BioDol

Main information

  • Trade name:
  • BioDol 50mg Hard Capsules
  • Dosage:
  • 50 mg
  • Pharmaceutical form:
  • Capsule hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BioDol 50mg Hard Capsules
    Ireland
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • Treatment of moderate to severe pain.

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/001/001
  • Authorization date:
  • 28-06-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BioDol50mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each50mgtramadolhydrochloridecapsulecontains:50mgtramadolhydrochloride

Excipients:Eachcapsulecontains70mgoflactosemonohydrate.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Capsule,hard.

Olive/yellowhardcapsulesimprinted“TRM”onthecapsulescapand“50”onthecapsulesbody.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmoderatetoseverepain.

4.2Posologyandmethodofadministration

Fororaladministration.

Aswithallanalgesicdrugs,thedoseoftramadolshouldbeadjustedaccordingtotheseverityofthepainandthe

clinicalresponseoftheindividualpatient.Treatmentperiodsshouldbeshortandintermittentasdependencecanoccur

withtramadol.Thebenefitsofcontinueduseshouldbereviewedinordertoensurethattheyoutweightherisksof

dependence(seeSpecialWarningsandPrecautionsforUseandUndesirableEffectssection).

AdultsandChildrenAged12YearsandOver

Acutepain

Aninitialdoseof100mgisusuallynecessary.Thiscanbefollowedbydosesof50or100mgnotmorefrequentlythan

4hourly,anddurationoftherapyshouldbematchedtoclinicalneed.

Painassociatedwithchronicconditions

Useaninitialdoseof50mgandthentitratedoseaccordingtopainseverity.Theneedforcontinuedtreatmentshould

beassessedatregularintervalsaswithdrawalsymptomsanddependencehavebeenreported(SeeSection4.4,Special

WarningsandPrecautionsforUse).

Atotaldailyoraldoseof400mgisnotusuallyrequiredorrecommended.

Elderly

Theusualdosagesmaybeusedalthoughitshouldbenotedthatinvolunteersagedover75yearstheeliminationhalf-

lifeoftramadolwasincreasedby17%followingoraladministration.

Renalimpairment/renaldialysis

Theeliminationoftramadolmaybeprolonged.Theusualinitialdosageshouldbeused.Forpatientswithcreatinine

clearance<30ml/min.,thedosageintervalshouldbeincreasedto12hours.Tramadolisnotrecommendedforpatients

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Hepaticimpairment

Theeliminationoftramadolmaybeprolonged.Theusualinitialdosageshouldbeusedbutinmoderatehepatic

impairmentthedosageintervalshouldbeincreasedto12hours.Tramadolisnotrecommendedinseverehepatic

impairment(see4.3Contraindications).

Childrenunder12years

Notrecommended.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1).

Tramadolshouldnotbeadministeredtopatientswhohavepreviouslydemonstratedhypersensitivitytoitorincasesof

acuteintoxicationwithalcohol,hypnotics,centrallyactinganalgesics,opioidsorpsychotropicdrugs,orinpatients

sufferingfromuncontrolledepilepsy.Tramadolmustnotbeusedfornarcoticwithdrawaltreatment.Incommonwith

otheropioidanalgesicsitshouldnotbeadministeredtopatientswhoarereceivingmonoamineoxidaseinhibitorsor

withintwoweeksoftheirwithdrawal(seesection4.5)ortopatientswithseverelyimpairedliverfunctionorcreatinine

clearance<10ml/min.

4.4Specialwarningsandprecautionsforuse

Warnings

Attherapeuticdoses,tramadolhasthepotentialtocausephysicaldependenceandwithdrawalsymptoms.Rarely,cases

ofdependenceandabusehavebeenreported.Tramadolhasalowdependencepotential.Onlong-termusetolerance,

psychicandphysicaldependencemaydevelop.

Attherapeuticdoses,withdrawalsymptomshavebeenreportedatareportingfrequencyof1in8,000.Reportsof

dependenceandabusehavebeenlessfrequent.Becauseofthispotential,theclinicalneedforcontinuedanalgesic

treatmentshouldbereviewedregularly.

Inpatientswithatendencytodrugabuseordependence,treatmentshouldbeforshortperiodsandunderstrictmedical

supervision.

Tramadolisnotsuitableasasubstituteinopioid-dependentpatients.Althoughitisanopioidagonist,tramadolcannot

suppressmorphinewithdrawalsymptoms.

Convulsionshavebeenreportedattherapeuticdosesandtheriskmaybeincreasedatdosesexceedingtheusualupper

dailydoselimit(400mg).Patientswithahistoryofepilepsyorthosesusceptibletoseizuresshouldonlybetreated

withtramadoliftherearecompellingreasons.Theriskofconvulsionsmayincreaseinpatientstakingtramadoland

concomitantmedicationthatcanlowertheseizurethreshold(seeSection4.5-InteractionswithotherMedicaments

andotherFormsofInteractions).

Precautions

Tramadolshouldbeusedwithcautioninpatientswithheadinjury,increasedintracranialpressure,opioid-dependent

patients,disordersoftherespiratorycentreorfunctionandinpatientspronetoconvulsivedisordersorinshock.

Cautionshouldbeexercisedinpatientswithhepaticorrenalinsufficiency(creatinineclearance<30ml/min).The

dosingintervalmayneedtobeprolonged(see4.2Posologyandmethodofadministrationand4.3Contraindications).

Careshouldbetakenwhentreatingpatientswithrespiratorydepression,orifconcomitantCNSdepressantdrugsare

beingadministered,4.5),oriftherecommendeddosageissignificantlyexceeded(seesection4.9)asthepossibilityof

respiratorydepressioncannotbeexcludedinthesesituations.Attherapeuticdoses,respiratorydepressionhas

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Inonestudy,useoftramadolduringgeneralanaesthesiawithenfluraneandnitrousoxidewasreportedtoenhance

intraoperativerecall.Untilfurtherinformationisavailableuseoftramadolduringlightplanesofgeneralanaesthesia

shouldbeavoided.

Cautionshouldbeexercisedinpatientswithaprevioushistoryofhypersensitivitytootheropiates,andinpatientswith

decreasedlevelofconsciousnessofuncertainorigin.

Excipients

Thetabletscontainlactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnotreceivethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantadministrationoftramadolwithothercentrallyactingdrugsincludingalcoholmaypotentiateCNS

depressanteffect.TramadolshouldnotbecombinedwithMAOinhibitors(seesection4.3Contraindications).

InpatientstreatedwithMAOinhibitorsinthe14dayspriortotheuseoftheopioidpethidine,life-threatening

interactionsonthecentralnervoussystem,respiratoryandcardiovascularfunctionhavebeenobserved.Thesame

interactionswithMAOinhibitorscannotberuledoutduringtreatmentwithTramadol.

Cautionshouldbeexercisedduringconcomitanttreatmentwithtramadolandcoumarinderivatives(e.g.warfarin)due

toreportsofincreasedINRandecchymosesinsomepatients.

Tramadolmayincreasethepotentialforbothselectiveserotoninre-uptakeinhibitors(SSRIs)andtricyclic

antidepressants(TCAs)tocauseconvulsions(SeeSections4.4-SpecialWarningsandSpecialPrecautionsforUseand

5.2-PharmacokineticProperties).

Tramadolmayalsoincreasethepotentialforanti-psychoticsandotherseizurethresholdloweringdrugstocause

convulsions.

Simultaneousadministrationofcarbamazepine(enzymeinducer)markedlydecreasesserumconcentrationsoftramadol

toanextentthatadecreaseinanalgesiceffectivenessandashorterdurationofactionmayoccur.

Simultaneousadministrationwithcimetidineisassociatedwithclinicallyinsignificantchangesinserumconcentrations

oftramadol.Thereforenoalterationofthetramadoldosageregimenisrecommendedforpatientsreceivingchronic

cimetidinetherapy.

Thereisatheoreticalpossibilitythattramadolcouldinteractwithlithiumduetotheirrespectivemechanismsofaction.

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

recommendedbecauseitistheoreticallypossiblethattheanalgesiceffectofapureagonistisattenuatedunderthese

circumstances.

Isolatedcasesofserotonergicsyndromehavebeenreportedwiththetherapeuticuseoftramadolincombinationwith

otherserotonergicagentssuchasselectiveserotoninre-uptakeinhibitors(SSRIs)orwithMAOinhibitors.

Serotonergicsyndromecanbemanifestedbysymptomssuchasconfusion,agitation,restlessness,feversweat,ataxia,

hyperreflexia,myocloniaanddiarrhoea.Thewithdrawaloftheserotonergicagentproducesarapidimprovement.

Treatmentdependsonthenatureandseverityofthesymptoms.

Administrationoftramadoltogetherwithcarbamazepineresultsinmarkedlydecreasedserumconcentrationsof

tramadolwhichmayreduceanalgesiceffectivenessandshortenthedurationofaction.

OtheractivesubstancesknowntoinhibitCYP3A4,suchasketoconazoleanderythromycin,mightinhibitthe

metabolismoftramadol(N-demethylation)probablyalsothemetabolismoftheactiveO-demethylatedmetabolite.The

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Inalimitednumberofstudiesthepre-orpostoperativeapplicationoftheantiemetic5-HT3antagonistondansetron

increasedtherequirementoftramadolinpatientswithpostoperativepain.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoftramadolinpregnantwomen.Animalstudieswithtramadolrevealedat

veryhighdoseseffectsonorgandevelopment,ossificationandneonatalmortality.Teratogeniceffectswerenot

observed.Tramadolcrossestheplacenta.Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).The

potentialriskforhumansisunknown.Tramadolshouldnotbeusedduringpregnancy.

Lactation

Tramadol-administeredbeforeorduringbirth-doesnotaffectuterinecontractility.Inneonatesitmayinducechanges

intherespiratoryratewhichareusuallynotclinicallyrelevant.Chronicuseduringpregnancymayleadtoneonatal

withdrawalsymptoms.Tramadolanditsmetabolitesarefoundinsmallamountsinhumanbreastmilk.Aninfantcould

ingestabout0.1%ofthedosegiventothemother.Tramadolshouldnotbeadministeredduringbreastfeeding.Aftera

singleadministrationoftramadolitisnotusuallynecessarytointerruptbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Evenwhentakenaccordingtoinstructions,Tramadolmaycausedrowsinessanddizzinessandthiseffectmaybe

potentiatedbyalcoholandotherandpsychotropicsubstances(CNSdepressants)andthereforemayimpairthereactions

ofdriversandmachineoperators.Ambulantpatientsshouldbewarnednottodriveoroperatemachineryifaffected.

4.8Undesirableeffects

Themostcommonlyreportedadversereactionsarenauseaanddizziness,bothoccurringinmorethan10%ofpatients.

Thefrequenciesaredefinedasfollows:

Verycommon: 1/10

Common: 1/100,<1/10

Uncommon: 1/1000,<1/100

Rare: 1/10000,<1/1000

Veryrare:<1/10000

Notknown:cannotbeestimatedfromtheavailabledata

Cardiovasculardisorders:

uncommon:cardiovascularregulation(palpitation,tachycardia,posturalhypotensionorcardiovascularcollapse).These

adversereactionsmayoccurespeciallyonintravenousadministrationandinpatientswhoarephysicallystressed.

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Nervoussystemdisorders:

verycommon:dizziness

common:headache,somnolence

rare:changesinappetite,paraesthesia,tremor,respiratorydepression,epileptiformconvulsions,involuntarymuscle

contractions,abnormalcoordination,syncope.

notknown:speechdisorders

Iftherecommendeddosesareconsiderablyexceededandothercentrallydepressantsubstancesareadministered

concomitantly(seesection4.5),respiratorydepressionmayoccur.

Epileptiformconvulsionsoccurredmainlyafteradministrationofhighdosesoftramadolorafterconcomitanttreatment

withmedicinalproductswhichcanlowertheseizurethreshold(seesections4.4and4.5).

Psychiatricdisorders:

rare:hallucinations,confusion,sleepdisturbance,anxietyandnightmares.Psychicadversereactionsmayoccur

followingadministrationofTramadolwhichvaryindividuallyinintensityandnature(dependingonpersonalityand

durationoftreatment).Theseincludechangesinmood(usuallyelation,occasionallydysphoria),changesinactivity

(usuallysuppression,occasionallyincrease)andchangesincognitiveandsensorialcapacity(e.g.decisionbehaviour,

perceptiondisorders).Dependencemayoccur.

Eyedisorders:

rare:blurredvision

notknown:mydriasis

Respiratorydisorders:

rare:dyspnoea

Worseningofasthmahasbeenreported,thoughacausalrelationshiphasnotbeenestablished.

Gastrointestinaldisorders:

verycommon:nausea

common:vomiting,constipation,drymouth

uncommon:retching;gastrointestinalirritation(afeelingofpressureinthestomach,bloating),diarrhoea

Skinandsubcutaneousdisorders:

common:sweating

uncommon:dermalreactions(e.g.pruritus,rash,urticaria)

Musculoskeletaldisorders:

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Hepatobiliarydisorders:

Inafewisolatedcasesanincreaseinliverenzymevalueshasbeenreportedinatemporalconnectionwiththe

therapeuticuseoftramadol.

Renalandurinarydisorders:

rare:micturitiondisorders(difficultyinpassingurine,dysuriaandurinaryretention)

Generaldisorders:

common:fatigue

rare:allergicreactions(e.g.dyspnoea,bronchospasm,wheezing,angioneuroticoedema)andanaphylaxis;Symptoms

ofwithdrawalreactions,similartothoseoccurringduringopiatewithdrawal,mayoccurasfollows:agitation,anxiety,

nervousness,insomnia,hyperkinesia,tremorandgastrointestinalsymptoms.Othersymptomsthathaveveryrarely

beenseenwithtramadoldiscontinuationinclude:panicattacks,severeanxiety,hallucinations,paraesthesias,tinnitus

andunusualCNSsymptoms(i.e.confusion,delusions,personalisation,derealisation,paranoia).

4.9Overdose

Inprinciple,onintoxicationwithtramadolSymptomsofoverdosagearetypicalofotheropioidanalgesics,andinclude

miosis,vomiting,cardiovascularcollapse,sedationandconsciousnessdisordersuptocoma,seizuresandrespiratory

depressionuptorespiratoryarrest.

Treatment

Thegeneralemergencymeasuresapply.Supportivemeasuressuchasmaintainingthepatencyoftheairwayand

maintainingcardiovascularfunctionshouldbeinstituted;naloxoneshouldbeusedtoreverserespiratorydepression.In

animalexperimentsnaloxonehadnoeffectonconvulsions:fitscanbecontrolledwithdiazepamgivenintravenously.

Incaseofintoxicationorally,gastrointestinaldecontaminationwithactivatedcharcoalorbygastriclavageisonly

recommendedwithin2hoursaftertramadolintake.Gastrointestinaldecontaminationatalatertimepointmaybeuseful

incaseofintoxicationwithexceptionallylargequantities.

Tramadolisminimallyeliminatedfromtheserumbyhaemodialysisorhaemofiltration.Thereforetreatmentofacute

intoxicationwithtramadolwithhaemodialysisorhaemofiltrationaloneisnotsuitablefordetoxification.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCode:N02AX02

Tramadolisacentrallyactinganalgesicwithtwomechanismsofaction.Itisanon-selectivepureagonistatopioid

receptorswithahigheraffinityfor µ

receptors.Itisalsoaninhibitorofneuronalreuptakeofnoradrenalineand

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5.2Pharmacokineticproperties

Tramadolisalmostcompletelyabsorbedfollowingoraladministration.Themeanabsolutebioavailabilityis

approximately70%duetolowfirst-passeffect.Thebioavailabilityisindependentofconcomitantintakeoffood.

Therapeuticserumlevelsareconsideredtobedoserelatedandareintherangeof100to300ng/mlwithconsiderable

inter-individualvariability.Tramadolhasahightissueaffinitywithavolumeofdistributionofabout203litres.

Proteinbindingisabout20%.

Tramadolcrossestheblood-brainandplacentalbarriers.Tramadolismetabolisedtoahighextentafteroral

administration.ThemainmetabolicpathwayappearstobebymeansofN-andO-demethylationandglucuronidation

orsulfationintheliver.TheO-desmethylmetabolitehasbeenshowntohaveanalgesiceffectsinanimalexperiments.

O-desmethylationiscatalyzedbythepolymorphicenzymeCYP2D6.

About5-10%ofthecaucasianpopulationareslowmetabolisersandhavereducedactivityoftheenzymeCYP2D6.

Theserumconcentrationoftramadolishigherinindividualswithslowmetabolismcomparedtothosewithfaster

metabolism,whiletheconcentrationofO-desmethyltramadolislower.

Theinhibitionofoneorbothtypesoftheiso-enzymesCYP3A4(eg.ketoconazole,erythromycin)andCYP2D6

(fluoxetine,paroxetine,quinidine,ritonavir)involvedinthebiotransformationoftramadolmayaffecttheplasma

concentrationoftramadolorit’sactivemetabolite.Thesameappliesforenzymeinducers(eg.rifampicin,fenytoin).

Uptonow,noclinicallyrelevantinteractionshavebeenreported.

About30%ofthedoseisexcretedunchangedintheurinewhile60%ofthedoseisexcretedasmetabolites.

Theeliminationhalf-lifeoftramadolisapproximately6hours.Inrenalorhepaticinsufficiency,aslightprolongation

ofthehalf-lifecanbeexpected.Insevereinsufficiency(eg.cirrhosisoftheliver,creatinineclearance<5ml/min),a2-

3foldprolongationofthehalf-lifecanbeexpected.Inelderlypatients(>75yearsofage),theeliminationhalf-life

maybeprolongedbyafactorof1.4.

5.3Preclinicalsafetydata

Onrepeatedoralandparenteraladministrationoftramadolfor6-26weeksinratsanddogsandoraladministrationfor

12monthsindogshaematological,clinico-chemicalandhistologicalinvestigationsshowednoevidenceofany

substance-relatedchanges.Centralnervousmanifestationsonlyoccurredafterhighdosesconsiderablyabovethe

therapeuticrange:restlessness,salivation,convulsions,andreducedweightgain.Ratsanddogstoleratedoraldosesof

20mg/kgand10mg/kgbodyweightrespectively,and

dogsrectaldosesof20mg/kgbodyweightwithoutanyreactions.

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

upwards)andanincreaseinpulmonarytumoursinfemalesofalldosagegroups(significant,butnotdose-dependent)

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityorcarcinogenicpotential.Studiesinratsandrabbitshaverevealednoteratogeniceffects.

However,embryotoxicitywasshownintheformofdelayedossification.Fertilityreproductiveperformanceand

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Microcrystallinecellulose(E460(i))

Croscarmellosesodium(E466)

Magnesiumstearate(E572)

Capsuleshellexcipients: Body: Erythrosin(E127)

Titaniumdioxide,(E171)

Yellowironoxide(E172)

Gelatin

Cap: Indigocarmine(E132)

Titaniumdioxide(E171)

Blackironoxide(E172)

Yellowironoxide(E172)

Gelatin

Ink: OpacodeBlackS-1-27794(Colorcon)

ShellacGlaze

BlackIronOxideJPE(E172)

PropyleneGlycol(E1520)

N-ButylAlcohol

6.2Incompatibilities

Notapplicable.

6.3Shelflife

4years.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

C.Storeintheoriginalpackage;inordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Al/PVC/PVdCblister.

Blisterpacksof10,20,3050,60and100capsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchin

Hertfordshire

SG40TW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28June2002

Dateoflastrenewal:29July2009

10DATEOFREVISIONOFTHETEXT

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