ALLOPURINOL TABLETS BP 300MG

Main information

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

Documents

Localization

  • Available in:
  • ALLOPURINOL TABLETS BP 300MG
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/013/002
  • Authorization date:
  • 25-02-1992
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AllopurinolTabletsBP300mg

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains:

Allopurinol300.00mg

Excipients:Alsoincludeslactosemonohydrate,154mgpertablet.

Forafulllistofexcipients,seesectionsection6.1

3PHARMACEUTICALFORM

Tablet

White,biconvextabletsabout11.0mmindiameter,markedAPover300ononesideandRonthereverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Allopurinolisindicatedforreducingurate/uricacidformationinconditionswhereurate/uricaciddepositionhas

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

malignancypotentiallyleadingtoacuteuricacidnephropathy).

Themainclinicalconditionswhereurate/uricaciddepositionmayoccurare:

Idiopathicgout

Uricacidlithiasis

Acuteuricacidnephropathy

Neoplasticdiseaseandmyeloproliferativediseasewithhighcellturnoverrates,inwhichhighuratelevels

occureitherspontaneously,oraftercytotoxictherapy

Certainenzymedisorderswhichleadtooverproductionofurate,forexample

hypoxanthine-guaninephosphoribosyltransferase,includingLesch-Nyhansyndrome

glucosephosphataseincludingglycogenstoragedisease

phosphoribosylpyrophosphatesynthetase

phosphoribosylpyrophosphateamidotransferase

adeninephosphoribosyltransferase

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

activityofadeninephosphoribosyltranferase

Allopurinolisindicatedforthemanagementofrecurrentmixedcalciumoxalaterenalstonesinthepresenceof

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4.2Posologyandmethodofadministration

Fororaladministrationonly.

Allopurinolshouldbeintroducedatlowdosagee.g.100mg/daytoreducetheriskofadversereactionsandincreased

onlyiftheserumurateresponseisunsatisfactory.Extracautionshouldbeexercisedifrenalfunctionispoor(see

Dosageinrenalimpairment).Thefollowingdosageschedulesaresuggested:

100mgto200mgdailyinmildconditions;

300mgto600mgdailyinmoderatelysevereconditions;

700mgto900mgdailyinsevereconditions.

Dosagehigherthan300mgshouldbegivenindivideddosesnotexceeding300mgatanytime.Ifdosageonamg/kg

bodyweightbasisisrequired,2to10mg/kgbodyweight/dayshouldbeused.

Dosageinchildren:

Childrenunder15years:10mgto20mg/kgbodyweight/dayuptoamaximumof400mgdaily.Useinchildrenis

rarelyindicated,exceptinmalignantconditions(especiallyleukaemia)andcertainenzymedisorderssuchasLesch-

Nyhansyndrome.

Dosageintheelderly:

Intheabsenceofspecificdata,thelowestdosagewhichproducessatisfactoryuratereductionshouldbeused.

ParticularattentionshouldbepaidtoadviceinDosageinrenalimpairmentandSection4.4,SpecialWarningsand

PrecautionsforUse.

Dosageinrenalimpairment:

SinceAllopurinolanditsmetabolitesareexcretedbythekidney,impairedrenalfunctionmayleadtoretentionofthe

drugand/oritsmetaboliteswithconsequentprolongationofplasmahalf-lives.Insevererenalinsufficiency,itmaybe

advisabletouselessthan100mgperdayortousesingledosesof100mgatlongerintervalsthanoneday.

Iffacilitiesareavailabletomonitorplasmaoxipurinolconcentrations,thedoseshouldbeadjustedtomaintainplasma

oxipurinollevelsbelow100micromol/litre(15.2mg/litre)

Allopurinolanditsmetabolitesareremovedbyrenaldialysis.Ifdialysisisrequiredtwotothreetimesaweek

considerationshouldbegiventoanalternativedosagescheduleof300mg-400mgAllopurinolimmediatelyaftereach

dialysiswithnoneintheinterim.

Dosageinhepaticimpairment:

Reduceddosesshouldbeusedinpatientswithhepaticimpairment.Periodicliverfunctiontestsarerecommended

duringtheearlystagesoftherapy.

Treatmentofhighurateturnoverconditionse.g.neoplasia,Lesch-Nyhansyndrome:

Itisadvisabletocorrectexistinghyperuricaemiaand/orhyperuricosuriawithAllopurinolbeforestartingcytotoxic

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Itisimportanttoensureadequatehydrationtomaintainoptimumdiuresisandtoattemptalkalinisationorurineto

increasesolubilityofurinaryurate/uricacid.DosageofAllopurinolshouldbeatthelowerendoftherecommended

dosageschedule.

Ifuratenephropathyorotherpathologyhascompromisedrenalfunction,theadvicegiveninDosageinrenal

impairmentshouldbefollowed.

Thesestepsmayreducetheriskofxanthineand/oroxipurinoldepositioncomplicatingtheclinicalsituation.Seealso

Section4.5,InteractionwithOtherMedicinalProductsandOtherFormsofInteractionandUndesirableEffects.

MonitoringAdvice:

Thedosageshouldbeadjustedbymonitoringserumurateconcentrationsandurinaryurate/uricacidlevelsat

appropriateintervals.

InstructionsforUse:

Allopurinolmaybetakenorallyonceadayafterameal.Itiswelltolerated,especiallyafterfood.Shouldthedaily

dosageexceed300mgandgastrointestinalintolerancebemanifested,adivideddoseregimenmaybeappropriate.

4.3Contraindications

UseinpatientshypersensitivetoAllopurinolortoanyofthecomponentsofthismedicine.Useinpatientswhoare

breastfeedinginfants.Useinacutegout.

4.4Specialwarningsandprecautionsforuse

Allopurinolshouldbewithdrawnimmediatelyifaskinrashorotherevidenceofsensitivityoccurs.

Reduceddosesshouldbeusedinpatientswithhepaticorrenalimpairment.Patientsundertreatmentforhypertension

orcardiacinsufficiency,forexamplewithdiureticsorACEinhibitors,mayhavesomeconcomitantimpairmentofrenal

functionandallopurinolshouldbeusedwithcareinthisgroup.

AsymptomatichyperuricaemiaperseisgenerallynotconsideredanindicationforuseofAllopurinol.Fluidand

dietarymodificationwithmanagementoftheunderlyingcausemaycorrectthecondition.

Acutegoutyattacks:

Allopurinoltreatmentshouldnotbestarteduntilanacuteattackofgouthascompletelysubsided,asfurtherattacksmay

beprecipitated.

IntheearlystagesoftreatmentwithAllopurinol,aswithuricosuricagents,anacuteattackofgoutyarthritismaybe

precipitated.Therefore,itisadvisabletogiveprophylaxiswithasuitableanti-inflammatoryagentorcolchicinesforat

leastonemonth.Theliteratureshouldbeconsultedfordetailsofappropriatedosageandprecautionsandwarnings.

Ifacuteattacksdevelopinpatientsreceivingallopurinol,treatmentshouldcontinueatthesamedosagewhiletheacute

attackistreatedwithasuitableanti-inflammatoryagent.

Xanthinedeposition:

Inconditionswheretherateofurateformationisgreatlyincreased(e.g.malignantdiseaseanditstreatment,Lesch-

NyhanSyndrome)theabsoluteconcentrationofxanthineinurinecould,inrarecases,risesufficientlytoallow

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Impactionofuricacidrenalstones:

AdequatetherapywithAllopurinolwillleadtodissolutionoflargeuricacidrenalpelvicstones,withtheremote

possibilityofimpactionintheureter.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

6-mercaptopurineandazathioprine:

Azathioprineismetabolisedto6-mercaptopurinewhichisinactivatedbytheactionofxanthineoxidase.When6-

mercaptopurioneorazathioprineisgivenconcurrentlywithAllopurinol,onlyonequarteroftheusualdoseof6-

mercaptopurineorazathioprineshouldbegivenbecauseinhibitionofxanthineoxidasewillprolongtheiractivity.

Vidarabine(AdenineArabinoside)

Evidencesuggeststhattheplasmahalf-lifeofvidarabineisincreasedinthepresenceofallopurinol.Whenthetwo

productsareusedconcomitantlyextravigilanceisnecessary,torecogniseenhancedtoxiceffects.

Salicylatesanduricosuricagents

Oxipurinol,themetaboliteofallopurinolanditselftherapeuticallyactive,isexcretedbythekidneyinsimilarwayto

urate.Hence,drugswithuricosuricactivitysuchasprobenecidorlargedosesofsalicylatemayacceleratetheexcretion

ofoxipurinol.ThismaydecreasethetherapeuticactivityofAllopurinol,butthesignificanceneedstobeassessedin

eachcase.

Chlorpropamide

IfAllopurinolisgivenconcomitantlywithchlorpropamidewhenrenalfunctionispoor,theremaybeanincreasedrisk

ofprolongedhypoglycaemicactivitybecauseallopurinolandchlorpropamidemaycompeteforexcretionintherenal

tubule.

Coumarinanticoagulants

Therehavebeenrarereportsofincreasedeffectofwarfarinandothercoumarinanticoagulantswhenco-administered

withallopurinol,allpatientsreceivinganticoagulantsmustbecarefullymonitored.

Phenytoin

Allopurinolmayinhibithepaticoxidationofphenytoinbuttheclinicalsignificancehasnotbeendemonstrated.

Theophylline

Inhibitionofthemetabolismoftheophyllinehasbeenreported.Themechanismoftheinteractionmaybeexplainedby

xanthineoxidasebeinginvolvedinthebiotransformationoftheophyllineinman.Theophyllinelevelsshouldbe

monitoredinpatientsstartingorincreasingallopurinoltherapy.

Ampicillin/Amoxicillin

Anincreaseinthefrequencyofskinrashhasbeenreportedamongpatientsreceivingampicillinoramoxicillin

concurrentlywithallopurinolcomparedtopatientswhoarenotreceivingbothdrugs.Thecauseofthereported

associationhasnotbeenestablished.However,itisrecommendedthatinpatientsreceivingallopurinolanalternative

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Cyclophosphamide,doxorubicin,bleomycin,procarbazine,mechloroethamine

Enhancedbonemarrowsuppressionbycyclophosphamideandothercytotoxicagentshasbeenreportedamongpatients

withneoplasticdisease(otherthanleukaemia),inthepresenceofallopurinol.Howeverinawellcontrolledstudyof

patientstreatedwithcyclophosphamide,doxorubicin,bleomycin,procarbazineand/ormechloroethamine(mustine

hydrochloride)allopurinoldidnotappeartoincreasethetoxicreactionofthesecytotoxicagents.

Cyclosporin

Reportssuggestthattheplasmaconcentrationofcyclosporinmaybeincreasedduringconcomitanttreatmentwith

allopurinol.Thepossibilityofenhancedcyclosporintoxicityshouldbeconsideredifthedrugsareco-administered.

Didanosine

InhealthyvolunteersandHIVpatientsreceivingdidanosine,plasmadidanosineCmaxandAUCvalueswere

approximatelydoubledwithconcomitantallopurinoltreatment(300mgdaily)withoutaffectingterminalhalflife.

Therefore,dosereductionsofdidanosinemayberequiredwhenusedconcomitantlywithallopurinol.

4.6Pregnancyandlactation

ThereisinadequateevidenceofsafetyofAllopurinolinhumanpregnancy,althoughithasbeeninwideuseformany

yearswithoutapparentillconsequence.

Useinpregnancyonlywhenthereisnosaferalternativeandwhenthediseaseitselfcarriesriskforthemotheror

unbornchild.

Lactation:

Reportsindicatethatallopurinolandoxipurinolareexcretedinhumanbreastmilk.Concentrationsof1.4mg/litre

allopurinoland53.7mg/litreoxipurinolhavebeendemonstratedinbreastmilkfromawomantakingAllopurinol

300mg/day.However,therearenodataconcerningtheeffectsofallopurinoloritsmetabolitesonthebreast-fedbaby.

4.7Effectsonabilitytodriveandusemachines

Sinceadversereactionssuchassomnolence,vertigoandataxiahavebeenreportedinpatientsreceivingallopurinol,

patientsshouldexercisecautionbeforedriving,usingmachineryorparticipatingindangerousactivitiesuntiltheyare

reasonablycertainthatallopurinoldosenotadverselyaffectperformance.

4.8Undesirableeffects

AdversereactionsinassociationwithAllopurinolarerareintheoveralltreatedpopulationandmostlyofaminor

nature.Theincidenceishigherinthepresenceofrenaland/orhepaticdisorder.

Skinandhypersensitivityreactions

Thesearethemostcommonreactionsandmayoccuratanytimeduringtreatment.Theymaybepruritic,

maculopapular,sometimesscaly,sometimespurpuricandrarelyexfoliative.Allopurinolshouldbewithdrawm

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,

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Corticosteroidsmaybebeneficialinovercominghypersensitivityskinreactions.Whengeneralisedhypersensitivity

reactionshaveoccurred,renaland/orhepaticdisorderhasusuallybeenpresentparticularlywhentheoutcomehasbeen

fatal.

Veryrarelyacuteanaphylacticshockhasbeenreported.

Angioimmunoblasticlymphadenopathy

Angioimmunoblasticlymphadenopathyhasbeendescribedrarelyfollowingbiopsyofageneralisedlymphadenopathy.

ItappearstobereversibleonwithdrawalofAllopurinol.

Hepaticfunction

Rarecasesofhepaticdysfunctionrangingfromasymptomaticrisesinliverfunctionteststohepatitis(includinghepatic

necrosisandgranulomatoushepatitis)havebeenreportedwithoutovertevidenceofmoregeneralisedhypersensitivity.

Gastrointestinaldisorder

Inearlyclinicalstudies,nauseaandvomitingwerereported.Furtherreportssuggestthatthisreactionisnota

significantproblemandcanbeavoidedbytakingAllopurinolaftermeals.

Recurrenthaematemesishasbeenreportedasanextremelyrareevent,ashassteatorrhoea.

Bloodandlymphaticsystem

Occasionalreportshavebeenreceivedofthrombocytopenia,agranulocytosisandaplasticanaemia,particularlyin

individualswithimpairedrenaland/orhepaticfunction,reinforcingtheneedforparticularcareinthisgroupofpatients

Miscellaneous

Thefollowingcomplaints,havebeenreportedoccasionally;fever,generalmalaise,asthenia,headache,vertigo,ataxia,

somnolence,coma,depression,paralysis,paraesthesia,neuropathy,visualdisorder,cataract,macularchanges,taste

perversion,stomatitis,changedbowelhabit,infertility,impotence,diabetesmellitus,hyperlipaemia,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-mercaptopurioneand/orazathioprine.

Adequatehydrationtomaintainoptimumdiuresisfacilitatesexcretionofallopurinolanditsmetabolites.Ifconsidered

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup

Allopurinolisaxanthine-oxidaseinhibitor.

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/kg,which

suggestsrelativelyextensiveuptakebytissues.Tissueconcentrationsofallopurinolhavenotbeenreportedinhumans,

butitislikelythatallopurinolandoxipurinolwillbepresentinthehighestconcentrationsintheliverandintestinal

mucosawherexanthineoxidaseactivityishigh.

Approximately20%oftheingestedallopurinolisexcretedinthefaeces.Eliminationofallopurinolismainlyby

metabolicconversiontooxipurinolbyxanthineoxidaseandaldehydeoxidasewithlessthan10%oftheunchanged

drugexcretedintheurine.Allopurinolhasaplasmahalf-lifeofabout1-2hours.

Oxipurinolisalesspotentinhibitorofxanthineoxidasethanallopurinol,buttheplasmahalf-lifeofoxipurinolisfar

moreprolonged.Estimatesrangefrom13to30hoursinman.Thereforeeffectiveinhibitionofxanthineoxidaseis

maintainedovera24-hourperiodwithasingledailydoseofAllopurinol.Patientswithnormalrenalfunctionwill

graduallyaccumulateoxipurinoluntilasteady-stateplasmaoxipurinolconcentrationisreached.Suchpatients,taking

300mgofallopurinolperdaywillgenerallyhaveplasmaoxipurinolconcentrationsof5-10mg/litre.

Oxipurinoliseliminatedunchangedintheurinebuthasalongeliminationhalf-lifebecauseitundergoestubular

reabsorption.Reportedvaluesfortheeliminationhalf-liferangefrom13.6hoursto29hours.Thelargediscrepancies

inthesevaluesmaybeaccountedforbyvariationsinstudydesignand/orcreatinineclearanceinthepatients.

Pharmacokineticsinpatientswithrenalimpairment

Allopurinolandoxipurinolclearanceisgreatlyreducedinpatientswithpoorrenalfunctionresultinginhigherplasma

levelsinchronictherapy.Patientswithrenalimpairment,wherecreatinineclearancevalueswerebetween10and

20ml/min,showedplasmaoxipurinolconcentrationsofapproximately30mg/litreafterprolongedtreatmentwith

300mgallopurinolperday.Thisisapproximatelytheconcentration,whichwouldbeachievedbydoseof600mg/day

inthosewithnormalrenalfunction.AreductioninthedoseofAllopurinolisthereforerequiredinpatientswithrenal

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Pharmacokineticsinelderlypatients

Thekineticsofthedrugarenotlikelytobealteredotherthanduetodeteriorationinrenalfunction(see

Pharmacokineticsinpatientswithrenalimpairment).

5.3Preclinicalsafetydata

Mutagenicity

Cytogenicitystudiesshowthatallopurinoldoesnotinducechromosomeaberrationsinhumanbloodcellsinvitroat

concentrationsupto100microgram/mlandinvivoatdosesupto600mg/dayforameanperiodof40months.

Allopurinoldoesnotproducenitrosocompoundsinvitrooraffectlymphocytetransformationinvitro.

Evidencefrombiochemicalandothercytologicalinvestigationsstronglysuggestthatallopurinolhasnodeleterious

effectsonDNAatanystageofthecellcycleandisnotmutagenic.

Carcinogenicity

Noevidenceofcarcinogenicityhasbeenfoundinmiceandratstreatedwithallopurinolforupto2years.

Teratogenicity

Onestudyinmicereceivingintraperitonealdosesof50or100mg/kgondays10to13ofgestationresultedinfoetal

abnormalities,howeverinasimilarstudyinratsat120mg/kgonday12ofgestationnoabnormalitieswereobserved.

Extensivestudiesofhighoraldosesofallopurinolinmiceupto100mg/kg/day,ratsupto200mg/kg/dayandrabbitsup

to150mg/kg/dayduringdays8to16ofthegestationproducednoteratogeniceffects.

Aninvitrostudyusingfoetalmousesalivaryglandsinculturetodetectembryotoxicityindicatedthatallopurinol

wouldnotbeexpectedtocauseembryotoxicitywithoutalsocausingmaternaltoxicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LactoseMonohydrate

MaizeStarch

Povidone

SodiumStarchGlycolate(TypeA)

MagnesiumStearate

6.2Incompatibilities

Notapplicable

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

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6.5Natureandcontentsofcontainer

Whitepolypropylenecontainerswithtamperevidentclosurescontaining1000,500or100tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLtd

Spafield

CorkRoad

Cashel

CoTipperary

8MARKETINGAUTHORISATIONNUMBER

PA0408/013/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 25February1992

Dateoflastrenewal: 25February2007

10DATEOFREVISIONOFTHETEXT

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