ACTIQ

Main information

  • Trade name:
  • ACTIQ Lozenges 200 Microgram
  • Dosage:
  • 200 Microgram
  • Pharmaceutical form:
  • Lozenges
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTIQ Lozenges 200 Microgram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0827/002/001
  • Authorization date:
  • 23-01-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Actiq200microgramscompressedlozengewithintegraloromucosalapplicator.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onelozengecontains200microgramsfentanyl(ascitrate).

Excipients(s):

Eachlozengecontainsdextrates(equivalenttoapproximately2gramsofglucose),sucrose(approximately30

milligramsconfectioner’ssugar)andpropyleneglycol(partoftheartificialberryflavourandimprintingink)as

excipients.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Compressedlozengewithintegraloromucosalapplicator.

Actiqisformulatedasawhitetooff-whitecompressedpowderdrugmatrixattachedusingediblegluetoafracture

resistantradioopaqueplasticapplicator,markedwiththedosagestrength.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Actiqisindicatedforthemanagementofbreakthroughpaininpatientsalreadyreceivingmaintenanceopioidtherapy

forchroniccancerpain.Breakthroughpainisatransitoryexacerbationofpainthatoccursonabackgroundof

otherwisecontrolledpersistentpain.

Patientsreceivingmaintenanceopioidtherapyarethosewhoaretakingatleast60mgoforalmorphinedaily,atleast

25microgramsoftransdermalfentanylperhour,atleast30mgofoxycodonedaily,atleast8mgoforal

hydromorphonedailyoranequianalgesicdoseofanotheropioidforaweekorlonger.

4.2Posologyandmethodofadministration

Inordertominimisetherisksofopioid-relatedside-effectsandtoidentifythe“successful”dose,itisimperativethat

patientsbemonitoredcloselybyhealthprofessionalsduringthetitrationprocess.AnyunusedActiqunitsthatthe

patientnolongerrequiresmustbedisposedofproperly.PatientsmustberemindedoftherequirementstokeepActiq

storedinalocationawayfromchildren.

Methodofadministration

Actiqisintendedfororomucosaladministration,andthereforeshouldbeplacedinthemouthagainstthecheekand

shouldbemovedaroundthemouthusingtheapplicator,withtheaimofmaximisingtheamountofmucosalexposure

totheproduct.TheActiqunitshouldbesucked,notchewed,asabsorptionoffentanylviathebuccalmucosaisrapid

incomparisonwithsystemicabsorptionviathegastrointestinaltract.Watermaybeusedtomoistenthebuccalmucosa

inpatientswithadrymouth.

TheActiqunitshouldbeconsumedovera15minuteperiod.Ifsignsofexcessiveopioideffectsappearbeforethe

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Adults

Dosetitrationandmaintenancetherapy

Actiqshouldbeindividuallytitratedtoa“successful”dosethatprovidesadequateanalgesiaandminimisesside

effects.InclinicaltrialsthesuccessfuldoseofActiqforbreakthroughpainwasnotpredictedfromthedaily

maintenancedoseofopioid.

a)Titration

BeforepatientsaretitratedwithActiq,itisexpectedthattheirbackgroundpersistentpainwillbecontrolledbyuseof

opioidtherapyandthattheyaretypicallyexperiencingnomorethan4episodesofbreakthroughpainperday.

TheinitialdoseofActiqusedshouldbe200micrograms,titratingupwardsasnecessarythroughtherangeofavailable

dosagestrengths(200,400,600,800,1200and1600micrograms).Patientsshouldbecarefullymonitoreduntiladose

isreachedthatprovidesadequateanalgesiawithacceptablesideeffectsusingasingledosageunitperepisodeof

breakthroughpain.Thisisdefinedasthesuccessfuldose.

Duringtitration,ifadequateanalgesiaisnotobtainedwithin15minutesafterthepatientcompletesconsumptionofa

singleActiqunit,asecondActiqunitofthesamestrengthmaybeconsumed.NomorethantwoActiqunitsshouldbe

usedtotreatanyindividualpainepisode.At1600micrograms,aseconddoseisonlylikelytoberequiredbya

minorityofpatients.

Iftreatmentofconsecutivebreakthroughpainepisodesrequiresmorethanonedosageunitperepisode,anincreasein

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b)Maintenance

Onceasuccessfuldosehasbeenestablished(i.e.,onaverage,anepisodeiseffectivelytreatedwithasingleunit),

patientsshouldbemaintainedonthisdoseandshouldlimitconsumptiontoamaximumoffourActiqunitsperday.

PatientsshouldbemonitoredbyahealthprofessionaltoensurethatthemaximumconsumptionoffourunitsofActiq

perdayisnotexceeded.

Dosere-adjustment

Ifmorethanfourepisodesofbreakthroughpainareexperiencedperday,overaperiodofmorethanfourconsecutive

daysthedoseofthelongactingopioidusedforpersistentpainshouldbere-evaluated.Ifthedoseofthelongacting

opioidisincreased,thedoseofActiqtotreatbreakthroughpainmayneedtobereviewed.

Itisimperativethatanydosere-titrationofanyanalgesicismonitoredbyahealthprofessional.

Discontinuationoftherapy

Actiqtherapymayusuallybeimmediatelydiscontinuedifnolongerrequiredforbreakthroughpainonly,inpatients

whocontinuetotaketheirchronicopioidtherapyforpersistentpain.

Forpatientsrequiringdiscontinuationofallopioidtherapy,accountshouldbetakenoftheActiqdoseinconsideration

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Useintheelderly

Elderlypatientshavebeenshowntobemoresensitivetotheeffectsoffentanylwhenadministeredintravenously.

Thereforedosetitrationneedstobeapproachedwithparticularcare.Intheelderly,eliminationoffentanylisslower

andtheterminaleliminationhalf-lifeislonger,whichmayresultinaccumulationoftheactivesubstanceandtoa

greaterriskofundesirableeffects.

FormalclinicaltrialswithActiqhavenotbeenconductedintheelderly.Ithasbeenobserved,however,inclinical

trialsthatpatientsover65yearsofagerequiredlowerdosesofActiqforsuccessfulreliefofbreakthroughpain.

Useinspecialpatientpopulations

Specialcareshouldbetakenduringthetitrationprocessinpatientswithkidneyorliverdysfunction.

Paediatricpopulation

Childrenaged16yearsandabove:followadultdosage

Childrenaged2to16yearsold:

ThereislimitedclinicaltrialexperienceoftheuseofACTIQinpaediatricpatientsalreadyreceivingmaintenance

opioidtherapy(seesections5.1and5.2).Safetyandefficacyinpaediatricpatientsbelowtheageof16yearshavenot

beenestablished;useinthispatientpopulationisthereforenotrecommended.

4.3Contraindications

Hypersensitivitytofentanylortoanyoftheexcipients.

Patientswithoutmaintenanceopioidtherapy(seesection4.1)asthereisanincreasedriskofrespiratorydepression.

Treatmentofacutepainotherthanbreakthroughpain(e.g.postoperativepain,headache,migraine).

Simultaneoususeofmonoamine-oxidase(MAO)inhibitors,orwithin2weeksafterthecessationoftheuseofMAO

inhibitors.

Severerespiratorydepressionorsevereobstructivelungconditions.

4.4Specialwarningsandprecautionsforuse

PatientsandtheircarersmustbeinstructedthatActiqcontainsanactivesubstanceinanamountthatcanbefataltoa

child.DeathhasbeenreportedinchildrenwhohaveaccidentallyingestedActiq.

Patientsandtheircarersmustbeinstructedtokeepallunitsoutofthereachandsightofchildrenandtodiscardopen

andunopenedunitsappropriately.Anevaluationofeachout-patientconcerningpossibleaccidentalchildexposures

shouldbeundertaken.

Theproductshouldnotbegiventopatientswithoutmaintenanceopioidtherapyasthereisanincreasedriskof

respiratorydepressionanddeath.Itisimportantthatthemaintenanceopioidtherapyusedtotreatthepatient’s

persistentpainhasbeenstabilisedbeforeActiqtherapybeginsandthatthepatientcontinuestobetreatedwiththe

maintenanceopioidtherapywhilsttakingActiq.

Toleranceandphysicaland/orpsychologicaldependencemaydevelopuponrepeatedadministrationofopioidssuchas

fentanyl.However,iatrogenicaddictionfollowingtherapeuticuseofopioidsisrare.

Aswithallopioids,thereisariskofclinicallysignificantrespiratorydepressionassociatedwiththeuseofActiq.

ParticularcautionshouldbeusedwhentitratingActiqinpatientswithnon-severechronicobstructivepulmonary

diseaseorothermedicalconditionspredisposingthemtorespiratorydepression,asevennormallytherapeuticdosesof

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Actiqshouldonlybeadministeredwithextremecautioninpatientswhomaybeparticularlysusceptibletothe

intracranialeffectsofCO2retention,suchasthosewithevidenceofincreasedintracranialpressure,orimpaired

consciousness.Opioidsmayobscuretheclinicalcourseofapatientwithaheadinjuryandshouldbeusedonlyif

clinicallywarranted.

Intravenousfentanylmayproducebradycardia.Therefore,Actiqshouldbeusedwithcautioninpatientswith

bradyarrhythmias.

Inaddition,Actiqshouldbeadministeredwithcautiontopatientswithliverorkidneydysfunction.Theinfluenceof

liverandrenalimpairmentonthepharmacokineticsofthemedicinalproducthasnotbeenevaluated,however,when

administeredintravenouslytheclearanceoffentanylhasbeenshowntobealteredinhepaticandrenaldiseasedueto

alterationsinmetabolicclearanceandplasmaproteins.AfteradministrationofActiq,impairedliverandrenalfunction

maybothincreasethebioavailabilityofswallowedfentanylanddecreaseitssystemicclearance,whichcouldleadto

increasedandprolongedopioideffects.Therefore,specialcareshouldbetakenduringthetitrationprocessinpatients

withmoderateorseverehepaticorrenaldisease.

Carefulconsiderationshouldbegiventopatientswithhypovolaemiaandhypotension.

Diabeticpatientsshouldbeadvisedthatthemedicineproductcontainsdextrates(dextratesarecomposedof93%

dextrosemonohydrateand7%maltodextrin.Thetotalglucoseloadperdosageunitisapproximately1.89gramsper

dose).

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

Normaloralhygieneisrecommendedtoreduceanypotentialharmtotheteeth.BecauseActiqcontainsapproximately

2gramsofsugar,frequentconsumptionincreasestheriskofdentaldecay.Theoccurrenceofdrymouthassociatedwith

theuseofopioidmedicationsmayaddtothisrisk.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

FentanylismetabolizedbytheCYP3A4isoenzymeintheliverandintestinalmucosa.PotentinhibitorsofCYP3A4

suchasmacrolideantibiotics(e.g.erythromycin),azoleantifungals(e.g.ketoconazole,itraconazole,andfluconazole)

andcertainproteaseinhibitors(e.g.ritonavir),mayincreasethebioavailabilityofswallowedfentanylandmayalso

decreaseitssystemicclearancewhichmayresultinincreasedorprolongedopioideffects.Similareffectscouldbe

seenafterconcurrentingestionofgrapefruitjuice,whichisknowntoinhibitCYP3A4.Hencecautionisadvisedif

fentanylisgivenconcomitantlywithCYP3A4inhibitors.

TheconcomitantuseofotherCNSdepressants,includingotheropioids,sedativesorhypnotics,generalanaesthetics,

phenothiazines,tranquillisers,skeletalmusclerelaxants,sedatingantihistaminesandalcoholmayproduceadditive

depressanteffects.

Withdrawalsymptomsmaybeprecipitatedthroughtheadministrationofdrugswithopioidantagonistactivity,e.g.,

naloxone,ormixedagonist/antagonistanalgesics(e.g.,pentazocine,butorphanol,buprenorphine,nalbuphine).

4.6Pregnancyandlactation

Therearenoadequatedatafromtheuseoffentanylinpregnantwomen.Studiesinanimalshaveshownreproductive

toxicity(seeSection5.3).Opioidanalgesicagentscancauseneonatalrespiratorydepression.Withlong-termuse

duringpregnancy,thereisariskofneonatalwithdrawalsymptoms.Actiqshouldnotbeusedinpregnancyunless

clearlynecessary.

Itisadvisednottousefentanylduringdeliverybecausefentanylpassesthroughtheplacentaandmaycauserespiratory

depressioninthefoetus.Theplacentaltransferratiois0.44(foetal:maternalratio1.00:2.27).

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ofsedationand/orrespiratorydepressionintheirinfants.Breastfeedingshouldnotberestarteduntilatleast48hours

afterthelastadministrationoffentanyl.

4.7Effectsonabilitytodriveandusemachines

Nostudiesoftheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,opioidanalgesics

mayimpairthementaland/orphysicalabilityrequiredfortheperformanceofpotentiallydangeroustasks(e.g.,driving

acaroroperatingmachinery).Patientsshouldbeadvisednottodriveoroperatemachineryiftheyexperience

somnolence,dizziness,blurredordoublevisionwhiletakingActiq.

4.8Undesirableeffects

TypicalopioidsideeffectsaretobeexpectedwithActiq.Frequently,thesewillceaseordecreaseinintensitywith

continueduseoftheproduct,asthepatientistitratedtothemostappropriatedose.However,themostseriousadverse

eventsarerespiratorydepression(potentiallyleadingtoapnoeaorrespiratoryarrest),circulatorydepression,

hypotensionandshockandallpatientsshouldbecloselymonitoredforthese.

Applicationsitereactions,includinggumbleeding,irritation,painandulcerhavebeenreportedinpost-marketinguse.

BecausetheclinicaltrialsofActiqweredesignedtoevaluatesafetyandefficacyintreatingbreakthroughpain,all

patientswerealsotakingconcomitantopioids,suchassustained-releasemorphineortransdermalfentanyl,fortheir

persistentpain.ThusitisnotpossibletodefinitivelyseparatetheeffectsofActiqalone.

ThefollowingadversereactionshavebeenreportedwithActiqduringclinicalstudiesandpostmarketingexperience.

AdversereactionsarelistedbelowasMedDRApreferredtermbysystemorganclassandfrequency(frequenciesare

definedas:verycommon ≥1/10,common≥1/100to<1/10,uncommon≥1/1,000to<1/100,notknown(cannotbe

estimatedfromtheavailabledata):

Metabolismandnutritiondisorders

Uncommon: anorexia

Psychiatricdisorders

Common: confusion,anxiety,hallucinations,abnormalthinking

Uncommon: abnormaldreams,depersonalisation,depression,emotionallability,euphoria

Nervoussystemdisorders

Verycommon:somnolence,sedation,dizziness

Common: lossofconsciousness,vertigo,headache,myoclonus,tasteperversion

Uncommon: coma,convulsion,paraesthesia(includinghyperaesthesia/circumoralparaesthesia),abnormal

gait/incoordination

Eyedisorders

Uncommon: abnormalvision(blurred,doublevision)

Vasculardisorders

Common: vasodilatation

Respiratory,thoracicandmediastinaldisorders

Uncommon: dyspnoea

Gastrointestinaldisorders

Verycommon:nausea,constipation

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example,burningsensation,ulcers)

Uncommon: ileus,flatulence,abdomenenlarged,dentalcaries

Notknown: toothloss,gingivalrecession

Skinandsubcutaneoustissuedisorders

Common: pruritus,sweating

Uncommon: rash

Renalandurinarydisorders

Uncommon: urinaryretention

Generaldisordersandadministrationsiteconditions

Common: asthenia,applicationsitereactionsincludinggumbleeding,irritation,painandulcer

Uncommon: malaise

Injury,poisoningandproceduralcomplications

Common: accidentalinjury(forexample,falls)

4.9Overdose

Thesymptomsoffentanyloverdosageareexpectedtobesimilarinnaturetothoseofintravenousfentanylandother

opioids,andareanextensionofitspharmacologicalactions,withthemostserioussignificanteffectsbeingaltered

mentalstatus,lossofconsciousness,coma,cardiorespiratoryarrest,respiratorydepression,respiratorydistress,and

respiratoryfailure,whichhaveresultedindeath.

ImmediatemanagementofopioidoverdoseincludesremovaloftheActiqunitviatheapplicator,ifstillinthemouth,

ensuringapatentairway,physicalandverbalstimulationofthepatient,assessmentofthelevelofconsciousness,

ventilatoryandcirculatorystatus,andassistedventilation(ventilatorysupport)ifnecessary.

Fortreatmentofoverdosage(accidentalingestion)intheopioidnaïveperson,intravenousaccessshouldbeobtained,

andnaloxoneorotheropioidantagonistsshouldbeemployedasclinicallyindicated.Thedurationofrespiratory

depressionfollowingoverdosemaybelongerthantheeffectsoftheopioidantagonist’saction(e.g.,thehalf-lifeof

naloxonerangesfrom30to81minutes)andrepeatedadministrationmaybenecessary.ConsulttheSummaryof

ProductCharacteristicsoftheindividualopioidantagonistfordetailsaboutsuchuse.

Fortreatmentofoverdoseinopioid-maintainedpatients,intravenousaccessshouldbeobtained.Thejudicioususeof

naloxoneoranotheropioidantagonistmaybewarrantedinsomeinstances,butitisassociatedwiththeriskof

precipitatinganacutewithdrawalsyndrome.

AlthoughmusclerigidityinterferingwithrespirationhasnotbeenseenfollowingtheuseofActiq,thisispossiblewith

fentanylandotheropioids.Ifitoccurs,itshouldbemanagedbytheuseofassistedventilation,byanopioidantagonist,

andasafinalalternative,byaneuromuscularblockingagent.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Opioidanalgesic,phenylpiperidonederivative.ATCcodeN02ABO3.

Fentanyl,apureopioidagonist,actsprimarilythroughinteractionwithmu-opioidreceptorslocatedinthebrain,spinal

cordandsmoothmuscle.Theprimarysiteoftherapeuticactionisthecentralnervoussystem(CNS).Themost

clinicallyusefulpharmacologicaleffectoftheinteractionoffentanylwithmu-opioidreceptorsisanalgesia.The

analgesiceffectsoffentanylarerelatedtothebloodleveloftheactivesubstance,ifproperallowanceismadeforthe

delayintoandoutoftheCNS(aprocesswitha3-5minutehalf-life).Inopioid-naïveindividuals,analgesiaoccursat

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respiratorydepression.

Inpatientswithchroniccancerpainonstabledosesofregularlyscheduledopioidstocontroltheirpersistentpain,Actiq

producedsignificantlymorebreakthroughpainreliefcomparedwithplaceboat15,30,45,and60minutesfollowing

administration.

Secondaryactionsincludeincreaseinthetoneanddecreaseinthecontractionsofthegastrointestinalsmoothmuscle,

whichresultsinprolongationofgastrointestinaltransittimeandmayberesponsiblefortheconstipatoryeffectof

opioids.

Whileopioidsgenerallyincreasethetoneofurinarytractsmoothmuscle,theoveralleffecttendstovary,insomecases

producingurinaryurgency,inothersdifficultyinurination.

Allopioidmu-receptoragonists,includingfentanyl,producedosedependentrespiratorydepression.Theriskof

respiratorydepressionislessinpatientswithpainandthosereceivingchronicopioidtherapywhodeveloptoleranceto

respiratorydepressionandotheropioideffects.Innon-tolerantsubjects,typicallypeakrespiratoryeffectsareseen15

to30minutesfollowingtheadministrationofActiq,andmaypersistforseveralhours.

ThereislimitedexperienceoftheuseofACTIQinpaediatricpatients,belowtheageof16.Inaclinicalstudy,15(out

of38)paediatricpatients,ranginginagefrom5to15years,alreadyreceivingmaintenanceopioidtherapyandwith

breakthroughpainweretreatedwithACTIQ.Thestudywastoosmalltoallowconclusionsonsafetyandefficacyin

thispatientpopulation.

5.2Pharmacokineticproperties

Generalintroduction

Fentanylishighlylipophilicandcanbeabsorbedveryrapidlythroughtheoralmucosaandmoreslowlybythe

conventionalgastrointestinalroute.Itissubjecttofirst-passhepaticandintestinalmetabolismandthemetabolitesdo

notcontributetofentanyl’stherapeuticeffects.

Absorption

TheabsorptionpharmacokineticsoffentanylfromActiqareacombinationofrapidoromucosalabsorptionandslower

gastrointestinalabsorptionofswallowedfentanyl.Approximately25%ofthetotaldoseofActiqisrapidlyabsorbed

fromthebuccalmucosa.Theremaining75%ofthedoseisswallowedandslowlyabsorbedfromthegastrointestinal

tract.About1/3ofthisamount(25%ofthetotaldose)escapeshepaticandintestinalfirst-passeliminationand

becomessystemicallyavailable.Absolutebioavailabilityisabout50%comparedtointravenousfentanyl,divided

equallybetweenrapidoromucosalandslowergastrointestinalabsorption.C

rangesfrom0.39to2.51ng/mlafter

consumptionofActiq(200microgramsto1600micrograms).T

isaround20to40minutesafterconsumptionofan

Actiqunit(range20–480minutes).

Distribution

Animaldatashowthatfentanylisrapidlydistributedtothebrain,heart,lungs,kidneysandspleenfollowedbyaslower

redistributiontomusclesandfat.Theplasmaproteinbindingoffentanylis80-85%.Themainbindingproteinis

alpha-1-acidglycoprotein,butbothalbuminandlipoproteinscontributetosomeextent.Thefreefractionoffentanyl

increaseswithacidosis.Themeanvolumeofdistributionatsteadystate(V

)is4l/kg.

Biotransformation

FentanylismetabolisedintheliverandintheintestinalmucosatonorfentanylbyCYP3A4isoform.Norfentanylisnot

pharmacologicallyactiveinanimalstudies.Morethan90%oftheadministereddoseoffentanyliseliminatedby

biotransformationtoN-dealkylatedandhydroxylatedinactivemetabolites.

Elimination

Lessthan7%ofthedoseisexcretedunchangedintheurine,andonlyabout1%isexcretedunchangedinthefaeces.

Themetabolitesaremainlyexcretedintheurine,whilefaecalexcretionislessimportant.Thetotalplasmaclearance

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hours.

Linearity/non-linearity

Doseproportionalityacrosstheavailablerangeofdosages(200microgramsto1600micrograms)ofActiqhasbeen

demonstrated.

Paediatricpopulation

Inaclinicalstudy,15paediatricpatients,ranginginagefrom5to15years,alreadyreceivingmaintenanceopioid

therapyandwithbreakthroughpainweretreatedwithACTIQatdosesrangingfrom200mcgto600mcg.Areaunder

thecurvevaluesbasedonobservedconcentrationswere2-foldhigherinyoungerchildrenthanadolescents(5.25versus

2.65ng.hr/mL,respectively)and4-foldhigherintheyoungerchildrenascomparedtoadults(5.25versus1.20

ng.hr/mL).Onaweight-adjustedbasis,clearanceandvolumeofdistributionvaluesweresimilaracrosstheagerange.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicity.

Embryo-foetaldevelopmentaltoxicitystudiesconductedinratsandrabbitsrevealednocompound-induced

malformationsordevelopmentalvariationswhenadministeredduringtheperiodoforganogenesis.

Inafertilityandearlyembryonicdevelopmentstudyinrats,amale-mediatedeffectwasobservedathighdoses(300

mcg/kg/day,s.c.)andisconsistentwiththesedativeeffectsoffentanylinanimalstudies.

Instudiesonpreandpostnataldevelopmentinratsthesurvivalrateofoffspringwassignificantlyreducedatdoses

causingseverematernaltoxicity.FurtherfindingsatmaternallytoxicdosesinF1pupsweredelayedphysical

development,sensoryfunctions,reflexesandbehaviour.Theseeffectscouldeitherbeindirecteffectsduetoaltered

maternalcareand/ordecreasedlactationrateoradirecteffectoffentanylonthepups.

Carcinogenicitystudies(26-weekdermalalternativebioassayinTg.ACtransgenicmice;twoyearsubcutaneous

carcinogenicitystudyinrats)didnotinduceanyfindingsindicativeofoncogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lozenge:

Dextrateshydrated(containingglucose)

Citricacid,anhydrous

Disodiumphosphate,anhydrous

Artificialberryflavour(maltodextrin,propyleneglycol,artificialflavoursandtriethylcitrate)

Magnesiumstearate

Edibleglueusedtoattachthelozengetothehandle:

Modifiedmaizebasedfoodstarch(E1450)

Confectioner’ssugar(sucroseandmaizestarch)

Water,purified

Imprintingink:

Ethanol

De-ionisedwater

De-waxedwhiteshellac

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Bluesyntheticcoaltardye(E133)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

EachActiqdosageunitiscontainedinaheatsealedblisterpackageconsistingofapaper/foillaminatedlid,anda

PVC/Aclarthermoformedblister,suppliedincartonsof3,6,15or30individualunits.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Lozengeswithresidualactivesubstanceshouldatnotimebediscardedormisplaced.Anyusedorunusedbutno

longerrequiredproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

CephalonUKLimited

1AlbanyPlace

HydeWay

WelwynGardenCity

HertfordshireAL73BT

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0827/002/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23January2002

Dateoflastrenewal:08October2005

10DATEOFREVISIONOFTHETEXT

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