DOXATAVIS XR

Main information

  • Trade name:
  • DOXATAVIS XR
  • Dosage:
  • 8 Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DOXATAVIS XR
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/128/001
  • Authorization date:
  • 25-11-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DoxatavisXR8mgprolongedreleasetablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolonged-releasetabletcontains8mgdoxazosin(asmesilate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasetablet.

White,round,biconvextabletswithDHembossedononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Essentialhypertension.

Symptomatictreatmentofbenignprostatichyperplasia.

4.2Posologyandmethodofadministration

Thetabletsmustbeswallowedwholewithasufficientamountofliquid.Thetabletsmustnotbechewed,devidedor

crushed.

DoxatavisXR

Themaximumrecommendeddoseis8mgdoxazosinoncedaily.

Essentialhypertension

Adultsandelderly:

Thestandarddoseis4mgdoxazosinoncedaily.Ifnecessary,thedosecanbeincreasedto8mgoncedaily.Itmaytake

uptofourweekstoachieveanoptimaleffect.

DoxatavisXR8mgcanbeusedasmonotherapyorincombinationwithanothermedicinalproduct,e.g.thiazide

diuretics,beta-adrenoceptorblockingagents,calciumantagonistsorACEinhibitors.

Symptomatictreatmentofprostatichyperplasia

Adultsandelderly:

Thestandarddoseis4mgdoxazosinoncedaily.Ifnecessary,thedosecanbeincreasedto8mgoncedaily.

Doxazosincanbeusedinbothnormotensiveandhypertensivepatientswithbenignprostatichyperplasia.Thefallin

bloodpressureinnormotensivepatientsisgenerallyinsignificant.Thepatientmustbecloselymonitoredduringthe

initialphaseofthetreatmentduetotheriskofposturalsideeffects.

Doseresponsestudieshavenotbeenperformedfordoxazosinprolonged-releasetablets,whichmeansthatanincreased

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Patientswithrenalimpairment:

Asthereisnochangeinthepharmacokineticsofdoxazosininpatientswithimpairedrenalfunction,andasthereareno

signsthatdoxazosinaggravatesexistingrenalimpairment,normaldosagecanbeusedinthesepatients.

Patientswithhepaticimpairment:

Doxazosinshouldbeadministeredwithparticularcautioninpatientswithsignsofhepaticimpairment.Asthereisno

clinicalexperienceinpatientswithseverehepaticimpairment,theuseofdoxazosinisnotrecommendedinthese

patients(seesection4.4).

Paediatricpopulation:

DoxatavisXR8mgisnotrecommendedforuseinpaediatricpatientsunder18yearsoldduetoinsufficientdataon

safetyandefficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Historyoforthostatichypotension.

Benignprostatichyperplasiaandconcomitantflowobstructionintheupperurinarytract,chronicurinarytract

infectionorbladderstones.

Historyofgastrointestinalobstruction,oesophagealobstruction,oranydegreeofdecreasedlumendiameterofthe

gastrointestinaltract.

Lactation(seesection4.6). 1

Hypotension. 2

Doxazosiniscontraindicatedasmonotherapyinpatientswithoverflowincontinenceoranuriawithorwithout

progressiverenalfailure.

4.4Specialwarningsandprecautionsforuse

Informationtobegiventothepatient:

Patientsshouldbeinformedthatdoxazosintabletsshouldbeswallowedwhole.Patientsshouldnotchew,divideor

crushthetablets.

InDoxatavisXR8mgtheactivecompoundissurroundedbyaninert,non-absorbablecoatingthatisdesignedto

controlthereleaseofthedrugoveraprolongedperiod.Aftertransitthroughthegastrointestinaltract,theempty

tabletshellisexcreted.Patientsshouldbeadvisednottobeconcernediftheyoccasionallyobservetablet-like

remainsintheirstools.

Abnormallyshorttransittimesthroughthegastrointestinaltract(e.g.followingsurgicalresection)mayresultin

incompleteabsorption.Inviewofthelonghalf-lifeofdoxazosintheclinicalsignificanceofthisisunclear.

Initiationoftherapy:

Onaccountofthealpha-blockingpropertiesofdoxazosin,patientsmayexperienceposturalhypotensionevidenced

bydizzinessandweakness,or,inrarecases,lossofconsciousness(syncope),particularlyatthecommencementof

therapy.Therefore,itisprudenttomonitorbloodpressureoninitiationoftherapytominimisethepotentialriskof

posturaleffects.Thepatientshouldbecautionedtoavoidsituationswhereinjurycouldresultshoulddizzinessor

weaknessoccuratthebeginningofdoxazosintherapy.

Forthehypertensionindicationonly

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Useinpatientswithacutecardiacconditions:

Aswithanyothervasodilatoranti-hypertensiveagentitisprudentmedicalpracticetoexercisecautionwhen

administeringdoxazosintopatientswiththefollowingacutecardiacconditions:

pulmonaryoedemaduetoaorticormitralstenosis

heartfailurewithhyperkineticcirculation

right-sidedheartfailureduetopulmonaryembolismorpericardialeffusion

leftventricularheartfailurewithlowfillingpressure.

Useinpatientswithimpairedhepaticfunction:

Aswithanyactivesubstancewhollymetabolisedbytheliver,doxazosinshouldbeadministeredwithparticular

cautiontopatientswithevidenceofimpairedhepaticfunction.Sincethereisnoclinicalexperienceinpatientswith

severehepaticimpairment,useinthesepatientsisnotrecommended.

UsewithPDE-5inhibitors:

Concomitantuseofdoxazosinwithphosphodiesterase-5-inhibitors(PDE-5inhibitors)(e.g.sildenafil,tadalafil,and

vardenafil)mayresultinsymptomatichypotensioninsomepatients.Toreducetheriskofposturalhypotension,the

patientshouldbestableonalpha-blockertherapybeforeinitiatingtreatmentwithPDE-5inhibitors.Itisalso

recommendedthatthetreatmentwithPDE-5inhibitorsbeinitiatedwiththelowestpossibledoseandthata6-hour

timeintervalfromintakeofdoxazosinberespected.Nostudieshavebeenconductedwithdoxazosinprolonged-

releaseformulations.

Useinpatientsundergoingcataractsurgery:

Duringcataractsurgeryinsomepatientsonorpreviouslytreatedwithtamsulosinithasbeenobservedthattheiris

musclehasbecomediffuseinconsistencyduringtheoperation(IFIS,“IntraoperativeFloppyIrisSyndrome”).

Isolatedreportshavealsobeennotedforotheralpha-1blockers,andthereforethepossibilityofaclasseffectcannot

beexcluded.AsIFISmayresultinincreasedcomplicationsduringthecataractoperation,currentorpastuseof

alpha-1blockersshouldbemadeknowntotheophthalmicsurgeoninadvanceofsurgery.

Doxazosincanaffectplasmareninactivityandurinaryexcretionofvanillylmandelicacid.

Thisshouldbetakenintoaccountwheninterpretinglaboratorydata.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantadministrationofdoxazosinwithPDE-5inhibitors(e.g.sildenafil,tadalafil,verdenafil)mayresultin

symptomatichypotensioninsomepatients(seesection4.4).

Most(98%)ofplasmadoxazosinisproteinbound.Invitrodatafromhumanplasmaindicatethatdoxazosinhasno

effectonproteinbindingofdigoxin,warfarin,phenytoinorindomethacin.

Inclinicaluse,conventionaldoxazosintabletshavebeenadministeredwithoutanyadversedruginteractionwith

thiazidediuretics,furosemide,beta-blockers,non-steroidalanti-inflammatorydrugs,antibiotics,oral

hypoglycaemicdrugs,uricosuricagents,andanticoagulants.However,therearenodatafromformalinteraction

studies.

Doxazosinpotentiatesthebloodpressureloweringactivityofotheralpha-blockersandotheranti-hypertensives.

Inanopen-label,randomised,placebo-controlledtrialin22healthymalevolunteers,theadministrationofasingle

1mgdoseofdoxazosinonday1ofafour-dayregimenoforalcimetidine(400mgtwicedaily)resultedina10%

increaseinmeanAUC,andnostatisticallysignificantchangesinmeanC

andmeanhalf-lifeofdoxazosin.The

10%increaseinthemeanAUCfordoxazosinwithcimetidineiswithinintersubjectvariation(27%)ofthemean

AUCfordoxazosinwithplacebo.

Non-steroidalantirheumaticdrugsoroestrogenscanreducethebloodpressureloweringeffectofdoxazosin.

Sympathomimeticscanreducethebloodpressureloweringeffectofdoxazosin;doxazosincanlowerbloodpressure

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Nostudieshavebeencarriedoutwithregardtointeractionswithagentsthatinfluencehepaticmetabolism.

4.6Fertility,pregnancyandlactation

Forthehypertensionindication:

Pregnancy

Astherearenoadequateandwellcontrolledstudiesorlimitedamountofdatafromtheuseofdoxazosinin

pregnantwomen,thesafetyofdoxazosinduringpregnancyhasnotbeenestablished.

Accordingly,duringpregnancy,doxazosinshouldbeusedonlyifthepotentialbenefitoutweighstherisk.

Althoughnoteratogeniceffectswereseeninanimaltesting,reducedfoetalsurvivalwasobservedinanimalsat

dosesequivalenttoapproximately300timesthemaximumrecommendedhumandose(seesection5.3).

Lactation

Doxazosiniscontraindicatedduringlactation(seesection4.3)asthedrugactivesubstanceaccumulatesinmilkof

lactatingratsandthereisnoinformationabouttheexcretionofdoxazosin/metabolitesintothemilkoflactating

women.

Alternatively,mothersshouldstopbreast-feedingwhentreatmentwithdoxazosinisnecessary.Adecisionmustbe

madewhethertodiscontinuebreast-feedingortodiscontinue/abstainfromDoxatavisXR8mgtherapytakinginto

accountthebenefitofbreastfeedingforthechildandthebenefitoftherapyforthewoman.

Fertility

Animalstudiesrevealedareductioninfertilityinmaleratstreatedwithdoxazosininconcentrations

(20mg/kg/day)exceedingtherecommendedhumandailydosemanytimesover(0.13mg/kg/day,i.e.8mg/day

forapersonof60kg).Thiseffectwasreversibletwoweeksafterthewithdrawalofthedrug(seesection5.3).

Therearenorecordsofanyeffectscausedbydoxazosininmalehumanfertility.

Forthebenignprostatichyperplasiaindication:

Thissectionisnotapplicable.

4.7Effectsonabilitytodriveandusemachines

Doxazosinhasminorormoderateinfluenceontheabilitytodriveandusemachines,especiallywheninitiatingtherapy.

4.8Undesirableeffects

Frequenciesusedareasfollows:

Verycommon 1/10

Common 1/100to <

1/10

Uncommon 1/1,000to <

1/100

Rare 1/10,000to <

1/1,000

Veryrare <

1/10,000

Notknown frequencycannotbeestimatedfromavailabledata

Systemorganclass Frequency UndesirableEffects

Infectionsandinfestations Common Respiratorytractinfection,urinarytractinfection

Bloodandlymphaticsystemdisorders Veryrare Leukopenia,thrombocytopenia

Immunesystemdisorders Uncommon Allergicdrugreaction

Metabolismandnutritiondisorders Uncommon Anorexia,gout,increasedappetite

Psychiatricdisorders Uncommon Anxiety,depression,insomnia

Veryrare Agitation,nervousness

Nervoussystemdisorders Common Dizziness,headache,somnolence

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4.9Overdose

Shouldoverdosageleadtohypotension,thepatientshouldbeimmediatelyplacedinasupine,headdownposition.

Othersupportivemeasuresshouldbeperformedifthoughtappropriateinindividualcases.

Toxicity:

Thereislimiteddataontheeffectofoverdoses.Syncopeoccurredinafastingadultwhohadtakendoxazosin16mg.

A13-year-oldexperiencedmoderateintoxicationfollowingamaximumdoseofdoxazosin40mg.

Symptoms:

Headache,dizziness,unconsciousness,syncope,dyspnoea,hypotension,palpitations,tachycardia,arrhythmia.Nausea,

vomiting.Possiblyhypoglycaemia,hypokalaemia.

Treatment:

Ventricleemptyingandcharcoalifrequired.Incasesofhypotension:lowertheheadposition,provideintravenous

syncope,tremor

Veryrare Posturaldizziness,paraesthesia

Eyedisorders Veryrare Blurredvision

Notknown Intraoperativefloppyirissyndrome

Earandlabyrinthdisorders Common Vertigo

Uncommon Tinnitus

Cardiacdisorders Common Palpitations,tachycardia

Uncommon Anginapectoris,myocardialinfarction

Veryrare Bradycardia,cardiacarrhythmia

Vasculardisorders Common Hypotension,posturalhypotension

Veryrare Flush

Respiratory,thoracicandmediastinal

disorders Common Bronchitis,cough,dyspnoea,rhinitis

Uncommon Epistaxis

Veryrare Bronchospasm

Gastrointestinaldisorders Common Abdominalpain,dyspepsia,drymouth,nausea

Uncommon Constipation,diarrhoea,flatulence,vomiting,

gastroenteritis

Hepatobiliarydisorders Uncommon Abnormalliverfunctiontests

Veryrare Cholestasis,hepatitis,jaundice

Skinandsubcutaneoustissuedisorders Common Pruritus

Uncommon Rash

Veryrare Alopecia,purpura,urticaria

Musculoskeletalandconnectivetissue

disorders Common BackPain,myalgia

Uncommon Arthralgia

Veryrare Musclecramps,muscleweakness

Renalandurinarydisorders Common Cystitis,urinaryincontinence

Uncommon Dysuria,haematura,increasedmictionfrequency

Veryrare Mictiondisorders,nocturia,polyuria,increased

diuresis

Reproductivesystemandbreast

disorders Uncommon Impotence

Veryrare Gynaecomastia,priapism

Unknown Retrogradeejaculation

Generaldisordersandadministrationsite

conditions Common Asthenia,chestpain,flu-likesymptoms,

peripheraloedema

Uncommon Pain,facialoedema

Veryrare Fatigue,malaise

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Sincedoxazosinishighlyproteinbound,dialysisisnotindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiadrenergicagents,peripherallyactinganddrugsusedinbenignprostatichypertrophy;

alpha-adrenoreceptorantagonists,ATCcode:C02CA04andG04CA05

TheactivesubstanceinDoxatavisXR8mgisdoxazosinandisaquinazolinederivative.Doxazosinhasavasodilator

effectthroughselectiveandcompetitiveblockingofpost-synapticalpha-1receptors.

Withoncedailydosing,clinicallysignificantreductionsinbloodpressurearepresentthroughoutthedayandfor24

hoursafterintake.

Tolerancedevelopmenthasnotbeenobservedduringlong-termtherapywithconventionaldoxazosintablets.An

increaseinplasmareninactivityandtachycardiaarerareduringmaintenancetherapy.

Doxazosinhasabeneficialeffectonbloodlipids,withamoderateincreaseofHDL/totalcholesterolratio

(approximately4-13%ofthebaselinevalue).Theclinicalsignificanceofthesefindingsremainstobeseen.

Doxazosinimprovesinsulinsensitivityinpatientswithimpairedsensitivity.Treatmentwithconventionaldoxazosin

tabletshasbeenshowntoresultintheregressionofleftventricularhypertrophy.Nostudiesinvestigatingtheeffecton

mortalityandmorbidityhavebeencompleted.

Hypertension:

Datafromtwodose-effectstudies(withatotalof630patientstreatedwithdoxazosin)haveshownthatpatientstreated

withconventionaltabletsindosagesof1mg,2mgor4mgareequallywell-controlledontreatmentwith4mg

doxazosinprolonged-releasetablets.

Interimanalysesofthestudy‘AntihypertensiveandLipidLoweringTreatmenttoPreventHeartAttack

Trial’(ALLHAT)haveshownthatpatientswithhypertensionandatleastoneotherclinicalriskfactorforcoronary

heartdisease,beingtreatedwithdoxazosin,areexposedtoadoubledriskofchronicheartfailurecomparedtopatients

treatedwithchlorthalidone.Theyalsohada25%higherriskofdevelopingclinicallysignificantcardiovascular

disorders.ThedoxazosinarmofALLHATwasdiscontinuedasaresultofthesefindings.Therewasnodifferencein

mortality.

Theseresultsaredifficulttointerpretfordifferentreasons,includingdifferencesintheeffectonsystolicbloodpressure

andthewithdrawalofdiureticsinthegrouptreatedwithdoxazosinbeforetreatmentwasstarted.Theresultshavenot

yetbeenfullyevaluated.

Benignprostatichyperplasia

Doxazosinhasbeenshowntoinhibitphenylephrine-inducedprostaticcontractionsintheprostate.Highlevelsofalpha-

1adrenoreceptorshavebeenfoundinthesmoothmuscleintheprostate,theproximalpartoftheurethraandthebaseof

theurinarybladder.Thesemediatethetonusinthesmoothmuscleintheprostaticpartoftheurethra.Blockingalpha-1

adrenoreceptorsthroughdoxazosinreducesthetonusofthemuscleintheprostaticpartoftheurethra,facilitatingthe

urinaryflow.Thisisthepharmacologicalbasisfortheclinicaluseofdoxazosininthetreatmentofbenignprostatic

hypertrophy.

Efficacyandsafetystudies(withatotalof1,317patientsbeingtreatedwithdoxazosin)haveonlybeenconductedin

patientswithabaselineofI-PSS>12andamaximumurinaryflowof<15ml/sec.Datafromthesestudiesindicatethat

patientsthatarewell-controlledonconventionaltabletsofdoxazosinindosagesof1mg,2mgor4mgareequally

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5.2Pharmacokineticproperties

Absorption/distribution

Followingoraladministrationoftherapeuticdoses,doxazosinfromprolonged-releasetabletsiswellabsorbedwith

peakbloodlevelsgraduallybeingreached8to9hoursafterdosing.Peakplasmalevelsareapproximatelyonethird

ofthelevelsachievedafterthesamedoseofaconventionaldoxazosintablet.However,troughlevelsat24hoursare

comparableforbothformulations.

Approximately98%ofdoxazosinisprotein-boundinplasma.

Biotransformation/elimination

Doxazosinisextensivelymetabolisedwith<5%excretedasunchangedproduct.Doxazosinisprimarilymetabolised

byO-demethylationandhydroxylation.

Theplasmaeliminationisbiphasicwithaterminalhalf-lifeof22hours,whichprovidesthebasisforonce-daily

dosing.

Elderly:

Pharmacokineticstudieswithdoxazosinprolonged-releasetabletsamongtheelderlyhavenotshownanysignificant

changescomparedtoyoungerpatients.

Renalimpairment:

Pharmacokineticstudieswithdoxazosininpatientswithrenalimpairmentdidnotshowanysignificantchanges

comparedtopatientswithnormalrenalfunction.

Liverimpairment:

Thereisonlylimiteddatafrompatientswithhepaticimpairmentandontheeffectsofmedicinalproductsthatare

knowntoinfluencehepaticmetabolism(e.g.cimetidine).Inaclinicalstudyoftwelvepatientswithmoderatehepatic

impairment,asingledoseofdoxazosinresultedinanincreaseinAUCof43%andadecreaseinoralclearanceof

30%.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotential,toxicitytoreproduction.

Carcinogenicity:

Chronicadministrationinthediet(for24months)ofdoxazosinatdosesuptomaximumtolerateddidnotcause

increasedincidenceoftumoursinrats.ThehighestdoseevaluatedinthisstudywasassociatedwithanAUCvalue(a

measureofsystemicexposure)around8timesthehumanAUC.Thedrugalsoshowednocarcinogenicactivityinmice.

Mutagenicity:

Invitroandinvivomutagenicitystudiesrevealednogenotoxicpotential.

Reproductivetoxicity:

Studieswithratsrevealedareductioninfertilityinmalestreatedwithdoxazosinatoraldosesof20mg/kg/day(but

notwithdosesof5or10mg/kg/day)withAUCapproximately4timesthehumanAUCreceivingdosesof12mg/

day.Thiseffectwasreversibletwoweeksafterthewithdrawalofthedrug.

Therearenorecordsofanyeffectscausedbydoxazosininmalehumanbeingfertility.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Polyethyleneoxide(MW200,000)

Polyethyleneoxide(MW900,000)

Microcrystallinecellulose

Povidone(K29-32)

Butylhydroxytoluene(E321)

all-rac--tocopherol

Colloidalanhydroussilica

Sodiumstearylfumarate

Tabletcoating

Methacrylicacid-ethylacrylatecopolymer(1:1),dispersion30%

Colloidalanhydroussilica

Macrogol1300-1600

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

5years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

PVC/PVdC/Alublister.

Packsizes:

7,10,14,15,28,30,50,56,60,98,100tablets.

Calendarpacks:7,14,28,56and98tablets.

Single-dosepack:50x1tablet.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur

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8MARKETINGAUTHORISATIONNUMBER

PA1380/128/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:09thSeptember2011

10DATEOFREVISIONOFTHETEXT

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