CONTRAMAL RETARD

Main information

  • Trade name:
  • CONTRAMAL RETARD
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CONTRAMAL RETARD
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1189/004/001
  • Authorization date:
  • 27-07-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1189/004/001

CaseNo:2043306

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

GrunenthalLtd

RegusLakesideHouse,1FurzegroundWay,StockleyParkEast,Uxbridge,MiddlesexUB111BD,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Contramalretard50mgprolonged-releasetablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom28/11/2007until26/07/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 29/11/2007 CRN 2043306 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Contramalretard50mgprolonged-releasetablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Contramalretard50mgprolonged-releasetablets

1prolonged-releasetabletcontains50mgtramadolhydrochloride.

Excipient:Eachprolonged-releasetabletcontains2.5mglactosemonohydrate(seesection4.4).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasetablet.

Round,biconvex,paleyellowcolouredfilm-coatedtablets,markedwiththemanufacturer‘slogoononeside,marked

T0ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmoderatetoseverepain.

4.2Posologyandmethodofadministration

Thedoseshouldbeadjustedtotheintensityofthepainandthesensitivityoftheindividualpatient.

Unlessotherwiseprescribed,Contramalretardshouldbeadministeredasfollows:

Adultsandadolescentsabovetheageof12years:

Theusualinitialdoseis50-100mgtramadolhydrochloridetwicedaily,morningandevening.Ifpainreliefis

insufficient,thedosemaybetitratedupwardsto150mgor200mgtramadolhydrochloridetwicedaily.

Fordosesnotpracticablewiththisstrength,otherstrengthsofthismedicinalproductareavailable.

Thetabletsaretobetakenwhole,notdividedorchewed,withsufficientliquid,independentofmeals.

Thelowestanalgesicallyeffectivedoseshouldgenerallybeselected.Dailydosesof400mgactivesubstanceshould

notbeexceeded,exceptinspecialclinicalcircumstances.

Contramalretardshouldundernocircumstancesbeadministeredforlongerthanabsolutelynecessary.Iflong-term

paintreatmentwithContramalretardisnecessaryinviewofthenatureandseverityoftheillness,thencarefuland

regularmonitoringshouldbecarriedout(ifnecessarywithbreaksintreatment)toestablishwhetherandtowhatextent

furthertreatmentisnecessary.

Children

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Geriatricpatients

Adoseadjustmentisnotusuallynecessaryinelderlypatients(upto75years)withoutclinicallymanifesthepaticor

renalinsufficiency.Inelderlypatients(over75years)eliminationmaybeprolonged.Therefore,ifnecessarythe

dosageintervalistobeextendedaccordingtothepatient'srequirements.

RenalInsufficiency/DialysisandHepaticInsufficiency

Inpatientswithsevererenaland/orhepaticinsufficiencyContramalretardisnotrecommended.Inmoderatecases

prolongationofthedosageintervalshouldbecarefullyconsidered.

4.3Contraindications

Contramalretardiscontraindicated

inhypersensitivitytotramadoloranyoftheexcipients(seesection6.1),

inacuteintoxicationwithalcohol,hypnotics,analgesics,opioids,orpsychotropicmedicinalproducts,

inpatientswhoarereceivingMAOinhibitorsorwhohavetakenthemwithinthelast14days(see

section4.5),

inpatientswithepilepsynotadequatelycontrolledbytreatment,

foruseinnarcoticwithdrawaltreatment.

4.4Specialwarningsandprecautionsforuse

Contramalretardmayonlybeusedwithparticularcautioninopioid-dependentpatients,patientswithheadinjury,

shock,areducedlevelofconsciousnessofuncertainorigin,disordersoftherespiratorycentreorfunction,increased

intracranialpressure.

Inpatientssensitivetoopiatestheproductshouldonlybeusedwithcaution.

Careshouldbetakenwhentreatingpatientswithrespiratorydepression,orifconcomitantCNSdepressantdrugsare

beingadministered(seesection4.5),oriftherecommendeddosageissignificantlyexceeded(seesection4.9)asthe

possibilityofrespiratorydepressioncannotbeexcludedinthesesituations.

Convulsionshavebeenreportedinpatientsreceivingtramadolattherecommendeddoselevels.Theriskmaybe

increasedwhendosesoftramadolexceedtherecommendedupperdailydoselimit(400mg).Inaddition,tramadolmay

increasetheseizureriskinpatientstakingothermedicinalproductsthatlowerstheseizurethreshold(seesection4.5).

Patientswithepilepsyorthosesusceptibletoseizuresshouldbeonlytreatedwithtramadoliftherearecompelling

circumstances.

Tramadolhasalowdependencepotential.Onlong-termusetolerance,psychicandphysicaldependencemaydevelop.

Inpatientswithatendencytodrugabuseordependence,treatmentwithContramalretardshouldonlybecarriedoutfor

shortperiodsunderstrictmedicalsupervision.

Tramadolisnotsuitableasasubstituteinopioid-dependentpatients.Althoughitisanopioidagonist,tramadolcannot

suppressmorphinewithdrawalsymptoms.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ContramalretardshouldnotbecombinedwithMAOinhibitors(seesection4.3).

InpatientstreatedwithMAOinhibitorsinthe14dayspriortotheuseoftheopioidpethidine,life-threatening

interactionsonthecentralnervoussystem,respiratoryandcardiovascularfunctionhavebeenobserved.Thesame

interactionswithMAOinhibitorscannotberuledoutduringtreatmentwithContramalretard.

ConcomitantadministrationofContramalretardwithothercentrallydepressantmedicinalproductsincludingalcohol

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Theresultsofpharmacokineticstudieshavesofarshownthatontheconcomitantorpreviousadministrationof

cimetidine(enzymeinhibitor)clinicallyrelevantinteractionsareunlikelytooccur.Simultaneousorprevious

administrationofcarbamazepine(enzymeinducer)mayreducetheanalgesiceffectandshortenthedurationofaction.

Thecombinationwithmixedagonist/antagonists(e.g.buprenorphine,nalbuphine,pentazocine)andtramadolisnot

advisable,becausetheanalgesiceffectofapureagonistmaybetheoreticallyreducedinsuchcircumstances.

Tramadolcaninduceconvulsionsandincreasethepotentialforselectiveserotoninre-uptakeinhibitors,tricyclicanti-

depressants,anti-psychoticsandotherseizurethresholdloweringmedicinalproductstocauseconvulsions.

Inisolatedcasestherehavebeenreportsofserotoninsyndromeinatemporalconnectionwiththetherapeuticuseof

tramadolincombinationwithotherserotoninergicmedicinalproductssuchasselectiveserotoninre-uptakeinhibitors

(SSRIs)orwithMAOinhibitors.Signsofserotoninsyndromemaybeforexampleconfusion,agitation,fever,

sweating,ataxia,hyperreflexia,myoclonusanddiarrhoea.Withdrawaloftheserotoninergicmedicinalproductsusually

bringsaboutarapidimprovement.Treatmentdependsonthenatureandseverityofthesymptoms.

Cautionshouldbeexercisedduringconcomitanttreatmentwithtramadolandcoumarinderivatives(e.g.warfarin)due

toreportsofincreasedINRwithmajorbleedingandecchymosesinsomepatients.

OtheractivesubstancesknowntoinhibitCYP3A4,suchasketoconazoleanderythromycin,mightinhibitthe

metabolismoftramadol(N-demethylation)probablyalsothemetabolismoftheactiveO-demethylatedmetabolite.The

clinicalimportanceofsuchaninteractionhasnotbeenstudied(seesection4.8).

Inalimitednumberofstudiesthepre-orpostoperativeapplicationoftheantiemetic5-HT3antagonistondansetron

increasedtherequirementoftramadolinpatientswithpostoperativepain.

4.6Pregnancyandlactation

Animalstudieswithtramadolrevealedatveryhighdoseseffectsonorgandevelopment,ossificationandneonatal

mortality.Teratogeniceffectswerenotobserved.Tramadolcrossestheplacenta.Thereisinadequateevidence

availableonthesafetyoftramadolinhumanpregnancy.ThereforeContramalretardshouldnotbeusedinpregnant

women.

Tramadol-administeredbeforeorduringbirth-doesnotaffectuterinecontractility.Inneonatesitmayinducechanges

intherespiratoryratewhichareusuallynotclinicallyrelevant.Chronicuseduringpregnancymayleadtoneonatal

withdrawalsymptoms.Duringlactationabout0.1%ofthematernaldoseissecretedintothemilk.Contramalretardis

notrecommendedduringbreast-feeding.Afterasingleadministrationoftramadolitisnotusuallynecessaryto

interruptbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Evenwhentakenaccordingtoinstructions,Contramalretardmaycauseeffectssuchassomnolenceanddizzinessand

thereforemayimpairthereactionsofdriversandmachineoperators.Thisappliesparticularlyinconjunctionwith

alcoholandotherpsychotropicsubstances.

4.8Undesirableeffects

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Cardiovasculardisorders:

uncommon(1/1000,<1/100):cardiovascularregulation(palpitation,tachycardia,posturalhypotensionor

cardiovascularcollapse).Theseadversereactionsmayoccurespeciallyonintravenousadministrationandinpatients

whoarephysicallystressed.

rare(1/10000,<1/1000):bradycardia,increaseinbloodpressure

Nervoussystemdisorders:

verycommon(1/10):dizziness

common(1/100,<1/10):headache,somnolence

rare(1/10000,<1/1000):changesinappetite,paraesthesia,tremor,respiratorydepression,epileptiformconvulsions,

involuntarymusclecontractions,abnormalcoordination,syncope.

Iftherecommendeddosesareconsiderablyexceededandothercentrallydepressantsubstancesareadministered

concomitantly(seesection4.5),respiratorydepressionmayoccur.

Epileptiformconvulsionsoccurredmainlyafteradministrationofhighdosesoftramadolorafterconcomitanttreatment

withmedicinalproductswhichcanlowertheseizurethreshold(seesections4.4and4.5).

Psychiatricdisorders:

rare(1/10000,<1/1000):hallucinations,confusion,sleepdisturbance,anxietyandnightmares.Psychicadverse

reactionsmayoccurfollowingadministrationofContramalretardwhichvaryindividuallyinintensityandnature

(dependingonpersonalityanddurationoftreatment).Theseincludechangesinmood(usuallyelation,occasionally

dysphoria),changesinactivity(usuallysuppression,occasionallyincrease)andchangesincognitiveandsensorial

capacity(e.g.decisionbehaviour,perceptiondisorders).Dependencemayoccur.

Eyedisorders:

rare(1/10000,<1/1000):blurredvision

Respiratorydisorders:

rare(1/10000,<1/1000):dyspnoea

Worseningofasthmahasbeenreported,thoughacausalrelationshiphasnotbeenestablished.

Gastrointestinaldisorders:

verycommon(1/10):nausea

common(1/100,<1/10):vomiting,constipation,drymouth

uncommon(1/1000,<1/100):retching;gastrointestinalirritation(afeelingofpressureinthestomach,bloating),

diarrhoea

Skinandsubcutaneousdisorders:

common(1/100,<1/10):sweating

uncommon(1/1000,<1/100):dermalreactions(e.g.pruritus,rash,urticaria)

Musculoskeletaldisorders:

rare(1/10000,<1/1000):motorialweakness

Hepatobiliarydisorders:

Inafewisolatedcasesanincreaseinliverenzymevalueshasbeenreportedinatemporalconnectionwiththe

therapeuticuseoftramadol.

Renalandurinarydisorders:

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Generaldisorders:

common(1/100,<1/10):fatigue

rare(1/10000,<1/1000):allergicreactions(e.g.dyspnoea,bronchospasm,wheezing,angioneuroticoedema)and

anaphylaxis;Symptomsofwithdrawalreactions,similartothoseoccurringduringopiatewithdrawal,mayoccuras

follows:agitation,anxiety,nervousness,insomnia,hyperkinesia,tremorandgastrointestinalsymptoms.Other

symptomsthathaveveryrarelybeenseenwithtramadoldiscontinuationinclude:panicattacks,severeanxiety,

hallucinations,paraesthesias,tinnitusandunusualCNSsymptoms.

4.9Overdose

Symptoms

Inprinciple,onintoxicationwithtramadolsymptomssimilartothoseofothercentrallyactinganalgesics(opioids)are

tobeexpected.Theseincludeinparticularmiosis,vomiting,cardiovascularcollapse,consciousnessdisordersupto

coma,convulsionsandrespiratorydepressionuptorespiratoryarrest.

Treatment

Thegeneralemergencymeasuresapply.Keepopentherespiratorytract(aspiration!),maintainrespirationand

circulationdependingonthesymptoms.Thestomachistobeemptiedbyvomiting(consciouspatient)orgastric

irrigation.Theantidoteforrespiratorydepressionisnaloxone.Inanimalexperimentsnaloxonehadnoeffecton

convulsions.Insuchcasesdiazepamshouldbegivenintravenously.

Tramadolisminimallyeliminatedfromtheserumbyhaemodialysisorhaemo-filtration.Thereforetreatmentofacute

intoxicationwithContramalretardwithhaemodialysisorhaemofiltrationaloneisnotsuitablefordetoxification.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:otheropioids;ATC-codeN02AX02

Tramadolisacentrallyactingopioidanalgesic.Itisanon-selectivepureagonistatµ, and opioidreceptorswitha

higheraffinityfortheµreceptor.Othermechanismswhichcontributetoitsanalgesiceffectareinhibitionofneuronal

reuptakeofnoradrenalineandenhancementofserotoninrelease.

Tramadolhasanantitussiveeffect.Incontrasttomorphine,analgesicdosesoftramadoloverawiderangehaveno

respiratorydepressanteffect.Alsogastrointestinalmotilityislessaffected.Effectsonthecardiovascularsystemtendto

beslight.Thepotencyoftramadolisreportedtobe1/10(onetenth)to1/6(onesixth)thatofmorphine.

5.2Pharmacokineticproperties

Morethan90%ofContramalretardisabsorbedafteroraladministration.Themeanabsolutebioavailabilityis

approximately70%,irrespectiveoftheconcomitantintakeoffood.Thedifferencebetweenabsorbedandnon-

metabolisedavailabletramadolisprobablyduetothelowfirst-passeffect.Thefirst-passeffectafteroral

administrationisamaximumof30%.

Tramadolhasahightissueaffinity(V =203+40l).Ithasaplasmaproteinbindingofabout20%.

AfteradministrationofContramalretard100mgthepeakplasmaconcentrationC =141+40ng/mlisreachedafter

4.9h.AfteradministrationofContramalretard200mgC 260+62ng/mlisreachedafter4.8hours.

Tramadolpassestheblood-brainandplacentalbarriers.VerysmallamountsofthesubstanceanditsO-desmethyl

derivativearefoundinthebreast-milk(0.1%and0.02%respectivelyoftheapplieddose). d,ß

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Eliminationhalf-lifet isapproximately6h,irrespectiveofthemodeofadministration.Inpatientsabove75years

ofageitmaybeprolongedbyafactorofapproximately1.4.

InhumanstramadolismainlymetabolisedbymeansofN-andO-demethylationandconjugationoftheO-

demethylationproductswithglucuronicacid.OnlyO-desmethyltramadolispharmacologicallyactive.Thereare

considerableinterindividualquantitativedifferencesbetweentheothermetabolites.Sofar,elevenmetaboliteshave

beenfoundintheurine.AnimalexperimentshaveshownthatO-desmethyltramadolismorepotentthantheparent

substancebythefactor2-4.Itshalf-lifet (6healthyvolunteers)is7.9h(range5.4-9.6h)andisapproximately

thatoftramadol.

TheinhibitionofoneorbothtypesoftheisoenzymesCYP3A4andCYP2D6involvedinthebiotransformationof

tramadolmayaffecttheplasmaconcentrationoftramadoloritsactivemetabolite.Uptonow,clinicallyrelevant

interactionshavenotbeenreported.

Tramadolanditsmetabolitesarealmostcompletelyexcretedviathekidneys.Cumulativeurinaryexcretionis90%of

thetotalradioactivityoftheadministereddose.Incasesofimpairedhepaticandrenalfunctionthehalf-lifemaybe

slightlyprolonged.Inpatientswithcirrhosisoftheliver,eliminationhalf-livesof13.3+4.9h(tramadol)and18.5+

9.4h(O-desmethyltramadol),inanextremecase22.3hand36hrespectively,havebeendetermined.Inpatientswith

renalinsufficiency(creatinineclearance<5ml/min)thevalueswere11+3.2hand16.9+3h,inanextremecase19.5

hand43.2hrespectively.

Tramadolhasalinearpharmacokineticprofilewithinthetherapeuticdosagerange.

Therelationshipbetweenserumconcentrationsandtheanalgesiceffectisdose-dependent,butvariesconsiderablyin

isolatedcases.Aserumconcentrationof100-300ng/mlisusuallyeffective.

5.3Preclinicalsafetydata

Onrepeatedoralandparenteraladministrationoftramadolfor6-26weeksinratsanddogsandoraladministrationfor

12monthsindogshaematological,clinico-chemicalandhistologicalinvestigationsshowednoevidenceofany

substance-relatedchanges.Centralnervousmanifestationsonlyoccurredafterhighdosesconsiderablyabovethe

therapeuticrange:restlessness,salivation,convulsions,andreducedweightgain.Ratsanddogstoleratedoraldosesof

20mg/kgand10mg/kgbodyweightrespectively,anddogsrectaldosesof20mg/kgbodyweightwithoutany

reactions.

Inratstramadoldosagesfrom50mg/kg/dayupwardscausedtoxiceffectsindamsandraisedneonatemortality.Inthe

offspringretardationoccurredintheformofossificationdisordersanddelayedvaginalandeyeopening.Malefertility

wasnotaffected.Afterhigherdoses(from50mg/kg/dayupwards)femalesexhibitedareducedpregnancyrate.In

rabbitsthereweretoxiceffectsindamsfrom125mg/kgupwardsandskeletalanomaliesintheoffspring.

Insomein-vitrotestsystemstherewasevidenceofmutageniceffects.In-vivostudiesshowednosucheffects.

Accordingtoknowledgegainedsofar,tramadolcanbeclassifiedasnon-mutagenic.

Studiesonthetumorigenicpotentialoftramadolhydrochloridehavebeencarriedoutinratsandmice.Thestudyinrats

showednoevidenceofanysubstance-relatedincreaseintheincidenceoftumours.Inthestudyinmicetherewasan

increasedincidenceoflivercelladenomasinmaleanimals(adose-dependent,non-significantincreasefrom15mg/kg

1/2,ß

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

microcrystallinecellulose

hypromellose100000mPa .

magnesiumstearate

colloidalanhydroussilica

Filmcoating:

hypromellose6mPa .

lactosemonohydrate

macrogol6000

propyleneglycol

talc

titaniumdioxide(E171)

yellowironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Aluminium/PolypropyleneorAluminium/PVC/PVDCfoilblisters.

Packsizesof10,20,30,50,60,100,150(10x15)prolonged-releasetablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

GrünenthalLtd.

RegusLakesideHouse

1FurzegroundWay

StockleyParkEast

Uxbridge

Middlesex

UB111BD

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8MARKETINGAUTHORISATIONNUMBER

PA1189/4/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27 th

July2007

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