Allopurinol Sandoz

Main information

  • Trade name:
  • Allopurinol Sandoz 300 mg Tablet
  • Dosage:
  • 300 mg
  • Pharmaceutical form:
  • Tablet
  • Units in package:
  • Bottle, plastic, HDPE, 30 tablets, 30 tablets
  • Class:
  • Prescription
  • Prescription type:
  • Prescription
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug
  • Manufactured by:
  • Sicor (Societa Italiana Corticosteroidi) Srl

Documents

Localization

  • Available in:
  • Allopurinol Sandoz 300 mg Tablet
    New Zealand
  • Language:
  • English

Other information

Status

  • Source:
  • Medsafe - Medicines Safety Authority - New Zealand
  • Authorization number:
  • 8598
  • Authorization date:
  • 28-10-1998
  • Last update:
  • 27-09-2017

Summary of Product characteristics: dosage,interactions,side effects

NEWZEALANDDATASHEET

Allopurinol Sandoz ®

AllopurinolPh Eur,tablets,100mgand300mg

Presentation

100 mg

White,round,plain,uncoatedtablets, scored on oneside.Each tabletcontainsallopurinol100 mg.

300 mg

Whitetooff-white,17 mmx7mmoblong,biconvexplain,uncoatedtabletswithabreakingnotch on

bothsides.Each tabletcontainsallopurinol300 mg.

Uses

Actions

Allopurinolisusedtodecrease uricacid concentrationsin plasma and/or urinewhenhyperuricaemia

isclinicallysignificant.

Pharmacotherapeuticgroup

M04AA01-Preparationsinhibitinguricacid production, allopurinol.

Mechanism ofaction

Allopurinolinhibitsxanthineoxidase, the enzymewhich catalysestheoxidation ofhypoxanthineto

xanthine,andofxanthineto urate/uricacid.

Pharmacodynamiceffects

Allopurinolanditsmain metabolite oxypurinollower the levelofuricacidinplasma and urinein two

ways:theinhibitionofxanthine oxidasereducesthe amountofhypoxanthineandxanthineconverted

tourate/uricacid;thisaction, in some butnotallhyperuricaemicpatients,makesmore hypoxanthine

and xanthineavailablefor reutilisation in the purine metaboliccycle,whichinturn,depressesoverall

denovopurinebiosynthesisviafeedbackinhibitionofhypoxanthine-guanine

phosphorbosyltransferase.

Withtheloweredurate/uricacidlevelsin serumandurineproducedbyallopurinolthere are also

increasedlevelsofthesubstrateshypoxanthineand xanthine. Plasma concentrationsofthese

oxypurinesare onlyslightlyincreased andthe rateandextentoftheirrenalclearance isgreaterthan

thatofuricacid.Intheabsence ofallopurinol, normalurinaryoutput ofoxypurinesisalmost solelyin

theformofuricacid.After administration ofallopurinol, itiscomposedofhypoxanthine,xanthineand

uricacid,eachwith different solubilityproperties. Consequently,theconcentrationofuricacidin

plasma isreducedwithoutexposing the urinarytract to anexcessiveloadofurate/uricacid,thus

decreasing the riskofcrystalluria. Byloweringtheuricacid concentrationintheplasma belowits

limitsofsolubility,allopurinolfacilitatesdissolutionoftophi. Althoughthelevelsofhypoxanthineand

xanthineare increased,theriskoftheirdeposition islessthanthatofuricacidastheyare more

solubleandare rapidlyclearedbythe kidney. Howevertoavoid xanthinestonesbeing deposited,itis

advisable to maintain ahigh fluidintake anda neutralor alkalineurinarypH, especiallyifinitialuric

acid concentrationsare high and the patientissymptomatic.

Reductionofthe urateconcentrationsinbodyfluidsbyallopurinolpermitsmobilisationand dissolution

ofuratedepositsanywherein thebody, thecommonest sitesbeingthoseintheskin,bones, joints

and kidneyinterstitialtissue.Therapeuticeffectstherefore include:theresolutionofskin tophiandthe

healing ofurate sinuses; eventualreductionin thefrequencyofattacksofacutegoutyarthritis,

improvement in jointmobility;reduction oftheurate load tobeexcreted viathekidney;preventionand

treatment ofacuteuricacidnephropathy; and,in thelong-term, reducedriskofrenalimpairment by

urate/uricacidand preventionanddissolution ofuricacid renalstones.

Onsetanddurationofaction

Serumurateconcentrationsusuallybegintodeclineslowlywithin 48 to72hoursreachingaplateau

after 1 to3weeksoftherapy.However,in patientswithtophaceousgoutor thosewhoare

undersecretorsofuricacid,adecline in serumuratelevelsmaybe delayed for thefirst fewmonths.

Pharmacokinetics

Absorption

Allopurinolisactivewhen givenorallyandisrapidlyabsorbedfromthe upper gastrointestinaltract.

Studieshave detected allopurinolintheblood30to 60 minutesafter dosing.Estimatesof

bioavailabilityvaryfrom67% to 90%.Peakplasma levelsofallopurinolgenerallyoccur approximately

1.5hoursafter oraladministration,butfallrapidlyandare barelydetectableafter sixhours. Peak

plasma levelsofoxypurinolgenerallyoccur threetofive hoursafter oraladministrationofallopurinol

andare muchmore sustained.

Distribution

Theapparentvolume ofdistributionofallopurinolisapproximately1.6litres/kg which suggests

relativelyextensiveuptakebytissues.Allopurinolisuniformlydistributedin totaltissuewaterwiththe

exclusionofthebrain,where concentrationsofthedrugsare approximately50%ofthose ofother

tissues.Within muscles, smallamountsofallopurinolandoxypurinolcrystalshavebeen found.

Allopurinolisnegligiblyboundbyplasma proteinsandtherefore variationsinprotein binding arenot

thought to significantlyalterclearance.Allopurinolandoxypurinolarepresent inbreast milk.

Biotransformation

Allopurinolisrapidlyconvertedin thebodytothepharmacologicallyactiveprincipalmetabolite

oxypurinolandother metabolitesincluding allopurinolriboside and oxypurinol-7-ribose.Peakplasma

levelsgenerallyoccur at1.5 hoursand4.5hoursfor allopurinolandoxypurinolrespectively.

Oxypurinolisalso an inhibitor ofxanthineoxidase.

Elimination

Eliminationofallopurinolismainlybymetabolicconversionto oxypurinolbyxanthineoxidaseand

aldehydeoxidase,withlessthan10%ofthe unchanged medicineand70%asoxypurinolexcretedin

theurine.Approximately20% ofthe ingestedallopurinolisexcretedunchangedinthe faeces.

Becauseofitsrapid oxidationtooxypurinoland arenalclearance rate approximatelythatof

glomerular filtration rate, allopurinolhasa plasma half-life ofaboutone totwohours.Littleallopurinol

isfoundin theurinesixhoursafter administration.Oxypurinol,however, hasalongerplasma half-life

(approximately15.0hours)andtherefore effectiveinhibitionofxanthineoxidase ismaintained over a

24hourperiodwith asingledailydoseofallopurinol.Patientswithnormalrenalfunctionwillgradually

accumulateoxypurinoluntilasteady-state plasma oxypurinolconcentration isreached.Such patients,

taking300mg ofallopurinolperdaywillgenerallyhaveplasma oxypurinolconcentrationsof5to10

mg/l.Whereasallopurinolisclearedessentiallybyglomerular filtration, oxypurinolisreabsorbed in the

kidneytubulesin amannersimilar to thereabsorptionofuricacid.

Therenalclearance ofhypoxanthineand xanthineisat least tentimesgreaterthan that ofuricacid.

Theincreasedxanthineand hypoxanthineintheurinehave notbeenaccompaniedbyproblemsof

nephrolithiasis.

Specialpatientconsiderations

Patientswithrenalimpairment:

Allopurinolandoxypurinolclearance isgreatlyreducedinpatientswithpoor renalfunction resultingin

higherplasma levelsin chronictherapy.Patientspresentingrenalimpairment, where creatinine

clearancevalueswerebetween10and20ml/min,showedplasma oxypurinolconcentrationsof

approximately30 mg/lafter prolongedtreatment with300mg allopurinolper day.Thisis

approximatelythe concentrationwhichwould be achievedbydosesof600 mg/dayin thosewith

normalrenalfunction.Areduction in the dose istherefore requiredinpatientswith renalimpairment.

Elderlypatients:

Pharmacokineticsin elderlyare not likelyto be alteredother thandue todeteriorationin renal

function.

Indications

Allopurinolismainlyusedin themanagement ofprimarygoutor secondaryhyperuricaemia

associatedwith chronicgout.Itisnot, however, used to treatanacuteattackofgoutasit hasno

analgesic,anti-Inflammatoryor uricosuricactivityandmayprolong the attack. Ifchanging therapy

fromauricosuricagent alone, thedose shouldbereducedgraduallywhileallopurinolisintroduced.In

severe casesofchronicgout,allopurinolcanbeusedtogetherwitha uricosuricagent unlessthelatter

iscontra-indicated.

Uricacidnephropathy.

Recurrent uricacidstoneformation.

Certainenzyme disordersorblood disorderswhichlead tooverproductionofurate(e.g. Lesch-Nyhan

syndrome;haemolyticanaemia).

Hyperuricaemia associatedwithmalignancyand cytotoxictherapywhich result inahighcellturnover

rate.

Thepreventionandtreatment ofcalciumoxalate/phosphate renalstonesin the presence ofhighuric

acidlevelsofthe blood and/or urine.

Dosageandadministration

AllopurinolSandozmaybetakenonce dailyafter a meal. Itisnormallywelltolerated, especiallyafter

food.Should thetotaldailydose exceed 300 mg and/orgastrointestinalintolerance be manifested,a

divideddosesregimenmaybeappropriate.Thedosage shouldbeadjustedbymonitoringserum

urate concentrationsandurinaryurate/uricacidlevelsatappropriateintervals.

Adults

Theaveragedailydoseis2to10 mg/kg bodyweight, or100 to 200mgformild conditions,300 to600

mgformoderatelysevere conditionsand700to 900mgforsevere conditions.

Initiatingtherapy

Allopurinolmayincrease the frequencyofacuteattacksduringthefirst fewmonthsoftherapy;itis

therefore recommended thatlowdosesbegiveninitiallyandslowlyincreased,and that anti-

inflammatoryagentsor colchicine shouldbegiven concomitantlyduringthisperiod asprophylactic

cover.In patientswithgoodrenalfunction,dosesof100 mg shouldbegivenandincreasedby50mg

to100 mg atweeklyintervalsuntilserumuratelevelsof0.6 mg permlare achieved.

Hyperuricaemia ofmalignancyor cancer therapy

Therapyshouldbeinitiated2to3 daysprior tocytotoxictherapyafterwhich maintenancedosesare

givenaccording toresponse.Adequatehydrationisessentialthroughout.

Children

Theaveragedailydoseis10 to20mg/kg bodyweightuptoa maximumof400mg daily. Usein

childrenisrarelyindicated,except in malignant conditionsand certain enzyme disorders.

Usein theelderly

Thelowestdose,whichproducessatisfactoryurate reduction,should beused.Specialattention to

dosageisnecessaryifthere isovert renaldysfunction.

Useinrenaldysfunction

Theexcretionofallopurinolanditsmetabolitesisprolongedso dosagereductionsare recommended.

Dosesof100 to 200mg dailyshould be used ifcreatinineclearanceisbetween 10to20ml/min.and

not more than100mg per dayshouldbeusedifclearance isless. These dosesmaybehalvedor

reducedevenfurtherwheninitiating therapyandthenslowlyincreased dependingonresponse.

Contraindications

Known hypersensitivitytoallopurinol, itsmetabolites, ortoanyofthe inactiveingredientslistedin

Further information.

Allopurinolshould notbe givenconcomitantlywithironsaltstopatientswith idiopathic

haemochromatosis, nor should itbegiven totheimmediate relativesofsuch patients.

Warningsandprecautions

Warnings

Allopurinolmustbewithdrawnimmediatelyand permanentlyatthefirst signsofintoleranceespecially

whena skin rash orotherallergicresponseoccurs.Insome instancesa skin rash maybefollowedby

more severe hypersensitivityreactionssuchasexfoliative,urticarial,and purpuriclesionsaswellas

Stevens-Johnsonsyndrome (erythemamultiforme exudativum), and/orgeneralised vasculitis,

irreversible hepatotoxicity,andonrareoccasionsdeath.

Precautions

Mild asymptomatichyperuricaemia per se isgenerallynot considered an indication forallopurinol

treatment. Fluid anddietarymodificationwithmanagement ofthe underlying cause maycorrect the

condition.Ingeneral, allopurinolshouldonlybeconsidered ifserumurateconcentrationsexceed0.8

to0.9 mg/mlwithan aimofreducing levelsto 0.6 mg/ml.

Allopurinoltreatment should notbestarteduntilanacuteattackofgouthascompletelysubsided,as

further attacksmaybeprecipitated.In the earlystagesoftreatment withallopurinol,aswithother

uricosuricagents,anacuteattackofgoutyarthritismaybeprecipitated. Therefore it isadvisable to

give prophylaxiswithasuitable anti-inflammatoryagentor colchicinefor atleastone month.The

literature should be consultedfor detailsofappropriatedosage and precuationsandwarnings.

Ifacuteattacksdevelop inpatientsreceiving allopurinol, treament should continue at thesame

dosagewhiletheacute attackistreatedwith asuitableanti-inflammatoryagent.

Inconditionswhere therate ofurateformationisgreatlyincreased (e.g.malignantdiseaseand its

treatment, Lesch-Nyhansyndrome) theconcentrationofxanthine in urinecouldapproach saturation

leadingtostoneformationin theurinarytract. Thisriskmaybeminimisedbyadequatefluidintaketo

achieveoptimalurine dilution.

Adequate therapywithallopurinolwilllead todissolutionoflarge uricacid renalpelvicstones,withthe

remotepossibilityofimpactionintheureter.

Theoccurrence ofhypersensitivityreactionstoallopurinolmaybe increasedinpatientswith

decreasedrenalfunction receivingthiazidesand allopurinolconcurrently. Forthisreason,inthis

clinicalsetting,such combinationsshouldbeadministeredwithcautionandpatientsshould be

observed closely.

Bone marrowdepressionhasbeen reportedinpatientsreceivingallopurinol, most ofwhomreceived

concomitant medicineswiththepotentialfor causingthiseffect. Thishasoccurredasearlyassix

weekstoaslong assixyearsafter theinitiationoftherapyofallopurinol.Rarelyapatient maydevelop

varying degreesofbonemarrow depression,affectingoneor more celllines,while receiving

allopurinolalone.

Allopurinol'sprimaryactionin treatinggoutistoinhibittheenzyme,xanthineoxidase.Xanthine

oxidase maybe involved inthe reductionand clearance ofhepaticallystored iron.Some rodent

studieshave found increasediron storagein animalstreatedwith allopurinol,while othershavenot.A

studyin28healthyvolunteersfoundnochangein hepaticiron storagewithallopurinoltreatment.

There are nohumanstudieswhich have investigated thesafetyofadministering allopurinoltopatients

withhaemochromatosis. Administrationofallopurinolto patientswith abnormaliron storage, including

haemochromatosis, shouldbeundertakenwithcaution.

Dosage reductionshould be considered for patientswithhepaticor renalimpairment.

Some patientswithpre-existingrenaldisease orpoorurate clearancehave shown arisein serum

urea during administrationofallopurinol. Althoughthemechanismresponsiblefor thishasnotbeen

established,patientswithimpairedrenalfunction shouldbecarefullyobserved duringtheearlystages

ofallopurinoladministrationanddosage decreasedor themedicinewithdrawn ifincreased

abnormalitiesin renalfunctionappear and persist.Patientsundertreatment for hypertensionor

cardiacinsufficiency, for example withdiureticsorACEinhibitors, mayhave some concomitant

impairment ofrenalfunction and allopurinolshouldbeusedwithcareinthisgroup.

Renalfailurein associationwithadministrationofallopurinolhasbeenobservedamong patientswith

hyperuricaemia secondarytoneoplasticdiseases.Concurrent conditionssuchasmultiple myeloma

and congestive myocardialdiseasewerepresentamongthose patientswhose renaldysfunction

increasedafter allopurinolwasbegun.Renalfailureisalso frequentlyassociatedwithgouty

nephropathyand rarelywith hypersensitivityreactionsassociatedwithallopurinol.Albuminuriahas

beenobservedamong patientswho developedclinicalgoutfollowing chronicglomerulonephritisand

chronicpyelonephritis.

Afew casesofreversibleclinicalhepatotoxicityhave beennoted in patientstakingallopurinol,andin

some patientsasymptomaticrisesin serumalkalinephosphatase orserumtransaminase have been

observed.Ifanorexia,weightlossor pruritusdevelopin patientsonallopurinol,evaluationofliver

functionshould bepartoftheirdiagnosticworkup. Inpatientswithpre-existingliverdisease,periodic

liver functiontestsare recommended duringtheearlystagesoftherapy.

Pregnancyand lactation

Usein pregnancy

Assigned CategoryB2bytheAustralianDrugEvaluationCommittee.Thiscategoryincludes

medicineswhichhavebeen takenbyonlyalimitednumberofpregnantwomenandwomenof

childbearingage,withoutan increase in the frequencyofmalformationor otherdirect orindirect

harmfuleffectsonthe humanfoetushaving beenobserved. Studiesin animalsareinadequate ormay

belacking, butavailable datashownoevidence ofanincreasedoccurrenceoffoetaldamage.

There isinadequate evidence ofsafetyofallopurinolinhumanpregancy,althoughit hasbeeninwide

use formanyyearswithoutapparentillconsequence.Use inpregnancyonlywhen thereisno safer

alternative andwhenthedisease itselfcarriesriskfor themother orunborn child.

Usein lactation

Reportsindicatethatallallopurinoland oxypurinolareexcreted in humanbreastmilk. Concentrations

of1.4 mg/litre allopurinoland53.7mg/litreoxypurinolhave beendemonstratedinbreast milkfroma

womantakingallopurinol300mg/day.However, thereare nodata concerning theeffectsof

allopurinoloritsmetabolitiesonthe breast-fedinfant.Allopurinolshould be usedwithcautionduring

breast feedingasthereisatheoreticalrisktotheinfantofallergicsensitisation.

Effects on abilitytodriveand usemachines

Thismedicineislikelyto produce minoror moderateadverseeffects.Since adverse effectssuch as

somnolence, vertigo andataxia have been reportedinpatientsreceiving allopurinol,patientsshould

exercise cautionbefore driving,using machineryorparticipatingin dangerousactivitieswhere

alertnessismandatoryuntiltheyare reasonablycertain that allopurinoldoesnotadverselyaffect

performance.

Other

Preclinicalsafetydata

Mutagenicity

Evidence frombiochemicalandother cytologicalinvestigationsstronglysuggeststhat allopurinolhas

nodeleteriouseffectsonDNAatanystageofthe cellcycle andisnotmutagenic.Cytogeneticstudies

showthatallopurinoldoesnotinduce chromosome aberrationsinhumanblood cellsin vitroat

concentrationsupto 100 mcg/mland invivo atdosesupto60mg/dayfor a mean period of40

months. Allopurinoldoesnotproduce nitroso compoundsinvitrooraffect lymphocyte transformation

in vitro.

Carcinogenicity

No evidenceofcarcinogenicityhasbeenfound in mice andratstreatedwithallopurinolfor up to two

years.

Teratogenicity

Onestudyofmice receiving intraperitonealdosesof50or 100 mg/kg on days10and13ofgestation

resultedin foetalabnormalities, howeverina similar studyinratsat120 mg/kgonday12ofgestation

noabnormalitieswereobserved.Extensive studiesofhighoraldosesofallopurinolofupto100

mg/kg/dayinmice, up to200 mg/kg/dayin ratsandupto150 mg/kg/dayinrabbitsduring days8 to16

ofthe gestationproduced no teratogeniceffects. An invitrostudyusingfoetalmouse salivaryglands

in culture to detectembryotoxicityindicatedthatallopurinolwouldnotbeexpectedtocause

embryotoxicitywithoutalsocausingmaternaltoxicity.

Adverseeffects

Adverse effectsin associationwithallopurinolare rarein theoveralltreatedpopulation andare mostly

ofaminornature. Theincidence ishigherin thepresence ofrenaland/orhepaticdisorders.

Adverse effectsare usuallyreversedbythe reductionofdosageor completewithdrawalofallopurinol.

Takingallopurinolafter mealsmayminimise gastrointestinaldisturbances.Where allergicreactions

occur, allopurinolshould bewithdrawnimmediately.

Skinreactions

These are themost common reactionsandmayoccuratanytime duringtreatment. Theymaybe

pruritic, maculopapular, sometimesscaly, sometimespurpuricand rarelyexfoliative.Severeskin

reactionsresemblingStevens-Johnsonand/or Lyellsyndrome associatedwith exfoliationandtoxic

epidermalnecrolysisoccurrarely.Skin reactionsmaybedelayed andrarelyhavebeen followedby

severehypersensitivityreactionswhich maybefatal.For thisreason,allopurinolshould bewithdrawn

immediatelyshouldsuch reactionsoccur. After recoveryfrommild reactions,allopurinolmay, if

desired,bereintroduced ata smalldoses(e.g.50mg/day)andgraduallyincreased. Ifthe rash recurs,

allopurinolshould bepermanentlywithdrawn.

Generalisedhypersensitivity

Hypersensitivityreactionscharacterised bypruritus,fever,chills,lymphadenopathy,arthralgia,

leucopeniaor leucocytosisand/or eosinophilia,have occurredoccasionally.Associatedvasculitisand

tissueresponse maybemanifestedinvariouswaysincludinghepatitis,intersitialnephritisand,very

rarely,epilepsy.Ifsuch reactionsdo occur, itmaybeat anytime during treatment.Inallcases,

allopurinolshould bewithdrawnimmediatelyandpermanently.

Corticosteroidsmaybebeneficialinovercominghypersensitivityskin reactions.Whengeneralised

hypersensitivityreactionshaveoccurred,concomitantthiazidediuretictreatment,a renaland/or

hepaticdisorderhasusuallybeenpresentparticularlywhentheoutcome hasbeen fatal.

Angioimmunoblasticlymphadenopathy

Angioimmunoblasticlymphadenopathyhasbeen described rarelyfollowingbiopsyofageneralised

lymphadenopathy. It appearstobereversibleonwithdrawalofallopurinol.

Hepaticfunction

Rare reportsofhepaticdysfunctionrangingfromasymptomaticrisesinliver functionteststo hepatitis

includinghepaticnecrosisandgranulomatoushepatitis,withoutovert evidenceofmore generalised

hypersensitivity,havebeendescribed.Granulomatoushepatitisappearsto bereversible on

withdrawalofallopurinol.

Gastrointestinal

Inearlyclincalstudies, nauseaand vomitingwere reported.Diarrhoea,abdominalpain,gastritisand

dyspepsiahavealsobeen reported.Further reportssuggest thatthesereactionsarenotasignificant

problemand canbe avoided bytakingallopurinolafter meals. Recurrent haematemesishasbeen

reportedasanextremelyrare event,ashassteatorrhoea.

Haematological

Bone marrowdepressionhasbeen reportedinpatientsduringallopurinoltherapy. However most

patientswere also receiving other medicineswithmyelosuppressive potentialconcomitantly. There

have beenoccasionalreportsoftransient reductioninthenumbersofcirculatingformedelementsof

theblood,usuallyin associationwithimpairedrenaland/orhepaticfunction.Adverse effectssuch as

leukocytosis,leukopenia, eosinophilia,thrombocytopenia,granulocytopenia,agranulocytosisand

aplasticanaemia,haveoccurredveryrarely. Theclinicalsignificancehasyettobe demonstrated.

Miscellaneous

Thefollowingcomplaintshavebeenreportedoccasionally:fever,generalmalaise,asthenia,

headache,vertigo,ataxia,somnolence,coma,depression, paralysis,paraesthesia,neuropathy,

peripheralneuritis, drowsiness, confusion,visualdisorder, cataract,macular changes, taste

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

furunculosis, alopecia, discolouredhair,angina,hypertension,bradycardia, oedema,uraemia,

haematuria,angioedema,gynaecomastia.

There have beenincidencesofxanthine stone depositionandofimpactionofpartlydissolvedrenal

uricacid stonesin theureter. Adequatehydrationisimportantespeciallyin patientswithsignificant

hyperuricaemia andtophaceousdeposits. Alkalinisation oftheurinewillfurther reduce crystalluria.

On initiatingtherapy,patientsmayexperienceanincrease inacutegoutyattacks(refer toDosage

andAdministration).

Interactions

6-mercaptopurine andazathioprine

Azathioprineismetabolisedto6-mercaptopurinewhichisinactivatedbytheactionofxanthine

oxidase.When 6-mercaptopurine orazathioprineisgivenconcurrentlywithallopurinol, onlyone-

quarterofthe usualdose of6-mercaptopurineor azathioprine shouldbegiven because inhibition of

xanthineoxidasewillprolong theiractivity.

Ampicillinandamoxicillin

Anincreasein thefrequencyofskin rash hasbeenreportedamong patientsreceivingampicillin or

amoxicillinconcurrentlywith allopurinolcomparedtopatientswho arenot receiving both medicines.

Thecause ofthe reportedassociationhasnotbeenestablished.However, itisrecommended thatfor

patientsreceiving allopurinolan alternativetoampicillin oramoxicillinisusedwhere available.

AngiotensinConvertingEnzymeinhibitors:

Isolatedreportsindicate thatconcurrentadministration ofcaptoprilandallopurinolmaypredisposeto

hypersensitivityreactionse.g.Stevens-Johnson syndrome.Patientsonthecombinationshould be

monitored and ifareactionoccurs, use ofthe medicinesdiscontinued.

Chlorpropamide

Ifallopurinolisgivenconcomitantlywithchlorpropamidewhen renalfunctionispoor, theremaybe an

increasedriskofprolongedhypoglycaemicactivitybecause allopurinolandchlorpropamidemay

competefor excretioninfthe renaltubule.

Coumarinanticoagulants

There isnoevidence thatinteractionbetweenallopurinolandthecoumarinsseen underexperimental

conditionshasanyclinicalsignificance. However, allpatientsreceivinganticoagulantsmust be

carefullymonitored.

Cyclophosphamide,doxorubicin, bleomycin,procarbazine, mechloroethamine

Enhancedbonemarrowsuppressionbycyclophosphamideand othercytotoxicagentshasbeen

reportedamong patientswithneoplasticdisease (otherthanleukaemia), in thepresence of

allopurinol. However,inawellcontrolledstudyofpatientstreatedwithcyclophosphamide,

doxorubicin,bleomycin,procarbazineand/ormechlorethamine(mustinehydrochloride)allopurinoldid

not appear toincreasethetoxicreactionofthese cytotoxicagents.

Cyclosporin

Reportssuggest that theplasma concentrationofcyclosporin maybe increasedduring concomitant

treatment withallopurinol.Thepossibilityofenhancedcyclosporin toxicityshouldbeconsidered ifthe

drugsare co-administered.

Diuretics

Thiazidediureticsmayincrease the riskofseriousallopurinoltoxicity,includinghypersensitivity

reactionsandthecombinationshouldbemonitored,especiallyifrenalfunctioniscompromised.

Phenytoin

Allopurinolmayinhibit hepaticoxidationofphenytoinbutthe clinicalsignificancehasnotbeen

demonstrated.

Salicylatesanduricosuric agents

Oxypurinol, the majormetaboliteofallopurinolanditselftherapeuticallyactive,isexcreted bythe

kidneyin asimilarwaytourate. Hence drugswith uricosuricactivitysuchasprobenecid orlarge

dosesofsalicylatemayaccelerate the excretionofoxypurinol. Thismaydecreasethe therapeutic

activityofallopurinol, but the significanceneedstobeassessedineach case.

Theophylline

Experimentalstudiesoftheeffect ofallopurinolon theophyllinemetabolismhaveproduced

contradictoryfindings. Inhibitionoftheophyllinemetabolismhasbeenreported in normalsubjects

givenrelativelyhighdosesofallopurinol(300 mgtwicedaily)underexperimentalconditions. The

mechanismofthe interaction maybe explained byxanthine oxidase beinginvolved inthe

biotransformationoftheophyllinein humans.To avoid toxicity, theophylline levelsshould be

monitored in patientsstartingorincreasingallopurinoltherapy.

Vidarabine (adenine arabinoside)

Evidence suggeststhattheplasma half-life ofvidarabineisincreased in the presence ofallopurinol.

Whenthe twomedicinesare usedconcomitantly,extra vigilanceisnecessarytorecognise enhanced

toxiceffects.

Overdosage

Signsandsymptoms

Ingestionofupto22.5gallopurinolwithoutadverse effect hasbeen reported.Nausea, vomiting,

diarrhoeaanddizzinesshavebeen reportedina patientwho ingested 20gallopurinol. Recovery

followed generalsupportivemeasures.Massiveabsorptionofallopurinolmayleadtoconsiderable

inhibitionofxanthineoxidase activity,whichshould havenountoward effectsunless6-

mercaptopurineand/orazathioprineisbeingtakenconcomitantly.

Management

Thepatientshould be monitored andreceive normalsupportive measures. Adequatehydration to

maintainoptimumdiuresisfacilitatesexcretion ofallopurinolanditsmetabolites.Haemodialysismay

beusedifnecessary.

Pharmaceuticalprecautions

Instructionsfor use/handling

Nil.

Incompatibilities

Noneknown.

Specialprecautionsfor storage

Storeatorbelow25°C.

Medicineclassification

PrescriptionMedicine.

Packagequantities

AllopurinolSandoz100mg-Bottlesof200and 250tablets.

AllopurinolSandoz300mg-Bottlesof30and60tablets.

Furtherinformation

Instructionstopatients

Wherever possiblea highfluidintake sufficient toyielda dailyurinaryoutputof2litresand the

maintenanceofaneutraloralkaline urineare desirableinhyperuricaemicpatientswhether ornot

theyareonallopurinoltherapy.Allopurinolisbetter toleratediftakenafter meals. Dueto the

occasionaloccurrenceofdrowsiness, patientsshould be alertedtotheneed for due precautions

whenengaginginactivitieswhere alertnessismandatory.

List ofexcipients

Microcrystallinecellulose,cellulose,povidone,crospovidone,macrogol4000, talc,magnesium

stearate.

Nameandaddress

NovartisNew Zealand Limited

PrivateBag 65904 MairangiBay

AUCKLAND0754

Telephone: (09) 361 8100

Dateofpreparation

01Feburary2011

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Europe - EFSA - European Food Safety Authority Publications

15-11-2018

Safety evaluation of the food enzyme acetolactate decarboxylase from a genetically modified Bacillus licheniformis (strain NZYM‐JB)

Safety evaluation of the food enzyme acetolactate decarboxylase from a genetically modified Bacillus licheniformis (strain NZYM‐JB)

Published on: Wed, 14 Nov 2018 The food enzyme acetolactate decarboxylase (α‐acetolactate decarboxylase; EC 4.1.1.5) is produced with a genetically modified Bacillus licheniformis strain NZYM‐JB by Novozymes A/S. The genetic modifications do not give rise to safety concerns. The food enzyme is free from viable cells of the production organism and recombinant DNA. This acetolactate decarboxylase is intended to be used in distilled alcohol production and brewing processes. Residual amounts of total organi...

Europe - EFSA - European Food Safety Authority Publications

14-11-2018

“Vita-X Revitalizing Capsules” for men may pose serious health risks

“Vita-X Revitalizing Capsules” for men may pose serious health risks

Health Canada is advising Canadians that two versions of “Vita-X Revitalizing Capsules” by Lanlay Healthmetic Inc., promoted for “long lasting vital energy for men,” may pose serious health risks. One version contains seven capsules and has “NPN 80053009,” a Natural Product Number (NPN) indicating Health Canada authorization, on the label. The second version contains one capsule, has no NPN on the label and is not authorized by Health Canada.

Health Canada

9-11-2018

Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Sandoz Inc. is voluntarily recalling one lot of Losartan Potassium Hydrochlorothiazide Tablets, USP 100mg/25mg to the consumer level. This product is being recalled due to the trace amount of an impurity, N-nitrosodiethylamine (NDEA) contained in the API Losartan, USP manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd. Sandoz Inc. Losartan Potassium Hydrochlorothiazide product is manufactured by Lek Pharmaceuticals dd, Ljubljana, Slovenia. This impurity, which is a substance that occurs naturally in ...

FDA - U.S. Food and Drug Administration

30-10-2018

Sciegen Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Irbesartan Tablets, USP  75 Mg, 150 Mg, and 300 Mg Due to The Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in The Active Pharmaceutical Ingredient (API)

Sciegen Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Irbesartan Tablets, USP 75 Mg, 150 Mg, and 300 Mg Due to The Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in The Active Pharmaceutical Ingredient (API)

ScieGen Pharmaceuticals, Inc. is voluntarily recalling listed lots, within expiry, of Irbesartan Tablets, USP 75 mg, 150 mg, and 300 mg dosage forms to the consumer level. These products are being recalled due to the presence of an impurity, N-nitrosodiethylamine (NDEA) contained in the API Irbesartan, USP manufactured by Aurobindo Pharma Limited. This impurity, which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, has been classified as a...

FDA - U.S. Food and Drug Administration

30-10-2018

Pest categorisation of Aleurocanthus spp.

Pest categorisation of Aleurocanthus spp.

Published on: Mon, 29 Oct 2018 00:00:00 +0100 The Panel on Plant Health performed a pest categorisation of Aleurocanthus spp., a well‐defined insect genus of the whitefly family Aleyrodidae (Arthropoda: Hemiptera). Difficulties within the taxonomy of the genus give doubt about the ability to accurately identify some members to species level. Nevertheless, the genus is thought to currently include about ninety species mainly reported from tropical and subtropical areas. The genus is listed in Council Dir...

Europe - EFSA - European Food Safety Authority Publications

18-10-2018

Stewart’s Shops Issues Allergy Alert on Undeclared Milk in Cranberry Apple Refresher

Stewart’s Shops Issues Allergy Alert on Undeclared Milk in Cranberry Apple Refresher

Saratoga Springs, NY - Stewart’s Shops Corp. is recalling units of Stewart’s Shops brand Cranberry Apple Refresher 16 fluid oz. because the product may contain undeclared milk. People who have an allergy to milk run the risk of serious or life-threatening allergic reaction if they consume this product. Approximately 2,300 units of affected product were distributed in upstate New York and Southern Vermont.

FDA - U.S. Food and Drug Administration

12-9-2018

FDA takes new steps to address epidemic of youth e-cigarette use, including a historic action against more than 1,300 retailers and 5 major manufacturers for their roles perpetuating youth access

FDA takes new steps to address epidemic of youth e-cigarette use, including a historic action against more than 1,300 retailers and 5 major manufacturers for their roles perpetuating youth access

FDA takes new steps to address epidemic of youth e-cigarette use, including a historic action against more than 1,300 retailers and 5 major manufacturers for their roles perpetuating youth access

FDA - U.S. Food and Drug Administration

22-8-2018

FDA Drug Safety Communication: FDA to evaluate increased risk of heart-related death and death from all causes with the gout medicine febuxostat (Uloric)

FDA Drug Safety Communication: FDA to evaluate increased risk of heart-related death and death from all causes with the gout medicine febuxostat (Uloric)

The U.S. Food and Drug Administration (FDA) is warning that preliminary results from a safety clinical trial show an increased risk of heart-related death with febuxostat (Uloric) compared to another gout medicine called allopurinol. We required the Uloric drug manufacturer, Takeda Pharmaceuticals, to conduct this safety study when we approved the medicine in 2009. Once we receive the final results from the manufacturer, we will conduct a comprehensive review and will update the public with any new inf...

FDA - U.S. Food and Drug Administration

19-7-2018

Openfoodtox: over 300 substances added to EFSA chemical hazards database

Openfoodtox: over 300 substances added to EFSA chemical hazards database

Openfoodtox: over 300 substances added to EFSA chemical hazards database

Europe - EFSA - European Food Safety Authority Press Releases & News Stories

17-5-2018

JAGUAR 30000 capsules

JAGUAR 30000 capsules

Safety advisory

Therapeutic Goods Administration - Australia

27-4-2018

EpiPen 300 mcg adrenaline auto-injector

EpiPen 300 mcg adrenaline auto-injector

Medicine shortages

Therapeutic Goods Administration - Australia

13-6-2017

Annual report 2016 - Clinical trials of medicines

Annual report 2016 - Clinical trials of medicines

LLast year, the Danish Medicines Agency received 286 clinical trial applications. This is a small decline compared to 2015. However, the number of clinical trial applications has remained stable at around 300 applications per year since 2013.

Danish Medicines Agency

6-4-2017

More batches of EpiPen® are withdrawn

More batches of EpiPen® are withdrawn

MEDA has decided to withdraw four more batches of EpiPen®. The withdrawal concerns two batches of EpiPen® 300 micrograms/dose and two batches of EpiPen® Jr 150 micrograms/dose. The latter is used for acute hypersensitivity reactions in children. The reason for the withdrawal is that there is a risk that the auto-injector does not work.

Danish Medicines Agency

17-3-2017

Withdrawal of a batch of EpiPen® 300 micrograms

Withdrawal of a batch of EpiPen® 300 micrograms

MEDA recalls a batch of the adrenaline product EpiPen® 300 micrograms/dose, which is used for sudden allergic reactions. There is a risk that the auto-injector does not work. The withdrawal concerns product number 578818 with batch number: 5FA665B and expiry date 03/2017.

Danish Medicines Agency

21-2-2017

Takeda Pharma A/S recalls batch of Pamol® in packs of 300 film-coated tablets

Takeda Pharma A/S recalls batch of Pamol® in packs of 300 film-coated tablets

Takeda Pharma A/S recalls a batch of Pamol® in packs of 300 film-coated tablets after the discovery of Ibumetin 600 mg containing ibuprofen in some packs. Both types of medicine are used for the treatment of mild pain, but they work in different ways and may cause different adverse reactions.

Danish Medicines Agency

26-11-2018

Ziextenzo (Sandoz GmbH)

Ziextenzo (Sandoz GmbH)

Ziextenzo (Active substance: pegfilgrastim) - Centralised - Authorisation - Commission Decision (2018)7961 of Mon, 26 Nov 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4802

Europe -DG Health and Food Safety

15-10-2018

Riximyo (Sandoz GmbH)

Riximyo (Sandoz GmbH)

Riximyo (Active substance: rituximab) - Centralised - Yearly update - Commission Decision (2018)6811 of Mon, 15 Oct 2018

Europe -DG Health and Food Safety

24-9-2018

Rixathon (Sandoz GmbH)

Rixathon (Sandoz GmbH)

Rixathon (Active substance: rituximab) - Centralised - Yearly update - Commission Decision (2018)6230 of Mon, 24 Sep 2018

Europe -DG Health and Food Safety

4-9-2018

Binocrit (Sandoz GmbH)

Binocrit (Sandoz GmbH)

Binocrit (Active substance: epoetin alfa) - Centralised - 2-Monthly update - Commission Decision (2018)5856 of Tue, 04 Sep 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/725/II/WS/1406

Europe -DG Health and Food Safety

29-8-2018

Zarzio (Sandoz GmbH)

Zarzio (Sandoz GmbH)

Zarzio (Active substance: Filgrastim) - Centralised - Yearly update - Commission Decision (2018)5764 of Wed, 29 Aug 2018

Europe -DG Health and Food Safety

27-8-2018

Duzallo (GrUnenthal GmbH)

Duzallo (GrUnenthal GmbH)

Duzallo (Active substance: allopurinol / lesinurad) - Centralised - Authorisation - Commission Decision (2018)5696 of Mon, 27 Aug 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4412

Europe -DG Health and Food Safety

30-7-2018

Hyrimoz (Sandoz GmbH)

Hyrimoz (Sandoz GmbH)

Hyrimoz (Active substance: adalimumab) - Centralised - Authorisation - Commission Decision (2018)5097 of Mon, 30 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4320

Europe -DG Health and Food Safety

30-7-2018

Halimatoz (Sandoz GmbH)

Halimatoz (Sandoz GmbH)

Halimatoz (Active substance: adalimumab) - Centralised - Authorisation - Commission Decision (2018)5098 of Mon, 30 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4866

Europe -DG Health and Food Safety

30-7-2018

Hefiya (Sandoz GmbH)

Hefiya (Sandoz GmbH)

Hefiya (Active substance: adalimumab) - Centralised - Authorisation - Commission Decision (2018)5099 of Mon, 30 Jul 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4865

Europe -DG Health and Food Safety

13-7-2018

Erelzi (Sandoz GmbH)

Erelzi (Sandoz GmbH)

Erelzi (Active substance: etanercept) - Centralised - Yearly update - Commission Decision (2018)4712 of Fri, 13 Jul 2018

Europe -DG Health and Food Safety

10-7-2018

Temozolomide Sandoz (Sandoz GmbH)

Temozolomide Sandoz (Sandoz GmbH)

Temozolomide Sandoz (Active substance: temozolomide) - Centralised - Yearly update - Commission Decision (2018)4480 of Tue, 10 Jul 2018

Europe -DG Health and Food Safety

10-7-2018

Pemetrexed Sandoz (Sandoz GmbH)

Pemetrexed Sandoz (Sandoz GmbH)

Pemetrexed Sandoz (Active substance: pemetrexed) - Centralised - Yearly update - Commission Decision (2018)4485 of Tue, 10 Jul 2018

Europe -DG Health and Food Safety

27-6-2018

Yondelis (Pharma Mar S.A.)

Yondelis (Pharma Mar S.A.)

Yondelis (Active substance: Trabectedin) - PSUSA - Modification - Commission Decision (2018)4096 of Wed, 27 Jun 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/PSUSA/3001/201709

Europe -DG Health and Food Safety

23-5-2018

Zessly (Sandoz GmbH)

Zessly (Sandoz GmbH)

Zessly (Active substance: infliximab) - Centralised - Authorisation - Commission Decision (2018)3215 of Wed, 23 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/4647

Europe -DG Health and Food Safety

16-5-2018

Busulfan Fresenius Kabi (Fresenius Kabi Deutschland GmbH)

Busulfan Fresenius Kabi (Fresenius Kabi Deutschland GmbH)

Busulfan Fresenius Kabi (Active substance: busulfan) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)3005 of Wed, 16 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2806/T/8

Europe -DG Health and Food Safety

15-5-2018

Lonquex (UAB Sicor Biotech)

Lonquex (UAB Sicor Biotech)

Lonquex (Active substance: lipegfilgrastim) - Centralised - Renewal - Commission Decision (2018)3009 of Tue, 15 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2556/R/39

Europe -DG Health and Food Safety

15-5-2018

Izba (Novartis Europharm Limited)

Izba (Novartis Europharm Limited)

Izba (Active substance: travoprost) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)3002 of Tue, 15 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/2738/T/10

Europe -DG Health and Food Safety

15-5-2018

KEYTRUDA (Merck Sharp and Dohme B.V.)

KEYTRUDA (Merck Sharp and Dohme B.V.)

KEYTRUDA (Active substance: pembrolizumab) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)3003 of Tue, 15 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/3820/T/45

Europe -DG Health and Food Safety

15-5-2018

LIFMIOR (Pfizer Limited)

LIFMIOR (Pfizer Limited)

LIFMIOR (Active substance: etanercept) - Centralised - Yearly update - Commission Decision (2018)3004 of Tue, 15 May 2018

Europe -DG Health and Food Safety

15-5-2018

Travatan (Novartis Europharm Limited)

Travatan (Novartis Europharm Limited)

Travatan (Active substance: Travoprost) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)3001 of Tue, 15 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/390/T/59

Europe -DG Health and Food Safety

15-5-2018

Imatinib Teva B.V. (Teva B.V.)

Imatinib Teva B.V. (Teva B.V.)

Imatinib Teva B.V. (Active substance: imatinib) - Centralised - Withdrawal - Commission Decision (2018)3008 of Tue, 15 May 2018

Europe -DG Health and Food Safety

15-5-2018

Instanyl (Takeda Pharma A/S)

Instanyl (Takeda Pharma A/S)

Instanyl (Active substance: Fentanyl ) - PSUSA - Modification - Commission Decision (2018)3006 of Tue, 15 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/959/PSUSA/1369/201704

Europe -DG Health and Food Safety

15-5-2018

PecFent (Kyowa Kirin Services Ltd)

PecFent (Kyowa Kirin Services Ltd)

PecFent (Active substance: Fentanyl ) - PSUSA - Modification - Commission Decision (2018)3007 of Tue, 15 May 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1164/PSUSA/1369-201704

Europe -DG Health and Food Safety