ABILIFY MAINTENA (aripiprazole) is indicated:

{ "type": "p", "children": [], "text": "ABILIFY MAINTENA (aripiprazole) is indicated:" }

{ "type": "ul", "children": [ "for the treatment of schizophrenia in adults", "for maintenance monotherapy treatment of bipolar I disorder in adults" ], "text": "" }

For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY MAINTENA. Due to the half-life of oral aripiprazole (i.e., 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively), it may take up to 2 weeks to fully assess tolerability.

ABILIFY MAINTENA must be administered by intramuscular injection by a healthcare professional. Do not administer by any other route.

For detailed preparation and administration instructions, [see Dosage and Administration (2.6, 2.7)].

The recommended dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection).

There are two ways to initiate treatment with ABILIFY MAINTENA in patients receiving oral antipsychotics:

1-day initiation:

14-day initiation:

If there are adverse reactions with the 400 mg dosage, the dosage may be reduced to 300 mg once monthly.

If the second or third doses are missed:

If the fourth or subsequent doses are missed:

Refer to Table 1 and Table 2 for dosage modifications for patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days.

If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased to the previous dose [see Dosage and Administration (2.2)].

Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.

Dosage modifications are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: Dosage Modifications for ABILIFY MAINTENA (1-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days</span> </caption> <col align="left" valign="top" width="80%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Factors</th><th align="center" class="Rrule">Adjusted Dose<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>No change for oral dosage required during initiation.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP2D6 Poor Metabolizers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers</td><td align="center" class="Rrule">300 mg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors</td><td align="center" class="Rrule" valign="middle">Avoid use</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Concomitant use with CYP Inhibitors and/or Inducers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Strong CYP2D6 <span class="Bold"><span class="Underline">or</span></span> CYP3A4 inhibitors</td><td align="center" class="Rrule">300 mg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">CYP2D6 <span class="Bold"><span class="Underline">and</span></span> CYP3A4 inhibitors</td><td align="center" class="Rrule">Avoid use</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">CYP3A4 inducers</td><td align="center" class="Rrule">Avoid use</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2: Dosage Modifications for ABILIFY MAINTENA (14-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days</span> </caption> <col align="left" valign="top" width="80%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Factors</th><th align="center" class="Rrule">Adjusted Dose<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>No change for oral dosage required during initiation.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>200 mg and 160 mg dosage adjustment is obtained only by using the 300 mg or 400 mg strength vials.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP2D6 Poor Metabolizers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers</td><td align="center" class="Rrule">300 mg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors</td><td align="center" class="Rrule">200 mg<a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Patients Taking 400 mg of ABILIFY MAINTENA</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Strong CYP2D6 <span class="Bold"><span class="Underline">or</span></span> CYP3A4 inhibitors</td><td align="center" class="Rrule">300 mg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">CYP2D6 <span class="Bold"><span class="Underline">and</span></span> CYP3A4 inhibitors</td><td align="center" class="Rrule">200 mg<a class="Sup" href="#footnote-3">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">CYP3A4 inducers</td><td align="center" class="Rrule">Avoid use</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Patients Taking 300 mg of ABILIFY MAINTENA</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Strong CYP2D6 <span class="Bold"><span class="Underline">or</span></span> CYP3A4 inhibitors</td><td align="center" class="Rrule">200 mg<a class="Sup" href="#footnote-3">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">CYP2D6 <span class="Bold"><span class="Underline">and</span></span> CYP3A4 inhibitors</td><td align="center" class="Rrule">160 mg<a class="Sup" href="#footnote-3">†</a></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">CYP3A4 inducers</td><td align="center" class="Rrule">Avoid use</td> </tr> </tbody> </table></div>

ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe [see Dosage and Administration (2.6)], and 2) Vials [see Dosage and Administration (2.7)].

ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe available in 300 mg or 400 mg strength syringes [see Dosage and Administration (2.6)], and 2) Single-dose vials available in 300 mg or 400 mg strength vials [see Dosage and Administration (2.7)].

The 200 mg and 160 mg dosage adjustments are obtained only by using the 300 mg or 400 mg strength vials.

Preparation Prior to Reconstitution

For deep intramuscular deltoid or gluteal injection by healthcare professionals only. Do not administer by any other route. Inject full syringe contents immediately following reconstitution. Administer once monthly.

Lay out and confirm that components listed below are provided in the kit:

Reconstitution of Lyophilized Powder in Pre-filled Dual Chamber Syringe

Reconstitute at room temperature.

Injection Procedure

Use appropriate aseptic techniques throughout injection procedure. For deep intramuscular injection only.

Disposal Procedure

Preparation Prior to Reconstitution

For deep intramuscular injection by healthcare professionals only. Do not administer by any other route. Inject immediately after reconstitution. Administer once monthly.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3: Amount of Sterile Water for Injection Needed for Reconstitution</span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" colspan="2">400 mg Vial</th><th align="center" class="Rrule" colspan="2">300 mg Vial</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Dose</th><th align="center" class="Rrule">Sterile Water for Injection</th><th align="center" class="Rrule">Dose</th><th align="center" class="Rrule">Sterile Water for Injection</th> </tr> </thead> <tbody> <tr class="First Last"> <td align="center" class="Lrule Rrule">400 mg</td><td align="center" class="Rrule">1.9 mL</td><td align="center" class="Rrule">300 mg</td><td align="center" class="Rrule">1.5 mL</td> </tr> </tbody> </table></div>

Important: There is more Sterile Water for Injection in the vial than is needed to reconstitute ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension. The vial will have excess Sterile Water for Injection; discard any unused portion.

Reconstitution of Lyophilized Powder in Vial

Preparation Prior to Injection

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 4: ABILIFY MAINTENA Reconstituted Suspension Volume to Inject</span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" colspan="2">400 mg Vial</th><th align="center" class="Rrule" colspan="2">300 mg Vial</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Dose</th><th align="center" class="Rrule">Volume to Inject</th><th align="center" class="Rrule">Dose</th><th align="center" class="Rrule">Volume to Inject</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">400 mg</td><td align="center" class="Rrule">2 mL</td><td align="center" class="Rrule">---</td><td align="center" class="Rrule">---</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">300 mg</td><td align="center" class="Rrule">1.5 mL</td><td align="center" class="Rrule">300 mg</td><td align="center" class="Rrule">1.5 mL</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">200 mg</td><td align="center" class="Rrule">1 mL</td><td align="center" class="Rrule">200 mg</td><td align="center" class="Rrule">1 mL</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">160 mg</td><td align="center" class="Rrule">0.8 mL</td><td align="center" class="Rrule">160 mg</td><td align="center" class="Rrule">0.8 mL</td> </tr> </tbody> </table></div>

Injection Procedure

For deltoid administration:

For gluteal administration:

Disposal Procedure

For extended-release injectable suspension: 300 mg and 400 mg of lyophilized powder for reconstitution in:

{ "type": "p", "children": [], "text": "\nFor extended-release injectable suspension: 300 mg and 400 mg of lyophilized powder for reconstitution in:" }

{ "type": "ul", "children": [ "single-dose, pre-filled, dual chamber syringe", "single-dose vial" ], "text": "" }

The reconstituted extended-release injectable suspension is a uniform, homogeneous suspension that is opaque and milky-white in color.

{ "type": "p", "children": [], "text": "The reconstituted extended-release injectable suspension is a uniform, homogeneous suspension that is opaque and milky-white in color." }

ABILIFY MAINTENA is contraindicated in patients with a known hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1 and 6.2)].

{ "type": "p", "children": [], "text": "ABILIFY MAINTENA is contraindicated in patients with a known hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1 and 6.2)]." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis.

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 reactions (e.g., stroke, transient ischemic attack), including fatalities, in oral aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse reactions in patients treated with oral aripiprazole. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY MAINTENA. Rare cases of NMS occurred during aripiprazole 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.

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

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

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

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

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and 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 diabetic ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1)]. 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 reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

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 atypical antipsychotic drug.

In a short-term, placebo-controlled randomized trial in adults with schizophrenia, the mean change in fasting glucose was +9.8 mg/dL (N=88) in the ABILIFY MAINTENA-treated patients and +0.7 mg/dL (N=59) in the placebo-treated patients. Table 5 shows the proportion of ABILIFY MAINTENA-treated patients with normal and borderline fasting glucose at baseline and their changes in fasting glucose measurements.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 5: Proportion of Patients with Potential Clinically Relevant Changes in Fasting Glucose from a 12-Week Placebo-Controlled Monotherapy Trial in Adult Patients with Schizophrenia </span> </caption> <col align="left" valign="middle" width="15%"/> <col align="center" valign="top" width="35%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <thead> <tr class="First Last"> <th align="left"></th><th align="center" valign="bottom">Category Change (at least once) from Baseline</th><th align="center" class="Lrule Rrule" valign="bottom">Treatment Arm</th><th align="center" class="Rrule" valign="bottom">n/N<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></th><th align="center" valign="bottom">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" rowspan="4"><span class="Bold">Fasting Glucose</span></td><td align="center" rowspan="2">Normal to High<br/>(&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Lrule Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">7/88</td><td align="center">8.0</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">0/75</td><td align="center">0.0</td> </tr> <tr class="Botrule"> <td align="center" rowspan="2">Borderline to High<br/>(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center" class="Lrule Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">1/33</td><td align="center">3.0</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">3/33</td><td align="center">9.1</td> </tr> </tbody> </table></div>

During a 52-week, open-label bipolar I disorder study in those patients who initiated ABILIFY MAINTENA treatment, 1.1% with normal baseline fasting glucose experienced a shift to high while receiving ABILIFY MAINTENA and 9.8% with borderline fasting glucose experienced a shift to high. Combined, 2.9% of these patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during this trial.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Table 6 shows the proportion of adult patients from one short-term, placebo-controlled randomized trial in adults with schizophrenia taking ABILIFY MAINTENA, with changes in total cholesterol, fasting triglycerides, fasting LDL cholesterol and HDL cholesterol.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 6: Proportion of Patients with Potential Clinically Relevant Changes in Blood Lipid Parameters From a 12-Week Placebo-Controlled Monotherapy Trial in Adults with Schizophrenia</span> </caption> <col align="left" valign="middle" width="35%"/> <col align="center" valign="middle" width="35%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="left" class="Rrule"></th><th align="center" class="Rrule">Treatment Arm</th><th align="center" class="Rrule">n/N<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></th><th align="center">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Rrule" rowspan="2"><span class="Bold">Total Cholesterol</span> <br/>Normal to High<br/>(&lt;200 mg/dL to ≥240 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">3/83</td><td align="center">3.6</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">2/73</td><td align="center">2.7</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2">Borderline to High<br/>(200~&lt;240 mg/dL to ≥240 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">6/27</td><td align="center">22.2</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">2/19</td><td align="center">10.5</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2">Any increase<br/>(≥40 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">15/122</td><td align="center">12.3</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">6/110</td><td align="center">5.5</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2"><span class="Bold">Fasting Triglycerides</span> <br/>Normal to High<br/>(&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">7/98</td><td align="center">7.1</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">4/78</td><td align="center">5.1</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2">Borderline to High<br/>(150~&lt;200 mg/dL to ≥200 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">3/11</td><td align="center">27.3</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">4/15</td><td align="center">26.7</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2">Any increase<br/>(≥50 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">24/122</td><td align="center">19.7</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">20/110</td><td align="center">18.2</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2"><span class="Bold">Fasting LDL Cholesterol</span> <br/>Normal to High<br/>(&lt;100 mg/dL to ≥160 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">1/59</td><td align="center">1.7</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">1/51</td><td align="center">2.0</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2">Borderline to High<br/>(100~&lt;160 mg/dL to ≥160 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">5/52</td><td align="center">9.6</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">1/41</td><td align="center">2.4</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2">Any increase<br/>(≥30 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">17/120</td><td align="center">14.2</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">9/103</td><td align="center">8.7</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2"><span class="Bold">HDL Cholesterol</span> <br/>Normal to Low<br/>(≥40 mg/dL to &lt;40 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">14/104</td><td align="center">13.5</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">11/87</td><td align="center">12.6</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule" rowspan="2">Any decrease<br/>(≥20 mg/dL)</td><td align="center" class="Rrule">ABILIFY MAINTENA</td><td align="center" class="Rrule">7/122</td><td align="center">5.7</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">12/110</td><td align="center">10.9</td> </tr> </tbody> </table></div>

During a 52-week, open-label bipolar I disorder study in those patients who initiated ABILIFY MAINTENA, shifts from baseline in fasting cholesterol from normal to high were reported in 2.1% (total cholesterol) and 2.2% (LDL cholesterol) and shifts from baseline from normal to low were reported in 8.5% (HDL cholesterol). Of these patients with normal baseline triglycerides, 3.6% experienced shifts to high, and 0.0% experienced shifts to very high. Combined, 1.0% of these patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during this trial.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

In one short-term, placebo-controlled trial in adult patients with schizophrenia with ABILIFY MAINTENA, the mean change in body weight at Week 12 was +3.5 kg (N=99) in the ABILIFY MAINTENA-treated patients and +0.8 kg (N=66) in the placebo-treated patients.

Table 7 shows the percentage of adult patients with schizophrenia with weight gain ≥7% of body weight in a short-term, placebo-controlled trial with ABILIFY MAINTENA.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 7: Percentage of Patients From a 12-Week Placebo-Controlled Trial in Adult Patients with Schizophrenia with Weight Gain ≥7% of Body Weight</span> </caption> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="34%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="29%"/> <thead> <tr class="First Last"> <th align="center"></th><th align="center">Treatment Arm</th><th align="center">N<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></th><th align="center">Patients n (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>N = the total number of subjects who had a measurement at baseline and at least one post-baseline result.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" rowspan="2" valign="bottom"><span class="Bold">Weight gain ≥7% of body weight</span></td><td align="center">ABILIFY MAINTENA</td><td align="center">144</td><td align="center">31 (21.5)</td> </tr> <tr class="Last"> <td align="center">Placebo</td><td align="center">141</td><td align="center">12 (8.5)</td> </tr> </tbody> </table></div>

During a 52-week, open-label bipolar I disorder study in those patients who initiated ABILIFY MAINTENA, 1.8% discontinued ABILIFY MAINTENA treatment due to weight increase. ABILIFY MAINTENA was associated with mean increase from baseline in weight of 1.0 kg at week 52. In this trial, 21.4% of these patients demonstrated ≥7% increase in body weight and 15.4% demonstrated a ≥7% decrease in body weight.

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

ABILIFY MAINTENA may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. In the short-term, placebo-controlled trial in adults with schizophrenia, the adverse event of presyncope was reported in 1/167 (0.6%) of patients treated with ABILIFY MAINTENA, while syncope and orthostatic hypotension were each reported in 1/172 (0.6%) of patients treated with placebo. During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, orthostasis-related adverse events were reported in 4/576 (0.7%) of patients treated with ABILIFY MAINTENA, including abnormal orthostatic blood pressure (1/576, 0.2%), postural dizziness (1/576, 0.2%), presyncope (1/576, 0.2%) and orthostatic hypotension (1/576, 0.2%).

In the short-term placebo-controlled trial in adults with schizophrenia, there were no patients in either treatment group with a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values). During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, the incidence of significant orthostatic change in blood pressure was 0.2% (1/575).

Antipsychotics, including ABILIFY MAINTENA, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trials and post-marketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY MAINTENA. Agranulocytosis has also been reported [see Adverse Reactions (6.1)].

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and a history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY MAINTENA at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY MAINTENA in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC counts until recovery.

As with other antipsychotic drugs, use ABILIFY MAINTENA cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

ABILIFY MAINTENA, like other antipsychotics, may impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that therapy with ABILIFY MAINTENA does not affect them adversely.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY MAINTENA for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY MAINTENA. ABILIFY MAINTENA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1)].

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.

Safety Database of ABILIFY MAINTENA and Oral Aripiprazole

Oral aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days.

ABILIFY MAINTENA has been evaluated for safety in 2,128 adult patients in clinical trials in schizophrenia, with approximately 2,633 patient-years of exposure to ABILIFY MAINTENA. A total of 1,229 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 935 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections).

ABILIFY MAINTENA has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to ABILIFY MAINTENA. A total of 419 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 287 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections).

The conditions and duration of treatment with ABILIFY MAINTENA included double-blind and open-label studies. The safety data presented below are derived from the 12-week double-blind placebo-controlled study of ABILIFY MAINTENA in adult patients with schizophrenia.

Adverse Reactions with ABILIFY MAINTENA

Most Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia

Based on the placebo-controlled trial of ABILIFY MAINTENA in schizophrenia, the most commonly observed adverse reactions associated with the use of ABILIFY MAINTENA in patients (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were increased weight (16.8% vs. 7.0%), akathisia (11.4% vs. 3.5%), injection site pain (5.4% vs. 0.6%) and sedation (5.4% vs. 1.2%).

Commonly Reported Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia

The following findings are based on the double-blind, placebo-controlled trial that compared ABILIFY MAINTENA 400 mg or 300 mg to placebo in patients with schizophrenia. Table 8 lists the adverse reactions reported in 2% or more of ABILIFY MAINTENA-treated subjects and at a greater proportion than in the placebo group.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 8: Adverse Reactions in ≥2% of ABILIFY MAINTENA-Treated Adult Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></span> </caption> <col align="left" valign="middle" width="35%"/> <col align="center" valign="middle" width="35%"/> <col align="center" valign="middle" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Percentage of Patients Reporting Reaction<a class="Sup" href="#footnote-7">*</a></th> </tr> <tr> <th align="left"></th><th align="center">ABILIFY MAINTENA</th><th align="center">Placebo</th> </tr> <tr class="Last"> <th align="left">  Preferred Term</th><th align="center">(n=167)</th><th align="center">(n=172)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>This table does not include adverse reactions which had an incidence equal to or less than placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" colspan="3"><span class="Bold">Gastrointestinal Disorders</span></td> </tr> <tr> <td align="left">  Constipation</td><td align="center">10</td><td align="center">7</td> </tr> <tr> <td align="left">  Dry Mouth</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Diarrhea</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left">  Vomiting</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left">  Abdominal Discomfort</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">General Disorders and Administration Site Conditions</span></td> </tr> <tr> <td align="left">  Injection Site Pain</td><td align="center">5</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Infections and Infestations</span></td> </tr> <tr> <td align="left">  Upper Respiratory Tract Infection</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Investigations</span></td> </tr> <tr> <td align="left">  Increased Weight</td><td align="center">17</td><td align="center">7</td> </tr> <tr> <td align="left">  Decreased Weight</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td> </tr> <tr> <td align="left">  Arthralgia</td><td align="center">4</td><td align="center">1</td> </tr> <tr> <td align="left">  Back Pain</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Myalgia</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Musculoskeletal Pain</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Nervous System Disorders</span></td> </tr> <tr> <td align="left">  Akathisia</td><td align="center">11</td><td align="center">4</td> </tr> <tr> <td align="left">  Sedation</td><td align="center">5</td><td align="center">1</td> </tr> <tr> <td align="left">  Dizziness</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Tremor</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="3"><span class="Bold">Respiratory, Thoracic and Mediastinal</span></td> </tr> <tr class="Last"> <td align="left">  Nasal Congestion</td><td align="center">2</td><td align="center">1</td> </tr> </tbody> </table></div>

Other Adverse Reactions Observed During the Clinical Trial Evaluation of ABILIFY MAINTENA

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:

Demographic Differences

An examination of population subgroups was performed across demographic subgroup categories for adverse reactions experienced by at least 5% of ABILIFY MAINTENA subjects at least twice rate of the placebo (i.e., increased weight, akathisia, injection site pain, and sedation) in the double-blind placebo-controlled trial. This analysis did not reveal evidence of differences in safety differential adverse reaction incidence on the basis of age, gender, or race alone; however, there were few subjects ≥65 years of age.

Injection Site Reactions of ABILIFY MAINTENA

In the data from the short-term, double-blind, placebo-controlled trial with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction (all reported as injection site pain) was 5.4% for patients treated with gluteal administered ABILIFY MAINTENA and 0.6% for placebo. The mean intensity of injection pain reported by subjects using a visual analog scale (0=no pain to 100=unbearably painful) approximately one hour after injection was 7.1 (SD 14.5) for the first injection and 4.8 (SD 12.4) at the last visit in the double-blind, placebo-controlled phase.

In an open-label study comparing bioavailability of ABILIFY MAINTENA administered in the deltoid or gluteal muscle, injection site pain was observed in both groups at approximately equal rates.

Extrapyramidal Symptoms (EPS)

In the short-term, placebo-controlled trial of ABILIFY MAINTENA in adults with schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY MAINTENA-treated patients was 9.6% vs. 5.2% for placebo. The incidence of akathisia-related events for ABILIFY MAINTENA-treated patients was 11.5% vs. 3.5% for 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. In the short-term, placebo-controlled trial of ABILIFY MAINTENA in adults with schizophrenia, the incidence of dystonia was 1.8% for ABILIFY MAINTENA vs. 0.6% for placebo.

Neutropenia

In the short-term, placebo-controlled trial of ABILIFY MAINTENA in adults with schizophrenia, the incidence of neutropenia (absolute neutrophil count ≤1.5 thous/mcL) for ABILIFY MAINTENA-treated patients was 5.7% vs. 2.1% for placebo. An absolute neutrophil count of <1 thous/mcL (i.e., 0.95 thous/mcL) was observed in only one patient on ABILIFY MAINTENA and resolved spontaneously without any associated adverse events [see Warnings and Precautions (5.9)].

Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole

The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for ABILIFY MAINTENA:

The following adverse reactions have been identified during post-approval use of oral aripiprazole or ABILIFY MAINTENA. 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), pathological gambling, hiccups, blood glucose fluctuation, drug reaction with eosinophilia and systemic symptoms (DRESS), and fecal incontinence.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 9: Clinically Important Drug Interactions with ABILIFY MAINTENA:</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="40%"/> <col align="left" valign="top" width="40%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">Concomitant Drug Name or Drug Class</th><th align="center" class="Rrule" valign="middle">Clinical Rationale</th><th align="center" class="Rrule" valign="middle">Clinical Recommendation</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Strong CYP3A4 Inhibitors (e.g., ketoconazole) or strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine)</td><td align="left" class="Rrule">The concomitant use of oral aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td><td align="left" class="Rrule">With concomitant use of ABILIFY MAINTENA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days, reduce the ABILIFY MAINTENA dosage <span class="Italics">[see <a href="#S2.4">Dosage and Administration (2.4)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Strong CYP3A4 Inducers (e.g., carbamazepine)</td><td align="left" class="Rrule">The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td><td align="left" class="Rrule">Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days <span class="Italics">[see <a href="#S2.4">Dosage and Administration (2.4)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" valign="middle">Antihypertensive Drugs</td><td align="left" class="Rrule">Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.</td><td align="left" class="Rrule">Monitor blood pressure and adjust dose accordingly <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>].</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Benzodiazepines (e.g., lorazepam)</td><td align="left" class="Rrule">The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>].</span></td><td align="left" class="Rrule">Monitor sedation and blood pressure. Adjust dose accordingly.</td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY MAINTENA is required when administered concomitantly with famotidine, valproate, lithium, lorazepam [see Clinical Pharmacology (12.3)].

In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin), or CYP3A4 (e.g., dextromethorphan) when coadministered with ABILIFY MAINTENA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY MAINTENA. [See Clinical Pharmacology (12.3)].

Pregnancy Exposure Registry

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

Risk Summary

Neonates exposed to antipsychotic drugs, including ABILIFY MAINTENA, 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 outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ABILIFY MAINTENA, during pregnancy (see Clinical Considerations). Aripiprazole exposure during pregnancy may decrease milk supply in the post-partum period [see Use in Specific Populations (8.2)].

In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 11 times, respectively, 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 10 times the MRHD produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data).

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

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

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

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 oral aripiprazole) 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 exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

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 which are approximately 1 to 10 times the MRHD of 30 mg/day on a mg/m2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m2 basis.

At 3 and 10 times the oral MRHD on a mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on a mg/m2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

In pregnant rats treated with aripiprazole intravenously at doses of 3, 9, and 27 mg/kg/day, which are 1 to 9 times the oral MRHD on mg/m2 basis, during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose which also caused maternal toxicity.

In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD of aripiprazole on mg/m2 basis during the period of organogenesis, decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the MRHD based on AUC.

In pregnant rabbits receiving aripiprazole injection intravenously at doses of 3, 10, and 30 mg/kg/day, which are 2 to 19 times the oral MRHD on mg/m2 basis during the period of organogenesis, the highest dose caused pronounced maternal toxicity that resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD on mg/m2 basis.

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

In rats treated with aripiprazole intravenously at doses of 3, 8, and 20 mg/kg/day which are 1 to 6 times the oral MRHD on mg/m2 basis from Day 6 of gestation through Day 20 postpartum, increased stillbirths were seen at 3 and 6 times the MRHD on mg/m2 basis, and decreases in early postnatal pup weight and survival were seen at the highest dose; these doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

Risk Summary

Aripiprazole is present in human breast milk. Based on published case reports and pharmacovigilance reports, aripiprazole exposure during pregnancy and/or the postpartum period may lead to clinically relevant decreases in milk supply which may be reversible with discontinuation of the drug. There are also reports of aripiprazole exposure during pregnancy and no maternal milk supply in the post-partum period. Effects on milk supply may be mediated through decreases in prolactin levels, which have been observed [see Adverse Reactions (6.1)]. Monitor the breastfed infant for dehydration and lack of appropriate weight gain. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ABILIFY MAINTENA and any potential adverse effects on the breastfed infant from ABILIFY MAINTENA or from the underlying maternal condition.

ABILIFY MAINTENA has not been studied in children 18 years of age or younger. However, juvenile animal studies have been conducted in rats and dogs.

Juvenile Animal Studies

Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.

Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.

Clinical studies of oral aripiprazole did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data have not identified differences in responses between the elderly and younger patients [see Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In single-dose and multiple-dose pharmacokinetic studies, there was no detectable age effect in the population pharmacokinetic analysis of oral aripiprazole in schizophrenia patients [see Clinical Pharmacology (12.3)]. No dosage adjustments are recommended based on age alone. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

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 (2.4)].

Human Experience

The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Management of Overdosage

In case of overdosage, call the Poison Control Center immediately at 1-800-222-1222.

Aripiprazole is an atypical antipsychotic which is present in ABILIFY MAINTENA as its monohydrate polymorphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C23H27Cl2N3O2∙H2O and its molecular weight is 466.40. The chemical structure is:

{ "type": "p", "children": [], "text": "Aripiprazole is an atypical antipsychotic which is present in ABILIFY MAINTENA as its monohydrate polymorphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C23H27Cl2N3O2∙H2O and its molecular weight is 466.40. The chemical structure is:" }

ABILIFY MAINTENA (aripiprazole) is an extended-release injectable suspension available in 400 mg or 300 mg strength pre-filled dual chamber syringes and 400 mg or 300 mg strength vials. The labeled strengths are calculated based on the anhydrous form (aripiprazole). Inactive ingredients (per administered dose) for 400 mg and 300 mg strength products, respectively, include carboxymethyl cellulose sodium (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), sodium phosphate monobasic monohydrate (1.48 mg and 1.11 mg) and sodium hydroxide (pH adjuster).

{ "type": "p", "children": [], "text": "ABILIFY MAINTENA (aripiprazole) is an extended-release injectable suspension available in 400 mg or 300 mg strength pre-filled dual chamber syringes and 400 mg or 300 mg strength vials. The labeled strengths are calculated based on the anhydrous form (aripiprazole). Inactive ingredients (per administered dose) for 400 mg and 300 mg strength products, respectively, include carboxymethyl cellulose sodium (16.64 mg and 12.48 mg), mannitol (83.2 mg and 62.4 mg), sodium phosphate monobasic monohydrate (1.48 mg and 1.11 mg) and sodium hydroxide (pH adjuster)." }

The mechanism of action of aripiprazole in the treatment of schizophrenia and bipolar I disorder is unknown.

The efficacy of aripiprazole could be mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

Aripiprazole exhibits high affinity for dopamine D2 and D3 (Kis 0.34 and 0.8 nM, respectively), serotonin 5-HT1A and 5-HT2A receptors (Kis 1.7 and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Kis 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). Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the other adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

Alcohol

There was no significant difference between oral aripiprazole coadministered with ethanol and placebo coadministered with ethanol on performance of gross motor skills or stimulus response in healthy subjects. As with most psychoactive medications, patients should be advised to avoid alcohol while taking ABILIFY MAINTENA.

ABILIFY MAINTENA 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.

Steady-state concentrations for the typical subject were attained by the fourth dose for both sites of administration. Approximate dose-proportional increases in aripiprazole and dehydro-aripiprazole exposure were observed after every four-week ABILIFY MAINTENA injections of 300 mg and 400 mg.

Absorption

Aripiprazole absorption into the systemic circulation is slow and prolonged following intramuscular injection due to low solubility of aripiprazole particles. Following a single-dose administration of ABILIFY MAINTENA in the deltoid and gluteal muscle, the extent of absorption (AUCtau, AUCinf) of aripiprazole was similar for both injection sites, but the rate of absorption (Cmax) was 31% higher following administration to the deltoid compared to the gluteal site. However, at steady state, AUCtau and Cmax were similar for both sites of injection. Following multiple intramuscular doses, the plasma concentrations of aripiprazole gradually rise to maximum plasma concentrations at a median Tmax of 5 to 7 days for the gluteal muscle and 4 days for the deltoid muscle.

Distribution

Based on results from trials with oral administration of aripiprazole, aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.

Elimination

Following single dose administration of ABILIFY MAINTENA, the mean apparent terminal elimination half-life of aripiprazole was 17.8 and 21 days, for deltoid and gluteal injections, respectively.

After multiple gluteal administrations, the mean apparent terminal elimination half-life of aripiprazole was 29.9 days and 46.5 days for every 4-week injection of ABILIFY MAINTENA 300 mg and 400 mg, respectively.

Metabolism

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. Dehydro aripiprazole represents about 29% of the parent drug AUC in plasma.

Excretion

Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces.

Studies in Specific Populations

No specific pharmacokinetic studies have been performed with ABILIFY MAINTENA in specific populations. All the information is obtained from studies with oral aripiprazole.

Exposures of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 19 and Figure 20, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with oral aripiprazole (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults.

Figure 19: Effects of intrinsic factors on aripiprazole pharmacokinetics

Figure 20: Effects of intrinsic factors on dehydro-aripiprazole pharmacokinetics:

Drug Interaction Studies

No specific drug interaction studies have been performed with ABILIFY MAINTENA. The information below is obtained from studies with oral aripiprazole.

Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 21 and Figure 22, respectively. Based on simulation, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. After oral administration, a 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.

Figure 21: The effects of other drugs on aripiprazole pharmacokinetics

Figure 22: The effects of other drugs on dehydro-aripiprazole pharmacokinetics

The effects of oral aripiprazole on the exposures of other drugs are summarized in Figure 23. A population PK analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of fluoxetine (20 mg/day or 40 mg/day), paroxetine CR (37.5 mg/day or 50 mg/day), or sertraline (100 mg/day or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively, and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole.

Figure 23: The effects of oral aripiprazole on pharmacokinetics of other drugs

In vitro

Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation.

Carcinogenesis

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

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

Mutagenesis

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

Impairment of Fertility

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

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

Oral Aripiprazole

Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg. The 40 and 60 mg/kg/day doses are 13 and 19 times the MRHD based on mg/m2 and 7 to 14 times human exposure at MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

Intramuscular Aripiprazole

The toxicological profile for aripiprazole administered to experimental animals by intramuscular injection is generally similar to that seen following oral administration at comparable plasma levels of the drug. With intramuscular injection, however, injection-site tissue reactions are observed that consist of localized inflammation, swelling, scabbing and foreign-body reactions to deposited drug. These effects gradually resolved with discontinuation of dosing.

After 26 weeks of treatment in rats, the no-observed-adverse-effect level (NOAEL) was 50 mg/kg in male rats and 100 mg/kg in female rats, which are approximately 1 and 2 times, respectively, the maximum recommended human 400-mg dose of aripiprazole extended-release injectable suspension on a mg/m2 body surface area. At the NOAEL in rats, the AUC7d values were 14.4 mcg∙h/mL in males and 104.1 mcg∙h/mL in females. In dogs at 52 weeks of treatment at the NOAEL of 40 mg/kg, which is approximately 3 times the MRHD (400 mg) on a mg/m2 body surface area, the AUC7d values were approximately 59 mcg∙h/mL in males and 44 mcg∙h/mL in females. In patients at the MRHD of 400 mg, the AUCτ (0-28 days) was 163 mcg∙h/mL. For comparison to this human AUC, extrapolating the animal AUC7d values to an AUC28d results in AUC28d values of approximately 58 and 416 mcg∙h/mL for male and female rats, respectively, and 236 and 175 mcg∙h/mL for male and female dogs, respectively.

The efficacy of ABILIFY MAINTENA for treatment of schizophrenia was established in:

Short-Term Efficacy

In the short-term (12-week), randomized, double-blind, placebo-controlled trial in acutely relapsed adults (Study 1), the primary measure used for assessing psychiatric signs and symptoms was 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 primary endpoint was the change from baseline in PANSS total score to week 10.

The inclusion criteria for this short-term trial included adult inpatients who met DSM-IV-TR criteria for schizophrenia. In addition, all patients entering the trial must have experienced an acute psychotic episode as defined by both PANSS Total Score ≥80 and a PANSS score of >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, unusual thought content) at screening and baseline. The key secondary endpoint was the change from baseline in Clinical Global Impression-Severity (CGI-S) assessment scale to week 10. The CGI-S rates the severity of mental illness on a scale of 1 (normal) to 7 (among the most extremely ill) based on the total clinical experience of the rater in treating patients with schizophrenia. Patients had a mean PANSS total score of 103 (range 82 to 144) and a CGI-S score of 5.2 (markedly ill) at entry.

In this 12-week study (n=339) comparing ABILIFY MAINTENA (n=167) to placebo (n=172), patients were administered ABILIFY MAINTENA 400 mg or placebo on Days 0, 28, and 56. The dose could be adjusted down and up within the range of 400 to 300 mg on a one-time basis. ABILIFY MAINTENA was superior to placebo in improving the PANSS total score at the end of week 10 (see Table 10).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 10: Schizophrenia Short-term Study</span> </caption> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="20%"/> <col align="center" valign="top" width="21%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First"> <th align="left" rowspan="2">Study Number</th><th align="left">Treatment Group</th><th align="center" class="Botrule" colspan="3">Primary Efficacy Measure: PANSS Total Score</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Mean Baseline Score (SD)</th><th align="center">LS Mean Change from Baseline (SE)</th><th align="center">Placebo-subtracted Difference<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a> <br/> (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Study 1</td><td align="left">ABILIFY MAINTENA (400 to 300 mg)</td><td align="center">102.4 (11.4)</td><td align="center">-26.8 (1.6)</td><td align="center">-15.1 (-19.4, -10.8)</td> </tr> <tr class="Last"> <td align="left"></td><td align="left">Placebo</td><td align="center">103.4 (11.1)</td><td align="center">-11.7 (1.6)</td><td align="center">--</td> </tr> </tbody> </table></div>

The change in PANSS total score by week is shown in Figure 24. ABILIFY MAINTENA also showed improvement in symptoms represented by CGI-S score mean change from baseline to week 10. The results of exploratory subgroup analyses by gender, race, age, ethnicity, and BMI were similar to the results of the overall population.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Figure 24: Weekly PANSS Total Score-Change in the 12-Week, Placebo-Controlled Study with ABILIFY MAINTENA</span></td> </tr> <tr> <td align="center"><img alt="Figure 24" src="/dailymed/image.cfm?name=abilify-figure-24.jpg&amp;setid=ee49f3b1-1650-47ff-9fb1-ea53fe0b92b6"/></td> </tr> </tbody> </table></div>

n = the number of patients remaining in the respective study arm at each time point

Longer-Term Efficacy

The efficacy of ABILIFY MAINTENA in maintaining symptomatic control in schizophrenia was established in a double-blind, placebo-controlled, randomized-withdrawal trial in adult patients (Study 2) who met DSM-IV-TR criteria for schizophrenia and who were being treated with at least one antipsychotic medication. Patients had at least a 3-year history of illness and a history of relapse or symptom exacerbation when not receiving antipsychotic treatment.

In addition to the PANSS and CGI-S, clinical ratings during this trial included the:

This trial included:

The primary efficacy endpoint was time from randomization to relapse. Relapse was defined as the first occurrence of one or more of the following criteria:

A pre-planned interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the ABILIFY MAINTENA group compared to placebo-treated patients and the trial was subsequently terminated early because maintenance of efficacy was demonstrated. The final analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the ABILIFY MAINTENA group than compared to placebo-treated patients. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for ABILIFY MAINTENA and placebo groups are shown in Figure 25.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>This figure is based on a total of 80 relapse events.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Figure 25: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse<a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a></span></td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Figure 25" src="/dailymed/image.cfm?name=abilify-figure-25.jpg&amp;setid=ee49f3b1-1650-47ff-9fb1-ea53fe0b92b6"/></p> </td> </tr> </tbody> </table></div>

The key secondary efficacy endpoint, percentage of subjects meeting the relapse criteria, was statistically significantly lower in patients randomized to the ABILIFY MAINTENA group (10%) than in the placebo group (40%).

The efficacy of ABILIFY MAINTENA for the maintenance treatment of bipolar I disorder was established in a 52-week, double-blind, placebo-controlled, randomized withdrawal trial in adult patients who were experiencing a manic episode at trial entry, met DSM-IV-TR criteria for bipolar I disorder, and had a history of at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer, and/or treatment with an antipsychotic agent.

Clinical ratings during this trial included:

This trial included:

The primary efficacy endpoint was time from randomization to recurrence of any mood episode. Recurrence was defined as the first occurrence of one or more of the following criteria:

Analysis demonstrated a statistically significantly longer time to recurrence of any mood episode in subjects randomized to the ABILIFY MAINTENA group than compared to placebo-treated subjects. The Kaplan-Meier curves of the time of recurrence to any mood episode during the double-blind treatment phase for ABILIFY MAINTENA and placebo groups are shown in Figure 26.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>This figure is based on a total of 103 recurrence events.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Figure 26: Kaplan-Meier Estimation of Cumulative Recurrence Rate for Any Mood Episode<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a></span></td> </tr> <tr> <td align="center"><img alt="Figure 26" src="/dailymed/image.cfm?name=abilify-figure-26.jpg&amp;setid=ee49f3b1-1650-47ff-9fb1-ea53fe0b92b6"/></td> </tr> </tbody> </table></div>

Analysis by type of mood recurrence demonstrated a statistically significantly longer time to recurrence for both manic and mixed mood episodes in subjects treated with ABILIFY MAINTENA compared to those treated with placebo. There was no substantial difference between treatment groups in delaying time to recurrence of depressive mood episodes.

An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, or race.

How Supplied

Pre-filled Dual Chamber Syringe:

ABILIFY MAINTENA (aripiprazole) pre-filled dual chamber syringe for extended-release injectable suspension in single-dose syringes is available in 300 mg or 400 mg strength syringes. The pre-filled dual chamber syringe consists of a front chamber that contains the lyophilized powder of aripiprazole monohydrate and a rear chamber that contains sterile water for injection.

<div class="scrollingtable"><table width="90%"> <col align="center" valign="top" width="30%"/> <col align="left" valign="top" width="70%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">300 mg kit <br/>(NDC 59148-045-80)</td><td align="left" class="Rrule"> <ul class="Disc"> <li>300 mg, single-dose, pre-filled, dual chamber syringe containing ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension lyophilized powder and Sterile Water for Injection</li> <li>One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients</li> <li>One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients</li> <li>One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients</li> </ul> </td> </tr> <tr class="Botrule Last"> <td align="center" class="Lrule Rrule">400 mg kit <br/>(NDC 59148-072-80)</td><td align="left" class="Rrule"> <ul class="Disc"> <li>400 mg, single-dose, pre-filled, dual chamber syringe containing ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension lyophilized powder and Sterile Water for Injection</li> <li>One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients</li> <li>One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients</li> <li>One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients</li> </ul> </td> </tr> </tbody> </table></div>

Single-Dose Vial:

ABILIFY MAINTENA (aripiprazole) extended-release injectable suspension in single-dose vials is available in 300 mg or 400 mg strength vials.

<div class="scrollingtable"><table width="90%"> <col align="center" valign="top" width="30%"/> <col align="left" valign="top" width="70%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">300 mg kit <br/>(NDC 59148-018-71)</td><td align="left" class="Rrule"> <ul class="Disc"> <li>300 mg, single-dose vial of ABILIFY MAINTENA (aripiprazole) extended-release injectable suspension lyophilized powder</li> <li>5 mL, single-dose vial of Sterile Water for Injection, USP</li> <li>One 3 mL, luer lock syringe with pre-attached 21-gauge, 1.5-inch hypodermic safety needle with needle protection device</li> <li>One 3 mL, luer lock disposable syringe with luer lock tip</li> <li>One vial adapter</li> <li>One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients</li> <li>One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients</li> <li>One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients</li> </ul> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">300 mg kit <br/>(NDC 59148-232-12)</td><td align="left" class="Rrule"> <ul class="Disc"> <li>300 mg, single-dose vial of ABILIFY MAINTENA (aripiprazole) extended-release injectable suspension lyophilized powder</li> <li>2.5 mL, single-dose vial of Sterile Water for Injection, USP</li> <li>One 3 mL, luer lock syringe with pre-attached 21-gauge, 1.5-inch hypodermic safety needle with needle protection device</li> <li>One 3 mL, luer lock disposable syringe with luer lock tip</li> <li>One vial adapter</li> <li>One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients</li> <li>One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients</li> <li>One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients</li> </ul> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">400 mg kit <br/>(NDC 59148-019-71)</td><td align="left" class="Rrule"> <ul class="Disc"> <li>400 mg, single-dose vial of ABILIFY MAINTENA (aripiprazole) extended-release injectable suspension lyophilized powder</li> <li>5 mL, single-dose vial of Sterile Water for Injection, USP</li> <li>One 3 mL, luer lock syringe with pre-attached 21-gauge, 1.5-inch hypodermic safety needle with needle protection device</li> <li>One 3 mL, luer lock disposable syringe with luer lock tip</li> <li>One vial adapter</li> <li>One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients</li> <li>One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients</li> <li>One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients</li> </ul> </td> </tr> <tr class="Botrule Last"> <td align="center" class="Lrule Rrule">400 mg kit <br/>(NDC 59148-245-12)</td><td align="left" class="Rrule"> <ul class="Disc"> <li>400 mg, single-dose vial of ABILIFY MAINTENA (aripiprazole) extended-release injectable suspension lyophilized powder</li> <li>2.5 mL, single-dose vial of Sterile Water for Injection, USP</li> <li>One 3 mL, luer lock syringe with pre-attached 21-gauge, 1.5-inch hypodermic safety needle with needle protection device</li> <li>One 3 mL, luer lock disposable syringe with luer lock tip</li> <li>One vial adapter</li> <li>One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients</li> <li>One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients</li> <li>One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients</li> </ul> </td> </tr> </tbody> </table></div>

Storage

Pre-filled dual chamber syringe:

Store below 30°C [86°F]. Do not freeze. Protect the syringe from light by storing in the original package until time of use.

Vial:

Store at 25°C (77°F), excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact a health care provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.3)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.4)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)].

Pathological Gambling and Other Compulsive Behaviors

Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, increased urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.6)].

Orthostatic Hypotension and Syncope

Educate patients about the risk of orthostatic hypotension and syncope especially early in treatment, and also at times of re-initiating treatment or increases in dosage [see Warnings and Precautions (5.7)].

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC count or a history of drug-induced leucopenia/neutropenia that they should have their CBC monitored while receiving ABILIFY MAINTENA [see Warnings and Precautions (5.9)].

Potential for Cognitive and Motor Impairment

Inform patients that ABILIFY MAINTENA has the potential to impair judgment, thinking, or motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that ABILIFY MAINTENA therapy does not affect them adversely [see Warnings and Precautions (5.11)].

Heat Exposure and Dehydration

Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.12)].

Concomitant Medication

Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications since there is a potential for clinically significant interactions [see Drug Interactions (7)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ABILIFY MAINTENA. Advise patients that ABILIFY MAINTENA 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 exposure registry that monitors pregnancy outcomes in women exposed to ABILIFY MAINTENA during pregnancy [see Use in Specific Populations (8.1)].

Lactation

ABILIFY MAINTENA use during pregnancy may affect milk supply. Advise the lactating patient to discuss any plans for breastfeeding with their healthcare provider, and to monitor the breastfed infant for dehydration and lack of appropriate weight gain [see Use in Specific Populations (8.2)].

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA

{ "type": "p", "children": [], "text": "Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA" }

Marketed by Lundbeck, Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Marketed by Lundbeck, Deerfield, IL 60015 USA" }

ABILIFY MAINTENA is a trademark of Otsuka Pharmaceutical Co., Ltd.

{ "type": "p", "children": [], "text": "ABILIFY MAINTENA is a trademark of Otsuka Pharmaceutical Co., Ltd." }

©2025, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

{ "type": "p", "children": [], "text": "©2025, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="43%"/> <col align="left" valign="top" width="51%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="3">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: 03/2025</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="4"><span class="Bold">MEDICATION GUIDE</span> <br/>ABILIFY MAINTENA<span class="Sup">®</span> (a-BIL-i-fy main-TEN-a)<br/>(aripiprazole) for extended-release injectable suspension, for intramuscular use</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold"><a name="Important"></a>What is the most important information I should know about ABILIFY MAINTENA?</span> <br/> <span class="Bold">ABILIFY MAINTENA may cause serious side effects, including:</span> <ul class="Disc"> <li> <span class="Bold">Increased risk of death in elderly people with dementia-related psychosis.</span> ABILIFY MAINTENA increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). ABILIFY MAINTENA is not for the treatment of people with dementia-related psychosis.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What is ABILIFY MAINTENA?</span> <br/>ABILIFY MAINTENA is a prescription medicine given by injection by a healthcare provider:<ul class="Disc"> <li>for the treatment of schizophrenia in adults</li> <li>alone as maintenance treatment of bipolar I disorder in adults</li> </ul>It is not known if ABILIFY MAINTENA is safe and effective in children under 18 years of age.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Who should not receive ABILIFY MAINTENA?<br/>Do not receive ABILIFY MAINTENA if you</span> are allergic to aripiprazole or any of the ingredients in ABILIFY MAINTENA. See the end of this Medication Guide for a complete list of ingredients in ABILIFY MAINTENA.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">Before receiving ABILIFY MAINTENA, tell your healthcare provider</span> about all of your medical conditions, including if you:<ul class="Disc"> <li>have never taken aripiprazole before</li> <li>have or had diabetes or high blood sugar or a family history of diabetes or high blood sugar</li> <li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li> <li>have or had low or high blood pressure</li> <li>have or had heart problems or a stroke</li> <li>have or had a low white blood cell count</li> <li>have or had seizures (convulsions)</li> <li>have problems that may affect you receiving an injection in your arm or buttocks</li> <li>are pregnant or plan to become pregnant. It is not known if ABILIFY MAINTENA will harm your unborn baby. Receiving ABILIFY MAINTENA during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you receive ABILIFY MAINTENA during pregnancy <ul class="Circle"> <li>Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ABILIFY MAINTENA.</li> <li>If you become pregnant while receiving ABILIFY MAINTENA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ </li> </ul> </li> <li>are breastfeeding or plan to breastfeed. ABILIFY MAINTENA can pass into your breast milk and it is not known if it may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you receive ABILIFY MAINTENA.</li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements.<br/>ABILIFY MAINTENA and other medicines may affect each other causing possible serious side effects. ABILIFY MAINTENA may affect the way other medicines work, and other medicines may affect how ABILIFY MAINTENA works.<br/>Your healthcare provider can tell you if it is safe to receive ABILIFY MAINTENA with your other medicines. Do not start or stop any medicines during treatment with ABILIFY MAINTENA without talking to your healthcare provider first. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">How should I receive ABILIFY MAINTENA?</span> <ul class="Disc"> <li>Follow your ABILIFY MAINTENA treatment schedule exactly as your healthcare provider tells you to.</li> <li>Your healthcare provider will tell you how much ABILIFY MAINTENA you will receive and when you will receive it.</li> <li>ABILIFY MAINTENA is an injection given in your arm or buttock by your healthcare provider 1 time every month.</li> <li>There are 2 ways to start (initiate) treatment with ABILIFY MAINTENA if you currently take an antipsychotic medicine by mouth (oral):<ul class="Disc"> <li>1-day initiation: You will receive 2 injections of ABILIFY MAINTENA on your first day of treatment. Each injection will be given in a different injection site. You will also take 1 dose of aripiprazole by mouth.<br/> </li> </ul> <span class="Bold">OR</span> <ul class="Disc"> <li>14-day initiation: You will receive 1 injection of ABILIFY MAINTENA. You will continue to take your oral aripiprazole or your current antipsychotic medicine by mouth for 14 days in a row.</li> </ul> </li> <li>You should not miss a dose of ABILIFY MAINTENA. If you miss a dose for some reason, call your healthcare provider right away to discuss what you should do next.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold"><a name="Avoid"></a>What should I avoid while receiving ABILIFY MAINTENA?</span> <ul class="Disc"> <li>Do not drive a car, operate machinery, or do other dangerous activities until you know how ABILIFY MAINTENA affects you. ABILIFY MAINTENA may affect your judgement, thinking, or motor skills.</li> <li>Do not drink alcohol during treatment with ABILIFY MAINTENA.</li> <li>Do not become too hot or dehydrated during treatment with ABILIFY MAINTENA.<ul class="Disc"> <li>Do not exercise too much.</li> <li>In hot weather, stay inside in a cool place if possible.</li> <li>Stay out of the sun.</li> <li>Do not wear too much clothing or heavy clothing.</li> <li>Drink plenty of water.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What are the possible side effects of ABILIFY MAINTENA?<br/>ABILIFY MAINTENA may cause serious side effects, including: </span> <ul class="Disc"> <li> <span class="Bold">See "<a href="#Important">What is the most important information I should know about ABILIFY MAINTENA?</a>"</span> </li> <li> <span class="Bold">Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. </span> </li> <li> <span class="Bold">Neuroleptic malignant syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider or go to the nearest emergency room right away if you have some or all of the following symptoms of NMS: </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul class="Circle"> <li>high fever</li> <li>confusion</li> <li>changes in pulse, heart rate, and blood pressure</li> </ul> </td><td align="left" class="Rrule"> <ul class="Circle"> <li>stiff muscles</li> <li>sweating</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4"> <ul class="Disc"> <li> <span class="Bold">Uncontrolled body movements (tardive dyskinesia).</span> ABILIFY MAINTENA 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 ABILIFY MAINTENA. Tardive dyskinesia may also start after you stop receiving ABILIFY MAINTENA.</li> <li> <span class="Bold">Problems with your metabolism such as:</span> <ul class="Disc"> <li> <span class="Bold">high blood sugar (hyperglycemia) and diabetes:</span> Increases in blood sugar can happen in some people who receive ABILIFY MAINTENA. 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 receiving ABILIFY MAINTENA and during your treatment.<br/> <span class="Bold">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving ABILIFY MAINTENA:</span> </li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"></td><td align="left"> <ul class="Square"> <li>feel very thirsty</li> <li>feel very hungry</li> <li>feel sick to your stomach</li> </ul> </td><td align="left" class="Rrule"> <ul class="Square"> <li>need to urinate more than usual</li> <li>feel weak or tired</li> <li>feel confused, or your breath smells fruity</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="3"> <ul class="Disc"> <li> <span class="Bold">Increased fat levels (cholesterol and triglycerides) in your blood.</span> </li> <li> <span class="Bold">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with ABILIFY MAINTENA.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <ul class="Disc"> <li> <span class="Bold">Unusual and uncontrollable (compulsive) urges.</span> Some people receiving ABILIFY MAINTENA have had unusual strong urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges including sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</li> <li> <span class="Bold">Decreased blood pressure (orthostatic hypotension).</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li> <li> <span class="Bold">Falls.</span> ABILIFY MAINTENA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li> <li> <span class="Bold">Low white blood cell count.</span> Your healthcare provider may do blood tests during your first few months of treatment with ABILIFY MAINTENA.</li> <li> <span class="Bold">Seizures (convulsions)</span> </li> <li> <span class="Bold">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities.</span> See <span class="Bold">"<a href="#Avoid">What should I avoid while receiving ABILIFY MAINTENA?</a>"</span> </li> <li> <span class="Bold">Problems controlling your body temperature so that you feel too warm. See "<a href="#Avoid">What should I avoid while receiving ABILIFY MAINTENA?</a>"</span> </li> <li> <span class="Bold">Difficulty swallowing</span> that can cause food or liquid to get into your lungs</li> </ul> <span class="Bold">The most common side effects of ABILIFY MAINTENA include:</span> weight gain, restlessness or feeling like you need to move (akathisia), injection site pain, or sleepiness (sedation).<br/>These are not all the possible side effects of ABILIFY MAINTENA.<br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">General information about the safe and effective use of ABILIFY MAINTENA.</span> <br/>If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ABILIFY MAINTENA that is written for healthcare professionals.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="4"><span class="Bold">What are the ingredients in ABILIFY MAINTENA?<br/>Active ingredient:</span> aripiprazole monohydrate<br/> <span class="Bold">Inactive ingredients:</span> carboxymethylcellulose sodium, mannitol, sodium phosphate monobasic monohydrate and sodium hydroxide<br/>ABILIFY MAINTENA is a trademark of Otsuka Pharmaceutical Co., Ltd.<br/>©2025, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan<br/>For more information, go to www.ABILIFYMAINTENA.com or call 1-800-441-6763.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"43%\"/>\n<col align=\"left\" valign=\"top\" width=\"51%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"3\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: 03/2025</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>ABILIFY MAINTENA<span class=\"Sup\">®</span> (a-BIL-i-fy main-TEN-a)<br/>(aripiprazole) for extended-release injectable suspension, for intramuscular use</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\"><a name=\"Important\"></a>What is the most important information I should know about ABILIFY MAINTENA?</span>\n<br/>\n<span class=\"Bold\">ABILIFY MAINTENA may cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased risk of death in elderly people with dementia-related psychosis.</span> ABILIFY MAINTENA increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). ABILIFY MAINTENA is not for the treatment of people with dementia-related psychosis.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What is ABILIFY MAINTENA?</span>\n<br/>ABILIFY MAINTENA is a prescription medicine given by injection by a healthcare provider:<ul class=\"Disc\">\n<li>for the treatment of schizophrenia in adults</li>\n<li>alone as maintenance treatment of bipolar I disorder in adults</li>\n</ul>It is not known if ABILIFY MAINTENA is safe and effective in children under 18 years of age.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Who should not receive ABILIFY MAINTENA?<br/>Do not receive ABILIFY MAINTENA if you</span> are allergic to aripiprazole or any of the ingredients in ABILIFY MAINTENA. See the end of this Medication Guide for a complete list of ingredients in ABILIFY MAINTENA.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">Before receiving ABILIFY MAINTENA, tell your healthcare provider</span> about all of your medical conditions, including if you:<ul class=\"Disc\">\n<li>have never taken aripiprazole before</li>\n<li>have or had diabetes or high blood sugar or a family history of diabetes or high blood sugar</li>\n<li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li>\n<li>have or had low or high blood pressure</li>\n<li>have or had heart problems or a stroke</li>\n<li>have or had a low white blood cell count</li>\n<li>have or had seizures (convulsions)</li>\n<li>have problems that may affect you receiving an injection in your arm or buttocks</li>\n<li>are pregnant or plan to become pregnant. It is not known if ABILIFY MAINTENA will harm your unborn baby. Receiving ABILIFY MAINTENA during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you receive ABILIFY MAINTENA during pregnancy \t\t\t\t\t\t\t\t\t\t\t<ul class=\"Circle\">\n<li>Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ABILIFY MAINTENA.</li>\n<li>If you become pregnant while receiving ABILIFY MAINTENA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ </li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. ABILIFY MAINTENA can pass into your breast milk and it is not known if it may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you receive ABILIFY MAINTENA.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements.<br/>ABILIFY MAINTENA and other medicines may affect each other causing possible serious side effects. ABILIFY MAINTENA may affect the way other medicines work, and other medicines may affect how ABILIFY MAINTENA works.<br/>Your healthcare provider can tell you if it is safe to receive ABILIFY MAINTENA with your other medicines. Do not start or stop any medicines during treatment with ABILIFY MAINTENA without talking to your healthcare provider first. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">How should I receive ABILIFY MAINTENA?</span>\n<ul class=\"Disc\">\n<li>Follow your ABILIFY MAINTENA treatment schedule exactly as your healthcare provider tells you to.</li>\n<li>Your healthcare provider will tell you how much ABILIFY MAINTENA you will receive and when you will receive it.</li>\n<li>ABILIFY MAINTENA is an injection given in your arm or buttock by your healthcare provider 1 time every month.</li>\n<li>There are 2 ways to start (initiate) treatment with ABILIFY MAINTENA if you currently take an antipsychotic medicine by mouth (oral):<ul class=\"Disc\">\n<li>1-day initiation: You will receive 2 injections of ABILIFY MAINTENA on your first day of treatment. Each injection will be given in a different injection site. You will also take 1 dose of aripiprazole by mouth.<br/>\n</li>\n</ul>\n<span class=\"Bold\">OR</span>\n<ul class=\"Disc\">\n<li>14-day initiation: You will receive 1 injection of ABILIFY MAINTENA. You will continue to take your oral aripiprazole or your current antipsychotic medicine by mouth for 14 days in a row.</li>\n</ul>\n</li>\n<li>You should not miss a dose of ABILIFY MAINTENA. If you miss a dose for some reason, call your healthcare provider right away to discuss what you should do next.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\"><a name=\"Avoid\"></a>What should I avoid while receiving ABILIFY MAINTENA?</span>\n<ul class=\"Disc\">\n<li>Do not drive a car, operate machinery, or do other dangerous activities until you know how ABILIFY MAINTENA affects you. ABILIFY MAINTENA may affect your judgement, thinking, or motor skills.</li>\n<li>Do not drink alcohol during treatment with ABILIFY MAINTENA.</li>\n<li>Do not become too hot or dehydrated during treatment with ABILIFY MAINTENA.<ul class=\"Disc\">\n<li>Do not exercise too much.</li>\n<li>In hot weather, stay inside in a cool place if possible.</li>\n<li>Stay out of the sun.</li>\n<li>Do not wear too much clothing or heavy clothing.</li>\n<li>Drink plenty of water.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What are the possible side effects of ABILIFY MAINTENA?<br/>ABILIFY MAINTENA may cause serious side effects, including: </span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">See \"<a href=\"#Important\">What is the most important information I should know about ABILIFY MAINTENA?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. </span>\n</li>\n<li>\n<span class=\"Bold\">Neuroleptic malignant syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider or go to the nearest emergency room right away if you have some or all of the following symptoms of NMS: </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>high fever</li>\n<li>confusion</li>\n<li>changes in pulse, heart rate, and blood pressure</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Circle\">\n<li>stiff muscles</li>\n<li>sweating</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Uncontrolled body movements (tardive dyskinesia).</span> ABILIFY MAINTENA 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 ABILIFY MAINTENA. Tardive dyskinesia may also start after you stop receiving ABILIFY MAINTENA.</li>\n<li>\n<span class=\"Bold\">Problems with your metabolism such as:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">high blood sugar (hyperglycemia) and diabetes:</span> Increases in blood sugar can happen in some people who receive ABILIFY MAINTENA. 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 receiving ABILIFY MAINTENA and during your treatment.<br/>\n<span class=\"Bold\">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving ABILIFY MAINTENA:</span>\n</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\"></td><td align=\"left\">\n<ul class=\"Square\">\n<li>feel very thirsty</li>\n<li>feel very hungry</li>\n<li>feel sick to your stomach</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Square\">\n<li>need to urinate more than usual</li>\n<li>feel weak or tired</li>\n<li>feel confused, or your breath smells fruity</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased fat levels (cholesterol and triglycerides) in your blood.</span>\n</li>\n<li>\n<span class=\"Bold\">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with ABILIFY MAINTENA.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Unusual and uncontrollable (compulsive) urges.</span> Some people receiving ABILIFY MAINTENA have had unusual strong urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges including sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</li>\n<li>\n<span class=\"Bold\">Decreased blood pressure (orthostatic hypotension).</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li>\n<li>\n<span class=\"Bold\">Falls.</span> ABILIFY MAINTENA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li>\n<li>\n<span class=\"Bold\">Low white blood cell count.</span> Your healthcare provider may do blood tests during your first few months of treatment with ABILIFY MAINTENA.</li>\n<li>\n<span class=\"Bold\">Seizures (convulsions)</span>\n</li>\n<li>\n<span class=\"Bold\">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities.</span> See <span class=\"Bold\">\"<a href=\"#Avoid\">What should I avoid while receiving ABILIFY MAINTENA?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Problems controlling your body temperature so that you feel too warm. See \"<a href=\"#Avoid\">What should I avoid while receiving ABILIFY MAINTENA?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Difficulty swallowing</span> that can cause food or liquid to get into your lungs</li>\n</ul>\n<span class=\"Bold\">The most common side effects of ABILIFY MAINTENA include:</span> weight gain, restlessness or feeling like you need to move (akathisia), injection site pain, or sleepiness (sedation).<br/>These are not all the possible side effects of ABILIFY MAINTENA.<br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">General information about the safe and effective use of ABILIFY MAINTENA.</span>\n<br/>If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ABILIFY MAINTENA that is written for healthcare professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\"><span class=\"Bold\">What are the ingredients in ABILIFY MAINTENA?<br/>Active ingredient:</span> aripiprazole monohydrate<br/>\n<span class=\"Bold\">Inactive ingredients:</span> carboxymethylcellulose sodium, mannitol, sodium phosphate monobasic monohydrate and sodium hydroxide<br/>ABILIFY MAINTENA is a trademark of Otsuka Pharmaceutical Co., Ltd.<br/>©2025, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan<br/>For more information, go to www.ABILIFYMAINTENA.com or call 1-800-441-6763.</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 59148-018-70Rx only300 mg per vial

{ "type": "p", "children": [], "text": "NDC 59148-018-70Rx only300 mg per vial" }

Abilify Maintena™ (aripiprazole)for extended release injectable suspensionSingle use only. Sterile. Discard any unused portion.For deltoid or gluteal intramuscular injection only.Usual Dosage: See package insert.

{ "type": "p", "children": [], "text": "Abilify Maintena™ (aripiprazole)for extended release injectable suspensionSingle use only. Sterile. Discard any unused portion.For deltoid or gluteal intramuscular injection only.Usual Dosage: See package insert." }

Manufactured by: Otsuka Pharmaceutical Co., Ltd.Distributed and Marketed by: Otsuka America Pharmaceutical, Inc.Marketed by: Lundbeck

{ "type": "p", "children": [], "text": "Manufactured by: Otsuka Pharmaceutical Co., Ltd.Distributed and Marketed by: Otsuka America Pharmaceutical, Inc.Marketed by: Lundbeck" }

NDC 59148-100-01

{ "type": "p", "children": [], "text": "NDC 59148-100-01" }

5mL

{ "type": "p", "children": [], "text": "5mL" }

Sterile Waterfor Injection, USPFor single use only.

{ "type": "p", "children": [], "text": "Sterile Waterfor Injection, USPFor single use only." }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

Store at 25 °C (77 °F), excursionspermitted between 15 °C and 30 °C(59 °F to 86 °F) [See USP].

{ "type": "p", "children": [], "text": "Store at 25 °C (77 °F), excursionspermitted between 15 °C and 30 °C(59 °F to 86 °F) [See USP]." }

09US12L-1008Rx only

{ "type": "p", "children": [], "text": "09US12L-1008Rx only" }

NDC 59148-018-71Rx only

{ "type": "p", "children": [], "text": "NDC 59148-018-71Rx only" }

Attention: Dispense an enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Attention: Dispense an enclosed Medication Guide to each patient." }

300 mgper vial

{ "type": "p", "children": [], "text": "300 mgper vial" }

Single use only. Discard Unused Portion.

{ "type": "p", "children": [], "text": "Single use only. Discard Unused Portion." }

For deltoid or gluteal intramuscular injection only.

{ "type": "p", "children": [], "text": "For deltoid or gluteal intramuscular injection only." }

Abilify Maintena™ (aripiprazole) for extended release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Maintena™ \t\t\t\t\t\t\t(aripiprazole) for extended release injectable suspension" }

Keep out of reach of children. Each injection must be administered by a healthcare professional only.

{ "type": "p", "children": [], "text": "Keep out of reach of children. Each injection must be administered by a healthcare professional only." }

To reconstitute: Add 1.5 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL.

{ "type": "p", "children": [], "text": "To reconstitute: Add 1.5 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL." }

Excess water will be left in the vial; discard vial with the unused portion.

{ "type": "p", "children": [], "text": "Excess water will be left in the vial; discard vial with the unused portion." }

NDC 59148-019-70Rx only400 mg per vial

{ "type": "p", "children": [], "text": "NDC 59148-019-70Rx only400 mg per vial" }

Abilify Maintena™ (aripiprazole)for extended release injectable suspensionSingle use only. Sterile. Discard any unused portion.For deltoid or gluteal intramuscular injection only.Usual Dosage: See package insert.

{ "type": "p", "children": [], "text": "Abilify Maintena™ (aripiprazole)for extended release injectable suspensionSingle use only. Sterile. Discard any unused portion.For deltoid or gluteal intramuscular injection only.Usual Dosage: See package insert." }

Manufactured by: Otsuka Pharmaceutical Co., Ltd.Distributed and Marketed by: Otsuka America Pharmaceutical, Inc.Marketed by: Lundbeck

{ "type": "p", "children": [], "text": "Manufactured by: Otsuka Pharmaceutical Co., Ltd.Distributed and Marketed by: Otsuka America Pharmaceutical, Inc.Marketed by: Lundbeck" }

NDC 59148-019-71Rx only

{ "type": "p", "children": [], "text": "NDC 59148-019-71Rx only" }

Attention: Dispense an enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Attention: Dispense an enclosed Medication Guide to each patient." }

400 mgper vial

{ "type": "p", "children": [], "text": "400 mgper vial" }

Single use only. Discard Unused Portion.

{ "type": "p", "children": [], "text": "Single use only. Discard Unused Portion." }

For deltoid or gluteal intramuscular injection only.

{ "type": "p", "children": [], "text": "For deltoid or gluteal intramuscular injection only." }

Abilify Maintena™ (aripiprazole) for extended release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Maintena™ \t\t\t\t\t\t\t(aripiprazole) for extended release injectable suspension" }

Keep out of reach of children. Each injection must be administered by a healthcare professional only.

{ "type": "p", "children": [], "text": "Keep out of reach of children. Each injection must be administered by a healthcare professional only." }

To reconstitute: Add 1.9 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL.

{ "type": "p", "children": [], "text": "To reconstitute: Add 1.9 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL." }

Excess water will be left in the vial; discard vial with the unused portion.

{ "type": "p", "children": [], "text": "Excess water will be left in the vial; discard vial with the unused portion." }

NDC 59148-045-80

{ "type": "p", "children": [], "text": "NDC 59148-045-80" }

300 mg

{ "type": "p", "children": [], "text": "300 mg" }

Abilify Maintena® (aripiprazole)for extended release injectable suspensionSingle use only.Sterile. Discard anyunused portion.For deltoid or glutealintramuscularinjection only.Usual Dosage:See package insert.

{ "type": "p", "children": [], "text": "Abilify Maintena®\n(aripiprazole)for extended release injectable suspensionSingle use only.Sterile. Discard anyunused portion.For deltoid or glutealintramuscularinjection only.Usual Dosage:See package insert." }

516628AA

{ "type": "p", "children": [], "text": "516628AA" }

For deltoid orgluteal intramuscularinjection only

{ "type": "p", "children": [], "text": "For deltoid orgluteal intramuscularinjection only" }

NDC 59148-045-80

{ "type": "p", "children": [], "text": "NDC 59148-045-80" }

Abilify Maintena® (aripiprazole) for extended release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Maintena®\n(aripiprazole) for extended release injectable suspension" }

300 mg PER PRE-FILLEDDUAL CHAMBER SYRINGE

{ "type": "p", "children": [], "text": "300 mg PER PRE-FILLEDDUAL CHAMBER SYRINGE" }

Single use only.Keep out of reachof children.

{ "type": "p", "children": [], "text": "Single use only.Keep out of reachof children." }

Each injection must be administered by a healthcare professional only.Attention: Dispense an enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Each injection must be administered by a healthcare professional only.Attention: Dispense an enclosed Medication Guide to each patient." }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 59148-072-80

{ "type": "p", "children": [], "text": "NDC 59148-072-80" }

400 mg

{ "type": "p", "children": [], "text": "400 mg" }

Abilify Maintena® (aripiprazole)for extended release injectable suspensionSingle use only.Sterile. Discard anyunused portion.For deltoid or glutealintramuscularinjection only.Usual Dosage:See package insert.

{ "type": "p", "children": [], "text": "Abilify Maintena®\n(aripiprazole)for extended release injectable suspensionSingle use only.Sterile. Discard anyunused portion.For deltoid or glutealintramuscularinjection only.Usual Dosage:See package insert." }

516629AA

{ "type": "p", "children": [], "text": "516629AA" }

For deltoid orgluteal intramuscularinjection only

{ "type": "p", "children": [], "text": "For deltoid orgluteal intramuscularinjection only" }

NDC 59148-072-80

{ "type": "p", "children": [], "text": "NDC 59148-072-80" }

Abilify Maintena® (aripiprazole) for extended release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Maintena®\n(aripiprazole) for extended release injectable suspension" }

400 mg PER PRE-FILLEDDUAL CHAMBER SYRINGE

{ "type": "p", "children": [], "text": "400 mg PER PRE-FILLEDDUAL CHAMBER SYRINGE" }

Single use only.Keep out of reachof children.

{ "type": "p", "children": [], "text": "Single use only.Keep out of reachof children." }

Each injection must be administered by a healthcare professional only.Attention: Dispense an enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Each injection must be administered by a healthcare professional only.Attention: Dispense an enclosed Medication Guide to each patient." }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

NDC 59148-245-12

{ "type": "p", "children": [], "text": "NDC 59148-245-12" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Attention: Dispense an enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Attention: Dispense an enclosed Medication Guide to each patient." }

400 mg per vial

{ "type": "p", "children": [], "text": "400 mg per vial" }

Single use only. Discard Unused Portion.

{ "type": "p", "children": [], "text": "Single use only. Discard Unused Portion." }

For deltoid or gluteal intramuscular injection only.

{ "type": "p", "children": [], "text": "For deltoid or gluteal intramuscular injection only." }

Abilify Maintena® (aripiprazole) for extended release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Maintena®\n(aripiprazole) for extended release injectable suspension" }

Keep out of reach of children. Each injection must be administered by a healthcare professional only.

{ "type": "p", "children": [], "text": "Keep out of reach of children. Each injection must be administered by a healthcare professional only." }

To reconstitute: Add 1.9 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL.

{ "type": "p", "children": [], "text": "To reconstitute: Add 1.9 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL." }

Excess water will be left in the vial; discard vial with the unused portion.

{ "type": "p", "children": [], "text": "Excess water will be left in the vial; discard vial with the unused portion." }

NDC 59148-232-12

{ "type": "p", "children": [], "text": "NDC 59148-232-12" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Attention: Dispense an enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Attention: Dispense an enclosed Medication Guide to each patient." }

300 mg per vial

{ "type": "p", "children": [], "text": "300 mg per vial" }

Single use only. Discard Unused Portion.

{ "type": "p", "children": [], "text": "Single use only. Discard Unused Portion." }

For deltoid or gluteal intramuscular injection only.

{ "type": "p", "children": [], "text": "For deltoid or gluteal intramuscular injection only." }

Abilify Maintena® (aripiprazole) for extended release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Maintena®\n(aripiprazole) for extended release injectable suspension" }

Keep out of reach of children. Each injection must be administered by a healthcare professional only.

{ "type": "p", "children": [], "text": "Keep out of reach of children. Each injection must be administered by a healthcare professional only." }

To reconstitute: Add 1.5 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL.

{ "type": "p", "children": [], "text": "To reconstitute: Add 1.5 mL of Sterile Water for Injection, USP (supplied in kit) to make injectable suspension containing 200 mg/mL." }

Excess water will be left in the vial; discard vial with the unused portion.

{ "type": "p", "children": [], "text": "Excess water will be left in the vial; discard vial with the unused portion." }

ABILIFY ASIMTUFII is indicated:

{ "type": "p", "children": [], "text": "ABILIFY ASIMTUFII is indicated:" }

{ "type": "ul", "children": [ "for the treatment of schizophrenia in adults", "for maintenance monotherapy treatment of bipolar I disorder in adults" ], "text": "" }

For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY ASIMTUFII. Due to the half-life of oral aripiprazole (i.e., 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively), it may take up to 2 weeks to fully assess tolerability.

ABILIFY ASIMTUFII must be administered as an intramuscular gluteal injection by a healthcare professional. Do not administer by any other route.

For detailed preparation and administration instructions, [see Dosage and Administration (2.5)].

The recommended dosage of ABILIFY ASIMTUFII is 960 mg, administered once every 2 months (56 days after previous injection).

Patients Receiving Oral Antipsychotics

There are two ways to initiate treatment with ABILIFY ASIMTUFII in patients receiving oral antipsychotics:

1-day initiation:

14-day initiation:

Patients Receiving Abilify Maintena

For patients receiving Abilify Maintena 400 mg (once monthly dosing), administer ABILIFY ASIMTUFII 960 mg (once every 2 month dosing) in place of the next scheduled injection of the Abilify Maintena. The first ABILIFY ASIMTUFII injection may be administered in place of the second, or later injection of Abilify Maintena.

If there are adverse reactions with the ABILIFY ASIMTUFII 960 mg dosage, the dosage may be reduced to 720 mg once every 2 months.

Patients may be given the ABILIFY ASIMTUFII injection up to 2 weeks before or 2 weeks after the 2-month scheduled timepoint.

If more than 8 weeks and less than 14 weeks have elapsed since the last injection, administer the next dose of ABILIFY ASIMTUFII as soon as possible. The once every 2 month schedule should be resumed.

If more than 14 weeks have elapsed since the last injection, restart treatment with either 1-day initiation or 14-day initiation with ABILIFY ASIMTUFII [see Dosage and Administration (2.2)].

Dosage adjustments for patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant strong CYP3A4 inhibitors or CYP2D6 inhibitors for more than 14 days are described in Table 1.

If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage of ABILIFY ASIMTUFII may need to be increased to the previous dose.

Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: Dosage Recommendations for ABILIFY ASIMTUFII in Patients Who are Known CYP2D6 Poor Metabolizers, Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, or CYP3A4 Inducers for Greater than 14 days</span> </caption> <col align="left" valign="middle" width="60%"/> <col align="center" valign="middle" width="40%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Factors</th><th align="center" class="Rrule">Dosage Recommendation</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>For the 1-day initiation regimen, administer a single 20 mg oral aripiprazole, 300 mg Abilify Maintena and 720 mg ABILIFY ASIMTUFII on Day 1.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP2D6 Poor Metabolizers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers</td><td align="center" class="Rrule">720 mg once every 2 months<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors</td><td align="center" class="Rrule">Avoid use</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Patients Taking 960 mg of ABILIFY ASIMTUFII</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Concomitant use of ABILIFY ASIMTUFII with Strong CYP2D6 inhibitors </td><td align="center" class="Rrule">720 mg once every 2 months<a class="Sup" href="#footnote-1">*</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Concomitant use of ABILIFY ASIMTUFII with Strong CYP3A4 inhibitors</td><td align="center" class="Rrule">720 mg once every 2 months<a class="Sup" href="#footnote-1">*</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Concomitant use of ABILIFY ASIMTUFII with Strong CYP2D6 <span class="Bold Underline">and</span> Strong CYP3A4 inhibitors</td><td align="center" class="Rrule">Avoid use</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Concomitant use of ABILIFY ASIMTUFII with CYP3A4 inducers</td><td align="center" class="Rrule">Avoid use</td> </tr> </tbody> </table></div>

Preparation Prior to Administration

Select the appropriate needle

Needle selection is determined by patient body type.

For gluteal intramuscular administration only.

Attach the needle

Expel Air

Inject the dose

Do not administer by any other route.

Do not massage the injection site.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 6</span></td> </tr> <tr> <td align="center"><img alt="Figure 6" src="/dailymed/image.cfm?name=abilify-07.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be"/></td> </tr> </tbody> </table></div>

Disposal Procedure

Extended-release injectable suspension: sterile, white to off-white, aqueous suspension in a single-dose, pre-filled syringe.

{ "type": "p", "children": [], "text": "Extended-release injectable suspension: sterile, white to off-white, aqueous suspension in a single-dose, pre-filled syringe." }

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2: ABILIFY ASIMTUFII Presentations</span> </caption> <col align="center" valign="middle" width="22%"/> <col align="center" valign="middle" width="22%"/> <col align="center" valign="middle" width="28%"/> <col align="center" valign="middle" width="28%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Dose Strength</th><th align="center" class="Rrule">Volume</th><th align="center" class="Rrule">Label Color</th><th align="center" class="Rrule">Syringe Tip Wrap</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">720 mg</td><td align="center" class="Rrule">2.4 mL</td><td align="center" class="Rrule">Light Blue</td><td align="center" class="Rrule">Aqua</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">960 mg</td><td align="center" class="Rrule">3.2 mL</td><td align="center" class="Rrule">Pink</td><td align="center" class="Rrule">Light Blue</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"85%\">\n<caption>\n<span>Table 2: ABILIFY ASIMTUFII Presentations</span>\n</caption>\n<col align=\"center\" valign=\"middle\" width=\"22%\"/>\n<col align=\"center\" valign=\"middle\" width=\"22%\"/>\n<col align=\"center\" valign=\"middle\" width=\"28%\"/>\n<col align=\"center\" valign=\"middle\" width=\"28%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\">Dose Strength</th><th align=\"center\" class=\"Rrule\">Volume</th><th align=\"center\" class=\"Rrule\">Label Color</th><th align=\"center\" class=\"Rrule\">Syringe Tip Wrap</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\">720 mg</td><td align=\"center\" class=\"Rrule\">2.4 mL</td><td align=\"center\" class=\"Rrule\">Light Blue</td><td align=\"center\" class=\"Rrule\">Aqua</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Lrule Rrule\">960 mg</td><td align=\"center\" class=\"Rrule\">3.2 mL</td><td align=\"center\" class=\"Rrule\">Pink</td><td align=\"center\" class=\"Rrule\">Light Blue</td>\n</tr>\n</tbody>\n</table></div>" }

ABILIFY ASIMTUFII is contraindicated in patients with a known hypersensitivity to aripiprazole, or any of the excipients. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1)].

{ "type": "p", "children": [], "text": "ABILIFY ASIMTUFII is contraindicated in patients with a known hypersensitivity to aripiprazole, or any of the excipients. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1)]." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

ABILIFY ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

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 reactions (e.g., stroke, transient ischemic attack), including fatalities, in oral aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse reactions in patients treated with oral aripiprazole. ABILIFY ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex has been reported with antipsychotic drugs, including aripiprazole. Rare cases of NMS have been reported during aripiprazole treatment in the global 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.

If NMS is suspected, immediately discontinue ABILIFY ASIMTUFII and provide symptomatic treatment and monitoring.

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 predict which patients will 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 appear to increase as the duration of treatment and the total cumulative dose increases. The syndrome can develop, after relatively brief treatment periods at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

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

Atypical antipsychotic drugs have been associated with metabolic changes including 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 diabetic ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1)]. 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 reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including ABILIFY ASIMTUFII, 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, including ABILIFY ASIMTUFII, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including ABILIFY ASIMTUFII, 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 atypical antipsychotic drug.

In a short-term, placebo-controlled randomized trial in adults with schizophrenia, the mean change in fasting glucose was +9.8 mg/dL (N=88) in the Abilify Maintena-treated patients (once monthly dosing) and +0.7 mg/dL (N=59) in the placebo-treated patients. Table 3 shows the proportion of Abilify Maintena-treated patients with normal and borderline fasting glucose at baseline and their changes in fasting glucose measurements.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3: Proportion of Patients with Potential Clinically Relevant Changes in Fasting Glucose from a 12-Week Placebo-Controlled Monotherapy Trial with Abilify Maintena in Adult Patients with Schizophrenia </span> </caption> <col align="center" valign="middle" width="13%"/> <col align="center" valign="middle" width="32%"/> <col align="center" valign="middle" width="32%"/> <col align="center" valign="middle" width="13%"/> <col align="center" valign="middle" width="10%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule">Category Change (at least once) from Baseline</th><th align="center" class="Rrule">Treatment Arm</th><th align="center" class="Rrule">n/N<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></th><th align="center" class="Rrule">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="4"><span class="Bold">Fasting Glucose</span></td><td align="center" class="Rrule" rowspan="2">Normal to High<br/>(&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">7/88</td><td align="center" class="Rrule">8.0</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">0/75</td><td align="center" class="Rrule">0.0</td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2">Borderline to High<br/>(≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule Rrule">Abilify Maintena</td><td align="center" class="Botrule Rrule">1/33</td><td align="center" class="Botrule Rrule">3.0</td> </tr> <tr class="Last"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">3/33</td><td align="center" class="Rrule">9.1</td> </tr> </tbody> </table></div>

During a 52-week, open-label bipolar I disorder study in those patients who initiated Abilify Maintena treatment, 1.1% with normal baseline fasting glucose experienced a shift to high while receiving Abilify Maintena and 9.8% with borderline fasting glucose experienced a shift to high. Combined, 2.9% of these patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during this trial.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Table 4 shows the proportion of adult patients from one short-term, placebo-controlled randomized trial in adults with schizophrenia taking Abilify Maintena (once monthly dosing), with changes in total cholesterol, fasting triglycerides, fasting LDL cholesterol and HDL cholesterol.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4: Proportion of Patients with Potential Clinically Relevant Changes in Blood Lipid Parameters From a 12-Week Placebo-Controlled Monotherapy Trial with Abilify Maintena in Adults with Schizophrenia </span> </caption> <col align="left" valign="middle" width="35%"/> <col align="center" valign="middle" width="35%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="10%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Treatment Arm</th><th align="center" class="Rrule">n/N<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></th><th align="center" class="Rrule">%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. n = the number of subjects with a potentially clinically relevant shift.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" rowspan="2"><span class="Bold">Total Cholesterol</span> <br/>Normal to High<br/>(&lt;200 mg/dL to ≥240 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">3/83</td><td align="center" class="Rrule">3.6</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">2/73</td><td align="center" class="Rrule">2.7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Borderline to High<br/>(200~&lt;240 mg/dL to ≥240 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">6/27</td><td align="center" class="Rrule">22.2</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">2/19</td><td align="center" class="Rrule">10.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Any increase<br/>(≥40 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">15/122</td><td align="center" class="Rrule">12.3</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">6/110</td><td align="center" class="Rrule">5.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2"><span class="Bold">Fasting Triglycerides</span> <br/>Normal to High<br/>(&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">7/98</td><td align="center" class="Rrule">7.1</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">4/78</td><td align="center" class="Rrule">5.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Borderline to High<br/>(150~&lt;200 mg/dL to ≥200 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">3/11</td><td align="center" class="Rrule">27.3</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">4/15</td><td align="center" class="Rrule">26.7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Any increase<br/>(≥50 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">24/122</td><td align="center" class="Rrule">19.7</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">20/110</td><td align="center" class="Rrule">18.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2"><span class="Bold">Fasting LDL Cholesterol</span> <br/>Normal to High<br/>(&lt;100 mg/dL to ≥160 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">1/59</td><td align="center" class="Rrule">1.7</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">1/51</td><td align="center" class="Rrule">2.0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Borderline to High<br/>(100~&lt;160 mg/dL to ≥160 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">5/52</td><td align="center" class="Rrule">9.6</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">1/41</td><td align="center" class="Rrule">2.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Any increase<br/>(≥30 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">17/120</td><td align="center" class="Rrule">14.2</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">9/103</td><td align="center" class="Rrule">8.7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2"><span class="Bold">HDL Cholesterol</span> <br/>Normal to Low<br/>(≥40 mg/dL to &lt;40 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">14/104</td><td align="center" class="Rrule">13.5</td> </tr> <tr class="Botrule"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">11/87</td><td align="center" class="Rrule">12.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Any decrease<br/>(≥20 mg/dL)</td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">7/122</td><td align="center" class="Rrule">5.7</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"></td><td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">12/110</td><td align="center" class="Rrule">10.9</td> </tr> </tbody> </table></div>

During a 52-week, open-label bipolar I disorder study in those patients who initiated Abilify Maintena, shifts from baseline in fasting cholesterol from normal to high were reported in 2.1% (total cholesterol) and 2.2% (LDL cholesterol) and shifts from baseline from normal to low were reported in 8.5% (HDL cholesterol). Of these patients with normal baseline triglycerides, 3.6% experienced shifts to high, and 0.0% experienced shifts to very high. Combined, 1.0% of these patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during this trial.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

In one short-term, placebo-controlled trial in adult patients with schizophrenia with Abilify Maintena (once monthly dosing), the mean change in body weight at Week 12 was +3.5 kg (N=99) in the Abilify Maintena-treated patients and +0.8 kg (N=66) in the placebo-treated patients.

Table 5 shows the percentage of adult patients with schizophrenia with weight gain ≥7% of body weight in a short-term, placebo-controlled trial with Abilify Maintena.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5: Percentage of Patients From a 12-Week Placebo-Controlled Trial with Abilify Maintena in Adult Patients with Schizophrenia with Weight Gain ≥7% of Body Weight</span> </caption> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="43%"/> <col align="center" valign="middle" width="7%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">Treatment Arm</th><th align="center" class="Rrule">N<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></th><th align="center" class="Rrule">Patients n (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>N = the total number of subjects who had a measurement at baseline and at least one post-baseline result.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" rowspan="2"><span class="Bold">Weight gain ≥7% of body weight</span></td><td align="center" class="Rrule">Abilify Maintena</td><td align="center" class="Rrule">144</td><td align="center" class="Rrule">31 (21.5)</td> </tr> <tr class="Last"> <td align="center" class="Rrule">Placebo</td><td align="center" class="Rrule">141</td><td align="center" class="Rrule">12 (8.5)</td> </tr> </tbody> </table></div>

During a 52-week, open-label bipolar I disorder study in those patients who initiated Abilify Maintena, 1.8% discontinued Abilify Maintena treatment due to weight increase. Abilify Maintena was associated with mean increase from baseline in weight of 1.0 kg at Week 52. In this trial, 21.4% of these patients demonstrated ≥7% increase in body weight and 15.4% demonstrated a ≥7% decrease in body weight.

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

ABILIFY ASIMTUFII may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Associated reactions related to orthostatic hypotension can include dizziness, tachycardia, and in some patients, syncope. In the short-term, placebo-controlled trial in adults with schizophrenia, the adverse reaction of presyncope was reported in 1/167 (0.6%) of patients treated with Abilify Maintena (once monthly dosing), while syncope and orthostatic hypotension were each reported in 1/172 (0.6%) of patients treated with placebo. During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, orthostasis-related adverse events were reported in 4/576 (0.7%) of patients treated with Abilify Maintena, including abnormal orthostatic blood pressure (1/576, 0.2%), postural dizziness (1/576, 0.2%), presyncope (1/576, 0.2%) and orthostatic hypotension (1/576, 0.2%).

In the short-term placebo-controlled trial of Abilify Maintena in adults with schizophrenia, there were no patients in either treatment group with a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values). During the stabilization phase of the randomized-withdrawal (maintenance) study in adult patients with schizophrenia, the incidence of significant orthostatic change in blood pressure was 0.2% (1/575).

Use ABILIFY ASIMTUFII with caution in patients with known cardiovascular disease (heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Antipsychotics, including ABILIFY ASIMTUFII, may cause somnolence, postural hypotension, motor and sensory instability which may lead to falls and, consequently, fractures or other fall-related injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trials and post-marketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported [see Adverse Reactions (6.1)].

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) absolute neutrophil count (ANC) and a history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY ASIMTUFII at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY ASIMTUFII in patients with severe neutropenia (ANC<1000/mm3) and follow their WBC counts until recovery.

As with other antipsychotic drugs, use ABILIFY ASIMTUFII cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

ABILIFY ASIMTUFII, like other antipsychotics, may impair judgment, thinking, or motor skills. Instruct patients to be cautious about performing activities that require mental alertness such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that therapy with ABILIFY ASIMTUFII does not affect them adversely.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY ASIMTUFII for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. ABILIFY ASIMTUFII and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.

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 safety of ABILIFY ASIMTUFII for the treatment of schizophrenia in adults and maintenance monotherapy treatment of bipolar I disorder in adults is based on adequate and well-controlled studies of Abilify Maintena. The safety data from those studies is presented below.

Safety Database of Abilify Maintena (once monthly dosing) and Oral Aripiprazole.

Oral aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days.

Abilify Maintena (once monthly dosing) has been evaluated for safety in 2,128 adult patients in clinical trials in schizophrenia, with approximately 2,633 patient-years of exposure to Abilify Maintena. A total of 1,229 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 935 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections).

Abilify Maintena has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to Abilify Maintena. A total of 419 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 287 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections).

Safety Database of ABILIFY ASIMTUFII (once every 2 month dosing)

In a 32 week open-label study of ABILIFY ASIMTUFII in adult patients with schizophrenia or bipolar I disorder, 266 patients were randomized to receive either ABILIFY ASIMTUFII 960 mg (132 patients) or Abilify Maintena 400 mg (134 patients). A total of the 132 patients received at least one injection of ABILIFY ASIMTUFII, a total of 114 patients received at least two consecutive injections (4 months treatment) of ABILIFY ASIMTUFII, and a total of 104 patients received at least four consecutive injections (8 months treatment) of ABILIFY ASIMTUFII. Of the total 266 patients receiving ABILIFY ASIMTUFII 960 mg or Abilify Maintena 400 mg, 185 had schizophrenia and 81 had bipolar I disorder. Injection site reactions for ABILIFY ASIMTUFII (once every 2 month dosing) presented in this section is based on this open-label study (see section titled "Injection Site Reactions with Abilify ASIMTUFII").

Adverse Reactions in Studies with Abilify Maintena (once monthly dosing)

The conditions and duration of treatment with Abilify Maintena included double-blind and open-label studies. The safety data presented below are derived from the 12-week double-blind placebo-controlled study of Abilify Maintena in adult patients with schizophrenia.

Most Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia with Abilify Maintena

Based on the placebo-controlled trial of Abilify Maintena in schizophrenia, the most commonly observed adverse reactions associated with the use of Abilify Maintena in patients (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were increased weight (16.8% vs. 7.0%), akathisia (11.4% vs. 3.5%), injection site pain (5.4% vs. 0.6%) and sedation (5.4% vs. 1.2%).

Commonly Reported Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia with Abilify Maintena

The following findings are based on the double-blind, placebo-controlled trial that compared Abilify Maintena 400 mg or 300 mg to placebo in patients with schizophrenia. Table 6 lists the adverse reactions reported in 2% or more of Abilify Maintena-treated patients and at a greater proportion than in the placebo group.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 6: Adverse Reactions in ≥2% of Adult Patients with Schizophrenia Treated with Abilify Maintena in a 12-Week Double-Blind, Placebo-Controlled Study<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></span> </caption> <col align="left" valign="middle" width="38%"/> <col align="center" valign="middle" width="29%"/> <col align="center" valign="middle" width="33%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule" valign="bottom">Preferred Term</th><th align="center" class="Rrule">Abilify Maintena<br/>(n=167)</th><th align="center" class="Rrule">Placebo<br/>(n=172)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>This table does not include adverse reactions which had an incidence equal to or less than placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Gastrointestinal Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Constipation</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dry Mouth</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Diarrhea</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Abdominal Discomfort</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">General Disorders and Administration Site Conditions</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Injection Site Pain</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Infections and Infestations</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Upper Respiratory Tract Infection</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Investigations</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Weight</td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Decreased Weight</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Arthralgia</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Back Pain</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Myalgia</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Musculoskeletal pain</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Nervous System Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Akathisia</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Sedation</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dizziness</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Tremor</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Respiratory, Thoracic and Mediastinal</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Nasal Congestion</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">1</td> </tr> </tbody> </table></div>

Demographic Differences

An examination of population subgroups was performed across demographic subgroup categories for adverse reactions experienced by at least 5% of Abilify Maintena patients at least twice the rate of placebo (i.e., increased weight, akathisia, injection site pain, and sedation) in the double-blind placebo-controlled trial. This analysis did not reveal evidence of differences in safety differential adverse reaction incidence on the basis of age, gender, or race alone; however, there were few patients ≥65 years of age.

Injection Site Reactions with ABILIFY ASIMTUFII

ABILIFY ASIMTUFII was evaluated in 266 patients with schizophrenia or bipolar I disorder in an open-label, multiple-dose, randomized, parallel-arm multi-center study.

The percentage of patients in the open-label study reporting any injection site-related adverse reactions (all reported as injection site pain) was 19% for patients treated with ABILIFY ASIMTUFII 960 mg and 9% for patients treated with Abilify Maintena 400 mg. In both treatment groups, the majority of the injection site pain events coincided with the first injection of ABILIFY ASIMTUFII 960 mg (21/24 patients) or Abilify Maintena 400 mg (7/12 patients), was reported with decreasing frequency upon subsequent injections. The overall mean visual analog scale scores (0=no pain to 100=unbearably painful) for patient reported rating of pain were similar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the ABILIFY ASIMTUFII 960 mg group compared to 1.3 post-dose for the Abilify Maintena 400 mg group.

Extrapyramidal Symptoms (EPS)

In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify Maintena-treated patients was 9.6% vs. 5.2% for placebo. The incidence of akathisia-related events for Abilify Maintena-treated patients was 11.5% vs. 3.5% for 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. In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of dystonia was 1.8% for Abilify Maintena vs. 0.6% for placebo.

Neutropenia

In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of neutropenia (absolute neutrophil count ≤1.5 thous/mcL) for Abilify Maintena-treated patients was 5.7% vs. 2.1% for placebo. An absolute neutrophil count of <1 thous/mcL (i.e., 0.95 thous/mcL) was observed in only one patient on Abilify Maintena and resolved spontaneously without any associated adverse reactions [see Warnings and Precautions (5.9)].

Other Adverse Reactions During the Clinical Trial Evaluation of Abilify Maintena

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.

Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole

The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for Abilify Maintena:

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, pathological gambling, and fecal incontinence.

Table 7 presents clinically significant drug interactions with ABILIFY ASIMTUFII.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 7: Clinically Important Drug Interactions with ABILIFY ASIMTUFII</span> </caption> <col align="left" valign="middle" width="35%"/> <col align="left" valign="middle" width="65%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" colspan="2"><span class="Bold">Strong CYP3A4 Inhibitors AND/OR strong CYP2D6 inhibitors</span></td> </tr> <tr class="Botrule"> <td align="left">Clinical Rationale</td><td align="left">Concomitant use of oral aripiprazole with strong CYP3A4 AND/OR CYP2D6 inhibitors increased the exposure of aripiprazole <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" valign="top">Clinical Recommendation</td><td align="left"><span class="Underline">Concomitant use of a strong CYP3A4 inhibitor <span class="Bold">OR</span> a strong CYP2D6 inhibitor</span> <br/>Reduce the dosage of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor <span class="Bold">OR</span> a strong CYP2D6 inhibitor for more than 14 days <span class="Italics">[see <a href="#S2.4">Dosage and Administration (2.4)</a>].</span> <br/> <span class="Underline">Concomitant Use of a strong CYP3A4 inhibitor <span class="Bold">AND</span> a strong CYP2D6 inhibitor</span> <br/>Avoid use of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor <span class="Bold">AND</span> a strong CYP2D6 inhibitor for more than 14 days <span class="Italics">[see <a href="#S2.4">Dosage and Administration (2.4)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" colspan="2"><span class="Bold">Strong CYP3A4 Inducers</span></td> </tr> <tr class="Botrule"> <td align="left">Clinical Rationale</td><td align="left">Concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left">Clinical Recommendation</td><td align="left">Avoid use of ABILIFY ASIMTUFII in combination with a strong CYP3A4 inducer (e.g., carbamazepine) for greater than 14 days <span class="Italics">[see <a href="#S2.4">Dosage and Administration (2.4)</a>]</span>. </td> </tr> <tr class="Botrule"> <td align="left" colspan="2"><span class="Bold">Antihypertensive Drugs</span></td> </tr> <tr class="Botrule"> <td align="left">Clinical Rationale</td><td align="left">Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. </td> </tr> <tr class="Botrule"> <td align="left">Clinical Recommendation</td><td align="left">Monitor blood pressure and adjust dose accordingly <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" colspan="2"><span class="Bold">Benzodiazepines</span></td> </tr> <tr class="Botrule"> <td align="left">Clinical Rationale</td><td align="left">The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>].</span></td> </tr> <tr class="Last"> <td align="left">Clinical Recommendation</td><td align="left">Monitor sedation and blood pressure. Adjust dose accordingly. </td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY ASIMTUFII is required when administered concomitantly with famotidine, valproate, lithium, lorazepam [see Clinical Pharmacology (12.3)].

In addition, no dosage adjustment is necessary for substrates of CYP2D6, CYP2C9, CYP2C19, or CYP3A4 when coadministered with ABILIFY ASIMTUFII. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY ASIMTUFII [see Clinical Pharmacology (12.3)].

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ABILIFY ASIMTUFII, 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 ABILIFY ASIMTUFII, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms (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 outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ABILIFY ASIMTUFII, during pregnancy (see Clinical Considerations). Aripiprazole exposure during pregnancy may decrease milk supply in the post-partum period [see Use in Specific Populations (8.2)].

In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 11 times, respectively, the maximum recommended human oral 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 10 times the oral MRHD produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data).

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

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

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

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 oral aripiprazole, 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 exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Data

Animal Data

No developmental toxicity studies were conducted with intramuscular aripiprazole suspension.

In animal oral or intravenous 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 which are approximately 1 to 10 times the oral MRHD of 30 mg/day on mg/m2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m2 basis.

At 3 and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on mg/m2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

In pregnant rats treated with aripiprazole intravenously at doses of 3, 9, and 27 mg/kg/day, which are 1 to 9 times the oral MRHD on mg/m2 basis, during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose which also caused maternal toxicity.

In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD of aripiprazole on mg/m2 basis during the period of organogenesis, decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the oral MRHD based on AUC.

In pregnant rabbits receiving aripiprazole injection intravenously at doses of 3, 10, and 30 mg/kg/day, which are 2 to 19 times the oral MRHD on mg/m2 basis during the period of organogenesis, the highest dose caused pronounced maternal toxicity that resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD on mg/m2 basis.

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

In rats treated with aripiprazole intravenously at doses of 3, 8, and 20 mg/kg/day which are 1 to 6 times the oral MRHD on mg/m2 basis from Day 6 of gestation through Day 20 postpartum, increased stillbirths were seen at 3 and 6 times the oral MRHD on mg/m2 basis, and decreases in early postnatal pup weight and survival were seen at the highest dose; these doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

Risk Summary

Aripiprazole is present in human breast milk. Based on published case reports and pharmacovigilance reports, aripiprazole exposure during pregnancy and/or the postpartum period may lead to clinically relevant decreases in milk supply which may be reversible with discontinuation of the drug. There are also reports of aripiprazole exposure during pregnancy and no maternal milk supply in the post-partum period. Effects on milk supply may be mediated through decreases in prolactin levels, which have been observed [see Adverse Reactions (6.1)]. Monitor the breastfed infant for dehydration and lack of appropriate weight gain. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ABILIFY ASIMTUFII and any potential adverse effects on the breastfed infant from ABILIFY ASIMTUFII or from the underlying maternal condition.

Safety and effectiveness of ABILIFY ASIMTUFII in pediatric patients have not been established.

Juvenile Animal Studies

No juvenile animal studies were conducted with intramuscular aripiprazole suspension. A study with oral aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended oral pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.

Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended oral pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.

Clinical studies of ABILIFY ASIMTUFII did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data have not identified differences in responses between the elderly and younger patients [see Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In single-dose and multiple-dose pharmacokinetic studies with oral aripiprazole, there was no detectable age effect in the population pharmacokinetic analysis in schizophrenia patients [see Clinical Pharmacology (12.3)]. No dosage adjustments are recommended based on age alone. ABILIFY ASIMTUFII is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

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 (2.4)].

Human Experience

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Management of Overdosage

In case of overdosage, call the Poison Control Center immediately at 1-800-222-1222 or medical toxicologist for additional overdosage management recommendations.

Aripiprazole is an atypical antipsychotic which is present in ABILIFY ASIMTUFII as its monohydrate polymorphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C23H27Cl2N3O2∙H2O and its molecular weight is 466.40. The chemical structure is:

{ "type": "p", "children": [], "text": "Aripiprazole is an atypical antipsychotic which is present in ABILIFY ASIMTUFII as its monohydrate polymorphic form. Aripiprazole monohydrate is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4 dihydrocarbostyril monohydrate. The empirical formula is C23H27Cl2N3O2∙H2O and its molecular weight is 466.40. The chemical structure is:" }

ABILIFY ASIMTUFII (aripiprazole) is available as a white to off-white, sterile, aqueous extended-release suspension for intramuscular injection in 720 mg or 960 mg dose strength, pre-filled syringes. The labeled strengths are calculated based on the anhydrous form (aripiprazole). Inactive ingredients are carboxymethylcellulose sodium (5 mg/mL), polyethylene glycol 400 (1 mg/mL), povidone (4 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate monobasic monohydrate (0.74 mg/mL), sodium hydroxide (to adjust pH) and water for injection (q.s.).

{ "type": "p", "children": [], "text": "ABILIFY ASIMTUFII (aripiprazole) is available as a white to off-white, sterile, aqueous extended-release suspension for intramuscular injection in 720 mg or 960 mg dose strength, pre-filled syringes. The labeled strengths are calculated based on the anhydrous form (aripiprazole). Inactive ingredients are carboxymethylcellulose sodium (5 mg/mL), polyethylene glycol 400 (1 mg/mL), povidone (4 mg/mL), sodium chloride (6.1 mg/mL), sodium phosphate monobasic monohydrate (0.74 mg/mL), sodium hydroxide (to adjust pH) and water for injection (q.s.)." }

The mechanism of action of aripiprazole in the treatment of schizophrenia and bipolar I disorder is unknown.

The efficacy of aripiprazole could be mediated through a combination of partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.

Aripiprazole exhibits high affinity for dopamine D2 and D3 (Kis 0.34 and 0.8 nM, respectively), serotonin 5-HT1A and 5-HT2A receptors (Kis 1.7 and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Kis 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). Actions at receptors other than D2, 5-HT1A, and 5-HT2A could explain some of the other adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).

ABILIFY ASIMTUFII 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.

ABILIFY ASIMTUFII delivers aripiprazole over a 2-month period. ABILIFY ASIMTUFII has linear pharmacokinetics in the approved dose range. Steady-state aripiprazole exposures were reached by the fourth dose. Plasma exposures at steady state were compared between ABILIFY ASIMTUFII (960 mg, once every 2 months) and Abilify Maintena (400 mg, once every month). The average plasma concentrations (Cavg) of aripiprazole were 263 ng/mL and 280 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively. The Cmax of aripiprazole were 342 ng/mL and 344 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively.

Figure 9: Mean Plasma Concentration of Aripiprazole Following the Fourth Administration of ABILIFY ASIMTUFII 960 mg versus the Seventh and Eighth Administration of Abilify Maintena 400 mg

Absorption

Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with Tmax ranging between 1 to 49 days following multiple gluteal administrations of 960 mg.

Distribution

Based on results from trials with oral administration of aripiprazole, aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.

Elimination

Following single dose administration of ABILIFY ASIMTUFII, the mean apparent terminal elimination half-life of aripiprazole was 21 days.

Metabolism

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. Following administration of multiple doses of ABILIFY ASIMTUFII, dehydro-aripiprazole, the active metabolite, represents approximately 29% of aripiprazole AUC in plasma.

Excretion

Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces.

Studies in Specific Populations

No specific pharmacokinetic studies have been performed with ABILIFY ASIMTUFII in specific populations. All the information is obtained from studies with oral aripiprazole or is based on the pharmacokinetic modeling of oral aripiprazole and/or ABILIFY ASIMTUFII.

Exposures of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 10 and Figure 11, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with oral aripiprazole (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults.

Figure 10: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics

Figure 11: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics

Drug Interaction Studies

No specific drug interaction studies have been performed with ABILIFY ASIMTUFII. The information below is obtained from studies with oral aripiprazole.

The effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 12 and Figure 13, respectively. Based on simulations, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. After oral administration, a 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.

Figure 12: The Effect of Other Drugs on Aripiprazole Pharmacokinetics

Figure 13: The Effect of Other Drugs on Dehydro-aripiprazole Pharmacokinetics

The effect of oral aripiprazole on the exposures of other drugs are summarized in Figure 14. A population PK analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of fluoxetine (20 mg/day or 40 mg/day), paroxetine CR (37.5 mg/day or 50 mg/day), or sertraline (100 mg/day or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively, and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole.

Figure 14: The Effect of Oral Aripiprazole on Pharmacokinetics of Other Drugs

In vitro

Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not undergo direct glucuronidation.

Carcinogenesis

No carcinogenicity studies were conducted with intramuscular aripiprazole suspension.

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

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

Mutagenesis

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

Impairment of Fertility

No mating and fertility studies were conducted with intramuscular aripiprazole suspension.

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

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

The toxicological profile for aripiprazole administered to experimental animals by intramuscular injection is generally similar to that seen following oral administration at comparable plasma levels of the drug. In dogs, repeated intramuscular dosing of the 2-month aripiprazole extended release injectable suspension over a period of 52 weeks produced no clinical evidence of significant local irritation, and resulted in slight foreign-body type of localized granulomatous inflammatory reaction to deposited drug at the injection site. These effects gradually resolved with discontinuation of dosing.

Oral aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg. The 40 and 60 mg/kg/day doses are 13 and 19 times the maximum recommended human oral dose (MRHD) based on mg/m2 body surface and 7 to 14 times human exposure at the oral MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

The efficacy of ABILIFY ASIMTUFII (once every 2 month dosing) for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of Abilify Maintena (once monthly dosing). The results of these adequate and well-controlled studies are presented below.

The efficacy of Abilify Maintena (once monthly dosing) for treatment of schizophrenia was established in:

• One short-term (12-week), randomized, double-blind, placebo-controlled trial in acutely relapsed adults (Study 1)

• One longer-term, double-blind, placebo-controlled, randomized-withdrawal (maintenance) trial in adults (Study 2).

Short-Term Efficacy

In the short-term (12-week), randomized, double-blind, placebo-controlled trial in acutely relapsed adults (Study 1), the primary measure used for assessing psychiatric signs and symptoms was 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 primary endpoint was the change from baseline in PANSS total score to week 10.

The inclusion criteria for this short-term trial included adult inpatients who met DSM-IV-TR criteria for schizophrenia. In addition, all patients entering the trial must have experienced an acute psychotic episode as defined by both PANSS Total Score ≥80 and a PANSS score of >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, unusual thought content) at screening and baseline. The key secondary endpoint was the change from baseline in Clinical Global Impression-Severity (CGI-S) assessment scale to week 10. The CGI-S rates the severity of mental illness on a scale of 1 (normal) to 7 (among the most extremely ill) based on the total clinical experience of the rater in treating patients with schizophrenia. Patients had a mean PANSS total score of 103 (range 82 to 144) and a CGI-S score of 5.2 (markedly ill) at entry.

In this 12-week study (n=339) comparing Abilify Maintena (n=167) to placebo (n=172), patients were administered 400 mg Abilify Maintena or placebo on days 0, 28, and 56. The dose could be adjusted down and up within the range of 400 to 300 mg on a one-time basis. Abilify Maintena was superior to placebo in improving the PANSS total score at the end of week 10 (see Table 8).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 8: Efficacy Results of Abilify Maintena in Short-term Schizophrenia Study 1 (Adults) </span> </caption> <col align="left" valign="middle" width="20%"/> <col align="left" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First"> <th align="left"></th><th align="left"></th><th align="center" class="Botrule" colspan="3">Primary Efficacy Measure: PANSS Total Score</th> </tr> <tr class="Last"> <th align="left" valign="bottom">Study Number</th><th align="left" valign="bottom">Treatment Group</th><th align="center">Mean Baseline Score (SD)</th><th align="center">LS Mean Change from Baseline (SE)</th><th align="center">Placebo-subtracted Difference<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a> <br/>(95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" rowspan="2">Study 1</td><td align="left">Abilify Maintena <br/>(400 to 300 mg)</td><td align="center">102.4 (11.4) </td><td align="center">-26.8 (1.6)</td><td align="center">-15.1<br/> (-19.4, -10.8)</td> </tr> <tr class="Last"> <td align="left">Placebo </td><td align="center">103.4 (11.1)</td><td align="center">-11.7 (1.6)</td><td align="center">--</td> </tr> </tbody> </table></div>

The change in PANSS total score by week is shown in Figure 15. Abilify Maintena also showed improvement in symptoms represented by CGI-S score mean change from baseline to week 10. The results of exploratory subgroup analyses by gender, race, age, ethnicity, and BMI were similar to the results of the overall population.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1" valign="top">n = the number of patients remaining in the respective study arm at each time point</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 15: Weekly PANSS Total Score-Change in the 12-Week, Placebo-Controlled Study with Abilify Maintena in Schizophrenia - Study 1 (Adults)</span></td> </tr> <tr> <td align="center"><img alt="Figure 15" src="/dailymed/image.cfm?name=abilify-17.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be"/></td> </tr> </tbody> </table></div>

Long-Term Efficacy

The efficacy of Abilify Maintena in maintaining symptomatic control in schizophrenia was established in a double-blind, placebo-controlled, randomized-withdrawal trial in adult patients (Study 2) who met DSM-IV-TR criteria for schizophrenia and who were being treated with at least one antipsychotic medication. Patients had at least a 3-year history of illness and a history of relapse or symptom exacerbation when not receiving antipsychotic treatment.

In addition to the PANSS and CGI-S, clinical ratings during this trial included the:

This trial included:

The primary efficacy endpoint was time from randomization to relapse. Relapse was defined as the first occurrence of one or more of the following criteria:

A pre-planned interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the Abilify Maintena group compared to placebo-treated patients and the trial was subsequently terminated early because maintenance of efficacy was demonstrated. The final analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the Abilify Maintena group than compared to placebo-treated patients. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for Abilify Maintena and placebo groups are shown in Figure 16.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>This figure is based on a total of 80 relapse events.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 16: Kaplan-Meier Estimation of Cumulative Proportion of Abilify Maintena-Treated Patients with Relapse<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a> (Adults) Study 2 </span></td> </tr> <tr> <td align="center"><img alt="Figure 16" src="/dailymed/image.cfm?name=abilify-18.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be"/></td> </tr> </tbody> </table></div>

The key secondary efficacy endpoint, percentage of patients meeting the relapse criteria, was statistically significantly lower in patients randomized to the Abilify Maintena group (10%) than in the placebo group (40%).

The efficacy of ABILIFY ASIMTUFII (once every 2 month dosing) for the treatment of maintenance monotherapy treatment of bipolar I disorder in adults is based on an adequate and well-controlled study of Abilify Maintena (once monthly dosing). The results of the adequate and well-controlled study are presented below.

The efficacy of Abilify Maintena (once monthly dosing) for the maintenance treatment of bipolar I disorder was established in a 52-week, double-blind, placebo-controlled, randomized withdrawal trial in adult patients who were experiencing a manic episode at trial entry, met DSM-IV-TR criteria for bipolar I disorder, and had a history of at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer, and/or treatment with an antipsychotic agent.

Clinical ratings during this trial included:

This trial included:

The primary efficacy endpoint was time from randomization to recurrence of any mood episode. Recurrence was defined as the first occurrence of one or more of the following criteria:

1) Hospitalization for any mood episode OR 2) Any of the following: a. YMRS total score ≥15 OR b. MADRS total score ≥15 OR c. Clinical Global Impression - Bipolar Version-Severity (CGI-BP-S) score >4 (overall score) OR 3) Serious adverse event (SAE) of worsening disease (bipolar I disorder) OR 4) Discontinuation due to lack of efficacy or discontinuation due to an adverse event (AE) of worsening disease OR 5) Clinical worsening with the need for addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, and/or increase greater than the allowed benzodiazepine doses for treatment of symptoms of an underlying mood disorder OR 6) Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of "yes" on question 4 or 5 on the C-SSRS

Analysis demonstrated a statistically significantly longer time to recurrence of any mood episode in subjects randomized to the Abilify Maintena group than compared to placebo-treated subjects. The Kaplan-Meier curves of the time of recurrence to any mood episode during the double-blind treatment phase for Abilify Maintena and placebo groups are shown in Figure 17.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" colspan="1"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>This figure is based on a total of 103 recurrence events.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center"><span class="Bold">Figure 17: Kaplan-Meier Estimation of Cumulative Recurrence Rate for Any Mood Episode<a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a> in Abilify Maintena-Treated Adults </span></td> </tr> <tr> <td align="center"><img alt="Figure 17" src="/dailymed/image.cfm?name=abilify-19.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be"/></td> </tr> </tbody> </table></div>

Analysis by type of mood recurrence demonstrated a statistically significantly longer time to recurrence for both manic and mixed mood episodes in subjects treated with Abilify Maintena compared to those treated with placebo. There was no substantial difference between treatment groups in delaying time to recurrence of depressive mood episodes.

An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, sex, or race.

How Supplied

ABILIFY ASIMTUFII (aripiprazole) is available as white to off-white, sterile aqueous extended-release injectable suspension in single-dose, pre-filled syringes in 720 mg/2.4 mL or 960 mg/3.2 mL strengths.

The single-use kit contains 1 pre-filled syringe and 2 safety needles (a 1.5 inch 22 gauge needle and a 2 inch 21 gauge needle).

Storage

Store at 25°C (77°F), excursions permitted between 15° and 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact a health care provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.3)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.4)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.5)].

Pathological Gambling and Other Compulsive Behaviors

Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, increased urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking ABILIFY ASIMTUFII. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.6)].

Orthostatic Hypotension and Syncope

Educate patients about the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dosage [see Warnings and Precautions (5.7)].

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC count or a history of drug-induced leucopenia/neutropenia that they should have their CBC monitored while receiving ABILIFY ASIMTUFII [see Warnings and Precautions (5.9)].

Potential for Cognitive and Motor Impairment

Inform patients that ABILIFY ASIMTUFII has the potential to impair judgment, thinking, or motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that ABILIFY ASIMTUFII therapy does not affect them adversely [see Warnings and Precautions (5.11)].

Heat Exposure and Dehydration

Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.12)].

Concomitant Medication

Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drug Interactions (7.1)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ABILIFY ASIMTUFII. Advise patients that ABILIFY ASIMTUFII 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 exposure registry that monitors pregnancy outcomes in women exposed to ABILIFY ASIMTUFII during pregnancy [see Use in Specific Populations (8.1)].

Lactation

ABILIFY ASIMTUFII use during pregnancy may affect milk supply. Advise the lactating patient to discuss any plans for breastfeeding with their healthcare provider, and to monitor the breastfed infant for dehydration and lack of appropriate weight gain [see Use in Specific Populations (8.2)].

Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA

{ "type": "p", "children": [], "text": "Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA" }

Marketed by Lundbeck, Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Marketed by Lundbeck, Deerfield, IL 60015 USA" }

ABILIFY ASIMTUFII is a trademark of Otsuka Pharmaceutical Co., Ltd.

{ "type": "p", "children": [], "text": "ABILIFY ASIMTUFII is a trademark of Otsuka Pharmaceutical Co., Ltd." }

©2025, Otsuka Pharmaceutical Co., Ltd., 2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo, 101-8535 Japan

{ "type": "p", "children": [], "text": "©2025, Otsuka Pharmaceutical Co., Ltd., 2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo, 101-8535 Japan" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="47%"/> <col align="left" valign="top" width="27%"/> <col align="left" valign="top" width="20%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="4">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right" colspan="1">Revised: 03/2025            </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="5"><span class="Bold">MEDICATION GUIDE<br/>ABILIFY ASIMTUFII<span class="Sup">®</span> (a-BIL-i-fy AH-SIM-TUH-FYE)<br/>(aripiprazole) for extended-release injectable suspension, for intramuscular use</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold"><a name="Important"></a>What is the most important information I should know about ABILIFY ASIMTUFII?<br/>ABILIFY ASIMTUFII may cause serious side effects, including:</span> <ul class="Disc"> <li> <span class="Bold">Increased risk of death in elderly people with dementia-related psychosis.</span> ABILIFY ASIMTUFII increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). ABILIFY ASIMTUFII is not for the treatment of people with dementia-related psychosis.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What is ABILIFY ASIMTUFII?</span> <br/>ABILIFY ASIMTUFII is a prescription medicine given by injection by a healthcare provider:<ul class="Disc"> <li>for the treatment of schizophrenia in adults</li> <li>alone as maintenance treatment of bipolar I disorder in adults</li> </ul>It is not known if ABILIFY ASIMTUFII is safe and effective in children under 18 years of age.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Who should not receive ABILIFY ASIMTUFII?</span> <br/> <span class="Bold">Do not receive ABILIFY ASIMTUFII if you</span> are allergic to aripiprazole or any of the ingredients in ABILIFY ASIMTUFII. See the end of this Medication Guide for a complete list of ingredients in ABILIFY ASIMTUFII.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Before receiving ABILIFY ASIMTUFII, tell your healthcare provider about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>have never taken aripiprazole before</li> <li>have or had diabetes or high blood sugar or a family history of diabetes or high blood sugar</li> <li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li> <li>have or had low or high blood pressure</li> <li>have or had heart problems or a stroke</li> <li>have or had a low white blood cell count</li> <li>have or had seizures (convulsions)</li> <li>have problems that may affect you receiving an injection in your buttocks</li> <li>are pregnant or plan to become pregnant. ABILIFY ASIMTUFII may harm your unborn baby. Receiving ABILIFY ASIMTUFII during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you receive ABILIFY ASIMTUFII during pregnancy.<ul class="Circle"> <li>Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ABILIFY ASIMTUFII.</li> <li>If you become pregnant during treatment with ABILIFY ASIMTUFII, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. ABILIFY ASIMTUFII can pass into your breast milk and it is not known if it may harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with ABILIFY ASIMTUFII.</li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements.<br/>ABILIFY ASIMTUFII and other medicines may affect each other causing possible serious side effects. ABILIFY ASIMTUFII may affect the way other medicines work, and other medicines may affect how ABILIFY ASIMTUFII works.<br/>Your healthcare provider can tell you if it is safe to receive ABILIFY ASIMTUFII with your other medicines. Do not start or stop any medicines during treatment with ABILIFY ASIMTUFII without first talking to your healthcare provider.<br/>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I receive ABILIFY ASIMTUFII?</span> <ul class="Disc"> <li>Follow your ABILIFY ASIMTUFII treatment schedule exactly as your healthcare provider tells you to.</li> <li>Your healthcare provider will tell you how much ABILIFY ASIMTUFII you will receive and when you will receive it.</li> <li>ABILIFY ASIMTUFII is an injection given only in your buttock by your healthcare provider 1 time every 2 months. </li> <li>There are 2 ways to start (initiate) treatment with ABILIFY ASIMTUFII if you currently take an antipsychotic medicine by mouth (oral): <ul class="Circle"> <li>1-day initiation: You will receive 1 injection of ABILIFY ASIMTUFII in your buttock and 1 injection of Abilify Maintena in your arm or other buttock on your first day of treatment. You will also take 1 dose of aripiprazole by mouth.<br/> <span class="Bold">OR</span> </li> <li>14-day initiation: You will receive 1 injection of ABILIFY ASIMTUFII in your buttock. You will also continue to take your oral aripiprazole or your current antipsychotic medicine by mouth for 14 days in a row.</li> </ul> </li> <li>If you are already treated with Abilify Maintena you will receive 1 injection of ABILIFY ASIMTUFII instead of your next dose of Abilify Maintena and then you will receive ABILIFY ASIMTUFII 1 time every 2 months thereafter.</li> <li>You should not miss a dose of ABILIFY ASIMTUFII. If you miss a dose for some reason, call your healthcare provider right away to discuss what you should do next.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold"><a name="Avoid"></a>What should I avoid while receiving ABILIFY ASIMTUFII?</span> <ul class="Disc"> <li> <span class="Bold">Do not</span> drive a car, operate machinery, or do other dangerous activities until you know how ABILIFY ASIMTUFII affects you. ABILIFY ASIMTUFII may affect your judgement, thinking or motor skills.</li> <li> <span class="Bold">Do not</span> drink alcohol during treatment with ABILIFY ASIMTUFII.</li> <li> <span class="Bold">Do not</span> become too hot or dehydrated during treatment with ABILIFY ASIMTUFII. <ul class="Circle"> <li> <span class="Bold">Do not</span> exercise too much.</li> <li>In hot weather, stay inside in a cool place if possible.</li> <li>Stay out of the sun.</li> <li> <span class="Bold">Do not</span> wear too much clothing or heavy clothing.</li> <li>Drink plenty of water.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the possible side effects of ABILIFY ASIMTUFII?<br/>ABILIFY ASIMTUFII may cause serious side effects, including: </span> <ul class="Disc"> <li> <span class="Bold">See "<a href="#Important">What is the most important information I should know about ABILIFY ASIMTUFII?</a>"</span> </li> <li> <span class="Bold">Stroke, (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. </span> </li> <li> <span class="Bold">Neuroleptic malignant syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider or go to the nearest emergency room right away if you have some or all of the following signs and symptoms of NMS: </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul class="Circle"> <li>high fever</li> <li>confusion</li> <li>changes in pulse, heart rate, and blood pressure</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Circle"> <li>stiff muscles</li> <li>increased sweating</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Uncontrolled body movements (tardive dyskinesia).</span> ABILIFY ASIMTUFII 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 ABILIFY ASIMTUFII. Tardive dyskinesia may also start after you stop receiving ABILIFY ASIMTUFII.</li> <li> <span class="Bold">Problems with your metabolism such as:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="4"> <ul class="Circle"> <li> <span class="Bold">high blood sugar (hyperglycemia) and diabetes:</span> Increases in blood sugar can happen in some people who are treated with ABILIFY ASIMTUFII. 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 treatment with ABILIFY ASIMTUFII, and during treatment with ABILIFY ASIMTUFII.<br/> <span class="Bold">Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with ABILIFY ASIMTUFII:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule" colspan="2"></td><td align="left"> <ul class="Square"> <li>feel very thirsty</li> <li>feel very hungry</li> <li>feel sick to your stomach</li> </ul> </td><td align="left"> <ul class="Square"> <li>need to urinate more than usual</li> <li>feel weak or tired</li> <li>feel confused, or your breath smells fruity</li> </ul> </td><td align="left" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="4"> <ul class="Circle"> <li> <span class="Bold">Increased fat levels (cholesterol and triglycerides) in your blood.</span> </li> <li> <span class="Bold">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with ABILIFY ASIMTUFII.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Unusual and uncontrollable (compulsive) urges.</span> Some people receiving ABILIFY ASIMTUFII have had unusual strong urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges including sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</li> <li> <span class="Bold">Decreased blood pressure (orthostatic hypotension).</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li> <li> <span class="Bold">Falls.</span> ABILIFY ASIMTUFII may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li> <li> <span class="Bold">Low white blood cell count</span>. Your healthcare provider may do blood tests during your first few months of treatment with ABILIFY ASIMTUFII. </li> <li> <span class="Bold">Seizures (convulsions)</span> </li> <li> <span class="Bold">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities. See "<a href="#Avoid">What should I avoid while receiving ABILIFY ASIMTUFII?</a>"</span> </li> <li> <span class="Bold">Problems controlling your body temperature so that you feel too warm.</span> See <span class="Bold">"<a href="#Avoid">What should I avoid while receiving ABILIFY ASIMTUFII?</a>"</span> </li> <li> <span class="Bold">Difficulty swallowing</span> that can cause food or liquid to get into your lungs<span class="Bold">.</span> </li> </ul> <span class="Bold">The most common side effects of ABILIFY ASIMTUFII include:</span> weight gain, restlessness or feeling like you need to move (akathisia), injection site pain, or sleepiness (sedation).<br/>These are not all the possible side effects of ABILIFY ASIMTUFII.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">General information about the safe and effective use of ABILIFY ASIMTUFII.</span> <br/>If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ABILIFY ASIMTUFII that is written for healthcare professionals.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the ingredients in ABILIFY ASIMTUFII?</span> <br/> <span class="Bold">Active ingredient:</span> aripiprazole monohydrate<br/> <span class="Bold">Inactive ingredients:</span> carboxymethylcellulose sodium, polyethylene glycol 400, povidone, sodium chloride, sodium phosphate monobasic monohydrate, sodium hydroxide and water for injection.<br/>ABILIFY ASIMTUFII is a trademark of Otsuka Pharmaceutical Co., Ltd.<br/>© 2025, Otsuka Pharmaceutical Co., Ltd., 2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo, 101-8535 Japan<br/>For more information about ABILIFY ASIMTUFII, go to www.ABILIFYASIMTUFII.com or call 1-800-441-6763.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"47%\"/>\n<col align=\"left\" valign=\"top\" width=\"27%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"4\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" colspan=\"1\">Revised: 03/2025            </td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">MEDICATION GUIDE<br/>ABILIFY ASIMTUFII<span class=\"Sup\">®</span> (a-BIL-i-fy AH-SIM-TUH-FYE)<br/>(aripiprazole) for extended-release injectable suspension, for intramuscular use</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\"><a name=\"Important\"></a>What is the most important information I should know about ABILIFY ASIMTUFII?<br/>ABILIFY ASIMTUFII may cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased risk of death in elderly people with dementia-related psychosis.</span> ABILIFY ASIMTUFII increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). ABILIFY ASIMTUFII is not for the treatment of people with dementia-related psychosis.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What is ABILIFY ASIMTUFII?</span>\n<br/>ABILIFY ASIMTUFII is a prescription medicine given by injection by a healthcare provider:<ul class=\"Disc\">\n<li>for the treatment of schizophrenia in adults</li>\n<li>alone as maintenance treatment of bipolar I disorder in adults</li>\n</ul>It is not known if ABILIFY ASIMTUFII is safe and effective in children under 18 years of age.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Who should not receive ABILIFY ASIMTUFII?</span>\n<br/>\n<span class=\"Bold\">Do not receive ABILIFY ASIMTUFII if you</span> are allergic to aripiprazole or any of the ingredients in ABILIFY ASIMTUFII. See the end of this Medication Guide for a complete list of ingredients in ABILIFY ASIMTUFII.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Before receiving ABILIFY ASIMTUFII, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have never taken aripiprazole before</li>\n<li>have or had diabetes or high blood sugar or a family history of diabetes or high blood sugar</li>\n<li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li>\n<li>have or had low or high blood pressure</li>\n<li>have or had heart problems or a stroke</li>\n<li>have or had a low white blood cell count</li>\n<li>have or had seizures (convulsions)</li>\n<li>have problems that may affect you receiving an injection in your buttocks</li>\n<li>are pregnant or plan to become pregnant. ABILIFY ASIMTUFII may harm your unborn baby. Receiving ABILIFY ASIMTUFII during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you receive ABILIFY ASIMTUFII during pregnancy.<ul class=\"Circle\">\n<li>Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ABILIFY ASIMTUFII.</li>\n<li>If you become pregnant during treatment with ABILIFY ASIMTUFII, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. ABILIFY ASIMTUFII can pass into your breast milk and it is not known if it may harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with ABILIFY ASIMTUFII.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements.<br/>ABILIFY ASIMTUFII and other medicines may affect each other causing possible serious side effects. ABILIFY ASIMTUFII may affect the way other medicines work, and other medicines may affect how ABILIFY ASIMTUFII works.<br/>Your healthcare provider can tell you if it is safe to receive ABILIFY ASIMTUFII with your other medicines. Do not start or stop any medicines during treatment with ABILIFY ASIMTUFII without first talking to your healthcare provider.<br/>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I receive ABILIFY ASIMTUFII?</span>\n<ul class=\"Disc\">\n<li>Follow your ABILIFY ASIMTUFII treatment schedule exactly as your healthcare provider tells you to.</li>\n<li>Your healthcare provider will tell you how much ABILIFY ASIMTUFII you will receive and when you will receive it.</li>\n<li>ABILIFY ASIMTUFII is an injection given only in your buttock by your healthcare provider 1 time every 2 months. </li>\n<li>There are 2 ways to start (initiate) treatment with ABILIFY ASIMTUFII if you currently take an antipsychotic medicine by mouth (oral): \t\t\t\t\t\t\t\t\t\t\t<ul class=\"Circle\">\n<li>1-day initiation: You will receive 1 injection of ABILIFY ASIMTUFII in your buttock and 1 injection of Abilify Maintena in your arm or other buttock on your first day of treatment. You will also take 1 dose of aripiprazole by mouth.<br/>\n<span class=\"Bold\">OR</span>\n</li>\n<li>14-day initiation: You will receive 1 injection of ABILIFY ASIMTUFII in your buttock. You will also continue to take your oral aripiprazole or your current antipsychotic medicine by mouth for 14 days in a row.</li>\n</ul>\n</li>\n<li>If you are already treated with Abilify Maintena you will receive 1 injection of ABILIFY ASIMTUFII instead of your next dose of Abilify Maintena and then you will receive ABILIFY ASIMTUFII 1 time every 2 months thereafter.</li>\n<li>You should not miss a dose of ABILIFY ASIMTUFII. If you miss a dose for some reason, call your healthcare provider right away to discuss what you should do next.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\"><a name=\"Avoid\"></a>What should I avoid while receiving ABILIFY ASIMTUFII?</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not</span> drive a car, operate machinery, or do other dangerous activities until you know how ABILIFY ASIMTUFII affects you. ABILIFY ASIMTUFII may affect your judgement, thinking or motor skills.</li>\n<li>\n<span class=\"Bold\">Do not</span> drink alcohol during treatment with ABILIFY ASIMTUFII.</li>\n<li>\n<span class=\"Bold\">Do not</span> become too hot or dehydrated during treatment with ABILIFY ASIMTUFII. <ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Do not</span> exercise too much.</li>\n<li>In hot weather, stay inside in a cool place if possible.</li>\n<li>Stay out of the sun.</li>\n<li>\n<span class=\"Bold\">Do not</span> wear too much clothing or heavy clothing.</li>\n<li>Drink plenty of water.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the possible side effects of ABILIFY ASIMTUFII?<br/>ABILIFY ASIMTUFII may cause serious side effects, including: </span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">See \"<a href=\"#Important\">What is the most important information I should know about ABILIFY ASIMTUFII?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Stroke, (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death. </span>\n</li>\n<li>\n<span class=\"Bold\">Neuroleptic malignant syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider or go to the nearest emergency room right away if you have some or all of the following signs and symptoms of NMS: </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>high fever</li>\n<li>confusion</li>\n<li>changes in pulse, heart rate, and blood pressure</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>stiff muscles</li>\n<li>increased sweating</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Uncontrolled body movements (tardive dyskinesia).</span> ABILIFY ASIMTUFII 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 ABILIFY ASIMTUFII. Tardive dyskinesia may also start after you stop receiving ABILIFY ASIMTUFII.</li>\n<li>\n<span class=\"Bold\">Problems with your metabolism such as:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">high blood sugar (hyperglycemia) and diabetes:</span> Increases in blood sugar can happen in some people who are treated with ABILIFY ASIMTUFII. 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 treatment with ABILIFY ASIMTUFII, and during treatment with ABILIFY ASIMTUFII.<br/>\n<span class=\"Bold\">Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with ABILIFY ASIMTUFII:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"2\"></td><td align=\"left\">\n<ul class=\"Square\">\n<li>feel very thirsty</li>\n<li>feel very hungry</li>\n<li>feel sick to your stomach</li>\n</ul>\n</td><td align=\"left\">\n<ul class=\"Square\">\n<li>need to urinate more than usual</li>\n<li>feel weak or tired</li>\n<li>feel confused, or your breath smells fruity</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Increased fat levels (cholesterol and triglycerides) in your blood.</span>\n</li>\n<li>\n<span class=\"Bold\">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with ABILIFY ASIMTUFII.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Unusual and uncontrollable (compulsive) urges.</span> Some people receiving ABILIFY ASIMTUFII have had unusual strong urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges including sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</li>\n<li>\n<span class=\"Bold\">Decreased blood pressure (orthostatic hypotension).</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li>\n<li>\n<span class=\"Bold\">Falls.</span> ABILIFY ASIMTUFII may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li>\n<li>\n<span class=\"Bold\">Low white blood cell count</span>. Your healthcare provider may do blood tests during your first few months of treatment with ABILIFY ASIMTUFII. </li>\n<li>\n<span class=\"Bold\">Seizures (convulsions)</span>\n</li>\n<li>\n<span class=\"Bold\">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities. See \"<a href=\"#Avoid\">What should I avoid while receiving ABILIFY ASIMTUFII?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Problems controlling your body temperature so that you feel too warm.</span> See <span class=\"Bold\">\"<a href=\"#Avoid\">What should I avoid while receiving ABILIFY ASIMTUFII?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Difficulty swallowing</span> that can cause food or liquid to get into your lungs<span class=\"Bold\">.</span>\n</li>\n</ul>\n<span class=\"Bold\">The most common side effects of ABILIFY ASIMTUFII include:</span> weight gain, restlessness or feeling like you need to move (akathisia), injection site pain, or sleepiness (sedation).<br/>These are not all the possible side effects of ABILIFY ASIMTUFII.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">General information about the safe and effective use of ABILIFY ASIMTUFII.</span>\n<br/>If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ABILIFY ASIMTUFII that is written for healthcare professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the ingredients in ABILIFY ASIMTUFII?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> aripiprazole monohydrate<br/>\n<span class=\"Bold\">Inactive ingredients:</span> carboxymethylcellulose sodium, polyethylene glycol 400, povidone, sodium chloride, sodium phosphate monobasic monohydrate, sodium hydroxide and water for injection.<br/>ABILIFY ASIMTUFII is a trademark of Otsuka Pharmaceutical Co., Ltd.<br/>© 2025, Otsuka Pharmaceutical Co., Ltd., 2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo, 101-8535 Japan<br/>For more information about ABILIFY ASIMTUFII, go to www.ABILIFYASIMTUFII.com or call 1-800-441-6763.</td>\n</tr>\n</tbody>\n</table></div>" }

ABILIFY ASIMTUFII (a-BIL-i-fy AH-SIM-TUH-FYE)

{ "type": "p", "children": [], "text": "\nABILIFY ASIMTUFII (a-BIL-i-fy AH-SIM-TUH-FYE)\n" }

(aripiprazole)

{ "type": "p", "children": [], "text": "\n(aripiprazole)\n" }

extended-release injectable suspension

{ "type": "p", "children": [], "text": "\nextended-release injectable suspension\n" }

The following information is intended for medical or healthcare professionals only and should be read by the medical or healthcare professional in conjunction with the full prescribing information.

{ "type": "p", "children": [], "text": "The following information is intended for medical or healthcare professionals only and should be read by the medical or healthcare professional in conjunction with the full prescribing information." }

{ "type": "ul", "children": [ "Read the complete instructions for preparation and administration below before administering ABILIFY ASIMTUFII.", "To be prepared and administered only by a healthcare professional once every two months.\n", "ABILIFY ASIMTUFII pre-filled syringe is single-dose only. Re-use may lead to infection or other illness/injury.", "For gluteal intramuscular injection only. Do not administer by any other route.", "Prior to administration, visually inspect ABILIFY ASIMTUFII pre-filled syringe for particulate matter and discoloration. The suspension should appear to be a uniform, homogeneous suspension that is opaque and milky-white in color. Do not use ABILIFY ASIMTUFII pre-filled syringe if the suspension is discolored, or particulate matter is present." ], "text": "" }

Contents of Kit

{ "type": "p", "children": [], "text": "\nContents of Kit\n" }

Each kit contains one sterile pre-filled syringe containing ABILIFY ASIMTUFII (aripiprazole) 720 mg or 960 mg extended-release injectable suspension and two safety needles:

{ "type": "p", "children": [], "text": "Each kit contains one sterile pre-filled syringe containing ABILIFY ASIMTUFII (aripiprazole) 720 mg or 960 mg extended-release injectable suspension and two safety needles:" }

{ "type": "ul", "children": [ "One sterile 1 ½ inch 22 gauge needle (in black packaging)", "One sterile 2 inch 21 gauge needle (in green packaging)" ], "text": "" }

Preparation Prior to Administration

{ "type": "p", "children": [], "text": "\nPreparation Prior to Administration\n" }

{ "type": "ul", "children": [ "Remove the ABILIFY ASIMTUFII pre-filled syringe from the package.", "Tap the syringe on your hand at least 10 (ten) times (Figure 1).", "After tapping, shake the syringe vigorously for at least 10 (ten) seconds until the medication is uniform (Figure 2).\n\n\n\n\n\n\nFigure 1\n\n\nFigure 2\n\n\n\n\n" ], "text": "" }

Select the appropriate needle

{ "type": "p", "children": [], "text": "\nSelect the appropriate needle\n" }

Needle selection is determined by patient body type.

{ "type": "p", "children": [], "text": "Needle selection is determined by patient body type." }

For gluteal intramuscular administration only.

{ "type": "p", "children": [], "text": "\nFor gluteal intramuscular administration only.\n" }

{ "type": "ul", "children": [ "For non-obese patients - 22-gauge, 1.5-inch (38 mm) safety needle with needle protection device (needle in black packaging)", "For obese patients - 21-gauge, 2-inch (51 mm) safety needle with needle protection device (needle in green packaging)" ], "text": "" }

Refer to Table 1 below for needle information:

{ "type": "p", "children": [], "text": "Refer to Table 1 below for needle information:" }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Needle Size Required by Body Type</span> </caption> <col align="right" valign="middle" width="17%"/> <col align="left" valign="bottom" width="17%"/> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="33%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="2">Body Type</th><th align="center" class="Rrule">Needle Size</th><th align="center" class="Rrule">Needle Packaging Color</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="right" class="Lrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=abilify-25.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be"/></p> </td><td align="left" class="Rrule"><span class="Bold">Non-obese</span></td><td align="center" class="Rrule">1 ½ inch, 22 gauge</td><td align="center" class="Rrule">black</td> </tr> <tr class="Last"> <td align="right" class="Lrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=abilify-26.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be"/></p> </td><td align="left" class="Rrule"><span class="Bold">Obese</span></td><td align="center" class="Rrule">2 inch, 21 gauge</td><td align="center" class="Rrule">green</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 1: Needle Size Required by Body Type</span>\n</caption>\n<col align=\"right\" valign=\"middle\" width=\"17%\"/>\n<col align=\"left\" valign=\"bottom\" width=\"17%\"/>\n<col align=\"center\" valign=\"middle\" width=\"33%\"/>\n<col align=\"center\" valign=\"middle\" width=\"33%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"2\">Body Type</th><th align=\"center\" class=\"Rrule\">Needle Size</th><th align=\"center\" class=\"Rrule\">Needle Packaging Color</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"right\" class=\"Lrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=abilify-25.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be\"/></p>\n</td><td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Non-obese</span></td><td align=\"center\" class=\"Rrule\">1 ½ inch, 22 gauge</td><td align=\"center\" class=\"Rrule\">black</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Lrule\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=abilify-26.jpg&amp;setid=da4c07fd-1130-4341-bb44-63acfa4162be\"/></p>\n</td><td align=\"left\" class=\"Rrule\"><span class=\"Bold\">Obese</span></td><td align=\"center\" class=\"Rrule\">2 inch, 21 gauge</td><td align=\"center\" class=\"Rrule\">green</td>\n</tr>\n</tbody>\n</table></div>" }

Attach the needle

{ "type": "p", "children": [], "text": "\nAttach the needle\n" }

{ "type": "ul", "children": [ "Twist and pull off the pre-filled syringe tip-cap (Figure 3).", "While holding the base of the needle, ensure the needle is firmly seated on the safety device with a push. Gently twist clockwise until SECURELY fitted (Figure 3)." ], "text": "" }

{ "type": "", "children": [], "text": "" }

Expel Air

{ "type": "p", "children": [], "text": "\nExpel Air\n" }

{ "type": "ul", "children": [ "When you are ready to administer the injection of ABILIFY ASIMTUFII, hold the pre-filled syringe upright and remove the needle-cap straight up (Figure 4). Do not twist the needle-cap, as this may loosen the needle from the syringe." ], "text": "" }

{ "type": "", "children": [], "text": "" }

{ "type": "ul", "children": [ "Slowly advance the plunger rod upward to expel the air and until the suspension fills needle base (Figure 5)." ], "text": "" }

{ "type": "", "children": [], "text": "" }

Inject the dose

{ "type": "p", "children": [], "text": "\nInject the dose\n" }

{ "type": "ul", "children": [ "Slowly inject the entire contents of the pre-filled syringe intramuscularly into the gluteal muscle of the patient (Figure 6)." ], "text": "" }

Do not administer by any other route.

{ "type": "p", "children": [], "text": "\nDo not administer by any other route.\n" }

Do not massage the injection site.

{ "type": "p", "children": [], "text": "Do not massage the injection site." }

{ "type": "", "children": [], "text": "" }

Disposal Procedure

{ "type": "p", "children": [], "text": "\nDisposal Procedure\n" }

{ "type": "ul", "children": [ "After the injection, press the safety shield on a hard surface to cover and lock shield over the needle (Figure 7 and 8)\n\n\n\n\n\n\n\n\nFigure 7Figure 8\n\n\n\n", "Immediately discard used syringe and the unused needle in an approved sharps container (Figure 9).", "The unused needle should not be saved for future use." ], "text": "" }

{ "type": "", "children": [], "text": "" }

NDC 59148-102-80Rx only

{ "type": "p", "children": [], "text": "NDC 59148-102-80Rx only" }

720 mg/2.4 mL(300 mg/mL)

{ "type": "p", "children": [], "text": "720 mg/2.4 mL(300 mg/mL)" }

Abilify Asimtufii® (aripiprazole) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Asimtufii®\n(aripiprazole) extended-release injectable suspension" }

FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY

{ "type": "p", "children": [], "text": "FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY" }

Contents: 1 single-dose prefilled syringe and 2 safety needles(a 1 ½ inch, 22 G needle and a 2 inch, 21 G needle)

{ "type": "p", "children": [], "text": "Contents: 1 single-dose prefilled syringe and 2 safety needles(a 1 ½ inch, 22 G needle and a 2 inch, 21 G needle)" }

NDC 59148-114-80Rx only

{ "type": "p", "children": [], "text": "NDC 59148-114-80Rx only" }

960 mg/3.2 mL(300 mg/mL)

{ "type": "p", "children": [], "text": "960 mg/3.2 mL(300 mg/mL)" }

Abilify Asimtufii® (aripiprazole) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Abilify Asimtufii®\n(aripiprazole) extended-release injectable suspension" }

FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY

{ "type": "p", "children": [], "text": "FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY" }

Contents: 1 single-dose prefilled syringe and 2 safety needles(a 1 ½ inch, 22 G needle and a 2 inch, 21 G needle)

{ "type": "p", "children": [], "text": "Contents: 1 single-dose prefilled syringe and 2 safety needles(a 1 ½ inch, 22 G needle and a 2 inch, 21 G needle)" }

Aripiprazole oral tablets are indicated for the treatment of:

{ "type": "p", "children": [], "text": "Aripiprazole oral tablets are indicated for the treatment of:" }

{ "type": "ul", "children": [ "Schizophrenia \n \n [see\n \n Clinical Studies (14.1)]\n \n \n", "Treatment of Tourette’s Disorder " ], "text": "" }

Adults  The recommended starting and target dose for aripiprazole tablets is 10 or 15 mg/day administered on a once-a-day schedule without regard 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. 

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.

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

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="603.82"> <col width="54.65859030837%"/> <col width="45.34140969163%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Factors</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">Dosage Adjustments for Aripiprazole Tablets</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Known CYP2D6 Poor Metabolizers <br/> </td><td class="Rrule" valign="top">Administer half of usual dose <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) <br/> </td><td class="Rrule" valign="middle">Administer a quarter of usual dose <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine)  <span class="Bold">or</span><span class="Bold"> </span>CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) <br/> </td><td class="Rrule" valign="middle">Administer half of usual dose <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Strong CYP2D6  <span class="Bold">and </span>CYP3A4 inhibitors <br/> </td><td class="Rrule" valign="middle">Administer a quarter of usual dose <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) <br/> </td><td class="Rrule" valign="middle">Double usual dose over 1 to 2 weeks <br/>   <br/> </td> </tr> </tbody> </table></div>

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)].

 Aripiprazole tablets, USP are available as described in 3. 

{ "type": "p", "children": [], "text": " Aripiprazole tablets, USP are available as described in 3. " }

                            Table 3: Aripiprazole Tablet Presentations

{ "type": "p", "children": [], "text": "                           \n \n Table 3: Aripiprazole Tablet Presentations\n" }

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="574.56"> <col width="26.0416666666667%"/> <col width="43.75%"/> <col width="30.2083333333333%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Tablet Strength</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Tablet Color/Shape</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Tablet Markings</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">2 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle">Light <span class="Bold"> </span>green to green <br/> modified rectangle <br/> </td><td align="center" class="Rrule" valign="middle">“I” and “94” <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">5 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle">Light <span class="Bold"> </span>blue to blue <br/> modified rectangle <br/> </td><td align="center" class="Rrule" valign="middle">“I” and “95” <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">10 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle">Light <span class="Bold"> </span>pink to pink <br/> modified rectangle <br/> </td><td align="center" class="Rrule" valign="middle">“I” and “96” <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">15 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle">Light <span class="Bold"> </span>yellow to yellow <br/> round <br/> </td><td align="center" class="Rrule" valign="middle">“I” and “97” <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">20 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle">White to off white <br/> round <br/> </td><td align="center" class="Rrule" valign="middle">“I” and “98” <br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">30 mg</span> <br/> </td><td align="center" class="Rrule" valign="middle">Light <span class="Bold"> </span>pink to pink <br/> round <br/> </td><td align="center" class="Rrule" valign="middle">“I ” and “99” <br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"574.56\">\n<col width=\"26.0416666666667%\"/>\n<col width=\"43.75%\"/>\n<col width=\"30.2083333333333%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">Tablet Strength</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\"><span class=\"Bold\">Tablet Color/Shape</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\"><span class=\"Bold\">Tablet Markings</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">2 mg</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">Light\n \n <span class=\"Bold\"> </span>green to green \n <br/> modified rectangle \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">“I” and “94” \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">5 mg</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">Light\n \n <span class=\"Bold\"> </span>blue to blue \n <br/> modified rectangle \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">“I” and “95” \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">10 mg</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">Light\n \n <span class=\"Bold\"> </span>pink to pink \n <br/> modified rectangle \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">“I” and “96” \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">15 mg</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">Light\n \n <span class=\"Bold\"> </span>yellow to yellow \n <br/> round \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">“I” and “97” \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">20 mg</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">White to off white \n <br/> round \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">“I” and “98” \n <br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\">30 mg</span>\n<br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">Light\n \n <span class=\"Bold\"> </span>pink to pink \n <br/> round \n <br/>\n</td><td align=\"center\" class=\"Rrule\" valign=\"middle\">“I ” and “99” \n <br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Aripiprazole tablets are contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions ( 6.2)] . 

{ "type": "p", "children": [], "text": "Aripiprazole tablets are contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis\n \n [see Adverse Reactions (\n \n 6.2)]\n \n . \n\n " }

Increased Mortality  Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis  [see Boxed Warning].  Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s Disease

In three, 10 week, placebo-controlled studies of aripiprazole tablets in elderly patients with psychosis associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56 to 99 years), the adverse reactions that were reported at an incidence of ≥3% and aripiprazole tablets incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole tablets 5%], somnolence (including sedation) [placebo 3%, aripiprazole tablets 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole tablets 5%], excessive salivation [placebo 0%, aripiprazole tablets 4%], and lightheadedness [placebo 1%, aripiprazole tablets 4%].  The safety and efficacy of aripiprazole in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with aripiprazole, assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration  [see  Boxed Warning].

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis  [see  Boxed Warning].  

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24 years) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years 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 1,000 patients treated) are provided in Table 5. Table 5: 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="0"> <col width="38.6259541984733%"/> <col width="61.3740458015267%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> <span class="Bold">Age Range</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Increases Compared to Placebo</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> &lt;18 </td><td align="justify" class="Rrule" valign="middle"> <br/> 14 additional cases </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> 18 to 24 </td><td align="justify" class="Rrule" valign="middle"> <br/> 5 additional cases </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Decreases Compared to Placebo</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> 25 to 64 </td><td align="justify" class="Rrule" valign="middle"> <br/> 1 fewer case </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> ≥65 </td><td align="justify" class="Rrule" valign="middle"> <br/> 6 fewer cases </td> </tr> </tbody> </table></div>

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.  It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.  All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. 

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for aripiprazole should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

It should be noted that aripiprazole is not approved for use in treating depression in the pediatric population.

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS occurred during aripiprazole 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.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.  The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.  Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.  Given these considerations, aripiprazole 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 aripiprazole, drug discontinuation should be considered. However, some patients may require treatment with aripiprazole despite the presence of the syndrome. 

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia/Diabetes Mellitus   Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole  [see Adverse Reactions ( 6.1,  6.2)].  Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Because aripiprazole was not marketed at the time these studies were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.  Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.  Adults  In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or another indication, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1,057) 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 aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).  Table 6:  Changes in Fasting Glucose from Placebo-Controlled Monotherapy Trials in Adult Patients

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="615.79"> <col width="14.2548596112311%"/> <col width="42.7645788336933%"/> <col width="20.5183585313175%"/> <col width="14.2548596112311%"/> <col width="8.207343412527%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Category Change (at least once)</span> <br/> <span class="Bold">from Baseline</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Treatment Arm</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">n/</span><span class="Bold">N</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">%</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="4" valign="middle"> <br/> <span class="Bold">Fasting Glucose</span></td><td align="justify" class="Rrule" rowspan="2" valign="middle"> <br/> Normal to High <br/> (&lt;100 mg/dL to ≥126 mg/dL) </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 31/822 </td><td align="justify" class="Rrule" valign="middle"> <br/> 3.8 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 22/605 </td><td align="justify" class="Rrule" valign="middle"> <br/> 3.6 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="middle"> <br/> Borderline to High <br/> (≥100 mg/dL and &lt;126 mg/dL to <br/> ≥126 mg/dL) </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 31/176 </td><td align="justify" class="Rrule" valign="middle"> <br/> 17.6 </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 13/142 </td><td align="justify" class="Rrule" valign="middle"> <br/> 9.2 </td> </tr> </tbody> </table></div>

At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].  Pediatric Patients and Adolescents In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another indication (10 to 17 years), the mean change in fasting glucose in aripiprazole-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123). In an analysis of two placebo-controlled trials in pediatric and adolescent patients with Tourette’s disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in aripiprazole 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 another indication (median exposure of 42 to 43 days).  Table 8: Changes in Fasting Glucose from Placebo-Controlled Trials in Pediatric and Adolescent Patients

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="458.185"> <col width="27.9825834542816%"/> <col width="30.8708272859216%"/> <col width="20.5660377358491%"/> <col width="10.2902757619739%"/> <col width="10.2902757619739%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> <span class="Bold">Category Change</span> <br/> <span class="Bold">(at least once)</span> <br/> <span class="Bold">from Baseline</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">I</span><span class="Bold">ndication</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">T</span><span class="Bold">reatment</span><span class="Bold"> A</span><span class="Bold">rm</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">n</span><span class="Bold">/N</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">%</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="middle"> <br/> <span class="Bold">Fasting Glucose</span> <br/> Normal to High <br/> (&lt;100 mg/dL to <br/> ≥126 mg/dL) </td><td align="justify" class="Rrule" rowspan="2" valign="middle"> <br/> Pooled Schizophrenia and another indication </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 2/236 </td><td align="justify" class="Rrule" valign="middle"> <br/> 0.8 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 2/110 </td><td align="justify" class="Rrule" valign="middle"> <br/> 1.8 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/>   </td><td align="justify" class="Rrule" rowspan="2" valign="middle"> <br/> Tourette’s Disorder </td><td align="justify" class="Rrule" valign="top"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="top"> <br/> 3/88 </td><td align="justify" class="Rrule" valign="top"> <br/> 3.4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Placebo </td><td align="justify" class="Rrule" valign="top"> <br/> 1/58 </td><td align="justify" class="Rrule" valign="top"> <br/> 1.7 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="middle"> <br/> <span class="Bold">Fasting Glucose</span> <br/> Borderline to High <br/> (≥100 mg/dL and <br/> &lt;126 mg/dL to ≥126 mg/dL) </td><td align="justify" class="Rrule" rowspan="2" valign="middle"> <br/> Pooled Schizophrenia and another indication </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 1/22 </td><td align="justify" class="Rrule" valign="middle"> <br/> 4.5 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Placebo </td><td align="justify" class="Rrule" valign="top"> <br/> 0/12 </td><td align="justify" class="Rrule" valign="top"> <br/> 0 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Tourette’s Disorder </td><td align="justify" class="Rrule" valign="top"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="top"> <br/> 0/11 </td><td align="justify" class="Rrule" valign="top"> <br/> 0 </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="top"> <br/> Placebo </td><td align="justify" class="Rrule" valign="top"> <br/> 0/4 </td><td align="justify" class="Rrule" valign="top"> <br/> 0 </td> </tr> </tbody> </table></div>

At 12 weeks in the pooled adolescent schizophrenia and another indication trials, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and  +0.1 mg/dL (n=15), respectively].  Dyslipidemia  Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.  There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.  Adults Table 9 shows the proportion of adult patients, primarily from pooled schizophrenia and another indication 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

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="424.2035"> <col width="46.5590217902492%"/> <col width="22.1037780216335%"/> <col width="16.021319956106%"/> <col width="15.3158802320113%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Treatment Arm</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">n/N</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">%</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Total Cholesterol</span> <br/> Normal to High <br/> (&lt;200 mg/dL to ≥240 mg/dL) <span class="Bold"></span></td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 34/1,357 </td><td align="justify" class="Rrule" valign="middle"> <br/> 2.5 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 27/973 </td><td align="justify" class="Rrule" valign="middle"> <br/> 2.8 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Fasting Triglycerides</span> <br/> Normal to High <br/> (&lt;150 mg/dL to ≥200 mg/dL) <span class="Bold"></span></td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 40/539 </td><td align="justify" class="Rrule" valign="middle"> <br/> 7.4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 30/431 </td><td align="justify" class="Rrule" valign="middle"> <br/> 7 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">Fasting LDL Cholesterol</span> <br/> Normal to High <br/> (&lt;100 mg/dL to ≥160 mg/dL) </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 2/332 </td><td align="justify" class="Rrule" valign="middle"> <br/> 0.6 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 2/268 </td><td align="justify" class="Rrule" valign="middle"> <br/> 0.7 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"> <br/> <span class="Bold">HDL Cholesterol</span> <br/> Normal to Low <br/> (≥40 mg/dL to &lt;40 mg/dL) <span class="Bold"></span></td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 121/1,066 </td><td align="justify" class="Rrule" valign="middle"> <br/> 11.4 </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 99/794 </td><td align="justify" class="Rrule" valign="middle"> <br/> 12.5 </td> </tr> </tbody> </table></div>

In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25  (4 %), 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 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

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="539.98"> <col width="44.3349753694581%"/> <col width="27.8325123152709%"/> <col width="11.576354679803%"/> <col width="16.256157635468%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="middle"> <br/> Total Cholesterol <br/> Normal to High <br/> (&lt;170 mg/dL to ≥200 mg/dL) </td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Treatment Arm</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">n/N</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">%</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 1/85 </td><td align="justify" class="Rrule" valign="middle"> <br/> 1.2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 0/46 </td><td align="justify" class="Rrule" valign="middle"> <br/> 0 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="middle"> <br/> Fasting Triglycerides <br/> Normal to High <br/> (&lt;150 mg/dL to ≥200 mg/dL) </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 5/94 </td><td align="justify" class="Rrule" valign="middle"> <br/> 5.3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 2/55 </td><td align="justify" class="Rrule" valign="middle"> <br/> 3.6 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="middle"> <br/> HDL Cholesterol <br/> Normal to Low <br/> (≥40 mg/dL to &lt;40 mg/dL) </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 4/108 </td><td align="justify" class="Rrule" valign="middle"> <br/> 3.7 </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 2/67 </td><td align="justify" class="Rrule" valign="middle"> <br/> 3.0 </td> </tr> </tbody> </table></div>

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 another indication, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to     –0.1 kg (N=1100) in placebo- controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients.  Table 14 shows the percentage of adult patients with weight gain ≥7% of body weight by indication. Table 14: Percentage of Patients from Placebo-Controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   <span class="Bold">Weight gain  ≥ 7% of body weight</span></td><td align="justify" class="Rrule" valign="middle"> <br/>    <span class="Bold">Indication</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Treatment Arm </span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">N </span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Patients <br/> n (%)  </span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> Schizophrenia* </td><td align="justify" class="Rrule" valign="middle"> <br/>  Aripiprazole Tablets  <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> 852  </td><td align="justify" class="Rrule" valign="middle"> <br/> 69 (8.1) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> Placebo  </td><td align="justify" class="Rrule" valign="middle"> <br/>  379 </td><td align="justify" class="Rrule" valign="middle"> <br/> 12 (3.2) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>  Other indication† </td><td align="justify" class="Rrule" valign="middle"> <br/>  Aripiprazole Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/>  719 </td><td align="justify" class="Rrule" valign="middle"> <br/>  16 (2.2) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>  Placebo  </td><td align="justify" class="Rrule" valign="middle"> <br/>  598 </td><td align="justify" class="Rrule" valign="middle"> <br/>  16 (2.7) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/>   * 4 to 6 weeks duration.  † 3 weeks duration.   </td><td align="justify" class="Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/>   </td> </tr> </tbody> </table></div>

Pediatric Patients and Adolescents  In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another indication (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients.  In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette’s Disorder with median exposure of 57 days, the mean change in body weight in aripiprazole-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients. Table 15 shows the percentage of pediatric and adolescent patients with weight gain ≥7% of body weight by indication.  Table 15: Percentage of Patients from Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain ≥7% of Body Weight

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <col width="15.0995098815601%"/> <col width="22.9397777001534%"/> <col width="25.2588905836076%"/> <col width="16.0595692425186%"/> <col width="20.6422525921603%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/>   </td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Indication</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Treatment Arm</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">N</span></td><td align="justify" class="Rrule" valign="middle"> <br/> <span class="Bold">Patients</span> <br/> <span class="Bold">n (%)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="4" valign="middle"> <br/>   <br/> <span class="Bold">Weight gain ≥7% of body weight</span></td><td align="justify" class="Rrule" rowspan="2" valign="middle"> <br/> Pooled Schizophrenia and another indication* </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 381 </td><td align="justify" class="Rrule" valign="middle"> <br/> 20 (5.2) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 187 </td><td align="justify" class="Rrule" valign="middle"> <br/> 3 (1.6) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="middle"> <br/> Tourette’s Disorder‡ </td><td align="justify" class="Rrule" valign="middle"> <br/> Aripiprazole <br/> Tablets </td><td align="justify" class="Rrule" valign="middle"> <br/> 105 </td><td align="justify" class="Rrule" valign="middle"> <br/> 21 (20.0) </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="middle"> <br/> Placebo </td><td align="justify" class="Rrule" valign="middle"> <br/> 66 </td><td align="justify" class="Rrule" valign="middle"> <br/> 5 (7.6) </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="5" valign="middle"> <br/> * 4 to 6 weeks duration  <br/> ‡ 8 to 10 weeks duration.  </td> </tr> </tbody> </table></div>

In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with another indication (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with aripiprazole. After 26 weeks, 32.8% of patients gained ≥7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients and adolescents by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD.  When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

Aripiprazole may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2,467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on oral aripiprazole included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%)  [see Adverse Reactions (6.1)]. The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adult oral aripiprazole-treated patients (4%, 2%), in pediatric oral aripiprazole-treated patients aged 6 to 18 years (0.4%, 1%).  Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications)  [see Drug Interactions (7.1)] .

Antipsychotics, including aripiprazole, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported.  Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of aripiprazole at the first sign of a clinically significant decline in WBC in the absence of other causative factors.  Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue aripiprazole in patients with severe neutropenia (absolute neutrophil count <1,000/mm3) and follow their WBC counts until recovery.

In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated with oral aripiprazole, in 0.1% (1/732) of pediatric patients (6 to 18 years). As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Aripiprazole, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients ((n=2,467) treated with oral aripiprazole (11%, 6%), in pediatric patients ages 6 to 17 years (n=611 ; 24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral aripiprazole in short-term, placebo-controlled trials. Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with aripiprazole does not affect them adversely.  

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration)  [see Adverse Reactions (6.2)].

The possibility of a suicide attempt is inherent in psychotic illnesses and close supervision of high-risk patients should accompany drug therapy. Prescriptions for aripiprazole should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose  [see Adverse Reactions (6.1,  6.2)] .

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions ( 6.2)] .

Adult Patients with Schizophrenia The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day. Commonly Observed Adverse Reactions  The only commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole tablets 8%; placebo 4%). 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 another indication), including only those reactions that occurred in 2% or more of patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset. Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole Tablets

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="738.15"> <col width="33.3333333333333%"/> <col width="33.3333333333333%"/> <col width="33.3333333333333%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/>   </td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Percentage of Patients Reporting Reaction <span class="Sup">*</span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">System Organ Class</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Aripiprazole Tablets</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Preferred Term</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">( n=1843)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">(n=1166)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Eye Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Blurred Vision </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Gastrointestinal Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Nausea </td><td align="justify" class="Rrule" valign="top"> <br/> 15 </td><td align="justify" class="Rrule" valign="top"> <br/> 11 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Constipation </td><td align="justify" class="Rrule" valign="top"> <br/> 11 </td><td align="justify" class="Rrule" valign="top"> <br/> 7 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Vomiting </td><td align="justify" class="Rrule" valign="top"> <br/> 11 </td><td align="justify" class="Rrule" valign="top"> <br/> 6 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Dyspepsia </td><td align="justify" class="Rrule" valign="top"> <br/> 9 </td><td align="justify" class="Rrule" valign="top"> <br/> 7 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Dry Mouth </td><td align="justify" class="Rrule" valign="top"> <br/> 5 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Toothache <br/> Abdominal Discomfort </td><td align="justify" class="Rrule" valign="top"> <br/> 4 <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Stomach Discomfort </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">General Disorders and Administration Site Conditions</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Fatigue </td><td align="justify" class="Rrule" valign="top"> <br/> 6 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Pain </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Musculoskeletal Stiffness </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Pain in Extremity </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Myalgia </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Muscle Spasms </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Nervous System Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Headache </td><td align="justify" class="Rrule" valign="top"> <br/> 27 </td><td align="justify" class="Rrule" valign="top"> <br/> 23 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Dizziness </td><td align="justify" class="Rrule" valign="top"> <br/> 10 </td><td align="justify" class="Rrule" valign="top"> <br/> 7 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Akathisia </td><td align="justify" class="Rrule" valign="top"> <br/> 10 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Sedation </td><td align="justify" class="Rrule" valign="top"> <br/> 7 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Extrapyramidal Disorder </td><td align="justify" class="Rrule" valign="top"> <br/> 5 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Tremor </td><td align="justify" class="Rrule" valign="top"> <br/> 5 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Somnolence </td><td align="justify" class="Rrule" valign="top"> <br/> 5 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Psychiatric Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Agitation </td><td align="justify" class="Rrule" valign="top"> <br/> 19 </td><td align="justify" class="Rrule" valign="top"> <br/> 17 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Insomnia </td><td align="justify" class="Rrule" valign="top"> <br/> 18 </td><td align="justify" class="Rrule" valign="top"> <br/> 13 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Anxiety </td><td align="justify" class="Rrule" valign="top"> <br/> 17 </td><td align="justify" class="Rrule" valign="top"> <br/> 13 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Restlessness </td><td align="justify" class="Rrule" valign="top"> <br/> 5 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Pharyngolaryngeal Pain </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Cough </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Sup">*</span>Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. </td> </tr> </tbody> </table></div>

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Tourette’s Disorder The following findings are based on one 8 week and one 10 week, placebo-controlled trials in which oral aripiprazole 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 aripiprazole--treated and placebotreated pediatric patients (6 to 18 years) was 7% and 1%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with Tourette’s disorder (incidence of 5% or greater and aripiprazole 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 Aripiprazole

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <col width="40.5%"/> <col width="29.76%"/> <col width="29.76%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top">  <br/>   <br/> <span class="Bold">Preferred Term</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">Percentage of Patients Reporting Reaction <span class="Sup">*</span></span><span class="Bold"><span class="Sup"></span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">Aripiprazole Tablets</span> <br/> <span class="Bold">(n=121)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">(n=72)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Sedation <br/> </td><td align="center" class="Rrule" valign="top">13 <br/> </td><td align="center" class="Rrule" valign="top">6 <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Somnolence <br/> </td><td align="center" class="Rrule" valign="top">13 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Nausea <br/> </td><td align="center" class="Rrule" valign="middle">11 <br/> </td><td align="center" class="Rrule" valign="middle">4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Headache <br/> </td><td align="center" class="Rrule" valign="middle">10 <br/> </td><td align="center" class="Rrule" valign="middle">3 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Nasopharyngitis <br/> </td><td align="center" class="Rrule" valign="middle">9 <br/> </td><td align="center" class="Rrule" valign="middle">0 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Fatigue <br/> </td><td align="center" class="Rrule" valign="top">8 <br/> </td><td align="center" class="Rrule" valign="top">0 <br/> </td> </tr> <tr class="Botrule Last"> <td class="Lrule Rrule" valign="top">Increased Appetite <br/> </td><td align="center" class="Rrule" valign="top">7 <br/> </td><td align="center" class="Rrule" valign="top">1 <br/> </td> </tr> </tbody> </table></div>

Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, or Other Indications 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 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 (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole 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 Aripiprazole Tablets

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="728.84"> <col width="40.5109489051095%"/> <col width="29.7445255474453%"/> <col width="29.7445255474453%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" valign="top"> <br/>   </td><td align="justify" class="Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Percentage of Patients Reporting Reaction <span class="Sup">*</span></span><span class="Bold"><span class="Sup"></span></span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">System Organ Class</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Aripiprazole Tablets</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">Placebo</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> <span class="Bold">Preferred Term</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">(n=732)</span></td><td align="justify" class="Rrule" valign="top"> <br/> <span class="Bold">(n=370)</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Eye Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Blurred Vision </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 0 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Gastrointestinal Disorders</span> <br/> Abdominal Discomfort21 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Vomiting </td><td align="justify" class="Rrule" valign="top"> <br/> 8 </td><td align="justify" class="Rrule" valign="top"> <br/> 7 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Nausea </td><td align="justify" class="Rrule" valign="top"> <br/> 8 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Diarrhea </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Salivary Hypersecretion </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Abdominal Pain Upper </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Constipation </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">General Disorders and Administration Site Conditions</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Fatigue </td><td align="justify" class="Rrule" valign="top"> <br/> 10 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Pyrexia </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Irritability </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Asthenia </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Infections and Infestations</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Nasopharyngitis </td><td align="justify" class="Rrule" valign="top"> <br/> 6 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Investigations</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Weight Increased </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Metabolism and Nutrition Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Increased Appetite </td><td align="justify" class="Rrule" valign="top"> <br/> 7 </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Decreased Appetite </td><td align="justify" class="Rrule" valign="top"> <br/> 5 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Musculoskeletal Stiffness </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Muscle Rigidity </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Nervous System Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Somnolence </td><td align="justify" class="Rrule" valign="top"> <br/> 16 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Headache </td><td align="justify" class="Rrule" valign="top"> <br/> 12 </td><td align="justify" class="Rrule" valign="top"> <br/> 10 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Sedation </td><td align="justify" class="Rrule" valign="top"> <br/> 9 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Tremor </td><td align="justify" class="Rrule" valign="top"> <br/> 9 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Extrapyramidal Disorder </td><td align="justify" class="Rrule" valign="top"> <br/> 6 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Akathisia </td><td align="justify" class="Rrule" valign="top"> <br/> 6 </td><td align="justify" class="Rrule" valign="top"> <br/> 4 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Drooling </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 0 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Lethargy </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 0 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Dizziness </td><td align="justify" class="Rrule" valign="top"> <br/> 3 </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Dystonia </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Epistaxis </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Bold">Skin and Subcutaneous Tissue Disorders</span></td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <br/> Rash </td><td align="justify" class="Rrule" valign="top"> <br/> 2 </td><td align="justify" class="Rrule" valign="top"> <br/> 1 </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" colspan="3" valign="top"> <br/> <span class="Sup">*</span>Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. </td> </tr> </tbody> </table></div>

Dose-Related Adverse Reactions

Schizophrenia  Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).  In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5%; 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%).

Tourette’s Disorder In a study of pediatric patients (7 to 17 years of age) with Tourette’s disorder, no common adverse reaction(s) had a dose response relationship.

Extrapyramidal Symptoms  Schizophrenia  In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% vs. 6% for placebo. Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole 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. Tourette’s Disorder  In the short-term, placebo-controlled trials in Tourette’s disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 4% vs. 6% for placebo.  In the pediatric (6 to 18 years) short-term Tourette’s disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for aripiprazole and placebo. Dystonia  Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Additional Findings Observed in Clinical Trials  Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials  The adverse reactions reported in a 26-week, double-blind trial comparing oral aripiprazole 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. In addition, in a long-term (52 week), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole. Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole  The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequentadverse reactions are those occurring in at least 1/100 patients; infrequentadverse reactions are those occurring in 1/100 to 1/1000 patients; rarereactions are those occurring in fewer than 1/1000 patients: Adults - Oral Administration 

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.

Table 25: Clinically Important Drug Interactions with Aripiprazole:

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="0"> <col width="22.7016885553471%"/> <col width="45.0281425891182%"/> <col width="32.2701688555347%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">Concomitant</span><span class="Bold"> </span><span class="Bold">Drug Name or</span><span class="Bold"> </span><span class="Bold">Drug</span><span class="Bold">Class</span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Clinical Rationale</span></td><td align="center" class="Rrule" valign="top"> <br/> <span class="Bold">Clinical</span><span class="Bold">Recommendation</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) <br/> </td><td class="Rrule" valign="top">  <br/> The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone <span class="Italics">[see <a href="#Section_12.3">Clinical Pharmacology (12.3</a>)]. </span> <br/> </td><td class="Rrule" valign="top">  <br/> With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage <span class="Italics">[see <a href="#Section_2.3">Dosage and Administration (2.7</a>)]. </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) <br/> </td><td class="Rrule" valign="top">The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone <span class="Italics">[see</span><span class="Italics"><a href="#Section_12.3">Clinical Pharmacology (12.3)</a>]. </span> <br/> </td><td class="Rrule" valign="top">With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage <span class="Italics">[see <a href="#Section_2.3">Dosage and Administration (2.7)</a>]. </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  <br/> Antihypertensive Drugs <br/> </td><td class="Rrule" valign="top">Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. <br/> </td><td class="Rrule" valign="top">Monitor blood pressure and adjust dose accordingly <span class="Italics">[see <a href="#Section_5.8">Warnings and Precautions (5.8)</a>]. </span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">  <br/>   <br/>   <br/> Benzodiazepines (e.g., lorazepam) <br/> </td><td class="Rrule" valign="top">The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone <span class="Italics">[see <a href="#Section_5.8">Warnings and Precautions (5.8)</a>]. </span> <br/> </td><td class="Rrule" valign="top">  <br/>   <br/>   <br/> Monitor sedation and blood pressure. Adjust dose accordingly. <br/> </td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, lorazepam.  In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole [see Clinical Pharmacology (12.3)].

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/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival  (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations  Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia 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/m2 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the MRHD; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.  In pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the MRHD of 30 mg/day based on mg/m2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the 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/m2 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.

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.

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.  Tourette’s Disorder  Safety and effectiveness of aripiprazole in pediatric patients with Tourette’s Disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients  [see Dosage and Administration (2.5), Adverse Reactions (6.1), and Clinical Studies (14.5)].  Maintenance efficacy in pediatric patients has not been systematically evaluated. Juvenile Animal Studies  Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0 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 (AUC0 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.

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 in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia or other indications did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.  Aripiprazole is not approved for the treatment of patients with psychosis associated with Alzheimer’s disease  [see Boxed Warning and Warnings and Precautions (5.1)].

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)]. 

No dosage adjustment for aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute)  [see Clinical Pharmacology (12.3)] .

No dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status  [see Clinical Pharmacology (12.3)] .

Aripiprazole is not a controlled substance. 

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). 

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

In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral aripiprazole tablet ingestions up to 195 mg with no fatalities.  Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. 

No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.  Charcoal: In the event of an overdose of aripiprazole, 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 aripiprazole, 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 aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

Aripiprazole is a psychotropic drug that is available as aripiprazole tablets. Aripiprazole tablets, USP are chemically designated as 7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone. The molecular formula is C23H27Cl2N3O2, and molecular weight is 448.39. The chemical structure is as follows:

{ "type": "p", "children": [], "text": "Aripiprazole is a psychotropic drug that is available as aripiprazole tablets. Aripiprazole tablets, USP are chemically designated as 7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone. The molecular formula is C23H27Cl2N3O2, and molecular weight is 448.39. The chemical structure is as follows:" }

  Aripiprazole tablets, USP 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. FDA approved dissolution test specifications differ from USP

{ "type": "p", "children": [], "text": "  \n Aripiprazole tablets, USP 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. \n FDA approved dissolution test specifications differ from USP\n " }

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

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 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. 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 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 maxor AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T maxby 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Distribution The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 to 30 mg/day aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans. Elimination Metabolism Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitrostudies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Excretion Following a single oral dose of [ 14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. Drug Interaction Studies Effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5 fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 3 fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors. Figure 1: The Effect of Other Drugs on Aripiprazole Pharmacokinetics 

Figure 2: The Effect of Other Drugs on Dehydro-Aripiprazole Pharmacokinetics 

The effect of aripiprazole on the exposures of other drugs are summarized in Figure 3. Figure 3: The Effect of Aripiprazole on Pharmacokinetics of Other Drugs  

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

Figure 5: Effect of Intrinsic Factors on Dehydro-Aripiprazole Pharmacokinetics

Carcinogenesis  Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and  30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of  60 mg/kg/day (19 times the MRHD).  An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. Mutagenesis  The mutagenic potential of aripiprazole was tested in the  in vitro bacterial reverse-mutation assay, the  in vitro bacterial DNA repair assay, the  in vitro forward gene mutation assay in mouse lymphoma cells, the  in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the  in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the  in  vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the  in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans.  Impairment of Fertility  Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased  pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD.  Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility.

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

Adults  The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five short-term (4 week and 6 week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish aripiprazole 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 and the active comparators.  In the four positive trials for aripiprazole, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.  In a 4 week trial (n=414) comparing two fixed doses of aripiprazole (15 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 1 in Table 26), PANSS positive subscale, and CGI-severity score. In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale.  In a 4 week trial (n=404) comparing two fixed doses of aripiprazole (20 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative subscale, and CGI-severity score.  In a 6 week trial (n=420) comparing three fixed doses of aripiprazole (10, 15, or 20 mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS negative subscale. In a 6 week trial (n=367) comparing three fixed doses of aripiprazole (2, 5, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole was superior to placebo in the PANSS total score (Study 4 in Table 26), the primary outcome measure of the study. 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 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 in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6week, placebocontrolled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing two fixed doses of aripiprazole (10 or 30 mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.  Table 26: Schizophrenia Studies

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="553.6125"> <col width="11.3633633633634%"/> <col width="36.5285285285285%"/> <col width="15.1351351351351%"/> <col width="14.9189189189189%"/> <col width="22.054054054054%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">S</span><span class="Bold">tudy</span> <br/> <span class="Bold">Number</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">Treatment Group</span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">P</span><span class="Bold">rimary Efficacy Measure: PANNS</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  <br/> </td><td class="Rrule" valign="top">  <br/> </td><td class="Rrule" valign="top"><span class="Bold">Mean</span> <br/> <span class="Bold">Baseline Score (SD)</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">LS M</span><span class="Bold">ean Change from Baseline (SE)</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">P</span><span class="Bold">lacebo subtracted Difference*</span> <br/> <span class="Bold">(95% CI)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 1 <br/> </td><td class="Rrule" valign="top">Aripiprazole Tablets (15 mg/day)† <br/> Aripiprazole Tablets (30 mg/day) † <br/> Placebo <br/> </td><td align="center" class="Rrule" valign="middle">98.5 (17.2) <br/> 99 (19.2) <br/> 100.2 (16.5) <br/> </td><td align="center" class="Rrule" valign="middle">-15.5(2.40) <br/> -11.4 (2.39) <br/> -2.9 (2.36) <br/> </td><td align="center" class="Rrule" valign="middle">-12.6 (-18.9, -6.2) <br/> -8.5 (-14.8, -2.1) <br/> -- <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 2 <br/> </td><td class="Rrule" valign="top">Aripiprazole Tablets (20 mg/day) † <br/> Aripiprazole Tablets (30 mg/day) † <br/> Placebo <br/> </td><td align="center" class="Rrule" valign="middle">92.6 (19.5) <br/> 94.2 (18.5) <br/> 94.3 (18.5) <br/> </td><td align="center" class="Rrule" valign="middle">-14.5(2.23) <br/> -13.9(2.24) <br/> -5.0 (2.17) <br/> </td><td align="center" class="Rrule" valign="middle">-9.6 (-15.4, -3.8) <br/> -9 (-14.8, -3.1) <br/> -- <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 3 <br/> </td><td class="Rrule" valign="top">Aripiprazole Tablets (10 mg/day) † <br/> Aripiprazole Tablets (15 mg/day) † <br/> Aripiprazole Tablets (20 mg/day) † <br/> Placebo <br/> </td><td align="center" class="Rrule" valign="top">92.7(19.5) <br/>   <br/> 93.2 (21.6) <br/>   <br/> 92.5 (20.9) <br/>   <br/> 92.3 (21.8) <br/> </td><td align="center" class="Rrule" valign="top">-15.0(2.38) <br/>   <br/> -11.7 (2.38) <br/>   <br/> -14.4(2.45) <br/>   <br/> -2.3 (2.35) <br/> </td><td align="center" class="Rrule" valign="top">-12.7 (-19, -6.41) <br/>   <br/>  -9.4 (-15.71, 3.08) <br/>   <br/>  -12.1(-18.53,5.68) <br/>  -- <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 4 <br/> </td><td class="Rrule" valign="top">Aripiprazole Tablets (2 mg/day) <br/> Aripiprazole Tablets (5 mg/day) <br/> Aripiprazole Tablets (10 mg/day) † <br/> Placebo <br/> </td><td align="center" class="Rrule" valign="middle">90.7(14.5) <br/> 92.0 (12.6) <br/> 90.0 (11.9) <br/> 90.8 (13.3) <br/> </td><td align="center" class="Rrule" valign="middle">-8.2 (1.90) <br/> -10.6(1.93) <br/> -11.3 (1.88) <br/> -5.3 (1.97) <br/> </td><td align="center" class="Rrule" valign="middle">-2.9 (-8.29, 2.47) <br/> -5.2 (-10.7, 0.19) <br/> -5.9 (-11.3, -0.58) <br/> -- <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Study 6 <br/> (Pediatric, <br/> 13 to 17 Years) <br/> </td><td class="Rrule" valign="top">Aripiprazole Tablets (10 mg/day) † <br/> Aripiprazole Tablets (30 mg/day) † <br/> Placebo <br/> </td><td align="center" class="Rrule" valign="top">93.6 (15.7) <br/> 94.0 (16.1) <br/> 94.6 (15.6) <br/> </td><td align="center" class="Rrule" valign="top">-26.7(1.91) <br/>   <br/> -28.6(1.92) <br/>   <br/> -21.2(1.93) <br/> </td><td align="center" class="Rrule" valign="top">-5.5 (-10.7, -0.21) <br/>   <br/> -7.4 (-12.7, -2.13) <br/>   <br/> -- <br/> </td> </tr> </tbody> </table></div>

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. Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

 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. Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7)

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.

Figure 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse to Any Mood Event (Bipolar Study 8)

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 CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9. Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette’s Disorder Study 1)

  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.

Table 30: Tourette’s Disorder Studies (Pediatric)

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="593.446"> <col width="11.362617660242%"/> <col width="36.5307037203048%"/> <col width="15.1389511429852%"/> <col width="14.9148363962349%"/> <col width="22.0528910802331%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">S</span><span class="Bold">tudy</span> <br/> <span class="Bold">Number</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">Treatment Group </span></td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">P</span><span class="Bold">rimary Efficacy Measure: YGTSS TTS</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  <br/> </td><td class="Rrule" valign="top">  <br/> </td><td class="Rrule" valign="top"><span class="Bold">Mean</span> <br/> <span class="Bold">Baseline Score (SD)</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">LS M</span><span class="Bold">ean Change from Baseline (SE)</span> <br/> </td><td class="Rrule" valign="top"><span class="Bold">P</span><span class="Bold">lacebo subtracted Difference*</span> <br/> <span class="Bold">(95% CI)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Study 1 <br/> </td><td class="Rrule" valign="top">Aripiprazole Tablets (low dose)† <br/> Aripiprazole Tablets (high dose) † <br/> Placebo <br/> </td><td align="center" class="Rrule" valign="middle">29.2 (5.63) <br/> 31.2 (6.40) <br/> 30.7 (5.95) <br/> </td><td align="center" class="Rrule" valign="middle">-13.4 (1.59) -16.9 (1.61) <br/> -7.1 (1.55) <br/> </td><td align="center" class="Rrule" valign="middle">-6.3 (-10.2, -2.3) <br/> -9.9 (-13.8, -5.9) <br/> -- <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Study 2 <br/> </td><td class="Rrule" valign="top">Aripiprazole Tablets (2 to 20 mg/day) † <br/> Placebo <br/> </td><td align="center" class="Rrule" valign="middle">28.3 (5.51) <br/>   <br/> 29.5 (5.60) <br/> </td><td align="center" class="Rrule" valign="middle">-15.0 (1.51) <br/>   <br/> -9.6 (1.64) <br/> </td><td align="center" class="Rrule" valign="middle">-5.3 (-9.8, -0.9) <br/>   <br/> -- <br/> </td> </tr> </tbody> </table></div>

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.

Aripiprazole tablets, USP 2 mg are light green to green, modified rectangular, bevel edged biconvex plain to mottled tablets debossed with ‘I’ on one side and ‘94’ on other side. Bottles of 30 Tablets NDC 16714-141-01 Aripiprazole tablets, USP 5 mg are light blue to blue, modified rectangular, bevel edged biconvex tablets debossed with ‘I’ on one side and ‘95’ on other side. Bottles of 30 Tablets NDC 16714-142-01 Aripiprazole tablets, USP 10 mg are light pink to pink, modified rectangular, bevel edged biconvex plain to mottled tablets debossed with ‘I’ on one side and ‘96’ on other side. Bottles of 30 Tablets NDC 16714-143-01 Aripiprazole tablets, USP 15 mg are light yellow to yellow, round, bevel edged biconvex plain to mottled tablets debossed with ‘I’ on one side and ‘97’ on other side. Bottles of 30 Tablets NDC 16714-144-01 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. Bottles of 30 Tablets NDC 16714-145-01 Aripiprazole tablets, USP 30 mg are light pink to pink, round, bevel edged biconvex plain to mottled tablets debossed with ‘I’ on one side and ‘99’ on other side. Bottles of 30 Tablets NDC 16714-146-01

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

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 behavior and 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. Pathological Gambling and Other Compulsive Behaviors Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.7)]. 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 therapy does not affect them adversely [see Warnings and Precautions (5.12)]. 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 (5.13)] . 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)].   ABILIFY ®is a trademark of Otsuka Pharmaceutical Company. Manufactured for: Northstar Rx LLC Memphis,TN 38141. By: HETEROTM Hetero Labs Limited, Unit V, Polepally, Jadcherla, Mahabubnagar - 509 301, India. Revised: 05/2023

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide). \n \nDiscuss the following issues with patients prescribed aripiprazole tablets: \n \nClinical Worsening of Depression and Suicide Risk \n \nPatients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication\n \n [see\n \n Warnings and Precautions (5.3)]\n \n . \n 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. \n \nPathological Gambling and Other Compulsive Behaviors \n \nAdvise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, \n the urges were reported to have stopped when the dose was reduced or stopped\n \n [see\n \n Warnings and Precautions (5.7)].\n \n \n\nInterference with Cognitive and Motor Performance \n \nBecause 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 therapy does not affect them adversely\n \n [see Warnings and Precautions (5.12)].\n\nConcomitant Medication \n \nPatients 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\n \n [see\n \n Drug Interactions (7)]\n \n . \n \nHeat Exposure and Dehydration \n \nPatients should be advised regarding appropriate care in avoiding overheating and dehydration\n \n [see\n \n Warnings and Precautions (5.13)]\n \n . \n \nPregnancy\n 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\n \n [see\n \n Use in Specific Populations (8.1)].\n \n \n\n \n ABILIFY\n \n ®is a trademark of Otsuka Pharmaceutical Company. \n Manufactured for: \n Northstar Rx LLC \n Memphis,TN 38141. \n By: HETEROTM \n Hetero Labs Limited, Unit V, Polepally, Jadcherla, \n Mahabubnagar - 509 301, India. \n Revised: 05/2023\n\n " }

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"> <br/> <span class="Bold">Aripiprazole Tablets USP <br/> (ar'' i pip' ra zole) </span>  </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> What is the most important information I should know about aripiprazole tablets?  <br/> </span>(For other side effects, also see “What are the possible side effects of aripiprazole tablets?”)  <br/> Serious side effects may happen when you take aripiprazole tablets, including:  <br/> <span class="Bold">• Increased risk of death in elderly patients with dementia-related psychosis: </span>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.  <br/> <span class="Bold">• Risk of suicidal thoughts or actions:</span> Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions:  <br/> •  <span class="Bold">Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.  <br/> • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions.  </span>These include people who have (or have a family history of) suicidal thoughts or actions. <br/> •   <span class="Bold">How can I watch for and try to prevent suicidal thoughts and actions in myself or a  family member? </span> <br/> • 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.  <br/> <span class="Bold"> Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.  <br/> </span>• 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.  <br/> 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: <br/> • thoughts about suicide or dying  <br/> • attempts to commit suicide  <br/> • new or worse depression  <br/> • new or worse anxiety  <br/> • feeling very agitated or restless  <br/> • panic attacks  <br/> • trouble sleeping (insomnia)  <br/> • new or worse irritability  <br/> • acting aggressive, being angry, or violent  <br/> • acting on dangerous impulses  <br/> • an extreme increase in activity and talking (mania)  <br/> • other unusual changes in behavior or mood  <br/> <br/> <span class="Bold">What else do I need to know about antidepressant medicines? <br/> </span>•  <span class="Bold">Never stop an antidepressant medicine without first talking to a healthcare provider.</span> Stopping an antidepressant medicine suddenly can cause other symptoms.  <br/> •  <span class="Bold">Antidepressants are medicines used to treat depression and other illnesses.</span> 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.  <br/> •  <span class="Bold">Antidepressant medicines have other side effects. </span>Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.  <br/> •  <span class="Bold">Antidepressant medicines can interact with other medicines.</span> 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.  <br/> •  <span class="Bold">Not all antidepressant medicines prescribed for children are FDA approved for use in children. </span>Talk to your child’s healthcare provider for more information.  </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> What are aripiprazole tablets? <br/> • Aripiprazole tablets are prescription medicine used to treat:  </span> <br/> • Schizophrenia  <br/> • Tourette’s disorder <br/> <span class="Bold">It is not known if aripiprazole tablets are safe or effective in children: <br/> </span>• under 13 years of age with schizophrenia   <br/> • under 6 years of age with Tourette’s disorder </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  <span class="Bold">Do not take aripiprazole tablets if you</span> 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. </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Before taking aripiprazole tablets, tell your healthcare provider about all your medical conditations, including if you have or had:  <br/> </span>• 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.  <br/> • seizures (convulsions).  <br/> • low or high blood pressure.  <br/> • heart problems or stroke.  <br/> • pregnancy or plans to become pregnant. It is not known if aripiprazole tablets will harm your unborn baby.  <br/> • If you become pregnant while receiving aripiprazole tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.   <br/> • breast-feeding or plans to breast-feed. Aripiprazole passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive aripiprazole tablets.  <br/> • low white blood cell count.  <br/> <span class="Bold">Tell your healthcare provider about all the medicines that you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. <br/> 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.  <br/> 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.  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">  <span class="Bold">How should I take aripiprazole tablets?</span> <br/> • Take aripiprazole tablets exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking aripiprazole tablets yourself.  <br/> • Aripiprazole tablets can be taken with or without food.  <br/> • Aripiprazole tablets should be swallowed whole.  <br/> • 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.  <br/> • 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. </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> What should I avoid while taking aripiprazole tablets? </span> <br/> • 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.  <br/> • Avoid getting over-heated or dehydrated.  <br/> • Do not over-exercise.  <br/> • In hot weather, stay inside in a cool place if possible.  <br/> • Stay out of the sun. Do not wear too much or heavy clothing.  <br/> • Drink plenty of water.  </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> What are the possible side effects of aripiprazole tablets?  <br/> </span><span class="Bold">Aripiprazole tablets may cause serious side effects, including: <br/> • See “What is the most important information I should know about aripiprazole tablets?”  <br/> • Stroke in elderly people (cerebrovascular problems) that can lead to death </span> <br/> •  <span class="Bold">Neuroleptic malignant syndrome (NMS):</span> 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.  <br/> •  <span class="Bold">Uncontrolled body movements (tardive dyskinesia).</span> 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. <br/> <span class="Bold">• Problems with your metabolism such as: <br/> </span>•  <span class="Bold">High blood sugar (hyperglycemia) and diabetes: </span>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.  <br/> <span class="Bold">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving aripiprazole tablets:  <br/> </span>• feel very thirsty  <br/> • need to urinate more than usual  <br/> • feel very hungry  <br/> • feel weak or tired  <br/> • feel sick to your stomach  <br/> • feel confused, or your breath smells fruity  <br/> <span class="Bold">• Increased fat levels (cholesterol and triglycerides) in your blood. <br/> </span>•  <span class="Bold">Weight gain.</span> You and your healthcare provider should check your weight regularly. <br/> •  <span class="Bold">Unusual urges.</span> Some people taking aripiprazole tablets have had unusual urges, such as gambling, binge eating or eating that you cannot control (compulsive), compulsive shopping and sexual urges.  <br/> If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider. <br/> •  <span class="Bold">Orthostatic hypotension (decreased blood pressure): </span>Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position.  <br/> •  <span class="Bold">Falls.</span> 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.  <br/> <span class="Bold">• Low white blood cell count  <br/> </span><span class="Bold">• Seizures (convulsions)  <br/> </span>•  <span class="Bold">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.</span> See “What should I avoid while receiving aripiprazole tablets?” <br/> <span class="Bold">The most common side effects of aripiprazole tablets in adults include:</span> <br/> • nausea                             <br/> • vomiting                    <br/> • constipation                     <br/> • headache                         <br/> • blurred vision <br/> • upper respiratory illness  <br/> • dizziness <br/> • anxiety <br/> • insomnia <br/> • restlessness  <br/> • inner sense of restlessness/need to move (akathisia) <br/>   <span class="Bold">The most common side effects of aripiprazole tablets in children include: </span> <br/> • feeling sleepy                              <br/> • headache                                    <br/> • vomiting                                       <br/> • fatigue                                         <br/> • increased or decreased appetite  <br/> • increased saliva or drooling  <br/> • insomnia <br/>  • nausea <br/> • stuffy nose <br/> • weight gain  <br/> • uncontrolled movement such as restlessness, tremor  <br/> • muscle stiffness <br/> <br/> These are not all the possible side effects of aripiprazole tablets.  <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.  </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> How should I store aripiprazole tablets?  <br/> </span>Store aripiprazole tablets at 68º to 77ºF (20º to 25º C). <br/> <span class="Bold">Keep aripiprazole tablets and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> General information about the safe and effective use of aripiprazole tablets  <br/> </span>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. You can ask your healthcare provider or pharmacist for information about aripiprazole tablets that was written for healthcare professionals.  <br/> For more information, call 1-866-495-1995 </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> What are the ingredients in aripiprazole tablets? <br/> </span><span class="Bold">Active ingredient:</span> aripiprazole USP <br/> <span class="Bold">Inactive ingredients:</span> corn starch, FD&amp;C Blue #2/Indigo Carmine Al, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose <br/> <span class="Bold">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.</span> <br/> <br/> <br/> ABILIFY® is a trademark of Otsuka Pharmaceutical Company. <br/> Medication Guide available at www.northstarrxllc.com/products or call 1-800-206-7821 <br/> Manufactured for: <br/> Northstar Rx LLC <br/> Memphis,TN 38141. <br/> By: <span class="Bold">HETERO <span class="Sup">TM</span></span> <br/> Hetero Labs Limited, Unit V, Polepally, Jadcherla, <br/> Mahabubnagar - 509 301, India </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"middle\">\n<br/>\n<span class=\"Bold\">Aripiprazole Tablets USP \n <br/> (ar'' i pip' ra zole)\n </span> \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> What is the most important information I should know about aripiprazole tablets?  \n <br/>\n</span>(For other side effects, also see “What are the possible side effects of aripiprazole tablets?”)  \n <br/> Serious side effects may happen when you take aripiprazole tablets, including:  \n <br/>\n<span class=\"Bold\">• Increased risk of death in elderly patients with dementia-related psychosis: </span>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.  \n <br/>\n<span class=\"Bold\">• Risk of suicidal thoughts or actions:</span> Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions:  \n <br/> • \n \n <span class=\"Bold\">Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.  \n <br/> • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. \n </span>These include people who have (or have a family history of) suicidal thoughts or actions. \n <br/> •  \n \n <span class=\"Bold\">How can I watch for and try to prevent suicidal thoughts and actions in myself or a  family member? </span>\n<br/> • 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.  \n <br/>\n<span class=\"Bold\"> Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.  \n <br/>\n</span>• 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.  \n <br/> 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: \n <br/> • thoughts about suicide or dying  \n <br/> • attempts to commit suicide  \n <br/> • new or worse depression  \n <br/> • new or worse anxiety  \n <br/> • feeling very agitated or restless  \n <br/> • panic attacks  \n <br/> • trouble sleeping (insomnia)  \n <br/> • new or worse irritability  \n <br/> • acting aggressive, being angry, or violent  \n <br/> • acting on dangerous impulses  \n <br/> • an extreme increase in activity and talking (mania)  \n <br/> • other unusual changes in behavior or mood  \n <br/>\n<br/>\n<span class=\"Bold\">What else do I need to know about antidepressant medicines? \n <br/>\n</span>• \n \n <span class=\"Bold\">Never stop an antidepressant medicine without first talking to a healthcare provider.</span> Stopping an antidepressant medicine suddenly can cause other symptoms.  \n <br/> • \n \n <span class=\"Bold\">Antidepressants are medicines used to treat depression and other illnesses.</span> 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.  \n <br/> • \n \n <span class=\"Bold\">Antidepressant medicines have other side effects. </span>Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.  \n <br/> • \n \n <span class=\"Bold\">Antidepressant medicines can interact with other medicines.</span> 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.  \n <br/> • \n \n <span class=\"Bold\">Not all antidepressant medicines prescribed for children are FDA approved for use in children. </span>Talk to your child’s healthcare provider for more information. \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> What are aripiprazole tablets? \n <br/> • Aripiprazole tablets are prescription medicine used to treat: \n </span>\n<br/> • Schizophrenia  \n <br/> • Tourette’s disorder \n <br/>\n<span class=\"Bold\">It is not known if aripiprazole tablets are safe or effective in children: \n <br/>\n</span>• under 13 years of age with schizophrenia   \n <br/> • under 6 years of age with Tourette’s disorder\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"> \n \n <span class=\"Bold\">Do not take aripiprazole tablets if you</span> 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.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> Before taking aripiprazole tablets, tell your healthcare provider about all your medical conditations, including if you have or had:  \n <br/>\n</span>• 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.  \n <br/> • seizures (convulsions).  \n <br/> • low or high blood pressure.  \n <br/> • heart problems or stroke.  \n <br/> • pregnancy or plans to become pregnant. It is not known if aripiprazole tablets will harm your unborn baby.  \n <br/> • If you become pregnant while receiving aripiprazole tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.   \n <br/> • breast-feeding or plans to breast-feed. Aripiprazole passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive aripiprazole tablets.  \n <br/> • low white blood cell count.  \n <br/>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines that you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. \n <br/> 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.  \n <br/> 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.  \n <br/>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"> \n \n <span class=\"Bold\">How should I take aripiprazole tablets?</span>\n<br/> • Take aripiprazole tablets exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking aripiprazole tablets yourself.  \n <br/> • Aripiprazole tablets can be taken with or without food.  \n <br/> • Aripiprazole tablets should be swallowed whole.  \n <br/> • 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.  \n <br/> • 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.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> What should I avoid while taking aripiprazole tablets? </span>\n<br/> • 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.  \n <br/> • Avoid getting over-heated or dehydrated.  \n <br/> • Do not over-exercise.  \n <br/> • In hot weather, stay inside in a cool place if possible.  \n <br/> • Stay out of the sun. Do not wear too much or heavy clothing.  \n <br/> • Drink plenty of water. \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> What are the possible side effects of aripiprazole tablets?  \n <br/>\n</span><span class=\"Bold\">Aripiprazole tablets may cause serious side effects, including: \n <br/> • See “What is the most important information I should know about aripiprazole tablets?”  \n <br/> • Stroke in elderly people (cerebrovascular problems) that can lead to death\n </span>\n<br/> • \n \n <span class=\"Bold\">Neuroleptic malignant syndrome (NMS):</span> 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.  \n <br/> • \n \n <span class=\"Bold\">Uncontrolled body movements (tardive dyskinesia).</span> 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. \n <br/>\n<span class=\"Bold\">• Problems with your metabolism such as: \n <br/>\n</span>• \n \n <span class=\"Bold\">High blood sugar (hyperglycemia) and diabetes: </span>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.  \n <br/>\n<span class=\"Bold\">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving aripiprazole tablets:  \n <br/>\n</span>• feel very thirsty  \n <br/> • need to urinate more than usual  \n <br/> • feel very hungry  \n <br/> • feel weak or tired  \n <br/> • feel sick to your stomach  \n <br/> • feel confused, or your breath smells fruity  \n <br/>\n<span class=\"Bold\">• Increased fat levels (cholesterol and triglycerides) in your blood. \n <br/>\n</span>• \n \n <span class=\"Bold\">Weight gain.</span> You and your healthcare provider should check your weight regularly. \n <br/> • \n \n <span class=\"Bold\">Unusual urges.</span> Some people taking aripiprazole tablets have had unusual urges, such as gambling, binge eating or eating that you cannot control (compulsive), compulsive shopping and sexual urges.  \n <br/> If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider. \n <br/> • \n \n <span class=\"Bold\">Orthostatic hypotension (decreased blood pressure): </span>Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position.  \n <br/> • \n \n <span class=\"Bold\">Falls.</span> 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.  \n <br/>\n<span class=\"Bold\">• Low white blood cell count  \n <br/>\n</span><span class=\"Bold\">• Seizures (convulsions)  \n <br/>\n</span>• \n \n <span class=\"Bold\">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.</span> See “What should I avoid while receiving aripiprazole tablets?” \n <br/>\n<span class=\"Bold\">The most common side effects of aripiprazole tablets in adults include:</span>\n<br/> • nausea                             \n <br/> • vomiting                    \n <br/> • constipation                     \n <br/> • headache                         \n <br/> • blurred vision \n <br/> • upper respiratory illness  \n <br/> • dizziness \n <br/> • anxiety \n <br/> • insomnia \n <br/> • restlessness  \n <br/> • inner sense of restlessness/need to move (akathisia) \n <br/>  \n \n <span class=\"Bold\">The most common side effects of aripiprazole tablets in children include: </span>\n<br/> • feeling sleepy                              \n <br/> • headache                                    \n <br/> • vomiting                                       \n <br/> • fatigue                                         \n <br/> • increased or decreased appetite  \n <br/> • increased saliva or drooling  \n <br/> • insomnia \n <br/>  • nausea \n <br/> • stuffy nose \n <br/> • weight gain  \n <br/> • uncontrolled movement such as restlessness, tremor  \n <br/> • muscle stiffness \n <br/>\n<br/> These are not all the possible side effects of aripiprazole tablets.  \n <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. \n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> How should I store aripiprazole tablets?  \n <br/>\n</span>Store aripiprazole tablets at 68º to 77ºF (20º to 25º C). \n <br/>\n<span class=\"Bold\">Keep aripiprazole tablets and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> General information about the safe and effective use of aripiprazole tablets  \n <br/>\n</span>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. You can ask your healthcare provider or pharmacist for information about aripiprazole tablets that was written for healthcare professionals.  \n <br/> For more information, call 1-866-495-1995\n \n </td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Lrule Rrule\" valign=\"middle\"><span class=\"Bold\"> What are the ingredients in aripiprazole tablets? \n <br/>\n</span><span class=\"Bold\">Active ingredient:</span> aripiprazole USP \n <br/>\n<span class=\"Bold\">Inactive ingredients:</span> corn starch, FD&amp;C Blue #2/Indigo Carmine Al, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose \n <br/>\n<span class=\"Bold\">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.</span>\n<br/>\n<br/>\n<br/> ABILIFY® is a trademark of Otsuka Pharmaceutical Company. \n <br/> Medication Guide available at www.northstarrxllc.com/products or call 1-800-206-7821 \n <br/> Manufactured for: \n <br/> Northstar Rx LLC \n <br/> Memphis,TN 38141. \n <br/> By:\n \n <span class=\"Bold\">HETERO\n \n <span class=\"Sup\">TM</span></span>\n<br/> Hetero Labs Limited, Unit V, Polepally, Jadcherla, \n <br/> Mahabubnagar - 509 301, India\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 05/2023

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration \n Revised: 05/2023\n " }

Aripiprazole oral solution is indicated for the treatment of:

{ "type": "p", "children": [], "text": "Aripiprazole oral solution is indicated for the treatment of:" }

{ "type": "ul", "children": [ "Schizophrenia\n \n [see\n \n Clinical Studies (14.1)]\n \n \n", "Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder\n \n [see\n \n Clinical Studies (14.2)]\n \n \n", "Adjunctive Treatment of Major Depressive Disorder\n \n [see\n \n Clinical Studies (14.3)]\n \n \n", "Irritability Associated with Autistic Disorder\n \n [see\n \n Clinical Studies (14.4)]\n \n \n", "Treatment of Tourette’s Disorder\n \n [see\n \n Clinical Studies (14.5)]\n \n \n" ], "text": "" }

Adults

The recommended starting and target dose for aripiprazole oral solution is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (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 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 oral solution 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 oral solution 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 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.

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. Aripiprazole oral solution can be given without regard to meals. The recommended target dose of aripiprazole oral solution 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. Aripiprazole oral solution can be given without regard to meals [see Clinical Studies (14.2)] .

Adults

The recommended starting dose for aripiprazole oral solution as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The recommended dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week [see Clinical Studies (14.3)] . Patients should be periodically reassessed to determine the continued need for maintenance treatment.

Pediatric Patients (6 to 17 years)

The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is 5 to 15 mg/day.

Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week [see Clinical Studies (14.4)] . Patients should be periodically reassessed to determine the continued need for maintenance treatment.

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. [See Clinical Studies (14.5)].

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

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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Factors</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dosage Adjustments for Aripiprazole Oral Solution</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Known CYP2D6 Poor Metabolizers</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Administer half of usual dose</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Known CYP2D6 Poor Metabolizers taking</p> <p>concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Administer a quarter of usual dose</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Strong CYP2D6 (e.g., quinidine, fluoxetine,</p> <p>paroxetine) <span class="Bold">or</span>CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Administer half of usual dose</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Strong CYP2D6 <span class="Bold">and</span>CYP3A4 inhibitors </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Administer a quarter of usual dose</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">Strong CYP3A4 inducers (e.g., carbamazepine, rifampin)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Double usual dose over 1 to 2 weeks</p> </td> </tr> </tbody> </table></div>

When adjunctive aripiprazole oral solution is administered to patients with major depressive disorder, aripiprazole oral solution should be administered without dosage adjustment as specified in Dosage and Administration (2.3).

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)] .

Aripiprazole oral solution (1 mg/mL) is a clear to pale yellow solution with orange flavor, supplied in child-resistant bottles.

{ "type": "p", "children": [], "text": "Aripiprazole oral solution (1 mg/mL) is a clear to pale yellow solution with orange flavor, supplied in child-resistant bottles." }

Aripiprazole oral solution is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6.2)] .

{ "type": "p", "children": [], "text": "Aripiprazole oral solution is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis\n \n [see\n \n Adverse Reactions (6.2)]\n \n .\n\n " }

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole is not approved for the treatment of patients with dementia- related psychosis [see Boxed Warning] .

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

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

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

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia- related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning] .

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 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 1,000 patients treated) are provided in Table 5.

Table 5:

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Age Range</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated</span> </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First">&lt;18</p> <p>18-24</p> </td><td align="left" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Increases Compared to Placebo</span> </p> <p>14 additional cases</p> <p>5 additional cases</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First">25-64</p> <p>≥65</p> </td><td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Decreases Compared to Placebo</span> </p> <p>1 fewer case</p> <p>6 fewer cases</p> </td> </tr> </tbody> </table></div>

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

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

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

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

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

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

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS occurred during aripiprazole 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.

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

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

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

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

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

Hyperglycemia/Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions ( 6.1, 6.2)] . Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Because aripiprazole was not marketed at the time these studies were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Adults

In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1,057) 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 aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment- emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).

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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Toprule" rowspan="2" valign="top"></td><td class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Category Change (at least once) from Baseline</span> </p> </td><td class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment</span><span class="Bold">Arm</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td align="center" valign="top"> <p class="First">Normal to High</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">31/822</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">3.8</p> </td> </tr> <tr> <td align="center" class="Botrule" rowspan="3" valign="top"> <p class="First"> <span class="Bold">Fasting Glucose</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(&lt;100 mg/dL to <span class="Underline">&gt;</span>126 mg/dL) </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">22/605</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">3.6</p> </td> </tr> <tr> <td align="center" valign="top"> <p class="First">Borderline to High</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">31/176</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">17.6</p> </td> </tr> <tr> <td align="center" class="Botrule" valign="top"> <p class="First">( <span class="Underline">&gt;</span>100 mg/dL and &lt;126 mg/dL to &gt;126 mg/dL) </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">13/142</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">9.2</p> </td> </tr> </tbody> </table></div>

At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].

The mean change in fasting glucose in adjunctive aripiprazole-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Toprule" valign="top"> <p class="First"> <span class="Bold">Fasting</span> </p> </td><td class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Category Change (at least once) from Baseline</span> </p> </td><td class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment</span><span class="Bold">Arm</span> </p> </td><td align="right" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Glucose</span> </p> </td><td align="center" valign="top"> <p class="First">Normal to High</p> </td><td class="Botrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="right" class="Botrule" valign="top"> <p class="First">2/201</p> </td><td class="Botrule" valign="top"> <p class="First">1.0</p> </td> </tr> <tr> <td valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">(&lt;100 mg/dL to <span class="Underline">&gt;</span>126 mg/dL) </p> </td><td class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="right" class="Botrule" valign="top"> <p class="First">2/204</p> </td><td class="Botrule" valign="top"> <p class="First">1.0</p> </td> </tr> <tr> <td valign="top"></td><td align="center" valign="top"> <p class="First">Borderline to High</p> </td><td class="Botrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">4/34</p> </td><td class="Botrule" valign="top"> <p class="First">11.8</p> </td> </tr> <tr> <td class="Botrule" valign="top"></td><td align="center" class="Botrule" valign="top"> <p class="First">(≥100 mg/dL and &lt;126 mg/dL to</p> <p>≥126 mg/dL)</p> </td><td class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="right" class="Botrule" valign="top"> <p class="First">3/37</p> </td><td class="Botrule" valign="top"> <p class="First">8.1</p> </td> </tr> </tbody> </table></div>

Pediatric Patients and Adolescents

In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), the mean change in fasting glucose in aripiprazole-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123).

In an analysis of two placebo-controlled trials in pediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in aripiprazole-treated patients (-0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (-0.6 mg/dL; N=33).

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 aripiprazole-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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Category Change (at least once) from Baseline</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6"> <p class="First"> <span class="Bold">Fasting Glucose</span> </p> <p>Normal to High</p> <p>(&lt;100 mg/dL to ≥126 mg/dL)</p> </td><td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Pooled Schizophrenia and Bipolar Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2/236</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0.8</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2/110</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.8</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Irritability Associated with Autistic Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/73</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/32</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Tourette’s Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3/88</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.4</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1/58</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.7</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6"> <p class="First"> <span class="Bold">Fasting Glucose</span> </p> <p>Borderline to High (≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</p> </td><td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Pooled Schizophrenia</p> <p>and Bipolar Disorder</p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">1/22</p> </td><td align="center" class="Botrule Rrule"> <p class="First">4.5</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/12</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Irritability Associated</p> <p>with Autistic Disorder</p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Tourette’s Disorder</p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/11</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder trials, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively].

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.

Adults

Table 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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2"> <p class="First"> <span class="Bold">Total Cholesterol</span> </p> <p>Normal to High</p> <p>(&lt;200 mg/dL to ≥240 mg/dL)</p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">34/1,357</p> </td><td align="center" class="Botrule Rrule"> <p class="First">2.5</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule"> <p class="First">27/973</p> </td><td align="center" class="Botrule Rrule"> <p class="First">2.8</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2"> <p class="First"> <span class="Bold">Fasting Triglycerides</span> </p> <p>Normal to High</p> <p>(&lt;150 mg/dL to ≥200 mg/dL)</p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">40/539</p> </td><td align="center" class="Botrule Rrule"> <p class="First">7.4</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule"> <p class="First">30/431</p> </td><td align="center" class="Botrule Rrule"> <p class="First">7.0</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2"> <p class="First"> <span class="Bold">Fasting LDL Cholesterol</span> </p> <p>Normal to High</p> <p>(&lt;100 mg/dL to ≥160 mg/dL)</p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">2/332</p> </td><td align="center" class="Botrule Rrule"> <p class="First">0.6</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule"> <p class="First">2/268</p> </td><td align="center" class="Botrule Rrule"> <p class="First">0.7</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="2"> <p class="First"> <span class="Bold">HDL Cholesterol</span> </p> <p>Normal to Low</p> <p>(≥40 mg/dL to &lt;40 mg/dL)</p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">121/1,066</p> </td><td align="center" class="Botrule Rrule"> <p class="First">11.4</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule"> <p class="First">99/794</p> </td><td align="center" class="Botrule Rrule"> <p class="First">12.5</p> </td> </tr> </tbody> </table></div>

In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.

Table 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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Total Cholesterol</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3/139</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Normal to High</p> <p>(&lt;200 mg/dL to <span class="Underline">&gt;</span>240 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7/135</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Fasting Triglycerides</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14/145</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Normal to High</p> <p>(&lt;150 mg/dL to <span class="Underline">&gt;</span>200 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6/147</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4.1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Fasting LDL Cholesterol</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/54</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Normal to High</p> <p>(&lt;100 mg/dL to <span class="Underline">&gt;</span>160 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/73</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HDL Cholesterol</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17/318</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Normal to Low</p> <p>( <span class="Underline">&gt;</span>40 mg/dL to &lt;40 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10/286</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.5</p> </td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Toprule" valign="top"></td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Total Cholesterol</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">3/220</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.4</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Normal to High</p> <p>(&lt;170 mg/dL to <span class="Underline">&gt;</span>200 mg/dL) </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0/116</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">Fasting Triglycerides</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">7/187</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">3.7</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Normal to High</p> <p>(&lt;150 mg/dL to <span class="Underline">&gt;</span>200 mg/dL) </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">4/85</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">4.7</p> </td> </tr> <tr> <td valign="top"> <p class="First"> <span class="Bold">HDL Cholesterol</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">27/236</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">11.4</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Normal to Low</p> <p>( <span class="Underline">&gt;</span>40 mg/dL to &lt;40 mg/dL) </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">22/109</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">20.2</p> </td> </tr> </tbody> </table></div>

In monotherapy trials of adolescents with schizophrenia and pediatric patients with bipolar disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.

Table 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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Total Cholesterol</span> </p> <p>Normal to High</p> <p>(&lt;170 mg/dL to <span class="Underline">&gt;</span>200 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1/95</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.1</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/34</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Fasting Triglycerides</span> </p> <p>Normal to High</p> <p>(&lt;150 mg/dL to <span class="Underline">&gt;</span>200 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/75</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/30</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">HDL Cholesterol</span> </p> <p>Normal to Low</p> <p>( <span class="Underline">&gt;</span>40 mg/dL to &lt;40 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9/107</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8.4</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5/49</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10.2</p> </td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">n/N</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Total Cholesterol</p> <p>Normal to High <br/> (&lt;170 mg/dL to <span class="Underline">&gt;</span>200 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1/85</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1.2</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0/46</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Fasting Triglycerides</p> <p>Normal to High <br/> (&lt;150 mg/dL to <span class="Underline">&gt;</span>200 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5/94</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5.3</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2/55</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">HDL Cholesterol <br/> Normal to Low <br/> ( <span class="Underline">&gt;</span>40 mg/dL to &lt;40 mg/dL) </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4/108</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.7</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2/67</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3.0</p> </td> </tr> </tbody> </table></div>

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Adults

In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1,673) compared to -0.1 kg (N=1,100) in placebo- controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole- treated patients was -1.5 kg (n=73) compared to -0.2 kg (n=46) in placebo-treated patients.

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

Table 14 shows the percentage of adult patients with weight gain greater than or equal to 7% of body weight by indication.

Table 14: Percentage of Patients From Placebo-Controlled Trials in Adult Patients with Weight Gain greater than or equal to 7% of Body Weight

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Patients n (%)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6"> <p class="First"> <span class="Bold">Weight gain ≥7% of</span> </p> <p> <span class="Bold">body weight</span> </p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Schizophrenia <span class="Sup">*</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">852</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">69 (8.1)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">379</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (3.2)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Bipolar Mania <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">719</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (2.2)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">598</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (2.7)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Major Depressive Disorder</p> <p>(Adjunctive Therapy) <span class="Sup">‡</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">347</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (5.2)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">330</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (0.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Sup">*</span>4 to 6 weeks duration. <span class="Sup">†</span>3 weeks duration. <span class="Sup">‡</span>6 weeks duration. </p> </td> </tr> </tbody> </table></div>

Pediatric Patients and Adolescents

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

In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients.

In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette’s Disorder with median exposure of 57 days, the mean change in body weight in aripiprazole-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients.

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

Table 15: Percentage of Patients From Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain greater than or equal to 7% of Body Weight

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"></td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Indication</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Treatment Arm</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Rrule Toprule"> <p class="First"> <span class="Bold">Patients n (%)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" rowspan="6"> <p class="First"> <span class="Bold">Weight gain ≥7% of</span> </p> <p> <span class="Bold">body weight</span> </p> </td><td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Pooled Schizophrenia and</p> <p>Bipolar Mania <span class="Sup">*</span> </p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">381</p> </td><td align="center" class="Botrule Rrule"> <p class="First">20 (5.2)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule"> <p class="First">187</p> </td><td align="center" class="Botrule Rrule"> <p class="First">3 (1.6)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Irritability Associated with Autistic Disorder <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">209</p> </td><td align="center" class="Botrule Rrule"> <p class="First">55 (26.3)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule"> <p class="First">98</p> </td><td align="center" class="Botrule Rrule"> <p class="First">7 (7.1)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" rowspan="2"> <p class="First">Tourette’s Disorder <span class="Sup">‡</span> </p> </td><td align="center" class="Botrule Rrule"> <p class="First">Aripiprazole</p> </td><td align="center" class="Botrule Rrule"> <p class="First">105</p> </td><td align="center" class="Botrule Rrule"> <p class="First">21 (20.0)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule"> <p class="First">66</p> </td><td align="center" class="Botrule Rrule"> <p class="First">5 (7.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5"> <p class="First"> <span class="Sup">*</span>4-6 weeks duration. <span class="Sup">†</span>8 weeks duration. <span class="Sup">‡</span>8-10 weeks duration. </p> </td> </tr> </tbody> </table></div>

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

In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novopatients, 60.3% (199/330) completed one year of therapy with aripiprazole. The mean change in weight z-score was 0.26 SDs for patients receiving greater than 9 months of treatment.

When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

Aripiprazole may cause orthostatic hypotension, perhaps due to its α 1-adrenergic receptor antagonism.

The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2,467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); and of pediatric patients 6 to 18 years of age (n=732) on oral aripiprazole included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%) [see Adverse Reactions (6.1)].

The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure greater than or equal to 20 mmHg accompanied by an increase in heart rate greater than or equal to 25 bpm when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adult oral aripiprazole-treated patients (4%, 2%) or in pediatric oral aripiprazole-treated patients aged 6 to 18 years (0.4%, 1%).

Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see Drug Interactions (7.1)] .

Antipsychotics, including aripiprazole, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of aripiprazole at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue aripiprazole in patients with severe neutropenia (absolute neutrophil count <1,000/mm 3) and follow their WBC counts until recovery.

In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2,467) of undiagnosed adult patients treated with oral aripiprazole and in 0.1% (1/732) of pediatric patients (6 to 18 years).

As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Aripiprazole, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2,467) treated with oral aripiprazole (11%, 6%) and in pediatric patients ages 6 to 17 (n=611) (24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral aripiprazole in short-term, placebo-controlled trials.

Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with aripiprazole does not affect them adversely.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see Adverse Reactions (6.2)] .

The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and major depressive disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for aripiprazole should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see Adverse Reactions ( 6.1, 6.2)] .

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1)and Adverse Reactions (6.2)] .

Adult Patients with Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6- week) in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day.

Commonly Observed Adverse Reactions

The only commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).

Adult Patients with Bipolar Mania

Monotherapy

The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral aripiprazole was administered at doses of 15 or 30 mg/day.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in patients with bipolar mania (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 16.

Table 16: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with Oral Aripiprazole Monotherapy

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule"> <p class="First"> <span class="Bold">Aripiprazole (n=917)</span> </p> </td><td align="center" class="Botrule Rrule"> <p class="First"> <span class="Bold">Placebo (n=753)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Akathisia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sedation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Restlessness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tremor</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Extrapyramidal Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

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 aripiprazole (doses greater than or equal to2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.

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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction <span class="Sup">*</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">System Organ Class</span> </p> <p> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Aripiprazole</span> </p> <p> <span class="Bold">(n=1843)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">(n=1166)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Eye Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Blurred Vision</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Nausea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Constipation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Vomiting</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dyspepsia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dry Mouth</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Toothache</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Abdominal Discomfort</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Stomach Discomfort</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">General Disorders and Administration Site Conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Fatigue</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Musculoskeletal Stiffness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Pain in Extremity</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Myalgia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Muscle Spasms</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Headache</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dizziness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Akathisia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Sedation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Extrapyramidal Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Tremor</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Somnolence</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Agitation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Insomnia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Anxiety</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Restlessness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Pharyngolaryngeal Pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Cough</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule" colspan="3" valign="top"> <p class="First"> <span class="Sup">*</span>Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. </p> </td> </tr> </tbody> </table></div>

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Adult Patients with Adjunctive Therapy with Bipolar Mania

The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which aripiprazole was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate.

Adverse Reactions Associated with Discontinuation of Treatment

In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive aripiprazole compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive aripiprazole-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively).

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with adjunctive aripiprazole and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder.

Less Common Adverse Reactions in Adult Patients with Adjunctive Therapy in Bipolar Mania

Table 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 aripiprazole (doses of 15 or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate.

Table 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction <span class="Sup">*</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">System Organ Class Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Aripiprazole <span class="Sup">+</span></span> </p> <p> <span class="Bold">Li or Val <span class="Sup">†</span>(n=253) </span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo <span class="Sup">+</span></span> </p> <p> <span class="Bold">Li or Val <span class="Sup">†</span>(n=130) </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">      Nausea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Vomiting</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Salivary Hypersecretion</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dry Mouth</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Infections and Infestations</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Nasopharyngitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Investigations</span> </p> <p>   Weight Increased</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Akathisia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tremor</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Extrapyramidal Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dizziness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Sedation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Insomnia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Anxiety</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Restlessness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Sup">*</span>Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. </p> <p> <span class="Sup">†</span>Lithium or Valproate </p> </td> </tr> </tbody> </table></div>

Pediatric Patients (13 to 17 years) with Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo- treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Pediatric Patients (10 to 17 years) with Bipolar Mania

The following findings are based on one 4-week, placebo-controlled trial in which oral aripiprazole was administered in doses of 10 or 30 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo- treated pediatric patients (10 to 17 years) was 7% and 2%, respectively.

Commonly Observed Adverse Reactions

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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Toprule" valign="top"></td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">Aripiprazole (n=197)</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">Placebo (n=97)</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Somnolence</p> </td><td align="center" valign="top"> <p class="First">23</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Extrapyramidal Disorder</p> </td><td align="center" valign="top"> <p class="First">20</p> </td><td align="center" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td valign="top"> <p class="First">Fatigue</p> </td><td align="center" valign="top"> <p class="First">11</p> </td><td align="center" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td valign="top"> <p class="First">Nausea</p> </td><td align="center" valign="top"> <p class="First">11</p> </td><td align="center" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td valign="top"> <p class="First">Akathisia</p> </td><td align="center" valign="top"> <p class="First">10</p> </td><td align="center" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td valign="top"> <p class="First">Blurred Vision</p> </td><td align="center" valign="top"> <p class="First">8</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First">Salivary Hypersecretion</p> </td><td align="center" valign="top"> <p class="First">6</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1</p> </td> </tr> </tbody> </table></div>

Pediatric Patients (6 to 17 years) with Autistic Disorder

The following findings are based on two 8-week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 to 15 mg/day.

Adverse Reactions Associated with Discontinuation of Treatment

The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo- treated pediatric patients (6 to 17 years) was 10% and 8%, respectively.

Commonly Observed Adverse Reactions

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with autistic disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 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 Aripiprazole

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <thead> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Aripiprazole (n=212)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo (n=101)</span> </p> </td> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sedation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">17</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Tremor</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pyrexia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Drooling</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Decreased Appetite</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Salivary Hypersecretion</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Extrapyramidal Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lethargy</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

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 aripiprazole 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 aripiprazole-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 aripiprazole in pediatric patients with Tourette's disorder (incidence of 5% or greater and aripiprazole 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 Aripiprazole

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Aripiprazole (n=121)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo (n=72)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Sedation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nasopharyngitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Increased Appetite</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> </tbody> </table></div>

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 aripiprazole (doses greater than or equal to 2 mg/day) and for which the incidence in patients treated with aripiprazole 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 Aripiprazole

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <thead> <tr> <td class="Botrule Toprule" valign="top"></td><td align="center" class="Botrule Toprule" colspan="4" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction <span class="Sup">*</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">System Organ Class</span> </p> <p> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Aripiprazole (n=732)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo (n=370)</span> </p> </td> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Eye Disorders</span> </p> <p>   Blurred Vision</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> </td><td class="Botrule Rrule" colspan="3" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Abdominal Discomfort</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Vomiting</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Diarrhea</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Salivary Hypersecretion</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Abdominal Pain Upper</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Constipation</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">General Disorders and Administration Site Conditions</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Fatigue</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Pyrexia</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Irritability</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Asthenia</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Infections and Infestations</span> </p> </td><td class="Botrule Rrule" colspan="3" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Nasopharyngitis</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Investigations</span> </p> </td><td class="Botrule Rrule" colspan="3" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Weight Increased</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Metabolism and Nutrition Disorders</span> </p> </td><td class="Botrule Rrule" colspan="3" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Increased Appetite</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Decreased Appetite</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Musculoskeletal Stiffness</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Muscle Rigidity</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> </td><td class="Botrule Rrule" colspan="3" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Somnolence</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">16</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Headache</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Sedation</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Tremor</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Extrapyramidal Disorder</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Akathisia</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Drooling</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Lethargy</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dizziness</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dystonia</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Epistaxis</p> </td><td align="center" class="Botrule Rrule" colspan="3" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Skin and Subcutaneous Tissue Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First">   Rash</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" colspan="2" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule" colspan="5" valign="top"> <p class="First"> <span class="Sup">*</span>Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. </p> </td> </tr> </tbody> </table></div>

Adult Patients Receiving Aripiprazole as Adjunctive Treatment of Major Depressive Disorder

The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which aripiprazole was administered at doses of 2 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 aripiprazole-treated patients and 2% for adjunctive placebo-treated patients.

Commonly Observed Adverse Reactions

The commonly observed adverse reactions associated with the use of adjunctive aripiprazole in patients with major depressive disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.

Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder

Table 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 aripiprazole (doses greater than or equal to 2 mg/day) and for which the incidence in patients treated with adjunctive aripiprazole was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

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

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <thead> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Percentage of Patients Reporting Reaction <span class="Sup">*</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">System Organ Class</span> </p> <p> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Aripiprazole + ADT <span class="Sup">†</span></span> </p> <p> <span class="Bold">(n=371)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo + ADT <span class="Sup">†</span></span> </p> <p> <span class="Bold">(n=366)</span> </p> </td> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Eye Disorders</span> </p> <p>   Blurred Vision</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal Disorders</span> </p> <p>   Constipation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General Disorders and Administration Site Conditions</span> </p> <p>   Fatigue <br/>    Feeling Jittery </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> 8 </p> <p>3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <br/> 4 </p> <p>1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Infections and Infestations</span> </p> <p>   Upper Respiratory Tract Infection</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Investigations</span> </p> <p>   Weight Increased</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Metabolism and Nutrition Disorders</span> </p> <p>   Increased Appetite</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Musculoskeletal and Connective Tissue Disorders</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Arthralgia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Myalgia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System Disorders</span> </p> <p>   Akathisia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Somnolence</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Tremor</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Sedation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Dizziness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Disturbance in Attention</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Extrapyramidal Disorder</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Psychiatric Disorders</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Restlessness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Insomnia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule" colspan="3" valign="top"> <p class="First"> <span class="Sup">*</span>Adverse reactions reported by at least 2% of patients treated with adjunctive aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. </p> <p> <span class="Sup">†</span>Antidepressant Therapy </p> </td> </tr> </tbody> </table></div>

Dose-Related Adverse Reactions

Schizophrenia

Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).

In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%).

Bipolar Mania

In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%).

Autistic Disorder

In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).

Tourette’s Disorder

In a study of pediatric patients (7 to 17 years of age) with Tourette’s disorder, no common adverse reaction(s) had a dose response relationship.

Extrapyramidal Symptoms

Schizophrenia

In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS- related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia- related events for aripiprazole-treated patients was 9% vs. 6% for placebo.

Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, -0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole, 0.24; placebo, -0.29).

Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo.

Bipolar Mania

In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS- related events, excluding events related to akathisia, for monotherapy aripiprazole-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy aripiprazole-treated patients was 13% vs. 4% for placebo. In the 6-week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive aripiprazole-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive aripiprazole- treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 10% vs. 2% for placebo.

In the adult bipolar mania trials with monotherapy aripiprazole, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.50; placebo, -0.01 and aripiprazole, 0.21; placebo, -0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. In the bipolar mania trials with aripiprazole as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.73; placebo, 0.07 and aripiprazole, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive aripiprazole and adjunctive placebo. In the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.90; placebo, -0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.

Major Depressive Disorder

In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive aripiprazole-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.

In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.31; placebo, 0.03 and aripiprazole, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo groups.

Autistic Disorder

In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole- treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 3% vs. 9% for placebo.

In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.1; placebo, - 0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.

Tourette’s Disorder

In the short-term, placebo-controlled trials in Tourette’s disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole- treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 4% vs. 6% for placebo.

In the pediatric (6 to 18 years) short-term Tourette’s disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for aripiprazole and placebo.

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Additional Findings Observed in Clinical Trials

Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials

The adverse reactions reported in a 26-week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 less than or equal to 49 days), and were of limited duration (7/12 less than or equal to 10 days). Tremor infrequently led to discontinuation (less than 1%) of aripiprazole. In addition, in a long-term (52 week), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole. A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder.

Other Adverse Reactions Observed During the Premarketing Evaluation of Aripiprazole

The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequentadverse reactions are those occurring in at least 1/100 patients; infrequentadverse reactions are those occurring in 1/100 to 1/1,000 patients; rarereactions are those occurring in fewer than 1/1,000 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– blood prolactin decreased, weight decreased, infrequent- hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare- blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased

Metabolism and Nutrition Disorders:

      frequent- anorexia; rare- hypokalemia, hyponatremia, hypoglycemia

Musculoskeletal and Connective Tissue Disorders:

      infrequent- muscular weakness, muscle tightness; rare- rhabdomyolysis, mobility decreased

Nervous System Disorders:

      infrequent- parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, bradykinesia; rare- akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; <1/10,000 patients- choreoathetosis

Psychiatric Disorders:

      infrequent- aggression, loss of libido, delirium; rare- libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking

Renal and Urinary Disorders:

      rare- urinary retention, nocturia

Reproductive System and Breast Disorders:

      infrequent- erectile dysfunction; rare- gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism

Respiratory, Thoracic, and Mediastinal Disorders: infrequent- nasal congestion, dyspnea

Skin and Subcutaneous Tissue Disorders:

      infrequent- rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare- urticaria

Vascular Disorders:

      infrequent- hypotension, hypertension

Pediatric Patients - Oral Administration

Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below.

Eye Disorders

      infrequent- oculogyric crisis

Gastrointestinal Disorders:

      infrequent-tongue dry, tongue spasm

Investigations:

      frequent- blood insulin increased

Nervous System Disorders: infrequent- sleep talking

Renal and Urinary Disorders frequent- enuresis

Skin and Subcutaneous Tissue Disorders: infrequent- hirsutism

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 establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups, blood glucose fluctuation, oculogyric crisis, drug reaction with eosinophilia and systemic symptoms (DRESS) and fecal incontinence.

Table 25: Clinically Important Drug Interactions with Aripiprazole:

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Concomitant Drug Name or Drug Class</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Clinical Rationale</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Clinical Recommendation</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g.,</p> <p>quinidine, fluoxetine, paroxetine)</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone <span class="Italics">[see <a href="#sec_6583667589">Clinical Pharmacology (12.3)</a>]. </span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage <span class="Italics">[see <a href="#sec_9089758673">Dosage and Administration (2.7)</a>]. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone <span class="Italics">[see <a href="#sec_6583667589">Clinical Pharmacology (12.3)</a>]. </span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage <span class="Italics">[see <a href="#sec_9089758673">Dosage and Administration (2.7)</a>]. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Antihypertensive Drugs</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor blood pressure and adjust dose accordingly <span class="Italics">[see <a href="#sec_7686898282">Warnings and Precautions (5.8)</a>]. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Benzodiazepines (e.g., lorazepam)</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone <span class="Italics">[see <a href="#sec_7686898282">Warnings and Precautions (5.8)</a>]. </span> </p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Monitor sedation and blood pressure. Adjust dose accordingly.</p> </td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, lorazepam.

In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole [see Clinical Pharmacology (12.3)].

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, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see Clinical Considerations).Aripiprazole exposure during pregnancy can have variable effects on milk supply in the post-partum period. [see Use in Specific Populations (8.2)].

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 2body 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 2body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data).

The 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 background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

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

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

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including 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 9,258 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 2body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the MRHD; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

In pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the MRHD of 30 mg/day based on mg/m 2body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the MRHD; this dose also caused maternal toxicity.

In pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the MRHD of 30 mg/day based on mg/m 2body 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 pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the MRHD of 30 mg/day based on mg/m 2body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the MRHD; this dose also caused maternal toxicity. The fetal no-effect dose was 10 mg/kg/day, which is 6 times the MRHD.

In rats treated orally with aripiprazole peri- and post-natally from gestation day 17 through postpartum day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the MRHD of 30 mg/day based on mg/m 2body 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.

In rats injected intravenously with aripiprazole from gestation day 6 through lactation day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the MRHD of 30 mg/day based on mg/m 2body surface area, increased stillbirths were observed at 3 and 6 times the MRHD; and decreases in early postnatal pup weight and survival were observed at 6 times the MRHD; these doses also caused some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

Risk Summary

Aripiprazole is present in human breast milk. Based on published case reports and pharmacovigilance reports, aripiprazole exposure during pregnancy and/or the postpartum period can lead to variable effects on milk supply in the post-partum period, including clinically relevant decreases in milk supply which may be reversible with discontinuation of the drug. There are also reports of aripiprazole exposure during pregnancy and no maternal milk supply in the post-partum period. Effects on milk supply are likely mediated through decreases in prolactin levels, which have been observed [see Adverse Reactions (6.2)] . The developmental 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.

Clinical Considerations

Monitor infants exposed to aripiprazole through breastmilk for dehydration and lack of appropriate weight gain.

Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established.

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (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.

Bipolar I Disorder

Safety and effectiveness in pediatric patients with bipolar mania were established in a 4-week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Studies (14.2)]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

The efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. However, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

Irritability Associated with Autistic Disorder

Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see Indications and Usage (1), Dosage and Administration (2.4), Adverse Reactions (6.1), and Clinical Studies (14.4)]. A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as greater than 25% improvement on the ABC-I subscale, and a CGI-I rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. In this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established.

Tourette’s Disorder

Safety and effectiveness of aripiprazole in pediatric patients with Tourette’s Disorder were established in one 8-week (aged 7 to 17) and one 10-week trial (aged 6 to 18) in 194 pediatric patients [see Dosage and Administration (2.5), Adverse Reactions (6.1), and Clinical Studies (14.5)]. Maintenance efficacy in pediatric patients has not been systematically evaluated.

Juvenile Animal Studies

Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24) 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 0-24) 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.

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 in clinical trials, 1,073 (8%) were greater than or equal to 65 years old and 799 (6%) were greater than or equal to 75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Aripiprazole is not approved for the treatment of patients with psychosis associated with Alzheimer’s disease [see Boxed Warningand Warnings and Precautions (5.1)].

Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.7)and Clinical Pharmacology (12.3)].

No dosage adjustment for aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)].

No dosage adjustment for aripiprazole is required on the basis of a patient’s sex, race, or smoking status [see Clinical Pharmacology (12.3)].

Aripiprazole is not a controlled substance.

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

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

In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.

Charcoal:In the event of an overdose of aripiprazole, 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 aripiprazole, decreased the mean AUC and C maxof aripiprazole by 50%.

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

Aripiprazole, USP is an atypical antipsychotic drug that is available as aripiprazole oral solution. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4- dihydrocarbostyril. The empirical formula is C 23H 27C l2N 3O 2and its molecular weight is 448.38. The chemical structure is:

{ "type": "p", "children": [], "text": "Aripiprazole, USP is an atypical antipsychotic drug that is available as aripiprazole oral solution. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4- dihydrocarbostyril. The empirical formula is C\n \n 23H\n \n 27C\n \n l2N\n \n 3O\n \n 2and its molecular weight is 448.38. The chemical structure is:\n\n " }

Aripiprazole oral solution is a clear to pale yellow solution with orange flavor available in a concentration of 1 mg/mL. The inactive ingredients for this solution include disodium edetate, fructose, glycerin, malic acid, methylparaben, orange flavor, propylene glycol, propylparaben, sodium hydroxide, sucrose and purified water.

{ "type": "p", "children": [], "text": "Aripiprazole oral solution is a clear to pale yellow solution with orange flavor available in a concentration of 1 mg/mL. The inactive ingredients for this solution include disodium edetate, fructose, glycerin, malic acid, methylparaben, orange flavor, propylene glycol, propylparaben, sodium hydroxide, sucrose and purified water." }

The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D 2and 5-HT 1Areceptors and antagonist activity at 5-HT 2Areceptors.

Aripiprazole exhibits high affinity for dopamine D 2and D 3, serotonin 5-HT 1Aand 5-HT 2Areceptors (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, alpha 1-adrenergic and histamine H 1receptors (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>1,000 nM).

Aripiprazole oral solution 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 2receptors 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

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 C maxand AUC values were 122% and 114%, respectively [see Dosage and Administration (2.6)]. 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 D 2receptor 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 vitrostudies, 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 maxand 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 maxand 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

Effect of Other Drugs on Aripiprazole

Figure 2: The effects of other drugs on dehydro-aripiprazole pharmacokinetics

Effect of Other Drugs on Aripiprazole

The effects of aripiprazole on the exposures of other drugs are summarized in Figure 3. A population PK analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of fluoxetine (20 or 40 mg/day), paroxetine CR (37.5 or 50 mg/day), or sertraline (100 or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively, and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole.

Figure 3: The effects of Aripiprazole on pharmacokinetics of other drugs

Effect of Aripiprazole on Other Drugs

Studies in Specific Populations

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

Figure 4: Effects of intrinsic factors on aripiprazole pharmacokinetics

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

Carcinogenesis

Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m 2body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m 2body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD).

An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D 2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4- week and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear.

Mutagenesis

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

Impairment of Fertility

Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m 2body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD.

Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m 2body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility.

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

Adults

The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five short-term (4- week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish aripiprazole from placebo, but one study, the smallest, did not. Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole and the active comparators.

In the four positive trials for aripiprazole, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

In a 4-week trial (n=414) comparing two fixed doses of aripiprazole (15 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 1 in Table 26), PANSS positive subscale, and CGI-severity score. In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale.

In a 4-week trial (n=404) comparing two fixed doses of aripiprazole (20 or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative subscale, and CGI- severity score.

In a 6-week trial (n=420) comparing three fixed doses of aripiprazole (10, 15, or 20 mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS negative subscale.

In a 6-week trial (n=367) comparing three fixed doses of aripiprazole (2, 5, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole was superior to placebo in the PANSS total score (Study 4 in Table 26), the primary outcome measure of the study. 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 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 greater than or equal to 5 (minimally worse), scores greater than or equal to 5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or greater than or equal to 20% increase in the PANSS total score. Patients receiving aripiprazole 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6).

Pediatric Patients

The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score greater than or equal to 70 at baseline. In this trial (n=302) comparing two fixed doses of aripiprazole (10 or 30 mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

Table 26: Schizophrenia Studies

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <thead> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Study Number</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Primary Efficacy Measure: PANSS</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Mean Baseline Score (SD)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">LS Mean</span> </p> <p> <span class="Bold">Change from Baseline (SE)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo-subtracted</span><span class="Bold">Difference* (95% CI)</span> </p> </td> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="top"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (15 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">98.5 (17.2)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-15.5 (2.40)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-12.6 (-18.9, -6.2)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (30 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">99.0 (19.2)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-11.4 (2.39)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.5 (-14.8, -2.1)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">100.2 (16.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-2.9 (2.36)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="top"> <p class="First">Study 2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (20 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">92.6 (19.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-14.5 (2.23)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-9.6 (-15.4, -3.8)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (30 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">94.2 (18.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-13.9 (2.24)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-9.0 (-14.8, -3.1)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">94.3 (18.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.0 (2.17)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="4" valign="top"> <p class="First">Study 3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (10 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">92.7 (19.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-15.0 (2.38)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-12.7 (-19.00, -6.41)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (15 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">93.2 (21.6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-11.7 (2.38)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-9.4 (-15.71, -3.08)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (20 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">92.5 (20.9)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-14.4 (2.45)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-12.1 (-18.53, -5.68)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">92.3 (21.8)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-2.3 (2.35)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="4" valign="top"> <p class="First">Study 4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (2 mg/day)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">90.7 (14.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.2 (1.90)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-2.9 (-8.29, 2.47)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (5 mg/day)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">92.0 (12.6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-10.6 (1.93)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.2 (-10.7, 0.19)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (10 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">90.0 (11.9)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-11.3 (1.88)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.9 (-11.3, -0.58)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">90.8 (13.3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.3 (1.97)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="top"> <p class="First">Study 6</p> <p>(Pediatric, 13-17 years)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (10 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">93.6 (15.7)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-26.7 (1.91)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.5 (-10.7, -0.21)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (30 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">94.0 (16.1)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-28.6 (1.92)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-7.4 (-12.7, -2.13)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">94.6 (15.6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-21.2 (1.93)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td colspan="5"> <p class="First">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</p> <p> <span class="Sup">*</span>Difference (drug minus placebo) in least-squares mean change from baseline. </p> <p> <span class="Sup">†</span>Doses statistically significantly superior to placebo. </p> </td> </tr> </tbody> </table></div>

Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

Acute Treatment of Manic and Mixed Episodes

Adults

Monotherapy

The efficacy of aripiprazole as monotherapy in the acute treatment of manic episodes was established in four 3-week, placebo-controlled trials in hospitalized patients who met the DSM- IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and two of the studies also included patients with or without a rapid-cycling course.

The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y- MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) Scale.

In the four positive, 3-week, placebo-controlled trials (n=268; n=248; n=480; n=485) which evaluated aripiprazole in a range of 15 mg to 30 mg, once daily (with a starting dose of 30 mg/day in two studies and 15 mg/day in two studies), aripiprazole was superior to placebo in the reduction of Y-MRS total score (Studies 1 to 4 in Table 27) and CGI-BP Severity of Illness score (mania). In the two studies with a starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint.

Adjunctive Therapy

The efficacy of adjunctive aripiprazole with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6-week, placebo-controlled study (n=384) with a 2- week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This study included patients with manic or mixed episodes and with or without psychotic features.

Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score greater than or equal to 16 and less than or equal to 25% improvement on the Y-MRS total score) to lithium or valproate were randomized to receive either aripiprazole (15 mg/day or an increase to 30 mg/day as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate. In the 6-week, placebo-controlled phase, adjunctive aripiprazole starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0.6 to 1.0 mEq/L or 50 to 125 μg/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the Y- MRS total score (Study 5 in Table 27) and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6-week endpoint.

Pediatric Patients

The efficacy of aripiprazole in the treatment of bipolar I disorder in pediatric patients (10 to 17 years of age) was evaluated in one 4-week, placebo-controlled trial (n=296) of outpatients who met DSM- IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score greater than or equal to 20 at baseline. This double-blind, placebo-controlled trial compared two fixed doses of aripiprazole (10 or 30 mg/day) to placebo. The aripiprazole dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm, and in 13 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in change from baseline to week 4 on the Y-MRS total score (Study 6 in Table 27).

Table 27: Bipolar Studies

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <thead> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Study Number</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Primary Efficacy Measure: Y-MRS</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Mean Baseline</span> </p> <p> <span class="Bold">Score (SD)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">LS Mean Change from</span> </p> <p> <span class="Bold">Baseline (SE)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo-subtracted</span><span class="Bold">Difference*</span> </p> <p> <span class="Bold">(95% CI)</span> </p> </td> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Aripiprazole (30 / 15 mg/day) <span class="Sup">†</span> </p> <p>Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29.0 (5.9)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-12.52 (1.05)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.33 (-7.90, -2.76)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.5 (4.6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-7.19 (1.07)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Study 2</p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Aripiprazole (30 / 15 mg/day) <span class="Sup">†</span> </p> <p>Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27.8 (5.7)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.15 (1.23)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-4.80 (-7.80, -1.80)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">29.1 (6.9)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-3.35 (1.22)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Study 3</p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Aripiprazole (15 - 30 mg/day) <span class="Sup">†</span> </p> <p>Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.5 (5.6)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-12.64 (0.84)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-3.63 (-5.75 , -1.51)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.9 (5.9)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9.01 (0.81)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Study 4</p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Aripiprazole (15 -30 mg/day) <span class="Sup">†</span> </p> <p>Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.0 (5.8)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-11.98 (0.80)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-2.28 (-4.44 , -0.11)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.3 (5.8)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-9.70 (0.83)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Study 5</p> </td><td align="center" class="Botrule Rrule" rowspan="2" valign="top"> <p class="First">Aripiprazole (15 or 30 mg/day) <span class="Sup">†</span> </p> <p>+ Lithium/Valproate</p> <p>Placebo + Lithium/Valproate</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23.2 (5.7)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-13.31 (0.50)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-2.62 (-4.29 , -0.95)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">23.0 (4.9)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-10.70 (0.69)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="top"> <p class="First">Study 6</p> <p>(Pediatric, 10 to 17 years)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (10 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29.8 (6.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-14.2 (0.89)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.99 (-8.49, -3.50)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (30 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29.5 (6.3)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-16.5 (0.87)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.26 (-10.7, -5.77)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30.7 (6.8)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.2 (0.91)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td colspan="5"> <p class="First">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</p> <p> <span class="Sup">*</span>Difference (drug minus placebo) in least-squares mean change from baseline. </p> <p> <span class="Sup">†</span>Doses statistically significantly superior to placebo. </p> </td> </tr> </tbody> </table></div>

Maintenance Treatment of Bipolar I Disorder

Monotherapy Maintenance Therapy

A maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label aripiprazole and who had maintained a clinical response for at least 6 weeks. The first phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label aripiprazole (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one outpatients were then randomized in a double-blind fashion, to either the same dose of aripiprazole they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse. During the randomization phase, aripiprazole was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study (Study 7 in Figure 7). A total of 55 mood events were observed during the double-blind treatment phase. Nineteen were from the aripiprazole group and 36 were from the placebo group. The number of observed manic episodes in the aripiprazole group (6) were fewer than that in the placebo group (19), while the number of depressive episodes in the aripiprazole group (9) was similar to that in the placebo group (11).

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences.

Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7)

Adjunctive Maintenance Therapy

An adjunctive maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode. Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score greater than or equal to 16 and less than or equal to 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 less than or equal to 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 greater than 16 and/or a MADRS greater than 16, or an SAE of worsening disease accompanied by Y-MRS score greater than 16 and/or a MADRS greater than 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 52- week, double-blind treatment phase for aripiprazole and placebo groups are shown in Figure 8.

Figure 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse to Any Mood Event (Bipolar Study 8)

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences.

Adults

The efficacy of aripiprazole in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). Inadequate response for prospective treatment was defined as less than 50% improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose.

The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme).

In the two trials (n=381, n=362), aripiprazole was superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 28). In one study, aripiprazole was also superior to placebo in reducing the mean SDS score.

In both trials, patients received aripiprazole adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4 mg/day.

An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females.

Table 28: Adjunctive Treatment of Major Depressive Disorder Studies

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <thead> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Study Number</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Primary Efficacy Measure: MADRS</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Mean Baseline</span> </p> <p> <span class="Bold">Score (SD)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">LS Mean Change from</span> </p> <p> <span class="Bold">Baseline (SE)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo-subtracted</span><span class="Bold">Difference <span class="Sup">*</span>(95% CI) </span> </p> </td> </tr> </thead> <tbody> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (5 to 20 mg/day) <span class="Sup">†</span> </p> <p>+ Antidepressant</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25.2 (6.2)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.49 (0.66)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-2.84 (-4.53, - 1.15)</p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo + Antidepressant</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27.0 (5.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.65 (0.64)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (5 to 20 mg/day) <span class="Sup">†</span> </p> <p>+ Antidepressant</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26.0 (6.0)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.78 (0.63)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-3.01 (-4.66, -1.37)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo + Antidepressant</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26.0 (6.5)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.77 (0.67)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td colspan="5"> <p class="First">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</p> <p> <span class="Sup">*</span>Difference (drug minus placebo) in least-squares mean change from baseline. </p> <p> <span class="Sup">†</span>Doses statistically significantly superior to placebo. </p> </td> </tr> </tbody> </table></div>

Pediatric Patients

The efficacy of aripiprazole in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these subjects were under 13 years of age.

Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured symptoms of irritability in autistic disorder.

The results of these trials are as follows:

In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or aripiprazole 2 to 15 mg/day. Aripiprazole, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of aripiprazole at the end of 8-week treatment was 8.6 mg/day (Study 1 in Table 29).

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

Table 29: Irritability Associated with Autistic Disorder Studies (Pediatric)

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Study</span> </p> <p> <span class="Bold">Number</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Primary Efficacy Measure: ABC-I</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Mean Baseline Score (SD)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">LS Mean Change from Baseline (SE)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo-subtracted</span> </p> <p> <span class="Bold">Difference <span class="Sup">*</span>(95% CI) </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (2-15 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29.6 (6.37)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-12.9 (1.44)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-7.9 (-11.7, -4.1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30.2 (6.52)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.0 (1.43)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (5 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.6 (7.56)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-12.4 (1.36)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-4.0 (-7.7, -0.4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (10 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.2 (7.36)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-13.2 (1.25)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-4.8 (-8.4, -1.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (15 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.9 (6.41)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-14.4 (1.31)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-6.0 (-9.6, -2.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.0 (6.89)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-8.4 (1.39)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td colspan="5"> <p class="First">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</p> <p> <span class="Sup">*</span>Difference (drug minus placebo) in least-squares mean change from baseline. </p> <span class="Sup">†</span>Doses statistically significantly superior to placebo. </td> </tr> </tbody> </table></div>

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) greater than or equal to 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., 0-50).

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 less than 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 greater than or equal to 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 less than 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 greater than or equal to 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 CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9.

Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette’s Disorder Study 1)

In the 10-week, placebo-controlled, flexible- dose trial in children and adolescents with Tourette’sdisorder (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.

Table 30: Tourette’s Disorder Studies (Pediatric)

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="60%"> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Study</span> </p> <p> <span class="Bold">Number</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Primary Efficacy Measure: YGTSS TTS</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Mean Baseline Score (SD)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">LS Mean Change from Baseline (SE)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Placebo-subtracted</span> </p> <p> <span class="Bold">Difference <span class="Sup">*</span>(95% CI) </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 1</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (low dose) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29.2 (5.63)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-13.4 (1.59)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-6.3 (-10.2, -2.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (high dose) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">31.2 (6.40)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-16.9 (1.61)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-9.9 (-13.8, -5.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30.7 (5.95)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-7.1 (1.55)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Study 2</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Aripiprazole (2-20 mg/day) <span class="Sup">†</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28.3 (5.51)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-15.0 (1.51)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-5.3 (-9.8, -0.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">Placebo</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29.5 (5.60)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-9.6 (1.64)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">--</p> </td> </tr> <tr> <td colspan="5"> <p class="First">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</p> <p> <span class="Sup">*</span>Difference (drug minus placebo) in least-squares mean change from baseline. </p> <p> <span class="Sup">†</span>Doses statistically significantly superior to placebo. </p> </td> </tr> </tbody> </table></div>

Aripiprazole Oral Solution (1 mg/mL) is supplied in child-resistant bottles. Aripiprazole oral solution is available as follows:

150 mL bottle     NDC 62135-904-51

Oral Solution

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Opened bottles of aripiprazole 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.

Advise the patient to read the FDA-approved patient labeling ( Medication Guide).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (\n \n Medication Guide).\n \n \n" }

Discuss the following issues with patients prescribed aripiprazole:

{ "type": "p", "children": [], "text": "\nDiscuss the following issues with patients prescribed aripiprazole:\n" }

Clinical Worsening of Depression and Suicide Risk

{ "type": "p", "children": [], "text": "\nClinical Worsening of Depression and Suicide Risk\n" }

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

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

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with aripiprazole 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. 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 is not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder.

{ "type": "p", "children": [], "text": "Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with aripiprazole 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. 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 is not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder." }

Pathological Gambling and Other Compulsive Behaviors

{ "type": "p", "children": [], "text": "\nPathological Gambling and Other Compulsive Behaviors\n" }

Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped\n \n [see\n \n Warnings and Precautions (5.7)].\n \n \n" }

Interference with Cognitive and Motor Performance

{ "type": "p", "children": [], "text": "\nInterference with Cognitive and Motor Performance\n" }

Because aripiprazole 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 therapy does not affect them adversely [see Warnings and Precautions (5.12)].

{ "type": "p", "children": [], "text": "Because aripiprazole 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 therapy does not affect them adversely\n \n [see\n \n Warnings and Precautions (5.12)].\n \n \n" }

Concomitant Medication

{ "type": "p", "children": [], "text": "\nConcomitant Medication\n" }

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)].

{ "type": "p", "children": [], "text": "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\n \n [see\n \n Drug Interactions (7)].\n \n \n" }

Heat Exposure and Dehydration

{ "type": "p", "children": [], "text": "\nHeat Exposure and Dehydration\n" }

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Patients should be advised regarding appropriate care in avoiding overheating and dehydration\n \n [see\n \n Warnings and Precautions (5.13)].\n \n \n" }

Sugar Content

{ "type": "p", "children": [], "text": "\nSugar Content\n" }

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

{ "type": "p", "children": [], "text": "Patients should be advised that each mL of Aripiprazole Oral Solution contains 400 mg of sucrose and 200 mg of fructose." }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

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)].

{ "type": "p", "children": [], "text": "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\n \n [see\n \n Use in Specific Populations (8.1)].\n \n \n" }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Aripiprazole use during pregnancy may affect milk supply. Advise the lactating patient to discuss any plans for breastfeeding with their healthcare provider, and to monitor the breastfed infant for dehydration and lack of appropriate weight gain [ see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Aripiprazole use during pregnancy may affect milk supply. Advise the lactating patient to discuss any plans for breastfeeding with their healthcare provider, and to monitor the breastfed infant for dehydration and lack of appropriate weight gain [\n \n see\n \n Use in Specific Populations (8.2)].\n \n \n" }

Manufactured for: Chartwell RX, LLC. Congers, NY 10920

{ "type": "p", "children": [], "text": "\n Manufactured for: \n Chartwell RX, LLC. \n Congers, NY 10920\n " }

L72628

{ "type": "p", "children": [], "text": "L72628" }

Rev. 04/2025

{ "type": "p", "children": [], "text": "Rev. 04/2025" }

<div class="scrollingtable"><table cellspacing="0" class="Noautorules" width="100%"> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">MEDICATION GUIDE</span> </p> <p> <span class="Bold">Aripiprazole</span> </p> <p> <span class="Bold">(ar″ i pip′ ra zole)</span> </p> <p> <span class="Bold">Oral Solution</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about aripiprazole oral solution?</span> </p> <p>(For other side effects, also see “What are the possible side effects of aripiprazole oral solution?”)</p> <p>Serious side effects may happen when you take aripiprazole oral solution, including:</p> <ul> <li> <span class="Bold">Increased risk of death in elderly patients with dementia-related psychosis:</span>Medicines like aripiprazole oral solution can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). Aripiprazole oral solution is not approved for the treatment of patients with dementia- related psychosis. </li> <li> <span class="Bold">Risk of suicidal thoughts or actions:</span>Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions: <ol> <li> <span class="Bold">Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.</span> </li> <li> <span class="Bold">Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions.</span>These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. </li> <li> <span class="Bold">How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?</span> <ul class="Disc"> <li>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.</li> <li>Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.</li> <li>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.</li> </ul> </li> </ol> </li> </ul> <p> <span class="Bold">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:</span> </p> <ul> <li>thoughts about suicide or dying</li> <li>attempts to commit suicide</li> <li>new or worse depression</li> <li>new or worse anxiety</li> <li>feeling very agitated or restless</li> <li>panic attacks</li> <li>trouble sleeping (insomnia)</li> <li>new or worse irritability</li> <li>acting aggressive, being angry, or violent</li> <li>acting on dangerous impulses</li> <li>an extreme increase in activity and talking (mania)</li> <li>other unusual changes in behavior or mood</li> </ul> <p> <span class="Bold">What else do I need to know about antidepressant medicines?</span> </p> <ul> <li> <span class="Bold">Never stop an antidepressant medicine without first talking to a healthcare provider.</span>Stopping an antidepressant medicine suddenly can cause other symptoms. </li> <li> <span class="Bold">Antidepressants are medicines used to treat depression and other illnesses.</span>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. </li> <li> <span class="Bold">Antidepressant medicines have other side effects.</span>Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. </li> <li> <span class="Bold">Antidepressant medicines can interact with other medicines.</span>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. </li> <li> <span class="Bold">Not all antidepressant medicines prescribed for children are FDA approved for use in children.</span>Talk to your child’s healthcare provider for more information. </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is aripiprazole oral solution?</span> </p> <ul class="Disc"> <li> <span class="Bold">Aripiprazole Oral Solution is prescription medicine used to treat:</span> <ul> <li>Schizophrenia</li> <li>manic or mixed episodes that happen with bipolar I disorder</li> <li>major depressive disorder (MDD) when aripiprazole oral solution is used with antidepressant medicines</li> <li>irritability associated with autistic disorder</li> <li>Tourette’s disorder</li> </ul> </li> </ul> <p> <span class="Bold">It is not known if aripiprazole oral solution is safe or effective in children:</span> </p> <ul> <li>under 13 years of age with schizophrenia</li> <li>under 10 years of age with bipolar I disorder</li> <li>under 6 years of age with irritability associated with autistic disorder</li> <li>under 6 years of age with Tourette’s disorder</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Do not take aripiprazole oral solution if you</span>are allergic to aripiprazole or any of the ingredients in aripiprazole oral solution. See the end of this Medication Guide for a complete list of ingredients in aripiprazole oral solution. </p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Before taking aripiprazole oral solution, tell your healthcare provider about all your medical conditions, including if you have or had:</span> </p> <ul> <li>diabetes or high blood sugar in you or your family; your healthcare provider should check your blood sugar before you start aripiprazole oral solution and also during therapy.</li> <li>seizures (convulsions).</li> <li>low or high blood pressure.</li> <li>heart problems or stroke.</li> <li>pregnancy or plans to become pregnant. It is not known if aripiprazole oral solution will harm your unborn baby. <ul class="Circle"> <li>If you become pregnant while receiving aripiprazole oral solution, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866- 961-2388 or go to <span class="Underline"><a href="http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/">http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/</a></span>. </li> </ul> </li> <li>breast-feeding or plans to breast-feed. Aripiprazole passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive aripiprazole oral solution.</li> <li>low white blood cell count.</li> </ul> <p> <span class="Bold">Tell your healthcare provider about all the medicines that you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p> <p>Aripiprazole oral solution and other medicines may affect each other causing possible serious side effects. <br/> Aripiprazole oral solution may affect the way other medicines work, and other medicines may affect how Aripiprazole oral solution works. <br/> Your healthcare provider can tell you if it is safe to take aripiprazole oral solution with your other medicines. Do not start or stop any medicines while taking aripiprazole oral solution 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. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I take aripiprazole oral solution?</span> </p> <ul> <li>Take aripiprazole oral solution exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking aripiprazole oral solution yourself.</li> <li>Aripiprazole oral solution can be taken with or without food.</li> <li>If you miss a dose of aripiprazole oral solution, 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 oral solution at the same time.</li> <li>If you take too much aripiprazole oral solution, call your healthcare provider or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What should I avoid while taking aripiprazole oral solution?</span> </p> <ul class="Disc"> <li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how aripiprazole oral solution affects you. Aripiprazole oral solution may make you drowsy.</li> <li>Avoid getting over-heated or dehydrated. <ul> <li>Do not over-exercise.</li> <li>In hot weather, stay inside in a cool place if possible.</li> <li>Stay out of the sun. Do not wear too much or heavy clothing.</li> <li>Drink plenty of water.</li> </ul> </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of aripiprazole oral solution?</span> </p> <p> <span class="Bold">Aripiprazole oral solution may cause serious side effects, including:</span> </p> <ul> <li> <span class="Bold">See “What is the most important information I should know about aripiprazole oral solution?”</span> </li> <li> <span class="Bold">Stroke in elderly people (cerebrovascular problems) that can lead to death</span> </li> <li> <span class="Bold">Neuroleptic malignant syndrome (NMS).</span>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. </li> <li> <span class="Bold">Uncontrolled body movements (tardive dyskinesia).</span>Aripiprazole oral solution 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 oral solution. Tardive dyskinesia may also start after you stop receiving aripiprazole oral solution. </li> <li> <span class="Bold">Problems with your metabolism such as:</span> <ul class="Square"> <li> <span class="Bold">High blood sugar (hyperglycemia) and diabetes.</span>Increases in blood sugar can happen in some people who take Aripiprazole oral solution. 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 oral solution and during your treatment. <p class="First"> <span class="Bold">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving</span>aripiprazole oral solution: </p> <ul class="Disc"> <li>feel very thirsty</li> <li>need to urinate more than usual</li> <li>feel very hungry</li> <li>feel weak or tired</li> <li>feel sick to your stomach</li> <li>feel confused, or your breath smells fruity</li> </ul> </li> </ul> <ul class="Circle"> <li> <span class="Bold">Increased fat levels (cholesterol and triglycerides) in your blood.</span> </li> <li> <span class="Bold">Weight gain.</span>You and your healthcare provider should check your weight regularly. </li> </ul> </li> </ul> <ul> <li> <span class="Bold">Unusual urges.</span>Some people taking aripiprazole oral solution have had unusual urges, such as gambling, binge eating or eating that you cannot control (compulsive), compulsive shopping and sexual urges. <p class="First">If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</p> </li> <li> <span class="Bold">Orthostatic hypotension (decreased blood pressure).</span>Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position. </li> <li> <span class="Bold">Falls.</span>Aripiprazole oral solution 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. </li> <li> <span class="Bold">Low white blood cell count</span> </li> <li> <span class="Bold">Seizures (convulsions)</span> </li> <li> <span class="Bold">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.</span>See “What should I avoid while receiving aripiprazole oral solution?” </li> <li> <span class="Bold">Difficulty swallowing that can cause food or liquid to get into your lungs.</span> </li> </ul> <p> <span class="Bold">The most common side effects of aripiprazole oral solution in adults include:</span> </p> <p>     • Nausea                                  • dizziness</p> <p>     • vomiting                               • anxiety</p> <p>     • constipation                          • insomnia</p> <p>     • headache                               • restlessness</p> <p>     • blurred vision                        • inner sense of restlessness/need to move (akathisia)</p> <p>     • upper respiratory illness</p> <p> <span class="Bold">The most common side effects of aripiprazole oral solution in children include:</span> </p> <p>     • feeling sleepy                                     • insomnia</p> <p>     • headache                                             • nausea</p> <p>     • vomiting                                            • stuffy nose</p> <p>     • fatigue                                               • weight gain</p> <p>     • increased or decreased appetite        • uncontrolled movement such as restlessness, tremor</p> <p>     • increased saliva or drooling              • muscle stiffness</p> <p>These are not all the possible side effects of aripiprazole oral solution.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I store aripiprazole oral solution?</span> </p> <ul> <li>Store aripiprazole oral solution at room temperature, between 68°F to 77°F (20°C to 25°C).</li> <li>Opened bottles of Aripiprazole Oral Solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle.</li> <li>Aripiprazole oral solution is supplied in child-resistant bottles.</li> </ul> <span class="Bold">Keep aripiprazole oral solution and all medicines out of the reach of children.</span></td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of aripiprazole oral solution</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use aripiprazole oral solution for a condition for which it was not prescribed. Do not give aripiprazole oral solution to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about aripiprazole oral solution that was written for healthcare professionals.</p> </td> </tr> <tr> <td align="justify" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in aripiprazole oral solution?</span> </p> <p> <span class="Bold">Active ingredient:</span>Aripiprazole, USP </p> <p> <span class="Bold">Inactive ingredients:</span> <br/> <span class="Bold">Aripiprazole oral solution:</span>disodium edetate, fructose, glycerin, malic acid, methylparaben, orange flavor, propylene glycol, propylparaben, sodium hydroxide, sucrose and purified water. </p> <br/> <p>For more information about aripiprazole oral solution contact <span class="Bold">Chartwell RX, LLC. at 1-845-232-1683</span>. </p> <p> <br/> Manufactured for: <br/> Chartwell RX, LLC. <br/> Congers, NY 10920 </p> <p> <br/> L72629 <br/> <br/> Rev. 04/2025 </p> </td> </tr> <tr> <td valign="top"> <p class="First">This Medication Guide has been approved by the U.S. Food and Drug Administration                                                                                                                                         Revised: 04/2025</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellspacing=\"0\" class=\"Noautorules\" width=\"100%\">\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">MEDICATION GUIDE</span>\n</p>\n<p>\n<span class=\"Bold\">Aripiprazole</span>\n</p>\n<p>\n<span class=\"Bold\">(ar″ i pip′ ra zole)</span>\n</p>\n<p>\n<span class=\"Bold\">Oral Solution</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about aripiprazole oral solution?</span>\n</p>\n<p>(For other side effects, also see “What are the possible side effects of aripiprazole oral solution?”)</p>\n<p>Serious side effects may happen when you take aripiprazole oral solution, including:</p>\n<ul>\n<li>\n<span class=\"Bold\">Increased risk of death in elderly patients with dementia-related psychosis:</span>Medicines like aripiprazole oral solution can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). Aripiprazole oral solution is not approved for the treatment of patients with dementia- related psychosis.\n \n </li>\n<li>\n<span class=\"Bold\">Risk of suicidal thoughts or actions:</span>Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions:\n \n <ol>\n<li>\n<span class=\"Bold\">Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.</span>\n</li>\n<li>\n<span class=\"Bold\">Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions.</span>These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.\n \n </li>\n<li>\n<span class=\"Bold\">How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?</span>\n<ul class=\"Disc\">\n<li>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.</li>\n<li>Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.</li>\n<li>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.</li>\n</ul>\n</li>\n</ol>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">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:</span>\n</p>\n<ul>\n<li>thoughts about suicide or dying</li>\n<li>attempts to commit suicide</li>\n<li>new or worse depression</li>\n<li>new or worse anxiety</li>\n<li>feeling very agitated or restless</li>\n<li>panic attacks</li>\n<li>trouble sleeping (insomnia)</li>\n<li>new or worse irritability</li>\n<li>acting aggressive, being angry, or violent</li>\n<li>acting on dangerous impulses</li>\n<li>an extreme increase in activity and talking (mania)</li>\n<li>other unusual changes in behavior or mood</li>\n</ul>\n<p>\n<span class=\"Bold\">What else do I need to know about antidepressant medicines?</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">Never stop an antidepressant medicine without first talking to a healthcare provider.</span>Stopping an antidepressant medicine suddenly can cause other symptoms.\n \n </li>\n<li>\n<span class=\"Bold\">Antidepressants are medicines used to treat depression and other illnesses.</span>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.\n \n </li>\n<li>\n<span class=\"Bold\">Antidepressant medicines have other side effects.</span>Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.\n \n </li>\n<li>\n<span class=\"Bold\">Antidepressant medicines can interact with other medicines.</span>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.\n \n </li>\n<li>\n<span class=\"Bold\">Not all antidepressant medicines prescribed for children are FDA approved for use in children.</span>Talk to your child’s healthcare provider for more information.\n \n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is aripiprazole oral solution?</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Aripiprazole Oral Solution is prescription medicine used to treat:</span>\n<ul>\n<li>Schizophrenia</li>\n<li>manic or mixed episodes that happen with bipolar I disorder</li>\n<li>major depressive disorder (MDD) when aripiprazole oral solution is used with antidepressant medicines</li>\n<li>irritability associated with autistic disorder</li>\n<li>Tourette’s disorder</li>\n</ul>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">It is not known if aripiprazole oral solution is safe or effective in children:</span>\n</p>\n<ul>\n<li>under 13 years of age with schizophrenia</li>\n<li>under 10 years of age with bipolar I disorder</li>\n<li>under 6 years of age with irritability associated with autistic disorder</li>\n<li>under 6 years of age with Tourette’s disorder</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Do not take aripiprazole oral solution if you</span>are allergic to aripiprazole or any of the ingredients in aripiprazole oral solution. See the end of this Medication Guide for a complete list of ingredients in aripiprazole oral solution.\n \n </p>\n</td>\n</tr>\n<tr>\n<td align=\"justify\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking aripiprazole oral solution, tell your healthcare provider about all your medical conditions, including if you have or had:</span>\n</p>\n<ul>\n<li>diabetes or high blood sugar in you or your family; your healthcare provider should check your blood sugar before you start aripiprazole oral solution and also during therapy.</li>\n<li>seizures (convulsions).</li>\n<li>low or high blood pressure.</li>\n<li>heart problems or stroke.</li>\n<li>pregnancy or plans to become pregnant. It is not known if aripiprazole oral solution will harm your unborn baby.\n \n <ul class=\"Circle\">\n<li>If you become pregnant while receiving aripiprazole oral solution, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866- 961-2388 or go to\n \n <span class=\"Underline\"><a href=\"http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/\">http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/</a></span>.\n \n </li>\n</ul>\n</li>\n<li>breast-feeding or plans to breast-feed. Aripiprazole passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive aripiprazole oral solution.</li>\n<li>low white blood cell count.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines that you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.\n \n </p>\n<p>Aripiprazole oral solution and other medicines may affect each other causing possible serious side effects. \n <br/> Aripiprazole oral solution may affect the way other medicines work, and other medicines may affect how Aripiprazole oral solution works. \n <br/> Your healthcare provider can tell you if it is safe to take aripiprazole oral solution with your other medicines. Do not start or stop any medicines while taking aripiprazole oral solution 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.\n </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take aripiprazole oral solution?</span>\n</p>\n<ul>\n<li>Take aripiprazole oral solution exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking aripiprazole oral solution yourself.</li>\n<li>Aripiprazole oral solution can be taken with or without food.</li>\n<li>If you miss a dose of aripiprazole oral solution, 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 oral solution at the same time.</li>\n<li>If you take too much aripiprazole oral solution, call your healthcare provider or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking aripiprazole oral solution?</span>\n</p>\n<ul class=\"Disc\">\n<li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how aripiprazole oral solution affects you. Aripiprazole oral solution may make you drowsy.</li>\n<li>Avoid getting over-heated or dehydrated.\n \n <ul>\n<li>Do not over-exercise.</li>\n<li>In hot weather, stay inside in a cool place if possible.</li>\n<li>Stay out of the sun. Do not wear too much or heavy clothing.</li>\n<li>Drink plenty of water.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of aripiprazole oral solution?</span>\n</p>\n<p>\n<span class=\"Bold\">Aripiprazole oral solution may cause serious side effects, including:</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">See “What is the most important information I should know about aripiprazole oral solution?”</span>\n</li>\n<li>\n<span class=\"Bold\">Stroke in elderly people (cerebrovascular problems) that can lead to death</span>\n</li>\n<li>\n<span class=\"Bold\">Neuroleptic malignant syndrome (NMS).</span>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.\n \n </li>\n<li>\n<span class=\"Bold\">Uncontrolled body movements (tardive dyskinesia).</span>Aripiprazole oral solution 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 oral solution. Tardive dyskinesia may also start after you stop receiving aripiprazole oral solution.\n \n </li>\n<li>\n<span class=\"Bold\">Problems with your metabolism such as:</span>\n<ul class=\"Square\">\n<li>\n<span class=\"Bold\">High blood sugar (hyperglycemia) and diabetes.</span>Increases in blood sugar can happen in some people who take Aripiprazole oral solution. 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 oral solution and during your treatment.\n \n <p class=\"First\">\n<span class=\"Bold\">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving</span>aripiprazole oral solution:\n \n </p>\n<ul class=\"Disc\">\n<li>feel very thirsty</li>\n<li>need to urinate more than usual</li>\n<li>feel very hungry</li>\n<li>feel weak or tired</li>\n<li>feel sick to your stomach</li>\n<li>feel confused, or your breath smells fruity</li>\n</ul>\n</li>\n</ul>\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Increased fat levels (cholesterol and triglycerides) in your blood.</span>\n</li>\n<li>\n<span class=\"Bold\">Weight gain.</span>You and your healthcare provider should check your weight regularly.\n \n </li>\n</ul>\n</li>\n</ul>\n<ul>\n<li>\n<span class=\"Bold\">Unusual urges.</span>Some people taking aripiprazole oral solution have had unusual urges, such as gambling, binge eating or eating that you cannot control (compulsive), compulsive shopping and sexual urges.\n \n <p class=\"First\">If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</p>\n</li>\n<li>\n<span class=\"Bold\">Orthostatic hypotension (decreased blood pressure).</span>Lightheadedness or fainting may happen when rising too quickly from a sitting or lying position.\n \n </li>\n<li>\n<span class=\"Bold\">Falls.</span>Aripiprazole oral solution 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.\n \n </li>\n<li>\n<span class=\"Bold\">Low white blood cell count</span>\n</li>\n<li>\n<span class=\"Bold\">Seizures (convulsions)</span>\n</li>\n<li>\n<span class=\"Bold\">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.</span>See “What should I avoid while receiving aripiprazole oral solution?”\n \n </li>\n<li>\n<span class=\"Bold\">Difficulty swallowing that can cause food or liquid to get into your lungs.</span>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">The most common side effects of aripiprazole oral solution in adults include:</span>\n</p>\n<p>     • Nausea                                  • dizziness</p>\n<p>     • vomiting                               • anxiety</p>\n<p>     • constipation                          • insomnia</p>\n<p>     • headache                               • restlessness</p>\n<p>     • blurred vision                        • inner sense of restlessness/need to move (akathisia)</p>\n<p>     • upper respiratory illness</p>\n<p>\n<span class=\"Bold\">The most common side effects of aripiprazole oral solution in children include:</span>\n</p>\n<p>     • feeling sleepy                                     • insomnia</p>\n<p>     • headache                                             • nausea</p>\n<p>     • vomiting                                            • stuffy nose</p>\n<p>     • fatigue                                               • weight gain</p>\n<p>     • increased or decreased appetite        • uncontrolled movement such as restlessness, tremor</p>\n<p>     • increased saliva or drooling              • muscle stiffness</p>\n<p>These are not all the possible side effects of aripiprazole oral solution.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store aripiprazole oral solution?</span>\n</p>\n<ul>\n<li>Store aripiprazole oral solution at room temperature, between 68°F to 77°F (20°C to 25°C).</li>\n<li>Opened bottles of Aripiprazole Oral Solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle.</li>\n<li>Aripiprazole oral solution is supplied in child-resistant bottles.</li>\n</ul>\n<span class=\"Bold\">Keep aripiprazole oral solution and all medicines out of the reach of children.</span></td>\n</tr>\n<tr>\n<td align=\"justify\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of aripiprazole oral solution</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use aripiprazole oral solution for a condition for which it was not prescribed. Do not give aripiprazole oral solution to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about aripiprazole oral solution that was written for healthcare professionals.</p>\n</td>\n</tr>\n<tr>\n<td align=\"justify\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in aripiprazole oral solution?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span>Aripiprazole, USP\n \n </p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span>\n<br/>\n<span class=\"Bold\">Aripiprazole oral solution:</span>disodium edetate, fructose, glycerin, malic acid, methylparaben, orange flavor, propylene glycol, propylparaben, sodium hydroxide, sucrose and purified water.\n \n </p>\n<br/>\n<p>For more information about aripiprazole oral solution contact\n \n <span class=\"Bold\">Chartwell RX, LLC. at 1-845-232-1683</span>.\n \n </p>\n<p>\n<br/> Manufactured for: \n <br/> Chartwell RX, LLC. \n <br/> Congers, NY 10920\n </p>\n<p>\n<br/> L72629 \n <br/>\n<br/> Rev. 04/2025\n </p>\n</td>\n</tr>\n<tr>\n<td valign=\"top\">\n<p class=\"First\">This Medication Guide has been approved by the U.S. Food and Drug Administration                                                                                                                                         Revised: 04/2025</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Aripiprazole Oral Solution 1 mg/mL - NDC 62135-904-51 - 150 mL Bottle Label

{ "type": "p", "children": [], "text": "\nAripiprazole Oral Solution 1 mg/mL - NDC 62135-904-51 - 150 mL Bottle Label\n" }

OPIPZA is indicated for the:

{ "type": "p", "children": [], "text": "OPIPZA is indicated for the:" }

{ "type": "ul", "children": [ "treatment of schizophrenia in patients ages 13 years and older", "adjunctive treatment of major depressive disorder (MDD) in adults", "treatment of irritability associated with autistic disorder in pediatric patients 6 years and older", "treatment of Tourette's disorder in pediatric patients 6 years and older" ], "text": "" }

Adults

The recommended starting and target dosage of OPIPZA for the treatment of schizophrenia in adults is 10 mg or 15 mg once daily. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 mg to 30 mg per day; however, doses higher than 10 mg or 15 mg per day were not more effective than 10 mg or 15 mg per day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.2)].

Pediatric Patients Ages 13 Years and Older

The recommended starting dosage of OPIPZA for the treatment of schizophrenia in pediatric patients 13 years and older is 2 mg once daily. The recommended target dosage of OPIPZA is 10 mg once daily. Aripiprazole was studied in pediatric patients 13 to 17 years of age with schizophrenia at daily dosages of 10 mg and 30 mg. The starting daily dosage 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 per day dosage was not shown to be more efficacious than the 10 mg per day dosage.

The recommended starting dosage for OPIPZA as adjunctive treatment of MDD in adults already taking an antidepressant is 2 mg to 5 mg once daily. The recommended dosage range is 2 mg to 15 mg once daily. Dosage adjustments of up to 5 mg per day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.3)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

The recommended dosage range for the treatment of pediatric patients 6 to 17 years with irritability associated with autistic disorder is 5 mg to 15 mg once daily.

Dosing should be initiated at 2 mg once daily. The dose should be increased to 5 mg per day, with subsequent increases to 10 mg or 15 mg per day if needed. Dose adjustments of up to 5 mg per day should occur gradually, at intervals of no less than one week [see Clinical Studies (14.4)]. Patients should be periodically reassessed to determine the continued need for maintenance treatment.

The recommended dosage range for treatment of Tourette's disorder in pediatric patients 6 years and older is 5 mg to 20 mg once daily.

For patients weighing less than 50 kg, dosage should be initiated at 2 mg once daily with a target dosage of 5 mg once daily after 2 days. The dosage can be increased to 10 mg once daily 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 once daily for 2 days, and then increased to 5 mg once daily for 5 days, with a target dosage of 10 mg once daily on Day 8. The dosage can be increased up to 20 mg once daily for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg per 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.

Instruct patients and/or caregivers to read the "Instruction for Use" carefully for complete directions on how to properly dose and administer OPIPZA.

Administer OPIPZA orally with or without food [see Clinical Pharmacology (12.3)].

Apply OPIPZA on top of the tongue where it dissolves in saliva and can be swallowed in a normal manner without the need for water or other liquids.

The patient should refrain from chewing the film and should not swallow an undissolved film. Do not cut or split OPIPZA.

Administer only one oral film at a time. If an additional film is needed to complete the dosage, administer after the previous film has completely dissolved.

Dosage recommendations and modifications for patients who are known CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers are described in Table 1.

When the coadministered drug is withdrawn from the combination therapy, Aripiprazole Oral Film dosage should be adjusted to its previous dose. When the coadministered CYP3A4 inducer is withdrawn, Aripiprazole Oral Film dosage should be reduced to the previous dose over 1 to 2 weeks. Patients 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 recommended dose initially and then adjusted to achieve clinical response [see Dosage and Administration (2.5)].

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 1: Dosage Recommendations and Modifications for OPIPZA in Patients Who are Known CYP2D6 Poor Metabolizers and in Patients Taking Concomitant CYP2D6 Inhibitors and/or 3A4 Inhibitors, CYP3A4 Inducers</span> </caption> <col align="left" valign="middle" width="55%"/> <col align="left" valign="middle" width="45%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Patient Population</th><th align="center" class="Rrule">Dosage Recommendations and Modifications for OPIPZA</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP2D6 Poor Metabolizers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers</td><td align="left" class="Rrule">Administer half of the recommended dose</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors</td><td align="left" class="Rrule">Administer a quarter of the recommended dose</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Patients Taking OPIPZA with CYP2D6 Inhibitors and/or CYP3A4 Inhibitors, CYP3A4 Inducers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Concomitant use of OPIPZA with strong CYP2D6 <span class="Bold">or</span> CYP3A4 inhibitors</td><td align="left" class="Rrule">Administer half of the recommended dose</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Concomitant use of OPIPZA with strong CYP2D6 <span class="Bold">and</span> CYP3A4 inhibitors</td><td align="left" class="Rrule">Administer a quarter of the recommended dose</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Concomitant use of OPIPZA with strong CYP3A4 inducers</td><td align="left" class="Rrule">Double the recommended dose over 1 to 2 weeks</td> </tr> </tbody> </table></div>

When adjunctive OPIPZA is administered to patients with major depressive disorder, OPIPZA should be administered without dosage adjustment as specified in Dosage and Administration (2.2).

OPIPZA is a rectangular white film in strengths of 2 mg (1 cm by 1.2 cm), 5 mg (2 cm by 1.5 cm), and 10 mg (2 cm by 3 cm) containing the markings A2, A5, and A10, respectively.

{ "type": "p", "children": [], "text": "OPIPZA is a rectangular white film in strengths of 2 mg (1 cm by 1.2 cm), 5 mg (2 cm by 1.5 cm), and 10 mg (2 cm by 3 cm) containing the markings A2, A5, and A10, respectively." }

OPIPZA is contraindicated in patients with a history of a hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1)].

{ "type": "p", "children": [], "text": "OPIPZA is contraindicated in patients with a history of a hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole [see Adverse Reactions (6.1)]." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)]

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 reactions (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole. OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 2: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> and Adult Patients</span> </caption> <col align="left" valign="top" width="35%"/> <col align="left" valign="top" width="65%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Age Range</th><th align="center" class="Rrule">Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated<a class="Sup" href="#footnote-1">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>OPIPZA is not approved in pediatric patients with MDD.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"></td><td align="left" class="Rrule"><span class="Bold">Increases Compared to Placebo</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">&lt;18 years old</td><td align="left" class="Rrule">14 additional patients</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">18 to 24 years old</td><td align="left" class="Rrule">5 additional patients</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"></td><td align="left" class="Rrule"><span class="Bold">Decreases Compared to Placebo</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">25 to 64 years old</td><td align="left" class="Rrule">1 fewer patient</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">≥65 years old</td><td align="left" class="Rrule">6 fewer patient</td> </tr> </tbody> </table></div>

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing OPIPZA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. It should be noted that OPIPZA is not approved for use in treating depression in the pediatric population.

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex has been reported with antipsychotic drugs, including aripiprazole. Rare cases of NMS have been reported during aripiprazole treatment in the global 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.

If NMS is suspected, immediately discontinue OPIPZA and provide symptomatic treatment and monitoring.

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 predict which patients will 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 appear to increase as the duration of treatment and the total cumulative dose increases. However, the syndrome can develop after relatively brief treatment periods at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself may suppress (or partially suppress) the signs and symptoms of the syndrome and 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, OPIPZA 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 treated with OPIPZA, drug discontinuation should be considered. However, some patients may require treatment with OPIPZA despite the presence of the syndrome.

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 diabetic ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1, 6.2)]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including OPIPZA, 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 atypical antipsychotic drug.

Adults

In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or another indication, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1,057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 3 shows the proportion of aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 3: Changes in Fasting Glucose from Placebo-Controlled Monotherapy Trials in Adults</span> </caption> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="40%"/> <col align="center" valign="middle" width="21%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <thead> <tr class="First Last"> <th align="center"></th><th align="center">Category Change (at least once) from Baseline</th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule" rowspan="4"><span class="Bold">Fasting Glucose</span></td><td align="center" class="Botrule" rowspan="2">Normal to High<br/> (&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">31/822</td><td align="center" class="Botrule">3.8</td> </tr> <tr> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">22/605</td><td align="center" class="Botrule">3.6</td> </tr> <tr class="Botrule"> <td align="center" rowspan="2">Borderline to High<br/> (≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center">Aripiprazole</td><td align="center">31/176</td><td align="center">17.6</td> </tr> <tr class="Last"> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">13/142</td><td align="center" class="Botrule">9.2</td> </tr> </tbody> </table></div>

At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].

The mean change in fasting glucose in adjunctive trials of aripiprazole-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 4 shows the proportion of adult patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median exposure 42 days) in patients with major depressive disorder.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 4: Changes in Fasting Glucose from Placebo-Controlled Adjunctive Trials in Adults with Major Depressive Disorder</span> </caption> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="40%"/> <col align="center" valign="middle" width="21%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <thead> <tr class="First Last"> <th align="center"></th><th align="center">Category Change (at least once) from Baseline</th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule" rowspan="4"><span class="Bold">Fasting Glucose</span></td><td align="center" class="Botrule" rowspan="2">Normal to High<br/> (&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">2/201</td><td align="center" class="Botrule">1.0</td> </tr> <tr> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">2/204</td><td align="center" class="Botrule">1.0</td> </tr> <tr class="Botrule"> <td align="center" rowspan="2">Borderline to High<br/> (≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center">Aripiprazole</td><td align="center">4/34</td><td align="center">11.8</td> </tr> <tr class="Last"> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">3/37</td><td align="center" class="Botrule">8.1</td> </tr> </tbody> </table></div>

Pediatric Patients 13 Years and Older

In an analysis of two placebo-controlled trials in pediatric patients 13 to 17 years with schizophrenia and pediatric patients 10 to 17 years with another indication, the mean change in fasting glucose in aripiprazole-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123).

In an analysis of two placebo-controlled trials in pediatric patients 6 to 17 years with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in aripiprazole-treated patients (–0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (–0.6 mg/dL; N=33).

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

Table 5 shows the proportion of patients with changes in fasting glucose levels from the pooled pediatric patients (13 to 17 years) with schizophrenia and pediatric patients (10 to 17 years) with another indication (median exposure of 42 to 43 days), from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in pediatric patients (6 to 18 years) with Tourette's disorder (median exposure 57 days).

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 5: Changes in Fasting Glucose from Placebo-Controlled Trials in Pediatric Patients 6 to 17 Years</span> </caption> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="center">Category Change (at least once) from Baseline</th><th align="center">Indication</th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Botrule" rowspan="6"><span class="Bold">Fasting Glucose</span> <br/>Normal to High<br/> (&lt;100 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule" rowspan="2">Pooled Schizophrenia and another indication</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">2/236</td><td align="center" class="Botrule">0.8</td> </tr> <tr> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">2/110</td><td align="center" class="Botrule">1.8</td> </tr> <tr class="Botrule"> <td align="center" rowspan="2">Irritability Associated with Autistic Disorder</td><td align="center">Aripiprazole</td><td align="center">0/73</td><td align="center">0</td> </tr> <tr> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">0/32</td><td align="center" class="Botrule">0</td> </tr> <tr class="Botrule"> <td align="center" rowspan="2">Tourette's Disorder</td><td align="center">Aripiprazole</td><td align="center">3/88</td><td align="center">3.4</td> </tr> <tr> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">1/58</td><td align="center" class="Botrule">1.7</td> </tr> <tr> <td align="center" class="Botrule" rowspan="6"><span class="Bold">Fasting Glucose</span> <br/>Borderline to High<br/> (≥100 mg/dL and &lt;126 mg/dL to ≥126 mg/dL)</td><td align="center" class="Botrule" rowspan="2">Pooled Schizophrenia and another indication</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">1/22</td><td align="center" class="Botrule">4.5</td> </tr> <tr> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">0/12</td><td align="center" class="Botrule">0</td> </tr> <tr class="Botrule"> <td align="center" rowspan="2">Irritability Associated with Autistic Disorder</td><td align="center">Aripiprazole</td><td align="center">0/9</td><td align="center">0</td> </tr> <tr> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">0/1</td><td align="center" class="Botrule">0</td> </tr> <tr class="Botrule"> <td align="center" rowspan="2">Tourette's Disorder</td><td align="center">Aripiprazole</td><td align="center">0/11</td><td align="center">0</td> </tr> <tr class="Last"> <td align="center" class="Botrule">Placebo</td><td align="center" class="Botrule">0/4</td><td align="center" class="Botrule">0</td> </tr> </tbody> </table></div>

In the pooled trials that enrolled pediatric patients 13 to 17 years with schizophrenia and another indication, the mean change in fasting glucose in aripiprazole-treated patients at 12 weeks was not significantly different than in placebotreated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively].

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

There were no significant differences between aripiprazole-treated patients and patients treated with placebo in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients.

Adults

Table 6 shows the proportion of adult patients, primarily from pooled schizophrenia and another indication 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).

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 6: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Adults</span> </caption> <col align="left" valign="middle" width="45%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="left"></th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Total Cholesterol</span> <br/>Normal to High<br/> (&lt;200 mg/dL to ≥240 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">34/1,357</td><td align="center" class="Botrule">2.5</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">27/973</td><td align="center">2.8</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Fasting Triglycerides</span> <br/>Normal to High<br/> (&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">40/539</td><td align="center" class="Botrule">7.4</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">30/431</td><td align="center">7.0</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Fasting LDL Cholesterol</span> <br/>Normal to High<br/> (&lt;100 mg/dL to ≥160 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">2/332</td><td align="center" class="Botrule">0.6</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">2/268</td><td align="center">0.7</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">HDL Cholesterol</span> <br/>Normal to Low<br/> (≥40 mg/dL to &lt;40 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">121/1,066</td><td align="center" class="Botrule">11.4</td> </tr> <tr class="Botrule Last"> <td align="center">Placebo</td><td align="center">99/794</td><td align="center">12.5</td> </tr> </tbody> </table></div>

In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole - and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.

Table 7 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials in adults with major depressive disorder (median exposure 42 days).

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 7: Changes in Blood Lipid Parameters from Placebo-Controlled Adjunctive Trials in Adults with Major Depressive Disorder</span> </caption> <col align="left" valign="middle" width="45%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="left"></th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Total Cholesterol</span> <br/>Normal to High<br/> (&lt;200 mg/dL to ≥240 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">3/139</td><td align="center" class="Botrule">2.2</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">7/135</td><td align="center">5.2</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Fasting Triglycerides</span> <br/>Normal to High<br/> (&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">14/145</td><td align="center" class="Botrule">9.7</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">6/147</td><td align="center">4.1</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Fasting LDL Cholesterol</span> <br/>Normal to High<br/> (&lt;100 mg/dL to ≥160 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">0/54</td><td align="center" class="Botrule">0</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">0/73</td><td align="center">0</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">HDL Cholesterol</span> <br/>Normal to Low<br/> (≥40 mg/dL to &lt;40 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">17/318</td><td align="center" class="Botrule">5.3</td> </tr> <tr class="Botrule Last"> <td align="center">Placebo</td><td align="center">10/286</td><td align="center">3.5</td> </tr> </tbody> </table></div>

Pediatric Patients 10 to 17 Years

Table 8 shows the proportion of pediatric patients (13 to 17 years) with schizophrenia and pediatric patients (10 to 17 years) with another indication 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).

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 8: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Pediatric Patients 10 to 17 Years with Schizophrenia and another Indication</span> </caption> <col align="left" valign="middle" width="45%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="left"></th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Total Cholesterol</span> <br/>Normal to High<br/> (&lt;170 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">3/220</td><td align="center" class="Botrule">1.4</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">0/116</td><td align="center">0</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Fasting Triglycerides</span> <br/>Normal to High<br/> (&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">7/187</td><td align="center" class="Botrule">3.7</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">4/85</td><td align="center">4.7</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">HDL Cholesterol</span> <br/>Normal to Low<br/> (≥40 mg/dL to &lt;40 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">27/236</td><td align="center" class="Botrule">11.4</td> </tr> <tr class="Botrule Last"> <td align="center">Placebo</td><td align="center">22/109</td><td align="center">20.2</td> </tr> </tbody> </table></div>

In monotherapy trials of pediatric patients with schizophrenia and pediatric patients with another indication, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebotreated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively.

Table 9 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 9: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients 6 to 17 Years with Autistic Disorder</span> </caption> <col align="left" valign="middle" width="45%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="left"></th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Total Cholesterol</span> <br/>Normal to High<br/> (&lt;170 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">1/95</td><td align="center" class="Botrule">1.1</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">0/34</td><td align="center">0</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Fasting Triglycerides</span> <br/>Normal to High<br/> (&lt;150 mg/dL to ≥200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">0/75</td><td align="center" class="Botrule">0</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">0/30</td><td align="center">0</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">HDL Cholesterol</span> <br/>Normal to Low<br/> (≥40 mg/dL to &lt;40 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">9/107</td><td align="center" class="Botrule">8.4</td> </tr> <tr class="Botrule Last"> <td align="center">Placebo</td><td align="center">5/49</td><td align="center">10.2</td> </tr> </tbody> </table></div>

Table 10 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.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 10: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients 6 to 18 Years with Tourette's Disorder</span> </caption> <col align="left" valign="middle" width="35%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="left"></th><th align="center">Treatment Arm</th><th align="center">n/N</th><th align="center">%</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Total Cholesterol</span> <br/>Normal to High<br/> (&lt;170 mg/dL to ⩾200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">1/85</td><td align="center" class="Botrule">1.2</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">0/46</td><td align="center">0</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">Fasting Triglycerides</span> <br/>Normal to High<br/> (&lt;150 mg/dL to ⩾200 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">5/94</td><td align="center" class="Botrule">5.3</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">2/55</td><td align="center">3.6</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2"><span class="Bold">HDL Cholesterol</span> <br/>Normal to Low<br/> (⩾40 mg/dL to &lt;40 mg/dL)</td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">4/108</td><td align="center" class="Botrule">3.7</td> </tr> <tr class="Botrule Last"> <td align="center">Placebo</td><td align="center">2/67</td><td align="center">3.0</td> </tr> </tbody> </table></div>

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 another indication, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to -0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was -1.5 kg (n=73) compared to -0.2 kg (n=46) in patients treated with placebo patients.

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

Table 11 shows the percentage of adult patients with weight gain ≥7% of body weight by indication.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 11: Percentage of Patients from Placebo-Controlled Trials in Adults with Weight Gain ≥7% of Body Weight</span> </caption> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="10%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="center"></th><th align="center">Indication</th><th align="center">Treatment Arm</th><th align="center">N</th><th align="center">Patients<br/> n (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>4 to 6 weeks duration;</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>3 weeks duration;</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">‡</a> </dt> <dd>6 weeks duration.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Botrule" rowspan="6"><span class="Bold">Weight gain ≥7% of body weight</span></td><td align="center" class="Botrule" rowspan="2">Schizophrenia<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">852</td><td align="center" class="Botrule">69 (8.1)</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">379</td><td align="center">12 (3.2)</td> </tr> <tr> <td align="center" class="Botrule" rowspan="2">Another indication<a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a></td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">719</td><td align="center" class="Botrule">16 (2.2)</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">598</td><td align="center">16 (2.7)</td> </tr> <tr> <td align="center" class="Botrule" rowspan="2">Major Depressive Disorder<br/> (Adjunctive Therapy)<a class="Sup" href="#footnote-4" name="footnote-reference-4">‡</a></td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">347</td><td align="center" class="Botrule">18 (5.2)</td> </tr> <tr class="Botrule Last"> <td align="center">Placebo</td><td align="center">330</td><td align="center">2 (0.6)</td> </tr> </tbody> </table></div>

Pediatric Patients 6 to 17 Years

In an analysis of two placebo-controlled trials in pediatric patients 13 to 17 years with schizophrenia and pediatric patients 10 to 17 years with another indication with median exposure of 42 to 43 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in patients treated with placebo.

In two short-term, placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in pediatric patients treated with placebo.

In two short-term, placebo-controlled trials in pediatric patients 6 to 18 years with Tourette's disorder with median exposure of 57 days, the mean change in body weight in aripiprazole-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in patients treated with placebo.

Table 12 shows the percentage of pediatric patients (6 to 17 years) with weight gain ≥7% of body weight by indication.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 12: Percentage of Patients from Placebo-Controlled Monotherapy Trials in Pediatric Patients 6 to 17 Years with Weight Gain ≥7% of Body Weight</span> </caption> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="10%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="First Last"> <th align="center"></th><th align="center">Indication</th><th align="center">Treatment Arm</th><th align="center">N</th><th align="center">Patients<br/> n (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>4 to 6 weeks duration;</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>8 weeks duration;</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>8 to 10 weeks duration.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Botrule" rowspan="6"><span class="Bold">Weight gain ≥7% of body weight</span></td><td align="center" class="Botrule" rowspan="2">Pooled Schizophrenia and another indication<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a></td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">381</td><td align="center" class="Botrule">20 (5.2)</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">187</td><td align="center">3 (1.6)</td> </tr> <tr> <td align="center" class="Botrule" rowspan="2">Irritability Associated with Autistic Disorder<a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">209</td><td align="center" class="Botrule">55 (26.3)</td> </tr> <tr class="Botrule"> <td align="center">Placebo</td><td align="center">98</td><td align="center">7 (7.1)</td> </tr> <tr> <td align="center" class="Botrule" rowspan="2">Tourette's Disorder<a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a></td><td align="center" class="Botrule">Aripiprazole</td><td align="center" class="Botrule">105</td><td align="center" class="Botrule">21 (20.0)</td> </tr> <tr class="Botrule Last"> <td align="center">Placebo</td><td align="center">66</td><td align="center">5 (7.6)</td> </tr> </tbody> </table></div>

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

In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, pediatric patients 6 to 17 years with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with aripiprazole. The mean change in weight z-score was 0.26 SDs for patients receiving >9 months of treatment.

When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth.

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.

OPIPZA may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients treated with another oral aripiprazole product (n=2,467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on another oral aripiprazole product included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%) [see Adverse Reactions (6.1)].

The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for another oral aripiprazole product was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adults treated with another oral aripiprazole product (4%, 2%), in pediatric patients treated with another oral aripiprazole-product aged 6 to 18 years (0.4%, 1%).

Use OPIPZA with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see Drug Interactions (7.1)]. Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Antipsychotics, including OPIPZA, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of OPIPZA at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue OPIPZA in patients with severe neutropenia (absolute neutrophil count <1,000/mm3) and follow their WBC counts until recovery.

In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2,467) of undiagnosed adult patients and in 0.1% (1/732) of pediatric patients (6 to 18 years) treated with another oral aripiprazole product.

As with other antipsychotic drugs, use OPIPZA cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

OPIPZA, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials of another oral aripiprazole product, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2,467) treated with oral aripiprazole (11%, 6%), in pediatric patients ages 6 to 17 years (n=611) (24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral aripiprazole in short-term, placebo-controlled trials.

Patients should be cautioned about operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that therapy with OPIPZA does not affect them adversely.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing OPIPZA for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see Adverse Reactions (6.2)].

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. OPIPZA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

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 safety of OPIPZA for the treatment of adults with schizophrenia in patients 13 years and older, adjunctive treatment of adults with MDD, treatment of irritability associated with autistic disorder in pediatric patients 6 years and older, and treatment of Tourette's disorder in pediatric patients 6 years and older is based on adequate and well-controlled studies of another oral aripiprazole product. Below is a display of adverse reactions of oral aripiprazole (referred to as "aripiprazole" in this section) from those adequate and well-controlled studies.

Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, major depressive disorder, and other indications, and who had approximately 7,619 patient-years of exposure to oral aripiprazole. A total of 3,390 patients were treated with oral aripiprazole for at least 180 days and 1,933 patients treated with oral aripiprazole had at least one year of exposure.

Aripiprazole has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, autistic disorder, Tourette's disorder or other indications 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 one year of exposure.

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

The most common adverse reactions of aripiprazole in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness.

The most common adverse reactions of aripiprazole in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased.

Adverse Reactions in Adult Patients with Schizophrenia

The following findings are based on a pool of five placebo-controlled trials (four 4 week and one 6 week) in which oral aripiprazole was administered in doses ranging from 2 mg/day to 30 mg/day.

The commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).

Table 13 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 another indication), including only those reactions that occurred in 2% or more of patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 13: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Percentage of Patients Reporting Reaction<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a></th> </tr> <tr class="Last"> <th align="left">Preferred Term</th><th align="center">Aripiprazole<br/> (n=1,843)</th><th align="center">Placebo<br/> (n=1,166)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left"><span class="Bold">Eye Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Blurred Vision</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Gastrointestinal Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Nausea</td><td align="center">15</td><td align="center">11</td> </tr> <tr> <td align="left">  Constipation</td><td align="center">11</td><td align="center">7</td> </tr> <tr> <td align="left">  Vomiting</td><td align="center">11</td><td align="center">6</td> </tr> <tr> <td align="left">  Dyspepsia</td><td align="center">9</td><td align="center">7</td> </tr> <tr> <td align="left">  Dry Mouth</td><td align="center">5</td><td align="center">4</td> </tr> <tr> <td align="left">  Toothache</td><td align="center">4</td><td align="center">3</td> </tr> <tr> <td align="left">  Abdominal Discomfort</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left">  Stomach Discomfort</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left"><span class="Bold">General Disorders and Administration Site Conditions</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Fatigue</td><td align="center">6</td><td align="center">4</td> </tr> <tr> <td align="left">  Pain</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Musculoskeletal Stiffness</td><td align="center">4</td><td align="center">3</td> </tr> <tr> <td align="left">  Pain in Extremity</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Myalgia</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left">  Muscle Spasms</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Nervous System Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Headache</td><td align="center">27</td><td align="center">23</td> </tr> <tr> <td align="left">  Dizziness</td><td align="center">10</td><td align="center">7</td> </tr> <tr> <td align="left">  Akathisia</td><td align="center">10</td><td align="center">4</td> </tr> <tr> <td align="left">  Sedation</td><td align="center">7</td><td align="center">4</td> </tr> <tr> <td align="left">  Extrapyramidal Disorder</td><td align="center">5</td><td align="center">3</td> </tr> <tr> <td align="left">  Tremor</td><td align="center">5</td><td align="center">3</td> </tr> <tr> <td align="left">  Somnolence</td><td align="center">5</td><td align="center">3</td> </tr> <tr> <td align="left"><span class="Bold">Psychiatric Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Agitation</td><td align="center">19</td><td align="center">17</td> </tr> <tr> <td align="left">  Insomnia</td><td align="center">18</td><td align="center">13</td> </tr> <tr> <td align="left">  Anxiety</td><td align="center">17</td><td align="center">13</td> </tr> <tr> <td align="left">  Restlessness</td><td align="center">5</td><td align="center">3</td> </tr> <tr> <td align="left"><span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Pharyngolaryngeal Pain</td><td align="center">3</td><td align="center">2</td> </tr> <tr class="Last"> <td align="left">  Cough</td><td align="center">3</td><td align="center">2</td> </tr> </tbody> </table></div>

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Adverse Reactions in Pediatric Patients (13 to 17 years) with Schizophrenia

The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day.

The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively.

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients 13 to 17 years with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor.

Adverse Reactions in Pediatric Patients (6 to 17 years) with Autistic Disorder

The following findings are based on two 8 week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 to 15 mg/day.

The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively.

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients (6 to 17 years) with autistic disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 14.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 14: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral Aripiprazole</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Percentage of Patients Reporting Reaction</th> </tr> <tr class="Last"> <th align="left">Preferred Term</th><th align="center">Aripiprazole <br/>(n=212)</th><th align="center">Placebo <br/>(n=101)</th> </tr> </thead> <tbody> <tr class="First"> <td align="left">Sedation</td><td align="center">21</td><td align="center">4</td> </tr> <tr> <td align="left">Fatigue</td><td align="center">17</td><td align="center">2</td> </tr> <tr> <td align="left">Vomiting</td><td align="center">14</td><td align="center">7</td> </tr> <tr> <td align="left">Somnolence</td><td align="center">10</td><td align="center">4</td> </tr> <tr> <td align="left">Tremor</td><td align="center">10</td><td align="center">0</td> </tr> <tr> <td align="left">Pyrexia</td><td align="center">9</td><td align="center">1</td> </tr> <tr> <td align="left">Drooling</td><td align="center">9</td><td align="center">0</td> </tr> <tr> <td align="left">Decreased Appetite</td><td align="center">7</td><td align="center">2</td> </tr> <tr> <td align="left">Salivary Hypersecretion</td><td align="center">6</td><td align="center">1</td> </tr> <tr> <td align="left">Extrapyramidal Disorder</td><td align="center">6</td><td align="center">0</td> </tr> <tr class="Last"> <td align="left">Lethargy</td><td align="center">5</td><td align="center">0</td> </tr> </tbody> </table></div>

Adverse Reactions in 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 aripiprazole was administered in doses of 2 to 20 mg/day.

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

Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients (6 to 18 years) with Tourette's disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 15.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 15: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with Oral Aripiprazole</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Percentage of Patients Reporting Reaction</th> </tr> <tr class="Last"> <th align="left">Preferred Term</th><th align="center">Aripiprazole <br/>(n=121)</th><th align="center">Placebo <br/>(n=72)</th> </tr> </thead> <tbody> <tr class="First"> <td align="left">Sedation</td><td align="center">13</td><td align="center">6</td> </tr> <tr> <td align="left">Somnolence</td><td align="center">13</td><td align="center">1</td> </tr> <tr> <td align="left">Nausea</td><td align="center">11</td><td align="center">4</td> </tr> <tr> <td align="left">Headache</td><td align="center">10</td><td align="center">3</td> </tr> <tr> <td align="left">Nasopharyngitis</td><td align="center">9</td><td align="center">0</td> </tr> <tr> <td align="left">Fatigue</td><td align="center">8</td><td align="center">0</td> </tr> <tr class="Last"> <td align="left">Increased Appetite</td><td align="center">7</td><td align="center">1</td> </tr> </tbody> </table></div>

Table 16 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 another indication, 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 aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 16: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral Aripiprazole</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" class="Botrule" colspan="2">Percentage of Patients Reporting Reaction<a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a></th> </tr> <tr class="Last"> <th align="left">Preferred Term</th><th align="center">Aripiprazole<br/> (n=732)</th><th align="center">Placebo<br/> (n=370)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left"><span class="Bold">Eye Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Blurred Vision</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left"><span class="Bold">Gastrointestinal Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Abdominal Discomfort</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left">  Vomiting</td><td align="center">8</td><td align="center">7</td> </tr> <tr> <td align="left">  Nausea</td><td align="center">8</td><td align="center">4</td> </tr> <tr> <td align="left">  Diarrhea</td><td align="center">4</td><td align="center">3</td> </tr> <tr> <td align="left">  Salivary Hypersecretion</td><td align="center">4</td><td align="center">1</td> </tr> <tr> <td align="left">  Abdominal Pain Upper</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left">  Constipation</td><td align="center">2</td><td align="center">2</td> </tr> <tr> <td align="left"><span class="Bold">General Disorders and Administration Site Conditions</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Fatigue</td><td align="center">10</td><td align="center">2</td> </tr> <tr> <td align="left">  Pyrexia</td><td align="center">4</td><td align="center">1</td> </tr> <tr> <td align="left">  Irritability</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left">  Asthenia</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Infections and Infestations</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Nasopharyngitis</td><td align="center">6</td><td align="center">3</td> </tr> <tr> <td align="left"><span class="Bold">Investigations</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Weight Increased</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Metabolism and Nutrition Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Increased Appetite</td><td align="center">7</td><td align="center">3</td> </tr> <tr> <td align="left">  Decreased Appetite</td><td align="center">5</td><td align="center">4</td> </tr> <tr> <td align="left"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Musculoskeletal Stiffness</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left">  Muscle Rigidity</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Nervous System Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Somnolence</td><td align="center">16</td><td align="center">4</td> </tr> <tr> <td align="left">  Headache</td><td align="center">12</td><td align="center">10</td> </tr> <tr> <td align="left">  Sedation</td><td align="center">9</td><td align="center">2</td> </tr> <tr> <td align="left">  Tremor</td><td align="center">9</td><td align="center">1</td> </tr> <tr> <td align="left">  Extrapyramidal Disorder</td><td align="center">6</td><td align="center">1</td> </tr> <tr> <td align="left">  Akathisia</td><td align="center">6</td><td align="center">4</td> </tr> <tr> <td align="left">  Drooling</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left">  Lethargy</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left">  Dizziness</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left">  Dystonia</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Respiratory, Thoracic, and Mediastinal Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Epistaxis</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr class="Last"> <td align="left">  Rash</td><td align="center">2</td><td align="center">1</td> </tr> </tbody> </table></div>

Adverse Reactions in Adult Patients Receiving Aripiprazole as Adjunctive Treatment of Major Depressive Disorder

The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which aripiprazole was administered at doses of 2 to 20 mg as adjunctive treatment to continued antidepressant therapy.

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

The commonly observed adverse reactions associated with the use of adjunctive aripiprazole in patients with major depressive disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.

Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with adjunctive aripiprazole was greater than the incidence in patients treated with adjunctive placebo in the combined dataset.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Percentage of Patients Reporting Reaction<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a></th> </tr> <tr class="Last"> <th align="left">Preferred Term</th><th align="center">Aripiprazole + ADT<a class="Sup" href="#footnote-11" name="footnote-reference-11">†</a> <br/> (n=371)</th><th align="center">Placebo + ADT<a class="Sup" href="#footnote-11">†</a> <br/> (n=366)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>Adverse reactions reported by at least 2% of patients treated with adjunctive Aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">†</a> </dt> <dd>Antidepressant Therapy</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left"><span class="Bold">Eye Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Blurred Vision</td><td align="center">6</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Gastrointestinal Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Constipation</td><td align="center">5</td><td align="center">2</td> </tr> <tr> <td align="left"><span class="Bold">General Disorders and Administration Site Conditions</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Fatigue</td><td align="center">8</td><td align="center">4</td> </tr> <tr> <td align="left">  Feeling Jittery</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Infections and Infestations</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Upper Respiratory Tract Infection</td><td align="center">6</td><td align="center">4</td> </tr> <tr> <td align="left"><span class="Bold">Investigations</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Weight Increased</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left"><span class="Bold">Metabolism and Nutrition Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Increased Appetite</td><td align="center">3</td><td align="center">2</td> </tr> <tr> <td align="left"><span class="Bold">Musculoskeletal and Connective Tissue Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Arthralgia</td><td align="center">4</td><td align="center">3</td> </tr> <tr> <td align="left">  Myalgia</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left"><span class="Bold">Nervous System Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Akathisia</td><td align="center">25</td><td align="center">4</td> </tr> <tr> <td align="left">  Somnolence</td><td align="center">6</td><td align="center">4</td> </tr> <tr> <td align="left">  Tremor</td><td align="center">5</td><td align="center">4</td> </tr> <tr> <td align="left">  Sedation</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Dizziness</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Disturbance in Attention</td><td align="center">3</td><td align="center">1</td> </tr> <tr> <td align="left">  Extrapyramidal Disorder</td><td align="center">2</td><td align="center">0</td> </tr> <tr> <td align="left"><span class="Bold">Psychiatric Disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  Restlessness</td><td align="center">12</td><td align="center">2</td> </tr> <tr class="Last"> <td align="left">  Insomnia</td><td align="center">8</td><td align="center">2</td> </tr> </tbody> </table></div>

Dose-Related Adverse Reactions

Schizophrenia

Dose response relationships for the incidence of adverse reactions were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).

In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%).

Autistic Disorder

In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%).

Tourette's Disorder

In a study of pediatric patients (7 to 17 years of age) with Tourette's disorder, no common adverse reaction(s) had a dose response relationship.

Extrapyramidal Symptoms

Schizophrenia

In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisiarelated events for aripiprazole-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% vs. 6% for placebo.

Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, –0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole, 0.24; placebo, –0.29).

Similarly, in a long-term (26 week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo.

Major Depressive Disorder

In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive aripiprazole- treated patients was 8% vs. 5% for adjunctive placebotreated patients; and the incidence of akathisia-related events for adjunctive aripiprazole-treated patients was 25% vs. 4% for adjunctive placebo-treated patients.

In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive aripiprazole and adjunctive placebo (aripiprazole, 0.31; placebo, 0.03 and aripiprazole, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive aripiprazole and adjunctive placebo groups.

Autistic Disorder

In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 3% vs. 9% for placebo.

In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (aripiprazole, 0.1; placebo, – 0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups.

Tourette's Disorder

In the short-term, placebo-controlled trials in Tourette's disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 4% vs. 6% for placebo.

In the pediatric (6 to 18 years) short-term Tourette's disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for aripiprazole and placebo.

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Additional Findings Observed in Clinical Trials

Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials

The adverse reactions reported in a 26-week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for aripiprazole 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 led to discontinuation (<1%) of aripiprazole. In addition, in a long-term (52 weeks), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole.

Other Adverse Reactions Observed During Clinical Trial Evaluation of Aripiprazole

Other adverse reactions associated with aripiprazole are presented below. 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients:

Adults - Oral Administration

Pediatric Patients - Oral Administration

Most adverse reactions 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.

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.

Table 18 includes clinically important drug interactions with OPIPZA.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 18: Clinically Important Drug Interactions with OPIPZA</span> </caption> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Strong CYP3A4 Inhibitors AND/OR Strong CYP2D6 Inhibitors</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clinical Rationale</td><td align="left" class="Rrule">Concomitant use of aripiprazole with strong CYP3A4 and/or CYP2D6 inhibitors increased the exposure of aripiprazole <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clinical Recommendation</td><td align="left" class="Rrule">Reduce the dosage of OPIPZA when administered concomitantly with a strong CYP3A4 inhibitor and/or strong CYP2D6 inhibitor <span class="Italics">[see <a href="#S2.6">Dosage and Administration (2.6)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Strong CYP3A4 Inducers</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clinical Rationale</td><td align="left" class="Rrule">Concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clinical Recommendation</td><td align="left" class="Rrule">Consider increasing the dosage of OPIPZA when administered concomitantly with a strong CYP3A4 inducer <span class="Italics">[see <a href="#S2.6">Dosage and Administration (2.6)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Antihypertensive Drugs</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clinical Rationale</td><td align="left" class="Rrule">Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clinical Recommendation</td><td align="left" class="Rrule">Monitor blood pressure and adjust dose accordingly <span class="Italics">[see <a href="#S5.8">Warnings and Precautions (5.8)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Benzodiazepines</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clinical Rationale</td><td align="left" class="Rrule">The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone <span class="Italics">[see <a href="#S5.8">Warnings and Precautions (5.8)</a>].</span></td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Clinical Recommendation</td><td align="left" class="Rrule">Monitor sedation and blood pressure. Adjust dose accordingly.</td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, lorazepam.

In addition, no dosage adjustment is necessary for substrates of CYP2D6, CYP2C9, CYP2C19, or CYP3A4 when coadministered with OPIPZA. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with OPIPZA [see Clinical Pharmacology (12.3)].

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 advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visiting online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including OPIPZA, 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, or major depressive disorder, and with exposure to antipsychotics, including OPIPZA during pregnancy (see Clinical Considerations).

In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data).

The 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 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

Animal Data

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

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

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

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

Safety and effectiveness of OPIPZA in pediatric patients with major depressive disorder have not been established.

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (12.3)].

Schizophrenia

Safety and effectiveness in pediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial of another oral aripiprazole product in 202 pediatric patients aged 13 to 17 years [see Clinical Studies (14.2)]. 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.

Irritability Associated with Autistic Disorder

Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials of another oral aripiprazole product in 212 pediatric patients aged 6 to 17 years [Clinical Studies (14.4)]. A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of "much improved" or "very much improved") on aripiprazole for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16 week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. In this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established.

Tourette's Disorder

Safety and effectiveness of aripiprazole in pediatric patients with Tourette's Disorder were established in one 8 week (aged 7 to 17 years) and one 10-week trial (aged 6 to 18 years) of another oral aripiprazole product in 194 pediatric patients [see Clinical Studies (14.5)]. Maintenance efficacy in pediatric patients has not been systematically evaluated.

Juvenile Animal Studies

Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2 month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies.

Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2 month recovery period.

No dosage adjustment of OPIPZA is recommended for geriatric patients [see Clinical Pharmacology (12.3)].

Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia, major depressive disorder, or another indication did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. OPIPZA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

OPIPZA 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 (2.6) and Clinical Pharmacology (12.3)].

No dosage adjustment for OPIPZA is required on the basis of a patient's renal function (glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)].

No dosage adjustment for OPIPZA is required on the basis of a patient's hepatic function (Child-Pugh scores between 5 and 15) [see Clinical Pharmacology (12.3)].

OPIPZA contains aripiprazole, which is not a controlled substance.

Aripiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of aripiprazole misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

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

Human Experience

In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in patients age 12 years and younger involving oral aripiprazole ingestions up to 195 mg (6.5 times the maximum recommended daily dose) with no fatalities.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Management of Overdosage

Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

No specific information is available on the treatment of overdose with OPIPZA. 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 OPIPZA, 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 aripiprazole, 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 OPIPZA, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

OPIPZA contains aripiprazole, an atypical antipsychotic drug. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. Aripiprazole has a pKa of 6.2. It is freely soluble in dichloromethane, sparingly soluble in toluene, and insoluble in methanol and water. The empirical formula is C23H27Cl2N3O2 with a molecular weight of 448.38. The chemical structure is:

{ "type": "p", "children": [], "text": "OPIPZA contains aripiprazole, an atypical antipsychotic drug. Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. Aripiprazole has a pKa of 6.2. It is freely soluble in dichloromethane, sparingly soluble in toluene, and insoluble in methanol and water. The empirical formula is C23H27Cl2N3O2 with a molecular weight of 448.38. The chemical structure is:" }

OPIPZA is for oral administration and is available in 2 mg, 5 mg, and 10 mg strengths. Inactive ingredients include hydroxypropyl cellulose, sodium lauryl sulfate, and sucralose. Imprinting ink contains glycerin, FD&C Blue No.1, polysorbate 20, and propylene glycol.

{ "type": "p", "children": [], "text": "OPIPZA is for oral administration and is available in 2 mg, 5 mg, and 10 mg strengths. Inactive ingredients include hydroxypropyl cellulose, sodium lauryl sulfate, and sucralose. Imprinting ink contains glycerin, FD&C Blue No.1, polysorbate 20, and propylene glycol." }

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

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 oral film 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.

Absorption

Following administration of aripiprazole oral film, the median (range) time to reach peak plasma concentrations (Tmax) occurs at of 1.5 (1, 6) hours. In two studies comparing the pharmacokinetics of 10 mg aripiprazole oral film to 10 mg aripiprazole tablets under fasting and fed conditions in healthy subjects, the oral film to tablet ratios of geometric mean Cmax and AUC values under fasting conditions were 114% and 106%, respectively, the oral film to tablet ratios of geometric mean Cmax and AUC values under fed conditions were 91% and 95%, 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.

Effect of Food

OPIPZA can be administered with or without food. Administration of a 10 mg aripiprazole oral film with a standard highfat (800 – 1,000 Kcal) meal did not significantly affect the Cmax or AUC of aripiprazole, but increased median (range) Tmax for aripiprazole from 1.5 (1, 6) to 6 (1.5, 12) hours.

Distribution

The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 to 30 mg/day aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans.

Elimination

The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours.

Metabolism

Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and Ndealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.

Excretion

Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces.

Drug Interaction Studies

Effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors.

Figure 1: The Effect of Other Drugs on Aripiprazole Tablet Pharmacokinetics

Figure 2: The Effect of Other Drugs on Dehydro-Aripiprazole Pharmacokinetics

The effect of aripiprazole on the exposures of other drugs are summarized in Figure 3. A population PK analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of fluoxetine (20 or 40 mg/day), paroxetine CR (37.5 or 50 mg/day), or sertraline (100 or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively, and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were co-administered with aripiprazole.

Figure 3: The Effect of Aripiprazole on Pharmacokinetics of Other Drugs

Specific Populations

Exposure of aripiprazole and dehydro-aripiprazole in specific populations is summarized in Figure 4 and Figure 5, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with aripiprazole (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults.

Figure 4: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics

Figure 5: Effect of Intrinsic Factors on Dehydro-Aripiprazole Pharmacokinetics

Carcinogenesis

Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD).

An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear.

Mutagenesis

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

Impairment of Fertility

Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased preimplantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD.

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

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

The efficacy of OPIPZA for the treatment of schizophrenia in patients ages 13 to 17 years, adjunctive treatment of adults with MDD, treatment of irritability associated with autistic disorder in pediatric patients 6 years and older, and treatment of Tourette's disorder in pediatric patients 6 years and older is based on the following adequate and well-controlled studies of another oral aripiprazole product (referred to as "aripiprazole" in this section):

Adults

The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five short-term (4 week and 6 week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish aripiprazole from placebo, but one study, the smallest, did not. Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole and the active comparators.

In the four positive trials for aripiprazole, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

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 15 mg/day or placebo for up to 26 weeks of observation for relapse. Relapse during the double-blind phase was defined as CGI-Improvement score of ≥5 (minimally worse), scores ≥5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or ≥20% increase in the PANSS total score. Patients receiving aripiprazole 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6).

Pediatric Patients (13 to 17 years)

The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing two fixed doses of aripiprazole (10 or 30 mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in the PANSS total score (Study 6 in Table 19), 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.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 19: Schizophrenia Studies (Adults and Pediatric Patients 13 to 17 years)</span> </caption> <col align="left" valign="middle" width="15%"/> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First"> <th align="left"></th><th align="left"></th><th align="center" class="Botrule" colspan="3">Primary Efficacy Measure: PANSS</th> </tr> <tr class="Last"> <th align="left">Study Number</th><th align="left">Treatment Group</th><th align="center">Mean Baseline Score (SD)</th><th align="center">LS Mean Change from Baseline (SE)</th><th align="center">Placebo-subtracted Difference<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>Doses statistically significantly superior to placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="3">Study 1</td><td align="left">Aripiprazole (15 mg/day) <a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a></td><td align="center">98.5 (17.2)</td><td align="center">-15.5 (2.40)</td><td align="center">-12.6 (-18.9, -6.2)</td> </tr> <tr> <td align="left">Aripiprazole (30 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">99.0 (19.2)</td><td align="center">-11.4 (2.39)</td><td align="center">-8.5 (-14.8, -2.1)</td> </tr> <tr class="Botrule"> <td align="left">Placebo</td><td align="center">100.2 (16.5)</td><td align="center">-2.9 (2.36)</td><td align="center">--</td> </tr> <tr> <td align="left" class="Botrule" rowspan="3">Study 2</td><td align="left">Aripiprazole (20 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">92.6 (19.5)</td><td align="center">-14.5 (2.23)</td><td align="center">-9.6 (-15.4, -3.8)</td> </tr> <tr> <td align="left">Aripiprazole (30 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">94.2 (18.5)</td><td align="center">-13.9 (2.24)</td><td align="center">-9.0 (-14.8, -3.1)</td> </tr> <tr class="Botrule"> <td align="left">Placebo</td><td align="center">94.3 (18.5)</td><td align="center">-5.0 (2.17)</td><td align="center">--</td> </tr> <tr> <td align="left" class="Botrule" rowspan="4">Study 3</td><td align="left">Aripiprazole (10 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">92.7 (19.5)</td><td align="center">-15.0 (2.38)</td><td align="center">-12.7 (-19.00, -6.41)</td> </tr> <tr> <td align="left">Aripiprazole (15 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">93.2 (21.6)</td><td align="center">-11.7 (2.38)</td><td align="center">-9.4 (-15.71, -3.08)</td> </tr> <tr> <td align="left">Aripiprazole (20 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">92.5 (20.9)</td><td align="center">-14.4 (2.45)</td><td align="center">-12.1 (-18.53, -5.68)</td> </tr> <tr class="Botrule"> <td align="left">Placebo</td><td align="center">92.3 (21.8)</td><td align="center">-2.3 (2.35)</td><td align="center">--</td> </tr> <tr> <td align="left" class="Botrule" rowspan="4">Study 4</td><td align="left">Aripiprazole (2 mg/day)</td><td align="center">90.7 (14.5)</td><td align="center">-8.2 (1.90)</td><td align="center">-2.9 (-8.29, 2.47)</td> </tr> <tr> <td align="left">Aripiprazole (5 mg/day)</td><td align="center">92.0 (12.6)</td><td align="center">-10.6 (1.93)</td><td align="center">-5.2 (-10.7, 0.19)</td> </tr> <tr> <td align="left">Aripiprazole (10 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">90.0 (11.9)</td><td align="center">-11.3 (1.88)</td><td align="center">-5.9 (-11.3, -0.58)</td> </tr> <tr class="Botrule"> <td align="left">Placebo</td><td align="center">90.8 (13.3)</td><td align="center">-5.3 (1.97)</td><td align="center">--</td> </tr> <tr> <td align="left" class="Botrule" rowspan="3">Study 6<br/> Pediatric patients<br/> (13 to 17 years)</td><td align="left">Aripiprazole (10 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">93.6 (15.7)</td><td align="center">-26.7 (1.91)</td><td align="center">-5.5 (-10.7, -0.21)</td> </tr> <tr> <td align="left">Aripiprazole (30 mg/day) <a class="Sup" href="#footnote-13">†</a></td><td align="center">94.0 (16.1)</td><td align="center">-28.6 (1.92)</td><td align="center">-7.4 (-12.7, -2.13)</td> </tr> <tr class="Last"> <td align="left">Placebo</td><td align="center">94.6 (15.6)</td><td align="center">-21.2 (1.93)</td><td align="center">--</td> </tr> </tbody> </table></div>

Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Adults with Relapse (Schizophrenia Study 5)

The efficacy of aripiprazole in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). Inadequate response for prospective treatment was defined as less than 50% improvement on the 17 item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose.

The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10 item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3 item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme).

In the two trials (n=381, n=362), aripiprazole was superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 28). In one study, aripiprazole was also superior to placebo in reducing the mean SDS score.

In both trials, patients received aripiprazole adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4 mg/day.

An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 20: Adjunctive Treatment of Major Depressive Disorder Studies (Adults)</span> </caption> <col align="center" valign="bottom" width="15%"/> <col align="left" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="20%"/> <col align="center" valign="bottom" width="25%"/> <thead> <tr class="First"> <th align="center"></th><th align="left"></th><th align="center" class="Botrule" colspan="3">Primary Efficacy Measure: MADRS</th> </tr> <tr class="Last"> <th align="left">Study Number</th><th align="left">Treatment Group</th><th align="center">Mean Baseline Score (SD)</th><th align="center">LS Mean Change from Baseline (SE)</th><th align="center">Placebo-subtracted Difference<a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a> (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>Doses statistically significantly superior to placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Botrule" rowspan="3" valign="middle">Study 1</td><td align="left">Aripiprazole (5 to 20 mg/day) <a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a>+ Antidepressant</td><td align="center">25.2 (6.2)</td><td align="center">-8.49 (0.66)</td><td align="center">-2.84 (-4.53, -1.15)</td> </tr> <tr> <td align="left">-------------------------------</td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr class="Botrule"> <td align="left">Placebo + Antidepressant</td><td align="center">27.0 (5.5)</td><td align="center">-5.65 (0.64)</td><td align="center">--</td> </tr> <tr> <td align="center" class="Botrule" rowspan="3" valign="middle">Study 2</td><td align="left">Aripiprazole (5 to 20 mg/day) <a class="Sup" href="#footnote-15">†</a>+ Antidepressant</td><td align="center">26.0 (6.0)</td><td align="center">-8.78 (0.63)</td><td align="center">-3.01 (-4.66, -1.37)</td> </tr> <tr> <td align="left">-------------------------------</td><td align="center"></td><td align="center"></td><td align="center"></td> </tr> <tr class="Botrule Last"> <td align="left">Placebo + Antidepressant</td><td align="center">26.0 (6.5)</td><td align="center">-5.77 (0.67)</td><td align="center">--</td> </tr> </tbody> </table></div>

Pediatric Patients (6 to 17 years)

The efficacy of aripiprazole in the treatment of irritability associated with autistic disorder was established in two 8 week, placebo-controlled trials in pediatric patients (6 to 17 years) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these patients were under 13 years of age.

Efficacy was evaluated using two assessment scales: The Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured symptoms of irritability in autistic disorder.

The results of these trials are as follows:

In one of the 8 week, placebo-controlled trials, pediatric patients 6 to 17 years with autistic disorder (n=98), received daily doses of placebo or aripiprazole 2 to 15 mg/day. Aripiprazole, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of aripiprazole at the end of 8 week treatment was 8.6 mg/day (Study 1 in Table 29).

In the other 8 week, placebo-controlled trial in pediatric patients 6 to 17 years with autistic disorder (n=218), three fixed doses of aripiprazole (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. aripiprazole dosing started at 2 mg/day and was increased to 5 mg/day after one week. After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table 21). All three doses of aripiprazole significantly improved scores on the ABC-I subscale compared with placebo.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 21: Irritability Associated with Autistic Disorder Studies (Pediatric Patients 6 to 17 years)</span> </caption> <col align="left" valign="middle" width="15%"/> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First"> <th align="left"></th><th align="left"></th><th align="center" class="Botrule" colspan="3">Primary Efficacy Measure: ABC-I</th> </tr> <tr class="Last"> <th align="left">Study Number</th><th align="left">Treatment Group</th><th align="center">Mean Baseline Score (SD)</th><th align="center">LS Mean Change from Baseline (SE)</th><th align="center">Placebo-subtracted Difference<a class="Sup" href="#footnote-16" name="footnote-reference-16">*</a> (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-16" name="footnote-16">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">†</a> </dt> <dd>Doses statistically significantly superior to placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="2">Study 1</td><td align="left">Aripiprazole (2 to 15 mg/day) <a class="Sup" href="#footnote-17" name="footnote-reference-17">†</a></td><td align="center">29.6 (6.37)</td><td align="center">-12.9 (1.44)</td><td align="center">-7.9 (-11.7, -4.1)</td> </tr> <tr class="Botrule"> <td align="left">Placebo</td><td align="center">30.2 (6.52)</td><td align="center">-5.0 (1.43)</td><td align="center">--</td> </tr> <tr> <td align="left" class="Botrule" rowspan="4">Study 2</td><td align="left">Aripiprazole (5 mg/day) <a class="Sup" href="#footnote-17">†</a></td><td align="center">28.6 (7.56)</td><td align="center">-12.4 (1.36)</td><td align="center">-4.0 (-7.7, -0.4)</td> </tr> <tr> <td align="left">Aripiprazole (10 mg/day) <a class="Sup" href="#footnote-17">†</a></td><td align="center">28.2 (7.36)</td><td align="center">-13.2 (1.25)</td><td align="center">-4.8 (-8.4, -1.3)</td> </tr> <tr> <td align="left">Aripiprazole (15 mg/day) <a class="Sup" href="#footnote-17">†</a></td><td align="center">28.9 (6.41)</td><td align="center">-14.4 (1.31)</td><td align="center">-6.0 (-9.6, -2.3)</td> </tr> <tr class="Last"> <td align="left">Placebo</td><td align="center">28.0 (6.89)</td><td align="center">-8.4 (1.39)</td><td align="center">--</td> </tr> </tbody> </table></div>

Pediatric Patients (6 to 18 years)

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, pediatric patients 7 to 17 years with Tourette's disorder (n=133), 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 22) and on the CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 7.

Figure 7: Least Square Means of Change from Baseline in YGTSS TTS by Week in Pediatric Patients 7 to 17 years (Tourette's Disorder Study 1)

In the 10 week, placebo-controlled, flexible-dose trial in pediatric patients 6 to 18 years with Tourette's disorder (n=61), 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 22). The mean daily dose of aripiprazole at the end of 10-week treatment was 6.54 mg/day.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 22: Tourette's Disorder Studies (Pediatric Patients)</span> </caption> <col align="left" valign="middle" width="15%"/> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First"> <th align="left"></th><th align="left"></th><th align="center" class="Botrule" colspan="3">Primary Efficacy Measure: YGTSS TTS</th> </tr> <tr class="Last"> <th align="center">Study Number <br/>Population <br/>(Age Range)</th><th align="center">Treatment Group</th><th align="center">Mean Baseline Score (SD)</th><th align="center">LS Mean Change from Baseline (SE)</th><th align="center">Placebo-subtracted Difference<a class="Sup" href="#footnote-18" name="footnote-reference-18">*</a> (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-18" name="footnote-18">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">†</a> </dt> <dd>Doses statistically significantly superior to placebo.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule" rowspan="3">Study 1<br/> Pediatric patients<br/> (7 to 17 years)</td><td align="left">Aripiprazole (low dose) <a class="Sup" href="#footnote-19" name="footnote-reference-19">†</a></td><td align="center">29.2 (5.63)</td><td align="center">-13.4 (1.59)</td><td align="center">-6.3 (-10.2, -2.3)</td> </tr> <tr> <td align="left">Aripiprazole (high dose) <a class="Sup" href="#footnote-19">†</a></td><td align="center">31.2 (6.40)</td><td align="center">-16.9 (1.61)</td><td align="center">-9.9 (-13.8, -5.9)</td> </tr> <tr class="Botrule"> <td align="left">Placebo</td><td align="center">30.7 (5.95)</td><td align="center">-7.1 (1.55)</td><td align="center">--</td> </tr> <tr> <td align="left" class="Botrule" rowspan="2">Study 2<br/> Pediatric patients<br/> (6 to 18 years)</td><td align="left">Aripiprazole (2 to 20 mg/day)<a class="Sup" href="#footnote-19">†</a></td><td align="center">28.3 (5.51)</td><td align="center">-15.0 (1.51)</td><td align="center">-5.3 (-9.8, -0.9)</td> </tr> <tr class="Last"> <td align="left">Placebo</td><td align="center">29.5 (5.60)</td><td align="center">-9.6 (1.64)</td><td align="center">--</td> </tr> </tbody> </table></div>

How Supplied

OPIPZA is available in the strengths and packages listed in Table 23.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 23: OPIPZA Presentations</span> </caption> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="center">Strength</th><th align="center">Color/Shape</th><th align="center">Markings</th><th align="center">Pack Size</th><th align="center">NDC Code</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center">2 mg</td><td align="center">1 cm × 1.2 cm<br/> Rectangular white film</td><td align="center">A2</td><td align="center">30 Pouches of 1</td><td align="center">15370-401-30</td> </tr> <tr class="Botrule"> <td align="center">5 mg</td><td align="center">2 cm × 1.5 cm<br/> Rectangular white film</td><td align="center">A5</td><td align="center">30 Pouches of 1</td><td align="center">15370-402-30</td> </tr> <tr class="Last"> <td align="center">10 mg</td><td align="center">2 cm × 3 cm <br/>Rectangular white film</td><td align="center">A10</td><td align="center">30 Pouches of 1</td><td align="center">15370-403-30</td> </tr> </tbody> </table></div>

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, and Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact a health care provider or report to the emergency room if they experience signs and symptoms of NMS [see Warnings and Precautions (5.4)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Pathological Gambling and Other Compulsive Behaviors

Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking OPIPZA . In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.7)].

Orthostatic Hypotension and Syncope

Educate patients about the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dosage [see Warnings and Precautions (5.8)].

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC count or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while receiving OPIPZA [see Warnings and Precautions (5.10)].

Potential for Cognitive and Motor Impairment

Inform patients that OPIPZA has the potential to impair judgment, thinking, or motor skills. Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle until they are reasonably certain that OPIPZA therapy does not affect them adversely [see Warnings and Precautions (5.12)].

Concomitant Medication

Advise patients to inform their healthcare providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drug Interactions (7.1)].

Heat Exposure and Dehydration

Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)].

Pregnancy

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

Administration Information

Advise the patient of the following [see Dosage and Administration (2.5)]:

Distributed by Carwin Pharmaceutical Associates, LLC Hazlet, NJ 07730

{ "type": "p", "children": [], "text": "Distributed by Carwin Pharmaceutical Associates, LLC Hazlet, NJ 07730" }

Manufactured by Xiamen LP Pharmaceutical Co., Ltd. 2010 Wengjiao West Road, Xiamen, Fujian 361027, China

{ "type": "p", "children": [], "text": "Manufactured by Xiamen LP Pharmaceutical Co., Ltd. 2010 Wengjiao West Road, Xiamen, Fujian 361027, China" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="44%"/> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="50%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="5">MEDICATION GUIDE<br/> OPIPZA™ (o-PIP-sah)<br/> (aripiprazole) oral film</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right" colspan="1">Issued: 8/2024          </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold"><a name="important"></a>What is the most important information I should know about OPIPZA?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5">OPIPZA may cause serious side effects, including:<ul class="Disc"> <li> <span class="Bold">Increased risk of death in elderly people with dementia-related psychosis:</span> Medicines like OPIPZA can increase the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). OPIPZA is not for the treatment of people with dementia-related psychosis.</li> <li> <span class="Bold">Increased risk of suicidal thoughts and actions:</span> OPIPZA and antidepressant medicines increase the risk of suicidal thoughts and actions in people 24 years of age and younger, <span class="Bold">especially within the first few months of treatment or when the dose is changed</span>.<ul class="Circle"> <li> <span class="Bold">Depression and other mental illnesses are the most important causes of suicidal thoughts and actions.</span> </li> </ul> <span class="Bold">How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?</span> <ul class="Circle"> <li>Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings or if you develop suicidal thoughts or actions. This is very important when OPIPZA or the antidepressant medicine is started or when the dose is changed.</li> <li>Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings of if you develop suicidal thoughts or actions.</li> <li>Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.</li> </ul> <span class="Bold">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:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule" colspan="2"></td><td align="left"> <ul class="Square"> <li>thoughts about suicide or dying</li> <li>attempts to commit suicide</li> <li>new or worsening depression</li> <li>new or worsening anxiety</li> <li>feeling very agitated or restless</li> <li>panic attacks</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Square"> <li>trouble sleeping (insomnia)</li> <li>new or worsening irritability</li> <li>acting aggressive, being angry, or violent</li> <li>acting on dangerous impulses</li> <li>an extreme increase in activity and talking (mania)</li> <li>other unusual changes in behavior or mood</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">See <span class="Bold">"<a href="#side">What are the possible side effects of OPIPZA?</a>"</span> for more information about side effects.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What is OPIPZA?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">OPIPZA is a prescription medicine used to treat:</span> <ul class="Disc"> <li>schizophrenia in people ages 13 years and older</li> <li>major depressive disorder (MDD) in adults when OPIPZA is used along with antidepressant medicines</li> <li>irritability associated with autistic disorder in children ages 6 years and older</li> <li>Tourette's disorder in children ages 6 years and older</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">It is not known if OPIPZA is safe and effective for treatment in children:</span> <ul class="Disc"> <li>under 13 years of age with schizophrenia</li> <li>with MDD</li> <li>under 6 years of age with irritability associated with autistic disorder</li> <li>under 6 years of age with Tourette's disorder</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Who should not take OPIPZA?</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Do not take OPIPZA if you</span> are allergic to aripiprazole or any of the ingredients in OPIPZA. See the end of this Medication Guide for a complete list of ingredients in OPIPZA.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Before taking OPIPZA, tell your healthcare provider about all your medical conditions, including if you:</span> <ul class="Disc"> <li>have or had diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start OPIPZA and during your treatment with OPIPZA.</li> <li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li> <li>have or had low or high blood pressure</li> <li>have or had heart problems or stroke</li> <li>have or had low white blood cell counts</li> <li>have or had seizures (convulsions)</li> <li>are pregnant or plan to become pregnant. OPIPZA may harm your unborn baby. Taking OPIPZA during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take OPIPZA during pregnancy.<ul class="Circle"> <li>Tell your healthcare provider right away if you become pregnant during treatment with OPIPZA.</li> <li>If you become pregnant during treatment with OPIPZA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. OPIPZA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with OPIPZA.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Tell your healthcare provider about all the medicines that you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5">OPIPZA and other medicines may affect each other causing possible serious side effects. OPIPZA may affect the way other medicines work, and other medicines may affect how OPIPZA works.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5">Your healthcare provider can tell you if it is safe to take OPIPZA with your other medicines. Do not start or stop any medicines during treatment with OPIPZA without first talking to your healthcare provider.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I take OPIPZA?</span> <ul class="Disc"> <li>Take OPIPZA exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking OPIPZA unless your healthcare provider tells you to.</li> <li>Take OPIPZA with or without food.</li> <li>Each OPIPZA film comes in a sealed child-resistant pouch. Do not open the pouch until you are ready to take your dose of OPIPZA.</li> <li>Let the film dissolve on your tongue before swallowing it.</li> <li>Do not chew the film or swallow it whole.</li> <li>Do not cut or split the film.</li> <li>See the detailed <span class="Bold"><a href="#IFU">Instructions for Use</a></span> for information on how to take a dose of OPIPZA.</li> <li>If you take too much OPIPZA, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold"><a name="avoid"></a>What should I avoid while taking OPIPZA?</span> <ul class="Disc"> <li> <span class="Bold">Do not</span> drive, operate heavy machinery, or do other dangerous activities until you know how OPIPZA affects you. OPIPZA may make you drowsy or may affect your judgement, thinking, or motor skills.</li> <li> <span class="Bold">Do not</span> become too hot or dehydrated during treatment with OPIPZA.<ul class="Circle"> <li>Do not exercise too much.</li> <li>In hot weather, stay inside in a cool place if possible.</li> <li>Stay out of the sun.</li> <li>Do not wear too much clothing or heavy clothing.</li> <li>Drink plenty of water.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold"><a name="side"></a>What are the possible side effects of OPIPZA?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">OPIPZA may cause serious side effects, including:</span> <ul class="Disc"> <li>See <span class="Bold">"<a href="#important">What is the most important information I should know about OPIPZA?</a>"</span> </li> <li> <span class="Bold">Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death</span> </li> <li> <span class="Bold">Neuroleptic malignant syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider right away or go to the nearest emergency room if you have some or all of the following signs and symptoms of NMS:</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="3"> <ul class="Circle"> <li>high fever</li> <li>confusion</li> <li>changes in pulse, heart rate, and blood pressure</li> </ul> </td><td align="left" class="Rrule"> <ul class="Circle"> <li>stiff muscles</li> <li>sweating</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Uncontrolled body movements (tardive dyskinesia).</span> OPIPZA 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 taking OPIPZA. Tardive dyskinesia may also start after you stop taking OPIPZA.</li> <li> <span class="Bold">Problems with your metabolism such as:</span> <ul class="Circle"> <li> <span class="Bold">High blood sugar (hyperglycemia) and diabetes.</span> Increases in blood sugar can happen in some people who are treated with OPIPZA. 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 treatment and during your treatment with OPIPZA. <br/> <span class="Bold">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving OPIPZA:</span> </li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule" colspan="2"></td><td align="left"> <ul class="Square"> <li>feel very thirsty</li> <li>feel very hungry</li> <li>feel sick to your stomach</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Square"> <li>need to urinate more than usual</li> <li>feel weak or tired</li> <li>feel confused, or your breath smells fruity</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="4"> <ul class="Circle"> <li> <span class="Bold">Increased fat levels (cholesterol and triglycerides) in your blood.</span> You healthcare provider may check your cholesterol and triglyceride levels during treatment with OPIPZA.</li> <li> <span class="Bold">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with OPIPZA.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Unusual and uncontrollable (compulsive) urges.</span> Some people taking OPIPZA have had unusual strong urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges can happen including sexual urges, shopping, and binge eating or eating that you cannot control. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</li> <li> <span class="Bold">Decreased blood pressure (orthostatic hypotension) and fainting.</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li> <li> <span class="Bold">Falls.</span> OPIPZA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li> <li> <span class="Bold">Low white blood cell count.</span> Your healthcare provider may do blood cell count tests during your first few months of treatment with OPIPZA.</li> <li> <span class="Bold">Seizures (convulsions).</span> </li> <li> <span class="Bold">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities.</span> See <span class="Bold">"<a href="#avoid">What should I avoid while taking OPIPZA?</a>"</span> </li> <li> <span class="Bold">Problems controlling your body temperature so that you feel too warm.</span> See "<span class="Bold"><a href="#avoid">What should I avoid while taking OPIPZA?</a></span>"</li> <li> <span class="Bold">Difficulty swallowing that can cause food or liquid to get into your lungs.</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">The most common side effects of OPIPZA in adults include:</span></td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>feeling like you need to move (akathisia)</li> <li>trouble sleeping (insomnia)</li> <li>restlessness</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>constipation</li> <li>feeling tired</li> <li>blurred vision</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">The most common side effects of OPIPZA in children include:</span></td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>feeling sleepy or tired</li> <li>headache</li> <li>vomiting</li> <li>nausea</li> <li>increased or decreased appetite</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>increased saliva or drooling</li> <li>uncontrolled movements, muscle stiffness, or tremors</li> <li>fever</li> <li>cold symptoms</li> <li>having no energy</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5">These are not all of the possible side effects of OPIPZA.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I store OPIPZA?</span> <ul class="Disc"> <li>Store OPIPZA at room temperature between 68°F to 77°F (20°C to 25°C).</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Keep OPIPZA and all medicines out of the reach of children.</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">General information about the safe and effective use of OPIPZA</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use OPIPZA for a condition for which it was not prescribed. Do not give OPIPZA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about OPIPZA that is written for health professionals.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the ingredients in OPIPZA?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Active ingredient:</span> aripiprazole.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Inactive ingredients:</span> hydroxypropyl cellulose, sodium lauryl sulfate, and sucralose. Imprinting ink contains glycerin, FD&amp;C Blue No.1, polysorbate 20, and propylene glycol.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5">Distributed by<br/> Carwin Pharmaceutical Associates, LLC<br/> Hazlet, NJ 07730</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5">Manufactured by<br/> Xiamen LP Pharmaceutical Co., Ltd.<br/> 2010 Wengjiao West Road, Xiamen, Fujian 361027, China</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="5">For more information about OPIPZA go to https://carwinpharma.com/opipza/ or call 1-877-676-0778.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"44%\"/>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"5\">MEDICATION GUIDE<br/> OPIPZA™ (o-PIP-sah)<br/> (aripiprazole) oral film</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"4\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" colspan=\"1\">Issued: 8/2024          </td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\"><a name=\"important\"></a>What is the most important information I should know about OPIPZA?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">OPIPZA may cause serious side effects, including:<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased risk of death in elderly people with dementia-related psychosis:</span> Medicines like OPIPZA can increase the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). OPIPZA is not for the treatment of people with dementia-related psychosis.</li>\n<li>\n<span class=\"Bold\">Increased risk of suicidal thoughts and actions:</span> OPIPZA and antidepressant medicines increase the risk of suicidal thoughts and actions in people 24 years of age and younger, <span class=\"Bold\">especially within the first few months of treatment or when the dose is changed</span>.<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Depression and other mental illnesses are the most important causes of suicidal thoughts and actions.</span>\n</li>\n</ul>\n<span class=\"Bold\">How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?</span>\n<ul class=\"Circle\">\n<li>Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings or if you develop suicidal thoughts or actions. This is very important when OPIPZA or the antidepressant medicine is started or when the dose is changed.</li>\n<li>Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings of if you develop suicidal thoughts or actions.</li>\n<li>Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.</li>\n</ul>\n<span class=\"Bold\">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:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"2\"></td><td align=\"left\">\n<ul class=\"Square\">\n<li>thoughts about suicide or dying</li>\n<li>attempts to commit suicide</li>\n<li>new or worsening depression</li>\n<li>new or worsening anxiety</li>\n<li>feeling very agitated or restless</li>\n<li>panic attacks</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Square\">\n<li>trouble sleeping (insomnia)</li>\n<li>new or worsening irritability</li>\n<li>acting aggressive, being angry, or violent</li>\n<li>acting on dangerous impulses</li>\n<li>an extreme increase in activity and talking (mania)</li>\n<li>other unusual changes in behavior or mood</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">See <span class=\"Bold\">\"<a href=\"#side\">What are the possible side effects of OPIPZA?</a>\"</span> for more information about side effects.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What is OPIPZA?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">OPIPZA is a prescription medicine used to treat:</span>\n<ul class=\"Disc\">\n<li>schizophrenia in people ages 13 years and older</li>\n<li>major depressive disorder (MDD) in adults when OPIPZA is used along with antidepressant medicines</li>\n<li>irritability associated with autistic disorder in children ages 6 years and older</li>\n<li>Tourette's disorder in children ages 6 years and older</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">It is not known if OPIPZA is safe and effective for treatment in children:</span>\n<ul class=\"Disc\">\n<li>under 13 years of age with schizophrenia</li>\n<li>with MDD</li>\n<li>under 6 years of age with irritability associated with autistic disorder</li>\n<li>under 6 years of age with Tourette's disorder</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Who should not take OPIPZA?</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Do not take OPIPZA if you</span> are allergic to aripiprazole or any of the ingredients in OPIPZA. See the end of this Medication Guide for a complete list of ingredients in OPIPZA.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Before taking OPIPZA, tell your healthcare provider about all your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have or had diabetes or high blood sugar in you or your family. Your healthcare provider should check your blood sugar before you start OPIPZA and during your treatment with OPIPZA.</li>\n<li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li>\n<li>have or had low or high blood pressure</li>\n<li>have or had heart problems or stroke</li>\n<li>have or had low white blood cell counts</li>\n<li>have or had seizures (convulsions)</li>\n<li>are pregnant or plan to become pregnant. OPIPZA may harm your unborn baby. Taking OPIPZA during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take OPIPZA during pregnancy.<ul class=\"Circle\">\n<li>Tell your healthcare provider right away if you become pregnant during treatment with OPIPZA.</li>\n<li>If you become pregnant during treatment with OPIPZA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or go to http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. OPIPZA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with OPIPZA.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Tell your healthcare provider about all the medicines that you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">OPIPZA and other medicines may affect each other causing possible serious side effects. OPIPZA may affect the way other medicines work, and other medicines may affect how OPIPZA works.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Your healthcare provider can tell you if it is safe to take OPIPZA with your other medicines. Do not start or stop any medicines during treatment with OPIPZA without first talking to your healthcare provider.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Know the medicines you take. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I take OPIPZA?</span>\n<ul class=\"Disc\">\n<li>Take OPIPZA exactly as your healthcare provider tells you to take it. Do not change the dose or stop taking OPIPZA unless your healthcare provider tells you to.</li>\n<li>Take OPIPZA with or without food.</li>\n<li>Each OPIPZA film comes in a sealed child-resistant pouch. Do not open the pouch until you are ready to take your dose of OPIPZA.</li>\n<li>Let the film dissolve on your tongue before swallowing it.</li>\n<li>Do not chew the film or swallow it whole.</li>\n<li>Do not cut or split the film.</li>\n<li>See the detailed <span class=\"Bold\"><a href=\"#IFU\">Instructions for Use</a></span> for information on how to take a dose of OPIPZA.</li>\n<li>If you take too much OPIPZA, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\"><a name=\"avoid\"></a>What should I avoid while taking OPIPZA?</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not</span> drive, operate heavy machinery, or do other dangerous activities until you know how OPIPZA affects you. OPIPZA may make you drowsy or may affect your judgement, thinking, or motor skills.</li>\n<li>\n<span class=\"Bold\">Do not</span> become too hot or dehydrated during treatment with OPIPZA.<ul class=\"Circle\">\n<li>Do not exercise too much.</li>\n<li>In hot weather, stay inside in a cool place if possible.</li>\n<li>Stay out of the sun.</li>\n<li>Do not wear too much clothing or heavy clothing.</li>\n<li>Drink plenty of water.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\"><a name=\"side\"></a>What are the possible side effects of OPIPZA?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">OPIPZA may cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>See <span class=\"Bold\">\"<a href=\"#important\">What is the most important information I should know about OPIPZA?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death</span>\n</li>\n<li>\n<span class=\"Bold\">Neuroleptic malignant syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider right away or go to the nearest emergency room if you have some or all of the following signs and symptoms of NMS:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"3\">\n<ul class=\"Circle\">\n<li>high fever</li>\n<li>confusion</li>\n<li>changes in pulse, heart rate, and blood pressure</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Circle\">\n<li>stiff muscles</li>\n<li>sweating</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Uncontrolled body movements (tardive dyskinesia).</span> OPIPZA 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 taking OPIPZA. Tardive dyskinesia may also start after you stop taking OPIPZA.</li>\n<li>\n<span class=\"Bold\">Problems with your metabolism such as:</span>\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">High blood sugar (hyperglycemia) and diabetes.</span> Increases in blood sugar can happen in some people who are treated with OPIPZA. 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 treatment and during your treatment with OPIPZA. <br/>\n<span class=\"Bold\">Call your healthcare provider if you have any of these symptoms of high blood sugar while receiving OPIPZA:</span>\n</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"2\"></td><td align=\"left\">\n<ul class=\"Square\">\n<li>feel very thirsty</li>\n<li>feel very hungry</li>\n<li>feel sick to your stomach</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Square\">\n<li>need to urinate more than usual</li>\n<li>feel weak or tired</li>\n<li>feel confused, or your breath smells fruity</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Increased fat levels (cholesterol and triglycerides) in your blood.</span> You healthcare provider may check your cholesterol and triglyceride levels during treatment with OPIPZA.</li>\n<li>\n<span class=\"Bold\">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with OPIPZA.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Unusual and uncontrollable (compulsive) urges.</span> Some people taking OPIPZA have had unusual strong urges to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges can happen including sexual urges, shopping, and binge eating or eating that you cannot control. If you or your family members notice that you are having unusual urges or behaviors, talk to your healthcare provider.</li>\n<li>\n<span class=\"Bold\">Decreased blood pressure (orthostatic hypotension) and fainting.</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li>\n<li>\n<span class=\"Bold\">Falls.</span> OPIPZA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li>\n<li>\n<span class=\"Bold\">Low white blood cell count.</span> Your healthcare provider may do blood cell count tests during your first few months of treatment with OPIPZA.</li>\n<li>\n<span class=\"Bold\">Seizures (convulsions).</span>\n</li>\n<li>\n<span class=\"Bold\">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities.</span> See <span class=\"Bold\">\"<a href=\"#avoid\">What should I avoid while taking OPIPZA?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Problems controlling your body temperature so that you feel too warm.</span> See \"<span class=\"Bold\"><a href=\"#avoid\">What should I avoid while taking OPIPZA?</a></span>\"</li>\n<li>\n<span class=\"Bold\">Difficulty swallowing that can cause food or liquid to get into your lungs.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">The most common side effects of OPIPZA in adults include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>feeling like you need to move (akathisia)</li>\n<li>trouble sleeping (insomnia)</li>\n<li>restlessness</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>constipation</li>\n<li>feeling tired</li>\n<li>blurred vision</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">The most common side effects of OPIPZA in children include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>feeling sleepy or tired</li>\n<li>headache</li>\n<li>vomiting</li>\n<li>nausea</li>\n<li>increased or decreased appetite</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>increased saliva or drooling</li>\n<li>uncontrolled movements, muscle stiffness, or tremors</li>\n<li>fever</li>\n<li>cold symptoms</li>\n<li>having no energy</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">These are not all of the possible side effects of OPIPZA.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I store OPIPZA?</span>\n<ul class=\"Disc\">\n<li>Store OPIPZA at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Keep OPIPZA and all medicines out of the reach of children.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">General information about the safe and effective use of OPIPZA</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use OPIPZA for a condition for which it was not prescribed. Do not give OPIPZA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about OPIPZA that is written for health professionals.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the ingredients in OPIPZA?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Active ingredient:</span> aripiprazole.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Inactive ingredients:</span> hydroxypropyl cellulose, sodium lauryl sulfate, and sucralose. Imprinting ink contains glycerin, FD&amp;C Blue No.1, polysorbate 20, and propylene glycol.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Distributed by<br/> Carwin Pharmaceutical Associates, LLC<br/> Hazlet, NJ 07730</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Manufactured by<br/> Xiamen LP Pharmaceutical Co., Ltd.<br/> 2010 Wengjiao West Road, Xiamen, Fujian 361027, China</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">For more information about OPIPZA go to https://carwinpharma.com/opipza/ or call 1-877-676-0778.</td>\n</tr>\n</tbody>\n</table></div>" }

This Instructions for Use contains information on how to take OPIPZA.

{ "type": "p", "children": [], "text": "This Instructions for Use contains information on how to take OPIPZA." }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="top" width="100%"/> <thead> <tr> <th align="center">Figure A</th> </tr> </thead> <tbody> <tr> <td align="center"><img alt="Figure A" src="/dailymed/image.cfm?name=opipza-09.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"center\" valign=\"top\" width=\"100%\"/>\n<thead>\n<tr>\n<th align=\"center\">Figure A</th>\n</tr>\n</thead>\n<tbody>\n<tr>\n<td align=\"center\"><img alt=\"Figure A\" src=\"/dailymed/image.cfm?name=opipza-09.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4\"/></td>\n</tr>\n</tbody>\n</table></div>" }

Important Information You Need to Know Before Taking OPIPZA.

{ "type": "p", "children": [], "text": "\nImportant Information You Need to Know Before Taking OPIPZA.\n" }

{ "type": "ul", "children": [ "\nDo not take OPIPZA until:\nyou have read and understand these instructions.\nyou have reviewed the steps with your healthcare provider on how to take it.\nyou know the right time, how often, and the dose to take.\nyou feel comfortable with how to use OPIPZA.\nIf you are not sure about how or when to take OPIPZA, call your healthcare provider.\n\n\n", "OPIPZA is for oral use only (taken by mouth).", "Take OPIPZA with or without food.", "Each OPIPZA film comes in a sealed child-resistant pouch. Do not open the pouch until you are ready to take your dose of OPIPZA.", "\nDo not chew the film or swallow it whole.", "\nDo not cut or split the film.", "Check the expiration date printed on the pouch. Do not take OPIPZA if it is expired or if the pouch has been previously cut or pierced. Instead, throw away OPIPZA in your household trash and get a new pouch that is not expired or damaged." ], "text": "" }

Step 1. Preparing to Take OPIPZA

{ "type": "p", "children": [], "text": "\nStep 1. Preparing to Take OPIPZA\n" }

{ "type": "ul", "children": [ "Wash and dry your hands before handling and taking OPIPZA (see Figure B).\n\n\n\nFigure B\n\n\n\n\n\n\n", "Remove the number of pouches that you need for your prescribed dose from the OPIPZA carton.", "If you need to take more than 1 OPIPZA film for your dose, open only 1 pouch and take only 1 film at a time." ], "text": "" }

Step 2. Opening the OPIPZA Pouch

{ "type": "p", "children": [], "text": "\nStep 2. Opening the OPIPZA Pouch\n" }

{ "type": "ul", "children": [ "Fold the pouch along the dashed line.", "Find the slit, the arrow, and the words \"TO OPEN\" on the OPIPZA pouch. Carefully tear the pouch in the direction of the arrow starting at the slit to open the pouch (see Figure C)." ], "text": "" }

<div class="scrollingtable"><table class="Noautorules" width="30%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold"><a name="figc"></a>Figure C</span></td> </tr> <tr> <td align="center"><img alt="Figure C" src="/dailymed/image.cfm?name=opipza-11.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"30%\">\n<col align=\"center\" valign=\"top\" width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\"><span class=\"Bold\"><a name=\"figc\"></a>Figure C</span></td>\n</tr>\n<tr>\n<td align=\"center\"><img alt=\"Figure C\" src=\"/dailymed/image.cfm?name=opipza-11.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4\"/></td>\n</tr>\n</tbody>\n</table></div>" }

Step 3. Taking OPIPZA

{ "type": "p", "children": [], "text": "\nStep 3. Taking OPIPZA\n" }

{ "type": "ul", "children": [ "Carefully remove the film from the OPIPZA pouch (see Figure D).\nIf the film tears or dissolves in your hands (hands were not dry enough) when it is removed from the pouch, throw away (dispose of) the film as described below (see \"Disposing of OPIPZA\") and get a new film. Repeat steps 1 to 3 with the new film." ], "text": "" }

<div class="scrollingtable"><table class="Noautorules" width="30%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold"><a name="figd"></a>Figure D</span></td> </tr> <tr> <td align="center"><img alt="Figure D" src="/dailymed/image.cfm?name=opipza-12.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"30%\">\n<col align=\"center\" valign=\"top\" width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\"><span class=\"Bold\"><a name=\"figd\"></a>Figure D</span></td>\n</tr>\n<tr>\n<td align=\"center\"><img alt=\"Figure D\" src=\"/dailymed/image.cfm?name=opipza-12.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4\"/></td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "ul", "children": [ "Take the OPIPZA film right away after opening the pouch and removing the film.", "\nDo not split or cut the OPIPZA film.", "Place the entire OPIPZA film on the top of your tongue and close your mouth. Let the film dissolve on your tongue before swallowing it. The film will dissolve quickly (see Figure E).", "\nDo not chew the film or swallow the film whole.", "\nDo not rinse your mouth with liquid." ], "text": "" }

<div class="scrollingtable"><table class="Noautorules" width="30%"> <col align="center" valign="top" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><span class="Bold"><a name="fige"></a>Figure E</span></td> </tr> <tr> <td align="center"><img alt="Figure E" src="/dailymed/image.cfm?name=opipza-13.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"30%\">\n<col align=\"center\" valign=\"top\" width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\"><span class=\"Bold\"><a name=\"fige\"></a>Figure E</span></td>\n</tr>\n<tr>\n<td align=\"center\"><img alt=\"Figure E\" src=\"/dailymed/image.cfm?name=opipza-13.jpg&amp;setid=b47ede68-8942-4432-af7e-57afc14b2ba4\"/></td>\n</tr>\n</tbody>\n</table></div>" }

If you need more than 1 film for your prescribed dose wait until the previous film has completely dissolved before taking another OPIPZA film. Repeat steps 1 to 3 with each additional film that you need to take for your prescribed dose.

{ "type": "p", "children": [], "text": "\nIf you need more than 1 film for your prescribed dose wait until the previous film has completely dissolved before taking another OPIPZA film. Repeat steps 1 to 3 with each additional film that you need to take for your prescribed dose.\n" }

When you are finished taking OPIPZA, wash and dry your hands.

{ "type": "p", "children": [], "text": "When you are finished taking OPIPZA, wash and dry your hands." }

Disposing of OPIPZA

{ "type": "p", "children": [], "text": "\nDisposing of OPIPZA\n" }

{ "type": "ul", "children": [ "Throw away (dispose of) any unused or expired OPIPZA in your household trash.", "Throw away the empty pouches in your household trash." ], "text": "" }

Storing OPIPZA

{ "type": "p", "children": [], "text": "\nStoring OPIPZA\n" }

{ "type": "ul", "children": [ "Store OPIPZA at room temperature between 68°F to 77°F (20°C to 25°C).", "Keep OPIPZA in the unopened pouch until you are ready to take your dose.", "\nKeep OPIPZA and all medicines out of the reach of children.\n" ], "text": "" }

Distributed by Carwin Pharmaceutical Associates, LLC Hazlet, NJ 07730

{ "type": "p", "children": [], "text": "Distributed by Carwin Pharmaceutical Associates, LLC Hazlet, NJ 07730" }

Manufactured by Xiamen LP Pharmaceutical Co., Ltd. 2010 Wengjiao West Road, Xiamen, Fujian 361027, China

{ "type": "p", "children": [], "text": "Manufactured by Xiamen LP Pharmaceutical Co., Ltd. 2010 Wengjiao West Road, Xiamen, Fujian 361027, China" }

For more information or support regarding OPIPZA: Call 1-877-676-0778

{ "type": "p", "children": [], "text": "For more information or support regarding OPIPZA: Call 1-877-676-0778" }

The Instructions for Use has been approved by the U.S. Food and Drug Administration.                               Approved: 8/2024

{ "type": "p", "children": [], "text": "The Instructions for Use has been approved by the U.S. Food and Drug Administration.                               Approved: 8/2024" }

NDC 15370-401-30

{ "type": "p", "children": [], "text": "NDC 15370-401-30" }

OPIPZA™ (aripiprazole) oral film

{ "type": "p", "children": [], "text": "OPIPZA™ (aripiprazole) oral film" }

2 mg

{ "type": "p", "children": [], "text": "2 mg" }

Do not cut or chew the oral film

{ "type": "p", "children": [], "text": "Do not cut or chew the oral film" }

Pharmacist: Dispense the enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Pharmacist: Dispense the enclosed Medication Guide to each patient." }

30 pouches each containing 1 oral filmRx Only

{ "type": "p", "children": [], "text": "30 pouches each containing 1 oral filmRx Only" }

NDC 15370-402-30

{ "type": "p", "children": [], "text": "NDC 15370-402-30" }

OPIPZA™ (aripiprazole) oral film

{ "type": "p", "children": [], "text": "OPIPZA™ (aripiprazole) oral film" }

5 mg

{ "type": "p", "children": [], "text": "5 mg" }

Do not cut or chew the oral film

{ "type": "p", "children": [], "text": "Do not cut or chew the oral film" }

Pharmacist: Dispense the enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Pharmacist: Dispense the enclosed Medication Guide to each patient." }

30 pouches each containing 1 oral filmRx Only

{ "type": "p", "children": [], "text": "30 pouches each containing 1 oral filmRx Only" }

NDC 15370-403-30

{ "type": "p", "children": [], "text": "NDC 15370-403-30" }

OPIPZA™ (aripiprazole) oral film

{ "type": "p", "children": [], "text": "OPIPZA™ (aripiprazole) oral film" }

10 mg

{ "type": "p", "children": [], "text": "10 mg" }

Do not cut or chew the oral film

{ "type": "p", "children": [], "text": "Do not cut or chew the oral film" }

Pharmacist: Dispense the enclosed Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Pharmacist: Dispense the enclosed Medication Guide to each patient." }

30 pouches each containing 1 oral filmRx Only

{ "type": "p", "children": [], "text": "30 pouches each containing 1 oral filmRx Only" }