Aripiprazole is a psychotropic drug that is available as ABILIFY® (aripiprazole) Tablets, ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets, ABILIFY® (aripiprazole) Oral Solution,and ABILIFY® (aripiprazole) Injection,a solution for intramuscular injection.Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C₂₃H₂₇C_l2N₃O₂ and its molecular weight is 448.38.The chemical structure is:

ABILIFY Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No.2 Aluminum Lake.

ABILIFY (aripiprazole) DISCMELT Orally Disintegrating Tablets are available in 10 mg and 15 mg strengths. Inactive ingredients include acesulfame potassium, aspartame, calcium silicate, croscarmellose sodium, crospovidone, crème de vanilla (natural and artificial flavors), magnesium stearate, microcrystalline cellulose, silicon dioxide, tartaric acid, and xylitol. Colorants include ferric oxide (yellow or red) and FD&C Blue No.2 Aluminum Lake.

ABILIFY Oral Solution is a clear,colorless to light yellow solution available in a concentration of 1 mg/mL.The inactive ingredients for this solution include disodium edetate,fructose,glycerin, dl-lactic acid,methylparaben,propylene glycol,propylparaben,sodium hydroxide,sucrose,and purified water.The oral solution is flavored with natural orange cream and other natural flavors. ABILIFY Injection is available in single-dose vials as a ready-to-use,9.75 mg/1.3 mL (7.5 mg/mL) clear,colorless,sterile,aqueous solution for intramuscular use only.Inactive ingredients for this solution include 150 mg/mL of sulfobutylether β-cyclodextrin (SBECD), tartaric acid, sodium hydroxide,and water for injection.

Schizophrenia

ABILIFY is indicated for acute and maintenance treatment of Schizophrenia in adults and in adolescents 13 to 17 years of age [see Clinical Studies].

Bipolar Disorder Monotherapy

ABILIFY is indicated for acute and maintenance treatment of manic and mixed episodes associated with Bipolar I Disorder with or without psychotic features in adults and in pediatric patients 10 to 17 years of age [see Clinical Studies].

Adjunctive Therapy

ABILIFY is indicated as an adjunctive therapy to either lithium or valproate for the acute treatment of manic and mixed episodes associated with Bipolar I Disorder with or without psychotic features in adults and in pediatric patients 10 to 17 years of age [see Clinical Studies].

Adjunctive Treatment of Major Depressive Disorder

ABILIFY is indicated for use as an adjunctive therapy to antidepressants for the acute treatment of Major Depressive Disorder in adults [see Clinical Studies].

Agitation Associated with Schizophrenia or Bipolar Mania

ABILIFY Injection is indicated for the acute treatment of agitation associated with Schizophrenia or Bipolar Disorder,manic or mixed in adults."Psychomotor agitation"is defined in DSM-IV as "excessive motor activity associated with a feeling of inner tension". Patients experiencing agitation often manifest behaviors that interfere with their diagnosis and care (eg,threatening behaviors, escalating or urgently distressing behavior, or self-exhausting behavior), leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation [see Clinical Studies].

Schizophrenia

Usual Dose for Acute Treatment

Adults

The recommended starting and target dose for ABILIFY is 10 mg/day or 15 mg/day administered on a once-a-day schedule without regard to meals.ABILIFY has been systematically evaluated and shown to be effective in a dose range of 10 mg/day to 30 mg/day, when administered as the tablet formulation; however,doses higher than 10 mg/day or 15 mg/day were not more effective than 10 mg/day or 15 mg/day. Dosage increases should not be made before 2 weeks,the time needed to achieve steady-state [see Clinical Studies].

Adolescents

The recommended target dose of ABILIFY is 10 mg/day.Aripiprazole was studied in pediatric patients 13 to 17 years of age with Schizophrenia at daily doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg,which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. ABILIFY (aripiprazole) can be administered without regard to meals [see Clinical Studies].

Maintenance Therapy

Adults

While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, systematic evaluation of patients with Schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer, were discontinued from those medications, and were then administered ABILIFY 15 mg/day and observed for relapse during a period of up to 26 weeks, has demonstrated a benefit of such maintenance treatment [see Clinical Studies]. Patients should be periodically reassessed to determine the need for maintenance treatment.

Adolescents

The efficacy of ABILIFY for the maintenance treatment of Schizophrenia in the pediatric population has not been evaluated.While there is no body of evidence available to answer the question of how long the adolescent patient treated with ABILIFY should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients with Schizophrenia from other antipsychotics to ABILIFY or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with Schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

Bipolar Disorder

Usual Dose for Acute Treatment

Adults

The recommended starting and target dose is 15 mg as monotherapy or as adjunctive therapy with lithium or valproate given once a day,without regard to meals.The dose can be increased to 30 mg/day based on clinical response.The safety of doses above 30 mg/day has not been evaluated in clinical trials [see Clinical Studies].

Pediatric Patients

The efficacy of aripiprazole has been established in the treatment of pediatric patients 10 to 17 years of age with Bipolar I Disorder at doses of 10 mg/day or 30 mg/day. The recommended target dose of ABILIFY is 10 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate. The starting daily dose of the tablet formulation in these patients was 2 mg/day,which was titrated to 5 mg/day after 2 days and to the target dose of 10 mg/day after 2 additional days. Subsequent dose increases should be administered in 5 mg/day increments. ABILIFY can be administered without regard to meals. [See Clinical Studies]

Maintenance Therapy

Adults

While there is no body of evidence available to answer the question of how long a patient treated with aripiprazole should remain on it, whether used as monotherapy or as adjunctive therapy,adult patients with Bipolar I Disorder who had been symptomatically stable on ABILIFY Tablets (15 mg/day or 30 mg/day as monotherapy with a starting dose of 30 mg/day) for at least 6 consecutive weeks and then randomized to ABILIFY Tablets (15 mg/day or 30 mg/day) or placebo and monitored for relapse, demonstrated a benefit of such maintenance treatment [see Clinical Studies]. While it is generally agreed that pharmacological treatment beyond an acute response in Mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes,there are no systematically obtained data to support the use of aripiprazole in such longer-term treatment (beyond 6 weeks). Physicians who elect to use ABILIFY for extended periods, that is, longer than 6 weeks, should periodically re-evaluate the long-term usefulness of the drug for the individual.

Pediatric Patients

The efficacy of ABILIFY for the maintenance treatment of Bipolar I Disorder in the pediatric population has not been evaluated.While there is no body of evidence available to answer the question of how long the pediatric patient treated with ABILIFY should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

Adjunctive Treatment of Major Depressive Disorder

Usual Dose for Acute Treatment

Adults

The recommended starting dose for ABILIFY as adjunctive treatment for patients already taking an antidepressant is 2 mg/day to 5 mg/day.The efficacy of ABILIFY as an adjunctive therapy for Major Depressive Disorder was established within a dose range of 2 mg/day to 15 mg/day.Dose adjustments of up to 5 mg/day should occur gradually,at intervals of no less than 1 week [see Clinical Studies].

Pediatric Patients

The efficacy of ABILIFY (aripiprazole) for the adjunctive treatment of Major Depressive Disorder in the pediatric population has not been evaluated.

Maintenance Therapy

The efficacy of ABILIFY for the adjunctive maintenance treatment of Major Depressive Disorder has not been evaluated.While there is no body of evidence available to answer the question of how long the patient treated with ABILIFY should be maintained, patients should be periodically reassessed to determine the need for maintenance treatment.

Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)

Usual Dose

Adults

The recommended dose in these patients is 9.75 mg.The effectiveness of aripiprazole injection in controlling agitation in Schizophrenia and Bipolar Mania was demonstrated over a dose range of 5.25 mg to 15 mg.No additional benefit was demonstrated for 15 mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical factors warrant. If agitation warranting a second dose persists following the initial dose, cumulative doses up to a total of 30 mg/day may be given. However, the efficacy of repeated doses of aripiprazole injection in agitated patients has not been systematically evaluated in controlled clinical trials. The safety of total daily doses greater than 30 mg or injections given more frequently than every 2 hours have not been adequately evaluated in clinical trials [see Clinical Studies].

If ongoing aripiprazole therapy is clinically indicated,oral aripiprazole in a range of 10 mg/day to 30 mg/day should replace aripiprazole injection as soon as possible [see DOSAGE AND ADMINISTRATION].

Administration of ABILIFY Injection

To administer ABILIFY Injection, draw up the required volume of solution into the syringe as shown in Table 1.Discard any unused portion.

Table 1: ABILIFY Injection Dosing Recommendations

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 intramuscular use only. Do not administer intravenously or subcutaneously.Inject slowly, deep into the muscle mass.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,whenever solution and container permit.

Pediatric Patients

ABILIFY Intramuscular Injection has not been evaluated in pediatric patients.

Dosage Adjustment

Dosage adjustments in adults are not routinely indicated on the basis of age, gender, race, or renal or hepatic impairment status [see Use In Specific Populations].

Dosage adjustment for patients taking aripiprazole concomitantly with strong CYP3A4 inhibitors: When concomitant administration of aripiprazole with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin is indicated, the aripiprazole dose should be reduced to one-half the usual dose.When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased [see DRUG INTERACTIONS].

Dosage adjustment for patients taking aripiprazole concomitantly with potential CYP2D6 inhibitors: When concomitant administration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole occurs, aripiprazole dose should be reduced at least to one-half of its normal dose.When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should then be increased [see DRUG INTERACTIONS].When adjunctive ABILIFY is administered to patients with Major Depressive Disorder, ABILIFY should be administered without dosage adjustment as specified in DOSAGE AND ADMINISTRATION.

Dosage adjustment for patients taking potential CYP3A4 inducers: When a potential CYP3A4 inducer such as carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should be reduced to 10 mg to 15 mg [see DRUG INTERACTIONS].

Dosing of Oral Solution

The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see CLINICAL PHARMACOLOGY].

Dosing of Orally Disintegrating Tablets

The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral tablets [see DOSAGE AND ADMINISTRATION].

Dosage Forms And Strengths

ABILIFY® (aripiprazole) Tablets are available as described in Table 2.

Table 2: ABILIFY Tablet
Presentations

Tablet Strength	Tablet Color/Shape	Tablet Markings
2 mg	green modified rectangle	"A-006"and "2"
5 mg	blue modified rectangle	"A-007"and "5"
10 mg	pink modified rectangle	"A-008"and "10"
15 mg	yellow round	"A-009"and "15"
20 mg	white round	"A-010"and "20"
30 mg	pink round	"A-011"and "30"

ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets are available as described in Table 3.

Table 3: ABILIFY DISCMELT
Orally Disintegrating Tablet Presentations

Tablet Strength	Tablet Color/Shape	Tablet Markings
10 mg	pink (with scattered specks) round	"A"and "640" "10"
15 mg	yellow (with scattered specks) round	"A"and "641" "15"

ABILIFY® (aripiprazole) Oral Solution (1 mg/mL) is a clear, colorless to light yellow solution, supplied in child-resistant bottles along with a calibrated oral dosing cup.

ABILIFY® (aripiprazole) Injection for Intramuscular Use is a clear,colorless solution available as a ready-to-use,9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials.

ABILIFY® (aripiprazole) Tablets have markings on one side and are available in the strengths and packages listed in Table 14.

Table 14: ABILIFY Tablet
Presentations

Tablet Strength	Tablet Color/Shape	Tablet Markings	Pack Size	NDC Code
2 mg	green modified rectangle	"A-006" and "2"	Bottle of 30	59148-006-13
5 mg	bluemodified rectangle	"A-007" and "5"	Bottle of 30 Blister of 100	59148-007-13 59148-007-35
10 mg	pink modified rectangle	"A-008" and "10"	Bottle of 30 Blister of 100	59148-008-13 59148-008-35
15 mg	yellowround	"A-009" and "15"	Bottle of 30 Blister of 100	59148-009-13 59148-009-35
20 mg	whiteround	"A-010" and "20"	Bottle of 30 Blister of 100	59148-010-13 59148-010-35
30 mg	pink round	"A-011" and "30"	Bottle of 30 Blister of 100	59148-011-13 59148-011-35

ABILIFYDISCMELT® (aripiprazole) Orally Disintegrating Tablets are round tablets with markings on either side.ABILIFY DISCMELT is available in the strengths and packages listed in Table 15.

Table 15: ABILIFY DISCMELT Orally Disintegrating Tablet Presentations

Tablet Strength	Tablet Color	Tablet Markings	Pack Size	NDC Code
10 mg	pink (with scattered specks)	"A" and "640" "10"	Blister of 30	59148-640-23
15 mg	yellow (with scattered specks)	"A" and "641" "15"	Blister of 30	59148-641-23

ABILIFY® (aripiprazole) Oral Solution (1 mg/mL) is supplied in child-resistant bottles along with a calibrated oral dosing cup.ABILIFY Oral Solution is available as follows:

150 mL bottle...................NDC 59148-013-15

ABILIFY® (aripiprazole) Injection for intramuscular use is available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear,Type 1 glass vials as follows:

9.75 mg/1.3 mL single-dose vial......................NDC 59148-016-65

Storage

Tablets

Store at 25° C (77° F); excursions permitted between 15° C to 30° C (59° F to 86° F) [see USP Controlled Room Temperature].

Oral Solution

Store at 25° C (77° F); excursions permitted between 15° C to 30° C (59° F to 86° F) [see USP Controlled Room Temperature]. Opened bottles of ABILIFY (aripiprazole) Oral Solution can be used for up to 6 months after opening,but not beyond the expiration date on the bottle.The bottle and its contents should be discarded after the expiration date.

Injection

Store at 25° C (77° F); excursions permitted between 15° C to 30° C (59° F to 86° F) [see USP Controlled Room Temperature]. Protect from light by storing in the original container. Retain in carton until time of use.

Tablets manufactured by Otsuka Pharmaceutical Co, Ltd,Tokyo, 101-8535, Japan or Bristol-Myers Squibb Company, Princeton, NJ 08543, USA. Orally Disintegrating Tablets, Oral Solution, and Injection manufactured by Bristol-Myers Squibb Company, Princeton, NJ 08543, USA. Distributed and marketed by Otsuka America Pharmaceutical, Inc, Rockville, MD 20850. USA. Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Rev May 2008. FDA rev date: 5/6/2008

Overall Adverse Reactions Profile

The following are discussed in more detail in other sections of the labeling:

• Use in Elderly Patients with Dementia-Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Clinical Worsening of Depression and Suicide Risk [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS]
• Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
• Hyperglycemia and Diabetes Mellitus [see WARNINGS AND PRECAUTIONS]
• Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Seizures/Convulsions [see WARNINGS AND PRECAUTIONS]
• Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
• Body Temperature Regulation [see WARNINGS AND PRECAUTIONS]
• Suicide [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]
• Use in Patients with Concomitant Illness [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions in adult patients in clinical trials ( ≥ 10%) were nausea, vomiting, constipation,headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

The most common adverse reactions in the pediatric clinical trials ( ≥ 10%) were somnolence, extrapyramidal disorder, headache, and nausea.

Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3390 patients were treated with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at least 1 year of exposure.

Aripiprazole has been evaluated for safety in 514 patients (10 to 17 years) who participated in multiple-dose, clinical trials in Schizophrenia or Bipolar Mania and who had approximately 205 patient-years of exposure to oral aripiprazole. A total of 278 pediatric patients were treated with oral aripiprazole for at least 180 days.

The conditions and duration of treatment with aripiprazole (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed-and flexible-dose studies,and short- and longer-term exposure.

Adverse events during exposure were obtained by collecting volunteered adverse events, as well as results of physical examinations, vital signs, weights, laboratory analyses, and ECG. Adverse experiences were recorded by clinical investigators using terminology of their own choosing. In the tables and tabulations that follow, MedDRA dictionary terminology has been used to classify reported adverse events into a smaller number of standardized event categories, in order to provide a meaningful estimate of the proportion of individuals experiencing adverse events.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once,a treatment-emergent adverse event of the type listed.An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. There was no attempt to use investigator causality assessments; ie, all events meeting the defined criteria, regardless of investigator causality are included.

Throughout this section, adverse reactions are reported. These are adverse events that were considered to be reasonably associated with the use of ABILIFY (aripiprazole) (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for ABILIFY often cannot be reliably established in individual cases.

The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses, and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Clinical Studies Experience

Adult Patients with Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

Overall, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (7%) and placebo-treated (9%) patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients.

Commonly Observed Adverse Reactions

The only commonly observed adverse reaction associated with the use of aripiprazole in patients with Schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).

Adult Patients with Bipolar Mania

Monotherapy

The following findings are based on a pool of 3-week, placebo-controlled,Bipolar Mania trials in which oral aripiprazole was administered at doses of 15 mg/day or 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

Overall,in patients with Bipolar Mania,there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (11%) and placebo-treated (10%) patients. The types of adverse reactions that led to discontinuation were similar between the aripiprazole-treated and placebo-treated patients.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in patients with Bipolar Mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 5.

Table 5: Commonly Observed Adverse Reactions in Short-Term,Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with Oral ABILIFY Monotherapy

Preferred Term	Percentage of Patients Aripiprazole (n=917)	Reporting Reaction Placebo (n=753)
Akathisia	13	4
Sedation	8	3
Restlessness	6	3
Tremor	6	3
Extrapyramidal Disorder	5	2

Less Common Adverse Reactions in Adults

Table 6 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in Schizophrenia and up to 3 weeks in Bipolar Mania), including only those reactions that occurred in 2% or more of patients treated with aripiprazole (doses ≥ 2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.

Table 6: Adverse Reactions in Short-Term,Placebo-Controlled Trials in Adult Patients Treated with Oral ABILIFY (aripiprazole)

	Percentage of Patients Reporting Reactiona
System Organ Class Preferred Term	Aripiprazole (n=1843)	Placebo (n=1166)
Eye Disorders
Blurred Vision	3	1
Gastrointestinal Disorders
Nausea	15	11
Constipation	11	7
Vomiting	11	6
Dyspepsia	9	7
Dry Mouth	5	4
Toothache	4	3
Abdominal Discomfort	3	2
Stomach Discomfort	3	2
General Disorders and Administration Site Conditions
Fatigue	6	4
Pain	3	2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Stiffness	4	3
Pain in Extremity	4	2
Myalgia	2	1
Muscle Spasms	2	1
Nervous System Disorders
Headache	27	23
Dizziness	10	7
Akathisia	10	4
Sedation	7	4
Extrapyramidal Disorder	5	3
Tremor	5	3
Somnolence	5	3
Psychiatric Disorders
Agitation	19	17
Insomnia	18	13
Anxiety	17	13
Restlessness	5	3
Respiratory,Thoracic,and Mediastinal Disorders
Pharyngolaryngeal Pain	3	2
Cough	3	2
aAdverse reactions reported by at least 2% of patients treated withoral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Adult Patients with Adjunctive Therapy with Bipolar Mania

The following findings are based on a placebo-controlled trial of adult patients with Bipolar Disorder in which aripiprazole was administered at doses of 15 mg/day or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive aripiprazole compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive aripiprazole-treated compared to placebo-treated patients were akathisia (5% and 1%,respectively) and tremor (2% and 1%, respectively).

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with adjunctive aripiprazole and lithium or valproate in patients with Bipolar Mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were:akathisia, insomnia, and extrapyramidal disorder.

Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania

Table 7 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses of 15 mg/day or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.

Table 7: Adverse Reactions in a Short-Term,Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

System Organ Class Preferred Term	Percentage of Patients Reporting Reactiona
	Aripiprazole +Li or Val* (n=253)	Placebo +Li or Val* (n=130)
Gastrointestinal Disorders
Nausea	8	5
Vomiting	4	0
Salivary Hypersecretion	4	2
Dry Mouth	2	1
Infections and Infestations
Nasopharyngitis	3	2
Investigations
Weight Increased	2	1
Nervous System Disorders
Akathisia	19	5
Tremor	9	6
Extrapyramidal Disorder	5	1
Dizziness	4	1
Sedation	4	2
Psychiatric Disorders
Insomnia	8	4
Anxiety	4	1
Restlessness	2	1
aAdverse reactions reported by at least 2% of patients treated withoral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. *Lithium or Valproate

Pediatric Patients (13 to 17 years) with Schizophrenia

The following findings are based on one 6-week placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%,respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with Schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Pediatric Patients (10 to 17 years) with Bipolar Mania

The following findings are based on one 4-week placebo-controlled trial in which oral aripiprazole was administered in doses of 10 mg/day or 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%,respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with Bipolar Mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 8.

Table 8: Commonly Observed Adverse Reactions in Short-Term,Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with Bipolar Mania Treated with Oral ABILIFY (aripiprazole)

Preferred Term	Percentage of Patients Reporting Reaction
	Aripiprazole (n=197)	Placebo (n=97)
Somnolence	23	3
Extrapyramidal Disorder	20	3
Fatigue	11	4
Nausea	11	4
Akathisia	10	2
Blurred Vision	8	0
Salivary Hypersecretion	6	0
Dizziness	5	1

Less Common Adverse Reactions in Pediatric Patients (10 to 17 years) with Schizophrenia or Bipolar Mania

Table 9 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in Schizophrenia and up to 4 weeks in Bipolar Mania), including only those reactions that occurred in 1% or more of pediatric patients treated with aripiprazole (doses ≥ 2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo.

Table 9: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) Treated with Oral ABILIFY (aripiprazole)

	Percentage of Patients Reporting Reactiona
System Organ Class Preferred Term	Aripiprazole (n=399)	Placebo (n=197)
Eye Disorders
Blurred Vision	5	0
Gastrointestinal Disorders
Nausea	10	5
Salivary Hypersecretion	4	1
Diarrhea	3	0
Stomach Discomfort	2	1
Dry Mouth	2	1
General Disorders and Administration Site Conditions
Fatigue	7	3
Pyrexia	3	1
Infections and Infestations
Nasopharyngitis	4	3
Investigations
Weight Increased	3	1
Metabolism and Nutrition Disorders
Increased Appetite	4	2
Musculoskeletal and Connective Tissue Disorders
Arthralgia	2	0
Nervous System Disorders
Somnolence	20	5
Extrapyramidal Disorder	19	4
Headache	16	13
Akathisia	9	4
Dizziness	5	2
Tremor	5	2
Dystonia	2	0
Dyskinesia	1	0
Sedation	1	0
Skin and Subcutaneous Disorders
Rash	2	1
Vascular Disorders
Orthostatic Hypotension	1	0
aAdverse reactions reported by at least 1% of pediatric patients treated with oral aripiprazole, except adverse reactions which had anincidence equal to orless than placebo.

Adult Patients Receiving ABILIFY as Adjunctive Treatment of Major Depressive Disorder

The following findings are based on a pool of two placebo-controlled trials of patients with Major Depressive Disorder in which aripiprazole was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions was 6% for adjunctive aripiprazole-treated patients and 2% for adjunctive placebo-treated patients.

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with the use of adjunctive aripiprazole in patients with Major Depressive Disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.

Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder

Table 10 enumerates the pooled incidence,rounded to the nearest percent,of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses ≥ 2 mg/day) and for which the incidence in patients treated with adjunctive aripiprazole was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

Table 10: Adverse Reactions in Short-Term,Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder

	Percentage of Patients Reporting Reactiona
System Organ Class Preferred Term	Aripiprazole+ADT* (n=371)	Placebo+ADT* (n=366)
Eye Disorders
Blurred Vision	6	1
Gastrointestinal Disorders
Constipation	5	2
General Disorders and Administration Site Conditions
Fatigue	8	4
Feeling Jittery	3	1
Infections and Infestations
Upper Respiratory Tract Infection	6	4
Investigations
Weight Increased	3	2
Metabolism and Nutrition Disorders
Increased Appetite	3	2
Musculoskeletal and ConnectiveTissue Disorders
Arthralgia	4	3
Myalgia	3	1
Nervous System Disorders
Akathisia	25	4
Somnolence	6	4
Tremor	5	4
Sedation	4	2
Dizziness	4	2
Disturbance in Attention	3	1
Extrapyramidal Disorder	2	0
Psychiatric Disorders
Restlessness	12	2
Insomnia	8	2
aAdverse reactions reported by at least 2% of patients treated with adjunctive aripiprazole, except adverse reactions which had an incidence equal to orless than placebo. * Antidepressant Therapy

Patients with Agitation Associated with Schizophrenia or Bipolar Mania (Intramuscular Injection)

The following findings are based on a pool of three placebo-controlled trials of patients with agitation associated with Schizophrenia or Bipolar Mania in which aripiprazole injection was administered at doses of 5.25 mg to 15 mg.

Adverse Reactions Associated with Discontinuation of Treatment

Overall, in patients with agitation associated with Schizophrenia or Bipolar Mania, there was little difference in the incidence of discontinuation due to adverse reactions between aripiprazole-treated (0.8%) and placebo-treated (0.5%) patients.

Commonly Observed Adverse Reactions

There was one commonly observed adverse reaction (nausea) associated with the use of aripiprazole injection in patients with agitation associated with Schizophrenia and Bipolar Mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo).

Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania

Table 11 enumerates the pooled incidence,rounded to the nearest percent,of adverse reactions that occurred during acute therapy (24-hour),including only those adverse reactions that occurred in 2% or more of patients treated with aripiprazole injection (doses ≥ 5.25 mg/day) and for which the incidence in patients treated with aripiprazole injection was greater than the incidence in patients treated with placebo in the combined dataset.

Table 11: Adverse Reactions in Short-Term,Placebo-Controlled Trials in Patients Treated with ABILIFY (aripiprazole) Injection

	Percentage of Patients Reporting Reactiona
System Organ Class Preferred Term	Aripiprazole (n=501)	Placebo (n=220)
Cardiac Disorders
Tachycardia	2	<1
Gastrointestinal Disorders
Nausea	9	3
Vomiting	3	1
General Disorders and Administration Site Conditions
Fatigue	2	1
Nervous System Disorders
Headache	12	7
Dizziness	8	5
Somnolence	7	4
Sedation	3	2
Akathisia	2	0
aAdverse reactions reported by at least 2% of patients treated with aripiprazole injection, except adverse reactions which had an incidence equal to or less than placebo.

Dose-Related Adverse Reactions

Schizophrenia

Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with Schizophrenia comparing various fixed doses (2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).

In the study of pediatric patients (13 to 17 years of age) with Schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo,5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg,11.8%).

Bipolar Mania

In the study of pediatric patients (10 to 17 years of age) with Bipolar Mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo,0%; 10 mg,3.1%; 30 mg,8.1%).

Extrapyramidal Symptoms

In short-term, placebo-controlled trials in Schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs.12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs.4% for placebo. In the short-term,placebo-controlled trial of Schizophrenia in pediatric (13 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% vs. 6% for placebo. In the short-term,placebo-controlled trials in Bipolar Mania in adults,the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy aripiprazole-treated patients was 16% vs.8% for placebo and the incidence of akathisia-related events for monotherapy aripiprazole-treated patients was 13% vs. 4% for placebo. In the 6-week, placebo-controlled trial in Bipolar Mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive aripiprazole-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in Bipolar Mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 10% vs. 2% for placebo. In the short-term,placebo-controlled trials in Major Depressive Disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive aripiprazole-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.

Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult Schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, -0.05). In the pediatric (13 to 17 years) Schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole, 0.24; placebo, -0.29). In the adult Bipolar Mania trials with monotherapy aripiprazole, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.50; placebo, -0.01 and aripiprazole, 0.21; placebo,-0.05).Changes in the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the Bipolar Mania trials with aripiprazole as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole,0.73; placebo,0.07 and aripiprazole,0.30; placebo, 0.11).Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive aripiprazole and adjunctive placebo.In the pediatric (10 to 17 years) short-term Bipolar Mania trial,the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole,0.90; placebo,-0.05).Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the Major Depressive Disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.31; placebo, 0.03 and aripiprazole, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo groups.

Similarly, in a long-term (26-week), placebo-controlled trial of Schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia),and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo.

In the placebo-controlled trials in patients with agitation associated with Schizophrenia or Bipolar Mania, the incidence of reported EPS-related events excluding events related to akathisia for aripiprazole-treated patients was 2% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 2% vs. 0% for placebo. Objectively collected data on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) for all treatment groups did not show a difference between aripiprazole and placebo.

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Laboratory Test Abnormalities

A between group comparison for 3-week to 6-week, placebo-controlled trials in adults or 4-week to 6-week, placebo-controlled trials in pediatric patients (10 to 17 years) revealed no medically important differences between the aripiprazole and placebo groups in the proportions of patients experiencing potentially clinically significant changes in routine serum chemistry, hematology,or urinalysis parameters.Similarly,there were no aripiprazole/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis in adult or pediatric patients.

In the 6-week trials of aripiprazole as adjunctive therapy for Major Depressive Disorder, there were no clinically important differences between the adjunctive aripiprazole-treated and adjunctive placebo-treated patients in the median change from baseline in prolactin, fasting glucose,HDL,LDL,or total cholesterol measurements. The median % change from baseline in triglycerides was 5% for adjunctive aripiprazole-treated patients vs.0% for adjunctive placebo-treated patients.

In a long-term (26-week), placebo-controlled trial there were no medically important differences between the aripiprazole and placebo patients in the mean change from baseline in prolactin, fasting glucose, triglyceride, HDL, LDL, or total cholesterol measurements.

Weight Gain

In 4-week to 6-week trials in adults with Schizophrenia,there was a slight difference in mean weight gain between aripiprazole and placebo patients (+0.7 kg vs.-0.05 kg,respectively) and also a difference in the proportion of patients meeting a weight gain criterion of ≥ 7% of body weight [aripiprazole (8%) compared to placebo (3%)].In a 6-week trial in pediatric patients (13 to 17 years) with Schizophrenia, there was a slight difference in mean weight gain between aripiprazole and placebo patients (+0.13 kg vs.-0.83 kg, respectively) and also a difference in the proportion of patients meeting a weight gain criterion of ≥ 7% of body weight [aripiprazole (5%) compared to placebo (1%)]. In 3-week trials in adults with Mania with monotherapy aripiprazole, the mean weight gain for aripiprazole and placebo patients was 0.1 kg vs.0.0 kg, respectively. The proportion of patients meeting a weight gain criterion of ≥ 7% of body weight was aripiprazole (2%) compared to placebo (3%).In the 6-week trial in Mania with aripiprazole as adjunctive therapy with either lithium or valproate,the mean weight gain for aripiprazole and placebo patients was 0.6 kg vs.0.2 kg,respectively.The proportion of patients meeting a weight gain criterion of ≥ 7% of body weight with adjunctive aripiprazole was 3% compared to adjunctive placebo 4%.

In the trials adding aripiprazole to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive aripiprazole or placebo in addition to their ongoing antidepressant treatment.The mean weight gain with adjunctive aripiprazole was 1.7 kg vs. 0.4 kg with adjunctive placebo. The proportion of patients meeting a weight gain criterion of ≥ 7% of body weight was 5% with adjunctive aripiprazole compared to 1% with adjunctive placebo.

Table 12 provides the weight change results from a long-term (26-week), placebo-controlled study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of ≥ 7% of body weight relative to baseline,categorized by BMI at baseline. Although there was no mean weight increase, the aripiprazole group tended to show more patients with a ≥ 7% weight gain.

Table 12: Weight Change Results Categorized by BMI at Baseline: Placebo-Controlled Study in Schizophrenia,Safety Sample

	BMI <23		BMI 23-27		BMI >27
	Placebo (n=54)	Aripiprazole (n=59)	Placebo (n=48)	Aripiprazole (n=39)	Placebo (n=49)	Aripiprazole (n=53)
Mean change from baseline (kg)	-0.5	-0.5	-0.6	-1.3	-1.5	-2.1
% with ≥ 7% increase BW	3.7%	6.8%	4.2%	5.1%	4.1%	5.7%

Table 13 provides the weight change results from a long-term (52-week) study of aripiprazole, both mean change from baseline and proportions of patients meeting a weight gain criterion of ≥ 7% of body weight relative to baseline,categorized by BMI at baseline:

Table 13: Weight Change Results Categorized by BMI at Baseline: Active-Controlled Study in Schizophrenia,Safety Sample

	BMI <23 (n=314)	BMI 23-27 (n=265)	BMI >27 (n=260)
Mean change from baseline (kg)	2.6	1.4	-1.2
% with ≥ 7% increase BW	30%	19%	8%

ECG Changes

Between group comparisons for a pooled analysis of placebo-controlled trials in patients with Schizophrenia,Bipolar Mania,or Major Depressive Disorder revealed no significant differences between oral aripiprazole and placebo in the proportion of patients experiencing potentially important changes in ECG parameters.Aripiprazole was associated with a median increase in heart rate of 2 beats per minute compared to no increase among placebo patients.

In the pooled,placebo-controlled trials in patients with agitation associated with Schizophrenia or Bipolar Mania, there were no significant differences between aripiprazole injection and placebo in the proportion of patients experiencing potentially important changes in ECG parameters,as measured by standard 12-lead ECGs.

Additional Findings Observed in Clinical Trials

Adverse Reactions in Long-Term,Double-Blind,Placebo-Controlled Trials

The adverse reactions reported in a 26-week, double-blind trial comparing oral ABILIFY (aripiprazole) and placebo in patients with Schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for ABILIFY vs.2% (3/153) for placebo].In this study,the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤ 49 days), and were of limited duration (7/12 ≤ 10 days). Tremor infrequently led to discontinuation ( < 1%) of ABILIFY.In addition,in a long-term (52-week),active-controlled study, the incidence of tremor was 5% (40/859) for ABILIFY.A similar profile was observed in a long-term study in Bipolar Disorder.

Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole

Following is a list of MedDRA terms that reflect adverse reactions as defined in ADVERSE REACTIONS reported by patients treated with oral aripiprazole at multiple doses ≥ 2 mg/day during any phase of a trial within the database of 13,543 adult patients.All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility,have been included.Events already listed in other parts of ADVERSE REACTIONS, or those considered in WARNINGS AND PRECAUTIONS or OVERDOSAGE have been excluded. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it.

Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions:those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients.

Adults - Oral Administration

Blood and Lymphatic System Disorders:

≥ 1/1000 patients and < 1/100 patients - leukopenia,neutropenia,thrombocytopenia

Cardiac Disorders:

≥ 1/1000 patients and < 1/100 patients - bradycardia, palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial fibrillation, angina pectoris, myocardial ischemia; < 1/1000 patients - atrial flutter, supraventricular tachycardia, ventricular tachycardia

Eye Disorders:

≥ 1/1000 patients and < 1/100 patients - photophobia, diplopia, eyelid edema, photopsia

Gastrointestinal Disorders:

≥ 1/1000 patients and < 1/100 patients - gastroesophageal reflux disease, swollen tongue,esophagitis; < 1/1000 patients - pancreatitis

General Disorders and Administration Site Conditions:

≥ 1/100 patients - asthenia,peripheral edema,irritability,chest pain; ≥ 1/1000 patients and < 1/100 patients - face edema, thirst, angioedema; < 1/1000 patients -hypothermia

Hepatobiliary Disorders:

< 1/1000 patients - hepatitis,jaundice

Immune System Disorders:

≥ 1/1000 patients and < 1/100 patients - hypersensitivity

Injury, Poisoning, and Procedural Complications:

≥ 1/100 patients - fall; ≥ 1/1000 patients and < 1/100 patients - self mutilation; < 1/1000 patients - heat stroke

Investigations:

≥ 1/100 patients - weight decreased, creatine phosphokinase increased; ≥ 1/1000 patients and < 1/100 patients - hepatic enzyme increased, blood glucose increased, blood prolactin increased,blood urea increased,electrocardiogram QT prolonged,blood creatinine increased, blood bilirubin increased; < 1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased, gamma-glutamyl transferase increased

Metabolism and Nutrition Disorders:

≥ 1/100 patients - decreased appetite; ≥ 1/1000 patients and < 1/100 patients -hyperlipidemia, anorexia, diabetes mellitus (including blood insulin increased, carbohydrate tolerance decreased, diabetes mellitus non-insulin-dependent, glucose tolerance impaired, glycosuria, glucose urine, glucose urine present), hyperglycemia, hypokalemia, hyponatremia, hypoglycemia, polydipsia; < 1/1000 patients - diabetic ketoacidosis

Musculoskeletal and Connective Tissue Disorders:

≥ 1/1000 patients and < 1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; < 1/1000 patients - rhabdomyolysis

Nervous System Disorders:

≥ 1/100 patients - coordination abnormal; ≥ 1/1000 patients and < 1/100 patients -speech disorder, parkinsonism, memory impairment, cogwheel rigidity, cerebrovascular accident, hypokinesia, tardive dyskinesia, hypotonia, myoclonus, hypertonia, akinesia, bradykinesia; < 1/1000 patients - Grand Mal convulsion,choreoathetosis

Psychiatric Disorders:

≥ 1/100 patients - suicidal ideation; ≥ 1/1000 patients and < 1/100 patients -aggression,loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; < 1/1000 patients - catatonia, sleep walking

Renal and Urinary Disorders:

≥ 1/1000 patients and < 1/100 patients - urinary retention,polyuria,nocturia

Reproductive System and Breast Disorders:

≥ 1/1000 patients and < 1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; < 1/1000 patients - gynaecomastia,priapism

Respiratory, Thoracic, and Mediastinal Disorders:

≥ 1/100 patients - nasal congestion, dyspnea, pneumonia aspiration

Skin and Subcutaneous Tissue Disorders:

≥ 1/100 patients - rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; ≥ 1/1000 patients and < 1/100 patients - pruritus, photosensitivity reaction, alopecia, urticaria

Vascular Disorders:

≥ 1/100 patients - hypertension; ≥ 1/1000 patients and < 1/100 patients - hypotension

Pediatric Patients - Oral Administration

Most adverse events observed in the pooled database of 514 pediatric patients aged 10 to 17 years were also observed in the adult population.Additional adverse reactions observed in the pediatric population are listed below.

Gastrointestinal Disorders:

≥ 1/1000 patients and < 1/100 patients - tongue dry,tongue spasm

Investigations: ≥ 1/100 patients - blood insulin increased

Nervous System Disorders:

≥ 1/1000 patients and < 1/100 patients - sleep talking

Skin and Subcutaneous Tissue Disorders:

≥ 1/1000 patients and < 1/100 patients - hirsutism

Adults - Intramuscular Injection

All adverse reactions observed in the pooled database of 749 adult patients treated with aripiprazole injection, were also observed in the adult population treated with oral aripiprazole. Additional adverse reactions observed in the aripiprazole injection population are listed below.

General Disorders and Administration Site Conditions:

≥ 1/100 patients - injection site reaction; ≥ 1/1000 patients and < 1/100 patients -venipuncture site bruise

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ABILIFY (aripiprazole). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), and blood glucose fluctuation.

Given the primary CNS effects of aripiprazole, caution should be used when ABILIFY is taken in combination with other centrally-acting drugs or alcohol.

Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

Potential for Other Drugs to Affect ABILIFY

Aripiprazole is not a substrate of CYP1A1,CYP1A2,CYP2A6,CYP2B6,CYP2C8,CYP2C9,CYP2C19, or CYP2E1 enzymes.Aripiprazole also does not undergo direct glucuronidation.This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes, or other factors, like smoking,is unlikely.

Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance and lower blood levels.Inhibitors of CYP3A4 (eg,ketoconazole) or CYP2D6 (eg,quinidine,fluoxetine,or paroxetine) can inhibit aripiprazole elimination and cause increased blood levels.

Ketoconazole and Other CYP3A4 Inhibitors

Coadministration of ketoconazole (200 mg/day for 14 days) with a 15 mg single dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively.The effect of a higher ketoconazole dose (400 mg/day) has not been studied.When ketoconazole is given concomitantly with aripiprazole,the aripiprazole dose should be reduced to one-half of its normal dose.Other strong inhibitors of CYP3A4 (itraconazole) would be expected to have similar effects and need similar dose reductions; moderate inhibitors (erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased.

Quinidine and Other CYP2D6 Inhibitors

Coadministration of a 10 mg single dose of aripiprazole with quinidine (166 mg/day for 13 days), a potent inhibitor of CYP2D6,increased the AUC of aripiprazole by 112% but decreased the AUC of its active metabolite, dehydro-aripiprazole, by 35%. Aripiprazole dose should be reduced to one-half of its normal dose when quinidine is given concomitantly with aripiprazole.

Other significant inhibitors of CYP2D6, such as fluoxetine or paroxetine, would be expected to have similar effects and should lead to similar dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased. When adjunctive ABILIFY (aripiprazole) is administered to patients with Major Depressive Disorder, ABILIFY should be administered without dosage adjustment as specified in DOSAGE AND ADMINISTRATION.

Carbamazepine and Other CYP3A4 Inducers

Coadministration of carbamazepine (200 mg twice daily), a potent CYP3A4 inducer, with aripiprazole (30 mg/day) resulted in an approximate 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite,dehydro-aripiprazole. When carbamazepine is added to aripiprazole therapy, aripiprazole dose should be doubled.Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy,the aripiprazole dose should be reduced.

Potential for ABILIFY to Affect Other Drugs

Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on metabolism by CYP2D6 (dextromethorphan),CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin), and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro.

No effect of aripiprazole was seen on the pharmacokinetics of lithium or valproate.

Alcohol

There was no significant difference between aripiprazole coadministered with ethanol and placebo coadministered with ethanol on performance of gross motor skills or stimulus response in healthy subjects.As with most psychoactive medications, patients should be advised to avoid alcohol while taking ABILIFY.

Drugs Having No Clinically Important Interactions with ABILIFY

Famotidine

Coadministration of aripiprazole (given in a single dose of 15 mg) with a 40 mg single dose of the H₂ antagonist famotidine, a potent gastric acid blocker, decreased the solubility of aripiprazole and, hence, its rate of absorption, reducing by 37% and 21% the Cmax of aripiprazole and dehydro-aripiprazole, respectively, and by 13% and 15%, respectively, the extent of absorption (AUC).No dosage adjustment of aripiprazole is required when administered concomitantly with famotidine.

Valproate

When valproate (500 mg/day-1500 mg/day) and aripiprazole (30 mg/day) were coadministered, at steady-state the Cmax and AUC of aripiprazole were decreased by 25%. No dosage adjustment of aripiprazole is required when administered concomitantly with valproate.

When aripiprazole (30 mg/day) and valproate (1000 mg/day) were coadministered, at steady- state there were no clinically significant changes in the Cmax or AUC of valproate. No dosage adjustment of valproate is required when administered concomitantly with aripiprazole.

Lithium

A pharmacokinetic interaction of aripiprazole with lithium is unlikely because lithium is not bound to plasma proteins, is not metabolized, and is almost entirely excreted unchanged in urine. Coadministration of therapeutic doses of lithium (1200 mg/day-1800 mg/day) for 21 days with aripiprazole (30 mg/day) did not result in clinically significant changes in the pharmacokinetics of aripiprazole or its active metabolite, dehydroaripiprazole (Cmax and AUC increased by less than 20%). No dosage adjustment of aripiprazole is required when administered concomitantly with lithium.

Coadministration of aripiprazole (30 mg/day) with lithium (900 mg/day) did not result in clinically significant changes in the pharmacokinetics of lithium. No dosage adjustment of lithium is required when administered concomitantly with aripiprazole.

Lamotrigine

Coadministration of 10 mg/day to 30 mg/day oral doses of aripiprazole for 14 days to patients with Bipolar I Disorder had no effect on the steady-state pharmacokinetics of 100 mg/day to 400 mg/day lamotrigine,a UDP-glucuronosyltransferase 1A4 substrate. No dosage adjustment of lamotrigine is required when aripiprazole is added to lamotrigine.

Dextromethorphan

Aripiprazole at doses of 10 mg/day to 30 mg/day for 14 days had no effect on dextromethorphan's O-dealkylation to its major metabolite,dextrorphan,a pathway dependent on CYP2D6 activity.Aripiprazole also had no effect on dextromethorphan's N-demethylation to its metabolite 3-methoxymorphinan, a pathway dependent on CYP3A4 activity. No dosage adjustment of dextromethorphan is required when administered concomitantly with aripiprazole.

Warfarin

Aripiprazole 10 mg/day for 14 days had no effect on the pharmacokinetics of R-warfarin and S-warfarin or on the pharmacodynamic end point of International Normalized Ratio, indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered concomitantly with aripiprazole.

Omeprazole

Aripiprazole 10 mg/day for 15 days had no effect on the pharmacokinetics of a single 20 mg dose of omeprazole, a CYP2C19 substrate, in healthy subjects. No dosage adjustment of omeprazole is required when administered concomitantly with aripiprazole.

Lorazepam

Coadministration of lorazepam injection (2 mg) and aripiprazole injection (15 mg) to healthy subjects (n=40: 35 males and 5 females; ages 19-45 years old) did not result in clinically important changes in the pharmacokinetics of either drug.No dosage adjustment of aripiprazole is required when administered concomitantly with lorazepam. However, the intensity of sedation was greater with the combination as compared to that observed with aripiprazole alone and the orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS].

Escitalopram

Coadministration of 10 mg/day oral doses of aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of 10 mg/day escitalopram, a substrate of CYP2C19 and CYP3A4.No dosage adjustment of escitalopram is required when aripiprazole is added to escitalopram.

Venlafaxine

Coadministration of 10 mg/day to 20 mg/day oral doses of aripiprazole for 14 days to healthy subjects had no effect on the steady-state pharmacokinetics of venlafaxine and O-desmethyl-venlafaxine following 75 mg/day venlafaxine XR,a CYP2D6 substrate.No dosage adjustment of venlafaxine is required when aripiprazole is added to venlafaxine.

Fluoxetine, Paroxetine,and Sertraline

A population pharmacokinetic analysis in patients with Major Depressive Disorder showed no substantial change in plasma concentrations of fluoxetine (20 mg/day or 40 mg/day), paroxetine CR (37.5 mg/day or 50 mg/day), or sertraline (100 mg/day or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole. Aripiprazole dosing was 2 mg/day to 15 mg/day (when given with fluoxetine or paroxetine) or 2 mg/day to 20 mg/day (when given with sertraline).

Drug Abuse And Dependence

Controlled Substance

ABILIFY (aripiprazole) is not a controlled substance.

Abuse and Dependence

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse,and such patients should be observed closely for signs of ABILIFY misuse or abuse (eg, development of tolerance, increases in dose, drug-seeking behavior).

Included as part of the PRECAUTIONS section.

Use in Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].

Cerebrovascular Adverse Events,Including Stroke

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age:84 years; range:78-88 years).In the fixed-dose study,there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING].

Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease

In three,10-week,placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the treatment-emergent adverse events that were reported at an incidence of ≥ 3% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation [placebo 0%, aripiprazole 4%],and lightheadedness [placebo 1%,aripiprazole 4%].

The safety and efficacy of ABILIFY in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with ABILIFY, vigilance should be exercised, particularly for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see also BOXED WARNING].

Clinical Worsening of Depression and Suicide Risk

Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders,and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,adolescents,and young adults (ages 18-24) with Major Depressive Disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.There were differences in absolute risk of suicidality across the different indications,with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications.These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 4.

Table 4

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
	Increases Compared to Placebo
<18	14 additional cases
18-24	5 additional cases
	Decreases Compared to Placebo
25-64	1 fewer case
≥ 65	6 fewer cases

No suicides occurred in any of the pediatric trials.There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior,especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for Major Depressive Disorder as well as for other indications,both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precurs