Target: 10 mg/day within several days Schizophrenia in adolescents (2.1)

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use ZYPREXA sfely nd effectively. See full prescribing informtion for ZYPREXA. ZYPREXA (olnzpine) Tblet for Orl use ZYPREXA ZYDIS (olnzpine) Tblet, Orlly Disintegrting for Orl use ZYPREXA IntrMusculr (olnzpine) Injection, Powder, For Solution for Intrmusculr use Initil U.S. Approvl: WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing informtion for complete boxed wrning. Elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth. ZYPREXA is not pproved for the tretment of ptients with dementi-relted psychosis. (.,., 7.) When using ZYPREXA nd fluoxetine in combintion, lso refer to the Boxed Wrning section of the pckge insert for Symbyx. Efficcy ws estblished with Symbyx (olnzpine nd fluoxetine in combintion) in dults; refer to the product lbel for Symbyx DOSAGE AND ADMINISTRATION Schizophreni in dults (.) Orl: Strt t - mg once dily; Trget: mg/dy within severl dys Schizophreni in dolescents (.) Orl: Strt t.- mg once dily; Trget: mg/dy Bipolr I Disorder (mnic or mixed episodes) in dults (.) Orl: Strt t or mg once dily Bipolr I Disorder (mnic or mixed episodes) in dolescents (.) Orl: Strt t.- mg once dily; Trget: mg/dy Bipolr I Disorder (mnic or mixed episodes) with lithium or vlprote in dults (.) Orl: Strt t mg once dily Agittion ssocited with Schizophreni nd Bipolr I Mni in dults (.) IM: mg ( mg or 7. mg when cliniclly wrrnted) Assess for orthosttic hypotension prior to subsequent dosing (mx. doses - hrs prt) Depressive Episodes ssocited with Bipolr I Disorder in dults (.) Orl in combintion with fluoxetine: Strt t mg of orl olnzpine nd mg of fluoxetine once dily Depressive Episodes ssocited with Bipolr I Disorder in children nd dolescents (.) Orl in combintion with fluoxetine: Strt t. mg of orl olnzpine nd mg of fluoxetine once dily Tretment Resistnt Depression in dults (.) Orl in combintion with fluoxetine: Strt t mg of orl olnzpine nd mg of fluoxetine once dily RECENT MAJOR CHANGES Wrnings nd Precutions: Metbolic Chnges (.) / Orthosttic Hypotension (.) 7/ Hyperprolctinemi (.) / INDICATIONS AND USAGE ZYPREXA (olnzpine) is n typicl ntipsychotic indicted: As orl formultion for the: Tretment of schizophreni. (.) Adults: Efficcy ws estblished in three clinicl trils in ptients with schizophreni: two -week trils nd one mintennce tril. (.) Adolescents (ges -7): Efficcy ws estblished in one week tril in ptients with schizophreni (.). The incresed potentil (in dolescents compred with dults) for weight gin nd dyslipidemi my led clinicins to consider prescribing other drugs first in dolescents. (.) Acute tretment of mnic or mixed episodes ssocited with bipolr I disorder nd mintennce tretment of bipolr I disorder. (.) Adults: Efficcy ws estblished in three clinicl trils in ptients with mnic or mixed episodes of bipolr I disorder: two - to -week trils nd one mintennce tril. (.) Adolescents (ges -7): Efficcy ws estblished in one week tril in ptients with mnic or mixed episodes ssocited with bipolr I disorder (.). The incresed potentil (in dolescents compred with dults) for weight gin nd dyslipidemi my led clinicins to consider prescribing other drugs first in dolescents. (.) Mediction therpy for peditric ptients with schizophreni or bipolr I disorder should be undertken only fter thorough dignostic evlution nd with creful considertion of the potentil risks. (.) Adjunct to vlprote or lithium in the tretment of mnic or mixed episodes ssocited with bipolr I disorder. (.) Efficcy ws estblished in two -week clinicl trils in dults (.). Mintennce efficcy hs not been systemticlly evluted. As ZYPREXA IntrMusculr for the: Tretment of cute gittion ssocited with schizophreni nd bipolr I mni. (.) Efficcy ws estblished in three -dy trils in dults. (.) As ZYPREXA nd Fluoxetine in Combintion for the: Tretment of depressive episodes ssocited with bipolr I disorder. (.) Efficcy ws estblished with Symbyx (olnzpine nd fluoxetine in combintion); refer to the product lbel for Symbyx. Tretment of tretment resistnt depression. (.) Lower strting dose recommended in debilitted or phrmcodynmiclly sensitive ptients or ptients with predisposition to hypotensive rections, or with potentil for slowed metbolism. (.) my be given without regrd to mels. (.) ZYPREXA nd Fluoxetine in Combintion: Dosge djustments, if indicted, should be mde with the individul components ccording to efficcy nd tolerbility. (.,.) monotherpy is not indicted for the tretment of depressive episodes ssocited with bipolr I disorder or tretment resistnt depression. (.,.) Sfety of co-dministrtion of doses bove 8 mg olnzpine with 7 mg fluoxetine hs not been evluted in dults. (.,.) Sfety of co-dministrtion of doses bove mg olnzpine with mg fluoxetine hs not been evluted in children nd dolescents ges to 7. (.) DOSAGE FORMS AND STRENGTHS Tblets (not scored):.,, 7.,,, mg () Orlly Disintegrting Tblets (not scored):,,, mg () Intrmusculr Injection: mg vil () CONTRAINDICATIONS None with ZYPREXA monotherpy. When using ZYPREXA nd fluoxetine in combintion, lso refer to the Contrindictions section of the pckge insert for Symbyx. () When using ZYPREXA in combintion with lithium or vlprote, refer to the Contrindictions section of the pckge inserts for those products. () WARNINGS AND PRECAUTIONS Elderly Ptients with Dementi-Relted Psychosis: Incresed risk of deth nd incresed incidence of cerebrovsculr dverse events (e.g., stroke, trnsient ischemic ttck). (.) Suicide: The possibility of suicide ttempt is inherent in schizophreni nd in bipolr I disorder, nd close supervision of high-risk ptients should ccompny drug therpy; when using in combintion with fluoxetine, lso refer to the Boxed Wrning nd

2 Wrnings nd Precutions sections of the pckge insert for Symbyx. (.) Neuroleptic Mlignnt Syndrome: Mnge with immedite discontinution nd close monitoring. (.) Metbolic Chnges: Atypicl ntipsychotic drugs hve been ssocited with metbolic chnges including hyperglycemi, dyslipidemi, nd weight gin. (.) Hyperglycemi nd Dibetes Mellitus: In some cses extreme nd ssocited with ketocidosis or hyperosmolr com or deth, hs been reported in ptients tking olnzpine. Ptients tking olnzpine should be monitored for symptoms of hyperglycemi nd undergo fsting blood glucose testing t the beginning of, nd periodiclly during, tretment. (.) Dyslipidemi: Undesirble ltertions in lipids hve been observed. Approprite clinicl monitoring is recommended, including fsting blood lipid testing t the beginning of, nd periodiclly during, tretment. (.) Weight Gin: Potentil consequences of weight gin should be considered. Ptients should receive regulr monitoring of weight. (.) Trdive Dyskinesi: Discontinue if cliniclly pproprite. (.) Orthosttic Hypotension: Orthosttic hypotension ssocited with dizziness, tchycrdi, brdycrdi nd, in some ptients, syncope, my occur especilly during initil dose titrtion. Use cution in ptients with crdiovsculr disese, cerebrovsculr disese, nd those conditions tht could ffect hemodynmic responses. (.) Leukopeni, Neutropeni, nd Agrnulocytosis: Hs been reported with ntipsychotics, including ZYPREXA. Ptients with history of cliniclly significnt low white blood cell count (WBC) or drug induced leukopeni/neutropeni should hve their complete blood count (CBC) monitored frequently during the first few months of therpy nd discontinution of ZYPREXA should be considered t the first sign of cliniclly significnt decline in WBC in the bsence of other custive fctors. (.7) Seizures: Use cutiously in ptients with history of seizures or with conditions tht potentilly lower the seizure threshold. (.) Potentil for Cognitive nd Motor Impirment: Hs potentil to impir judgment, thinking, nd motor skills. Use cution when operting mchinery. (.) Hyperprolctinemi: My elevte prolctin levels. (.) Use in Combintion with Fluoxetine, Lithium or Vlprote: Also refer to the pckge inserts for Symbyx, lithium, or vlprote. (.) Lbortory Tests: Monitor fsting blood glucose nd lipid profiles t the beginning of, nd periodiclly during, tretment. (.) ADVERSE REACTIONS Most common dverse rections ( % nd t lest twice tht for plcebo) ssocited with: Orl Monotherpy: Schizophreni (Adults) posturl hypotension, constiption, weight gin, dizziness, personlity disorder, kthisi (.) Schizophreni (Adolescents) sedtion, weight incresed, hedche, incresed ppetite, dizziness, bdominl pin, pin in extremity, ftigue, dry mouth (.) Mnic or Mixed Episodes, Bipolr I Disorder (Adults) stheni, dry mouth, constiption, incresed ppetite, somnolence, dizziness, tremor (.) Mnic or Mixed Episodes, Bipolr I Disorder (Adolescents) sedtion, weight incresed, incresed ppetite, hedche, ftigue, dizziness, dry mouth, bdominl pin, pin in extremity (.) Combintion of ZYPREXA nd Lithium or Vlprote: Mnic or Mixed Episodes, Bipolr I Disorder (Adults) dry mouth, weight gin, incresed ppetite, dizziness, bck pin, constiption, speech disorder, incresed slivtion, mnesi, presthesi (.) ZYPREXA nd Fluoxetine in Combintion: Also refer to the Adverse Rections section of the pckge insert for Symbyx. () ZYPREXA IntrMusculr for Injection: Agittion with Schizophreni nd Bipolr I Mni (Adults) somnolence (.) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t -8-LillyRx (-8--7) or FDA t -8-FDA-88 or DRUG INTERACTIONS Dizepm: My potentite orthosttic hypotension. (7., 7.) Alcohol: My potentite orthosttic hypotension. (7.) Crbmzepine: Incresed clernce of olnzpine. (7.) Fluvoxmine: My increse olnzpine levels. (7.) ZYPREXA nd Fluoxetine in Combintion: Also refer to the Drug Interctions section of the pckge insert for Symbyx. (7.) CNS Acting Drugs: Cution should be used when tken in combintion with other centrlly cting drugs nd lcohol. (7.) Antihypertensive Agents: Enhnced ntihypertensive effect. (7.) Levodop nd Dopmine Agonists: My ntgonize levodop/dopmine gonists. (7.) Lorzepm (IM): Incresed somnolence with IM olnzpine. (7.) Other Concomitnt Drug Therpy: When using olnzpine in combintion with lithium or vlprote, refer to the Drug Interctions sections of the pckge insert for those products. (7.) USE IN SPECIFIC POPULATIONS Pregnncy: ZYPREXA should be used during pregnncy only if the potentil benefit justifies the potentil risk to the fetus. (8.) Nursing Mothers: Brest-feeding is not recommended. (8.) Peditric Use: Sfety nd effectiveness of ZYPREXA in children < yers of ge hve not been estblished. Sfety nd effectiveness of ZYPREXA nd fluoxetine in combintion in children < yers of ge hve not been estblished. (8.) See 7 for PATIENT COUNSELING INFORMATION nd FDApproved Mediction Guide Revised: 7/ FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS... INDICATIONS AND USAGE. Schizophreni. Bipolr I Disorder (Mnic or Mixed Episodes). Specil Considertions in Treting Peditric Schizophreni nd Bipolr I Disorder. ZYPREXA IntrMusculr: Agittion Associted with Schizophreni nd Bipolr I Mni. ZYPREXA nd Fluoxetine in Combintion: Depressive Episodes Associted with Bipolr I Disorder. ZYPREXA nd Fluoxetine in Combintion: Tretment Resistnt Depression DOSAGE AND ADMINISTRATION. Schizophreni...7 Bipolr I Disorder (Mnic or Mixed Episodes) Administrtion of ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) ZYPREXA IntrMusculr: Agittion Associted with Schizophreni nd Bipolr I Mni ZYPREXA nd Fluoxetine in Combintion: Depressive Episodes Associted with Bipolr I Disorder ZYPREXA nd Fluoxetine in Combintion: Tretment Resistnt Depression ZYPREXA nd Fluoxetine in Combintion: Dosing in Specil Popultions DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Elderly Ptients with Dementi-Relted Psychosis

3 Suicide Neuroleptic Mlignnt Syndrome (NMS) Metbolic Chnges Trdive Dyskinesi Orthosttic Hypotension Leukopeni, Neutropeni, nd Agrnulocytosis Dysphgi Seizures Potentil for Cognitive nd Motor Impirment Body Temperture Regultion Use in Ptients with Concomitnt Illness Hyperprolctinemi Use in Combintion with Fluoxetine, Lithium, or Vlprote Lbortory Tests ADVERSE REACTIONS. Clinicl Trils Experience. Extrpyrmidl Symptoms. Other Adverse Rections. Postmrketing Experience 7 DRUG INTERACTIONS 7. Potentil for Other Drugs to Affect 7. Potentil for to Affect Other Drugs 8 USE IN SPECIFIC POPULATIONS 8. Pregnncy 8. Lbor nd Delivery 8. Nursing Mothers 8. Peditric Use 8. Geritric Use DRUG ABUSE AND DEPENDENCE. Dependence OVERDOSAGE. Humn Experience. Mngement of Overdose DESCRIPTION CLINICAL PHARMACOLOGY. Mechnism of Action.. Phrmcodynmics Phrmcokinetics NONCLINICAL TOXICOLOGY. Crcinogenesis, Mutgenesis, Impirment of Fertility. Animl Toxicology nd/or Phrmcology CLINICAL STUDIES. Schizophreni. Bipolr I Disorder (Mnic or Mixed Episodes). Agittion Associted with Schizophreni nd Bipolr I Mni HOW SUPPLIED/STORAGE AND HANDLING. How Supplied. Storge nd Hndling 7 PATIENT COUNSELING INFORMATION 7. Informtion on Mediction Guide 7. Elderly Ptients with Dementi-Relted Psychosis: Incresed Mortlity nd Cerebrovsculr Adverse Events (CVAE), Including Stroke 7. Neuroleptic Mlignnt Syndrome (NMS) 7. Hyperglycemi nd Dibetes Mellitus 7. Dyslipidemi 7. Weight Gin 7.7 Orthosttic Hypotension 7.8 Potentil for Cognitive nd Motor Impirment 7. Body Temperture Regultion 7. Concomitnt Mediction 7. Alcohol 7. Phenylketonurics 7. Use in Specific Popultions 7. Need for Comprehensive Tretment Progrm in Peditric Ptients *Sections or subsections omitted from the full prescribing informtion re not listed FULL PRESCRIBING INFORMATION WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth. Anlyses of seventeen plcebo-controlled trils (modl durtion of weeks), lrgely in ptients tking typicl ntipsychotic drugs, reveled risk of deth in drug-treted ptients of between. to.7 times the risk of deth in plcebo-treted ptients. Over the course of typicl -week controlled tril, the rte of deth in drug-treted ptients ws bout.%, compred to rte of bout.% in the plcebo group. Although the cuses of deth were vried, most of the deths ppered to be either crdiovsculr (e.g., hert filure, sudden deth) or infectious (e.g., pneumoni) in nture. Observtionl studies suggest tht, similr to typicl ntipsychotic drugs, tretment with conventionl ntipsychotic drugs my increse mortlity. The extent to which the findings of incresed mortlity in observtionl studies my be ttributed to the ntipsychotic drug s opposed to some chrcteristic(s) of the ptients is not cler. ZYPREXA (olnzpine) is not pproved for the tretment of ptients with dementi-relted psychosis [see Wrnings nd Precutions (.,.) nd Ptient Counseling Informtion (7.)]. When using ZYPREXA nd fluoxetine in combintion, lso refer to the Boxed Wrning section of the pckge insert for Symbyx.. INDICATIONS AND USAGE Schizophreni Orl ZYPREXA is indicted for the tretment of schizophreni. Efficcy ws estblished in three clinicl trils in dult ptients with schizophreni: two -week trils nd one mintennce tril. In dolescent ptients with schizophreni (ges -7), efficcy ws estblished in one -week tril [see Clinicl Studies (.)]. When deciding mong the lterntive tretments vilble for dolescents, clinicins should consider the incresed potentil (in dolescents s compred with dults) for weight gin nd dyslipidemi. Clinicins should consider

4 the potentil long-term risks when prescribing to dolescents, nd in mny cses this my led them to consider prescribing other drugs first in dolescents [see Wrnings nd Precutions (.)].. Bipolr I Disorder (Mnic or Mixed Episodes) Monotherpy Orl ZYPREXA is indicted for the cute tretment of mnic or mixed episodes ssocited with bipolr I disorder nd mintennce tretment of bipolr I disorder. Efficcy ws estblished in three clinicl trils in dult ptients with mnic or mixed episodes of bipolr I disorder: two - to -week trils nd one monotherpy mintennce tril. In dolescent ptients with mnic or mixed episodes ssocited with bipolr I disorder (ges -7), efficcy ws estblished in one -week tril [see Clinicl Studies (.)]. When deciding mong the lterntive tretments vilble for dolescents, clinicins should consider the incresed potentil (in dolescents s compred with dults) for weight gin nd dyslipidemi. Clinicins should consider the potentil long-term risks when prescribing to dolescents, nd in mny cses this my led them to consider prescribing other drugs first in dolescents [see Wrnings nd Precutions (.)]. Adjunctive Therpy to Lithium or Vlprote Orl ZYPREXA is indicted for the tretment of mnic or mixed episodes ssocited with bipolr I disorder s n djunct to lithium or vlprote. Efficcy ws estblished in two -week clinicl trils in dults. The effectiveness of djunctive therpy for longer-term use hs not been systemticlly evluted in controlled trils [see Clinicl Studies (.)].. Specil Considertions in Treting Peditric Schizophreni nd Bipolr I Disorder Peditric schizophreni nd bipolr I disorder re serious mentl disorders; however, dignosis cn be chllenging. For peditric schizophreni, symptom profiles cn be vrible, nd for bipolr I disorder, peditric ptients my hve vrible ptterns of periodicity of mnic or mixed symptoms. It is recommended tht mediction therpy for peditric schizophreni nd bipolr I disorder be initited only fter thorough dignostic evlution hs been performed nd creful considertion given to the risks ssocited with mediction tretment. Mediction tretment for both peditric schizophreni nd bipolr I disorder should be prt of totl tretment progrm tht often includes psychologicl, eductionl nd socil interventions.. ZYPREXA IntrMusculr: Agittion Associted with Schizophreni nd Bipolr I Mni ZYPREXA IntrMusculr is indicted for the tretment of cute gittion ssocited with schizophreni nd bipolr I mni. Efficcy ws demonstrted in short-term ( hours of IM tretment) plcebo-controlled trils in gitted dult inptients with: schizophreni or bipolr I disorder (mnic or mixed episodes) [see Clinicl Studies (.)]. Psychomotor gittion is defined in DSM-IV s excessive motor ctivity ssocited with feeling of inner tension. Ptients experiencing gittion often mnifest behviors tht interfere with their dignosis nd cre, e.g., thretening behviors, esclting or urgently distressing behvior, or self-exhusting behvior, leding clinicins to the use of intrmusculr ntipsychotic medictions to chieve immedite control of the gittion.. ZYPREXA nd Fluoxetine in Combintion: Depressive Episodes Associted with Bipolr I Disorder Orl ZYPREXA nd fluoxetine in combintion is indicted for the tretment of depressive episodes ssocited with bipolr I disorder, bsed on clinicl studies. When using ZYPREXA nd fluoxetine in combintion, refer to the Clinicl Studies section of the pckge insert for Symbyx. ZYPREXA monotherpy is not indicted for the tretment of depressive episodes ssocited with bipolr I disorder.. ZYPREXA nd Fluoxetine in Combintion: Tretment Resistnt Depression Orl ZYPREXA nd fluoxetine in combintion is indicted for the tretment of tretment resistnt depression (mjor depressive disorder in ptients who do not respond to seprte trils of different ntidepressnts of dequte dose nd durtion in the current episode), bsed on clinicl studies in dult ptients. When using ZYPREXA nd fluoxetine in combintion, refer to the Clinicl Studies section of the pckge insert for Symbyx. ZYPREXA monotherpy is not indicted for the tretment of tretment resistnt depression. DOSAGE AND ADMINISTRATION. Schizophreni Adults Dose Selection Orl olnzpine should be dministered on once--dy schedule without regrd to mels, generlly beginning with to mg initilly, with trget dose of mg/dy within severl dys. Further dosge djustments, if indicted, should generlly occur t intervls of not less thn week, since stedy stte for olnzpine would not be chieved for pproximtely week in the typicl ptient. When dosge djustments re necessry, dose increments/decrements of mg QD re recommended. Efficcy in schizophreni ws demonstrted in dose rnge of to mg/dy in clinicl trils. However, doses bove mg/dy were not demonstrted to be more efficcious thn the mg/dy dose. An increse to dose greter thn the trget dose of mg/dy (i.e., to dose of mg/dy or greter) is recommended only fter clinicl ssessment. is not indicted for use in doses bove mg/dy. Dosing in Specil Popultions The recommended strting dose is mg in ptients who re debilitted, who hve predisposition to hypotensive rections, who otherwise exhibit combintion of fctors tht my result in slower

5 metbolism of olnzpine (e.g., nonsmoking femle ptients yers of ge), or who my be more phrmcodynmiclly sensitive to olnzpine [see Wrnings nd Precutions (.), Drug Interctions (7), nd Clinicl Phrmcology (.)]. When indicted, dose escltion should be performed with cution in these ptients. Mintennce Tretment The effectiveness of orl olnzpine, mg/dy to mg/dy, in mintining tretment response in schizophrenic ptients who hd been stble on ZYPREXA for pproximtely 8 weeks nd were then followed for relpse hs been demonstrted in plcebo-controlled tril [see Clinicl Studies (.)]. The physicin who elects to use ZYPREXA for extended periods should periodiclly reevlute the long-term usefulness of the drug for the individul ptient. Adolescents Dose Selection Orl olnzpine should be dministered on once--dy schedule without regrd to mels with recommended strting dose of. or mg, with trget dose of mg/dy. Efficcy in dolescents with schizophreni ws demonstrted bsed on flexible dose rnge of. to mg/dy in clinicl trils, with men modl dose of. mg/dy (men dose of. mg/dy). When dosge djustments re necessry, dose increments/decrements of. or mg re recommended. The sfety nd effectiveness of doses bove mg/dy hve not been evluted in clinicl trils [see Clinicl Studies (.)]. Mintennce Tretment The efficcy of ZYPREXA for the mintennce tretment of schizophreni in the dolescent popultion hs not been systemticlly evluted; however, mintennce efficcy cn be extrpolted from dult dt long with comprisons of olnzpine phrmcokinetic prmeters in dult nd dolescent ptients. Thus, it is generlly recommended tht responding ptients be continued beyond the cute response, but t the lowest dose needed to mintin remission. Ptients should be periodiclly ressessed to determine the need for mintennce tretment.. Bipolr I Disorder (Mnic or Mixed Episodes) Adults Dose Selection for Monotherpy Orl olnzpine should be dministered on once--dy schedule without regrd to mels, generlly beginning with or mg. Dosge djustments, if indicted, should generlly occur t intervls of not less thn hours, reflecting the procedures in the plcebo-controlled trils. When dosge djustments re necessry, dose increments/decrements of mg QD re recommended. Short-term (- weeks) ntimnic efficcy ws demonstrted in dose rnge of mg to mg/dy in clinicl trils. The sfety of doses bove mg/dy hs not been evluted in clinicl trils [see Clinicl Studies (.)]. Mintennce Monotherpy The benefit of mintining bipolr I ptients on monotherpy with orl ZYPREXA t dose of to mg/dy, fter chieving responder sttus for n verge durtion of weeks, ws demonstrted in controlled tril [see Clinicl Studies (.)]. The physicin who elects to use ZYPREXA for extended periods should periodiclly reevlute the long-term usefulness of the drug for the individul ptient. Dose Selection for Adjunctive Tretment When dministered s djunctive tretment to lithium or vlprote, orl olnzpine dosing should generlly begin with mg once--dy without regrd to mels. Antimnic efficcy ws demonstrted in dose rnge of mg to mg/dy in clinicl trils [see Clinicl Studies (.)]. The sfety of doses bove mg/dy hs not been evluted in clinicl trils. Adolescents Dose Selection Orl olnzpine should be dministered on once--dy schedule without regrd to mels with recommended strting dose of. or mg, with trget dose of mg/dy. Efficcy in dolescents with bipolr I disorder (mnic or mixed episodes) ws demonstrted bsed on flexible dose rnge of. to mg/dy in clinicl trils, with men modl dose of.7 mg/dy (men dose of 8. mg/dy). When dosge djustments re necessry, dose increments/decrements of. or mg re recommended. The sfety nd effectiveness of doses bove mg/dy hve not been evluted in clinicl trils [see Clinicl Studies (.)]. Mintennce Tretment The efficcy of ZYPREXA for the mintennce tretment of bipolr I disorder in the dolescent popultion hs not been evluted; however, mintennce efficcy cn be extrpolted from dult dt long with comprisons of olnzpine phrmcokinetic prmeters in dult nd dolescent ptients. Thus, it is generlly recommended tht responding ptients be continued beyond the cute response, but t the lowest dose needed to mintin remission. Ptients should be periodiclly ressessed to determine the need for mintennce tretment.. Administrtion of ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) After opening schet, peel bck foil on blister. Do not push tblet through foil. Immeditely upon opening the blister, using dry hnds, remove tblet nd plce entire ZYPREXA ZYDIS in the mouth. Tblet disintegrtion occurs rpidly in sliv so it cn be esily swllowed with or without liquid.. ZYPREXA IntrMusculr: Agittion Associted with Schizophreni nd Bipolr I Mni Dose Selection for Agitted Adult Ptients with Schizophreni nd Bipolr I Mni The efficcy of intrmusculr olnzpine for injection in controlling gittion in these disorders ws demonstrted in dose rnge of. mg to mg. The recommended dose in these ptients is mg. A lower dose of or 7. mg my be considered when clinicl fctors

6 wrrnt [see Clinicl Studies (.)]. If gittion wrrnting dditionl intrmusculr doses persists following the initil dose, subsequent doses up to mg my be given. However, the efficcy of repeted doses of intrmusculr olnzpine for injection in gitted ptients hs not been systemticlly evluted in controlled clinicl trils. Also, the sfety of totl dily doses greter thn mg, or mg injections given more frequently thn hours fter the initil dose, nd hours fter the second dose hve not been evluted in clinicl trils. Mximl dosing of intrmusculr olnzpine (e.g., doses of mg dministered - hours prt) my be ssocited with substntil occurrence of significnt orthosttic hypotension [see Wrnings nd Precutions (.)]. Thus, it is recommended tht ptients requiring subsequent intrmusculr injections be ssessed for orthosttic hypotension prior to the dministrtion of ny subsequent doses of intrmusculr olnzpine for injection. The dministrtion of n dditionl dose to ptient with cliniclly significnt posturl chnge in systolic blood pressure is not recommended. If ongoing olnzpine therpy is cliniclly indicted, orl olnzpine my be initited in rnge of - mg/dy s soon s cliniclly pproprite [see Dosge nd Administrtion (.,.)]. Intrmusculr Dosing in Specil Popultions A dose of mg/injection should be considered for geritric ptients or when other clinicl fctors wrrnt. A lower dose of. mg/injection should be considered for ptients who otherwise might be debilitted, be predisposed to hypotensive rections, or be more phrmcodynmiclly sensitive to olnzpine [see Wrnings nd Precutions (.), Drug Interctions (7), nd Clinicl Phrmcology (.)]. Administrtion of ZYPREXA IntrMusculr ZYPREXA IntrMusculr is intended for intrmusculr use only. Do not dminister intrvenously or subcutneously. Inject slowly, deep into the muscle mss. Prenterl drug products should be inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. Directions for Preprtion of ZYPREXA IntrMusculr with Sterile Wter for Injection Dissolve the contents of the vil using. ml of Sterile Wter for Injection to provide solution contining pproximtely mg/ml of olnzpine. The resulting solution should pper cler nd yellow. ZYPREXA IntrMusculr reconstituted with Sterile Wter for Injection should be used immeditely (within hour) fter reconstitution. Discrd ny unused portion. The following tble provides injection volumes for delivering vrious doses of intrmusculr olnzpine for injection reconstituted with Sterile Wter for Injection. Dose, mg 7.. Volume of Injection, ml Withdrw totl contents of vil.. Physicl Incomptibility Informtion ZYPREXA IntrMusculr should be reconstituted only with Sterile Wter for Injection. ZYPREXA IntrMusculr should not be combined in syringe with dizepm injection becuse precipittion occurs when these products re mixed. Lorzepm injection should not be used to reconstitute ZYPREXA IntrMusculr s this combintion results in delyed reconstitution time. ZYPREXA IntrMusculr should not be combined in syringe with hloperidol injection becuse the resulting low ph hs been shown to degrde olnzpine over time.. ZYPREXA nd Fluoxetine in Combintion: Depressive Episodes Associted with Bipolr I Disorder When using ZYPREXA nd fluoxetine in combintion, lso refer to the Clinicl Studies section of the pckge insert for Symbyx. Adults Orl olnzpine should be dministered in combintion with fluoxetine once dily in the evening, without regrd to mels, generlly beginning with mg of orl olnzpine nd mg of fluoxetine. Dosge djustments, if indicted, cn be mde ccording to efficcy nd tolerbility within dose rnges of orl olnzpine to. mg nd fluoxetine to mg. Antidepressnt efficcy ws demonstrted with ZYPREXA nd fluoxetine in combintion in dult ptients with dose rnge of olnzpine to mg nd fluoxetine to mg. Sfety of co-dministrtion of doses bove 8 mg olnzpine with 7 mg fluoxetine hs not been evluted in clinicl studies. Children nd Adolescents (-7 yers of ge) Orl olnzpine should be dministered in combintion with fluoxetine once dily in the evening, without regrd to mels, generlly beginning with. mg of orl olnzpine nd mg of fluoxetine. Dosge djustments, if indicted, cn be mde ccording to efficcy nd tolerbility. Sfety of co-dministrtion of doses bove mg olnzpine with mg fluoxetine hs not been evluted in peditric clinicl studies. Sfety nd efficcy of ZYPREXA nd fluoxetine in combintion ws determined in clinicl trils supporting pprovl of Symbyx (fixed dose combintion of ZYPREXA nd fluoxetine). Symbyx is dosed between mg/ mg (olnzpine/fluoxetine) per dy nd mg/ mg (olnzpine/fluoxetine) per dy. The following tble demonstrtes the pproprite individul component doses of ZYPREXA nd fluoxetine versus Symbyx. Dosge djustments, if indicted, should be mde with the individul components ccording to efficcy nd tolerbility.

7 7 Tble : Approximte Dose Correspondence Between Symbyx nd the Combintion of ZYPREXA nd Fluoxetine For Use in Combintion Symbyx ZYPREXA Fluoxetine (mg/dy) (mg/dy) (mg/dy) mg olnzpine/ mg fluoxetine. mg olnzpine/ mg fluoxetine mg olnzpine/ mg fluoxetine +. mg olnzpine/ mg fluoxetine + mg olnzpine/ mg fluoxetine +. + Symbyx (olnzpine/fluoxetine HCl) is fixed-dose combintion of ZYPREXA nd fluoxetine. While there is no body of evidence to nswer the question of how long ptient treted with ZYPREXA nd fluoxetine in combintion should remin on it, it is generlly ccepted tht bipolr I disorder, including the depressive episodes ssocited with bipolr I disorder, is chronic illness requiring chronic tretment. The physicin should periodiclly reexmine the need for continued phrmcotherpy. ZYPREXA monotherpy is not indicted for the tretment of depressive episodes ssocited with bipolr I disorder.. ZYPREXA nd Fluoxetine in Combintion: Tretment Resistnt Depression When using ZYPREXA nd fluoxetine in combintion, lso refer to the Clinicl Studies section of the pckge insert for Symbyx. Orl olnzpine should be dministered in combintion with fluoxetine once dily in the evening, without regrd to mels, generlly beginning with mg of orl olnzpine nd mg of fluoxetine. Dosge djustments, if indicted, cn be mde ccording to efficcy nd tolerbility within dose rnges of orl olnzpine to mg nd fluoxetine to mg. Antidepressnt efficcy ws demonstrted with olnzpine nd fluoxetine in combintion in dult ptients with dose rnge of olnzpine to 8 mg nd fluoxetine to mg. Sfety nd efficcy of olnzpine in combintion with fluoxetine ws determined in clinicl trils supporting pprovl of Symbyx (fixed dose combintion of olnzpine nd fluoxetine). Symbyx is dosed between mg/ mg (olnzpine/fluoxetine) per dy nd mg/ mg (olnzpine/fluoxetine) per dy. Tble bove demonstrtes the pproprite individul component doses of ZYPREXA nd fluoxetine versus Symbyx. Dosge djustments, if indicted, should be mde with the individul components ccording to efficcy nd tolerbility. While there is no body of evidence to nswer the question of how long ptient treted with ZYPREXA nd fluoxetine in combintion should remin on it, it is generlly ccepted tht tretment resistnt depression (mjor depressive disorder in dult ptients who do not respond to seprte trils of different ntidepressnts of dequte dose nd durtion in the current episode) is chronic illness requiring chronic tretment. The physicin should periodiclly reexmine the need for continued phrmcotherpy. Sfety of co-dministrtion of doses bove 8 mg olnzpine with 7 mg fluoxetine hs not been evluted in clinicl studies. ZYPREXA monotherpy is not indicted for tretment of tretment resistnt depression (mjor depressive disorder in ptients who do not respond to ntidepressnts of dequte dose nd durtion in the current episode)..7 ZYPREXA nd Fluoxetine in Combintion: Dosing in Specil Popultions The strting dose of orl olnzpine.- mg with fluoxetine mg should be used for ptients with predisposition to hypotensive rections, ptients with heptic impirment, or ptients who exhibit combintion of fctors tht my slow the metbolism of olnzpine or fluoxetine in combintion (femle gender, geritric ge, nonsmoking sttus), or those ptients who my be phrmcodynmiclly sensitive to olnzpine. Dosing modifiction my be necessry in ptients who exhibit combintion of fctors tht my slow metbolism. When indicted, dose escltion should be performed with cution in these ptients. ZYPREXA nd fluoxetine in combintion hve not been systemticlly studied in ptients over yers of ge or in ptients under yers of ge [see Wrnings nd Precutions (.), Drug Interctions (7), nd Clinicl Phrmcology (.)]. DOSAGE FORMS AND STRENGTHS The ZYPREXA. mg, mg, 7. mg, nd mg tblets re white, round, nd imprinted in blue ink with LILLY nd tblet number. The mg tblets re ellipticl, blue, nd debossed with LILLY nd tblet number. The mg tblets re ellipticl, pink, nd debossed with LILLY nd tblet number. Tblets re not scored. The tblets re vilble s follows: Tblet No. Identifiction. mg LILLY mg LILLY TABLET STRENGTH 7. mg mg 7 LILLY LILLY 7 mg LILLY mg LILLY

8 8 ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) re yellow, round, nd debossed with the tblet strength. Tblets re not scored. The tblets re vilble s follows: ZYPREXA ZYDIS Tblets Tblet No. Debossed mg TABLET STRENGTH mg mg mg ZYPREXA IntrMusculr is vilble in mg vil (s). CONTRAINDICATIONS None with ZYPREXA monotherpy. When using ZYPREXA nd fluoxetine in combintion, lso refer to the Contrindictions section of the pckge insert for Symbyx. For specific informtion bout the contrindictions of lithium or vlprote, refer to the Contrindictions section of the pckge inserts for these other products. WARNINGS AND PRECAUTIONS When using ZYPREXA nd fluoxetine in combintion, lso refer to the Wrnings nd Precutions section of the pckge insert for Symbyx.. Elderly Ptients with Dementi-Relted Psychosis Incresed Mortlity Elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth. ZYPREXA is not pproved for the tretment of ptients with dementi-relted psychosis [see Boxed Wrning, Wrnings nd Precutions (.), nd Ptient Counseling Informtion (7.)]. In plcebo-controlled clinicl trils of elderly ptients with dementi-relted psychosis, the incidence of deth in olnzpine-treted ptients ws significntly greter thn plcebo-treted ptients (.% vs.%, respectively). Cerebrovsculr Adverse Events (CVAE), Including Stroke Cerebrovsculr dverse events (e.g., stroke, trnsient ischemic ttck), including ftlities, were reported in ptients in trils of olnzpine in elderly ptients with dementi-relted psychosis. In plcebo-controlled trils, there ws significntly higher incidence of cerebrovsculr dverse events in ptients treted with olnzpine compred to ptients treted with plcebo. is not pproved for the tretment of ptients with dementi-relted psychosis [see Boxed Wrning nd Ptient Counseling Informtion (7.)].. Suicide The possibility of suicide ttempt is inherent in schizophreni nd in bipolr I disorder, nd close supervision of high-risk ptients should ccompny drug therpy. Prescriptions for olnzpine should be written for the smllest quntity of tblets consistent with good ptient mngement, in order to reduce the risk of overdose.. Neuroleptic Mlignnt Syndrome (NMS) A potentilly ftl symptom complex sometimes referred to s Neuroleptic Mlignnt Syndrome (NMS) hs been reported in ssocition with dministrtion of ntipsychotic drugs, including olnzpine. Clinicl mnifesttions of NMS re hyperpyrexi, muscle rigidity, ltered mentl sttus nd evidence of utonomic instbility (irregulr pulse or blood pressure, tchycrdi, diphoresis nd crdic dysrhythmi). Additionl signs my include elevted cretinine phosphokinse, myoglobinuri (rhbdomyolysis), nd cute renl filure. The dignostic evlution of ptients with this syndrome is complicted. In rriving t dignosis, it is importnt to exclude cses where the clinicl presenttion includes both serious medicl illness (e.g., pneumoni, systemic infection, etc.) nd untreted or indequtely treted extrpyrmidl signs nd symptoms (EPS). Other importnt considertions in the differentil dignosis include centrl nticholinergic toxicity, het stroke, drug fever, nd primry centrl nervous system pthology. The mngement of NMS should include: ) immedite discontinution of ntipsychotic drugs nd other drugs not essentil to concurrent therpy; ) intensive symptomtic tretment nd medicl monitoring; nd ) tretment of ny concomitnt serious medicl problems for which specific tretments re vilble. There is no generl greement bout specific phrmcologicl tretment regimens for NMS. If ptient requires ntipsychotic drug tretment fter recovery from NMS, the potentil reintroduction of drug therpy should be crefully considered. The ptient should be crefully monitored, since recurrences of NMS hve been reported [see Ptient Counseling Informtion (7.)].. Metbolic Chnges Atypicl ntipsychotic drugs hve been ssocited with metbolic chnges including hyperglycemi, dyslipidemi, nd weight gin. Metbolic chnges my be ssocited with incresed crdiovsculr/cerebrovsculr risk. s specific metbolic profile is presented below. Hyperglycemi nd Dibetes Mellitus

9 Physicins should consider the risks nd benefits when prescribing olnzpine to ptients with n estblished dignosis of dibetes mellitus, or hving borderline incresed blood glucose level (fsting - mg/dl, nonfsting - mg/dl). Ptients tking olnzpine should be monitored regulrly for worsening of glucose control. Ptients strting tretment with olnzpine should undergo fsting blood glucose testing t the beginning of tretment nd periodiclly during tretment. Any ptient treted with typicl ntipsychotics should be monitored for symptoms of hyperglycemi including polydipsi, polyuri, polyphgi, nd wekness. Ptients who develop symptoms of hyperglycemi during tretment with typicl ntipsychotics should undergo fsting blood glucose testing. In some cses, hyperglycemi hs resolved when the typicl ntipsychotic ws discontinued; however, some ptients required continution of nti-dibetic tretment despite discontinution of the suspect drug [see Ptient Counseling Informtion (7.)]. Hyperglycemi, in some cses extreme nd ssocited with ketocidosis or hyperosmolr com or deth, hs been reported in ptients treted with typicl ntipsychotics including olnzpine. Assessment of the reltionship between typicl ntipsychotic use nd glucose bnormlities is complicted by the possibility of n incresed bckground risk of dibetes mellitus in ptients with schizophreni nd the incresing incidence of dibetes mellitus in the generl popultion. Epidemiologicl studies suggest n incresed risk of tretment-emergent hyperglycemi-relted dverse rections in ptients treted with the typicl ntipsychotics. While reltive risk estimtes re inconsistent, the ssocition between typicl ntipsychotics nd increses in glucose levels ppers to fll on continuum nd olnzpine ppers to hve greter ssocition thn some other typicl ntipsychotics. Men increses in blood glucose hve been observed in ptients treted (medin exposure of. months) with olnzpine in phse of the Clinicl Antipsychotic Trils of Intervention Effectiveness (CATIE). The men increse of serum glucose (fsting nd nonfsting smples) from bseline to the verge of the highest serum concentrtions ws. mg/dl. In study of helthy volunteers, subjects who received olnzpine (N=) for weeks hd men increse compred to bseline in fsting blood glucose of. mg/dl. Plcebo-treted subjects (N=) hd men increse in fsting blood glucose compred to bseline of. mg/dl. Monotherpy in Adults In n nlysis of plcebo-controlled dult olnzpine monotherpy studies with medin tretment durtion of pproximtely weeks, olnzpine ws ssocited with greter men chnge in fsting glucose levels compred to plcebo (.7 mg/dl versus.7 mg/dl). The difference in men chnges between olnzpine nd plcebo ws greter in ptients with evidence of glucose dysregultion t bseline (ptients dignosed with dibetes mellitus or relted dverse rections, ptients treted with nti-dibetic gents, ptients with bseline rndom glucose level mg/dl, nd/or bseline fsting glucose level mg/dl). -treted ptients hd greter men HbAc increse from bseline of.% (medin exposure dys), compred to men HbAc decrese of.% in plcebo-treted subjects (medin exposure 7 dys). In n nlysis of 8 plcebo-controlled studies (medin tretment exposure - weeks),.% of olnzpine-treted subjects (N=8) hd tretment-emergent glycosuri compred to.8% of plcebo-treted subjects (N=). Tble shows short-term nd long-term chnges in fsting glucose levels from dult olnzpine monotherpy studies. Tble : Chnges in Fsting Glucose Levels from Adult Monotherpy Studies Up to weeks At lest 8 weeks exposure exposure Lbortory Ctegory Chnge (t lest once) Tretment Anlyte from Bseline Arm N Ptients N Ptients Norml to High.%.8% Fsting (< mg/dl to mg/dl) Plcebo.% Glucose Borderline to High 78 7.% 7.% ( mg/dl nd < mg/dl to mg/dl) Plcebo.% Not Applicble. The men chnge in fsting glucose for ptients exposed t lest 8 weeks ws. mg/dl (N=87). In nlyses of ptients who completed - months of olnzpine therpy, men chnge in fsting nd nonfsting glucose levels continued to increse over time. Monotherpy in Adolescents The sfety nd efficcy of olnzpine hve not been estblished in ptients under the ge of yers. In n nlysis of plcebo-controlled olnzpine monotherpy studies of dolescent ptients, including those with schizophreni ( weeks) or bipolr I disorder (mnic or mixed episodes) ( weeks), olnzpine ws ssocited with greter men chnge from bseline in fsting glucose levels compred to plcebo (.8 mg/dl versus -. mg/dl). The men chnge in fsting glucose for dolescents exposed t lest weeks ws. mg/dl (N=). Tble shows short-term nd long-term chnges in fsting blood glucose from dolescent olnzpine monotherpy studies.

10 Tble : Chnges in Fsting Glucose Levels from Adolescent Monotherpy Studies Up to weeks At lest weeks exposure exposure Lbortory Ctegory Chnge (t lest once) Tretment Anlyte from Bseline Arm N Ptients N Ptients Norml to High % 8.% Fsting (< mg/dl to mg/dl) Plcebo.% Glucose Borderline to High.%.% ( mg/dl nd < mg/dl to mg/dl) Plcebo % Not Applicble. Dyslipidemi Undesirble ltertions in lipids hve been observed with olnzpine use. Clinicl monitoring, including bseline nd periodic follow-up lipid evlutions in ptients using olnzpine, is recommended [see Ptient Counseling Informtion (7.)]. Cliniclly significnt, nd sometimes very high (> mg/dl), elevtions in triglyceride levels hve been observed with olnzpine use. Modest men increses in totl cholesterol hve lso been seen with olnzpine use. Monotherpy in Adults In n nlysis of plcebo-controlled olnzpine monotherpy studies with tretment durtion up to weeks, olnzpine-treted ptients hd increses from bseline in men fsting totl cholesterol, LDL cholesterol, nd triglycerides of. mg/dl,. mg/dl, nd.8 mg/dl respectively compred to decreses from bseline in men fsting totl cholesterol, LDL cholesterol, nd triglycerides of. mg/dl,. mg/dl, nd.7 mg/dl for plcebo-treted ptients. For fsting HDL cholesterol, no cliniclly meningful differences were observed between olnzpine-treted ptients nd plcebo-treted ptients. Men increses in fsting lipid vlues (totl cholesterol, LDL cholesterol, nd triglycerides) were greter in ptients without evidence of lipid dysregultion t bseline, where lipid dysregultion ws defined s ptients dignosed with dyslipidemi or relted dverse rections, ptients treted with lipid lowering gents, or ptients with high bseline lipid levels. In long-term studies (t lest 8 weeks), ptients hd increses from bseline in men fsting totl cholesterol, LDL cholesterol, nd triglycerides of. mg/dl,. mg/dl, nd 8.7 mg/dl, respectively, nd men decrese in fsting HDL cholesterol of. mg/dl. In n nlysis of ptients who completed months of therpy, the men nonfsting totl cholesterol did not increse further fter pproximtely - months. The proportion of ptients who hd chnges (t lest once) in totl cholesterol, LDL cholesterol or triglycerides from norml or borderline to high, or chnges in HDL cholesterol from norml or borderline to low, ws greter in longterm studies (t lest 8 weeks) s compred with short-term studies. Tble shows ctegoricl chnges in fsting lipids vlues. Tble : Chnges in Fsting Lipids Vlues from Adult Monotherpy Studies Up to weeks At lest 8 weeks exposure exposure Lbortory Ctegory Chnge (t lest once) Tretment Anlyte from Bseline Arm N Ptients N Ptients Increse by mg/dl 7.% 87.% Plcebo.% Fsting Norml to High 7.%.% Triglycerides (< mg/dl to mg/dl) Plcebo.% Borderline to High.% 7 7.7% ( mg/dl nd < mg/dl to mg/dl) Plcebo.% Increse by mg/dl Fsting Totl Cholesterol Norml to High (< mg/dl to mg/dl) Borderline to High ( mg/dl nd < mg/dl to mg/dl) Increse by mg/dl Fsting LDL Cholesterol Norml to High (< mg/dl to mg/dl) Borderline to High Plcebo Plcebo Plcebo 7 7.%.%.8%.%.%.% 8 8.%.8%.% Plcebo Plcebo 8.7%.% %.%.% 8 8.8% 7.%.%

11 ( mg/dl nd < mg/dl to mg/dl) Not Applicble. Plcebo 7 8.% In phse of the Clinicl Antipsychotic Trils of Intervention Effectiveness (CATIE), over medin exposure of. months, the men increse in triglycerides in ptients tking olnzpine ws. mg/dl. In phse of CATIE, the men increse in totl cholesterol ws. mg/dl. Monotherpy in Adolescents The sfety nd efficcy of olnzpine hve not been estblished in ptients under the ge of yers. In n nlysis of plcebo-controlled olnzpine monotherpy studies of dolescents, including those with schizophreni ( weeks) or bipolr I disorder (mnic or mixed episodes) ( weeks), olnzpinetreted dolescents hd increses from bseline in men fsting totl cholesterol, LDL cholesterol, nd triglycerides of. mg/dl,. mg/dl, nd 8. mg/dl, respectively, compred to increses from bseline in men fsting totl cholesterol nd LDL cholesterol of. mg/dl nd. mg/dl, nd decrese in triglycerides of. mg/dl for plcebotreted dolescents. For fsting HDL cholesterol, no cliniclly meningful differences were observed between olnzpinetreted dolescents nd plcebo-treted dolescents. In long-term studies (t lest weeks), dolescents hd increses from bseline in men fsting totl cholesterol, LDL cholesterol, nd triglycerides of. mg/dl,. mg/dl, nd. mg/dl, respectively, nd men decrese in fsting HDL cholesterol of. mg/dl. Tble shows ctegoricl chnges in fsting lipids vlues in dolescents. Tble : Chnges in Fsting Lipids Vlues from Adolescent Monotherpy Studies Up to weeks At lest weeks exposure exposure Lbortory Ctegory Chnge (t lest once) Tretment Anlyte from Bseline Arm N Ptients N Ptients Increse by mg/dl 8 7.%.% Plcebo.% Fsting Norml to High 7.%.% Triglycerides (< mg/dl to > mg/dl) Plcebo 8.7% Borderline to High 7.%.% ( mg/dl nd mg/dl to > mg/dl) Plcebo 7.% Increse by mg/dl Fsting Totl Cholesterol Norml to High (<7 mg/dl to mg/dl) Borderline to High ( 7 mg/dl nd < mg/dl to mg/dl) Increse by mg/dl Fsting LDL Cholesterol Norml to High (< mg/dl to mg/dl) Borderline to High ( mg/dl nd < mg/dl to mg/dl) Not Applicble. Plcebo Plcebo Plcebo 8 87.%.%.%.% 8.% 7.7% 78.8% 7.7% 7.% Plcebo Plcebo Plcebo %.%.%.% 8.% %.%.% 7.% Weight Gin Potentil consequences of weight gin should be considered prior to strting olnzpine. Ptients receiving olnzpine should receive regulr monitoring of weight [see Ptient Counseling Informtion (7.)]. Monotherpy in Adults In n nlysis of plcebo-controlled olnzpine monotherpy studies, olnzpine-treted ptients gined n verge of. kg (.7 lb) compred to n verge. kg (. lb) weight loss in plcebo-treted ptients with medin exposure of weeks;.% of olnzpine-treted ptients gined t lest 7% of their bseline weight, compred to % of plcebo-treted ptients, with medin exposure to event of 8 weeks;.% of olnzpine-treted ptients gined t lest % of their bseline weight, compred to.% of plcebo-treted ptients, with medin exposure to event of weeks. Cliniclly significnt weight gin ws observed cross ll bseline Body Mss Index (BMI) ctegories. Discontinution due to weight gin occurred in.% of olnzpine-treted ptients nd in % of plcebo-treted ptients. In long-term studies (t lest 8 weeks), the men weight gin ws. kg (. lb) (medin exposure of 7 dys, N=). The percentges of ptients who gined t lest 7%, %, or % of their bseline body weight with long-term exposure were %, %, nd %, respectively. Discontinution due to weight gin occurred in.% of olnzpinetreted ptients following t lest 8 weeks of exposure.

12 Tble includes dt on dult weight gin with olnzpine pooled from 8 clinicl trils. The dt in ech column represent dt for those ptients who completed tretment periods of the durtions specified. Tble : Weight Gin with Use in Adults Weeks Months Months Months Months Amount Gined (N=7) (N=) (N=) (N=7) (N=7) kg (lb) (%) (%) (%) (%) (%) to (- lb) > to (- lb) > to (- lb) > to (- lb) > to (- lb).... > to (- lb)....8 > (> lb)..8. Dose group differences with respect to weight gin hve been observed. In single 8-week rndomized, doubleblind, fixed-dose study compring (N=), (N=) nd (N=) mg/dy of orl olnzpine in dult ptients with schizophreni or schizoffective disorder, men bseline to endpoint increse in weight ( mg/dy:. kg; mg/dy:. kg; mg/dy: kg) ws observed with significnt differences between vs mg/dy. Monotherpy in Adolescents The sfety nd efficcy of olnzpine hve not been estblished in ptients under the ge of yers. Men increse in weight in dolescents ws greter thn in dults. In plcebocontrolled trils, discontinution due to weight gin occurred in % of olnzpine-treted ptients, compred to % of plcebo-treted ptients. Tble 7: Weight Gin with Use in Adolescents from Plcebo-Controlled Trils -treted ptients Plcebo-treted ptients Men chnge in body weight from. kg (. lb). kg (.7 lb) bseline (medin exposure = weeks) Percentge of ptients who gined t.%.8% lest 7% of bseline body weight (medin exposure to 7% = weeks) (medin exposure to 7% = 8 weeks) Percentge of ptients who gined t 7.%.7% lest % of bseline body weight (medin exposure to % = weeks) (medin exposure to % = 8 weeks) In long-term studies (t lest weeks), the men weight gin ws. kg (. lb); (medin exposure of dys, N=7). The percentges of dolescents who gined t lest 7%, %, or % of their bseline body weight with long-term exposure were 8%, %, nd %, respectively. Among dolescent ptients, men weight gin by bseline BMI ctegory ws. kg (. lb),. kg (. lb), nd.7 kg (7. lb), respectively, for norml (N=), overweight (N=) nd obese (N=7). Discontinution due to weight gin occurred in.% of olnzpine-treted ptients following t lest weeks of exposure. Tble 8 shows dt on dolescent weight gin with olnzpine pooled from clinicl trils. The dt in ech column represent dt for those ptients who completed tretment periods of the durtions specified. Little clinicl tril dt is vilble on weight gin in dolescents with olnzpine beyond months of tretment. Tble 8: Weight Gin with Use in Adolescents Weeks Months Amount Gined (N=) (N=) kg (lb) (%) (%).. to (- lb) 7.. > to (- lb)..7 > to (- lb).8. > to (- lb).8. > to (- lb).8. > to (- lb). > to (-77 lb) > to (77-88 lb) > (>88 lb).

13 Trdive Dyskinesi A syndrome of potentilly irreversible, involuntry, dyskinetic movements my develop in ptients treted with ntipsychotic drugs. Although the prevlence of the syndrome ppers to be highest mong the elderly, especilly elderly women, it is impossible to rely upon prevlence estimtes to predict, t the inception of ntipsychotic tretment, which ptients re likely to develop the syndrome. Whether ntipsychotic drug products differ in their potentil to cuse trdive dyskinesi is unknown. The risk of developing trdive dyskinesi nd the likelihood tht it will become irreversible re believed to increse s the durtion of tretment nd the totl cumultive dose of ntipsychotic drugs dministered to the ptient increse. However, the syndrome cn develop, lthough much less commonly, fter reltively brief tretment periods t low doses or my even rise fter discontinution of tretment. There is no known tretment for estblished cses of trdive dyskinesi, lthough the syndrome my remit, prtilly or completely, if ntipsychotic tretment is withdrwn. Antipsychotic tretment, itself, however, my suppress (or prtilly suppress) the signs nd symptoms of the syndrome nd thereby my possibly msk the underlying process. The effect tht symptomtic suppression hs upon the long-term course of the syndrome is unknown. Given these considertions, olnzpine should be prescribed in mnner tht is most likely to minimize the occurrence of trdive dyskinesi. Chronic ntipsychotic tretment should generlly be reserved for ptients () who suffer from chronic illness tht is known to respond to ntipsychotic drugs, nd () for whom lterntive, eqully effective, but potentilly less hrmful tretments re not vilble or pproprite. In ptients who do require chronic tretment, the smllest dose nd the shortest durtion of tretment producing stisfctory clinicl response should be sought. The need for continued tretment should be ressessed periodiclly. If signs nd symptoms of trdive dyskinesi pper in ptient on olnzpine, drug discontinution should be considered. However, some ptients my require tretment with olnzpine despite the presence of the syndrome. For specific informtion bout the wrnings of lithium or vlprote, refer to the Wrnings section of the pckge inserts for these other products.. Orthosttic Hypotension my induce orthosttic hypotension ssocited with dizziness, tchycrdi, brdycrdi nd, in some ptients, syncope, especilly during the initil dose-titrtion period, probbly reflecting its α-drenergic ntgonistic properties [see Ptient Counseling Informtion (7.7)]. From n nlysis of the vitl sign dt in n integrted dtbse of completed clinicl studies in dult ptients treted with orl olnzpine, orthosttic hypotension ws recorded in % (77/) of ptients. For orl olnzpine therpy, the risk of orthosttic hypotension nd syncope my be minimized by inititing therpy with mg QD [see Dosge nd Administrtion ()]. A more grdul titrtion to the trget dose should be considered if hypotension occurs. Hypotension, brdycrdi with or without hypotension, tchycrdi, nd syncope were lso reported during the clinicl trils with intrmusculr olnzpine for injection. In n open-lbel clinicl phrmcology study in nongitted ptients with schizophreni in which the sfety nd tolerbility of intrmusculr olnzpine were evluted under mximl dosing regimen (three mg doses dministered hours prt), pproximtely one-third of these ptients experienced significnt orthosttic decrese in systolic blood pressure (i.e., decrese mmhg) [see Dosge nd Administrtion (.)]. Syncope ws reported in.% (/) of olnzpine-treted ptients in phse - orl olnzpine studies nd in.% (/7) of olnzpine-treted ptients with gittion in the intrmusculr olnzpine for injection studies. Three norml volunteers in phse studies with intrmusculr olnzpine experienced hypotension, brdycrdi, nd sinus puses of up to seconds tht spontneously resolved (in cses the rections occurred on intrmusculr olnzpine, nd in cse, on orl olnzpine). The risk for this sequence of hypotension, brdycrdi, nd sinus puse my be greter in nonpsychitric ptients compred to psychitric ptients who re possibly more dpted to certin effects of psychotropic drugs. For intrmusculr olnzpine for injection therpy, ptients should remin recumbent if drowsy or dizzy fter injection until exmintion hs indicted tht they re not experiencing posturl hypotension, brdycrdi, nd/or hypoventiltion. should be used with prticulr cution in ptients with known crdiovsculr disese (history of myocrdil infrction or ischemi, hert filure, or conduction bnormlities), cerebrovsculr disese, nd conditions which would predispose ptients to hypotension (dehydrtion, hypovolemi, nd tretment with ntihypertensive medictions) where the occurrence of syncope, or hypotension nd/or brdycrdi might put the ptient t incresed medicl risk. Cution is necessry in ptients who receive tretment with other drugs hving effects tht cn induce hypotension, brdycrdi, respirtory or centrl nervous system depression [see Drug Interctions (7)]. Concomitnt dministrtion of intrmusculr olnzpine nd prenterl benzodizepine is not recommended due to the potentil for excessive sedtion nd crdiorespirtory depression..7 Leukopeni, Neutropeni, nd Agrnulocytosis Clss Effect In clinicl tril nd/or postmrketing experience, events of leukopeni/neutropeni hve been reported temporlly relted to ntipsychotic gents, including ZYPREXA. Agrnulocytosis hs lso been reported. Possible risk fctors for leukopeni/neutropeni include pre-existing low white blood cell count (WBC) nd history of drug induced leukopeni/neutropeni. Ptients with history of cliniclly significnt low WBC or drug induced.

14 leukopeni/neutropeni should hve their complete blood count (CBC) monitored frequently during the first few months of therpy nd discontinution of ZYPREXA should be considered t the first sign of cliniclly significnt decline in WBC in the bsence of other custive fctors. Ptients with cliniclly significnt neutropeni should be crefully monitored for fever or other symptoms or signs of infection nd treted promptly if such symptoms or signs occur. Ptients with severe neutropeni (bsolute neutrophil count </mm) should discontinue ZYPREXA nd hve their WBC followed until recovery..8 Dysphgi Esophgel dysmotility nd spirtion hve been ssocited with ntipsychotic drug use. Aspirtion pneumoni is common cuse of morbidity nd mortlity in ptients with dvnced Alzheimer s disese. is not pproved for the tretment of ptients with Alzheimer s disese.. Seizures During premrketing testing, seizures occurred in.% (/) of olnzpine-treted ptients. There were confounding fctors tht my hve contributed to the occurrence of seizures in mny of these cses. should be used cutiously in ptients with history of seizures or with conditions tht potentilly lower the seizure threshold, e.g., Alzheimer s dementi. is not pproved for the tretment of ptients with Alzheimer s disese. Conditions tht lower the seizure threshold my be more prevlent in popultion of yers or older.. Potentil for Cognitive nd Motor Impirment Somnolence ws commonly reported dverse rection ssocited with olnzpine tretment, occurring t n incidence of % in olnzpine ptients compred to % in plcebo ptients. This dverse rection ws lso dose relted. Somnolence led to discontinution in.% (/) of ptients in the premrketing dtbse. Since olnzpine hs the potentil to impir judgment, thinking, or motor skills, ptients should be cutioned bout operting hzrdous mchinery, including utomobiles, until they re resonbly certin tht olnzpine therpy does not ffect them dversely [see Ptient Counseling Informtion (7.8)].. Body Temperture Regultion Disruption of the body s bility to reduce core body temperture hs been ttributed to ntipsychotic gents. Approprite cre is dvised when prescribing olnzpine for ptients who will be experiencing conditions which my contribute to n elevtion in core body temperture, e.g., exercising strenuously, exposure to extreme het, receiving concomitnt mediction with nticholinergic ctivity, or being subject to dehydrtion [see Ptient Counseling Informtion (7.)].. Use in Ptients with Concomitnt Illness Clinicl experience with olnzpine in ptients with certin concomitnt systemic illnesses is limited [see Clinicl Phrmcology (.)]. exhibits in vitro muscrinic receptor ffinity. In premrketing clinicl trils with olnzpine, olnzpine ws ssocited with constiption, dry mouth, nd tchycrdi, ll dverse rections possibly relted to cholinergic ntgonism. Such dverse rections were not often the bsis for discontinutions from olnzpine, but olnzpine should be used with cution in ptients with cliniclly significnt prosttic hypertrophy, nrrow ngle glucom, or history of prlytic ileus or relted conditions. In plcebo-controlled studies of olnzpine in elderly ptients with dementi-relted psychosis (n=8), the following tretment-emergent dverse rections were reported in olnzpine-treted ptients t n incidence of t lest % nd significntly greter thn plcebo-treted ptients: flls, somnolence, peripherl edem, bnorml git, urinry incontinence, lethrgy, incresed weight, stheni, pyrexi, pneumoni, dry mouth nd visul hllucintions. The rte of discontinution due to dverse rections ws greter with olnzpine thn plcebo (% vs 7%). Elderly ptients with dementi-relted psychosis treted with olnzpine re t n incresed risk of deth compred to plcebo. is not pproved for the tretment of ptients with dementi-relted psychosis [see Boxed Wrning, Wrnings nd Precutions (.), nd Ptient Counseling Informtion (7.)]. hs not been evluted or used to ny pprecible extent in ptients with recent history of myocrdil infrction or unstble hert disese. Ptients with these dignoses were excluded from premrketing clinicl studies. Becuse of the risk of orthosttic hypotension with olnzpine, cution should be observed in crdic ptients [see Wrnings nd Precutions (.)].. Hyperprolctinemi As with other drugs tht ntgonize dopmine D receptors, olnzpine elevtes prolctin levels, nd the elevtion persists during chronic dministrtion. Hyperprolctinemi my suppress hypothlmic GnRH, resulting in reduced pituitry gondotropin secretion. This, in turn, my inhibit reproductive function by impiring gondl steroidogenesis in both femle nd mle ptients. Glctorrhe, menorrhe, gynecomsti, nd impotence hve been reported in ptients receiving prolctin-elevting compounds. Long-stnding hyperprolctinemi when ssocited with hypogondism my led to decresed bone density in both femle nd mle subjects. Tissue culture experiments indicte tht pproximtely one-third of humn brest cncers re prolctin dependent in vitro, fctor of potentil importnce if the prescription of these drugs is contemplted in ptient with previously detected brest cncer. As is common with compounds which increse prolctin relese, n increse in mmmry glnd neoplsi ws observed in the olnzpine crcinogenicity studies conducted in mice nd rts [see Nonclinicl Toxicology

15 (.)]. Neither clinicl studies nor epidemiologic studies conducted to dte hve shown n ssocition between chronic dministrtion of this clss of drugs nd tumorigenesis in humns; the vilble evidence is considered too limited to be conclusive t this time. In plcebo-controlled olnzpine clinicl studies (up to weeks), chnges from norml to high in prolctin concentrtions were observed in % of dults treted with olnzpine s compred to.% of dults treted with plcebo. In pooled nlysis from clinicl studies including 8 dults treted with olnzpine, potentilly ssocited clinicl mnifesttions included menstrul-relted events (% [/] of femles), sexul function-relted events (% [/8] of femles nd mles), nd brest-relted events (.7% [/] of femles,.% [/8] of mles). In plcebo-controlled olnzpine monotherpy studies in dolescent ptients (up to weeks) with schizophreni or bipolr I disorder (mnic or mixed episodes), chnges from norml to high in prolctin concentrtions were observed in 7% of olnzpine-treted ptients compred to 7% of plcebo-treted ptients. In pooled nlysis from clinicl trils including dolescents treted with olnzpine, potentilly ssocited clinicl mnifesttions included menstrul relted events (% [/8] of femles), sexul function-relted events (.7% [/] of femles nd mles), nd brest relted events (% [/8] of femles, % [7/8] of mles) [see Use in Specific Popultions (8.)]. Bsed on serch of the following terms: menorrhe, hypomenorrhe, menstrution delyed, nd oligomenorrhe. Bsed on serch of the following terms: norgsmi, delyed ejcultion, erectile dysfunction, decresed libido, loss of libido, bnorml orgsm, nd sexul dysfunction. Bsed on serch of the following terms: brest dischrge, enlrgement or swelling, glctorrhe, gynecomsti, nd lcttion disorder. Dose group differences with respect to prolctin elevtion hve been observed. In single 8-week rndomized, double-blind, fixed-dose study compring (N=), (N=) nd (N=) mg/dy of orl olnzpine in dult ptients with schizophreni or schizoffective disorder, incidence of prolctin elevtion >. ng/ml (femle) or >8.77 ng/ml (mle) t ny time during the tril ( mg/dy:.%; mg/dy:.7%; mg/dy:.%) indicted significnt differences between vs mg/dy nd vs mg/dy.. Use in Combintion with Fluoxetine, Lithium, or Vlprote When using ZYPREXA nd fluoxetine in combintion, the prescriber should lso refer to the Wrnings nd Precutions section of the pckge insert for Symbyx. When using ZYPREXA in combintion with lithium or vlprote, the prescriber should refer to the Wrnings nd Precutions sections of the pckge inserts for lithium or vlprote [see Drug Interctions (7)].. Lbortory Tests Fsting blood glucose testing nd lipid profile t the beginning of, nd periodiclly during, tretment is recommended [see Wrnings nd Precutions (.) nd Ptient Counseling Informtion (7., 7.)]. ADVERSE REACTIONS When using ZYPREXA nd fluoxetine in combintion, lso refer to the Adverse Rections section of the pckge insert for Symbyx.. Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect or predict the rtes observed in prctice. Clinicl Trils in Adults The informtion below for olnzpine is derived from clinicl tril dtbse for olnzpine consisting of, dult ptients with pproximtely 7 ptient-yers of exposure to olnzpine plus 7 ptients with exposure to intrmusculr olnzpine for injection. This dtbse includes: () ptients who prticipted in multiple-dose orl olnzpine premrketing trils in schizophreni nd Alzheimer s disese representing pproximtely ptient-yers of exposure s of Februry, ; () 8 ptients who prticipted in orl olnzpine premrketing bipolr I disorder (mnic or mixed episodes) trils representing pproximtely ptient-yers of exposure; () ptients who prticipted in n orl olnzpine tril of ptients hving vrious psychitric symptoms in ssocition with Alzheimer s disese representing pproximtely ptient-yers of exposure; () 788 dditionl ptients from 88 orl olnzpine clinicl trils s of December, ; () 8 dditionl ptients from olnzpine clinicl trils s of October, ; nd () 7 ptients who prticipted in intrmusculr olnzpine for injection premrketing trils in gitted ptients with schizophreni, bipolr I disorder (mnic or mixed episodes), or dementi. Also included below is informtion from the premrketing -week clinicl study dtbse for olnzpine in combintion with lithium or vlprote, consisting of ptients who prticipted in bipolr I disorder (mnic or mixed episodes) trils with pproximtely ptient-yers of exposure. The conditions nd durtion of tretment with olnzpine vried gretly nd included (in overlpping ctegories) open-lbel nd double-blind phses of studies, inptients nd outptients, fixed-dose nd dose-titrtion studies, nd short-term or longer-term exposure. Adverse rections were ssessed by collecting dverse rections, results of physicl exmintions, vitl signs, weights, lbortory nlytes, ECGs, chest x-rys, nd results of ophthlmologic exmintions.

16 Certin portions of the discussion below relting to objective or numeric sfety prmeters, nmely, dosedependent dverse rections, vitl sign chnges, weight gin, lbortory chnges, nd ECG chnges re derived from studies in ptients with schizophreni nd hve not been duplicted for bipolr I disorder (mnic or mixed episodes) or gittion. However, this informtion is lso generlly pplicble to bipolr I disorder (mnic or mixed episodes) nd gittion. Adverse rections during exposure were obtined by spontneous report nd recorded by clinicl investigtors using terminology of their own choosing. Consequently, it is not possible to provide meningful estimte of the proportion of individuls experiencing dverse rections without first grouping similr types of rections into smller number of stndrdized rection ctegories. In the tbles nd tbultions tht follow, MedDRA nd COSTART Dictionry terminology hs been used to clssify reported dverse rections. The stted frequencies of dverse rections represent the proportion of individuls who experienced, t lest once, tretment-emergent dverse rection of the type listed. A rection ws considered tretment emergent if it occurred for the first time or worsened while receiving therpy following bseline evlution. The reported rections do not include those rection terms tht were so generl s to be uninformtive. Rections listed elsewhere in lbeling my not be repeted below. It is importnt to emphsize tht, lthough the rections occurred during tretment with olnzpine, they were not necessrily cused by it. The entire lbel should be red to gin complete understnding of the sfety profile of olnzpine. The prescriber should be wre tht the figures in the tbles nd tbultions cnnot be used to predict the incidence of side effects in the course of usul medicl prctice where ptient chrcteristics nd other fctors differ from those tht previled in the clinicl trils. Similrly, the cited frequencies cnnot be compred with figures obtined from other clinicl investigtions involving different tretments, uses, nd investigtors. The cited figures, however, do provide the prescribing physicin with some bsis for estimting the reltive contribution of drug nd nondrug fctors to the dverse rections incidence in the popultion studied. Incidence of Adverse Rections in Short-Term, Plcebo-Controlled nd Combintion Trils The following findings re bsed on premrketing trils of () orl olnzpine for schizophreni, bipolr I disorder (mnic or mixed episodes), subsequent tril of ptients hving vrious psychitric symptoms in ssocition with Alzheimer s disese, nd premrketing combintion trils, nd () intrmusculr olnzpine for injection in gitted ptients with schizophreni or bipolr I mni. Adverse Rections Associted with Discontinution of Tretment in Short-Term, Plcebo-Controlled Trils Schizophreni Overll, there ws no difference in the incidence of discontinution due to dverse rections (% for orl olnzpine vs % for plcebo). However, discontinutions due to increses in ALT were considered to be drug relted (% for orl olnzpine vs % for plcebo). Bipolr I Disorder (Mnic or Mixed Episodes) Monotherpy Overll, there ws no difference in the incidence of discontinution due to dverse rections (% for orl olnzpine vs % for plcebo). Agittion Overll, there ws no difference in the incidence of discontinution due to dverse rections (.% for intrmusculr olnzpine for injection vs % for plcebo). Adverse Rections Associted with Discontinution of Tretment in Short-Term Combintion Trils Bipolr I Disorder (Mnic or Mixed Episodes), s Adjunct to Lithium or Vlprote In study of ptients who were lredy tolerting either lithium or vlprote s monotherpy, discontinution rtes due to dverse rections were % for the combintion of orl olnzpine with lithium or vlprote compred to % for ptients who remined on lithium or vlprote monotherpy. Discontinutions with the combintion of orl olnzpine nd lithium or vlprote tht occurred in more thn ptient were: somnolence (%), weight gin (%), nd peripherl edem (%). Commonly Observed Adverse Rections in Short-Term, Plcebo-Controlled Trils The most commonly observed dverse rections ssocited with the use of orl olnzpine (incidence of % or greter) nd not observed t n equivlent incidence mong plcebo-treted ptients (olnzpine incidence t lest twice tht for plcebo) were: Tble : Common Tretment-Emergent Adverse Rections Associted with the Use of Orl in -Week Trils SCHIZOPHRENIA Percentge of Ptients Reporting Event Plcebo Adverse Rection (N=8) (N=8) Posturl hypotension Constiption Weight gin Dizziness Personlity disorder 8

17 7 Akthisi Personlity disorder is the COSTART term for designting nonggressive objectionble behvior. Tble : Common Tretment-Emergent Adverse Rections Associted with the Use of Orl in -Week nd -Week Trils Bipolr I Disorder (Mnic or Mixed Episodes) Percentge of Ptients Reporting Event Plcebo Adverse Rection (N=) (N=) Astheni Dry mouth 7 Constiption Dyspepsi Incresed ppetite Somnolence Dizziness 8 Tremor Intrmusculr There ws dverse rection (somnolence) observed t n incidence of % or greter mong intrmusculr olnzpine for injection-treted ptients nd not observed t n equivlent incidence mong plcebo-treted ptients (olnzpine incidence t lest twice tht for plcebo) during the plcebo-controlled premrketing studies. The incidence of somnolence during the hour IM tretment period in clinicl trils in gitted ptients with schizophreni or bipolr I mni ws % for intrmusculr olnzpine for injection nd % for plcebo. Adverse Rections Occurring t n Incidence of % or More mong Orl -Treted Ptients in ShortTerm, Plcebo-Controlled Trils Tble enumertes the incidence, rounded to the nerest percent, of tretment-emergent dverse rections tht occurred in % or more of ptients treted with orl olnzpine (doses. mg/dy) nd with incidence greter thn plcebo who prticipted in the cute phse of plcebo-controlled trils. Tble : Tretment-Emergent Adverse Rections: Incidence in Short-Term, Plcebo-Controlled Clinicl Trils with Orl Percentge of Ptients Reporting Event Plcebo Body System/Adverse Rection (N=) (N=) Body s Whole Accidentl injury 8 Astheni Fever Bck pin Chest pin Crdiovsculr System Posturl hypotension Tchycrdi Hypertension Digestive System Dry mouth Constiption Dyspepsi 7 Vomiting Incresed ppetite Hemic nd Lymphtic System Ecchymosis Metbolic nd Nutritionl Disorders Weight gin Peripherl edem Musculoskeletl System Extremity pin (other thn joint) Joint pin Nervous System Somnolence

18 8 Insomni Dizziness Abnorml git Tremor Akthisi Hypertoni Articultion impirment Respirtory System Rhinitis Cough incresed Phryngitis Specil Senses Amblyopi Urogenitl System Urinry incontinence Urinry trct infection 7 Dose Dependency of Adverse Rections A dose group difference hs been observed for ftigue, dizziness, weight gin nd prolctin elevtion. In single 8-week rndomized, double-blind, fixed-dose study compring (N=), (N=) nd (N=) mg/dy of orl olnzpine in dult ptients with schizophreni or schizoffective disorder, incidence of ftigue ( mg/dy:.%; mg/dy:.%; mg/dy:.%) ws observed with significnt differences between vs nd vs mg/dy. The incidence of dizziness ( mg/dy:.%; mg/dy:.%; mg/dy:.%) ws observed with significnt differences between vs mg. Dose group differences were lso noted for weight gin nd prolctin elevtion [see Wrnings nd Precutions (.,.)]. The following tble ddresses dose reltedness for other dverse rections using dt from schizophreni tril involving fixed dosge rnges of orl olnzpine. It enumertes the percentge of ptients with tretment-emergent dverse rections for the fixed-dose rnge groups nd plcebo. The dt were nlyzed using the Cochrn-Armitge test, excluding the plcebo group, nd the tble includes only those dverse rections for which there ws trend. Tble : Percentge of Ptients from Schizophreni Tril with Tretment-Emergent Adverse Rections for the Dose Rnge Groups nd Plcebo Percentge of Ptients Reporting Event Plcebo ±. mg/dy ±. mg/dy ±. mg/dy Adverse Rection (N=8) (N=) (N=) (N=) Astheni 8 Dry mouth Nuse Somnolence Tremor 7 Commonly Observed Adverse Rections in Short-Term Trils of Orl s Adjunct to Lithium or Vlprote In the bipolr I disorder (mnic or mixed episodes) djunct plcebo-controlled trils, the most commonly observed dverse rections ssocited with the combintion of olnzpine nd lithium or vlprote (incidence of % nd t lest twice plcebo) were: Tble : Common Tretment-Emergent Adverse Rections Associted with the Use of Orl in -Week Adjunct to Lithium or Vlprote Trils Bipolr I Disorder (Mnic or Mixed Episodes) Percentge of Ptients Reporting Event with Plcebo with lithium or vlprote lithium or vlprote Adverse Rection (N=) (N=) Dry mouth Weight gin 7 Incresed ppetite 8 Dizziness 7 Bck pin 8

19 Constiption Speech disorder Incresed slivtion Amnesi Presthesi 8 7 Adverse Rections Occurring t n Incidence of % or More mong Orl -Treted Ptients in ShortTerm Trils of s Adjunct to Lithium or Vlprote Tble enumertes the incidence, rounded to the nerest percent, of tretment-emergent dverse rections tht occurred in % or more of ptients treted with the combintion of olnzpine (doses mg/dy) nd lithium or vlprote nd with incidence greter thn lithium or vlprote lone who prticipted in the cute phse of plcebo-controlled combintion trils. Tble : Tretment-Emergent Adverse Rections: Incidence in Short-Term, Plcebo-Controlled Clinicl Trils of Orl s Adjunct to Lithium or Vlprote Percentge of Ptients Reporting Event with Plcebo with lithium or vlprote lithium or vlprote Body System/Adverse Rection (N=) (N=) Body s Whole Astheni 8 Bck pin 8 Accidentl injury Chest pin Crdiovsculr System Hypertension Digestive System Dry mouth Incresed ppetite 8 Thirst Constiption 8 Incresed slivtion Metbolic nd Nutritionl Disorders Weight gin 7 Peripherl edem Edem Nervous System Somnolence 7 Tremor Depression 8 7 Dizziness 7 Speech disorder 7 Amnesi Presthesi Apthy Confusion Euphori Incoordintion Respirtory System Phryngitis Dyspne Skin nd Appendges Sweting Acne Dry skin Specil Senses Amblyopi Abnorml vision Urogenitl System Dysmenorrhe

20 Vginitis Denomintor used ws for femles only (olnzpine, N=8; plcebo, N=). For specific informtion bout the dverse rections observed with lithium or vlprote, refer to the Adverse Rections section of the pckge inserts for these other products. Adverse Rections Occurring t n Incidence of % or More mong Intrmusculr for InjectionTreted Ptients in Short-Term, Plcebo-Controlled Trils Tble enumertes the incidence, rounded to the nerest percent, of tretment-emergent dverse rections tht occurred in % or more of ptients treted with intrmusculr olnzpine for injection (dose rnge of.- mg/injection) nd with incidence greter thn plcebo who prticipted in the short-term, plcebo-controlled trils in gitted ptients with schizophreni or bipolr I mni. Tble : Tretment-Emergent Adverse Rections: Incidence in Short-Term ( Hour), Plcebo-Controlled Clinicl Trils with Intrmusculr for Injection in Agitted Ptients with Schizophreni or Bipolr I Mni Percentge of Ptients Reporting Event Plcebo Body System/Adverse Rection (N=) (N=) Body s Whole Astheni Crdiovsculr System Hypotension Posturl hypotension Nervous System Somnolence Dizziness Tremor. Extrpyrmidl Symptoms The following tble enumertes the percentge of ptients with tretment-emergent extrpyrmidl symptoms s ssessed by ctegoricl nlyses of forml rting scles during cute therpy in controlled clinicl tril compring orl olnzpine t fixed doses with plcebo in the tretment of schizophreni in -week tril. Tble : Tretment-Emergent Extrpyrmidl Symptoms Assessed by Rting Scles Incidence in Fixed Dosge Rnge, Plcebo-Controlled Clinicl Tril of Orl in Schizophreni Acute Phse Percentge of Ptients Reporting Event Plcebo ±. mg/dy ±. mg/dy ±. mg/dy Prkinsonism b Akthisi 7 Percentge of ptients with Simpson-Angus Scle totl score >. b Percentge of ptients with Brnes Akthisi Scle globl score. The following tble enumertes the percentge of ptients with tretment-emergent extrpyrmidl symptoms s ssessed by spontneously reported dverse rections during cute therpy in the sme controlled clinicl tril compring olnzpine t fixed doses with plcebo in the tretment of schizophreni in -week tril. Tble 7: Tretment-Emergent Extrpyrmidl Symptoms Assessed by Adverse Rections Incidence in Fixed Dosge Rnge, Plcebo-Controlled Clinicl Tril of Orl in Schizophreni Acute Phse Percentge of Ptients Reporting Event Plcebo ±. mg/dy ±. mg/dy ±. mg/dy (N=8) (N=) (N=) (N=) Dystonic events b Prkinsonism events 8 c Akthisi events d Dyskinetic events e Residul events

21 Any extrpyrmidl event Ptients with the following COSTART terms were counted in this ctegory: dystoni, generlized spsm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Ptients with the following COSTART terms were counted in this ctegory: kinesi, cogwheel rigidity, extrpyrmidl syndrome, hypertoni, hypokinesi, msked fcies, tremor. c Ptients with the following COSTART terms were counted in this ctegory: kthisi, hyperkinesi. d Ptients with the following COSTART terms were counted in this ctegory: buccoglossl syndrome, choreothetosis, dyskinesi, trdive dyskinesi. e Ptients with the following COSTART terms were counted in this ctegory: movement disorder, myoclonus, twitching. The following tble enumertes the percentge of dolescent ptients with tretment-emergent extrpyrmidl symptoms s ssessed by spontneously reported dverse rections during cute therpy (dose rnge:. to mg/dy). Tble 8: Tretment-Emergent Extrpyrmidl Symptoms Assessed by Adverse Rections Incidence in Plcebo-Controlled Clinicl Trils of Orl in Schizophreni nd Bipolr I Disorder Adolescents Percentge of Ptients Reporting Event Plcebo Ctegories (N=8) (N=7) Dystonic events Prkinsonism events Akthisi events Dyskinetic events Nonspecific events Any extrpyrmidl event Ctegories re bsed on Stndrd MedDRA Queries (SMQ) for extrpyrmidl symptoms s defined in MedDRA version.. The following tble enumertes the percentge of ptients with tretment-emergent extrpyrmidl symptoms s ssessed by ctegoricl nlyses of forml rting scles during controlled clinicl trils compring fixed doses of intrmusculr olnzpine for injection with plcebo in gittion. Ptients in ech dose group could receive up to injections during the trils [see Clinicl Studies (.)]. Ptient ssessments were conducted during the hours following the initil dose of intrmusculr olnzpine for injection. Tble : Tretment-Emergent Extrpyrmidl Symptoms Assessed by Rting Scles Incidence in Fixed Dose, Plcebo-Controlled Clinicl Tril of Intrmusculr for Injection in Agitted Ptients with Schizophreni Percentge of Ptients Reporting Event IM IM IM IM Plcebo. mg mg 7. mg mg Prkinsonism b Akthisi Percentge of ptients with Simpson-Angus Scle totl score >. b Percentge of ptients with Brnes Akthisi Scle globl score. The following tble enumertes the percentge of ptients with tretment-emergent extrpyrmidl symptoms s ssessed by spontneously reported dverse rections in the sme controlled clinicl tril compring fixed doses of intrmusculr olnzpine for injection with plcebo in gitted ptients with schizophreni. Tble : Tretment-Emergent Extrpyrmidl Symptoms Assessed by Adverse Rections Incidence in Fixed Dose, Plcebo-Controlled Clinicl Tril of Intrmusculr for Injection in Agitted Ptients with Schizophreni Percentge of Ptients Reporting Event IM IM IM IM Plcebo. mg mg 7. mg mg (N=) (N=8) (N=) (N=) (N=) Dystonic events

22 Prkinsonism eventsb Akthisi eventsc Dyskinetic eventsd Residul eventse Any extrpyrmidl events Ptients with the following COSTART terms were counted in this ctegory: dystoni, generlized spsm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Ptients with the following COSTART terms were counted in this ctegory: kinesi, cogwheel rigidity, extrpyrmidl syndrome, hypertoni, hypokinesi, msked fcies, tremor. c Ptients with the following COSTART terms were counted in this ctegory: kthisi, hyperkinesi. d Ptients with the following COSTART terms were counted in this ctegory: buccoglossl syndrome, choreothetosis, dyskinesi, trdive dyskinesi. e Ptients with the following COSTART terms were counted in this ctegory: movement disorder, myoclonus, twitching. Dystoni, Clss Effect: Symptoms of dystoni, prolonged bnorml contrctions of muscle groups, my occur in susceptible individuls during the first few dys of tretment. Dystonic symptoms include: spsm of the neck muscles, sometimes progressing to tightness of the throt, swllowing difficulty, difficulty brething, nd/or protrusion of the tongue. While these symptoms cn occur t low doses, the frequency nd severity re greter with high potency nd t higher doses of first genertion ntipsychotic drugs. In generl, n elevted risk of cute dystoni my be observed in mles nd younger ge groups receiving ntipsychotics; however, events of dystoni hve been reported infrequently (<%) with olnzpine use.. Other Adverse Rections Other Adverse Rections Observed During the Clinicl Tril Evlution of Orl Following is list of tretment-emergent dverse rections reported by ptients treted with orl olnzpine (t multiple doses mg/dy) in clinicl trils. This listing is not intended to include rections () lredy listed in previous tbles or elsewhere in lbeling, () for which drug cuse ws remote, () which were so generl s to be uninformtive, () which were not considered to hve significnt clinicl implictions, or () which occurred t rte equl to or less thn plcebo. Rections re clssified by body system using the following definitions: frequent dverse rections re those occurring in t lest / ptients; infrequent dverse rections re those occurring in / to / ptients; rre rections re those occurring in fewer thn / ptients. Body s Whole Infrequent: chills, fce edem, photosensitivity rection, suicide ttempt; Rre: chills nd fever, hngover effect, sudden deth. Crdiovsculr System Infrequent: cerebrovsculr ccident, vsodilttion. Digestive System Infrequent: bdominl distension, nuse nd vomiting, tongue edem; Rre: ileus, intestinl obstruction, liver ftty deposit. Hemic nd Lymphtic System Infrequent: thrombocytopeni. Metbolic nd Nutritionl Disorders Frequent: lkline phosphtse incresed; Infrequent: bilirubinemi, hypoproteinemi. Musculoskeletl System Rre: osteoporosis. Nervous System Infrequent: txi, dysrthri, libido decresed, stupor; Rre: com. Respirtory System Infrequent: epistxis; Rre: lung edem. Skin nd Appendges Infrequent: lopeci. Specil Senses Infrequent: bnormlity of ccommodtion, dry eyes; Rre: mydrisis. Urogenitl System Infrequent: menorrhe, brest pin, decresed menstrution, impotence, incresed menstrution, menorrhgi, metrorrhgi, polyuri, urinry frequency, urinry retention, urinry urgency, urintion impired. These terms represent serious dverse events but do not meet the definition for dverse drug rections. They re included here becuse of their seriousness. Adjusted for gender. Other Adverse Rections Observed During the Clinicl Tril Evlution of Intrmusculr for Injection Following is list of tretment-emergent dverse rections reported by ptients treted with intrmusculr olnzpine for injection (t or more doses. mg/injection) in clinicl trils. This listing is not intended to include rections () lredy listed in previous tbles or elsewhere in lbeling, () for which drug cuse ws remote, () which were so generl s to be uninformtive, () which were not considered to hve significnt clinicl implictions, or () for which occurred t rte equl to or less thn plcebo. Rections re clssified by body system using the following definitions: frequent dverse rections re those occurring in t lest / ptients; infrequent dverse rections re those occurring in / to / ptients. Body s Whole Frequent: injection site pin. Crdiovsculr System Infrequent: syncope.

23 Digestive System Infrequent: nuse. Metbolic nd Nutritionl Disorders Infrequent: cretine phosphokinse incresed. Clinicl Trils in Adolescent Ptients (ge to 7 yers) Commonly Observed Adverse Rections in Orl Short-Term, Plcebo-Controlled Trils Adverse rections in dolescent ptients treted with orl olnzpine (doses. mg) reported with n incidence of % or more nd reported t lest twice s frequently s plcebo-treted ptients re listed in Tble. Tble : Tretment-Emergent Adverse Rections of % Incidence mong Adolescents (-7 Yers Old) with Schizophreni or Bipolr I Disorder (Mnic or Mixed Episodes) Percentge of Ptients Reporting Event Week Tril Week Tril % Schizophreni Ptients % Bipolr Ptients Plcebo Plcebo Adverse Rections (N=7) (N=) (N=7) (N=) Sedtion 8 Weight incresed Hedche Incresed ppetite 7 Dizziness 8 7 Abdominl pinb 7 Pin in extremity Ftigue Dry mouth 7 Ptients with the following MedDRA terms were counted in this ctegory: hypersomni, lethrgy, sedtion, somnolence. b Ptients with the following MedDRA terms were counted in this ctegory: bdominl pin, bdominl pin lower, bdominl pin upper. Adverse Rections Occurring t n Incidence of % or More mong Orl -Treted Ptients in ShortTerm (- weeks), Plcebo-Controlled Trils Adverse rections in dolescent ptients treted with orl olnzpine (doses. mg) reported with n incidence of % or more nd greter thn plcebo re listed in Tble. Tble : Tretment-Emergent Adverse Rections of % Incidence mong Adolescents (-7 Yers Old) (Combined Incidence from Short-Term, Plcebo-Controlled Clinicl Trils of Schizophreni or Bipolr I Disorder [Mnic or Mixed Episodes]) Percentge of Ptients Reporting Event Plcebo Adverse Rection (N=7) (N=8) Sedtion Weight incresed Incresed ppetite Hedche 7 Ftigue Dizziness 7 Dry mouth Pin in extremity Constiption Nsophryngitis Dirrhe Restlessness Liver enzymes incresedb 8 Dyspepsi Epistxis Respirtory trct infectionc Sinusitis Arthrlgi Musculoskeletl stiffness Ptients with the following MedDRA terms were counted in this ctegory: hypersomni, lethrgy, sedtion, somnolence.

24 b c The terms lnine minotrnsferse (ALT), sprtte minotrnsferse (AST), nd heptic enzyme were combined under liver enzymes. Ptients with the following MedDRA terms were counted in this ctegory: lower respirtory trct infection, respirtory trct infection, respirtory trct infection virl, upper respirtory trct infection, virl upper respirtory trct infection. Vitl Signs nd Lbortory Studies Vitl Sign Chnges Orl olnzpine ws ssocited with orthosttic hypotension nd tchycrdi in clinicl trils. Intrmusculr olnzpine for injection ws ssocited with brdycrdi, hypotension, nd tchycrdi in clinicl trils [see Wrnings nd Precutions ()]. Lbortory Chnges Monotherpy in Adults: An ssessment of the premrketing experience for olnzpine reveled n ssocition with symptomtic increses in ALT, AST, nd GGT. Within the originl premrketing dtbse of bout dult ptients with bseline ALT IU/L, the incidence of ALT elevtions to > IU/L ws % (/8). None of these ptients experienced jundice or other symptoms ttributble to liver impirment nd most hd trnsient chnges tht tended to normlize while olnzpine tretment ws continued. In plcebo-controlled olnzpine monotherpy studies in dults, cliniclly significnt ALT elevtions (chnge from < times the upper limit of norml [ULN] t bseline to times ULN) were observed in % (77/) of ptients exposed to olnzpine compred to % (/87) of ptients exposed to plcebo. ALT elevtions times ULN were observed in % (/8) of olnzpine-treted ptients, compred to.% (/) of plcebo-treted ptients. ALT vlues returned to norml, or were decresing, t lst follow-up in the mjority of ptients who either continued tretment with olnzpine or discontinued olnzpine. No ptient with elevted ALT vlues experienced jundice, liver filure, or met the criteri for Hy s Rule. From n nlysis of the lbortory dt in n integrted dtbse of completed clinicl studies in dult ptients treted with orl olnzpine, high GGT levels were recorded in % (88/) of ptients. Cution should be exercised in ptients with signs nd symptoms of heptic impirment, in ptients with preexisting conditions ssocited with limited heptic functionl reserve, nd in ptients who re being treted with potentilly heptotoxic drugs. dministrtion ws lso ssocited with increses in serum prolctin [see Wrnings nd Precutions (.)], with n symptomtic elevtion of the eosinophil count in.% of ptients, nd with n increse in CPK. From n nlysis of the lbortory dt in n integrted dtbse of completed clinicl studies in dult ptients treted with orl olnzpine, elevted uric cid ws recorded in % (7/) of ptients. Monotherpy in Adolescents: In plcebo-controlled clinicl trils of dolescent ptients with schizophreni or bipolr I disorder (mnic or mixed episodes), greter frequencies for the following tretment-emergent findings, t nytime, were observed in lbortory nlytes compred to plcebo: elevted ALT ( X ULN in ptients with ALT t bseline <X ULN), (% vs %); elevted AST (8% vs %); low totl bilirubin (% vs 7%); elevted GGT (% vs %); nd elevted prolctin (7% vs 7%). In plcebo-controlled olnzpine monotherpy studies in dolescents, cliniclly significnt ALT elevtions (chnge from < times ULN t bseline to times ULN) were observed in % (/) of ptients exposed to olnzpine compred to % (/) of ptients exposed to plcebo. ALT elevtions times ULN were observed in % (8/) of olnzpine-treted ptients, compred to % (/) of plcebo-treted ptients. ALT vlues returned to norml, or were decresing, t lst follow-up in the mjority of ptients who either continued tretment with olnzpine or discontinued olnzpine. No dolescent ptient with elevted ALT vlues experienced jundice, liver filure, or met the criteri for Hy s Rule. ECG Chnges In pooled studies of dults s well s pooled studies of dolescents, there were no significnt differences between olnzpine nd plcebo in the proportions of ptients experiencing potentilly importnt chnges in ECG prmeters, including QT, QTc (Friderici corrected), nd PR intervls. use ws ssocited with men increse in hert rte compred to plcebo (dults: +. bets per minute vs no chnge with plcebo; dolescents: +. bets per minute vs -. bets per minute with plcebo). This increse in hert rte my be relted to olnzpine s potentil for inducing orthosttic chnges [see Wrnings nd Precutions (.)].. Postmrketing Experience The following dverse rections hve been identified during post-pprovl use of ZYPREXA. Becuse these rections re reported voluntrily from popultion of uncertin size, it is difficult to relibly estimte their frequency or evlute cusl reltionship to drug exposure. Adverse rections reported since mrket introduction tht were temporlly (but not necessrily cuslly) relted to ZYPREXA therpy include the following: llergic rection (e.g., nphylctoid rection, ngioedem, pruritus or urticri), cholesttic or mixed liver injury, dibetic com, dibetic ketocidosis, discontinution rection (diphoresis, nuse or vomiting), heptitis, jundice, neutropeni, pncretitis, pripism, rsh, rhbdomyolysis, nd venous thromboembolic events (including pulmonry embolism nd deep venous thrombosis). Rndom cholesterol levels of mg/dl nd rndom triglyceride levels of mg/dl hve been reported. 7 DRUG INTERACTIONS

25 The risks of using olnzpine in combintion with other drugs hve not been extensively evluted in systemtic studies. 7. Potentil for Other Drugs to Affect Dizepm The co-dministrtion of dizepm with olnzpine potentited the orthosttic hypotension observed with olnzpine [see Drug Interctions (7.)]. Cimetidine nd Antcids Single doses of cimetidine (8 mg) or luminum- nd mgnesium-contining ntcids did not ffect the orl biovilbility of olnzpine. Inducers of CYPA Crbmzepine therpy ( mg bid) cuses n pproximtely % increse in the clernce of olnzpine. This increse is likely due to the fct tht crbmzepine is potent inducer of CYPA ctivity. Higher dily doses of crbmzepine my cuse n even greter increse in olnzpine clernce. Alcohol Ethnol ( mg/7 kg single dose) did not hve n effect on olnzpine phrmcokinetics. The codministrtion of lcohol (i.e., ethnol) with olnzpine potentited the orthosttic hypotension observed with olnzpine [see Drug Interctions (7.)]. Inhibitors of CYPA Fluvoxmine: Fluvoxmine, CYPA inhibitor, decreses the clernce of olnzpine. This results in men increse in olnzpine Cmx following fluvoxmine of % in femle nonsmokers nd 77% in mle smokers. The men increse in olnzpine AUC is % nd 8%, respectively. Lower doses of olnzpine should be considered in ptients receiving concomitnt tretment with fluvoxmine. Inhibitors of CYPD Fluoxetine: Fluoxetine ( mg single dose or mg dily dose for 8 dys) cuses smll (men %) increse in the mximum concentrtion of olnzpine nd smll (men %) decrese in olnzpine clernce. The mgnitude of the impct of this fctor is smll in comprison to the overll vribility between individuls, nd therefore dose modifiction is not routinely recommended. When using ZYPREXA nd fluoxetine in combintion, lso refer to the Drug Interctions section of the pckge insert for Symbyx. Wrfrin Wrfrin ( mg single dose) did not ffect olnzpine phrmcokinetics [see Drug Interctions (7.)]. Inducers of CYPA or Glucuronyl Trnsferse Omeprzole nd rifmpin my cuse n increse in olnzpine clernce. Chrcol The dministrtion of ctivted chrcol ( g) reduced the Cmx nd AUC of orl olnzpine by bout %. As pek olnzpine levels re not typiclly obtined until bout hours fter dosing, chrcol my be useful tretment for olnzpine overdose. 7. Potentil for to Affect Other Drugs CNS Acting Drugs Given the primry CNS effects of olnzpine, cution should be used when olnzpine is tken in combintion with other centrlly cting drugs nd lcohol. Antihypertensive Agents, becuse of its potentil for inducing hypotension, my enhnce the effects of certin ntihypertensive gents. Levodop nd Dopmine Agonists my ntgonize the effects of levodop nd dopmine gonists. Lorzepm (IM) Administrtion of intrmusculr lorzepm ( mg) hour fter intrmusculr olnzpine for injection ( mg) did not significntly ffect the phrmcokinetics of olnzpine, unconjugted lorzepm, or totl lorzepm. However, this co-dministrtion of intrmusculr lorzepm nd intrmusculr olnzpine for injection dded to the somnolence observed with either drug lone [see Wrnings nd Precutions (.)]. Lithium Multiple doses of olnzpine ( mg for 8 dys) did not influence the kinetics of lithium. Therefore, concomitnt olnzpine dministrtion does not require dosge djustment of lithium [see Wrnings nd Precutions (.)]. Vlprote ( mg dily for weeks) did not ffect the stedy stte plsm concentrtions of vlprote. Therefore, concomitnt olnzpine dministrtion does not require dosge djustment of vlprote [see Wrnings nd Precutions (.)]. Effect of on Drug Metbolizing Enzymes In vitro studies utilizing humn liver microsomes suggest tht olnzpine hs little potentil to inhibit CYPA, CYPC, CYPC, CYPD, nd CYPA. Thus, olnzpine is unlikely to cuse cliniclly importnt drug interctions medited by these enzymes. Imiprmine Single doses of olnzpine did not ffect the phrmcokinetics of imiprmine or its ctive metbolite desiprmine. Wrfrin Single doses of olnzpine did not ffect the phrmcokinetics of wrfrin [see Drug Interctions (7.)]. Dizepm did not influence the phrmcokinetics of dizepm or its ctive metbolite Ndesmethyldizepm. However, dizepm co-dministered with olnzpine incresed the orthosttic hypotension observed with either drug given lone [see Drug Interctions (7.)]. Alcohol Multiple doses of olnzpine did not influence the kinetics of ethnol [see Drug Interctions (7.)]. Biperiden Multiple doses of olnzpine did not influence the kinetics of biperiden. Theophylline Multiple doses of olnzpine did not ffect the phrmcokinetics of theophylline or its metbolites. 8 USE IN SPECIFIC POPULATIONS

26 When using ZYPREXA nd fluoxetine in combintion, lso refer to the Use in Specific Popultions section of the pckge insert for Symbyx. 8. Pregnncy Tertogenic Effects, Pregnncy Ctegory C In orl reproduction studies in rts t doses up to 8 mg/kg/dy nd in rbbits t doses up to mg/kg/dy ( nd times the mximum recommended humn dily orl dose on mg/m bsis, respectively) no evidence of tertogenicity ws observed. In n orl rt tertology study, erly resorptions nd incresed numbers of nonvible fetuses were observed t dose of 8 mg/kg/dy ( times the mximum recommended humn dily orl dose on mg/m bsis). Gesttion ws prolonged t mg/kg/dy ( times the mximum recommended humn dily orl dose on mg/m bsis). In n orl rbbit tertology study, fetl toxicity (mnifested s incresed resorptions nd decresed fetl weight) occurred t mternlly toxic dose of mg/kg/dy ( times the mximum recommended humn dily orl dose on mg/m bsis). Becuse niml reproduction studies re not lwys predictive of humn response, this drug should be used during pregnncy only if the potentil benefit justifies the potentil risk to the fetus. Plcentl trnsfer of olnzpine occurs in rt pups. There re no dequte nd well-controlled trils with olnzpine in pregnnt femles. Seven pregnncies were observed during clinicl trils with olnzpine, including resulting in norml births, resulting in neontl deth due to crdiovsculr defect, therpeutic bortions, nd spontneous bortion. Nontertogenic Effects Neontes exposed to ntipsychotic drugs (including ZYPREXA), during the third trimester of pregnncy re t risk for extrpyrmidl nd/or withdrwl symptoms following delivery. There hve been reports of gittion, hypertoni, hypotoni, tremor, somnolence, respirtory distress nd feeding disorder in these neontes. These complictions hve vried in severity; while in some cses symptoms hve been self-limited, in other cses neontes hve required intensive cre unit support nd prolonged hospitliztion. ZYPREXA should be used during pregnncy only if the potentil benefit justifies the potentil risk to the fetus. 8. Lbor nd Delivery The effect of olnzpine on lbor nd delivery in humns is unknown. Prturition in rts ws not ffected by olnzpine. 8. Nursing Mothers In study in lctting, helthy women, olnzpine ws excreted in brest milk. Men infnt dose t stedy stte ws estimted to be.8% of the mternl olnzpine dose. It is recommended tht women receiving olnzpine should not brest-feed. 8. Peditric Use The sfety nd effectiveness of orl ZYPREXA in the tretment of schizophreni nd mnic or mixed episodes ssocited with bipolr I disorder were estblished in short-term studies in dolescents (ges to 7 yers). Use of ZYPREXA in dolescents is supported by evidence from dequte nd well-controlled studies of ZYPREXA in which 8 dolescents received ZYPREXA in rnge of. to mg/dy [see Clinicl Studies (.,.)]. Recommended strting dose for dolescents is lower thn tht for dults [see Dosge nd Administrtion (.,.)]. Compred to ptients from dult clinicl trils, dolescents were likely to gin more weight, experience incresed sedtion, nd hve greter increses in totl cholesterol, triglycerides, LDL cholesterol, prolctin nd heptic minotrnsferse levels [see Wrnings nd Precutions (.,.,.) nd Adverse Rections (.)]. When deciding mong the lterntive tretments vilble for dolescents, clinicins should consider the incresed potentil (in dolescents s compred with dults) for weight gin nd dyslipidemi. Clinicins should consider the potentil long-term risks when prescribing to dolescents, nd in mny cses this my led them to consider prescribing other drugs first in dolescents [see Indictions nd Usge (.,.)]. Sfety nd effectiveness of olnzpine in children < yers of ge hve not been estblished [see Ptient Counseling Informtion (7.)]. Sfety nd efficcy of ZYPREXA nd fluoxetine in combintion in children nd dolescents ( to 7 yers of ge) hve been estblished for the cute tretment of depressive episodes ssocited with bipolr I disorder. Sfety nd effectiveness of ZYPREXA nd fluoxetine in combintion in children < yers of ge hve not been estblished. 8. Geritric Use Of the ptients in premrketing clinicl studies with orl olnzpine, % () were yers of ge or over. In ptients with schizophreni, there ws no indiction of ny different tolerbility of olnzpine in the elderly compred to younger ptients. Studies in elderly ptients with dementi-relted psychosis hve suggested tht there my be different tolerbility profile in this popultion compred to younger ptients with schizophreni. Elderly ptients with dementirelted psychosis treted with olnzpine re t n incresed risk of deth compred to plcebo. In plcebo-controlled studies of olnzpine in elderly ptients with dementi-relted psychosis, there ws higher incidence of cerebrovsculr dverse events (e.g., stroke, trnsient ischemic ttck) in ptients treted with olnzpine compred to ptients treted with plcebo. is not pproved for the tretment of ptients with dementi-relted psychosis. Also, the presence of fctors tht might decrese phrmcokinetic clernce or increse the phrmcodynmic response to

27 7 olnzpine should led to considertion of lower strting dose for ny geritric ptient [see Boxed Wrning, Dosge nd Administrtion (.), nd Wrnings nd Precutions (.)]. Clinicl studies of ZYPREXA nd fluoxetine in combintion did not include sufficient numbers of ptients yers of ge to determine whether they respond differently from younger ptients.. DRUG ABUSE AND DEPENDENCE Dependence In studies prospectively designed to ssess buse nd dependence potentil, olnzpine ws shown to hve cute depressive CNS effects but little or no potentil of buse or physicl dependence in rts dministered orl doses up to times the mximum recommended humn dily orl dose ( mg) nd rhesus monkeys dministered orl doses up to 8 times the mximum recommended humn dily orl dose on mg/m bsis. hs not been systemticlly studied in humns for its potentil for buse, tolernce, or physicl dependence. While the clinicl trils did not revel ny tendency for ny drug-seeking behvior, these observtions were not systemtic, nd it is not possible to predict on the bsis of this limited experience the extent to which CNS-ctive drug will be misused, diverted, nd/or bused once mrketed. Consequently, ptients should be evluted crefully for history of drug buse, nd such ptients should be observed closely for signs of misuse or buse of olnzpine (e.g., development of tolernce, increses in dose, drug-seeking behvior).. OVERDOSAGE Humn Experience In premrketing trils involving more thn ptients nd/or norml subjects, ccidentl or intentionl cute overdosge of olnzpine ws identified in 7 ptients. In the ptient tking the lrgest identified mount, mg, the only symptoms reported were drowsiness nd slurred speech. In the limited number of ptients who were evluted in hospitls, including the ptient tking mg, there were no observtions indicting n dverse chnge in lbortory nlytes or ECG. Vitl signs were usully within norml limits following overdoses. In postmrketing reports of overdose with olnzpine lone, symptoms hve been reported in the mjority of cses. In symptomtic ptients, symptoms with % incidence included gittion/ggressiveness, dysrthri, tchycrdi, vrious extrpyrmidl symptoms, nd reduced level of consciousness rnging from sedtion to com. Among less commonly reported symptoms were the following potentilly mediclly serious rections: spirtion, crdiopulmonry rrest, crdic rrhythmis (such s suprventriculr tchycrdi nd ptient experiencing sinus puse with spontneous resumption of norml rhythm), delirium, possible neuroleptic mlignnt syndrome, respirtory depression/rrest, convulsion, hypertension, nd hypotension. Eli Lilly nd Compny hs received reports of ftlity in ssocition with overdose of olnzpine lone. In cse of deth, the mount of cutely ingested olnzpine ws reported to be possibly s low s mg of orl olnzpine; however, in nother cse, ptient ws reported to survive n cute olnzpine ingestion of pproximtely g of orl olnzpine.. Mngement of Overdose For current informtion on the mngement of ZYPREXA (olnzpine) overdose, contct certified poison control center (-8-- or The possibility of multiple drug involvement should be considered. In cse of cute overdosge, estblish nd mintin n irwy nd ensure dequte oxygention nd ventiltion, which my include intubtion. Gstric lvge (fter intubtion, if ptient is unconscious) nd dministrtion of ctivted chrcol together with lxtive should be considered. The dministrtion of ctivted chrcol ( g) reduced the Cmx nd AUC of orl olnzpine by bout %. As pek olnzpine levels re not typiclly obtined until bout hours fter dosing, chrcol my be useful tretment for olnzpine overdose. The possibility of obtundtion, seizures, or dystonic rection of the hed nd neck following overdose my crete risk of spirtion with induced emesis. Crdiovsculr monitoring should commence immeditely nd should include continuous electrocrdiogrphic monitoring to detect possible rrhythmis. There is no specific ntidote to olnzpine. Therefore, pproprite supportive mesures should be initited. Hypotension nd circultory collpse should be treted with pproprite mesures such s intrvenous fluids nd/or sympthomimetic gents. (Do not use epinephrine, dopmine, or other sympthomimetics with bet-gonist ctivity, since bet stimultion my worsen hypotension in the setting of olnzpine-induced lph blockde.) Close medicl supervision nd monitoring should continue until the ptient recovers. For specific informtion bout overdosge with lithium or vlprote, refer to the Overdosge section of the pckge inserts for these products. For specific informtion bout overdosge with olnzpine nd fluoxetine in combintion, refer to the Overdosge section of the Symbyx pckge insert. DESCRIPTION ZYPREXA (olnzpine) is n typicl ntipsychotic tht belongs to the thienobenzodizepine clss. The chemicl designtion is -methyl--(-methyl--piperzinyl)-h-thieno[,-b] [,]benzodizepine. The moleculr formul is C7HNS, which corresponds to moleculr weight of.. The chemicl structure is:

28 8 is yellow crystlline solid, which is prcticlly insoluble in wter. ZYPREXA tblets re intended for orl dministrtion only. Ech tblet contins olnzpine equivlent to. mg (8 µmol), mg ( µmol), 7. mg ( µmol), mg ( µmol), mg (8 µmol), or mg ( µmol). Inctive ingredients re crnub wx, crospovidone, hydroxypropyl cellulose, hypromellose, lctose, mgnesium sterte, microcrystlline cellulose, nd other inctive ingredients. The color coting contins Titnium Dioxide (ll strengths), FD&C Blue No. Aluminum Lke ( mg), or Synthetic Red Iron Oxide ( mg). The.,, 7., nd mg tblets re imprinted with edible ink which contins FD&C Blue No. Aluminum Lke. ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) is intended for orl dministrtion only. Ech orlly disintegrting tblet contins olnzpine equivlent to mg ( µmol), mg ( µmol), mg (8 µmol) or mg ( µmol). It begins disintegrting in the mouth within seconds, llowing its contents to be subsequently swllowed with or without liquid. ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) lso contins the following inctive ingredients: geltin, mnnitol, sprtme, sodium methyl prben, nd sodium propyl prben. ZYPREXA IntrMusculr (olnzpine for injection) is intended for intrmusculr use only. Ech vil provides for the dministrtion of mg ( µmol) olnzpine with inctive ingredients mg lctose monohydrte nd. mg trtric cid. Hydrochloric cid nd/or sodium hydroxide my hve been dded during mnufcturing to djust ph. CLINICAL PHARMACOLOGY. Mechnism of Action The mechnism of ction of olnzpine, s with other drugs hving efficcy in schizophreni, is unknown. However, it hs been proposed tht this drug s efficcy in schizophreni is medited through combintion of dopmine nd serotonin type (HT ) ntgonism. The mechnism of ction of olnzpine in the tretment of cute mnic or mixed episodes ssocited with bipolr I disorder is unknown.. Phrmcodynmics binds with high ffinity to the following receptors: serotonin HT A/C, HT (K i =,, nd nm, respectively), dopmine D - (K i =- nm), histmine H (K i =7 nm), nd drenergic α receptors (K i = nm). is n ntgonist with moderte ffinity binding for serotonin HT (K i =7 nm) nd muscrinic M - (K i =7,,,, nd 8 nm, respectively). binds wekly to GABA A, BZD, nd β-drenergic receptors (K i > µm). Antgonism t receptors other thn dopmine nd HT my explin some of the other therpeutic nd side effects of olnzpine. s ntgonism of muscrinic M - receptors my explin its nticholinergic-like effects. s ntgonism of histmine H receptors my explin the somnolence observed with this drug. s ntgonism of drenergic α receptors my explin the orthosttic hypotension observed with this drug.. Phrmcokinetics Orl Administrtion, Monotherpy is well bsorbed nd reches pek concentrtions in pproximtely hours following n orl dose. It is eliminted extensively by first pss metbolism, with pproximtely % of the dose metbolized before reching the systemic circultion. Food does not ffect the rte or extent of olnzpine bsorption. Phrmcokinetic studies showed tht ZYPREXA tblets nd ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) dosge forms of olnzpine re bioequivlent. displys liner kinetics over the clinicl dosing rnge. Its hlf-life rnges from to hours (th to th percentile; men of hr), nd pprent plsm clernce rnges from to 7 L/hr (th to th percentile; men of L/hr). Administrtion of olnzpine once dily leds to stedy-stte concentrtions in bout week tht re pproximtely twice the concentrtions fter single doses. Plsm concentrtions, hlf-life, nd clernce of olnzpine my vry between individuls on the bsis of smoking sttus, gender, nd ge. is extensively distributed throughout the body, with volume of distribution of pproximtely L. It is % bound to plsm proteins over the concentrtion rnge of 7 to ng/ml, binding primrily to lbumin nd α -cid glycoprotein. Metbolism nd Elimintion Following single orl dose of C lbeled olnzpine, 7% of the dose of olnzpine ws recovered in the urine s unchnged drug, indicting tht olnzpine is highly metbolized. Approximtely

29 7% nd % of the dose ws recovered in the urine nd feces, respectively. In the plsm, olnzpine ccounted for only % of the AUC for totl rdioctivity, indicting significnt exposure to metbolites. After multiple dosing, the mjor circulting metbolites were the -N-glucuronide, present t stedy stte t % of the concentrtion of olnzpine, nd -N-desmethyl olnzpine, present t stedy stte t % of the concentrtion of olnzpine. Both metbolites lck phrmcologicl ctivity t the concentrtions observed. Direct glucuronidtion nd cytochrome P (CYP) medited oxidtion re the primry metbolic pthwys for olnzpine. In vitro studies suggest tht CYPs A nd D, nd the flvin-contining monooxygense system re involved in olnzpine oxidtion. CYPD medited oxidtion ppers to be minor metbolic pthwy in vivo, becuse the clernce of olnzpine is not reduced in subjects who re deficient in this enzyme. Intrmusculr Administrtion ZYPREXA IntrMusculr results in rpid bsorption with pek plsm concentrtions occurring within to minutes. Bsed upon phrmcokinetic study in helthy volunteers, mg dose of intrmusculr olnzpine for injection produces, on verge, mximum plsm concentrtion pproximtely times higher thn the mximum plsm concentrtion produced by mg dose of orl olnzpine. Are under the curve chieved fter n intrmusculr dose is similr to tht chieved fter orl dministrtion of the sme dose. The hlf-life observed fter intrmusculr dministrtion is similr to tht observed fter orl dosing. The phrmcokinetics re liner over the clinicl dosing rnge. Metbolic profiles fter intrmusculr dministrtion re qulittively similr to metbolic profiles fter orl dministrtion. Specific Popultions Renl Impirment Becuse olnzpine is highly metbolized before excretion nd only 7% of the drug is excreted unchnged, renl dysfunction lone is unlikely to hve mjor impct on the phrmcokinetics of olnzpine. The phrmcokinetic chrcteristics of olnzpine were similr in ptients with severe renl impirment nd norml subjects, indicting tht dosge djustment bsed upon the degree of renl impirment is not required. In ddition, olnzpine is not removed by dilysis. The effect of renl impirment on metbolite elimintion hs not been studied. Heptic Impirment Although the presence of heptic impirment my be expected to reduce the clernce of olnzpine, study of the effect of impired liver function in subjects (n=) with cliniclly significnt (Childs Pugh Clssifiction A nd B) cirrhosis reveled little effect on the phrmcokinetics of olnzpine. Geritric In study involving helthy subjects, the men elimintion hlf-life of olnzpine ws bout. times greter in elderly ( yers) thn in nonelderly subjects (< yers). Cution should be used in dosing the elderly, especilly if there re other fctors tht might dditively influence drug metbolism nd/or phrmcodynmic sensitivity [see Dosge nd Administrtion ()]. Gender Clernce of olnzpine is pproximtely % lower in women thn in men. There were, however, no pprent differences between men nd women in effectiveness or dverse effects. Dosge modifictions bsed on gender should not be needed. Smoking Sttus clernce is bout % higher in smokers thn in nonsmokers, lthough dosge modifictions re not routinely recommended. Rce In vivo studies hve shown tht exposures re similr mong Jpnese, Chinese nd Cucsins, especilly fter normliztion for body weight differences. Dosge modifictions for rce re, therefore, not recommended. Combined Effects The combined effects of ge, smoking, nd gender could led to substntil phrmcokinetic differences in popultions. The clernce in young smoking mles, for exmple, my be times higher thn tht in elderly nonsmoking femles. Dosing modifiction my be necessry in ptients who exhibit combintion of fctors tht my result in slower metbolism of olnzpine [see Dosge nd Administrtion ()]. Adolescents (ges to 7 yers) In clinicl studies, most dolescents were nonsmokers nd this popultion hd lower verge body weight, which resulted in higher verge olnzpine exposure compred to dults.. NONCLINICAL TOXICOLOGY Crcinogenesis, Mutgenesis, Impirment of Fertility Crcinogenesis Orl crcinogenicity studies were conducted in mice nd rts. ws dministered to mice in two 78-week studies t doses of,, / mg/kg/dy (equivlent to.8- times the mximum recommended humn dily orl dose on mg/m bsis) nd.,, 8 mg/kg/dy (equivlent to.- times the mximum recommended humn dily orl dose on mg/m bsis). Rts were dosed for yers t doses of.,,., mg/kg/dy (mles) nd.,,, 8 mg/kg/dy (femles) (equivlent to.- nd.- times the mximum recommended humn dily orl dose on mg/m bsis, respectively). The incidence of liver hemngioms nd hemngiosrcoms ws significntly incresed in mouse study in femle mice dosed t 8 mg/kg/dy ( times the mximum recommended humn dily orl dose on mg/m bsis). These tumors were not incresed in nother mouse study in femles dosed t or / mg/kg/dy (- times the mximum recommended humn dily orl dose on mg/m bsis); in this study, there ws high incidence of erly mortlities in mles of the / mg/kg/dy group. The incidence of mmmry glnd denoms nd denocrcinoms ws significntly incresed in femle mice dosed t mg/kg/dy nd in femle rts dosed t mg/kg/dy (. nd times the mximum recommended humn dily orl dose on mg/m bsis, respectively). Antipsychotic drugs hve been shown to chroniclly elevte prolctin levels in rodents. Serum prolctin levels were not mesured during the olnzpine crcinogenicity studies; however,

30 mesurements during subchronic toxicity studies showed tht olnzpine elevted serum prolctin levels up to -fold in rts t the sme doses used in the crcinogenicity study. An increse in mmmry glnd neoplsms hs been found in rodents fter chronic dministrtion of other ntipsychotic drugs nd is considered to be prolctin medited. The relevnce for humn risk of the finding of prolctin medited endocrine tumors in rodents is unknown [see Wrnings nd Precutions (.)]. Mutgenesis No evidence of genotoxic potentil for olnzpine ws found in the Ames reverse muttion test, in vivo micronucleus test in mice, the chromosoml berrtion test in Chinese hmster ovry cells, unscheduled D synthesis test in rt heptocytes, induction of forwrd muttion test in mouse lymphom cells, or in vivo sister chromtid exchnge test in bone mrrow of Chinese hmsters. Impirment of Fertility In n orl fertility nd reproductive performnce study in rts, mle mting performnce, but not fertility, ws impired t dose of. mg/kg/dy nd femle fertility ws decresed t dose of mg/kg/dy ( nd. times the mximum recommended humn dily orl dose on mg/m bsis, respectively). Discontinunce of olnzpine tretment reversed the effects on mle mting performnce. In femle rts, the precoitl period ws incresed nd the mting index reduced t mg/kg/dy (. times the mximum recommended humn dily orl dose on mg/m bsis). Diestrous ws prolonged nd estrous delyed t. mg/kg/dy (. times the mximum recommended humn dily orl dose on mg/m bsis); therefore olnzpine my produce dely in ovultion.. Animl Toxicology nd/or Phrmcology In niml studies with olnzpine, the principl hemtologic findings were reversible peripherl cytopenis in individul dogs dosed t mg/kg (7 times the mximum recommended humn dily orl dose on mg/m bsis), doserelted decreses in lymphocytes nd neutrophils in mice, nd lymphopeni in rts. A few dogs treted with mg/kg developed reversible neutropeni nd/or reversible hemolytic nemi between nd months of tretment. Doserelted decreses in lymphocytes nd neutrophils were seen in mice given doses of mg/kg (equl to times the mximum recommended humn dily orl dose on mg/m bsis) in studies of months durtion. Nonspecific lymphopeni, consistent with decresed body weight gin, occurred in rts receiving. mg/kg ( times the mximum recommended humn dily orl dose on mg/m bsis) for months or mg/kg (8 times the mximum recommended humn dily orl dose on mg/m bsis) for or months. No evidence of bone mrrow cytotoxicity ws found in ny of the species exmined. Bone mrrows were normocellulr or hypercellulr, indicting tht the reductions in circulting blood cells were probbly due to peripherl (non-mrrow) fctors. CLINICAL STUDIES When using ZYPREXA nd fluoxetine in combintion, lso refer to the Clinicl Studies section of the pckge insert for Symbyx.. Schizophreni Adults The efficcy of orl olnzpine in the tretment of schizophreni ws estblished in short-term (-week) controlled trils of dult inptients who met DSM III-R criteri for schizophreni. A single hloperidol rm ws included s comprtive tretment in of the trils, but this tril did not compre these drugs on the full rnge of cliniclly relevnt doses for both. Severl instruments were used for ssessing psychitric signs nd symptoms in these studies, mong them the Brief Psychitric Rting Scle (BPRS), multi-item inventory of generl psychopthology trditionlly used to evlute the effects of drug tretment in schizophreni. The BPRS psychosis cluster (conceptul disorgniztion, hllucintory behvior, suspiciousness, nd unusul thought content) is considered prticulrly useful subset for ssessing ctively psychotic schizophrenic ptients. A second trditionl ssessment, the Clinicl Globl Impression (CGI), reflects the impression of skilled observer, fully fmilir with the mnifesttions of schizophreni, bout the overll clinicl stte of the ptient. In ddition, more recently developed scles were employed; these included the -item Positive nd Negtive Symptoms Scle (PANSS), in which re embedded the 8 items of the BPRS, nd the Scle for Assessing Negtive Symptoms (SANS). The tril summries below focus on the following outcomes: PANSS totl nd/or BPRS totl; BPRS psychosis cluster; PANSS negtive subscle or SANS; nd CGI Severity. The results of the trils follow: () In -week, plcebo-controlled tril (n=) involving fixed olnzpine doses of nd mg/dy (once dily schedule), olnzpine, t mg/dy (but not t mg/dy), ws superior to plcebo on the PANSS totl score (lso on the extrcted BPRS totl), on the BPRS psychosis cluster, on the PANSS Negtive subscle, nd on CGI Severity. () In -week, plcebo-controlled tril (n=) involving fixed dose rnges of olnzpine ( ±. mg/dy, ±. mg/dy, nd ±. mg/dy) on once dily schedule, the highest olnzpine dose groups (ctul men doses of nd mg/dy, respectively) were superior to plcebo on BPRS totl score, BPRS psychosis cluster, nd CGI severity score; the highest olnzpine dose group ws superior to plcebo on the SANS. There ws no cler dvntge for the high-dose group over the medium-dose group. () In longer-term tril, dult outptients (n=) who predominntly met DSM-IV criteri for schizophreni nd who remined stble on olnzpine during open-lbel tretment for t lest 8 weeks were rndomized to continution on their current olnzpine doses (rnging from to mg/dy) or to plcebo. The follow-up period to observe ptients for relpse, defined in terms of increses in BPRS positive symptoms or hospitliztion, ws plnned for months, however, criteri were met for stopping the tril erly due to n excess of plcebo relpses compred to olnzpine

31 relpses, nd olnzpine ws superior to plcebo on time to relpse, the primry outcome for this study. Thus, olnzpine ws more effective thn plcebo t mintining efficcy in ptients stbilized for pproximtely 8 weeks nd followed for n observtion period of up to 8 months. Exmintion of popultion subsets (rce nd gender) did not revel ny differentil responsiveness on the bsis of these subgroupings. Adolescents The efficcy of orl olnzpine in the cute tretment of schizophreni in dolescents (ges to 7 yers) ws estblished in -week double-blind, plcebo-controlled, rndomized tril of inptients nd outptients with schizophreni (n=7) who met dignostic criteri ccording to DSM-IV-TR nd confirmed by the Kiddie Schedule for Affective Disorders nd Schizophreni for School Aged Children-Present nd Lifetime Version (K-SADS-PL). The primry rting instrument used for ssessing psychitric signs nd symptoms in this tril ws the Anchored Version of the Brief Psychitric Rting Scle for Children (BPRS-C) totl score. In this flexible-dose tril, olnzpine. to mg/dy (men modl dose. mg/dy, men dose of. mg/dy) ws more effective thn plcebo in the tretment of dolescents dignosed with schizophreni, s supported by the sttisticlly significntly greter men reduction in BPRS-C totl score for ptients in the olnzpine tretment group thn in the plcebo group. While there is no body of evidence vilble to nswer the question of how long the dolescent ptient treted with ZYPREXA should be mintined, mintennce efficcy cn be extrpolted from dult dt long with comprisons of olnzpine phrmcokinetic prmeters in dult nd dolescent ptients. It is generlly recommended tht responding ptients be continued beyond the cute response, but t the lowest dose needed to mintin remission. Ptients should be periodiclly ressessed to determine the need for mintennce tretment.. Bipolr I Disorder (Mnic or Mixed Episodes) Adults Monotherpy The efficcy of orl olnzpine in the tretment of mnic or mixed episodes ws estblished in short-term (one -week nd one -week) plcebo-controlled trils in dult ptients who met the DSM-IV criteri for bipolr I disorder with mnic or mixed episodes. These trils included ptients with or without psychotic fetures nd with or without rpid-cycling course. The primry rting instrument used for ssessing mnic symptoms in these trils ws the Young Mni Rting Scle (Y-MRS), n -item clinicin-rted scle trditionlly used to ssess the degree of mnic symptomtology (irritbility, disruptive/ggressive behvior, sleep, elevted mood, speech, incresed ctivity, sexul interest, lnguge/thought disorder, thought content, ppernce, nd insight) in rnge from (no mnic fetures) to (mximum score). The primry outcome in these trils ws chnge from bseline in the Y-MRS totl score. The results of the trils follow: () In one -week plcebo-controlled tril (n=7) which involved dose rnge of olnzpine (- mg/dy, once dily, strting t mg/dy), olnzpine ws superior to plcebo in the reduction of Y-MRS totl score. In n identiclly designed tril conducted simultneously with the first tril, olnzpine demonstrted similr tretment difference, but possibly due to smple size nd site vribility, ws not shown to be superior to plcebo on this outcome. () In -week plcebo-controlled tril (n=) which involved dose rnge of olnzpine (- mg/dy, once dily, strting t mg/dy), olnzpine ws superior to plcebo in the reduction of Y-MRS totl score. () In nother tril, ptients meeting DSM-IV criteri for mnic or mixed episode of bipolr I disorder who hd responded during n initil open-lbel tretment phse for bout weeks, on verge, to olnzpine to mg/dy were rndomized to either continution of olnzpine t their sme dose (n=) or to plcebo (n=), for observtion of relpse. Approximtely % of the ptients hd discontinued from the olnzpine group by dy nd % of the plcebo group hd discontinued by dy of double-blind tretment. Response during the open-lbel phse ws defined by hving decrese of the Y-MRS totl score to nd HAM-D to 8. Relpse during the double-blind phse ws defined s n increse of the Y-MRS or HAM-D totl score to, or being hospitlized for either mni or depression. In the rndomized phse, ptients receiving continued olnzpine experienced significntly longer time to relpse. Adjunct to Lithium or Vlprote The efficcy of orl olnzpine with concomitnt lithium or vlprote in the tretment of mnic or mixed episodes ws estblished in controlled trils in ptients who met the DSM-IV criteri for bipolr I disorder with mnic or mixed episodes. These trils included ptients with or without psychotic fetures nd with or without rpid-cycling course. The results of the trils follow: () In one -week plcebo-controlled combintion tril, 7 outptients on lithium or vlprote therpy with indequtely controlled mnic or mixed symptoms (Y-MRS ) were rndomized to receive either olnzpine or plcebo, in combintion with their originl therpy. (in dose rnge of - mg/dy, once dily, strting t mg/dy) combined with lithium or vlprote (in therpeutic rnge of. meq/l to. meq/l or µg/ml to µg/ml, respectively) ws superior to lithium or vlprote lone in the reduction of Y-MRS totl score. () In second -week plcebo-controlled combintion tril, outptients on lithium or vlprote therpy with indequtely controlled mnic or mixed symptoms (Y-MRS ) were rndomized to receive either olnzpine or plcebo, in combintion with their originl therpy. (in dose rnge of - mg/dy, once dily, strting t mg/dy)

32 combined with lithium or vlprote (in therpeutic rnge of. meq/l to. meq/l or µg/ml to µg/ml, respectively) ws superior to lithium or vlprote lone in the reduction of Y-MRS totl score. Adolescents Acute Monotherpy The efficcy of orl olnzpine in the tretment of cute mnic or mixed episodes in dolescents (ges to 7 yers) ws estblished in -week, double-blind, plcebo-controlled, rndomized tril of dolescent inptients nd outptients who met the dignostic criteri for mnic or mixed episodes ssocited with bipolr I disorder (with or without psychotic fetures) ccording to the DSM-IV-TR (n=). Dignosis ws confirmed by the K-SADS-PL. The primry rting instrument used for ssessing mnic symptoms in this tril ws the Adolescent Structured Young-Mni Rting Scle (Y-MRS) totl score. In this flexible-dose tril, olnzpine. to mg/dy (men modl dose.7 mg/dy, men dose of 8. mg/dy) ws more effective thn plcebo in the tretment of dolescents with mnic or mixed episodes ssocited with bipolr I disorder, s supported by the sttisticlly significntly greter men reduction in Y-MRS totl score for ptients in the olnzpine tretment group thn in the plcebo group. While there is no body of evidence vilble to nswer the question of how long the dolescent ptient treted with ZYPREXA should be mintined, mintennce efficcy cn be extrpolted from dult dt long with comprisons of olnzpine phrmcokinetic prmeters in dult nd dolescent ptients. It is generlly recommended tht responding ptients be continued beyond the cute response, but t the lowest dose needed to mintin remission. Ptients should be periodiclly ressessed to determine the need for mintennce tretment.. Agittion Associted with Schizophreni nd Bipolr I Mni The efficcy of intrmusculr olnzpine for injection for the tretment of gittion ws estblished in short-term ( hours of IM tretment) plcebo-controlled trils in gitted dult inptients from dignostic groups: schizophreni nd bipolr I disorder (mnic or mixed episodes). Ech of the trils included single ctive comprtor tretment rm of either hloperidol injection (schizophreni studies) or lorzepm injection (bipolr I mni study). Ptients enrolled in the trils needed to be: () judged by the clinicl investigtors s cliniclly gitted nd cliniclly pproprite cndidtes for tretment with intrmusculr mediction, nd () exhibiting level of gittion tht met or exceeded threshold score of on the items comprising the Positive nd Negtive Syndrome Scle (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncoopertiveness nd excitement items) with t lest individul item score using -7 scoring system (=bsent, =moderte, 7=extreme). In the studies, the men bseline PANSS Excited Component score ws 8., with scores rnging from to (out of mximum score of ), thus suggesting predominntly moderte levels of gittion with some ptients experiencing mild or severe levels of gittion. The primry efficcy mesure used for ssessing gittion signs nd symptoms in these trils ws the chnge from bseline in the PANSS Excited Component t hours post-injection. Ptients could receive up to injections during the hour IM tretment periods; however, ptients could not receive the second injection until fter the initil hour period when the primry efficcy mesure ws ssessed. The results of the trils follow: () In plcebo-controlled tril in gitted inptients meeting DSM-IV criteri for schizophreni (n=7), fixed intrmusculr olnzpine for injection doses of. mg, mg, 7. mg nd mg were evluted. All doses were sttisticlly superior to plcebo on the PANSS Excited Component t hours post-injection. However, the effect ws lrger nd more consistent for the highest doses. There were no significnt pirwise differences for the 7. nd mg doses over the mg dose. () In second plcebo-controlled tril in gitted inptients meeting DSM-IV criteri for schizophreni (n=), fixed intrmusculr olnzpine for injection dose of mg ws evluted. for injection ws sttisticlly superior to plcebo on the PANSS Excited Component t hours post-injection. () In plcebo-controlled tril in gitted inptients meeting DSM-IV criteri for bipolr I disorder (nd currently displying n cute mnic or mixed episode with or without psychotic fetures) (n=), fixed intrmusculr olnzpine for injection dose of mg ws evluted. for injection ws sttisticlly superior to plcebo on the PANSS Excited Component t hours post-injection. Exmintion of popultion subsets (ge, rce, nd gender) did not revel ny differentil responsiveness on the bsis of these subgroupings. HOW SUPPLIED/STORAGE AND HANDLING. How Supplied The ZYPREXA. mg, mg, 7. mg, nd mg tblets re white, round, nd imprinted in blue ink with LILLY nd tblet number. The mg tblets re ellipticl, blue, nd debossed with LILLY nd tblet number. The mg tblets re ellipticl, pink, nd debossed with LILLY nd tblet number. The tblets re vilble s follows:

33 Tblet No. Identifiction NDC Codes: Bottles. mg LILLY mg LILLY NDC - NDC - TABLET STRENGTH 7. mg mg 7 LILLY LILLY 7 NDC - NDC 7- mg LILLY mg LILLY NDC - NDC - ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) re yellow, round, nd debossed with the tblet strength. The tblets re vilble s follows: ZYPREXA ZYDIS Tblets Tblet No. Debossed NDC Codes: Dose Pck (Child Resistnt) TABLET STRENGTH mg mg mg NDC --8 NDC --8 NDC --8 mg NDC --8 ZYPREXA is registered trdemrk of Eli Lilly nd Compny. ZYDIS is registered trdemrk of Ctlent Phrm Solutions. ZYPREXA IntrMusculr is vilble in: NDC -77- (No. VL77) mg vil (s). Storge nd Hndling Store ZYPREXA tblets, ZYPREXA ZYDIS, nd ZYPREXA IntrMusculr vils (before reconstitution) t controlled room temperture, to C (8 to 77 F) [see USP]. Reconstituted ZYPREXA IntrMusculr my be stored t controlled room temperture, to C (8 to 77 F) [see USP] for up to hour if necessry. Discrd ny unused portion of reconstituted ZYPREXA IntrMusculr. The USP defines controlled room temperture s temperture mintined thermostticlly tht encompsses the usul nd customry working environment of to C (8 to 77 F); tht results in men kinetic temperture clculted to be not more thn C; nd tht llows for excursions between nd C ( nd 8 F) tht re experienced in phrmcies, hospitls, nd wrehouses. Protect ZYPREXA tblets nd ZYPREXA ZYDIS from light nd moisture. Protect ZYPREXA IntrMusculr from light, do not freeze. 7 PATIENT COUNSELING INFORMATION See FDA-pproved Mediction Guide for the orl formultions. Ptients should be dvised of the following issues nd sked to lert their prescriber if these occur while tking ZYPREXA s monotherpy or in combintion with fluoxetine. If you do not think you re getting better or hve ny concerns bout your condition while tking ZYPREXA, cll your doctor. When using ZYPREXA nd fluoxetine in combintion, lso refer to the Ptient Counseling Informtion section of the pckge insert for Symbyx. 7. Informtion on Mediction Guide Prescribers or other helth professionls should inform ptients, their fmilies, nd their cregivers bout the potentil benefits nd potentil risks ssocited with tretment with ZYPREXA, nd should counsel them in its pproprite use. A ptient Mediction Guide is vilble for ZYPREXA. Prescribers or other helth professionls should instruct ptients, their fmilies, nd their cregivers to red the Mediction Guide nd should ssist them in understnding its contents. Ptients should be given the opportunity to discuss the contents of the Mediction Guide nd to obtin nswers to ny questions they my hve. When using ZYPREXA nd fluoxetine in combintion, lso refer to the Mediction Guide for Symbyx. 7. Elderly Ptients with Dementi-Relted Psychosis: Incresed Mortlity nd Cerebrovsculr Adverse Events (CVAE), Including Stroke Ptients nd cregivers should be dvised tht elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth. Ptients nd cregivers should be dvised tht elderly ptients with dementi-relted psychosis treted with ZYPREXA hd significntly higher incidence of cerebrovsculr dverse events (e.g., stroke, trnsient ischemic ttck) compred with plcebo. ZYPREXA is not pproved for elderly ptients with dementi-relted psychosis [see Boxed Wrning nd Wrnings nd Precutions (.)]. 7. Neuroleptic Mlignnt Syndrome (NMS)

34 Ptients nd cregivers should be counseled tht potentilly ftl symptom complex sometimes referred to s NMS hs been reported in ssocition with dministrtion of ntipsychotic drugs, including ZYPREXA. Signs nd symptoms of NMS include hyperpyrexi, muscle rigidity, ltered mentl sttus, nd evidence of utonomic instbility (irregulr pulse or blood pressure, tchycrdi, diphoresis, nd crdic dysrhythmi) [see Wrnings nd Precutions (.)]. 7. Hyperglycemi nd Dibetes Mellitus Ptients should be dvised of the potentil risk of hyperglycemi-relted dverse rections. Ptients should be monitored regulrly for worsening of glucose control. Ptients who hve dibetes should follow their doctor s instructions bout how often to check their blood sugr while tking ZYPREXA [see Wrnings nd Precutions (.)]. 7. Dyslipidemi Ptients should be counseled tht dyslipidemi hs occurred during tretment with ZYPREXA. Ptients should hve their lipid profile monitored regulrly [see Wrnings nd Precutions (.)]. 7. Weight Gin Ptients should be counseled tht weight gin hs occurred during tretment with ZYPREXA. Ptients should hve their weight monitored regulrly [see Wrnings nd Precutions (.)]. 7.7 Orthosttic Hypotension Ptients should be dvised of the risk of orthosttic hypotension, especilly during the period of initil dose titrtion nd in ssocition with the use of concomitnt drugs tht my potentite the orthosttic effect of ZYPREXA, e.g., dizepm or lcohol [see Wrnings nd Precutions (.) nd Drug Interctions (7)]. Ptients should be dvised to chnge positions crefully to help prevent orthosttic hypotension, nd to lie down if they feel dizzy or fint, until they feel better. Ptients should be dvised to cll their doctor if they experience ny of the following signs nd symptoms ssocited with orthosttic hypotension: dizziness, fst or slow hert bet, or finting. 7.8 Potentil for Cognitive nd Motor Impirment Becuse ZYPREXA hs the potentil to impir judgment, thinking, or motor skills, ptients should be cutioned bout operting hzrdous mchinery, including utomobiles, until they re resonbly certin tht ZYPREXA therpy does not ffect them dversely [see Wrnings nd Precutions (.)]. 7. Body Temperture Regultion Ptients should be dvised regrding pproprite cre in voiding overheting nd dehydrtion. Ptients should be dvised to cll their doctor right wy if they become severely ill nd hve some or ll of these symptoms of dehydrtion: sweting too much or not t ll, dry mouth, feeling very hot, feeling thirsty, not ble to produce urine [see Wrnings nd Precutions (.)]. 7. Concomitnt Mediction Ptients should be dvised to inform their physicins if they re tking, or pln to tke, Symbyx. Ptients should lso be dvised to inform their physicins if they re tking, pln to tke, or hve stopped tking ny prescription or overthe-counter drugs, including herbl supplements, since there is potentil for interctions [see Drug Interctions (7)]. 7. Alcohol Ptients should be dvised to void lcohol while tking ZYPREXA [see Drug Interctions (7)]. 7. Phenylketonurics ZYPREXA ZYDIS (olnzpine orlly disintegrting tblets) contins phenyllnine (.,.,.7, or. mg per,,, or mg tblet, respectively) [see Description ()]. 7. Use in Specific Popultions Pregnncy Ptients should be dvised to notify their physicin if they become pregnnt or intend to become pregnnt during therpy with ZYPREXA [see Use in Specific Popultions (8.)]. Nursing Mothers Ptients should be dvised not to brest-feed n infnt if they re tking ZYPREXA [see Use in Specific Popultions (8.)]. Peditric Use ZYPREXA is indicted for tretment of schizophreni nd mnic or mixed episodes ssocited with bipolr I disorder in dolescents to 7 yers of ge. Compred to ptients from dult clinicl trils, dolescents were likely to gin more weight, experience incresed sedtion, nd hve greter increses in totl cholesterol, triglycerides, LDL cholesterol, prolctin, nd heptic minotrnsferse levels. Ptients should be counseled bout the potentil long-term risks ssocited with ZYPREXA nd dvised tht these risks my led them to consider other drugs first [see Indictions nd Usge (.,.)]. Sfety nd effectiveness of ZYPREXA in ptients under yers of ge hve not been estblished. Sfety nd efficcy of ZYPREXA nd fluoxetine in combintion in ptients to 7 yers of ge hve been estblished for the cute tretment of depressive episodes ssocited with bipolr I disorder. Sfety nd effectiveness of ZYPREXA nd fluoxetine in combintion in ptients < yers of ge hve not been estblished [see Wrnings nd Precutions (.) nd Use in Specific Popultions (8.)]. 7. Need for Comprehensive Tretment Progrm in Peditric Ptients ZYPREXA is indicted s n integrl prt of totl tretment progrm for peditric ptients with schizophreni nd bipolr disorder tht my include other mesures (psychologicl, eductionl, socil) for ptients with the disorder.

35 Effectiveness nd sfety of ZYPREXA hve not been estblished in peditric ptients less thn yers of ge. Atypicl ntipsychotics re not intended for use in the peditric ptient who exhibits symptoms secondry to environmentl fctors nd/or other primry psychitric disorders. Approprite eductionl plcement is essentil nd psychosocil intervention is often helpful. The decision to prescribe typicl ntipsychotic mediction will depend upon the physicin s ssessment of the chronicity nd severity of the ptient s symptoms [see Indictions nd Usge (.)]. Literture revised July, Mrketed by: Lilly USA, LLC, Indinpolis, IN 8, USA Copyright 7,, Eli Lilly nd Compny. All rights reserved. ZYP--USPI-7