DANTRIUM INTRAVENOUS

Main information

  • Trade name:
  • DANTRIUM INTRAVENOUS
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Pdr for Soln for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DANTRIUM INTRAVENOUS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1556/001/003
  • Authorization date:
  • 30-01-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DantriumIntravenous20mgPowderforSolutionforinjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains20mgdantrolenesodium.Afterreconstitution,thesolutioncontains0.33mg/ml.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinjection.

Apaleorangetoyellowpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthetreatmentofmalignanthyperthermia.

4.2Posologyandmethodofadministration

AssoonastheMHreactionisrecognised,allanaestheticagentsshouldbediscontinued;theadministrationof100%

oxygenisrecommended.DantriumIVshouldbeadministeredbycontinuousrapidintravenouspushbeginningata

minimumdoseof1mg/kg,andcontinuinguntilsymptomssubsideorthemaximumcumulativedoseof10mg/kghas

beenreached.

Ifthephysiologicandmetabolicabnormalitiesreappear,theregimenmayberepeated.Itisimportanttonotethat

administrationofDantriumIVshouldbecontinuousuntilsymptomssubside.Theeffectivedosetoreversethecrisisis

directlydependentupontheindividual'sdegreeofsusceptibilitytoMH,theamountandtimeofexposuretothe

triggeringagent,andthetimeelapsedbetweenonsetofthecrisisandadministrationoftreatment.

Children'sDose

Experiencetodateindicatesthatthedoseforchildrenisthesameasforadults.

4.3Contraindications

Dantriumshouldnotbeusedinpatientswithknownhypersensitivitytodantrolenesodiumoranyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

TheuseofDantriumIVinthemanagementofMHcrisisisnotasubstituteforpreviouslyknownsupportivemeasures.

Thesemeasuresmustbeindividualised,butitwillusuallybenecessarytodiscontinuethesuspecttriggeringagents,

attendtoincreasedoxygenrequirements,managethemetabolicacidosis,institutecoolingwhennecessary,monitor

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2099989 page number: 1

Sincetheeffectofdiseasestateandotherdrugsondantrolenesodiumrelatedskeletalmuscleweakness,including

possiblerespiratorydepression,cannotbepredicted,patientswhoreceiveIVdantrolenesodiumpreoperativelyshould

havevitalsignsmonitored.

IfpatientsjudgedwithMHSareadministeredintravenousororaldantrolenesodiumpreoperatively,anesthetic

preparationmuststillfollowastandardMHSregimen,includingtheavoidanceofknowntriggeringagents.

MonitoringforearlyclinicalandmetabolicsignsofMHisindicatedbecauseattenuationofMH,ratherthan

prevention,ispossible.ThesesignsusuallycallfortheadministrationofadditionalIVdantrolenesodium.

Whenmannitolisusedtopreventortreattherenalcomplicationsofmalignanthyperthermia,themannitolcontentin

theDantriumviali.e.3000milligramsofmannitolper20mgofdantrolenesodiumshouldbetakenintoconsideration.

BecauseofthehighpHofDantriumIVandthepotentialfortissuenecrosis,caremustbetakentoprevent

extravasationoftheintravenoussolutionintothesurroundingtissues.

Insomesubjectsasmuchas10mg/kgofdantrolenesodiumhasbeenneededtoreversethecrisis.Ina70kgmanthis

dosewouldrequireapproximately36vials.Suchavolumehasbeenadministeredinapproximatelyoneandahalf

hours.

InformationforPatients

Basedupondatainhumanvolunteers,ifwillsometimesbeappropriatetotellpatientswhoreceivedantrolenesodium

intravenousthatdecreaseingripstrengthandweaknessoflegmuscles,especiallywalkingdownstairs,canbeexpected

postoperatively.Inaddition,symptomssuchas“lightheadedness”maybenoted.Sincesomeofthesesymptomsmay

persistforupto48hours,patientsmustnotoperateanautomobileorengageinotherhazardousactivityduringthis

time.Cautionisalsoindicatedatmealsonthedayofadministrationbecausedifficultyswallowingandchokinghas

beenreported.Cautionshouldbeexercisedintheconcomitantadministrationoftranquilizingagents.

Hepatotoxicityseenwithdantrolenesodiumcapsules

Dantrolenehasapotentialforhepatotoxicity,andsymptomatichepatitis,sometimesfatal,hasbeenreported.Factors

thatmayberelatedtoapoorerprognosisincludehigherdailydoses,femalegender,andincreasingpatientage.

Spontaneousreportsalsosuggestahigherproportionofhepaticeventswithfataloutcomeinelderlypatients.

Hepaticdysfunction,includingfatalhepaticfailure,canoccurwithdantroleneuse,andappearstoberelatedtodose

anddurationoftherapy.Fatalandnon-fatalliverdisordersofidiosyncraticorhypersensitivitytypemayalsooccurwith

dantrolenesodiumtherapy.

Evaluationofhepaticfunctionshouldbedonebeforeinitiatingtreatment,andhepaticfunctionshouldbemonitoredat

appropriateintervalsthoroughttreatment.Ifmonitoringrevealsabnormalliverfunction,orifsignsorsymptomsof

hepatotoxicityoccurduringtherapy,dantroleneshouldbewithdrawn.Ifadecisionismadetorestarttreatmentafter

recoveryfromhepaticdysfunction,liverfunctionshouldbemonitoredandthedrugdiscontinuedifabnormalvaluesare

observed.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Dantroleneismetabolisedbytheliver,anditistheoreticallypossiblethatitsmetabolismmaybeenhancedbydrugs

knowntoinducehepaticmicrosomalenzymes.However,neitherphenobarbitalnordiazepamappearstoaffect

dantrolene'smetabolism.Bindingtoplasmaproteinisnotsignificantlyalteredbydiazepam,diphenylhydantoin,or

phenylbutazone.Bindingtoplasmaproteinsisreducedbywarfarinandclofibrateandincreasedbytolbutamide.

Thecombinationoftherapeuticdosesofintravenousdantrolenesodiumandverapamilinhalothane/alpha-chloralose

anaesthetisedswinehasresultedinventricularfibrillationandcardiovascularcollapseinassociationwithmarked

hyperkalaemia.

Hyperkalaemiaandmyocardialdepressionhavealsobeenreportedrarelyinmalignanthyperthermia-susceptible

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2099989 page number: 2

andcalciumchannelblockersincombinationisnotrecommended,untiltherelevanceofthesefindingstohumansis

established.

Administrationofdantrolenemaypotentiatevecuronium-inducedneuromuscularblock.

4.6Fertility,pregnancyandlactation

ThesafetyofDantriumIVinpregnantwomenhasnotbeenestablished:Dantrolenecrossestheplacenta,andshouldbe

givenonlywhenthepotentialbenefitshavebeenweighedagainstthepossiblerisktomotherandchild.

Dantrolenehasbeendetectedinhumanmilkandlowconcentrations(lessthan2microgramspermilliliter)during

repeatintravenousadministrationover3days.DantriumIntravenousshouldbeusedbynursingmothersonlyifthe

potentialbenefitjustifiesthepotentialrisktotheinfant.

4.7Effectsonabilitytodriveandusemachines

Adecreaseingripstrengthandweaknessoflegmuscles,especiallywalkingdownstairs,canbeexpected

postoperatively.Inaddition,symptomssuchas"lightheadedness"maybenoted.Sincesomeofthesesymptomsmay

persistforupto48hours,patientsmustnotoperateanautomobileorengageinotherhazardousactivityduringthis

time.

4.8Undesirableeffects

TherehavebeenoccasionalreportsofdeathfollowingMHcrisisevenwhentreatedwithintravenousdantrolene.

Incidencefiguresarenotavailable(thepre-dantrolenemortalityofMHcrisiswasapproximately50%).Mostofthese

deathscanbeaccountedforbylaterecognition,delayedtreatment,inadequatedosage,lackofsupportivetherapy,

intercurrentdiseaseand/orthedevelopmentofdelayedcomplicationssuchasrenalfailureordisseminated

intravascularcoagulopathy.Insomecasesthereareinsufficientdatatocompletelyruleouttherapeuticfailureof

dantrolene.

TherearerarereportsoffatalityinMHcrisis,despiteinitialsatisfactoryresponsetoDantriumIV,whichinvolve

patientswhocouldnotbeweanedfromdantroleneafterinitialtreatment.Theadministrationofintravenousdantrolene

tohumanvolunteersisassociatedwithlossofgripstrengthandweaknessinthelegs,aswellassubjectiveCNS

complaints.

Thefollowingadversereactionsareinapproximateorderofseverity:

TherearerarereportsofpulmonaryoedemadevelopingduringthetreatmentofMHcrisisinwhichthediluent

volumeandmannitolneededtodeliverDantriumIVpossiblycontributed.

Therehavebeenreportsofthrombophlebitisandrarereportsofurticaria,erythemaandanaphylaxis,possibly

associatedwiththeadministrationofDantriumIV.

Localinjectionsitereactionsarecommonlyobserved.

Fororallyadministereddantrolenesodiumthemostfrequentlyreportedunwantedeffectsassociatedwiththeuse

ofDantriumhavebeendrowsiness,dizziness,weakness,generalmalaise,fatigueanddiarrhoea.Theseare

generallytransientandmild.DiarrhoeamaybesevereandmaynecessitatetemporarywithdrawalofDantrium

therapy.

Otherundesirableeffectsreportedcommonly( ≥1%)orlesscommonly(≤1%)inpost-marketingreportsfororally

administereddantrolenesodiumare:

Metabolismandnutritiondisorders

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2099989 page number: 3

Psychiatricdisorders

Lesscommon:Mentaldepression,mentalconfusion.

Nervoussystemdisorders

Common:Seizure,speechdisturbance,headache.

Eyedisorders

Common:Visualdisturbances.

Cardiacdisorders

Common:Pericarditis.

Lesscommon:Exacerbationofcardiacinsufficiency,tachycardia.

Vasulardisorders

Lesscommon:Labilebloodpressure.

Respiratory,thoracicandmediastinaldisorders

Common:Pleuraleffusionwithassociatedeosinophilia,respiratorydepression.

Lesscommon:Dyspnoea.

Gastrointestinaldisorders

Common:Nauseaand/orvomiting,abdominalpain.

Lesscommon:Swallowingdifficulties,constipation(rarelyprogressingtosignsofintestinalobstruction).

Hepato-biliarydisorders

Common:hepatotoxicity(seesection4.4)liverfunctiontestdisturbances.

Skinandsubcutaneoustissuedisorders

Common:acne-likerash,skineruptions.

Lesscommon:Sweating.

Renalandurinarydisorders:

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

Generaldisordersandadministrationsiteconditions

Common:Chillsand/orfever.

4.9Overdose

Symptomswhichmayoccurincaseofoverdoseinclude,butarenotlimitedto,muscularweaknessandalterationsin

thestateofconsciousness(e.g.lethargy,coma),vomiting,diarrhoea,andcrystalluria.

Foracuteoverdose,generalsupportivemeasuresshouldbeemployed.

Intravenousfluidsshouldbeadministeredinfairlylargequantitiestoavertthepossibilityofcrystalluria.Anadequate

airwayshouldbemaintainedandartificialresuscitationequipmentshouldbeathand.

Electrocardiographicmonitoringshouldbeinstituted,andthepatientcarefullyobserved.Thevalueofdialysisin

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2099989 page number: 4

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATC:M03CA01,musclerelaxants,directlyactingagents.

Dantroleneisclassifiedasadirect-actingskeletalmusclerelaxant.Inisolatednerve-musclepreparation,dantrolene

sodiumhasbeenshowntoproducerelaxationbyaffectingthecontractileresponseoftheskeletalmuscleatasite

beyondthemyoneuraljunction,directlyonthemuscleitself.Inskeletalmuscle,dantrolenedissociatestheexcitation-

contractioncoupling,probablybyinterferingwiththereleaseofCa fromthesarcoplasmicreticulum.Thiseffect

appearstobemorepronouncedinfastmusclefibresascomparedtoslowones,butgenerallyaffectsboth.Acentral

nervoussystemeffectoccurs,withdrowsiness,dizziness,andgeneralisedweaknessoccasionallypresent.Although

dantrolenedoesnotappeartodirectlyaffecttheCNS,theextentofitsindirecteffectisunknown.

5.2Pharmacokineticproperties

Specificmetabolicpathwaysforthedegradationandeliminationofdantroleneinhumanshavebeenestablished.

Dantroleneisfoundinmeasurableamountsinbloodandurine.Itsmajormetabolitesinbodyfluidsare5-hydroxy

dantroleneandanacetylaminometaboliteofdantrolene.Anothermetabolitewithanunknownstructureappearsrelated

tothelatter.Dantrolenemayalsoundergohydrolysisandsubsequentoxidationformingnitrophenylfuroicacid.

Themeanbiologichalf-lifeofdantroleneafterintravenousadministrationisvariable,between4to8hoursundermost

experimentalconditions.Basedonassaysofwholebloodandplasma,slightlygreateramountsofdantroleneare

associatedwithredbloodcellsthanwiththeplasmafractionofblood.Significantamountsofdantroleneareboundto

plasmaproteins,mostlyalbumin,andthisbindingisreadilyreversible.

5.3Preclinicalsafetydata

DantrolenesodiumshowedsomeevidenceoftumourgenicityathighdoselevelsinSprague-Dawleyfemalerats.

TheseeffectswerenotseeninotherstudiesinFischer344ratsorHaM/ICRmice.Thereisnoclinicalevidenceof

carcinogenicityinhumans;however,thispossibilitycannotbeabsolutelyexcluded.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol

Sodiumhydroxide(forpHadjustment)

6.2Incompatibilities

5%dextroseinjection,0.9%sodiumchlorideinjectionandotheracidicsolutionsarenotcompatiblewithDantriumIV

andshouldnotbeused.

6.3Shelflife

Unopened:3years.

Reconstitutedsolution:Chemicalandphysicalin-usestabilityhasbeendemonstratedfor6hoursat25 o

c.Froma

microbiologicalpointofviewtheproductshouldbeusedimmediately.

6.4Specialprecautionsforstorage

UnopenedProduct:Donotstoreabove25 °

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2099989 page number: 5

Reconstitutedsolution:Donotstoreabove25 °

C.Donotrefrigerateorfreeze.Protectfromdirectlight.

6.5Natureandcontentsofcontainer

Clear70mlvials,glasstypeIIItreatedfortypeII(Ph.Eur.),withsiliconisedchlorobutyllyophilisationstopperstypeI

(Ph.Eur.).Thevialsaresealedwithaluminiumcapswithpolypropyleneflip-offdisks.Suppliedinpacksof12or36

vials.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

EachvialofDantriumIVshouldbereconstitutedbyadding60mlofWaterforInjectionPh.Eur.andshakinguntilthe

solutionisclear.Anyunusedportionofthereconstitutedsolutionshouldbediscarded.Therearenospecial

requirementsrelatingtothedisposalofthecontainerorcontents.

7MARKETINGAUTHORISATIONHOLDER

SpePharmHoldingB.V.

Kingsfordweg151

1043GRAmsterdam

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA1556/1/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:2 nd

December1980

Dateoflastrenewal:2 nd

December2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2099989 page number: 6