August 31, 2015
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Abilify

"Feb. 22, 2011 -- The FDA has issued a safety announcement notifying health care professionals that it has updated the pregnancy section of drug labels for the entire class of antipsychotic medications.

Antipsychotic drugs are used to "...

Abilify




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING].

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

In three, 10-week, placebo-controlled studies of 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 ABILIFY incidence at least twice that for placebo were lethargy [placebo 2%, ABILIFY 5%], somnolence (including sedation) [placebo 3%, ABILIFY 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, ABILIFY 5%], excessive salivation [placebo 0%, ABILIFY 4%], and lightheadedness [placebo 1%, ABILIFY 4%].

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

Cerebrovascular Adverse Events, Including Stroke

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in 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 ABILIFY. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING].

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 5.

Table 5

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

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

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

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

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for 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 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 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 ABILIFY. Rare cases of NMS occurred during 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, 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 ABILIFY, drug discontinuation should be considered. However, some patients may require treatment with 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 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 ABILIFY was not marketed at the time these studies were performed, it is not known if 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 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 6shows the proportion of ABILIFY-treated patients with normal and borderline fasting

Table 6: Changes in Fasting Glucose From Placebo-Controlled Monotherapy Trials in Adult Patients

  Category Change (at least once)
from Baseline
Treatment Arm n/N %
Fasting Glucose Normal to High
( < 100 mg/dL to ≥ 126 mg/dL)
ABILIFY 31/822 3.8
Placebo 22/605 3.6
Borderline to High
( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL)
ABILIFY 31/176 17.6
Placebo 13/142 9.2

glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).

At 24 weeks, the mean change in fasting glucose in 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 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 7 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.

Table 7: Changes in Fasting Glucose From Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder

  Category Change (at least once) from Baseline Treatment Arm n/N %
Fastinq Glucose Normal to High
( < 100 mg/dL to ≥ 126 mg/dL)
ABILIFY 2/201 1.0
Placebo 2/204 1.0
Borderline to High
(≥100 mg/dL to ≥ 126 mg/dL)
ABILIFY 4/34 11.8
Placebo 3/37 8.1

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 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 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 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 8 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).

Table 8: Changes in Fasting Glucose From Placebo-Controlled Trials in Pediatric and Adolescent Patients

Category Change (at least once) from Baseline Indication Treatment Arm n/N %
Fasting Glucose Normal to High
( < 100 mg/dL to ≥ 126 mg/dL)
Pooled Schizophrenia and Bipolar Disorder ABILIFY 2/236 i 0.8
Placebo 2/110 1.8
Irritability Associated with Autistic Disorder ABILIFY 0/73 0
Placebo 0/32 0
Tourette's Disorder ABILIFY 3/88 3.4
Placebo 1/58 1.7
Fasting Glucose Borderline High
( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL)
Pooled Schizophrenia and Bipolar Disorder ABILIFY 1/22 4.5
Placebo 0/12 0
Irritability Associated with Autistic Disorder ABILIFY 0/9 0
Placebo 0/1 0
Tourette’s Disorder ABILIFY 0/11 0
Placebo 0/4 0

40At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder trials, the mean change in fasting glucose in 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 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 9 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).

Table 9: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Adults

  Treatment Arm n/N %
Total Cholesterol Normal to High
( < 200 mg/dL to ≥ 240 mg/dL)
ABILIFY 34/1357 2.5
Placebo 27/973 2.8
Fasting Triglycerides Normal to High
( < 150 mg/dL to ≥ 200 mg/dL)
ABILIFY 40/539 7.4
Placebo 30/431 7.0
Fasting LDL Cholesterol Normal to High
( < 100 mg/dL to ≥ 160 mg/dL)
ABILIFY 2/332 0.6
Placebo 2/268 0.7
HDL Cholesterol Normal to Low
( ≥ 40 mg/dL to < 40 mg/dL)
ABILIFY 121/1066 11.4
Placebo 99/794 12.5

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 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 10 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).

Table 10: Changes in Blood Lipid Parameters From Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder

  Treatment Arm n/N %
Total Cholesterol Normal to High
( < 200 mg/dL to ≥ 240 mg/dL)
ABILIFY 3/139 2.2
Placebo 7/135 5.2
Fasting Triglycerides Normal to High
( < 150 mg/dL to ≥ 200 mg/dL)
ABILIFY 14/145 9.7
Placebo 6/147 4.1
Fasting LDL Cholesterol Normal to High
( < 100 mg/dL to ≥ 160 mg/dL)
ABILIFY 0/54 0
Placebo 0/73 0
HDL Cholesterol Normal to Low
( ≥ 40 mg/dL to < 40 mg/dL)
ABILIFY 17/318 5.3
Placebo 10/286 3.5

Pediatric Patients and Adolescents

Table 11 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).

Table 11: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients in Schizophrenia and Bipolar Disorder

  Treatment Arm n/N %
Total Cholesterol
Normal to High
( < 170 mg/dL to ≥ 200 mg/dL)
ABILIFY 3/220 1.4
Placebo 0/116 0
Fasting Triglycerides
Normal to High
( < 150 mg/dL to ≥ 200 mg/dL)
ABILIFY 7/187 3.7
Placebo 4/85 4.7
HDL Cholesterol
Normal to Low
( ≥ 40 mg/dL to < 40 mg/dL)
ABILIFY 27/236 11.4
Placebo 22/109 20.2
HDL Cholesterol
Normal to Low
( ≥ 40 mg/dL to < 40 mg/dL)
ABILIFY 27/236 11.4
Placebo 22/109 20.2

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 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 12 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.

Table 12: Changes in Blood Lipid Parameters From Placebo-Controlled Trials in Pediatric Patients with Autistic Disorder

  Treatment Arm n/N %
Total Cholesterol
Normal to High
( < 170 mg/dL to ≥ 200 mg/dL)
ABILIFY 1/95 1.1
Placebo 0/34 0
Fasting Triglycerides
Normal to High
( < 150 mg/dL to ≥ 200 mg/dL)
ABILIFY 0/75 0
Placebo 0/30 0
HDL Cholesterol
Normal to Low
( ≥ 40 mg/dL to < 40 mg/dL)
ABILIFY 9/107 8.4
Placebo 5/49 10.2

Table13 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.

Table 13: Changes in Blood Lipid Parameters From Placebo-Controlled Trials in Pediatric Patients with Tourette's Disorder

  Treatment Arm n/N %
Total Cholesterol
Normal to High
( < 170 mg/dL to ≥ 200 mg/dL)
ABILIFY 1/85 1.2
Placebo 0/46 0
Fasting Triglycerides
Normal to High
( < 150 mg/dL to ≥ 200 mg/dL)
ABILIFY 5/94 5.3
Placebo 2/55 3.6
HDL Cholesterol
Normal to Low
( ≥ 40 mg/dL to < 40 mg/dL)
ABILIFY 4/108 3.7
Placebo 2/67 3.0

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 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 ABILIFY-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients.

In the trials adding ABILIFY to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive ABILIFY or placebo in addition to their ongoing antidepressant treatment. The mean change in body weight in patients receiving adjunctive ABILIFY was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo.

Table 14 shows the percentage of adult patients with weight gain ≥ 7% of body weight by indication.

Table 14: Percentage of Patients From Placebo-Controlled Trials in Adult Patients with Weight Gain ≥ 7% of Body Weight

  Indication Treatment Arm N Patients
n (%)
Weight gain ≥ 7% of body weight Schizophreniaa ABILIFY
Placebo
852 379 69 (8.1)
12 (3.2)
Bipolar Maniab ABILIFY
Placebo
719 598 16 (2.2)
16 (2.7)
Major Depressive Disorder (Adjunctive Therapy)c ABILIFY
Placebo
347 330 18 (5.2)
2 (0.6)
a 4-6 weeks duration.
b 3 weeks duration.
c 6 weeks duration.

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 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 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 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 ABILIFY-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients.

Table 15 shows the percentage of pediatric and adolescent patients with weight gain ≥ 7% of body weight by indication.

Table 15: Percentage of Patients From Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain ≥ 7% of Body Weight

  Indication Treatment Arm N Patients
n (%)
Weight gain ≥ 7% of body weight Pooled Schizophrenia and Bipolar Maniaa ABILIFY 381 20 (5.2)
Placebo 187 3 (1.6)
Irritability Associated with Autistic Disorderb ABILIFY 209 55 (26.3)
Placebo 98 7 (7.1)
Tourette's Disorderc ABILIFY 105 21 (20.0)
Placebo 66 5 (7.6)
a 4-6 weeks duration.
b 8 weeks duration.
c 8-10 weeks duration.

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 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 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.

Orthostatic Hypotension

ABILIFY may cause orthostatic hypotension, perhaps due to its a1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral ABILIFY (n=2467) included (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 ABILIFY included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0 %), and syncope (0.2%, 0%); and of patients on ABILIFY Injection (n=501) included orthostatic hypotension (0.6%, 0%), postural dizziness (0.2%, 0.5%), and syncope (0.4%, 0%). [see 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 ABILIFY was not meaningfully different from placebo (ABILIFY incidence, placebo incidence): in adult oral ABILIFY-treated patients (4%, 2%), in pediatric oral ABILIFY-treated patients aged 6 to 18 years (0.4%, 1%), or in ABILIFY injection-treated patients (3%, 2%).

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 DRUG INTERACTIONS].

If parenteral benzodiazepine therapy is deemed necessary in addition to ABILIFY injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension [see DRUG INTERACTIONS].

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 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 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 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 ABILIFY, in 0.1% (1/732) of pediatric patients (6 to 18 years), and in 0.2% (1/501) of adult ABILIFY injection-treated patients.

As with other antipsychotic drugs, 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.

Potential For Cognitive And Motor Impairment

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 (ABILIFY incidence, placebo incidence): in adult patients (n=2467) treated with oral ABILIFY (11%, 6%), in pediatric patients ages 6 to 17 (n=611) (24%, 6%), and in adult patients (n=501) on ABILIFY Injection (9%, 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 ABILIFY in short-term, placebo-controlled trials, but did not lead to discontinuation of any adult patients on ABILIFY Injection.

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 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 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 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 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 ABILIFY. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. ABILIFY and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Patient Counseling Information

See Medication Guide

Discuss the following issues with patients prescribed ABILIFY:

Clinical Worsening of Depression and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see WARNINGS AND PRECAUTIONS].

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with ABILIFY and should counsel them in its appropriate use. A patient Medication Guide including information about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for ABILIFY. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. It should be noted that ABILIFY is not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder.

Use of Orally Disintegrating Tablet

Do not open the blister until ready to administer. For single tablet removal, open the package and peel back the foil on the blister to expose the tablet. Do not push the tablet through the foil because this could damage the tablet. Immediately upon opening the blister, using dry hands, remove the tablet and place the entire ABILIFY DISCMELT Orally Disintegrating Tablet on the tongue. Tablet disintegration occurs rapidly in saliva. It is recommended that ABILIFY DISCMELT be taken without liquid. However, if needed, it can be taken with liquid. Do not attempt to split the tablet.

Interference with Cognitive and Motor Performance

Because ABILIFY may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ABILIFY therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Nursing

Advise patients that breastfeeding is not recommended with ABILIFY treatment because of the potential for serious adverse reactions in a nursing infant [see Use In Specific Populations].

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see DRUG INTERACTIONS].

Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].

Sugar Content

Patients should be advised that each mL of ABILIFY Oral Solution contains 400 mg of sucrose and 200 mg of fructose.

Phenylketonurics

Phenylalanine is a component of aspartame. Each ABILIFY DISCMELT Orally Disintegrating Tablet contains the following amounts: 10 mg, 1.12 mg phenylalanine and 15 mg, 1.68 mg phenylalanine.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Lifetime carcinogenicity studies were conducted in ICR mice, Sprague-Dawley (SD) rats, and F344 rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 times and 0.3 to 3 times the maximum recommended human dose [MRHD] based on mg/m²,respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the MRHD based on mg/m²). Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.1 to 0.9 times human exposure at MRHD based on AUC and 0.5 to 5 times the MRHD based on mg/m²). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (0.1 times human exposure at MRHD based on AUC and 3 times the MRHD based on mg/m²); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (14 times human exposure at MRHD based on AUC and 19 times the MRHD based on mg/m²).

Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4-week and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.

Mutagenesis

The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans.

Impairment of Fertility

Female rats were treated with oral doses of 2, 6, and 20 mg/kg/day (0.6, 2, and 6 times the maximum recommended human dose [MRHD] on a mg/m² basis) of aripiprazole from 2 weeks prior to mating through day 7 of gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 6 and 20 mg/kg/day and decreased fetal weight was seen at 20 mg/kg/day.

Male rats were treated with oral doses of 20, 40, and 60 mg/kg/day (6, 13, and 19 times the MRHD on a mg/m² basis) of aripiprazole from 9 weeks prior to mating through mating. Disturbances in spermatogenesis were seen at 60 mg/kg and prostate atrophy was seen at 40 and 60 mg/kg, but no impairment of fertility was seen.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ABILIFY during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs (including ABILIFY) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Adequate and well controlled studies with ABILIFY have not been conducted in pregnant women. Animal reproduction studies were conducted with aripiprazole in rats and rabbits during organogenesis, and in rats during the pre-and post-natal period. Oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses higher than the maximum recommended human dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses higher than the maximum recommended human dose (MRHD) produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. Administer ABILIFY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including ABILIFY) during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms.

Data

Animal Data

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the maximum recommended human dose [MRHD] on a mg/m² basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg/day. Treatment at the high dose of 30 mg/kg/day caused a slight delay in fetal development (decreased fetal weight), undescended testes, and delayed skeletal ossification (also seen at 10 mg/kg/day). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg/day), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg/day and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg/day. Some maternal toxicity was seen at 30 mg/kg/day however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

In pregnant rats receiving aripiprazole injection intravenously (3, 9, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose where it also caused maternal toxicity.

Pregnant rabbits were treated with oral doses of 10, 30 , and 100 mg/kg/day (2, 3, and 11 times human exposure at MRHD based on AUC and 6, 19, and 65 times the MRHD based on mg/m²) of aripiprazole during the period of organogenesis. At the high dose of 100 mg/kg/day decreased maternal food consumption, and increased abortions were seen as well as increased fetal mortality, decreased fetal weight (also seen at 30 mg/kg/day), increased incidence of a skeletal abnormality (fused sternebrae) (also seen at 30 mg/kg/day).

In pregnant rabbits receiving aripiprazole injection intravenously (3, 10, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg/day, which is 5 times the human exposure at the MRHD based on AUC and is 6 times the MRHD based on mg/m².

In a study in which rats were treated peri- and post-natally with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on a mg/m² basis) of aripiprazole from gestation day 17 through day 21 postpartum, slight maternal toxicity, slightly prolonged gestation an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were seen at 30 mg/kg/day.

In rats receiving aripiprazole injection intravenously (3, 8, and 20 mg/kg/day) from gestation day 6 through day 20 postpartum, an increase in stillbirths was seen at 8 and 20 mg/kg/day, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg/day; these effects were seen in presence of maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

Labor And Delivery

The effect of ABILIFY on labor and delivery in humans is unknown.

Nursing Mothers

ABILIFY is present in human breast milk. Because of the potential for serious adverse reactions in nursing infants from ABILIFY, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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 CLINICAL PHARMACOLOGY].

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 AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. 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 AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies ]. 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 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 AND USAGE, DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. 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 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 ABILIFY treatment or switch to placebo. In this trial, the efficacy of 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 AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. 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.

Geriatric Use

No dosage adjustment is recommended for elderly patients [see also BOXED WARNING, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

Of the 13,543 patients treated with oral ABILIFY in clinical trials, 1073 (8%) were ≥ 65 years old and 799 (6%) were ≥ 75 years old. Placebo-controlled studies of oral 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 ABILIFY injection in clinical trials, 99 (13%) were ≥ 65 years old and 78 (10%) were ≥ 75 years old. Placebo-controlled studies of 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.

ABILIFY is not approved for the treatment of patients with psychosis associated with Alzheimer's disease [see also BOXED WARNING and WARNINGS AND PRECAUTIONS].

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 AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic And Renal Impairment

No dosage adjustment for 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 CLINICAL PHARMACOLOGY].

Other Specific Populations

No dosage adjustment for ABILIFY is required on the basis of a patient's sex, race, or smoking status [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 8/20/2015
This monograph has been modified to include the generic and brand name in many instances.

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