DETERODINE SR

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/144/001
  • Authorization date:
  • 16-03-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DeterodineSR2mgprolonged-releasecapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each2mgprolonged-releasecapsulecontains2mgoftolterodinetartrate,equivalentto1.368mgoftolterodine.

Excipientwithknowneffect:

Each2mgprolonged-releasecapsulecontainsamaximumof68.69mgofsucrose.

Forthefulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasecapsules,hard

DeterodineSR2mgprolonged-releasecapsule:greenopaquecapandgreenopaquebody,hard-shellgelatin‘size

4’capsulefilledwithwhitetooff-whitebeads.ThecapsuleisaxiallyprintedwithMYLANover3402inblackinkon

boththecapandbodyandisapproximately14.3mmlong.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomatictreatmentofurgeincontinenceand/orincreasedurinaryfrequencyandurgencyasmayoccurinpatients

withoveractivebladdersyndrome.

4.2Posologyandmethodofadministration

Posology

Adults(includingtheelderly)

Therecommendeddoseis4mgoncedailyexceptinpatientswithimpairedliverfunctionorseverelyimpairedrenal

function(GFR30ml/min)forwhomtherecommendeddoseis2mgoncedaily(seesections4.4and5.2).Incaseof

troublesomeside-effectsthedosemaybereducedfrom4mgto2mgoncedaily.

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

Paediatricpopulation

Thesafetyandefficacyoftolterodineinchildrenhavenotbeenestablished(seesection5.1).Thereforetolterodineis

notrecommendedforchildren.

Methodofadministration

Fororaluse.

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4.3Contraindications

Tolterodineiscontraindicatedinpatientswith:

Knownhypersensitivitytotolterodineortoanyoftheexcipientslistedinsection6.1

Urinaryretention

Uncontrollednarrowangleglaucoma

Myastheniagravis

Severeulcerativecolitis

Toxicmegacolon

4.4Specialwarningsandprecautionsforuse

Tolterodineshouldbeusedwithcautioninpatientswith:

Significantbladderoutletobstructionatriskofurinaryretention

Gastrointestinalobstructivedisorders,e.g.pyloricstenosis

Renalimpairment(seesections4.2and5.2)

Hepaticdisease(seesections4.2and5.2)

Autonomicneuropathy

Hiatushernia

Riskofdecreasedgastrointestinalmotility

QTprolongation

Multipleoraltotaldailydosesofimmediaterelease4mg(therapeutic)and8mg(supratherapeutic)tolterodinehave

beenshowntoprolongtheQTcinterval(seesection5.1).

Theclinicalrelevanceofthesefindingsisunclearandwilldependonindividualpatientriskfactorsandsusceptibilities

present.

TolterodineshouldbeusedwithcautioninpatientswithriskfactorsforQTprolongationincluding:

CongenitalordocumentedacquiredQTprolongation

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemia

Bradycardia

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

failure)

ConcomitantadministrationofdrugsknowntoprolongQT-intervalincludingClassIA(e.g.quinidine,

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

ThisespeciallyholdstruewhentakingpotentCYP3A4inhibitors(seesection5.1).

ConcomitanttreatmentwithpotentCYP3A4inhibitorsshouldbeavoided(seesection4.5).

Aswithalltreatmentsforsymptomsofurgencyandurgeincontinence,organicreasonsforurgeandfrequencyshould

beconsideredbeforetreatment.

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantsystemicmedicationwithpotentCYP3A4inhibitorssuchasmacrolideantibiotics(erythromycinand

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

increasedserumconcentrationsoftolterodineinpoorCYP2D6metaboliserswith(subsequent)riskofoverdosage(see

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Concomitantmedicationwithotherdrugsthatpossessantimuscarinicpropertiesmayresultinmorepronounced

therapeuticeffectandside-effects.Conversely,thetherapeuticeffectoftolterodinemaybereducedbyconcomitant

administrationofmuscariniccholinergicreceptoragonists.

Theeffectofprokineticslikemetoclopramideandcisapridemaybedecreasedbytolterodine.

Concomitanttreatmentwithfluoxetine(apotentCYP2D6inhibitor)doesnotresultinaclinicallysignificant

interactionsincetolterodineanditsCYP2D6-dependentmetabolite,5-hydroxymethyltolterodineareequipotent.

Druginteractionstudieshaveshownnointeractionswithwarfarinorcombinedoralcontraceptives(ethinyl

estradiol/levonorgestrel).

AclinicalstudyhasindicatedthattolterodineisnotametabolicinhibitorofCYP2D6,2C19,2C9,3A4or1A2.

Thereforeanincreaseofplasmalevelsofdrugsmetabolisedbytheseisoenzymesisnotexpectedwhendosedin

combinationwithtolterodine.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoftolterodineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Consequently,tolterodineisnotrecommendedduringpregnancy.

Breast-feeding

Nodataconcerningtheexcretionoftolterodineintohumanmilkareavailable.Tolterodineshouldbeavoidedduring

breast-feeding.

Fertility

Animalstudiesdonotshowaneffectoftolterodineonfertility(seesection5.3).Therearenohumandata.

4.7Effectsonabilitytodriveandusemachines

Tolterodinehasamajorinfluenceontheabilitytodriveandusemachines.Tolterodinemaycauseaccommodation

disturbancesandinfluencereactiontime.

4.8Undesirableeffects

Duetothepharmacologicaleffectoftolterodineitmaycausemildtomoderateantimuscariniceffects,likedrynessof

themouth,dyspepsiaanddryeyes.

ThetablebelowreflectsthedataobtainedwithTolterodineinclinicaltrialsandfrompostmarketingexperience.The

mostcommonlyreportedadversereactionwasdrymouth,whichoccurredin23.4%ofpatientstreatedwithandin

7.7%ofplacebo-treatedpatients.

Very

Common

(1/10) Common

(1/100and

<1/10) Uncommon

(1/1000and

<1/100) Notknown

(cannotbe

estimatedfromthe

availabledata)

Infectionsand

infestations Sinusitis

Immunesystem

disorders Hypersensitivity

nototherwise

specified Anaphylactic

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

tolterodinetherapywasinitiatedinpatientstakingcholinesteraseinhibitorsforthetreatmentofdementia.

Paediatricpopulation

IntwopaediatricphaseIIIrandomised,placebo-controlled,double-blindstudiesconductedover12weekswhereatotal

of710paediatricpatientswererecruited,theproportionofpatientswithurinarytractinfections,diarrhoeaand

abnormalbehaviourwashigherinpatientstreatedwithtolterodinethanplacebo(urinarytractinfection:tolterodine

6.8%,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

Psychiatric

disorders Nervousness Confusion,

hallucinations,

disorientation

Nervoussystem

disorders Dizziness,

somnolence,

headache Paresthesia,

memory

impairment

Eyedisorders Dryeyes,

abnormalvision

(including

abnormal

accommodation)

Earandlabyrinth

disorders Vertigo

Cardiacdisorders Palpitations,

cardiacfailure,

arrhythmia Tachycardia

Vascular

disorders Flushing

Gastrointestinal

disorders Drymouth Dyspepsia,

constipation,

abdominalpain,

flatulence,

diarrhoea Gastroesophageal

reflux,

vomiting

Skinand

subcutaneous

tissuedisorders Angioedema,

dryskin

Renaland

urinarydisorders Dysuria Urinaryretention

General

disordersand

administration

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

Mechanismofaction

Tolterodineisacompetitive,specificmuscarinicreceptorantagonistwithaselectivityfortheurinarybladderover

salivaryglandsinvivo.Oneofthetolterodinemetabolites(5-hydroxymethylderivative)exhibitsapharmacological

profilesimilartothatoftheparentcompound.Inextensivemetabolisersthismetabolitecontributessignificantlytothe

therapeuticeffect(seesection5.2).

Pharmacodynamiceffect

Effectofthetreatmentcanbeexpectedwithin4weeks.

InthePhaseIIIprogram,theprimaryendpointwasreductionofincontinenceepisodesperweekandthesecondary

endpointswerereductionofmicturitionsper24hoursandincreaseofmeanvolumevoidedpermicturition.

Clinicalefficacyandsafety

Theseparametersarepresentedinthefollowingtable.

EffectoftreatmentwithTolterodine4mgprolonged-releasecapsulesoncedailyafter12weeks,comparedwith

placebo.Absolutechangeandpercentagechangerelativetobaseline.Treatmentdifferencetolterodinetartratevs.

placebo:LeastSquaresestimatedmeanchangeand95%confidenceinterval.

*97.5%confidenceintervalaccordingtoBonferroni

After12weeksoftreatment23.8%(121/507)intheTolterodineprolonged-releasegroupand15.7%(80/508)inthe

Tolterodine

4mg

oncedaily

(n=507) Placebo

(n=508) Treatmentdifferencevs.

placebo:

Meanchangeand95%CI Statistical

significancevs.

placebo(p-value)

Numberof

incontinence

episodesperweek -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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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)

whichwasusedasanactiveinternalcontrol.Apharmacokinetic/pharmacodynamicmodelestimatedthatQTcinterval

increasesinpoormetabolisers(devoidofCYP2D6)treatedwithtolterodine2mgBIDarecomparabletothose

observedinextensivemetabolisersreceiving4mgBID.Atbothdosesoftolterodine,nosubject,irrespectiveoftheir

metabolicprofile,exceeded500msecforabsoluteQTcFor60msecforchangefrombaselinethatareconsidered

thresholdsofparticularconcern.The4mgBIDdosecorrespondstoapeakexposure(C

)ofthreetimesthat

obtainedwiththehighesttherapeuticdoseofTolterodinecapsules.

Paediatricpopulation

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,

resultingintheformationofthe5-hydroxymethylderivative,amajorpharmacologicallyequipotentmetabolite.

Theabsolutebioavailabilityoftolterodineis17%inextensivemetabolisers,themajorityofthepatients,and65%in

poormetabolisers(devoidofCYP2D6).

Distribution:Tolterodineandthe5-hydroxymethylmetabolitebindprimarilytoorosomucoid.Theunboundfractions

are3.7%and36%,respectively.Thevolumeofdistributionoftolterodineis113L.

Biotransformation:Tolterodineisextensivelymetabolisedbytheliverfollowingoraldosing.Theprimarymetabolic

routeismediatedbythepolymorphicenzymeCYP2D6andleadstotheformationofthe5 -hydroxymethylmetabolite.

Furthermetabolismleadstoformationofthe5-carboxylicacidandN -dealkylated5-carboxylicacidmetabolites,

whichaccountfor51%and29%ofthemetabolitesrecoveredintheurine,respectively.Asubset(about7%)ofthe

populationisdevoidofCYP2D6activity.Theidentifiedpathwayofmetabolismfortheseindividuals(poor

metabolisers)isdealkylationviaCYP3A4toN-dealkylatedtolterodine,whichdoesnotcontributetotheclinicaleffect.

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Thesystemicclearanceoftolterodineinextensivemetabolisersisabout30L/h.Inpoormetabolisersthereduced

clearanceleadstosignificantlyhigherserumconcentrationsoftolterodine(about7-fold)andnegligibleconcentrations

ofthe5-hydroxymethylmetaboliteareobserved.

The5-hydroxymethylmetaboliteispharmacologicallyactiveandequipotentwithtolterodine.Becauseofthe

differencesintheprotein-bindingcharacteristicsoftolterodineandthe5-hydroxymethylmetabolite,theexposure

(AUC)ofunboundtolterodineinpoormetabolisersissimilartothecombinedexposureofunboundtolterodineandthe

5-hydroxymethylmetaboliteinpatientswithCYP2D6activitygiventhesamedosageregimen.Thesafety,tolerability

andclinicalresponsearesimilarirrespectiveofphenotype.

Elimination:Theexcretionofradioactivityafteradministrationof[14C]-tolterodineisabout77%inurineand17%in

faeces.Lessthan1%ofthedoseisrecoveredasunchangeddrug,andabout4%asthe5 -hydroxymethylmetabolite.

Thecarboxylatedmetaboliteandthecorrespondingdealkylatedmetaboliteaccountforabout51%and29%ofthe

urinaryrecovery,respectively.

Linearity:Thepharmacokineticsislinearinthetherapeuticdosagerange.

Specialpopulation

Impairedliverfunction:About2-foldhigherexposureofunboundtolterodineandthe5 -hydroxymethylmetaboliteis

foundinsubjectswithlivercirrhosis(seesections4.2and4.4).

Impairedrenalfunction:Themeanexposureofunboundtolterodineandits5-hydroxymethylmetaboliteisdoubledin

patientswithsevererenalimpairment(inulinclearanceGFR30ml/min).Theplasmalevelsofothermetaboliteswere

markedly(upto12-fold)increasedinthesepatients.Theclinicalrelevanceoftheincreasedexposureofthese

metabolitesisunknown.Thereisnodatainmildtomoderaterenalimpairment(seesections4.2and4.4).

Paediatricpopulation

Theexposureoftheactivemoietypermgdoseissimilarinadultsandadolescents.Themeanexposureoftheactive

moietypermgdoseisapproximatelytwo-foldhigherinchildrenbetween5-10yearsthaninadults(Seesections4.2

and5.1).

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).Theclinicalrelevanceof

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sugarspheres(containingsucroseandmaizestarch)

Hypromellose2910(E464)

Ethylcellulose(E462)

Talc(E553b)

Capsulebody&cap

Indigocarmine(E132)

Yellowironoxide(E172)

Titaniumdioxide(E171)

Gelatin(E441)

Printingink

Shellac(E904)

Propyleneglycol(E1520)

Blackironoxide(E172)

Potassiumhydroxide

6.2Incompatibilities

Notapplicable

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Storebelow30°C.

6.5Natureandcontentsofcontainer

BeigeHDPEbottlewithbeigepolypropylene(PP)capwithpacksizeof30,100,250and500prolonged-release

capsules(securitainer).

PVC/Alblisterorperforatedunitdoseblisterpackedincardboardcartonswithpacksizeof10,14,20,28,30,60,84,

90,and100or28x1prolonged-releasecapsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedmedicinalproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtdt/aGerardLaboratories

35/36BaldoyleIndustrialEstate

GrangeRoad

Dublin13

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8MARKETINGAUTHORISATIONNUMBER

PA0577/144/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16thMarch2012

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