ALLOPURINOL

Main information

  • Trade name:
  • ALLOPURINOL Tablets 300 Milligram
  • Dosage:
  • 300 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALLOPURINOL Tablets 300 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0282/021/002
  • Authorization date:
  • 01-12-1982
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Allopurinol300mgTabletsBP.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains300mgAllopurinol.

Excipients:Eachtabletcontains175mgoflactoseaslactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Round,biconvex,whitetabletswithabreaklineand“ALL300”ononesideandatwintrianglelogoonreverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Allopurinolisindicatedforreducingurate/uricacidformationinconditionswhereurate/uricaciddepositionhas

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

malignancypotentiallyleadingtoacuteuricacidnephropathy).

Themainclinicalconditionswhereurate/uricaciddepositionmayoccurare:

Idiopathicgout;

Uricacidlithiasis;

Acuteuricacidnephropathy;

Neoplasticdiseaseandmyeloproliferativediseasewithhighcellturnoverrates,inwhichhighuratelevelsoccur

eitherspontaneously,oraftercytotoxictherapy;

Certainenzymedisorderswhichleadtooverproductionofurate,forexample;

hypoxanthine-guaninephosphoribosyltransferase,includingLesch-Nyhansyndrome;

glucose-6-phosphataseincludingglycogenstoragedisease;

phosphoribosylpyrophosphatesynthetase;

phosphoribosylpyrophosphateamidotransferase;

adeninephosphoribosyltransferase;

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

activityofadeninephosphoribosyltransferase.

Allopurinolisindicatedforthemanagementofrecurrentmixedcalciumoxalaterenalstonesinthepresenceof

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4.2Posologyandmethodofadministration

Adults:-

Allopurinolshouldbeintroducedatlowdosagee.g.100mg/daytoreducetheriskofadversereactionsandincreased

onlyiftheserumurateresponseisunsatisfactory.Extracautionshouldbeexercisedifrenalfunctionispoor(see

Dosageinrenalimpairment).Thefollowingdosageschedulesaresuggested:

100to200mgdailyinmildconditions,

300to600mgdailyinmoderatelysevereconditions,

700to900mgdailyinsevereconditions.

Dosagehigherthan300mgshouldbegivenindivideddosesnotexceeding300mgatanytime.Ifdosageonamg/kg

bodyweightbasisisrequired,2to10mg/kgbodyweight/dayshouldbeused.Whereavailable,Zyloricgranulesshould

beusedinpreferencetothehalvingoftablets.

Children:-

Under15yearsofage:10to20mg/kgbodyweightuptoamaximumof400mg.Useismainlyinmalignantconditions

orenzymedisorderssuchasLesch-Nyhansyndrome.

Elderly:-

Intheabsenceofspecificdata,thelowestdosagewhichproducessatisfactoryuratereductionshouldbeused.Particular

attentionshouldbepaidtoadvicein(DosageinrenalimpairmentandSpecialWarningsandPrecautionsforUse).

Renalimpairment:-

Sinceallopurinolanditsmetabolitesareexcretedbythekidney,impairedrenalfunctionmayleadtoretentionofthe

drugand/oritsmetaboliteswithconsequentprolongationofplasmahalf-lives.Insevererenalinsufficiency,itmaybe

advisabletouselessthan100mgperdayortousesingledosesof100mgatlongerintervalsthanoneday.

Iffacilitiesareavailabletomonitorplasmaoxipurinolconcentrations,thedoseshouldbeadjustedtomaintainplasma

oxipurinollevelsbelow100µmol/litre(15.2mg/litre).

Allopurinolanditsmetabolitesareremovedbyrenaldialysis.Ifdialysisisrequiredtwotothreetimesaweek

considerationshouldbegiventoanalternativedosagescheduleof300-400mgAllopurinolimmediatelyaftereach

dialysiswithnoneintheinterim.

Dosageinhepaticimpairment:-

Reduceddosesshouldbeusedinpatientswithhepaticimpairment.Periodicliverfunctiontestsarerecommended

duringtheearlystagesoftherapy.

Treatmentofhighurateturnoverconditions,e.g.neoplasia,Lesch-Nyhansyndrome:-

Itisadvisabletocorrectexistinghyperuricaemiaand/orhyperuricosuriawithAllopurinolbeforestartingcytotoxic

therapy.Itisimportanttoensureadequatehydrationtomaintainoptimumdiuresisandtoattemptalkalinisationofurine

toincreasesolubilityofurinaryurate/uricacid.DosageofAllopurinolshouldbeatthelowerendoftherecommended

dosageschedule.

Ifuratenephropathyorotherpathologyhascompromisedrenalfunction,theadvicegiveninDosageinrenal

impairmentshouldbefollowed.

Thesestepsmayreducetheriskofxanthineand/oroxipurinoldepositioncomplicatingtheclinicalsituation.

MonitoringAdvice

Thedosageshouldbeadjustedbymonitoringserumurateconcentrationsandurinaryurate/uricacidlevelsat

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InstructionsforUse

Allopurinolmaybetakenorallyonceadayafterameal.Itiswelltolerated,especiallyafterfood.Shouldthedaily

dosageexceed300mgandgastrointestinalintolerancebemanifested,adivideddoseregimenmaybeappropriate.

RouteofAdministration

Oral.

4.3Contraindications

Useinpatientshypersensitivetoallopurinol.

Useinpatientswhoarebreastfeedinginfants.

Useinacutegout.

Useinpatientswhoareallergictotheexcipientspresentinthismedicinalproduct.

4.4Specialwarningsandprecautionsforuse

Allopurinolshouldbewithdrawnimmediatelyifaskinrashorotherevidenceofsensitivityoccurs.Skinreactions

maybepruritic,maculopapular,sometimesscalyorpurpuricandrarelyexfoliative.Allopurinolshouldbewithdrawn

immediatelyandpermanentlyatthefirstsignofintolerance.

Reduceddosesshouldbeusedinpatientswithhepaticorrenalimpairment.Patientsundertreatmentforhypertension

orcardiacinsufficiency,forexamplewithdiureticsorACEinhibitors,mayhavesomeconcomitantimpairmentofrenal

functionandallopurinolshouldbeusedwithcareinthisgroup.

AsymptomatichyperuricaemiaisgenerallynotconsideredanindicationforuseofAllopurinol.Fluidanddietary

modificationwithmanagementoftheunderlyingcausemaycorrectthecondition.

Acutegoutyattacks:-

Allopurinoltreatmentshouldnotbestarteduntilandacuteattackofgouthascompletelysubsided,asfurtherattacks

maybeprecipitated.

IntheearlystagesoftreatmentwithAllopurinol,aswithuricosuricagents,anacuteattackofgoutyarthritismaybe

precipitated.Thereforeitisadvisabletogiveaprophylacticdosewithasuitableanti-inflammatoryagentorcolchicines

foratleastonemonth.Theliteratureshouldbeconsultedfordetailsofappropriatedosageandprecautionsand

warnings.

Ifacuteattacksdevelopinpatientsreceivingallopurinol,treatmentshouldcontinueatthesamedosagewhiletheacute

attackistreatedwithasuitableanti-inflammatoryagent.

Xanthinedeposition;-

Inconditionswheretherateofusrateformationisgreatlyincreased(e.g.Malignantdiseaseanditstreatment,Lesch-

Nyhansyndrome),theabsoluteconcentrationofxanthineinurinecould,inrarecases,risesufficientlytoallow

depositionintheurinarytract.Thisriskmaybeminimisedbyadequatehydrationtoachieveoptimaldilution.

Impactionofuricacidrenalstones;-

AdequatetherapywithAllopurinolwillleadtodissolutionoflargeuricacidrenalpelvicstoneswiththeremote

possibilityofimpactionintheureter.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

6-mercaptopurineandazathioprine

Allopurinolinhibitsthemetabolismof6-mercaptopurineorazathioprinewhengivenconcurrently.Thedoseof6-

mercaptopurineandazathioprineshouldbereducedtoone-quarteroftheusualdose.

Vidarabine(AdenineArabinoside)

Evidencesuggeststhattheplasmahalf-lifeofvidarabineisincreasedinthepresenceofallopurinol.Whenthetwo

productsareusedconcomitantlyextravigilanceisnecessary,torecogniseenhancedtoxiceffects.

Salicylatesanduricosuricagents

Concurrentadministrationwithuricosuricsincludingprobenecidandsalicylatesmayleadtoanincreasedrateof

excretionofoxipurinol.ThismaydecreasethetherapeuticactivityofAllopurinoltherefore,dosagemayrequire

adjustment.

Chlorpropanamide

IfAllopurinolisgivenconcomitantlywithchlorpropamidewhenrenalfunctionispoor,theremaybeanincreasedrisk

ofprolongedhypoglycaemicactivitybecauseallopurinolandchlorpropamidemaycompeteforexcretionintherenal

tubule.

Coumarinanticoagulants

Therehavebeenrarereportsofincreasedeffectofwarfarinandothercoumarinanticoagulantswhenco-administered

withallopurinol,therefore,allpatientsreceivinganticoagulantsmustbecarefullymonitored.

Phenytoin

Allopurinolmayinhibithepaticoxidationofphenytoinbuttheclinicalsignificancehasnotbeendemonstrated.

Theophylline

Inhibitionofthemetabolismoftheophyllinehasbeenreported.Themechanismoftheinteractionmaybeexplainedby

xanthineoxidasebeinginvolvedinthebiotransformationoftheophyllineinman.Theophyllinelevelsshouldbe

monitoredinpatientsstartingorincreasingallopurinoltherapy.

Ampicillin/Amoxicillin

Anincreaseinthefrequencyofskinrasheshasbeenreportedamongpatientsreceivingampicillinoramoxicillin

concurrentlywithallopurinolcomparedtopatientswhoarenotreceivingbothdrugs.Thecauseofthereported

associationhasnotbeenestablished.However,itisrecommendedthatinpatientsreceivingallopurinolanalternativeto

ampicillinoramoxicillinisusedwhereavailable.

Cyclophosphamide,doxorubicin,bleomycin,procarbazine,mechloroethamine

Enhancebonemarrowsuppressionbycyclophosphamideandothercytotoxicagentshasbeenreportedamongpatients

withneoplasticdisease(otherthanleukaemia),inthepresenceofallopurinol.Howeverinawell-controlledstudyof

patientstreatedwithcyclophosphamide,doxorubicin,bleomycin,procarbazineand/ormechloroethamine(mustine

hydrochloride)allopurinoldidnotappeartoincreasethetoxicreactionofthesecytotoxicagents.

Cyclosporin

Reportssuggestthattheplasmaconcentrationofcyclosporinemaybeincreasedduringconcomitanttreatmentwith

allopurinol.Thepossibilityofenhancedcyclosporinetoxicityshouldbeconsideredifthedrugsareco-administered.

Didanosine

InhealthyvolunteersandHIVpatientsreceivingdidanosine,plasmadidanosineCmaxandAUCvalueswere

approximatelydoubledwithconcomitantallopurinoltreatment(300mgdaily)withoutaffectingterminalhalflife.

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4.6Pregnancyandlactation

Allopurinolshouldnotbeusedduringpregnancyunlessconsideredessentialbythephysician.

Allopurinolanditsmetabolitesweredemonstratedtobeinthebreastmilkofanindividualstudiedafterasingledose

ofallopurinol.Therearenodataconcerningtheeffectofthesemetabolitesonthebreast-fedbaby.

4.7Effectsonabilitytodriveandusemachines

Sinceadversereactionssuchassomnolence,vertigoandataxiahavebeenreportedinpatientsreceivingallopurinol,

patientsshouldexercisecautionbeforedriving,usingmachineryorparticipatingindangerousactivitiesuntiltheyare

reasonablycertainthatallopurinoldoesnotadverselyaffectperformances.

4.8Undesirableeffects

Skinandhypersensitivityreactions

Skinreactionsarethemostcommonadverseeffect,andmayoccuratanytimeduringtreatment.Theymaybepruritic,

maculopapular,sometimesscalyorprupuricandrarelyexfoliative.

Allopurinolshouldbewithdrawnimmediatelyshouldsuchreactionsoccur.

Afterrecoveryfrommildskinreactions,allopurinolmaybere-introducedatlowdose(e.g.50mg/day);thismaybe

graduallyincreased.

Iftherashrecurs,allopurinolshouldbewithdrawnimmediatelyandpermanently.

Skinreactionsassociatedwithexfoliation,fever,lymphadenopathy,arthralgiaandeosinophilaresemblingStevens-

Johnsonand/orLyell’ssyndromeoccurrarely.Associatedvasculitisandtissueresponsemaybemanifestedinvarious

waysincludinghepatitis,interstitialnephritisand,veryrarely,epilepsy.Ifsuchreactionsdooccurallopurinolshould

bewithdrawnimmediatelyandpermanently.

Corticosteroidsmaybebeneficialintreatingsuchreactions.Whengeneralisedhypersensitivityreactionshave

occurred,hepaticand/orrenaldisorderhasusuallybeenpresentparticularlywhentheoutcomehasbeenfatal.

Veryrarelyacuteanaphylacticshockhasbeenreported.

Angioimmunoblasticlymphadenopathy

Angioimmunoblasticlymphadenopathyhasbeendescribedrarelyfollowingbiopsyofageneralisedlymphadenopathy.

Itappearstobereversibleonwithdrawalofallopurinol.

Hepaticfunction

Rarecasesofhepaticdisfunctionrangingfromasymptomaticrisesinliverfunctionteststohepatitis(includinghepatic

necrosisandgranulomatoushepatitis)havebeenreportedwithoutovertevidenceofmoregeneralisedhypersensitivity.

Gastrointestinaldisorder

Nauseaandvomitingcanlargelybeavoidedbytakingallopurinolaftermeals.

Recurrenthaematemesishasbeenreportedasanextremelyrareevent,ashassteatorrhoea.

Bloodandlymphaticsystem

Therehavebeenoccasionalreportsofthrombocytopenia,agranulocytosisandaplasticanaemia,usuallyinassociation

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Miscellaneous

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

somnolence,coma,depression,paralysis,paraesthesiae,neuropathy,visualdisorders,cataracts,macularchanges,taste

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

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

gynaecomastia.

4.9Overdose

Accidentalordeliberateingestionofupto22.5gallopurinolwithoutadverseeffecthasbeenreported.Symptomsand

signsincludingnausea,vomiting,diarrhoeaanddizzinesshavebeenreportedinapatientwhoingested20gallopurinol.

Recoveryfollowedgeneralsupportivemeasures.

Themostlikelyreactionwouldbegastrointestinalintolerance.Massiveabsorptionofallopurinolmayleadto

considerableinhibitionofxanthineoxidaseactivitywhichshouldhavenountowardeffectsunless6-mercaptopurine,

adeninearabinoside,and/orazathioprineisbeingtakenconcomitantly.

Inthesecasestheriskofincreasedactivityofthesedrugsmustberecognised.Adequatehydrationtomaintainoptimum

diuresisfacilitatesexcretionofallopurinolanditsmetabolites.Dialysismayberesortedtoifconsiderednecessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Allopurinolisaxanthineoxidaseinhibitorwhichreducestheoxidationofhypoxanthinetoxanthineandxanthineto

uricacid.Inadditiontotheinhibitionofpurinecatabolism,insomebutnotallhyperuricaemicpatients,denovopurine

biosynthesesisdepressedviafeedbackinhibitionofhypoxanthine-guaninephosphoribosyltransferase.Other

metabolitesofallopurinolincludeallopurinol-ribosideandoxipurinol-7-riboside.

5.2Pharmacokineticproperties

Allopurinolisactivewhengivenorallyandisrapidlyabsorbedfromtheuppergastrointestinaltract.Studieshave

detectedallopurinolintheblood30-60minutesafterdosing.Estimatesofbioavailabliltyvaryfrom67%to90%.Peak

plasmalevelsofallopurinolgenerallyoccurapproximately1.5hoursafteroraladministrationofallopurinol,butfall

rapidlyandarebarelydetectableafter6hours.Peakplasmalevelsofoxipurinolgenerallyoccurafter3-5hoursafter

oraladministrationofallopurinolandaremuchmoresustained.

Allopurinolisnegligiblyboundbyplasmaproteinsandthereforevariationisproteinbindingarenotthoughtto

significantlyalterclearance.Theapparentvolumeofdistributionofallopurinolisapproximately1.6litre/Kgwhich

suggestsrelativelyextensiveuptakebytissues.Tissueconcentrationsofallopurinolhavenotbeenreportedinhumans,

butitislikelythatallopurinolandoxipurinolwillbepresentinthehighestconcentrationsintheliverandintestinal

mucosawherexanthineoxidaseactivityishigh.

Approximately20%oftheingestedallopurinolisexcretedinthefaeces.Eliminationofallopurinolismainlyby

metabolicconversiontooxipurinolbyxanthineoxidaseandaldehydeoxidase,withlessthan10%oftheunchanged

drugexcretedintheurine.Allopurinolhasaplasmahalf-lifeofabout1to2hours.

Oxipurinolisalesspotentinhibitorofxanthineoxidasethanallopurinol,buttheplasmahalf-lifeofoxipurinolisfar

moreprolonged.Estimatesrangefrom13to30hoursinman.Thereforeeffectiveinhibitionofxanthineoxidaseis

maintainedovera24hourperiodwithasingledailydoseofallopurinol.Patientswithnormalrenalfunctionwill

graduallyaccumulateoxipurinoluntilasteady-stateplasmaoxipurinolconcentrationisreached.

Suchpatientstaking300mgofallopurinolperdaywillgenerallyhaveplasmaoxipurinolconcentrationsof5-

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Oxipurinoliseliminatedunchangedintheurinebuthasalongeliminationhalf-lifebecauseitundergoestubular

reabsorption.Reportedvaluesfortheeliminationhalf-lifefrom13.6hoursto29hours.Thelargediscrepanciesinthese

valuesmaybeaccountedforbyvariationinstudydesignand/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.

Evidencefrombiochemicalandothercytologicalinvestigationsstronglysuggeststhatallopurinolhasnodeleterious

effectsonDNAatanystageofthecellcycleandisnotmutagenic.

Carcinogenicity

Noevidenceofcarcinogenicityhasbeenfoundinmiceandratstreatedwithallopurinolforupto2years.

Teratogenicity

Onestudyinmicereceivingintraperitonealdosesof50or100mg/kgondays10or13ofgestationresultedinfoetal

abnormalities,howeverinasimilarstudyinratsat120mg/kgonday12orgestationnoabnormalitieswereobserved.

Extensivestudiesofhighoraldosesofallopurinolinmiceupto100mg/kg/day,ratsupto200mg/kg/dayandrabbitsup

to150mg/kg/dayduringdays8to16ofthegestationproducednoteratogeniceffects.

Aninvitrostudyusingfoetalmousesalivaryglandsinculturetodetectembryotoxicitywithoutalsocausingmaternal

toxicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Pregelatinisedmaizestarch1500

Sodiumstarchglycolate(TypeA)

Colloidalanhydroussilica

Magnesiumstearate

PovidoneK30

6.2Incompatibilities

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6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Donotstoreabove25 0

C.Keeptabletcontainertightlyclosed.

6.5Natureandcontentsofcontainer

Polypropylenecontainerswithtamper-evidentpolyethyleneclosures.Eachcontainerisofasuitablesizetohold50,

100,250,500and1000tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NortonHealthcareLimited

AlbertBasin

RoyalDocks

London

E162QJ

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0282/021/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization: 01December1982

Dateoflastrenewal: 01December2007

10DATEOFREVISIONOFTHETEXT

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