GAMANIL

Main information

  • Trade name:
  • GAMANIL Film Coated Tablet 70 Milligram
  • Dosage:
  • 70 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GAMANIL Film Coated Tablet 70 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0654/011/001
  • Authorization date:
  • 14-05-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gamanil70mgFilm-CoatedTablet.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainslofepraminehydrochloride76.10mgequivalenttolofepramine70mg.

Excipents:Eachtabletcontainslactose126.05mgandPonceau4RAluminiumLake(E124)1.15mg.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Round,lacquered,brown-violettablet,withoccasionalwhitedots,withaspindleshapedscoringononeside.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inthetreatmentofsymptomsofdepressiveillness.Thisincludesdepression/anxietystatesassociatedwithpanic

disorderfeatures.

4.2Posologyandmethodofadministration

Routeofadministration:Oral

Recommendeddosage:

Theusualdoseis70mgtwicedaily(140mg)orthreetimesdaily(210mg)dependinguponpatientresponse.Thedaily

doseshouldalwaysbegivenindivideddosesnotexceeding70mgperdose.

Inthetreatmentofdepression/anxietystatesassociatedwithpanicdisorderfeatures,theinitialdosageshouldbe70mg

dailyforthefirstweek.

Paediatricpatients

Useinchildrenandadolescentsundertheageof18isnotrecommended(seesection4.4).

Elderly

Elderlypatientsmayrespondtolowerdosesinsomecases.

4.3Contraindications

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Lofepraminemustnotbeusedinpatients

withmania,

withsevereliverimpairment,

withsevererenalimpairment,

withheartblock,

withcardiacarrhythmias,

intherecoveryphasefollowingamyocardialinfarction,

withuntreatednarrowangleglaucoma

withprostatichypertrophywithurinaryretention.

atriskforparalyticileus

Lofepraminemustnotbeadministeredwithorwithin2weeksofcessationoftherapywithmonoamineoxidase

inhibitors.

Lofepraminemustnotbeadministeredinpatientswithacutealcoholic,hypnotic,analgesicandpsychotropicdrug

poisoningandacutedeliria.

4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).

Thisriskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormore

oftreatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethat

theriskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichlofepramineareprescribedcanalsobeassociatedwithanincreasedriskof

suicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.

Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsinadultpatientswithpsychiatricdisorders

showedanincreasedriskofsuicidalbehaviourwithantidepressantscomparedtoplaceboinpatientslessthan25years

old.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Patientsreceivinganti-depressanttherapyshouldbekeptunderregularsurveillancewithparticularattentiontothe

effectsoncerebralfunction,haemopoieticfunction,cardiacconductiondisorders.

Lofepramineshouldbeusedwithcautioninpatientswithcardiovasculardisease,becauseitisassociatedwithariskof

cardiovascularadverseeventsinallagegroups.Moreover,cautionisalsorequiredinpatientswithimpairedliveror

renalfunction,narrowangleglaucoma,symptomssuggestiveofprostatichypertrophy,ahistoryofepilepsyorrecent

convulsions,hyperthyroidism,blooddyscrasias,porphyriaorasusceptibilitytoparalyticileus.

Cautionisneededinpatientswithhyperthyroidism,orduringconcomitanttreatmentwiththyroidpreparations,since

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LofepraminecanprolongtheQT-intervalinTheECGandmayleadtoTorsadesdePointes.Lofepraminemayonlybe

usedwithparticularcautionwhenotherriskfactorsforTorsadesdePointesarepresent,suchas:

congenitallongQTsyndrome

otherclinicallysignificantcardiacdisorders

paralleltreatmentwithmedicinalproducts,

whichalsoprolongtheQTintervalintheECGorcancausehypokalaemia.IfTorsadesdePointesoccurthetreatment

withLofepraminehastobestopped.

Lofepraminemaylowertheconvulsionthreshold;thereforeextremecautionisnecessaryinpatientswithahistoryof

epilepsyorrecentconvulsionsorotherpredisposingfactors,orduringwithdrawalfromalcoholorothermedicinal

productswithanticonvulsantproperties.

Concurrentelectroconvulsivetherapymustonlybeundertakenwithcarefulsupervision.

CautionisrecommendedifLofepramineisusedinpatientswithimpairedliverfunction,impairedrenalfunction,blood

dyscrasiasorporphyria.

Cautionisrecommendedinpatientswithahistoryofprostatichypertrophy,narrowangleglaucomaorincreasedintra-

ocularpressure,becauseofLofepramine’santicholinergicproperties.Inpatientswithnarrowangleglaucoma.

Lofepraminemayonlybeusedifadequateglaucomatreatmentisgiven.

Inchronicconstipation,Lofepraminemaycauseparalyticileus.

Cautionisrecommendedinpatientswithtumoursoftheadrenalmedullainwhomtricyclicantidepressants,suchas

Lofepramine,mayprovokehypertensivecrises.

Itisrecommendedthatbloodpressurebecheckedbeforeinitiatingtreatmentbecauseindividualswithhypertension,or

anunstablecirculation,mayreacttolofepraminewithafallinbloodpressure.

Anaestheticsmayincreasetherisksofarrhythmiasandhypotension,thereforebeforelocalorgeneralanaesthesia,the

anaesthetistmustbeinformedthatthepatienthasbeentakingLofepramine.

Cautionisrequiredinpatientswithahistoryofmania.

Psychoticsymptomsmaybeaggravated.Therehavealsobeenreportsofhypomanicormanicepisodesduringa

depressivephaseinpatientswithcyclicaffectivedisordersreceivingtricyclicantidepressantsincludingLofepramine.

ItisrecommendedthatabruptwithdrawalofLofepraminebeavoidedunlessessential,becausewithdrawalsymptoms

mayoccuronabruptcessationoftherapy.Withdrawalsymptoms

mayincludeinsomnia,irritabilityandexcessiveperspiration.

Monitoringofhaemopoeiticfunctionisrecommendedparticularlyinpatientswithblooddyscrasias.

Lofepraminecontainslactose;thereforeitsuseisnotrecommendedinpatientswithrarehereditaryproblemsof

galactose-intolerance,theLapplactasedeficiencyorglucosegalactosemalabsorption.

Elderly

Theelderlyareparticularlyliabletoexperienceadversereactionstotricyclicantidepressants,especiallyagitation,

confusionandrarely,posturalhypotension.

Paediatricpatients

Lofepramineisnotrecommendedforthetreatmentofchildrenandadolescentsundertheageof18years.

Studiesindepressioninthisagegroupdidnotshowabeneficialeffectfortricyclicantidepressants.Studieswithother

classesofantidepressantshaveshownariskofsuicidality,self-harmandhostilityrelatedtothesecompounds.Thisrisk

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Furthermore,long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveand

behaviouraldevelopmentarenotavailable.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

MAOInhibitors:Lofepraminemustnotbeadministeredwithorwithin2weeksofcessationoftherapywith

monoamineoxidaseinhibitors.Thereafter,cautiousinitiationoftherapyisrecommendedusingalowinitialdoseand

theeffectsmonitored.

Antiarrhythmicagents:Thereisanincreasedriskofventriculararrhythmias,whichmayleadtoTorsadesdePointesif

Lofepramineisgivenwithanti-arrhythmicagentswhichprolongtheQTintervale.g.disopyramide,procainamide,

propafenone,quinidine,sotalolandamiodarone.ParticularcautionisadvisedifLofepramineisusedincombination

withsuchagents.

Non-antiarrhythmicagentswhichmayprolongtheQTinterval:Thereisanincreasedriskofventriculararrhythmias

whichmayleadtoTorsadesdePointesifLofepramineisgivenwithnon-anti-arrhythmicagentswhichprolongtheQT

intervale.g.certainantibiotics(e.g.macrolides),cisapride,

malariaagents,antihistamines(e.g.terfenadine),neurolepticagents.ParticularcautionisadvisedifLofepramineis

usedincombinationwithsuchagents.

Medicinalproductsthatmaycausehypokalaemia:Combinationwithmedicinalproductsthatmaycausehypokalaemia

mayincreasetheriskforventriculararrhythmiasincludingTorsadesdePointes.Particularcautionisadvisedif

Lofepramineisusedincombinationwithsuchagents.

Sympathomimeticagents:ConcomitantuseofLofepraminewithsympathomimeticagentsisnotrecommendedsince

theircardiovasculareffectsmaybepotentiated.

Adrenergicneuroneblockers:Lofepraminemaydecreaseorabolishtheantihypertensiveeffectsofsomeadrenergic

neuroneblockingdrugs.Antihypertensiveagentsofadifferenttypearethereforerecommendedwherepatientsrequire

co-medicationforhypertension.

CNSdepressants:Lofepramine’seffectsmaybepotentiatedwhenadministeredwithCNSdepressantsubstancese.g.

barbiturates,generalanaestheticsandalcohol.Ifsurgeryisnecessary,theanaesthetistshouldbeinformedthatapatient

isbeingsotreatedbecauseoftheincreasedriskofarrhythmias

andhypotension.

Anti-cholinergicagents:Lofepraminemaypotentiatetheeffectsofthesedrugsonthecentralnervoussystem,eye,

bowelandbladder.

SSRIInhibitors:co-medicationmayleadtoadditiveeffectsontheserotonergicsystem.Fluvoxamineandfluoxetine

mayalsoincreaseplasmaconcentrationsofLofepramineresultinginaloweredconvulsionthresholdandseizures.

Neurolepticagents:Inadditiontoanincreasedriskofarrythmias,theremaybeanincreasedplasmalevelof

thetricyclicantidepressant,aloweredconvulsionthresholdandseizures.

Anticoagulants:Lofepraminemayinhibithepaticmetabolismleadingtoanenhancementofanticoagulanteffect.

Carefulmonitoringofplasmaprothrombinisadvised.

Analgesics:Thereisanincreasedriskofventriculararrhythmias.

Anti-epileptics:Antagonismcanleadtoaloweringoftheconvulsivethreshold.Plasmalevelsofsometricyclic

antidepressants,andthereforethetherapeuticeffect,maybereduced.

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Diuretics:Thereisanincreasedriskofposturalhypotension.

Rifampicin:ThemetabolismofLofepramineisacceleratedbyrifampicinleadingtoareducedplasmaconcentration.

Digitalisglycosides:Withdigitalisglycosidesthereisahigherriskofarrhythmias.

Cimetidine:Cimetidinecanincreasetheplasmaconcentrationoflofepramine.

Altretamine:Thereisariskofsevereposturalhypotensionwhencoadministeredwithtricyclicantidepressants.

Disulfiramandalprazolam:Co-medicationwitheitherdisulfiramoralprazolammayrequireareductioninthedoseof

Lofepramine.

Nitrates:Theeffectivenessofsublingualnitratesmaybereducedwherethetricyclicantidepressant’santicholinergic

effecthasleadtodrynessofthemouth.

Ritonavir:TheremaybeanincreasedplasmaconcentrationofLofepramine.

Oralcontraceptives:Oestrogensandprogestogensmayantagonizethetherapeuticeffectoftricyclicantidepressants.

Adversereactionsoftricyclicantidepressantsmaybeexacerbatedduetoanincreasedplasmaconcentration

Thyroidhormonetherapy:Duringconcomitanttreatment,theremaybeaggravationofunwantedcardiaceffects.

4.6Fertility,pregnancyandlactation

Pregnancy

ThesafetyofLofepramineforuseduringpregnancyhasnotbeenestablishedandthereisevidenceofharmfuleffects

inpregnancyinanimalswhenhighdosesaregiven.Lofepraminehasbeenshowntocrosstheplacenta.The

administrationofLofepramineinpregnancythereforeisnotadvisedunlesstherearecompellingmedicalreasons.

Adverseeffectssuchaswithdrawalsymptoms,respiratorydepressionandagitationhavebeenreportedinneonates

whosemothershavetakentricyclicantidepressantsduringthelasttrimesterofpregnancy.

Lactation

Lofepramineisexcretedinbreastmilk.TheadministrationofLofepramineduringbreast-feedingisnotadvisedunless

therearecompellingmedicalreasons.

4.7Effectsonabilitytodriveandusemachines

Aswithotherantidepressants,abilitytodriveacarandoperatemachinerymaybeaffected,especiallyinconjunction

withalcohol.Thereforecautionisrecommendedinitiallyuntiltheindividualreactiontotreatmentisknown.

4.8Undesirableeffects

ThefollowingsideeffectshavebeenreportedwithLofepramine:

Investigations:

Changesofbloodsugarlevel

Cardiacdisorders:

tachycardia,cardiacconductiondisorders,

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QT-prolongation,arrhythmias

(includingventriculararrhythmiasorTorsadesdePointes.)

Nervoussystemdisorders:

Dizziness,headache,paraesthesia,

tremor;rarely,drowsiness,convulsions,

impairmentofthesenseoftaste;very

rarely,uncoordinatedmovement.

Reproductivesystemandbreastdisorders:

Interferencewithsexualfunction,testiculardisorders(e,gtesticularpain),gynaecomastia,alactorrhoea.

Skinandsubcutaneoustissuedisorders:

skinrash,allergicskinreactions,“photosensitivityreactions”,

rarely,cutaneousbleeding,sweating.

Gastrointestinaldisorders:

Gastrointestinaldisturbancesincludingnausea,vomiting,diarrhoea;constipationanddrynessofmouth.

Endocrinedisorders:

Rarely,inappropriatesecretionofantidiuretichormoneleadingtohyponatraemia

Bloodandlymphaticsystemdisorders:

Rarely,bonemarrowdepressionincludingisolatedreportsof:agranulocytosis,eosinophilia,granulocytopenia,

leucopenia,pancytopenia,thrombocytopenia.

Eyedisorders:

Visualdisturbancesincludingblurredvision,mydriasis,disturbancesofaccommodation;inductionofglaucoma

Earandlabyrinthdisorders:

Veryrarely,tinnitus

Renalandurinarydisorders:

Urinaryhesitancy,urinaryretention

Vasculardisorders:

Hypotension

Generaldisordersandadministrationsiteconditions

Malaise,facialoedema;rarely,

inflammationofmucosalmembranes.

Hepatobiliarydisorders:

Increasesinliverenzymes,sometimesprogressingtoclinicalhepatitisandjaundice,havebeenreportedinsome

patients,usuallyoccurringwithinthefirst3monthsofstartingtherapy

Psychiatricdisorders:

Sleepdisturbances,agitation,confusion,nightmares,hallucinations,hypomania,mania,psychoses,delirium.

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringlofepraminetherapyorearlyafter

discontinuation(seesection4.4)

Itshouldberememberedthatseverelydepressedpatientsareatriskofsuicideuntilthereisacompleteremissionof

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Anticholinergic:

SomeoftheabovementionedadversereactionsmaybeduetotheanticholinergicactivityofLofepramine,these

include:

drynessofmouth,constipation,visualdisturbancesincludinge.g.blurredvision,

mydriasis,disturbancesofaccommodation

inductionofglaucoma,

urinaryhesitancy,urinaryretention,

sweating,tachycardia,impairmentofthesenseoftaste

tremor,confusion,delirium,

nightmares,hallucinations,psychoses,

maniaandhypomania

Classeffects

Epidemiologicalstudies,mainlyinpatients50yearsofageandolder,showanincreasedriskofbonefracturesin

patientsreceivingSSRlsandTCAs.Themechanismleadingtothisriskisunknown.

Thefollowingadverseeffectshavebeenencounteredinpatientsundertreatmentwithtricyclicantidepressantsand

shouldthereforebeconsideredastheoreticalhazardsoflofepramineevenintheabsenceofsubstantiation:psychotic

manifestations,includingmaniaandparanoiddelusionsmaybe

exacerbatedduringtreatmentwithtricyclicantidepressants;withdrawalsymptomsmayoccuronabruptcessationof

therapyandincludeinsomnia,irritabilityandexcessiveperspiration;adverseeffectssuchaswithdrawalsymptoms,

respiratorydepressionandagitationhavebeenreportedinneonateswhosemothershavetakentricyclicantidepressants

duringthelasttrimesterofpregnancy.

4.9Overdose

Symptoms

Overdosemaybecharacterisedbycentralnervoussystemdepressionorexcitation,severeanticholinergiceffectsor

cardiotoxicity.

Inparticular,dependingontheamounttaken,overdosewithLofepraminemayleadtoepileptiformseizuresorcardiac

events,suchasconductiondisorders,QT-prolongation,arrhythmiasincludingTorsadesdePointes.

Management

Thetreatmentofoverdoseisdirectedtosymptoms.

Itshouldincludeimmediategastriclavageandroutineclosemonitoringofcardiacfunction.Reportsofoverdosage

with0.7–6.72ghaveshownnoserioussequelaedirectlyattributabletolofepramine.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antidepressant,non-selectivemonoaminereuptakeinhibitor.

ATCCode:N06AA07

Lofepramineisatricyclicantidepressant.Itexertsitstherapeuticeffectbyblockingtheuptakeofnoradrenalinebythe

nervecellthusincreasingtheamineinthesynapticcleftandhencetheeffectonthereceptors.Thereisevidenceto

suggestthatserotoninmayalsobeinvolved.Otherpharmacologicaleffectsareduetoanti-cholinergicactivity,butless

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5.2Pharmacokineticproperties

Lofepramineisatertiaryamine,similarinstructuretoimipraminebutwithimprovedlipophilicityandlowerbase

strength.Itisreadilyabsorbedwhengivenorally.Fromtheplasmaitisdistributedthroughoutthebodynotablytothe

brain,lungs,liverandkidney.Itismetabolisedintheliverbycleavageofthep-chlorophenacylgroupfromthe

lofepraminemoleculeleavingdesmethylimipramine(DMI).Thelatterispharmacologicallyactive.Thep-

chlorobenzoylportionismainlymetabolisedtop-chlorobenzoicacidwhichisthenconjugatedwithglycine.The

conjugateisexcretedmostlyintheurine.DMIhasbeenfoundexcretedinthefaeces.Inastudyofproteinbinding

capabilityithasbeenfoundthatlofepramineisupto99%proteinbound.

5.3Preclinicalsafetydata

Notapplicable.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Excipients

Lactose

Cornstarch

L(+)ascorbicacid

Talc

Glycerol

Glycerolmonostearate

Ethylenedinitriletetraaceticaciddisodiumsalt(dihydrate)

Dimeticone1000

Colloidalanhydroussilica

Hypromellose

Filmcoating

Propyleneglycol

Hypromellose

Ponceau4Raluminiumlake(E124)

Talc

Titaniumdioxide(E171)

Indigotinelake(E132)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Storebelow25 o

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6.5Natureandcontentsofcontainer

PVDC/ALfoilblistercalendarpackscontaining56tablets

Polypropylenecontainersof250tablets.

Amberglassbottlescontaining56tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

MerckSeronoLimited

BedfontCross

StanwellRoad

Feltham

Middlesex

TW148NX

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0654/011/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14May1984

Dateoflastrenewal:14May2009

10DATEOFREVISIONOFTHETEXT

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