ABILIFY (aripiprazole 30 mg) Dailymed

Adverse Reactions

6.1 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 (5.1)]
• Clinical Worsening of Depression and Suicide Risk [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.2)]
• Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS (5.3)]
• Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS (5.4)]
• Hyperglycemia and Diabetes Mellitus [see WARNINGS AND PRECAUTIONS (5.5)]
• Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS (5.6)]
• Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS (5.7)]
• Seizures/Convulsions [see WARNINGS AND PRECAUTIONS (5.8)]
• Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS (5.9)]
• Body Temperature Regulation [see WARNINGS AND PRECAUTIONS (5.10)]
• Suicide [see WARNINGS AND PRECAUTIONS (5.11)]
• Dysphagia [see WARNINGS AND PRECAUTIONS (5.12)]
• Use in Patients with Concomitant Illness [see WARNINGS AND PRECAUTIONS (5.13)]

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

The most common adverse reactions in the pediatric clinical trials (less then 10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

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 920 patients (6 to 17 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, or autistic disorder and who had approximately 517 patient-years of exposure to oral aripiprazole. A total of 465 pediatric patients were treated with oral aripiprazole for at least 180 days and 117 pediatric patients treated with oral aripiprazole had at least 1 year of exposure.

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 uled. 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 (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.

6.2 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

	Percentage of Patients Reporting Reaction
Preferred Term	Aripiprazole(n=917)	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 less then 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

	Percentage of Patients Reporting Reactiona
System Organ Class Preferred Term	Aripiprazole(n=1843)	Placebo(n=1166)
a Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.
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

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

	Percentage of Patients Reporting Reactiona
System Organ Class  Preferred Term	Aripiprazole +Li or Val*(n=253)	Placebo +Li or Val*(n=130)
a Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.* Lithium or Valproate
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

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

	Percentage of Patients Reporting Reaction
Preferred Term	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

Pediatric Patients (6 to 17 years) with Autistic Disorder

The following findings are based on two 8-week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 mg/day to 15 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 (6 to 17 years) was 10% and 8%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with autistic disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 9.

Table 9: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral ABILIFY

	Percentage of Patients Reporting Reaction
Preferred Term	Aripiprazole(n=212)	Placebo(n=101)
Sedation	21	4
Fatigue	17	2
Vomiting	14	7
Somnolence	10	4
Tremor	10	0
Pyrexia	9	1
Drooling	9	0
Decreased Appetite	7	2
Salivary Hypersecretion	6	1
Extrapyramidal Disorder	6	0
Lethargy	5	0

Less Common Adverse Reactions in Pediatric Patients (6 to 17 years) with Schizophrenia, Bipolar Mania, or Autistic Disorder

Table 10 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, and up to 8 weeks in autistic disorder), including only those reactions that occurred in 1% or more of pediatric patients treated with aripiprazole (doses less then 2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo.

Table 10: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) Treated with Oral ABILIFY

	Percentage of Patients Reporting Reactiona
System Organ Class  Preferred Term	Aripiprazole(n=611)	Placebo(n=298)
a Adverse reactions reported by at least 1% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.
* Adjusted for gender.
Eye Disorders
Blurred Vision	3	0
Gastrointestinal Disorders
Vomiting	9	7
Nausea	8	4
Diarrhea	5	3
Salivary Hypersecretion	4	1
Abdominal Pain Upper	3	2
Constipation	3	2
Dry Mouth	1	0
General Disorders and Administration Site Conditions
Fatigue	10	2
Pyrexia	5	1
Irritability	1	0
Thirst	1	0
Infections and Infestations
Nasopharyngitis	6	3
Investigations
Weight Increased	2	1
Metabolism and Nutrition Disorders
Increased Appetite	7	3
Decreased Appetite	4	2
Musculoskeletal and Connective Tissue Disorders
Arthralgia	1	0
Musculoskeletal Stiffness	1	0
Nervous System Disorders
Somnolence	16	4
Extrapyramidal Disorder	14	2
Headache	13	12
Sedation	8	1
Akathisia	6	1
Tremor	6	1
Drooling	4	0
Dizziness	3	1
Lethargy	2	0
Dystonia	1	0
Dyskinesia	1	0
Hypersomnia	1	0
Reproductive System and Breast Disorders
Dysmenorrhoea*	2	1
Respiratory, Thoracic, and Mediastinal Disorders
Rhinorrhoea	2	1
Skin and Subcutaneous Tissue Disorders
Rash	2	1

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 11 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 less then 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 11: 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)
a Adverse reactions reported by at least 2% of patients treated with adjunctive aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.* Antidepressant Therapy
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 Connective Tissue 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

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 12 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 less then 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.tabel 12

Table 12: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Patients Treated with ABILIFY Injection

	Percentage of Patients Reporting Reactiona
System Organ Class  Preferred Term	Aripiprazole(n=501)	Placebo(n=220)
a Adverse 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.
Cardiac Disorders
Tachycardia	2	greater then 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

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%).

Autistic Disorder

In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).

Extrapyramidal Symptoms

Schizophrenia

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.

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).

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.

Bipolar Mania

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 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.

Major Depressive Disorder

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.

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.

Autistic Disorder

In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 3% vs. 9% for placebo.

In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.1; placebo, -0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.

Agitation Associated with Schizophrenia or Bipolar Mania

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 8-week, placebo-controlled trials in pediatric patients (6 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 less then 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 less then 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 less then 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 less then 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 less then 7% of body weight was 5% with adjunctive aripiprazole compared to 1% with adjunctive placebo.

In the two short term, placebo-controlled trials in patients (6 to 17 years) with autistic disorder, the mean increase in body weight in the aripiprazole group was 1.6 kg vs. 0.4 kg in the placebo group. The proportion of patients meeting a weight gain criterion of less then 7% of body weight was 26% in aripiprazole group compared to 7% in placebo group.

Table 13 provides the weight change results from a long-term (26-week), placebo-controlled study of aripiprazole in adults with schizophrenia, both mean change from baseline and proportions of patients meeting a weight gain criterion of less then 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 less then 7% weight gain.

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

	BMI greater then 23	BMI 23-27	BMI less then 27
	Placebo(n=54)	Aripiprazole(n=59)	Placebo(n=48)	Aripiprazole(n=39)	Placebo(n=49)	Aripiprazole(n=53)
Mean change frombaseline (kg)	-0.5	-0.5	-0.6	-1.3	-1.5	-2.1
% with less then 7% increase BW	3.7%	6.8%	4.2%	5.1%	4.1%	5.7%

Table 14 provides the weight change results from a long-term (52-week) study of aripiprazole in adults with schizophrenia, both mean change from baseline and proportions of patients meeting a weight gain criterion of less then 7% of body weight relative to baseline, categorized by BMI at baseline:

Table 14: Weight Change Results Categorized by BMI at Baseline: Active-Controlled Study in Schizophrenia, Safety Sample

	BMI greater then 23(n=314)	BMI 23-27(n=265)	BMI less then 27(n=260)
Mean change from baseline (kg)	2.6	1.4	-1.2
% with less then 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 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 greater then 49 days), and were of limited duration (7/12 greater then 10 days). Tremor infrequently led to discontinuation (greater then 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 ul of MedDRA terms that reflect adverse reactions as defined in ADVERSE REACTIONS(6.1) reported by patients treated with oral aripiprazole at multiple doses less then 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 uled in other parts of ADVERSE REACTIONS(6), or those considered in WARNINGS AND PRECAUTIONS (5) or OVERDOSAGE (10) 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 uled in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already uled in the tabulated results from placebo-controlled trials appear in this uling); 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:

 less then 1/1000 patients and greater then 1/100 patients - leukopenia, neutropenia, thrombocytopenia

Cardiac Disorders:

 less then 1/1000 patients and greater then 1/100 patients - bradycardia, palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, sinus tachycardia, atrial fibrillation, angina pectoris, myocardial ischemia;

greater then 1/1000 patients - atrial flutter, supraventricular tachycardia, ventricular tachycardia

Eye Disorders:

 less then 1/1000 patients and greater then 1/100 patients - photophobia, diplopia, eyelid edema, photopsia

Gastrointestinal Disorders:

less then 1/1000 patients and greater then 1/100 patients - gastroesophageal reflux disease, swollen tongue, esophagitis;

greater then 1/1000 patients - pancreatitis

General Disorders and Administration Site Conditions:

 less then 1/100 patients - asthenia, peripheral edema, chest pain; less then 1/1000 patients and greater then 1/100 patients - face edema, angioedema; greater then 1/1000 patients - hypothermia

Hepatobiliary Disorders:

greater then 1/1000 patients - hepatitis, jaundice

Immune System Disorders:

 less then 1/1000 patients and greater then 1/100 patients - hypersensitivity

Injury, Poisoning, and Procedural Complications:

less then 1/100 patients - fall; less then 1/1000 patients and greater then 1/100 patients - self mutilation; greater then 1/1000 patients - heat stroke

Investigations:

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

Metabolism and Nutrition Disorders:

 less then 1/1000 patients and greater then 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; greater then 1/1000 patients - diabetic ketoacidosis

Musculoskeletal and Connective Tissue Disorders:

 less then 1/1000 patients and greater then 1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; greater then 1/1000 patients - rhabdomyolysis

Nervous System Disorders:

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

Psychiatric Disorders:

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

Renal and Urinary Disorders:

 less then 1/1000 patients and greater then 1/100 patients - urinary retention, polyuria, nocturia

Reproductive System and Breast Disorders:

 less then 1/1000 patients and greater then 1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; greater then 1/1000 patients - gynaecomastia, priapism

Respiratory, Thoracic, and Mediastinal Disorders:

 less then 1/100 patients - nasal congestion, dyspnea, pneumonia aspiration

Skin and Subcutaneous Tissue Disorders:

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

Vascular Disorders:

 less then 1/100 patients

- hypertension; less then 1/1000 patients and greater then 1/100 patients

- hypotension

Pediatric Patients - Oral Administration

Most adverse events observed in the pooled database of 920 pediatric patients aged 6 to 17 years were also observed in the adult population. Additional adverse reactions observed in the pediatric population are uled below.

Gastrointestinal Disorders:

less then 1/1000 patients and greater then 1/100 patients

- tongue dry, tongue spasm

Investigations:

less then 1/100 patients

- blood insulin increased

Nervous System Disorders:

 less then 1/1000 patients and greater then 1/100 patients

- sleep talking

Skin and Subcutaneous Tissue Disorders:

 less then 1/1000 patients and greater then 1/100 patients

- hirsutism

Adults - Intramuscular Injection

Most 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 uled below.

General Disorders and Administration Site Conditions:

 less then 1/100 patients - injection site reaction; less then 1/1000 patients and greater then 1/100 patients - venipuncture site bruise

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ABILIFY. 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.


Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were (6.2):

• Adult patients with schizophrenia: akathisia
• Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor
• Adult patients (monotherapy) with bipolar mania: akathisia, sedation, restlessness, tremor, and extrapyramidal disorder
• Adult patients (adjunctive therapy with lithium or valproate) with bipolar mania: akathisia, insomnia, and extrapyramidal disorder
• Pediatric patients (10 to 17 years) with bipolar mania: somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness
• Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy): akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision
• Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy
• Adult patients with agitation associated with schizophrenia or bipolar mania: nausea.

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch