Known CYP2D6 Poor Metabolizers

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use ABILIFY sfely nd effectively. See full prescribing informtion for ABILIFY. Tblets ABILIFY DISCMELT (ripiprzole) Orlly Disintegrting Tblets Orl Solution Injection FOR INTRAMUSCULAR USE ONLY Initil U.S. Approvl: 2002 WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS nd SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS 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. ABILIFY is not pproved for the tretment of ptients with dementi-relted psychosis. (5.1) Incresed risk of suicidl thinking nd behvior in children, dolescents, nd young dults tking ntidepressnts. Monitor for worsening nd emergence of suicidl thoughts nd behviors. (5.3) RECENT MAJOR CHANGES Wrnings nd Precutions, Pthologicl Gmbling nd Other Compulsive Behviors (5.7) 08/2016 -INDICATIONS AND USAGE ABILIFY is n typicl ntipsychotic. The orl formultions re indicted for: Schizophreni (14.1) Acute Tretment of Mnic nd Mixed Episodes ssocited with Bipolr I (14.2) Adjunctive Tretment of Mjor Depressive Disorder (14.3) Irritbility Associted with Autistic Disorder (14.4) Tretment of Tourette s disorder (14.5) The injection is indicted for: Agittion ssocited with schizophreni or bipolr mni (14.6) DOSAGE AND ADMINISTRATION Initil Recommended Mximum Dose Dose Dose Schizophreni dults (2.1) mg/dy mg/dy 30 mg/dy Schizophreni dolescents (2.1) 2 mg/dy 10 mg/dy 30 mg/dy Bipolr mni dults: monotherpy (2.2) 15 mg/dy 15 mg/dy 30 mg/dy Bipolr mni dults: djunct to lithium or vlprote (2.2) mg/dy 15 mg/dy 30 mg/dy Bipolr mni peditric ptients: monotherpy or s n djunct to lithium or 2 mg/dy 10 mg/dy 30 mg/dy vlprote (2.2) Mjor Depressive Disorder Adults djunct to ntidepressnts (2.3) 2-5 mg/dy 5-10 mg/dy 15 mg/dy Irritbility ssocited with utistic disorder peditric ptients (2.4) 2 mg/dy 5-10 mg/dy 15 mg/dy Tourette s disorder Ptients <50 kg 2 mg/dy 5 mg/dy 10 mg/dy (2.5) Ptients 50 kg 2 mg/dy 10 mg/dy 20 mg/dy Agittion ssocited with schizophreni or bipolr mni dults (2.6) 9.75 mg/1.3 ml injected IM 30 mg/dy injected IM Orl formultions: Administer once dily without regrd to mels (2) IM injection: Wit t lest 2 hours between doses. Mximum dily dose 30 mg (2.5) Known CYP2D6 pr metbolizers: Hlf of the usul dose (2.7) DOSAGE FORMS AND STRENGTHS Tblets: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, nd 30 mg (3) Orlly Disintegrting Tblets: 10 mg nd 15 mg (3) Orl Solution: 1 mg/ml (3) Injection: 9.75 mg/1.3 ml single-dose vil (3) CONTRAINDICATIONS- Known hypersensitivity to ABILIFY (4) WARNINGS AND PRECAUTIONS- Cerebrovsculr Adverse Rections in Elderly Ptients with Dementi-Relted Psychosis: Incresed incidence of cerebrovsculr dverse rections (e.g., stroke, trnsient ischemic ttck, including ftlities) (5.2) Neuroleptic Mlignnt Syndrome: Mnge with immedite discontinution nd close monitoring (5.4) Trdive Dyskinesi: Discontinue if cliniclly pproprite (5.5) Metbolic Chnges: Atypicl ntipsychotic drugs hve been ssocited with metbolic chnges tht include hyperglycemi/dibetes mellitus, dyslipidemi, nd body weight gin (5.6) Hyperglycemi/Dibetes Mellitus: Monitor glucose regulrly in ptients with nd t risk for dibetes (5.6) Dyslipidemi: Undesirble ltertions in lipid levels hve been observed in ptients treted with typicl ntipsychotics (5.6) Weight Gin: Weight gin hs been observed with typicl ntipsychotic use. Monitor weight (5.6) Pthologicl Gmbling nd Other Compulsive Behviors: Consider dose reduction or discontinution (5.7) Orthosttic Hypotension: Monitor hert rte nd bld pressure nd wrn ptients with known crdiovsculr or cerebrovsculr disese, nd risk of dehydrtion or syncope (5.8) Leukopeni, Neutropeni, nd Agrnulocytosis: hve been reported with ntipsychotics including ABILIFY. Ptients with history of cliniclly significnt low white bld cell count (WBC) or drug-induced leukopeni/neutropeni should hve their complete bld count (CBC) monitored frequently during the first few months of therpy nd discontinution of ABILIFY should be considered t the first sign of cliniclly significnt decline in WBC in the bsence of other custive fctors (5.9) Seizures/Convulsions: Use cutiously in ptients with history of seizures or with conditions tht lower the seizure threshold (5.10) Potentil for Cognitive nd Motor Impirment: Use cution when operting mchinery (5.11) Suicide: The possibility of suicide ttempt is inherent in schizophreni nd bipolr disorder. Closely supervise high-risk ptients (5.13) ADVERSE REACTIONS- Commonly observed dverse rections (incidence 5% nd t lest twice tht for plcebo) were (6.1): Adult ptients with schizophreni: kthisi Peditric ptients (13 to 17 yers) with schizophreni: extrpyrmidl disorder, somnolence, nd tremor Adult ptients (monotherpy) with bipolr mni: kthisi, sedtion, restlessness, tremor, nd extrpyrmidl disorder Adult ptients (djunctive therpy with lithium or vlprote) with bipolr mni: kthisi, insomni, nd extrpyrmidl disorder Peditric ptients (10 to 17 yers) with bipolr mni: somnolence, extrpyrmidl disorder, ftigue, nuse, kthisi, blurred vision, slivry hypersecretion, nd dizziness Adult ptients with mjor depressive disorder (djunctive tretment to ntidepressnt therpy): kthisi, restlessness, insomni, constiption, ftigue, nd blurred vision Peditric ptients (6 to 17 yers) with utistic disorder: sedtion, ftigue, vomiting, somnolence, tremor, pyrexi, drling, decresed ppetite, slivry hypersecretion, extrpyrmidl disorder, nd lethrgy Peditric ptients (6 to 18 yers) with Tourette s disorder: sedtion, somnolence, nuse, hedche, nsophryngitis, ftigue, incresed ppetite Adult ptients with gittion ssocited with schizophreni or bipolr mni: nuse To report SUSPECTED ADVERSE REACTIONS, contct Bristol-Myers Squibb t or FDA t FDA-1088 or -DRUG INTERACTIONS Dosge djustment due to drug interctions (7.1): Fctors Dosge Adjustments for ABILIFY Known CYP2D6 Pr Administer hlf of usul dose Metbolizers Known CYP2D6 Pr Metbolizers Administer qurter of usul dose nd strong CYP3A4 inhibitors Strong CYP2D6 or CYP3A4 Administer hlf of usul dose inhibitors Strong CYP2D6 nd CYP3A4 Administer qurter of usul dose inhibitors Strong CYP3A4 inducers Double usul dose over 1 to 2 weeks -USE IN SPECIFIC POPULATIONS- Pregnncy: My cuse extrpyrmidl nd/or withdrwl symptoms in neontes with third trimester exposure (8.1) Nursing Mothers: Discontinue drug or nursing, tking into considertion importnce of drug to the mother (8.3) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 08/2016

2 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS nd SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Schizophreni 2.2 Bipolr I Disorder 2.3 Adjunctive Tretment of Mjor Depressive Disorder 2.4 Irritbility Associted with Autistic Disorder 2.5 Tourette s Disorder 2.6 Agittion Associted with Schizophreni or Bipolr Mni (Intrmusculr Injection) 2.7 Dosge Adjustments for Cytochrome P450 Considertions 2.8 Dosing of Orl Solution 2.9 Dosing of Orlly Disintegrting Tblets 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Incresed Mortlity in Elderly Ptients with Dementi-Relted Psychosis 5.2 Cerebrovsculr Adverse Events, Including Stroke 5.3 Suicidl Thoughts nd Behviors in Children, Adolescents, nd Young Adults 5.4 Neuroleptic Mlignnt Syndrome (NMS) 5.5 Trdive Dyskinesi 5.6 Metbolic Chnges 5.7 Pthologicl Gmbling nd Other Compulsive Behviors 5.8 Orthosttic Hypotension 5.9 Leukopeni, Neutropeni, nd Agrnulocytosis 5.10 Seizures/Convulsions 5.11 Potentil for Cognitive nd Motor Impirment 5.12 Body Temperture Regultion 5.13 Suicide 5.14 Dysphgi 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Postmrketing Experience 7 DRUG INTERACTIONS 7.1 Drugs Hving Cliniclly Importnt Interctions with ABILIFY 7.2 Drugs Hving No Cliniclly Importnt Interctions with ABILIFY 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lbor nd Delivery 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 CYP2D6 Pr Metbolizers 8.7 Heptic nd Renl Impirment 8.8 Other Specific Popultions 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substnce 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Humn Experience 10.2 Mngement of Overdosge 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Schizophreni 14.2 Bipolr Disorder 14.3 Adjunctive Tretment of Mjor Depressive Disorder 14.4 Irritbility Associted with Autistic Disorder 14.5 Tourette s Disorder 14.6 Agittion Associted with Schizophreni or Bipolr Mni 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge 17 PATIENT COUNSELING INFORMATION * 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 nd SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS Elderly ptients with dementi-relted psychosis treted with ntipsychotic drugs re t n incresed risk of deth. ABILIFY is not pproved for the tretment of ptients with dementi-relted psychosis [see WARNINGS AND PRECAUTIONS (5.1)]. Antidepressnts incresed the risk of suicidl thoughts nd behvior in children, dolescents, nd young dults in short-term studies. These studies did not show n increse in the risk of suicidl thoughts nd behvior with ntidepressnt use in ptients over ge 24; there ws reduction in risk with ntidepressnt use in ptients ged 65 nd older [see WARNINGS AND PRECAUTIONS (5.3)]. In ptients of ll ges who re strted on ntidepressnt therpy, monitor closely for worsening, nd for emergence of suicidl thoughts nd behviors. Advise fmilies nd cregivers of the need for close observtion nd communiction with the prescriber [see WARNINGS AND PRECAUTIONS (5.3)]. 1 INDICATIONS AND USAGE ABILIFY Orl Tblets, Orlly-Disintegrting Tblets, nd Orl Solution re indicted for the tretment of: Schizophreni [see CLINICAL STUDIES (14.1)] Acute Tretment of Mnic nd Mixed Episodes ssocited with Bipolr I Disorder [see CLINICAL STUDIES (14.2)] Adjunctive Tretment of Mjor Depressive Disorder [see CLINICAL STUDIES (14.3)] Irritbility Associted with Autistic Disorder [see CLINICAL STUDIES (14.4)] Tretment of Tourette s Disorder [see CLINICAL STUDIES (14.5)] ABILIFY Injection is indicted for the tretment of: Agittion ssocited with schizophreni or bipolr mni [see CLINICAL STUDIES (14.6)] 2 2 DOSAGE AND ADMINISTRATION 2.1 Schizophreni Adults The recommended strting nd trget dose for ABILIFY is 10 or 15 mg/dy dministered on once--dy schedule without regrd to mels. ABILIFY hs been systemticlly evluted nd shown to be effective in dose rnge of 10 to 30 mg/dy, when dministered s the tblet formultion; however, doses higher thn 10 or 15 mg/dy were not more effective thn 10 or 15 mg/dy. Dosge increses should generlly not be mde before 2 weeks, the time needed to chieve stedy-stte [see CLINICAL STUDIES (14.1)]. Mintennce Tretment: Mintennce of efficcy in schizophreni ws demonstrted in tril involving ptients with schizophreni who hd been symptomticlly stble on other ntipsychotic medictions for periods of 3 months or longer. These ptients were discontinued from those medictions nd rndomized to either ABILIFY 15 mg/dy or plcebo, nd observed for relpse [see CLINICAL STUDIES (14.1)]. Ptients should be periodiclly ressessed to determine the continued need for mintennce tretment. Adolescents The recommended trget dose of ABILIFY is 10 mg/dy. Aripiprzole ws studied in dolescent ptients 13 to 17 yers of ge with schizophreni t dily doses of 10 mg nd 30 mg. The strting dily dose of the tblet formultion in these ptients ws 2 mg, which ws titrted to 5 mg fter 2 dys nd to the trget dose of 10 mg fter 2 dditionl dys. Subsequent dose increses should be dministered in 5 mg increments. The 30 mg/dy dose ws not shown to be more efficcious thn the 10 mg/dy dose. ABILIFY cn be dministered without regrd to mels [see CLINICAL STUDIES (14.1)]. Ptients should be periodiclly ressessed to determine the need for mintennce tretment. Switching from Other Antipsychotics There re no systemticlly collected dt to specificlly ddress switching ptients with schizophreni from other ntipsychotics to ABILIFY or concerning concomitnt dministrtion with other ntipsychotics. While immedite discontinution of the previous ntipsychotic tretment my be cceptble for some ptients with schizophreni, more grdul discontinution my be most pproprite for others. In ll cses, the period of overlpping ntipsychotic dministrtion should be minimized.

3 2.2 Bipolr I Disorder Acute Tretment of Mnic nd Mixed Episodes Adults: The recommended strting dose in dults is 15 mg given once dily s monotherpy nd 10 mg to 15 mg given once dily s djunctive therpy with lithium or vlprote. ABILIFY cn be given without regrd to mels. The recommended trget dose of ABILIFY is 15 mg/dy, s monotherpy or s djunctive therpy with lithium or vlprote. The dose my be incresed to 30 mg/dy bsed on clinicl response. The sfety of doses bove 30 mg/dy hs not been evluted in clinicl trils. Peditrics: The recommended strting dose in peditric ptients (10 to 17 yers) s monotherpy is 2 mg/dy, with titrtion to 5 mg/dy fter 2 dys, nd trget dose of 10 mg/dy fter 2 dditionl dys. Recommended dosing s djunctive therpy to lithium or vlprote is the sme. Subsequent dose increses, if needed, should be dministered in 5 mg/dy increments. ABILIFY cn be given without regrd to mels [see CLINICAL STUDIES (14.2)]. 2.3 Adjunctive Tretment of Mjor Depressive Disorder Adults The recommended strting dose for ABILIFY s djunctive tretment for ptients lredy tking n ntidepressnt is 2 to 5 mg/dy. The recommended dosge rnge is 2 to 15 mg/dy. Dosge djustments of up to 5 mg/dy should occur grdully, t intervls of no less thn 1 week [see CLINICAL STUDIES (14.3)]. Ptients should be periodiclly ressessed to determine the continued need for mintennce tretment. 2.4 Irritbility Associted with Autistic Disorder Peditric Ptients (6 to 17 yers) The recommended dosge rnge for the tretment of peditric ptients with irritbility ssocited with utistic disorder is 5 to 15 mg/dy. Dosing should be initited t 2 mg/dy. The dose should be incresed to 5 mg/dy, with subsequent increses to 10 or 15 mg/dy if needed. Dose djustments of up to 5 mg/dy should occur grdully, t intervls of no less thn 1 week [see CLINICAL STUDIES (14.4)]. Ptients should be periodiclly ressessed to determine the continued need for mintennce tretment. 2.5 Tourette s Disorder Peditric Ptients (6 to 18 yers) The recommended dosge rnge for Tourette s Disorder is 5 to 20 mg/dy. For ptients weighing less thn 50 kg, dosing should be initited t 2 mg/dy with trget dose of 5 mg/dy fter 2 dys. The dose cn be incresed to 10 mg/dy in ptients who do not chieve optiml control of tics. Dosge djustments should occur grdully t intervls of no less thn 1 week. For ptients weighing 50 kg or more, dosing should be initited t 2 mg/dy for 2 dys, nd then incresed to 5 mg/dy for 5 dys, with trget dose of 10 mg/dy on dy 8. The dose cn be incresed up to 20 mg/dy for ptients who do not chieve optiml control of tics. Dosge djustments should occur grdully in increments of 5 mg/dy t intervls of no less thn 1 week. [see CLINICAL STUDIES (14.5)]. Ptients should be periodiclly ressessed to determine the continued need for mintennce tretment. 2.6 Agittion Associted with Schizophreni or Bipolr Mni (Intrmusculr Injection) Adults The recommended dose in these ptients is 9.75 mg. The recommended dosge rnge is 5.25 to 15 mg. No dditionl benefit ws demonstrted for 15 mg compred to 9.75 mg. A lower dose of 5.25 mg my be considered when clinicl fctors wrrnt. If gittion wrrnting second dose persists following the initil dose, cumultive doses up to totl of 30 mg/dy my be given. However, the efficcy of repeted doses of ABILIFY injection in gitted ptients hs not been systemticlly evluted in controlled clinicl trils. The sfety of totl dily doses greter thn 30 mg or injections given more frequently thn every 2 hours hve not been dequtely evluted in clinicl trils [see CLINICAL STUDIES (14.6)]. If ongoing ABILIFY therpy is cliniclly indicted, orl ABILIFY in rnge of 10 to 30 mg/dy should replce ABILIFY injection s sn s possible [see DOSAGE AND ADMINISTRATION (2.1 nd 2.2)]. Administrtion of ABILIFY Injection To dminister ABILIFY Injection, drw up the required volume of solution into the syringe s shown in Tble 1. Discrd ny unused portion. Tble 1: ABILIFY Injection Dosing Recommendtions Single-Dose Required Volume of Solution 5.25 mg 0.7 ml 9.75 mg 1.3 ml 15 mg 2 ml ABILIFY Injection 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. 2.7 Dosge Adjustments for Cytochrome P450 Considertions Dosge djustments re recommended in ptients who re known CYP2D6 pr metbolizers nd in ptients tking concomitnt CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Tble 2). When the codministered drug is withdrwn from the combintion therpy, ABILIFY dosge should then be djusted to its originl level. When the codministered CYP3A4 inducer is withdrwn, ABILIFY dosge should be reduced to the originl level over 1 to 2 weeks. Ptients who my be receiving combintion of strong, moderte, nd wek inhibitors of CYP3A4 nd CYP2D6 (e.g., strong CYP3A4 inhibitor nd moderte CYP2D6 inhibitor or moderte CYP3A4 inhibitor with moderte CYP2D6 inhibitor), the dosing my be reduced to one-qurter (25%) of the usul dose initilly nd then djusted to chieve fvorble clinicl response. Tble 2: Dose Adjustments for ABILIFY in Ptients who re known CYP2D6 Pr Metbolizers nd Ptients Tking Concomitnt CYP2D6 Inhibitors, 3A4 Inhibitors, nd/or CYP3A4 Inducers Fctors Known CYP2D6 Pr Metbolizers Dosge Adjustments for ABILIFY Administer hlf of usul dose Known CYP2D6 Pr Metbolizers tking concomitnt strong CYP3A4 inhibitors Administer qurter of usul dose (e.g., itrconzole, clrithromycin) Strong CYP2D6 (e.g., quinidine, fluoxetine, proxetine) or CYP3A4 inhibitors (e.g., Administer hlf of usul dose itrconzole, clrithromycin) Strong CYP2D6 nd CYP3A4 inhibitors Administer qurter of usul dose Strong CYP3A4 inducers (e.g., crbmzepine, Double usul dose over 1 to 2 rifmpin) weeks When djunctive ABILIFY is dministered to ptients with mjor depressive disorder, ABILIFY should be dministered without dosge djustment s specified in DOSAGE AND ADMINISTRATION (2.3). 2.8 Dosing of Orl Solution The orl solution cn be substituted for tblets on mg-per-mg bsis up to the 25 mg dose level. Ptients receiving 30 mg tblets should receive 25 mg of the solution [see CLINICAL PHARMACOLOGY (12.3)]. 2.9 Dosing of Orlly Disintegrting Tblets The dosing for ABILIFY Orlly Disintegrting Tblets is the sme s for the orl tblets [see DOSAGE AND ADMINISTRATION (2.1, 2.2, 2.3, nd 2.4)]. 3 DOSAGE FORMS AND STRENGTHS Tblets re vilble s described in Tble 3. Tble 3: ABILIFY Tblet Presenttions Tblet Strength Tblet Color/Shpe Tblet Mrkings 2 mg green/modified rectngle A-006 nd 2 5 mg blue/modified rectngle A-007 nd 5 10 mg pink/modified rectngle A-008 nd mg yellow/round A-009 nd mg white/round A-010 nd mg pink/round A-011 nd 30 ABILIFY DISCMELT (ripiprzole) Orlly Disintegrting Tblets re vilble s described in Tble 4. Tble 4: ABILIFY DISCMELT Orlly Disintegrting Tblet Presenttions Tblet Strength Tblet Color/Shpe Tblet Mrkings 10 mg pink (with scttered specks) A nd 640 round mg yellow (with scttered specks) A nd 641 round 15 Orl Solution (1 mg/ml) is cler, colorless to light-yellow solution, supplied in child-resistnt bottles long with clibrted orl dosing cup. Injection for Intrmusculr Use is cler, colorless solution vilble s redy-to-use, 9.75 mg/1.3 ml (7.5 mg/ml) solution in cler, Type 1 glss vils. 4 CONTRAINDICATIONS ABILIFY is contrindicted in ptients with history of hypersensitivity rection to ripiprzole. Rections hve rnged from pruritus/urticri to nphylxis [see ADVERSE REACTIONS (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Incresed Mortlity in 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. ABILIFY (ripiprzole) is not pproved for the tretment of ptients with dementi-relted psychosis [see BOXED WARNING]. 3

4 Sfety Experience in Elderly Ptients with Psychosis Associted with Alzheimer s Disese In three, 10-week, plcebo-controlled studies of ABILIFY in elderly ptients with psychosis ssocited with Alzheimer s disese (n=938; men ge: 82.4 yers; rnge: yers), the dverse rections tht were reported t n incidence of 3% nd ABILIFY incidence t lest twice tht for plcebo were lethrgy [plcebo 2%, ABILIFY 5%], somnolence (including sedtion) [plcebo 3%, ABILIFY 8%], nd incontinence (primrily, urinry incontinence) [plcebo 1%, ABILIFY 5%], excessive slivtion [plcebo 0%, ABILIFY 4%], nd lighthededness [plcebo 1%, ABILIFY 4%]. The sfety nd efficcy of ABILIFY in the tretment of ptients with psychosis ssocited with dementi hve not been estblished. If the prescriber elects to tret such ptients with ABILIFY, ssess for the emergence of difficulty swllowing or excessive somnolence, which could predispose to ccidentl injury or spirtion [see BOXED WARNING]. 5.2 Cerebrovsculr Adverse Events, Including Stroke In plcebo-controlled clinicl studies (two flexible dose nd one fixed dose study) of dementi-relted psychosis, there ws n incresed incidence of cerebrovsculr dverse events (e.g., stroke, trnsient ischemic ttck), including ftlities, in ABILIFY-treted ptients (men ge: 84 yers; rnge: yers). In the fixed-dose study, there ws sttisticlly significnt dose response reltionship for cerebrovsculr dverse events in ptients treted with ABILIFY. ABILIFY is not pproved for the tretment of ptients with dementi-relted psychosis [see BOXED WARNING]. 5.3 Suicidl Thoughts nd Behviors in Children, Adolescents, nd Young Adults Ptients with mjor depressive disorder (MDD), both dult nd peditric, my experience worsening of their depression nd/or the emergence of suicidl idetion nd behvior (suicidlity) or unusul chnges in behvior, whether or not they re tking ntidepressnt medictions, nd this risk my persist until significnt remission occurs. Suicide is known risk of depression nd certin other psychitric disorders, nd these disorders themselves re the strongest predictors of suicide. There hs been long-stnding concern, however, tht ntidepressnts my hve role in inducing worsening of depression nd the emergence of suicidlity in certin ptients during the erly phses of tretment. Pled nlyses of short-term, plcebo-controlled trils of ntidepressnt drugs (SSRIs nd others) showed tht these drugs increse the risk of suicidl thinking nd behvior (suicidlity) in children, dolescents, nd young dults (ges 18-24) with MDD nd other psychitric disorders. Short-term studies did not show n increse in the risk of suicidlity with ntidepressnts compred to plcebo in dults beyond ge 24; there ws reduction with ntidepressnts compred to plcebo in dults ged 65 nd older. The pled nlyses of plcebo-controlled trils in children nd dolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychitric disorders included totl of 24 short-term trils of 9 ntidepressnt drugs in over 4400 ptients. The pled nlyses of plcebo-controlled trils in dults with MDD or other psychitric disorders included totl of 295 short-term trils (medin durtion of 2 months) of 11 ntidepressnt drugs in over 77,000 ptients. There ws considerble vrition in risk of suicidlity mong drugs, but tendency towrd n increse in the younger ptients for lmost ll drugs studied. There were differences in bsolute risk of suicidlity cross the different indictions, with the highest incidence in MDD. The risk differences (drug vs. plcebo), however, were reltively stble within ge strt nd cross indictions. These risk differences (drug-plcebo difference in the number of cses of suicidlity per 1000 ptients treted) re provided in Tble 5. Tble 5: Age Rnge Drug- Difference in Number of Cses of Suicidlity per 1000 Ptients Treted Increses Compred to <18 14 dditionl cses dditionl cses Decreses Compred to fewer cse 65 6 fewer cses No suicides occurred in ny of the peditric trils. There were suicides in the dult trils, but the number ws not sufficient to rech ny conclusion bout drug effect on suicide. It is unknown whether the suicidlity risk extends to longer-term use, i.e., beyond severl months. However, there is substntil evidence from plcebo-controlled mintennce trils in dults with depression tht the use of ntidepressnts cn dely the recurrence of depression. All ptients being treted with ntidepressnts for ny indiction should be monitored ppropritely nd observed closely for clinicl worsening, suicidlity, nd unusul chnges in behvior, especilly during the initil few months of course of drug therpy, or t times of dose chnges, either increses or decreses. The following symptoms, nxiety, gittion, pnic ttcks, insomni, irritbility, hostility, ggressiveness, impulsivity, kthisi (psychomotor restlessness), hypomni, nd mni, hve been reported in dult nd peditric ptients being treted with ntidepressnts for MDD s well s for other indictions, both psychitric nd nonpsychitric. Although cusl link between the emergence of such symptoms nd either the worsening of depression nd/or the emergence of suicidl impulses hs not been estblished, there is concern tht such symptoms my represent precursors to emerging suicidlity. Considertion should be given to chnging the therpeutic regimen, including possibly discontinuing the mediction, in ptients whose depression is persistently worse, or who re experiencing emergent suicidlity or symptoms tht might be precursors to worsening depression or suicidlity, especilly if these symptoms re severe, brupt in onset, or were not prt of the ptient s presenting symptoms. 4 Fmilies nd cregivers of ptients being treted with ntidepressnts for mjor depressive disorder or other indictions, both psychitric nd nonpsychitric, should be lerted bout the need to monitor ptients for the emergence of gittion, irritbility, unusul chnges in behvior, nd the other symptoms described bove, s well s the emergence of suicidlity, nd to report such symptoms immeditely to helthcre providers. Such monitoring should include dily observtion by fmilies nd cregivers. Prescriptions for ABILIFY should be written for the smllest quntity of tblets consistent with gd ptient mngement, in order to reduce the risk of overdose. Screening Ptients for Bipolr Disorder: A mjor depressive episode my be the initil presenttion of bipolr disorder. It is generlly believed (though not estblished in controlled trils) tht treting such n episode with n ntidepressnt lone my increse the likelihd of precipittion of mixed/mnic episode in ptients t risk for bipolr disorder. Whether ny of the symptoms described bove represent such conversion is unknown. However, prior to inititing tretment with n ntidepressnt, ptients with depressive symptoms should be dequtely screened to determine if they re t risk for bipolr disorder; such screening should include detiled psychitric history, including fmily history of suicide, bipolr disorder, nd depression. It should be noted tht ABILIFY is not pproved for use in treting depression in the peditric popultion. 5.4 Neuroleptic Mlignnt Syndrome (NMS) A potentilly ftl symptom complex sometimes referred to s Neuroleptic Mlignnt Syndrome (NMS) my occur with dministrtion of ntipsychotic drugs, including ABILIFY. Rre cses of NMS occurred during ABILIFY tretment in the worldwide clinicl dtbse. Clinicl mnifesttions of NMS re hyperpyrexi, muscle rigidity, ltered mentl sttus, nd evidence of utonomic instbility (irregulr pulse or bld pressure, tchycrdi, diphoresis, nd crdic dysrhythmi). Additionl signs my include elevted cretine 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) 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: 1) immedite discontinution of ntipsychotic drugs nd other drugs not essentil to concurrent therpy; 2) intensive symptomtic tretment nd medicl monitoring; nd 3) tretment of ny concomitnt serious medicl problems for which specific tretments re vilble. There is no generl greement bout specific phrmcologicl tretment regimens for uncomplicted 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. 5.5 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 likelihd 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. 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, ABILIFY 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 (1) is known to respond to ntipsychotic drugs nd (2) 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 ABILIFY, drug discontinution should be considered. However, some ptients my require tretment with ABILIFY despite the presence of the syndrome. 5.6 Metbolic Chnges Atypicl ntipsychotic drugs hve been ssocited with metbolic chnges tht include hyperglycemi/dibetes mellitus, dyslipidemi, nd body weight gin. While ll drugs in the clss hve been shown to produce some metbolic chnges, ech drug hs its own specific risk profile.

5 Hyperglycemi/Dibetes Mellitus Hyperglycemi, in some cses extreme nd ssocited with ketocidosis or hyperosmolr com or deth, hs been reported in ptients treted with typicl ntipsychotics. There hve been reports of hyperglycemi in ptients treted with ABILIFY [see ADVERSE REACTIONS (6.1, 6.2)]. 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. Given these confounders, the reltionship between typicl ntipsychotic use nd hyperglycemi-relted dverse events is not completely understd. However, epidemiologicl studies suggest n incresed risk of hyperglycemi-relted dverse rections in ptients treted with the typicl ntipsychotics. Becuse ABILIFY ws not mrketed t the time these studies were performed, it is not known if ABILIFY is ssocited with this incresed risk. Precise risk estimtes for hyperglycemi-relted dverse rections in ptients treted with typicl ntipsychotics re not vilble. Ptients with n estblished dignosis of dibetes mellitus who re strted on typicl ntipsychotics should be monitored regulrly for worsening of glucose control. Ptients with risk fctors for dibetes mellitus (e.g., obesity, fmily history of dibetes) who re strting tretment with typicl ntipsychotics should undergo fsting bld 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 bld 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. Adults In n nlysis of 13 plcebo-controlled monotherpy trils in dults, primrily with schizophreni or bipolr disorder, the men chnge in fsting glucose in ABILIFY-treted ptients (+4.4 mg/dl; medin exposure 25 dys; N=1057) ws not significntly different thn in plcebo-treted ptients (+2.5 mg/dl; medin exposure 22 dys; N=799). Tble 6 shows the proportion of ABILIFY-treted ptients with norml nd borderline fsting glucose t bseline (medin exposure 25 dys) tht hd tretment-emergent high fsting glucose mesurements compred to plcebo-treted ptients (medin exposure 22 dys). Tble 6: Chnges in Fsting Glucose From -Controlled Monotherpy Trils in Adult Ptients Ctegory Chnge (t lest once) from Bseline Tretment Arm n/n % Fsting Glucose At 24 weeks, the men chnge in fsting glucose in ABILIFY-treted ptients ws not significntly different thn in plcebo-treted ptients [+2.2 mg/dl (n=42) nd +9.6 mg/dl (n=28), respectively]. The men chnge in fsting glucose in djunctive ABILIFY-treted ptients with mjor depressive disorder (+0.7 mg/dl; medin exposure 42 dys; N=241) ws not significntly different thn in plcebo-treted ptients (+0.8 mg/dl; medin exposure 42 dys; N=246). Tble 7 shows the proportion of dult ptients with chnges in fsting glucose levels from two plcebo-controlled, djunctive trils (medin exposure 42 dys) in ptients with mjor depressive disorder. Tble 7: Fsting Glucose (<100 mg/dl to 126 mg/dl) Borderline to High ( 100 mg/dl nd <126 mg/dl to 126 mg/dl) ABILIFY 31/ / ABILIFY 31/ / Chnges in Fsting Glucose From -Controlled Adjunctive Trils in Adult Ptients with Mjor Depressive Disorder Ctegory Chnge (t lest once) from Bseline Tretment Arm n/n % ABILIFY 2/ (<100 mg/dl to 126 mg/dl) 2/ Borderline to High ABILIFY 4/ ( 100 mg/dl nd <126 mg/dl to 126 mg/dl) 3/ Peditric Ptients nd Adolescents In n nlysis of two plcebo-controlled trils in dolescents with schizophreni (13 to 17 yers) nd peditric ptients with bipolr disorder (10 to 17 yers), the men chnge in fsting glucose in ABILIFY-treted ptients (+4.8 mg/dl; with medin exposure of 43 dys; N=259) ws not significntly different thn in plcebo-treted ptients (+1.7 mg/dl; with medin exposure of 42 dys; N=123). In n nlysis of two plcebo-controlled trils in peditric nd dolescent ptients with irritbility ssocited with utistic disorder (6 to 17 yers) with medin exposure of 56 dys, the men chnge in fsting glucose in ABILIFY-treted ptients ( 0.2 mg/dl; N=83) ws not significntly different thn in plcebo-treted ptients ( 0.6 mg/dl; N=33). In n nlysis of two plcebo-controlled trils in peditric nd dolescent ptients with Tourette s disorder (6 to 18 yers) with medin exposure of 57 dys, the men chnge in fsting glucose in ABILIFY-treted ptients (0.79 mg/dl; N=90) ws not significntly different thn in plcebo-treted ptients ( 1.66 mg/dl; N=58). 5 Tble 8 shows the proportion of ptients with chnges in fsting glucose levels from the pled dolescent schizophreni nd peditric bipolr ptients (medin exposure of dys), from two plcebo-controlled trils in peditric ptients (6 to 17 yers) with irritbility ssocited with utistic disorder (medin exposure of 56 dys), nd from the two plcebo-controlled trils in peditric ptients (6 to 18 yer) with Tourette s Disorder (medin exposure 57 dys). Tble 8: Chnges in Fsting Glucose From -Controlled Trils in Peditric nd Adolescent Ptients Ctegory Chnge (t lest once) from Bseline Indiction Tretment Arm n/n % Pled Schizophreni nd ABILIFY 2/ Bipolr Disorder 2/ Fsting Glucose Irritbility Associted with ABILIFY 0/73 0 (<100 mg/dl Autistic Disorder 0/32 0 to 126 mg/dl) ABILIFY 3/ Tourette s Disorder 1/ Pled Schizophreni nd ABILIFY 1/ Fsting Glucose Bipolr Disorder 0/12 0 Borderline to High Irritbility Associted with ABILIFY 0/9 0 ( 100 mg/dl Autistic Disorder nd <126 mg/dl 0/1 0 to 126 mg/dl) ABILIFY 0/11 0 Tourette s Disorder 0/4 0 At 12 weeks in the pled dolescent schizophreni nd peditric bipolr disorder trils, the men chnge in fsting glucose in ABILIFY-treted ptients ws not significntly different thn in plcebo-treted ptients [+2.4 mg/dl (n=81) nd +0.1 mg/dl (n=15), respectively]. Dyslipidemi Undesirble ltertions in lipids hve been observed in ptients treted with typicl ntipsychotics. There were no significnt differences between ABILIFY- nd plcebo-treted ptients in the proportion with chnges from norml to cliniclly significnt levels for fsting/nonfsting totl cholesterol, fsting triglycerides, fsting LDLs, nd fsting/nonfsting HDLs. Anlyses of ptients with t lest 12 or 24 weeks of exposure were limited by smll numbers of ptients. Adults Tble 9 shows the proportion of dult ptients, primrily from pled schizophreni nd bipolr disorder monotherpy plcebo-controlled trils, with chnges in totl cholesterol (pled from 17 trils; medin exposure 21 to 25 dys), fsting triglycerides (pled from eight trils; medin exposure 42 dys), fsting LDL cholesterol (pled from eight trils; medin exposure 39 to 45 dys, except for plcebo-treted ptients with bseline norml fsting LDL mesurements, who hd medin tretment exposure of 24 dys) nd HDL cholesterol (pled from nine trils; medin exposure 40 to 42 dys). Tble 9: Chnges in Bld Lipid Prmeters From -Controlled Monotherpy Trils in Adults Totl Cholesterol (<200 mg/dl to 240 mg/dl) Fsting Triglycerides (<150 mg/dl to 200 mg/dl) Fsting LDL Cholesterol (<100 mg/dl to 160 mg/dl) HDL Cholesterol Norml to Low ( 40 mg/dl to <40 mg/dl) Tretment Arm n/n % ABILIFY 34/ / ABILIFY 40/ / ABILIFY 2/ / ABILIFY 121/ / In monotherpy trils in dults, the proportion of ptients t 12 weeks nd 24 weeks with chnges from in totl cholesterol (fsting/nonfsting), fsting triglycerides, nd fsting LDL cholesterol were similr between ABILIFY- nd plcebo-treted ptients: t 12 weeks, Totl Cholesterol (fsting/nonfsting), 1/71 (1.4%) vs. 3/74 (4.1%); Fsting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fsting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; nd t 24 weeks, Totl Cholesterol (fsting/nonfsting), 1/42 (2.4%) vs. 3/37 (8.1%); Fsting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fsting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively. Tble 10 shows the proportion of ptients with chnges in totl cholesterol (fsting/ nonfsting), fsting triglycerides, fsting LDL cholesterol, nd HDL cholesterol from two plcebo-controlled djunctive trils in dult ptients with mjor depressive disorder (medin exposure 42 dys).

6 Tble 10: Chnges in Bld Lipid Prmeters From -Controlled Adjunctive Trils in Adult Ptients with Mjor Depressive Disorder Totl Cholesterol (<200 mg/dl to 240 mg/dl) Fsting Triglycerides (<150 mg/dl to 200 mg/dl) Fsting LDL Cholesterol (<100 mg/dl to 160 mg/dl) HDL Cholesterol Norml to Low ( 40 mg/dl to <40 mg/dl) Tretment Arm n/n % ABILIFY 3/ / ABILIFY 14/ / ABILIFY 0/54 0 0/73 0 ABILIFY 17/ / Peditric Ptients nd Adolescents Tble 11 shows the proportion of dolescents with schizophreni (13 to 17 yers) nd peditric ptients with bipolr disorder (10 to 17 yers) with chnges in totl cholesterol nd HDL cholesterol (pled from two plcebo-controlled trils; medin exposure 42 to 43 dys) nd fsting triglycerides (pled from two plcebo-controlled trils; medin exposure 42 to 44 dys). Tble 11: Chnges in Bld Lipid Prmeters From -Controlled Monotherpy Trils in Peditric nd Adolescent Ptients in Schizophreni nd Bipolr Disorder Totl Cholesterol (<170 mg/dl to 200 mg/dl) Fsting Triglycerides (<150 mg/dl to 200 mg/dl) HDL Cholesterol Norml to Low ( 40 mg/dl to <40 mg/dl) Tretment Arm n/n % ABILIFY 3/ /116 0 ABILIFY 7/ / ABILIFY 27/ / In monotherpy trils of dolescents with schizophreni nd peditric ptients with bipolr disorder, the proportion of ptients t 12 weeks nd 24 weeks with chnges from Norml to High in totl cholesterol (fsting/nonfsting), fsting triglycerides, nd fsting LDL cholesterol were similr between ABILIFY- nd plcebo-treted ptients: t 12 weeks, Totl Cholesterol (fsting/nonfsting), 0/57 (0%) vs. 0/15 (0%); Fsting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; nd t 24 weeks, Totl Cholesterol (fsting/ nonfsting), 0/36 (0%) vs. 0/12 (0%); Fsting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively. Tble 12 shows the proportion of ptients with chnges in totl cholesterol (fsting/nonfsting) nd fsting triglycerides (medin exposure 56 dys) nd HDL cholesterol (medin exposure 55 to 56 dys) from two plcebo-controlled trils in peditric ptients (6 to 17 yers) with irritbility ssocited with utistic disorder. Tble 12: Chnges in Bld Lipid Prmeters From -Controlled Trils in Peditric Ptients with Autistic Disorder Totl Cholesterol (<170 mg/dl to 200 mg/dl) Fsting Triglycerides (<150 mg/dl to 200 mg/dl) HDL Cholesterol Norml to Low ( 40 mg/dl to <40 mg/dl) Tretment Arm n/n % ABILIFY 1/ /34 0 ABILIFY 0/75 0 0/30 0 ABILIFY 9/ / Tble 13 shows the proportion of ptients with chnges in totl cholesterol (fsting/ nonfsting) nd fsting triglycerides (medin exposure 57 dys) nd HDL cholesterol (medin exposure 57 dys) from two plcebo-controlled trils in peditric ptients (6 to 18 yers) with Tourette s Disorder. Tble 13: Chnges in Bld Lipid Prmeters From -Controlled Trils in Peditric Ptients with Tourette s Disorder Totl Cholesterol (<170 mg/dl to 200 mg/dl) Fsting Triglycerides (<150 mg/dl to 200 mg/dl) HDL Cholesterol Norml to Low ( 40 mg/dl to <40 mg/dl) Tretment Arm n/n % ABILIFY 1/ /46 0 ABILIFY 5/ / ABILIFY 4/ / Weight Gin Weight gin hs been observed with typicl ntipsychotic use. Clinicl monitoring of weight is recommended. Adults In n nlysis of 13 plcebo-controlled monotherpy trils, primrily from pled schizophreni nd bipolr disorder, with medin exposure of 21 to 25 dys, the men chnge in body weight in ABILIFY-treted ptients ws +0.3 kg (N=1673) compred to 0.1 kg (N=1100) in plcebo-controlled ptients. At 24 weeks, the men chnge from bseline in body weight in ABILIFY-treted ptients ws 1.5 kg (n=73) compred to 0.2 kg (n=46) in plcebo-treted ptients. In the trils dding ABILIFY to ntidepressnts, ptients first received 8 weeks of ntidepressnt tretment followed by 6 weeks of djunctive ABILIFY or plcebo in ddition to their ongoing ntidepressnt tretment. The men chnge in body weight in ptients receiving djunctive ABILIFY ws +1.7 kg (N=347) compred to +0.4 kg (N=330) in ptients receiving djunctive plcebo. Tble 14 shows the percentge of dult ptients with weight gin 7% of body weight by indiction. Tble 14: Weight gin 7% of body weight Percentge of Ptients From -Controlled Trils in Adult Ptients with Weight Gin 7% of Body Weight Tretment Ptients Indiction Arm N n (%) Schizophreni ABILIFY (8.1) (3.2) Bipolr Mni b ABILIFY (2.2) (2.7) Mjor Depressive Disorder ABILIFY (5.2) (Adjunctive Therpy) c (0.6) 4-6 weeks durtion. b 3 weeks durtion. c 6 weeks durtion. Peditric Ptients nd Adolescents In n nlysis of two plcebo-controlled trils in dolescents with schizophreni (13 to 17 yers) nd peditric ptients with bipolr disorder (10 to 17 yers) with medin exposure of 42 to 43 dys, the men chnge in body weight in ABILIFY-treted ptients ws +1.6 kg (N=381) compred to +0.3 kg (N=187) in plcebo-treted ptients. At 24 weeks, the men chnge from bseline in body weight in ABILIFY-treted ptients ws +5.8 kg (n=62) compred to +1.4 kg (n=13) in plcebo-treted ptients. In two short-term, plcebo-controlled trils in ptients (6 to 17 yers) with irritbility ssocited with utistic disorder with medin exposure of 56 dys, the men chnge in body weight in ABILIFY-treted ptients ws +1.6 kg (n=209) compred to +0.4 kg (n=98) in plcebo-treted ptients. In two short-term, plcebo-controlled trils in ptients (6 to 18 yers) with Tourette s Disorder with medin exposure of 57 dys, the men chnge in body weight in ABILIFY-treted ptients ws +1.5 kg (n=105) compred to +0.4 kg (n=66) in plcebo-treted ptients. Tble 15 shows the percentge of peditric nd dolescent ptients with weight gin 7% of body weight by indiction. Tble 15: Percentge of Ptients From -Controlled Monotherpy Trils in Peditric nd Adolescent Ptients with Weight Gin 7% of Body Weight Weight gin 7% of body weight 4-6 weeks durtion. Tretment Arm Ptients n (%) Indiction N Pled Schizophreni nd ABILIFY (5.2) Bipolr Mni (1.6) Irritbility Associted with ABILIFY (26.3) Autistic Disorder b 98 7 (7.1) Tourette s Disorder c ABILIFY (20.0) 66 5 (7.6) b 8 weeks durtion. c 8-10 weeks durtion. 6

7 In n open-lbel tril tht enrolled ptients from the two plcebo-controlled trils of dolescents with schizophreni (13 to 17 yers) nd peditric ptients with bipolr disorder (10 to 17 yers), 73.2% of ptients (238/325) completed 26 weeks of therpy with ABILIFY. After 26 weeks, 32.8% of ptients gined 7% of their body weight, not djusted for norml growth. To djust for norml growth, z-scores were derived (mesured in stndrd devitions [SD]), which normlize for the nturl growth of peditric ptients nd dolescents by comprisons to ge- nd gender-mtched popultion stndrds. A z-score chnge <0.5 SD is considered not cliniclly significnt. After 26 weeks, the men chnge in z-score ws 0.09 SD. In n open-lbel tril tht enrolled ptients from two short-term, plcebo-controlled trils, ptients (6 to 17 yers) with irritbility ssocited with utistic disorder, s well s de novo ptients, 60.3% (199/330) completed one yer of therpy with ABILIFY. The men chnge in weight z-score ws 0.26 SDs for ptients receiving >9 months of tretment. When treting peditric ptients for ny indiction, weight gin should be monitored nd ssessed ginst tht expected for norml growth. 5.7 Pthologicl Gmbling nd Other Compulsive Behviors Post-mrketing cse reports suggest tht ptients cn experience intense urges, prticulrly for gmbling, nd the inbility to control these urges while tking ripiprzole. Other compulsive urges, reported less frequently include: sexul urges, shopping, eting or binge eting, nd other impulsive or compulsive behviors. Becuse ptients my not recognize these behviors s bnorml, it is importnt for prescribers to sk ptients or their cregivers specificlly bout the development of new or intense gmbling urges, compulsive sexul urges, compulsive shopping, binge or compulsive eting, or other urges while being treted with ripiprzole. It should be noted tht impulse-control symptoms cn be ssocited with the underlying disorder. In some cses, lthough not ll, urges were reported to hve stopped when the dose ws reduced or the mediction ws discontinued. Compulsive behviors my result in hrm to the ptient nd others if not recognized. Consider dose reduction or stopping the mediction if ptient develops such urges. 5.8 Orthosttic Hypotension ABILIFY my cuse orthosttic hypotension, perhps due to its 1 -drenergic receptor ntgonism. The incidence of orthosttic hypotension-ssocited events from short-term, plcebo-controlled trils of dult ptients on orl ABILIFY (n=2467) included (ABILIFY incidence, plcebo incidence) orthosttic hypotension (1%, 0.3%), posturl dizziness (0.5%, 0.3%), nd syncope (0.5%, 0.4%); of peditric ptients 6 to 18 yers of ge (n=732) on orl ABILIFY included orthosttic hypotension (0.5%, 0%), posturl dizziness (0.4%, 0%), nd syncope (0.2%, 0%); nd of ptients on ABILIFY Injection (n=501) included orthosttic hypotension (0.6%, 0%), posturl dizziness (0.2%, 0.5%), nd syncope (0.4%, 0%). [see ADVERSE REACTIONS (6.1)] The incidence of significnt orthosttic chnge in bld pressure (defined s decrese in systolic bld pressure 20 mmhg ccompnied by n increse in hert rte 25 bpm when compring stnding to supine vlues) for ABILIFY ws not meningfully different from plcebo (ABILIFY incidence, plcebo incidence): in dult orl ABILIFY-treted ptients (4%, 2%), in peditric orl ABILIFY-treted ptients ged 6 to 18 yers (0.4%, 1%), or in ABILIFY injection-treted ptients (3%, 2%). ABILIFY should be used with cution in ptients with known crdiovsculr disese (history of myocrdil infrction or ischemic hert disese, hert filure or conduction bnormlities), cerebrovsculr disese, or conditions which would predispose ptients to hypotension (dehydrtion, hypovolemi, nd tretment with ntihypertensive medictions) [see DRUG INTERACTIONS (7.1)]. If prenterl benzodizepine therpy is deemed necessry in ddition to ABILIFY injection tretment, ptients should be monitored for excessive sedtion nd for orthosttic hypotension [see DRUG INTERACTIONS (7.1)]. 5.9 Leukopeni, Neutropeni, nd Agrnulocytosis In clinicl trils nd/or postmrketing experience, events of leukopeni nd neutropeni hve been reported temporlly relted to ntipsychotic gents, including ABILIFY. Agrnulocytosis hs lso been reported. Possible risk fctors for leukopeni/neutropeni include pre-existing low white bld cell count (WBC)/bsolute neutrophil count (ANC) nd history of drug-induced leukopeni/ neutropeni. In ptients with history of cliniclly significnt low WBC/ANC or drug-induced leukopeni/neutropeni, perform complete bld count (CBC) frequently during the first few months of therpy. In such ptients, consider discontinution of ABILIFY t the first sign of cliniclly significnt decline in WBC in the bsence of other custive fctors. Monitor ptients with cliniclly significnt neutropeni for fever or other symptoms or signs of infection nd tret promptly if such symptoms or signs occur. Discontinue ABILIFY in ptients with severe neutropeni (bsolute neutrophil count <1000/mm3) nd follow their WBC counts until recovery Seizures/Convulsions In short-term, plcebo-controlled trils, ptients with history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undignosed dult ptients treted with orl ABILIFY, in 0.1% (1/732) of peditric ptients (6 to 18 yers), nd in 0.2% (1/501) of dult ABILIFY injection-treted ptients. As with other ntipsychotic drugs, ABILIFY should be used cutiously in ptients with history of seizures or with conditions tht lower the seizure threshold. Conditions tht lower the seizure threshold my be more prevlent in popultion of 65 yers or older Potentil for Cognitive nd Motor Impirment ABILIFY, like other ntipsychotics, my hve the potentil to impir judgment, thinking, or motor skills. For exmple, in short-term, plcebo-controlled trils, somnolence (including sedtion) ws reported s follows (ABILIFY incidence, plcebo incidence): in dult ptients (n=2467) treted with orl ABILIFY (11%, 6%), in peditric ptients ges 6 to 17 (n=611) (24%, 6%), nd in dult ptients (n=501) on ABILIFY Injection (9%, 6%). Somnolence (including sedtion) led to discontinution in 0.3% (8/2467) of dult ptients nd 3% (20/732) of peditric ptients (6 to 18 yers) on orl ABILIFY in short-term, plcebocontrolled trils, but did not led to discontinution of ny dult ptients on ABILIFY Injection. Despite the reltively modest incresed incidence of these events compred to plcebo, ptients should be cutioned bout operting hzrdous mchinery, including utomobiles, until they re resonbly certin tht therpy with ABILIFY does not ffect them dversely 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 ABILIFY 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 ADVERSE REACTIONS (6.2)] Suicide The possibility of suicide ttempt is inherent in psychotic illnesses, bipolr disorder, nd mjor depressive disorder, nd close supervision of high-risk ptients should ccompny drug therpy. Prescriptions for ABILIFY should be written for the smllest quntity consistent with gd ptient mngement in order to reduce the risk of overdose [see ADVERSE REACTIONS (6.1, 6.2)] Dysphgi Esophgel dysmotility nd spirtion hve been ssocited with ntipsychotic drug use, including ABILIFY. Aspirtion pneumoni is common cuse of morbidity nd mortlity in elderly ptients, in prticulr those with dvnced Alzheimer s dementi. ABILIFY nd other ntipsychotic drugs should be used cutiously in ptients t risk for spirtion pneumoni [see WARNINGS AND PRECAUTIONS (5.1) nd ADVERSE REACTIONS (6.2)]. 6 ADVERSE REACTIONS 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 the rtes observed in prctice. The following dverse rections re discussed in more detil in other sections of the lbeling: Incresed Mortlity in Elderly Ptients with Dementi-Relted Psychosis [see BOXED WARNING nd WARNINGS AND PRECAUTIONS (5.1)] Cerebrovsculr Adverse Events, Including Stroke [see WARNINGS AND PRECAUTIONS (5.2)] Suicidl Thoughts nd Behviors in Children, Adolescents, nd Young Adults [see BOXED WARNING nd WARNINGS AND PRECAUTIONS (5.3)] Neuroleptic Mlignnt Syndrome (NMS) [see WARNINGS AND PRECAUTIONS (5.4)] Trdive Dyskinesi [see WARNINGS AND PRECAUTIONS (5.5)] Metbolic Chnges [see WARNINGS AND PRECAUTIONS (5.6)] Pthologicl Gmbling nd Other Compulsive Behviors [see WARNINGS AND PRECAUTIONS (5.7)] Orthosttic Hypotension [see WARNINGS AND PRECAUTIONS (5.8)] Leukopeni, Neutropeni, nd Agrnulocytosis [see WARNINGS AND PRECAUTIONS (5.9)] Seizures/Convulsions [see WARNINGS AND PRECAUTIONS (5.10)] Potentil for Cognitive nd Motor Impirment [see WARNINGS AND PRECAUTIONS (5.11)] Body Temperture Regultion [see WARNINGS AND PRECAUTIONS (5.12)] Suicide [see WARNINGS AND PRECAUTIONS (5.13)] Dysphgi [see WARNINGS AND PRECAUTIONS (5.14)] The most common dverse rections in dult ptients in clinicl trils ( 10%) were nuse, vomiting, constiption, hedche, dizziness, kthisi, nxiety, insomni, nd restlessness. The most common dverse rections in the peditric clinicl trils ( 10%) were somnolence, hedche, vomiting, extrpyrmidl disorder, ftigue, incresed ppetite, insomni, nuse, nsophryngitis, nd weight incresed. 7

8 ABILIFY hs been evluted for sfety in 13,543 dult ptients who prticipted in multiple-dose, clinicl trils in schizophreni, bipolr disorder, mjor depressive disorder, Dementi of the Alzheimer s type, Prkinson s disese, nd lcoholism, nd who hd pproximtely 7619 ptient-yers of exposure to orl ABILIFY nd 749 ptients with exposure to ABILIFY injection. A totl of 3390 ptients were treted with orl ABILIFY for t lest 180 dys nd 1933 ptients treted with orl ABILIFY hd t lest 1 yer of exposure. ABILIFY hs been evluted for sfety in 1,686 ptients (6 to 18 yers) who prticipted in multiple-dose, clinicl trils in schizophreni, bipolr mni, utistic disorder, or Tourette s disorder nd who hd pproximtely 1,342 ptient-yers of exposure to orl ABILIFY. A totl of 959 peditric ptients were treted with orl ABILIFY for t lest 180 dys nd 556 peditric ptients treted with orl ABILIFY hd t lest 1 yer of exposure. The conditions nd durtion of tretment with ABILIFY (monotherpy nd djunctive therpy with ntidepressnts or md stbilizers) included (in overlpping ctegories) double-blind, comprtive nd noncomprtive open-lbel studies, inptient nd outptient studies, fixed- nd flexible-dose studies, nd short- nd longer-term exposure. 6.1 Clinicl Trils Experience Adult Ptients with Schizophreni The following findings re bsed on pl of five plcebo-controlled trils (four 4-week nd one 6-week) in which orl ABILIFY ws dministered in doses rnging from 2 to 30 mg/dy. Commonly Observed Adverse Rections The only commonly observed dverse rection ssocited with the use of ABILIFY in ptients with schizophreni (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo) ws kthisi (ABILIFY 8%; plcebo 4%). Adult Ptients with Bipolr Mni Monotherpy The following findings re bsed on pl of 3-week, plcebo-controlled, bipolr mni trils in which orl ABILIFY ws dministered t doses of 15 or 30 mg/dy. Commonly Observed Adverse Rections Commonly observed dverse rections ssocited with the use of ABILIFY in ptients with bipolr mni (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo) re shown in Tble 16. Tble 16: Commonly Observed Adverse Rections in Short-Term, -Controlled Trils of Adult Ptients with Bipolr Mni Treted with Orl ABILIFY Monotherpy Percentge of Ptients Reporting Rection ABILIFY Preferred Term (n=917) (n=753) Akthisi 13 4 Sedtion 8 3 Restlessness 6 3 Tremor 6 3 Extrpyrmidl Disorder 5 2 Less Common Adverse Rections in Adults Tble 17 enumertes the pled incidence, rounded to the nerest percent, of dverse rections tht occurred during cute therpy (up to 6 weeks in schizophreni nd up to 3 weeks in bipolr mni), including only those rections tht occurred in 2% or more of ptients treted with ABILIFY (doses 2 mg/dy) nd for which the incidence in ptients treted with ABILIFY ws greter thn the incidence in ptients treted with plcebo in the combined dtset. Tble 17: Adverse Rections in Short-Term, -Controlled Trils in Adult Ptients Treted with Orl ABILIFY Percentge of Ptients Reporting Rection System Orgn Clss ABILIFY Preferred Term (n=1843) (n=1166) Eye Disorders Blurred Vision 3 1 Gstrointestinl Disorders Nuse Constiption 11 7 Vomiting 11 6 Dyspepsi 9 7 Dry Mouth 5 4 Tthche 4 3 Abdominl Discomfort 3 2 Stomch Discomfort 3 2 Generl Disorders nd Administrtion Site Conditions Ftigue 6 4 Pin 3 2 Musculoskeletl nd Connective Tissue Disorders Musculoskeletl Stiffness 4 3 Pin in Extremity 4 2 Mylgi 2 1 Muscle Spsms 2 1 Nervous System Disorders Hedche Dizziness 10 7 Akthisi 10 4 Sedtion 7 4 Extrpyrmidl Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychitric Disorders Agittion Insomni Anxiety Restlessness 5 3 Respirtory, Thorcic, nd Medistinl Disorders Phryngolryngel Pin 3 2 Cough 3 2 Adverse rections reported by t lest 2% of ptients treted with orl ABILIFY, except dverse rections which hd n incidence equl to or less thn plcebo. An exmintion of popultion subgroups did not revel ny cler evidence of differentil dverse rection incidence on the bsis of ge, gender, or rce. Adult Ptients with Adjunctive Therpy with Bipolr Mni The following findings re bsed on plcebo-controlled tril of dult ptients with bipolr disorder in which ABILIFY ws dministered t doses of 15 or 30 mg/dy s djunctive therpy with lithium or vlprote. Adverse Rections Associted with Discontinution of Tretment In study of ptients who were lredy tolerting either lithium or vlprote s monotherpy, discontinution rtes due to dverse rections were 12% for ptients treted with djunctive ABILIFY compred to 6% for ptients treted with djunctive plcebo. The most common dverse drug rections ssocited with discontinution in the djunctive ABILIFY-treted compred to plcebo-treted ptients were kthisi (5% nd 1%, respectively) nd tremor (2% nd 1%, respectively). Commonly Observed Adverse Rections The commonly observed dverse rections ssocited with djunctive ABILIFY nd lithium or vlprote in ptients with bipolr mni (incidence of 5% or greter nd incidence t lest twice tht for djunctive plcebo) were: kthisi, insomni, nd extrpyrmidl disorder. Less Common Adverse Rections in Adult Ptients with Adjunctive Therpy in Bipolr Mni Tble 18 enumertes the incidence, rounded to the nerest percent, of dverse rections tht occurred during cute tretment (up to 6 weeks), including only those rections tht occurred in 2% or more of ptients treted with djunctive ABILIFY (doses of 15 or 30 mg/dy) nd lithium or vlprote nd for which the incidence in ptients treted with this combintion ws greter thn the incidence in ptients treted with plcebo plus lithium or vlprote. 8

9 Tble 18: Adverse Rections in Short-Term, -Controlled Tril of Adjunctive Therpy in Ptients with Bipolr Disorder Percentge of Ptients Reporting Rection ABILIFY + + System Orgn Clss Li or Vl* Li or Vl* Preferred Term (n=253) (n=130) Gstrointestinl Disorders Nuse 8 5 Vomiting 4 0 Slivry Hypersecretion 4 2 Dry Mouth 2 1 Infections nd Infesttions Nsophryngitis 3 2 Investigtions Weight Incresed 2 1 Nervous System Disorders Akthisi 19 5 Tremor 9 6 Extrpyrmidl Disorder 5 1 Dizziness 4 1 Sedtion 4 2 Psychitric Disorders Insomni 8 4 Anxiety 4 1 Restlessness 2 1 Adverse rections reported by t lest 2% of ptients treted with orl ABILIFY, except dverse rections which hd n incidence equl to or less thn plcebo. * Lithium or Vlprote Peditric Ptients (13 to 17 yers) with Schizophreni The following findings re bsed on one 6-week, plcebo-controlled tril in which orl ABILIFY ws dministered in doses rnging from 2 to 30 mg/dy. Adverse Rections Associted with Discontinution of Tretment The incidence of discontinution due to dverse rections between ABILIFY-treted nd plcebo-treted peditric ptients (13 to 17 yers) ws 5% nd 2%, respectively. Commonly Observed Adverse Rections Commonly observed dverse rections ssocited with the use of ABILIFY in dolescent ptients with schizophreni (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo) were extrpyrmidl disorder, somnolence, nd tremor. Peditric Ptients (10 to 17 yers) with Bipolr Mni The following findings re bsed on one 4-week, plcebo-controlled tril in which orl ABILIFY ws dministered in doses of 10 or 30 mg/dy. Adverse Rections Associted with Discontinution of Tretment The incidence of discontinution due to dverse rections between ABILIFY-treted nd plcebo-treted peditric ptients (10 to 17 yers) ws 7% nd 2%, respectively. Commonly Observed Adverse Rections Commonly observed dverse rections ssocited with the use of ABILIFY in peditric ptients with bipolr mni (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo) re shown in Tble 19. Tble 19: Commonly Observed Adverse Rections in Short-Term, -Controlled Trils of Peditric Ptients (10 to 17 yers) with Bipolr Mni Treted with Orl ABILIFY Percentge of Ptients Reporting Rection ABILIFY Preferred Term (n=197) (n=97) Somnolence 23 3 Extrpyrmidl Disorder 20 3 Ftigue 11 4 Nuse 11 4 Akthisi 10 2 Blurred Vision 8 0 Slivry Hypersecretion 6 0 Dizziness 5 1 Peditric Ptients (6 to 17 yers) with Autistic Disorder The following findings re bsed on two 8-week, plcebo-controlled trils in which orl ABILIFY ws dministered in doses of 2 to 15 mg/dy. Adverse Rections Associted with Discontinution of Tretment The incidence of discontinution due to dverse rections between ABILIFY-treted nd plcebo-treted peditric ptients (6 to 17 yers) ws 10% nd 8%, respectively. Commonly Observed Adverse Rections Commonly observed dverse rections ssocited with the use of ABILIFY in peditric ptients with utistic disorder (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo) re shown in Tble 20. Tble 20: Commonly Observed Adverse Rections in Short-Term, -Controlled Trils of Peditric Ptients (6 to 17 yers) with Autistic Disorder Treted with Orl ABILIFY Percentge of Ptients Reporting Rection ABILIFY Preferred Term (n=212) (n=101) Sedtion 21 4 Ftigue 17 2 Vomiting 14 7 Somnolence 10 4 Tremor 10 0 Pyrexi 9 1 Drling 9 0 Decresed Appetite 7 2 Slivry Hypersecretion 6 1 Extrpyrmidl Disorder 6 0 Lethrgy 5 0 Peditric Ptients (6 to 18 yers) with Tourette s Disorder The following findings re bsed on one 8-week nd one 10-week, plcebo-controlled trils in which orl ABILIFY ws dministered in doses of 2 to 20 mg/dy. Adverse Rections Associted with Discontinution of Tretment The incidence of discontinution due to dverse rections between ABILIFY-treted nd plcebo-treted peditric ptients (6 to 18 yers) ws 7% nd 1%, respectively. Commonly Observed Adverse Rections Commonly observed dverse rections ssocited with the use of ABILIFY in peditric ptients with Tourette s disorder (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo) re shown in Tble 21. Tble 21: Commonly Observed Adverse Rections in Short-Term, -Controlled Trils of Peditric Ptients (6 to 18 yers) with Tourette s Disorder Treted with Orl ABILIFY Percentge of Ptients Reporting Rection Preferred Term ABILIFY (n=121) (n=72) Sedtion 13 6 Somnolence 13 1 Nuse 11 4 Hedche 10 3 Nsophryngitis 9 0 Ftigue 8 0 Incresed Appetite 7 1 Less Common Adverse Rections in Peditric Ptients (6 to 18 yers) with Schizophreni, Bipolr Mni, Autistic Disorder, or Tourette s Disorder Tble 22 enumertes the pled incidence, rounded to the nerest percent, of dverse rections tht occurred during cute therpy (up to 6 weeks in schizophreni, up to 4 weeks in bipolr mni, up to 8 weeks in utistic disorder, nd up to 10 weeks in Tourette s disorder), including only those rections tht occurred in 2% or more of peditric ptients treted with ABILIFY (doses 2 mg/dy) nd for which the incidence in ptients treted with ABILIFY ws greter thn the incidence in ptients treted with plcebo. 9

10 Tble 22: Adverse Rections in Short-Term, -Controlled Trils of Peditric Ptients (6 to 18 yers) Treted with Orl ABILIFY Percentge of Ptients Reporting Rection System Orgn Clss ABILIFY Preferred Term (n=732) (n=370) Eye Disorders Blurred Vision 3 0 Gstrointestinl Disorders Abdominl Discomfort 2 1 Vomiting 8 7 Nuse 8 4 Dirrhe 4 3 Slivry Hypersecretion 4 1 Abdominl Pin Upper 3 2 Constiption 2 2 Generl Disorders nd Administrtion Site Conditions Ftigue 10 2 Pyrexi 4 1 Irritbility 2 1 Astheni 2 1 Infections nd Infesttions Nsophryngitis 6 3 Investigtions Weight Incresed 3 1 Metbolism nd Nutrition Disorders Incresed Appetite 7 3 Decresed Appetite 5 4 Musculoskeletl nd Connective Tissue Disorders Musculoskeletl Stiffness 2 1 Muscle Rigidity 2 1 Nervous System Disorders Somnolence 16 4 Hedche Sedtion 9 2 Tremor 9 1 Extrpyrmidl Disorder 6 1 Akthisi 6 4 Drling 3 0 Lethrgy 3 0 Dizziness 3 2 Dystoni 2 1 Respirtory, Thorcic, nd Medistinl Disorders Epistxis 2 1 Skin nd Subcutneous Tissue Disorders Rsh 2 1 Adverse rections reported by t lest 2% of peditric ptients treted with orl ABILIFY, except dverse rections which hd n incidence equl to or less thn plcebo. Adult Ptients Receiving ABILIFY s Adjunctive Tretment of Mjor Depressive Disorder The following findings re bsed on pl of two plcebo-controlled trils of ptients with mjor depressive disorder in which ABILIFY ws dministered t doses of 2 mg to 20 mg s djunctive tretment to continued ntidepressnt therpy. Adverse Rections Associted with Discontinution of Tretment The incidence of discontinution due to dverse rections ws 6% for djunctive ABILIFY-treted ptients nd 2% for djunctive plcebo-treted ptients. Commonly Observed Adverse Rections The commonly observed dverse rections ssocited with the use of djunctive ABILIFY in ptients with mjor depressive disorder (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo) were: kthisi, restlessness, insomni, constiption, ftigue, nd blurred vision. Less Common Adverse Rections in Adult Ptients with Mjor Depressive Disorder Tble 23 enumertes the pled incidence, rounded to the nerest percent, of dverse rections tht occurred during cute therpy (up to 6 weeks), including only those dverse rections tht occurred in 2% or more of ptients treted with djunctive ABILIFY (doses 2 mg/dy) nd for which the incidence in ptients treted with djunctive ABILIFY ws greter thn the incidence in ptients treted with djunctive plcebo in the combined dtset. Tble 23: Adverse Rections in Short-Term, -Controlled Adjunctive Trils in Ptients with Mjor Depressive Disorder Percentge of Ptients Reporting Rection System Orgn Clss ABILIFY+ADT* +ADT* Preferred Term (n=371) (n=366) Eye Disorders Blurred Vision 6 1 Gstrointestinl Disorders Constiption 5 2 Generl Disorders nd Administrtion Site Conditions Ftigue 8 4 Feeling Jittery 3 1 Infections nd Infesttions Upper Respirtory Trct Infection 6 4 Investigtions Weight Incresed 3 2 Metbolism nd Nutrition Disorders Incresed Appetite 3 2 Musculoskeletl nd Connective Tissue Disorders Arthrlgi 4 3 Mylgi 3 1 Nervous System Disorders Akthisi 25 4 Somnolence 6 4 Tremor 5 4 Sedtion 4 2 Dizziness 4 2 Disturbnce in Attention 3 1 Extrpyrmidl Disorder 2 0 Psychitric Disorders Restlessness 12 2 Insomni 8 2 Adverse rections reported by t lest 2% of ptients treted with djunctive ABILIFY, except dverse rections which hd n incidence equl to or less thn plcebo. * Antidepressnt Therpy Ptients with Agittion Associted with Schizophreni or Bipolr Mni (Intrmusculr Injection) The following findings re bsed on pl of three plcebo-controlled trils of ptients with gittion ssocited with schizophreni or bipolr mni in which ABILIFY injection ws dministered t doses of 5.25 mg to 15 mg. Commonly Observed Adverse Rections There ws one commonly observed dverse rection (nuse) ssocited with the use of ABILIFY injection in ptients with gittion ssocited with schizophreni nd bipolr mni (incidence of 5% or greter nd ABILIFY incidence t lest twice tht for plcebo). Less Common Adverse Rections in Ptients with Agittion Associted with Schizophreni or Bipolr Mni Tble 24 enumertes the pled incidence, rounded to the nerest percent, of dverse rections tht occurred during cute therpy (24-hour), including only those dverse rections tht occurred in 2% or more of ptients treted with ABILIFY injection (doses 5.25 mg/dy) nd for which the incidence in ptients treted with ABILIFY injection ws greter thn the incidence in ptients treted with plcebo in the combined dtset. Tble 24: Adverse Rections in Short-Term, -Controlled Trils in Ptients Treted with ABILIFY Injection Percentge of Ptients Reporting Rection System Orgn Clss ABILIFY Preferred Term (n=501) (n=220) Crdic Disorders Tchycrdi 2 <1 Gstrointestinl Disorders Nuse 9 3 Vomiting 3 1 Generl Disorders nd Administrtion Site Conditions Ftigue 2 1 Nervous System Disorders Hedche 12 7 Dizziness 8 5 Somnolence 7 4 Sedtion 3 2 Akthisi 2 0 Adverse rections reported by t lest 2% of ptients treted with ABILIFY injection, except dverse rections which hd n incidence equl to or less thn plcebo. 10

11 Dose-Relted Adverse Rections Schizophreni Dose response reltionships for the incidence of tretment-emergent dverse events were evluted from four trils in dult ptients with schizophreni compring vrious fixed doses (2, 5, 10, 15, 20, nd 30 mg/dy) of orl ABILIFY to plcebo. This nlysis, strtified by study, indicted tht the only dverse rection to hve possible dose response reltionship, nd then most prominent only with 30 mg, ws somnolence [including sedtion]; (incidences were plcebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%). In the study of peditric ptients (13 to 17 yers of ge) with schizophreni, three common dverse rections ppered to hve possible dose response reltionship: extrpyrmidl disorder (incidences were plcebo, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were plcebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); nd tremor (incidences were plcebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%). Bipolr Mni In the study of peditric ptients (10 to 17 yers of ge) with bipolr mni, four common dverse rections hd possible dose response reltionship t 4 weeks; extrpyrmidl disorder (incidences were plcebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were plcebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); kthisi (incidences were plcebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); nd slivry hypersecretion (incidences were plcebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%). Autistic Disorder In study of peditric ptients (6 to 17 yers of ge) with utistic disorder, one common dverse rection hd possible dose response reltionship: ftigue (incidences were plcebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%). Tourette s Disorder In study of peditric ptients (7 to 17 yers of ge) with Tourette s disorder, no common dverse rection(s) hd dose response reltionship. Extrpyrmidl Symptoms Schizophreni In short-term, plcebo-controlled trils in schizophreni in dults, the incidence of reported EPS-relted events, excluding events relted to kthisi, for ABILIFY-treted ptients ws 13% vs. 12% for plcebo; nd the incidence of kthisi-relted events for ABILIFY-treted ptients ws 8% vs. 4% for plcebo. In the short-term, plcebo-controlled tril of schizophreni in peditric ptients (13 to 17 yers), the incidence of reported EPS-relted events, excluding events relted to kthisi, for ABILIFY-treted ptients ws 25% vs. 7% for plcebo; nd the incidence of kthisi-relted events for ABILIFY-treted ptients ws 9% vs. 6% for plcebo. Objectively collected dt from those trils ws collected on the Simpson Angus Rting Scle (for EPS), the Brnes Akthisi Scle (for kthisi), nd the Assessments of Involuntry Movement Scles (for dyskinesis). In the dult schizophreni trils, the objectively collected dt did not show difference between ABILIFY nd plcebo, with the exception of the Brnes Akthisi Scle (ABILIFY, 0.08; plcebo, 0.05). In the peditric (13 to 17 yers) schizophreni tril, the objectively collected dt did not show difference between ABILIFY nd plcebo, with the exception of the Simpson Angus Rting Scle (ABILIFY, 0.24; plcebo, 0.29). Similrly, in long-term (26-week), plcebo-controlled tril of schizophreni in dults, objectively collected dt on the Simpson Angus Rting Scle (for EPS), the Brnes Akthisi Scle (for kthisi), nd the Assessments of Involuntry Movement Scles (for dyskinesis) did not show difference between ABILIFY nd plcebo. Bipolr Mni In the short-term, plcebo-controlled trils in bipolr mni in dults, the incidence of reported EPS-relted events, excluding events relted to kthisi, for monotherpy ABILIFY-treted ptients ws 16% vs. 8% for plcebo nd the incidence of kthisi-relted events for monotherpy ABILIFY-treted ptients ws 13% vs. 4% for plcebo. In the 6-week, plcebo-controlled tril in bipolr mni for djunctive therpy with lithium or vlprote, the incidence of reported EPS-relted events, excluding events relted to kthisi for djunctive ABILIFY-treted ptients ws 15% vs. 8% for djunctive plcebo nd the incidence of kthisi-relted events for djunctive ABILIFY-treted ptients ws 19% vs. 5% for djunctive plcebo. In the short-term, plcebo-controlled tril in bipolr mni in peditric (10 to 17 yers) ptients, the incidence of reported EPS-relted events, excluding events relted to kthisi, for ABILIFY-treted ptients ws 26% vs. 5% for plcebo nd the incidence of kthisi-relted events for ABILIFY-treted ptients ws 10% vs. 2% for plcebo. In the dult bipolr mni trils with monotherpy ABILIFY, the Simpson Angus Rting Scle nd the Brnes Akthisi Scle showed significnt difference between ABILIFY nd plcebo (ABILIFY, 0.50; plcebo, 0.01 nd ABILIFY, 0.21; plcebo, 0.05). Chnges in the Assessments of Involuntry Movement Scles were similr for the ABILIFY nd plcebo groups. In the bipolr mni trils with ABILIFY s djunctive therpy with either lithium or vlprote, the Simpson Angus Rting Scle nd the Brnes Akthisi Scle showed significnt difference between djunctive ABILIFY nd djunctive plcebo (ABILIFY, 0.73; plcebo, 0.07 nd ABILIFY, 0.30; plcebo, 0.11). Chnges in the Assessments of Involuntry Movement Scles were similr for djunctive ABILIFY nd djunctive plcebo. In the peditric (10 to 17 yers), short-term, bipolr mni tril, the Simpson Angus Rting Scle showed significnt difference between ABILIFY nd plcebo (ABILIFY, 0.90; plcebo, 0.05). Chnges in the Brnes Akthisi Scle nd the Assessments of Involuntry Movement Scles were similr for the ABILIFY nd plcebo groups. Mjor Depressive Disorder In the short-term, plcebo-controlled trils in mjor depressive disorder, the incidence of reported EPS-relted events, excluding events relted to kthisi, for djunctive ABILIFY-treted ptients ws 8% vs. 5% for djunctive plcebo-treted ptients; nd the incidence of kthisi-relted events for djunctive ABILIFY-treted ptients ws 25% vs. 4% for djunctive plcebo-treted ptients. In the mjor depressive disorder trils, the Simpson Angus Rting Scle nd the Brnes Akthisi Scle showed significnt difference between djunctive ABILIFY nd djunctive plcebo (ABILIFY, 0.31; plcebo, 0.03 nd ABILIFY, 0.22; plcebo, 0.02). Chnges in the Assessments of Involuntry Movement Scles were similr for the djunctive ABILIFY nd djunctive plcebo groups. Autistic Disorder In the short-term, plcebo-controlled trils in utistic disorder in peditric ptients (6 to 17 yers), the incidence of reported EPS-relted events, excluding events relted to kthisi, for ABILIFY-treted ptients ws 18% vs. 2% for plcebo nd the incidence of kthisi-relted events for ABILIFY-treted ptients ws 3% vs. 9% for plcebo. In the peditric (6 to 17 yers) short-term utistic disorder trils, the Simpson Angus Rting Scle showed significnt difference between ABILIFY nd plcebo (ABILIFY, 0.1; plcebo, 0.4). Chnges in the Brnes Akthisi Scle nd the Assessments of Involuntry Movement Scles were similr for the ABILIFY nd plcebo groups. Tourette s Disorder In the short-term, plcebo-controlled trils in Tourette s disorder in peditric ptients (6 to 18 yers), the incidence of reported EPS-relted events, excluding events relted to kthisi, for ABILIFY-treted ptients ws 7% vs. 6% for plcebo nd the incidence of kthisi-relted events for ABILIFY-treted ptients ws 4% vs. 6% for plcebo. In the peditric (6 to 18 yers) short-term Tourette s disorder trils, chnges in the Simpson Angus Rting Scle, Brnes Akthisi Scle nd Assessments of Involuntry Movement Scle were not cliniclly meningfully different for ABILIFY nd plcebo. Agittion Associted with Schizophreni or Bipolr Mni In the plcebo-controlled trils in ptients with gittion ssocited with schizophreni or bipolr mni, the incidence of reported EPS-relted events excluding events relted to kthisi for ABILIFY-treted ptients ws 2% vs. 2% for plcebo nd the incidence of kthisi-relted events for ABILIFY-treted ptients ws 2% vs. 0% for plcebo. Objectively collected dt on the Simpson Angus Rting Scle (for EPS) nd the Brnes Akthisi Scle (for kthisi) for ll tretment groups did not show difference between ABILIFY nd plcebo. Dystoni 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, they occur more frequently nd with greter severity with high potency nd t higher doses of first genertion ntipsychotic drugs. An elevted risk of cute dystoni is observed in mles nd younger ge groups. Additionl Findings Observed in Clinicl Trils Adverse Rections in Long-Term, Double-Blind, -Controlled Trils The dverse rections reported in 26-week, double-blind tril compring orl ABILIFY nd plcebo in ptients with schizophreni were generlly consistent with those reported in the short-term, plcebo-controlled trils, except for higher incidence of tremor [8% (12/153) for ABILIFY vs. 2% (3/153) for plcebo]. In this study, the mjority of the cses of tremor were of mild intensity (8/12 mild nd 4/12 moderte), occurred erly in therpy (9/12 49 dys), nd were of limited durtion (7/12 10 dys). Tremor infrequently led to discontinution (<1%) of ABILIFY. In ddition, in long-term (52 week), ctive-controlled study, the incidence of tremor ws 5% (40/859) for ABILIFY. A similr profile ws observed in long-term monotherpy study nd long-term djunctive study with lithium nd vlprote in bipolr disorder. Other Adverse Rections Observed During the Premrketing Evlution of ABILIFY The following listing does not include rections: 1) lredy listed in previous tbles or elsewhere in lbeling, 2) for which drug cuse ws remote, 3) which were so generl s to be uninformtive, 4) which were not considered to hve significnt clinicl implictions, or 5) which occurred t rte equl to or less thn plcebo. Rections re ctegorized by body system ccording to the following definitions: frequent dverse rections re those occurring in t lest 1/100 ptients; infrequent dverse rections re those occurring in 1/100 to 1/1000 ptients; rre rections re those occurring in fewer thn 1/1000 ptients: Adults - Orl Administrtion Bld nd Lymphtic System Disorders: rre - thrombocytopeni Crdic Disorders: infrequent brdycrdi, plpittions, rre tril flutter, crdio-respirtory rrest, trioventriculr block, tril fibrilltion, ngin pectoris, myocrdil ischemi, myocrdil infrction, crdiopulmonry filure Eye Disorders: infrequent photophobi; rre - diplopi Gstrointestinl Disorders: infrequent - gstroesophgel reflux disese 11

12 Generl Disorders nd Administrtion Site Conditions: frequent - stheni; infrequent peripherl edem, chest pin; rre fce edem Heptobiliry Disorders: rre - heptitis, jundice Immune System Disorders: rre - hypersensitivity Injury, Poisoning, nd Procedurl Complictions: infrequent - fll; rre - het stroke Investigtions: frequent - weight decresed, infrequent - heptic enzyme incresed, bld glucose incresed, bld lctte dehydrogense incresed, gmm glutmyl trnsferse incresed; rre bld prolctin incresed, bld ure incresed, bld cretinine incresed, bld bilirubin incresed, electrocrdiogrm QT prolonged, glycosylted hemoglobin incresed Metbolism nd Nutrition Disorders: frequent norexi; infrequent - rre - hypoklemi, hypontremi, hypoglycemi Musculoskeletl nd Connective Tissue Disorders: infrequent - musculr wekness, muscle tightness; rre rhbdomyolysis, mobility decresed Nervous System Disorders: infrequent - prkinsonism, memory impirment, cogwheel rigidity, hypokinesi, myoclonus, brdykinesi; rre kinesi, myoclonus, crdintion bnorml, speech disorder, Grnd Ml convulsion; <1/10,000 ptients - choreothetosis Psychitric Disorders: infrequent ggression, loss of libido, delirium; rre libido incresed, norgsmi, tic, homicidl idetion, cttoni, sleep wlking Renl nd Urinry Disorders: rre - urinry retention, nocturi Reproductive System nd Brest Disorders: infrequent - erectile dysfunction; rre gynecomsti, menstrution irregulr, menorrhe, brest pin, pripism Respirtory, Thorcic, nd Medistinl Disorders: infrequent - nsl congestion, dyspne Skin nd Subcutneous Tissue Disorders: infrequent - rsh, hyperhidrosis, pruritus, photosensitivity rection, lopeci; rre - urticri Vsculr Disorders: infrequent - hypotension, hypertension Peditric Ptients - Orl Administrtion Most dverse events observed in the pled dtbse of 1,686 peditric ptients, ged 6 to 18 yers, were lso observed in the dult popultion. Additionl dverse rections observed in the peditric popultion re listed below. Eye Disorders infrequent - oculogyric crisis Gstrointestinl Disorders: infrequent - tongue dry, tongue spsm Investigtions: frequent - bld insulin incresed Nervous System Disorders: infrequent - sleep tlking Renl nd Urinry Disorders frequent - enuresis Skin nd Subcutneous Tissue Disorders: infrequent - hirsutism Adults - Intrmusculr Injection Most dverse rections observed in the pled dtbse of 749 dult ptients treted with ABILIFY injection, were lso observed in the dult popultion treted with orl ABILIFY. Additionl dverse rections observed in the ABILIFY injection popultion re listed below. Generl Disorders nd Administrtion Site Conditions: 1/100 ptients - injection site rection; 1/1000 ptients nd <1/100 ptients - venipuncture site bruise 6.2 Postmrketing Experience The following dverse rections hve been identified during post-pprovl use of ABILIFY. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to estblish cusl reltionship to drug exposure: occurrences of llergic rection (nphylctic rection, ngioedem, lryngospsm, pruritus/urticri, or orophryngel spsm), pthologicl gmbling, hiccups nd bld glucose fluctution DRUG INTERACTIONS 7.1 Drugs Hving Cliniclly Importnt Interctions with ABILIFY Tble 25: Cliniclly Importnt Drug Interctions with ABILIFY: Concomitnt Drug Nme or Drug Clss Strong CYP3A4 Inhibitors (e.g., itrconzole, clrithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, proxetine) Strong CYP3A4 Inducers (e.g., crbmzepine, rifmpin) Antihypertensive Drugs Benzodizepines (e.g., lorzepm) Clinicl Rtionle The concomitnt use of ABILIFY with strong CYP3A4 or CYP2D6 inhibitors incresed the exposure of ripiprzole compred to the use of ABILIFY lone [see CLINICAL PHARMACOLOGY (12.3)]. The concomitnt use of ABILIFY nd crbmzepine decresed the exposure of ripiprzole compred to the use of ABILIFY lone [see CLINICAL PHARMACOLOGY (12.3)]. Due to its lph drenergic ntgonism, ripiprzole hs the potentil to enhnce the effect of certin ntihypertensive gents. The intensity of sedtion ws greter with the combintion of orl ripiprzole nd lorzepm s compred to tht observed with ripiprzole lone. The orthosttic hypotension observed ws greter with the combintion s compred to tht observed with lorzepm lone [see WARNINGS AND PRECAUTIONS (5.7)] Clinicl Recommendtion With concomitnt use of ABILIFY with strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosge [see DOSAGE AND ADMINISTRATION (2.7)]. With concomitnt use of ABILIFY with strong CYP3A4 inducer, consider incresing the ABILIFY dosge [see DOSAGE AND ADMINISTRATION (2.7)]. Monitor bld pressure nd djust dose ccordingly [see WARNINGS AND PRECAUTIONS (5.8)]. Monitor sedtion nd bld pressure. Adjust dose ccordingly. 7.2 Drugs Hving No Cliniclly Importnt Interctions with ABILIFY Bsed on phrmcokinetic studies, no dosge djustment of ABILIFY is required when dministered concomitntly with fmotidine, vlprote, lithium, lorzepm. In ddition, no dosge djustment is necessry for substrtes of CYP2D6 (e.g., dextromethorphn, fluoxetine, proxetine, or venlfxine), CYP2C9 (e.g., wrfrin), CYP2C19 (e.g., omeprzole, wrfrin, escitloprm), or CYP3A4 (e.g., dextromethorphn) when co-dministered with ABILIFY. Additionlly, no dosge djustment is necessry for vlprote, lithium, lmotrigine, lorzepm, or sertrline when co-dministered with ABILIFY [see CLINICAL PHARMACOLOGY (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Pregnncy Ctegory C Pregnncy Exposure Registry There is pregnncy exposure registry tht monitors pregnncy outcomes in women exposed to ABILIFY during pregnncy. For more informtion contct the Ntionl Pregnncy Registry for Atypicl Antipsychotics t or visit org/clinicl-nd-reserch-progrms/pregnncyregistry/. Risk Summry Neontes exposed to ntipsychotic drugs (including ABILIFY) during the third trimester of pregnncy re t risk for extrpyrmidl nd/or withdrwl symptoms. Adequte nd well controlled studies with ABILIFY hve not been conducted in pregnnt women. Animl reproduction studies were conducted with ripiprzole in rts nd rbbits during orgnogenesis, nd in rts during the pre-nd post-ntl period. Orl nd intrvenous ripiprzole dministrtion during orgnogenesis in rts nd/or rbbits t doses higher thn the mximum recommended humn dose (MRHD) produced fetl deth, decresed fetl weight, undescended testicles, delyed skeletl ossifiction, skeletl bnormlities, nd diphrgmtic herni. Orl nd intrvenous ripiprzole dministrtion during the pre- nd post-ntl period in rts t doses higher thn the mximum recommended humn dose (MRHD) produced prolonged gesttion, stillbirths, decresed pup weight, nd decresed pup survivl. Administer ABILIFY during pregnncy only if the potentil benefit justifies the potentil risk to the fetus. Clinicl Considertions Fetl/Neontl Adverse Rections Extrpyrmidl nd/or withdrwl symptoms, including gittion, hypertoni, hypotoni, tremor, somnolence, respirtory distress nd feeding disorder hve been reported in neontes who were exposed to ntipsychotic drugs (including ABILIFY) during the third trimester of pregnncy. These symptoms hve vried in severity. Some neontes recovered within hours or dys without specific tretment; others required prolonged hospitliztion. Monitor neontes for extrpyrmidl nd/or withdrwl symptoms.

13 Dt Animl Dt In niml studies, ripiprzole demonstrted developmentl toxicity, including possible tertogenic effects in rts nd rbbits. Pregnnt rts were treted with orl doses of 3, 10, nd 30 mg/kg/dy (1, 3, nd 10 times the mximum recommended humn dose [MRHD] on mg/m 2 bsis) of ripiprzole during the period of orgnogenesis. Gesttion ws slightly prolonged t 30 mg/kg/dy. Tretment t the high dose of 30 mg/kg/dy cused slight dely in fetl development (decresed fetl weight), undescended testes, nd delyed skeletl ossifiction (lso seen t 10 mg/kg/dy). There were no dverse effects on embryofetl or pup survivl. Delivered offspring hd decresed body weights (10 nd 30 mg/kg/dy), nd incresed incidences of heptodiphrgmtic nodules nd diphrgmtic herni t 30 mg/kg (the other dose groups were not exmined for these findings). Postntlly, delyed vginl opening ws seen t 10 nd 30 mg/kg/dy nd impired reproductive performnce (decresed fertility rte, corpor lute, implnts, live fetuses, nd incresed post-implnttion loss, likely medited through effects on femle offspring) ws seen t 30 mg/kg/dy. Some mternl toxicity ws seen t 30 mg/kg/dy however, there ws no evidence to suggest tht these developmentl effects were secondry to mternl toxicity. In pregnnt rts receiving ripiprzole injection intrvenously (3, 9, nd 27 mg/kg/dy) during the period of orgnogenesis, decresed fetl weight nd delyed skeletl ossifiction were seen t the highest dose where it lso cused mternl toxicity. Pregnnt rbbits were treted with orl doses of 10, 30, nd 100 mg/kg/dy (2, 3, nd 11 times humn exposure t MRHD bsed on nd 6, 19, nd 65 times the MRHD bsed on mg/m 2 ) of ripiprzole during the period of orgnogenesis. At the high dose of 100 mg/kg/dy decresed mternl fd consumption, nd incresed bortions were seen s well s incresed fetl mortlity, decresed fetl weight (lso seen t 30 mg/kg/dy), incresed incidence of skeletl bnormlity (fused sternebre) (lso seen t 30 mg/kg/dy). In pregnnt rbbits receiving ripiprzole injection intrvenously (3, 10, nd 30 mg/kg/dy) during the period of orgnogenesis, the highest dose, which cused pronounced mternl toxicity, resulted in decresed fetl weight, incresed fetl bnormlities (primrily skeletl), nd decresed fetl skeletl ossifiction. The fetl no-effect dose ws 10 mg/kg/dy, which is 5 times the humn exposure t the MRHD bsed on nd is 6 times the MRHD bsed on mg/m 2. In study in which rts were treted peri- nd post-ntlly with orl doses of 3, 10, nd 30 mg/kg/dy (1, 3, nd 10 times the MRHD on mg/m 2 bsis) of ripiprzole from gesttion dy 17 through dy 21 postprtum, slight mternl toxicity, slightly prolonged gesttion n increse in stillbirths nd, decreses in pup weight (persisting into dulthd) nd survivl were seen t 30 mg/kg/dy. In rts receiving ripiprzole injection intrvenously (3, 8, nd 20 mg/kg/dy) from gesttion dy 6 through dy 20 postprtum, n increse in stillbirths ws seen t 8 nd 20 mg/kg/dy, nd decreses in erly postntl pup weights nd survivl were seen t 20 mg/kg/dy; these effects were seen in presence of mternl toxicity. There were no effects on postntl behviorl nd reproductive development. 8.2 Lbor nd Delivery The effect of ABILIFY on lbor nd delivery in humns is unknown. 8.3 Nursing Mothers ABILIFY is present in humn brest milk. Becuse of the potentil for serious dverse rections in nursing infnts from ABILIFY, decision should be mde whether to discontinue nursing or to discontinue the drug, tking into ccount the importnce of the drug to the mother. 8.4 Peditric Use Sfety nd effectiveness in peditric ptients with mjor depressive disorder or gittion ssocited with schizophreni or bipolr mni hve not been estblished. The phrmcokinetics of ripiprzole nd dehydro-ripiprzole in peditric ptients, 10 to 17 yers of ge, were similr to those in dults fter correcting for the differences in body weight [see CLINICAL PHARMACOLOGY (12.3)]. Schizophreni Sfety nd effectiveness in peditric ptients with schizophreni were estblished in 6-week, plcebo-controlled clinicl tril in 202 peditric ptients ged 13 to 17 yers [see DOSAGE AND ADMINISTRATION (2.1), ADVERSE REACTIONS (6.1), nd CLINICAL STUDIES (14.1)]. Although mintennce efficcy in peditric ptients hs not been systemticlly evluted, mintennce efficcy cn be extrpolted from dult dt long with comprisons of ripiprzole phrmcokinetic prmeters in dult nd peditric ptients. Bipolr I Disorder Sfety nd effectiveness in peditric ptients with bipolr mni were estblished in 4-week, plcebo-controlled clinicl tril in 197 peditric ptients ged 10 to 17 yers [see DOSAGE AND ADMINISTRATION (2.2), ADVERSE REACTIONS (6.1), nd CLINICAL STUDIES (14.2)]. Although mintennce efficcy in peditric ptients hs not been systemticlly evluted, mintennce efficcy cn be extrpolted from dult dt long with comprisons of ripiprzole phrmcokinetic prmeters in dult nd peditric ptients. The efficcy of djunctive ABILIFY with concomitnt lithium or vlprote in the tretment of mnic or mixed episodes in peditric ptients hs not been systemticlly evluted. However, such efficcy nd lck of phrmcokinetic interction between ripiprzole nd lithium or vlprote cn be extrpolted from dult dt, long with comprisons of ripiprzole phrmcokinetic prmeters in dult nd peditric ptients. 13 Irritbility Associted with Autistic Disorder Sfety nd effectiveness in peditric ptients demonstrting irritbility ssocited with utistic disorder were estblished in two 8-week, plcebo-controlled clinicl trils in 212 peditric ptients ged 6 to 17 yers [see INDICATIONS AND USAGE (1), DOSAGE AND ADMINISTRATION (2.4), ADVERSE REACTIONS (6.1), nd CLINICAL STUDIES (14.4)]. A mintennce tril ws conducted in peditric ptients (6 to 17 yers of ge) with irritbility ssocited with utistic disorder. The first phse of this tril ws n open-lbel, flexibly dosed (ripiprzole 2 to 15 mg/dy) phse in which ptients were stbilized (defined s >25% improvement on the ABC-I subscle, nd CGI-I rting of much improved or very much improved ) on ABILIFY for 12 consecutive weeks. Overll, 85 ptients were stbilized nd entered the second, 16-week, double-blind phse where they were rndomized to either continue ABILIFY tretment or switch to plcebo. In this tril, the efficcy of ABILIFY for the mintennce tretment of irritbility ssocited with utistic disorder ws not estblished. Tourette s Disorder Sfety nd effectiveness of ripiprzole in peditric ptients with Tourette s Disorder were estblished in one 8-week (ged 7 to 17) nd one 10-week tril (ged 6 to 18) in 194 peditric ptients [see DOSAGE AND ADMINISTRATION (2.5), ADVERSE REACTIONS (6.1), nd CLINICAL STUDIES (14.5)]. Mintennce efficcy in peditric ptients hs not been systemticlly evluted. Juvenile Animl Studies Aripiprzole in juvenile rts cused mortlity, CNS clinicl signs, impired memory nd lerning, nd delyed sexul mturtion when dministered t orl doses of 10, 20, 40 mg/kg/dy from wening (21 dys old) through mturity (80 dys old). At 40 mg/kg/dy, mortlity, decresed ctivity, splyed hind limbs, hunched posture, txi, tremors nd other CNS signs were observed in both genders. In ddition, delyed sexul mturtion ws observed in mles. At ll doses nd in dose-dependent mnner, impired memory nd lerning, incresed motor ctivity, nd histopthology chnges in the pituitry (trophy), drenls (drenocorticl hypertrophy), mmmry glnds (hyperplsi nd incresed secretion), nd femle reproductive orgns (vginl mucifiction, endometril trophy, decrese in ovrin corpor lute) were observed. The chnges in femle reproductive orgns were considered secondry to the increse in prolctin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined nd, t the lowest tested dose of 10 mg/kg/dy, there is no sfety mrgin reltive to the systemic exposures (0-24) for ripiprzole or its mjor ctive metbolite in dolescents t the mximum recommended peditric dose of 15 mg/dy. All drug-relted effects were reversible fter 2-month recovery period, nd most of the drug effects in juvenile rts were lso observed in dult rts from previously conducted studies. Aripiprzole in juvenile dogs (2 months old) cused CNS clinicl signs of tremors, hypoctivity, txi, recumbency nd limited use of hind limbs when dministered orlly for 6 months t 3, 10, 30 mg/kg/dy. Men body weight nd weight gin were decresed up to 18% in femles in ll drug groups reltive to control vlues. A NOAEL could not be determined nd, t the lowest tested dose of 3 mg/kg/dy, there is no sfety mrgin reltive to the systemic exposures (0-24) for ripiprzole or its mjor ctive metbolite in dolescents t the mximum recommended peditric dose of 15 mg/dy. All drug-relted effects were reversible fter 2-month recovery period. 8.5 Geritric Use No dosge djustment is recommended for elderly ptients [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1), nd CLINICAL PHARMACOLOGY (12.3)]. Of the 13,543 ptients treted with orl ABILIFY in clinicl trils, 1073 (8%) were 65 yers old nd 799 (6%) were 75 yers old. -controlled studies of orl ABILIFY in schizophreni, bipolr mni, or mjor depressive disorder did not include sufficient numbers of subjects ged 65 nd over to determine whether they respond differently from younger subjects. Of the 749 ptients treted with ABILIFY injection in clinicl trils, 99 (13%) were 65 yers old nd 78 (10%) were 75 yers old. -controlled studies of ABILIFY injection in ptients with gittion ssocited with schizophreni or bipolr mni did not include sufficient numbers of subjects ged 65 nd over to determine whether they respond differently from younger subjects. ABILIFY is not pproved for the tretment of ptients with psychosis ssocited with Alzheimer s disese [see BOXED WARNING nd WARNINGS AND PRECAUTIONS (5.1)]. 8.6 CYP2D6 Pr Metbolizers Dosge djustment is recommended in known CYP2D6 pr metbolizers due to high ripiprzole concentrtions. Approximtely 8% of Cucsins nd 3 8% of Blck/Africn Americns cnnot metbolize CYP2D6 substrtes nd re clssified s pr metbolizers (PM) [see DOSAGE AND ADMINISTRATION (2.7) nd CLINICAL PHARMACOLOGY (12.3)]. 8.7 Heptic nd Renl Impirment No dosge djustment for ABILIFY is required on the bsis of ptient s heptic function (mild to severe heptic impirment, Child-Pugh score between 5 nd 15), or renl function (mild to severe renl impirment, glomerulr filtrtion rte between 15 nd 90 ml/minute) [see CLINICAL PHARMACOLOGY (12.3)]. 8.8 Other Specific Popultions No dosge djustment for ABILIFY is required on the bsis of ptient s sex, rce, or smoking sttus [see CLINICAL PHARMACOLOGY (12.3)].

14 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substnce ABILIFY is not controlled substnce. 9.2 Abuse ABILIFY hs not been systemticlly studied in humns for its potentil for buse, tolernce, or physicl dependence. Consequently, ptients should be evluted crefully for history of drug buse, nd such ptients should be observed closely for signs of ABILIFY misuse or buse (e.g., development of tolernce, increses in dose, drug-seeking behvior). 9.3 Dependence In physicl dependence studies in monkeys, withdrwl symptoms were observed upon brupt cesstion of dosing. 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. 10 OVERDOSAGE MedDRA terminology hs been used to clssify the dverse rections Humn Experience In clinicl trils nd in postmrketing experience, dverse rections of deliberte or ccidentl overdosge with orl ABILIFY hve been reported worldwide. These include overdoses with orl ABILIFY lone nd in combintion with other substnces. No ftlity ws reported with ABILIFY lone. The lrgest known dose with known outcome involved cute ingestion of 1260 mg of orl ABILIFY (42 times the mximum recommended dily dose) by ptient who fully recovered. Deliberte or ccidentl overdosge ws lso reported in children (ge 12 nd younger) involving orl ABILIFY ingestions up to 195 mg with no ftlities. Common dverse rections (reported in t lest 5% of ll overdose cses) reported with orl ABILIFY overdosge (lone or in combintion with other substnces) include vomiting, somnolence, nd tremor. Other cliniclly importnt signs nd symptoms observed in one or more ptients with ABILIFY overdoses (lone or with other substnces) include cidosis, ggression, sprtte minotrnsferse incresed, tril fibrilltion, brdycrdi, com, confusionl stte, convulsion, bld cretine phosphokinse incresed, depressed level of consciousness, hypertension, hypoklemi, hypotension, lethrgy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumoni spirtion, respirtory rrest, sttus epilepticus, nd tchycrdi Mngement of Overdosge No specific informtion is vilble on the tretment of overdose with ABILIFY. An electrocrdiogrm should be obtined in cse of overdosge nd if QT intervl prolongtion is present, crdic monitoring should be instituted. Otherwise, mngement of overdose should concentrte on supportive therpy, mintining n dequte irwy, oxygention nd ventiltion, nd mngement of symptoms. Close medicl supervision nd monitoring should continue until the ptient recovers. Chrcol: In the event of n overdose of ABILIFY, n erly chrcol dministrtion my be useful in prtilly preventing the bsorption of ripiprzole. Administrtion of 50 g of ctivted chrcol, one hour fter single 15 mg orl dose of ABILIFY, decresed the men nd of ripiprzole by 50%. Hemodilysis: Although there is no informtion on the effect of hemodilysis in treting n overdose with ABILIFY, hemodilysis is unlikely to be useful in overdose mngement since ripiprzole is highly bound to plsm proteins. 11 DESCRIPTION Aripiprzole is psychotropic drug tht is vilble s Tblets, ABILIFY DISCMELT (ripiprzole) Orlly Disintegrting Tblets, Orl Solution, nd Injection, solution for intrmusculr injection. Aripiprzole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperzinyl]butoxy]-3,4-dihydrocrbostyril. The empiricl formul is C 23 H 27 Cl 2 N 3 O 2 nd its moleculr weight is The chemicl structure is: ABILIFY Tblets re vilble in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, nd 30 mg strengths. Inctive ingredients include cornstrch, hydroxypropyl cellulose, lctose monohydrte, mgnesium sterte, nd microcrystlline cellulose. Colornts include ferric oxide (yellow or red) nd FD&C Blue No. 2 Aluminum Lke. ABILIFY DISCMELT Orlly Disintegrting Tblets re vilble in 10 mg nd 15 mg strengths. Inctive ingredients include cesulfme potssium, sprtme, clcium silicte, croscrmellose sodium, crospovidone, crème de vnill (nturl nd rtificil flvors), mgnesium sterte, microcrystlline cellulose, silicon dioxide, trtric cid, nd xylitol. Colornts include ferric oxide (yellow or red) nd FD&C Blue No. 2 Aluminum Lke. ABILIFY Orl Solution is cler, colorless to light-yellow solution vilble in concentrtion of 1 mg/ml. The inctive ingredients for this solution include disodium edette, fructose, glycerin, dl-lctic cid, methylprben, propylene glycol, propylprben, sodium hydroxide, sucrose, nd purified wter. The orl solution is flvored with nturl ornge crem nd other nturl flvors. 14 ABILIFY Injection is vilble in single-dose vils s redy-to-use, 9.75 mg/1.3 ml (7.5 mg/ml) cler, colorless, sterile, queous solution for intrmusculr use only. Inctive ingredients for this solution include mg of sulfobutylether b-cyclodextrin (SBECD), 10.4 mg of trtric cid, qs to ph 4.3 of sodium hydroxide, nd qs to 1.33 ml of wter for injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action The mechnism of ction of ripiprzole in schizophreni or bipolr mni, is unknown. However, the efficcy of ripiprzole could be medited through combintion of prtil gonist ctivity t D2 nd 5-HT 1A receptors nd ntgonist ctivity t 5-HT 2A receptors. Actions t receptors other thn D2, 5-HT 1A, nd 5-HT 2A my explin some of the other clinicl effects of ripiprzole (e.g., the orthosttic hypotension observed with ripiprzole my be explined by its ntgonist ctivity t drenergic lph1 receptors) Phrmcodynmics Aripiprzole exhibits high ffinity for dopmine D 2 nd D 3, serotonin 5-HT 1A nd 5-HT 2A receptors (K i vlues of 0.34 nm, 0.8 nm, 1.7 nm, nd 3.4 nm, respectively), moderte ffinity for dopmine D 4, serotonin 5-HT 2C nd 5-HT 7, lph 1 -drenergic nd histmine H 1 receptors (K i vlues of 44 nm, 15 nm, 39 nm, 57 nm, nd 61 nm, respectively), nd moderte ffinity for the serotonin reuptke site (K i =98 nm). Aripiprzole hs no pprecible ffinity for cholinergic muscrinic receptors (IC 50 >1000 nm). [Aripiprzole functions s prtil gonist t the dopmine D 2 nd the serotonin 5-HT 1A receptors, nd s n ntgonist t serotonin 5-HT 2A receptor.] 12.3 Phrmcokinetics ABILIFY ctivity is presumbly primrily due to the prent drug, ripiprzole, nd to lesser extent, to its mjor metbolite, dehydro-ripiprzole, which hs been shown to hve ffinities for D 2 receptors similr to the prent drug nd represents 40% of the prent drug exposure in plsm. The men elimintion hlf-lives re bout 75 hours nd 94 hours for ripiprzole nd dehydro-ripiprzole, respectively. Stedy-stte concentrtions re ttined within 14 dys of dosing for both ctive moieties. Aripiprzole ccumultion is predictble from single-dose phrmcokinetics. At stedy-stte, the phrmcokinetics of ripiprzole is dose-proportionl. Elimintion of ripiprzole is minly through heptic metbolism involving two P450 isozymes, CYP2D6 nd CYP3A4. For CYP2D6 pr metbolizers, the men elimintion hlf-life for ripiprzole is bout 146 hours. Phrmcokinetic studies showed tht ABILIFY DISCMELT Orlly Disintegrting Tblets re bioequivlent to ABILIFY Tblets. ORAL ADMINISTRATION Absorption Tblet: Aripiprzole is well bsorbed fter dministrtion of the tblet, with pek plsm concentrtions occurring within 3 hours to 5 hours; the bsolute orl biovilbility of the tblet formultion is 87%. ABILIFY cn be dministered with or without fd. Administrtion of 15 mg ABILIFY Tblet with stndrd high-ft mel did not significntly ffect the or of ripiprzole or its ctive metbolite, dehydro-ripiprzole, but delyed Tmx by 3 hours for ripiprzole nd 12 hours for dehydro-ripiprzole. Orl Solution: Aripiprzole is well bsorbed when dministered orlly s the solution. At equivlent doses, the plsm concentrtions of ripiprzole from the solution were higher thn tht from the tblet formultion. In reltive biovilbility study compring the phrmcokinetics of 30 mg ripiprzole s the orl solution to 30 mg ripiprzole tblets in helthy subjects, the solution to tblet rtios of geometric men nd vlues were 122% nd 114%, respectively [see DOSAGE AND ADMINISTRATION (2.6)]. The single-dose phrmcokinetics of ripiprzole were liner nd dose-proportionl between the doses of 5 mg to 30 mg. Distribution The stedy-stte volume of distribution of ripiprzole following intrvenous dministrtion is high (404 L or 4.9 L/kg), indicting extensive extrvsculr distribution. At therpeutic concentrtions, ripiprzole nd its mjor metbolite re greter thn 99% bound to serum proteins, primrily to lbumin. In helthy humn volunteers dministered 0.5 to 30 mg/dy ripiprzole for 14 dys, there ws dose-dependent D2 receptor occupncy indicting brin penetrtion of ripiprzole in humns. Metbolism nd Elimintion Aripiprzole is metbolized primrily by three biotrnsformtion pthwys: dehydrogention, hydroxyltion, nd N-delkyltion. Bsed on in vitro studies, CYP3A4 nd CYP2D6 enzymes re responsible for dehydrogention nd hydroxyltion of ripiprzole, nd N-delkyltion is ctlyzed by CYP3A4. Aripiprzole is the predominnt drug moiety in the systemic circultion. At stedy-stte, dehydro-ripiprzole, the ctive metbolite, represents bout 40% of ripiprzole in plsm. Following single orl dose of [ 14 C]-lbeled ripiprzole, pproximtely 25% nd 55% of the dministered rdioctivity ws recovered in the urine nd feces, respectively. Less thn 1% of unchnged ripiprzole ws excreted in the urine nd pproximtely 18% of the orl dose ws recovered unchnged in the feces. Drug Interction Studies Effects of other drugs on the exposures of ripiprzole nd dehydro-ripiprzole re summrized in Figure 1 nd Figure 2, respectively. Bsed on simultion, 4.5-fold increse in men nd vlues t stedy-stte is expected when extensive metbolizers of CYP2D6 re dministered with both strong CYP2D6 nd CYP3A4 inhibitors. A 3-fold increse in men nd vlues t stedy-stte is expected in pr metbolizers of CYP2D6 dministered with strong CYP3A4 inhibitors.

15 Figure 1: The effects of other drugs on ripiprzole phrmcokinetics Effect of Other Drugs on Abilify CYP3A4 Inhibitor: ketoconzole CYP2D6 Inhibitor: quinidine CYP3A4 Inducer: crbmzepine Gstric Acid Blockers: fmotidine Other: vlprote lithium lorzepm PK Aripiprzole Fold Chnge nd 90% CI Chnge Reltive to Reference (without intercting drug) Figure 2: The effects of other drugs on dehydro-ripiprzole phrmcokinetics Effect of Other Drugs on Abilify CYP3A4 Inhibitor: ketoconzole CYP2D6 Inhibitor: quinidine CYP3A4 Inducer: crbmzepine Gstric Acid Blockers: fmotidine Other: vlprote lithium lorzepm PK Dehydro-Aripiprzole Fold Chnge nd 90% CI Chnge Reltive to Reference (without intercting drug) The effects of ABILIFY on the exposures of other drugs re summrized in Figure 3. A popultion PK nlysis in ptients with mjor depressive disorder showed no substntil chnge in plsm concentrtions of fluoxetine (20 or 40 mg/dy), proxetine CR (37.5 or 50 mg/dy), or sertrline (100 or 150 mg/dy) dosed to stedy-stte. The stedy-stte plsm concentrtions of fluoxetine nd norfluoxetine incresed by bout 18% nd 36%, respectively, nd concentrtions of proxetine decresed by bout 27%. The stedy-stte plsm concentrtions of sertrline nd desmethylsertrline were not substntilly chnged when these ntidepressnt therpies were codministered with ripiprzole. Figure 3: The effects of ABILIFY on phrmcokinetics of other drugs Effect of Abilify on Other Drugs CYP2D6 dextropmethorphn CYP2C9, 2C19 wrfrin omeprzole UGT1A4 lmotrigine Other vlprote lithium lorzepm venlfxine PK DM/DRP S-wrfrin R-wrfrin INR venlfxine O-desmethylvenlfxine escitloprm Fold Chnge nd 90% CI Studies in Specific Popultions Exposures of ripiprzole nd dehydro-ripiprzole in specific popultions re summrized in Figure 4 nd Figure 5, respectively. In ddition, in peditric ptients (10 to 17 yers of ge) dministered with ABILIFY (20 mg to 30 mg), the body weight corrected ripiprzole clernce ws similr to the dults. Figure 4: Effects of intrinsic fctors on ripiprzole phrmcokinetics Specil Popultions CYP2D6 pr vs. extensive metbolizer Gender femle vs. mle Age vs. >65 yers old Heptic Impirment: mild vs. norml moderte vs. norml severe vs. norml Renl Impirment: Severe PK Aripiprzole Fold Chnge nd 90% CI Chnge Reltive to Reference Figure 5: Effects of intrinsic fctors on dehydro-ripiprzole phrmcokinetics CYP2D6 pr vs. extensive metbolizer Gender femle vs. mle Age vs. >65 yers old Heptic Impirment: mild vs. norml moderte vs. norml severe vs. norml Renl Impirment: Severe PK Dehydro-Aripiprzole Fold Chnge nd 90% CI Chnge Reltive to Reference INTRAMUSCULAR ADMINISTRATION In two phrmcokinetic studies of ripiprzole injection dministered intrmusculrly to helthy subjects, the medin times to the pek plsm concentrtions were t 1 hour nd 3 hours. A 5 mg intrmusculr injection of ripiprzole hd n bsolute biovilbility of 100%. The geometric men mximum concentrtion chieved fter n intrmusculr dose ws on verge 19% higher thn the of the orl tblet. While the systemic exposure over 24 hours ws generlly similr between ripiprzole injection given intrmusculrly nd fter orl tblet dministrtion, the ripiprzole in the first 2 hours fter n intrmusculr injection ws 90% greter thn the fter the sme dose s tblet. In stble ptients with schizophreni or schizoffective disorder, the phrmcokinetics of ripiprzole fter intrmusculr dministrtion were liner over dose rnge of 1 mg to 45 mg. Although the metbolism of ripiprzole injection ws not systemticlly evluted, the intrmusculr route of dministrtion would not be expected to lter the metbolic pthwys Chnge Reltive to Reference (without intercting drug) 15

16 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility Crcinogenesis Lifetime crcinogenicity studies were conducted in ICR mice, Sprgue-Dwley (SD) rts, nd F344 rts. Aripiprzole ws dministered for 2 yers in the diet t doses of 1, 3, 10, nd 30 mg/kg/dy to ICR mice nd 1, 3, nd 10 mg/kg/dy to F344 rts (0.2 to 5 times nd 0.3 to 3 times the mximum recommended humn dose [MRHD] bsed on mg/m 2, respectively). In ddition, SD rts were dosed orlly for 2 yers t 10, 20, 40, nd 60 mg/kg/dy (3 to 19 times the MRHD bsed on mg/m 2 ). Aripiprzole did not induce tumors in mle mice or mle rts. In femle mice, the incidences of pituitry glnd denoms nd mmmry glnd denocrcinoms nd denocnthoms were incresed t dietry doses of 3 to 30 mg/kg/dy (0.1 to 0.9 times humn exposure t MRHD bsed on nd 0.5 to 5 times the MRHD bsed on mg/m 2 ). In femle rts, the incidence of mmmry glnd fibrodenoms ws incresed t dietry dose of 10 mg/kg/dy (0.1 times humn exposure t MRHD bsed on nd 3 times the MRHD bsed on mg/m 2 ); nd the incidences of drenocorticl crcinoms nd combined drenocorticl denoms/crcinoms were incresed t n orl dose of 60 mg/kg/dy (14 times humn exposure t MRHD bsed on nd 19 times the MRHD bsed on mg/m 2 ). Prolifertive chnges in the pituitry nd mmmry glnd of rodents hve been observed following chronic dministrtion of other ntipsychotic gents nd re considered prolctin-medited. Serum prolctin ws not mesured in the ripiprzole crcinogenicity studies. However, increses in serum prolctin levels were observed in femle mice in 13-week dietry study t the doses ssocited with mmmry glnd nd pituitry tumors. Serum prolctin ws not incresed in femle rts in 4-week nd 13-week dietry studies t the dose ssocited with mmmry glnd tumors. The relevnce for humn risk of the findings of prolctin-medited endocrine tumors in rodents is unknown. Mutgenesis The mutgenic potentil of ripiprzole ws tested in the in vitro bcteril reverse-muttion ssy, the in vitro bcteril DNA repir ssy, the in vitro forwrd gene muttion ssy in mouse lymphom cells, the in vitro chromosoml berrtion ssy in Chinese hmster lung (CHL) cells, the in vivo micronucleus ssy in mice, nd the unscheduled DNA synthesis ssy in rts. Aripiprzole nd metbolite (2,3-DCPP) were clstogenic in the in vitro chromosoml berrtion ssy in CHL cells with nd without metbolic ctivtion. The metbolite, 2,3-DCPP, produced increses in numericl berrtions in the in vitro ssy in CHL cells in the bsence of metbolic ctivtion. A positive response ws obtined in the in vivo micronucleus ssy in mice; however, the response ws due to mechnism not considered relevnt to humns. Impirment of Fertility Femle rts were treted with orl doses of 2, 6, nd 20 mg/kg/dy (0.6, 2, nd 6 times the mximum recommended humn dose [MRHD] on mg/m 2 bsis) of ripiprzole from 2 weeks prior to mting through dy 7 of gesttion. Estrus cycle irregulrities nd incresed corpor lute were seen t ll doses, but no impirment of fertility ws seen. Incresed pre-implnttion loss ws seen t 6 nd 20 mg/kg/dy nd decresed fetl weight ws seen t 20 mg/kg/dy. Mle rts were treted with orl doses of 20, 40, nd 60 mg/kg/dy (6, 13, nd 19 times the MRHD on mg/m 2 bsis) of ripiprzole from 9 weeks prior to mting through mting. Disturbnces in spermtogenesis were seen t 60 mg/kg nd prostte trophy ws seen t 40 nd 60 mg/kg, but no impirment of fertility ws seen Animl Toxicology nd/or Phrmcology Aripiprzole produced retinl degenertion in lbino rts in 26-week chronic toxicity study t dose of 60 mg/kg nd in 2-yer crcinogenicity study t doses of 40 nd 60 mg/kg. The 40 nd 60 mg/kg/dy doses re 13 nd 19 times the mximum recommended humn dose (MRHD) bsed on mg/m 2 nd 7 to 14 times humn exposure t MRHD bsed on. Evlution of the retins of lbino mice nd of monkeys did not revel evidence of retinl degenertion. Additionl studies to further evlute the mechnism hve not been performed. The relevnce of this finding to humn risk is unknown. 14 CLINICAL STUDIES Efficcy of the orl formultions of ABILIFY (ripiprzole) ws estblished in the following dequte nd well-controlled trils: Four short-term trils nd one mintennce tril in dult ptients nd one short-term tril in dolescents (ges 13-17) with schizophreni [see CLINICAL STUDIES (14.1)] Four short-term monotherpy trils nd one 6-week djunctive tril in dult ptients nd one short-term monotherpy tril in peditric ptients (ges 10-17) with mnic or mixed episodes [see CLINICAL STUDIES (14.2)] One mintennce monotherpy tril nd in one mintennce djunctive tril in dult ptients with bipolr I disorder [see CLINICAL STUDIES (14.2)] Two short-term trils in dult ptients with MDD who hd n indequte response to ntidepressnt therpy during the current episode [see CLINICAL STUDIES (14.3)] Two short-term trils in peditric ptients (ges 6-17 yers) for the tretment of irritbility ssocited with utistic disorder [see CLINICAL STUDIES (14.4)] Two short-term trils in peditric ptients (ges 6-18 yers) with Tourette s disorder [see CLINICAL STUDIES (14.5)] Efficcy of the injectble formultion of ABILIFY (ripiprzole) ws estblished in the following dequte nd well-controlled trils: Three 24-hour trils in gitted dult ptients with schizophreni or mnic/mixed episodes of bipolr I disorder [see CLINICAL STUDIES (14.6)] 14.1 Schizophreni Adults The efficcy of ABILIFY in the tretment of schizophreni ws evluted in five short-term (4-week nd 6-week), plcebo-controlled trils of cutely relpsed inptients who predominntly met DSM-III/IV criteri for schizophreni. Four of the five trils were ble to distinguish ABILIFY from plcebo, but one study, the smllest, did not. Three of these studies lso included n ctive control group consisting of either risperidone (one tril) or hloperidol (two trils), but they were not designed to llow for comprison of ABILIFY nd the ctive comprtors. In the four positive trils for ABILIFY, four primry mesures were used for ssessing psychitric signs nd symptoms. Efficcy ws evluted using the totl score on the Positive nd Negtive Syndrome Scle (PANSS). The PANSS is 30 item scle tht mesures positive symptoms of schizophreni (7 items), negtive symptoms of schizophreni (7 items), nd generl psychopthology (16 items), ech rted on scle of 1 (bsent) to 7 (extreme); totl PANSS scores rnge from 30 to 210. The Clinicl Globl Impression (CGI) ssessment reflects the impression of skilled observer, fully fmilir with the mnifesttions of schizophreni, bout the overll clinicl stte of the ptient. In 4-week tril (n=414) compring two fixed doses of ABILIFY (15 or 30 mg/dy) to plcebo, both doses of ABILIFY were superior to plcebo in the PANSS totl score (Study 1 in Tble 26), PANSS positive subscle, nd CGI-severity score. In ddition, the 15 mg dose ws superior to plcebo in the PANSS negtive subscle. In 4-week tril (n=404) compring two fixed doses of ABILIFY (20 or 30 mg/dy) to plcebo, both doses of ABILIFY were superior to plcebo in the PANSS totl score (Study 2 in Tble 26), PANSS positive subscle, PANSS negtive subscle, nd CGI-severity score. In 6-week tril (n=420) compring three fixed doses of ABILIFY (10, 15, or 20 mg/dy) to plcebo, ll three doses of ABILIFY were superior to plcebo in the PANSS totl score (Study 3 in Tble 26), PANSS positive subscle, nd the PANSS negtive subscle. In 6-week tril (n=367) compring three fixed doses of ABILIFY (2, 5, or 10 mg/dy) to plcebo, the 10 mg dose of ABILIFY ws superior to plcebo in the PANSS totl score (Study 4 in Tble 26), the primry outcome mesure of the study. The 2 nd 5 mg doses did not demonstrte superiority to plcebo on the primry outcome mesure. Thus, the efficcy of 10, 15, 20, nd 30 mg dily doses ws estblished in two studies for ech dose. Among these doses, there ws no evidence tht the higher dose groups offered ny dvntge over the lowest dose group of these studies. An exmintion of popultion subgroups did not revel ny cler evidence of differentil responsiveness on the bsis of ge, gender, or rce. A longer-term tril enrolled 310 inptients or outptients meeting DSM-IV criteri for schizophreni who were, by history, symptomticlly stble on other ntipsychotic medictions for periods of 3 months or longer. These ptients were discontinued from their ntipsychotic medictions nd rndomized to ABILIFY 15 mg/dy or plcebo for up to 26 weeks of observtion for relpse. Relpse during the double-blind phse ws defined s CGI-Improvement score of 5 (minimlly worse), scores 5 (modertely severe) on the hostility or uncpertiveness items of the PANSS, or 20% increse in the PANSS totl score. Ptients receiving ABILIFY 15 mg/dy experienced significntly longer time to relpse over the subsequent 26 weeks compred to those receiving plcebo (Study 5 in Figure 6). Peditric Ptients The efficcy of ABILIFY (ripiprzole) in the tretment of schizophreni in peditric ptients (13 to 17 yers of ge) ws evluted in one 6-week, plcebo-controlled tril of outptients who met DSM-IV criteri for schizophreni nd hd PANSS score 70 t bseline. In this tril (n=302) compring two fixed doses of ABILIFY (10 or 30 mg/dy) to plcebo, ABILIFY ws titrted strting from 2 mg/dy to the trget dose in 5 dys in the 10 mg/dy tretment rm nd in 11 dys in the 30 mg/dy tretment rm. Both doses of ABILIFY were superior to plcebo in the PANSS totl score (Study 6 in Tble 26), the primry outcome mesure of the study. The 30 mg/dy dosge ws not shown to be more efficcious thn the 10 mg/dy dose. Although mintennce efficcy in peditric ptients hs not been systemticlly evluted, mintennce efficcy cn be extrpolted from dult dt long with comprisons of ripiprzole phrmcokinetic prmeters in dult nd peditric ptients. 16

17 Tble 26: Schizophreni Studies Study Number Tretment Group Primry Efficcy Mesure: PANSS LS Men subtrcted Chnge from Bseline Difference (SE) (95% CI) Men Bseline Score (SD) Study 1 ABILIFY (15 mg/dy)* 98.5 (17.2) (2.40) (-18.9, -6.2) ABILIFY (30 mg/dy)* 99.0 (19.2) (2.39) -8.5 (-14.8, -2.1) (16.5) -2.9 (2.36) Study 2 ABILIFY (20 mg/dy)* 92.6 (19.5) (2.23) -9.6 (-15.4, -3.8) ABILIFY (30 mg/dy)* 94.2 (18.5) (2.24) -9.0 (-14.8, -3.1) 94.3 (18.5) -5.0 (2.17) Study 3 ABILIFY (10 mg/dy)* 92.7 (19.5) (2.38) (-19.00, -6.41) ABILIFY (15 mg/dy)* 93.2 (21.6) (2.38) -9.4 (-15.71, -3.08) ABILIFY (20 mg/dy)* 92.5 (20.9) (2.45) (-18.53, -5.68) (21.8) (2.35) Study 4 ABILIFY (2 mg/dy) 90.7 (14.5) -8.2 (1.90) -2.9 (-8.29, 2.47) ABILIFY (5 mg/dy) 92.0 (12.6) (1.93) -5.2 (-10.7, 0.19) ABILIFY (10 mg/dy)* 90.0 (11.9) (1.88) -5.9 (-11.3, -0.58) 90.8 (13.3) -5.3 (1.97) Study 6 (Peditric, ABILIFY (10 mg/dy)* 93.6 (15.7) (1.91) -5.5 (-10.7, -0.21) yers) ABILIFY (30 mg/dy)* (16.1) (1.92) (-12.7, -2.13) 94.6 (15.6) (1.93) SD: stndrd devition; SE: stndrd error; LS Men: lest-squres men; CI: undjusted confidence intervl. Difference (drug minus plcebo) in lest-squres men chnge from bseline. * Doses sttisticlly significntly superior to plcebo. Figure 6: Kpln-Meier Estimtion of Cumultive Proportion of Ptients with Relpse (Schizophreni Study 5) Proportion with Relpse Number of Subjects t Risk ABILIFY PLACEBO ABILIFY PLACEBO Dys from Rndomiztion 14.2 Bipolr Disorder Acute Tretment of Mnic nd Mixed Episodes Adults Monotherpy The efficcy of ABILIFY s monotherpy in the cute tretment of mnic episodes ws estblished in four 3-week, plcebo-controlled trils in hospitlized ptients who met the DSM-IV criteri for bipolr I disorder with mnic or mixed episodes. These studies included ptients with or without psychotic fetures nd two of the studies lso included ptients with or without rpid-cycling course. 17 The primry instrument used for ssessing mnic symptoms ws the Young Mni Rting Scle (Y-MRS), n 11-item clinicin-rted scle trditionlly used to ssess the degree of mnic symptomtology in rnge from 0 (no mnic fetures) to 60 (mximum score). A key secondry instrument included the Clinicl Globl Impression-Bipolr (CGI-BP) Scle. In the four positive, 3-week, plcebo-controlled trils (n=268; n=248; n=480; n=485) which evluted ABILIFY in rnge of 15 mg to 30 mg, once dily (with strting dose of 30 mg/dy in two studies nd 15 mg/dy in two studies), ABILIFY ws superior to plcebo in the reduction of Y-MRS totl score (Studies 1-4 in Tble 27) nd CGI-BP Severity of Illness score (mni). In the two studies with strting dose of 15 mg/dy, 48% nd 44% of ptients were on 15 mg/dy t endpoint. In the two studies with strting dose of 30 mg/dy, 86% nd 85% of ptients were on 30 mg/dy t endpoint. Adjunctive Therpy The efficcy of djunctive ABILIFY with concomitnt lithium or vlprote in the tretment of mnic or mixed episodes ws estblished in 6-week, plcebo-controlled study (n=384) with 2-week led-in md stbilizer monotherpy phse in dult ptients who met DSM-IV criteri for bipolr I disorder. This study included ptients with mnic or mixed episodes nd with or without psychotic fetures. Ptients were initited on open-lbel lithium (0.6 to 1.0 meq/l) or vlprote (50 to 125 μg/ml) t therpeutic serum levels, nd remined on stble doses for 2 weeks. At the end of 2 weeks, ptients demonstrting indequte response (Y-MRS totl score 16 nd 25% improvement on the Y-MRS totl score) to lithium or vlprote were rndomized to receive either ABILIFY (15 mg/dy or n increse to 30 mg/dy s erly s dy 7) or plcebo s djunctive therpy with open-lbel lithium or vlprote. In the 6-week, plcebocontrolled phse, djunctive ABILIFY strting t 15 mg/dy with concomitnt lithium or vlprote (in therpeutic rnge of 0.6 to 1.0 meq/l or 50 to 125 μg/ml, respectively) ws superior to lithium or vlprote with djunctive plcebo in the reduction of the Y-MRS totl score (Study 5 in Tble 27) nd CGI-BP Severity of Illness score (mni). Seventy-one percent of the ptients codministered vlprote nd 62% of the ptients codministered lithium were on 15 mg/dy t 6-week endpoint. Peditric Ptients The efficcy of ABILIFY in the tretment of bipolr I disorder in peditric ptients (10 to 17 yers of ge) ws evluted in one 4-week, plcebo-controlled tril (n=296) of outptients who met DSM-IV criteri for bipolr I disorder mnic or mixed episodes with or without psychotic fetures nd hd Y-MRS score 20 t bseline. This double-blind, plcebo-controlled tril compred two fixed doses of ABILIFY (10 or 30 mg/dy) to plcebo. The ABILIFY dose ws strted t 2 mg/dy, which ws titrted to 5 mg/dy fter 2 dys, nd to the trget dose in 5 dys in the 10 mg/dy tretment rm, nd in 13 dys in the 30 mg/dy tretment rm. Both doses of ABILIFY were superior to plcebo in chnge from bseline to week 4 on the Y-MRS totl score (Study 6 in Tble 27). Tble 27: Bipolr Studies Study Number Study 1 Study 2 Study 3 Tretment Group ABILIFY (30/15 mg/dy)* ABILIFY (30/15 mg/dy)* ABILIFY (15-30 mg/dy)* Primry Efficcy Mesure: Y-MRS LS Men Chnge from Bseline (SE) Men Bseline Score (SD) 29.0 (5.9) 28.5 (4.6) 27.8 (5.7) 29.1 (6.9) 28.5 (5.6) 28.9 (5.9) (1.05) (1.07) (1.23) (1.22) (0.84) 9.01 (0.81) subtrcted Difference (95% CI) (-7.90, -2.76) (-7.80, -1.80) (-5.75, -1.51) Study 4 ABILIFY (15-30 mg/dy)* 28.0 (5.8) (0.80) (-4.44, -0.11) 28.3 (5.8) (0.83) Study 5 ABILIFY (15 or 30 mg/dy)* + Lithium/Vlprote 23.2 (5.7) (0.50) (-4.29, -0.95) Lithium/Vlprote (4.9) (0.69) Study 6 (Peditric, ABILIFY (10 mg/dy)* 29.8 (6.5) (0.89) (-8.49, -3.50) yers) ABILIFY (30 mg/dy)* (6.3) (0.87) (-10.7, -5.77) 30.7 (6.8) -8.2 (0.91) SD: stndrd devition; SE: stndrd error; LS Men: lest-squres men; CI: undjusted confidence intervl. Difference (drug minus plcebo) in lest-squres men chnge from bseline. * Doses sttisticlly significntly superior to plcebo.

18 Mintennce Tretment of Bipolr I Disorder Monotherpy Mintennce Therpy A mintennce tril ws conducted in dult ptients meeting DSM-IV criteri for bipolr I disorder with recent mnic or mixed episode who hd been stbilized on open-lbel ABILIFY nd who hd mintined clinicl response for t lest 6 weeks. The first phse of this tril ws n open-lbel stbiliztion period in which inptients nd outptients were cliniclly stbilized nd then mintined on open-lbel ABILIFY (15 or 30 mg/dy, with strting dose of 30 mg/dy) for t lest 6 consecutive weeks. One hundred sixty-one outptients were then rndomized in double-blind fshion, to either the sme dose of ABILIFY they were on t the end of the stbiliztion nd mintennce period or plcebo nd were then monitored for mnic or depressive relpse. During the rndomiztion phse, ABILIFY ws superior to plcebo on time to the number of combined ffective relpses (mnic plus depressive), the primry outcome mesure for this study (Study 7 in Figure 7). A totl of 55 md events were observed during the double-blind tretment phse. Nineteen were from the ABILIFY group nd 36 were from the plcebo group. The number of observed mnic episodes in the ABILIFY group (6) were fewer thn tht in the plcebo group (19), while the number of depressive episodes in the ABILIFY group (9) ws similr to tht in the plcebo group (11). An exmintion of popultion subgroups did not revel ny cler evidence of differentil responsiveness on the bsis of ge nd gender; however, there were insufficient numbers of ptients in ech of the ethnic groups to dequtely ssess inter-group differences. Figure 7: Kpln-Meier Estimtion of Cumultive Proportion of Ptients with Relpse (Bipolr Study 7) Proportion with Relpse ABILIFY PLACEBO ABILIFY PLACEBO Number of Subjects t Risk Dys from Rndomiztion Adjunctive Mintennce Therpy An djunctive mintennce tril ws conducted in dult ptients meeting DSM-IV criteri for bipolr I disorder with recent mnic or mixed episode. Ptients were initited on open-lbel lithium (0.6 to 1.0 meq/l) or vlprote (50 to 125 μg/ml) t therpeutic serum levels, nd remined on stble doses for 2 weeks. At the end of 2 weeks, ptients demonstrting indequte response (Y-MRS totl score 16 nd 35% improvement on the Y-MRS totl score) to lithium or vlprote received ABILIFY with strting dose of 15 mg/dy with the option to increse to 30 mg or reduce to 10 mg s erly s dy 4, s djunctive therpy with open-lbel lithium or vlprote. Prior to rndomiztion, ptients on the combintion of single-blind ABILIFY nd lithium or vlprote were required to mintin stbility (Y-MRS nd MADRS totl scores 12) for 12 consecutive weeks. Three hundred thirty-seven ptients were then rndomized in double-blind fshion, to either the sme dose of ABILIFY they were on t the end of the stbiliztion period or plcebo plus lithium or vlprote nd were then monitored for mnic, mixed, or depressive relpse for mximum of 52 weeks. ABILIFY ws superior to plcebo on the primry endpoint, time from rndomiztion to relpse to ny md event (Study 8 in Figure 8). A md event ws defined s hospitliztion for mnic, mixed, or depressive episode, study discontinution due to lck of efficcy ccompnied by Y-MRS score >16 nd/or MADRS >16, or n SAE of worsening disese ccompnied by Y-MRS score >16 nd/or MADRS >16. A totl of 68 md events were observed during the double-blind tretment phse. Twenty-five were from the ABILIFY group nd 43 were from the plcebo group. The number of observed mnic episodes in the ABILIFY group (7) were fewer thn tht in the plcebo group (19), while the number of depressive episodes in the ABILIFY group (14) ws similr to tht in the plcebo group (18). The Kpln-Meier curves of the time from rndomiztion to relpse to ny md event during the 52-week, double-blind tretment phse for ABILIFY nd plcebo groups re shown in Figure 8. Figure 8: Kpln-Meier Estimtion of Cumultive Proportion of Ptients with Relpse to Any Md Event (Bipolr Study 8) Proportion with Relpse ABILIFY PLACEBO Number of Subjects t Risk Dys from Rndomiztion ABILIFY PLACEBO An exmintion of popultion subgroups did not revel ny cler evidence of differentil responsiveness on the bsis of ge nd gender; however, there were insufficient numbers of ptients in ech of the ethnic groups to dequtely ssess inter-group differences Adjunctive Tretment of Mjor Depressive Disorder Adults The efficcy of ABILIFY in the djunctive tretment of mjor depressive disorder (MDD) ws demonstrted in two short-term (6-week), plcebo-controlled trils of dult ptients meeting DSM-IV criteri for MDD who hd hd n indequte response to prior ntidepressnt therpy (1 to 3 courses) in the current episode nd who hd lso demonstrted n indequte response to 8 weeks of prospective ntidepressnt therpy (proxetine controlled-relese, venlfxine extended-relese, fluoxetine, escitloprm, or sertrline). Indequte response for prospective tretment ws defined s less thn 50% improvement on the 17-item version of the Hmilton Depression Rting Scle (HAMD17), miniml HAMD17 score of 14, nd Clinicl Globl Impressions Improvement rting of no better thn miniml improvement. Indequte response to prior tretment ws defined s less thn 50% improvement s perceived by the ptient fter minimum of 6 weeks of ntidepressnt therpy t or bove the miniml effective dose. The primry instrument used for ssessing depressive symptoms ws the Montgomery-Asberg Depression Rting Scle (MADRS), 10-item clinicin-rted scle used to ssess the degree of depressive symptomtology. The key secondry instrument ws the Sheehn Disbility Scle (SDS), 3-item self-rted instrument used to ssess the impct of depression on three domins of functioning with ech item scored from 0 (not t ll) to 10 (extreme). In the two trils (n=381, n=362), ABILIFY ws superior to plcebo in reducing men MADRS totl scores (Studies 1, 2 in Tble 28). In one study, ABILIFY ws lso superior to plcebo in reducing the men SDS score. In both trils, ptients received ABILIFY djunctive to ntidepressnts t dose of 5 mg/dy. Bsed on tolerbility nd efficcy, doses could be djusted by 5 mg increments, one week prt. Allowble doses were: 2, 5, 10, 15 mg/dy, nd for ptients who were not on potent CYP2D6 inhibitors fluoxetine nd proxetine, 20 mg/dy. The men finl dose t the end point for the two trils ws 10.7 nd 11.4 mg/dy. An exmintion of popultion subgroups did not revel evidence of differentil response bsed on ge, choice of prospective ntidepressnt, or rce. With regrd to gender, smller men reduction on the MADRS totl score ws seen in mles thn in femles. 18

19 Tble 28: Adjunctive Tretment of Mjor Depressive Disorder Studies Study Number Tretment Group Primry Efficcy Mesure: MADRS Study 1 Study 2 ABILIFY (5-20 mg/dy)* + Antidepressnt + Antidepressnt ABILIFY (5-20 mg/dy)* + Antidepressnt + Antidepressnt Men Bseline Score (SD) 25.2 (6.2) 27.0 (5.5) 26.0 (6.0) 26.0 (6.5) LS Men Chnge from Bseline (SE) (0.66) (0.64) (0.63) (0.67) subtrcted Difference (95% CI) (-4.53, -1.15) (-4.66, -1.37) SD: stndrd devition; SE: stndrd error; LS Men: lest-squres men; CI: undjusted confidence intervl. Difference (drug minus plcebo) in lest-squres men chnge from bseline. * Doses sttisticlly significntly superior to plcebo Irritbility Associted with Autistic Disorder Peditric Ptients The efficcy of ABILIFY (ripiprzole) in the tretment of irritbility ssocited with utistic disorder ws estblished in two 8-week, plcebo-controlled trils in peditric ptients (6 to 17 yers of ge) who met the DSM-IV criteri for utistic disorder nd demonstrted behviors such s tntrums, ggression, self-injurious behvior, or combintion of these problems. Over 75% of these subjects were under 13 yers of ge. Efficcy ws evluted using two ssessment scles: the Aberrnt Behvior Checklist (ABC) nd the Clinicl Globl Impression-Improvement (CGI-I) scle. The primry outcome mesure in both trils ws the chnge from bseline to endpoint in the Irritbility subscle of the ABC (ABC-I). The ABC-I subscle mesured symptoms of irritbility in utistic disorder. The results of these trils re s follows: In one of the 8-week, plcebo-controlled trils, children nd dolescents with utistic disorder (n=98), ged 6 to 17 yers, received dily doses of plcebo or ABILIFY 2 to 15 mg/dy. ABILIFY, strting t 2 mg/dy with increses llowed up to 15 mg/dy bsed on clinicl response, significntly improved scores on the ABC-I subscle nd on the CGI-I scle compred with plcebo. The men dily dose of ABILIFY t the end of 8-week tretment ws 8.6 mg/dy (Study 1 in Tble 29). In the other 8-week, plcebo-controlled tril in children nd dolescents with utistic disorder (n=218), ged 6 to 17 yers, three fixed doses of ABILIFY (5 mg/dy, 10 mg/dy, or 15 mg/dy) were compred to plcebo. ABILIFY dosing strted t 2 mg/dy nd ws incresed to 5 mg/dy fter one week. After second week, it ws incresed to 10 mg/dy for ptients in the 10 nd 15 mg dose rms, nd fter third week, it ws incresed to 15 mg/dy in the 15 mg/dy tretment rm (Study 2 in Tble 29). All three doses of ABILIFY significntly improved scores on the ABC-I subscle compred with plcebo. Tble 29: Irritbility Associted with Autistic Disorder Studies (Peditric) Study Number Study 1 Study 2 Tretment Group ABILIFY (2-15 mg/dy)* ABILIFY (5 mg/dy)* ABILIFY (10 mg/dy)* ABILIFY (15 mg/dy)* Men Bseline Score (SD) 29.6 (6.37) 30.2 (6.52) 28.6 (7.56) 28.2 (7.36) 28.9 (6.41) 28.0 (6.89) Primry Efficcy Mesure: ABC-I LS Men Chnge from Bseline (SE) (1.44) -5.0 (1.43) (1.36) (1.25) (1.31) -8.4 (1.39) subtrcted Difference (95% CI) -7.9 (-11.7, -4.1) -4.0 (-7.7, -0.4) -4.8 (-8.4, -1.3) -6.0 (-9.6, -2.3) SD: stndrd devition; SE: stndrd error; LS Men: lest-squres men; CI: undjusted confidence intervl. Difference (drug minus plcebo) in lest-squres men chnge from bseline. * Doses sttisticlly significntly superior to plcebo Tourette s Disorder Peditric Ptients The efficcy of ABILIFY (ripiprzole) in the tretment of Tourette s disorder ws estblished in one 8-week (7 to 17 yers of ge) nd one 10-week (6 to 18 yers of ge), plcebo-controlled trils in peditric ptients (6 to 18 yers of ge) who met the DSM-IV criteri for Tourette s disorder nd hd Totl Tic score (TTS) on the Yle Globl Tic Severity Scle (YGTSS). The YGTSS is fully vlidted scle designed to mesure current tic severity. Efficcy ws evluted using two ssessment scles: 1) the Totl Tic score (TTS) of the YGTSS nd 2) the Clinicl Globl Impressions Scle for Tourette s Syndrome (CGI-TS), clinicin-determined summry mesure tht tkes into ccount ll vilble ptient informtion. Over 65% of these ptients were under 13 yers of ge. The primry outcome mesure in both trils ws the chnge from bseline to endpoint in the TTS of the YGTSS. Rtings for the TTS re mde long 5 different dimensions on scle of 0 to 5 for motor nd vocl tics ech. Summtion of these 10 scores provides TTS (i.e., 0-50). The results of these trils re s follows: In the 8-week, plcebo-controlled, fixed-dose tril, children nd dolescents with Tourette s disorder (n=133), ged 7 to 17 yers, were rndomized 1:1:1 to low dose ABILIFY, high dose ABILIFY, or plcebo. The trget doses for the low nd high dose ABILIFY groups were bsed on weight. Ptients < 50 kg in the low dose ABILIFY group strted t 2 mg per dy with trget dose of 5 mg per dy fter 2 dys. Ptients 50 kg in the low dose ABILIFY group, strted t 2 mg per dy incresed to 5 mg per dy fter 2 dys, with subsequent increse to trget dose of 10 mg per dy t dy 7. Ptients <50 kg in the high dose ABILIFY group strted t 2 mg per dy incresed to 5 mg per dy fter 2 dys, with subsequent increse to trget dose of 10 mg per dy t dy 7. Ptients 50 kg in the high dose ABILIFY group, strted t 2 mg per dy incresed to 5 mg per dy fter 2 dys, with subsequent increse to dose of 10 mg per dy t dy 7 nd were llowed weekly increses of 5 mg per dy up to trget dose 20 mg per dy t Dy 21. ABILIFY (both high nd low dose groups) demonstrted sttisticlly significntly improved scores on the YGTSS TTS (Study 1 in Tble 30) nd on the CGI-TS scle compred with plcebo. The estimted improvements on the YGTSS TTS over the course of the study re displyed in Figure 9. Figure 9: Lest Squre Mens of Chnge from Bseline in YGTSS TTS by Week (Tourette s Disorder Study 1) Lest-Squres Men Chnge in YGTSS Totl TIC Score CHANGE IN YGTSS TOTAL TIC SCORE FROM BASELINE ABILIFY LOW ABILIFY HIGH PLACEBO Weeks of Tretment In the 10-week, plcebo-controlled, flexible-dose tril in children nd dolescents with Tourette s disorder (n=61), ged 6 to 18 yers, ptients received dily doses of plcebo or ABILIFY, strting t 2 mg/dy with increses llowed up to 20 mg/dy bsed on clinicl response. ABILIFY demonstrted sttisticlly significntly improved scores on the YGTSS TTS scle compred with plcebo (Study 2 in Tble 30). The men dily dose of ABILIFY t the end of 10-week tretment ws 6.54 mg/dy. 19

20 Tble 30: Tourette s Disorder Studies (Peditric) Study Primry Efficcy Mesure: YGTSS TTS Number Tretment Group Men LS Men subtrcted Bseline Score (SD) Chnge from Bseline (SE) Difference (95% CI) Study 1 Study 2 ABILIFY (low dose)* ABILIFY (high dose)* ABILIFY (2-20 mg/dy)* 29.2 (5.63) 31.2 (6.40) 30.7 (5.95) 28.3 (5.51) 29.5 (5.60) (1.59) (1.61) -7.1 (1.55) (1.51) -9.6 (1.64) -6.3 (-10.2, -2.3) -9.9 (-13.8, -5.9) -5.3 (-9.8, -0.9) SD: stndrd devition; SE: stndrd error; LS Men: lest-squres men; CI: undjusted confidence intervl. Difference (drug minus plcebo) in lest-squres men chnge from bseline. * Doses sttisticlly significntly superior to plcebo Agittion Associted with Schizophreni or Bipolr Mni The efficcy of intrmusculr ABILIFY for injection for the tretment of gittion ws estblished in three short-term (24-hour), plcebo-controlled trils in gitted inptients from two dignostic groups: schizophreni nd bipolr I disorder (mnic or mixed episodes, with or without psychotic fetures). Ech of the trils included single ctive comprtor tretment rm of either hloperidol injection (schizophreni studies) or lorzepm injection (bipolr mni study). Ptients could receive up to three injections during the 24-hour tretment periods; however, ptients could not receive the second injection until fter the initil 2-hour period when the primry efficcy mesure ws ssessed. Ptients enrolled in the trils needed to be: (1) judged by the clinicl investigtors s cliniclly gitted nd cliniclly pproprite cndidtes for tretment with intrmusculr mediction, nd (2) exhibiting level of gittion tht met or exceeded threshold score of 15 on the five items comprising the Positive nd Negtive Syndrome Scle (PANSS) Excited Component (i.e., pr impulse control, tension, hostility, uncpertiveness, nd excitement items) with t lest two individul item scores 4 using 1-7 scoring system (1 = bsent, 4 = moderte, 7 = extreme). In the studies, the men bseline PANSS Excited Component score ws 19, with scores rnging from 15 to 34 (out of mximum score of 35), 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 2 hours post-injection. A key secondry mesure ws the Clinicl Globl Impression of Improvement (CGI-I) Scle. The results of the trils follow: In plcebo-controlled tril in gitted inptients predominntly meeting DSM-IV criteri for schizophreni (n=350), four fixed ABILIFY injection doses of 1 mg, 5.25 mg, 9.75 mg, nd 15 mg were evluted. At 2 hours post-injection, the 5.25 mg, 9.75 mg, nd 15 mg doses were sttisticlly superior to plcebo in the PANSS Excited Component (Study 1 in Tble 31) nd on the CGI-I Scle. In second plcebo-controlled tril in gitted inptients predominntly meeting DSM-IV criteri for schizophreni (n=445), one fixed ABILIFY injection dose of 9.75 mg ws evluted. At 2 hours post-injection, ABILIFY for injection ws sttisticlly superior to plcebo in the PANSS Excited Component (Study 2 in Tble 31) nd on the CGI-I Scle. In plcebo-controlled tril in gitted inptients meeting DSM-IV criteri for bipolr I disorder (mnic or mixed) (n=291), two fixed ABILIFY injection doses of 9.75 mg nd 15 mg were evluted. At 2 hours post-injection, both doses were sttisticlly superior to plcebo in the PANSS Excited Component (Study 3 in Tble 31). Exmintion of popultion subsets (ge, rce, nd gender) did not revel ny differentil responsiveness on the bsis of these subgroupings. Tble 31: Study Number Agittion Associted with Schizophreni or Bipolr Mni Studies Tretment Group Agittion Associted with Schizophreni Study 1 Study 2 ABILIFY (1 mg) ABILIFY (5.25 mg)* ABILIFY (9.75 mg)* ABILIFY (15 mg)* ABILIFY (9.75 mg)* Agittion Associted with Bipolr Mni Study 3 ABILIFY (9.75 mg)* ABILIFY (15 mg)* Men Bseline Score (SD) (3.26) (3.31) (2.80) (2.38) (2.95) (2.67) (2.71) (2.45) (2.49) (2.63) Primry Efficcy Mesure: PANSS Excited Component LS Men Chnge from Bseline (SE) (0.72) (0.68) (0.72) (0.72) (0.70) (0.59) (0.69) (0.57) (0.57) (0.58) subtrcted Difference (95% CI) (-2.96, 0.59) (-4.10, -0.63) (-5.18, -1.62) (-4.21, -0.68) (-3.77, -1.19) (-4.53, -1.44) (-4.44, -1.38) SD: stndrd devition; SE: stndrd error; LS Men: lest-squres men; CI: undjusted confidence intervl. Difference (drug minus plcebo) in lest-squres men chnge from bseline. * Doses sttisticlly significntly superior to plcebo. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tblets hve mrkings on one side nd re vilble in the strengths nd pckges listed in Tble 32. Tble 32: ABILIFY Tblet Presenttions Tblet Tblet Tblet Pck NDC Strength Color/Shpe Mrkings Size Code 2 mg green A-006 Bottle of modified rectngle nd 2 5 mg blue A-007 Bottle of modified rectngle nd 5 Blister of mg pink A-008 Bottle of modified rectngle nd 10 Blister of mg yellow A-009 Bottle of round nd 15 Blister of mg white A-010 Bottle of round nd 20 Blister of mg pink A-011 Bottle of round nd 30 Blister of ABILIFY DISCMELT (ripiprzole) Orlly Disintegrting Tblets re round tblets with mrkings on either side. ABILIFY DISCMELT is vilble in the strengths nd pckges listed in Tble 33. Tble 33: ABILIFY DISCMELT Orlly Disintegrting Tblet Presenttions Tblet Tblet Tblet Pck NDC Strength Color Mrkings Size Code 10 mg pink A nd 640 Blister of (with scttered specks) mg yellow A nd 641 Blister of (with scttered specks) 15 20

21 Orl Solution (1 mg/ml) is supplied in child-resistnt bottles long with clibrted orl dosing cup. ABILIFY Orl Solution is vilble s follows: 150 ml bottle NDC Injection for intrmusculr use is vilble s redy-to-use, 9.75 mg/1.3 ml (7.5 mg/ml) solution in cler, Type 1 glss vils s follows: 9.75 mg/1.3 ml single-dose vil NDC Storge Tblets Store t 25 C (77 F); excursions permitted between 15 C to 30 C (59 F to 86 F) [see USP Controlled Rm Temperture]. Orl Solution Store t 25 C (77 F); excursions permitted between 15 C to 30 C (59 F to 86 F) [see USP Controlled Rm Temperture]. Opened bottles of ABILIFY Orl Solution cn be used for up to 6 months fter opening, but not beyond the expirtion dte on the bottle. The bottle nd its contents should be discrded fter the expirtion dte. Injection Store t 25 C (77 F); excursions permitted between 15 C to 30 C (59 F to 86 F) [see USP Controlled Rm Temperture]. Protect from light by storing in the originl continer. Retin in crton until time of use. 17 PATIENT COUNSELING INFORMATION See Mediction Guide Discuss the following issues with ptients prescribed ABILIFY: Clinicl Worsening of Depression nd Suicide Risk Ptients, their fmilies, nd their cregivers should be encourged to be lert to the emergence of nxiety, gittion, pnic ttcks, insomni, irritbility, hostility, ggressiveness, impulsivity, kthisi (psychomotor restlessness), hypomni, mni, other unusul chnges in behvior, worsening of depression, nd suicidl idetion, especilly erly during ntidepressnt tretment nd when the dose is djusted up or down. Fmilies nd cregivers of ptients should be dvised to lk for the emergence of such symptoms on dy-to-dy bsis, since chnges my be brupt. Such symptoms should be reported to the ptient s prescriber or helth professionl, especilly if they re severe, brupt in onset, or were not prt of the ptient s presenting symptoms. Symptoms such s these my be ssocited with n incresed risk for suicidl thinking nd behvior nd indicte need for very close monitoring nd possibly chnges in the mediction [see WARNINGS AND PRECAUTIONS (5.3)]. Prescribers or other helth professionls should inform ptients, their fmilies, nd their cregivers bout the benefits nd risks ssocited with tretment with ABILIFY nd should counsel them in its pproprite use. A ptient Mediction Guide including informtion bout Antidepressnt Medicines, Depression nd other Serious Mentl Illness, nd Suicidl Thoughts or Actions is vilble for ABILIFY. The prescriber or helth professionl 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. It should be noted tht ABILIFY is not pproved s single gent for tretment of depression nd hs not been evluted in peditric mjor depressive disorder. Pthologicl Gmbling nd Other Compulsive Behviors Advise ptients nd their cregivers of the possibility tht they my experience compulsive urges to shop, intense urges to gmble, compulsive sexul urges, binge eting nd/or other compulsive urges nd the inbility to control these urges while tking ripiprzole. In some cses, but not ll, the urges were reported to hve stopped when the dose ws reduced or stopped [see WARNINGS AND PRECAUTIONS, (5.7)]. Use of Orlly Disintegrting Tblet Do not open the blister until redy to dminister. For single tblet removl, open the pckge nd peel bck the foil on the blister to expose the tblet. Do not push the tblet through the foil becuse this could dmge the tblet. Immeditely upon opening the blister, using dry hnds, remove the tblet nd plce the entire ABILIFY DISCMELT Orlly Disintegrting Tblet on the tongue. Tblet disintegrtion occurs rpidly in sliv. It is recommended tht ABILIFY DISCMELT be tken without liquid. However, if needed, it cn be tken with liquid. Do not ttempt to split the tblet. Interference with Cognitive nd Motor Performnce Becuse ABILIFY my hve 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 ABILIFY therpy does not ffect them dversely [see WARNINGS AND PRECAUTIONS (5.11)]. Nursing Advise ptients tht brestfeeding is not recommended with ABILIFY tretment becuse of the potentil for serious dverse rections in nursing infnt [see USE IN SPECIFIC POPULATIONS (8.3)]. Concomitnt Mediction Ptients should be dvised to inform their physicins if they re tking, or pln to tke, ny prescription or over-the-counter drugs, since there is potentil for interctions [see DRUG INTERACTIONS (7)]. Het Exposure nd Dehydrtion Ptients should be dvised regrding pproprite cre in voiding overheting nd dehydrtion [see WARNINGS AND PRECAUTIONS (5.12)]. Sugr Content Ptients should be dvised tht ech ml of ABILIFY Orl Solution contins 400 mg of sucrose nd 200 mg of fructose. Phenylketonurics Phenyllnine is component of sprtme. Ech ABILIFY DISCMELT Orlly Disintegrting Tblet contins the following mounts: 10 mg, 1.12 mg phenyllnine nd 15 mg, 1.68 mg phenyllnine. Tblets mnufctured by Otsuk Phrmceuticl Co., Ltd., Tokyo, Jpn Orlly Disintegrting Tblets, Orl Solution, nd Injection mnufctured by Bristol-Myers Squibb Compny, Princeton, NJ USA Distributed nd mrketed by Otsuk Americ Phrmceuticl, Inc., Rockville, MD USA ABILIFY is trdemrk of Otsuk Phrmceuticl Compny. Rev August , Otsuk Phrmceuticl Co., Ltd., Tokyo, Jpn 03US16IBR

22 MEDICATION GUIDE ABILIFY ( BIL ĭ fī) ABILIFY ( BIL ĭ fī) ABILIFY ( BIL ĭ fī) ABILIFY ( BIL ĭ fī) (ripiprzole) (ripiprzole) (ripiprzole) (ripiprzole) Tblets Orlly Disintegrting Tblets Orl Solution Injection, for intrmusculr use Wht is the most importnt informtion I should know bout ABILIFY? (For other side effects, lso see Wht re the possible side effects of ABILIFY? ) Serious side effects my hppen when you tke ABILIFY, including: Incresed risk of deth in elderly ptients with dementi-relted psychosis: Medicines like ABILIFY cn rise the risk of deth in elderly people who hve lost touch with relity (psychosis) due to confusion nd memory loss (dementi). ABILIFY is not pproved for the tretment of ptients with dementi-relted psychosis. Risk of suicidl thoughts or ctions: Antidepressnt medicines, depression nd other serious mentl illnesses, nd suicidl thoughts or ctions: 1. Antidepressnt medicines my increse suicidl thoughts or ctions in some children, teengers, nd young dults within the first few months of tretment. 2. Depression nd other serious mentl illnesses re the most importnt cuses of suicidl thoughts nd ctions. Some people my hve prticulrly high risk of hving suicidl thoughts or ctions. These include people who hve (or hve fmily history of) bipolr illness (lso clled mnic-depressive illness) or suicidl thoughts or ctions. 3. How cn I wtch for nd try to prevent suicidl thoughts nd ctions in myself or fmily member? Py close ttention to ny chnges, especilly sudden chnges, in md, behviors, thoughts, or feelings. This is very importnt when n ntidepressnt medicine is strted or when the dose is chnged. Cll the helthcre provider right wy to report new or sudden chnges in md, behvior, thoughts, or feelings. Keep ll follow-up visits with the helthcre provider s scheduled. Cll the helthcre provider between visits s needed, especilly if you hve concerns bout symptoms. Cll helthcre provider right wy if you or your fmily member hs ny of the following symptoms, especilly if they re new, worse, or worry you: thoughts bout suicide or dying ttempts to commit suicide new or worse depression new or worse nxiety feeling very gitted or restless pnic ttcks trouble sleeping (insomni) new or worse irritbility cting ggressive, being ngry, or violent cting on dngerous impulses n extreme increse in ctivity nd tlking (mni) other unusul chnges in behvior or md Wht else do I need to know bout ntidepressnt medicines? Never stop n ntidepressnt medicine without first tlking to helthcre provider. Stopping n ntidepressnt medicine suddenly cn cuse other symptoms. Antidepressnts re medicines used to tret depression nd other illnesses. It is importnt to discuss ll the risks of treting depression nd lso the risks of not treting it. Ptients nd their fmilies or other cregivers should discuss ll tretment choices with the helthcre provider, not just the use of ntidepressnts. Antidepressnt medicines hve other side effects. Tlk to the helthcre provider bout the side effects of the medicine prescribed for you or your fmily member. Antidepressnt medicines cn interct with other medicines. Know ll of the medicines tht you or your fmily member tkes. Keep list of ll medicines to show the helthcre provider. Do not strt new medicines without first checking with your helthcre provider. Not ll ntidepressnt medicines prescribed for children re FDA pproved for use in children. Tlk to your child s helthcre provider for more informtion. Wht is ABILIFY? ABILIFY Orl Tblets, Orlly-Disintegrting Tblets, nd Orl Solution re prescription medicines used to tret: Schizophreni mnic or mixed episodes tht hppen with bipolr I disorder mjor depressive disorder (MDD) when ABILIFY is used with ntidepressnt medicines irritbility ssocited with utistic disorder Tourette s disorder ABILIFY Injection is prescription medicine used to tret: gittion ssocited with schizophreni or bipolr mni It is not known if ABILIFY is sfe or effective in children: under 13 yers of ge with schizophreni under 10 yers of ge with bipolr I disorder under 6 yers of ge with irritbility ssocited with utistic disorder under 6 yers of ge with Tourette s disorder 22

23 Do not tke ABILIFY if you re llergic to ripiprzole or ny of the ingredients in ABILIFY. See the end of this Mediction Guide for complete list of ingredients in ABILIFY. Before tking ABILIFY, tell your helthcre provider bout ll your medicl conditions, including if you hve or hd: dibetes or high bld sugr in you or your fmily; your helthcre provider should check your bld sugr before you strt ABILIFY nd lso during therpy. seizures (convulsions). low or high bld pressure. hert problems or stroke. pregnncy or plns to become pregnnt. It is not known if ABILIFY will hrm your unborn bby. brest-feeding or plns to brest-feed. ABILIFY cn pss into your brest milk nd my hrm your bby. Tlk to your helthcre provider bout the best wy to feed your bby if you receive ABILIFY. low white bld cell count. phenylketonuri. ABILIFY DISCMELT Orlly Disintegrting Tblets contin phenyllnine. Tell your helthcre provider bout ll the medicines tht you tke, including prescription nd over-the-counter medicines, vitmins, nd herbl supplements. ABILIFY nd other medicines my ffect ech other cusing possible serious side effects. ABILIFY my ffect the wy other medicines work, nd other medicines my ffect how ABILIFY works. Your helthcre provider cn tell you if it is sfe to tke ABILIFY with your other medicines. Do not strt or stop ny medicines while tking ABILIFY without tlking to your helthcre provider first. Know the medicines you tke. Keep list of your medicines to show your helthcre provider nd phrmcist when you get new medicine. How should I tke ABILIFY? Tke ABILIFY exctly s your helthcre provider tells you to tke it. Do not chnge the dose or stop tking ABILIFY yourself. ABILIFY cn be tken with or without fd. ABILIFY tblets should be swllowed whole. If you miss dose of ABILIFY, tke the missed dose s sn s you remember. If it is lmost time for the next dose, just skip the missed dose nd tke your next dose t the regulr time. Do not tke two doses of ABILIFY t the sme time. If you hve been prescribed ABILIFY DISCMELT, tke it s follows: o o Do not open the blister until redy to tke the DISCMELT tblet. o o To remove one DISCMELT tblet, open the pckge nd peel bck the foil on the blister to expose the tblet. o o Do not push the tblet through the foil becuse this could dmge the tblet. o o Immeditely upon opening the blister, using dry hnds, remove the tblet nd plce the entire ABILIFY DISCMELT Orlly Disintegrting Tblet on the tongue. o o Tblet disintegrtion occurs rpidly in sliv. It is recommended tht ABILIFY DISCMELT be tken without liquid. However, if needed, it cn be tken with liquid. Do not ttempt to split the DISCMELT tblet. If you tke t much ABILIFY, cll your helthcre provider or poison control center t right wy, or go to the nerest hospitl emergency rm. Wht should I void while tking ABILIFY? Do not drive, operte hevy mchinery, or do other dngerous ctivities until you know how ABILIFY ffects you. ABILIFY my mke you drowsy. Avoid getting over-heted or dehydrted. Do not over-exercise. o o In hot wether, sty inside in cl plce if possible. o o Sty out of the sun. Do not wer t much or hevy clothing. Drink plenty of wter. Wht re the possible side effects of ABILIFY? ABILIFY my cuse serious side effects, including: See Wht is the most importnt informtion I should know bout ABILIFY? Stroke in elderly people (cerebrovsculr problems) tht cn led to deth Neuroleptic mlignnt syndrome (NMS). Tell your helthcre provider right wy if you hve some or ll of the following symptoms: high fever, stiff muscles, confusion, sweting, chnges in pulse, hert rte, nd bld pressure. These my be symptoms of rre nd serious condition tht cn led to deth. Cll your helthcre provider right wy if you hve ny of these symptoms. Uncontrolled body movements (trdive dyskinesi). ABILIFY my cuse movements tht you cnnot control in your fce, tongue, or other body prts. Trdive dyskinesi my not go wy, even if you stop receiving ABILIFY. Trdive dyskinesi my lso strt fter you stop receiving ABILIFY. Problems with your metbolism such s: High bld sugr (hyperglycemi) nd dibetes. Increses in bld sugr cn hppen in some people who tke ABILIFY. Extremely high bld sugr cn led to com or deth. If you hve dibetes or risk fctors for dibetes (such s being overweight or fmily history of dibetes), your helthcre provider should check your bld sugr before you strt ABILIFY nd during your tretment. 23

24 Cll your helthcre provider if you hve ny of these symptoms of high bld sugr while receiving ABILIFY: ¾ feel very thirsty ¾ need to urinte more thn usul ¾ feel very hungry ¾ feel wek or tired ¾ feel sick to your stomch ¾ feel confused, or your breth smells fruity Incresed ft levels (cholesterol nd triglycerides) in your bld. Weight gin. You nd your helthcre provider should check your weight regulrly. Unusul urges. Some people tking ABILIFY hve hd unusul urges, such s gmbling, binge eting or eting tht you cnnot control (compulsive), compulsive shopping nd sexul urges. If you or your fmily members notice tht you re hving unusul urges or behviors, tlk to your helthcre provider. Orthosttic hypotension (decresed bld pressure). Lighthededness or finting my hppen when rising t quickly from sitting or lying position. Low white bld cell count Seizures (convulsions) Problems with control of your body temperture especilly when you exercise lot or re in n re tht is very hot. It is importnt for you to drink wter to void dehydrtion. See Wht should I void while receiving ABILIFY? Difficulty swllowing tht cn cuse fd or liquid to get into your lungs. The most common side effects of ABILIFY in dults include: nuse dizziness vomiting nxiety constiption insomni hedche restlessness blurred vision inner sense of restlessness/need to move (kthisi) upper respirtory illness The most common side effects of ABILIFY in children include: feeling sleepy insomni hedche nuse vomiting stuffy nose ftigue weight gin incresed or decresed ppetite uncontrolled movement such s restlessness, tremor incresed sliv or drling muscle stiffness Cll your doctor for medicl dvice bout side effects. You my report side effects to FDA t FDA How should I store ABILIFY? Store ABILIFY t rm temperture, between 68 F to 77 F (20 C to 25 C). Opened bottles of ABILIFY Orl Solution cn be used for up to 6 months fter opening, but not beyond the expirtion dte on the bottle. Keep ABILIFY nd ll medicines out of the rech of children. Generl informtion bout the sfe nd effective use of ABILIFY Medicines re sometimes prescribed for purposes other thn those listed in Mediction Guide. Do not use ABILIFY for condition for which it ws not prescribed. Do not give ABILIFY to other people, even if they hve the sme symptoms you hve. It my hrm them. You cn sk your helthcre provider or phrmcist for informtion bout ABILIFY tht ws written for helthcre professionls. Wht re the ingredients in ABILIFY? Active ingredient: ripiprzole Inctive ingredients: Tblets: cornstrch, hydroxypropyl cellulose, lctose monohydrte, mgnesium sterte, nd microcrystlline cellulose. Colornts include ferric oxide (yellow or red) nd FD&C Blue No. 2 Aluminum Lke ABILIFY DISCMELT Orlly Disintegrting Tblets: cesulfme potssium, sprtme (which contins phenyllnine), clcium silicte, croscrmellose sodium, crospovidone, crème de vnill (nturl nd rtificil flvors), mgnesium sterte, microcrystlline cellulose, silicon dioxide, trtric cid, nd xylitol. Colornts include ferric oxide (yellow or red) nd FD&C Blue No. 2 Aluminum Lke ABILIFY Orl Solution: disodium edette, fructose (200 mg per ml), glycerin, dl-lctic cid, methylprben, propylene glycol, propylprben, sodium hydroxide, sucrose (400 mg per ml), nd purified wter. The orl solution is flvored with nturl ornge crem nd other nturl flvors For more informtion bout ABILIFY go to or cll Tblets mnufctured by Otsuk Phrmceuticl Co., Ltd., Tokyo, Jpn Orlly Disintegrting Tblets, Orl Solution, nd Injection mnufctured by Bristol-Myers Squibb Compny, Princeton, NJ USA Distributed nd mrketed by Otsuk Americ Phrmceuticl, Inc., Rockville, MD USA ABILIFY is trdemrk of Otsuk Phrmceuticl Compny. 2016, Otsuk Phrmceuticl Co., Ltd., Tokyo, Jpn This Mediction Guide hs been pproved by the U.S. Fd nd Drug Administrtion Revised: August US16IBR