DETRUSITOL

Main information

  • Trade name:
  • DETRUSITOL Film Coated Tablet 2 Milligram
  • Dosage:
  • 2 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DETRUSITOL Film Coated Tablet 2 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/061/002
  • Authorization date:
  • 29-09-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PPA1328/061/002

CaseNo:2034068

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrants

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Detrusitol2mgFilm-CoatedTablet

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjectto

thegeneralconditionsasmaybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/03/2007until28/09/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Detrusitol2mgFilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainstolterodinetartrate2mgcorrespondingto1.37mgtolterodine.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromtheNetherlands:

White,roundandbiconvex,tabletisengravedwitharcsaboveandbelowthelettersDT

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomatictreatmentofurgeincontinenceand/orincreasedurinaryfrequencyandurgencyasmayoccurinpatients

withoveractivebladdersyndrome.

4.2Posologyandmethodofadministration

Adults(includingtheelderly):

Therecommendeddoseis2mgtwicedailyexceptinpatientswithimpairedliverfunctionorseverely

impairedrenalfunction(GFR ≤

30ml/min)forwhomtherecommendeddoseis1mgtwicedaily(see

section4.4).Incaseoftroublesomesideeffectsthedosemaybereducedfrom2mgto1mgtwice

daily.

Theeffectoftreatmentshouldbere-evaluatedafter2-3months(seesection5.1).

Children:

Safetyandeffectivenessinchildrenhavenotyetbeenestablished.ThereforeDetrusitolisnotrecommendedfor

children,untilmoreinformationisavailable.

4.3Contraindications

Tolterodineiscontra-indicatedinpatientswith:

urinaryretention

uncontrollednarrowangleglaucoma

myastheniagravis

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Severeulcerativecolitis

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4.4Specialwarningsandprecautionsforuse

Tolterodineshallbeusedwithcautioninpatientswith:

significantbladderoutletobstructionatriskofurinaryretention

gastrointestinalobstructivedisorderse.g.pyloricstenosis

renalimpairment(seesection4.2)

hepaticdisease.(seesection4.2and5.2)

autonomicneuropathy

hiatushernia

riskfordecreasedgastrointestinalmotility

Multipleoraltotaldailydosesofimmediaterelease4mg(therapeutic)and8mg(supratherapeutic)

tolterodinehavebeenshowntoprolongtheQTcinterval(seesection5.1).Theclinicalrelevanceof

thesefindingsisunclearandwilldependonindividualpatientriskfactorsandsusceptibilitiespresent.

TolterodineshouldbeusedwithcautioninpatientswithriskfactorsforQT-prolongationincluding:

CongenitalordocumentedacquiredQTprolongation

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemia

Bradycardia

Relevantpre-existingcardiacdiseases(i.e.cardiomyopathy,myocardialischaemia,arrhythmia,

congestiveheartfailure)

ConcomitantadministrationofdrugsknowtoprolongQT-intervalincludingClassIA(e.g.

quinidine,procainamide)andClassIII(e.g.amiodarone,sotalol)anti-arrhythmics.

ThisespeciallyholdstruewhentakingpotentCYP3A4inhibitors(seesection5.1).Concomitant

treatmentwithpotentCYP3A4inhibitorsshouldbeavoided(seesection4.5,Interactions).

Aswithalltreatmentsforsymptomsofurgencyandurgeincontinence,organicreasonsforurgeandfrequencyshould

beconsideredbeforetreatment.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantsystemicmedicationwithpotentCYP3A4inhibitorssuchasmacrolideantibiotics(e.g.

erythromycinandclarithromycin),antifungalagents(e.g.ketoconazoleanditraconazole)and

antiproteasesisnotrecommendedduetoincreasedserumconcentrationsoftolterodineinpoor

CYP2D6metaboliserswith(subsequent)riskofoverdosage(seesection4.4).

Concomitantmedicationwithotherdrugsthatpossessantimuscarinicpropertiesmayresultinmore

pronouncedtherapeuticeffectandside-effects.Conversely,thetherapeuticeffectoftolterodinemay

bereducedbyconcomitantadministrationofmuscariniccholinergicreceptoragonists.

Theeffectsofprokineticslikemetoclopramideandcisapridemaybedecreasedbytolterodine.

Concomitanttreatmentwithfluoxetine(apotentCYP2D6inhibitor)doesnotresultinaclinically

significantinteractionsincetolterodineanditsCYP2D6-dependentmetabolite,5-hydroxymethyl

tolterodineareequipotent.

Druginteractionstudieshaveshownnointeractionswithwarfarinorcombinedoralcontraceptives

(ethinylestradiol/levonorgestrel).

AclinicalstudyhasindicatedthattolterodineisnotametabolicinhibitorofCYP2D6,2C19,3A4or1A2.Thereforean

increaseofplasmalevelsofdrugsmetabolisedbytheisoenzymesystemsisnotexpectedwhendosedincombination

withtolterodine.

4.6Pregnancyandlactation

Pregnancy

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Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansis

unknown.

Consequently,Detrusitolisnotrecommendedduringpregnancy.

Lactation

Nodataconcerningtheexcretionoftolterodineintohumanmilkareavailable.Tolterodineshouldbeavoidedduring

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4.7Effectsonabilitytodriveandusemachines

Sincethisdrugmaycauseaccommodationdisturbancesandinfluencereactiontime,theabilitytodriveanduse

machinesmaybenegativelyaffected.

4.8Undesirableeffects

Duetothepharmacologicaleffectoftolterodineitmaycausemildtomoderateantimuscariniceffects,

likedrynessofthemouth,dyspepsiaanddryeyes.

ThetablebelowreflectsthedataobtainedwithDetrusitolinclinicaltrialsandfrompostmarketing

experience.Themostcommonlyreportedadversereactionwasdrymouth,whichoccurredin35%of

patientstreatedwithDetrusitoltabletsandin10%ofplacebotreatedpatients.

Otheradverseeffectsreportedwiththeuseoftolterodineareanaphylactoidreactionsincluding

angioedema(veryrare)andcardiacfailure(veryrare).

Common>1/100,<

1/10 Uncommon

>1/1000,<1/100 Rare

>1/10000,

<1/1000

Immunesystem

disorders Hypersensitivity

nototherwise

specified

Psychiatricdisorders Nervousness Confusion Hallucinations

Nervoussystem

disorders Dizziness,somnolence,

paresthesia

Eyedisorders Dryeyes,abnormal

visionincluding

abnormalaccomodation

Cardiacdisorders Tachycardia

Gastrointestinal

disorders Dyspepsia,

constipation,abdominal

pain,flatulence,

vomiting

Skinand

subcutaneoustissue

disorders Dryskin

Renalandurinary

disorders Urinaryretention

Generaldisorders Fatigue,Headache,

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4.9Overdose

ThehighestdosegiventohumanvolunteersoftolterodineLtartrateis12.8mgassingledose.The

mostsevereadverseeventsobservedwereaccommodationdisturbancesandmicturitiondifficulties.

Intheeventoftolterodineoverdose,treatwithgastriclavageandgiveactivatedcharcoal.Treat

symptomsasfollows:

Severecentralanticholinergiceffects(e.g.hallucinations,severeexcitation):treatwith

physostigmine.

Convulsionsorpronouncedexcitation:treatwithbenzodiazepines.

Respiratoryinsufficiency:treatwithartificialrespiration.

Tachycardia:treatwithbeta-blockers.

Urinaryretention:treatedwithcatheterization.

Mydriasis:treatwithpilocarpineeyedropsand/orplacepatientindarkroom

AnincreaseinQTintervalwasobservedatatotaldailydoseof8mgimmediatereleasetolterodine(twicethe

recommendeddailydoseoftheimmediatereleaseformulationandequivalenttothreetimesthepeakexposureofthe

prolongedreleasecapsuleformulation)administeredoverfourdays.Intheeventoftolterodineoverdose,standard

supportivemeasuresformanagingQTprolongationshouldbeadopted.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Urinaryantispasmodics/

ATCcode:G04BD07

Tolterodineisacompetitive,specificmuscarinicreceptorantagonistwithaselectivityfortheurinary

bladderoversalivaryglandsinvivo.Oneofthetolterodinemetabolites(5-hydroxymethylderivative)

exhibitsapharmacologicalprofilesimilartothatoftheparentcompound.Inextensivemetabolisers

thismetabolitecontributessignificantlytothetherapeuticeffect(seeSection5.2).

Effectofthetreatmentcanbeexpectedwithin4weeks.

EffectoftreatmentwithDetrusitol2mgtwicedailyafter4and12weeks,respectively,

comparedwithplacebo(pooleddata).Absolutechangeandpercentagechangerelativeto

baseline.

Variable 4-weekstudies 12-weekstudies

Detrusitol

2mg

b.i.d. PlaceboStatistical

significance

placebo Detrusitol

2mg

b.i.d. PlaceboStatistical

significance

placebo

Numberof

micturitions

per24hours -1.6

(-14%)

n=392 -0.9

(-8%)

n=189 * -2.3

(-20%)

n=354 -1.4

(-12%)

n=176 **

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n.s.=notsignificant;*=p ≤

0.05;**=p ≤

0.01;***=p ≤

0.001

Theeffectoftolterodinewasevaluatedinpatients,examinedwithurodynamicassessmentatbaseline

and,dependingontheurodynamicresult,theywereallocatedtoaurodynamicpositive(motor

urgency)oraurodynamicnegative(sensoryurgency)group.Withineachgroup,thepatientswere

randomisedtoreceiveeithertolterodineorplacebo.Thestudycouldnotprovideconvincingevidence

thattolterodinehadeffectsoverplaceboinpatientswithsensoryurgency.

TheclinicaleffectsoftolterodineonQTintervalwerestudiedinECGsobtainedfromover600treated

patients,includingtheelderlyandpatientswithpre-existingcardiovasculardisease.Thechangesin

QTintervalsdidnotsignificantlydifferbetweenplaceboandtreatmentgroups.

TheeffectoftolterodineonQT-prolongationwasinvestigatedfurtherin48healthymaleandfemalevolunteersaged

18–55years.Subjectswereadministered2mgBIDand4mgBIDtolterodineastheimmediatereleaseformulations.

Theresults(Fridericiacorrected)atpeaktolterodineconcentration(1hour)showedmeanQTcintervalincreasesof5.0

and11.8msecfortolterodinedosesof2mgBIDand4mgBIDrespectivelyand19.8msecformoxifloxacin(400mg)

whichwasusedasanactive,internalcontrol.Apharmacokinetic/pharmacodynamicmodelestimatedthatQTcinterval

increasesinpoormetabolisers(devoidofCYP2D6)treatedwithtolterodine2mgBIDarecomparabletothose

observedinextensivemetabolisersreceiving4mgBID.Atbothdosesoftolterodine,nosubject,irrespectiveoftheir

metabolicprofile,exceeded500msecforabsoluteQTcFor60msecforchangefrombaselinethatareconsidered

thresholdsofparticularconcern.The4mgBIDdosecorrespondstoapeakexposure(C

)ofthreetimesthat

obtainedwiththehighesttherapeuticdoseofDetrusitolSRcapsules.

5.2Pharmacokineticproperties

Pharmacokineticcharacteristicsspecificforthisformulation:Tolterodineisrapidlyabsorbed.Both

tolterodineandthe5-hydroxymethylmetabolitereachmaximalserumconcentrations1-3hoursafter

dose.

Thehalf-lifefortolterodinegivenasthetabletis2-3hoursinextensiveandabout10hoursinpoor

metabolisers(devoidofCYP2D6).Steadystateconcentrationsarereachedwithin2daysafter

administrationofthetablets.

Fooddoesnotinfluencetheexposuretotheunboundtolterodineandtheactive5-hydroxymethyl

metaboliteinextensivemetabolisers,althoughthetolterodinelevelsincreasewhentakenwithfood.

Clinicallyrelevantchangesarelikewisenotexpectedinpoormetabolisers.

Absorption:AfteroraladministrationtolterodineissubjecttoCYP2D6catalysedfirst-pass

metabolismintheliver,resultingintheformationofthe5-hydroxymethylderivative,amajor

pharmacologicallyequipotentmetabolite.

incontinence

episodesper24

hours (-38%)

n=288 (-26%)

n=151 (-47%)

n=299 (-32%)

n=145

Meanvolumevoided

permicturition(ml) +25

(+17%)

n=385 +12

(+8%)

n=185 *** +35

(+22%)

n=354 +10

(+6%)

n=176 ***

Numberofpatients

withnoorminimal

bladderproblems

aftertreatment(%) 16%

n=394 7%

n=190 ** 19%

n=356 15%

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patients,and65%inpoormetabolisers(devoidofCYP2D6).

Distribution:Tolterodineandthe5-hydroxymethylmetabolitebindprimarilytoorosomucoid.The

unboundfractionsare3.7%and36%,respectively.Thevolumeofdistributionoftolterodineis113L.

Elimination:Tolterodineisextensivelymetabolisedbytheliverfollowingoraldosing.Theprimary

metabolicrouteismediatedbythepolymorphicenzymeCYP2D6andleadstotheformationofthe5-

hydroxymethylmetabolite.Furthermetabolismleadstoformationofthe5-carboxylicacidandN-

dealkylated5-carboxylicacidmetabolites,whichaccountfor51%and29%ofthemetabolites

recoveredintheurine,respectively.Asubset(about7%)ofthepopulationisdevoidofCYP2D6

activity.Theidentifiedpathwayofmetabolismfortheseindividuals(poormetabolisers)is

dealkylationviaCYP3A4toN-dealkylatedtolterodine,whichdoesnotcontributetotheclinical

effect.Theremainderofthepopulationisreferredtoasextensivemetabolisers.Thesystemic

clearanceoftolterodineinextensivemetabolisersisabout30L/h.Inpoormetabolisersthereduced

clearanceleadstosignificantlyhigherserumconcentrationsoftolterodine(about7-fold)and

negligibleconcentrationsofthe5-hydroxymethylmetaboliteareobserved.

The5-hydroxymethylmetaboliteispharmacologicallyactiveandequipotentwithtolterodine.Because

ofthedifferencesintheprotein-bindingcharacteristicsoftolterodineandthe5-hydroxymethyl

metabolite,theexposure(AUC)ofunboundtolterodineinpoormetabolisersissimilartothe

combinedexposureofunboundtolterodineandthe5-hydroxymethylmetaboliteinpatientswith

CYP2D6activitygiventhesamedosageregimen.Thesafety,tolerabilityandclinicalresponseare

similarirrespectiveofphenotype.

Theexcretionofradioactivityafteradministrationof[ 14

C]-tolterodineisabout77%inurineand17%

infaeces.Lessthan1%ofthedoseisrecoveredasunchangeddrug,andabout4%asthe5-

hydroxymethylmetabolite.Thecarboxylatedmetaboliteandthecorrespondingdealkylatedmetabolite

accountforabout51%and29%oftheurinaryrecovery,respectively.

Thepharmacokineticsislinearinthetherapeuticdosagerange.

Specificpatientgroups:

Impairedliverfunction:About2-foldhigherexposureofunboundtolterodineandthe5-

hydroxymethylmetaboliteisfoundinsubjectswithlivercirrhosis(seesection4.2and4.4).

Impairedrenalfunction:Themeanexposureofunboundtolterodineandits5-hydroxymethylmetaboliteisdoubledin

patientswithsevererenalimpairment(inulinclearanceGFR ≤30ml/min).Theplasmalevelsofothermetaboliteswere

markedly(upto12-fold)increasedinthesepatients.Theclinicalrelevanceoftheincreasedexposureofthese

metabolitesisunknown.Thereisnodatainmildtomoderaterenalimpairment(seesection4.2and4.4).

5.3Preclinicalsafetydata

Intoxicity,genotoxicity,carcinogenicityandsafetypharmacologystudiesnoclinicallyrelevant

effectshavebeenobserved,exceptthoserelatedtothepharmacologicaleffectofthedrug.

Reproductionstudieshavebeenperformedinmiceandrabbits.

Inmice,therewasnoeffectoftolterodineonfertilityorreproductivefunction.Tolterodineproduced

embryodeathandmalformationsatplasmaexposures(C

orAUC)20or7timeshigherthanthose

seenintreatedhumans.

Inrabbits,nomalformativeeffectwasseen,butthestudieswereconductedat20or3timeshigher

plasmaexposure(C

orAUC)thanthoseexpectedintreatedhumans.

Tolterodine,aswellasitsactivehumanmetabolitesprolongactionpotentialduration(90%repolarisation)incanine

purkinjefibres(14–75timestherapeuticlevels)andblocktheK+-currentinclonedhumanether-a-go-go-relatedgene

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applicationoftolterodineanditshumanmetabolites(3,1–61,0timestherapeuticlevels).Theclinicalrelevanceof

thesefindingsisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Cellulose,microcrystalline

Calciumhydrogenphosphatedihydrate

Sodiumstarchglycollate(typeB)

Magnesiumstearate

Colloidalanhydroussilica

Hypromellose

Cellulose,microcrystalline

Stearicacid

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageof

theproductonthemarketinthecountryoforigin .

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage.

6.5Natureandcontentsofcontainer

PVC/PVDCandaluminiumfoilwithaheatsealcoatingofPVDC.Tabletscomeinblisterpacksof56

(4x14tablets).

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerials

derivedfromsuchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

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8ParallelProductAuthorisationNumber

PPA1328/61/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:29thSeptember2006

10DATEOFREVISIONOFTHETEXT

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