BY-MADOL SR

Main information

  • Trade name:
  • BY-MADOL SR
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Prolonged Release Capsules
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BY-MADOL SR
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0915/026/003
  • Authorization date:
  • 24-04-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

By-MadolSR100mgprolonged-releasecapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1prolonged-releasecapsulecontains100mgoftramadolhydrochlorideequivalentto87.82mgtramadol.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Prolonged-releasecapsule,hard

Capsuleswithopaqueyellowcapandnaturaltransparentbody,containingwhitesphericalmicrogranules

4CLINICALPARTICULARS

4.1TherapeuticIndications

Formoderatetoseverepain.

4.2Posologyandmethodofadministration

Thedosageshouldbeadjustedtotheseverityofthepatient'spainandhis/hersensitivity.

Adultsandadolescentsaged12yearsandover:

100-200mgtramadolhydrochloridetwicedaily(correspondingto200-400ofmgtramadolhydrochloride/day),

morningandeveningadministrationrecommended.

Thesmallesteffectiveanalgesicdoseshouldalwaysbeused.Dailydosesof400mgofactivesubstancemustnotbe

exceeded,unlessexceptionalmedicalreasonsrequireso.Aminimumintervalof8hoursmustberespectedbetween

administrations.

Children:

BY-MADOLSRisnotsuitableforuseinchildrenbelow25kgbodyweightwhichingeneraldoesnotallowfor

individualizeddosageinchildrenbelow12yearsofage.Consequently,amoresuitableformofadministrationshould

beused.

Elderlypeople(over75years)

Asarule,dosageadjustmentinelderlypatients(upto75yearsofage)isnotrequiredintheabsenceofclinically

manifesthepaticorrenalinsufficiency.Eliminationmaybeprolongedinelderlypatients(over75yearsofage).

Consequently,dosageintervalsshouldbeprolongedaccordingtoindividualneeds.

Hepaticandrenalinsufficiency/dialysis

BY-MADOLSRshouldnotbeadministeredtopatientswithseverehepaticand/orrenalinsufficiency.Inlesssevere

Excipients: 0.0075mgMethylparahydroxybenzoate/prolonged-releasecapsule

0.0023mgPropylparahydroxybenzoate/prolonged-releasecapsule

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Note:

Therecommendeddosagesareindicativeonly.Ingeneral,thesmallesteffectiveanalgesicdoseshouldbeused.Forthe

treatmentofchronicpain,apre-establishedposologymustberespected.

Fordosesnotrealisable/practicablewiththismedicinalproductotherstrengthsofthismedicinalproductorother

pharmaceuticalformsandproductsareavailable.

Methodofadministration

Theprolonged-releasecapsule,hard,mustbeswallowedwholewithsufficientliquid,irrespectiveofmealtimes.

BY-MADOLSRmustneverbeusedforlongerthantherapeuticallyabsolutelynecessary.Shouldprolongedpain

treatmentaccordingtothenatureandseverityoftheillnessbenecessary,acarefulevaluationshouldbecarriedoutat

shortregularintervals(ifnecessarybyinstitutingtreatmentpauses)tocheckwhetherortowhatextentprolonged

treatmentismedicallynecessary.

4.3Contraindications

BY-MADOLSRmustnotbeusedinthefollowingcases:

hypersensitivitytoTramadol,methylparahydroxybenzoate,propylparahydroxybenzoate,ortoanyofthe

excipients;

acuteintoxicationwithalcohol,hypnotics,analgesics,opioidsorpsychotropicdrugs;

patientswhoaretakingmonoamineoxidaseinhibitorsorhavebeentakingthemwithintheprevioustwoweeks

(seesection4.5);

epilepsyuncontrolledbytreatment.

BY-MADOLSRmustnotbeusedforthetreatmentofopioiddependence.

BY-MADOLSRisnotsuitableforuseinchildrenbelow25kgbodyweightwhichingeneraldoesnotallowfor

individualiseddosageinchildrenbelow12yearsofage.Consequently,amoresuitableformofadministationshould

beused.

Thismedicinalproductiscontraindicatedinchildrenbelow12yearsofage.

4.4Specialwarningsandprecautionsforuse

BY-MADOLSRshouldonlybeusedfollowingastrictbenefit-riskevaluationandappropriateprecautionarymeasures

inthefollowingcases:

opioid-dependentpatients,

impairedconsciousnessofunclearaetiology,shock

impairedrespiratorycentreorfunction,

increasedintracranialpressure,headinjury,orbraindisease,

impairedliverorkidneyfunction

Themedicinalproductshouldbeusedwithcautioninpatientsshowingsensitivityreactionstoopiates.

ConvulsionshavebeenreportedinpatientstakingTramadolattherecommendeddosage.Increasedriskmaybe

associatedwiththeadministrationofdosesexceedingtherecommendeddailydose(400mg).Tramadolcanincrease

theriskofconvulsionsifcombinedwithothermedicinalproductsthatlowertheconvulsionthreshold(seesection4.5).

PatientswithahistoryofepilepsyorthosesusceptibletoconvulsionsshouldonlybetreatedwithTramadolifthereare

compellingcircumstances.

Tramadolhasaslightpotentialfordependence.Incaseofprolongeduse,patientsmaydeveloptolerance,andpsychic

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Attherapeuticdoses,withdrawalsymptomshavebeenreportedwithafrequencyof1in8,000.Inpatientswitha

tendencytodrugabuseordrugdependence,treatmentwithBY-MADOLSRshouldonlybeforshortperiodsand

understrictmedicalsupervision.

BY-MADOLSRisnotsuitableforuseasasubstituteinopioid-dependentpatients.Althoughitisanopiateagonist,

Tramadolcannotsuppressmorphinewithdrawalsymptoms.

Themedicinalproductcontainmethylparahydroxybenzoateandpropylparahydroxybenzoatewhichmaycause

allergicreactions(possiblydelayed).

Thismedicinalproductcontainssucrose.Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-

galactosemalabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Life-threateninginteractionsaffectingthecentralnervoussystemaswellasrespiratoryandcardiovascularfunction

havebeenobservedinpatientswhohadbeentreatedwithMAOinhibitorswithin14dayspriortotheadministrationof

theopioidpethidine.ThesameinteractionswithBY-MADOLSRaswithMAOinhibitorscannotberuledout.

TheconcurrentadministrationofBY-MADOLSRwithothercentrallyactingdrugs,includingalcohol,maymutually

potentiateeffectsontheCNS.

Basedonavailablepharmacokineticresults,noclinicallyrelevantinteractionsareexpectedwiththeco-administration

orpreviousadministrationofTramadolwithcimetidine(enzymeinhibitor).Concurrentorprevioustreatmentwith

carbamazepine(enzymeinducer)mayreduceandshortentheanalgesiceffect.

Thecombinationofamixtureofagonists/antoganists(e.g.,buprenorphine,nalbuphine,pentazocine)andTramadolis

notrecommended,sincethereisatheoreticalpossibilitythattheanalgesiceffectofapureagonistbecomesdecreased

insuchconditions.

Tramadolmayinduceconvulsionsandincreasetheconvulsion-inducingpotentialofselectiveserotoninreuptake

inhibitors,tricyclicantidepressants,anti-psychoticsandotherconvulsionthreshold-loweringdrugs.

Inisolatedcases,aserotoninsyndromehasbeenreportedwiththeconcurrenttherapeuticuseofTramadolin

combinationwithotherserotoninergicsubstances,suchasselectiveserotoninreuptakeinhibitors(SSRIs).Symptoms

ofserotoninsyndromeincludeconfusion,agitation,fever,sweating,ataxia,hyperreflexia,myoclonusanddiarrhoea.

Cessationofserotoninergicdrugsgenerallyleadstorapidimprovement.Treatmentdependsonthenatureandseverity

ofsymptoms.

Cautionshouldbeexercisedduringconcomitanttreatmentwithtramadolandcoumarinderivatives(e.g.warfarin)due

toreportsofincreasedINRwithmajorbleedingandecchymosesinsomepatients.

Inalimitednumberofstudiesthepre-orpostoperativeapplicationoftheantiemetic5-HT

antagonistondansetron

increasedtherequirementoftramadolinpatientswithpostoperativepain.

OtherCYP3A4inhibitors,suchasketoconazoleanderythromycinmayinhibitboththemetabolismofTramadol(N-

demethylation)andpossiblyalsothemetabolismoftheactiveO-demethylatedmetabolites.Theclinicalsignificanceof

thisinteractionisnotknown.

4.6Fertility,pregnancyandlactation

Tramadolcrossestheplacenta.

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TherepeatedadministrationofTramadolduringpregnancycanleadtoincreasedtoleranceofTramadolinthefoetus

andconsequentlytowithdrawalsymptomsinthenew–borninfantafterbirth.ForthisreasonBY-MADOLSRshould

notbeusedduringpregnancy.

Tramadoladministeredbeforeorduringbirthdoesnotaffectuterinecontractility.Innew–borninfantsitmayinduce

respiratoryratechangeswhichnormallyarenotclinicallysignificant.

Tramadolisexcretedinverysmallamounts(approx.0.1%ofanintravenousdose)inhumanbreastmilk.

ForthisreasonTramadolshouldnotbeusedduringlactation.Discontinuationofbreast-feedingisgenerallynot

necessaryfollowingasingledoseofTramadol.

4.7Effectsonabilitytodriveandusemachines

BY-MADOLSRmaycausedrowsinessandblurredvisionalteringone'scapacitytoreact,sothattheabilitytodrive

andusemachinesorworkwithoutasteadyfootholdisreduced.Thisappliesespeciallyatthestartoftreatment,when

changingovertoanothertreatment,incombinationwithothercentrallyactivedrugs,andparticularlyifcombinedwith

alcohol.

4.8Undesirableeffects

ThemostfrequentsideeffectsoccurringduringtreatmentwithBY-MADOLSRarenauseaandvertigo,whichoccurin

morethan1outof10patients.

Cardiacdisorders:

Uncommon(1/1,000to<1/100)theremaybeeffectsoncardiovascularregulation(palpitations,tachycardia,faintness

orcardiovascularcollapse).Theseadverseeffectsmayoccurespeciallyifthepatientisstandinguprightor

experiencingphysicalstress.

Rare(1/10,000to<1/1,000):bradycardia(reducedheartrate),elevatedbloodpressure.

NervousSystemdisorders:

Verycommon,(1/10):vertigo.

Common(1/100to<1/10):headaches,drowsiness.

Rare(1/10,000to<1/1,000):changeinappetite,paraesthesia,trembling,respiratorydepression,epileptiform

seizures,involuntarymusclecontractions,abnormalcoordination,syncope.

DepressedrespirationcanoccurinpatientsexceedingtherecommendeddosageorsimultaneouslyusingotherCNS-

depressantdrugs.

EpileptiformseizuresprincipallyoccurringfollowingtheuseofhighTramadoldosesorfollowingtheconcomitantuse

ofpotentiallyseizure-inducingorseizure-threshold-loweringdrugs

Psychiatricdisorders:

Rare(1/10,000to<1/1,000):hallucinations,confusion,sleepdisturbance,anxietyandnightmares.

Psychiccomplaints,whichmaydifferintheirnatureordegreeofintensity(dependingonthepatient'spersonalityand

durationoftreatment),mayoccurfollowingtreatmentwithBY-MADOLSR.Symptomsmayincludemoodchanges

(mostlyelation,occasionallyalsoirritability),changesinactivity(mostlyreduced,occasionallyincreased)and

alterationsofcognitiveandsensoryperformance(changesinsensoryperceptionandrecognitionthatcanleadtoerrors

indecision-making).

Dependencecanoccur.

Eyedisorders:

Rare(1/10,000to<1/1,000):blurredvision

Respiratorydisorders:

Rare(1/10,000to<1/1,000):dyspnoea.

Increaseddifficultyinbreathingandaworseningofasthmahavebeenreported.However,acausalrelationshipwith

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Gastrointestinaldisorders:

Verycommon(1/10):nausea

Common(1/100to<1/10):vomiting,constipation,drymouth.

Uncommon(1/10,000to<1/1000):retching,diarrhoea,gastriccomplaints(e.g.,stomachpressure,bloating).

Skinandsubcutaneoustissuedisorders:

Common(1/100to<1/10):sweating

Uncommon(1/10,000to<1/1000):skinmanifestations(e.g.,itching,rash,hotflushes)

Musculoskeletalandconnectivetissuedisorders:

Rare(1/10,000to<1/1,000):reducedmusclestrength.

Hepatobiliarydisorders:

Veryrare(1/10,000):elevatedtransaminases.

Renalandurinarydisorders:

Rare(1/10,000to<1/1,000):disordersofmicturitionorreduceddiuresis.

Generaldisorders:

Common(1/100to<1/10):fatigue

Rare(1/10,000to<1/1,000):allergicreactions(e.g.,dyspnoea,bronchospasm,wheezing,angioneuroticoedema,

swollenskin)andanaphylaxis.

Thelong-termuseofBY-MADOLSRcanleadtodependence,eveniftheriskislow.Followingcessationof

treatment,symptomsofwithdrawalreactions,similartothoseoccurringduringopiatewithdrawal,mayoccuras

follows:agitation,anxiety,nervousness,insomnia,hyperkinesias,tremorandgastroinstestinalsymptoms.

Methylparahydroxybenzoateandpropylparahydroxybenzoatecancausehypersensitivity,evendelayed

hypersensitivityreactions.

4.9Overdose

Symptoms

ThesymptomsofTramadolpoisoningaretypicalofothercentrallyactiveanalgesics(opioids).Inparticular,miosis,

vomiting,cardiovascularcollapse,impairedconsciousnessandcoma,convulsionsandrespiratorydepressionaswellas

respiratoryarrestmayoccur.

Treatment

Dependingonsymptoms,treatmentordinarilyconsistsofgeneralemergencymeasuresforfreeingtheairways(beware

ofaspiration!)andformaintainingbreathingandcardiovascularfunction.Naloxonecanbeusedasantidoteincaseof

respiratorydepression.Naloxonehasbeenshowntohavenoeffectonconvulsionsinanimalexperiments.Intravenous

Diazepamshouldbeusedinstead.

Tramadolisonlyslightlydialysable.Forthisreason,haemodialysisorhaemofiltrationontheirownarenotsuitablefor

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Analgesics,otheropioids.

ATCCode:N02AX02

Tramadolisacentrally-actingopioidanalgesic.Itisanon-selectivepureagonistatµ,,and opioidreceptorswitha

higheraffinityattheµreceptors.Othermechanismsthatcontributetoitsanalgesiceffectareinhibitionofneuronalre-

uptakeofnoradrenalineaswellasincreasedserotoninrelease.

Tramadolhasanantitussiveeffect.Incontrasttomorphine,Tramadolinanalgesicdoseshasnorespiratorydepression

effectoverawiderangeandnoeffectongastrointestinalmotility.Ithasonlyaslighteffectonthecardiovascular

system.Tramadolpotencyisgivenas1/10to1/6ofthatformorphine.

5.2Pharmacokineticproperties

FollowingoraluseTramadolabsorptionisgreaterthan90%.Absoluteaveragebioavailabilityis70%,irrespectiveof

concurrentfoodintake.ThedifferencebetweenavailableabsorbedandunmetabolizedTramadolcanbeexplainedby

thefactthatthereisonlyslightfirst-passmetabolism.First-passmetabolismfollowingoraladministrationis30%at

most.

Followingoraluse(100mg)inliquidform,peakplasmaconcentrations(C

)after1.2hoursarecalculatedtobe309

±90ng/mlandfollowingasimilardoseinsolidoralformpeakplasmaconcentrations(C

)after2hoursare280±

49ng/ml.Tramadolhashightissueaffinity(Vd, =203±40l).Serumproteinbindingisapproximately20%.

FollowingtheadministrationofBY-MADOLSR100mgpeakplasmaconcentrations(C

)after4.9hoursare141±

40ng/ml.FollowingtheadministrationofBY-MADOLSR200mg,peakplasmaconcentrations(C

)after4.8hours

are260±62ng/ml.

Tramadolcrossestheblood-brainbarrierandtheplacenta.VeryslightamountsofthedrugtogetherwithitsO-

demethylderivativearefoundinmaternalmilk(0.1%and0.02%oftheadministereddose,respectively).

Theeliminationhalf-life(t½)ofTramadolisabout6hours,irrespectiveofthemethodofadministration.Inpatients

over75yearsofage,eliminationhalf-lifemaybeprolongedbyafactorofapprox.1.4.

Inhumans,TramadolisessentiallymetabolizedbyN-andO-demethylationaswellasbyconjugationoftheO-

demethylationproductswithglucuronicacid.OnlyO-demethyltramadolispharmacologicallyactive.Thereare

considerablequantitativeinterindividualvariationsasregardstheothermetabolites.11metaboliteshavebeenfoundin

urinetodate.Accordingtoresultsofanimalexperiments,O-demethyltramadolexceedsthepotencyoftheparent

substancebyafactorof2to4.Itshalf-life(t½)(6healthyvolunteers)is7.9hours(rangingbetween5.4to9.6hours)

andissimilartothatoftramadol.

InhibitionoftheisoenzymesCYP3A4and/orCYP2D6involvedinthebiotransformationofTramadolcaninfluence

theplasmaconcentrationofTramadolorthatofitsactivemetabolites.Noclinicallyrelevantinteractionshavebeen

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Tramadolanditsmetabolitesarealmostcompletelyexcretedviathekidneys.Cumulativeurinaryexcretionis90%of

thetotalradioactivityoftheadministereddose.Tramadolhalf-lifemaybeslightlyprolongedinpatientswithimpaired

liverorkidneyfunction.Eliminationhalf-livesof13.3±4.9hours(tramadol)andof18.5±9.4hours(O-demethyl

tramadol)andinextremecasesof22.3and36hours,respectivelyhavebeendeterminedinpatientswithcirrhosisofthe

liver.Eliminationhalf-livesof11±3.2hoursand16.9±3hours,andinextremecasesof19.5hoursand43.2hours,

respectivelyhavebeendeterminedinpatientswithrenalinsufficiency(creatinineclearance<5ml/min).

Tramadolattherapeuticdosesshowsalinearpharmacokineticprofile.

Therelationbetweenserumconcentrationsandanalgesiceffectisdose-dependentwhileshowingsignificantindividual

variations.Asarule,serumconcentrationsof100-300ng/mlareeffective.

5.3Preclinicalsafetydata

Somein-vitrotestsystemshaveindicatedmutageniceffects.Invivotestshavegivennoindicationsofmutagenic

effects.AccordingtocurrentknowledgeTramadolcanbeclassifiedasanon-mutagenicsubstance.

StudiesonthetumorigenicpotentialofTramadolhydrochloridehavebeencarriedoutintheratandmouse.Therat

studygavenoindicationsofsubstance-relatedincreasesintumourincidence.Inthemousestudy,increasedincidence

oflivercelladenomawasobservedinthemales(dose-dependent,non-significantincreasesfrom15mg/kg)andan

increaseinlungtumoursinthefemalesofalldosegroups(significantbutnon-dosedependentincreases).

InstudiesonreproductiontoxicityTramadoldosagesfrom50mg/kg/dayintheratproducedmaternaltoxiceffectsand

ledtoincreasedneonatemortality.Delayedgrowthintheformofdisordersofossificationanddelayedvaginalandeye

openingoccurredintheprogeny.Thefertilityofmaleratswasnotimpaired.Femalesonhighdoses(from50

mg/kg/day)showedareducedgestationindex.

From125mg/kgmaternaltoxiceffectsoccurredinrabbitsaswellasskeletalanomaliesintheprogeny.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents:

Sugarspheres(maizestarchandsucrose)

Macrogol4000

Polyacylatedispersion30%(ethylacrylate,methylmethacrylate,nonoxynol)

Dimeticoneemulsion(dimethicone,(t-octylphenoxy)polyethoxyethanol,Macrogol600,polyethyleneglycol-sorbitan-

laurate,sodiumbenzoate,propyl-4-hydroxybenzoate(E216),methyl-4-hydroxybenzoate(E218),propyleneglycol,

sorbicacid)

Hypromellose

Talc

Capsuleshell:

Gelatin

Titaniumdioxide(E171)

YellowIronOxide(E172)

6.2Incompatibilities

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6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Aluminium/PVCblisters

Packsizes:10,20,28,30,50,56,60,100prolonged-releasecapsules,hard.

Hospitalpacks:500prolonged-releasecapsules,hard

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HelsinnBirexTherapeuticLtd.

Damastown,

Mulhuddart,

Dublin15.

8MARKETINGAUTHORISATIONNUMBER

PA915/26/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27thOctober2006

Dateoflastrenewal:12thJuly2011

10DATEOFREVISIONOFTHETEXT

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