartothatofchildrenaged2to12years.Lamotrigine2mgtabletsaretheloweststrengthavailable,

thereforethestandarddosingschedulewasadaptedinsomecasesduringthetitrationphase(forexample,by

administeringa2mgtabletonalternatedayswhenthecalculateddosewaslessthan2mg).Serumlevelswere

measuredattheendofweek2oftitrationandthesubsequentdoseeitherreducedornotincreasediftheconcentration

exceeded0.41µg/mL,theexpectedconcentrationinadultsatthistimepoint.Dosereductionsofupto90%were

requiredinsomepatientsattheendofweek2.Thirty-eightresponders(>40%decreaseinseizurefrequency)were

randomisedtoplaceboorcontinuationoflamotrigine.Theproportionofsubjectswithtreatmentfailurewas84%

(16/19subjects)intheplaceboarmand58%(11/19subjects)inthelamotriginearm.Thedifferencewasnot

statisticallysignificant:26.3%,CI95%-2.6%<>50.2%,p=0.07.

Atotalof256subjectsbetween1to24monthsofagehavebeenexposedtolamotrigineinthedoserange1to15

mg/kg/dayforupto72weeks.Thesafetyprofileoflamotrigineinchildrenaged1monthto2yearswassimilartothat

inolderchildrenexceptthatclinicallysignificantworseningofseizures(>=50%)wasreportedmoreofteninchildren

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 15

ClinicalefficacyandsafetyinLennox-Gastautsyndrome

TherearenodataformonotherapyinseizuresassociatedwithLennox-Gastautsyndrome.

Studyoftheeffectoflamotrigineoncardiacconduction

Astudyinhealthyadultvolunteersevaluatedtheeffectofrepeatdosesoflamotrigine(upto400mg/day)oncardiac

conduction,asassessedby12-leadECG.TherewasnoclinicallysignificanteffectoflamotrigineonQTinterval

comparedtoplacebo.

5.2Pharmacokineticproperties

Absorption

Lamotrigineisrapidlyandcompletelyabsorbedfromthegutwithnosignificantfirst-passmetabolism.Peakplasma

concentrationsoccurapproximately2.5hoursafteroraladministrationoflamotrigine.Timetomaximumconcentration

isslightlydelayedafterfoodbuttheextentofabsorptionisunaffected.Thereisconsiderableinter-individualvariation

insteadystatemaximumconcentrationsbutwithinanindividual,concentrationsrarelyvary.

Distribution

Bindingtoplasmaproteinsisabout55%;itisveryunlikelythatdisplacementfromplasmaproteinswouldresultin

toxicity.

Thevolumeofdistributionis0.92to1.22L/kg.

Metabolism

UDP-glucuronyltransferaseshavebeenidentifiedastheenzymesresponsibleformetabolismoflamotrigine.

Lamotrigineinducesitsownmetabolismtoamodestextentdependingondose.However,thereisnoevidencethat

lamotrigineaffectsthepharmacokineticsofotherAEDsanddatasuggestthatinteractionsbetweenlamotrigineand

medicinalproductsmetabolisedbycytochromeP450enzymesareunlikelytooccur.

Elimination

Theapparentplasmaclearanceinhealthysubjectsisapproximately30mL/min.Clearanceoflamotrigineisprimarily

metabolicwithsubsequenteliminationofglucuronide-conjugatedmaterialinurine.Lessthan10%isexcreted

unchangedintheurine.Onlyabout2%oflamotrigine-relatedmaterialisexcretedinfaeces.Clearanceandhalf-lifeare

independentofdose.Theapparentplasmahalf-lifeinhealthysubjectsisestimatedtobeapproximately33hours(range

14to103hours).InastudyofsubjectswithGilbert'sSyndrome,meanapparentclearancewasreducedby32%

comparedwithnormalcontrolsbutthevaluesarewithintherangeforthegeneralpopulation.

Thehalf-lifeoflamotrigineisgreatlyaffectedbyconcomitantmedicinalproducts.Meanhalf-lifeisreducedto

approximately14hourswhengivenwithglucuronidation-inducingmedicinalproductssuchascarbamazepineand

phenytoinandisincreasedtoameanofapproximately70hourswhenco-administeredwithvalproatealone(see

section4.2).

Linearity

Thepharmacokineticsoflamotriginearelinearupto450mg,thehighestsingledosetested.

Specialpatientpopulations

Children

Clearanceadjustedforbodyweightishigherinchildrenthaninadultswiththehighestvaluesinchildrenunderfive

years.Thehalf-lifeoflamotrigineisgenerallyshorterinchildrenthaninadultswithameanvalueofapproximately7

hourswhengivenwithenzyme-inducingmedicinalproductssuchascarbamazepineandphenytoinandincreasingto

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 16

Infantsaged2to26months

In143paediatricpatientsaged2to26months,weighing3to16kg,clearancewasreducedcomparedtoolderchildren

withthesamebodyweight,receivingsimilaroraldosesperkgbodyweightaschildrenolderthan2years.Themean

half-lifewasestimatedat23hoursininfantsyoungerthan26monthsonenzyme-inducingtherapy,136hourswhenco-

administeredwithvalproateand38hoursinsubjectstreatedwithoutenzymeinducers/inhibitors.Theinter-individual

variabilityfororalclearancewashighinthegroupofpaediatricpatientsof2to26months(47%).Thepredictedserum

concentrationlevelsinchildrenof2to26monthswereingeneralinthesamerangeasthoseinolderchildren,though

higherCmaxlevelsarelikelytobeobservedinsomechildrenwithabodyweightbelow10kg.

Elderly

Resultsofapopulationpharmacokineticanalysisincludingbothyoungandelderlypatientswithepilepsy,enrolledin

thesametrials,indicatedthattheclearanceoflamotriginedidnotchangetoaclinicallyrelevantextent.Aftersingle

dosesapparentclearancedecreasedby12%from35mL/minatage20to31mL/minat70years.Thedecreaseafter48

weeksoftreatmentwas10%from41to37mL/minbetweentheyoungandelderlygroups.Inaddition,

pharmacokineticsoflamotriginewasstudiedin12healthyelderlysubjectsfollowinga150mgsingledose.Themean

clearanceintheelderly(0.39mL/min/kg)lieswithintherangeofthemeanclearancevalues(0.31to0.65mL/min/kg)

obtainedinninestudieswithnon-elderlyadultsaftersingledosesof30to450mg.

Renalimpairment

Twelvevolunteerswithchronicrenalfailureandanothersixindividualsundergoinghaemodialysiswereeachgivena

single100mgdoseoflamotrigine.Meanclearanceswere0.42mL/min/kg(chronicrenalfailure),0.33mL/min/kg

(betweenhaemodialysis)and1.57mL/min/kg(duringhaemodialysis),comparedwith0.58mL/min/kginhealthy

volunteers.Meanplasmahalf-liveswere42.9hours(chronicrenalfailure),57.4hours(betweenhaemodialysis)and

13.0hours(duringhaemodialysis),comparedwith26.2hoursinhealthyvolunteers.Onaverage,approximately20%

(range=5.6to35.1)oftheamountoflamotriginepresentinthebodywaseliminatedduringa4-hourhaemodialysis

session.Forthispatientpopulation,initialdosesoflamotrigineshouldbebasedonthepatient’sconcomitantmedicinal

products;reducedmaintenancedosesmaybeeffectiveforpatientswithsignificantrenalfunctionalimpairment(see

sections4.2and4.4).

Hepaticimpairment

Asingledosepharmacokineticstudywasperformedin24subjectswithvariousdegreesofhepaticimpairmentand12

healthysubjectsascontrols.Themedianapparentclearanceoflamotriginewas0.31,0.24or0.10mL/min/kgin

patientswithGradeA,B,orC(Child-PughClassification)hepaticimpairment,respectively,comparedwith0.34

mL/min/kginthehealthycontrols.Initial,escalationandmaintenancedosesshouldgenerallybereducedinpatients

withmoderateorseverehepaticimpairment(seesection4.2).

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonstudiesofsafetypharmacology,repeateddosetoxicity,

genotoxicityandcarcinogenicpotential.

Inreproductiveanddevelopmentaltoxicitystudiesinrodentsandrabbits,noteratogeniceffectsbutreducedfoetal

weightandretardedskeletalossificationwereobserved,atexposurelevelsbeloworsimilartotheexpectedclinical

exposure.Sincehigherexposurelevelscouldnotbetestedinanimalsduetotheseverityofmaternaltoxicity,the

teratogenicpotentialoflamotriginehasnotbeencharacterisedaboveclinicalexposure.

Inrats,enhancedfoetalaswellaspost-natalmortalitywasobservedwhenlamotriginewasadministeredduringlate

gestationandthroughtheearlypost-natalperiod.Theseeffectswereobservedattheexpectedclinicalexposure.

Injuvenilerats,aneffectonlearningintheBielmazetest,aslightdelayinbalanopreputialseparationandvaginal

patencyandadecreasedpostnatalbodyweightgaininF1animalswereobservedatexposuresapproximatelytwo-times

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 17

Animalexperimentsdidnotrevealimpairmentoffertilitybylamotrigine.Lamotriginereducedfoetalfolicacidlevels

inrats.Folicaciddeficiencyisassumedtobeassociatedwithanenhancedriskofcongenitalmalformationsinanimals

aswellasinhumans.

Lamotriginecausedadose-relatedinhibitionofthehERGchanneltailcurrentinhumanembryonickidneycells.The

IC50wasapproximatelynine-timesabovethemaximumtherapeuticfreeconcentration.LamotriginedidnotcauseQT

prolongationinanimalsatexposuresuptoapproximatelytwo-timesthemaximumtherapeuticfreeconcentration.Ina

clinicalstudy,therewasnoclinicallysignificanteffectoflamotrigineonQTintervalinhealthyadultvolunteers(see

section5.1).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Cellulosemicrocrystalline

Sodiumstarchglycolate(TypeA)

Maizestarchpregelatinised

Croscarmellosesodium

Silicacolloidalanhydrous

Sodiumstearylfumarate

Saccharinsodium

ArtificialCherryFlavour(constituentsincludemodifiedfoodstarch(E1450))

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

TransparentPVC/PVdC/aluminiumblisters

TransparentPVC/PE/PVdC/aluminiumblisters

Blistersincardboardboxescontaining:28,30,42,50,56,60,90,100and200tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 18

7MARKETINGAUTHORISATIONHOLDER

ErghaHealthcareLtd.

Damastown

Mulhuddart

Dublin15

8MARKETINGAUTHORISATIONNUMBER

PA966/16/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:25thAugust2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/02/2009 CRN 2054755 page number: 19