DISTAMINE

Main information

  • Trade name:
  • DISTAMINE Film Coated Tablet 250 Milligram
  • Dosage:
  • 250 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DISTAMINE Film Coated Tablet 250 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0943/003/002
  • Authorization date:
  • 01-10-2000
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Distamine250mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains250mgpenicillamine.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablet.

Awhite,film-coatedtabletwithadiameterof10mm,marked'DM'ononefaceand'250'ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

a)Severeactiverheumatoidarthritis,includingjuvenileforms

b)Wilson’sdisease(hepatolenticulardegeneration)

c)Cystinuria–dissolutionandpreventionofcystinestones

d)Leadpoisoning

e)Chronicactivehepatitis

4.2Posologyandmethodofadministration

Fororaladministration

Ifpossible,Distamineshouldbetakenatleasthalfanhourbeforemeals,oronretiring.

a)Rheumatoidarthritis

Adults:

125to250mgdailyforthefirstmonth.Increasebythesameamounteveryfourto12weeksuntilremissionoccurs.

Theminimummaintenancedosetoachievesuppressionofsymptomsshouldbeusedandtreatmentshouldbe

discontinuedifnobenefitisobtainedwithin12months.Improvementmaynotoccurforsomemonths.

Theusualmaintenancedoseis500to750mgdaily.Upto1500mgdailymayberequired.

Ifremissionisestablishedandhasbeensustainedforsixmonths,gradualreductionby125to250mgamountsevery12

weeksmaybeattempted.

Theelderly:

Increasedtoxicityhasbeenobservedinthispatientpopulationregardlessofrenalfunction.Initialdoseshouldnot

exceed125mgdailyforthefirstmonth,increasingbyasimilarincrementeveryfourto12weeksuntiltheminimum

maintenancedosetosuppresssymptomsisreached.Dailydosageshouldnotexceed1000mg.

Children:

15to20mg/kg/dayisconsideredappropriateinthemajorityofcases.Theinitialdoseshouldbelower(2.5to

5mg/kg/day)andincreasedatfour-weeklyintervalsoveraperiodofthreetosixmonths.Pleasenotethatasthe

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b)Wilson’sdisease

Adults:

1500to2000mgdailyindivideddoses.Dosemaybereducedto750mgto1000mgdailywhencontrolofthediseaseis

achieved.Patientsmustbemaintainedinnegativecopperbalanceandtheminimumdoseofpenicillaminerequiredto

achievethisshouldbegiven.

Itisadvisablethatadoseof2000mg/dayshouldnotbecontinuedformorethanayear.

Theelderly:

20mg/kg/dayindivideddoses.Adjustdosetocontroldiseaseandmaintainnegativecopperbalance.

Children:

Upto20mg/kg/dayindivideddoses.Minimumdose500mg/day.

c)Cystinuria

Ideally,establishthelowesteffectivedosebyquantitativeaminoacidchromatographyofurine.

(i)Dissolutionofcystinestones:

Adults:

1000to3000mgdailyindivideddoses.

Urinecystinelevelsofnotmorethan200mg/lshouldbemaintained.

(ii)Preventionofcystinestones:

Adults:

500mgto1000mgonretiring.Fluidintakeshouldbenotlessthan3litres/day.

Urinecystinelevelsofnotmorethan300mg/lshouldbemaintained.

Theelderly:

Usetheminimumdosetomaintainurinarycystinelevelsbelow200mg/l.

Children:

Nodoserangeestablished,buturinarycystinelevelsmustbekeptbelow200mg/l.Theminimumdoseofpenicillamine

requiredtoachievethisshouldbegiven.

d)Leadpoisoning

Adults:

1000to1500mgdailyindivideddosesuntilurinaryleadisstabilisedatlessthan0.5mg/day.

Theelderly:

20mg/kg/dayindivideddosesuntilurinaryleadisstabilisedatlessthan0.5mg/day.

Children:

20mg/kg/day.

e)Chronicactivehepatitis

Adults:

Formaintenancetreatmentafterthediseaseprocesshasbeenbroughtundercontrolwithcorticosteroids.Theinitial

doseof500mgdaily,individeddoses,shouldbeincreasedgraduallyoverthreemonthstoamaintenancedoseof

1250mgdaily.Duringthisperiod,thedoseofcorticosteroidsshouldbephasedout.Throughouttherapy,liverfunction

testsshouldbecarriedoutperiodicallytoassessthediseasestatus.

f)Desensitisation

SeeSection5.1,“Pharmacodynamicproperties”.

Renalinsufficiencywillrequiremorecarefulmonitoring,asfollows:

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Distaminetherapyshouldbeinitiatedatalowdosewithintervalsbetweendoseincreaseofatleasttwelveweeks.

Fortnightlymonitoringfortoxicityismandatorythroughouttreatment.

b)Wilson’sdisease:

Itisnecessarytomaintainpatientsinnegativecopperbalanceevenincasesofrenalinsufficiency.Extraprecautions

shouldbetakentomonitorthecourseofsuchpatientsforadverseeffects.

c)Cystinuria:

Renalinsufficiencymaybepresentattheonsetoftherapy.Alowerstartingdoseshouldbeselected,butitwillbe

necessarytogivesufficientDistaminetoachieveurinecystinelevelsofnotmorethan300mg/l.Themaintenancedose

shouldbereviewedatintervalsofnotmorethanfourweeks.

4.3Contraindications

Hypersensitivitytopenicillamineoranyoftheexcipients(seeSection6.1),exceptinalife-threateningsituation,when

desensitisationshouldbeattempted(seeSection5.1,“Pharmacodynamicproperties”).

Agranulocytosis,aplasticanaemiaorseverethrombocytopeniaduetopenicillamine.

Lupuserythematosus.

Persistentproteinuria.

Moderateorsevererenalimpairment.

4.4Specialwarningsandprecautionsforuse

Fullbloodcountsincludingplatelets,andrenalfunctionshouldbeassessedpriortotreatmentwithpenicillamine.

Monitoringofbloodandplateletcountsshouldbecarriedoutatappropriateintervals,togetherwithurinalysisfor

detectionofhaematuriaandproteinuria(seeSection4.8“Undesirableeffects”).

Fullbloodcountsshouldbecarriedoutweeklyorfortnightlyduringthefirsteightweeksoftherapy,intheweekafter

anyincreaseindose,andotherwisemonthlythereafter.IncystinuriaorWilson'sdisease,longerintervalsmaybe

adequate.

Withdrawaloftreatmentshouldbeconsideredifplateletsfallbelow120,000orwhitebloodcellsbelow2,500/mm3,or

ifthreesuccessivefallsarenotedwithinthenormalrange.Treatmentmayberestartedatareduceddosewhencounts

returntonormal,butshouldbepermanentlywithdrawnonrecurrenceofneutropeniaorthrombocytopenia.

Penicillaminemaypotentiatethebonemarrowsupressioncausedbyclozapine.

Inpatientswithnormalrenalfunction,urineshouldbetestedweeklyatfirst,andfollowingeachincreaseindose,then

monthly,althoughlongerintervalsmaybeadequateforcystinuriaandWilson’sdisease.Increasingproteinuriamay

necessitatewithdrawaloftherapy.

Careshouldbeexercisedinpatientswithrenalinsufficiency;modificationofdosagemaybenecessary(seeSection

4.2,“Posologyandmethodofadminstration”).

Especiallycarefulmonitoringisnecessaryintheelderlysinceincreasedtoxicityhasbeenobservedinthispatient

populationregardlessofrenalfailure.

ConcomitantuseofNSAIDsandothernephrotoxicdrugsmayincreasetheriskofrenaldamage(seeSection4.5,

"Interactionwithothermedicinalproductsandotherformsofinteraction").

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Concomitantorprevioustreatmentwithgoldmayincreasetheriskofsideeffectswithpenicillaminetreatment.

Thereforepenicillamineshouldbeusedwithcautioninpatientswhohavepreviouslyhadadversereactionstogoldand

concomitanttreatmentwithgoldshouldbeavoided(seeSection4.5,"Interactionwithothermedicinalproductsand

otherformsofinteraction").

Ifconcomitantoraliron,digoxinorantacidtherapyisindicated,thisshouldnotbegivenwithintwohoursoftaking

penicillamine(seeSection4.5,"Interactionwithothermedicinalproductsandotherformsofinteraction").

Antihistamines,steroidcover,ortemporaryreductionofdosewillcontrolurticarialreactions(seeSection4.8

“Undesirableeffects”).

Reversiblelossoftastemayoccur.Mineralsupplementstoovercomethisarenotrecommended(seeSection4.8

“Undesirableeffects”).

Haematuriaisrare,butifitoccursintheabsenceofrenalstonesorotherknowncause,treatmentshouldbestopped

immediately(seeSection4.8“Undesirableeffects”).

Alaterash,describedasacquiredepidermolysisbullosaandpenicillaminedermopathy,mayoccurafterseveralmonths

oryearsoftherapy.Thismay

necessitateareductionindosage(seeSection4.8“Undesirableeffects”).

Breastenlargementhasbeenreportedasararecomplicationofpenicillaminetherapyinbothwomenandmen(see

Section4.8“Undesirableeffects”).Insomepatientsbreastenlargementwasconsiderableand/orprolongedwithpoor

resolutionandothersrequiredsurgery.Danazolhasbeenusedsuccessfullytotreatbreastenlargementwhichdoesnot

regressondrugdiscontinuation.

TheuseofDMARDs,includingpenicillamine,hasbeenlinkedtothedevelopmentofsepticarthritisinpatientswith

rheumatoidarthritis,althoughrheumatoidarthritisisastrongerpredictorforthedevelopmentofsepticarthritisthanthe

useofaDMARD(seeSection4.8“Undesirableeffects”).

DeteriorationoftheneurologicalsymptomsofWilson’sdisease(dystonia,rigidity,tremor,dysarthria)havebeen

reportedfollowingintroductionofpenicillamineinpatientstreatedforthiscondition.Thismaybeaconsequenceof

mobilisationandredistributionofcopperfromthelivertothebrain(seeSection4.8“Undesirableeffects”).

Pyroxidinedailymaybegiventopatientsonlongtermtherapy,especiallyiftheyareonarestricteddiet,since

penicillamineincreasestherequirementforthisvitamin.(seeSection4.5InteractionswithOtherMedicinalProducts

andOtherformsofInteraction).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantuseofironorantacids:oralabsorptionofpenicillaminemaybereducedbyconcomitantadministrationof

ironorantacids(seeSection4.4"SpecialWarningsandPrecautionsforUse").

Concomitantuseofdigoxin:oralabsorptionofdigoxinmaybereducedbyconcomitantadministrationofpenicillamine

(seeSection4.4"SpecialWarningsandPrecautionsforUse").

ConcomitantuseofNSAIDsandothernephrotoxicdrugsmayincreasetheriskofrenaldamage(seeSection4.4

"SpecialWarningsandPrecautionsforUse").

Concomitantuseofgold:concomitantusenotrecommended(seeSection4.4"SpecialWarningsandPrecautionsfor

Use").

Concomitantuseofclozapine:penicillaminemaypotentiatetheblooddyscrasiasseenwithclozapine(seeSection4.4"

SpecialWarningsandPrecautionsforUse").

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absorptionofzincmayalsoreducedpenicillamine.

Pyroxidinedailymaybegiventopatientsonlongtermtherapy,especiallyiftheyareonarestricteddiet,since

penicillamineincreasestherequirementforthisvitamin(seeSection4.4SpecialWarningsandPrecautionsforUse).

4.6Fertility,pregnancyandlactation

Usageinpregnancy:

Thesafetyofpenicillamineforuseduringpregnancyhasnotbeenestablished.Ithasbeenshowntobeteratogenicin

ratswhengivenindosesseveraltimeshigherthanthoserecommendedforhumanuse.

Lactation:Duetothelackofdataonuseinbreastfeedingpatientsandthepossibiltythatpenicillaminemaybe

transmittedtonewbornsthroughbreastmilk,Distamineshouldonlybeusedinbreastfeedingpatientswhenitis

consideredabsolutelyessentialbythephysician.

Wilson’sdisease:

Therehavebeenseveralcasesofreversiblecutislaxaininfantsborntomotherstakingpenicillaminethroughout

pregnancy.Althoughtherehavebeennocontrolledstudiesontheuseofpenicillamineduringpregnancy,two

retrospectivestudieshavereportedthesuccessfuldeliveryof43normalinfantsto28womenreceivingbetween500mg

and2000mgofpenicillaminedaily.Therearealsoanecdotalreportsbothofcongenitalabnormalitiesandofsuccessful

outcomesinpatientswhohaveremainedonpenicillamineduringpregnancy.Iftreatmentwithpenicillamineistobe

continued,followingarisk-benefitanalysis,considerationshouldbegiventoreducingthedoseofpenicillaminetothe

lowesteffectivedose.

Cystinuria:

Whilstnormalinfantshavebeendelivered,thereisonereportofasevereconnectivetissueabnormalityintheinfantof

amotherwhoreceived2000mgpenicillaminedailythroughoutpregnancy.Wheneverpossible,penicillamineshouldbe

withheldduringpregnancy,butifstonescontinuetoform,thebenefitofresumingtreatmentmustbeweighedagainst

thepossiblerisktothefoetus.

Rheumatoidarthritisorchronicactivehepatitis:

Penicillamineshouldnotbeadministeredtopatientswhoarepregnant,andtherapyshouldbestoppedwhenpregnancy

isdiagnosedorsuspected,unlessconsideredtobeabsolutelyessentialbythephysician.

4.7Effectsonabilitytodriveandusemachines

Noneknown.

4.8Undesirableeffects

Themostcommonofallside-effectsarethrombocytopeniaandproteinuria.

Thrombocytopeniaoccurscommonly.Thereactionmayoccuratanytimeduringtreatmentandareusuallyreversible

(seeSection4.4“SpecialWarningsandPrecautionsforUse”).

Proteinuriaoccursinupto30%ofpatientsandispartiallydose-related(seeSection4.4“SpecialWarningsand

PrecautionsforUse”).

Adversereactions(Table1)arerankedunderheadingoffrequency,themostfrequentfirst,usingthefollowing

convention:verycommon(greaterthanorequalto1in10);common(lessthanorequalto1in100,lessthan1in10);

uncommon(greaterthanorequalto1in1,000,lessthan1in100);rare(greaterthanorlessthan1in10,000,lessthan

1in1,000)veryrare(lessthan1in10,000),notknown(wherenovalidestimateoftheincidencehasbeenderived).

NB:Theincidenceandseverityofsomeoftheadversereactions,notedbelow,variesaccordingtothedosageand

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Deathsfromagranulocytosisandaplasticanaemiahaveoccurred.

Nausea,anorexia,feverandrashmayoccurearlyintherapy,especiallywhenfull

dosesaregivenfromthestart.

Antihistamines,steroidcover,ortemporaryreductionofdosewillcontrolurticarial

reactions(seeSection4.4“SpecialWarningsandPrecautionsforUse”).

Reversiblelossoftastemayoccur.Mineralsupplementstoovercomethisarenot

recommended(seeSection4.4“SpecialWarningsandPrecautionsforUse”).

Haematuriaisrare,butifitoccursintheabsenceofrenalstonesorotherknown

cause,treatmentshouldbestoppedimmediately(seeSection4.4“SpecialWarnings

andPrecautionsforUse”).

Alaterash,describedasacquiredepidermolysisbullosaandpenicillamine

dermopathy,mayoccurafterseveralmonthsoryearsoftherapy(seeSection4.4

“SpecialWarningsandPrecautionsforUse”).

Breastenlargementhasbeenreportedasararecomplicationofpenicillamine

therapyinbothwomenandmen(seeSection4.4“SpecialWarningsandPrecautions

forUse”).

Thereactionmayoccuratanytimeduringtreatmentandareusuallyreversible

(seeSection4.4“SpecialWarningsandPrecautionsforUse”).

ThedevelopmentofsepticarthritisinpatientswithrheumatoidarthritishasbeenlinkedtotheuseofDMARDs,

includingpenicillamine(seeSection4.4“SpecialWarningsandPrecautionsforUse”).

DeteriorationoftheneurologicalsymptomsofWilson’sdisease(dystonia,rigidity,tremor,dysarthria)havebeen

reportedfollowingintroductionofpenicillamineinpatientstreatedforthiscondition(seeSection4.4“Special

WarningsandPrecautionsforUse”).

4.9Overdose

Noinstancesofadversereactionstoanoverdoseofpenicillaminehavebeenrecordedandnospecificmeasuresare

indicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:M01CC

PenicillamineisusedtotreatsevereactiverheumatoidarthritisnotadequatelycontrolledbyNSAIDtherapy.

Penicillamineisachelatingagentwhichaidstheeliminationfromthebodyofcertainheavymetalions,including

copper,leadandmercury,byformingstablesolublecomplexeswiththem,thatarereadilyexcretedbythekidney.

ItisusedinthetreatmentofWilson’sdisease(hepatolenticulardegeneration),inconjunctionwithalowcopper

diet,topromotetheexcretionofcopper.

Itmaybeusedtotreatasymptomaticleadintoxication.

Penicillamineisusedasanadjuncttodietandurinaryalkalinisationinthemanagementofcystinuria.Byreducing

urinaryconcentrationsofcystine,penicillaminepreventstheformationofcalculiandpromotesthegradual

dissolutionofexistingcalculi.

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accordancewiththepatient’sresponse.Higherinitialdoseshavebeenemployedincystinuricpatients.

5.2Pharmacokineticproperties

Penicillamineisathiol-groupcontainingchelatingagent,variablyabsorbedfromthegastrointestinaltract.Thedrug

undergoesarapiddistributionphase,followedbyaslowereliminationphase.

Penicillamineisstronglyplasma-proteinbound.Mostpenicillamineisboundtoalbuminbutsomeisboundto-

globulinsorceruloplasmin.

Penicillamineisnotextensivelymetabolisedinman.

About80%oftheabsorbeddoseisexcretedrapidlyintheurine,mostlyasmixeddisulphides.Someofthedoseis

excretedasapenicillaminecoppercomplexandsomeastheS-methylderivative.

5.3Preclinicalsafetydata

Penicillaminehasbeenshowntobeteratogenicinratswhengivenindosesseveraltimeshigherthanthose

recommendedforhumanuse.

ThereisnoknownLD valueforpenicillamine.Instudiessomeratsdiedafteroraladministrationof10,000mg/kg,

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore

Microcrystallinecellulose

Magnesiumstearate

Povidone

Sodiumstarchglycolate(TypeA)

TabletCoating

Glycerol

Titaniumdioxide(E171)

Hypromellose

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Keepthebottletightlyclosed.

6.5Natureandcontentsofcontainer

HDPEbottlewithscrewcap,containing100tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AlliancePharmaceuticalsLtd

AvonbridgeHouse

BathRoad

Chippenham

WiltshireSN152BB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12 th

October1975

Dateoflastrenewal:1 st

October2010

10DATEOFREVISIONOFTHETEXT

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