ABILIFY Aripiprazole 15mg Tablet 1's

Overdosage

Warnings

Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Increased Mortality: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole (Abilify) is not approved for the treatment of patients with dementia-related psychosis [see Warnings].
Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer's Disease: In three, 10-week, placebo-controlled studies of Aripiprazole (Abilify) in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the adverse reactions that were reported at an incidence of ≥3% and Aripiprazole (Abilify) incidence at least twice that for placebo were lethargy [placebo 2%, Aripiprazole (Abilify) 5%], somnolence (including sedation) [placebo 3%, Aripiprazole (Abilify) 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, Aripiprazole (Abilify) 5%], excessive salivation [placebo 0%, Aripiprazole (Abilify) 4%], and lightheadedness [placebo 1%, Aripiprazole (Abilify) 4%].
The safety and efficacy of Aripiprazole (Abilify) in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with Aripiprazole (Abilify), assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see Warnings].
Cerebrovascular Adverse Events, Including Stroke: In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in Aripiprazole (Abilify)-treated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with Aripiprazole (Abilify). Aripiprazole (Abilify) is not approved for the treatment of patients with dementia-related psychosis [see Warnings].
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 9. (See Table 9.)

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Aripiprazole (Abilify) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Aripiprazole (Abilify) is not approved for use in treating depression in the pediatric population.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including Aripiprazole (Abilify). Rare cases of NMS occurred during Aripiprazole (Abilify) treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, Aripiprazole (Abilify) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on Aripiprazole (Abilify), drug discontinuation should be considered. However, some patients may require treatment with Aripiprazole (Abilify) despite the presence of the syndrome.
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with Aripiprazole (Abilify) [see Adverse Reactions]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Because Aripiprazole (Abilify) was not marketed at the time these studies were performed, it is not known if Aripiprazole (Abilify) is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Adults: In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in Aripiprazole (Abilify)-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 10 shows the proportion of Aripiprazole (Abilify)-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days). (See Table 10.)

At 24 weeks, the mean change in fasting glucose in Aripiprazole (Abilify)-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].
The mean change in fasting glucose in adjunctive Aripiprazole (Abilify)-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 11 shows the proportion of adult patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median exposure 42 days) in patients with major depressive disorder. (See Table 11.)

Pediatric Patients and Adolescents: In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), the mean change in fasting glucose in Aripiprazole (Abilify)-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123).
In an analysis of two placebo-controlled trials in pediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in Aripiprazole (Abilify)-treated patients (-0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (-0.6 mg/dL; N=33).
In an analysis of two placebo-controlled trials in pediatric and adolescent patients with Tourette's disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in Aripiprazole (Abilify)-treated patients (0.79 mg/dL; N=90) was not significantly different than in placebo-treated patients (-1.66 mg/dL; N=58).
Table 12 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and pediatric bipolar patients (median exposure of 42-43 days), from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in pediatric patients (6 to 18 year) with Tourette's Disorder (median exposure 57 days). (See Table 12.)

At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder trials, the mean change in fasting glucose in Aripiprazole (Abilify)-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively].
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
There were no significant differences between Aripiprazole (Abilify)- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.
Adults: Table 13 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days). (See Table 13.)

In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between Aripiprazole (Abilify)- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.
Table 14 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials in adult patients with major depressive disorder (median exposure 42 days). (See Table 14.)

Pediatric Patients and Adolescents: Table 15 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days) and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days). (See Table 15.)

In monotherapy trials of adolescents with schizophrenia and pediatric patients with bipolar disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between Aripiprazole (Abilify)- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.
Table 16 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder. (See Table 16.)

Table 17 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 57 days) and HDL cholesterol (median exposure 57 days) from two placebo-controlled trials in pediatric patients (6 to 18 years) with Tourette's Disorder. (See Table 17.)

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Adults: In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in Aripiprazole (Abilify)-treated patients was +0.3 kg (N=1673) compared to -0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in Aripiprazole (Abilify)-treated patients was -1.5 kg (n=73) compared to -0.2 kg (n=46) in placebo-treated patients.
In the trials adding Aripiprazole (Abilify) to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive Aripiprazole (Abilify) or placebo in addition to their ongoing antidepressant treatment. The mean change in body weight in patients receiving adjunctive Aripiprazole (Abilify) was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo.
Table 18 shows the percentage of adult patients with weight gain ≥7% of body weight by indication. (See Table 18.)

Pediatric Patients and Adolescents: In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in Aripiprazole (Abilify)-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in Aripiprazole (Abilify)-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients.
In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in Aripiprazole (Abilify)-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients.
In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette's Disorder with median exposure of 57 days, the mean change in body weight in Aripiprazole (Abilify)-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients.
Table 19 shows the percentage of pediatric and adolescent patients with weight gain ≥7% of body weight by indication. (See Table 19.)

In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with Aripiprazole (Abilify). After 26 weeks, 32.8% of patients gained ≥7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients and adolescents by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD.
In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with Aripiprazole (Abilify). The mean change in weight z-score was 0.26 SDs for patients receiving >9 months of treatment.
When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.
Pathological Gambling and Other Compulsive Behaviors: Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
Orthostatic Hypotension: Aripiprazole (Abilify) may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral Aripiprazole (Abilify) (n=2467) included (Aripiprazole (Abilify) incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on oral Aripiprazole (Abilify) included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0 %), and syncope (0.2%, 0%); and of patients on Aripiprazole (Abilify) Injection (n=501) included orthostatic hypotension (0.6%, 0%), postural dizziness (0.2%, 0.5%), and syncope (0.4%, 0%). [See Clinical Trials Experience under Adverse Reactions].
The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for Aripiprazole (Abilify) was not meaningfully different from placebo (Aripiprazole (Abilify) incidence, placebo incidence): in adult oral Aripiprazole (Abilify)-treated patients (4%, 2%), in pediatric oral Aripiprazole (Abilify)-treated patients aged 6 to 18 years (0.4%, 1%), or in Aripiprazole (Abilify) injection-treated patients (3%, 2%).
Aripiprazole (Abilify) should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see Interactions].
If parenteral benzodiazepine therapy is deemed necessary in addition to Aripiprazole (Abilify) injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension [see Interactions].
Falls: Antipsychotics, including Aripiprazole (Abilify), may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Leukopenia, Neutropenia, and Agranulocytosis: In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including Aripiprazole (Abilify). Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Aripiprazole (Abilify) at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Aripiprazole (Abilify) in patients with severe neutropenia (absolute neutrophil count <1000/mm³) and follow their WBC counts until recovery.
Seizures/Convulsions: In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated with oral Aripiprazole (Abilify), in 0.1% (1/732) of pediatric patients (6 to 18 years), and in 0.2% (1/501) of adult Aripiprazole (Abilify) injection-treated patients.
As with other antipsychotic drugs, Aripiprazole (Abilify) should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
Aripiprazole (Abilify), like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (Aripiprazole (Abilify) incidence, placebo incidence): in adult patients (n=2467) treated with oral Aripiprazole (Abilify) (11%, 6%), in pediatric patients ages 6 to 17 (n=611) (24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral Aripiprazole (Abilify) in short-term, placebo-controlled trials.
Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Aripiprazole (Abilify) does not affect them adversely.
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Aripiprazole (Abilify) for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see Postmarketing Experience under Adverse Reactions].
Suicide: The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and major depressive disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Aripiprazole (Abilify) should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see Adverse Reactions].
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including Aripiprazole (Abilify). Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Aripiprazole (Abilify) and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Increased Mortality in Elderly Patients with Dementia-Related Psychosis previously and Postmarketing Experience under Adverse Reactions].
Drug Abuse and Dependence: Controlled Substance: Aripiprazole (Abilify) is not a controlled substance.
Abuse: Aripiprazole (Abilify) has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of Aripiprazole (Abilify) misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).
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.
CYP2D6 Poor Metabolizers: Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions].
Hepatic and Renal Impairment: No dosage adjustment for Aripiprazole (Abilify) is required on the basis of a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Pharmacology: Pharmacokinetics under Actions].
Other Specific Populations: No dosage adjustment for Aripiprazole (Abilify) is required on the basis of a patient's sex, race, or smoking status [see Pharmacology: Pharmacokinetics under Actions].
Patients with Lactose Intolerance: Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should be aware that aripiprazole tablets and orally disintegrating tablets contain lactose. 
Use in Children: Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Pharmacology: Pharmacokinetics under Actions].
Schizophrenia: Safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see Dosage & Administration, Adverse Reactions, and Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
Bipolar I Disorder: Safety and effectiveness in pediatric patients with bipolar mania were established in a 4 week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see Dosage & Administration, Adverse Reactions, and Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
The efficacy of adjunctive Aripiprazole (Abilify) with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. However, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
Irritability Associated with Autistic Disorder: Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see Indications, Dosage & Administration, Adverse Reactions, and Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of "much improved" or "very much improved") on Aripiprazole (Abilify) for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue Aripiprazole (Abilify) treatment or switch to placebo. In this trial, the efficacy of Aripiprazole (Abilify) for the maintenance treatment of irritability associated with autistic disorder was not established.
Tourette's Disorder: Safety and effectiveness of aripiprazole in pediatric patients with Tourette's Disorder were established in one 8-week (aged 7 to 17) and one 10-week trial (aged 6 to 18) in 194 pediatric patients [see Dosage & Administration, Adverse Reactions, and Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Maintenance efficacy in pediatric patients has not been systematically evaluated.
Juvenile Animal Studies: Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.
Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.
Use in Elderly: No dosage adjustment is recommended for elderly patients [see Warnings and Pharmacology: Pharmacokinetics under Actions].
Of the 13,543 patients treated with oral Aripiprazole (Abilify) in clinical trials, 1073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral Aripiprazole (Abilify) in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Of the 749 patients treated with Aripiprazole (Abilify) injection in clinical trials, 99 (13%) were ≥65 years old and 78 (10%) were ≥75 years old. Placebo-controlled studies of Aripiprazole (Abilify) injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Aripiprazole (Abilify) is not approved for the treatment of patients with psychosis associated with Alzheimer's disease [see Warnings].

Use In Pregnancy & Lactation

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 monograph: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions].
Cerebrovascular Adverse Events, Including Stroke [see Precautions].
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Warnings and Precautions].
Neuroleptic Malignant Syndrome (NMS) [see Precautions].
Tardive Dyskinesia [see Precautions].
Metabolic Changes [see Precautions].
Pathological Gambling and Other Compulsive Behaviors [see Precautions].
Orthostatic Hypotension [see Precautions].
Falls [see Precautions].
Leukopenia, Neutropenia, and Agranulocytosis [see Precautions].
Seizures/Convulsions [see Precautions].
Potential for Cognitive and Motor Impairment [see Precautions].
Body Temperature Regulation [see Precautions].
Suicide [see Precautions].
Dysphagia [see Precautions].
The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.
The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.
Aripiprazole (Abilify) 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 (Abilify) and 749 patients with exposure to Aripiprazole (Abilify) injection. A total of 3390 patients were treated with oral Aripiprazole (Abilify) for at least 180 days and 1933 patients treated with oral Aripiprazole (Abilify) had at least 1 year of exposure.
Aripiprazole (Abilify) has been evaluated for safety in 1,686 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 exposure to oral Aripiprazole (Abilify). A total of 959 pediatric patients were treated with oral Aripiprazole (Abilify) for at least 180 days and 556 pediatric patients treated with oral Aripiprazole (Abilify) had at least 1 year of exposure.
The conditions and duration of treatment with Aripiprazole (Abilify) (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.
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 (Abilify) 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 Aripiprazole (Abilify) in patients with schizophrenia (incidence of 5% or greater and Aripiprazole (Abilify) incidence at least twice that for placebo) was akathisia (Aripiprazole (Abilify) 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 (Abilify) was administered at doses of 15 or 30 mg/day.
Commonly Observed Adverse Reactions: Commonly observed adverse reactions associated with the use of Aripiprazole (Abilify) in patients with bipolar mania (incidence of 5% or greater and Aripiprazole (Abilify) incidence at least twice that for placebo) are shown in Table 20. (See Table 20.)

Less Common Adverse Reactions in Adults: Table 21 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 (Abilify) (doses ≥2 mg/day) and for which the incidence in patients treated with Aripiprazole (Abilify) was greater than the incidence in patients treated with placebo in the combined dataset. (See Table 21.)

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 (Abilify) was administered at doses of 15 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 (Abilify) compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive Aripiprazole (Abilify)-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 (Abilify) 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 22 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 (Abilify) (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. (See Table 22.)

Pediatric Patients (13 to 17 years) with Schizophrenia: The following findings are based on one 6-week, placebo-controlled trial in which oral Aripiprazole (Abilify) 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 (Abilify)-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 (Abilify) in adolescent patients with schizophrenia (incidence of 5% or greater and Aripiprazole (Abilify) 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 (Abilify) 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 (Abilify)-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 (Abilify) in pediatric patients with bipolar mania (incidence of 5% or greater and Aripiprazole (Abilify) incidence at least twice that for placebo) are shown in Table 23. (See Table 23.)

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 (Abilify) 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 (Abilify)-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 (Abilify) in pediatric patients with autistic disorder (incidence of 5% or greater and Aripiprazole (Abilify) incidence at least twice that for placebo) are shown in Table 24. (See Table 24.)

Pediatric Patients (6 to 18 years) with Tourette's Disorder: The following findings are based on one 8-week and one 10-week, placebo-controlled trials in which oral Aripiprazole (Abilify) was administered in doses of 2 to 20 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between Aripiprazole (Abilify)-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively.
Commonly Observed Adverse Reactions: Commonly observed adverse reactions associated with the use of Aripiprazole (Abilify) in pediatric patients with Tourette's disorder (incidence of 5% or greater and Aripiprazole (Abilify) incidence at least twice that for placebo) are shown in Table 25. (See Table 25.)

Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Bipolar Mania, Autistic Disorder, or Tourette's Disorder: Table 26 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, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette's disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with Aripiprazole (Abilify) (doses ≥2 mg/day) and for which the incidence in patients treated with Aripiprazole (Abilify) was greater than the incidence in patients treated with placebo. (See Table 26.)

Adult Patients Receiving Aripiprazole (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 (Abilify) 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 (Abilify)-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 (Abilify) in patients with major depressive disorder (incidence of 5% or greater and Aripiprazole (Abilify) 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 27 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 (Abilify) (doses ≥2 mg/day) and for which the incidence in patients treated with adjunctive Aripiprazole (Abilify) was greater than the incidence in patients treated with adjunctive placebo in the combined dataset. (See Table 27.)

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 (Abilify) 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%).
Tourette's Disorder: In a study of pediatric patients (7 to 17 years of age) with Tourette's disorder, no common adverse reaction(s) had a dose response relationship.
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 (Abilify)-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for Aripiprazole (Abilify)-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 (Abilify)-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for Aripiprazole (Abilify)-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 (Abilify) and placebo, with the exception of the Barnes Akathisia Scale (Aripiprazole (Abilify), 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 (Abilify) and placebo, with the exception of the Simpson Angus Rating Scale (Aripiprazole (Abilify), 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 (Abilify) 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 (Abilify)-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy Aripiprazole (Abilify)-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 (Abilify)-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive Aripiprazole (Abilify)-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 (Abilify)-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for Aripiprazole (Abilify)-treated patients was 10% vs. 2% for placebo.
In the adult bipolar mania trials with monotherapy Aripiprazole (Abilify), the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between Aripiprazole (Abilify) and placebo (Aripiprazole (Abilify), 0.50; placebo, -0.01 and Aripiprazole (Abilify), 0.21; placebo, -0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the Aripiprazole (Abilify) and placebo groups. In the bipolar mania trials with Aripiprazole (Abilify) 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 (Abilify) and adjunctive placebo (Aripiprazole (Abilify), 0.73; placebo, 0.07 and Aripiprazole (Abilify), 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive Aripiprazole (Abilify) 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 (Abilify) and placebo (Aripiprazole (Abilify), 0.90; placebo, -0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the Aripiprazole (Abilify) 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 (Abilify)-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive Aripiprazole (Abilify)-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 (Abilify) and adjunctive placebo (Aripiprazole (Abilify), 0.31; placebo, 0.03 and Aripiprazole (Abilify), 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive Aripiprazole (Abilify) 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 (Abilify)-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for Aripiprazole (Abilify)-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 (Abilify) and placebo (Aripiprazole (Abilify), 0.1; placebo, -0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the Aripiprazole (Abilify) and placebo groups.
Tourette's Disorder In the short-term, placebo-controlled trials in Tourette's disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for Aripiprazole (Abilify)-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for Aripiprazole (Abilify)-treated patients was 4% vs. 6% for placebo.
In the pediatric (6 to 18 years) short-term Tourette's disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for Aripiprazole (Abilify) 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, and/or spasmodic deviations of the eyes, most commonly upward. 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 (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 Aripiprazole (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 Aripiprazole (Abilify). In addition, in a long-term (52 week), active-controlled study, the incidence of tremor was 5% (40/859) for Aripiprazole (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 (Abilify): 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.
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: 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, myoclonus, 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 as follows.
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.
Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Aripiprazole (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: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups and blood glucose fluctuation.

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