DIAZEPAM RECTUBES

Main information

  • Trade name:
  • DIAZEPAM RECTUBES
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Rectal Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIAZEPAM RECTUBES
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0409/003/008
  • Authorization date:
  • 05-09-1997
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DiazepamRecTubes20mgRectalSolution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Diazepam20mgin5.0ml(4mg/ml).

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Rectalsolution

Aclear,colourlessoralmostyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Diazepamrectaltubesmaybeusedinsevereordisablinganxietyandagitation;epilepticandfebrileconvulsions;to

relievemusclespasmcausedbytetanus;asasedativeinminorsurgicalanddentalprocedures,orothercircumstances

inwhicharapideffectisrequiredbutwhereintravenousinjectionisimpracticableorundesirable.

Diazepamrectaltubesmaybeofparticularvaluefortheimmediatetreatmentofconvulsionsinchildren.

4.2Posologyandmethodofadministration

Dosagedependsonageandweight.

Children:0.5mg/kg.

(Notrecommendedforuseinchildrenlessthanoneyearold)

Adults:0.5mg/kg.

Ifconvulsionsarenotcontrolledotheranticonvulsivemeasuresshouldbeinstituted.

Thedosecanberepeatedevery12hours.

Elderlyanddebilitatedpatientsshouldbegivennotmorethanonehalftheappropriateadultdose.

Dosagereductionmayalsoberequiredinpatientswithliverorkidneydysfunction.

Thesolutionisadministeredrectally.Adultsshouldbeinthelateralposition;childrenshouldbeintheproneorlateral

position.

Tearopenthefoilpack.Removethecap.

(b)Insertthetubenozzlecompletelyintotherectum.Forchildrenunder15kg,insertonlyhalf

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Inanxiety,thedurationoftreatmentshouldbeasshortaspossibleandgenerallynotmorethan8-12weeks,includinga

taperingoffprocess(see4.4Specialwarningsandspecialprecautionsforuse).

Patientsrequiringchronicdosingshouldbecheckedregularlyatthestartoftreatmentinordertodecrease,ifnecessary,

thedoseorfrequencyofadministration,topreventoverdoseduetoaccumulation.

4.3Contraindications

Knownhypersensitivitytobenzodiazepinesoranyoftheingredients.

Severeoracuterespiratoryinsufficiency/depression.

Sleepapnoeasyndrome.

Severehepaticinsufficiency.

Diazepamshouldnotbeusedinphobicorobsessionalstates,norbeusedaloneinthetreatmentofdepressionor

anxietyassociatedwithdepressionduetotheriskofsuicidebeingprecipitatedinthispatientgroup.Diazepamshould

notbeusedfortheprimarytreatmentofpsychoticillness.Incommonwithotherbenzodiazepinestheuseofdiazepam

maybeassociatedwithamnesiaanddiazepamshouldnotbeusedincasesoflossorbereavementaspsychological

adjustmentsmaybeinhibited.

4.4Specialwarningsandprecautionsforuse

Diazepamshouldbeusedwithcautioninpatientswithrenalorhepaticdysfunction(see4.2PosologyandMethodof

Administration),chronicpulmonaryinsufficiency,porphyria,myastheniagravis,coma,organicbrainchanges

particularlyarteriosclerosis.

DiazepammayenhancetheeffectsofotherCNSdepressants;theirconcurrentuseshouldbeavoided.

ElderlyanddebilitatedpatientsaremorepronetotheCNSeffectsofbenzodiazepinesand,therefore,lowerdosesare

required(seesection4.2PosologyandMethodofAdministration).

Dependenceandwithdrawalsymptoms

Useofbenzodiazepinesmayleadtothedevelopmentofphysicalandpsychologicaldependenceupontheseproducts.

Thisshouldbeconsideredwhentreatingpatientsformorethanafewdays.Thedependencepotentialofdiazepamis

lowwhenlimitedtoshort-termuse,butincreaseswiththedoseanddurationoftreatment,itisalsogreaterinpatients

withahistoryofalcoholordrugabuse.

Oncephysicaldependencehasdeveloped,abruptterminationoftreatmentwillbeaccompaniedbywithdrawal

symptoms(SeeSection4.8WithdrawalSymptoms).

Sincetheriskofwithdrawalphenomena/reboundphenomenaisgreaterafterabruptdiscontinuationoftreatment,itis

recommendedthatdoseisdecreasedgradually.

Whenbenzodiazepineswithalongdurationofaction,suchasdiazepam,arebeingused,itisimportanttowarnagainst

changingtoabenzodiazepinewithashortdurationofaction,aswithdrawalsymptomsmaydevelop.

Treatmentofanxiety(see4.2PosologyandMethodofAdministration)

Itmaybeusefultoinformthepatientwhentreatmentisstartedthatitwillbeoflimiteddurationandtoexplain

preciselyhowthedosagewillbeprogressivelydecreased.Incertaincases,extensionbeyondthemaximumtreatment

emptiedbyusingfirmpressurewiththeindexfingerandthumb.

Toavoidsuction,maintainpressureonthetubeuntilitiswithdrawnfromtherectum.Press

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expertise.

Reboundanxiety,atransientsyndromewherebythesymptomsthatledtotreatmentwithabenzodiazepinerecurinan

enhancedform,mayoccuronwithdrawaloftreatment.Itmaybeaccompaniedbyotherreactionsincludingmood

changesorsleepdisturbancesandrestlessness.Itisimportantthatthepatientshouldbeawareofthepossibilityof

reboundphenomena,therebyminimisinganxietyoversuchsymptomsshouldtheyoccurwhilethemedicinalproductis

beingdiscontinued.

Benzodiazepinesshouldnotbegiventochildrenforanxietywithoutcarefulassessmentoftheneedtodoso.

Amnesia

Benzodiazepinesmayinduceanterogradeamnesia(see4.8Undesirableeffects).Theconditionoccursmostoften

severalhoursafteradministration.Toreducetherisk,whereappropriateandpossible,patientsshouldbeabletohave

anuninterruptedsleepof7-8hoursafteradministration.

Psychiatricandparadoxicalreactions

Reactionslikerestlessness,agitation,irritability,aggressiveness,delusion,rages,nightmares,hallucinations,psychoses,

inappropriatebehaviourandotheradversebehaviouraleffectsareknowntooccurwhenusingbenzodiazepines(see4.8

Undesirableeffects).Shouldtheyoccur,useofdiazepamshouldbediscontinued.

Useinpatientswithconcomitantmentalillnessoraddiction

Benzodiazepinesshouldbeusedwithextremecautioninpatientswithahistoryofalcoholordrugabuse.Aswithother

benzodiazepines,extremecautionshouldbeusedifprescribingdiazepamforpatientswithpersonalitydisorders.The

disinhibitingeffectsofbenzodiazepinesmaybemanifestedastheprecipitationofsuicideinpatientswhoshow

aggressivebehaviourtowardsselfandothers.

Theexcipientbenzoicacidmaybemildlyirritanttomucousmembranes.

20mg:

Thismedicinalproductcontains1.70mmolsodiumperdose.Tobetakenintoconsiderationbypatientsonacontrolled

sodiumdiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Alcohol:Concomitantintakeofalcoholisnotrecommended.Thesedativeeffectofdiazepammaybeenhanced.This

affectstheabilitytodriveorusemachines(see4.7Effectsonabilitytodriveandusemachines).

Anaestheticsandnarcoticanalgesics:Enhancedsedationorrespiratoryandcardiovasculardepression.Inthecaseof

narcoticanalgesics,enhancementofeuphoriamayalsooccurleadingtoanincreaseinpsychologicaldependence.

Antibacterials:Agentsthatinterferewithmetabolismbyhepaticenzymes(e.g.erythromycinandisoniazid)mayreduce

theclearanceofbenzodiazepinesandpotentiatetheiractions.Knowninducersofhepaticenzymes,forexample,

rifampicin,mayincreasetheclearanceofbenzodiazepines.

Antidepressants:Enhancedsedationorrespiratoryandcardiovasculardepression.Diazepamplasmalevelsincreasedby

concomitantfluvoxamine.

Antiepileptics:Enhancedsedationorrespiratoryandcardiovasculardepression.Knowninducersofhepaticenzymes,

forexample,carbamazepineandphenytoin,mayincreasetheclearanceofbenzodiazepines.Serumphenytoinlevels

mayrise,fallorremainunaltered.Inaddition,phenytoinmaycausediazepamserumlevelstofall.Concomitant

sodiumvalproatemayincreaseserumlevelsofdiazepam,withassociateddrowsiness.

Antihistamines:Enhancedsedationorrespiratoryandcardiovasculardepressionwithsedativeantihistamines.

Antihypertensives:Enhancedhypotensiveeffect,enhancedsedativeeffectwithalpha-blockersandpossibly

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Antipsychotics:Enhancedsedationorrespiratoryandcardiovasculardepression.Increasedplasmaconcentrationsof

zotepine.Severehypotension,collapse,respiratorydepression,potentiallyfatalrespiratoryarrestandunconsciousness

havebeenreportedinafewpatientsonbenzodiazepinesandclozapine.Cautionidadvisedwheninitiatingclozapine

therapyinpatientstakingbenzodiazepines.

Antivirals:Amprenavirandritonavirhavebeenshowntoreducetheclearanceofbenzodiazepinesandmaypotentiate

theiractions,withriskofextremesedationandrespiratorydepression–avoidconcomitantuse.

Anxiolytics:Enhancedsedationorrespiratoryandcardiovasculardepressionwithotheranxiolytics.

Digoxin:Reducedclearanceofdigoxin.

Disulfiram:hasbeenshowntoreduceclearanceandmaypotentiateactionsofbenzodiazepines.

Dopaminergicagents:diazepammaycauseinhibitionoflevodopa.

Hypnotics:Enhancedsedationorrespiratoryandcardiovasculardepression.

Lofexidine:Enhancedsedationorrespiratoryandcardiovasculardepression.

Musclerelaxants:IncreasedCNSdepressanteffectswithbaclofenandtizanidine.

Nabilone:Enhancedsedationorrespiratoryandcardiovasculardepression.

Nicotine:Diazepammetabolismisacceleratedbysmoking.

Oralcontraceptives:Reducetheclearanceofbenzodiazepinesandmaypotentiatetheiractions.

Sedatives:Enhancedsedationorrespiratoryandcardiovasculardepression.

Theophylline:Diazepammetabolismisacceleratedbytheophylline.

Ulcer-healingdrugs:Cimetidineandomeprazolemayreducetheclearanceofbenzodiazepinesandpotentiatetheir

actions.

4.6Pregnancyandlactation

Thereisnoevidenceregardingthesafetyofdiazepaminpregnancy.Itshouldnotbeused,especiallyinthefirstand

thirdtrimesters,unlessthebenefitisconsideredtooutweightherisk.

Ifdiazepamisprescribedtoawomanofchildbearingpotential,sheshouldbewarnedtocontactherphysician

regardingdiscontinuationoftheproductifsheintendstobecome,orsuspectsthatsheis,pregnant.

Theremaybeasmallincreaseintheriskofcongenitalmalformation,particularlyoralcleft,withtheuseof

benzodiazepinesinthefirsttrimester.Inlabourhighsingledosesorrepeatedlowdoseshavebeenreportedtoproduce

effectsontheneonate,suchashypothermia,hypotonia,moderaterespiratorydepressionandpoorsuckling(floppy

infantsyndrome)andirregularitiesinthefoetalheart.

Infantsborntomotherswhotakebenzodiazepineschronicallyduringthelatterstagesofpregnancymaydevelop

physicaldependenceandmaybeatsomeriskfordevelopingwithdrawalsymptomsinthepostnatalperiod.

Asmallnumberofchildrenexposedtouterotobenzodiazepineshaveshownslowdevelopmentintheearlyyearsbut

byfouryearsofagehavedevelopednormally.

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4.7Effectsonabilitytodriveandusemachines

PatientstreatedwithDiazepamRectalTubesshouldnotdriveoroperatemachinesassedation,amnesia,impaired

concentrationandimpairedmuscularfunctionmayadverselyaffecttheirability.Ifinsufficientsleepdurationoccurs,

thelikelihoodofimpairedalertnessmaybeincreased.

4.8Undesirableeffects

ElderlyordebilitatedpatientsareparticularlysusceptibletotheCNSeffectsofbenzodiazepines.Itisrecommended

thatdosagebelimitedtothesmallesteffectivedoseandincreasedgradually,ifnecessary,todecreasethepossibilityof

developmentofataxia,dizziness,andoversedation,whichmayleadtofallsandotheraccidents(see4.2Posologyand

methodofadministration).

Cardiovascular:Hypotension,particularlywithhighdosage,bradycardia,chestpain.

Disordersoftheeye:Visualdisturbances.

Gastrointestinal:Drymouth,gastrointestinaldisturbances.

General:Fatigueandahangovereffect.

Haematological:Blooddyscrasias.

Hepatic:Raisedliverenzymes,jaundice.

Immunological:Hypersensitivityreactions,includinganaphylaxis,arerare.

Musculosketal:Muscleweakness.

Neurological:Headaches,confusion,slurredspeech,tremor,reducedalertness.Anterogradeamnesiamayoccurusing

therapeuticdoses,theriskincreasingathigherdoses(see4.4SpecialWarningsandSpecialPrecautionsforUse).

Amnesticeffectsmaybeassociatedwithinappropriatebehaviour.

Psychiatric:Numbedemotions.Insusceptiblepatients,anunnoticeddepressionmaybecomeevident.Paradoxical

reactions(includingaggressivebehaviour,hostility,disinhibition,euphoria,excitation,irritability,increasedanxiety

andinsomniaareknowntooccurwithbenzodiazepinesandmaybequiteseverewithdiazepam(see4.4Special

WarningsandSpecialPrecautionsforUse).Theyaremorelikelytooccurinchildrenandtheelderly.

Reproductive:Changesinlibido,gynaecomastia.

Respiratory:Rarely,respiratorydepressionandapnoea,particularlywithhighdosage.

Skin:Skinreactions.

Urinary:Urinaryretention,incontinence.

Withdrawalsymptoms:Developmentofdependenceiscommonafterregularuse,evenintherapeuticdosesforshort

periods,particularlyinpatientswithahistoryofdrugoralcoholabuseormarkedpersonalitydisorders.

Discontinuationmayresultinwithdrawalorreboundphenomena(see4.4SpecialWarningsandSpecialPrecautionsfor

Use).

Symptomsofbenzodiazepinewithdrawalincludeanxiety,depression,impairedconcentration,insomnia,headache,

dizziness,tinnitus,lossofappetite,tremor,perspiration,irritability,perceptualdisturbancessuchashypersensitivityto

physical,visualandauditorystimuliandabnormaltaste,nausea,vomiting,abdominalcramps,palpitations,mild

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Rareandmoreserioussymptomsincludemuscletwitching,confusionalorparanoidpsychosis,convulsions,

hallucinationsandastateresemblingdeliriumtremens.BrokensleepwithvividdreamsandincreasedREMsleepmay

persistforsomeweeksafterwithdrawalofbenzodiazepines.

4.9Overdose

(a)Symptoms

Thesymptomsofmildoverdosemayincludeconfusion,impairmentofconsciousnesswithsomnolenceorasleep-like

state,littleornorespiratorydepression,ataxia,dysarthria,hypotension,andmuscularweakness.Cardiacrateand

rhythmremainnormalintheabsenceofanoxiaorseverehypotension.

Insevereoverdose,deepcomaorothermanifestationsofseveredepressionofbrainstemvitalfunctions,particularly

therespiratorycentre,mayoccur.Asdruglevelsfallsevereagitation,insomniaand,possibly,majorconvulsionsmay

develop.

(b)Treatment

Treatmentissymptomatic.Respiration,heartrate,bloodpressureandbodytemperatureshouldbemonitoredin

intensivecareandsupportivemeasurestakentomaintaincardiovascularandrespiratoryfunction.Activatedcharcoal

maybeadministeredtoincreaseclearanceaswellasdecreaseabsorptionofdiazepam.Flumazenilmaybeindicatedto

counteractthecentraldepressiveeffectofbenzodiazepinesbutexpertadviceisessentialsinceadverseeffectsmay

occur(e.g.convulsionsinpatientsdependentonbenzodiazepines).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Diazepamisapsychotropicsubstancefromtheclassof1,4-benzodiazepineswithmarkedpropertiesofsuppressionof

tension,agitationandanxietyaswellassedativeandhypnoticeffects.Inaddition,diazepamdemonstratesmuscle

relaxantandanticonvulsiveproperties.Itisusedintheshort-termtreatmentofanxietyandtensionstates,asasedative

andpremedicant,inthecontrolofmusclespasmandinthemanagementofalcoholwithdrawalsymptoms.

Diazepambindstospecificreceptorsinthecentralnervoussystemandparticularperipheralorgans.The

benzodiazepinereceptorsintheCNShaveaclosefunctionalconnectionwithreceptorsoftheGABA-ergictransmitter

system.Afterbindingtothebenzodiazepinereceptor,diazepamaugmentstheinhibitoryeffectofGABA-ergic

transmission.

5.2Pharmacokineticproperties

Afterrectaladministrationofthesolution,diazepamisabsorbedrapidlyandalmostcompletelyfromtherectum.

Theonsetofthetherapeuticeffectoccurswithinafewminutesofrectaladministration.Therapidityoftheriseinthe

serumlevelfollowingrectaladministrationcorrespondsapproximatelytothatfollowinganintravenousdosebutpeak

plasmaconcentrationsareloweraftertherectaltubesthanafterintravenousadministration.Inadultsmaximalplasma

concentrationsfollowingtheadministrationof10mgdiazepaminrectalsolutionarereachedafterabout10-30minutes

(ca.150-400ng/ml).

Diazepamisextensivelyproteinbound(95-99%).Thevolumeofdistributionisbetween0.95and21/kgdependingon

age.Diazepamislipophilicandrapidlyentersthecerebrospinalfluid.Diazepamanditsmainmetabolite,N-

desmethyldiazepam,crosstheplacentaandaresecretedinbreastmilk.

Diazepamismetabolisedpredominantlyintheliver.Itsmetabolites,N-desmethyldiazepam(nordiazepam),temazepam

andoxazepam,whichappearintheurineasglucuronides,arealsopharmacologicallyactivesubstances.Only20%of

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Diazepamhasabiphasichalf-lifewithaninitialrapiddistributionphasefollowedbyaprolongedterminalelimination

phaseof1-2days.Thetimetoreachsteadystateplasmalevelsistherefore4-10days.Fortheactivemetabolites,N-

desmethyldiazepam,temazepamandoxazepam,thehalf-livesare30-100hours,10-20hoursand5-15hours,

respectively.

Excretionismainlyrenalandalsopartlybiliary.Itisdependentonageaswellashepaticandrenalfunction.

Metabolismandeliminationintheneonatearemarkedlyslowerthaninchildrenandadults.Intheelderly,elimination

isprolongedbyafactorof2to4.Inpatientswithimpairedrenalfunction,eliminationisalsoprolonged.Inpatients

withhepaticdisorders(livercirrhosis,hepatitis),eliminationisprolongedbyafactorof2.

5.3Preclinicalsafetydata

Chronictoxicitystudiesinanimalshavedemonstratednoevidenceofdrug-inducedchanges.Therearenolong-term

animalstudiestoinvestigatethecarcinogenicpotentialofdiazepam.Severalinvestigationspointedtoaweakly

mutagenicpotentialatdosesfarabovethehumantherapeuticdose.

Localtolerabilityhasbeenstudiedfollowingsingleandrepeatdoseapplicationsintotheconjunctivalsacofrabbitsand

therectumofdogs.Onlyminimalirritationwasobserved.Therewerenosystemicchanges.

Inhumansitwouldappearthattheriskofcongenitalabnormalitiesfromtheingestionoftherapeuticdosesof

benzodiazepinesisslight,althoughafewepidemiologicalstudieshavepointedtoanincreasedriskofcleftpalate.

Therearecasereportsofcongenitalabnormalitiesandmentalretardationinprenatallyexposedchildrenfollowing

overdosageandintoxicationwithbenzodiazepines.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzylalcohol

Ethanol96%

Propyleneglycol

Benzoicacid

Sodiumbenzoate

Purifiedwater

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Packsof2or5rectaltubeseachcontaining5mlofsolution.

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Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

CPPharmaceuticalsLtd

Wrexham

LL139UF

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA409/3/8

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:05September1997

Dateoflastrenewal:15August2004

10DATEOFREVISIONOFTHETEXT

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