DETRUSITOL SR

Main information

  • Trade name:
  • DETRUSITOL SR
  • Dosage:
  • 4 Milligram
  • Pharmaceutical form:
  • Prolonged Release Capsules
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DETRUSITOL SR
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/061/003
  • Authorization date:
  • 15-01-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1328/061/003

CaseNo:2071688

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

DetrusitolSR4mgprolonged-releasehardcapsules

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom15/01/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DetrusitolSR4mgprolonged-releasehardcapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolonged-releasecapsulecontainstolterodinetartrate4mgcorrespondingto2.74mgtolterodine.

Each4mgprolonged-releasecapsulecontainsamaximumof123.07mgofsucrose.

Forafulllistofexcipientsseesection6.1

3PHARMACEUTICALFORM

Prolonged-releasecapsule,hard

ProductImportedfromtheUK:

The4mgprolonged-releasecapsuleisbluewithwhiteprinting(symboland4).

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomatictreatmentofurgeincontinenceand/orincreasedurinaryfrequencyandurgencyasmayoccurinpatients

withoveractivebladdersyndrome.

4.2Posologyandmethodofadministration

Adults(includingtheelderly):

Therecommendeddoseis4mgoncedailyexceptinpatientswithimpairedliverfunctionorseverelyimpairedrenal

function(GFR 30ml/min)forwhomtherecommendeddoseis2mgoncedaily(seesections4.4and5.2).Incaseof

troublesomeside-effectsthedosemaybereducedfrom4mgto2mgoncedaily.

Theprolonged-releasecapsulescanbetakenwithorwithoutfoodandmustbeswallowedwhole.

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

Paediatricpatients:

EfficacyofDetrusitolSRhasnotbeendemonstratedinchildren(Seesection5.1).Therefore,DetrusitolSRisnot

recommendedforchildren.

4.3Contraindications

Tolterodineiscontraindicatedinpatientswith

Urinaryretention

Uncontrollednarrowangleglaucoma

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Knownhypersensitivitytotolterodineorexcipients

Severeulcerativecolitis

Toxicmegacolon

4.4Specialwarningsandprecautionsforuse

Tolterodineshallbeusedwithcautioninpatientswith

Significantbladderoutletobstructionatriskofurinaryretention

Gastrointestinalobstructivedisorders,e.g.pyloricstenosis

Renalimpairment(seesections4.2and5.2)

Hepaticdisease(seesections4.2and5.2)

Autonomicneuropathy

Hiatushernia

Riskofdecreasedgastrointestinalmotility

Multipleoraltotaldailydosesofimmediaterelease4mg(therapeutic)and8mg(supratherapeutic)tolterodinehave

beenshowntoprolongtheQTcinterval(seesection5.1).Theclinicalrelevanceofthesefindingsisunclearandwill

dependonindividualpatientriskfactorsandsusceptibilitiespresent.

TolterodineshouldbeusedwithcautioninpatientswithriskfactorsforQT-prolongationincluding:

CongenitalordocumentedacquiredQTprolongation

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemia

Bradycardia

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

heartfailure)

ConcomitantadministrationofdrugsknowntoprolongQT-intervalincludingClassIA(e.g.quinidine,

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

ThisespeciallyholdstruewhentakingpotentCYP3A4inhibitors(seesection5.1).Concomitanttreatmentwithpotent

CYP3A4inhibitorsshouldbeavoided(seesection4.5,Interactions).

Aswithalltreatmentsforsymptomsofurgencyandurgeincontinence,organicreasonsforurgeandfrequencyshould

beconsideredbeforetreatment.

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantsystemicmedicationwithpotentCYP3A4inhibitorssuchasmacrolideantibiotics(erythromycinand

clarithromycin),antifungalagents(e.g.ketoconazoleanditraconazole)andantiproteasesisnotrecommendeddueto

increasedserumconcentrationsoftolterodineinpoorCYP2D6metaboliserswith(subsequent)riskofoverdosage(see

section4.4).

Concomitantmedicationwithotherdrugsthatpossessantimuscarinicpropertiesmayresultinmorepronounced

therapeuticeffectandside-effects.Conversely,thetherapeuticeffectoftolterodinemaybereducedbyconcomitant

administrationofmuscariniccholinergicreceptoragonists.

Theeffectofprokineticslikemetoclopramideandcisapridemaybedecreasedbytolterodine.

Concomitanttreatmentwithfluoxetine(apotentCYP2D6inhibitor)doesnotresultinaclinicallysignificant

interactionsincetolterodineanditsCYP2D6-dependentmetabolite,5-hydroxymethyltolterodineareequipotent.

Druginteractionstudieshaveshownnointeractionswithwarfarinorcombinedoralcontraceptives(ethinyl

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AclinicalstudyhasindicatedthattolterodineisnotametabolicinhibitorofCYP2D6,2C19,2C9,3A4or1A2.

Thereforeanincreaseofplasmalevelsofdrugsmetabolisedbytheseisoenzymesisnotexpectedwhendosedin

combinationwithtolterodine.

4.6Pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoftolterodineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Consequently,DetrusitolSRisnotrecommendedduringpregnancy.

Lactation

Nodataconcerningtheexcretionoftolterodineintohumanmilkareavailable.Tolterodineshouldbeavoidedduring

lactation.

4.7Effectsonabilitytodriveandusemachines

Sincethisdrugmaycauseaccommodationdisturbancesandinfluencereactiontime,theabilitytodriveanduse

machinesmaybenegativelyaffected.

4.8Undesirableeffects

Duetothepharmacologicaleffectoftolterodineitmaycausemildtomoderateantimuscariniceffects,likedrynessof

themouth,dyspepsiaanddryeyes.

ThetablebelowreflectsthedataobtainedwithDetrusitolSRinclinicaltrialsandfrompostmarketingexperience.The

mostcommonlyreportedadversereactionwasdrymouth,whichoccurredin23.4%ofpatientstreatedwithDetrusitol

SRandin7.7%ofplacebo-treatedpatients.

VeryCommon

≥1/10) Common

≥1/100and

<1/10) Uncommon

≥1/1000and

<1/100) Notknown(cannot

beestimatedfromthe

availabledata)

Infectionsand

infestations Sinusitis

Immunesystem

disorders Hypersensitivitynot

otherwisespecified Anaphylactoid

reactions

Psychiatric

disorders Nervousness Confusion,

hallucinations,

disorientation

Nervoussystem

disorders Dizziness,

somnolence,

headache Paresthesia,

memoryimpairment

Eyedisorders Dryeyes,

abnormalvision

(including

abnormal

accomodation)

Earandlabyrinth

disorders Vertigo

Cardiacdisorders Palpitations,

cardiacfailure,

arrhythmia Tachycardia

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Casesofaggravationofsymptomsofdementia(e.g.confusion,disorientation,delusion)havebeenreportedafter

tolterodinetherapywasinitiatedinpatientstakingcholinesteraseinhibitorsforthetreatmentofdementia.

Paediatricpatients

IntwopaediatricphaseIIIrandomised,placebo-controlled,double-blindstudiesconductedover12weekswhereatotal

of710paediatricpatientswererecruited,theproportionofpatientswithurinarytractinfections,diarrhoeaand

abnormalbehaviourwashigherinpatientstreatedwithtolterodinethanplacebo(urinarytractinfection:tolterodine6.8

%,placebo3.6%;diarrhoea:tolterodine3.3%,placebo0.9%;abnormalbehaviour:tolterodine1.6%,placebo0.4%).

(Seesection5.1)

4.9Overdose

Thehighestdosegiventohumanvolunteersoftolterodinetartrateis12.8mgasasingledoseoftheimmediaterelease

formulation.Themostsevereadverseeventsobservedwereaccommodationdisturbancesandmicturitiondifficulties.

Intheeventoftolterodineoverdose,treatwithgastriclavageandgiveactivatedcharcoal.Treatsymptomsasfollows:

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

Convulsionsorpronouncedexcitation:treatwithbenzodiazepines

Respiratoryinsufficiency:treatwithartificialrespiration

Tachycardia:treatwithbeta-blockers

Urinaryretention:treatwithcatheterisation

Mydriasis:treatwithpilocarpineeyedropsand/orplacepatientindarkroom.

AnincreaseinQTintervalwasobservedatatotaldailydoseof8mgimmediatereleasetolterodine(twicethe

recommendeddailydoseoftheimmediatereleaseformulationandequivalenttothreetimesthepeakexposureofthe

prolongedreleasecapsuleformulation)administeredoverfourdays.Intheeventoftolterodineoverdose,standard

supportivemeasuresformanagingQTprolongationshouldbeadopted.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Urinaryantispasmodics

ATCcode:G04BD07

Tolterodineisacompetitive,specificmuscarinicreceptorantagonistwithaselectivityfortheurinarybladderover

salivaryglandsinvivo.Oneofthetolterodinemetabolites(5-hydroxymethylderivative)exhibitsapharmacological

profilesimilartothatoftheparentcompound.Inextensivemetabolisersthismetabolitecontributessignificantlytothe

therapeuticeffect(see5.2).

Gastrointestinal

disorders Drymouth Dyspepsia,

constipation,

abdominalpain,

flatulence,

diarrhoea Gastroesophageal

reflux,

vomiting

Skinand

subcutaneoustissue

disorders Angioedema,

dryskin

Renalandurinary

disorders Dysuria Urinaryretention

Generaldisorders

andadministration

siteconditions Fatigue,peripheral

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InthePhaseIIIprogram,theprimaryendpointwasreductionofincontinenceepisodesperweekandthesecondary

endpointswerereductionofmicturitionsper24hoursandincreaseofmeanvolumevoidedpermicturition.These

parametersarepresentedinthefollowingtable.

EffectoftreatmentwithDetrusitolSR4mgoncedailyafter12weeks,comparedwithplacebo.Absolutechangeand

percentagechangerelativetobaseline.TreatmentdifferenceDetrusitolvs.placebo:LeastSquaresestimatedmean

changeand95%confidenceinterval.

*)97.5%confidenceintervalaccordingtoBonferroni

After12weeksoftreatment23.8%(121/507)intheDetrusitolSRgroupand15.7%(80/508)intheplacebogroup

reportedthattheysubjectivelyhadnoorminimalbladderproblems.

Theeffectoftolterodinewasevaluatedinpatients,examinedwithurodynamicassessmentatbaselineand,depending

ontheurodynamicresult,theywereallocatedtoaurodynamicpositive(motorurgency)oraurodynamicnegative

(sensoryurgency)group.Withineachgroup,thepatientswererandomisedtoreceiveeithertolterodineorplacebo.The

studycouldnotprovideconvincingevidencethattolterodinehadeffectsoverplaceboinpatientswithsensoryurgency.

TheclinicaleffectsoftolterodineonQTintervalwerestudiedinECGsobtainedfromover600treatedpatients,

includingtheelderlyandpatientswithpre-existingcardiovasculardisease.ThechangesinQTintervalsdidnot

significantlydifferbetweenplaceboandtreatmentgroups.

TheeffectoftolterodineonQT-prolongationwasinvestigatedfurtherin48healthymaleandfemalevolunteersaged

18-55years.Subjectswereadministered2mgBIDand4mgBIDtolterodineastheimmediatereleaseformulations.

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

and11.8msecfortolterodinedosesof2mgBIDand4mgBIDrespectivelyand19.3msecformoxifloxacin(400mg)

whichwasusedasanactive,internalcontrol.Apharmacokinetic/pharmacodynamicmodelestimatedthatQTcinterval

increasesinpoormetabolisers(devoidofCYP2D6)treatedwithtolterodine2mgBIDarecomparabletothose

observedinextensivemetabolisersreceiving4mgBID.Atbothdosesoftolterodine,nosubject,irrespectiveoftheir

metabolicprofile,exceeded500msecforabsoluteQTcFor60msecforchangefrombaselinethatareconsidered

thresholdsofparticularconcern.The4mgBIDdosecorrespondstoapeakexposure(C

)ofthreetimesthat

obtainedwiththehighesttherapeuticdoseofDetrusitolSRcapsules.

Paediatricpatients

Efficacyinthepaediatricpopulationhasnotbeendemonstrated.Twopaediatricphase3randomised,placebo-

controlled,double-blind12weekstudieswereconductedusingtolterodineextendedreleasecapsules.Atotalof710

paediatricpatients(486ontolterodineand224onplacebo)aged5-10yearswithurinaryfrequencyandurgeurinary

incontinencewerestudied.Nosignificantdifferencebetweenthetwogroupswasobservedineitherstudywithregard

Detrusitol

SR4mg

oncedaily

(n=507) Placebo

(n=508) Treatmentdifferencevs.

placebo:Meanchange

and95%CI Statistical

significance

vs.Placebo

(p-value)

Numberof

incontinence

episodesper

week -11.8

(-54%) -6.9

(-28%) -4.8

(-7.2;-2.5)* <0.001

Numberof

micturitionsper

24hours -1.8

(-13%) -1.2

(-8%) -0.6

(-1.0;-0.2) 0.005

Meanvolume

voidedper

micturition(ml) +34(+27%) +14(+12%) +20

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5.2Pharmacokineticproperties

Pharmacokineticcharacteristicsspecificforthisformulation:Tolterodineprolonged-releasecapsulesgiveaslower

absorptionoftolterodinethantheimmediate-releasetabletsdo.Asaresult,themaximumserumconcentrationsare

observed4(2-6)hoursafteradministrationofthecapsules.Theapparenthalf-lifefortolterodinegivenasthecapsuleis

about6hoursinextensiveandabout10hoursinpoormetabolisers(devoidofCYP2D6).Steadystateconcentrations

arereachedwithin4daysafteradministrationofthecapsules.

Thereisnoeffectoffoodonthebioavailabilityofthecapsules.

Absorption:AfteroraladministrationtolterodineissubjecttoCYP2D6catalysedfirst-passmetabolismintheliver,

resultingintheformationofthe5-hydroxymethylderivative,amajorpharmacologicallyequipotentmetabolite.

Theabsolutebioavailabilityoftolterodineis17%inextensivemetabolisers,themajorityofthepatients,and65%in

poormetabolisers(devoidofCYP2D6).

Distribution:Tolterodineandthe5-hydroxymethylmetabolitebindprimarilytoorosomucoid.Theunboundfractions

are3.7%and36%,respectively.Thevolumeofdistributionoftolterodineis113l.

Elimination:Tolterodineisextensivelymetabolisedbytheliverfollowingoraldosing.Theprimarymetabolicrouteis

mediatedbythepolymorphicenzymeCYP2D6andleadstotheformationofthe5-hydroxymethylmetabolite.Further

metabolismleadstoformationofthe5-carboxylicacidandN-dealkylated5-carboxylicacidmetabolites,whichaccount

for51%and29%ofthemetabolitesrecoveredintheurine,respectively.Asubset(about7%)ofthepopulationis

devoidofCYP2D6activity.Theidentifiedpathwayofmetabolismfortheseindividuals(poormetabolisers)is

dealkylationviaCYP3A4toN-dealkylatedtolterodine,whichdoesnotcontributetotheclinicaleffect.Theremainder

ofthepopulationisreferredtoasextensivemetabolisers.Thesystemicclearanceoftolterodineinextensive

metabolisersisabout30L/h.Inpoormetabolisersthereducedclearanceleadstosignificantlyhigherserum

concentrationsoftolterodine(about7-fold)andnegligibleconcentrationsofthe5-hydroxymethylmetaboliteare

observed.

The5-hydroxymethylmetaboliteispharmacologicallyactiveandequipotentwithtolterodine.Becauseofthe

differencesintheprotein-bindingcharacteristicsoftolterodineandthe5-hydroxymethylmetabolite,theexposure

(AUC)ofunboundtolterodineinpoormetabolisersissimilartothecombinedexposureofunboundtolterodineandthe

5-hydroxymethylmetaboliteinpatientswithCYP2D6activitygiventhesamedosageregimen.Thesafety,tolerability

andclinicalresponsearesimilarirrespectiveofphenotype.

Theexcretionofradioactivityafteradministrationof [ 14

-tolterodineisabout77%inurineand17%infaeces.Less

than1%ofthedoseisrecoveredasunchangeddrug,andabout4%asthe5-hydroxymethylmetabolite.The

carboxylatedmetaboliteandthecorrespondingdealkylatedmetaboliteaccountforabout51%and29%oftheurinary

recovery,respectively.

Thepharmacokineticsislinearinthetherapeuticdosagerange.

Specificpatientgroups:

Impairedliverfunction:About2-foldhigherexposureofunboundtolterodineandthe5-hydroxymethylmetaboliteis

foundinsubjectswithlivercirrhosis(seesection4.2and4.4).

Impairedrenalfunction:Themeanexposureofunboundtolterodineandits5-hydroxymethylmetaboliteisdoubledin

patientswithsevererenalimpairment(inulinclearanceGFR 30ml/min).Theplasmalevelsofothermetaboliteswere

markedly(upto12-fold)increasedinthesepatients.Theclinicalrelevanceoftheincreasedexposureofthese

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

Paediatricpatients

Theexposureoftheactivemoietypermgdoseissimilarinadultsandadolescents.Themeanexposureoftheactive

moietypermgdoseisapproximatelytwo-foldhigherinchildrenbetween5-10yearsthaninadults(Seesections4.2

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5.3Preclinicalsafetydata

Intoxicity,genotoxicity,carcinogenicityandsafetypharmacologystudiesnoclinicallyrelevanteffectshavebeen

observedexceptthoserelatedtothepharmacologicaleffectofthedrug.

Reproductionstudieshavebeenperformedinmiceandrabbits.

Inmice,therewasnoeffectoftolterodineonfertilityorreproductivefunction.Tolterodineproducedembryodeathand

malformationsatplasmaexposures(C

orAUC)20or7timeshigherthanthoseseenintreatedhumans.

Inrabbits,nomalformativeeffectwasseen,butthestudieswereconductedat20or3timeshigherplasmaexposure

orAUC)thanthoseexpectedintreatedhumans.

Tolterodine,aswellasitsactivehumanmetabolitesprolongactionpotentialduration(90%repolarisation)incanine

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

(hERG)channels(0,5-26,1timestherapeuticlevels).IndogsprolongationoftheQTintervalhasbeenobservedafter

applicationoftolterodineanditshumanmetabolites(3,1-61,0timestherapeuticlevels).Theclinicalrelevanceofthese

findingsisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Prolongedreleasecapsulecontents:

Sugarspheres(containingsucroseandmaizestarch)

Hypromellose

SureleaseE-7-9010clear:

Ethylcellulose

MediumChainTriglycerides

Oleicacid

Prolongedreleasecapsuleshellcontents:

Gelatin

Printingink:

Shellacglaze

Titaniumdioxide,E171

Propyleneglycol

Simeticone

Colorantsintheblue4mgprolongedreleasecapsule:

Indigocarmine,E132

Titaniumdioxide,E171

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandoutercartonoftheproductas

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6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Keepcontainerintheoutercarton.

6.5Natureandcontentsofcontainer

Blisterpacksof28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4,BradfieldRoad

Ruislip

MiddlesexHA40NU

UnitedKingdom

8ParallelProductAuthorisationNumber

PPA1328/61/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15 th

January2010

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