ATRIDOX

Main information

  • Trade name:
  • ATRIDOX Powder and solvent for gingival gel 44 Milligram
  • Dosage:
  • 44 Milligram
  • Pharmaceutical form:
  • Powder and solvent for gingival gel
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATRIDOX Powder and solvent for gingival gel 44 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1501/001/001
  • Authorization date:
  • 08-08-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atridox44mgpowderandsolventforgingivalgel,pre-filledsyringes

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachpre-filledsyringeBcontainsdoxycyclinehyclateequivalentto44mgdoxycycline.

Afterreconstitution:502mgofgelcontains44mgdoxycycline(8.8%w/w)asdoxycyclinehyclate.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Powderandsolventforgingivalgel.

SyringeAandSyringeB:SyringeAcontainsacolourlessgel.SyringeBcontainsayellowpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Foruseinadultswithchronicperiodontitisatsiteswithprobingdepthsof>5mm,asanadjuncttoconventionalnon-

surgicalmanagementofperiodontaldisease.

4.2Posologyandmethodofadministration

Gingivaluse.

Atridoxisintendedforadultsandtheelderly.

Atridoxisnotindicatedforuseinchildrenandadolescentsto18yearsofage.

Atridoxshouldonlybeadministeredbydentalcareprofessionals.

Thefinalblendedproductis502mgofformulationcontaining44mgofdoxycycline(8.8%w/wdoxycycline)andis

sufficientmaterialtotreatuptosixteensiteswithpocketdepthsaveraging6mm.

Atridoxisavariabledoseproductdependentonsize,shapeandnumberofpocketsbeingtreated.Atridoxisintended

forimmediateuseandforuseinonlyonepatient.Detailedinstructionsonadministeringtheproductarecontainedin

section6.6.Instructionsforuseandhandling.

Followingplacementviaasyringe,ifnecessaryAtridoxispackedintothepocketwithadentalinstrumentuntilthe

pocketiscompletelyfilledwithcoagulatedmaterial.

Mechanicaloralhygieneproceduresotherthanbrushingtheocclusalsurfacesofthedentitionandthetongueshouldbe

avoidedonallareastreatedwithAtridoxforthefirst7daysaftertreatment.

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4.3Contraindications

Atridoxiscontraindicatedin:

Hypersensitivitytodoxycyclinehyclateandanyactivesubstanceinthetetracyclineclassortoanyoftheexcipients.

Toothdevelopment.

Pregnancyandlactation.

Patientsonwhomprophylacticantibioticsaretobeadministeredpriortoperiodontaltreatment.

Patientsatriskofacuteporphyria.

Patientswithseverehepaticimpairment.

Childrenandadolescentsto18yearsofage.

4.4Specialwarningsandprecautionsforuse

Warnings

Tetracyclinesasaclassareassociatedwithphotosensitivityandmaygiveanexaggeratedsunburnreaction.Treatment

shouldbediscontinuedatthefirstsignofcutaneouserythema.

DatafromclinicaltrialshavenotestablishedtheuseofAtridoxin:

Patientswithcompromisedheartconditionsrequiringsubacutebacterialendocarditis(SBE)prophylaxis.

Patientswithahistoryofrheumaticfever.

PatientswhoareHIVpositiveand/orwithAIDS.

Patientstakingmedicationsthatcouldcausegingivalhyperplasia(e.g.phenytoin,cyclosporine,etc.)withinone

monthofstartinginitialtherapy.

Immunocompromised patients such as those receiving cancer therapy and/or radiation therapy,

immunosuppressivetherapyandrheumaticpatientsreceivinganti-rheumatictherapye.g.corticosteroidsandnon-

steroidalanti-inflammatorydrugs.

Precautionsforuse

Doxycyclinecompoundsshouldbeadministeredwithcautiontopatientswithhepaticimpairments.

Inpatientswithrenalfailure,tetracyclinesmayaccumulatewhichmayresultinhepato-toxicity.Theseeffectsare

unlikelytooccurwithAtridoxinviewofthelowplasmaconcentrationsofdoxycycline.

Inpatientswithahistoryofcandidiasis,doxycyclinemayincreasethepotentialfororalcandidiasis.

Aswithotherantibioticpreparations,useofthisdrugmayresultinovergrowthofnonsusceptibleorganisms,including

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ThesystemicexposureofdoxycyclineafteradministrationofAtridoxisverylow.Systemicinteractionsareunlikelyto

occurinviewofthelowplasmaconcentrationsofdoxycycline(<0.1µg/ml,seesection5.2.).

Incaseofcombinationoforallyadministereddoxycyclinewithretinoids,intracranialhypertensionmayoccur.The

combinationshouldthereforebeavoided.

Becausethetetracyclineshavebeenshowntodepressplasmaprothrombinactivity,patientswhoareonanticoagulant

therapymayrequiredownwardadjustmentoftheiranticoagulantdosage.Althoughtheseeffectsareunlikelytooccur

withAtridoxbecauseoflowplasmaconcentrationsofdoxycycline,cautionshouldbeexercised.

4.6Fertility,pregnancyandlactation

Resultsofanimalstudiesindicatethattetracyclinescrosstheplacenta,arefoundinfoetaltissuesandcanhavetoxic

effectsonthedevelopingfoetus(oftenrelatedtoretardationofskeletaldevelopment).Evidenceofembryotoxicityhas

alsobeennotedinanimalstreatedearlyinpregnancy.Theuseoftetracyclinesduringtoothdevelopmentmaycause

permanentdiscolourationoftheteeth.

Inanimalstudies,N-methyl-2-pyrrolidonehasbeenassociatedwithembryotoxicityandteratogenicityatmaternally

toxicdoses.

Tetracyclinesarepresentinthemilkofbreast-feedingwomenwhoaretakingadrugofthiskindandshouldtherefore

notbeusedinbreast-feedingmothers.

Consequently,Atridoxiscontraindicatedinpregnancyandlactation(See4.3).

4.7Effectsonabilitytodriveandusemachines

Notapplicable.

4.8Undesirableeffects

TreatmentrelatedadverseeventsassociatedwiththeuseofAtridoxwerenomoreseriousnorfrequentthanevents

associatedwithstandardperiodontaltreatments.In3PhaseIIIclinicaltrialsinvolving609patients,adverseevents

werereportedwiththefollowingfrequencies:

Organsystem Common

(1/100to<1/10) Uncommon

(1/1000to<1/100)

Infectionsand

infestations Acuteperiodontitis0.4%;

periapicalabscesswithsinus

0.3%;acutegingivitis0.2%;

oralaphthae0.1%;pulpitis

0.1%

Neoplasms

benign,malignant

andunspecified

(includingcysts

andpolyps) Swelling,massorlumpin

headandneck0.1%

Nervoussystem

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TheuseofAtridoxresultsinverylowbloodlevelsofdoxycycline.Consequently,themajorityofsystemic

complicationsofdoxycyclineareunlikelytooccur.Inpost-marketingexperience,administrationofAtridoxhasrarely

(>1/10000to<1/1000)beenassociatedwithmildallergicreactionsthatmanifestasswellingand/orinflammation

aroundthesiteofplacementoramoregeneralisedrash.Melanoglossia(blacktongue)hasbeendescribedveryrarely

(<1/10000).

Oraladministrationoftetracyclinehasinfrequentlybeenassociatedwiththefollowingsideeffectswhicharenot

alreadymentionedabove:

Gastro-intestinal:Anorexia,diarrhoea,inflammatorylesions(withmonilialovergrowth)intheanogenitalregion.

Oesophagitisandoesophagealulcerationhavebeenreportedinpatientsreceivingdoxycycline.Asignificantproportion

ofthesecaseshasoccurredwiththehydrochloridesaltinthecapsuleform.Mostofthesepatientstookmedication

immediatelybeforegoingtobed.

Veryrarely,dysphagiahasbeenreported.

Respiratory:Hoarsenesshasbeendescribedveryrarely.

Skin:Photosensitivity.Inveryrarecaseswithdoxycyclinetherapy,severeskinreactionswithlifethreateningreactions

(exfoliativedermatitis,Lyell-syndrome(toxicepidermalnecrolysis))havebeenreported.

Renaltoxicity:Riseinbloodureahasbeenreportedwithtetracyclinesandisapparentlydoserelated.

Centralnervoussystem:Inveryrarecases,increaseofintracranialpressure(pseudotumourcerebri).Thesymptomsare

headache,nausea,vomitingandvisualdisturbancecausedbyapapillaryoedema.

Other:Hypersensitivityreactions(includingurticariaandangioneuroticoedema),pericarditisandexacerbationof

systemiclupuserythematosushavebeenreported.Severeacutehypersensitivityreactionshavebeenveryrarely

described,includinganaphylaxisandanaphylactoidpurpura.Symptomsandsignsincludefacialoedema,glossoncus

(swollentongue)andlaryngealoedemaleadingtolifethreateningnarrowingoftheairway;tachycardia,hypotension,

shockandcardiacarrestmayoccurinthissituation.

Blood:Haemolyticanaemia,thrombocytopenia,neutropeniaandeosinophiliahavebeenreportedwithtetracyclines.

Whengivenoverprolongedperiods,tetracyclineshavebeenreportedtoproducebrown-blackmicroscopic

discolourationofthyroidtissue.Noabnormalitiesofthyroidfunctionareknowntooccur.

4.9Overdose

Acuteoverdosageisnotanticipated.Intheeventofoverdosage,removeAtridoxfromthepockets,applygastriclavage

Gastrointestinal

disorders Glossodynia0.3%;nauseaand

vomiting0.3%;acute

pharyngitis0.1%;non-

infectiousgastroenteritisand

colitis0.1%;stomatitis0.1%

Skinand

subcutaneous

tissuedisorders Disturbanceofskinsensation

0.2%

Generaldisorders

administration

siteconditions Gumpain,increased

probingdepth1.9%;

toothsensitivity

(thermal)1.1% Oralpain,redness,erythema

andtrauma0.5%;toothache,

pressuresensitivity0.3%;

bleedinggums,ulceration

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiinfectivesforlocaloraltreatment

ATCcode:A01AB22

Doxycyclineisabroad-spectrumsemisynthetictetracyclinethatismorelipophilicthantetracycline.Doxycyclineis

bacteriostaticandinhibitsbacterialproteinsynthesisduetodisruptionoftransferRNAandmessengerRNAat

ribosomalsites.InvitrotestinghasshownperiodontalpathogenssuchasActinobacillusactinomycetemcomitans,

Porphyromonasgingivalis,Prevotellaintermedia,Campylobacterrectus,andFusobacteriumnucleatumtobe

susceptibleto0.06-6.0µg/mldoxycycline.AclinicalstudydemonstratedthatasingletreatmentwithAtridoxin

patientswithperiodontaldiseaseresultedinreducedlevelsofPorphyromonasgingivalis,Prevotellaintermedia,

Campylobacterrectus,Fusobacteriumnucleatum,BacteroidesforsythusandEikenellacorrodensinsubgingival

plaque.Levelsofaerobicbacteriawerealsoreduced.

Cross-resistancebetweentetracyclinesmaydevelopinmicro-organismsandpatientsmaybecomecross-sensitisedto

tetracyclines.

ReporteddoxycyclineinvitroMIC

levelsforsuspectedperiodontalpathogensrangefrom1-6µg/ml.Thehighestin

vitroMIC

levelsare32µg/ml.Invivodoxycyclinelevelsareinitially30-40timesthehighestreportedlevelsandat

Day7posttreatmentarestill4-10timestheselevels.

Whiletheantibacterialactivityofdoxycyclineistheprincipaltherapeuticactionintreatingperiodontitisthecompound

hasotherpropertieswhichareofvaluewhichmayaffectthiscondition.Theseincludeanti-collagenaseproperties,with

thosederivedfromneutrophilsbeingmostsusceptible,anti-inflammatoryactivityandinhibitionofboneresorption.

Theseactivitiesarethoughttoslowtheprogressionofperiodontitis.

5.2Pharmacokineticproperties

Gingivalandcrevicularfluid,salivaandserumlevelsofdoxycyclinehavebeenestablishedfollowingthe

administrationofeitherAtridoxororaldoxycycline.

Atridoxwhencoveredwitharetentivematerialhadinitialmeangingivalcrevicularfluidlevelsof1282-1500µg/ml.

Aftersevendayslevelswere152-317µg/ml.

Studiesindicatethat>95%ofthedoxycyclinewillbereleasedinthefirst10daysfollowingplacement.Approximately

Susceptible

Actinobacillusactinomycetemcomitans

Bacteroidesforsythus

Campylobacterrectus

Eikenellacorrodens

Fusobacteriumnucleatum

Porphyromonasgingivalis

MinimumInhibitory

Concentrations(MIC90)

6µg/ml

<

6µg/ml

1µg/ml

6µg/ml

2µg/ml

1µg/ml

3µg/ml

Intermediate Notapplicable

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ThemaximumconcentrationofdoxycyclineinsalivatwohoursafterAtridoxtreatmentwas4.05µg/mlanddecreased

to0.36µg/mlattheseventhday.

TheconcentrationofdoxycyclineinserumfollowingAtridoxtreatmentneverexceeded0.1µg/ml.

5.3Preclinicalsafetydata

Doxycycline,NMP(N-methyl-2-pyrrolidone)andPLA(Poly[DL-lactide])havealowpotentialforacutetoxicityin

particularregardtotheadministrationanddosageinquestion.(Seepoints4.8and4.9).

Doxycyclinecrossestheplacenta.Furthermore,embryotoxicity,butnotteratogenicity,hasbeenreported.NMPis

associatedwithembryotoxicityandteratogenicityinmiceandrabbitsatmaternaltoxicdoses.

NodataonmutagenicityofdoxycyclineandPLAhavebeensubmitted.NMPhasbeentestedandtheresultsdonot

indicateamutagenicpotential.

Subgingivaladministrationofthedoxycyclineformulationsinthedogresultsintransientslightirritationwhichquickly

resolves.Theconstituentsofthepolymerformulation,PLAandNMP,andthepolymeritself,haveshownlittleorno

increaseinirritativepotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Poly(DL-lactide)

N-methyl-2pyrrolidone

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2yearsinthepouch.Forimmediateuseafterreconstitution.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Interlockingdisposablepre-filledsyringeshavingPPbarrels,PPcollar,PEandPPcapsandPPplungerswithnatural

thermoplasticrubbertips.Onecartoncontains1,2or6pouches,eachofwhichcontainsonepre-filledsyringeA

(450mgATRIGELdeliverysystem),onepre-filledsyringeB(44mgdoxycyclineasdoxycyclinehyclate)andablunt-

endedcannula.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

EachAtridoxsyringesystemisintendedforimmediateuseandforuseonlyinonepatient.Donotuseifthepouchhas

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CoupleSyringeA(liquiddeliverysystem)andSyringeB(drugpowder).

SyringeA SyringeB

InjecttheliquidcontentsofSyringeA(indicatedonsyringebytealstripe)intoSyringeB(doxycyclinepowder)

andthenpushthecontentsbackintoSyringeA.Thisentireoperationisonemixingcycle.

Complete100mixingcyclesatapaceofonecyclepersecondusingbriskstrokes.

ThecontentswillbeinSyringeA(indicatedbytealstripe).HoldthecoupledsyringesverticallywithSyringeA

atthebottom.PullbackontheSyringeAplungerandallowthecontentstoflowdownthebarrelforseveralseconds.

Anopaqueringmaybeobservedafterconstitution.However,ifadditionalunmixeddrugpowderisevident,orif

seepageoftheformulationoutsideofthebarrelsisobserved,discardthecoupledsyringes.

Uncouplethetwosyringesandattachtheblunt-endedcannulatoSyringeA.

SyringeA BluntCannula

Productisnowreadyforapplication

Atridoxdoesnotrequirelocalanaesthesiaforplacement.Bendthecannulatoresembleaperiodontalprobeandexplore

theperiodontalpocketinamannersimilartoperiodontalprobing.Keepingthecannulatipnearthebaseofthepocket,

expresstheproductintothepocketuntilthepolymerreachesthetopofthegingivalmargin.Withdrawthecannulatip

fromthepocket.Inordertoseparatethetipfromthepolymer,turnthetipofthecannulatowardsthetooth,pressthetip

againstthetoothsurface,andpinchthestringofpolymerfromthetipofthecannula.Variationsonthistechniquemay

beneededtoachieveseparationbetweenAtridoxandcannula.

Whennecessary,usinganappropriatedentalinstrument,packtheAtridoxintothepocket.Dippingtheedgeofthe

instrumentinwaterbeforepackingwillhelpkeepAtridoxfromstickingtotheinstrument,andwillhelpspeed

coagulationofAtridox.AfewdropsofwaterdrippedontothesurfaceofAtridoxonceinthepocketwillalsoaid

coagulation.Ifnecessary,addmoreAtridoxasdescribedaboveuntilthepocketisfull.

Forsingleuseonly.

Discardanyexcessafteruse.

7MARKETINGAUTHORISATIONHOLDER

TolmarGmbH

Feldbergstr.27-29

D-61440Oberursel

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8MARKETINGAUTHORISATIONNUMBER

PA1501/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:31 st

March2000

Dateoflastrenewal:4 th

November2008

10DATEOFREVISIONOFTHETEXT

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