DOXEL

Main information

  • Trade name:
  • DOXEL Tablet Prolonged Release 4 Base Milligrams
  • Dosage:
  • 4 Base Milligrams
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DOXEL Tablet Prolonged Release 4 Base Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1124/001/001
  • Authorization date:
  • 18-11-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Doxel4mgProlongedReleaseTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontainsdoxazosin4mg(asmesilate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasetablet

White,round,biconvextabletembossedwithDLononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthetreatmentofhypertension,andmaybeusedasasoleagenttocontrolbloodpressureinhypertensive

patients.

Inpatientsinadequatelycontrolledonsingleantihypertensivetherapy,Doxel4mgProlongedReleaseTablets

maybeusedincombinationwithathiazidediuretic,beta-adrenoceptorblockingagent,calciumantagonistor

anangiotensin-convertingenzymeinhibitor.

4.2Posologyandmethodofadministration

Doxel4mgProlongedReleaseTabletscanbetakenwithorwithoutfood.Thetabletsmustbeswallowed

wholewithasufficientamountofliquid.Theprolonged-releasetabletsshouldnotbechewed,dividedor

crushed(seesection4.4“Specialwarningsandprecautionsforuse”).

Themaximumrecommendeddoseis8mgdoxazosinoncedaily.

Arterialhypertension:

Adults:Usually4mgdoxazosinoncedaily.Ifnecessary,thedosagemaybeincreasedto8mgdoxazosinonce

daily.

Elderly:Samedosageasforadults.Thedosageshouldbekeptaslowaspossibleandincrementsmadeunder

closesupervision.

Patientswithrenalimpairment:Sincethereisnochangeinpharmacokineticsinpatientswithimpairedrenal

function,andsincetherearenosignsthatdoxazosinaggravatesexistingrenalimpairment,theusualdosecan

beusedinthesepatients.

Patientswithhepaticimpairment:Seesection4.4”Specialwarningsandprecautionsforuse”.

Paediatricuse:Doxel4mgProlongedReleaseTabletsarenotrecommendedforpatientsundertheageof12

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/12/2010 CRN 2083862 page number: 1

4.3Contraindications

Doxazosiniscontraindicatedin

(1)Patientswithaknownhypersensitivitytoquinazolines(e.g.prazosin,terazosin,doxazosin),oranyoftheexcipients

(2)Patientswithahistoryoforthostatichypotension

(3)Patientswithbenignprostatichyperplasiaandconcomitantcongestionoftheupperurinarytract,chronicurinary

tractinfectionorbladderstones.

(4)Patientswithahistoryofgastro-intestinalobstruction,oesophagealobstruction,oranydegreeofdecreasedlumen

diameterofthegastro-intestinaltract

(5)Duringlactation(pleaseseesection4.6)

Doxazosiniscontraindicatedasmonotherapyinpatientswitheitheroverflowbladderoranuriawithorwithout

progressiverenalinsufficiency.

4.4Specialwarningsandprecautionsforuse

InformationtobegiventothePatient:

Patientsshouldbeinformedthatdoxazosintabletsshouldbeswallowedwhole.Patientsshouldnotchew,divideor

crushthetablets.

Abnormallyshorttransittimesthroughthegastrointestinaltract(e.g.followingsurgicalresection)couldresultin

incompleteabsorption.Inviewofthelonghalflifeofdoxazosintheclinicalsignificanceofthisisunclear.

InitiationofTherapy:

Inrelationwiththealpha-blockingpropertiesofdoxazosin,patientsmayexperienceposturalhypotensionevidencedby

dizzinessandweakness,orrarelylossofconsciousness(syncope),particularlywiththecommencementoftherapy.

Therefore,itisprudentmedicalpracticetomonitorbloodpressureoninitiationoftherapytominimisethepotentialfor

posturaleffects.Thepatientshouldbecautionedtoavoidsituationswhereinjurycouldresultshoulddizzinessor

weaknessoccurduringtheinitiationofdoxazosintherapy.

UseinPatientswithAcuteCardiacConditions:

Aswithanyothervasodilatoryanti-hypertensiveagentitisprudentmedicalpracticetoadvisecautionwhen

administeringdoxazosintopatientswiththefollowingacutecardiacconditions:

-pulmonaryoedemaduetoaorticormitralstenosis

-heartfailureathighoutput

-right-sidedheartfailureduetopulmonaryembolismorpericardialeffusion

-leftventricularheartfailurewithlowfillingpressure.

UseinHepaticallyImpairedPatients:

Aswithanydrugwhollymetabolisedbytheliver,doxazosinshouldbeadministeredwithparticularcautiontopatients

withevidenceofimpairedhepaticfunction.Sincethereisnoclinicalexperienceinpatientswithseverehepatic

impairmentuseinthesepatientsisnotrecommended.

UsewithPDE-5Inhibitors:

Concomitantuseofphosphodiesterase-5-inhibitors(e.g.sildenafil,tadalafil,andvardenafil)anddoxazosinmaylead

symptomatichypotensioninsomepatients.Inordertoreducetheriskfordevelopingposturalhypotensionthepatient

shouldbestableonthealpha-blockertherapybeforeinitiatinguseofphosphodiesterase-5-inhibitor.

UseinPatientsundergoingcataractsurgery:

The‘IntraoperativeFloppyIrisSyndrome’(IFIS,avariantofsmallpupilsyndrome)hasbeenobservedduringcataract

surgeryinsomepatientsonorpreviouslytreatedwithtamsulosin.Isolatedreportshavealsobeenreceivedwithother

alpha-1blockersandthepossibilityofaclasseffectcannotbeexcluded.AsIFISmayleadtoincreasedprocedural

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/12/2010 CRN 2083862 page number: 2

ophthalmicsurgeoninadvanceofsurgery.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantuseofphosphodiesterase-5-inhibitors(e.g.sildenafil,tadalafil,andvardenafil)anddoxazosinmayleadto

symptomatichypotensioninsomepatients(seeSection4.4).Nostudieshavebeenconductedwithdoxazosin

prolongedreleaseformulations.

Most(98%)ofplasmaDoxazosinisproteinbound.Invitrodatainhumanplasmaindicatethatdoxazosinhasnoeffect

onproteinbindingofdigoxin,warfarin,phenytoinorindomethacin.

Conventionaldoxazosinhasbeenadministeredwithoutanyadversedruginteractioninclinicalexperiencetogether

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

hypoglycaemicdrugs,uricosuricagents,andanticoagulants.However,datafromformaldrug/druginteractionstudies

arenotpresent.Doxazosinpotentiatesthebloodpressureloweringactivityofotheralpha-blockersandother

antihypertensives.

Inanopen-label,randomized,placebo-controlledtrialin22healthymalevolunteers,theadministrationofasingle1

mgdoseofdoxazosinonday1ofafour-dayregimenoforalcimetidine(400mgtwicedaily)resultedina10%

increaseinmeanAUCofdoxazosin,andnostatisticallysignificantchangesinmeanCmaxandmeanhalf-lifeof

doxazosin.The10%increaseinthemeanAUCfordoxazosinwithcimetidineiswithinintersubjectvariation(27%)of

themeanAUCfordoxazosinwithplacebo.

4.6Fertility,pregnancyandlactation

Astherearenoadequateandwellcontrolledstudiesinpregnantwomen,thesafetyofDoxel4mgProlongedRelease

Tabletsduringpregnancyhasnotyetbeenestablished.Accordingly,duringpregnancy,doxazosinshouldbeusedonly

if,thepotentialbenefitoutweighstherisk.Althoughnoteratogeniceffectswereseeninanimaltesting,reducedfoetal

survivalwasobservedinanimalsathighdoses(seeSection5.3:PreclinicalSafetyData).

Doxazosiniscontraindicatedduringlactationasthedrugaccumulatesinmilkoflactatingratsandthereisno

informationabouttheexcretionofthedrugintothemilkoflactatingwomen.

Alternatively,mothersshouldstopbreast-feedingwhentreatmentwithdoxazosinisnecessary(Pleaseseesection5.3).

4.7Effectsonabilitytodriveandusemachines

Theabilitytoengageinactivitiessuchasoperatingmachineryoroperatingamotorvehiclemaybeimpaired,

especiallywheninitiatingtherapy.

4.8Undesirableeffects

Frequenciesusedareasfollows:Verycommon 1/10,Common 1/100and <

1/10,Uncommon 1/1,000and <

1/100,Rare 1/10,000and <

1/1,000,Veryrare <

1/10,000

MedDRA

SystemOrganClass Frequency UndesirableEffects

Infectionsandinfestations Common Respiratorytractinfection,urinarytract

infection

Bloodandlymphaticsystem

disorders VeryRare Leukopenia,thrombocytopenia

ImmuneSystemDisorders Uncommon Allergicdrugreaction

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/12/2010 CRN 2083862 page number: 3

Disorders

PsychiatricDisorders Uncommon Anxiety,depression,insomnia

VeryRare Agitation,nervousness

NervousSystemDisorders Common Dizziness,headache,somnolence

Uncommon Cerebrovascularaccident,hypoesthesia,

syncope,tremor

VeryRare Dizzinesspostural,paresthesia

EyeDisorders VeryRare Blurredvision

Unknown Introperativefloppyirissyndrome(seeSection

4.4)

EarandLabyrinthDisorders Common Vertigo

Uncommon Tinnitus

CardiacDisorders Common Palpitation,tachycardia

Uncommon Anginapectoris,myocardialinfarction

VeryRare Bradycardia,cardiacarrhythmias

VascularDisorders Common Hypotension,posturalhypotension

VeryRare Flush

Respiratory,Thoracicand

MediastinalDisorders Common Bronchitis,cough,dyspnea,rhinitis

Uncommon Epistaxis

VeryRare Bronchospasm

GastrointestinalDisorders Common Abdominalpain,dyspepsia,drymouth,nausea

Uncommon Constipation,diarrhoea,flatulence,vomiting,

gastroenteritis

Unknown Tastedisturbances

HepatobiliaryDisorders Uncommon Abnormalliverfunctiontests

VeryRare Cholestasis,hepatitis,jaundice

SkinandSubcutaneousTissue

Disorders Common Pruritus

Uncommon Skinrash

VeryRare Alopecia,purpura,urticaria

MusculoskeletalandConnective

TissueDisorders Common Backpain,myalgia

Uncommon Arthralgia

VeryRare Musclecramps,muscleweakness

RenalandUrinaryDisorders Common Cystitis,urinaryincontinence

Uncommon Dysuria,hematuria,micturitionfrequency

VeryRare Micturitiondisorder,nocturia,polyuria,

increaseddiuresis

ReproductiveSystemandBreast

Disorders Uncommon Impotence

VeryRare Gynecomastia,priapism

Unknown Retrogradeejaculation

GeneralDisordersand

AdministrationSiteConditions Common Asthenia,chestpain,influenza-likesymptoms,

peripheraledema

Uncommon Pain

VeryRare Fatigue,malaise,facialoedema

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/12/2010 CRN 2083862 page number: 4

4.9Overdose

Shouldoverdosageleadtohypotension,thepatientshouldbeimmediatelyplacedinasupine,headdownposition.

Othersupportivemeasuresshouldbeperformedifthoughtappropriateinindividualcases.Sincedoxazosinisstrongly

boundtoplasmaproteinsdialysisisnotindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Alpha-adrenoceptorantagonists

ATCcode:C02CA04

Hypertension:

AdministrationofDoxel4mgProlongedReleaseTabletsinhypertensivepatientscausesaclinicallysignificant

reductioninbloodpressureasaresultofareductioninsystemicvascularresistance.Thiseffectisthoughtto

resultfromselectiveblockadeofthealpha-1-adrenoceptorslocatedinthevasculature.

Withoncedailydosing,clinicallysignificantreductionsinbloodpressurearepresentthroughoutthedayandat

24-hourspostdose.ThemajorityofpatientsarecontrolledontheinitialdoseofDoxel4mgProlongedRelease

Tablets.Inpatientswithhypertension,thedecreaseinbloodpressureduringtreatmentwithDoxel4mg

ProlongedReleaseTabletswassimilarinboththesittingandstandingposition.

PatientstreatedwithimmediatereleasedoxazosintabletsagainsthypertensioncanbetransferredtoDoxel4mg

ProlongedReleaseTabletsandthedosetitratedupwardsasneeded,whilemaintainingeffectandtolerability.

Habituationhasnotbeenobservedduringlong-termtreatmentwithdoxazosin.Increaseinplasmareninactivity

andtachycardiahaverarelybeenseenduringlong-termtreatment.

DoxazosinhasabeneficialeffectonbloodlipidswithsignificantincreaseofHDL/totalcholesterolratio(app.

4-13%ofbaselinevalues),andsignificantreductionintotalglyceridesandtotalcholesterol.

Treatmentwithdoxazosinhasbeenshowntoresultinregressionofleftventricularhypertrophy,inhibitionof

plateletaggregationaswellasenhancedcapacityoftissueplasminogen-activator.

Additionally,doxazosinimprovesinsulinsensitivityinpatientswithimpairedsensitivitytoinsulin.

Doxazosinhasshowntobefreeofmetabolicadverseeffectsandissuitablefortreatmentofpatientswith

coexistentasthma,diabetes,leftventriculardysfunctionorgout.

5.2Pharmacokineticproperties

Absorption:

Afteroraladministrationoftherapeuticdoses,doxazosininDoxel4mgProlongedReleaseTabletsiswellabsorbed

withpeakbloodlevelsgraduallyreachedat6to8hoursafterdosing.Peakplasmalevelsareapproximatelyonethirdof

thoseofthesamedoseofimmediatereleasedoxazosintablets.

Troughlevelsat24hoursare,however,similar.Thepharmacokineticpropertiesofdoxazosinin

Doxel4mgProlongedReleaseTabletsleadtoaminorvariationinplasmalevels.Peak/troughratioofDoxel4mg

ProlongedReleaseTabletsislessthanhalfthatofimmediatereleasedoxazosintablets.

Atsteady-state,therelativebioavailabilityofdoxazosinfromDoxel4mgProlongedReleaseTabletscomparedto

immediatereleaseformwas54%atthe4mgdoseand59%atthe8mgdose.

Distribution:

App.98%ofdoxazosinisprotein-boundinplasma.

Biotransformation:

Doxazosinisextensivelymetabolisedwith<5%excretedasunchangeddrug.Doxazosinis

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/12/2010 CRN 2083862 page number: 5

Elimination:

Theplasmaeliminationisbiphasicwiththeterminaleliminationhalf-lifebeing22hoursandhence

thisprovidesthebasicforoncedailydosing.

Elderly:

Pharmacokineticstudieswithdoxazosinintheelderlyhaveshownnosignificantalterations

comparedtoyoungerpatients.

Renalimpairment:

Pharmacokineticstudieswithdoxazosininpatientswithrenalimpairmentalsoshowedno

significantalterationscomparedtopatientswithnormalrenalfunction.

Liverimpairment:

Thereareonlylimiteddatainpatientswithliverimpairmentandontheeffectsofdrugsknowntoinfluence

hepaticmetabolism(e.g.cimetidine).Inaclinicalstudyin12subjectswithmoderatehepaticimpairment,single

doseadministrationofdoxazosinresultedinanincreaseofAUCof43%andadecreaseinoralclearanceofapp.

40%.Doxazosintherapyinpatientswithhepaticimpairmentshouldbeperformedwithcaution(seesection4.4.

"Specialwarningandprecautionsforuse").

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicity.Studiesinpregnantrabbitsandratsatdailydosesresultinginplasma

concentrations4and10timesthehumanexposure(CmaxandAUC),respectively,revealednoevidenceofharmtothe

foetus.Adosageregimeof82mg/kg/day(8timesthehumanexposure)wasassociatedwithreducedfoetalsurvival.

Studiesinlactatingratsgivenasingleoraldoseofradioactivedoxazosingaveanaccumulationinthebreastmilkwith

amaximumconcentrationofabout20timesgreaterthanthematernalplasmaconcentration.Radioactivitywasfound

tocrosstheplacentafollowingoraladministrationoflabelleddoxazosintopregnantrats.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

PolyethyleneOxide

Cellulose,Microcrystalline

Povidone

Butylhydroxytoluene(E321)

-Tocopherol

Silica,ColloidalAnhydrous

SodiumStearylFumarate

Tabletcoat

Methacrylicacidcopolymer(EudragitL30D-55)

Macrogol1300-1600

Titaniumdioxide(E171)

SilicaColloidalAnhydrous

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/12/2010 CRN 2083862 page number: 6

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageprecautions.

6.5Natureandcontentsofcontainer

TransparentPVC/PVDC/aluminiumblisterstrips.

Blisterpackswith:28,30,98,and100ProlongedReleaseTablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ClarendonPharmaLimited.

19KingStreet,Seagrave

Leicestershire,LE127LY

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1124/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18November2005

Dateoflastrenewal:18November2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 15/12/2010 CRN 2083862 page number: 7