Dosage Forms And Strengths

%medicine_name%® (aripiprazole) Tablets are available as described in Table 3.

Table 3: %medicine_name% Tablet Presentations

%medicine_name% DISCMELT® (aripiprazole) Orally Disintegrating Tablets are available as described in Table 4.

Table 4: %medicine_name% DISCMELT Orally Disintegrating Tablet Presentations

%medicine_name%® (aripiprazole) Oral Solution (1 mg/mL) is a clear, colorless to light-yellow solution, supplied in child-resistant bottles along with a calibrated oral dosing cup.

%medicine_name%® (aripiprazole) Injection for Intramuscular Use is a clear, colorless solution available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials.

Storage And Handling

%medicine_name%® (aripiprazole) Tablets have markings on one side and are available in the strengths and packages listed in Table 32.

Table 32: %medicine_name% Tablet Presentations

%medicine_name% DISCMELT® (aripiprazole) Orally Disintegrating Tablets are round tablets with markings on either side. %medicine_name% DISCMELT is available in the strengths and packages listed in Table 33.

Table 33: %medicine_name% DISCMELT Orally Disintegrating Tablet Presentations

%medicine_name%® (aripiprazole) Oral Solution (1 mg/mL) is supplied in child-resistant bottles along with a calibrated oral dosing cup. %medicine_name% Oral Solution is available as follows:

150 mL bottle NDC 59148-013-15

%medicine_name%® (aripiprazole) Injection for intramuscular use is available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials as follows:

9.75 mg/1.3 mL single-dose vial NDC 59148-016-65

Storage

Tablets

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Oral Solution

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Opened bottles of %medicine_name% Oral Solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle. The bottle and its contents should be discarded after the expiration date.

Injection

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from light by storing in the original container. Retain in carton until time of use.

Tablets manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Orally Disintegrating Tablets, Oral Solution, and Injection manufactured by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA. Revised: Aug 2016

%medicine_name% Oral Tablets, Orally-Disintegrating Tablets, and Oral Solution are indicated for the treatment of:

• Schizophrenia
• Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder
• Adjunctive Treatment of Major Depressive Disorder
• Irritability Associated with Autistic Disorder
• Treatment of Tourette's Disorder

%medicine_name% Injection is indicated for the treatment of:

• Agitation associated with schizophrenia or bipolar mania

Schizophrenia

Adults

The recommended starting and target dose for %medicine_name% is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. %medicine_name% 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.

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 %medicine_name% 15 mg/day or placebo, and observed for relapse. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

Adolescents

The recommended target dose of %medicine_name% 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. %medicine_name% can be administered without regard to meals. 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 %medicine_name% 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.

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. %medicine_name% can be given without regard to meals. The recommended target dose of %medicine_name% 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. %medicine_name% can be given without regard to meals.

Adjunctive Treatment Of Major Depressive Disorder

Adults

The recommended starting dose for %medicine_name% 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. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

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

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 1 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 1 week..

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

Agitation Associated With Schizophrenia Or Bipolar Mania (Intramuscular Injection)

Adults

The recommended dose in these patients is 9.75 mg. The recommended dosage range is 5.25 to 15 mg. No additional benefit was demonstrated for 15 mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical factors warrant. If agitation warranting a second dose persists following the initial dose, cumulative doses up to a total of 30 mg/day may be given. However, the efficacy of repeated doses of %medicine_name% injection in agitated patients has not been systematically evaluated in controlled clinical trials. The safety of total daily doses greater than 30 mg or injections given more frequently than every 2 hours have not been adequately evaluated in clinical trials.

If ongoing %medicine_name% therapy is clinically indicated, oral %medicine_name% in a range of 10 to 30 mg/day should replace %medicine_name% injection as soon as possible.

Administration Of %medicine_name% Injection

To administer %medicine_name% Injection, draw up the required volume of solution into the syringe as shown in Table 1. Discard any unused portion.

Table 1: %medicine_name% Injection Dosing Recommendations

%medicine_name% Injection is intended for intramuscular use only. Do not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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, %medicine_name% dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, %medicine_name% 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 %medicine_name% in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers

When adjunctive %medicine_name% is administered to patients with major depressive disorder, %medicine_name% should be administered without dosage adjustment as specified in sections above.

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.

Dosing Of Orally Disintegrating Tablets

The dosing for %medicine_name% Orally Disintegrating Tablets is the same as for the oral tablets.

%medicine_name% is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Increased Mortality In Elderly Patients With Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. %medicine_name% (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis.

Safety Experience In Elderly Patients With Psychosis Associated With Alzheimer's Disease

In three, 10-week, placebo-controlled studies of %medicine_name% in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the adverse reactions that were reported at an incidence of ≥ 3% and %medicine_name% incidence at least twice that for placebo were lethargy [placebo 2%, %medicine_name% 5%], somnolence (including sedation) [placebo 3%, %medicine_name% 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, %medicine_name% 5%], excessive salivation [placebo 0%, %medicine_name% 4%], and lightheadedness [placebo 1%, %medicine_name% 4%].

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

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 %medicine_name%-treated patients (mean age: 84 years; range: 7888 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with %medicine_name%. %medicine_name% is not approved for the treatment of patients with dementia-related psychosis.

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 1824) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 5.

Table 5

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

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

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

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for %medicine_name% 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 %medicine_name% is not approved for use in treating depression in the pediatric population.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including %medicine_name%. Rare cases of NMS occurred during %medicine_name% treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, %medicine_name% 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 %medicine_name%, drug discontinuation should be considered. However, some patients may require treatment with %medicine_name% despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia/Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with %medicine_name%. 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 %medicine_name% was not marketed at the time these studies were performed, it is not known if %medicine_name% 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 %medicine_name%-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 6 shows the proportion of %medicine_name%-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).

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

At 24 weeks, the mean change in fasting glucose in %medicine_name%-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 %medicine_name%-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 7 shows the proportion of adult patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median exposure 42 days) in patients with major depressive disorder.

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

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 %medicine_name%-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 %medicine_name%-treated patients (-0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (-0.6 mg/dL; N=33).

In an analysis of two placebo-controlled trials in pediatric and adolescent patients with Tourette's disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in %medicine_name%-treated patients (0.79 mg/dL; N=90) was not significantly different than in placebo-treated patients (-1.66 mg/dL; N=58).

Table 8 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and pediatric bipolar patients (median exposure of 42-43 days), from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in pediatric patients (6 to 18 year) with Tourette's Disorder (median exposure 57 days).

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

At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder trials, the mean change in fasting glucose in %medicine_name%-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 %medicine_name%-and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.

Adults

Table 9 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days).

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

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 %medicine_name%-and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.

Table 10 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials in adult patients with major depressive disorder (median exposure 42 days).

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

Pediatric Patients And Adolescents

Table 11 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days) and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days).

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

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 %medicine_name%-and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.

Table 12 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder.

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

Table 13 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 57 days) and HDL cholesterol (median exposure 57 days) from two placebo-controlled trials in pediatric patients (6 to 18 years) with Tourette's Disorder.

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

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

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

SIDE EFFECTS

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
• Cerebrovascular Adverse Events, Including Stroke
• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
• Neuroleptic Malignant Syndrome (NMS)
• Tardive Dyskinesia
• Metabolic Changes
• Pathological Gambling and Other Compulsive Behaviors
• Orthostatic Hypotension
• Leukopenia, Neutropenia, and Agranulocytosis
• Seizures/Convulsions
• Potential for Cognitive and Motor Impairment
• Body Temperature Regulation
• Suicide
• Dysphagia

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.

%medicine_name% 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 %medicine_name% and 749 patients with exposure to %medicine_name% injection. A total of 3390 patients were treated with oral %medicine_name% for at least 180 days and 1933 patients treated with oral %medicine_name% had at least 1 year of exposure.

%medicine_name% has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's disorder and who had approximately 1,342 patient-years of exposure to oral %medicine_name%. A total of 959 pediatric patients were treated with oral %medicine_name% for at least 180 days and 556 pediatric patients treated with oral %medicine_name% had at least 1 year of exposure.

The conditions and duration of treatment with %medicine_name% (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed-and flexible-dose studies, and short-and longer-term exposure.

Clinical Trials Experience

Adult Patients With Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral %medicine_name% 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 %medicine_name% in patients with schizophrenia (incidence of 5% or greater and

%medicine_name% incidence at least twice that for placebo) was akathisia (%medicine_name% 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 %medicine_name% was administered at doses of 15 or 30 mg/day.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of %medicine_name% in patients with bipolar mania (incidence of 5% or greater and %medicine_name% 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 Adult Patients with Bipolar Mania Treated with Oral %medicine_name% Monotherapy

Less Common Adverse Reactions In Adults

Table 17 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 %medicine_name% (doses ≥ 2 mg/day) and for which the incidence in patients treated with %medicine_name% was greater than the incidence in patients treated with placebo in the combined dataset.

Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral %medicine_name%

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 %medicine_name% was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive %medicine_name% compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive %medicine_name%-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 %medicine_name% 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 18 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 %medicine_name% (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 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

Pediatric Patients (13 to 17 years) With Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which oral %medicine_name% 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 %medicine_name%-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 %medicine_name% in adolescent patients with schizophrenia (incidence of 5% or greater and %medicine_name% 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 %medicine_name% 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 %medicine_name%-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of %medicine_name% in pediatric patients with bipolar mania (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo) are shown in Table 19.

Table 19: Commonly Observed Adverse Reactions in Short- Term, Placebo-Controlled Trials of Pediatric Patients(10 to 17 years) with Bipolar Mania Treated with Oral %medicine_name%

Pediatric Patients (6 to 17 years) With Autistic Disorder

The following findings are based on two 8-week, placebo-controlled trials in which oral %medicine_name% 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 %medicine_name%-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 %medicine_name% in pediatric patients with autistic disorder (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo) are shown in Table 20.

Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral %medicine_name%

Pediatric Patients (6 to 18 years) With Tourette's Disorder

The following findings are based on one 8-week and one 10-week, placebo-controlled trials in which oral %medicine_name% was administered in doses of 2 to 20 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between %medicine_name%-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of %medicine_name% in pediatric patients with Tourette's disorder (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo) are shown in Table 21.

Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with Oral %medicine_name%

Less Common Adverse Reactions In Pediatric Patients (6 to 18 years) With Schizophrenia, Bipolar Mania, Autistic Disorder, Or Tourette's Disorder

Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette's disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with %medicine_name% (doses ≥ 2 mg/day) and for which the incidence in patients treated with %medicine_name% was greater than the incidence in patients treated with placebo.

Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral %medicine_name%

Adult Patients Receiving %medicine_name% 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 %medicine_name% was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions was 6% for adjunctive %medicine_name%-treated patients and 2% for adjunctive placebo-treated patients.

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with the use of adjunctive %medicine_name% in patients with major depressive disorder (incidence of 5% or greater and %medicine_name% 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 23 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 %medicine_name% (doses ≥ 2 mg/day) and for which the incidence in patients treated with adjunctive %medicine_name% was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

Table 23: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder

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 %medicine_name% injection was administered at doses of 5.25 mg to 15 mg.

Commonly Observed Adverse Reactions

There was one commonly observed adverse reaction (nausea) associated with the use of %medicine_name% injection in patients with agitation associated with schizophrenia and bipolar mania (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo).

Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania

Table 24 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (24-hour), including only those adverse reactions that occurred in 2% or more of patients treated with %medicine_name% injection (doses ≥ 5.25 mg/day) and for which the incidence in patients treated with %medicine_name% injection was greater than the incidence in patients treated with placebo in the combined dataset.

Table 24: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Patients Treated with %medicine_name% Injection

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

Pregnancy Category C

Pregnancy Exposure Registry

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

Risk Summary

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

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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

Data

Animal Data

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

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the maximum recommended human dose [MRHD] on a mg/m²basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg/day. Treatment at the high dose of 30 mg/kg/day caused a slight delay in fetal development (decreased fetal weight), undescended testes, and delayed skeletal ossification (also seen at 10 mg/kg/day). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg/day), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg/day and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg/day. Some maternal toxicity was seen at 30 mg/kg/day however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

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

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

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

In a study in which rats were treated peri-and post-natally with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on a mg/m²basis) of aripiprazole from gestation day 17 through day 21 postpartum, slight maternal toxicity, slightly prolonged gestation an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were seen at 30 mg/kg/day.

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

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
• Cerebrovascular Adverse Events, Including Stroke
• Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
• Neuroleptic Malignant Syndrome (NMS)
• Tardive Dyskinesia
• Metabolic Changes
• Pathological Gambling and Other Compulsive Behaviors
• Orthostatic Hypotension
• Leukopenia, Neutropenia, and Agranulocytosis
• Seizures/Convulsions
• Potential for Cognitive and Motor Impairment
• Body Temperature Regulation
• Suicide
• Dysphagia

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.

%medicine_name% 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 %medicine_name% and 749 patients with exposure to %medicine_name% injection. A total of 3390 patients were treated with oral %medicine_name% for at least 180 days and 1933 patients treated with oral %medicine_name% had at least 1 year of exposure.

%medicine_name% has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's disorder and who had approximately 1,342 patient-years of exposure to oral %medicine_name%. A total of 959 pediatric patients were treated with oral %medicine_name% for at least 180 days and 556 pediatric patients treated with oral %medicine_name% had at least 1 year of exposure.

The conditions and duration of treatment with %medicine_name% (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed-and flexible-dose studies, and short-and longer-term exposure.

Clinical Trials Experience

Adult Patients With Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral %medicine_name% 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 %medicine_name% in patients with schizophrenia (incidence of 5% or greater and

%medicine_name% incidence at least twice that for placebo) was akathisia (%medicine_name% 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 %medicine_name% was administered at doses of 15 or 30 mg/day.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of %medicine_name% in patients with bipolar mania (incidence of 5% or greater and %medicine_name% 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 Adult Patients with Bipolar Mania Treated with Oral %medicine_name% Monotherapy

Less Common Adverse Reactions In Adults

Table 17 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 %medicine_name% (doses ≥ 2 mg/day) and for which the incidence in patients treated with %medicine_name% was greater than the incidence in patients treated with placebo in the combined dataset.

Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral %medicine_name%

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 %medicine_name% was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive %medicine_name% compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive %medicine_name%-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 %medicine_name% 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 18 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 %medicine_name% (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 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

Pediatric Patients (13 to 17 years) With Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which oral %medicine_name% 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 %medicine_name%-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 %medicine_name% in adolescent patients with schizophrenia (incidence of 5% or greater and %medicine_name% 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 %medicine_name% 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 %medicine_name%-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of %medicine_name% in pediatric patients with bipolar mania (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo) are shown in Table 19.

Table 19: Commonly Observed Adverse Reactions in Short- Term, Placebo-Controlled Trials of Pediatric Patients(10 to 17 years) with Bipolar Mania Treated with Oral %medicine_name%

Pediatric Patients (6 to 17 years) With Autistic Disorder

The following findings are based on two 8-week, placebo-controlled trials in which oral %medicine_name% 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 %medicine_name%-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 %medicine_name% in pediatric patients with autistic disorder (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo) are shown in Table 20.

Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral %medicine_name%

Pediatric Patients (6 to 18 years) With Tourette's Disorder

The following findings are based on one 8-week and one 10-week, placebo-controlled trials in which oral %medicine_name% was administered in doses of 2 to 20 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between %medicine_name%-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of %medicine_name% in pediatric patients with Tourette's disorder (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo) are shown in Table 21.

Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with Oral %medicine_name%

Less Common Adverse Reactions In Pediatric Patients (6 to 18 years) With Schizophrenia, Bipolar Mania, Autistic Disorder, Or Tourette's Disorder

Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette's disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with %medicine_name% (doses ≥ 2 mg/day) and for which the incidence in patients treated with %medicine_name% was greater than the incidence in patients treated with placebo.

Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral %medicine_name%

Adult Patients Receiving %medicine_name% 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 %medicine_name% was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions was 6% for adjunctive %medicine_name%-treated patients and 2% for adjunctive placebo-treated patients.

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with the use of adjunctive %medicine_name% in patients with major depressive disorder (incidence of 5% or greater and %medicine_name% 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 23 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 %medicine_name% (doses ≥ 2 mg/day) and for which the incidence in patients treated with adjunctive %medicine_name% was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

Table 23: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder

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 %medicine_name% injection was administered at doses of 5.25 mg to 15 mg.

Commonly Observed Adverse Reactions

There was one commonly observed adverse reaction (nausea) associated with the use of %medicine_name% injection in patients with agitation associated with schizophrenia and bipolar mania (incidence of 5% or greater and %medicine_name% incidence at least twice that for placebo).

Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania

Table 24 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (24-hour), including only those adverse reactions that occurred in 2% or more of patients treated with %medicine_name% injection (doses ≥ 5.25 mg/day) and for which the incidence in patients treated with %medicine_name% injection was greater than the incidence in patients treated with placebo in the combined dataset.

Table 24: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Patients Treated with %medicine_name% Injection

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 fixe

MedDRA terminology has been used to classify the adverse reactions.

Human Experience

In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral %medicine_name% have been reported worldwide.

These include overdoses with oral %medicine_name% alone and in combination with other substances. No fatality was reported with %medicine_name% alone. The largest known dose with a known outcome involved acute ingestion of 1260 mg of oral %medicine_name% (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 and younger) involving oral %medicine_name% ingestions up to 195 mg with no fatalities.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral %medicine_name% 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 %medicine_name% 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.

Management Of Overdosage

No specific information is available on the treatment of overdose with %medicine_name%. 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 %medicine_name%, 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 %medicine_name%, decreased the mean AUC and Cmax of aripiprazole by 50%.

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

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). [Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.]

%medicine_name% 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 dehydroaripiprazole, 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.

Pharmacokinetic studies showed that %medicine_name% DISCMELT Orally Disintegrating Tablets are bioequivalent to %medicine_name% Tablets.

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%. %medicine_name% can be administered with or without food. Administration of a 15 mg %medicine_name% 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.

Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution to tablet ratios of geometric mean Cmax and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg.

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.

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.