FDA label 5247f695-6721-4388-a127-1613a2abfe13

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS 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. Cariprazine is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for the emergence of suicidal thoughts and behaviors [see Warnings and Precautions ( 5.2 )] . The safety and effectiveness of cariprazine have not been established in pediatric patients [see Use in Specific Populations ( 8.4 )] . WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS 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. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. ( 5.1 ) Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Safety and effectiveness of cariprazine have not been established in pediatric patients ( 5.2 , 8.4 )

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) ( 5.3 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.4 ) Tardive Dyskinesia: Discontinue if appropriate ( 5.5 ) Late-Occurring Adverse Reactions: Because of cariprazine's long half-life, monitor for adverse reactions and patient response for several weeks after starting cariprazine and with each dosage change ( 5.6 ) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain ( 5.7 ) Leukopenia, Neutropenia and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell counts (WBC) or history of leukopenia or neutropenia. Consider discontinuing cariprazine if a clinically significant decline in WBC occurs in absence of other causative factors ( 5.8 ) Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease and risk of dehydration or syncope ( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.11 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery ( 5.12 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that 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 placebo-treated patients. 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. Cariprazine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.3 )] . 5.2 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults 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 1. Table 1 Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric Cariprazine is not approved for use in pediatric patients. and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18 years to 24 years old 5 additional patients Decreases Compared to Placebo 25 years to 64 years old 1 fewer patient ≥ 65 years old 6 fewer patients 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 cariprazine, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.3 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Cariprazine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.1 )] . 5.4 Neuroleptic Malignant Syndrome (NMS) Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. If NMS is suspected, immediately discontinue cariprazine and provide intensive symptomatic treatment and monitoring. 5.5 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including cariprazine. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict 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 tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even 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, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, cariprazine should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on cariprazine, drug discontinuation should be considered. However, some patients may require treatment with cariprazine despite the presence of the syndrome. 5.6 Late-Occurring Adverse Reactions Adverse events may first appear several weeks after the initiation of cariprazine treatment, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures [see Dosage and Administration ( 2.1 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . Monitor for adverse reactions, including extrapyramidal symptoms (EPS) or akathisia and patient response for several weeks after a patient has begun cariprazine and after each dosage increase. Consider reducing the dose or discontinuing the drug. 5.7 Metabolic Changes Atypical antipsychotic drugs, including cariprazine, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and 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. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment. Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (< 100 mg/dL) to high (≥ 126 mg/dL) and borderline (≥ 100 and < 126 mg/dL) to high were similar in patients treated with cariprazine and placebo. In the long-term, open-label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%). Bipolar Disorder In six placebo-controlled trials up to 8-weeks of adult patients with bipolar disorder (mania or depression), the proportion of patients with shifts in fasting glucose from normal (< 100 mg/dL) to high (≥ 126 mg/dL) and borderline (≥ 100 and < 126 mg/dL) to high were similar in patients treated with cariprazine and placebo. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%). Dyslipidemia Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with cariprazine and placebo. Bipolar Disorder In six placebo-controlled trials up to 8-weeks of adult patients with bipolar disorder (mania or depression), the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with cariprazine and placebo. Weight Gain Weight gain has been observed with use of atypical antipsychotics, including cariprazine. Monitor weight at baseline and frequently thereafter. Tables 2, 3 and 4 show the change in body weight occurring from baseline to endpoint in 6-week schizophrenia, 3-week bipolar mania and 6-week and 8-week bipolar depression trials, respectively. Table 2 Change in Body Weight (kg) in 6-Week Schizophrenia Trials * Data shown by modal daily dose, defined as most frequently administered dose per patient ○ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Cariprazine * Placebo (N=573) 1.5 mg/day to 3 mg/day (N=512) 4.5 mg/day to 6 mg/day (N=570) 9 mg/day to 12 mg/day ○ (N=203) Mean Change at Endpoint +0.3 +0.8 +1 +1 Proportion of Patients with Weight Increase (≥ 7%) 5% 8% 8% 17% In long-term, uncontrolled trials with cariprazine in schizophrenia, the mean changes from baseline in weight at 12, 24 and 48 weeks were 1.2 kg, 1.7 kg and 2.5 kg, respectively. Table 3 Change in Body Weight (kg) in 3-Week Bipolar Mania Trials * Data shown by modal daily dose, defined as most frequently administered dose per patient ○ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Cariprazine * Placebo (N=439) 3 mg/day to 6 mg/day (N=259) 9 mg/day to 12 mg/day ○ (N=360) Mean Change at Endpoint +0.2 +0.5 +0.6 Proportion of Patients with Weight Increase (≥ 7%) 2% 1% 3% Table 4 Change in Body Weight (kg) in two 6-Week and one 8-Week Bipolar Depression Trials Cariprazine Placebo (N=463) 1.5 mg/day (N=467) 3 mg/day (N=465) Mean Change at Endpoint -0.1 +0.7 +0.4 Proportion of Patients with Weight Increase (≥7%) 1% 3% 3% 5.8 Leukopenia, Neutropenia and Agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including cariprazine. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of cariprazine 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 cariprazine in patients with absolute neutrophil count < 1,000/mm 3 and follow their WBC until recovery. 5.9 Orthostatic Hypotension and Syncope Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of cariprazine and was not more frequent on cariprazine than placebo. Syncope was not observed. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities) and patients with cerebrovascular disease. Cariprazine has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. 5.10 Falls Antipsychotics, including cariprazine, 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. 5.11 Seizures Like other antipsychotic drugs, cariprazine may cause seizures. This risk is greatest 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 older patients. 5.12 Potential for Cognitive and Motor Impairment Cariprazine, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week schizophrenia trials, somnolence (hypersomnia, sedation and somnolence) was reported in 7% of cariprazine-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of cariprazine-treated patients compared to 4% of placebo-treated patients. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with cariprazine does not affect them adversely. 5.13 Body Temperature Dysregulation Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration and anticholinergic medications may contribute to an elevation in core body temperature; use cariprazine with caution in patient who may experience these conditions. 5.14 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with cariprazine. Cariprazine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.

<table ID="ID46" width="576" styleCode="Noautorules"><caption> Table 1 Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric<footnote ID="ID460"> Cariprazine is not approved for use in pediatric patients.</footnote> and Adult Patients </caption><col width="186"/><col width="390"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Age Range</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Increases Compared to Placebo</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> &lt; 18 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14 additional patients </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 18 years to 24 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 additional patients </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Decreases Compared to Placebo</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 25 years to 64 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 fewer patient </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> &#x2265; 65 years old </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 fewer patients </td></tr></tbody></table>

<table ID="ID58" width="588" styleCode="Noautorules"><caption> Table 2 Change in Body Weight (kg) in 6-Week Schizophrenia Trials </caption><col width="198"/><col width="78"/><col width="102"/><col width="108"/><col width="102"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^*Data shown by modal daily dose, defined as most frequently administered dose per patient </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^&#x25CB;The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Cariprazine ^*</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo (N=573)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 1.5 mg/day to </content> <content styleCode="bold"> 3 mg/day (N=512)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 4.5</content><content styleCode="bold"> mg/day</content> <content styleCode="bold"> to</content> <content styleCode="bold"> 6 mg/day (N=570)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 9 mg/day </content> <content styleCode="bold"> to </content> <content styleCode="bold"> 12 mg/day^&#x25CB;</content><content styleCode="bold"> (N=203)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Mean Change at Endpoint </td><td styleCode=" Botrule Rrule" align="center"> +0.3 </td><td styleCode=" Botrule Rrule" align="center"> +0.8 </td><td styleCode=" Botrule Rrule" align="center"> +1 </td><td styleCode=" Botrule Rrule" align="center"> +1 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Proportion of Patients with Weight Increase (&#x2265; 7%) </td><td styleCode=" Botrule Rrule" align="center"> 5% </td><td styleCode=" Botrule Rrule" align="center"> 8% </td><td styleCode=" Botrule Rrule" align="center"> 8% </td><td styleCode=" Botrule Rrule" align="center"> 17% </td></tr></tbody></table>

<table ID="ID60" width="576" styleCode="Noautorules"><caption> Table 3 Change in Body Weight (kg) in 3-Week Bipolar Mania Trials </caption><col width="276"/><col width="84"/><col width="102"/><col width="114"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^*Data shown by modal daily dose, defined as most frequently administered dose per patient</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^&#x25CB;</content> The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"> </td><td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Cariprazine ^*</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (N=439)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 3 mg/day </content> <content styleCode="bold"> to</content> <content styleCode="bold"> 6 mg/day (N=259)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 9 mg/day </content> <content styleCode="bold"> to </content> <content styleCode="bold"> 12</content><content styleCode="bold"> mg/day^&#x25CB;</content><content styleCode="bold"> (N=360)</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Mean Change at Endpoint </td><td styleCode=" Botrule Rrule" align="center"> +0.2 </td><td styleCode=" Botrule Rrule" align="center"> +0.5 </td><td styleCode=" Botrule Rrule" align="center"> +0.6 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Proportion of Patients with Weight Increase (&#x2265; 7%) </td><td styleCode=" Botrule Rrule" align="center"> 2% </td><td styleCode=" Botrule Rrule" align="center"> 1% </td><td styleCode=" Botrule Rrule" align="center"> 3% </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 [see Boxed Warning and Warnings and Precautions ( 5.1 )] Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions ( 5.2 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.3 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.4 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.5 )] Late Occurring Adverse Reactions [see Warnings and Precautions ( 5.6 )] Metabolic Changes [see Warnings and Precautions ( 5.7 )] Leukopenia, Neutropenia and Agranulocytosis [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.12 )] Body Temperature Dysregulation [see Warnings and Precautions ( 5.13 )] Dysphagia [see Warnings and Precautions ( 5.14 )] Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) were ( 6.1 ): Schizophrenia: extrapyramidal symptoms and akathisia Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence and restlessness Bipolar depression: nausea, akathisia, restlessness and extrapyramidal symptoms To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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. The information below is derived from an integrated clinical study database for cariprazine consisting of 4,753 adult patients exposed to one or more doses of cariprazine for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 940.3 patient-years. A total of 2,568 cariprazine-treated patients had at least 6 weeks and 296 cariprazine-treated patients had at least 48 weeks of exposure. Patients with Schizophrenia The following findings are based on four placebo-controlled, 6-week schizophrenia trials with cariprazine doses ranging from 1.5 mg to 12 mg once daily. The maximum recommended dosage is 6 mg daily. Adverse Reactions Associated with Discontinuation of Treatment : There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in cariprazine-treated patients and at least twice the rate of placebo. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo) : extrapyramidal symptoms and akathisia. Adverse Reactions with an incidence of ≥ 2% and greater than placebo, at any dose are shown in Table 5. Table 5 Adverse Reactions Occurring in ≥ 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials Note: Figures rounded to the nearest integer * Data shown by modal daily dose, defined as most frequently administered dose per patient a Tachycardia terms : heart rate increased, sinus tachycardia, tachycardia b Abdominal pain terms : abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain c Diarrhea terms : diarrhea, frequent bowel movements d Fatigue terms : asthenia, fatigue e Hepatic enzyme increase terms : alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased f Extrapyramidal Symptoms terms : bradykinesia, cogwheel rigidity, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, masked facies, muscle rigidity, muscle tightness, Musculoskeletal stiffness, oculogyric crisis, oromandibular dystonia, parkinsonism, salivary hypersecretion, tardive dyskinesia, torticollis, tremor, trismus g Headache terms : headache, tension headache h Somnolence terms : hypersomnia, sedation, somnolence i Insomnia terms : initial insomnia, insomnia, middle insomnia, terminal insomnia j Hypertension terms : blood pressure diastolic increased, blood pressure increased, blood pressure systolic increased, hypertension ○ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. System Organ Class / Preferred Term Placebo (N= 584) (%) Cariprazine * 1.5 mg/day to 3 mg/day (N=539) (%) 4.5 mg/day to 6 mg/day (N=575) (%) 9 mg/day to 12 mg/day ○ (N=203) (%) Cardiac Disorders Tachycardia a 1 2 2 3 Gastrointestinal Disorders Abdominal pain b 5 3 4 7 Constipation 5 6 7 10 Diarrhea c 3 1 4 5 Dry Mouth 2 1 2 3 Dyspepsia 4 4 5 5 Nausea 5 5 7 8 Toothache 4 3 3 6 Vomiting 3 4 5 5 General Disorders/Administration Site Conditions Fatigue d 1 1 3 2 Infections and infestations Nasopharyngitis 1 1 1 2 Urinary tract infection 1 1 < 1 2 Investigations Blood creatine phosphokinase increased 1 1 2 3 Hepatic enzyme increased e < 1 1 1 2 Weight increased 1 3 2 3 Metabolism and nutrition disorders Decreased appetite 2 1 3 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 1 2 1 2 Back pain 2 3 3 1 Pain in extremity 3 2 2 4 Nervous System Disorders Akathisia 4 9 13 14 Extrapyramidal Symptoms f 8 15 19 20 Headache g 13 9 11 18 Somnolence h 5 5 8 10 Dizziness 2 3 5 5 Psychiatric Disorders Agitation 4 3 5 3 Insomnia i 11 12 13 11 Restlessness 3 4 6 5 Anxiety 4 6 5 3 Respiratory, thoracic and mediastinal disorders Cough 2 1 2 4 Skin and subcutaneous disorders Rash 1 < 1 1 2 Vascular Disorders Hypertension j 1 2 3 6 Patients with Bipolar Mania The following findings are based on three placebo-controlled, 3-week bipolar mania trials with cariprazine doses ranging from 3 mg to 12 mg once daily. The maximum recommended dosage is 6 mg daily. Adverse Reactions Associated with Discontinuation of Treatment : The adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in cariprazine-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received cariprazine discontinued treatment due to an adverse reaction, compared with 7% of placebo-treated patients in these trials. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo) : extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence and restlessness. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in Table 6. Table 6 Adverse Reactions Occurring in ≥ 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials Note: Figures rounded to the nearest integer * Data shown by modal daily dose, defined as most frequently administered dose per patient a Tachycardia terms: heart rate increased, sinus tachycardia, tachycardia b Abdominal pain terms: abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, c Diarrhea: diarrhea, frequent bowel movements d Fatigue terms: asthenia, fatigue e Pyrexia terms: body temperature increased, pyrexia f Hepatic enzymes increased terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased g Extrapyramidal Symptoms terms: bradykinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, oromandibular dystonia, parkinsonism, salivary hypersecretion, tremor h Headache terms: headache, tension headache i Somnolence terms: hypersomnia, sedation, somnolence j Insomnia terms: initial insomnia, insomnia, middle insomnia k Hypertension terms: blood pressure diastolic increased, blood pressure increased, hypertension ⸰ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. System Organ Class / Preferred Term Placebo (N= 442) (%) Cariprazine * 3 mg/day to 6 mg/day (N=263) (%) 9 mg/day to 12 mg/day ○ (N=360) (%) Cardiac Disorders Tachycardia a 1 2 1 Eye Disorders Vision blurred 1 4 4 Gastrointestinal Disorders Nausea 7 13 11 Constipation 5 6 11 Vomiting 4 10 8 Dry mouth 2 3 2 Dyspepsia 4 7 9 Abdominal pain b 5 6 8 Diarrhea c 5 5 6 Toothache 2 4 3 General Disorders/Administration Site Conditions Fatigue d 2 4 5 Pyrexia e 2 1 4 Investigations Blood creatine phosphokinase increased 2 2 3 Hepatic enzymes increased f < 1 1 3 Weight increased 2 2 3 Metabolism and Nutrition Disorders Decreased appetite 3 3 4 Musculoskeletal and Connective Tissue Disorders Pain in extremity 2 4 2 Back pain 1 1 3 Nervous System Disorders Akathisia 5 20 21 Extrapyramidal Symptoms g 12 26 29 Headache h 13 14 13 Dizziness 4 7 6 Somnolence i 4 7 8 Psychiatric Disorders Insomnia j 7 9 8 Restlessness 2 7 7 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 2 1 3 Vascular Disorders Hypertension k 1 5 4 Patients with Bipolar Depression The following findings are based on three placebo-controlled, two 6-week and one 8-week bipolar depression trials with cariprazine doses of 1.5 mg and 3 mg once daily. Adverse Reactions Associated with Discontinuation of Treatment : There were no adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in cariprazine-treated patients and at least twice the rate of placebo. Overall, 6% of the patients who received cariprazine discontinued treatment due to an adverse reaction, compared with 5% of placebo-treated patients in these trials. C ommon Adverse Reactions (≥ 5% and at least twice the rate of placebo) : nausea, akathisia, restlessness and extrapyramidal symptoms. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1.5 mg or 3 mg doses are shown in Table 7. Table 7 Adverse Reactions Occurring in ≥ 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in two 6-week trials and one 8-week trial a Extrapyramidal symptoms terms: akinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle tightness, musculoskeletal stiffness, myoclonus, oculogyric crisis, salivary hypersecretion, tardive dyskinesia, tremor b Somnolence terms: hypersomnia, sedation, somnolence c Fatigue terms: asthenia, fatigue, malaise d Insomnia terms: initial insomnia, insomnia, insomnia related to another mental condition, middle insomnia, sleep disorder terminal insomnia Placebo (N=468) (%) Cariprazine 1.5 mg/day (N=470) (%) 3 mg/day (N=469) (%) Restlessness 3 2 7 Akathisia 2 6 10 Extrapyramidal symptoms a 2 4 6 Dizziness 2 4 3 Somnolence b 4 7 6 Nausea 3 7 7 Increased appetite 1 3 3 Weight increase < 1 2 2 Fatigue c 2 4 3 Insomnia d 7 7 10 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. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Extrapyramidal Symptoms (EPS) and Akathisia In schizophrenia, bipolar mania and bipolar depression trials, data were objectively collected using the Simpson Angus Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score ≤ 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Rating Scale (BARS) for treatment-emergent akathisia (BARS total score ≤ 2 at baseline and > 2 post-baseline). In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for cariprazine-treated patients versus 8% for placebo-treated patients. These events led to discontinuation in 0.3% of cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for cariprazine-treated patients versus 4% for placebo-treated patients. These events led to discontinuation in 0.5% of cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of EPS is shown in Table 8. Table 8 Incidence of EPS Compared to Placebo in 6-Week Schizophrenia Studies Note: Figures rounded to the nearest integer * Data shown by modal daily dose, defined as most frequently administered dose per patient ** Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, trismus, torticollis § Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypokinesia, masked facies, muscle rigidity, muscle tightness, parkinsonism, tremor, salivary hypersecretion ○ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Adverse Event Term Placebo (N= 584) (%) Cariprazine * 1.5 mg/day to 3 mg/day (N=539) (%) 4.5 mg/day to 6 mg/day (N=575) (%) 9 mg/day to 12 mg/day ○ (N=203) (%) All EPS events 14 24 32 33 All EPS events, excluding Akathisia/Restlessness 8 15 19 20 Akathisia 4 9 13 14 Dystonia ** < 1 2 2 2 Parkinsonism § 7 13 16 18 Restlessness 3 4 6 5 Musculoskeletal stiffness 1 1 3 1 In 3-week bipolar mania trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for cariprazine-treated patients versus 12% for placebo-treated patients. These events led to a discontinuation in 1% of cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for cariprazine-treated patients versus 5% for placebo-treated patients. These events led to discontinuation in 2% of cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of EPS is provided in Table 9. Table 9 Incidence of EPS Compared to Placebo in 3-Week Bipolar Mania Trials Note: Figures rounded to the nearest integer * Data shown by modal daily dose, defined as most frequently administered dose per patient ** Dystonia includes adverse event terms: dystonia, oromandibular dystonia § Parkinsonism includes adverse event terms: bradykinesia, drooling, dyskinesia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, parkinsonism, salivary hypersecretion, tremor ○ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Adverse Event Term Placebo (N= 442) (%) Cariprazine * 3 mg/day to 6 mg/day (N=263) (%) 9 mg/day to 12 mg/day ○ (N=360) (%) All EPS events 18 41 45 All EPS events, excluding Akathisia/Restlessness 12 26 29 Akathisia 5 20 21 Dystonia ** 1 5 3 Parkinsonism § 10 21 26 Restlessness 2 7 7 Musculoskeletal stiffness 1 2 2 In the two 6-week and one 8-week bipolar depression trials, the incidence of reported events related to EPS, excluding akathisia and restlessness was 4% for cariprazine-treated patients versus 2% for placebo-treated patients. These events led to discontinuation in 0.4% of cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of akathisia was 8% for cariprazine-treated patients versus 2% for placebo-treated patients. These events led to discontinuation in 1.5% of cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of EPS is shown in Table 10. Table 10 Incidence of EPS Compared to Placebo in two 6-Week and one 8-Week Bipolar Depression Trials Note: Figures rounded to the nearest integer * Dystonia includes adverse event terms: dystonia, myoclonus, oculogyric crisis § Parkinsonism includes adverse event terms: akinesia, drooling, dyskinesia, extrapyramidal disorder, hypokinesia, muscle tightness, salivary hypersecretion and tremor. Adverse Event Term Placebo (N=468) (%) Cariprazine * 1.5 mg/day (N=470) (%) 3 mg/day (N=469) (%) All EPS events 7 10 19 All EPS events, excluding Akathisia/Restlessness 2 4 6 Akathisia 2 6 10 Dystonia * < 1 < 1 < 1 Parkinsonism § 2 3 4 Restlessness 3 2 7 Musculoskeletal stiffness < 1 < 1 1 Tardive Dyskinesia 0 0 < 1 Cataracts In the long-term uncontrolled schizophrenia (48-week) and bipolar mania (16-week) trials, the incidence of cataracts was 0.1% and 0.2%, respectively. The development of cataracts was observed in nonclinical studies [see Nonclinical Toxicology ( 13.2 )] . The possibility of lenticular changes or cataracts cannot be excluded at this time. Vital Signs Changes There were no clinically meaningful differences between cariprazine-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 mg/day to 12 mg/day cariprazine-treated patients with schizophrenia. Pooled data from 6-week schizophrenia trials are shown in Table 11 and from 3-week bipolar mania trials are shown in Table 12. Table 11 Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials * Data shown by modal daily dose, defined as most frequently administered dose per patient ○ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Placebo (N=574) Cariprazine * 1.5 mg/day to 3 mg/day (N=512) 4.5 mg/day to 6 mg/day (N=570) 9 mg/day to 12 mg/day ○ (N=203) Supine Systolic Blood Pressure (mmHg) +0.9 +0.6 +1.3 +2.1 Supine Diastolic Blood Pressure (mmHg) +0.4 +0.2 +1.6 +3.4 Table 12 Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials * Data shown by modal daily dose, defined as most frequently administered dose per patient ○ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Placebo (N=439) Cariprazine * 3 mg/day to 6 mg/day (N=259) 9 mg/day to 12 mg/day ○ (N=360) Supine Systolic Blood Pressure (mmHg) -0.5 +0.8 +1.8 Supine Diastolic Blood Pressure (mmHg) +0.9 +1.5 +1.9 In the two 6-week and one 8-week bipolar depression trials, there were no clinically meaningful differences between cariprazine-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine systolic and diastolic blood pressure. Pooled data from two 6-week and one 8-week bipolar depression trials are shown in Table 13. Table 13 Mean Change in Blood Pressure at Endpoint in two 6-Week and one 8-Week Bipolar Depression Trials Placebo (N=468) Cariprazine * 1.5 mg/day (N=572) 3 mg/day (N=426) Supine Systolic Blood Pressure (mmHg) -0.2 0.2 -0.1 Supine Diastolic Blood Pressure (mmHg) 0.2 0.1 -0.3 Changes in Laboratory Tests The proportions of patients with transaminase elevations of ≥ 3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for cariprazine-treated patients, increasing with dose and was 1% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥ 3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for cariprazine-treated patients depending on dose group administered and 2% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥ 3 times the upper limits of the normal reference range in 6-week and 8-week bipolar depression trials ranged between 0% and 0.5% for cariprazine-treated patients depending on dose group administered and 0.4% for placebo-treated patients. The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1,000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for cariprazine-treated patients, increasing with dose and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1,000 U/L in 3-week bipolar mania trials was about 4% in cariprazine and placebo-treated patients. The proportions of patients with elevations of CPK greater than 1,000 U/L in 6-week and 8-week bipolar depression trials ranged between 0.2% and 1% for cariprazine-treated patients versus 0.2% for placebo-treated patients. Other Adverse Reactions Observed During the Pre-marketing Evaluation of Cariprazine Adverse reactions listed below were reported by patients treated with cariprazine at doses of ≥ 1.5 mg once daily within the premarketing database of 3,988 cariprazine-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the cariprazine label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency, according to the following definition: those occurring in at least 1/100 patients (frequent) [only those not already listed in the tabulated results from placebo-controlled studies appear in this listing]; those occurring in 1/100 to 1/1,000 patients (infrequent); and those occurring in fewer than 1/1,000 patients (rare). Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis Hepatobiliary Disorders: Rare: hepatitis Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyponatremia Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Rare: ischemic stroke Psychiatric Disorders: Infrequent: suicide attempts, suicide ideation; Rare: completed suicide Renal and Urinary Disorders: Infrequent: pollakiuria Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of cariprazine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders – Stevens-Johnson syndrome

<table ID="ID83" width="600" styleCode="Noautorules"><caption> Table 5 Adverse Reactions Occurring in &#x2265; 2% of Cariprazine-treated Patients and &gt; Placebo-treated Adult Patients in 6-Week Schizophrenia Trials </caption><col width="162"/><col width="113"/><col width="109"/><col width="114"/><col width="102"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">Note: Figures rounded to the nearest integer</paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^*Data shown by modal daily dose, defined as most frequently administered dose per patient </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^a</content><content styleCode="bold"> Tachycardia terms</content> : heart rate increased, sinus tachycardia, tachycardia </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^b</content><content styleCode="bold"> Abdominal pain terms</content> : abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^c</content><content styleCode="bold"> Diarrhea terms</content> : diarrhea, frequent bowel movements </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^d</content><content styleCode="bold"> Fatigue terms</content> : asthenia, fatigue </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^e</content><content styleCode="bold"> Hepatic enzyme increase terms</content> : alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased</paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^f</content><content styleCode="bold"> Extrapyramidal Symptoms terms</content> : bradykinesia, cogwheel rigidity, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, masked facies, muscle rigidity, muscle tightness, Musculoskeletal stiffness, oculogyric crisis, oromandibular dystonia, parkinsonism, salivary hypersecretion, tardive dyskinesia, torticollis, tremor, trismus </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^g</content><content styleCode="bold"> Headache terms</content> : headache, tension headache </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^h</content><content styleCode="bold"> Somnolence terms</content> : hypersomnia, sedation, somnolence </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">ⁱ</content><content styleCode="bold"> Insomnia terms</content> : initial insomnia, insomnia, middle insomnia, terminal insomnia </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote"><content styleCode="bold">^j</content><content styleCode="bold"> Hypertension terms</content> : blood pressure diastolic increased, blood pressure increased, blood pressure systolic increased, hypertension </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">^&#x25CB;The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> System Organ Class / Preferred Term</content> </td><td rowspan="2" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (N= 584)</content> <content styleCode="bold"> (%)</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Cariprazine^*</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 1.5 mg/day to 3 mg/day (N=539) </content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 4.5 mg/day to 6 mg/day (N=575) </content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 9 mg/day to 12 mg/day^&#x25CB; (N=203) </content> <content styleCode="bold"> (%)</content> </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Cardiac Disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Tachycardia^a </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Gastrointestinal Disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Abdominal pain^b </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Constipation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Diarrhea^c </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dry Mouth </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dyspepsia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Toothache </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> General Disorders/Administration Site Conditions</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fatigue^d </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Infections and infestations</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nasopharyngitis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Urinary tract infection </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt; 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Investigations</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Blood creatine phosphokinase increased </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hepatic enzyme increased^e </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt; 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Weight increased </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Metabolism and nutrition disorders </content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Decreased appetite </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Musculoskeletal and Connective Tissue Disorders </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Arthralgia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Back pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Pain in extremity </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Nervous System Disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Akathisia </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 9 </td><td styleCode=" Botrule Rrule" align="center"> 13 </td><td styleCode=" Botrule Rrule" align="center"> 14 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Extrapyramidal Symptoms^f </td><td styleCode=" Botrule Rrule" align="center"> 8 </td><td styleCode=" Botrule Rrule" align="center"> 15 </td><td styleCode=" Botrule Rrule" align="center"> 19 </td><td styleCode=" Botrule Rrule" align="center"> 20 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Headache^g </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 18 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Somnolence^h </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Dizziness </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 5 </td><td styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Psychiatric Disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Agitation </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 5 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Insomniaⁱ </td><td styleCode=" Botrule Rrule" align="center"> 11 </td><td styleCode=" Botrule Rrule" align="center"> 12 </td><td styleCode=" Botrule Rrule" align="center"> 13 </td><td styleCode=" Botrule Rrule" align="center"> 11 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Restlessness </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 6 </td><td styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Anxiety </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Respiratory, thoracic and mediastinal disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Cough </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Skin and subcutaneous disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Rash </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> &lt; 1 </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Vascular Disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension^j </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td></tr></tbody></table>

<table ID="ID85" width="612" styleCode="Noautorules"><caption> Table 6 Adverse Reactions Occurring in &#x2265; 2% of Cariprazine-treated Patients and &gt; Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials </caption><col width="184"/><col width="146"/><col width="141"/><col width="141"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">Note: Figures rounded to the nearest integer </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^*Data shown by modal daily dose, defined as most frequently administered dose per patient </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^a</content><content styleCode="bold"> Tachycardia terms:</content> heart rate increased, sinus tachycardia, tachycardia </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^b</content><content styleCode="bold"> Abdominal pain terms:</content> abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^c</content><content styleCode="bold"> Diarrhea:</content> diarrhea, frequent bowel movements </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^d</content><content styleCode="bold"> Fatigue terms:</content> asthenia, fatigue </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^e</content><content styleCode="bold"> Pyrexia terms:</content> body temperature increased, pyrexia </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^f</content><content styleCode="bold"> Hepatic enzymes increased terms: </content> alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^g</content><content styleCode="bold"> Extrapyramidal Symptoms terms:</content> bradykinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, oromandibular dystonia, parkinsonism, salivary hypersecretion, tremor</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^h</content><content styleCode="bold"> Headache terms:</content> headache, tension headache </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">ⁱ</content><content styleCode="bold"> Somnolence terms:</content> hypersomnia, sedation, somnolence </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^j</content><content styleCode="bold"> Insomnia terms:</content> initial insomnia, insomnia, middle insomnia </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^k</content><content styleCode="bold"> Hypertension terms:</content> blood pressure diastolic increased, blood pressure increased, hypertension </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">&#x2E30; The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> System Organ Class / Preferred Term</content> </td><td rowspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (N= 442) </content> <content styleCode="bold"> (%)</content> </td><td colspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Cariprazine^*</content> </td></tr><tr><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 3 mg/day </content> <content styleCode="bold"> to 6 mg/day (N=263) </content> <content styleCode="bold"> (%)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 9 mg/day</content> <content styleCode="bold"> to 12 mg/day^&#x25CB;(N=360) </content> <content styleCode="bold"> (%)</content> </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Cardiac Disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Tachycardia^a </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 1 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Eye Disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Vision blurred </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Gastrointestinal Disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Constipation </td><td styleCode=" Botrule Rrule" align="center"> 5 </td><td styleCode=" Botrule Rrule" align="center"> 6 </td><td styleCode=" Botrule Rrule" align="center"> 11 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 10 </td><td styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Dry mouth </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Dyspepsia </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 7 </td><td styleCode=" Botrule Rrule" align="center"> 9 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Abdominal pain^b </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Diarrhea^c </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Toothache </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> General Disorders/Administration Site Conditions</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fatigue^d </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Pyrexia^e </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Investigations</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Blood creatine phosphokinase increased </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hepatic enzymes increased^f </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt; 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Weight increased </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Metabolism and Nutrition Disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Decreased appetite </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Musculoskeletal and Connective Tissue Disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pain in extremity </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Back pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Nervous System Disorders</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Akathisia </td><td styleCode=" Botrule Rrule" align="center"> 5 </td><td styleCode=" Botrule Rrule" align="center"> 20 </td><td styleCode=" Botrule Rrule" align="center"> 21 </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Extrapyramidal Symptoms^g </td><td styleCode=" Botrule Rrule" align="center"> 12 </td><td styleCode=" Botrule Rrule" align="center"> 26 </td><td styleCode=" Botrule Rrule" align="center"> 29 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Headache^h </td><td styleCode=" Botrule Rrule" align="center"> 13 </td><td styleCode=" Botrule Rrule" align="center"> 14 </td><td styleCode=" Botrule Rrule" align="center"> 13 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dizziness </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Somnolenceⁱ </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Psychiatric Disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Insomnia^j </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Restlessness </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Respiratory, thoracic and mediastinal disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Oropharyngeal pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Vascular Disorders</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension^k </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td></tr></tbody></table>

<table ID="ID87" width="576" styleCode="Noautorules"><caption> Table 7 Adverse Reactions Occurring in &#x2265; 2% of Cariprazine-treated Patients and &gt; Placebo-treated Adult Patients in two 6-week trials and one 8-week trial </caption><col width="222"/><col width="120"/><col width="126"/><col width="108"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^a</content><content styleCode="bold"> Extrapyramidal symptoms terms:</content> akinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle tightness, musculoskeletal stiffness, myoclonus, oculogyric crisis, salivary hypersecretion, tardive dyskinesia, tremor</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^b</content><content styleCode="bold"> Somnolence terms:</content> hypersomnia, sedation, somnolence</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^c</content><content styleCode="bold"> Fatigue terms:</content> asthenia, fatigue, malaise</paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote"><content styleCode="bold">^d</content><content styleCode="bold"> Insomnia terms:</content> initial insomnia, insomnia, insomnia related to another mental condition, middle insomnia, sleep disorder terminal insomnia</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> </td><td rowspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (N=468)</content> <content styleCode="bold"> (%)</content> </td><td colspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Cariprazine</content> </td></tr><tr><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 1.5 mg/day</content> <content styleCode="bold"> (N=470)</content> <content styleCode="bold"> (%)</content> </td><td styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 3 mg/day</content> <content styleCode="bold"> (N=469)</content> <content styleCode="bold"> (%)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Restlessness </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 7 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Akathisia </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 6 </td><td styleCode=" Botrule Rrule" align="center"> 10 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Extrapyramidal symptoms^a </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dizziness </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Somnolence^b </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 7 </td><td styleCode=" Botrule Rrule" align="center"> 6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 7 </td><td styleCode=" Botrule Rrule" align="center"> 7 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Increased appetite </td><td styleCode=" Botrule Rrule" align="center"> 1 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Weight increase </td><td styleCode=" Botrule Rrule" align="center"> &lt; 1 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fatigue^c </td><td styleCode=" Botrule Rrule" align="center"> 2 </td><td styleCode=" Botrule Rrule" align="center"> 4 </td><td styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Insomnia^d </td><td styleCode=" Botrule Rrule" align="center"> 7 </td><td styleCode=" Botrule Rrule" align="center"> 7 </td><td styleCode=" Botrule Rrule" align="center"> 10 </td></tr></tbody></table>