ALLOPURINOL

Main information

  • Trade name:
  • ALLOPURINOL Tablets 100 Milligram
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALLOPURINOL Tablets 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/013/001
  • Authorization date:
  • 13-12-1996
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0577/013/001

CaseNo:2031808

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

McDermottLaboratoriesLtdt/aGerardLaboratories

35/36BaldoyleIndustrialEstate,GrangeRoad,Dublin13,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Allopurinol100mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom05/12/2007.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Allopurinol100mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains100mgallopurinol.

Excipients:Lactosemonohydrate

Forfulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablet.

Round,biconvex,whitetabletswithbreaklineand“ALL100”ononesideandtwintrianglelogoonthereverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Allopurinolisindicatedforreducingurate/uricacidformationinconditionswhereurate/uricaciddepositionhas

alreadyoccurred(e.g.goutyarthritis,skintophi,nephrolithiasis)orisapredictableclinicalrisk(e.g.treatmentof

malignancypotentiallyleadingtoacuteuricacidnephropathy).

Themainclinicalconditionswhereurate/uricaciddepositionmayoccurare:

Idiopathicgout

Uricacidlithiasis

Acuteuricacidnephropathy

Neoplasticdiseaseandmyeloproliferativediseasewithhighcellturnoverrates,inwhichhighuratelevelsoccur

spontaneouslyoraftercytotoxictherapy

Certainenzymedisorderswhichleadtooverproductionofurate,forexample:

Hypoxanthineguaninephosphoribosyltransferase,includingLesch-Nyhansyndrome

Glucose-6-phosphataseincludingglycogenstoragedisease

Phosphoribosylpyrophosphatesynthetase

Phosphoribosylpyrophosphateamidotransferase

Adeninephosphoribosyltransferase

Allopurinolisindicatedforthemanagementof2,8-dihydroxyadenine(2,8-DHA)renalstonesrelatedtodeficient

activityofadeninephosphoribosyltransferase.

Allopurinolisindicatedforthemanagementofrecurrentmixedcalciumoxalaterenalstonesinthepresenceof

hyperuricosuria,whenfluid,dietaryandsimilarmeasureshavefailed.

4.2Posologyandmethodofadministration

Adults

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onlyiftheserumurateresponseisunsatisfactory.Extracautionshouldbeexercisedifrenalfunctionispoor(see

Dosageinrenalimpairment).Thefollowingdosageschedulesaresuggested:

Mildconditions:100to200mgdaily

Moderatelysevereconditions:300to600mgdaily

Severeconditions:700to900mgdaily

Dosagehigherthan300mgshouldbegivenindivideddosednotexceeding300mgatanytime.Ifadosageonamg/Kg

bodyweightbasisisrequired,2to10mg/Kgbodyweight/dayshouldbeused.

Children

Childrenunder15years:10to20mg/Kgbodyweight/dayuptoamaximumof400mgdaily.Useinchildrenisrarely

indicated,exceptinmalignantconditions(especiallyleukaemia)orcertainenzymedisorderssuchasLesch-Nyhan

syndrome.

Elderly

Intheabsenceofspecificdata,thelowestdosagewhichproducessatisfactoryuratereductionshouldbeused.Particular

attentionshouldbepaidtoadviceinRenalimpairmentandSpecialWarninsandPrecautionsforUse.

Renalimpairment

Allopurinolanditsmetabolitesareexcretedviathekidney.Impairmentofkidneyfunctionmayleadtoretentionofthe

drugand/oritsmetabolites,withconsequentprolongationofplasmahalf-lives.Insevererenalinsufficiency,itmaybe

advisabletouselessthan100mgperdayortousesingledosesofa100mgatlongerdosingintervalsthanoneday.

Iffacilitiesareavailabletomonitorplasmaoxipurinolconcentrations,thedoseshouldbeadjustedtomaintainplasma

oxipurinollevelsbelow100micromol/litre(15.2mg/litre).

Allopurinolanditsmetabolitesareremovedbyrenaldialysis.Ifdialysisisrequiredtwotothreetimesaweek,

considerationshouldbegiventoanalternativedosagescheduleof300to400mgallopurinolimmediatelyaftereach

dialysiswithnoneintheinterim.

Hepaticimpairment

Reduceddosesshouldbeusedinpatientswithhepaticimpairment.Periodicliverfunctiontestsarerecommended

duringtheearlystagesoftherapy.

Treatmentofhighurateturnoverconditions,e.g.neoplasia,Lesch-Nyhansyndrome

Itisadvisabletocorrectexistinghyperuricaemiaand/orhyperuricosuriawithAllopurinolbeforestartingcytotoxic

therapy.Itisimportanttoensureadequatehydrationtomaintainoptimumdiuresisandtoattemptalkalinisationofurine

toincreasesolubilityofurinaryurate/uricacid.DosageofAllopurinolshouldbeatthelowerendoftherecommended

dosageschedule.

Ifrenalfunctioniscompromisedduetorenalnephropathyorotherpathology,theadvicegiveninRenalimpairment

shouldbefollowed.

Thesestepsmayreducetheriskofxanthineand/oroxipurinoldepositioncomplicatingtheclinicalsituation.Seealso

InteractionwithOtherMedicinalProductsandOtherFormsofInteractionandUndesirableEffects.

MonitoringAdvice

Thedosageshouldbeadjustedbymonitoringserumurateconcentrationsandurinaryurate/uricacidlevelsat

appropriateintervals.

InstructionsforUse

Allopurinolmaybetakenorallyonceadayafterameal.Itiswelltolerated,especiallyafterfood.Shouldthedaily

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4.3Contraindications

AllopurinolTabletsarecontraindicated

inpatientshypersensitivetoallopurinolortoanyoftheexcipients.

inpatienswhoarebreastfeedinginfants.

inacutegout.

4.4Specialwarningsandprecautionsforuse

Allopurinolshouldbewithdrawnimmediatelyifaskinrashorotherevidenceofsensitivityoccurs.

Reduceddosesshouldbeusedinpatientswithhepaticorrenalimpairment.Patientsundertreatmentforhypertension

orcardiacinsufficiency,forexamplewithdiureticsorACEinhibitors,mayhavesomeconcomitantimpairmentofrenal

functionandallopurinolshouldbeusedwithcareinthisgroup.

Asymptomatichyperuricaemiaperseisgenerallynotconsideredanindicationforuseofallopurinol.Fluidanddietary

modificationwithmanagementoftheunderlyingcausemaycorrectthecondition.

Acutegoutyattacks

Allopurinoltreatmentshouldnotbestarteduntilanacuteattackofgouthascompletelysubsided,asfurtherattacksmay

beprecipitated.

IntheearlystagesoftreatmentwithAllopurinol,aswithuricosuricagents,anacuteattackofgoutyarthritismaybe

precipitated.Therefore,itisadvisabletogiveprophylaxiswithasuitableanti-inflammatoryagentorcolchicineforat

leastonemonth.Theliteratureshouldbeconsultedfordetailsofappropriatedosageandprecautionsandwarnings.

Ifacuteattacksdevelopinpatientsreceivingallopurinol,treatmentshouldcontinueatthesamedosagewhiletheacute

attackistreatedwithasuitableanti-inflammatoryagent.

Xanthinedeposition

Inconditionswheretherateofurateformationisgreatlyincreased(e.g.malignantdiseaseanditstreatment,Lesch-

Nyhansyndrome),theabsoluteconcentrationofxanthineinurinecould,inrarecases,risesufficientlytoallow

depositionintheurinarytract.Thisriskmaybeminimisedbyadequatehydrationtoachieveoptimalurinedilution.

Impactionofuricacidrenalstones

AdequatetherapywithAllopurinolwillleadtodissolutionoflargeuricacidrenalpelvicstones,withtheremote

possibilityofimpactionintheureter.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

6-mercaptopurineandazathioprine

Azathioprineismetabolisedto6-mercaptopurinewhichisinactivatedbytheactionofxanthineoxidase.When6-

mercaptopurineorazathioprineisgivenconcurrentlywithAllopurinol,onlyonequarteroftheusualdoseof6-

mercaptopurineorazathioprineshouldbegivenbecauseinhibitionofxanthineoxidasewillprolongtheiractivity.

Vidarabine(AdenineArabinoside)

Evidencesuggeststhattheplasmahalf-lifeofvidarabineisincreasedinthepresenceofallopurinol.Whenthetwo

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Salicylatesanduricosuricagents

Oxipurinol,themetaboliteofallopurinolanditselftherapeuticallyactive,isexcretedbythekidneyinasimilarwayto

urate.Hence,drugswithuricosuricactivitysuchasprobenecidorlargedosesofsalicylatemayacceleratetheexcretion

ofoxipurinol.ThismaydecreasethetherapeuticactivityofAllopurinol,butthesignificanceneedstobeassessedin

eachcase.

Chlorpropamide

IfAllopurinolisgivenconcurrentlywithchlorpropamidewhenrenalfunctionispoor,theremaybeanincreasedriskof

prolongedhypoglycaemicactivitybecauseallopurinolandchlorpropamidemaycompeteforexcretionintherenal

tubule.

Coumarinanticoagulants

Therehavebeenrarereportsofincreasedeffectofwarfarinorothercoumarinanticoagulantswhenco-administered

withallopurinol,therefore,allpatientsreceivinganticoagulantsmustbecarefullybemonitored.

Phenytoin

Allopurinolmayinhibithepaticoxidationofphenytoinbuttheclinicalsignificancehasnotbeendemonstrated.

Theophylline

Inhibitionofthemetabolismoftheophyllinehasbeenreported.Themechanismoftheinteractionmaybeexplainedby

xanthineoxidasebeinginvolvedinthebiotransformationoftheophyllineinman.Theophyllinelevelsshouldbe

monitoredinpatientsstartingorincreasingallopurinoltherapy.

Ampicillin/Amoxicillin

Anincreaseinthefrequencyofskinrasheshasbeenreportedamongpatientsreceivingampicillinoramoxicillin

concurrentlywithallopurinolcomparedtopatientswhoarenotreceivingbothdrugs.Thecauseofthereported

associationhasnotbeenestablished.However,itisrecommendedthatinpatientsreceivingallopurinolanalternativeto

ampicillinoramoxicillinisusedwhereavailable.

Cyclophosphamide,doxorubicin,bleomycin,procarbazine,mechloroethamine

Enhancedbonemarrowsuppressionbycyclophosphamideandothercytotoxicagentshasbeenreportedamongpatients

withneoplasticdisease(otherthanleukaemia),inthepresenceofallopurinol.Howeverinawell-controlledstudyof

patientstreatedwithcyclophosphamide,doxorubicin,bleomycin,procarbazineand/ormechloroethamine(mustine

hydrochloride)allopurinoldidnotappeartoincreasethetoxicreactionofthesecytotoxicagents.

Cyclosporin

Reportssuggestthattheplasmaconcentrationofcyclosporinmaybeincreasedduringconcomitanttreatmentwith

allopurinol.Thepossibilityofenhancedcyclosporintoxicityshouldbeconsideredifthedrugsareco-administered.

Didanosine

InhealthyvolunteersandHIVpatientsreceivingdidanosine,plasmadidanosineC

andAUCvalueswere

approximatelydoubledwithconcomitantallopurinoltreatment(300mgdaily)withoutaffectingterminalhalflife.

Therefore,dosereductionsofdidanosinemayberequiredwhenusedconcomitantlywithallopurinol.

4.6Pregnancyandlactation

Pregnancy

ThereisinadequateevidenceofsafetyofAllopurinolinhumanpregnancy,althoughithasbeeninwideuseformany

yearswithoutapparentillconsequence.Useinpregnancyonlywhenthereisnosaferalternativeandwhenthedisease

itselfcarriesrisksforthemotherorunbornchild.

Lactation

Reportsindicatethatallopurinolandoxipurinolareexcretedinhumanbreastmilk.Concentrationsof1.4mg/litre

allopurinoland53.7mg/litreoxipurinolhavebeendemonstratedinbreastmilkfromawomantakingAllopurinol

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4.7Effectsonabilitytodriveandusemachines

Sinceadversereactionssuchassomnolence,vertigoandataxiahavebeenreportedinpatientsreceivingallopurinol,

patientsshouldexercisecautionbeforedriving,usingmachineryorparticipatingindangerousactivitiesuntiltheyare

reasonablycertainthatallopurinoldoesnotadverselyaffectperformance.

4.8Undesirableeffects

AdversereactionsinassociationwithAllopurinolarerareintheoveralltreatedpopulationandmostlyofaminor

nature.Theincidenceishigherinthepresenceofrenaland/orhepaticdisorder.

Skinandhypersensitivityreactions

Thesearethemostcommonreactionsandmayoccuratanytimeduringtreatment.Theymaybepruritic,

maculopapular,sometimesscaly,sometimespurpuricandrarelyexfoliative.Allopurinolshouldbewithdrawn

immediatelyshouldsuchreactionsoccur.Afterrecoveryfrommildreactions,Allopurinolmay,ifdesired,bere-

introducedatasmalldose(e.g.50mg/day)andgraduallyincreased.Iftherashrecurs,Allopurinolshouldbe

permanentlywithdrawnasmoreseverehypersensitivityreactionsmayoccur.

Skinreactionsassociatedwithexfoliation,fever,lymphadenopathy,arthralgiaand/oreosinophiliaincludingStevens-

Johnsonsyndromeandtoxicepidermalnecrolysisoccurrarely.Associatedvasculitisandtissueresponsemaybe

manifestedinvariouswaysincludinghepatitis,renalimpairmentand,veryrarely,seizures.Ifsuchreactionsdooccur,

itmaybeatanytimeduringtreatment.Allopurinolshouldbewithdrawnimmediatelyandpermanently.

Corticosteroidsmaybebeneficialinovercominghypersensitivityskinreactions.Whengeneralisedhypersensitivity

reactionshaveoccurred,renaland/orhepaticdisorderhasusuallybeenpresentparticularlywhentheoutcomehasbeen

fatal.

Veryrarelyacuteanaphylacticshockhasbeenreported.

Angioimmunoblasticlymphadenopathy

Angioimmunoblasticlymphadenopathyhasbeendescribedrarelyfollowingbiopsyofageneralisedlymphadenopathy.

ItappearstobereversibleonwithdrawalofAllopurinol.

Hepaticfunction

Rarecasesofhepaticdysfunctionrangingfromasymptomaticrisesinliverfunctionteststohepatitis(includinghepatic

necrosisandgranulomatoushepatitis)havebeenreportedwithoutovertevidenceofmoregeneralisedhypersensitivity.

Gastrointestinaldisorders

Inearlyclinicalstudies,nauseaandvomitingwerereported.Furtherreportssuggestthatthisreactionisnota

significantproblemandcanbeavoidedbytakingAllopurinolaftermeals.Recurrenthaematemesishasbeenreported

asanextremelyrareevent,ashassteatorrhoea.

Bloodandlymphaticsystem

Occasionalreportshavebeenreceivedofthrombocytopenia,agranulocytosisandaplasticanaemia,particularlyin

individualswithimpairedrenaland/orhepaticfunction,reinforcingtheneedforparticularcareinthisgroupof

patients.

Miscellaneous

Thefollowingcomplaintshavebeenreportedoccasionally:fever,generalmalaise,asthenia,headache,vertigo,ataxia,

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perversion,stomatitis,changedbowelhabit,infertility,impotence,diabetesmellitus,hyperlipidaemia,furunculosis,

alopecia,discolouredhair,angina,hypertension,bradycardia,oedema,uraemia,haematuria,angioedemaand

gynaecomastia.

4.9Overdose

SymptomsandSigns

Ingestionofupto22.5gallopurinolwithoutadverseeffecthasbeenreported.Symptomsandsignsincludingnausea,

vomiting,diarrhoeaanddizzinesshavebeenreportedinapatientwhoingested20gallopurinol.Recoveryfollowed

generalsupportivemeasures.

Management

Massiveabsorptionofallopurinolmayleadtoconsiderableinhibitionofxanthineoxidaseactivity,whichshouldhave

nountowardeffectsunlessaffectingconcomitantmedicationespeciallywith6-mercaptopurineand/orazathioprine.

Adequatehydrationtomaintainoptimumdiuresisfacilitatesexcretionofallopurinolanditsmetabolites.Ifconsidered

necessaryhaemodialysismaybeused.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup

ATCCodeM04AA01

Allopurinolisaxanthineoxidaseinhibitor.

Modeofaction

Allopurinolanditsmainmetaboliteoxipurinollowerthelevelofuricacidinplasmaandurinebyinhibitionofxanthine

oxidase,theenzymecatalyzingtheoxidationofhypoxanthinetoxanthineandxanthinetouricacid.Inadditiontothe

inhibitionofpurinecatabolism,insomebutnotallhyperuricaemicpatients,denovopurinebiosynthesisisdepressed

viafeedbackinhibitionofhypoxanthine-guaninephosphoribosyltransferase.Othermetabolitesofallopurinolinclude

allopurinol-ribosideandoxipurinol-7-riboside.

5.2Pharmacokineticproperties

Allopurinolisactivewhengivenorallyandisrapidlyabsorbedfromtheuppergastrointestinaltract.Studieshave

detectedallopurinolintheblood30-60minutesafterdosing.Estimatesofbioavailabilityvaryfrom67%to90%.Peak

plasmalevelsofallopurinolgenerallyoccurapproximately1.5hoursafteroraladministrationofAllopurinol,butfall

rapidlyandarebarelydetectableafter6hours.Peakplasmalevelsofoxipurinolgenerallyoccurafter3-5hoursafter

oraladministrationofAllopurinolandaremuchmoresustained.

Allopurinolisnegligiblyboundbyplasmaproteinsandthereforevariationsinproteinbindingarenotthoughtto

significantlyalterclearance.Theapparentvolumeofdistributionofallopurinolisapproximately1.6litre/Kgwhich

suggestsrelativelyextensiveuptakebytissues.Tissueconcentrationsofallopurinolhavenotbeenreportedinhumans,

butitislikelythatallopurinolandoxipurinolwillbepresentinthehighestconcentrationsintheliverandintestinal

mucosawherexanthineoxidaseactivityishigh.

Approximately20%oftheingestedallopurinolisexcretedinthefaeces.Eliminationofallopurinolismainlyby

metabolicconversiontooxipurinolbyxanthineoxidaseandaldehydeoxidase,withlessthan10%oftheunchanged

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Oxipurinolisalesspotentinhibitorofxanthineoxidasethanallopurinol,buttheplasmahalf-lifeofoxipurinolisfar

moreprolonged.Estimatesrangefrom13to30hoursinman.Thereforeeffectiveinhibitionofxanthineoxidaseis

maintainedovera24hourperiodwithasingledailydoseofAllopurinol.Patientswithnormalrenalfunctionwill

graduallyaccumulateoxipurinoluntilasteady-stateplasmaoxipurinolconcentrationisreached.Suchpatients,taking

300mgofallopurinolperdaywillgenerallyhaveplasmaoxipurinolconcentrationsof5-10mg/litre.

Oxipurinoliseliminatedunchangedintheurinebuthasalongeliminationhalf-lifebecauseitundergoestubular

reabsorption.Reportedvaluesfortheeliminationhalf-liferangefrom13.6hoursto29hours.Thelargediscrepanciesin

thesevaluesmaybeaccountedforbyvariationsinstudydesignand/orcreatinineclearanceinthepatients.

Pharmacokineticsinpatientswithrenalimpairment

Allopurinolandoxipurinolclearanceisgreatlyreducedinpatientswithpoorrenalfunctionresultinginhigherplasma

levelsinchronictherapy.Patientswithrenalimpairment,wherecreatinineclearancevalueswerebetween10and

20ml/min,showedplasmaoxipurinolconcentrationsofapproximately30mg/litreafterprolongedtreatmentwith

300mgallopurinolperday.Thisisapproximatelytheconcentrationwhichwouldbeachievedbydosesof600mg/day

inthosewithnormalrenalfunction.AreductioninthedoseofAllopurinolisthereforerequiredinpatientswithrenal

impairment.

Pharmacokineticsinelderlypatients

Thekineticsofthedrugarenotlikelytobealteredotherthanduetodeteriorationinrenalfunction(see

Pharmacokineticsinpatientswithrenalimpairment).

5.3Preclinicalsafetydata

Mutagenicity

Cytogeneticstudiesshowthatallopurinoldoesnotinducechromosomeaberrationsinhumanbloodcellsinvitroat

concentrationsupto100µg/mlandinvivoatdosesupto600mg/dayforameanperiodof40months.

Allopurinoldoesnotproducenitrosocompoundsinvitrooraffectlymphocytetransformationinvitro.

Evidencefrombiochemicalandcytologicalinvestigationsstronglysuggeststhatallopurinolhasnodeleteriouseffects

onDNAatanystageofthecellcycleandisnotmutagenic.

Carcinogenicity

Noevidenceofcarcinogenicityhasbeenfoundinmiceandratstreatedwithallopurinolforupto2years.

Teratogenicity

Onestudyinmicereceivingintraperitonealdosesof50or100mg/Kgondays10or13ofgestationresultedinfoetal

abnormalities,howeverinasimilarstudyinratsat120mg/Kgonday12ofgestationnoabnormalitieswereobserved.

Extensivestudiesofhighoraldosesofallopurinolinmiceupto100mg/Kg/day,ratsupto200mg/Kg/dayandrabbits

upto150mg/Kg/dayduringdays8to16ofthegestationproducednoteratogeniceffects.

Aninvitrostudyusingfoetalmousesalivaryglandsinculturetodetectembryotoxicityindicatedthatallopurinol

wouldnotbeexpectedtocauseembryotoxicitywithoutalsocausingmaternaltoxicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Pregelatinisedmaizestarch1500

Sodiumstarchglycolate(TypeA)

Colloidalanhydroussilica

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Povidone

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keepthetabletcontainertightlyclosed.

6.5Natureandcontentsofcontainer

Polypropylenecontainerswithtamper-evidentpolyethyleneclosures.Eachcontainerisofsuitablesizetohold100

tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLimited

TradingasGerardLaboratories

35/36BaldoyleIndustrialEstate

GrangeRoad

Dublin13

8MARKETINGAUTHORISATIONNUMBER

PA577/13/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:13 th

December1996

Dateoflastrenewal:13 th

December2006

10DATEOFREVISIONOFTHETEXT

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