PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

1 INDICATIONS & USAGE

Aripiprazole oral tablets are indicated for the treatment of:
• Schizophrenia
• Treatment of Tourette’s Disorder

6 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 WARNINGand WARNINGS AND PRECAUTIONS ( 5.1)]

• Cerebrovascular Adverse Events, Including Stroke [see WARNINGS AND PRECAUTIONS ( 5.2)]

• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see BOXED WARNINGand WARNINGS AND PRECAUTIONS ( 5.3)]

• Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS ( 5.4)]

• Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS ( 5.5)]

• Metabolic Changes [see WARNINGS AND PRECAUTIONS ( 5.6)]

• Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS ( 5.7)]

• Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS ( 5.8)]

• Seizures/Convulsions [see WARNINGS AND PRECAUTIONS ( 5.9)]

• Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS ( 5.10)]

• Body Temperature Regulation [see WARNINGS AND PRECAUTIONS ( 5.11)]

• Suicide [see WARNINGS AND PRECAUTIONS ( 5.12)]

• Dysphagia [see WARNINGS AND PRECAUTIONS ( 5.13)]

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, other indications, Dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole tablets . A total of 3390 patients were treated with oral aripiprazole tablets for at least 180 days and 1933 patients treated with oral aripiprazole tablets had at least 1 year of exposure.

Aripiprazole has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, or other indications and who had approximately 1,342 patient-years of 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 tablets 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.

6.1 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 tablets were administered in doses ranging from 2 to 30 mg/day.
Commonly Observed Adverse Reactions
The only commonly observed adverse reaction associated with the use of aripiprazole tablets in patients with schizophrenia (incidence of 5% or greater and aripiprazole tablets incidence at least twice that for placebo) was akathisia (aripiprazole tablets 8%; placebo 4%).
Less Common Adverse Reactions in Adults
Table 10 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 another indication), including only those reactions that occurred in 2% or more of patients treated with aripiprazole tablets (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole tablets was greater than the incidence in patients treated with placebo in the combined dataset.
Table 10: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole Tablets

	Percentage of Patients Reporting Reaction****a
System Organ Class	Aripiprazole tablets	Placebo
** Preferred Term**	( n=1843)	(n=1166)
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 Abdominal Discomfort	4 3	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
a Adverse reactions reported by at least 2% of patients treated with oral aripiprazole tablets, except adverse reactions which had an incidence equal to or less than placebo.

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.
P****ediatric Patients (13 to 17 years) with Schizophrenia
The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole tablet 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 tablets-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.
Commonly Observed Adverse Reactions
Commonly observed adverse reactions associated with the use of aripiprazole tablets in adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole tablets incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.
Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Bipolar Mania or Other Indications
Table 11 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in one indication, up to 8 weeks in another indication, and up to 10 weeks in another indication), including only those reactions that occurred in 2% or more of pediatric patients treated with aripiprazole tablets (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole tablets was greater than the incidence in patients treated with placebo.
Table 11: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral Aripiprazole Tablets

	Percentage of Patients Reporting Reaction****a
System Organ Class	Aripiprazole tablets	Placebo
** Preferred Term**	(n=732)	(n=370)
Eye Disorders
****Blurred Vision	3	0
Gastrointestinal Disorders ****Abdominal Discomfort 2 1
Vomiting	8	7
Nausea	8	4
Diarrhea	4	3
Salivary Hypersecretion	4	1
Abdominal Pain Upper	3	2
Constipation	2	2
General Disorders and Administration Site Conditions
****Fatigue	10	2
Pyrexia	4	1
Irritability	2	1
Asthenia	2	1
Infections and Infestations
****Nasopharyngitis	6	3
Investigations
****Weight Increased	3	1
Metabolism and Nutrition Disorders
****Increased Appetite	7	3
Decreased Appetite	5	4
Musculoskeletal and Connective Tissue Disorders
****Musculoskeletal Stiffness	2	1
Muscle Rigidity	2	1
Nervous System Disorders
****Somnolence	16	4
Headache	12	10
Sedation	9	2
Tremor	9	1
Extrapyramidal Disorder	6	1
Akathisia	6	4
Drooling	3	0
Lethargy	3	0
Dizziness	3	2
Dystonia	2	1
Respiratory, Thoracic, and Mediastinal Disorders
**** Epistaxis	2	1
Skin and Subcutaneous Tissue Disorders
****Rash	2	1
a Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole tablets, except adverse reactions which had an incidence equal to or less than 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 tablets 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%; 10 mg, 13%; 30 mg, 21.6%); somnolence (incidences were placebo, 6%; 10 mg, 11%; 30 mg, 21.6%); and tremor (incidences were placebo, 2%; 10 mg, 2%; 30 mg, 11.8%).
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 tablets-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole tablets-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 tablets-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole tablets-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 tablets 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 tablets and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole tablets, 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 tablets 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 tablets 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 tablets 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 tablets. In addition, in a long-term (52-week), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole tablets.
Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole Tablets
The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients:
Adults - Oral Administration
Blood and Lymphatic System Disorders:
rare - thrombocytopenia
Cardiac Disorders:
infrequent –bradycardia, palpitations, rare - atrial flutter, cardio- respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure
Eye Disorders:
infrequent - photophobia; rare -diplopia
Gastrointestinal Disorders:
infrequent - gastroesophageal reflux disease
General Disorders and Administration Site Conditions:
frequent - asthenia; infrequent – peripheral edema, chest pain; rare – face edema
Hepatobiliary Disorders:
rare - hepatitis, jaundice
Immune System Disorders:
rare -hypersensitivity
Injury, Poisoning, and Procedural Complications:
infrequent – fall; rare – heat stroke
Investigations:
frequent - weight decreased, infrequent - hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare – blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased
Metabolism and Nutrition Disorders:
frequent –anorexia; infrequent -rare -hypokalemia, hyponatremia, hypoglycemia
Musculoskeletal and Connective Tissue Disorders:
infrequent -muscular weakness, muscle tightness; rare – rhabdomyolysis, mobility decreased
Nervous System Disorders:
infrequent - parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia; rare –akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; <1/10,000 patients -choreoathetosis
Psychiatric Disorders:
infrequent – aggression, loss of libido, delirium; rare - libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking
Renal and Urinary Disorders:
rare - urinary retention, nocturia
Reproductive System and Breast Disorders:
infrequent - erectile dysfunction; rare – gynaecomastia, menstruation irregular, amenorrhea, breast pain,priapism
Respiratory, Thoracic, and Mediastinal Disorders:
infrequent -nasal congestion, dyspnea
Skin and Subcutaneous Tissue Disorders:
infrequent - rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare -urticaria
Vascular Disorders:
infrequent – hypotension, hypertension;
Pediatric Patients - Oral Administration
Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed 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
Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.'s ABILIFY® (aripiprazole) product.wever, due to Otsuka America Pharmaceutical, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

6.2 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.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; emaildrugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

2 DOSAGE & ADMINISTRATION

2.1 Schizophrenia
Adults
The recommended starting and target dose for aripiprazole tablets is 10 or 15 mg/day administered on a once-a-day schedule wit houtregard to meals. Aripiprazole tablets have 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 ( 14.1)] .

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 aripiprazole tablets 15 mg/day or placebo, and observed for relapse [see Clinical\ Studies ( 14.1)] . Patients should be periodically reassessed to determine the continued need for maintenance treatment.

Adolescents
The recommended target dose of aripiprazole tablets is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 mg 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.

Aripiprazole tablets can be administered without regard to meals [see Clinical Studies ( 14.1)] . 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 aripiprazole tablets 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.

2.5 Tourette’s Disorder
Pediatric Patients (6 to 18 years)
The recommended dosage range for Tourette’s Disorder is 5 to 20 mg/day. For patients weighing less than 50 kg, dosing should
be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days. The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually at intervals of no less than one week. For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with
a target dose of 10 mg/day on Day 8. The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than one week [see Clinical Studies (14.5)].

Patients should be periodically reassessed to determine the continued need for maintenance treatment.

2.7 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 2). When the coadministered drug is withdrawn from the combination therapy, aripiprazole tablets dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, aripiprazole tablets 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 2: Dose Adjustments for Aripiprazole Tablets in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking
Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers

2.8 Dosing of Oral Solution
The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see Clinical Pharmacology (12.3)] .

14 CLINICAL STUDIES

• Efficacy of the oral formulations of 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 ( 14.1)]
• Two short-term trials in pediatric patients (ages 6 to 18 years) with Tourette’s disorder [see Clinical Studies ( 14.5)]

14.1 Schizophrenia

Adults
The efficacy of aripiprazole tablets 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 tablets 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 tablets and the active comparators.
In the four positive trials for aripiprazole tablets, 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 tablets (15 or 30 mg/day) to placebo, both doses of aripiprazole tablets were superior to placebo in the PANSS total score (Study 1 in Table 16), 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 tablets (20 or 30 mg/day) to placebo, both doses of aripiprazole tablets were superior to placebo in the PANSS total score (Study 2 in Table 13), PANSS positive subscale, PANSS negative subscale, and CGI-severity score.
In a 6-week trial (n=420) comparing three fixed doses of aripiprazole tablets (10, 15, or 20 mg/day) to placebo, all three doses of aripiprazole tablets were superior to placebo in the PANSS total score (Study 3 in Table 13), PANSS positive subscale, and the PANSS negative subscale.
In a 6-week trial (n=367) comparing three fixed doses of aripiprazole tablets (2, 5, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole tablets was superior to placebo in the PANSS total score (Study 4 in Table 13), the primary outcome measure of the study. The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure.
Thus, the efficacy of 10, 15, 20, 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 tablets 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 tablets 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 tablets 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 tablets (10 or 30 mg/day) to placebo, aripiprazole tablets were 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 tablets were superior to placebo in the PANSS total score (Study 6 in Table 13), 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 13: Schizophrenia Studies

S****tudy Number	T****reatment Group	P****rimary Efficacy Measure: PANNS
		m****ean Baseline Score (SD)	LS M****ean Change from Baseline (SE)	Placebo subtracted Differencea (95% CI)
Study 1	Aripiprazole tablets (15 mg/day)* Aripiprazole tablets (30 mg/day)* Placebo	98.5 (17.2) 99 (19.2) 100.2 (16.5)	-15.5 (2.40) -11.4 (2.39) -2.9 (2.36)	-12.6 (-18.9, -6.2) -8.5 (-14.8, -2.1) --
Study 2	Aripiprazole tablets (20 mg/day)* Aripiprazole (30 mg/day)* Placebo	92.6 (19.5) 94.2 (18.5) 94.3 (18.5)	-14.5 (2.23) -13.9 (2.24) -5 (2.17)	-9.6 (-15.4, -3.8) -9 (-14.8, -3.1) --
Study 3	Aripiprazole (10 mg/day)* Aripiprazole tablets (15 mg/day)* Aripiprazole tablets (20 mg/day)* Placebo	92.7(19.5) 93.2 (21.6) 92.5 (20.9) 92.3 (21.8)	-15 (2.38) -11.7 (2.38) -14.4 (2.45) -2.3 (2.35)	-12.7 (-19, -6.41) -9.4 (-15.71, 3.08) -12.1 (-18.53,5.68) --
Study 4	Aripiprazole tablets (2 mg/day) Aripiprazole tablets (5 mg/day) Aripiprazole tablets (10 mg/day)* Placebo	90.7(14.5) 92 (12.6) 90 (11.9) 90.8 (13.3)	-8.2 (1.90) -10.6 (1.93) -11.3 (1.88) -5.3 (1.97)	-2.9 (-8.29, 2.47) -5.2 (-10.7, 0.19) -5.9 (-11.3, -0.58) --
Study 6 (Pediatric 13-17 Years)	Aripiprazole tablets (10 mg/day)* Aripiprazole tablets (30 mg/day)* Placebo	93.6 (15.7) 94 (16.1) 94.6 (15.6)	-26.7 (1.91) -28.6 (1.92) -21.2 (1.93)	-5.5 (-10.7, -0.21) -7.4 (-12.7, -2.13) --

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
aDifference (drug minus placebo) in least-squares mean change from baseline.
*Doses statistically significantly superior to placebo.
Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

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Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.'s ABILIFY ® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

14.2 Bipolar Disorder

Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY ® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
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.

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 mcg /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. 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 52week, double-blind treatment phase for aripiprazole and placebo groups are shown in Figure 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.

14.5 Tourette's Disorder

Pediatric Patients
The efficacy of aripiprazole in the treatment of Tourette’s disorder was established in one 8 week (7 to 17 years of age)
and one 10 week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette’s disorder and had a Total Tic score (TTS) ≥20 to 22 on the Yale Global Tic Severity Scale (YGTSS). The YGTSS is a fully validated scale designed to measure current tic severity. Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information. Over 65% of these patients were under 13 years of age. The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS. Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each. Summation of these 10 scores provides a TTS (i.e., 0 to 50).

The results of these trials are as follows:
In the 8 week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette’s disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose aripiprazole, high dose aripiprazole, or placebo. The target doses for the low and high dose aripiprazole groups were based on weight. Patients <50 kg in the low dose aripiprazole group started at 2 mg per day with a target dose of 5 mg per day after 2 days. Patients ≥50 kg in the low dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at Day 7. Patients <50 kg in the high dose aripiprazole group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at Day 7. Patients ≥50 kg in the high dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at Day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21. Aripiprazole (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) and on the CGITS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9.

In the 10 week, placebo-controlled, flexible-dose trial in children and adolescents with Tourette’s disorder (n=61), aged 6 to 18 years, patients received daily doses of placebo or aripiprazole, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response. Aripiprazole demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30). The mean daily dose of aripiprazole at the end of 10 week treatment was 6.54 mg/day.

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.
Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.’s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including
aripiprazole, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research programs/pregnancyregistry/.

Risk Summary
Neonates exposed to antipsychotic drugs, including aripiprazole, 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, 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/m 2 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/m 2 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 including increased risk of relapse, hospitalization, and suicide.
Schizophrenia is 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. 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/m 2 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 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/m 2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the MRHD. Decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the MRHD. In rats treated orally with aripiprazole peri- and postnatally 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/m 2 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the MRHD. An increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.

8.2 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 aripiprazole and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition.

8.4 Pediatric Use

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 ( 12.3)].

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 ( 2.1), ADVERSE REACTIONS ( 6.1), and CLINICAL STUDIES ( 14.1)]. 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.

Information describing a clinical study in which efficacy was not demonstrated in patients ages 6 to 17 years is approved for Otsuka America Pharmaceutical, Inc.'s ABILIFY® (aripiprazole). Additional pediatric use information in patients ages 6 to 18 years is approved for Otsuka America Pharmaceutical, Inc.'s ABILIFY® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

---

** 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, 40mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40mg/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 10mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0 to 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 (AUC 0 to 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.

8.5 Geriatric Use

No dosage adjustment is recommended for elderly patients [see BOXED WARNING, WARNINGS AND PRECAUTIONS ( 5.1), and CLINICAL PHARMACOLOGY ( 12.3)].
Of the 13,543 patients treated with oral aripiprazole tablets in clinical trials, 1073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo- controlled studies of oral aripiprazole in schizophrenia, other indications did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Aripiprazole tablets are not approved for the treatment of patients with psychosis associated with Alzheimer's disease [see BOXED WARNINGand WARNINGS AND PRECAUTIONS ( 5.1)] .

8.6 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 ( 2.7) and CLINICAL PHARMACOLOGY ( 12.3)].

8.7 Hepatic and Renal Impairment

No dosage adjustment for aripiprazole tablets 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 ( 12.3)].

8.8 Other Specific Populations

No dosage adjustment for aripiprazole tablets are required on the basis of a patient's sex, race, or smoking status [see CLINICAL PHARMACOLOGY ( 12.3)]

11 DESCRIPTION

Aripiprazole is a psychotropic drug that is available as aripiprazole tablets. Aripiprazole tablets are chemically designated as 7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone. The empirical formula is C 23H 27Cl 2N 3O 2, and molecular weight is 448.39. The chemical structure is as follows:

Aripiprazole tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include corn starch, FD&C Blue #2/Indigo Carmine Al, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of aripiprazole in schizophrenia is unknown. However, the efficacy of aripiprazole could be mediated through a combination of partial agonist activity at D 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors. Actions at receptors other than D 2, 5-HT 1A, and 5-HT 2A may explain some of the other clinical effects of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

12.2 Pharmacodynamics

Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1A and 5-HT 2A receptors (K i values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2C and 5-HT 7, alpha 1-adrenergic and histamine H 1 receptors (K i values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50>1000 nM). [Aripiprazole functions as a partial agonist at the dopamine D 2 and the serotonin 5-HT 1A receptors, and as an antagonist at serotonin 5-HT 2A receptor.]

12.3 Pharmacokinetics

Aripiprazole tablets 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 D 2 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, CYP2D6 and CYP3A4. For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours.
ORAL ADMINISTRATION
Absorption
Tablet: Aripiprazole 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%. Aripiprazole tablets can be administered with or without food. Administration of a 15 mg aripiprazole tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-¬aripiprazole, but delayed T max 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 mg/day to 30 mg/day aripiprazole for 14 days, there was dose-dependent D 2 receptor occupancy indicating brain penetration of aripiprazole in humans.
Metabolism and Elimination
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.
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 C max 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 C max 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
****
Figure 2: The effects of other drugs on dehydro-aripiprazole pharmacokinetics

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The effects of aripiprazole tablets on the exposures of other drugs are summarized in Figure 3.
Figure 3: The effects of aripiprazole on pharmacokinetics of other drugs

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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 tablets (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
****
Figure 5: Effects of intrinsic factors on dehydro-aripiprazole pharmacokinetics

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16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Aripiprazole tablets, 2 mg are light green to green, modified rectangular, bevel edged biconvex tablets debossed with 'I' on one side and '94' on other side.

NDC 50268-087-12

10 Tablets per card, 2 cards per carton

Aripiprazole tablets, 5 mg are light blue to blue, modified rectangular, bevel edged biconvex tablets debossed with 'I' on one side and '95' on other side.

NDC 50268-088-15

10 Tablets per card, 5 cards per carton

Aripiprazole tablets, 10 mg are light pink to pink, modified rectangular, bevel edged biconvex tablets debossed with 'I' on one side and '96' on other side.

NDC 50268-089-15

10 Tablets per card, 5 cards per carton

Aripiprazole tablets, 15 mg are light yellow to yellow, round, bevel edged biconvex tablets debossed with 'I' on one side and '97' on other side.

NDC 50268-090-12

10 Tablets per card, 2 cards per carton

Aripiprazole tablets, 20 mg are white to off-white, round, bevel edged biconvex tablets debossed with 'I' on one side and '98' on other side.

NDC 50268-091-12

10 Tablets per card, 2 cards per carton

Aripiprazole tablets, 30 mg are light pink to pink, round, bevel edged biconvex tablets debossed with 'I' on one side and '99' on other side.

NDC 50268-092-12

10 Tablets per card, 2 cards per carton

16.2 Storage

Store at 20º to 25º C (68º to 77ºF) [see USP Controlled Room Temperature].

Dispensed in Blister Punch Material. For Institutional Use Only.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling ( Medication Guide).
Discuss the following issues with patients prescribed aripiprazole tablets:

Clinical Worsening of Depression and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behaviorand indicate a need for very close monitoring and possibly changes in the medication [see WARNINGS AND PRECAUTIONS (5.3)].

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

Interference with Cognitive and Motor Performance
Because aripiprazole tablets may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that aripiprazole tablets therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS (5.10)].

Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see DRUG INTERACTIONS ( 7)].

Heat Exposure and Dehydration
Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS ( 5.11)].

Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with
aripiprazole. Advise patients that aripiprazole may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to Aripiprazole during pregnancy [see Use in Specific Populations ( 8.1)].

Manufactured for:
AvKARE
Pulaski, TN 38478
Mfg. Rev. 05/23
AV Rev. 01/25 (M)
AvPAK

MEDICATION GUIDE

Aripiprazole Tablets

(air-eh-PIP-rah-zole)

Read this Medication Guide before you start taking aripiprazole tablets and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about aripiprazole tablets?

(For other side effects, also see "What are the possible side effects of aripiprazole tablets?"

Serious side effects may happen when you take aripiprazole tablets, including:
• Increased risk of death in elderly patients with dementia-related psychosis:

Medicines like aripiprazole tablets can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). Aripiprazole tablets are not approved for the treatment of patients with dementia-related psychosis.

• Risk of suicidal thoughts or actions: Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions:
• Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
• Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) suicidal thoughts or actions.
• How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.

Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.

• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.

• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.

What are aripiprazole tablets?
Aripiprazole tablets are prescription medicine used to treat:
• Schizophrenia

• Tourette's disorder

It is not known if aripiprazole tablets are safe or effective in children:
• under 13 years of age with schizophrenia

• under 6 years of age with Tourette's disorder

Do not take aripiprazole tablets if you are allergic to aripiprazole or any of the ingredients in aripiprazole tablets. See the end of this Medication Guide for a complete list of ingredients in aripiprazole tablets.

Before taking aripiprazole tablets, tell your healthcare provider if you have or had:
• diabetes or high blood sugar in you or your family; your healthcare provider should check your blood sugar before you start aripiprazole tablets and also during therapy.
• seizures (convulsions).
• low or high blood pressure.
• heart problems or stroke.
• pregnancy or plans to become pregnant. It is not known if aripiprazole tablets will harm your unborn baby.
• breast-feeding or plans to breast-feed. Aripiprazole can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you receive aripiprazole tablets.
• low white blood cell count.

Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Aripiprazole tablets and other medicines may affect each other causing possible serious side effects. Aripiprazole tablets may affect the way other medicines work, and other medicines may affect how aripiprazole tablets works.

Your healthcare provider can tell you if it is safe to take aripiprazole tablets with your other medicines. Do not start or stop any medicines while taking aripiprazole tablets without talking to your healthcare provider first. Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.

How should I take aripiprazole tablets?
• Take aripiprazole tablets exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking aripiprazole tablets yourself.
• Aripiprazole tablets can be taken with or without food.
• Aripiprazole tablets should be swallowed whole.
• If you miss a dose of aripiprazole tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, just skip the missed dose and take your next dose at the regular time. Do not take two doses of aripiprazole tablets at the same time.
• If you take too much aripiprazole tablets, call your healthcare provider or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.

What should I avoid while taking aripiprazole tablets?
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how aripiprazole tablets affects you. Aripiprazole tablets may make you drowsy.
• Avoid getting over-heated or dehydrated.
• Do not over-exercise.
• In hot weather, stay inside in a cool place if possible.
• Stay out of the sun. Do not wear too much or heavy clothing.
• Drink plenty of water.

What are the possible side effects of aripiprazole tablets?
Aripiprazole tablets may cause serious side effects, including:
• See "What is the most important information I should know about aripiprazole tablets?'
• Stroke in elderly people (cerebrovascular problems) that can lead to death
• Neuroleptic malignant syndrome (NMS): Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms.
• Uncontrolled body movements (tardive dyskinesia). Aripiprazole tablets may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving aripiprazole tablets. Tardive dyskinesia may also start after you stop receiving aripiprazole tablets.
• Problems with your metabolism such as:
• high blood sugar (hyperglycemia) and diabetes: Increases in blood sugar can happen in some people who take aripiprazole tablets. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes), your healthcare provider should check your blood sugar before you start aripiprazole tablets and during your treatment.

Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving aripiprazole tablets:

• feel very thirsty
• need to urinate more than usual
• feel very hungry
• feel weak or tired
• feel sick to your stomach
• feel confused, or your breath smells fruity.
• increased fat levels (cholesterol and triglycerides) in your blood.
• weight gain. You and your healthcare provider should check your weight regularly.
• Orthostatic hypotension (decreased blood pressure):
• Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position.

• Falls. Aripiprazole tablets may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.
• Low white blood cell count
• Seizures (convulsions)
• problems with control of your body temperature especially when you exercise a lot or are in an area that is very hot. It is important for you to drink water to avoid dehydration. See "What should I avoid while receiving aripiprazole tablets?"
• difficulty swallowing that can cause food or liquid to get into your lungs.

The most common side effects with aripiprazole tablets in adults include:
• nausea

• dizziness
• vomiting

• anxiety
• constipation

• insomnia
• headache

• restlessness
• blurred vision

• inner sense of restlessness/need to move (akathisia)
• upper respiratory illness

The most common side effects with aripiprazole tablets in children include:
• feeling sleepy

• insomnia
• headache

• nausea
• vomiting

• stuffy nose
• fatigue

• weight gain
• increased or decreased appetite • uncontrolled movement such as restlessness, tremor, muscle stiffness
• increased saliva or drooling

These are not all the possible side effects of aripiprazole tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store aripiprazole tablets?

• Store aripiprazole tablets at 20º to 25º C (68º to 77ºF) [see USP Controlled Room Temperature].

Keep aripiprazole tablets and all medicines out of the reach of children.

General information about the safe and effective use of aripiprazole tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use aripiprazole tablets for a condition for which it was not prescribed. Do not give aripiprazole tablets to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about aripiprazole tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about aripiprazole tablets that was written for healthcare professionals.

For more information, call 1-855-361-3993.

What are the ingredients in aripiprazole tablets?
Active ingredient: aripiprazole USP
Inactive ingredients: corn starch, FD&C Blue #2/Indigo Carmine Al, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose

Additional pediatric use information is approved for Otsuka America Pharmaceutical, Inc.'s ABILIFY ® (aripiprazole) product. However, due to Otsuka America Pharmaceutical, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
AvKARE
Pulaski, TN 38478
Mfg. Rev. 05/23
AV Rev. 01/25 (M)
AvPAK