SEROXAT

Israel - English - Ministry of Health

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Active ingredient:
PAROXETINE AS HYDROCHLORIDE 20 MG
Available from:
GLAXO SMITH KLINE (ISRAEL) LTD
ATC code:
N06AB05
Pharmaceutical form:
TABLETS
Administration route:
PER OS
Manufactured by:
GLAXO WELLCOME PRODUCTION, FRANCE
Therapeutic group:
PAROXETINE
Therapeutic indications:
Treatment of symptoms of depressive illness of all types including depression accompanied by anxiety. Treatment of symptoms and prevention of relapse of obsessive compulsive disorder (OCD). Treatment of symptoms and prevention of relapse of panic disorder with or without agoraphobia.Treatment of symptoms of social phobia. Post traumatic stress disorder. Generalised anxiety disorders.
Authorization number:
131272759205
Authorization date:
2009-07-01

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Patient Information leaflet Patient Information leaflet - Hebrew

21-01-2021

Theformat of thisleafletwasdeterminedbytheMinistryof Healthanditscontent wascheckedandapprovedonFebruary2011

Seroxat

TITLE

Paroxetinehydrochloride.

SCOPE

Trade Name

SEROXAT 

Formulation and Strength

Eachfilm-coatedtabletcontains22.8mgparoxetinehydrochloride,equivalentto20mgparoxetine.Fororal

administration.

Excipients

Dibasic calciumPhosphateDihydrate

SodiumStarch Glycollate

MagnesiumStearate

FilmCoat:

OpadryWhite YS-1R-7003

-Hydroxypropylmethylcellulose

TitaniumDioxide(EECNo. 171)

PolyethyleneGlycol400

Polysorbate 80

CLINICALINFORMATION

Indications

Adults:

Depressive disorders

Obsessive compulsive disorder

Panicdisorderwith orwithoutagoraphobia

Socialphobia

Generalised AnxietyDisorder

Posttraumatic stress disorder

Children andadolescents(<18years)

Paroxetineis notindicatedforusein childrenoradolescents aged <18years(seeWarnings and Precautions).

Controlled clinicalstudies in children and adolescents withmajordepressivedisorder failed todemonstrate

efficacyand do notsupportthe useofparoxetine in thetreatmentofdepressioninthis population. (SeeWarnings

and Precautions)

Thesafetyand efficacyof paroxetinein children aged<7years has notbeen studied.

DosageandAdministration

ItisrecommendedthatSeroxatisadministeredoncedailyinthemorningwithfood.Thetabletshouldbe

swallowedwhole.

Depressive disorder:

Adults

Therecommended doseis20 mgdaily.Some patientsnotrespondingtoa 20 mgdosemaybenefitfromdose

increasesin 10mg/dayincrements,up to a maximumof50mg/dayaccordingtothe patient's response.

As withallantidepressantdrugs, dosage shouldbe reviewed andadjusted ifnecessarywithin 2to 3 weeks of

initiation oftherapyand thereafterasjudged clinicallyappropriate.

Patients with depression should be treatedfora sufficientperiod to ensurethattheyare freefromsymptoms.This

period maybe severalmonths.

Obsessive compulsive disorder:

Adults

Therecommendeddoseis40mgdaily.Patientsshouldstarton20mgandthedosecanbeincreasedweeklyin10

mgincrements.Some patientswillbenefitfromhavingtheirdoseincreased up toamaximumof60 mg/day.

PatientswithOCDshould betreatedforasufficientperiodtoensurethattheyarefreefromsymptoms.Thisperiod

maybe severalmonthsoreven longer.

Panic disorder:

Adults

Therecommended doseis40 mgdaily.Patients should be startedon10mg/dayandthedoseincreased weeklyin 10

mgincrementsaccordingtopatient'sresponse.Somepatientsmaybenefitfromhavingtheirdoseincreaseduptoa

maximumof60mg/day.

Alowinitialstartingdoseisrecommendedtominimisethepotentialworseningofpanicsymptomatology,whichis

generallyrecognisedtooccurearlyinthetreatmentofthis disorder.

Patientswithpanicdisordershouldbetreatedforasufficientperiodtoensurethattheyarefreefromsymptoms.

This period maybe severalmonths oreven longer.

SocialPhobia

Adults

Therecommendeddoseis20mgdaily.Somepatientsnotrespondingtoa20mgdosemaybenefitfromhaving

doseincreasesin 10mgincrements as required,up toamaximumof50 mg/dayaccordingto the patient's response.

Generalised AnxietyDisorder

Adults

Therecommendeddoseis20mgdaily.Somepatientsnotrespondingtoa20mgdosemaybenefitfromhaving

doseincreasesin 10 mgincrementsas required,up toamaximumof50 mg/dayaccordingtothe patient's response.

Post-traumaticstressdisorder

Adults

Therecommendeddoseis20mgdaily.Somepatientsnotrespondingtoa20mgdosemaybenefitfromhaving

doseincreasesin 10mgincrements as required,up toamaximumof50mg/dayaccordingto the patient's response.

GeneralInformation

DISCONTINUATIONOF PAROXETINE

Aswithotherpsychoactivemedications,abruptdiscontinuationshouldgenerallybeavoided(seesections

WarningsandPrecautions&AdverseReactions).Thetaperphaseregimenusedinrecentclinicaltrialsinvolveda

decrease inthedailydoseby10mg/dayatweeklyintervals.

Whenadailydoseof20mg/daywasreached,patientswerecontinuedonthisdoseforoneweekbeforetreatment

wasstopped.Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,

thenresumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinue

decreasingthe dose,butata more gradualrate.

Populations

Elderly:

Increasedplasmaconcentrationsofparoxetineoccurinelderlysubjects,buttherangeofconcentrationsoverlaps

withthatobserved in youngersubjects.

Dosingshould commence atthe adultstartingdose andmaybe increased upto 40mgdaily.

Children and adolescents(<18years)

Paroxetineisnotindicatedforuseinchildrenoradolescentsaged<18years(seeIndicationsandWarningsand

Precautions).

Renal/hepaticimpairment:

Increasedplasmaconcentrationsofparoxetineoccurinpatientswithsevererenalimpairment(creatinineclearance

lessthan 30 ml/min)orin thosewithhepatic impairment. Therefore, dosage should be restricted to the lowerend of

the dosage range .

Contraindications

Known hypersensitivityto paroxetineand excipients.

Paroxetineshouldnotbeusedincombinationwithmonoamineoxidase(MAO)inhibitors(including

linezolid,anantibioticwhichisareversiblenon-selectiveMAOinhibitorandmethylthioniniumchloride

(methyleneblue))orwithin2weeksofterminatingtreatmentwithMAOinhibitors.Likewise,MAO

inhibitorsshouldnotbeintroducedwithin2weeksofcessationoftherapywithparoxetine(see

Interactions).

Paroxetineshouldnotbeusedincombinationwiththioridazine,because,aswithotherdrugswhich

inhibitthehepaticenzymeCYP4502D6,paroxetinecanelevateplasmalevelsofthioridazine(see

Interactions).AdministrationofthioridazinealonecanleadtoQTcintervalprolongationwithassociated

serious ventriculararrhythmiasuchas torsades depointes, andsudden death.

Paroxetineshould not be used in combination with pimozide(seeInteractions).

Warnings andPrecautions

Children and Adolescents(<18 years)

Treatmentwithantidepressantsisassociatedwithanincreasedriskofsuicidalthinkingandbehaviourin

childrenandadolescentswithMajorDepressive D isorder(MDD)andotherpsychiatricdisorders.In

clinicaltrialsofparoxetineinchildrenandadolescents,adverseeventsrelatedtosuicidality(suicide

attemptsandsuicidalthoughts)andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinpatientstreatedwithparoxetinecomparedtothosetreatedwith

placebo(seeAdverseReactions).Long-termsafetydatainchildrenandadolescentsconcerninggrowth,

maturation and cognitiveand behavioural development arelacking.

Clinical worsening andsuicideriskinadults

Youngadults, especiallythosewithMDD,maybe atincreasedriskforsuicidalbehaviourduringtreatmentwith

paroxetine. An analysisofplacebo controlled trials of adults withpsychiatricdisorders showedahigher

frequencyof suicidal behaviour inyoungadults (prospectivelydefined as aged 18-24years)treatedwith

paroxetinecomparedwith placebo (17/776 [2.19%]versus 5/542 [0.92%]), although this differencewas

not statisticallysignificant. In the older agegroups (aged 25-64yearsand≥65years), no such increase

was observed. In adultswith MDD(allages), therewasastatisticallysignificant increasein the

frequencyof suicidal behaviour in patients treatedwith paroxetinecompared with placebo(11/3455

[0.32%]versus 1/1978 [0.05%]; all of theevents weresuicideattempts). However, themajorityofthese

attempts forparoxetine(8 of 11)wereinyoungeradults aged 18-30years. TheseMDDdata suggestthat

the higher frequencyobserved in theyounger adult population across psychiatricdisorders mayextend

beyond theageof 24.

Patientswithdepressionmayexperienceworseningoftheirdepressivesymptomsand/ortheemergence

ofsuicidalideationandbehaviours(suicidality)whetherornottheyaretakingantidepressant

medications.Thisriskpersistsuntilsignificantremissionoccurs.Itisgeneralclinicalexperiencewithall

antidepressant therapies that therisk of suicide mayincreasein theearlystages of recovery.

Other psychiatricconditions forwhich paroxetineis prescribedcan beassociated with an increased risk of

suicidal behaviourandtheseconditionsmayalsobeco-morbid withMDD.

Additionally,patientswithahistoryofsuicidalbehaviourorthoughts,youngadults,andthosepatients

exhibitingasignificantdegreeofsuicidalideationpriortocommencementoftreatment,areatagreater

riskofsuicidalthoughtsorsuicideattempts.Allpatientsshouldbemonitoredforclinicalworsening

(includingdevelopmentofnewsymptoms)andsuicidalitythroughouttreatment,andespeciallyatthe

beginningofacourseoftreatment, or at thetimeofdosechanges, either increases or decreases.

Patients,(andcaregiversofpatients)shouldbealertedabouttheneedtomonitorforanyworseningof

theircondition(includingdevelopmentofnewsymptoms)and/ortheemergenceofsuicidal

ideation/behaviourorthoughtsofharmingthemselvesandtoseekmedicaladviceimmediatelyifthese

symptomspresent.Itshouldberecognisedthattheonsetofsomesymptoms,suchasagitation,akathisia

ormania,couldberelatedeithertotheunderlyingdiseasestateorthedrugtherapy(seeAkathisiaand

Mania and BipolarDisorderbelow;AdverseReactions).

Considerationshouldbegiventochangingthetherapeuticregimen,includingpossiblydiscontinuingthe

medication,inpatientswhoexperienceclinicalworsening(includingdevelopmentofnewsymptoms)

and/ortheemergenceofsuicidalideation/behaviour,especiallyifthesesymptomsaresevere,abruptin

onset, orwerenot part ofthe patient’s presentingsymptoms.

Akathisia

Rarely, the use ofparoxetine orotherSSRIs has beenassociated withthe developmentofakathisia, which is

characterised byan innersenseofrestlessnessand psychomotoragitation such asan inabilityto sitorstandstill

usuallyassociated with subjective distress.Thisis mostlikelyto occurwithinthefirstfew weeks oftreatment.

Serotonin Syndrome orNeurolepticMalignantSyndrome(NMS)-like Reactions

Thedevelopmentofa potentiallylife-threateningserotonin syndrome orNeurolepticMalignantSyndrome (NMS)-

like reactions have been reported with SNRIs and SSRIs alone,includingtreatmentwith Seroxat, butparticularly

with concomitantuseofserotonergic drugs (includingtriptans)with drugs whichimpairmetabolismofserotonin

(includingMAOIs), orwithantipsychotics orotherdopamine antagonists. Serotonin syndrome symptomsmay

include mentalstatus changes(e.g., agitation,hallucinations, coma), autonomicinstability(e.g., tachycardia,labile

blood pressure, hyperthermia),neuromuscularaberrations (e.g., hyperreflexia,incoordination)and/or

gastrointestinalsymptoms (e.g., nausea,vomiting, diarrhea). Serotonin syndrome, in its mostsevereformcan

resemble neuroleptic malignantsyndrome, which includeshyperthermia, muscle rigidity, autonomic instability

with possible rapidfluctuation ofvitalsigns, and mentalstatus changes. Patients should be monitoredforthe

emergence ofserotonin syndrome orNMS-like signs and symptoms.

TheconcomitantuseofSeroxatwithMAOIs intendedto treatdepressionis contraindicated.

IfconcomitanttreatmentofSeroxatwitha 5-hydroxytryptamine receptoragonist(triptan)is clinicallywarranted,

carefulobservation ofthe patientisadvised,particularlyduringtreatmentinitiation and doseincreases.

TheconcomitantuseofSeroxatwithserotonin precursors(suchastryptophan)isnotrecommended.

TreatmentwithSeroxatandanyconcomitantserotonergic orantidopaminergicagents,includingantipsychotics,

should be discontinued immediatelyifthe above events occurand supportive symptomatictreatmentshould be

initiated.

ManiaandBipolar disorder

Amajordepressive episodemaybe theinitialpresentation ofbipolardisorder.Itisgenerallybelieved (though not

established incontrolled trials)thattreatingsuchan episodewith anantidepressantalone canincrease the

likelihood ofprecipitationofa mixed/manic episode in patients atriskforbipolardisorder. Priortoinitiating

treatmentwith an antidepressant, patients shouldbe adequatelyscreenedto determine iftheyareatriskforbipolar

disorder;suchscreeningshouldincludea detailed psychiatric history, includinga familyhistoryofsuicide, bipolar

disorder, anddepression.Itshould be notedthatparoxetine isnotapproved forusein treatingbipolardepression.

As withallantidepressants,paroxetineshould beusedwith cautionin patients with a historyofmania.

Tamoxifen

Some studies haveshown that theefficacyof tamoxifen, as measured bytherisk of breast cancer

relapse/mortality, maybereducedwhen co-prescribed with paroxetineas aresultof paroxetine’s

irreversible inhibition ofCYP2D6 (seeInteractions). This risk mayincreasewith longer duration ofco-

administration.When tamoxifen is used forthe treatment or prevention ofbreast cancer, prescribers

should consider usinganalternativeantidepressantwith littleor noCYP2D6 inhibition.

Bonefracture

Epidemiologicalstudies onbone fracture riskfollowingexposureto some antidepressants, includingSSRIs, have

reported anassociation with fractures.Theriskoccursduringtreatmentandis greatestin the earlystagesof

therapy. The possibilityoffracture should be considered inthe care ofpatientstreated with paroxetine.

MonoamineOxidase Inhibitors

Treatmentwithparoxetineshould beinitiated cautiouslyatleast2 weeks afterterminatingtreatmentwithMAO

inhibitors anddosage ofparoxetineshould beincreasedgraduallyuntiloptimalresponseisreached(see

ContraindicationsandInteractions).

Renal/hepaticimpairment

Caution is recommended inpatients with severerenalimpairmentorinthosewithhepaticimpairment. (See

DosageandAdministration).

EPILEPSY:Aswith otherantidepressants, paroxetine should beusedwith caution in patients withepilepsy.

SEIZURES: Overalltheincidenceofseizures is lessthan 0.1%in patientstreated withparoxetine.

Thedrugshould be discontinuedin anypatientwho develops seizures.

ECT:There is little clinicalexperience oftheconcurrentadministration ofparoxetine with ECT.

GLAUCOMA:AswithotherSSRIs,paroxetinecancausemydriasisandshouldbeusedwithcautioninpatients

with narrowangle glaucoma.

HYPONATRAEMIA:Hyponatraemiahasbeenreportedrarely,predominantlyintheelderly.Thehyponatraemia

generallyreverses on discontinuation ofparoxetine.

HAEMORRHAGE:Skinandmucousmembranebleedings(includinggastrointestinalbleeding)havebeen

reportedfollowingtreatmentwithparoxetine.Paroxetineshouldthereforebeusedwithcautioninpatients

concomitantlytreated withdrugs thatgive anincreased risk forbleeding, andin patients with a knowntendency for

bleedingorthose with predisposingconditions.

CARDIACCONDITIONS:The usualprecautionsshould beobserved inpatientswith cardiac conditions.

Symptomsseenon discontinuationofparoxetine treatmentin adults:

In clinicalstrialsin adults,adverseevents seen on treatmentdiscontinuation occurredin 30%ofpatientstreated

with paroxetinecompared to 20%ofpatients treated with placebo.The occurrence ofdiscontinuation symptoms is

notthe same as thedrugbeingaddictive ordependenceproducingaswitha substanceofabuse.

Dizziness, sensorydisturbances(includingparaesthesia,electric shocksensationsand tinnitus),sleep disturbances

(includingintense dreams),agitation oranxiety, nausea, tremor, confusion, sweating, headache,diarrhoeahave

beenreported. Generallythesesymptoms are mild tomoderate, however, insome patientstheymaybe severe in

intensity. Theyusuallyoccurwithinthe firstfew daysofdiscontinuingtreatment,butthere have been veryrare

reportsofsuchsymptoms in patients whohave inadvertentlymisseda dose. Generallythesesymptoms are self-

limitingand usuallyresolve within 2 weeks, though insome individualstheymaybe prolonged (2-3months or

more). Itis therefore advised thatparoxetineshould be graduallytapered when discontinuingtreatmentovera

periodofseveralweeks ormonths, accordingto the patient's needs(seeDiscontinuation ofParoxetine,Dosage and

Administration).

Symptomsseenon discontinuationofparoxetine treatmentin children andadolescents:

In clinicaltrials inchildrenand adolescents,adverseeventsseen ontreatmentdiscontinuationoccurred in 32%of

patients treated with paroxetine comparedto 24%ofpatientstreated with placebo.Events reported upon

discontinuation ofparoxetine ata frequencyofatleast2%ofpatients and whichoccured atarate atleasttwice that

ofplacebo were:emotionallability(includingsuicidalideation,suicide attempt, mood changesandtearfulness),

nervousness, dizziness, nausea and abdominalpain(seeAdverse Reactions).

Interactions

Serotonergic drugs

As with otherSSRIs, co-administration with serotonergic drugs maylead to anincidenceof5-HTassociated

effects (serotoninsyndrome;seeWarningsandPrecautions).

Caution shouldbe advisedand acloserclinicalmonitoringisrequired whenserotonergic drugs (such as

L-tryptophan,triptans, tramadol, SSRIs,lithium,fentanyland St.John's Wort–Hypericumperforatum–

preparations)are combinedwith paroxetine.

Concomitant useof paroxetineand MAOinhibitors (includinglinezolid, an antibioticwhich is a

reversible non-selectiveMAOinhibitorand methylthioninium chloride (methyleneblue)) is

contraindicated(seeContraindications).

Pimozide

Increased pimozide levels have been demonstratedin astudyofasingle lowdosepimozide (2mg)when

co-administeredwith paroxetine. Thisis explained bythe known CYP2D6 inhibitorypropertiesofparoxetine.

Due tothe narrowtherapeuticindex ofpimozide andits known abilityto prolongQTinterval, concomitantuseof

pimozide and paroxetine iscontraindicated(seeContraindications).

Drug metabolisingenzymes

Themetabolismand pharmacokinetics ofparoxetine maybe affected bytheinduction orinhibition ofdrug

metabolisingenzymes.

When paroxetineisto be co-administered witha known drugmetabolisingenzyme inhibitor,considerationshould

be given to usingdosesatthe lowerend oftherange.

No initialdosage adjustmentis considered necessarywhen the drugistobe co-administered with known drug

metabolisingenzyme inducers(e.g. carbamazepine, rifampicin, phenobarbital, phenytoin). Anysubsequentdosage

adjustmentshouldbe guided byclinicaleffect(tolerabilityand efficacy).

Fosamprenavir/ritonavir: Co-administration offosamprenavir/ritonavirwith paroxetine significantlydecreased

plasma levels ofparoxetine. Anydoseadjustmentshould be guided byclinicaleffect(tolerabilityandefficacy).

Procyclidine:Dailyadministration ofparoxetineincreasessignificantlythe plasma levels ofprocyclidine. Ifanti-

cholinergic effectsare seen,the doseofprocyclidine should be reduced.

Anticonvulsants:carbamazepine, phenytoin,sodiumvalproate. Concomitantadministration doesnotseemto

show anyeffecton pharmacokinetic/dynamic profile in epileptic patients.

CYP2D6inhibitory potency ofparoxetine:

As with otherantidepressants,includingotherSSRIs, paroxetineinhibitsthe hepatic cytochrome P450 enzyme

CYP2D6 . InhibitionofCYP2D6 maylead to increased plasma concentrations ofco-administereddrugs

metabolised bythis enzyme. Theseinclude certain tricyclicantidepressants (e.g. amitriptyline, nortriptyline,

imipramine and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see

Contraindications),risperidone,atomoxetine,certainType 1c antiarrhythmics (e.g. propafenoneandflecainide)

and metoprolol.

Tamoxifenhasanimportantactivemetabolite,endoxifen,whichisproducedbyCYP2D6andcontributes

significantlytotheefficacyoftamoxifen.IrreversibleinhibitionofCYP2D6byparoxetineleadsto

reduced plasma concentrations of endoxifen (seeWarnings and Precautions).

CYP3A4

An in vivo interaction studyinvolvingthe co-administration understeadystateconditions ofparoxetineand

terfenadine, asubstrateforcytochrome CYP3A4, revealedno effectofparoxetineon terfenadine pharmacokinetics.

Asimilarin vivo interaction studyrevealed no effectofparoxetine on alprazolampharmacokineticsand vice-versa.

Concurrentadministrationofparoxetine withterfenadine, alprazolamand otherdrugs thatareCYP3A4 substrates

would notbeexpected tocausea hazard.

Clinicalstudieshave shown theabsorptionand pharmacokinetics ofparoxetine tobe unaffected oronlymarginally

affected (i.e.ata levelwhich warrants no change indosingregimen)by:

food

antacids

digoxin

propranolol

alcohol:paroxetine doesnotincreasetheimpairmentofmentaland motorskillscaused byalcohol, however,

the concomitantuseofparoxetine and alcoholis notadvised.

Pregnancyand Lactation

Fertility

Some clinical studies haveshown that SSRIs (includingparoxetine) mayaffect sperm quality. This effect

appears to bereversible followingdiscontinuation oftreatment. Changes insperm qualitymayaffect

fertilityin some men.

Pregnancy

Animal studies havenot shown anyteratogenic orselectiveembryotoxic effects.

Recent epidemiological studies of pregnancyoutcomes followingmaternalexposureto antidepressants in

the first trimester havereported an increasein therisk ofcongenital malformations, particularly

cardiovascular(e.g. ventricular and atrial septal defects), associated with theuse of paroxetine.

Thedata suggest that therisk ofhavingan infantwith a cardiovasculardefect followingmaternal

paroxetineexposureis approximately1/50, compared with an expectedrateforsuchdefects of

approximately1/100 infants in the general population.

Theprescribingphysician willneed to weigh theoption ofalternativetreatments in women who are

pregnant orareplanningto become pregnant, andshould onlyprescribeparoxetineif thepotential benefit

outweighs thepotentialrisk. If adecision istaken to discontinueparoxetinetreatment in apregnant

woman, the prescriber should consultDosageand Administration-Discontinuation of Paroxetineand

Warnings and Precautions–Symptoms seen on discontinuation of paroxetinetreatment in adults.

Therehavebeen reports ofprematurebirth in pregnant women exposedto paroxetineor others SSRIs,

although acausalrelationship with drugtherapyhas notbeen established.

Neonatesshouldbe observed ifmaternaluseofparoxetine continues intothelaterstagesofpregnancy, because

there have been reportsofcomplicationsin neonates exposedto paroxetine orotherSSRIs latein the third trimester

ofpregnancy. However, acausalassociation with drugtherapyhasnotbeenconfirmed. Reportedclinicalfindings

have included:respiratorydistress, cyanosis, apnoea,seizures, temperature instability, feedingdifficulty, vomiting,

hypoglycemia, hypertonia,hypotonia,hyperreflexia,tremor, jitteriness,irritability, lethargy, constantcryingand

somnolence. In some instancesthereported symptomswere described asneonatalwithdrawalsymptoms.In a

majorityofinstancesthecomplications werereported to have ariseneitherimmediatelyorsoon(<24 hours)after

delivery.

Epidemiologicalstudieshave shown thatthe use ofSSRIs (includingparoxetine)in pregnancy, particularlyuse in

late pregnancy,wasassociated with an increased riskofpersistentpulmonaryhypertension ofthe newborn

(PPHN). Theincreasedriskamonginfantsbornto womenwho used SSRIs latein pregnancywasreported to be4

to 5timeshigherthan observedin thegeneralpopulation(rateof1to 2per1000 pregnancies).

Lactation

Smallamounts ofparoxetine areexcretedinto breastmilk. In published studies,serumconcentrations in breast-fed

infantswereundetectable(<2ng/ml)orverylow(<4ng/ml). No signs ofdrugeffects were observedin these

infants. Nevertheless,paroxetine should notbe used duringlactation unlessthe expected benefits to the mother

justifythe potentialrisks forthe infant.

Abilitytoperform tasks that require judgement, motor orcognitiveskills

Clinicalexperiencehasshownthattherapywithparoxetineisnotassociatedwithimpairmentofcognitiveor

psychomotorfunction.However,aswithallpsychoactivedrugs,patientsshouldbecautionedabouttheirabilityto

drive acarand operate machinery .

Althoughparoxetinedoesnotincreasethementalandmotorskillimpairmentscausedbyalcohol,theconcomitant

useofparoxetine andalcoholis notadvised .

Adverse Reactions

Someoftheadverseexperienceslistedbelowmaydecreaseinintensityandfrequencywithcontinuedtreatment

and do notgenerallyleadtocessation oftherapy.

Adversedrugreactionsarelistedbelowbysystemorganclassandfrequency.Frequenciesaredefinedas:very

common(

1/10),common(

1/100,<1/10),uncommon(

1/1,000,<1/100),rare(

1/10,000,<1/1,000),veryrare

(<1/10,000),includingisolatedreports.Thefrequenciesofcommonanduncommoneventsweregenerally

determinedfrompooledsafetydatafromaclinicaltrialpopulationof>8000paroxetine-treatedpatientsandare

quotedasexcessincidenceoverplacebo.Rareandveryrareeventsweregenerallydeterminedfrompost-

marketingdata andrefertoreportingrate ratherthantrue frequency.

Blood &lymphaticsystemdisorders

Uncommon:abnormalbleeding, predominantlyoftheskin and mucousmembranes (mostlyecchymosis).

Veryrare:thrombocytopenia.

Immune systemdisorders

Veryrare:allergicreactions (includingurticariaand angioedema).

Endocrine disorders

Veryrare:syndrome ofinappropriateanti-diuretichormone secretion (SIADH).

Metabolism&nutrition disorders

Common:increasesincholesterollevels,decreased appetite.

Rare:hyponatraemia.

Hyponatraemiahasbeenreportedpredominantlyinelderlypatientsandissometimesduetosyndromeof

inappropriateanti-diuretichormone secretion(SIADH).

Psychiatric disorders

Common:somnolence, insomnia,agitation,abnormaldreams (includingnightmares).

Uncommon:confusion,hallucinations.

Rare:manic reactions.

Thesesymptomsmaybe duetotheunderlyingdisease.

Nervous systemdisorders

Common:dizziness, tremor, headache.

Uncommon:extrapyramidaldisorders.

Rare:convulsions,akathisia, restless legs syndrome (RLS).

Veryrare:serotonin syndrome (symptomsmayincludeagitation,confusion, diaphoresis, hallucinations,

hyperreflexia,myoclonus,shiveringtachycardiaand tremor).

Reports ofextrapyramidaldisordersincludingoro-facialdystoniahave beenreceived in patientssometimeswith

underlyingmovementdisordersorwho were usingneuroleptic medication.

Eye disorders

Common:blurred vision.

Uncommon:mydriasis(seeWarnings and Precautions).

Veryrare:acute glaucoma.

Cardiac disorders

Uncommon:sinustachycardia.

Vascular disorders

Uncommon:posturalhypotension.

Respiratory, thoracic andmediastinaldisorders

Common:yawning.

Gastrointestinaldisorders

Verycommon:nausea.

Common:constipation,diarrhoea,vomiting,drymouth.

Veryrare:gastrointestinalbleeding.

Hepato-biliary disorders

Rare:elevation ofhepatic enzymes.

Veryrare:hepaticevents(such ashepatitis, sometimesassociated withjaundiceand/orliverfailure).

Elevation ofhepatic enzymeshas been reported. Post-marketingreports ofhepatic events(such ashepatitis,

sometimesassociated withjaundice, and/orliverfailure)have also beenreceivedveryrarely. Discontinuation of

paroxetineshould beconsideredifthereisprolongedelevation ofliverfunctiontestresults.

Skin &subcutaneous tissue disorders

Common:sweating.

Uncommon:skin rashes.

Veryrare: severecutaneous adversereactions (includingerythema multiforme, Stevens-Johnson syndrome

and toxic epidermal necrolysis), photosensitivityreactions.

Renal&urinary disorders

Uncommon:urinaryretention, urinaryincontinence.

Reproductivesystem&breastdisorders

Verycommon:sexualdysfunction.

Rare:hyperprolactinaemia /galactorrhoea.

Generaldisorders &administration siteconditions

Common:asthenia, bodyweightgain.

Veryrare:peripheraloedema.

Symptomsseenon discontinuationofparoxetine treatment:

Common:Dizziness, sensorydisturbances, sleepdisturbances, anxiety, headache.

Uncommon:Agitation, nausea,tremor, confusion,sweating,diarrhoea.

As with manypsychoactive medicines,discontinuationofparoxetine (particularlywhen abrupt)maylead to

symptoms such as dizziness, sensorydisturbances(includingparaesthesia,electricshocksensationsandtinnitus),

sleep disturbances(includingintense dreams), agitationoranxiety, nausea, headache, tremor, confusion, diarrhoea

and sweating.In the majorityofpatients,theseeventsare mildto moderate and are self-limiting. No particular

patientgroup appears to beathigherriskofthese symptoms;itistherefore advisedthatwhen paroxetinetreatment

is nolongerrequired, gradualdiscontinuation bydosetaperingbe carriedout(seeDosageandAdministration&

Warnings and Precautions).

AdverseEvents fromPaediatric ClinicalTrials

In paediatricclinicaltrialsthe followingadverseevents, werereported atafrequencyofatleast2%ofpatients and

occurredata rateatleasttwicethatofplacebo:emotionallability(includingself-harm, suicidalthoughts,

attempted suicide cryingand mood fluctuations), hostility, decreased appetite,tremor, sweating, hyperkinesia and

agitation. Suicidalthoughts and suicideattempts weremainlyobserved inclinicaltrials ofadolescents withMajor

Depressive Disorder. Hostilityoccurred particularlyinchildren with obsessive compulsive disorder, andespecially

in youngerchildrenless than 12 years ofage).

In studiesthatused ataperingregimen(dailydosedecreasedby10mg/dayatweeklyintervalsto adoseof

10mg/dayforoneweek), symptoms reportedduringthe taperphase orupon discontinuationofparoxetineata

frequencyofatleast2%ofpatients and occurred atarateatleasttwice thatofplacebo were:emotionallability,

nervousness, dizziness, nausea and abdominalpain.(seeWarnings andPrecautions).

Overdose

SymptomsandSigns

Awide margin ofsafetyisevidentfromavailableoverdoseinformation on paroxetine.

Experience ofparoxetine inoverdosehasindicatedthat, in additiontothosesymptomsmentionedunder'Adverse

Reactions', fever, blood pressure changes, involuntarymuscle contractions,anxietyand tachycardia have been

reported.

Patients have generallyrecovered withoutserious sequelae even when dosesofup to 2000 mghave been taken

alone.EventssuchascomaorECGchangeshave occasionallybeen reportedand,veryrarelya fataloutcome,but

generallywhen paroxetinewastakenin conjunctionwith otherpsychotropicdrugs, with orwithoutalcohol.

Treatment

No specific antidote is known.

Thetreatmentshould consistofthosegeneralmeasures employed in the managementofoverdose with any

antidepressant. WhereSupportive care with frequentmonitoringofvitalsigns and carefulobservationisindicated.

Patientmanagementshouldbe asclinicallyindicated,orasrecommended bythe nationalpoisonscentre, where

available.

Clinical Pharmacology

Pharmacodynamics

MechanismofAction

Paroxetineisapotentandselectiveinhibitorof5-hydroxytryptamine(5-HT,serotonin)uptakeandits

antidepressantactionandeffectivenessinthetreatmentofOCDandPanicDisorderisthoughttoberelatedtoits

specificinhibitionof5-HTuptake inbrain neurones .

Paroxetineis chemicallyunrelated tothetricyclic,tetracyclicand otheravailable antidepressants.

Paroxetinehaslowaffinityformuscariniccholinergicreceptorsandanimalstudieshaveindicatedonlyweak

anticholinergic properties .

Inaccordancewiththisselectiveaction,invitrostudieshaveindicatedthat,incontrasttotricyclicantidepressants,

paroxetinehaslittleaffinityforalpha1,alpha2andbeta-adrenoceptors,dopamine(D2),5-HT1like,5-HT2and

histamine(H1)receptors.Thislackofinteractionwithpost-synapticreceptorsinvitroissubstantiatedbyinvivo

studieswhichdemonstratelackofCNS depressantandhypotensive properties .

Pharmacodynamic Effects

Paroxetine doesnotimpairpsychomotorfunction anddoesnotpotentiate the depressanteffects ofethanol.

Aswithotherselective5-HTuptakeinhibitors,paroxetinecausessymptomsofexcessive5-HTreceptor

stimulationwhen administeredto animals previouslygivenmonoamine oxidase(MAO)inhibitors ortryptophan.

BehaviouralandEEGstudiesindicatethatparoxetineisweaklyactivatingatdosesgenerallyabovethoserequired

to inhibit5-HTuptake.Theactivatingpropertiesarenot"amphetamine-like"in nature.

Animalstudiesindicatethatparoxetine is welltolerated bythe cardiovascularsystem.

Paroxetineproducesnoclinicallysignificantchangesinbloodpressure,heartrateandECGafteradministrationto

healthysubjects.

Studiesindicatethat,incontrasttoantidepressantswhichinhibittheuptakeofnor-adrenaline,paroxetinehasa

much reducedpropensitytoinhibitthe antihypertensive effects ofguanethidine.

Pharmacokinetics

Absorption

Paroxetineis wellabsorbedafteroraldosingand undergoesfirst-pass metabolism.

Duetofirst-passmetabolism,theamountofparoxetineavailabletothesystemiccirculationislessthanthat

absorbedfromthegastrointestinaltract.Partialsaturationofthefirst-passeffectandreducedplasmaclearance

occurasthebodyburdenincreaseswithhighersingledosesoronmultipledosing.Thisresultsindisproportionate

increasesinplasmaconcentrationsofparoxetineandhencepharmacokineticparametersarenotconstant,resulting

innon-linearkinetics.However,thenon-linearityisgenerallysmallandisconfinedtothosesubjectswhoachieve

lowplasma levelsatlowdoses .

Steadystatesystemiclevelsareattainedby7to14daysafterstartingtreatmentwithimmediateorcontrolled

release formulationsand pharmacokineticsdo notappearto change duringlong-termtherapy .

Distribution

Paroxetineisextensivelydistributedintotissuesandpharmacokineticcalculationsindicatethatonly1%ofthe

paroxetineinthe bodyresidesintheplasma .

Approximately95%oftheparoxetine presentintheplasma is protein bound attherapeutic concentrations .

Nocorrelationhasbeenfoundbetweenparoxetineplasmaconcentrationsandclinicaleffect(adverseexperiences

and efficacy) .

Metabolism

Theprincipalmetabolitesofparoxetinearepolarandconjugatedproductsofoxidationandmethylationwhichare

readilycleared.Inviewoftheirrelativelackofpharmacologicalactivity,itismostunlikelythattheycontributeto

paroxetine's therapeutic effects .

Metabolismdoesnotcompromiseparoxetine's selective actionon neuronal5-HTuptake .

Elimination

Urinaryexcretionofunchangedparoxetineisgenerallylessthan2%ofdosewhilstthatofmetabolitesisabout

64%ofdose.About36%ofthedoseisexcretedinfaeces,probablyviathebile,ofwhichunchangedparoxetine

representslessthan 1%ofthe dose.Thusparoxetineiseliminated almostentirelybymetabolism .

NOTE:The alternative wordinggiven belowmaybe used to replacetheabove statement:

About64%ofthe doseis excreted in the urine;urinaryexcretion ofunchanged paroxetine is generallyless than 2%

ofthedose.About36%ofthedoseisexcretedinthefaeces,probablyviathebile;faecalexcretionofunchanged

paroxetinerepresents lessthan 1%ofthedose.Thus paroxetineis eliminated almostentirelybymetabolism.

Metaboliteexcretionisbiphasic,beinginitiallyaresultoffirst-passmetabolismandsubsequentlycontrolledby

systemic elimination ofparoxetine.

Theelimination half-life isvariable butis generallyabout1 day.

SpecialPatient Populations

Elderly andRenal/Hepatic Impairment

Increased plasma concentrations ofparoxetine occurinelderlysubjects,insubjects withsevererenalandin those

withhepaticimpairment, butthe range ofplasma concentrationsoverlapsthatofhealthyadultsubjects.

NON-CLINICALINFORMATION

Toxicologystudieshavebeenconductedinrhesusmonkeysandalbinorats;inboth,themetabolicpathwayis

similartothatdescribedforhumans.Asexpectedwithlipophilicamines,includingtricyclicantidepressants,

phospholipidosiswasdetectedinrats.Phospholipidosiswasnotobservedinprimatestudiesofuptooneyear

durationatdoses thatwere6 timeshigherthan the recommended range ofclinicaldoses.

Carcinogenesis: In two yearstudiesconductedin miceand rats, paroxetine hadnotumorigeniceffect.

Genotoxicity: Genotoxicitywasnotobserved in a batteryofinvitroandin vivo tests.

PHARMACEUTICALINFORMATION

ShelfLife

3years

Storage

Storeattemperature notexceeding30°C.

Natureand Contents of Container

Seroxatfilm-coatedtabletsarepackedinPVC/PVdCblistersbackedwithaluminiumfoil.Theblisterscontain10

tablets perstrip.

Packs of10,20, 30film-coatedtablets.

Incompatibilities

Thereareno knownincompatibilitieswith paroxetinetablets. Thetabletshould be swallowed whole,notchewed.

Instruction forUse/Handling

No specialinstructions.

Manufacturer

S.C. EuropharmS.A., Brasov, Romania.

Or

GlaxoWellcome Production, Marly-Le-Roi, France.

LicenseHolderandImporter

GlaxoSmithKline(Israel)Ltd.,

25 BaselSt.,PetachTikva.

LicenseNumber

131-27-27592-06

131-27-27592-05

Sero DR v2

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