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Abilify

SIDE EFFECTS

Overall Adverse Reactions Profile

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

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, 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 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 (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 14.

Table 14: 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 Reporting Reaction
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 15 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 15: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral ABILIFY

System Organ Class
Preferred Term
Percentage of Patients Reporting Reactiona
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
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.

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 16 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 16: 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
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

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 17.

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

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

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 18.

Table 18: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral ABILIFY

Preferred Term Percentage of Patients Reporting Reaction
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 19 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 ≥ 2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo.

Table 19: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) Treated with Oral ABILIFY

System Organ Class
Preferred Term
Percentage of Patients Reporting Reactiona
Aripiprazole
(n=611)
Placebo
(n=298)
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
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.

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 20 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 20: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder

System Organ Class
Preferred Term
Percentage of Patients Reporting Reactiona
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 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
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

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 21 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 21: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Patients Treated with ABILIFY Injection

System Organ Class
Preferred Term
Percentage of Patients Reporting Reactiona
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
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.

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 patients (13 to 17 years), 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 akathisiarelated 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 akathisiarelated 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, í0.05). 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.

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 ≤ 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 monotherapy study and a long-term adjunctive study with lithium and valproate 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 (6.1) 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 (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 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, chest pain; ≥ 1/1000 patients and < 1/100 patients -face edema, 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, gammaglutamyl transferase increased

Metabolism and Nutrition Disorders:

≥ 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 920 pediatric patients, aged 6 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

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 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. 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.

Read the Abilify (aripiprazole) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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 is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment as specified in DOSAGE AND ADMINISTRATION (2.3).

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 dehydroaripiprazole 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/day1800 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, dehydro-aripiprazole (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-desmethylvenlafaxine 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 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).

Read the Abilify Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/19/2014
This monograph has been modified to include the generic and brand name in many instances.

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