DETRUSITOL SR

Main information

  • Trade name:
  • DETRUSITOL SR
  • Dosage:
  • 2 Milligram
  • Pharmaceutical form:
  • Capsule
  • 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:
  • PPA0465/080/004
  • Authorization date:
  • 31-03-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Detrusitol®SR2mgProlongedReleaseCapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains2mgtolterodinetartrate.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Prolongedreleasecapsule,hard

Green,two-pieceprolongedreleasecapsuleswith“2”printedononehalfandasymbolontheotherhalf.

4CLINICALPARTICULARS

4.1TherapeuticIndications

DetrusitolSRisindicatedforthetreatmentofurgeincontinenceand/orincreasedurinaryfrequencyassociatedwith

urgencyasmayoccurinpatientswithunstablebladder.

4.2Posologyandmethodofadministration

Adults(includingtheelderly):

Therecommendeddoseis4mgoncedailyexceptinpatientswithimpairedliverfunctionorseverelyimpairedrenal

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

troublesomeside-effectsthedosemaybereducedfrom4mgto2mgoncedaily.

Theprolonged-releasecapsulescanbetakenwithorwithoutfoodandmustbeswallowedwhole.

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

Children:

Safetyandeffectivenessinchildrenhavenotyetbeenestablished.ThereforeDetrusitolSRprolonged-releasecapsules

arenotrecommendedforchildren,untilmoreinformationisavailable.

4.3Contraindications

Tolterodineiscontraindicatedinpatientswith

Urinaryretention

Uncontrollednarrowangleglaucoma

Myastheniagravis

Knownhypersensitivitytotolterodineorexcipients

Severeulcerativecolitis

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4.4Specialwarningsandprecautionsforuse

Tolterodineshallbeusedwithcautioninpatientswith

Significantbladderoutletobstructionatriskofurinaryretention

Gastrointestinalobstructivedisorders,e.g.pyloricstenosis

Renalimpairment(seesections4.2and5.2)

Hepaticdisease(seesections4.2and5.2)

Autonomicneuropathy

Hiatushernia

Riskofdecreasedgastrointestinalmotility

CautionshouldbeusedinpatientswithknownriskfactorsforQT-prolongation(i.e.hypokalaemia,bradycardiaand

concurrentadministrationofdrugsknowntoprolongQTinterval)andrelevantpre-existingcardiacdiseases(i.e.

myocardialischaemia,arrhythmia,congestiveheartfailure).(Seesection5.3).

Aswithalltreatmentsforunstablebladder,organicreasonsforurgeandfrequencyshouldbeconsideredbefore

treatment.

ThecombinationoftolterodinewithstronginhibitorsofCYP3A4isnotrecommended(seeSection4.5.Interactions).

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantsystemicmedicationwithpotentCYP3A4inhibitorssuchasmacrolideantibiotics(erythromycinand

clarithromycin),antifungalagents(ketoconazoleanditraconazole)andantiproteasesisnotrecommendeddueto

increasedserumconcentrationsoftolterodineinpoorCYP2D6metaboliserswith(subsequent)riskofoverdosage(see

section4.4).Concomitantmedicationwithotherdrugsthatpossessantimuscarinicpropertiesmayresultinmore

pronouncedtherapeuticeffectandside-effects.Conversely,thetherapeuticeffectoftolterodinemaybereducedby

concomitantadministrationofmuscariniccholinergicreceptoragonists.

Theeffectofprokineticslikemetoclopramideandcisapridemaybedecreasedbytolterodine.Concomitanttreatment

withfluoxetine(apotentCYP2D6inhibitor)doesnotresultinaclinicallysignificantinteractionsincetolterodineand

itsCYP2D6-dependentmetabolite,5-hydroxymethyltolterodineareequipotent.

Druginteractionstudieshaveshownnointeractionswithwarfarinorcombinedoralcontraceptives(ethinyl

estradiol/levonorgestrel).

AclinicalstudyhasindicatedthattolterodineisnotametabolicinhibitorofCYP2D6,2C19,3A4or1A2.Thereforean

increaseofplasmalevelsofdrugsmetabolisedbytheisoenzymesystemsisunexpectedwhendosedincombination

withtolterodine.

4.6Pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoftolterodineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Consequently,DetrusitolSRisnotrecommendedduringpregnancy.

Lactation

Nodataconcerningtheexcretionoftolterodineintohumanmilkareavailable.Tolterodineshouldbeavoidedduring

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4.7Effectsonabilitytodriveandusemachines

Sincethisdrugmaycauseaccommodationdisturbancesandinfluencereactiontime,theabilitytodriveanduse

machinesmaybenegativelyaffected.

4.8Undesirableeffects

Duetothepharmacologicaleffectoftolterodineitmaycausemildtomoderateantimuscariniceffects,likedrynessof

themouth,dyspepsiaanddryeyes.

ThetablebelowreflectsthedataobtainedwithDetrusitolinclinicaltrialsandfrompostmarketingexperience.The

mostcommonlyreportedadversereactionwasdrymouth,whichoccurredin23.4%ofpatientstreatedwithDetrusitol

SRandin7.7%ofplacebo-treatedpatients.

Otheradverseeffectsreportedwiththeuseoftolterodineareanaphylactoidreactionincludingangiodema(veryrare)

Common

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

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

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

Eyedisorders Dryeyes,abnormal

vision(including

abnormal

accommodation)

Generaldisordersand

administrationsite

conditions Fatigue,headache,

chestpain Oedema,

Peripheraloedema

Gastrointestinal

disorders Dyspepsia,

constipation,abdominal

pain,flatulence,

vomiting

Immunesystem

disorders Hypersensitivitynot

otherwisespecified

Nervoussystem

disorders Dizziness,somnolence,

paresthesia

Psychiatricdisorders Nervousness Confusion Hallucinations

Renalandurinary

disorders Urinaryretention

Cardiacdisorders Tachycardia

Skinandsubcutaneous

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4.9Overdose

Thehighestdosegiventohumanvolunteersoftolterodinetartrateis12.8mgassingledoseoftheimmediaterelease

formulation.Themostsevereadverseeventsobservedwereaccommodationdisturbancesandmicturitiondifficulties.

Intheeventoftolterodineoverdose,treatwithgastriclavageandgiveactivatedcharcoal.Treatsymptomsasfollows:

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

Convulsionsorpronouncedexcitation:treatwithbenzodiazepines

Respiratoryinsufficiency:treatwithartificialrespiration

Tachycardia:treatwithbeta-blockers

Urinaryretention:treatwithcatheterisation

Mydriasis:treatwithpilocarpineeyedropsand/orplacepatientindarkroom

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.Absolutechange

andpercentagechangerelativetobaseline.TreatmentdifferenceDetrusitolvs.placebo:LeastSquares

estimatedmeanchangeand95%confidenceinterval.

(*)97.5%confidenceintervalaccordingtoBonferroni

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

DetrusitolSR4

mgoncedaily

(n=507) Placebo

(n=508) Treatment

differencevs.

placebo:Mean

changeand95%

CI Statistical

significancevs.

placebo(p-value)

Numberof

incontinence

episodesperweek -11.8

(-54%) -6.9

(-28%) -4.8

(-7.2;-2.5)* <0.001

Numberof

micturitionsper24

hours -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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Theeffectoftolterodinewasevaluatedinpatients,examinedwithurodynamicassessmentatbaselineand,depending

ontheurodynamicresult,theywereallocatedtoaurodynamicpositive(motorurgency)oraurodynamicnegative

(sensoryurgency)group.Withineachgroup,thepatientswererandomisedtoreceiveeithertolterodineorplacebo.

Thestudycouldnotprovideconvincingevidencethattolterodinehadeffectsoverplaceboinpatientswithsensory

urgency.

ClinicaleffectsoftolterodineonQTintervalwereinvestigatedinavarietyofclinicalstudies.Theclinicaltrial

informationisbasedonECGsthatwereobtainedfromover600treatedpatients,andwhichincludedtheelderlyand

patientswithpre-exisitingcardiovasculardisease.ThechangesinQTintervalsdidnotsignificantlydifferbetween

placeboandtreatmentgroups.Overall,theredoesnotappeartobeasignificantchangeinQTinterval.

5.2Pharmacokineticproperties

Pharmacokineticcharacteristicsspecificforthisformulation:

Tolterodineprolonged-releasecapsulesgiveaslowerabsorptionoftolterodinethantheimmediate-releasetabletsdo.

Asaresult,themaximumserumconcentrationsareobserved4(2-6)hoursafteradministrationofthecapsules.The

apparenthalf-lifefortolterodinegivenasthecapsuleisabout6hoursinextensiveandabout10hoursinpoor

metabolisers(devoidofCYP2D6).Steadystateconcentrationsarereachedwithin4daysafteradministrationofthe

capsules.

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,which

accountfor51%and29%ofthemetabolitesrecoveredintheurine,respectively.Asubset(about7%)ofthe

populationisdevoidofCYP2D6activity.Theidentifiedpathwayofmetabolismfortheseindividuals(poor

metabolisers)isdealkylationviaCYP3A4toN-dealkylatedtolterodine,whichdoesnotcontributetotheclinicaleffect.

Theremainderofthepopulationisreferredtoasextensivemetabolisers.Thesystemicclearanceoftolterodinein

extensivemetabolisersisabout30L/h.Inpoormetabolisersthereducedclearanceleadstosignificantlyhigherserum

concentrationsoftolterodine(about7-fold)andnegligibleconcentrationsofthe5-hydroxymethylmetaboliteare

observed.

The5-hydroxymethylmetaboliteispharmacologicallyactiveandequipotentwithtolterodine.Becauseofthe

differencesintheprotein-bindingcharacteristicsoftolterodineandthe5-hydroxymethylmetabolite,theexposure

(AUC)ofunboundtolterodineinpoormetabolisersissimilartothecombinedexposureofunboundtolterodineandthe

5-hydroxymethylmetaboliteinpatientswithCYP2D6activitygiventhesamedosageregimen.Thesafety,tolerability

andclinicalresponsearesimilarirrespectiveofphenotype.

Theexcretionofradioactivityafteradministrationof[ 14

C]-tolterodineisabout77%inurineand17%infaeces.Less

than1%ofthedoseisrecoveredasunchangeddrug,andabout4%asthe5-hydroxymethylmetabolite.The

carboxylatedmetaboliteandthecorrespondingdealkylatedmetaboliteaccountforabout51%and29%oftheurinary

recovery,respectively.

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Specificpatientgroups:

Impairedliverfunction:About2-foldhigherexposureofunboundtolterodineandthe5-hydroxymethylmetaboliteis

foundinsubjectswithlivercirrhosis(seesection4.2and4.4).Impairedrenalfunction:Themeanexposureofunbound

tolterodineandits5-hydroxymethylmetaboliteisdoubledinpatientswithsevererenalimpairment(inulinclearance

GFR>30ml/min).Theplasmalevelsofothermetabolitesweremarkedly(upto12-fold)increasedinthesepatients.

Theclinicalrelevanceoftheincreasedexposureofthesemetabolitesisunknown.Thereisnodatainmildtomoderate

renalimpairment(seesection4.2and4.4).

5.3Preclinicalsafetydata

Intoxicity,genotoxicity,carcinogenicityandsafetypharmacologystudiesnoclinicallyrelevanteffectshavebeen

observedexceptthoserelatedtothepharmacologicaleffectofthedrug.

Reproductionstudieshavebeenperformedinmiceandrabbits.

Inmice,therewasnoeffectoftolterodineonfertilityorreproductivefunction.Tolterodineproducedembryodeathand

malformationsatplasmaexposures(C

orAUC)20or7timeshigherthanthoseseenintreatedhumans.

Tolterodine,aswellasitsactivehumanmetabolitesprolongactionpotentialduration(90%repolarisation)incanine

purkinjefibres(14-75timestherapeuticlevels)andblocktheK+-currentinclonedhumaneither-a-go-gorelatedgene

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

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

findingsisunknown.Inclinicaltrials,overalltheredoesnotappeartobeasignificantchangesinQTinterval.

Inrabbitsnomalformativeeffectwasseen,butthestudieswereconductedat20or30timeshigherplasmaexposure

(CmaxorAUC)thenthoseexpectedintreatedhumans.

IndogsaslightprolongationoftheQTintervalhasbeenobservedathighconcentrationsoftolterodineoritsmain

metabolite(50-100timestherapeuticlevels).Inclinicaltrials,noQTintervalprolongationhasbeenfoundinalarge

andrepresentativepatientsampleonrecommendeddosesoftolterodinetablets.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sucrose

Maizestarch

Ethylcellulose

Mediumchaintriglycerides

Oleicacid

Hypromellose

Gelatin

Shellacglaze

Titaniumdioxide(E171)

Indigocarmine(E132)

Propyleneglycol

Yellowironoxide(E172).

6.2Incompatibilities

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6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeinoriginalpackage.

6.5Natureandcontentsofcontainer

Blisterpackof28capsulescontainedinanoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

PCOManufacturingLimited

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8ParallelProductAuthorisationNumber

PPA0465/080/004

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:31March2006

10DATEOFREVISIONOFTHETEXT

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