DANTRIUM

Main information

  • Trade name:
  • DANTRIUM Capsule 100 Milligram
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DANTRIUM Capsule 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1556/001/002
  • Authorization date:
  • 30-01-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA1556/001/002

CaseNo:2078449

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

SpePharmHoldingB.V.

Kingsfordweg151,1043GRAmsterdam,Netherlands

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Dantrium100mgCapsules

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom19/03/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 05/07/2010 CRN 2078449 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dantrium100mgCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Dantriumcapsules100mgcontain100mgdantrolenesodiumpercapsule.

Excipients-ContainsLactoseMonohydrate189.0mgandSunsetYellow(E110)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

Dantriumcapsulesarepresentedinorange/lightbrownhardcapsules.The100mgcapsulecarriesthemonogram

‘Dantrium100mg’onthecapand‘0149’,‘0033’andtriplecodingbarsonthebody.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthetreatmentofchronic,severespasticityresultingfromsuchdisordersasstroke,multiplesclerosis,spinalcord

injuryandcerebralpalsy.

4.2Posologyandmethodofadministration

Adultsandtheelderly

Thedosageshouldbetitratedagainstclinicalimprovementandincreaseduntilthemaximumbenefitcompatiblewith

thepatient'sneurologicaldeficitisachieved.Thelowestdosecompatiblewithoptimalresponseisrecommended.

Arecommendeddosageincrementscaleisshownbelow:-

Adultsandtheelderly

Eachdosagelevelshouldbemaintainedforsevendaysinordertodeterminethepatient'sresponse.Themaximum

dailydoseshouldnotexceed400mg.Inviewofthepotentialforhepatoxicityinlongtermuse,ifnoobservablebenefit

Week Recommendeddosage

First One25mgcapsuledaily

Second One25mgcapsuletwicedaily

Third Two25mgcapsulestwicedaily

Fourth Two25mgcapsulesthreetimesdaily

Fifth Three25mgcapsulesthreetimesdaily

Sixth Three25mgcapsulesfourtimesdaily

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Manypatientsexperienceside-effectssuchasweaknessandfatigueduringthefirstfourweeksoftherapywhilstthey

adjusttothechangesinmuscletoneinducedbythedrug.Theyareusuallytransientandmildinnature.Shoulditbe

necessary,thedosagemaybereducedandthengraduallyincreasedaccordingtothepatient'stolerance.

Children

ThesafetyofDantriumininfantsundertheageoffiveyearshasnotbeenestablished.

4.3Contraindications

Wherespasticityisutilisedtosustainuprightpostureandbalanceinlocomotion,orwheneverspasticityisutilisedto

obtainormaintainincreasedfunction.

Inpatientswithevidenceofhepaticdysfunction.

4.4Specialwarningsandprecautionsforuse

ThereareisolatedcasesofpossiblysignificanteffectsofDantriumoncardiovascularandrespiratorysystemsand

thereforeDantriumshouldbeusedwithcautioninpatientswithcardiovascularorrespiratorydisease.

FatalandnonfatalliverdisordersofanidiosyncraticorhypersensitivitytypemayoccurwithDantriumtherapy.

Patientsshouldbeinstructedtocontacttheirphysicianshouldsignsorsymptomsofhepatotoxicity(e.g.,discoloured

faeces,generalizedpruritus,jaundice,anorexia,nausea,vomiting)occurduringtherapy.

Factorsthatmayincreasetheriskofdevelopinghepatotoxicityinclude:

Higherdailydoses(dosesexceeding400mgdaily)

Durationoftherapy(mostfrequentlyreportedbetween2and12monthsoftreatment.

Femalegender

Agegreaterthan30years

Priorhistoryofliverdisease/dysfunction

Receivingotherhepatotoxictherapiesconcomitantly

Spontaneousreportsalsosuggestahigherproportionofhepaticeventswithfataloutcomeinelderlypatients.

AtthestartofDantriumtherapy,liverfunctiontestsshouldbeperformedinallpatientstoestablishabase-line,and

excludepre-existingliverdisease.Thesetestsshouldberepeateduponhospitaldischargeoratsixweeksafterstarting

therapy.Furthertestsmaybecarriedoutatappropriateintervalsthroughouttreatment.Generally,ifthesestudies

revealabnormalvalues,therapyshouldnotbecommencedorshouldbediscontinued.Inpatientswithsymptoms

compatiblewithhepatitisorwherejaundiceappears,Dantriumshouldbediscontinued.Ifadecisionismadetorestart

treatmentafterrecoveryfromhepaticdysfunction,liverfunctionshouldbemonitoredandthedrugdiscontinuedif

abnormalvaluesareobserved.

Patientswithrarehereditaryproblemsofgalactoseintolerance,thelapplactasedeficiencyorglucose-galactose

Week Recommendeddosage

First 0.5mg/kgtwicedaily

Second 1mg/kgtwicedaily

Third 2mg/kgtwicedaily

Fourth 2mg/kgthreetimesdaily

Fifth 3mg/kgthreetimesdaily

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

TheuseofDantriumwithotherpotentiallyhepatotoxicdrugsshouldbeavoided.Thereisalsosomeevidencethat

hepaticinjuryismorelikelyinpatientsusingconcomitantoestrogen.

AlthoughtheprimarypharmacologicaleffectofDantriumisexerteddirectlyonskeletalmuscle,cautionshouldbe

exercisedintheconcomitantadministrationoftranquillisingagentsandalcohol.

DiazepamandphenobarbitonedonotaffectthemetabolismofDantrium.

Theeffectsofnon-depolarizingmusclerelaxantsmaybepotentiatedinpatientsadministeredDantrium.

Hyperkalemiaandmyocardialdepressionhavebeenobservedinmalignanthyperthermia-susceptiblepatientsreceiving

intravenousdantroleneandconcomitantcalciumchannelblockers.

4.6Pregnancyandlactation

Dantrolenecrossestheplacenta,andhasbeendetectedinhumanmilk.Althoughteratologicalstudiesinanimalshave

provedsatisfactory,theuseofDantriumisnotadvisedinpregnantornursingmothers.

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbeadvisednottodriveamotorvehicleorparticipateinhazardousoccupationsbecausesomepatients

experiencedrowsinessanddizziness

4.8Undesirableeffects

ThosemostfrequentlyreportedunwantedeffectsassociatedwiththeuseofDantriumhavebeendrowsiness,dizziness,

weakness,generalmalaise,fatigueanddiarrhoea.Thesearegenerallytransientandmild.Diarrhoeamaybesevereand

maynecessitatetemporarywithdrawalofDantriumtherapy.

Otherundesirableeffectsreportedcommonly(>1%)orlesscommonly(<1%)inpost-marketingreportsare:

Metabolismandnutritiondisorders:

Common:Anorexia.

Psychiatricdisorders:

Lesscommon:Mentaldepression,mentalconfusion.

Nervousdisorders:

Common:Seizure,visualdisturbances,speechdisturbances,headache.

Cardiacdisorders:

Common:Pericarditis.

LessCommon:Exacerbationofcardiacinsufficiency,tachycardia.

Vasculardisorders:

Lesscommon:Labilebloodpressure.

Respiratory,thoracicandmediastinaldisorders:

Common:Pleuraleffusionwithassociatedeosinophilia,respiratorydepression.

LessCommon:Dyspnoea.

Gastrointestinaldisorders:

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LessCommon:Swallowingdifficulties,constipation(rarelyprogressingtosignsofintestinalobstruction).

Hepato-biliarydisorders:

Common:Hepatotoxicity(seesection4.4),liverfunctiontestdisturbances.

Skinandsubcutaneoustissuedisorders:

Common:Acne-likerash,skineruptions.

LessCommon:Sweating.

Renalandurinarydisorders:

Lesscommon:Incontinence,increasedurinaryfrequency,urinaryretention,haematuria,crystalluria.

Generaldisordersandadministrationsiteconditions:

Common:Chillsand/orfever.

ThecolouringagentE110cancauseallergic-typereactionsincludingasthma.Allergyismorecommoninthosepeople

whoareallergictoaspirin.

Dantriumhasapotentialforhepatotoxicity.Symptomatichepatitis(fatalandnon-fatal)hasbeenreportedatvarious

doselevelsalthoughtheincidenceisgreaterinpatientstakingmorethan400mg/day.Liverdysfunctionasevidenced

bybloodchemicalabnormalitiesalone(liverenzymeelevation)hasbeenobservedinpatientsexposedtoDantriumfor

varyingperiodsoftime.

Overthepatitishasoccurredatvaryingintervalsafterinitiationoftherapy,buthasmostfrequentlybeenobserved

betweenthesecondandtwelfthmonthoftreatment.Theriskofhepaticinjuryappearstobegreaterinfemales,in

patientsover30yearsoldandinpatientstakingconcomitantmedication.Thereissomeevidencethathepaticinjuryis

morelikelyinpatientsusingconcomitantoraloestrogen.

4.9Overdose

Thereisnoknownconstellationofsymptomswithacuteoverdose.Symptomsthatmayoccurinclude,butarenot

limitedto,muscularweakness,alterationsinthestateofconsciousness(e.g.lethargy,coma),vomiting,anddiarrhoea.

Foracuteoverdosage,generalsupportivemeasuresshouldbeemployedalongwithimmediategastriclavage.Fluids

shouldbeadministeredinlargequantitiestoavertthetheoreticalpossibilityofcrystalluria.

Thevalueofdialysisindantroleneoverdoseisnotknown.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Dantriumisclassifiedasadirect-actingskeletalmusclerelaxant.Inisolatednerve-musclepreparation,Dantriumhas

beenshowntoproducerelaxationbyaffectingthecontractileresponseoftheskeletalmuscleatasitebeyondthe

myoneuraljunction,directlyonthemuscleitself.Inskeletalmuscle,Dantriumdissociatestheexcitation-contraction

coupling,probablybyinterferingwiththereleaseofCa ++

fromthesarcoplasmicreticulum.

Thiseffectappearstobemorepronouncedinfastmusclefibresascomparedtoslowones,butgenerallyaffectsboth.A

centralnervoussystemeffectoccurs,withdrowsiness,dizziness,andgeneralisedweaknessoccasionallypresent.

AlthoughDantriumdoesnotappeartodirectlyaffecttheCNS,theextentofitsindirecteffectisunknown.

5.2Pharmacokineticproperties

TheabsorptionofDantriumafteroraladministrationinhumansinincompleteandslowbutconsistent,anddose-related

bloodlevelsareobtained.Thedurationandintensityofskeletalmusclerelaxationisrelatedtothedosageandblood

levels.Themeanbiologichalf-lifeofDantriuminadultsis8.7hoursaftera100-mgdose.Specificmetabolicpathways

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Metabolicpatternsaresimilarinadultsandchildren.Inadditiontotheparentcompound,dantrolene,whichisfoundin

measurableamountsinbloodandurine,themajormetabolitesnotedinbodyfluidsarethe5-hydroxyanalogueandthe

acetamidoanalogue.SinceDantriumisprobablymetabolisedbyhepaticmicrosomalenzymes,enhancementofits

metabolismbyotherdrugsispossible.

However,neitherphenobarbitalnordiazepamappearstoaffectDantriummetabolism.Bindingtoplasmaproteinisnot

significantlyalteredbydiazepam,diphenylhydantoin,orphenylbutazone.Bindingtoplasmaproteinsisreducedby

warfarinandclofibrateandincreasedbytolbutamide.

5.3Preclinicalsafetydata

DantrolenesodiumshowedsomeevidenceoftumourgenicityathighdoselevelsinSprague-Dawleyfemalerats.

However,theseeffectswerenotseeninotherstudiesinFischer344ratsorHaM/ICRmice.Thereisnoclinical

evidenceofcarcinogenicityinhumans;however,thispossibilitycannotbeabsolutelyexcluded.

Dantrolenesodiumhasproducedpositiveresultsinabacterialmutagenesisassay.Inreproductiontoxicitystudiesin

rats,dantrolenesodiumshowednoadverseeffectsonfertilityorgeneralreproductiveperformance.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

MaizeStarch

Talc

MagnesiumStearate

LactoseMonohydrate

Capsuleshell

SunsetYellow(E110)

Gelatin

TitaniumDioxide(E171)

IronOxide(E172)

EdibleBlackInk(Shellac,IronOxide(E172))

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

6.5Natureandcontentsofcontainer

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

SpepharmHoldingB.V.

Kingsfordweg151

1043GRAmsterdam

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA1556/1/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19March1975.

Dateoflastrenewal:19March2010.

10DATEOFREVISIONOFTHETEXT

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