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Psychotropic Drug, Side Effects, Interactions, Warning, Uses & Dosage

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 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 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, 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 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.

Tardive dyskinesia 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 6
shows the proportion of 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).

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 %
FastingGlucose 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

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 %
Fasting 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 and <126 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 ABILIFY 2/236 0.8
Schizophrenia and Bipolar Disorder Placebo 2/110 1.8
Irritability ABILIFY 0/73 0
Associated with Autistic Disorder Placebo 0/32 0
ABILIFY 3/88 3.4
Tourette s Disorder Placebo 1/58 1.7
Pooled ABILIFY 1/22 4.5
Fasting Glucose Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Schizophrenia and Bipolar Disorder Placebo 0/12 0
Irritability ABILIFY 0/9 0
Associated with Autistic Disorder Placebo 0/1 0
ABILIFY 0/11 0
Tourette s Disorder Placebo 0/4 0

At 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 ABILIFY 34/1357 2.5
Normal to High (<200 mg/dL to ≥240 mg/dL) Placebo 27/973 2.8
Fasting Triglycerides ABILIFY 40/539 7.4
Normal to High (<150 mg/dL to≥200 mg/dL) Placebo 30/431 7.0
Fasting LDL Cholesterol ABILIFY 2/332 0.6
Normal to High (<100 mg/dL to ≥160 mg/dL) Placebo 2/268 0.7
HDL Cholesterol ABILIFY 121/1066 11.4
Normal to Low (≥40 mg/dL to <40 mg/dL) 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 ABILIFY 3/139 2.2
Normal to High (<200 mg/dL to ≥240 mg/dL) Placebo 7/135 5.2
Fasting Triglycerides ABILIFY 14/145 9.7
Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 6/147 4.1
Fasting LDL Cholesterol ABILIFY 0/54 0
Normal to High (<100 mg/dL to ≥160 mg/dL) Placebo 0/73 0
HDL Cholesterol ABILIFY 17/318 5.3
Normal to Low (≥40 mg/dL to <40 mg/dL) 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 ABILIFY 3/220 1.4
Normal to High (<170 mg/dL to ≥200 mg/dL) Placebo 0/116 0
Fasting Triglycerides ABILIFY 7/187 3.7
Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 4/85 4.7
HDL Cholesterol ABILIFY 27/236 11.4
Normal to Low (≥40 mg/dL to <40 mg/dL) 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 ABILIFY 1/95 1.1
Normal to High (<170 mg/dL to ≥200 mg/dL) Placebo 0/34 0
Fasting Triglycerides ABILIFY 0/75 0
Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 0/30 0
HDL Cholesterol ABILIFY 9/107 8.4
Normal to Low (≥40 mg/dL to <40 mg/dL) Placebo 5/49 10.2

Table 13 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 ABILIFY 1/85 1.2
Normal to High (<170 mg/dL to ≥200 mg/dL) Placebo 0/46 0
Fasting Triglycerides ABILIFY 5/94 5.3
Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 2/55 3.6
HDL Cholesterol ABILIFY 4/108 3.7
Normal to Low (≥40 mg/dL to <40 mg/dL) 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 bodyweight Schizophreniaa ABILIFY 852 69 (8.1)
Placebo 379 12 (3.2)
Bipolar Maniab ABILIFY 719 16 (2.2)
Placebo 598 16 (2.7)
Major Depressive Disorder (Adjunctive Therapy)c ABILIFY 347 18 (5.2)
Placebo 330 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.

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

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 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].

Falls

Antipsychotics, including 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 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 Increased Mortality in Elderly Patients with Dementia-Related Psychosis  and ADVERSE REACTIONS].

Patient Counseling Information

Advise the patient to read the FDA-approved patient
labeling (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.

Pathological Gambling And Other Compulsive Behaviors

Advise patients and their caregivers of the possibility
that they may experience compulsive urges to shop, intense urges to gamble,
compulsive sexual urges, binge eating and/or other compulsive urges and the
inability to control these urges while taking aripiprazole. In some cases, but
not all, the urges were reported to have stopped when the dose was reduced or
stopped [see WARNINGS AND PRECAUTIONS].

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
].

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.

Pregnancy

Advise patients to notify their healthcare provider if
they become pregnant or intend to become pregnant during treatment with
ABILIFY. Advise patients that ABILIFY may cause extrapyramidal and/or
withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence,
respiratory distress, and feeding disorder) in a neonate. Advise patients that
there is a pregnancy registry that monitors pregnancy outcomes in women exposed
to ABILIFY during pregnancy [see Use In Specific Populations].

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, F344 rats, and Sprague-Dawley (SD) 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, 0.5, 2 and 5 times and 0.3, 1 and 3
times the MRHD of 30 mg/day based on mg/m² body surface area, respectively). In
addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60
mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m² body surface
area. 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 (0.5 to 5 times the MRHD). In female rats, the incidence of mammary
gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times
the MRHD); and the incidences of adrenocortical carcinomas and combined
adrenocortical adenomas/carcinomas were increased at an oral dose of 60
mg/kg/day (19 times the MRHD).

An increase in mammary, pituitary, and endocrine pancreas
neoplasms has been found in rodents after chronic administration of other
antipsychotic drugs and is considered to be mediated by prolonged dopamine
D2-receptor antagonism and hyperprolactinemia. 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 unclear.

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, 2,3DCPP, increased 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 orally with aripiprazole from 2
weeks prior to mating through gestation day 7 at doses of 2, 6, and 20
mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m² body
surface area. 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 2 and 6 times the MRHD, and decreased fetal
weight was seen at 6 times the MRHD.

Male rats were treated orally with aripiprazole from 9
weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day,
which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m² body surface
area. Disturbances in spermatogenesis were seen at 19 times the MRHD and
prostate atrophy was seen at 13 and 19 times the MRHD without impairment of
fertility.

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to atypical antipsychotics, including
ABILIFY, during pregnancy. Healthcare providers are encouraged to register
patients by contacting the National Pregnancy Registry for Atypical
Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/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 following delivery (see Clinical Considerations).
Overall available data from published epidemiologic studies of pregnant women
exposed to aripiprazole have not established a drug-associated risk of major
birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).
There are risks to the mother associated with untreated schizophrenia, bipolar
I disorder, or major depressive disorder, and with exposure to antipsychotics,
including ABILIFY, during pregnancy (see Clinical Considerations).

In animal reproduction studies, oral and intravenous
aripiprazole administration during organogenesis in rats and/or rabbits at
doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD)
of 30 mg/day based on mg/m² body surface area, 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 postnatal period in rats at doses 10 times
the MRHD based on mg/m² body surface area, produced prolonged gestation,
stillbirths, decreased pup weight, and decreased pup survival (see Data).

The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

There is a risk to the mother from untreated
schizophrenia or bipolar I disorder, including increased risk of relapse,
hospitalization, and suicide. Schizophrenia and bipolar I disorder are
associated with increased adverse perinatal outcomes, including preterm birth.
It is not known if this is a direct result of the illness or other comorbid
factors.

A prospective, longitudinal study followed 201 pregnant
women with a history of major depressive disorder who were euthymic and taking
antidepressants at the beginning of pregnancy. The women who discontinued
antidepressants during pregnancy were more likely to experience a relapse of
major depression than women who continued antidepressants. Consider the risk of
untreated depression when discontinuing or changing treatment with
antidepressant medication during pregnancy and postpartum.

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. Monitor neonates for extrapyramidal and/or withdrawal
symptoms, and manage symptoms appropriately. Some neonates recovered within
hours or days without specific treatment; others required prolonged
hospitalization.

Data

Human Data

Published data from observational studies, birth
registries, and case reports on the use of atypical antipsychotics during
pregnancy do not report a clear association with antipsychotics and major birth
defects. A retrospective study from a Medicaid database of 9258 women exposed
to antipsychotics during pregnancy did not indicate an overall increased risk
for major birth defects.

Animal Data

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

In pregnant rats treated orally with aripiprazole during
organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3
and 10 times the MRHD of 30 mg/day based on mg/m² body surface area, a slight
prolongation of gestation and delay in fetal development, as evidenced by
decreased fetal weight and undescended testes, were observed at 10 times the
MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD.
Delivered offspring had increased incidences of hepatodiaphragmatic nodules and
diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups
were not examined for these findings). Postnatally, delayed vaginal opening was
seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased
fertility rate, corpora lutea, implants, live fetuses, and increased
post-implantation loss, likely mediated through effects on female offspring)
were observed at 10 times the MRHD; however, there was no evidence to suggest
that these developmental effects were secondary to maternal toxicity.

In pregnant rats injected intravenously with aripiprazole
during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9
times the MRHD of 30 mg/day based on mg/m² body surface area, decreased fetal
weight and delayed skeletal ossification were observed at 9 times the MRHD;
this dose also caused maternal toxicity.

In pregnant rabbits treated orally with aripiprazole
during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and
65 times the MRHD of 30 mg/day based on mg/m² body surface area, decreased
maternal food consumption, and increased abortions as well as increased fetal
mortality were observed at 65 times the MHRD. Decreased fetal weight and
increased incidence of fused sternebrae were observed at 19 and 65 times the
MRHD.

In pregnant rabbits injected intravenously with
aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which
are 2, 6, and 19 times the MRHD of 30 mg/day based on mg/m² body surface area,
decreased fetal weight, increased fetal abnormalities (primarily skeletal), and
decreased fetal skeletal ossification were observed at 19 times the MRHD; this
dose also caused maternal toxicity. The fetal no-effect dose was 10 mg/kg/day,
which is 6 times the MRHD.

In rats treated orally with aripiprazole peri- and
post-natally from gestation day 17 through postpartum day 21 at doses of 3, 10,
and 30 mg/kg/day which are 1, 3, and 10 times the MRHD of 30 mg/day based on
mg/m² body surface area slight maternal toxicity and slightly prolonged
gestation were observed at 10 times the MHRD. An increase in stillbirths and,
decreases in pup weight (persisting into adulthood) and survival were also seen
at this dose.

In rats injected intravenously with aripiprazole from
gestation day 6 through lactation day 20 at doses of 3, 8, and 20 mg/kg/day,
which are 1, 3, and 6 times the MRHD of 30 mg/day based on mg/m² body surface
area, increased stillbirths were observed at 3 and 6 times the MRHD; and
decreases in early postnatal pup weight and survival were observed at 6 times
the MRHD; these doses also caused some maternal toxicity. There were no effects
on postnatal behavioral and reproductive development.

Lactation

Risk Summary

Limited data from published literature report the
presence of aripiprazole in human breast milk, at relative infant doses ranging
between 0.7% to 8.3% of the maternal weight-adjusted dosage. There are reports
of poor weight gain in breastfed infants exposed to aripiprazole and reports of
inadequate milk supply in lactating women taking aripiprazole.

The development and health benefits of breastfeeding
should be considered along with the mother’s clinical need for ABILIFY and any
potential adverse effects on the breastfed infant from ABILIFY or from the
underlying maternal condition.

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
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 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].

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