ARIPLY 5;10;15;30

1. Name of the medicinal product:

ARIPLY 5; ARIPLY 10; ARIPLY 15 and ARIPLY 30

1.1 Qualitative and quantitative composition

• ARIPLY 5- Aripiprazole 5 mg, Tablet
• ARIPLY 10 - Aripiprazole 10 mg, Tablet
• ARIPLY 15- Aripiprazole 15 mg, Tablet
• ARIPLY 30- Aripiprazole 30 mg, Tablet

2. Therapeutic indications:
Ariply 5;10;15 and 30 Oral Tablets are indicated for the treatment of:
• For the treatment of schizophrenia.
• Acute Treatment of Manic and Mixed Episodes associated with Bipolar
I [see Clinical Studies (15.2)]
Ariply 5;10 and 15 Oral Tablets are indicated for the treatment of:
• use as an adjunctive therapy to antidepressants for the treatment of
major depressive disorder (MDD). Efficacy was established in two 6-
week trials in adults with MDD who had an inadequate response to
antidepressant therapy during the current episode.
• Irritability Associated with Autistic Disorder in Pediatric Patients (6
to 17 years) [see Clinical Studies (14.4)]

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH

DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND
BEHAVIORS WITH ANTIDEPRESSANT DRUGS
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are
at an increased risk of death. Aripiprazole is not approved for the treatment of patients
with dementia-related psychosis [see Warnings and Precautions (6.1)].
Antidepressants increased the risk of suicidal thoughts and behavior in children,
adolescents, and young adults in short-term studies. These studies did not show an
increase in the risk of suicidal thoughts and behavior with antidepressant use in
patients over age 24 years; there was a reduction in risk with antidepressant use in
patients aged 65 years and older [see Warnings and Precautions (6.3)].
In patients of all ages who are started on antidepressant therapy, monitor closely for
worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
caregivers of the need for close observation and communication with the prescriber
[see Warnings and Precautions (6.3)].
3 DOSAGE AND ADMINISTRATION

3.1 Schizophrenia
Adults
The recommended starting and target dose for ARIPLY is 10 or 15 mg/day
administered on a once-a-day schedule without regard to meals. ARIPLY has
been systematically evaluated and shown to be effective in a dose range of 10 to
30 mg/day, when administered as the tablet formulation; however, doses higher
than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage
increases should generally not be made before 2 weeks, the time needed to
achieve steady-
state [see Clinical Studies (15.1)].
Maintenance Treatment: Maintenance of efficacy in schizophrenia was
demonstrated in a trial involving patients with schizophrenia who had been
symptomatically stable on other antipsychotic medications for periods of 3
months or longer. These patients were discontinued from those medications
and randomized to either ARIPLY 15 mg/day or placebo, and observed for
relapse [see Clinical Studies (15.1)]. Patients should be periodically reassessed
to determine the continued need for maintenance treatment.
Adolescents
The recommended target dose of ARIPLY is 10 mg/day. Aripiprazole was
studied in adolescent patients 13 to 17 years of age with schizophrenia at daily
doses of 10 and 30 mg. The starting daily dose of the tablet formulation in
these patients was 2 mg, which was titrated to 5 mg after 2 days and to the
target dose of 10 mg after 2 additional days. Subsequent dose increases should
be administered in 5 mg increments. The 30 mg/day dose was not shown to be
more efficacious than the 10 mg/day dose. ARIPLY can be administered
without regard to meals [see Clinical Studies (15.1)]. Patients should be
periodically reassessed to determine the need for maintenance treatment.
Switching from Other Antipsychotics
There are no systematically collected data to specifically address switching
patients with schizophrenia from other antipsychotics to ARIPLY or concerning
concomitant administration with other antipsychotics. While immediate
discontinuation of the previous antipsychotic treatment may be acceptable for
some patients with schizophrenia, more gradual discontinuation may be most
appropriate for others. In all cases, the period of overlapping antipsychotic
administration should be minimized.

3.2 Bipolar I Disorder

Acute Treatment of Manic and Mixed Episodes
Adults: The recommended starting dose in adults is 15 mg given once daily as
monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with
lithium or valproate. ARIPLY can be given without regard to meals. The
recommended target dose of ARIPLY is 15 mg/day, as monotherapy or as
adjunctive therapy with lithium or valproate. The dose may be increased to 30
 mg/day based on clinical response. The safety of doses above 30 mg/day has not
been evaluated in clinical trials.
Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years)
as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a
target dose of 10 mg/day after 2 additional days. Recommended dosing as
adjunctive therapy to lithium or valproate is the same. Subsequent dose
increases, if needed, should be administered in 5 mg/day increments. ARIPLY
can be given without regard to
meals [see Clinical Studies (15.2)].

3.3 Adjunctive Treatment of Major Depressive Disorder

Adults
The recommended starting dose for ARIPLY as adjunctive treatment for
patients already taking an antidepressant is 2 to 5 mg/day. The recommended
dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should
occur gradually, at intervals of no less than 1 week [see Clinical Studies
(15.3)]. Patients should be periodically reassessed to determine the continued
need for maintenance treatment.

3.4 Irritability Associated with Autistic Disorder

Pediatric Patients (6 to 17 years)
The recommended dosage range for the treatment of pediatric patients with
irritability associated with autistic disorder is 5 to 15 mg/day.
Dosing should be initiated at 2 mg/day. The dose should be increased to 5
mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose
adjustments of up to 5 mg/day should occur gradually, at intervals of no less
than 1 week [see Clinical Studies (15.4)]. Patients should be periodically
reassessed to determine the continued need for maintenance treatment.

3.5 Dosage Adjustments for Cytochrome P450 Considerations

Dosage adjustments are recommended in patients who are known CYP2D6 poor
metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6
inhibitors or strong CYP3A4 inducers (see Table 1). When the coadministered
drug is withdrawn from the combination therapy, ARIPIPRAZOLE dosage
should then be adjusted to its original level. When the coadministered CYP3A4
inducer is withdrawn, ARIPIPRAZOLE dosage should be reduced to the
original level over 1 to 2 weeks. Patients who may be receiving a combination
of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a
strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate
CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be
reduced to one-quarter (25%) of the usual dose initially and then adjusted to
achieve a favorable clinical response.

Table 1: Dose Adjustments for Aripiprazole in Patients who are known CYP2D6 Poor Metabolizers and Patients
Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers
 Dosage Adjustments
Factors
for ARIPIPRAZOLE

Administer half of
Known CYP2D6 Poor Metabolizers
usual dose

Known CYP2D6 Poor Metabolizers

taking concomitant strong CYP3A4 Administer a quarter of
inhibitors (e.g., itraconazole, usual dose
clarithromycin)

Strong CYP2D6 (e.g., quinidine,

fluoxetine, paroxetine) or CYP3A4 Administer half of
inhibitors (e.g., itraconazole, usual dose
clarithromycin)

Strong CYP2D6 and CYP3A4 Administer a quarter of

inhibitors usual dose

Strong CYP3A4 inducers (e.g., Double usual dose over

carbamazepine, rifampin) 1 to 2 weeks

When adjunctive ARIPLY is administered to patients with major depressive

disorder, ARIPLY should be administered without dosage adjustment as
specified in Dosage and Administration (3.3).

4 DOSAGE FORMS
Ariply 5 drug product is presented as round, biconvex, pale- yellow
tablet with breakline on one side.
Ariply 10;15 and 30 drug product is presented as round, biconvex, pale yellow tablet.

5 CONTRAINDICATIONS
ARIPLY is contraindicated in patients with a history of a hypersensitivity
reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to
anaphylaxis [see Adverse Reactions (7.2)].
6 WARNINGS AND PRECAUTIONS
6.1 Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death. ARIPLY
(aripiprazole) is not approved for the treatment of patients with
dementia-related psychosis [see Boxed Warning].
6.2 Cerebrovascular Adverse Events, Including Stroke
In placebo-controlled clinical studies (two flexible dose and one fixed dose
study) of dementia-related psychosis, there was an increased incidence of
cerebrovascular adverse events (e.g., stroke, transient ischemic attack),
including fatalities, in aripiprazole -treated patients (mean age: 84 years; range:
78 to 88 years). In the fixed- dose study, there was a statistically significant
dose response relationship for cerebrovascular adverse events in patients treated
with aripiprazole. ARIPLY is not approved for the treatment of patients with
dementia-related psychosis [see Boxed Warning].

6.3 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 to
24 years) with MDD and other psychiatric disorders. Short-term studies did not
show an increase in the risk of suicidality with antidepressants
compared antidepressants compared to placebo in adults aged 65 years and [Link]
placebo in adults beyond age 24 years; there was a reduction with
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 2:

Age Drug-Placebo Difference in Number of Cases of

Range Suicidality per 1000 Patients Treated

Increases Compared to Placebo

<18 14 additional cases

18 to 24 5 additional cases

Decreases Compared to Placebo

25 to 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 ARIPIPRAZOLE
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 ARIPLY is not approved for use in treating depression in the
pediatric population.

6.4 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
ARIPLY. Rare cases of NMS occurred during ARIPLY 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.

6.5 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, ARIPLY 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 ARIPLY, drug
discontinuation should be considered. However, some patients may require treatment
with ARIPLY despite the presence of the syndrome.
6.6 Metabolic Changes
Atypical antipsychotic drugs have been associated with metabolic changes that
include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While
all drugs in the class have been shown to produce some metabolic changes, each
drug has its own specific risk profile.
Hyperglycemia/Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or
hyperosmolar coma or death, has been reported in patients treated with atypical
antipsychotics. There have been reports of hyperglycemia in patients treated with
aripiprazole [see Adverse Reactions (7.1, 7.2)]. Assessment of the relationship
between atypical antipsychotic use and glucose abnormalities is complicated by the
possibility of an increased background risk of diabetes mellitus in patients with
schizophrenia and the increasing incidence of diabetes mellitus in the general
population. Given these confounders, the relationship between atypical antipsychotic
use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of hyperglycemia-related
adverse reactions in patients treated with the atypical antipsychotics. Because
aripiprazole was not marketed at the time these studies were performed, it is not
known if aripiprazole is associated with this increased risk. Precise risk estimates for
hyperglycemia-related adverse reactions in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control.
Patients with risk factors for diabetes mellitus (e.g., obesity, family history of
diabetes) who are starting treatment with atypical antipsychotics should undergo
fasting blood glucose testing at the beginning of treatment and periodically during
treatment. Any patient treated with atypical antipsychotics should be monitored for
symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and
weakness. Patients who develop symptoms of hyperglycemia during treatment with
atypical antipsychotics should undergo fasting blood glucose testing. In some cases,
hyperglycemia has resolved when the atypical antipsychotic was discontinued;
however, some patients required continuation of anti-diabetic treatment despite
discontinuation of the suspect drug.
Adults
In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with
schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazole -
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 3 shows the proportion of aripiprazole -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 3: Changes in Fasting Glucose from Placebo-Controlled
Monotherapy Trials in Adult Patients

Category Change (at least Treatment

once) from Baseline Arm n/N %

Normal to High Aripiprazole 31/822 3.8

(<100 mg/dL to ≥126 mg/dL)
Fasting
Glucose Placebo 22/605 3.6

Borderline to High Aripiprazole 31/176 17.6

(≥100 mg/dL and <126 mg/dL
to ≥126 mg/dL) Placebo 13/142 9.2

At 24 weeks, the mean change in fasting glucose in aripiprazole -treated patients was
not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and
+9.6 mg/dL (n=28), respectively].
The mean change in fasting glucose in adjunctive aripiprazole -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 4 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 4: Changes in Fasting Glucose from Placebo-Controlled

Adjunctive Trials in Adult Patients with Major Depressive Disorder

Category Change (at least Treatment

once) from Baseline Arm n/N %

Normal to High Aripiprazole 2/201 1.0

(<100 mg/dL to ≥126 mg/dL)
Fasting
Glucose Placebo 2/204 1.0

Borderline to High Aripiprazole 4/34 11.8

(≥100 mg/dL and <126
mg/dL to ≥126 mg/dL) 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 aripiprazole -treated patients (+4.8 mg/dL; with a median
exposure of 43 days; N=259) was not significantly different than in placebo-treated
patients (+1.7 mg/dL; with a median exposure of 42 days; N=123).
In an analysis of two placebo-controlled trials in pediatric and adolescent patients
with irritability associated with autistic disorder (6 to 17 years) with median exposure
of 56 days, the mean change in fasting glucose in aripiprazole -treated patients (–0.2
mg/dL; N=83) was not significantly different than in placebo-treated patients (–0.6
mg/dL; N=33).
Table 5 shows the proportion of patients with changes in fasting glucose levels from
the pooled adolescent schizophrenia and pediatric bipolar patients (median exposure
of 42 to 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).

11
Table 5: Changes in Fasting Glucose from Placebo-Controlled Trials
in Pediatric and Adolescent Patients

Category Change (at

least once) from Treatment
Baseline Indication Arm n/N %

Aripiprazole 2/236 0.8

Pooled Schizophrenia
and Bipolar Disorder
Placebo 2/110 1.8

Fasting Glucose Aripiprazole 0/73 0

Normal to High Irritability Associated
(<100 mg/dL to ≥126 with Autistic Disorder
mg/dL) Placebo 0/32 0

Aripiprazole 3/88 3.4

Tourette's Disorder
Placebo 1/58 1.7

Aripiprazole 1/22 4.5

Pooled Schizophrenia
and Bipolar Disorder
Placebo 0/12 0
Fasting Glucose
Borderline to High
Aripiprazole 0/9 0
(≥100 mg/dL and <126 Irritability Associated
mg/dL to ≥126 mg/dL) with Autistic Disorder
Placebo 0/1 0

Tourette's Disorder Aripiprazole 0/11 0

12
Table 5: Changes in Fasting Glucose from Placebo-Controlled Trials
in Pediatric and Adolescent Patients

Category Change (at

least once) from Treatment
Baseline Indication Arm n/N %

Placebo 0/4 0

At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder

trials, the mean change in fasting glucose in aripiprazole -treated patients was not
significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1
mg/dL (n=15), respectively].
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical
antipsychotics.
There were no significant differences between aripiprazole - 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 6 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 6: Changes in Blood Lipid Parameters from Placebo-
Controlled Monotherapy Trials in Adults

Treatment Arm n/N %

Total Cholesterol Aripiprazole 34/1357 2.5

Normal to High
(<200 mg/dL to ≥240 mg/dL) Placebo 27/973 2.8

Aripiprazole 40/539 7.4

13
 Table 6: Changes in Blood Lipid Parameters from Placebo-
Controlled Monotherapy Trials in Adults

Treatment Arm n/N %

Fasting Triglycerides
Normal to High Placebo 30/431 7.0
(<150 mg/dL to ≥200 mg/dL)

Fasting LDL Cholesterol Aripiprazole 2/332 0.6

Normal to High
(<100 mg/dL to ≥160 mg/dL) Placebo 2/268 0.7

HDL Cholesterol Aripiprazole 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 Aripiprazole - 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 7 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 7: Changes in Blood Lipid Parameters from Placebo-
Controlled Adjunctive Trials in Adult Patients with Major
Depressive Disorder

Treatment Arm n/N %

Total Cholesterol Aripiprazole 3/139 2.2

Normal to High
(<200 mg/dL to ≥240 mg/dL) Placebo 7/135 5.2

Aripiprazole 14/145 9.7

14
 Table 7: Changes in Blood Lipid Parameters from Placebo-
Controlled Adjunctive Trials in Adult Patients with Major
Depressive Disorder

Treatment Arm n/N %

Fasting Triglycerides
Normal to High Placebo 6/147 4.1
(<150 mg/dL to ≥200 mg/dL)

Fasting LDL Cholesterol Aripiprazole 0/54 0

Normal to High
(<100 mg/dL to ≥160 mg/dL) Placebo 0/73 0

HDL Cholesterol Aripiprazole 17/318 5.3

Normal to Low
(≥40 mg/dL to <40 mg/dL) Placebo 10/286 3.5

Pediatric Patients and Adolescents

Table 8 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 8: 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 Aripiprazole 3/220 1.4

Normal to High
(<170 mg/dL to ≥200 mg/dL) Placebo 0/116 0

Fasting Triglycerides Aripiprazole 7/187 3.7

Normal to High
(<150 mg/dL to ≥200 mg/dL) Placebo 4/85 4.7

Aripiprazole 27/236 11.4

15
 Table 8: Changes in Blood Lipid Parameters from Placebo-
Controlled Monotherapy Trials in Pediatric and Adolescent Patients
in Schizophrenia and Bipolar Disorder

Treatment Arm n/N %

HDL Cholesterol
Normal to Low Placebo 22/109 20.2
(≥40 mg/dL to <40 mg/dL)

In monotherapy trials of adolescents with schizophrenia and pediatric patients with

bipolar disorder, the proportion of patients at 12 weeks and 24 weeks with changes
from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides,
and fasting LDL cholesterol were similar between Aripiprazole - 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 9 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 9: Changes in Blood Lipid Parameters from Placebo-
Controlled Trials in Pediatric Patients with Autistic Disorder

Treatment Arm n/N %

Total Cholesterol Aripiprazole 1/95 1.1

Normal to High
(<170 mg/dL to ≥200 mg/dL) Placebo 0/34 0

Fasting Triglycerides Aripiprazole 0/75 0

Normal to High
(<150 mg/dL to ≥200 mg/dL) Placebo 0/30 0

HDL Cholesterol Aripiprazole 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

16
cholesterol (median exposure 57 days) from two placebo-controlled trials in pediatric
patients (6 to 18 years) with Tourette's Disorder.
Table 10: Changes in Blood Lipid Parameters from Placebo-
Controlled Trials in Pediatric Patients with Tourette's Disorder

Treatment Arm n/N %

Total Cholesterol Aripiprazole 1/85 1.2

Normal to High
(<170 mg/dL to ≥200 mg/dL) Placebo 0/46 0

Fasting Triglycerides Aripiprazole 5/94 5.3

Normal to High
(<150 mg/dL to ≥200 mg/dL) Placebo 2/55 3.6

HDL Cholesterol Aripiprazole 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 aripiprazole -treated patients was +0.3 kg (N=1673)
compared to –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean
change from baseline in body weight in aripiprazole -treated patients was –1.5 kg
(n=73) compared to –0.2 kg (n=46) in placebo-treated patients.
In the trials adding aripiprazole to antidepressants, patients first received 8 weeks of
antidepressant treatment followed by 6 weeks of adjunctive aripiprazole or placebo in
addition to their ongoing antidepressant treatment. The mean change in body weight
in patients receiving adjunctive aripiprazole was +1.7 kg (N=347) compared to +0.4
kg (N=330) in patients receiving adjunctive placebo.
Table 11 shows the percentage of adult patients with weight gain ≥7% of body weight
by indication.

17
 Table 11: Percentage of Patients from Placebo-Controlled Trials in
Adult Patients with Weight Gain ≥7% of Body Weight

Treatment Patients
Indication Arm N n (%)

*
4 to 6 weeks duration
†
3 weeks duration.
‡
6 weeks duration.
Aripiprazole 852 69 (8.1)
Schizophrenia*
Placebo 379 12 (3.2)
Aripiprazole 719 16 (2.2)
Bipolar Mania†
Weight gain ≥7% Placebo 598 16 (2.7)
of body weight Major Depressive Aripiprazole 347 18 (5.2)
Disorder
(Adjunctive Placebo 330 2 (0.6)
Therapy)‡

Pediatric Patients and Adolescents

In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13
to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with median
exposure of 42 to 43 days, the mean change in body weight in aripiprazole -treated
patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated
patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole -
treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated
patients.
In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability
associated with autistic disorder with median exposure of 56 days, the mean change in
body weight in aripiprazole -treated patients was +1.6 kg (n=209) compared to +0.4
kg (n=98) in placebo-treated patients.

Table 12 shows the percentage of pediatric and adolescent patients with weight gain
≥7% of body weight by indication.
Table 12: Percentage of Patients from Placebo-Controlled
Monotherapy Trials in Pediatric and Adolescent Patients with
Weight Gain ≥7% of Body Weight

Treatment Patients n
Indication Arm N (%)

*
4 to 6 weeks duration

18
 Table 12: Percentage of Patients from Placebo-Controlled
Monotherapy Trials in Pediatric and Adolescent Patients with
Weight Gain ≥7% of Body Weight

Treatment Patients n
Indication Arm N (%)

†
8 weeks duration.
‡
8 to 10 weeks duration.
Pooled Schizophrenia Aripiprazole 381 20 (5.2)
and Bipolar Mania* Placebo 187 3 (1.6)
Weight gain Aripiprazole 209 55 (26.3)
Irritability Associated
≥7% of body
with Autistic Disorder† Placebo 98 7 (7.1)
weight
Aripiprazole 105 21 (20.0)
Tourette's Disorder‡
Placebo 66 5 (7.6)

In an open-label trial that enrolled patients from the two placebo-controlled trials of
adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar
disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy
with aripiprazole. After 26 weeks, 32.8% of patients gained ≥7% of their body
weight, not adjusted for normal growth. To adjust for normal growth, z-scores were
derived (measured in standard deviations [SD]), which normalize for the natural
growth of pediatric patients and adolescents by comparisons to age- and gender-
matched population standards. A z-score change <0.5 SD is considered not clinically
significant. After 26 weeks, the mean change in z-score was 0.09 SD.
In an open-label trial that enrolled patients from two short-term, placebo-controlled
trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well
as de novo patients, 60.3% (199/330) completed one year of therapy with aripiprazole.
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.

6.7 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

19
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.

6.8 Orthostatic Hypotension

ARIPLY may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor
antagonism. The incidence of orthostatic hypotension-associated events from short-
term, placebo-controlled trials of adult patients on oral aripiprazole (n=2467) included
(aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%),
postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to
18 years of age (n=732) on oral aripiprazole included orthostatic hypotension (0.5%,
0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%); and of patients on
[see Adverse Reactions (7.1)].
The incidence of a significant orthostatic change in blood pressure (defined as a
decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart
rate ≥25 bpm when comparing standing to supine values) for aripiprazole was not
meaningfully different from placebo (aripiprazole incidence, placebo incidence): in
adult oral aripiprazole treated patients (4%, 2%), in pediatric oral aripiprazole -treated
patients aged 6 to 18 years (0.4%, 1%).
ARIPLY 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 (8.1)].

6.9 Falls
Antipsychotics, including ARIPLY, 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.

6.10 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
ARIPLY. 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 ARIPLY 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
ARIPLY in patients with severe neutropenia (absolute neutrophil count <1000/mm3)
and follow their WBC counts until recovery.

20
6.11 Seizures/Convulsions
In short-term, placebo-controlled trials, patients with a history of seizures excluded
seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated
with oral aripiprazole, in 0.1% (1/732) of pediatric patients (6 to 18 years).
As with other antipsychotic drugs, ARIPLY 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.

6.12 Potential for Cognitive and Motor Impairment

ARIPLY, like other antipsychotics, may have the potential to impair judgment,
thinking, or motor skills. For example, in short-term, placebo-controlled trials,
somnolence (including sedation) was reported as follows (aripiprazole incidence,
placebo incidence): in adult patients (n=2467) treated with oral aripiprazole (11%,
6%), in pediatric patients ages 6 to 17 years (n=611; 24%, 6%), and in adult patients
(n=501) on aripiprazole 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 aripiprazole in short-term, placebo-controlled trials,
but did not lead to discontinuation of any adult patients on aripiprazole 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 ARIPLY does not
affect them adversely.

6.13 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 ARIPLY 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 (7.2)].

6.14 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 ARIPLY should be written for the smallest
quantity consistent with good patient management in order to reduce the risk of
overdose [see Adverse Reactions (7.1, 7.2)].

6.15 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug
use, including ARIPLY. Aspiration pneumonia is a common cause of morbidity and
mortality in elderly patients, in particular those with advanced Alzheimer's dementia.
ARIPLY and other antipsychotic drugs should be used cautiously in patients at risk
for aspiration pneumonia [see Warnings and Precautions (6.1) and Adverse Reactions
(7.2)].

21
7 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates observed in
practice.
The following adverse reactions are discussed in more detail in other sections of the
labeling:
• Increased Mortality in Elderly Patients with Dementia-Related
Psychosis [see Boxed Warning and Warnings and Precautions (6.1)]
• Cerebrovascular Adverse Events, Including Stroke [see Warnings and
Precautions (6.2)]
• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young
Adults [see Boxed Warning and Warnings Precautions (6.3)]
• Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions
(6.4)]
• Tardive Dyskinesia [see Warnings and Precautions (6.5)]
• Metabolic Changes [see Warnings and Precautions (6.6)]
• Pathological Gambling and Other Compulsive Behaviors [see Warnings
and Precautions (6.7)]
• Orthostatic Hypotension [see Warnings and Precautions (6.8)]
• Falls [see Warnings and Precautions (6.9)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and
Precautions (6.10)]
• Seizures/Convulsions [see Warnings and Precautions (6.11)]
• Potential for Cognitive and Motor Impairment [see Warnings and
Precautions (6.12)]
• Body Temperature Regulation [see Warnings and Precautions (6.13)]
• Suicide [see Warnings and Precautions (6.14)]
• Dysphagia [see Warnings and Precautions (6.15)]

The most common adverse reactions in adult patients in clinical trials (≥10%) were
nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and
restlessness.
The most common adverse reactions in the pediatric clinical trials (≥10%) were
somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite,
insomnia, nausea, nasopharyngitis, and weight increased.
Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in
multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive
disorder, Dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and
who had approximately 7619 patient-years of exposure to oral aripiprazole and 749
patients with exposure to aripiprazole injection. A total of 3390 patients were treated
with oral aripiprazole for at least 180 days and 1933 patients treated with oral
aripiprazole had at least 1 year of exposure.
Aripiprazole has been evaluated for safety in 1,686 pediatric patients (6 to 18
years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar
mania, autistic disorder, or Tourette's disorder and who had approximately 1,342
patient-years of
22
exposure to oral aripiprazole. A total of 959 pediatric patients were treated with oral
aripiprazole for at least 180 days and 556 pediatric patients treated with oral
aripiprazole had at least 1 year of exposure.
The conditions and duration of treatment with aripiprazole (monotherapy and
adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping
categories) double-blind, comparative and noncomparative open-label studies,
inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and
longer-term exposure.

7.1 Clinical Trials Experience

Adult Patients with Schizophrenia
The following findings are based on a pool of five placebo-controlled trials (four 4-
week and one 6-week) in which oral aripiprazole was administered in doses ranging
from 2 to 30 mg/day.
Commonly Observed Adverse Reactions
The only commonly observed adverse reaction associated with the use of ARIPLY in
patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at
least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).
Adult Patients with Bipolar Mania
Monotherapy
The following findings are based on a pool of 3-week, placebo-controlled, bipolar
mania trials in which oral aripiprazole was administered at doses of 15 or 30 mg/day.
Commonly Observed Adverse Reactions
Commonly observed adverse reactions associated with the use of ARIPLY in patients
with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least
twice that for placebo) are shown in Table 13.
Table 13: Commonly Observed Adverse Reactions in Short-
Term, Placebo-Controlled Trials of Adult Patients with
Bipolar Mania Treated with Oral aripiprazole Monotherapy

Percentage of Patients
Reporting Reaction

Aripiprazole Placebo
Preferred Term
(n=917) (n=753)

Akathisia 13 4

Sedation 8 3

Restlessness 6 3

23
Table 13: Commonly Observed Adverse Reactions in Short-
Term, Placebo-Controlled Trials of Adult Patients with
Bipolar Mania Treated with Oral aripiprazole Monotherapy

Percentage of Patients
Reporting Reaction

Aripiprazole Placebo
Preferred Term
(n=917) (n=753)

Tremor 6 3

Extrapyramidal Disorder 5 2

Less Common Adverse Reactions in Adults

Table 14 enumerates the pooled incidence, rounded to the nearest percent, of adverse
reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to
3 weeks in bipolar mania), including only those reactions that occurred in 2% or more
of patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in
patients treated with aripiprazole was greater than the incidence in patients treated
with placebo in the combined dataset.
Table 14: Adverse Reactions in Short-Term, Placebo-Controlled
Trials in Adult Patients Treated with Oral aripiprazole

Percentage of Patients Reporting

Reaction*

System Organ Class Aripiprazole Placebo

Preferred Term (n=1843) (n=1166)

*
Adverse reactions reported by at least 2% of patients treated with oral
aripiprazole, except adverse reactions which had an incidence equal to
or less than placebo.
Eye Disorders
Blurred Vision 3 1
Gastrointestinal Disorders
Nausea 15 11
Constipation 11 7
Vomiting 11 6
Dyspepsia 9 7
Dry Mouth 5 4
Toothache 4 3

24
 Table 14: Adverse Reactions in Short-Term, Placebo-Controlled
Trials in Adult Patients Treated with Oral aripiprazole

Percentage of Patients Reporting

Reaction*

System Organ Class Aripiprazole Placebo

Preferred Term (n=1843) (n=1166)

Abdominal Discomfort 3 2
Stomach Discomfort 3 2
General Disorders and Administration Site Conditions
Fatigue 6 4
Pain 3 2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Stiffness 4 3
Pain in Extremity 4 2
Myalgia 2 1
Muscle Spasms 2 1
Nervous System Disorders
Headache 27 23
Dizziness 10 7
Akathisia 10 4
Sedation 7 4
Extrapyramidal Disorder 5 3
Tremor 5 3
Somnolence 5 3
Psychiatric Disorders
Agitation 19 17
Insomnia 18 13
Anxiety 17 13
Restlessness 5 3
Respiratory, Thoracic, and Mediastinal Disorders
Pharyngolaryngeal Pain 3 2
Cough 3 2

An examination of population subgroups did not reveal any clear evidence of

differential adverse reaction incidence on the basis of age, gender, or race.
Adult Patients with Adjunctive Therapy with Bipolar Mania
The following findings are based on a placebo-controlled trial of adult patients with
bipolar disorder in which aripiprazole was administered at doses of 15 or 30 mg/day
as adjunctive therapy with lithium or valproate.
Adverse Reactions Associated with Discontinuation of Treatment

25
In a study of patients who were already tolerating either lithium or valproate as
monotherapy, discontinuation rates due to adverse reactions were 12% for patients
treated with adjunctive aripiprazole compared to 6% for patients treated with
adjunctive placebo. The most common adverse drug reactions associated with
discontinuation in the adjunctive aripiprazole -treated compared to placebo-treated
patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%,
respectively).
Commonly Observed Adverse Reactions
The commonly observed adverse reactions associated with adjunctive aripiprazole
and lithium or valproate in patients with bipolar mania (incidence of 5% or greater
and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia,
and extrapyramidal disorder.
Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in
Bipolar Mania
Table 15 enumerates the incidence, rounded to the nearest percent, of adverse
reactions that occurred during acute treatment (up to 6 weeks), including only those
reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole
(doses of 15 or 30 mg/day) and lithium or valproate and for which the incidence in
patients treated with this combination was greater than the incidence in patients
treated with placebo plus lithium or valproate.
Table 15: Adverse Reactions in a Short-Term, Placebo-Controlled
Trial of Adjunctive Therapy in Patients with Bipolar Disorder

Percentage of Patients Reporting

Reaction*

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

*
Adverse reactions reported by at least 2% of patients treated with oral
aripiprazole, except adverse reactions which had an incidence equal to
or less than placebo.
†
Lithium or Valproate
Gastrointestinal Disorders
Nausea 8 5
Vomiting 4 0
Salivary Hypersecretion 4 2
Dry Mouth 2 1
Infections and Infestations
Nasopharyngitis 3 2
Investigations
Weight Increased 2 1

26
 Table 15: Adverse Reactions in a Short-Term, Placebo-Controlled
Trial of Adjunctive Therapy in Patients with Bipolar Disorder

Percentage of Patients Reporting

Reaction*

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

Nervous System Disorders

Akathisia 19 5
Tremor 9 6
Extrapyramidal Disorder 5 1
Dizziness 4 1
Sedation 4 2
Psychiatric Disorders
Insomnia 8 4
Anxiety 4 1
Restlessness 2 1

Pediatric Patients (13 to 17 years) with Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which
oral aripirazole was administered in doses ranging from 2 to 30 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions between aripiprazole treated
and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.
Commonly Observed Adverse Reactions
Commonly observed adverse reactions associated with the use of ARIPLY in
adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole
incidence at least twice that for placebo) were extrapyramidal disorder, somnolence,
and tremor.
Pediatric Patients (10 to 17 years) with Bipolar Mania
The following findings are based on one 4-week, placebo-controlled trial in which
oral aripiprazole was administered in doses of 10 or 30 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions between aripiprazole-
treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%,
respectively.
Commonly Observed Adverse Reactions

27
Commonly observed adverse reactions associated with the use of aripiprazole in
pediatric patients with bipolar mania (incidence of 5% or greater and aripiprazole
incidence at least twice that for placebo) are shown in Table 16.
Table 16: Commonly Observed Adverse Reactions in Short-Term,
Placebo-Controlled Trials of Pediatric Patients (10 to 17 years) with
Bipolar Mania Treated with Oral aripiprazole

Percentage of Patients Reporting

Reaction

Aripiprazole Placebo
Preferred Term
(n=197) (n=97)

Somnolence 23 3

Extrapyramidal Disorder 20 3

Fatigue 11 4

Nausea 11 4

Akathisia 10 2

Blurred Vision 8 0

Salivary Hypersecretion 6 0

Dizziness 5 1

Pediatric Patients (6 to 17 years) with Autistic Disorder

The following findings are based on two 8-week, placebo-controlled trials in which
oral aripiprazole was administered in doses of 2 to 15 mg/day.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions between aripiprazole -
treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%,
respectively.
Commonly Observed Adverse Reactions
Commonly observed adverse reactions associated with the use of aripiprazole in
pediatric patients with autistic disorder (incidence of 5% or greater and aripiprazole
incidence at least twice that for placebo) are shown in Table 17.

28
 Table 17: Commonly Observed Adverse Reactions in Short-Term,
Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with
Autistic Disorder Treated with Oral aripiprazole

Percentage of Patients Reporting

Reaction

Aripiprazole Placebo
Preferred Term
(n=212) (n=101)

Sedation 21 4

Fatigue 17 2

Vomiting 14 7

Somnolence 10 4

Tremor 10 0

Pyrexia 9 1

Drooling 9 0

Decreased Appetite 7 2

Salivary Hypersecretion 6 1

Extrapyramidal Disorder 6 0

Lethargy 5 0

Adult Patients Receiving aripiprazole as Adjunctive Treatment of Major Depressive

Disorder
The following findings are based on a pool of two placebo-controlled trials of patients
with major depressive disorder in which aripiprazole was administered at doses of 2
to 20 mg as adjunctive treatment to continued antidepressant therapy.
Adverse Reactions Associated with Discontinuation of Treatment
The incidence of discontinuation due to adverse reactions was 6% for adjunctive
aripiprazole -treated patients and 2% for adjunctive placebo-treated patients.
Commonly Observed Adverse Reactions

29
The commonly observed adverse reactions associated with the use of adjunctive
aripiprazole in patients with major depressive disorder (incidence of 5% or greater
and aripiprazole incidence at least twice that for placebo) were: akathisia, restlessness,
insomnia, constipation, fatigue, and blurred vision.
Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder
Table 18 enumerates the pooled incidence, rounded to the nearest percent, of adverse
reactions that occurred during acute therapy (up to 6 weeks), including only those
adverse reactions that occurred in 2% or more of patients treated with adjunctive
aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with
adjunctive aripiprazole was greater than the incidence in patients treated with
adjunctive placebo in the combined dataset.
Table 18: Adverse Reactions in Short-Term, Placebo-Controlled
Adjunctive Trials in Patients with Major Depressive Disorder

Percentage of Patients Reporting

Reaction*

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

*
Adverse reactions reported by at least 2% of patients treated with
adjunctive aripiprazole, except adverse reactions which had an
incidence equal to or less than placebo.
†
Antidepressant Therapy
Eye Disorders
Blurred Vision 6 1
Gastrointestinal Disorders
Constipation 5 2
General Disorders and Administration Site
Conditions
Fatigue 8 4
Feeling Jittery 3 1
Infections and Infestations
Upper Respiratory Tract
6 4
Infection
Investigations
Weight Increased 3 2
Metabolism and Nutrition Disorders
Increased Appetite 3 2
Musculoskeletal and Connective Tissue Disorders
Arthralgia 4 3
Myalgia 3 1
Nervous System Disorders

30
 Table 18: Adverse Reactions in Short-Term, Placebo-Controlled
Adjunctive Trials in Patients with Major Depressive Disorder

Percentage of Patients Reporting

Reaction*

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

Akathisia 25 4
Somnolence 6 4
Tremor 5 4
Sedation 4 2
Dizziness 4 2
Disturbance in Attention 3 1
Extrapyramidal Disorder 2 0
Psychiatric Disorders
Restlessness 12 2
Insomnia 8 2

Patients with Agitation Associated with Schizophrenia or Bipolar Mania

(Intramuscular Injection)
The following findings are based on a pool of three placebo-controlled trials of
patients with agitation associated with schizophrenia or bipolar mania in which
aripiprazole injection was administered at doses of 5.25 to 15 mg.
Commonly Observed Adverse Reactions
There was one commonly observed adverse reaction (nausea) associated with the use
of aripiprazole injection in patients with agitation associated with schizophrenia and
bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice
that for placebo).
Dose-Related Adverse Reactions
Schizophrenia
Dose response relationships for the incidence of treatment-emergent adverse events
were evaluated from four trials in adult patients with schizophrenia comparing various
fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo. This
analysis, stratified by study, indicated that the only adverse reaction to have a possible
dose response relationship, and then most prominent only with 30 mg, was
somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15
mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).
In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three
common adverse reactions appeared to have a possible dose response relationship:
extrapyramidal disorder (incidences were placebo, 5.0%; 10 mg, 13.0%; 30 mg,

31
21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%);
and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%).
Bipolar Mania
In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four
common adverse reactions had a possible dose response relationship at 4 weeks;
extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg,
27.3 %); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%);
akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary
hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%).
Autistic Disorder
In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one
common adverse reaction had a possible dose response relationship: fatigue
(incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).
Extrapyramidal Symptoms
Schizophrenia
In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of
reported EPS-related events, excluding events related to akathisia, for aripiprazole -
treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related
events for aripiprazole -treated patients was 8% vs. 4% for placebo. In the short-term,
placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the
incidence of reported EPS-related events, excluding events related to akathisia, for
aripiprazole treated patients was 25% vs. 7% for placebo; and the incidence of
akathisia-related events for aripiprazole-treated patients was 9% vs. 6% for placebo.
Objectively collected data from those trials was collected on the Simpson Angus
Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the
Assessments of Involuntary Movement Scales (for dyskinesias). In the adult
schizophrenia trials, the objectively collected data did not show a difference between
aripiprazole and placebo, with the exception of the Barnes Akathisia Scale
(aripiprazole, 0.08; placebo, –0.05). In the pediatric (13 to 17 years) schizophrenia
trial, the objectively collected data did not show a difference between aripiprazole
and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole ,
0.24; placebo, –0.29).
Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in
adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the
Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement
Scales (for dyskinesias) did not show a difference between ARIPIPRAZOLE and
placebo.
Bipolar Mania
In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of
reported EPS-related events, excluding events related to akathisia, for monotherapy
aripiprazole -treated patients was 16% vs. 8% for placebo and the incidence of
akathisia-related events for monotherapy aripiprazole -treated patients was 13% vs.
4% for placebo. In the 6-week, placebo-controlled trial in bipolar mania for adjunctive
therapy with lithium or valproate, the incidence of reported EPS-related events,

32
excluding events related to akathisia for adjunctive aripiprazole -treated patients was
15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for
adjunctive aripiprazole -treated patients was 19% vs. 5% for adjunctive placebo. In
the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years)
patients, the incidence of reported EPS-related events, excluding events related to
akathisia, for aripiprazole -treated patients was 26% vs. 5% for placebo and the
incidence of akathisia-related events for aripiprazole -treated patients was 10% vs. 2%
for placebo.
In the adult bipolar mania trials with monotherapy aripiprazole, the Simpson Angus
Rating Scale and the Barnes Akathisia Scale showed a significant difference between
aripiprazole and placebo (aripiprazole, 0.50; placebo, –0.01 and aripiprazole, 0.21;
placebo, –0.05). Changes in the Assessments of Involuntary Movement Scales were
similar for the aripiprazole and placebo groups. In the bipolar mania trials with
aripiprazole as adjunctive therapy with either lithium or valproate, the Simpson Angus
Rating Scale and the Barnes Akathisia Scale showed a significant difference between
adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.73; placebo, 0.07 and
aripiprazole, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary
Movement Scales were similar for adjunctive aripiprazole and adjunctive placebo. In
the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus
Rating Scale showed a significant difference between aripiprazole and placebo
(aripiprazole, 0.90; placebo, −0.05). Changes in the Barnes Akathisia Scale and the
Assessments of Involuntary Movement Scales were similar for the aripiprazole and
placebo groups.
Major Depressive Disorder
In the short-term, placebo-controlled trials in major depressive disorder, the incidence
of reported EPS-related events, excluding events related to akathisia, for adjunctive
aripiprazole-treated patients was 8% vs. 5% for adjunctive placebo-treated patients;
and the incidence of akathisia-related events for adjunctive aripiprazole-treated
patients was 25% vs. 4% for adjunctive placebo-treated patients.
In the major depressive disorder trials, the Simpson Angus Rating Scale and the
Barnes Akathisia Scale showed a significant difference between adjunctive
aripiprazole and adjunctive placebo (aripiprazole, 0.31; placebo, 0.03 and
aripiprazole, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary
Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo
groups.
Autistic Disorder
In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6
to 17 years), the incidence of reported EPS-related events, excluding events related to
akathisia, for aripiprazole-treated patients was 18% vs. 2% for placebo and the
incidence of akathisia-related events for aripiprazole-treated patients was 3% vs. 9%
for placebo.
In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus
Rating Scale showed a significant difference between aripiprazole and placebo
(aripiprazole, 0.1; placebo, –0.4). Changes in the Barnes Akathisia Scale and the
Assessments of Involuntary Movement Scales were similar for the aripiprazole and
placebo groups.

33
Agitation Associated with Schizophrenia or Bipolar Mania
In the placebo-controlled trials in patients with agitation associated with
schizophrenia or bipolar mania, the incidence of reported EPS-related events
excluding events related to akathisia for aripiprazole-treated patients was 2% vs. 2%
for placebo and the incidence of akathisia-related events for aripiprazole-treated
patients was 2% vs. 0% for placebo. Objectively collected data on the Simpson Angus
Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) for all treatment
groups did not show a difference between aripiprazole and placebo.
Dystonia
Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur
in susceptible individuals during the first few days of treatment. Dystonic symptoms
include: spasm of the neck muscles, sometimes progressing to tightness of the throat,
swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While
these symptoms can occur at low doses, they occur more frequently and with greater
severity with high potency and at higher doses of first- generation antipsychotic drugs.
An elevated risk of acute dystonia is observed in males and younger age groups.
Additional Findings Observed in Clinical Trials
Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials
The adverse reactions reported in a 26-week, double-blind trial comparing oral
aripiprazole and placebo in patients with schizophrenia were generally consistent with
those reported in the short-term, placebo-controlled trials, except for a higher
incidence of tremor [8% (12/153) for aripiprazole vs. 2% (3/153) for placebo]. In this
study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12
moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration
(7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of aripiprazole. In
addition, in a long-term (52 weeks), active-controlled study, the incidence of tremor
was 5% (40/859) for aripiprazole. A similar profile was observed in a long-term
monotherapy study and a long-term adjunctive study with lithium and valproate in
bipolar disorder.
Other Adverse Reactions Observed During Clinical Trial Evaluation of
aripiprazole
The following listing does not include reactions: 1) already listed in previous tables or
elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general
as to be uninformative, 4) which were not considered to have significant clinical
implications, or 5) which occurred at a rate equal to or less than placebo.
Reactions are categorized by body system according to the following
definitions: frequent adverse reactions are those occurring in at least 1/100
patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000
patients; rare reactions are those occurring in fewer than 1/1000 patients:
Adults - Oral Administration
• Blood and Lymphatic System Disorders: rare - thrombocytopenia
• Cardiac Disorders: infrequent – bradycardia, palpitations, rare – atrial
flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation,
angina pectoris, myocardial ischemia, myocardial infarction,
cardiopulmonary failure

34
 • Eye Disorders: infrequent – photophobia; rare - diplopia
• Gastrointestinal Disorders: infrequent - gastroesophageal reflux disease
• General Disorders and Administration Site Conditions: frequent -
asthenia; infrequent – peripheral edema, chest pain; rare – face edema
• Hepatobiliary Disorders: rare - hepatitis, jaundice
• Immune System Disorders: rare - hypersensitivity
• Injury, Poisoning, and Procedural Complications: infrequent – fall; rare –
heat stroke
• Investigations: frequent – blood prolactin decreased, weight decreased,
infrequent - hepatic enzyme increased, blood glucose increased, blood
lactate dehydrogenase increased, gamma glutamyl transferase increased;
rare – blood prolactin increased, blood urea increased, blood creatinine
increased, blood bilirubin increased, electrocardiogram QT prolonged,
glycosylated hemoglobin increased
• Metabolism and Nutrition Disorders: frequent – anorexia; rare -
hypokalemia, hyponatremia, hypoglycemia
• Musculoskeletal and Connective Tissue Disorders: infrequent - muscular
weakness, muscle tightness; rare – rhabdomyolysis, mobility decreased
• Nervous System Disorders: infrequent - parkinsonism, memory
impairment, cogwheel rigidity, hypokinesia, bradykinesia; rare – akinesia,
myoclonus, coordination abnormal, speech disorder, Grand Mal
convulsion; <1/10,000 patients - choreoathetosis
• Psychiatric Disorders: infrequent – aggression, loss of libido,
delirium; rare – libido increased, anorgasmia, tic, homicidal ideation,
catatonia, sleep walking
• Renal and Urinary Disorders: rare - urinary retention, nocturia
• Reproductive System and Breast Disorders: infrequent - erectile
dysfunction; rare – gynaecomastia, menstruation irregular, amenorrhea,
breast pain, priapism
• Respiratory, Thoracic, and Mediastinal Disorders: infrequent - nasal
congestion, dyspnea
• Skin and Subcutaneous Tissue Disorders: infrequent - rash, hyperhidrosis,
pruritus, photosensitivity reaction, alopecia; rare - urticaria
• Vascular Disorders: infrequent – hypotension, hypertension

Pediatric Patients - Oral Administration

Most adverse events observed in the pooled database of 1,686 pediatric patients, aged
6 to 18 years, were also observed in the adult population. Additional adverse reactions
observed in the pediatric population are listed below.
• Eye Disorders: infrequent - oculogyric crisis
• Gastrointestinal Disorders: infrequent -tongue dry, tongue spasm
• Investigations: frequent - blood insulin increased
• Nervous System Disorders: infrequent - sleep talking
• Renal and Urinary Disorders frequent – enuresis
• Skin and Subcutaneous Tissue Disorders: infrequent - hirsutism

35
7.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
aripiprazole. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure: occurrences of allergic reaction
(anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or
oropharyngeal spasm), blood glucose fluctuation, Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS), hiccups, oculogyric crisis and
pathological gambling.

7.3 Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Any suspected adverse events should be reported to the Ministry of Health
according to the National Regulation by using an online form.
[Link]

8 DRUG INTERACTIONS
8.1 Drugs Having Clinically Important Interactions with ARIPLY
Table 19: Clinically Important Drug Interactions with ARIPLY:

Concomitant Clinical Rationale Clinical Recommendation

Drug Name or
Drug Class
Strong CYP3A4 The concomitant use of
Inhibitors (e.g., ABILIFY with strong With concomitant use of
itraconazole, CYP 3A4 or CYP2D6 ABILIFY with a strong
clarithromycin) or inhibitors increased the CYP3A4 inhibitor or
strong CYP2D6 exposure of aripiprazole CYP2D6 inhibitor, reduce
inhibitors (e.g., compared to the use of the ABILIFY
quinidine, ABILIFY dosage [see Dosage and
fluoxetine, alone [see Clinical Administration (3.7)].
paroxetine) Pharmacology (13.3)].
The concomitant use of
ARIPLY and
With concomitant use of
carbamazepine
Strong CYP3A4 ARIPLY with a strong
decreased the exposure
Inducers (e.g., CYP3A4 inducer, consider
of aripiprazole
carbamazepine, increasing the ARIPLY
compared to the use of
rifampin) dosage [see Dosage and
ARIPLY
Administration (3.7)].
alone [see Clinical
Pharmacology (13.3)].
Due to its alpha
Antihypertensive Monitor blood pressure and
adrenergic antagonism,
Drugs adjust dose
aripiprazole has the

36
Table 19: Clinically Important Drug Interactions with ARIPLY:

Concomitant Clinical Rationale Clinical Recommendation

Drug Name or
Drug Class
potential to enhance the accordingly [see Warnings
effect of certain and Precautions (6.8)].
antihypertensive agents.
The intensity of sedation
was greater with the
combination of oral
aripiprazole and
lorazepam as compared
to that observed with
aripiprazole alone. The Monitor sedation and blood
Benzodiazepines
orthostatic hypotension pressure. Adjust dose
(e.g., lorazepam)
observed was greater accordingly.
with the combination as
compared to that
observed with
lorazepam
alone [see Warnings
and Precautions (6.8)].

8.2 Drugs Having No Clinically Important Interactions with ARIPLY

Based on pharmacokinetic studies, no dosage adjustment of ARIPLY is required
when administered concomitantly with famotidine, valproate, lithium, lorazepam.
In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g.,
dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin),
CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g.,
dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage
adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline
when co-administered with aripiprazole [see Clinical Pharmacology (13.3)].

9 USE IN SPECIFIC POPULATIONS

9.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to atypical antipsychotics, including ARIPLY, during pregnancy. Healthcare
providers are encouraged to register patients by contacting the National Pregnancy

37
Registry for Atypical Antipsychotics at 1-866-961-2388 or visit
[Link]
Risk Summary
Neonates exposed to antipsychotic drugs, including ARIPLY, 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 aripiprazole, 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 post-natal 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 to 4% and 15 to 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 aripiprazole)
during the third trimester of pregnancy. These symptoms have varied in severity.

38
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.

39
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.

9.2 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 ARIPLY and any potential adverse effects on the
breastfed infant from ARIPLY or from the underlying maternal condition.

9.3 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 (13.3)].
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 (3.1), Adverse Reactions (7.1), and Clinical
Studies (15.1)]. 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 (3.2), Adverse Reactions (7.1), and Clinical
Studies (15.2)]. Although maintenance efficacy in pediatric patients has not been
systematically evaluated, maintenance efficacy can be extrapolated from adult data

40
along with comparisons of aripiprazole pharmacokinetic parameters in adult and
pediatric patients.
The efficacy of adjunctive aripiprazole 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 (2), Dosage and
Administration (3.4), Adverse Reactions (7.1), and Clinical Studies (15.4)]. A
maintenance trial was conducted in pediatric patients (6 to 17 years of age) with
irritability associated with autistic disorder. The first phase of this trial was an open-
label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were
stabilized (defined as >25% improvement on the ABC-I subscale, and a CGI-I rating
of "much improved" or "very much improved") on aripiprazole for 12 consecutive
weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-
blind phase where they were randomized to either continue aripiprazole treatment or
switch to placebo. In this trial, the efficacy of aripiprazole for the maintenance
treatment of irritability associated with autistic disorder was not established.
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

41
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.

9.4 Geriatric Use

No dosage adjustment is recommended for elderly patients [see Boxed
Warning, Warnings and Precautions (6.1), and Clinical Pharmacology (13.3)].
Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1073 (8%) were
≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral
aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not
include sufficient numbers of patients aged 65 and over to determine whether they
respond differently from younger patients.
Of the 749 patients treated with aripiprazole injection in clinical trials, 99 (13%) were
≥65 years old and 78 (10%) were ≥75 years old. Placebo-controlled studies of
aripiprazole injection in patients with agitation associated with schizophrenia or
bipolar mania did not include sufficient numbers of patients aged 65 years and over to
determine whether they respond differently from younger patients.
aripiprazole is not approved for the treatment of patients with psychosis associated
with Alzheimer's disease [see Boxed Warning and Warnings and Precautions (6.1)].

9.5 CYP2D6 Poor Metabolizers

Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high
aripiprazole concentrations. Approximately 8% of Caucasians and 3 to 8% of
Black/African Americans cannot metabolize CYP2D6 substrates and are classified as
poor metabolizers (PM) [see Dosage and Administration (3.7) and Clinical
Pharmacology (13.3)].

9.6 Hepatic and Renal Impairment

No dosage adjustment for aripiprazole 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 (13.3)].

9.7 Other Specific Populations

No dosage adjustment for aripiprazole is required on the basis of a patient's sex, race,
or smoking status [see Clinical Pharmacology (13.3)].

10 DRUG ABUSE AND DEPENDENCE

10.1 Controlled Substance

Aripiprazole is not a controlled substance.

10.2 Abuse
Aripiprazole has not been systematically studied in humans for its potential for abuse,
tolerance, or physical dependence. Consequently, patients should be evaluated

42
carefully for a history of drug abuse, and such patients should be observed closely for
signs of ARIPLY misuse or abuse (e.g., development of tolerance, increases in dose,
drug-seeking behavior).

10.3 Dependence
In physical dependence studies in monkeys, withdrawal symptoms were observed
upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency
for any drug-seeking behavior, these observations were not systematic and it is not
possible to predict on the basis of this limited experience the extent to which a CNS-
active drug will be misused, diverted, and/or abused once marketed.

11 OVERDOSAGE
MedDRA terminology has been used to classify the adverse reactions.

11.1 Human Experience

In clinical trials and in postmarketing experience, adverse reactions of deliberate or
accidental overdosage with oral aripiprazole have been reported worldwide. These
include overdoses with oral aripiprazole alone and in combination with other
substances. No fatality was reported with aripiprazole alone. The largest known dose
with a known outcome involved acute ingestion of 1260 mg of oral aripiprazole (42
times the maximum recommended daily dose) by a patient who fully recovered.
Deliberate or accidental overdosage was also reported in children (age 12 years and
younger) involving oral aripiprazole-[o/\
ingestions up to 195 mg with no fatalities.
Common adverse reactions (reported in at least 5% of all overdose cases) reported
with oral aripiprazole overdosage (alone or in combination with other substances)
include vomiting, somnolence, and tremor. Other clinically important signs and
symptoms observed in one or more patients with aripiprazole overdoses (alone or with
other substances) include acidosis, aggression, aspartate aminotransferase increased,
atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine
phosphokinase increased, depressed level of consciousness, hypertension,
hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged,
QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and
tachycardia.

11.2 Management of Overdosage

No specific information is available on the treatment of overdose with aripiprazole.
An electrocardiogram should be obtained in case of overdosage and if QT interval
prolongation is present, cardiac monitoring should be instituted. Otherwise,
management of overdose should concentrate on supportive therapy, maintaining an
adequate airway, oxygenation and ventilation, and management of symptoms. Close
medical supervision and monitoring should continue until the patient recovers.
Charcoal: In the event of an overdose of ARIPLY, an early charcoal administration
may be useful in partially preventing the absorption of aripiprazole. Administration of
50 g of activated charcoal, one hour after a single 15 mg oral dose of ARIPLY,
decreased the mean AUC and Cmax of ARIPLY by 50%.

43
Hemodialysis: Although there is no information on the effect of hemodialysis in
treating an overdose with ARIPLY, hemodialysis is unlikely to be useful in overdose
management since aripiprazole is highly bound to plasma proteins.

12 DESCRIPTION
Aripiprazole is an atypical antipsychotic drug that is available as
ARIPLY(aripiprazole) Tablets, dihydrocarbostyril. The empirical formula is
C23H27Cl2N3O2 and its molecular weight is 448.38. The chemical structure is:

ARIPLY Tablets are available in 5, 10, 15, and 30 mg strengths. Inactive ingredients
include: Maize starch, hydroxypropyl cellulose, lactose monohydrate, magnesium
stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow).

13 CLINICAL PHARMACOLOGY

13.1 Mechanism of Action

The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear.
However, the efficacy of aripiprazole in the listed indications could be mediated
through a combination of partial agonist activity at D2 and 5-HT1A receptors and
antagonist activity at 5-HT2A receptors.

13.2 Pharmacodynamics
Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-
HT2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively),
moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic
and histamine H1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM,
respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM).
Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors
(IC50>1000 nM).

13.3 Pharmacokinetics
ARIPLY activity is presumably primarily due to the parent drug, aripiprazole, and to
a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown
to have affinities for D2 receptors similar to the parent drug and represents 40% of the
parent drug exposure in plasma. The mean elimination half-lives are about 75 hours
and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. Steady-state
concentrations are attained within 14 days of dosing for both active moieties.
Aripiprazole accumulation is predictable from single-dose pharmacokinetics. At
steady-state, the pharmacokinetics of aripiprazole is dose-proportional. Elimination of
aripiprazole is mainly through hepatic metabolism involving two P450 isozymes,

44
CYP2D6 and CYP3A4. For CYP2D6 poor metabolizers, the mean elimination half-
life for aripiprazole is about 146 hours.
Oral administration
Absorption
Tablet: ARIPLY is well absorbed after administration of the tablet, with peak plasma
concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of
the tablet formulation is 87%. ARIPLY can be administered with or without food.
Administration of a 15 mg ARIPLY Tablet with a standard high-fat meal did not
significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-
aripiprazole, but delayed Tmax by 3 hours for aripiprazole and 12 hours for dehydro-
aripiprazole.
Distribution
The steady-state volume of distribution of aripiprazole following intravenous
administration is high (404 L or 4.9 L/kg), indicating extensive extravascular
distribution. At therapeutic concentrations, aripiprazole and its major metabolite are
greater than 99% bound to serum proteins, primarily to albumin. In healthy human
volunteers administered 0.5 to 30 mg/day aripiprazole for 14 days, there was dose-
dependent D2 receptor occupancy indicating brain penetration of aripiprazole in
humans.
Elimination
Metabolism
Aripiprazole is metabolized primarily by three biotransformation pathways:
dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies,
CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and
hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4.
Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-
state, dehydro-aripiprazole, the active metabolite, represents about 40% of
aripiprazole AUC in plasma.

Excretion
Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and
55% of the administered radioactivity was recovered in the urine and feces,
respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and
approximately 18% of the oral dose was recovered unchanged in the feces.
Drug Interaction Studies
Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are
summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5-fold
increase in mean Cmax and AUC values at steady-state is expected when extensive
metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4
inhibitors. A 3-fold increase in mean Cmax and AUC values at steady-state is expected
in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.
Figure 1: The Effects of Other Drugs on Aripiprazole Pharmacokinetics

45
Figure 2: The Effects of Other Drugs on Dehydro-aripiprazole Pharmacokinetics

The effects of aripiprazole on the exposures of other drugs are summarized in Figure
3. A population PK analysis in patients with major depressive disorder showed no

46
substantial change in plasma concentrations of fluoxetine (20 or 40 mg/day),
paroxetine CR (37.5 or 50 mg/day), or sertraline (100 or 150 mg/day) dosed to steady-
state. The steady-state plasma concentrations of fluoxetine and norfluoxetine
increased by about 18% and 36%, respectively, and concentrations of paroxetine
decreased by about 27%. The steady-state plasma concentrations of sertraline and
desmethylsertraline were not substantially changed when these antidepressant
therapies were coadministered with aripiprazole.
Figure 3: The Effects of aripiprazole on Pharmacokinetics of Other Drugs

Studies in Specific Populations

Exposures of aripiprazole and dehydro-aripiprazole in specific populations are
summarized in Figure 4 and Figure 5, respectively. In addition, in pediatric patients
(10 to 17 years of age) administered with aripiprazole (20 mg to 30 mg), the body
weight corrected aripiprazole clearance was similar to the adults.
Figure 4: Effects of Intrinsic Factors on aripiprazole Pharmacokinetics

47
Figure 5: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics

48
14 NONCLINICAL TOXICOLOGY

14.1 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

49
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, 2,3-DCPP, 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.

14.2 Animal Toxicology and/or Pharmacology

Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic
toxicity study at a dose of 60 mg/kg/day and in a 2-year carcinogenicity study at doses
of 40 and 60 mg/kg/day which are 13 and 19 times the MRHD of 30 mg/day based on
mg/m2 body surface area. Evaluation of the retinas of albino mice and of monkeys did
not reveal evidence of retinal degeneration. Additional studies to further evaluate the
mechanism have not been performed. The relevance of this finding to human risk is
unknown.

15 CLINICAL STUDIES
Efficacy of the oral formulations of ARIPLY (aripiprazole) was established in the
following adequate and well-controlled trials:
• Four short-term trials and one maintenance trial in adult patients and one
short-term trial in adolescents (ages 13 to 17 years) with
schizophrenia [see Clinical Studies (15.1)]

50
 • Four short-term monotherapy trials and one 6-week adjunctive trial in
adult patients and one short-term monotherapy trial in pediatric patients
(ages 10 to 17 years) with manic or mixed episodes [see Clinical Studies
(15.2)]
• One maintenance monotherapy trial and in one maintenance adjunctive
trial in adult patients with bipolar I disorder [see Clinical Studies (15.2)]
• Two short-term trials in adult patients with MDD who had an inadequate
response to antidepressant therapy during the current episode [see Clinical
Studies (15.3)]
• Two short-term trials in pediatric patients (ages 6 to 17 years) for the
treatment of irritability associated with autistic disorder [see Clinical
Studies (15.4)]

15.1 Schizophrenia
Adults
The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five
short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed
inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the
five trials were able to distinguish aripiprazole from placebo, but one study, the
smallest, did not. Three of these studies also included an active control group
consisting of either risperidone (one trial) or haloperidol (two trials), but they were
not designed to allow for a comparison of aripiprazole and the active comparators.
In the four positive trials for aripiprazole, four primary measures were used for
assessing psychiatric signs and symptoms. Efficacy was evaluated using the total
score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-
item scale that measures positive symptoms of schizophrenia (7 items), negative
symptoms of schizophrenia (7 items), and general psychopathology (16 items), each
rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to
210. The Clinical Global Impression (CGI) assessment reflects the impression of a
skilled observer, fully familiar with the manifestations of schizophrenia, about the
overall clinical state of the patient.
In a 4-week trial (n=414) comparing two fixed doses of aripiprazole (15 or 30
mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS
total score (Study 1 in Table 26), PANSS positive subscale, and CGI-severity score.
In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale.
In a 4-week trial (n=404) comparing two fixed doses of aripiprazole (20 or 30
mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS
total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative
subscale, and CGI-severity score.
In a 6-week trial (n=420) comparing three fixed doses of aripiprazole (10, 15, or 20
mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the
PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS
negative subscale.
In a 6-week trial (n=367) comparing three fixed doses of aripiprazole (2, 5, or 10
mg/day) to placebo, the 10 mg dose of aripiprazole was superior to placebo in the
PANSS total score (Study 4 in Table 26), the primary outcome measure of the study.

51
The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary
outcome measure.
Thus, the efficacy of 10, 15 and 30 mg daily doses was established in two studies for
each dose. Among these doses, there was no evidence that the higher dose groups
offered any advantage over the lowest dose group of these studies.
An examination of population subgroups did not reveal any clear evidence of
differential responsiveness on the basis of age, gender, or race.
A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for
schizophrenia who were, by history, symptomatically stable on other antipsychotic
medications for periods of 3 months or longer. These patients were discontinued from
their antipsychotic medications and randomized to aripiprazole 15 mg/day or placebo
for up to 26 weeks of observation for relapse. Relapse during the double-blind phase
was defined as CGI-Improvement score of ≥5 (minimally worse), scores ≥5
(moderately severe) on the hostility or uncooperativeness items of the PANSS, or
≥20% increase in the PANSS total score. Patients receiving aripiprazole 15 mg/day
experienced a significantly longer time to relapse over the subsequent 26 weeks
compared to those receiving placebo (Study 5 in Figure 6).
Pediatric Patients
The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13
to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of
outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70
at baseline. In this trial (n=302) comparing two fixed doses of aripiprazole (10 or 30
mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose
in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment
arm. Both doses of aripiprazole were superior to placebo in the PANSS total score
(Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day
dosage was not shown to be more efficacious than the 10 mg/day dose. 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.
Table 20 Schizophrenia Studies

Study Treatment
Primary Efficacy Measure: PANSS
Number Group

LS Mean
Mean
Change Placebo-subtracted
Baseline
from Difference* (95%
Score
Baseline CI)
(SD)
(SE)

SD: standard deviation; SE: standard error; LS Mean: least-squares

mean; CI: unadjusted confidence interval.

52
 Table 20 Schizophrenia Studies

Study Treatment
Primary Efficacy Measure: PANSS
Number Group

LS Mean
Mean
Change Placebo-subtracted
Baseline
from Difference* (95%
Score
Baseline CI)
(SD)
(SE)

Difference (drug minus placebo) in least-squares mean change from

baseline.
†
Doses statistically significantly superior to placebo.
Aripiprazole 98.5
Study 1 -15.5 (2.40) -12.6 (-18.9, -6.2)
(15 mg/day) † (17.2)
Aripiprazole 99.0
-11.4 (2.39) -8.5 (-14.8, -2.1)
(30 mg/day) † (19.2)
100.2
Placebo -2.9 (2.36) --
(16.5)
Aripiprazole 92.6
Study 2 -14.5 (2.23) -9.6 (-15.4, -3.8)
(20 mg/day) † (19.5)
Aripiprazole 94.2
-13.9 (2.24) -9.0 (-14.8, -3.1)
(30 mg/day) † (18.5)
94.3
Placebo -5.0 (2.17) --
(18.5)
Aripiprazole 92.7
Study 3 -15.0 (2.38) -12.7 (-19.00, -6.41)
(10 mg/day) † (19.5)
Aripiprazole 93.2
-11.7 (2.38) -9.4 (-15.71, -3.08)
(15 mg/day) † (21.6)
Aripiprazole 92.5
-14.4 (2.45) -12.1 (-18.53, -5.68)
(20 mg/day) † (20.9)
92.3
Placebo -2.3 (2.35) --
(21.8)
Aripiprazole 90.7
Study 4 -8.2 (1.90) -2.9 (-8.29, 2.47)
(2 mg/day) (14.5)
Aripiprazole 92.0
-10.6 (1.93) -5.2 (-10.7, 0.19)
(5 mg/day) (12.6)
Aripiprazole 90.0
-11.3 (1.88) -5.9 (-11.3, -0.58)
(10 mg/day) † (11.9)
90.8
Placebo -5.3 (1.97) --
(13.3)
Study 6 Aripiprazole 93.6
-26.7 (1.91) -5.5 (-10.7, -0.21)
(Pediatric, (10 mg/day) † (15.7)

53
 Table 20 Schizophrenia Studies

Study Treatment
Primary Efficacy Measure: PANSS
Number Group

LS Mean
Mean
Change Placebo-subtracted
Baseline
from Difference* (95%
Score
Baseline CI)
(SD)
(SE)

13 to 17 Aripiprazole 94.0
-28.6 (1.92) -7.4 (-12.7, -2.13)
years) (30 mg/day) † (16.1)
94.6
Placebo -21.2 (1.93) --
(15.6)

Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with

Relapse (Schizophrenia Study 5)

14.2 Bipolar Disorder

Acute Treatment of Manic and Mixed Episodes
Adults
Monotherapy

54
The efficacy of aripiprazole as monotherapy in the acute treatment of manic episodes
was established in four 3-week, placebo-controlled trials in hospitalized patients who
met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These
studies included patients with or without psychotic features and two of the studies
also included patients with or without a rapid-cycling course.
The primary instrument used for assessing manic symptoms was the Young Mania
Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess
the degree of manic symptomatology in a range from 0 (no manic features) to 60
(maximum score). A key secondary instrument included the Clinical Global
Impression-Bipolar (CGI-BP) Scale.
In the four positive, 3-week, placebo-controlled trials (n=268; n=248; n=480; n=485)
which evaluated aripiprazole in a range of 15 mg to 30 mg, once daily (with a starting
dose of 30 mg/day in two studies and 15 mg/day in two studies), aripiprazole was
superior to placebo in the reduction of Y-MRS total score (Studies 1 to 4 in Table 27)
and CGI-BP Severity of Illness score (mania). In the two studies with a starting dose
of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two
studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30
mg/day at endpoint.
Adjunctive Therapy
The efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the
treatment of manic or mixed episodes was established in a 6-week, placebo-controlled
study (n=384) with a 2-week lead-in mood stabilizer monotherapy phase in adult
patients who met DSM-IV criteria for bipolar I disorder. This study included patients
with manic or mixed episodes and with or without psychotic features.
Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to
125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At
the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score
≥16 and ≤25% improvement on the Y-MRS total score) to lithium or valproate were
randomized to receive either aripiprazole (15 mg/day or an increase to 30 mg/day as
early as Day 7) or placebo as adjunctive therapy with open-label lithium or valproate.
In the 6-week, placebo-controlled phase, adjunctive aripiprazole starting at 15 mg/day
with concomitant lithium or valproate (in a therapeutic range of 0.6 to 1.0 mEq/L or
50 to 125 μg/mL, respectively) was superior to lithium or valproate with adjunctive
placebo in the reduction of the Y-MRS total score (Study 5 in Table 27) and CGI-BP
Severity of Illness score (mania). Seventy-one percent of the patients coadministered
valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6-
week endpoint.
Pediatric Patients
The efficacy of aripiprazole in the treatment of bipolar I disorder in pediatric patients
(10 to 17 years of age) was evaluated in one 4-week, placebo-controlled trial (n=296)
of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed
episodes with or without psychotic features and had a Y-MRS score ≥20 at baseline.
This double-blind, placebo-controlled trial compared two fixed doses of aripiprazole
(10 or 30 mg/day) to placebo. The aripiprazole dose was started at 2 mg/day, which
was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day
treatment arm, and in 13 days in the 30 mg/day treatment arm. Both doses of

55
aripiprazole were superior to placebo in change from baseline to week 4 on the Y-
MRS total score (Study 6 in Table 21).
Table 21: Bipolar Studies

Study
Treatment Group Primary Efficacy Measure: Y-MRS
Number

LS Mean
Mean
Change Placebo-subtracted
Baseline
from Difference* (95%
Score
Baseline CI)
(SD)
(SE)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean;

CI: unadjusted confidence interval.

*
Difference (drug minus placebo) in least-squares mean change from
baseline.
†
Doses statistically significantly superior to placebo.
Aripiprazole (30/15 -12.52
Study 1 29.0 (5.9) -5.33 (-7.90, -2.76)
mg/day) † (1.05)
-7.19
Placebo 28.5 (4.6) --
(1.07)
Aripiprazole (30/15 -8.15
Study 2 27.8 (5.7) -4.80 (-7.80, -1.80)
mg/day) † (1.23)
-3.35
Placebo 29.1 (6.9) --
(1.22)
Aripiprazole (15 to -12.64
Study 3 28.5 (5.6) -3.63 (-5.75, -1.51)
30 mg/day) † (0.84)
Placebo 28.9 (5.9) 9.01 (0.81) --
Aripiprazole (15 to -11.98
Study 4 28.0 (5.8) -2.28 (-4.44, -0.11)
30 mg/day) † (0.80)
-9.70
Placebo 28.3 (5.8) --
(0.83)
Aripiprazole (15 or
-13.31
30 mg/day) † + 23.2 (5.7) -2.62 (-4.29, -0.95)
(0.50)
Study 5 Lithium/Valproate
Placebo + -10.70
23.0 (4.9) --
Lithium/Valproate (0.69)
Aripiprazole (10 -14.2
Study 6 29.8 (6.5) -5.99 (-8.49, -3.50)
mg/day) † (0.89)
(Pediatric,
Aripiprazole (30 -16.5
10 to 17 29.5 (6.3) -8.26 (-10.7, -5.77)
mg/day) † (0.87)
years)
Placebo 30.7 (6.8) -8.2 (0.91) --

56
Maintenance Treatment of Bipolar I Disorder
Monotherapy Maintenance Therapy
A maintenance trial was conducted in adult patients meeting DSM-IV criteria for
bipolar I disorder with a recent manic or mixed episode who had been stabilized on
open-label aripiprazole and who had maintained a clinical response for at least 6
weeks. The first phase of this trial was an open-label stabilization period in which
inpatients and outpatients were clinically stabilized and then maintained on open-label
aripiprazole (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6
consecutive weeks. One hundred sixty-one outpatients were then randomized in a
double-blind fashion, to either the same dose of aripiprazole they were on at the end
of the stabilization and maintenance period or placebo and were then monitored for
manic or depressive relapse. During the randomization phase, aripiprazole was
superior to placebo on time to the number of combined affective relapses (manic plus
depressive), the primary outcome measure for this study (Study 7 in Figure 7). A total
of 55 mood events were observed during the double-blind treatment phase. Nineteen
were from the aripiprazole group and 36 were from the placebo group. The number of
observed manic episodes in the aripiprazole group (6) were fewer than that in the
placebo group (19), while the number of depressive episodes in the aripiprazole group
(9) was similar to that in the placebo group (11).
An examination of population subgroups did not reveal any clear evidence of
differential responsiveness on the basis of age and gender; however, there were
insufficient numbers of patients in each of the ethnic groups to adequately assess
inter-group differences.
Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with
Relapse (Bipolar Study 7)

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Adjunctive Maintenance Therapy
An adjunctive maintenance trial was conducted in adult patients meeting DSM-IV
criteria for bipolar I disorder with a recent manic or mixed episode. Patients were
initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 μg/mL) at
therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2
weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and
≤35% improvement on the Y-MRS total score) to lithium or valproate received
aripiprazole with a starting dose of 15 mg/day with the option to increase to 30 mg or
reduce to 10 mg as early as Day 4, as adjunctive therapy with open-label lithium or
valproate. Prior to randomization, patients on the combination of single-blind
aripiprazole and lithium or valproate were required to maintain stability (Y-MRS and
MADRS total scores ≤12) for 12 consecutive weeks. Three hundred thirty-seven
patients were then randomized in a double-blind fashion, to either the same dose of
aripiprazole they were on at the end of the stabilization period or placebo plus lithium
or valproate and were then monitored for manic, mixed, or depressive relapse for a
maximum of 52 weeks. aripiprazole was superior to placebo on the primary endpoint,
time from randomization to relapse to any mood event (Study 8 in Figure 8). A mood
event was defined as hospitalization for a manic, mixed, or depressive episode, study
discontinuation due to lack of efficacy accompanied by Y-MRS score >16 and/or a
MADRS >16, or an SAE of worsening disease accompanied by Y-MRS score >16
and/or a MADRS >16.

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A total of 68 mood events were observed during the double-blind treatment phase.
Twenty-five were from the aripiprazole group and 43 were from the placebo group.
The number of observed manic episodes in the aripiprazole group (7) were fewer than
that in the placebo group (19), while the number of depressive episodes in the
aripiprazole group (14) was similar to that in the placebo group (18). The Kaplan-
Meier curves of the time from randomization to relapse to any mood event during the
52-week, double-blind treatment phase for aripiprazole and placebo groups are shown
in Figure 8.
Figure 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with
Relapse to Any Mood Event (Bipolar Study 8)

An examination of population subgroups did not reveal any clear evidence of

differential responsiveness on the basis of age and gender; however, there were
insufficient numbers of patients in each of the ethnic groups to adequately assess
inter-group differences.

14.3 Adjunctive Treatment of Major Depressive Disorder

Adults
The efficacy of aripiprazole in the adjunctive treatment of major depressive disorder
(MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of
adult patients meeting DSM-IV criteria for MDD who had had an inadequate response
to prior antidepressant therapy (1 to 3 courses) in the current episode and who had
also demonstrated an inadequate response to 8 weeks of prospective antidepressant
therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine,
escitalopram, or sertraline). Inadequate response for prospective treatment was

59
defined as less than 50% improvement on the 17-item version of the Hamilton
Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical
Global Impressions Improvement rating of no better than minimal improvement.
Inadequate response to prior treatment was defined as less than 50% improvement as
perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or
above the minimal effective dose.
The primary instrument used for assessing depressive symptoms was the
Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated
scale used to assess the degree of depressive symptomatology. The key secondary
instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument
used to assess the impact of depression on three domains of functioning with each
item scored from 0 (not at all) to 10 (extreme).
In the two trials (n=381, n=362), aripiprazole was superior to placebo in reducing
mean MADRS total scores (Studies 1, 2 in Table 22). In one study, aripiprazole was
also superior to placebo in reducing the mean SDS score.
In both trials, patients received aripiprazole adjunctive to antidepressants at a dose of
5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg
increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for
patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20
mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4
mg/day.
An examination of population subgroups did not reveal evidence of differential
response based on age, choice of prospective antidepressant, or race. With regard to
gender, a smaller mean reduction on the MADRS total score was seen in males than
in females.
Table 22: Adjunctive Treatment of Major Depressive Disorder
Studies

Study Treatment
Primary Efficacy Measure: MADRS
Number Group

LS Mean
Mean
Change Placebo-subtracted
Baseline
from Difference* (95%
Score
Baseline CI)
(SD)
(SE)

SD: standard deviation; SE: standard error; LS Mean: least-squares

mean; CI: unadjusted confidence interval.

*
Difference (drug minus placebo) in least-squares mean change from
baseline.
†
Doses statistically significantly superior to placebo.

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 Table 22: Adjunctive Treatment of Major Depressive Disorder
Studies

Study Treatment
Primary Efficacy Measure: MADRS
Number Group

LS Mean
Mean
Change Placebo-subtracted
Baseline
from Difference* (95%
Score
Baseline CI)
(SD)
(SE)

Aripiprazole (5 to
Study 1 20 mg/day) † + 25.2 (6.2) -8.49 (0.66) -2.84 (-4.53, -1.15)
Antidepressant
Placebo +
27.0 (5.5) -5.65 (0.64) --
Antidepressant
Aripiprazole (5 to
Study 2 20 mg/day) † + 26.0 (6.0) -8.78 (0.63) -3.01 (-4.66, -1.37)
Antidepressant
Placebo +
26.0 (6.5) -5.77 (0.67) --
Antidepressant

14.4 Irritability Associated with Autistic Disorder

Pediatric Patients
The efficacy of aripiprazole in the treatment of irritability associated with autistic
disorder was established in two 8-week, placebo-controlled trials in pediatric patients
(6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and
demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a
combination of these problems. Over 75% of these patients were under 13 years of
age.
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist
(ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary
outcome measure in both trials was the change from baseline to endpoint in the
Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured symptoms of
irritability in autistic disorder.
The results of these trials are as follows:
In one of the 8-week, placebo-controlled trials, children and adolescents with autistic
disorder (n=98), aged 6 to 17 years, received daily doses of placebo or aripiprazole 2
to 15 mg/day. Aripiprazole, starting at 2 mg/day with increases allowed up to 15
mg/day based on clinical response, significantly improved scores on the ABC-I
subscale and on the CGI-I scale compared with placebo. The mean daily dose of
aripiprazole at the end of 8-week treatment was 8.6 mg/day (Study 1 in Table 23).

61
In the other 8-week, placebo-controlled trial in children and adolescents with autistic
disorder (n=218), aged 6 to 17 years, three fixed doses of aripiprazole (5 mg/day, 10
mg/day, or 15 mg/day) were compared to placebo. aripiprazole dosing started at 2
mg/day and was increased to 5 mg/day after one week. After a second week, it was
increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third
week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table
29). All three doses of aripiprazole significantly improved scores on the ABC-I
subscale compared with placebo.
Table 23: Irritability Associated with Autistic Disorder Studies (Pediatric)

Study
Treatment Group Primary Efficacy Measure: ABC-I
Number

Mean LS Mean Placebo-subtracted

Baseline Change from Difference* (95%
Score (SD) Baseline (SE) CI)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI:
unadjusted confidence interval.

*
Difference (drug minus placebo) in least-squares mean change from baseline.
†
Doses statistically significantly superior to placebo.
Study 1 Aripiprazole (2 to
29.6 (6.37) -12.9 (1.44) -7.9 (-11.7, -4.1)
15 mg/day) †
Placebo 30.2 (6.52) -5.0 (1.43) --
Study 2 Aripiprazole (5
28.6 (7.56) -12.4 (1.36) -4.0 (-7.7, -0.4)
mg/day) †
Aripiprazole (10
28.2 (7.36) -13.2 (1.25) -4.8 (-8.4, -1.3)
mg/day) †
Aripiprazole (15
28.9 (6.41) -14.4 (1.31) -6.0 (-9.6, -2.3)
mg/day) †
Placebo 28.0 (6.89) -8.4 (1.39) --

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 Table 23: Irritability Associated with Autistic Disorder Studies (Pediatric)

Study
Treatment Group Primary Efficacy Measure: ABC-I
Number

Mean LS Mean Placebo-subtracted

Baseline Change from Difference* (95%
Score (SD) Baseline (SE) CI)

15 HOW SUPPLIED/STORAGE AND HANDLING

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15.1 How Supplied

ARIPLY 5

Blister (Clear PVC/Aluminium): 5,7,10,14,15,20,28 and 60 tablets. Not all pack sizes
may be marketed.

ARIPLY 10;15;30
Blister (Clear PVC/Aluminium): 5,7,10,14,15,20,28,30 and 60 tablets. Not all pack
sizes may be marketed.

15.2 storage
ARIPLY 5;10;15 and 30 tablets- should be stored at a temperature below 25ºC and in
a place protected from light.

15.3 Shelf life

The expiry date of the product is indicated on the packing materials

16 Marketing authorisation holder and address

Unipharm Ltd. - "Mevo Carmel" Industrial Park.
Unipharm Ltd. P.O.B.21429 Tel-Aviv 61213.

Revised on March 2023.

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