ABILIFY MAINTENA

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1) ]. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death ( 5.1 ) ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis ( 5.1 )

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.3 ) Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.4 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain ( 5.5 ) – Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with and at risk for diabetes ( 5.5 ) – Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics ( 5.5 ) – Weight Gain: Gain in body weight has been observed; clinical monitoring of weight is recommended ( 5.5 ) Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation ( 5.6 ) Orthostatic Hypotension: Use with caution in patients with known cardiovascular or cerebrovascular disease ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of a clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC). Consider discontinuation if clinically significant decline in WBC/ANC in the absence of other causative factors ( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.10 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery ( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia- Related Psychosis 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. 5.2 Cerebrovascular Adverse Reactions, Including Stroke in Elderly 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 . 5.3 Neuroleptic Malignant Syndrome 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. 5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect 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. 5.5 Metabolic Changes 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. 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 Category Change (at least once) from Baseline Treatment Arm n/N 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. % Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) ABILIFY MAINTENA 7/88 8.0 Placebo 0/75 0.0 Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) ABILIFY MAINTENA 1/33 3.0 Placebo 3/33 9.1 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. 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 Treatment Arm n/N 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. % Total Cholesterol Normal to High (<200 mg/dL to ≥240 mg/dL) ABILIFY MAINTENA 3/83 3.6 Placebo 2/73 2.7 Borderline to High (200~<240 mg/dL to ≥240 mg/dL) ABILIFY MAINTENA 6/27 22.2 Placebo 2/19 10.5 Any increase (≥40 mg/dL) ABILIFY MAINTENA 15/122 12.3 Placebo 6/110 5.5 Fasting Triglycerides Normal to High (<150 mg/dL to ≥200 mg/dL) ABILIFY MAINTENA 7/98 7.1 Placebo 4/78 5.1 Borderline to High (150~<200 mg/dL to ≥200 mg/dL) ABILIFY MAINTENA 3/11 27.3 Placebo 4/15 26.7 Any increase (≥50 mg/dL) ABILIFY MAINTENA 24/122 19.7 Placebo 20/110 18.2 Fasting LDL Cholesterol Normal to High (<100 mg/dL to ≥160 mg/dL) ABILIFY MAINTENA 1/59 1.7 Placebo 1/51 2.0 Borderline to High (100~<160 mg/dL to ≥160 mg/dL) ABILIFY MAINTENA 5/52 9.6 Placebo 1/41 2.4 Any increase (≥30 mg/dL) ABILIFY MAINTENA 17/120 14.2 Placebo 9/103 8.7 HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) ABILIFY MAINTENA 14/104 13.5 Placebo 11/87 12.6 Any decrease (≥20 mg/dL) ABILIFY MAINTENA 7/122 5.7 Placebo 12/110 10.9 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. Table 7: Percentage of Patients From a 12-Week Placebo-Controlled Trial in Adult Patients with Schizophrenia with Weight Gain ≥7% of Body Weight Treatment Arm N N = the total number of subjects who had a measurement at baseline and at least one post-baseline result. Patients n (%) Weight gain ≥7% of body weight ABILIFY MAINTENA 144 31 (21.5) Placebo 141 12 (8.5) 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. 5.6 Pathological Gambling and Other Compulsive Behaviors Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges. 5.7 Orthostatic Hypotension and Syncope ABILIFY MAINTENA may cause orthostatic hypotension, perhaps due to its α 1 -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). 5.8 Falls 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. 5.9 Leukopenia, Neutropenia, and Agranulocytosis 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/mm 3 ) and follow their WBC counts until recovery. 5.10 Seizures 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. 5.11 Potential for Cognitive and Motor Impairment 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. 5.12 Body Temperature Regulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY 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). 5.13 Dysphagia 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) ] .

<table width="75%" ID="table5"><caption>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 </caption><col width="15%" align="left" valign="middle"/><col width="35%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><thead><tr><th/><th valign="bottom">Category Change (at least once) from Baseline</th><th valign="bottom" styleCode="Lrule Rrule">Treatment Arm</th><th valign="bottom" styleCode="Rrule">n/N<footnote>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.</footnote></th><th valign="bottom">%</th></tr></thead><tbody><tr styleCode="Botrule"><td rowspan="4"><content styleCode="bold">Fasting Glucose</content></td><td rowspan="2">Normal to High (&lt;100 mg/dL to &#x2265;126 mg/dL)</td><td styleCode="Lrule Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">7/88</td><td>8.0</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">0/75</td><td>0.0</td></tr><tr styleCode="Botrule"><td rowspan="2" align="center">Borderline to High (&#x2265;100 mg/dL and &lt;126 mg/dL to &#x2265;126 mg/dL)</td><td styleCode="Lrule Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">1/33</td><td>3.0</td></tr><tr><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">3/33</td><td>9.1</td></tr></tbody></table>

<table width="75%" ID="table6"><caption>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</caption><col width="35%" align="left" valign="middle"/><col width="35%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><thead><tr><th styleCode="Rrule"/><th styleCode="Rrule">Treatment Arm</th><th styleCode="Rrule">n/N<footnote>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.</footnote></th><th>%</th></tr></thead><tbody><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule"><content styleCode="bold">Total Cholesterol</content> Normal to High (&lt;200 mg/dL to &#x2265;240 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">3/83</td><td>3.6</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">2/73</td><td>2.7</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule">Borderline to High (200~&lt;240 mg/dL to &#x2265;240 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">6/27</td><td>22.2</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">2/19</td><td>10.5</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule">Any increase (&#x2265;40 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">15/122</td><td>12.3</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">6/110</td><td>5.5</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule"><content styleCode="bold">Fasting Triglycerides</content> Normal to High (&lt;150 mg/dL to &#x2265;200 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">7/98</td><td>7.1</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">4/78</td><td>5.1</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule">Borderline to High (150~&lt;200 mg/dL to &#x2265;200 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">3/11</td><td>27.3</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">4/15</td><td>26.7</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule">Any increase (&#x2265;50 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">24/122</td><td>19.7</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">20/110</td><td>18.2</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule"><content styleCode="bold">Fasting LDL Cholesterol</content> Normal to High (&lt;100 mg/dL to &#x2265;160 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">1/59</td><td>1.7</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">1/51</td><td>2.0</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule">Borderline to High (100~&lt;160 mg/dL to &#x2265;160 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">5/52</td><td>9.6</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">1/41</td><td>2.4</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule">Any increase (&#x2265;30 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">17/120</td><td>14.2</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">9/103</td><td>8.7</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule"><content styleCode="bold">HDL Cholesterol</content> Normal to Low (&#x2265;40 mg/dL to &lt;40 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">14/104</td><td>13.5</td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">11/87</td><td>12.6</td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Rrule">Any decrease (&#x2265;20 mg/dL)</td><td styleCode="Rrule">ABILIFY MAINTENA</td><td styleCode="Rrule">7/122</td><td>5.7</td></tr><tr><td align="center" styleCode="Lrule Rrule">Placebo</td><td styleCode="Rrule">12/110</td><td>10.9</td></tr></tbody></table>

<table width="75%" ID="table7"><caption>Table 7: Percentage of Patients From a 12-Week Placebo-Controlled Trial in Adult Patients with Schizophrenia with Weight Gain &#x2265;7% of Body Weight</caption><col width="25%" align="center" valign="middle"/><col width="34%" align="center" valign="middle"/><col width="12%" align="center" valign="middle"/><col width="29%" align="center" valign="middle"/><thead><tr><th/><th>Treatment Arm</th><th>N<footnote>N = the total number of subjects who had a measurement at baseline and at least one post-baseline result.</footnote></th><th>Patients n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td valign="bottom" rowspan="2"><content styleCode="bold">Weight gain &#x2265;7% of body weight</content></td><td>ABILIFY MAINTENA</td><td>144</td><td>31 (21.5)</td></tr><tr><td>Placebo</td><td>141</td><td>12 (8.5)</td></tr></tbody></table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia - Related Psychosis Use [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.2) ] Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3) ] Tardive Dyskinesia [see Warnings and Precautions (5.4) ] Metabolic Changes [see Warnings and Precautions (5.5) ] Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (5.6) ] Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.7) ] Falls [see Warnings and Precautions (5.8) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.11) ] Body Temperature Regulation [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Most commonly observed adverse reactions with ABILIFY MAINTENA in patients with schizophrenia (incidence ≥5% and at least twice that for placebo) were increased weight, akathisia, injection site pain, and sedation ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Table 8: Adverse Reactions in ≥2% of ABILIFY MAINTENA-Treated Adult Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial This table does not include adverse reactions which had an incidence equal to or less than placebo. Percentage of Patients Reporting Reaction ABILIFY MAINTENA Placebo Preferred Term (n=167) (n=172) Gastrointestinal Disorders Constipation 10 7 Dry Mouth 4 2 Diarrhea 3 2 Vomiting 3 1 Abdominal Discomfort 2 1 General Disorders and Administration Site Conditions Injection Site Pain 5 1 Infections and Infestations Upper Respiratory Tract Infection 4 2 Investigations Increased Weight 17 7 Decreased Weight 4 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 1 Back Pain 4 2 Myalgia 4 2 Musculoskeletal Pain 3 1 Nervous System Disorders Akathisia 11 4 Sedation 5 1 Dizziness 4 2 Tremor 3 1 Respiratory, Thoracic and Mediastinal Nasal Congestion 2 1 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: Blood and Lymphatic System Disorders: rare - thrombocytopenia Cardiac Disorders: infrequent - tachycardia; rare - bradycardia, sinus tachycardia Endocrine Disorders: rare - hypoprolactinemia Eye Disorders: infrequent - vision blurred, oculogyric crisis Gastrointestinal Disorders: infrequent - abdominal pain upper, dyspepsia, nausea; rare -swollen tongue General Disorders and Administration Site Conditions: frequent - fatigue, injection site reactions (including erythema, induration, pruritus, injection site reaction, swelling, rash, inflammation, hemorrhage); infrequent - chest discomfort, gait disturbance; rare -irritability, pyrexia Hepatobiliary Disorders: rare - drug induced liver injury Immune System Disorders: rare - drug hypersensitivity Infections and Infestations: rare - nasopharyngitis Investigations: infrequent - blood creatine phosphokinase increased, blood pressure decreased, hepatic enzyme increased, liver function test abnormal, electrocardiogram QT-prolonged; rare - blood triglycerides decreased, blood cholesterol decreased, electrocardiogram T-wave abnormal Metabolism and Nutrition Disorders: infrequent - decreased appetite, obesity, hyperinsulinemia Musculoskeletal and Connective Tissue Disorders: infrequent - joint stiffness, muscle twitching, trismus; rare - rhabdomyolysis Nervous System Disorders: infrequent - extrapyramidal disorder, hypersomnia, lethargy; rare - bradykinesia, convulsion, dysgeusia, memory impairment, oromandibular dystonia Psychiatric Disorders: frequent - anxiety, insomnia, restlessness; infrequent - agitation, bruxism, psychotic disorder, suicidal ideation; rare - aggression, hypersexuality, panic attack Renal and Urinary Disorders : rare - glycosuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: infrequent - ejaculation delayed Vascular Disorders: infrequent - hypertension 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: Cardiac Disorders: palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, angina pectoris, myocardial ischemia, atrial flutter, supraventricular tachycardia, ventricular tachycardia Eye Disorders: photophobia, diplopia, eyelid edema, photopsia Gastrointestinal Disorders: gastroesophageal reflux disease, swollen tongue, esophagitis, pancreatitis, stomach discomfort, toothache General Disorders and Administration Site Conditions: asthenia, peripheral edema, chest pain, face edema, angioedema, hypothermia, pain Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivity Injury, Poisoning, and Procedural Complications: heat stroke Investigations: blood prolactin decreased, blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, blood lactate dehydrogenase increased, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: anorexia, hyponatremia, hypoglycemia, polydipsia, diabetic ketoacidosis Musculoskeletal and Connective Tissue Disorders: muscle rigidity, muscular weakness, muscle tightness, decreased mobility, rhabdomyolysis, musculoskeletal stiffness, pain in extremity, muscle spasms Nervous System Disorders: coordination abnormal, speech disorder, hypokinesia, hypotonia, myoclonus, akinesia, bradykinesia, choreoathetosis Psychiatric Disorders: loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self-injury, completed suicide, tic, homicidal ideation, catatonia, sleepwalking Renal and Urinary Disorders: urinary retention, polyuria, nocturia Reproductive System and Breast Disorders: menstruation irregular, erectile dysfunction, amenorrhea, breast pain, gynecomastia, priapism Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea, pharyngolaryngeal pain, cough Skin and Subcutaneous Tissue Disorders: rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhidrosis, pruritus, photosensitivity reaction, alopecia, urticaria 6.2 Postmarketing Experience 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.

<table width="75%" ID="table8"><caption>Table 8: Adverse Reactions in &#x2265;2% of ABILIFY MAINTENA-Treated Adult Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial<footnote ID="t7fa">This table does not include adverse reactions which had an incidence equal to or less than placebo.</footnote></caption><col width="35%" align="left" valign="middle"/><col width="35%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th/><th colspan="2">Percentage of Patients Reporting Reaction<footnoteRef IDREF="t7fa"/></th></tr><tr><th/><th>ABILIFY MAINTENA</th><th>Placebo</th></tr><tr><th> Preferred Term</th><th>(n=167)</th><th>(n=172)</th></tr></thead><tbody><tr><td colspan="3"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td> Constipation</td><td>10</td><td>7</td></tr><tr><td> Dry Mouth</td><td>4</td><td>2</td></tr><tr><td> Diarrhea</td><td>3</td><td>2</td></tr><tr><td> Vomiting</td><td>3</td><td>1</td></tr><tr><td> Abdominal Discomfort</td><td>2</td><td>1</td></tr><tr><td colspan="3"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr><td> Injection Site Pain</td><td>5</td><td>1</td></tr><tr><td colspan="3"><content styleCode="bold">Infections and Infestations</content></td></tr><tr><td> Upper Respiratory Tract Infection</td><td>4</td><td>2</td></tr><tr><td colspan="3"><content styleCode="bold">Investigations</content></td></tr><tr><td> Increased Weight</td><td>17</td><td>7</td></tr><tr><td> Decreased Weight</td><td>4</td><td>2</td></tr><tr><td colspan="3"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr><td> Arthralgia</td><td>4</td><td>1</td></tr><tr><td> Back Pain</td><td>4</td><td>2</td></tr><tr><td> Myalgia</td><td>4</td><td>2</td></tr><tr><td> Musculoskeletal Pain</td><td>3</td><td>1</td></tr><tr><td colspan="3"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr><td> Akathisia</td><td>11</td><td>4</td></tr><tr><td> Sedation</td><td>5</td><td>1</td></tr><tr><td> Dizziness</td><td>4</td><td>2</td></tr><tr><td> Tremor</td><td>3</td><td>1</td></tr><tr><td colspan="3"><content styleCode="bold">Respiratory, Thoracic and Mediastinal</content></td></tr><tr><td> Nasal Congestion</td><td>2</td><td>1</td></tr></tbody></table>