PRODUCT MONOGRAPH PAROXETINE-10 PAROXETINE-20 PAROXETINE-30. Paroxetine Tablets. Pro Doc Standard

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1 PRODUCT MONOGRAPH PAROXETINE-10 PAROXETINE-20 PAROXETINE-30 Paoxtin Tablts Po Doc Standad 10 mg, 20 mg and 30 mg (as Paoxtin Hydochloid) Antidpssant Antiobsssional Antipanic Anxiolytic Agnt Social Phobia (Social Anxity Disod) Posttaumatic Stss Disod Thapy PRO DOC LTÉE DATE OF REVISION: 2925, boul. Industil Fbuay 27, 2018 Laval, Qubc H7L 3W9 Contol No.: Pag 1 of 51

2 Tabl of Contnts PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 INDICATIONS AND CLINICAL USE... 3 CONTRAINDICATIONS... 5 WARNINGS AND PRECAUTIONS... 5 ADVERSE REACTIONS DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY TOXICOLOGY REFERENCES PART III: CONSUMER INFORMATION Pag 2 of 51

3 PAROXETINE-10 PAROXETINE-20 PAROXETINE-30 Paoxtin (as Paoxtin Hydochloid) Tablts Po Doc Standad PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Rout of Dosag Fom / Administation Stngth Oal Tablt 10 mg, 20 mg, 30 mg All Nonmdicinal Ingdints Anhydous lactos, hydoxypopyl cllulos, hydoxypopyl mthylcllulos, magnsium staat, polythyln glycol, sodium stach glycolat, titanium dioxid, and th following colouing agnts all xtndd on an aluminum substat: D&C yllow #10 and FD&C yllow #6 (10 mg tablts only), D&C d #30 (20 mg tablts only), and FD&C blu #2 (30 mg tablts only) INDICATIONS AND CLINICAL USE Adults Dpssion PAROXETINE (paoxtin hydochloid) is indicatd fo symptomatic lif of Majo Dpssiv Disod (MDD). Clinical tials hav povidd vidnc that continuation tatmnt with paoxtin in patints with modat to modatly sv dpssiv disod is ffctiv fo at last 6 months (s Clinical Tials, Dpssion). Obsssiv-Compulsiv Disod PAROXETINE is indicatd fo th symptomatic tatmnt of obsssiv-compulsiv disod (OCD). Th obsssions o compulsions must b xpincd as intusiv, makdly distssing, tim-consuming, o intfing significantly with th pson s social o occupational functioning. Panic Disod PAROXETINE is indicatd fo th symptomatic tatmnt of panic disod, with o without agoaphobia. Panic disod (DSM-IV) is chaactizd by cunt unxpctd panic attacks, i.., a disct piod of intns fa o discomfot in which fou (o mo) of th following symptoms dvlop abuptly and ach a pak within 10 minuts: (1) palpitations, pounding hat, o acclatd hat Pag 3 of 51

4 at; (2) swating; (3) tmbling o shaking; (4) snsations of shotnss of bath o smothing; (5) fling of choking; (6) chst pain o discomfot; (7) nausa o abdominal distss; (8) fling dizzy, unstady, lighthadd, o faint; (9) dalization (flings of unality) o dpsonalization (bing dtachd fom onslf); (10) fa of losing contol; (11) fa of dying; (12) pasthsias (numbnss o tingling snsations); (13) chills o hot flushs. Social Phobia (Social Anxity Disod) PAROXETINE is indicatd fo th symptomatic lif of gnalizd social phobia (social anxity disod), a disod chaactizd by makd and psistnt fa, anxious anticipation, o avoidanc of multipl social situations (.g. intacting with stangs, attnding social gathings, daling with authoity figus) and/o pfomanc situations (.g. ating, witing, woking whil bing obsvd, o public spaking). A diagnosis of social phobia/social anxity disod should not b mad unlss th fa, anxious anticipation, o avoidanc of social and/o pfomanc situations intfs significantly with th pson s nomal outin, occupational functioning, social lif, o causs makd distss. Gnalizd Anxity Disod PAROXETINE is indicatd fo th symptomatic lif of anxity causing significant distss in patints with Gnalizd Anxity Disod (GAD). Posttaumatic Stss Disod PAROXETINE is indicatd fo th symptomatic tatmnt of posttaumatic stss disod (PTSD). PTSD as dfind by DSM-IV quis xposu to a taumatic vnt that involvd actual o thatnd dath o sious injuy, o that to th physical intgity of slf o oths, and a spons which involvs intns fa, hlplssnss, o hoo. Symptoms that occu as a sult of xposu to th taumatic vnt includ xpincing of th vnt in th fom of intusiv thoughts, flashbacks o dams, and intns psychological distss and physiological activity on xposu to clus to th vnt; avoidanc of situations miniscnt of th taumatic vnt, inability to call dtails of th vnt, and/o numbing of gnal sponsivnss manifstd as diminishd intst in significant activitis, stangmnt fom oths, stictd ang of affct, o sns of foshotnd futu; and symptoms of autonomic aousal including hypvigilanc, xaggatd statl spons, slp distubanc, impaid concntation, and iitability o outbusts of ang. A diagnosis of PTSD quis that th symptoms a psnt fo at last on month and that thy caus clinically significant distss o impaimnt in social, occupational, o oth impotant aas of functioning. Long-Tm Us Of PAROXETINE Th ffctivnss of paoxtin in long-tm us (i.. mo than 8 wks fo GAD and 12 wks fo oth indications) has not yt bn stablishd in contolld tials fo OCD, panic disod, social phobia (social anxity disod), gnalizd anxity disod and posttaumatic stss disod. Thfo, th physician who lcts to us PAROXETINE fo xtndd piods in ths indications should piodically -valuat th long-tm usfulnss of th dug fo individual patints (s DOSAGE AND ADMINISTRATION, Dosing Considations). Giatics (>65 yas of ag) Evidnc fom clinical studis indicats that th a diffncs in th phamacokintic pofil of paoxtin in th giatic population lativ to young adults, which may b associatd with diffncs in safty o ffctivnss. A bif discussion can b found in th appopiat sctions (s WARNINGS AND PRECAUTIONS Spcial Populations-Giatics; ACTIONS AND CLINICAL PHARMACOLOGY; DOSAGE AND ADMINISTRATION). Pag 4 of 51

5 Pdiatics (<18 yas of ag) PAROXETINE is not indicatd fo us in patints blow th ag of 18 yas (s WARNINGS AND PRECAUTIONS, Gnal, Potntial Association With Bhavioal and Emotional Changs, Including Slf-Ham) CONTRAINDICATIONS Hypsnsitivity: PAROXETINE is containdicatd in patints who a known to b hypsnsitiv to th dug o any of its componnts. Fo a complt listing, s DOSAGE FORMS, COMPOSITION AND PACKAGING. Monoamin Oxidas Inhibitos: In patints civing sotonin uptak inhibitos (SSRIs) in combination with a MAO inhibito, th hav bn pots of sious, somtims fatal, actions including hypthmia, igidity, myoclonus, autonomic instability with possibl apid fluctuations of vital signs, and mntal status changs that includ xtm agitation pogssing to dliium and coma. Ths actions hav also bn potd in patints who hav cntly discontinud SSRI tatmnt and hav bgun tatmnt on a MAO inhibito. Som cass psntd with fatus smbling sotonin syndom o nuolptic malignant syndom (s WARNINGS AND PRECAUTIONS, Sotonin Syndom/Nuolptic Malignant Syndom). Thfo, PAROXETINE should not b usd in combination with MAO inhibitos [including linzolid, an antibiotic which is a vsibl non-slctiv MAO inhibito and mthylthioninium chloid (mthyln blu)] o within a minimum of 2 wks of tminating tatmnt with MAO inhibitos. Tatmnt with PAROXETINE should thn b initiatd cautiously and dosag incasd gadually until optimal spons is achd. MAO inhibitos should not b intoducd within 2 wks of cssation of thapy with PAROXETINE. Thioidazin: Thioidazin administation alon poducs polongation of th QTc intval, which is associatd with sious vnticula ahythmias, such as tosad d points-typ ahythmias, and suddn dath. This ffct appas to b dos-latd. An in vivo study suggsts that dugs which inhibit P450 2D6, including ctain SSRIs such as paoxtin, fluoxtin and fluvoxamin, will lvat plasma lvls of thioidazin. Thfo, PAROXETINE should not b usd in combination with thioidazin o within a minimum of 2 wks of tminating tatmnt with thioidazin. At last 2 wks should b allowd aft discontinuing PAROXETINE thapy bfo initiating tatmnt with thioidazin. Pimozid: Th concomitant us of PAROXETINE and pimozid is containdicatd as paoxtin has bn shown to incas plasma pimozid lvls. Elvation of pimozid blood concntation may sult in QT intval polongation and sv ahythmias including tosad d points (s Dug Intactions). WARNINGS AND PRECAUTIONS Gnal POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM. Pdiatics: Placbo-Contolld Clinical Tial Data Rcnt analyss of placbo-contolld clinical tial safty databass fom SSRIs and oth nw antidpssants suggsts that us of ths dugs in patints und Pag 5 of 51

6 th ag of 18 may b associatd with bhavioual and motional changs, including an incasd isk of suicidal idation and bhaviou ov that of placbo. Th small dnominatos in th clinical tial databas, as wll as th vaiability in placbo ats, pclud liabl conclusions on th lativ safty pofils among ths dugs. Adult and Pdiatics: Additional data Th a clinical tial and post-makting pots with SSRIs and oth nw antidpssants, in both pdiatics and adults, of sv agitation-typ advs vnts coupld with slf-ham o ham to oths. Th agitation-typ vnts includ: akathisia, agitation, disinhibition, motional lability, hostility, aggssion, and dpsonalization. In som cass, th vnts occud within sval wks of stating tatmnt. Rigoous clinical monitoing fo suicidal idation o oth indicatos of potntial fo suicidal bhaviou is advisd in patints of all ags. This includs monitoing fo agitationtyp motional and bhavioual changs. An FDA mta-analysis of placbo-contolld clinical tials of antidpssant dugs in adult patints ags 18 to 24 yas with psychiatic disods showd an incasd isk of suicidal bhaviou with antidpssant compad to placbo. Discontinuation Symptoms: Patints cuntly taking PAROXETINE should NOT b discontinud abuptly, du to isk of discontinuation symptoms. At th tim that a mdical dcision is mad to discontinu an SSRI o oth nw antidpssant dug, a gadual duction in th dos ath than an abupt cssation is commndd. Discontinuation of Tatmnt with PAROXETINE Whn discontinuing tatmnt, gadlss of th indication fo which PAROXETINE is bing pscibd, patints should b monitod fo symptoms which may b associatd with discontinuation (.g. dizzinss, slp distubancs including abnomal dams, snsoy distubancs (including pasthsias, lctic shock snsations and tinnitus), agitation, anxity, hadach, tmo, confusion, diaha, nausa, vomiting and swating) o oth symptoms which may b of clinical significanc [s ADVERSE REACTIONS, Advs Evnts following Discontinuation of Tatmnt (o Dos Rduction)-Post-Makting]. A gadual duction in th dos ath than abupt cssation is commndd whnv possibl. If intolabl symptoms occu following a dcas in th dos o upon discontinuation of tatmnt, dos titation should b managd on th basis of th patint s clinical spons (s ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). PAROXETINE Tatmnt Duing Pgnancy Effcts on Nwbons Epidmiological studis of pgnancy outcoms following matnal xposu to antidpssants in th fist timst hav potd an incas in th isk of congnital malfomations, paticulaly cadiovascula (.g. vnticula and atial sptal dfcts), associatd with th us of paoxtin. If a patint bcoms pgnant whil taking PAROXETINE considation should b givn to switching to oth tatmnt options. Tatmnt with PAROXETINE should only b continud fo an individual pgnant patint, if th potntial bnfits outwigh th potntial isks. Initiation of paoxtin, fo womn who intnd to bcom pgnant, o a in thi fist timst of pgnancy, should b considd only aft oth tatmnt options hav bn valuatd (s WARNINGS AND PRECAUTIONS, Spcial Populations) Pag 6 of 51

7 Post-makting pots indicat that som nonats xposd to paoxtin, SSRIs (Slctiv Sotonin Ruptak Inhibitos), o oth nw antidpssants lat in th thid timst hav dvlopd complications quiing polongd hospitalization, spiatoy suppot, and tub fding. Such complications can ais immdiatly upon dlivy. Whn tating a pgnant woman with PAROXETINE duing th thid timst, th physician should cafully consid th potntial isks and bnfits of tatmnt (s WARNINGS AND PRECAUTIONS, Spcial Populations and DOSAGE AND ADMINISTRATION, Spcial Patint Populations-Tatmnt of Pgnant Womn Duing th Thid Timst). Potntial fo ducd fficacy of Tamoxifn with concomitant SSRI us, including Paoxtin Th antitumo agnt tamoxifn is a po-dug quiing mtabolic activation by CYP2D6. Inhibition of CYP2D6 can lad to ducd plasma concntations of a pimay activ mtabolit (ndoxifn). Chonic us of CYP2D6 inhibitos, including ctain SSRIs, togth with tamoxifn can lad to psistnt duction in lvls of ndoxifn (s also DRUG INTERACTIONS, Tamoxifn). Som studis hav shown that th fficacy of tamoxifn, as masud by th isk of bast canc laps/motality, may b ducd whn copscibd with paoxtin as a sult of paoxtin s ivsibl inhibition of CYP2D6. This isk may incas with long duation of coadministation. Whn tamoxifn is usd fo th tatmnt of bast canc, pscibs should consid using an altnativ antidpssant with littl o no CYP2D6 inhibition. Psychomoto Impaimnt Although paoxtin did not caus sdation o intf with psychomoto pfomanc in placbo-contolld studis in nomal subjcts, patints should b advisd to avoid diving a ca o opating hazadous machiny until thy a asonably ctain that PAROXETINE dos not affct thm advsly. Bon Factu Risk Epidmiological studis show an incasd isk of bon factus following xposu to som antidpssants, including SSRIs. Th isks appa to b gat at th initial stags of tatmnt, but significant incasd isks w also obsvd at lat stags of tatmnt. Th possibility of factu should b considd in th ca of patints tatd with Paoxtin. Eldly patints and patints with impotant isk factos fo bon factus should b advisd of possibl advs vnts which incas th isk of falls, such as dizzinss and othostatic hypotnsion, spcially at th aly stags of tatmnt but also soon aft withdawal. Pliminay data fom obsvational studis show association of SSRIs and low bon minal dnsity in old mn and womn. Until futh infomation bcoms availabl, a possibl ffct on bon minal dnsity with long-tm tatmnt with SSRIs, including paoxtin, cannot b xcludd, and may b a potntial concn fo patints with ostopoosis o majo isk factos fo bon factus. Th following additional pcautions a listd alphabtically. Cacinognsis and Mutagnsis S TOXICOLOGY fo animal data. Cadiovascula Paoxtin has not bn valuatd o usd to any appciabl xtnt in patints with a cnt histoy of myocadial infaction o unstabl hat disas. Th usual pcautions should b obsvd in patints with cadiac conditions. Pag 7 of 51

8 Concomitant Illnsss Clinical xpinc with paoxtin in patints with ctain concomitant systmic illnsss is limitd. Caution is advisabl in using PAROXETINE in patints with disass o conditions that could affct mtabolism o hmodynamic sponss. Dpndnc Liability Paoxtin has not bn systmatically studid, in animals o humans, fo its potntial fo abus, tolanc, o physical dpndnc. Physicians should cafully valuat patints fo histoy of dug abus and follow such patints closly, obsving thm fo signs of misus o abus of PAROXETINE. Endocin and Mtabolism Sum Cholstol Elvation: Sval public domain studis hav shown incasd LDL-cholstol lvls of ~10% in volunts and patints taking paoxtin fo 8 to 12 wks, which gnally nomalizd aft paoxtin discontinuation. In addition, of th patints in placbo-contolld clinical tials fo whom baslin and on-tatmnt masumnts w takn, total sum lvls of cholstol showd a man incas of ~1.5 mg/dl in paoxtin-tatd patints (n = 653), compad to a man dcas of ~ 5.0 mg/dl in placbo-tatd patints (n = 379). Incass fom baslin of 45 mg/dl o gat w codd in 6.6% of paoxtin-tatd patints compad to 2.6% of placbo-tatd patints (s Monitoing and Laboatoy Tsts, Sum Cholstol Elvation). Ths data should b takn into considation whn tating patints with undlying cadiac isk factos. Hmatologic Abnomal Blding: SSRIs including PAROXETINE may incas th isk of blding vnts by causing abnomal platlt agggation. Concomitant us of actylsalicylic acid (ASA), nonstoidal anti-inflammatoy dugs (NSAIDs), wafain and oth anticoagulants may add to th isk. Cas pots and pidmiological studis (cas-contol and cohot dsign) hav dmonstatd an association btwn us of dugs that intf with sotonin uptak and th occunc of gastointstinal blding. Blding vnts latd to SSRIs us hav angd fom cchymoss, hmatomas, pistaxis, and ptchia to lif-thatning hamohags. Gastointstinal and gynacological blding hav also bn potd following tatmnt with paoxtin. Patints should b cautiond about th isk of blding associatd with th concomitant us of PAROXETINE and NSAIDs, ASA, o oth dugs that affct coagulation (s DRUG INTERACTIONS, Dugs Affcting Platlt Function). Caution is advisd in patints with a histoy of blding disod o pdisposing conditions (.g. thombocytopnia) (s ADVERSE REACTIONS). Hpatic/Biliay/Pancatic Hpatic Impaimnt: Phamacokintic studis of paoxtin in subjcts with clinically significant hpatic impaimnt suggst that polongation of th limination half-lif and incasd plasma lvls can b xpctd in this patint goup. PAROXETINE should b usd with caution and dosags stictd to th low nd of th ang in patints with clinically significant hpatic impaimnt (s DOSAGE AND ADMINISTRATION, Spcial Patint Populations and ACTIONS AND CLINICAL PHARMACOLOGY, Hpatic Insufficincy). Pag 8 of 51

9 Nuologic Epilpsy: As with oth antidpssants, PAROXETINE should b usd with caution in patints with pilpsy. Sizus: Duing clinical tials, th ovall incidnc of sizus was 0.15% in patints tatd with paoxtin. Howv, patints with a histoy of convulsiv disods w xcludd fom ths studis. Caution is commndd whn th dug is administd to patints with a histoy of sizus. Th dug should b discontinud in any patint who dvlops sizus. Sotonin Syndom/Nuolptic Malignant Syndom: On a occasions sotonin syndom o nuolptic malignant syndom-lik vnts hav occud in association with tatmnt of paoxtin, paticulaly whn givn in combination with oth sotongic and/o nuolptic/antipsychotic dugs. As ths syndoms may sult in potntially lif-thatning conditions, tatmnt with PAROXETINE should b discontinud if patints dvlop a combination of symptoms possibly including hypthmia, igidity, myoclonus, autonomic instability with possibl apid fluctuations of vital signs, mntal status changs including confusion, iitability, xtm agitation pogssing to dliium and coma, and suppotiv symptomatic tatmnt should b initiatd. Du to th isk of sotongic syndom o nuolptic malignant syndom PAROXETINE should not b usd in combination with MAO inhibitos [including linzolid, an antibiotic which is a vsibl non-slctiv MAO inhibito and mthylthioninium chloid (mthyln blu)] o sotonin pcusos (such as L-typtophan, oxitiptan) and should b usd with caution in patints civing oth sotongic dugs (.g., tiptans, lithium, tamadol, St. John s Wot, most ticyclic antidpssants) o nuolptics/antipsychotics (s CONTRAINDICATIONS and DRUG INTERACTIONS). Ophthalmologic Angl-Closu Glaucoma: As with oth antidpssants, paoxtin can caus mydiasis which may tigg an angl-closu attack in a patint with anatomically naow ocula angls. Caution should b usd whn paoxtin is pscibd fo patints with untatd naow angls. Opnangl glaucoma is not a isk facto fo angl-closu glaucoma. Patints should b infomd to sk immdiat mdical assistanc if thy xpinc y pain, changs in vision o swlling o dnss in o aound th y. Psychiatic Suicid: Th possibility of a suicid attmpt is inhnt in dpssion and may psist until mission occus. Patints with dpssion may xpinc wosning of thi dpssiv symptoms and/o th mgnc of suicidal idation and bhavious (suicidality) whth o not thy a taking antidpssant mdications. Notwithstanding, high isk patints should b closly supvisd thoughout thapy with appopiat considation to th possibl nd fo hospitalization. In od to minimiz th oppotunity fo ovdosag, psciptions fo PAROXETINE should b wittn fo th smallst quantity of dug consistnt with good patint managmnt. Bcaus of th wll stablishd comobidity btwn dpssion and oth psychiatic disods, th sam pcautions obsvd whn tating patints with dpssion should b obsvd whn tating patints with oth psychiatic disods (s WARNINGS AND PRECAUTIONS, Potntial Association with Bhavioual and Emotional Changs, Including Slf-Ham). Pag 9 of 51

10 Activation of Mania/Hypomania: Duing clinical tsting in a patint population compisd pimaily of unipola dpssd patints, appoximatly 1% of paoxtin-tatd patints xpincd manic actions. Whn bipola patints w considd as a sub-goup th incidnc of mania was 2%. As with all dugs ffctiv in th tatmnt of dpssion, PAROXETINE should b usd with caution in patints with a histoy of mania. A majo dpssiv pisod may b th initial psntation of bipola disod. Patints with bipola disod may b at an incasd isk of xpincing manic pisods whn tatd with antidpssants alon. Thfo, th dcision to initiat symptomatic tatmnt of dpssion should only b mad aft patints hav bn adquatly assssd to dtmin if thy a at isk fo bipola disod. Elctoconvulsiv Thapy (ECT): Th fficacy and safty of th concunt us of PAROXETINE and ECT hav not bn studid. Rnal Hyponatmia: Sval cass of hyponatmia hav bn potd. Th hyponatmia appad to b vsibl whn paoxtin was discontinud. Th majoity of ths occuncs hav bn in ldly individuals, som in patints taking diutics o who w othwis volum dpltd. Rnal Impaimnt: Sinc PAROXETINE is xtnsivly mtabolizd by th liv xction of unchangd dug in uin is a mino out of limination. Howv, singl dos phamacokintic studis in subjcts with clinically significant nal impaimnt suggst that plasma lvls of paoxtin a lvatd in such subjcts. Paoxtin should thfo b usd with caution and th dosag stictd to th low nd of th ang in patints with clinically significant nal impaimnt (s DOSAGE AND ADMINISTRATION, Spcial Patint Populations; ACTIONS AND CLINICAL PHARMACOLOGY, Rnal Insufficincy). Sxual Function/Rpoduction Som clinical studis hav shown that SSRIs (including paoxtin) may affct spm quality. This ffct appas to b vsibl following discontinuation of tatmnt. Changs in spm quality may affct ftility in som mn (s also Pat II: TOXICOLOGY, Rpoduction and Impaimnt of Ftility Studis). Spcial Populations Pgnant Womn and Nwbons: Risk of Cadiovascula Malfomations following fist timst xposu to SSRIs: Epidmiological studis of pgnancy outcoms following matnal xposu to antidpssants in th fist timst hav potd an incas in th isk of congnital malfomations, paticulaly cadiovascula (.g. vnticula and atial sptal dfcts), associatd with th us of paoxtin. Th data suggst that th isk of having an infant with a cadiovascula dfct following matnal paoxtin xposu is appoximatly 1/50 (2%), compad with an xpctd at fo such dfcts of appoximatly 1/100 (1%) infants in th gnal population. In gnal, sptal dfcts ang fom thos that a symptomatic and may qui sugy, to thos that a asymptomatic and may solv spontanously. Infomation about th svity of th sptal dfcts potd in th studis is not availabl. Whil on PAROXETINE: Pgnancy, o intnt to bcom pgnant: If a patint bcoms pgnant whil taking PAROXETINE, o intnds to bcom pgnant, sh should b infomd of th cunt stimat of incasd isk to th ftus with PAROXETINE ov oth antidpssants. Examinations of additional databass, as wll as updatd analyss, may Pag 10 of 51

11 sult in changs to th cunt isk stimats. Considation should b givn to switching to oth tatmnt options, including anoth antidpssant o non-phamacutical tatmnt such as cognitiv bhavioal thapy. Tatmnt with PAROXETINE should only b continud fo an individual patint, if th potntial bnfits outwigh th potntial isks. Du to th potntial fo discontinuation symptoms, if a dcision is takn to discontinu PAROXETINE tatmnt, a gadual duction in th dos ath than an abupt cssation is commndd (s WARNINGS AND PRECAUTIONS, Discontinuation of Tatmnt With PAROXETINE, ADVERSE REACTIONS, Advs Ractions Following Discontinuation of Tatmnt and DOSAGE AND ADMINISTRATION, Discontinuation of Tatmnt). Initiation of paoxtin: Fo womn who intnd to bcom pgnant, o a in thi fist timst of pgnancy, initiation of paoxtin should b considd only aft oth tatmnt options hav bn valuatd. Complications following lat thid timst xposu to SSRIs: Post-makting pots indicat that som nonats xposd to paoxtin, SSRIs (Slctiv Sotonin Ruptak Inhibitos), o oth nw antidpssants lat in th thid timst hav dvlopd complications quiing polongd hospitalization, spiatoy suppot, and tub fding. Such complications can ais immdiatly upon dlivy. Rpotd clinical findings hav includd spiatoy distss, cyanosis, apna, sizus, tmpatu instability, fding difficulty, vomiting, hypoglycmia, hypotonia, hyptonia, hypflxia, tmo, jittinss, iitability, and constant cying. Ths fatus a consistnt with ith a dict toxic ffct of SSRIs and oth nw antidpssants, o, possibly, a dug discontinuation syndom. It should b notd that, in som cass, th clinical pictu is consistnt with sotonin syndom (s WARNINGS AND PRECAUTIONS, Nuologic-Sotonin Syndom/Nuolptic Malignant Syndom). Whn tating a pgnant woman with PAROXETINE duing th thid timst, th physician should cafully consid th potntial isks and bnfits of tatmnt (s DOSAGE AND ADMINISTRATION, Spcial Patint Populations-Tatmnt of Pgnant Womn Duing th Thid Timst). Risk of PPHN and xposu to SSRIs (including paoxtin): Epidmiological studis on psistnt pulmonay hyptnsion of th nwbon (PPHN) hav shown that th us of SSRIs (including paoxtin) in pgnancy, paticulaly us in lat pgnancy, was associatd with an incasd isk of PPHN. PPHN occus in 1 to 2 p 1000 liv biths in th gnal population and is associatd with substantial nonatal mobidity and motality. In a tospctiv cas-contol study of 377 womn whos infants w bon with PPHN and 836 womn whos infants w bon halthy, th isk fo dvloping PPHN was appoximatly six-fold high fo infants xposd to SSRIs aft th 20th wk of gstation compad to infants who had not bn xposd to antidpssants duing pgnancy (Odds Ratio 6.1, 95% CI 2.2 to 16.8). A study using data fom th Swdish Mdical Bith Rgist fo 831,324 infants bon in 1997 to 2005 found an incasd isk of PPHN of appoximatly 2-fold associatd with patint-potd matnal us of SSRIs in th fist timst of pgnancy (Risk Ratio 2.4, 95% CI 1.2 to 4.3), and an incasd isk of PPHN of appoximatly 4-fold associatd with a combination of patint-potd matnal us of SSRIs in th fist timst and an antnatal SSRI psciption in lat pgnancy (Risk Ratio 3.6, 95% CI 1.2 to 8.3). Nusing Womn: Th concntations of paoxtin dtctd in th bast milk of lactating womn a simila to thos in th moth s plasma. Lactating womn should not nus thi infants whil civing paoxtin unlss in th opinion of th tating physician, bast fding is ncssay, in which cas th infant should b closly monitod. Pag 11 of 51

12 Pdiatics (< 18 yas of ag): PAROXETINE is not indicatd fo us in patints blow th ag of 18 yas (s WARNINGS AND PRECAUTIONS, Potntial Association with Bhavioual and Emotional Changs, Including Slf Ham). (S also INDICATIONS, Pdiatics and DOSAGE AND ADMINISTRATION, Spcial Patint Populations-Childn). Contolld clinical studis in dpssion faild to dmonstat fficacy and do not suppot th us of paoxtin in th tatmnt of childn und th ag of 18 yas with dpssion. Moov, a high incidnc of advs vnts latd to bhavioal and motional changs, including slf ham, was potd with paoxtin tatmnt compad to placbo duing contolld clinical tials in dpssion, OCD and social anxity disod (s ADVERSE DRUG REACTIONS, Clinical Tial Advs Dug Ractions-Pdiatics). Giatics ( 65 yas of ag): Administation of paoxtin to th ldly is associatd with incasd plasma lvls and polongation of th limination half lif lativ to young adults (s ACTION AND CLINICAL PHARMACOLOGY). Eldly patints should b initiatd and maintaind at th lowst daily dos of paoxtin which is associatd with clinical fficacy (s DOSAGE AND ADMINISTRATION). Evaluation of appoximatly 800 ldly patints ( 65 yas) tatd with paoxtin (10 to 40 mg daily) in woldwid pmakting clinical tials vald no unusual pattn of advs vnts lativ to th clinical xpinc in young patints. Howv, it is not possibl to ul out potntial ag-latd diffncs in safty and ffctivnss duing chonic us, paticulaly in ldly patints who hav concomitant systmic illnsss o who a civing concomitant dugs. Monitoing and Laboatoy Tsts Sum Cholstol Elvation: Of th patints in placbo-contolld clinical tials fo whom baslin and on-tatmnt masumnts w takn, incass fom baslin of 45 mg/dl o gat w codd in 6.6% of paoxtin-tatd patints compad to 2.6% of placbotatd patints (s ADVERSE REACTIONS, Laboatoy Changs-Cholstol and WARNINGS AND PRECAUTIONS, Endocin and Mtabolism). Ths data should b takn into considation whn tating patints with undlying cadiac isk factos. ADVERSE REACTIONS Advs Dug Raction Ovviw Commonly Obsvd Advs Evnts: Th most commonly obsvd advs xpincs associatd with th us of paoxtin in clinical tials and not sn at an quivalnt incidnc among placbo-tatd patints w: nausa, somnolnc, swating, tmo, asthnia, dizzinss, dy mouth, insomnia, constipation, diaha, dcasd apptit and mal sxual dysfunction (s Tabls 1 and 2). Advs Evnts Lading to Discontinuation of Tatmnt: Twnty-on pcnt of ov 4000 patints who civd paoxtin in woldwid clinical tials in dpssion discontinud tatmnt du to an advs xpinc. In obsssiv-compulsiv disod, panic disod, social phobia (social anxity disod), gnalizd anxity disod and posttaumatic stss disod studis, 11.8% (64/542), 9.4 % (44/469), 16.1% (84/522) 10.7% (79/735) and 11.7% (79/676), spctivly, of patints tatd with paoxtin discontinud tatmnt bcaus of advs vnts. Th most common vnts lading to discontinuation Pag 12 of 51

13 (potd by 1% o mo of subjcts) includd: asthnia, hadach, nausa, somnolnc, insomnia, agitation, tmo, dizzinss, constipation, impotnc, abnomal jaculation, swating and diaha. Advs Evnts following Discontinuation of Tatmnt (o Dos Rduction) Clinical Tials Th following advs vnts hav bn potd at an incidnc of 2% o gat fo paoxtin and w at last twic that potd fo placbo: abnomal dams (2.3% vs 0.5%), pasthsias (2.0% vs 0.4%), and dizzinss (7.1% vs 1.5%). Th majoity of ths vnts w mild to modat, slf-limiting and did not qui mdical intvntion. Ths advs vnts w notd in GAD and PTSD clinical tials mploying a tap phas gimn fo discontinuation of tatmnt. This gimn involvd an incmntal dcas in th daily dos by 10 mg/day at wkly intvals. Whn a daily dos of 20 mg/day was achd, patints w continud on this dos fo 1 wk bfo tatmnt was stoppd. Post-Makting Th hav bn spontanous pots of advs vnts upon th discontinuation of paoxtin (paticulaly whn abupt), including but not limitd to th following: dizzinss, snsoy distubancs (including pasthsias, lctic shock snsations and tinnitus), agitation/stlssnss, anxity, nausa, tmo, confusion, diaha, vomiting, swating, hadach, and slp distubancs (abnomal dams). Gnally ths symptoms a mild to modat, howv, in som patints thy may b sv in intnsity. Thy usually occu within th fist fw days of discontinuing tatmnt, but th hav bn vy a pots of such symptoms in patints who hav inadvtntly missd a dos. Gnally ths symptoms a slflimiting and usually solv within 2 wks, though in som individuals thy may b polongd (2 to 3 months o mo). Symptoms associatd with discontinuation hav bn potd fo oth slctiv sotonin uptak inhibitos. Patints should b monitod fo ths o any oth symptoms whn discontinuing tatmnt, gadlss of th indication fo which PAROXETINE is bing pscibd. If intolabl symptoms occu following a dcas in th dos o upon discontinuation of tatmnt, dos titation should b managd on th basis of th patint s clinical spons (s WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION). Clinical Tial Advs Dug Ractions Bcaus clinical tials a conductd und vy spcific conditions th advs action ats obsvd in th clinical tials may not flct th ats obsvd in pactic and should not b compad to th ats in th clinical tials of anoth dug. Advs dug action infomation fom clinical tials is usful fo idntifying dug-latd advs vnts and fo appoximating ats. Pag 13 of 51

14 Incidnc in Contolld Clinical Tials Adults Multipl doss of paoxtin w administd to 4126 subjcts in clinical tials fo dpssion, 542 subjcts in clinical tials fo OCD, 469 subjcts in clinical tials fo panic disod, 522 subjcts in clinical tials fo social phobia (social anxity disod), 735 subjcts in clinical tials fo gnalizd anxity disod and 676 subjcts in clinical tials fo posttaumatic stss disod. Untowad xpincs associatd with this xposu w codd by clinical invstigatos using dsciptiv tminology of thi own choosing. Consquntly, it is not possibl to povid a maningful stimat of th popotion of individuals xpincing advs xpincs without fist gouping simila typs of untowad xpincs into a limitd (i.. ducd) numb of standadizd xpinc catgois. Tabl 1 lists advs xpincs that occud at an incidnc of 1% o high in shot tm (6- wk) flxibl dos (20 to 50 mg/day) placbo-contolld tials in dpssion. (An additional 460 patints paticipatd in a fixd-dos placbo-contolld study). Tabl 2 numats advs vnts that occud at a fquncy of 2% o mo among patints on paoxtin who paticipatd in placbo-contolld OCD tials of 12-wks duation in which patints w dosd in th ang of 20 to 60 mg/day, in placbo-contolld panic disod tials of 10 to 12 wks duation in which patints w dosd in th ang of 10 to 60 mg/day, in placbocontolld social phobia (social anxity disod) tials of 12 wks duation in which patints w dosd in a ang of 20 to 50 mg/day, in placbo-contolld gnalizd anxity disod tials of 8 wks in which patints w dosd in a ang fom 10 to 50 mg/day and in placbo-contolld posttaumatic stss disod tials of 12 wks in which patints w dosd in a ang fom 20 to 50 mg/day. Th pscib should b awa that ths figus cannot b usd to pdict th incidnc of sid ffcts in th cous of usual mdical pactic wh patint chaactistics and oth factos diff fom thos which pvaild in th clinical tials. Similaly th citd incidncs cannot b compad with figus obtaind fom oth clinical invstigations involving diffnt tatmnts, uss and invstigatos. Th citd fquncis do howv povid th pscibing physician with som basis fo stimating th lativ contibution of dug and non-dug factos to th sid ffct incidnc at in th population studid. Rpotd advs xpincs w classifid using a COSTART-basd dictionay tminology fo th dpssion tials and an ADECS (a modifid COSTART dictionay) fo OCD and panic disod tials. Pag 14 of 51

15 Tabl 1 Tatmnt-Emgnt Advs Evnts in Shot Tm Flxibl Dos Placbo-Contolld Clinical Tials in Dpssion 1 Body Systm Pfd Tm Paoxtin (n=421) Placbo (n=421) Body as a Whol Hadach 17.6% 17.3% Asthnia 15.0% 5.9% Abdominal Pain 3.1% 4.0% Fv 1.7% 1.7% Chst Pain 1.4% 2.1% Tauma 1.4% 0.5% Back Pain 1.2% 2.4% Cadiovascula Palpitation 2.9% 1.4% Vasodilation 2.6% 0.7% Postual Hypotnsion 1.2% 0.5% Dmatological Swating 11.2% 2.4% Rash 1.7% 0.7% Gastointstinal Nausa 25.7% 9.3% Dy Mouth 18.1% 12.1% Constipation 13.8% 8.6% Diaha 11.6% 7.6% Dcasd Apptit 6.4% 1.9% Flatulnc 4.0% 1.7% Vomiting 2.4% 1.7% Oophaynx Disod 2 2.1% 0.0% Dysppsia 1.9% 1.0% Incasd Apptit 1.4% 0.5% Musculoskltal Myopathy 2.4% 1.4% Myalgia 1.7% 0.7% Myasthnia 1.4% 0.2% Nvous Systm Somnolnc 23.3% 9.0% Dizzinss 13.3% 5.5% Insomnia 13.3% 6.2% Tmo 8.3% 1.9% Nvousnss 5.2% 2.6% Anxity 5.0% 2.9% Paasthsia 3.8% 1.7% Libido Dcasd 3.3% 0.0% Agitation 2.1% 1.9% Duggd Fling 1.7% 0.7% Myoclonus 1.4% 0.7% CNS Stimulation 1.2% 3.6% Confusion 1.2% 0.2% Rspiation Rspiatoy Disod 3 5.9% 6.4% Yawn 3.8% 0.0% Phayngitis 2.1% 2.9% Spcial Snss Blud Vision 3.6% 1.4% Tast Pvsion 2.4% 0.2% Uognital Systm *Abnomal Ejaculation % 0.0% *Mal Gnital Disods 4 8.0% 0.0% Uinay Fquncy 3.1% 0.7% Uination Impaid 5 2.9% 0.2% *Impotnc 2.5% 0.5% *Fmal Gnital Disods 6 1.8% 0.0% 1 Evnts potd by at last 1% of patints tatd with paoxtin a includd. * Pcntag coctd fo gnd Placbo: mal, n=206 fmal, n=215 Paoxtin: mal, n=201 fmal, n=220 + Pimaily jaculatoy dlay. In a tial of fixd doss of paoxtin, th incidnc of jaculatoy distubanc in mals with 20 mg p day of paoxtin was 6.5% (3/46) vsus 0% (0/23) in th placbo goup. 2 Includs mostly lump in thoat and tightnss in thoat 3 Includs mostly cold symptoms o URI 4 Includs anogasmia, ctil difficultis, dlayd jaculation/ogasm, sxual dysfunction and impotnc 5 Includs difficulty with mictuition and uinay hsitancy 6 Includs anogasmia and difficulty aching climax/ogasm Pag 15 of 51

16 Tabl 2 Tatmnt-Emgnt Advs Expinc Incidnc in Placbo-Contolld Clinical Tials fo Obsssiv-Compulsiv Disod, Panic Disod, Social Phobia (Social Anxity Disod), Gnalizd Anxity Disod and Posttaumatic Stss Disod. 1 Obsssiv- Compulsiv Disod Body Systm Pfd Tm Paoxtin (n=542) Placbo (n=265) Panic Disod Paoxtin (n=469) Placbo (n=324) Social Phobia (Social Anxity Disod) Paoxtin (n=425) Placbo (n=339) Gnalizd Anxity Disod Paoxtin (n=735) Placbo (n=529) Posttaumatic Stss Disod Paoxtin (n=676) Placbo (n=504) Body as a Whol Hadach 25.3% 29.1% 25.4% 25.3% 22.4% 21.8% 16.9% 14.0% 18.9% 19.2% Asthnia 21.8% 13.6% 13.6% 4.6% 22.4% 13.6% 14.3% 6.4% 11.8% 4.2% Infction 5.4% 4.9% 5.3% 6.8% 3.8% 5.9% 5.6% 3.4% 4.9% 3.8% Abdominal Pain 4.8% 4.9% 4.3% 3.1% 2.1% 4.7% 4.5% 3.6% 4.3% 3.2% Chst Pain 2.8% 1.9% 2.3% 3.1% 0.7% 0.3% 1.0% 0.6% 1.2% 0.8% Back Pain 2.4% 4.9% 3.2% 2.2% 1.6% 4.1% 2.3% 3.6% 3.4% 3.4% Chills 2.0% 0.8% 2.3% 0.6% 0.2% 0.3% 1.0% 0.0% 0.1% 0.4% Tauma 3.1% 3.8% 3.6% 3.7% 2.6% 0.9% 2.6% 3.4% 5.8% 5.2% Cadiovascula Vasodilation 3.9% 1.1% 2.1% 2.8% 1.4% 0.6% 2.7% 0.8% 2.2% 1.2% Palpitation 2.0% 0.4% 2.3% 2.5% 1.2% 1.8% 1.1% 1.1% 1.0% 0.8% Dmatologic Swating 8.9% 3.0% 14.3% 5.9% 9.2% 2.1% 6.3% 1.5% 4.6% 1.4% Rash 3.1% 1.9% 2.3% 1.5% 0.7% 0.3% 1.5% 0.9% 1.5% 2.0% Gastointstinal Nausa 23.2% 9.8% 22.8% 17.3% 24.7% 6.5% 20.1% 5.3% 19.2% 8.3% Dy Mouth 18.1% 8.7% 18.1% 10.8% 8.9% 2.9% 10.9% 4.7% 10.1% 4.8% Constipation 15.7% 6.4% 7.9% 5.2% 5.4% 1.8% 10.5% 1.7% 5.5% 3.4% Diaha 10.3% 9.8% 11.7% 6.5% 8.5% 5.9% 9.1% 6.6% 10.5% 5.4% Dcasd Apptit 9.0% 3.4% 7.0% 2.8% 7.8% 1.5% 5.2% 1.1% 5.9% 2.6% Dysppsia 3.9% 6.8% 3.8% 6.8% 4.0% 2.4% 4.5% 4.9% 4.6% 3.4% Flatulnc 3.0% 4.2% 1.7% 2.8% 4.0% 2.4% 1.4% 2.1% 1.0% 1.0% Incasd Apptit 4.2% 3.0% 2.1% 0.6% 1.2% 1.8% 0.4% 1.1% 1.5% 1.0% Vomiting 2.2% 3.4% 1.9% 1.5% 2.4% 0.6% 2.7% 2.5% 3.0% 2.0% Musculoskltal Myalgia 3.1% 3.8% 2.3% 3.4% 4.0% 2.7% 2.9% 2.6% 1.8% 1.8% Nvous Systm Somnolnc 24.4% 7.2% 18.8% 10.8% 21.6% 5.3% 15.4% 4.5% 16.0% 4.6% Insomnia 23.8% 13.2% 17.9% 10.2% 20.9% 15.9% 10.7% 7.9% 11.8% 11.3% Dizzinss 12.4% 6.0% 14.1% 9.9% 11.3% 7.1% 6.1% 4.5% 6.1% 4.6% Tmo 10.5% 1.1% 8.5% 1.2% 8.7% 1.2% 4.6% 0.8% 4.3% 1.4% Nvousnss 8.5% 8.3% 7.9% 8.3% 7.5% 6.5% 3.9% 2.8% 3.0% 4.4% Libido Dcasd 7.2% 3.8% 8.5% 1.2% 11.5% 0.9% 9.4% 1.5% 5.2% 1.8% Anxity 4.1% 6.8% 4.5% 4.0% 4.7% 4.1% 1.6% 0.9% 3.8% 4.0% Abnomal Dams 3.9% 1.1% 2.8% 3.4% 1.9% 1.5% 0.5% 1.1% 2.5% 1.6% Myoclonus 3.3% 0.4% 3.2% 1.5% 2.1% 0.9% 1.6% 0.6% 1.0% 0.6% Concntation Impaid 2.8% 1.5% 1.1% 0.9% 3.5% 0.6% 1.1% 0.6% 1.5% 1.0% Dpsonalization 2.6% 0.4% 1.7% 2.2% 0.7% 0.9% 0.7% 0.0% 0.9% 0.2% Amnsia 2.2% 1.1% 0.6% 0.0% 0.5% 0.3% 0.4% 0.6% 1.3% 1.0% Hypkinsia 2.2% 1.5% 0.9% 0.9% 1.2% 0.0% 0.8% 0.0% 1.3% 0.2% Agitation 1.7% 2.3% 4.7% 3.7% 2.6% 0.9% 1.8% 1.1% 1.9% 3.2% Rspiatoy Phayngitis 3.7% 4.9% 3.2% 3.1% 3.8% 2.1% 2.3% 2.1% 2.4% 2.2% Systm Rhinitis 1.5% 3.4% 2.6% 0.3% 1.2% 3.2% 1.5% 1.1% 1.0% 2.0% Sinusitis 1.5% 4.9% 5.8% 4.6% 2.1% 2.4% 3.5% 3.4% 3.8% 4.4% Yawn 1.7% 0.4% 1.9% 0.0% 4.9% 0.3% 4.2% 0.2% 2.1% 0.2% Cough Incasd 1.1% 1.9% 2.3% 1.5% 0.7% 0.9% 0.8% 0.8% 1.2% 0.6% Rspiatoy Disod % 5.1% 3.3% 1.0% Spcial Snss Abnomal Vision 3.7% 2.3% 3.0% 2.8% 4.0% 0.3% 2.2% 0.6% 0.3% 0.0% Tast Pvsion 2.0% 0.0% 1.1% 0.6% 0.7% 0.6% 0.7% 0.8% 0.7% 0.8% Pag 16 of 51

17 Tabl 2 (cont d) Tatmnt-Emgnt Advs Expinc Incidnc in Placbo-Contolld Clinical Tials fo Obsssiv-Compulsiv Disod, Panic Disod, Social Phobia (Social Anxity Disod), Gnalizd Anxity Disod and Posttaumatic Stss Disod. 1 Obsssiv- Compulsiv Disod Body Systm Pfd Tm Paoxtin (n=542) Uognital Systm Placbo (n=265) Panic Disod Paoxtin (n=469) Placbo (n=324) Social Phobia (Social Anxity Disod) Paoxtin (n=425) Placbo (n=339) Gnalizd Anxity Disod Paoxtin (n=735) Placbo (n=529) Posttaumatic Stss Disod Paoxtin (n=676) Placbo (n=504) Abnomal Ejaculation % 1.3% 20.5% 0.9% 27.6% 1.1% 24.7% 2.0% 12.6% 1.6% Dysmnoha 2 1.4% 1.9% 2.0% 2.3% 4.6% 4.4% 1.3% 1.2% 1.6% 1.3% Impotnc 2 8.2% 1.3% 5.4% 0.0% 5.3% 1.1% 4.2% 3.0% 9.2% 0.5% Fmal Gnital Disod 2,3 3.3% 0.0% 8.9% 0.5% 8.6% 0.6% 4.4% 0.6% 4.8% 0.6% Uinay Fquncy 3.3% 1.1% 2.1% 0.3% 1.6% 1.8% 1.0% 0.6% 1.0% 0.2% Uination Impaid 3.3% 0.4% 0.4% 0.3% 1.9% 0.0% 1.0% 0.0% 0.6% 0.0% Uinay Tact Infction 1.5% 1.1% 2.1% 1.2% 0.2% 1.2% 1.2% 1.1% 0.6% 0.8% 1. Evnts potd by at last 2% of ith OCD, Panic Disod, Social Phobia (Social Anxity Disod), Gnalizd Anxity Disod o Posttaumatic Stss Disod paoxtin-tatd patints a includd, xcpt th following vnts which had an incidnc on placbo paoxtin: [OCD]: dpssion, paasthsia, and spiatoy disod. [Panic Disod]: flu syndom, dpssion, paasthsia, spiatoy disod. [Social Phobia (Social Anxity Disod)]: dpssion, spiatoy disod. [Gnalizd Anxity Disod]: not applicabl, [Posttaumatic Stss Disod]: dpssion, spiatoy disod 2. Incidnc is gnd-coctd. OCD: Placbo: mal, n=158; fmal, n=107 Paoxtin: mal, n=330; fmal, n= Includs anogasmia and difficulty aching climax/ogasm PANIC: Placbo: mal, n=111; fmal, n=213 Paoxtin: mal, n=166; fmal, n=303 SOCIAL PHOBIA: Placbo: mal, n=180; fmal, n=159 (SOCIAL ANXIETY DISORDER) Paoxtin: mal, n=228; fmal, n=197 GENERALIZED ANXIETY DISORDER: Placbo: mal, n=197; fmal, n=332 Paoxtin: mal, n=283; fmal, n=452 POSTTRAUMATIC STRESS DISORDER: Placbo: mal, n=190; fmal, n=314 Paoxtin: mal, n=238; fmal, n=438 Mal and Fmal Sxual Dysfunction With SSRIs: Although changs in sxual dsi, sxual pfomanc and sxual satisfaction oftn occu as manifstations of a psychiatic disod, thy may also b a consqunc of phamacologic tatmnt. In paticula, som vidnc suggsts that slctiv sotonin uptak inhibitos (SSRIs) can caus such untowad sxual xpincs. Rliabl stimats of th incidnc and svity of untowad xpincs involving sxual dsi, pfomanc and satisfaction a difficult to obtain, howv, in pat bcaus patints and physicians may b luctant to discuss thm. Accodingly, stimats of th incidnc of untowad sxual xpinc and pfomanc citd in poduct labling a likly to undstimat thi actual incidnc. In placbo-contolld clinical tials involving mo than 3,200 patints, th angs fo th potd incidnc of sxual sid ffcts in mals and fmals with majo dpssiv disod, OCD, panic disod, social anxity disod, GAD and PTSD a displayd in Tabl 3 blow. Pag 17 of 51

18 Tabl 3 Incidnc of Sxual Advs Evnts in Contolld Clinical Tials Paoxtin Placbo n (mals) Dcasd Libido 6-15% 0-5% Ejaculatoy Distubanc 13-28% 0-2% Impotnc 2-9% 0-3 % n (fmals) Dcasd Libido 0-9% 0-2% Ogasmic Distubanc 2-9% 0-1% Th a no adquat and wll-contolld studis xamining sxual dysfunction with paoxtin tatmnt. Paoxtin tatmnt has bn associatd with sval cass of piapism. In thos cass with a known outcom, patints covd without squla. Whil it is difficult to know th pcis isk of sxual dysfunction associatd with th us of SSRIs, physicians should outinly inqui about such possibl sid ffcts. Laboatoy Changs - Cholstol Clinically and statistically lvant incass in cholstol lvls hav bn notd in studis using paoxtin (s WARNINGS AND PRECAUTIONS, Endocin and Mtabolism). Of th patints in placbo-contolld clinical tials fo whom baslin and on-tatmnt masumnts w takn, total sum lvls of cholstol showd a man incas of ~ 1.5 mg/dl in paoxtin-tatd patints (n = 653), compad to a man dcas of ~ 5.0 mg/dl in placbo-tatd patints (n = 379). Incass fom baslin of 45 mg/dl o gat w codd in 6.6% of paoxtin-tatd patints compad to 2.6% of placbo-tatd patints. Pdiatics In placbo-contolld clinical tials conductd with pdiatic patints agd 7 to 18 yas with dpssion, OCD and Social Anxity Disod (involving 633 patints tatd with paoxtin and 542 patints tatd with placbo), th following advs vnts w potd in at last 2% of pdiatic patints tatd with paoxtin and occud at a at at last twic that fo pdiatic patints civing placbo: motional lability (including slf-ham, suicidal thoughts, attmptd suicid, cying, and mood fluctuations), hostility, (pdominantly aggssion, oppositional bhaviou and ang) dcasd apptit, tmo, swating, hypkinsia, and agitation. In th pdiatic clinical tials in dpssion, OCD and Social Anxity Disod that includd a tap phas gimn (307 patints agd 7 to 18 yas tatd with paoxtin and 291 patints tatd with placbo), vnts potd upon discontinuation of tatmnt, which occud in at last 2% of patints who civd paoxtin and which occud at a at at last twic that of placbo, w: motional lability (including suicidal idation, suicid attmpt, mood changs, and tafulnss), nvousnss, dizzinss, nausa, and abdominal pain (s WARNINGS AND PRECAUTIONS, Discontinuation of Tatmnt With PAROXETINE). Oth Evnts Obsvd Duing th Clinical Dvlopmnt of Paoxtin In th tabulations which follow, a COSTART o modifid COSTART-basd dictionay tminology has bn usd to classify potd advs xpincs. Th fquncis psntd thfo psnt th potion of th 4126, 542, 469, 522, 735 and 676 paoxtin-xposd individuals in dpssion, OCD, panic, social phobia (social anxity disod), gnalizd anxity disod and Pag 18 of 51

19 posttaumatic stss disod tials, spctivly, who xpincd an vnt of th typ citd on at last on occasion whil civing paoxtin. Expincs a futh classifid within body systm catgois and numatd in od of dcasing fquncy using th following dfinitions: fqunt xpincs a dfind as thos occuing on on o mo occasion in at last 1/100 patints; infqunt advs xpincs a thos occuing in lss than 1/100 but at last 1/1000 patints; a xpincs a thos occuing in lss than 1/1000 patints. All advs xpincs a includd xcpt thos alady listd in Tabl 1 and Tabl 2, thos potd in tms so gnal as to b uninfomativ and thos xpincs fo which th dug caus was mot. It is impotant to mphasiz that although th xpincs potd did occu duing tatmnt with paoxtin, thy w not ncssaily causd by it. Body as a Whol Fqunt: Malais, pain. Infqunt: Allgic action, chills, fac dma, infction, moniliasis, nck pain, ovdos. Ra: Abnomal laboatoy valu, abscss, adngic syndom, cllulitis, chills and fv, cyst, hnia, intntional ovdos, nck igidity, plvic pain, pitonitis, substnal chst pain, spsis, ulc. Immun Systm Disods: Vy a w sv allgic actions (including anaphylactoid actions and angiodma). Cadiovascula Systm Fqunt: Hyptnsion, syncop, tachycadia. Infqunt: Badycadia, conduction abnomalitis, lctocadiogam abnomal, hypotnsion, migain, vnticula xtasystols. Ra: Angina pctois, ahythmia, atial ahythmia, atial fibillation, bundl banch block, cadiac disod, cbal ischmia, cbovascula accidnt, cbovascula disod, congstiv hat failu, xtasystols, low cadiac output, myocadial infact, myocadial ischmia, pallo, phlbitis, pulmonay mbolus, supavnticula xtasystols, thombosis, vaicos vin, vascula disod, vascula hadach. Dmatological Fqunt: Puitus. Infqunt: Acn, alopcia, dy skin, cchymosis, czma, fuunculosis, hps simplx, uticaia. Ra: Angiodma, contact dmatitis, ythma nodosum, xfoliativ dmatitis, hps zost, maculopapula ash, photosnsitivity, skin discolouation, skin ulc, skin hyptophy, swating dcasd. Vy a: sv cutanous advs actions (including ythma multifom, Stvns-Johnson syndom and toxic pidmal ncolysis). Endocin Ra: Diabts mllitus, ftility dcasd fmal, goit, hypthyoidism, hypothyoidism, thyoiditis. Gastointstinal Fqunt: Nausa and vomiting. Infqunt: Buxism, buccal cavity disods, dysphagia, uctation, gastontitis, gastointstinal flu, glossitis, incasd salivation, liv function tsts abnomal, mouth ulcation, vomiting and diaha, ctal hmohag. Ra: Aphthous stomatitis, bloody diaha, bulimia, cadiospasm, colitis, duodnitis, sophagitis, fcal impaction, fcal incontinnc, gastitis, gingivitis, hmatmsis, hpatitis, ilitis, ilus, jaundic, mlna, pptic ulc, salivay gland nlagmnt, sialadnitis, stomach ulc, stomatitis, tongu dma, tooth cais. Pag 19 of 51

20 Hmatologic and Lymphatic Infqunt: Anmia, lukopnia, lymphadnopathy, pupua, WBC abnomality. Ra: Abnomal blding, pdominatly of th skin and mucous mmbans, blding tim incasd, osinophilia, ion dficincy anmia, lukocytosis, lymphdma, lymphocytosis, micocytic anmia, monocytosis, nomocytic anmia, thombocytopnia. Mtabolic and Nutitional Fqunt: Wight gain, wight loss, incass in cholstol lvls. Infqunt: Edma, hypglycmia, piphal dma, thist. Ra: Alkalin phosphatas incasd, biliubinmia, cachxia, dhydation, gout, hypocalcmia, hypoglycmia, hypokalmia, hyponatmia (pdominantly in th ldly) which is somtims du to syndom of inappopiat anti-diutic homon sction (SIADH), non-potin nitogn (NPN) incasd, obsity, SGOT incasd, SGPT incasd. Musculoskltal Infqunt: Athalgia, athitis, taumatic factu. Ra: Athosis, bon disod, busitis, catilag disod, myositis, ostopoosis, ttany. Nvous Systm Fqunt: CNS stimulation, concntation impaid, dpssion, motional lability, vtigo. Infqunt: Akinsia, alcohol abus, amnsia, ataxia, convulsion, dpsonalization, hallucinations, hypkinsia, hyptonia, incoodination, lack of motion, manic action, paanoid action, thinking abnomal, hypsthsia. Ra: Abnomal lctoncphalogam, abnomal gait, antisocial action, bain dma, chooathtosis, cicumoal paasthsia, confusion, dliium, dlusions, diplopia, dug dpndnc, dysathia, dyskinsia, dystonia, uphoia, fasciculations, gand mal convulsion, hostility, hypalgsia, hypokinsia, hystia, libido incasd, manic dpssiv action, mningitis, mylitis, nualgia, nuopathy, nystagmus, psychosis, psychotic dpssion, flxs incasd, stupo, toticollis, withdawal syndom. Rspiatoy Systm Fqunt: Cough incasd, hinitis. Infqunt: Asthma, bonchitis, dyspna, pistaxis, hypvntilation, pnumonia, spiatoy flu, sinusitis. Ra: Hiccup, lung fibosis, sputum incasd, stido, tacha disod, voic altation. Spcial Snss Infqunt: Abnomality of accommodation, conjunctivitis, a pain, y pain, mydiasis, otitis mdia, tinnitus. Ra: Amblyopia, cataact spcifid, conjunctival dma, conal lsion, conal ulc, xophthalmos, y hmohag, acut glaucoma, hypacusis, otitis xtna, photophobia, tinal hmohag, tast loss, anisocoia, dafnss, katoconjunctivitis. Uognital systm Infqunt: Abotion*, amnoha*, bast pain*, cystitis, dysmnoha*, dysuia, mnohagia*, noctuia, polyuia, uinay incontinnc, uinay tntion, uinay tact infction, uinay ugncy, vaginitis*. Ra: Bast atophy*, cvix disod*, ndomtial disod*, fmal lactation*, hmatuia, kidny calculus, kidny function abnomal, kidny pain, mastitis*, nphitis, oliguia, salpingitis*, spmatognsis ast* uthitis, uinay casts, uin abnomality, utin noplasm*, vaginal moniliasis*. * Incidnc coctd fo gnd. Post-Makting Advs Dug Ractions Advs vnts not listd abov which hav bn potd sinc makt intoduction in patints taking paoxtin includ acut pancatitis, hpatic vnts such as lvation of hpatic nzyms, Pag 20 of 51

21 and hpatitis, somtims associatd with jaundic, and/o liv failu (in vy a cicumstancs, with fatal outcoms), Guillain-Baé syndom, piapism, thombocytopnia, aggavatd hyptnsion, syndom of inappopiat ADH sction, symptoms suggstiv of hyppolactinmia and galactoha, mnstual disods (including mnohagia, mtohagia and amnoha), blud vision; xtapyamidal symptoms which hav includd akathisia, (chaactizd by an inn sns of stlssnss and psychomoto agitation such as an inability to sit o stand still usually associatd with subjctiv distss), badykinsia, cogwhl igidity, dystonia, hyptonia, oculogyic cisis which has bn associatd with concomitant us of pimozid, tmo and tismus, abnomal dams (including nightmas), stlss lgs syndom (RLS), nuolptic malignant syndom-lik vnts and sotonin syndom (s, WARNINGS AND PRECAUTIONS, Nuologic-Sotonin Syndom/Nuolptic Malignant Syndom), psistnt pulmonay hyptnsion (PPHN; s also WARNINGS AND PRECAUTIONS, Pgnant Womn and Nwbons, Risk of PPHN and xposu to SSRIs). Th has bn a cas pot of an lvatd phnytoin lvl aft 4 wks of paoxtin and phnytoin co-administation. Th has bn a cas pot of sv hypotnsion whn paoxtin was addd to chonic mtopolol tatmnt. Th causal lationship btwn paoxtin and th mgnc of ths vnts has not bn stablishd. Th hav bn spontanous pots of advs vnts upon th discontinuation of paoxtin and oth slctiv sotonin uptak inhibitos (paticulaly whn abupt) (s, WARNINGS AND PRECAUTIONS, Gnal-Discontinuation of Tatmnt with PAROXETINE and ADVERSE REACTIONS, Advs Evnts Following Discontinuation of Tatmnt). DRUG INTERACTIONS Sious Dug Intactions Monoamin Oxidas Inhibitos: S CONTRAINDICATIONS Thioidazin: S CONTRAINDICATIONS Pimozid: S CONTRAINDICATIONS Ovviw Lik som oth slctiv sotonin -uptak inhibitos, paoxtin inhibits th spcific hpatic cytochom P450 isozym CYP2D6 which is sponsibl fo th mtabolism of dbisoquin and spatin. Poo mtabolizs of dbisoquin/spatin psnt appoximatly 5 to 10% of Caucasians. Th mdian C min (ss) fo paoxtin (20 mg daily) at stady stat in poo mtabolizs (n=8) was almost tipl that potd fo xtnsiv mtabolizs (n=9). Although th full clinical significanc of this ffct has not bn stablishd, inhibition of CYP2D6 can lad to lvatd plasma lvls of co-administd dugs which a mtabolizd by this isozym. Considation should b givn to dcasing th dos of th CYP2D6 mtabolizd dug o paoxtin and/o monitoing of dug plasma lvls, spcially whn paoxtin is coadministd with dugs with a naow thaputic indx. Paoxtin co-administation has bn associatd with lvatd lvls of th anti-cholingic pocyclidin, ctain nuolptics/antipsychotics (.g. pphnazin, ispidon), ticyclic antidpssants (.g. dsipamin), atomoxtin, typ 1C antiahythmics (.g., popafnon), and thophyllin. Co-administation of phnobabitol o phnytoin with paoxtin has bn associatd with dcasd lvls of paoxtin. Whn co-administd with cimtidin, paoxtin lvls w lvatd. Pag 21 of 51