10-15 mg/day 15 mg/day 30 mg/day. 2-5 mg/day 5-10 mg/day 15 mg/day. 2 mg/day 5-10 mg/day 15 mg/day. 30 mg/day injected IM

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 Wrnings nd Precutions, Flls (5.9) 02/2017 -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 Dose Recommended Dose Mximum 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 (5.10) Seizures/Convulsions: Use cutiously in ptients with history of seizures or with conditions tht lower the seizure threshold (5.11) Potentil for Cognitive nd Motor Impirment: Use cution when operting mchinery (5.12) Suicide: The possibility of suicide ttempt is inherent in schizophreni nd bipolr disorder. Closely supervise high-risk ptients (5.14) 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: 02/2017

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 Flls 5.10 Leukopeni, Neutropeni, nd Agrnulocytosis 5.11 Seizures/Convulsions 5.12 Potentil for Cognitive nd Motor Impirment 5.13 Body Temperture Regultion 5.14 Suicide 5.15 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 Dosge Adjustments for ABILIFY Known CYP2D6 Pr Metbolizers 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, rifmpin) Double usul dose over 1 to 2 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 Flls Antipsychotics, including ABILIFY, my cuse somnolence, posturl hypotension, motor nd sensory instbility, which my led to flls nd, consequently, frctures or other injuries. For ptients with diseses, conditions, or medictions tht could excerbte these effects, complete fll risk ssessments when inititing ntipsychotic tretment nd recurrently for ptients on long-term ntipsychotic therpy 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)] Flls [see WARNINGS AND PRECAUTIONS (5.9)] Leukopeni, Neutropeni, nd Agrnulocytosis [see WARNINGS AND PRECAUTIONS (5.10)] Seizures/Convulsions [see WARNINGS AND PRECAUTIONS (5.11)] Potentil for Cognitive nd Motor Impirment [see WARNINGS AND PRECAUTIONS (5.12)] Body Temperture Regultion [see WARNINGS AND PRECAUTIONS (5.13)] Suicide [see WARNINGS AND PRECAUTIONS (5.14)] Dysphgi [see WARNINGS AND PRECAUTIONS (5.15)] 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.