If Eligible, Get EFFEXOR XR Co-Pay Card Savings on Your Branded Prescription*

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1 If Eligible, Get EFFEXOR XR Co-Py Crd Svings on Your Brnded Prescription* REMEMBER: You must be prescribed brnd-nme EFFEXOR XR to receive the monthly svings tht come with your Co-Py Crd. *Terms nd conditions pply. See below. Ptients my py less by receiving generic. The following tips will help ensure you receive brnd-nme EFFEXOR XR... TIP #1 If your doctor hs determined tht brnd-nme EFFEXOR XR is right for you, be sure tht the prescription reds No Substitutions, Dispense As Written, or Brnd Mediclly Necessry, depending on your stte s requirements TIP #2 Alwys check your bg nd bottle lbel t the phrmcy counter to mke sure you hve been given brnd-nme EFFEXOR XR TIP #3 Hve the phrmcist note your preference for brnd-nme EFFEXOR XR for future refills With the EFFEXOR XR Co-Py Crd, you my continue to sve through December 31, 2017 * Terms nd conditions pply. Crd will be ccepted only t prticipting phrmcies. Crd is not helth insurnce. No membership fees. Mximum svings per yer is $2,500. For more informtion, cll or write to Pfizer, EFFEXOR XR Co-Py Crd, Weston Prkwy, Suite 103, Cry, NC LEARN MORE AT EFFEXORXR.COM OR CALL EFFEXOR XR is vilble in different dosge strengths (37.5 mg, 75 mg, nd 150 mg). Importnt Sfety Informtion Suicidlity nd Antidepressnt Drugs Antidepressnts incresed the risk compred to plcebo of suicidl thinking nd behvior (suicidlity) in children, teens, nd young dults. Depression nd certin other psychitric disorders re themselves ssocited with increses in the risk of suicide. Ptients of ll ges who re strted on ntidepressnt therpy should be monitored ppropritely nd observed closely for clinicl worsening, suicidlity, or unusul chnges in behvior. is not pproved for use in children nd teens. Do not tke if you currently tke, or hve tken within the lst 14 dys, ny medicine known s n MAOI such s linezolid or methylene blue. Do not tke n MAOI within 7 dys of stopping. Ask your doctor or phrmcist if you re not sure if your medicine is n MAOI. Plese see dditionl Importnt Sfety Informtion on following pge nd ccompnying Full Prescribing Informtion, including BOXED WARNING, nd Mediction Guide.

2 Importnt Sfety Informtion (continued) All ptients tking ntidepressnts should be wtched closely for signs tht their condition is getting worse or tht they re becoming suicidl, especilly when they first strt therpy, or when their dose is incresed or decresed. Ptients should lso be wtched for becoming gitted, irritble, hostile, ggressive, impulsive, or restless. Such symptoms should be reported to the ptient s doctor right wy. Before strting, tell your doctor if you re tking or pln to tke ny prescription or over-the-counter drugs, including migrine hedche mediction, herbl preprtions, nd nutritionl supplements, to void potentilly life-thretening condition. my rise blood pressure in some ptients. Your blood pressure should be controlled before strting tretment nd should be monitored regulrly. Tking with spirin, nonsteroidl nti-inflmmtory drugs, wrfrin, or other drugs tht ffect cogultion my increse the risk of bleeding events. Some people re t risk for visul problems such s eye pin, chnges in vision, or swelling or redness round the eye. You my wnt to undergo n eye exmintion to see if you re t risk nd get preventtive tretment if you re. When people suddenly stop using or quickly lower their dily dose of, discontinution symptoms my occur. Tlk to your doctor before discontinuing or reducing your dose of. Pregnnt or nursing women shouldn t tke ny ntidepressnt without consulting their doctor. Until you see how ffects you, be creful doing such ctivities s driving cr or operting mchinery. Avoid drinking lcohol while tking. In clinicl studies, the most common side effects with (reported in t lest 5% of ptients nd t lest twice s often s with plcebo) were constiption, dizziness, dry mouth, insomni, loss of ppetite, nuse, nervousness, sexul side effects, sleepiness, sweting, nd wekness. Indictions extended-relese cpsules re prescription medicine indicted for the tretment, in dults, of Depression, Generlized Anxiety Disorder (GAD), Socil Anxiety Disorder (SAD), nd Pnic Disorder (PD) with or without gorphobi. Get Vluble Offers on Select Pfizer Brnds Find out if you re eligible to strt sving on your prescriptions tody. Terms nd conditions pply. Lern more t Plese see ccompnying Full Prescribing Informtion, including BOXED WARNING, nd Mediction Guide. PP-EFX-USA Pfizer Inc. All rights reserved. November 2015

3 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use EFFEXOR XR sfely nd effectively. See full prescribing informtion for EFFEXOR XR. EFFEXOR XR ( Extended-Relese) Cpsules Initil U.S. Approvl: 1997 WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing informtion for complete boxed wrning. Incresed risk of suicidl thinking nd behvior in children, dolescents nd young dults tking ntidepressnts (5.1) Monitor for worsening nd emergence of suicidl thoughts nd behviors (5.1) is not pproved for use in peditric ptients (8.4) INDICATIONS AND USAGE is serotonin nd norepinephrine reuptke inhibitor (SNRI) indicted for the tretment of: Mjor Depressive Disorder (MDD) Generlized Anxiety Disorder (GAD) Socil Anxiety Disorder (SAD) Pnic Disorder (PD) DOSAGE AND ADMINISTRATION Indiction Strting Dose Trget Dose Mximum Dose MDD (2.1) mg/dy 75 mg/dy 225 mg/dy GAD (2.2) mg/dy 75 mg/dy 225 mg/dy SAD (2.3) 75 mg/dy 75 mg/dy 75 mg/dy PD (2.4) 37.5 mg/dy 75 mg/dy 225 mg/dy Tke once dily with food (2). Cpsules should be tken whole; do not divide, crush, chew, or dissolve (2). When discontinuing tretment, reduce the dose grdully (2.8, 5.7). Renl impirment: reduce the totl dily dose by 25% to 50% in ptients with renl impirment. Reduce the totl dily dose by 50% or more in ptients undergoing dilysis or with severe renl impirment (2.6). Heptic impirment: reduce the dily dose by 50% in ptients with mild to moderte heptic impirment. In ptients with severe heptic impirment or heptic cirrhosis, it my be necessry to reduce the dose by more thn 50% (2.6). FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE 1.1 Mjor Depressive Disorder 1.2 Generlized Anxiety Disorder 1.3 Socil Anxiety Disorder 1.4 Pnic Disorder 2 DOSAGE AND ADMINISTRATION 2.1 Mjor Depressive Disorder 2.2 Generlized Anxiety Disorder 2.3 Socil Anxiety Disorder (Socil Phobi) 2.4 Pnic Disorder 2.5 Switching Ptients from Effexor Tblets 2.6 Specific Popultions 2.7 Mintennce Tretment 2.8 Discontinuing 2.9 Switching Ptients to or from Monomine Oxidse Inhibitor (MAOI) Intended to Tret Psychitric Disorders 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Concomitnt Use with Monomine Oxidse Inhibitors (MAOIs) 5 WARNINGS AND PRECAUTIONS 5.1 Suicidl Thoughts nd Behviors in Children, Adolescents, nd Young Adults 5.2 Serotonin Syndrome 5.3 Elevtions in Blood Pressure 5.4 Abnorml Bleeding 5.5 Angle Closure Glucom 5.6 Activtion of Mni/Hypomni 5.7 Discontinution Syndrome 5.8 Seizures 5.9 Hypontremi 5.10 Weight nd Height Chnges in Peditric Ptients 5.11 Appetite Chnges in Peditric Ptients 5.12 Interstitil Lung Disese nd Eosinophilic Pneumoni 6 ADVERSE REACTIONS 6.1 Clinicl Studies Experience 6.2 Vitl Sign Chnges 6.3 Lbortory Chnges 6.4 Peditric Ptients 6.5 Adverse Rections Identified During Postpprovl Use DOSAGE FORMS AND STRENGTHS cpsules re vilble s 37.5 mg, 75 mg nd 150 mg strengths (3). Ech cpsule contins hydrochloride equivlent to 37.5 mg, 75 mg or 150 mg of (3) CONTRAINDICATIONS Hypersensitivity to hydrochloride, des succinte, or ny excipients in the formultion (4.1). Do not use with n MAOI or within 14 dys of stopping n MAOI. Allow 7 dys fter stopping before strting n MAOI, becuse of the risk of serotonin syndrome (4.2, 5.2, 7.3) WARNINGS AND PRECAUTIONS Clinicl Worsening/Suicide Risk: Monitor for clinicl worsening nd suicide risk (5.1). Serotonin Syndrome: Risk increses with concomitnt use of other serotonergic drugs. Discontinue nd initite supportive tretment if serotonin syndrome occurs (4.2, 5.2, 7.3). Elevtions in Blood Pressure: Control hypertension before inititing tretment. Monitor blood pressure regulrly during tretment (5.3). Abnorml Bleeding: my increse risk of bleeding events. Cution ptients bout the risk of bleeding ssocited with the concomitnt use of nd NSAIDs, spirin, or other drugs tht ffect cogultion (5.4). Angle Closure Glucom: Angle closure glucom hs occurred in ptients with untreted ntomiclly nrrow ngles treted with ntidepressnts. (5.5). Activtion of Mni/Hypomni: Use cutiously in ptients with bipolr disorder. Cution ptients bout the risk of ctivtion of mni/hypomni (5.6) ADVERSE REACTIONS Most common dverse rections (incidence 5% nd t lest twice the rte of plcebo): nuse, somnolence, dry mouth, sweting, bnorml ejcultion, norexi, constiption, erectile dysfunction, nd libido decresed (6.1). To report SUSPECTED ADVERSE REACTIONS, contct Wyeth Phrmceuticls Inc. t or FDA t FDA-1088 or DRUG INTERACTIONS Serotonergic Drugs (e.g., MAOIs, triptns, SSRIs, other SNRIs, linezolid, lithium, trmdol, or St. John s wort): Potentil for serotonin syndrome. Creful ptient observtion is dvised (4.2, 5.2, 7.3) USE IN SPECIFIC POPULATIONS Pregnncy: Bsed on niml dt, my cuse fetl hrm (8.1). Nursing Mothers: Discontinue drug or nursing, tking into considertion importnce of drug to mother (8.3) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 8/ DRUG INTERACTIONS 7.1 Centrl Nervous System (CNS)-Active Drugs 7.2 Monomine Oxidse Inhibitors 7.3 Serotonergic Drugs 7.4 Drugs tht Interfere with Hemostsis (e.g., NSAIDs, Aspirin, nd Wrfrin) 7.5 Weight Loss Agents 7.6 Effects of Other Drugs on 7.7 Effects of on Other Drugs 7.8 Drug-Lbortory Test Interctions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lbor nd Delivery 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Age nd Gender 8.7 Use in Ptient Subgroups 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substnce 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Humn Experience 10.2 Mngement of Overdosge 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Mjor Depressive Disorder 14.2 Generlized Anxiety Disorder 14.3 Socil Anxiety Disorder (lso known s Socil Phobi) 14.4 Pnic Disorder 14.5 Peditric Ptients 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing informtion re not listed.

4 FULL PRESCRIBING INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressnts incresed the risk of suicidl thoughts nd behvior in children, dolescents, nd young dults in short-term studies. These studies did not show n increse in the risk of suicidl thoughts nd behvior with ntidepressnt use in ptients over ge 24; there ws reduction in risk with ntidepressnt use in ptients ged 65 nd older [see Wrnings nd Precutions (5.1)]. In ptients of ll ges who re strted on ntidepressnt therpy monitor closely for clinicl worsening nd emergence of suicidl thoughts nd behviors. Advise fmilies nd cregivers of the need for close observtion nd communiction with the prescriber [see Wrnings nd Precutions (5.1) nd Ptient Counseling Informtion (17)]. 1 INDICATIONS AND USAGE 1.1 Mjor Depressive Disorder ( hydrochloride) extended-relese cpsules re indicted for the tretment of mjor depressive disorder (MDD). Efficcy ws estblished in three short-term (4, 8, nd 12 weeks) nd two long-term, mintennce trils. 1.2 Generlized Anxiety Disorder is indicted for the tretment of Generlized Anxiety Disorder (GAD). Efficcy ws estblished in two 8-week nd two 26-week plcebo-controlled trils. 1.3 Socil Anxiety Disorder is indicted for the tretment of Socil Anxiety Disorder (SAD), lso known s socil phobi. Efficcy ws estblished in four 12-week nd one 26-week, plcebo-controlled trils. 1.4 Pnic Disorder is indicted for the tretment of Pnic Disorder (PD), with or without gorphobi. Efficcy ws estblished in two 12-week plcebo-controlled trils. 2 DOSAGE AND ADMINISTRATION should be dministered in single dose with food, either in the morning or in the evening t pproximtely the sme time ech dy [see Clinicl Phrmcology (12.3)]. Ech cpsule should be swllowed whole with fluid nd not divided, crushed, chewed, or plced in wter or it my be dministered by crefully opening the cpsule nd sprinkling the entire contents on spoonful of pplesuce. This drug/food mixture should be swllowed immeditely without chewing nd followed with glss of wter to ensure complete swllowing of the pellets (spheroids). 2.1 Mjor Depressive Disorder For most ptients, the recommended strting dose for is 75 mg per dy, dministered in single dose. For some ptients, it my be desirble to strt t 37.5 mg per dy for 4 to 7 dys to llow new ptients to djust to the mediction before incresing to 75 mg per dy. Ptients not responding to the initil 75 mg per dy dose my benefit from dose increses to mximum of 225 mg per dy. Dose increses should be in increments of up to 75 mg per dy, s needed, nd should be mde t intervls of not less thn 4 dys, since stedy-stte plsm levels of nd its mjor metbolites re chieved in most ptients by dy 4 [see Clinicl Phrmcology (12.3)]. In the clinicl studies estblishing efficcy, upwrd titrtion ws permitted t intervls of 2 weeks or more. It should be noted tht, while the mximum recommended dose for modertely depressed outptients is lso 225 mg per dy for Effexor (immedite-relese), more severely depressed inptients in one study of the development progrm for tht product responded to men dose of 350 mg per dy (rnge of 150 to 375 mg per dy). Whether or not higher doses of re needed for more severely depressed ptients is unknown; however, the experience with doses higher thn 225 mg per dy is very limited. 2.2 Generlized Anxiety Disorder For most ptients, the recommended strting dose for is 75 mg per dy, dministered in single dose. For some ptients, it my be desirble to strt t 37.5 mg per dy for 4 to 7 dys to llow new ptients to djust to the mediction before incresing to 75 mg per dy. Ptients not responding to the initil 75 mg per dy dose my benefit from dose increses to mximum of 225 mg per dy. Dose increses should be in increments of up to 75 mg per dy, s needed, nd should be mde t intervls of not less thn 4 dys, since stedy-stte plsm levels of nd its mjor metbolites re chieved in most ptients by dy 4 [see Clinicl Phrmcology (12.3)]. 2.3 Socil Anxiety Disorder (Socil Phobi) The recommended dose is 75 mg per dy, dministered in single dose. There ws no evidence tht higher doses confer ny dditionl benefit. 2.4 Pnic Disorder The recommended strting dose is 37.5 mg per dy of for 7 dys. Ptients not responding to 75 mg per dy my benefit from dose increses to mximum of pproximtely 225 mg per dy. Dose increses should be in increments of up to 75 mg per dy, s needed, nd should be mde t intervls of not less thn 7 dys. 2.5 Switching Ptients from Effexor Tblets Depressed ptients who re currently being treted t therpeutic dose with Effexor (immedite relese) my be switched to t the nerest equivlent dose (mg per dy), e.g., 37.5 mg twice dy to 75 mg once dily. However, individul dosge djustments my be necessry. 2.6 Specific Popultions Ptients with Heptic Impirment The totl dily dose should be reduced by 50% in ptients with mild (Child-Pugh=5-6) to moderte (Child-Pugh=7-9) heptic impirment. In ptients with severe heptic impirment (Child-Pugh=10-15) or heptic cirrhosis, it my be necessry to reduce the dose by 50% or more [See Use in Specific Popultions ( 8.7)]. Ptients with Renl Impirment The totl dily dose should be reduced by 25% to 50% in ptients with mild (CLcr= ml/min) or moderte (CLcr= ml/min) renl impirment. In ptients undergoing hemodilysis or with severe renl impirment (CLcr < 30 ml/min), the totl dily dose should be reduced by 50% or more. Becuse there ws much individul vribility in clernce between ptients with renl impirment, individuliztion of dosge my be desirble in some ptients [see Use in Specific Popultions ( 8.7)]. 2.7 Mintennce Tretment There is no body of evidence vilble from controlled studies to indicte how long ptients with MDD, GAD, SAD, or PD should be treted with. It is generlly greed tht cute episodes of MDD require severl months or longer of sustined phrmcologicl therpy beyond response to the cute episode. /Effexor hve demonstrted continution of response in clinicl studies up to 52 weeks, t the sme dose t which ptients responded during the initil tretment [see Clinicl Studies (14.1)]. It is not known whether or not the dose of needed for mintennce tretment is identicl to the dose needed to chieve n initil response. Ptients should be periodiclly ressessed to determine the need for mintennce tretment nd the pproprite dose for such tretment. In ptients with GAD nd SAD, hs been shown to be effective in 6-month clinicl studies. The need for continuing mediction in ptients with GAD nd SAD who improve with tretment should be periodiclly ressessed. In clinicl study for PD, ptients continuing t the sme dose t which they responded during the initil 12 weeks of tretment experienced sttisticlly significntly longer time to relpse thn ptients rndomized to plcebo [see Clinicl Studies (14.4)]. The need for continuing mediction in ptients with PD who improve with tretment should be periodiclly ressessed. 2.8 Discontinuing A grdul reduction in the dose, rther thn brupt cesstion, is recommended whenever possible. In clinicl studies with, tpering ws chieved by reducing the dily dose by 75 mg t one-week intervls. Individuliztion of tpering my be necessry [see Wrnings nd Precutions (5.7)]. 2.9 Switching Ptients to or from Monomine Oxidse Inhibitor (MAOI) Intended to Tret Psychitric Disorders At lest 14 dys should elpse between discontinution of n MAOI (intended to tret psychitric disorders) nd initition of therpy with. In ddition, t lest 7 dys should be llowed fter stopping before strting n MAOI intended to tret psychitric disorders [see Contrindictions (4.2), Wrnings nd Precutions (5.2), nd Drug Interctions (7.2)]. Use of with other MAOIs such s Linezolid or Intrvenous Methylene Blue Do not strt in ptient who is being treted with linezolid or intrvenous methylene blue, becuse there is n incresed risk of serotonin syndrome. In ptient who requires more urgent tretment of psychitric condition, other interventions, including hospitliztion should be considered [see Contrindictions 4.2)]. In some cses, ptient lredy receiving therpy my require urgent tretment with linezolid or intrvenous methylene blue. If cceptble lterntives to linezolid or intrvenous methylene blue re not vilble nd the potentil benefits of linezolid or intrvenous methylene blue tretment re judged to outweigh the risks of serotonin syndrome in prticulr ptient, should be stopped promptly, nd linezolid or intrvenous methylene blue cn be dministered. Monitor the ptient for symptoms of serotonin syndrome for 7 dys or until 24 hours fter the lst dose of linezolid or intrvenous methylene blue, whichever comes first. Therpy with cn be resumed 24 hours fter the lst dose of linezolid or intrvenous methylene blue [see Wrnings nd Precutions (5.2)]. The risk of dministering methylene blue by non-intrvenous routes (such s orl tblets or by locl injection) or in intrvenous doses much lower thn 1 mg/kg concomitntly with is uncler. The clinicin should, nevertheless, be wre of the possibility of emergent symptoms of serotonin syndrome with such use [see Wrnings nd Precutions (5.2)]. 3 DOSAGE FORMS AND STRENGTHS ( hydrochloride) extended-relese cpsules re vilble in the following strengths: 37.5 mg cpsules (grey cp/pech body with W nd on the cp nd 37.5 on the body) 75 mg cpsules (pech cp nd body with W nd on the cp nd 75 on the body) 150 mg cpsules (drk ornge cp nd body with W nd on the cp nd 150 on the body) 4 CONTRAINDICATIONS 4.1 Hypersensitivity Hypersensitivity to hydrochloride, des succinte or to ny excipients in the formultion 4.2 Concomitnt Use with Monomine Oxidse Inhibitors (MAOIs) The use of MAOIs (intended to tret psychitric disorders) concomitntly with or within 7 dys of discontinuing tretment with is contrindicted becuse of n incresed risk of serotonin syndrome. The use of within 14 dys of discontinuing tretment with n MAOI (intended to tret psychitric disorders) is lso contrindicted [see Dosge nd Administrtion (2.9), Wrnings nd Precutions (5.2), nd Drug Interctions (7.2)]. Strting in ptient who is being treted with n MAOI such s linezolid or intrvenous methylene blue is lso contrindicted, becuse of n incresed risk of serotonin syndrome [see Dosge nd Administrtion (2.9), Wrnings nd Precutions (5.2), nd Drug Interctions (7.3)].

5 5 WARNINGS AND PRECAUTIONS 5.1 Suicidl Thoughts nd Behviors in Children, Adolescents, nd Young Adults Ptients with mjor depressive disorder (MDD), both dult nd peditric, my experience worsening of their depression nd/or the emergence of suicidl idetion nd behvior (suicidlity) or unusul chnges in behvior, whether or not they re tking ntidepressnt medictions, nd this risk my persist until significnt remission occurs. Suicide is known risk of depression nd certin other psychitric disorders, nd these disorders themselves re the strongest predictors of suicide. There hs been long-stnding concern, however, tht ntidepressnts my hve role in inducing worsening of depression nd the emergence of suicidlity in certin ptients during the erly phses of tretment. Pooled nlyses of short-term plcebo-controlled studies of ntidepressnt drugs (SSRIs nd others) showed tht these drugs increse the risk of suicidl thinking nd behvior (suicidlity) in children, dolescents, nd young dults (ges 18-24) with MDD nd other psychitric disorders. Short-term studies did not show n increse in the risk of suicidlity with ntidepressnts compred to plcebo in dults beyond ge 24; there ws reduction with ntidepressnts compred to plcebo in dults ged 65 nd older. The pooled nlyses of plcebo-controlled studies in children nd dolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychitric disorders included totl of 24 short-term studies of 9 ntidepressnt drugs in over 4,400 ptients. The pooled nlyses of plcebo-controlled studies in dults with MDD or other psychitric disorders included totl of 295 short-term studies (medin durtion of 2 months) of 11 ntidepressnt drugs in over 77,000 ptients. There ws considerble vrition in risk of suicidlity mong drugs, but tendency towrd n increse in the younger ptients for lmost ll drugs studied. There were differences in bsolute risk of suicidlity cross the different indictions, with the highest incidence in MDD. The risk differences (drug versus plcebo), however, were reltively stble within ge strt nd cross indictions. These risk differences (drug-plcebo difference in the number of cses of suicidlity per 1,000 ptients treted) re provided in Tble 1. Tble 1: Difference in the Number of Cses of Suicidlity per 1,000 Ptients Treted versus Plcebo Age Rnge Increses Compred to Plcebo < dditionl cses dditionl cses Decreses Compred to Plcebo fewer cse 65 6 fewer cses No suicides occurred in ny of the peditric studies. There were suicides in the dult studies, but the number ws not sufficient to rech ny conclusion bout drug effect on suicide. It is unknown whether the suicidlity risk extends to longer term use, i.e., beyond severl months. However, there is substntil evidence from plcebo-controlled mintennce studies in dults with depression tht the use of ntidepressnts cn dely the recurrence of depression. All ptients being treted with ntidepressnts for ny indiction should be monitored ppropritely nd observed closely for clinicl worsening, suicidlity, nd unusul chnges in behvior, especilly during the initil few months of course of drug therpy, or t times of dose chnges, either increses or decreses. The following symptoms, nxiety, gittion, pnic ttcks, insomni, irritbility, hostility, ggressiveness, impulsivity, kthisi (psychomotor restlessness), hypomni, nd mni, hve been reported in dult nd peditric ptients being treted with ntidepressnts for MDD, s well s for other indictions, both psychitric nd nonpsychitric. Although cusl link between the emergence of such symptoms nd either the worsening of depression nd/or the emergence of suicidl impulses hs not been estblished, there is concern tht such symptoms my represent precursors to emerging suicidlity. Considertion should be given to chnging the therpeutic regimen, including possibly discontinuing the mediction, in ptients whose depression is persistently worse, or who re experiencing emergent suicidlity or symptoms tht might be precursors to worsening depression or suicidlity, especilly if these symptoms re severe, brupt in onset, or were not prt of the ptient s presenting symptoms. If the decision hs been mde to discontinue tretment, mediction should be tpered, s rpidly s is fesible, but with recognition tht brupt discontinution cn be ssocited with certin symptoms [see Wrnings nd Precutions (5.7) nd Dosge nd Administrtion (2.8)]. Fmilies nd cregivers of ptients being treted with ntidepressnts for MDD or other indictions, both psychitric nd nonpsychitric, should be lerted bout the need to monitor ptients for the emergence of gittion, irritbility, unusul chnges in behvior, nd the other symptoms described bove, s well s the emergence of suicidlity, nd to report such symptoms immeditely to helthcre providers. Such monitoring should include dily observtion by fmilies nd cregivers. Prescriptions for should be written for the smllest quntity of cpsules consistent with good ptient mngement, in order to reduce the risk of overdose. Screening Ptients for Bipolr Disorder A mjor depressive episode my be the initil presenttion of bipolr disorder. It is generlly believed (though not estblished in controlled studies) tht treting such n episode with n ntidepressnt lone my increse the likelihood of precipittion of mixed/mnic episode in ptients t risk for bipolr disorder. Whether ny of the symptoms described bove represent such conversion is unknown. However, prior to inititing tretment with n ntidepressnt, ptients with depressive symptoms should be dequtely screened to determine if they re t risk for bipolr disorder; such screening should include detiled psychitric history, including fmily history of suicide, bipolr disorder, nd depression. It should be noted tht is not pproved for use in treting bipolr depression. 5.2 Serotonin Syndrome The development of potentilly life-thretening serotonin syndrome hs been reported with SNRIs nd SSRIs, including lone, but prticulrly with concomitnt use of other serotonergic drugs (including triptns, tricyclic ntidepressnts, fentnyl, lithium, trmdol, tryptophn, buspirone, nd St. John s wort) nd with drugs tht impir metbolism of serotonin in prticulr, MAOIs, both those intended to tret psychitric disorders nd others, such s linezolid or intrvenous methylene blue). Serotonin syndrome symptoms my include mentl sttus chnges (e.g., gittion, hllucintions, delirium, com) utonomic instbility (e.g., tchycrdi, lbile blood pressure, hyperthermi, diphoresis, flushing, nd dizziness), neuromusculr symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexi, incoordintion); seizures nd gstrointestinl symptoms (e.g., nuse, vomiting, dirrhe). Ptients should be monitored for the emergence of serotonin syndrome. The concomitnt use of with MAOIs (intended to tret psychitric disorders) is contrindicted. should lso not be strted in ptient who is being treted with MAOIs such s linezolid or intrvenous methylene blue. All reports with methylene blue tht provided informtion on the route of dministrtion involved intrvenous dministrtion in the dose rnge of 1 mg/kg to 8 mg/kg. No reports involved the dministrtion of methylene blue by other routes (such s orl tblets or locl tissue injection) or t lower doses. There my be circumstnces when it is necessry to initite tretment with MAOI such s linezolid or intrvenous methylene blue in ptient tking. should be discontinued before inititing tretment with the MAOI [see Contrindictions (4.2), Dosge nd Administrtion (2.6), nd Drug Interctions (7.3)]. If concomitnt use of with other serotonergic drugs (e.g., triptns, tricyclic ntidepressnts, mirtzpine, fentnyl, lithium, trmdol, buspirone, tryptophn, or St. John s wort) is cliniclly wrrnted, creful observtion of the ptient is dvised, prticulrly during tretment initition nd dose increses [see Drug Interctions (7.3)]. Ptients should be mde wre of the potentil risk of serotonin syndrome. Tretment with nd ny concomitnt serotonergic gents should be discontinued immeditely if the bove events occur, nd supportive symptomtic tretment should be initited. 5.3 Elevtions in Blood Pressure In controlled trils, there were dose-relted increses in systolic nd distolic blood pressure, s well s cses of sustined hypertension [see Adverse Rections (6.2)]. Monitor blood pressure before inititing tretment with nd regulrly during tretment. Control pre-existing hypertension before inititing tretment with. Use cution in treting ptients with pre-existing hypertension or crdiovsculr or cerebrovsculr conditions tht might be compromised by increses in blood pressure. Sustined blood pressure elevtion cn led to dverse outcomes. Cses of elevted blood pressure requiring immedite tretment hve been reported with. Consider dose reduction or discontinution of tretment for ptients who experience sustined increse in blood pressure. Across ll clinicl studies with Effexor, 1.4% of ptients in the treted groups experienced 15 mm Hg increse in supine distolic blood pressure (SDBP ) 105 mm Hg, compred to 0.9% of ptients in the plcebo groups. Similrly, 1% of ptients in the treted groups experienced 20 mm Hg increse in supine systolic blood pressure (SSBP) with blood pressure 180 mm Hg, compred to 0.3% of ptients in the plcebo groups [see Tble 10 in Adverse Rections (6.2)]. tretment ws ssocited with sustined hypertension (defined s tretment-emergent SDBP 90 mm Hg nd 10 mm Hg bove bseline for three consecutive on-therpy visits [see Tble 11 in Adverse Rections (6.2)]. An insufficient number of ptients received men doses of over 300 mg per dy in clinicl studies to fully evlute the incidence of sustined increses in blood pressure t these higher doses. 5.4 Abnorml Bleeding SSRIs nd SNRIs, including, my increse the risk of bleeding events, rnging from ecchymoses, hemtoms, epistxis, petechie, nd gstrointestinl hemorrhge to life-thretening hemorrhge. Concomitnt use of spirin, Nonsteroidl Anti-Inflmmtory Drugs (NSAIDs), wrfrin, nd other nti-cogulnts or other drugs known to ffect pltelet function my dd to this risk. Cse reports nd epidemiologicl studies (cse-control nd cohort design) hve demonstrted n ssocition between use of drugs tht interfere with serotonin reuptke nd the occurrence of gstrointestinl bleeding. Cution ptients bout the risk of bleeding ssocited with the concomitnt use of nd NSAIDs, spirin, or other drugs tht ffect cogultion. 5.5 Angle-Closure Glucom The pupillry diltion tht occurs following use of mny ntidepressnt drugs including Effexor XR my trigger n ngle closure ttck in ptient with ntomiclly nrrow ngles who does not hve ptent iridectomy. 5.6 Activtion of Mni/Hypomni Mni or hypomni ws reported in treted ptients in the premrketing studies in MDD, SAD, nd PD (see Tble 2). Mni/hypomni hs lso been reported in smll proportion of ptients with mood disorders who were treted with other mrketed drugs to tret MDD. should be used cutiously in ptients with history of mni or hypomni. Tble 2: Incidence (%) of Mni or Hypomni Reported in Treted Ptients in the Premrketing Studies Indiction Plcebo MDD GAD SAD PD Discontinution Syndrome Discontinution symptoms hve been systemticlly evluted in ptients tking, including prospective nlyses of clinicl studies in GAD nd retrospective surveys of studies in MDD nd SAD. Abrupt discontinution or dose reduction of t vrious doses hs been found to be ssocited with the ppernce of new symptoms, the frequency of which incresed with incresed dose level nd with longer durtion of tretment. Reported symptoms include gittion, norexi, nxiety, confusion, impired coordintion nd blnce, dirrhe, dizziness, dry mouth, dysphoric mood, fscicultion, ftigue, flu-like symptoms, hedches, hypomni, insomni, nuse, nervousness, nightmres, sensory disturbnces (including shock-like electricl senstions), somnolence, sweting, tremor, vertigo, nd vomiting. During mrketing of, other SNRIs, nd SSRIs, there hve been spontneous reports of dverse events occurring upon discontinution of these drugs, prticulrly when brupt, including the following: dysphoric mood, irritbility, gittion, dizziness, sensory disturbnces (e.g., presthesi, such s electric shock senstions), nxiety, confusion, hedche, lethrgy, emotionl lbility, insomni, hypomni, tinnitus, nd seizures. While these events re generlly self-limiting, there hve been reports of serious discontinution symptoms.

6 Ptients should be monitored for these symptoms when discontinuing tretment with Effexor XR. A grdul reduction in the dose, rther thn brupt cesstion, is recommended whenever possible. If intolerble symptoms occur following decrese in the dose or upon discontinution of tretment, then resuming the previously prescribed dose my be considered. Subsequently, the physicin my continue decresing the dose, but t more grdul rte [see Dosge nd Administrtion (2.8)]. 5.8 Seizures Seizures hve occurred with therpy., like mny ntidepressnts, should be used cutiously in ptients with history of seizures nd should be discontinued in ny ptient who develops seizures. [Must mitigte the risk: Risk fctors, concomitnt meds tht lower the seizure threshold.] 5.9 Hypontremi Hypontremi cn occur s result of tretment with SSRIs nd SNRIs, including. In mny cses, the hypontremi ppers to be the result of the Syndrome of Inpproprite Antidiuretic Hormone (SIADH) secretion. Cses with serum sodium lower thn 110 mmol/l hve been reported. Elderly ptients my be t greter risk of developing hypontremi with SSRIs nd SNRIs [see Use in Specific Popultions (8.5)]. Also, ptients tking diuretics, or those who re otherwise volumedepleted, my be t greter risk. Consider discontinution of in ptients with symptomtic hypontremi, nd institute pproprite medicl intervention. Signs nd symptoms of hypontremi include hedche, difficulty concentrting, memory impirment, confusion, wekness, nd unstediness, which my led to flls. Signs nd symptoms ssocited with more severe nd/or cute cses hve included hllucintion, syncope, seizure, com, respirtory rrest, nd deth Weight nd Height Chnges in Peditric Ptients Weight Chnges The verge chnge in body weight nd incidence of weight loss (percentge of ptients who lost 3.5% or more) in the plcebo-controlled peditric studies in MDD, GAD, nd SAD re shown in Tbles 3 nd 4. Tble 3: Averge Chnge in Body Weight (kg) From Beginning of Tretment in Peditric Ptients in Double-blind, Plcebo-controlled Studies of Indiction Plcebo (Durtion) MDD nd GAD (4 pooled studies, 8 weeks) (n = 333) (n = 333) SAD (16 weeks) (n = 137) (n = 148) Tble 4: Incidence (%) of Peditric Ptients Experiencing Weight Loss (3.5% or more) in Double-blind, Plcebo-controlled Studies of Indiction Plcebo (Durtion) MDD nd GAD (4 pooled studies, 8 weeks) 18 (n = 333) 3.6 (n = 333) SAD (16 weeks) 47 (n = 137) 14 (n = 148) p < versus plcebo Weight loss ws not limited to ptients with tretment-emergent norexi [see Wrnings nd Precutions (5.11)]. The risks ssocited with longer term use were ssessed in n open-lbel MDD study of children nd dolescents who received for up to six months. The children nd dolescents in the study hd increses in weight tht were less thn expected, bsed on dt from ge- nd sex-mtched peers. The difference between observed weight gin nd expected weight gin ws lrger for children (< 12 yers old) thn for dolescents ( 12 yers old). Height Chnges Tble 5 shows the verge height increse in peditric ptients in the short-term, plcebocontrolled MDD, GAD, nd SAD studies. The differences in height increses in GAD nd MDD studies were most notble in ptients younger thn twelve. Tble 5: Averge Height Increses (cm) in Peditric Ptients in Plcebo-controlled Studies of Indiction (Durtion) Plcebo MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147) GAD (8 weeks) 0.3 (n = 122) 1.0 (n = 132) SAD (16 weeks) 1.0 (n = 109) 1.0 (n = 112) p = In the six-month, open-lbel MDD study, children nd dolescents hd height increses tht were less thn expected, bsed on dt from ge- nd sex-mtched peers. The difference between observed nd expected growth rtes ws lrger for children (< 12 yers old) thn for dolescents ( 12 yers old) Appetite Chnges in Peditric Ptients Decresed ppetite (reported s tretment-emergent norexi) ws more commonly observed in treted ptients versus plcebo-treted ptients in the premrketing evlution of for MDD, GAD, nd SAD (see Tble 6). Tble 6: Incidence (%) of Decresed Appetite nd Associted Discontinution Rtes (%) in Peditric Ptients in Plcebo-controlled Studies of Indiction (Durtion) Incidence Discontinution Plcebo Incidence Discontinution MDD nd GAD (pooled, 8 weeks) SAD (16 weeks) The discontinution rtes for weight loss were 0.7% for ptients receiving either or plcebo Interstitil Lung Disese nd Eosinophilic Pneumoni Interstitil lung disese nd eosinophilic pneumoni ssocited with therpy hve been rrely reported. The possibility of these dverse events should be considered in -treted ptients who present with progressive dyspne, cough or chest discomfort. Such ptients should undergo prompt medicl evlution, nd discontinution of therpy should be considered. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the lbel: Hypersensitivity [see Contrindictions (4.1)] Suicidl Thoughts nd Behviors in Children, Adolescents, nd Adults [see Wrnings nd Precutions (5.1)] Serotonin Syndrome [see Wrnings nd Precutions (5.2)] Elevtions in Blood Pressure [see Wrnings nd Precutions (5.3)] Abnorml Bleeding [see Wrnings nd Precutions (5.4)] Angle Closure Glucom [see Wrnings nd Precutions (5.5)] Activtion of Mni/Hypomni [see Wrnings nd Precutions (5.6)] Discontinution Syndrome [see Wrnings nd Precutions (5.7)] Renl Impirment [see Wrnings nd Precutions (2.6)] Heptic Impirment [see Wrnings nd Precutions (2.6)] Seizure [see Wrnings nd Precutions (5.8)] Hypontremi [see Wrnings nd Precutions (5.9)] Weight nd Height chnges in Peditric Ptients [see Wrnings nd Precutions (5.10)] Appetite Chnges in Peditric Ptients [see Wrnings nd Precutions (5.11)] Interstitil Lung Disese nd Eosinophilic Pneumoni [see Wrnings nd Precutions (5.12)] 6.1 Clinicl Studies Experience Becuse clinicl studies re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl studies of drug cnnot be directly compred to rtes in the clinicl studies of nother drug nd my not reflect the rtes observed in prctice. Most Common Adverse Rections The most commonly observed dverse rections in the clinicl study dtbse in treted ptients in MDD, GAD, SAD, nd PD (incidence 5% nd t lest twice the rte of plcebo) were: nuse (30.0%), somnolence (15.3%), dry mouth (14.8%), sweting (11.4%), bnorml ejcultion (9.9%), norexi (9.8%), constiption (9.3%), impotence (5.3%) nd decresed libido (5.1%). Adverse Rections Reported s Resons for Discontinution of Tretment Combined cross short-term, plcebo-controlled premrketing studies for ll indictions, 12% of the 3,558 ptients who received ( mg) discontinued tretment due to n dverse experience, compred with 4% of the 2,197 plcebo-treted ptients in those studies. The most common dverse rections leding to discontinution in 1% of the treted ptients in the short-term studies (up to 12 weeks) cross indictions re shown in Tble 7. Tble 7: Incidence (%) of Ptients Reporting Adverse Rections Leding to Discontinution in Plcebo-controlled Clinicl Studies (up to 12 Weeks Durtion) Body System Adverse Rection n = 3,558 Plcebo n = 2,197 Body s whole Astheni Hedche Digestive system Nuse Nervous system Dizziness Insomni Somnolence Skin nd ppendges Sweting Common Adverse Rections in Plcebo-controlled Studies The number of ptients receiving multiple doses of during the premrketing ssessment for ech pproved indiction is shown in Tble 8. The conditions nd durtion of exposure to in ll development progrms vried gretly, nd included (in overlpping ctegories) open nd double-blind studies, uncontrolled nd controlled studies, inptient (Effexor only) nd outptient studies, fixed-dose, nd titrtion studies.

7 Tble 8: Ptients Receiving in Premrketing Clinicl Studies Indiction MDD 705 GAD 1,381 SAD 819 PD 1,314 In ddition, in the premrketing ssessment of Effexor, multiple doses were dministered to 2,897 ptients in studies for MDD. The incidences of common dverse rections (those tht occurred in 2% of treted ptients [357 MDD ptients, 1,381 GAD ptients, 819 SAD ptients, nd 1,001 PD ptients] nd more frequently thn plcebo) in treted ptients in short-term, plcebo-controlled, fixed- nd flexible-dose clinicl studies (doses 37.5 to 225 mg per dy) re shown in Tble 9. The dverse rection profile did not differ substntilly between the different ptient popultions. Tble 9: Common Adverse Rections: Percentge of Ptients Reporting Adverse Rections ( 2% nd > plcebo) in Plcebo-controlled Studies (up to 12 Weeks Durtion) cross All Indictions Body System Adverse Rection n = 3,558 Plcebo n = 2,197 Body s whole Astheni Crdiovsculr system Hypertension Plpittion Vsodilttion Digestive system Anorexi Constiption Dirrhe Dry mouth Nuse Vomiting Nervous system Abnorml drems Dizziness Insomni Libido decresed Nervousness Presthesi Somnolence Tremor Respirtory system Ywn Skin nd ppendges Sweting (including night swets) Specil senses Abnorml vision Urogenitl system Abnorml ejcultion/orgsm (men) Anorgsmi (men) Anorgsmi (women) b Impotence (men) Percentges bsed on the number of men (, n = 1,440; plcebo, n = 923) b Percentges bsed on the number of women (, n = 2,118; plcebo, n = 1,274) Other Adverse Rections Observed in Clinicl Studies Body s whole Photosensitivity rection, chills Crdiovsculr system Posturl hypotension, syncope, hypotension, tchycrdi Digestive system Gstrointestinl hemorrhge [see Wrnings nd Precutions (5.4)], bruxism Hemic/Lymphtic system Ecchymosis [see Wrnings nd Precutions (5.4)] Metbolic/Nutritionl Hypercholesterolemi, weight gin [see Wrnings nd Precutions (5.10)], weight loss [see Wrnings nd Precutions (5.10)] Nervous system Seizures [see Wrnings nd Precutions (5.8)], mnic rection [see Wrnings nd Precutions (5.6)], gittion, confusion, kthisi, hllucintions, hypertoni, myoclonus, depersonliztion, pthy Skin nd ppendges Urticri, pruritus, rsh, lopeci Specil senses Mydrisis, bnormlity of ccommodtion, tinnitus, tste perversion Urogenitl system Urinry retention, urintion impired, urinry incontinence, urinry frequency incresed, menstrul disorders ssocited with incresed bleeding or incresed irregulr bleeding (e.g., menorrhgi, metrorrhgi) 6.2 Vitl Sign Chnges In plcebo-controlled premrketing studies, there were increses in men blood pressure (see Tble 10). Across most indictions, dose-relted increse in men supine systolic nd distolic blood pressure ws evident in ptients treted with s. Across ll clinicl studies in MDD, GAD, SAD nd PD, 1.4% of ptients in the groups experienced n increse in SDBP of 15 mm Hg long with blood pressure 105 mm Hg, compred to 0.9% of ptients in the plcebo groups. Similrly, 1% of ptients in the groups experienced n increse in SSBP of 20 mm Hg with blood pressure 180 mm Hg, compred to 0.3% of ptients in the plcebo groups. Tble 10: Finl On-therpy Men Chnges From Bseline in Supine Systolic (SSBP) nd Distolic (SDBP) Blood Pressure (mm Hg) in Plcebo-controlled Studies Plcebo Indiction 75 mg per dy > 75 mg per dy (Durtion) SSBP SDBP SSBP SDBP SSBP SDBP MDD (8-12 weeks) GAD (8 weeks) (6 months) SAD (12 weeks) (6 months) PD (10-12 weeks) tretment ws ssocited with sustined hypertension (defined s tretment-emergent Supine Distolic Blood Pressure [SDBP] 90 mm Hg nd 10 mm Hg bove bseline for three consecutive on-therpy visits (see Tble 11). An insufficient number of ptients received men doses of over 300 mg per dy in clinicl studies to fully evlute the incidence of sustined increses in blood pressure t these higher doses. Tble 11: Sustined Elevtions in SDBP in Premrketing Studies Indiction Dose Rnge (mg per dy) Incidence (%) MDD /705 (3) GAD /1011 (0.5) SAD /771 (0.6) PD /973 (0.9) ws ssocited with men increses in pulse rte compred with plcebo in premrketing plcebo-controlled studies (see Tble 12) [see Wrnings nd Precutions (5.3, 5.4)]. Tble 12: Approximte Men Finl On-therpy Increse in Pulse Rte (bets/min) in Premrketing Plcebo-controlled Studies (up to 12 Weeks Durtion) Indiction Plcebo (Durtion) MDD (12 weeks) 2 1 GAD (8 weeks) 2 < 1 SAD (12 weeks) 3 1 PD (12 weeks) 1 < Lbortory Chnges Serum Cholesterol ws ssocited with men finl increses in serum cholesterol concentrtions compred with men finl decreses for plcebo in premrketing MDD, GAD, SAD nd PD clinicl studies (Tble 13). Tble 13: Men Finl On-therpy Chnges in Cholesterol Concentrtions (mg/dl) in Premrketing Studies Indiction Plcebo (Durtion) MDD (12 weeks) GAD (8 weeks) (6 months) SAD (12 weeks) (6 months) PD (12 weeks) ( hydrochloride) extended-relese cpsules tretment for up to 12 weeks in premrketing plcebo-controlled trils for mjor depressive disorder ws ssocited with men finl on-therpy increse in serum cholesterol concentrtion of pproximtely 1.5 mg/dl compred with men finl decrese of 7.4 mg/dl for plcebo. tretment for up to 8 weeks nd up to 6 months in premrketing plcebo-controlled GAD trils ws ssocited with men finl on-therpy increses in serum cholesterol concentrtion of pproximtely 1.0 mg/dl nd 2.3 mg/dl, respectively while plcebo subjects experienced men finl decreses of 4.9 mg/dl nd 7.7 mg/dl, respectively. tretment for up to 12 weeks nd up to 6 months in premrketing plcebo-controlled Socil Anxiety Disorder trils ws ssocited with men finl on-therpy increses in serum cholesterol concentrtion of pproximtely 7.9 mg/dl nd 5.6 mg/dl, respectively, compred with men finl decreses of 2.9 nd 4.2 mg/dl, respectively, for plcebo. tretment for up to 12 weeks in premrketing plcebo-controlled pnic disorder trils ws ssocited with men finl on-therpy increses in serum cholesterol concentrtion of pproximtely 5.8 mg/dl compred with men finl decrese of 3.7 mg/dl for plcebo.

8 Ptients treted with Effexor (immedite relese) for t lest 3 months in plcebo-controlled 12-month extension trils hd men finl on-therpy increse in totl cholesterol of 9.1 mg/dl compred with decrese of 7.1 mg/dl mong plcebo-treted ptients. This increse ws durtion dependent over the study period nd tended to be greter with higher doses. Cliniclly relevnt increses in serum cholesterol, defined s 1) finl on-therpy increse in serum cholesterol 50 mg/dl from bseline nd to vlue 261 mg/dl, or 2) n verge on-therpy increse in serum cholesterol 50 mg/dl from bseline nd to vlue 261 mg/dl, were recorded in 5.3% of -treted ptients nd 0.0% of plcebo-treted ptients. Serum Triglycerides ws ssocited with men finl on-therpy increses in fsting serum triglycerides compred with plcebo in premrketing clinicl studies of SAD nd PD up to 12 weeks (pooled dt) nd 6 months durtion (Tble 14). Tble 14: Men Finl On-therpy Increses in Triglyceride Concentrtions (mg/dl) in Premrketing Studies Indiction Plcebo (Durtion) SAD (12 weeks) SAD (6 months) PD (12 weeks) PD (6 months) 6.4 Peditric Ptients In generl, the dverse rection profile of (in plcebo-controlled clinicl studies) in children nd dolescents (ges 6 to 17) ws similr to tht seen for dults. As with dults, decresed ppetite, weight loss, incresed blood pressure, nd incresed serum cholesterol were observed [see Wrnings nd Precutions (5.3, 5.10, 5.11) nd Use in Specific Popultions (8.4)]. In peditric clinicl studies, the dverse rection, suicidl idetion, ws observed. Prticulrly, the following dverse rections were observed in peditric ptients: bdominl pin, gittion, dyspepsi, ecchymosis, epistxis, nd mylgi. 6.5 Adverse Rections Identified During Postpprovl Use The following dverse rections hve been identified during postpprovl use of. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure: Body s whole Anphylxis, ngioedem Crdiovsculr system QT prolongtion, ventriculr fibrilltion, ventriculr tchycrdi (including torsde de pointes) Digestive system Pncretitis Hemic/Lymphtic system Mucous membrne bleeding [see Wrnings nd Precutions (5.4)], blood dyscrsis (including grnulocytosis, plstic nemi, neutropeni nd pncytopeni), prolonged bleeding time, thrombocytopeni Metbolic/Nutritionl Hypontremi [see Wrnings nd Precutions (5.9)], Syndrome of Inpproprite Antidiuretic Hormone (SIADH) secretion [see Wrnings nd Precutions (5.9)], bnorml liver function tests, heptitis, prolctin incresed Musculoskeletl Rhbdomyolysis Nervous system Neuroleptic Mlignnt Syndrome (NMS) [see Wrnings nd Precutions (5.2)], serotonergic syndrome [see Wrnings nd Precutions (5.2)], delirium, extrpyrmidl rections (including dystoni nd dyskinesi), impired coordintion nd blnce, trdive dyskinesi Respirtory system Dyspne, interstitil lung disese, pulmonry eosinophili [see Wrnings nd Precutions (5.12)] Skin nd ppendges Stevens-Johnson syndrome, toxic epiderml necrolysis, erythem multiforme Specil senses Angle-closure glucom [see Wrnings nd Precutions (5.5)] 7 DRUG INTERACTIONS 7.1 Centrl Nervous System (CNS)-Active Drugs The risk of using in combintion with other CNS-ctive drugs hs not been systemticlly evluted. Consequently, cution is dvised when is tken in combintion with other CNS-ctive drugs. 7.2 Monomine Oxidse Inhibitors Adverse rections, some of which were serious, hve been reported in ptients who hve recently been discontinued from n MAOI nd strted on ntidepressnts with phrmcologicl properties similr to (SNRIs or SSRIs), or who hve recently hd SNRI or SSRI therpy discontinued prior to initition of n MAOI [see Dosge nd Administrtion (2.9), Contrindictions (4.2) nd Wrnings nd Precutions (5.2)]. 7.3 Serotonergic Drugs Bsed on the mechnism of ction of nd the potentil for serotonin syndrome, cution is dvised when is codministered with other drugs tht my ffect the serotonergic neurotrnsmitter systems, such s triptns, SSRIs, other SNRIs, linezolid (n ntibiotic which is reversible non-selective MAOI), lithium, trmdol, or St. John s wort. If concomitnt tretment with nd these drugs is cliniclly wrrnted, creful observtion of the ptient is dvised, prticulrly during tretment initition nd dose increses. The concomitnt use of with tryptophn supplements is not recommended [see Dosge nd Administrtion (2.9), Contrindictions (4.2), nd Wrnings nd Precutions (5.2)]. 7.4 Drugs tht Interfere with Hemostsis (e.g., NSAIDs, Aspirin, nd Wrfrin) Serotonin relese by pltelets plys n importnt role in hemostsis. The use of psychotropic drugs tht interfere with serotonin reuptke is ssocited with the occurrence of upper gstrointestinl bleeding nd concurrent use of n NSAID or spirin my potentite this risk of bleeding [see Wrnings nd Precutions (5.4)]. Altered nticogulnt effects, including incresed bleeding, hve been reported when SSRIs nd SNRIs re codministered with wrfrin. Ptients receiving wrfrin therpy should be crefully monitored when is initited or discontinued. 7.5 Weight Loss Agents The sfety nd efficcy of therpy in combintion with weight loss gents, including phentermine, hve not been estblished. Codministrtion of nd weight loss gents is not recommended. is not indicted for weight loss lone or in combintion with other products. 7.6 Effects of Other Drugs on Figure 1: Effect of intercting drugs on the phrmcokinetics of nd ctive metbolite O-desmethyl (). Intercting Drug Anlyte PK Fold Chnge nd 90% CI Recommendtion Ethnol Avoid concomitnt use Dizepm No dose djustment Cimetidine Use with cution in ptients with hypertension, elderly or heptic dysfunction. Ketoconzole Use with cution in CYP2D6 EM's Ketoconzole in CYP2D6 PM's Indinvir Clinicl significnce unknown Metoprolol Use with cution, monitor blood pressure Imiprmine Clinicl significnce unknown Lithium No dose djustment Chnge reltive to the reference vlue Abbrevitions:, O-desmethyl;, re under the curve;, pek plsm concentrtions; EM s, extensive metbolizers; PM s, poor metbolizers * No dose djustment on co-dministrtion with CYP2D6 inhibitors (Fig 3 nd Metbolism Section 12.3) 7.7 Effects of on Other Drugs Figure 2: Effect of on the phrmcokinetics intercting drugs nd their ctive metbolites. Intercting Drug Anlyte PK Fold Chnge nd 90% CI Recommendtion Ethnol* ethnol Avoid concomitnt use Dizepm Alprzolm Indinvir Metoprolol Risperidone Imiprmine Hloperidol Cffeine Tolbutmide Lithium ethnol dizepm dizepm desmethyldizepm desmethyldizepm lprzolm lprzolm indinvir indinvir metprolol metprolol OH-metprolol OH-metprolol risperidone risperidone ctive moiety ctive moiety imiprmine imiprmine 2-OH imiprmine 2-OH imiprmine desiprmine desiprmine 2-OH desiprmine* 2-OH desiprmine* hloperidol hloperidol cffeine cffeine tolbutmide tolbutmide 4-OH-tolbutmide 4-OH-tolbutmide lithium lithium No dose djustment No dose djustment Clinicl significnce unknown Use with cution, monitor blood pressure No dose djustment Clinicl significnce unknown (see footnote) (see footnote) Clinicl significnce unknown No restriction No dose djustment No dose djustment Chnge reltive to the reference vlue Abbrevitions:, re under the curve;, pek plsm concentrtions; OH, hydroxyl * Dt for 2-OH desiprmine were not plotted to enhnce clrity; the fold chnge nd 90% CI for nd of 2-OH desiprmine were 6.6 (5.5, 7.9) nd 4.4 (3.8, 5.0), respectively. Note: *: Administrtion of in stble regimen did not exggerte the psychomotor nd psychometric effects induced by ethnol in these sme subjects when they were not receiving. 7.8 Drug-Lbortory Test Interctions Flse-positive urine immunossy screening tests for phencyclidine (PCP) nd mphetmine hve been reported in ptients tking. This is due to lck of specificity of the screening tests. Flse positive test results my be expected for severl dys following discontinution of therpy. Confirmtory tests, such s gs chromtogrphy/mss spectrometry, will distinguish from PCP nd mphetmine.