Adverse reactions : תופעות לוואי

7 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following adverse reactions are discussed in more detail in other sections of the labeling:
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (6.1)] • Cerebrovascular Adverse Events, Including Stroke [see Warnings and Precautions (6.2)]
• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings Precautions (6.3)]
• Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (6.4)]
• Tardive Dyskinesia [see Warnings and Precautions (6.5)]
• Metabolic Changes [see Warnings and Precautions (6.6)]
• Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (6.7)]
• Orthostatic Hypotension [see Warnings and Precautions (6.8)] • Falls [see Warnings and Precautions (6.9)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (6.10)]
• Seizures/Convulsions [see Warnings and Precautions (6.11)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (6.12)]
• Body Temperature Regulation [see Warnings and Precautions (6.13)] • Suicide [see Warnings and Precautions (6.14)]
• Dysphagia [see Warnings and Precautions (6.15)]

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 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's disorder and who had approximately 1,342 patient-years of
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exposure to oral aripiprazole. A total of 959 pediatric patients were treated with oral aripiprazole for at least 180 days and 556 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.

7.1 Clinical Trials 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 to 30 mg/day.
Commonly Observed Adverse Reactions
The only commonly observed adverse reaction associated with the use of ARIPLY 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 or 30 mg/day.
Commonly Observed Adverse Reactions
Commonly observed adverse reactions associated with the use of ARIPLY in patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 13.
Table 13: Commonly Observed Adverse Reactions in Short-
Term, Placebo-Controlled Trials of Adult Patients with
Bipolar Mania Treated with Oral aripiprazole Monotherapy

Percentage of Patients
Reporting Reaction

Aripiprazole        Placebo
Preferred Term
(n=917)           (n=753)
Akathisia                                13                4

Sedation                                  8                3

Restlessness                              6                3

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Table 13: Commonly Observed Adverse Reactions in Short-
Term, Placebo-Controlled Trials of Adult Patients with
Bipolar Mania Treated with Oral aripiprazole Monotherapy

Percentage of Patients
Reporting Reaction
Aripiprazole          Placebo
Preferred Term
(n=917)             (n=753)

Tremor                                       6                  3 
Extrapyramidal Disorder                      5                  2 

Less Common Adverse Reactions in Adults
Table 14 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 14: Adverse Reactions in Short-Term, Placebo-Controlled
Trials in Adult Patients Treated with Oral aripiprazole

Percentage of Patients Reporting
Reaction*

System Organ Class                           Aripiprazole            Placebo Preferred Term                                (n=1843)              (n=1166) 
*
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 
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Table 14: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral aripiprazole

Percentage of Patients Reporting
Reaction*

System Organ Class                       Aripiprazole         Placebo Preferred Term                            (n=1843)           (n=1166) 
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 or 30 mg/day as adjunctive therapy with lithium or valproate.
Adverse Reactions Associated with Discontinuation of Treatment 

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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 15 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 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 15: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

Percentage of Patients Reporting
Reaction*

Aripiprazole + Li or       Placebo + Li or
System Organ Class
Val†                     Val†
Preferred Term
(n=253)                  (n=130)
*
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 

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Table 15: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

Percentage of Patients Reporting
Reaction*

Aripiprazole + Li or      Placebo + Li or
System Organ Class
Val†                    Val†
Preferred Term
(n=253)                 (n=130)
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 aripirazole was administered in doses ranging from 2 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 ARIPLY 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 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


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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 16.
Table 16: Commonly Observed Adverse Reactions in Short-Term,
Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with Bipolar Mania Treated with Oral aripiprazole

Percentage of Patients Reporting
Reaction

Aripiprazole          Placebo
Preferred Term
(n=197)             (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 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 17.


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

Percentage of Patients Reporting
Reaction

Aripiprazole          Placebo
Preferred Term
(n=212)             (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 

Adult Patients Receiving aripiprazole 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 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

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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 18 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 18: Adverse Reactions in Short-Term, Placebo-Controlled
Adjunctive Trials in Patients with Major Depressive Disorder

Percentage of Patients Reporting
Reaction*

Placebo +
System Organ Class                   Aripiprazole + ADT†
ADT†
Preferred Term                             (n=371)
(n=366)
*
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
6                             4
Infection
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

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Table 18: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder

Percentage of Patients Reporting
Reaction*

Placebo +
System Organ Class                 Aripiprazole + ADT†
ADT†
Preferred Term                           (n=371)
(n=366)
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 to 15 mg.
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).
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, 5, 10, 15, 20, 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, 

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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 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, 
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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.


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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
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.
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 aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for aripiprazole 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 aripiprazole. In addition, in a long-term (52 weeks), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole. 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 Clinical Trial Evaluation of aripiprazole
The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients: Adults - Oral Administration
• Blood and Lymphatic System Disorders: rare - thrombocytopenia • Cardiac Disorders: infrequent – bradycardia, palpitations, rare – atrial flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction,
cardiopulmonary failure

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•   Eye Disorders: infrequent – photophobia; rare - diplopia •   Gastrointestinal Disorders: infrequent - gastroesophageal reflux disease •   General Disorders and Administration Site Conditions: frequent - asthenia; infrequent – peripheral edema, chest pain; rare – face edema •   Hepatobiliary Disorders: rare - hepatitis, jaundice
•   Immune System Disorders: rare - hypersensitivity
•   Injury, Poisoning, and Procedural Complications: infrequent – fall; rare – heat stroke
•   Investigations: frequent – blood prolactin decreased, weight decreased, infrequent - hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare – blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased
•   Metabolism and Nutrition Disorders: frequent – anorexia; rare - hypokalemia, hyponatremia, hypoglycemia
•   Musculoskeletal and Connective Tissue Disorders: infrequent - muscular weakness, muscle tightness; rare – rhabdomyolysis, mobility decreased •   Nervous System Disorders: infrequent - parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, bradykinesia; rare – akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; <1/10,000 patients - choreoathetosis
•   Psychiatric Disorders: infrequent – aggression, loss of libido, delirium; rare – libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking
•   Renal and Urinary Disorders: rare - urinary retention, nocturia •   Reproductive System and Breast Disorders: infrequent - erectile dysfunction; rare – gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism
•   Respiratory, Thoracic, and Mediastinal Disorders: infrequent - nasal congestion, dyspnea
•   Skin and Subcutaneous Tissue Disorders: infrequent - rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare - urticaria •   Vascular Disorders: infrequent – hypotension, hypertension 
Pediatric Patients - Oral Administration
Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.
• Eye Disorders: infrequent - oculogyric crisis
• Gastrointestinal Disorders: infrequent -tongue dry, tongue spasm • Investigations: frequent - blood insulin increased
• Nervous System Disorders: infrequent - sleep talking
• Renal and Urinary Disorders frequent – enuresis
• Skin and Subcutaneous Tissue Disorders: infrequent - hirsutism 


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7.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hiccups, oculogyric crisis and pathological gambling.

7.3 Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form.
http://forms.gov.il/globaldata/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il