DETRUSITOL SR

Main information

  • Trade name:
  • DETRUSITOL SR
  • Dosage:
  • 4 Milligram
  • Pharmaceutical form:
  • Capsules Modified Release
  • 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:
  • PPA0465/080/003A
  • Authorization date:
  • 25-07-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DetrusitolSR4mgProlongedReleaseCapsules,hard.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolonged-releasecapsulecontainstolterodinetartrate4mgcorrespondingto2.74mgtolterodine.

Excipients:containssucrose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasecapsule,hard

ProductimportedfromGreece,theNetherlandsandtheUnitedKingdom:

The4mgprolonged-releasecapsuleisbluewithwhiteprinting(symboland4).

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomatictreatmentofurgeincontinenceand/orincreasedurinaryfrequencyandurgencyasmayoccurwith

patientswithoveractivebladdersyndrome.

4.2Posologyandmethodofadministration

Adults(includingtheelderly):

Therecommendeddoseis4mgoncedailyexceptinpatientswithimpairedliverfunctionorseverelyimpairedrenal

function(GFR30ml/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

Myastheniagravis

Knownhypersensitivitytotolterodineorexcipients

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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,congestiveheart

failure)

-ConcomitantadministrationofdrugsknowntoprolongQT-intervalincludingClassIA(e.g.quinidine,procainamide)

andClassIII(e.g.amiodarone,soltalol)anti-arrhythmics.

ThisespeciallyholdstruewhentakingpotentCYP3A4inhibitors(seesection5.1).Concomitanttreatmentwithpotent

CYP3A4inhibitorsshouldbeavoided(seesection4.5,Interactions).

Aswithalltreatmentsforsymptomsofurgencyandurgeincontinenceorganicreasonsforurgeandfrequencyshould

beconsideredbeforetreatment.

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantsystemicmedicationwithpotentCYP3A4inhibitorssuchasmacrolideantibiotics(erythromycin

andclarithromycin),antifungalagents(ketoconazoleanditraconazole)andantiproteasesisnotrecommendeddue

toincreasedserumconcentrationsoftolterodineinpoorCYP2D6metaboliserswith(subsequent)riskof

overdosage(seesection4.4,Specialwarningsandprecautionsforuse).

Concomitantmedicationwithotherdrugsthatpossessantimuscarinicpropertiesmayresultinmorepronounced

therapeuticeffectandside-effects.Conversely,thetherapeuticeffectoftolterodinemaybereducedby

concomitantadministrationofmuscariniccholinergicreceptoragonists.

Theeffectofprokineticslikemetoclopramideandcisapridemaybedecreasedbytolterodine.

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interactionsincetolterodineanditsCYP2D6-dependentmetabolite,5-hydroxymethyltolterodineareequipotent.

Druginteractionstudieshaveshownnointeractionswithwarfarinorcombinedoralcontraceptives(ethinyl

estradiol/levonorgestrel).

AclinicalstudyhasindicatedthattolterodineisnotametabolicinhibitorofCYP2D6,2C19,3A4or1A2.

Thereforeanincreaseofplasmalevelsofdrugsmetabolisedbytheisoenzymesystemsisunexpectedwhendosed

incombinationwithtolterodine.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoftolterodineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3,Preclinicalsafetydata).Thepotentialriskfor

humansisunknown.

Consequently,DetrusitolXLisnotrecommendedduringpregnancy.

Lactation

Nodataconcerningtheexcretionoftolterodineintohumanmilkareavailable.Tolterodineshouldbeavoidedduring

lactation.

4.7Effectsonabilitytodriveandusemachines

Sincethisdrugmaycauseaccommodationdisturbancesandinfluencereactiontime,theabilitytodriveanduse

machinesmaybenegativelyaffected.

4.8Undesirableeffects

Duetothepharmacologicaleffectoftolterodineitmaycausemildtomoderateantimuscariniceffects,likedrynessof

themouth,dyspepsiaanddryeyes.

ThetablebelowreflectsthedataobtainedwithDetrusitolinclinicaltrialsandfrompostmarketingexperience.The

mostcommonlyreportedadversereactionwasdrymouth,whichoccurredin23.4%ofpatientstreatedwithDetrusitol

XLandin7.7%ofplacebo-treatedpatients.

Common

(1/100and<1/10) Uncommon

(1/1000and

<1/100) Notknown

(cannotbeestimated

fromtheavailable

data)

Infectionsand

infestations Sinusitis

Immunesystem

disorders Hypersensitivity

nototherwise

specified Anaphylactoid

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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)

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

tolterodinetherapywasinitiatedinpatientstakingcholinesteraseinhibitorsforthetreatmentofdementia.

4.9Overdose

Thehighestdosegiventohumanvolunteersoftolterodinetartrateis12.8mgassingledoseoftheimmediaterelease

formulation.Themostsevereadverseeventsobservedwereaccommodationdisturbancesandmicturitiondifficulties.

Intheeventoftolterodineoverdose,treatwithgastriclavageandgiveactivatedcharcoal.Treatsymptomsasfollows:

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

-Convulsionsorpronouncedexcitation:treatwithbenzodiazepines

Psychiatric

disorders Nervousness Confusion,

hallucinations,

disorientation

Nervoussystem

disorders Dizziness,

somnolence,

headache Paresthesia,

memory

impairment

Eyedisorders Dryeyes,abnormal

vision(including

abnormal

accomodation)

Earandlabyrinth

disorders Vertigo

Cardiacdisorders Palpitations,

cardiacfailure,

arrhythmia Tachycardia

Vasculardisorders Flushing

Gastrointestinal

disorders 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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-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).

Effectofthetreatmentcanbeexpectedwithin4weeks.

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

Detrusitol

XL4mg

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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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(Cmax)ofthreetimesthat

obtainedwiththehighesttherapeuticdoseofDetrusitolSRcapsules.

Paediatricpatients

Efficacyinthepaediatricpopulationhasnotbeendemonstrated.Twopaediatricphase3randomised,placebo-

controlled,double-blind12weekstudieswereconductedusingtolterodineextendedreleasecapsules.Atotalof710

paediatricpatients(486ontolterodineand224onplacebo)aged5-10yearswithurinaryfrequencyandurgeurinary

incontinencewerestudied.Nosignificantdifferencebetweenthetwogroupswasobservedineitherstudywithregard

tochangefrombaselineintotalnumberofincontinenceepisodes/week.(Seesection4.8)

5.2Pharmacokineticproperties

Pharmacokineticcharacteristicsspecificforthisformulation:

Tolterodineprolonged-releasecapsulesgiveaslowerabsorptionoftolterodinethantheimmediate-releasetabletsdo.

Asaresult,themaximumserumconcentrationsareobserved4(2-6)hoursafteradministrationofthecapsules.The

apparenthalf-lifefortolterodinegivenasthecapsuleisabout6hoursinextensiveandabout10hoursinpoor

metabolisers(devoidofCYP2D6).Steadystateconcentrationsarereachedwithin4daysafteradministrationofthe

capsules.

Thereisnoeffectoffoodonthebioavailabilityofthecapsules.

Absorption:

AfteroraladministrationtolterodineissubjecttoCYP2D6catalysedfirst-passmetabolismintheliver,resultinginthe

formationofthe5-hydroxymethylderivative,amajorpharmacologicallyequipotentmetabolite.

Theabsolutebioavailabilityoftolterodineis17%inextensivemetabolisers,themajorityofthepatients,and65%in

poormetabolisers(devoidofCYP2D6).

Distribution:

Tolterodineandthe5-hydroxymethylmetabolitebindprimarilytoorosomucoid.Theunboundfractionsare3.7%and

36%,respectively.Thevolumeofdistributionoftolterodineis113L.

Elimination:

Tolterodineisextensivelymetabolisedbytheliverfollowingoraldosing.Theprimarymetabolicrouteismediatedby

thepolymorphicenzymeCYP2D6andleadstotheformationofthe5-hydroxymethylmetabolite.Furthermetabolism

leadstoformationofthe5-carboxylicacidandN-dealkylated5-carboxylicacidmetabolites,whichaccountfor51%

and29%ofthemetabolitesrecoveredintheurine,respectively.Asubset(about7%)ofthepopulationisdevoidof

CYP2D6activity.Theidentifiedpathwayofmetabolismfortheseindividuals(poormetabolisers)isdealkylationvia

CYP3A4toN-dealkylatedtolterodine,whichdoesnotcontributetotheclinicaleffect.Theremainderofthepopulation

isreferredtoasextensivemetabolisers.Thesystemicclearanceoftolterodineinextensivemetabolisersisabout30L/h.

Inpoormetabolisersthereducedclearanceleadstosignificantlyhigherserumconcentrationsoftolterodine(about7-

fold)andnegligibleconcentrationsofthe5-hydroxymethylmetaboliteareobserved.

The5-hydroxymethylmetaboliteispharmacologicallyactiveandequipotentwithtolterodine.Becauseofthe

differencesintheprotein-bindingcharacteristicsoftolterodineandthe5-hydroxymethylmetabolite,theexposure

(AUC)ofunboundtolterodineinpoormetabolisersissimilartothecombinedexposureofunboundtolterodineandthe

5-hydroxymethylmetaboliteinpatientswithCYP2D6activitygiventhesamedosageregimen.Thesafety,tolerability

andclinicalresponsearesimilarirrespectiveofphenotype.

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than1%ofthedoseisrecoveredasunchangeddrug,andabout4%asthe5-hydroxymethylmetabolite.The

carboxylatedmetaboliteandthecorrespondingdealkylatedmetaboliteaccountforabout51%and29%oftheurinary

recovery,respectively.

Thepharmacokineticsarelinearinthetherapeuticdosagerange.

Specificpatientgroups:

Impairedliverfunction:About2-foldhigherexposureofunboundtolterodineandthe5-hydroxymethylmetaboliteis

foundinsubjectswithlivercirrhosis(seesection4.2and4.4).

Impairedrenalfunction:

Themeanexposureofunboundtolterodineandits5-hydroxymethylmetaboliteisdoubledinpatientswithsevererenal

impairment(inulinclearanceGFR 30ml/min).Theplasmalevelsofothermetabolitesweremarkedly(upto12-fold)

increasedinthesepatients.Theclinicalrelevanceoftheincreasedexposureofthesemetabolitesisunknown.Thereis

nodatainmildtomoderaterenalimpairment(seesection4.2and4.4).

Paediatricpatients

Theexposureoftheactivemoietypermgdoseissimilarinadultsandadolescents.Themeanexposureoftheactive

moietypermgdoseisapproximatelytwo-foldhigherinchildrenbetween5-10yearsthaninadults(Seesections4.2

and5.1).

5.3Preclinicalsafetydata

Intoxicity,genotoxicity,carcinogenicityandsafetypharmacologystudiesnoclinicallyrelevanteffectshavebeen

observedexceptthoserelatedtothepharmacologicaleffectofthedrug.

Reproductionstudieshavebeenperformedinmiceandrabbits.

Inmice,therewasnoeffectoftolterodineonfertilityorreproductivefunction.Tolterodineproducedembryodeathand

malformationsatplasmaexposures(CmaxorAUC)20or7timeshigherthanthoseseenintreatedhumans.

Inrabbits,nomalformativeeffectwasseen,butthestudieswereconductedat20or3timeshigherplasmaexposure

(CmaxorAUC)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

Capsulecontent:

Sugarspheres(containssucroseandmaizestarch)

Ethylcellulsoe

MediumChainTriglycerides

Oleicacid

Hypromellose

Capsuleshellcontent:

Gelatin

Printingink:

Shellacglaze

TitaniumdioxideE171

Propyleneglycol

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Colourants:

TitaniumdioxideE171

IndigocarmineE132

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproduct

onthemarkedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Keeptheblisterintheoutercarton.

6.5Natureandcontentsofcontainer

Blisterpackscontaining28capsulesinanover-labelledoutercarton.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA0465/080/003

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:25July2003

Dateoflastrenewal:25July2008

10DATEOFREVISIONOFTHETEXT

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