Cariprazine

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 VRAYLAR’s long half-life, monitor for adverse reactions and patient response for several weeks after starting VRAYLAR 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 VRAYLAR if a clinically significant decline in WBC occurs in absence of other causative factors ( 5.8 ) Orthostatic H ypotension and Syncope : 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. VRAYLAR 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 1000 patients treated are provided in Table 3. Table 3: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 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 VRAYLAR, 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 patients with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. VRAYLAR 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 VRAYLAR 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 VRAYLAR. 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, VRAYLAR 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 VRAYLAR, drug discontinuation should be considered. However, some patients may require treatment with VRAYLAR despite the presence of the syndrome. 5. 6 Late – Occurring Adverse Reactions Adverse reactions may first appear several weeks after the initiation of VRAYLAR 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 VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug. 5. 7 Metabolic Changes Atypical antipsychotic drugs, including VRAYLAR, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. There have been reports of hyperglycemia in patients treated with VRAYLAR. Although all 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. Adult Patients with 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 VRAYLAR and placebo. In the long-term, open-label schizophrenia studies, 4% of patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%). Pediatric Patients with Schizophrenia (13 to 17 years of age) In a long term, open-label study in pediatric patients, no patients with schizophrenia with normal (<100 mg/dL) baseline fasting serum glucose experienced a shift to high (≥126 mg/dL) while taking VRAYLAR. Adult Patients with 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 VRAYLAR and placebo. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%). Pediatric Patients with Bipolar I Mania/Mixed Episodes (10 to 17 years of age) In a long term, open-label study in pediatric patients, 4.6% (4/87) of patients with bipolar disorder with normal (<100 mg/dL) baseline fasting serum glucose experienced a shift to high (≥126 mg/dL) while taking VRAYLAR. Adjunctive Treatment of Major Depressive Disorder in Adult Patients In two 6-week placebo-controlled trials of adult patients with major depressive disorder, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) was greatest in the VRAYLAR 3 mg per day + antidepressant therapy arm (3.2%) compared with those taking VRAYLAR 1.5 mg per day + antidepressant therapy (2%) or those placebo-treated (1.3%). The proportion of patients with shifts from normal to borderline (≥100 and 6%). In one 8-week placebo-controlled trial of adult patients with major depressive disorder, the changes from baseline to end of the trial in fasting glucose were similar among the VRAYLAR and placebo + antidepressant therapy treatment groups. During the 8-week trial, serum insulin levels increased by 12 pmol/L in the VRAYLAR 1 mg to 2 mg per day group, 20 pmol/L in the VRAYLAR 2 mg to 4.5 mg per day group, and 8.5 pmol/L in the placebo group. 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. Adult Patients with 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 VRAYLAR and placebo. Pediatric Patients with Schizophrenia (13 to 17 years of age) In a long term, open-label study in pediatric patients, no patients with schizophrenia experienced shifts in normal (45 mg/dL) to low (<40 mg/dL). Of patients with normal baseline fasting triglycerides, 25% (2/8) experienced shifts from normal to high (<90 to ≥ 130 mg/dL). Adult Patients with 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 VRAYLAR and placebo. Pediatric Patients with Bipolar I Mania/Mixed Episodes (10 to 17 years of age) In a long term, open-label study in pediatric patients, 1.2% (1/81) of patients with bipolar disorder experienced shifts in normal (45 mg/dL) to low (<40 mg/dL). Of patients with normal fasting baseline triglycerides, 20% (12/60) experienced shifts from normal to high (<90 to ≥130 mg/dL). Adjunctive Treatment of Major Depressive Disorder in Adult Patients In two 6-week placebo-controlled trials of adult patients with major depressive disorder, the proportion of patients with shifts in total cholesterol, fasting LDL, HDL, and fasting triglycerides were similar in patients treated with VRAYLAR and placebo. Weight Gain Weight gain has been observed with use of atypical antipsychotics, including VRAYLAR. Monitor weight at baseline and frequently thereafter. Tables 4, 5 , 6, and 7 show the change in body weight occurring from baseline to endpoint in 6-week trials of schizophrenia, 3-week bipolar mania trials, 6-week and 8-week bipolar depression trials, and 6-week and 8-week trials of adjunctive treatment for major depressive disorder, respectively. Adult Patients with Schizophrenia Table 4. Change in Body Weight (kg) in 6-Week Schizophrenia Trials (Adult Patients) VRAYLAR * Placebo (N=573) 1.5 – 3 mg/day (N=512) 4.5 – 6 mg/day (N=570) 9 – 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% *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. In long-term, uncontrolled trials with VRAYLAR 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. Pediatric Patients with Schizophrenia (13 to 17 years of age) In a long term, open-label study in pediatric patients, no subjects with schizophrenia discontinued due to weight increase. The mean change in weight from baseline to last available visit was 2.4 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this study, the mean change in z-score from baseline to last available visit was 0.1 SD for body weight, and no subjects had a change in z-score ≥ 0.5 SD. Adult Patients with Bipolar Disorder Table 5. Change in Body Weight (kg) in 3-Week Bipolar Mania Trials (Adult Patients) VRAYLAR * Placebo (N=439) 3 – 6 mg/day (N=259) 9 – 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% *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. Pediatric Patients with Bipolar I Mania/Mixed Episodes (10 to 17 years of age) In a long term, open-label study in pediatric patients, no subjects with bipolar I disorder discontinued due to weight increase. The mean change in weight from baseline to last available visit was 3.1 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this study, the mean change in z-score from baseline to last available visit was 0.2 SD for body weight, and 14.6% of subjects had an increase in age- and sex-adjusted body weight z-score of at least 0.5 SD from baseline. Table 6. Change in Body Weight (kg) in two 6-Week and one 8-Week Bipolar Depression Trials (Adult Patients) VRAYLAR Placebo 1.5 mg/day 3 mg/day (N=463) (N=467) (N=465) Mean Change at Endpoint -0.1 +0.7 +0.4 Proportion of Patients with Weight Increase (≥7%) 1% 3% 3% Adjunctive Treatment of Major Depressive Disorder in Adult Patients Table 7. Change in Body Weight (kg) in two 6-Week and one 8-Week Adjunctive Treatment for Major Depressive Disorder Trials (Adult Patients) VRAYLAR 6- W eek Trials Placebo +ADT 1.5 mg/day +ADT 3 mg/day +ADT (N=503) (N=502) (N=503) Mean Change at Endpoint +0.2 +0.7 +0.7 Proportion of Patients with Weight Increase (≥7%) 1% 2% 2% 8- W eek Trial Placebo + ADT (N=266) 1 to 2 mg/day + ADT (N=273) 2 to 4.5 mg/day + ADT (N=273) Mean Change at Endpoint 0 +0.9 +0.9 Proportion of Patients with Weight Increase (≥7%) 2% 2% 3% In the long-term, open-label adjunctive treatment of MDD trial, 2 patients (0.6%) discontinued due to weight increase. VRAYLAR was associated with mean change from baseline in weight of 1.7 kg at Week 26. In the long-term, open-label adjunctive treatment of MDD trial, 19% of patients demonstrated a ≥7% increase in body weight, and 5% demonstrated a ≥7% decrease in body weight. 5. 8 Leukopenia, Neutropenia, and Agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including VRAYLAR. 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 VRAYLAR 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 VRAYLAR in patients with absolute neutrophil count < 1000/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 VRAYLAR and was not more frequent on VRAYLAR 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. VRAYLAR 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 VRAYLAR, 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, VRAYLAR 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 VRAYLAR, like other antipsychotics, may cause somnolence and 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 VRAYLAR-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of VRAYLAR-treated patients compared to 4% of placebo-treated patients. In two 6-week and one 8-week trials of depressive episodes of bipolar I disorder, VRAYLAR-treated patients reported 7% somnolence and 4% in the placebo-treated patients. In 6-week adjunctive treatment of major depressive disorder trials, somnolence was reported in 6% of VRAYLAR-treated patients compared to 4% of placebo-treated patients. In one 8-week adjunctive treatment of major depressive disorder trial, somnolence was reported in 11% of VRAYLAR-treated patients compared to 6% of placebo-treated patients. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with VRAYLAR does not affect them adversely. 5. 13 Body Temperature Dysr egulation 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 VRAYLAR 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 VRAYLAR. VRAYLAR and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.

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 in adults (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 Adjunctive treatment of MDD: akathisia, restlessness, fatigue, constipation, nausea, insomnia, increased appetite, dizziness, and extrapyramidal symptoms To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-633-9110 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 VRAYLAR consisting of 6,722 adult patients exposed to one or more doses of VRAYLAR for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder, bipolar depression, and adjunctive treatment of major depressive disorder in placebo-controlled studies. This experience corresponds with a total experience of 1,182.8 patient-years. A total of 4,329 VRAYLAR-treated patients had at least 6 weeks and 296 VRAYLAR-treated patients had at least 48 weeks of exposure. Adult Patients with Schizophrenia The following findings are based on four placebo-controlled, 6-week schizophrenia trials with VRAYLAR doses ranging from 1.5 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 VRAYLAR-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 8. Table 8. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials VRAYLAR * System Organ Class / Preferred Term Placebo (N= 584) (%) 1.5 to 3 mg/day (N=539) (%) 4.5 to 6 mg/day (N=575) (%) 9 to 12 mg/day ⸰ (N=203) (%) Cardiac Disorder s 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 D isorders Cough 2 1 2 4 Skin and S ubcutaneous D isorders Rash 1 Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials VRAYLAR * System Organ Class / Preferred Term Placebo (N= 442) (%) 3 to 6 mg/day (N=263) (%) 9 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 Placebo-treated Adult Patients in Two 6-Week and One 8-Week Bipolar Depression Trials VRAYLAR Placebo (N=468) (%) 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 Placebo-Treated Adult Patients in Two Fixed-Dose 6-Week Placebo-Controlled Trials of Adjunctive Treatment of Major Depressive Disorder System Organ Class/ Preferred Term Placebo + ADT (N=503) (%) VRAYLAR 1.5 mg/day + ADT (N=502) (%) 3 mg/day + ADT (N=503) (%) Eye Disorders Vision Blurred <1 Placebo-Treated Adult Patients in a Flexible-dose 8-Week Placebo-Controlled Trial of Adjunctive Treatment of Major Depressive Disorder System Organ Class/ Preferred Term Placebo + ADT (N=266) (%) VRAYLAR 1 to 2 mg/day + ADT (N=273) (%) VRAYLAR 2 to 4.5 mg/day + ADT (N=273) (%) Cardiac disorders Palpitations 1 2 <1 Eye disorders Vision blurred 1 1 4 Gastrointestinal disorders Nausea 5 7 13 Constipation 2 2 5 Dry mouth 3 5 4 Vomiting <1 1 3 General disorders Fatigue 4 7 10 Edema <1 2 1 Infections Nasopharyngitis 2 4 1 Investigations Increased appetite 2 2 5 Weight increased 1 2 3 Musculoskeletal and Connective Tissue disorders Back pain 1 2 3 Myalgia 0 1 2 Nervous System disorders Akathisia a 3 8 23 Extrapyramidal symptoms b 5 12 18 Somnolence c 6 10 11 Dizziness 2 4 5 Psychiatric disorders Insomnia d 8 14 16 Restlessness 3 8 8 Agitation <1 <1 3 Anxiety 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 adverse reactions related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for VRAYLAR-treated patients versus 8% for placebo-treated patients. These reactions led to discontinuation in 0.3% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 0.5% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. In 3-week bipolar mania trials, the incidence of reported adverse reactions related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for VRAYLAR-treated patients versus 12% for placebo-treated patients. These reactions led to a discontinuation in 1% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for VRAYLAR-treated patients versus 5% for placebo-treated patients. These reactions led to discontinuation in 2% of VRAYLAR-treated patients versus 0% of placebo-treated patients. In the two 6-week and one 8-week bipolar depression trials, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness was 4% for VRAYLAR-treated patients versus 2% for placebo-treated patients. These reactions led to discontinuation in 0.4% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of akathisia was 8% for VRAYLAR-treated patients versus 2% for placebo-treated patients. These reactions led to discontinuation in 1.5% of VRAYLAR-treated patients versus 0% of placebo-treated patients. In the two 6-week adjunctive treatment of major depressive disorder trials, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness, was 6% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 0.3% of VRAYLAR-treated patients versus 0.6% of placebo-treated patients. The combined incidence of akathisia and restlessness was 12% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These reactions led to discontinuation in 2% of VRAYLAR-treated patients versus 0.4% of placebo-treated patients. In one 8-week adjunctive treatment of major depressive disorder trial, the incidence of reported adverse reactions related to EPS, excluding akathisia and restlessness, was 12% for VRAYLAR-treated patients versus 5% for placebo-treated patients. These reactions led to discontinuation in 1% of VRAYLAR-treated patients versus 0.4% of placebo-treated patients. The incidence of akathisia and restlessness was 22% for VRAYLAR-treated patients versus 6% for placebo-treated patients. These reactions led to discontinuation in 3% of VRAYLAR-treated patients versus 0.0% of placebo-treated patients. Cataracts The development of cataracts was observed in nonclinical studies [ see Nonclinical Toxicology ( 13.2 ) ] . Cataracts were reported during the premarketing clinical trials of cariprazine; however, the duration of trials was too short to assess any association to cariprazine usage. Vital Signs Changes There were no clinically meaningful differences between VRAYLAR-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 – 12 mg/day VRAYLAR-treated patients with schizophrenia. Pooled data from 6-week schizophrenia trials are shown in Table 13, and from 3-week bipolar mania trials are shown in Table 14. Table 13. Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials (Adult Patients) Placebo (N=574) VRAYLAR* 1.5 – 3 mg/day (N=512) 4.5 – 6 mg/day (N=570) 9 – 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 * 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. Table 14. Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials (Adult Patients) Placebo (N=439) VRAYLAR* 3 – 6 mg/day (N=259) 9 – 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 * 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. In the two 6-week and one 8-week bipolar depression trials, there were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine systolic and diastolic blood pressure. VRAYLAR-treated patients’ supine blood pressure increased by 0.1 to 0.3 mmHg; placebo-treated patients’ supine blood pressure increased by 0.2 mmHg. In two 6-week and one 8-week adjunctive treatment of major depressive disorder trials, there were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine systolic and diastolic blood pressure. At the end of the 6-week trials, VRAYLAR-treated patients’ supine systolic blood pressure decreased by 0.1 to 0.7 mmHg; placebo-treated patients’ supine systolic blood pressure decreased by 0.1 mmHg. VRAYLAR-treated patients’ supine diastolic blood pressure increased by 0.1 mmHg and placebo-treated patients’ supine diastolic blood pressure increased by 0.2 mmHg. 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 VRAYLAR-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 VRAYLAR-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 VRAYLAR-treated patients depending on dose group administered and 0.4% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in two 6-week adjunctive treatment of major depressive disorder trials ranged between 0% and 1% for VRAYLAR-treated patients depending on dose group administered and 0% for placebo-treated patients. The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for VRAYLAR-treated patients, increasing with dose, and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in VRAYLAR and placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 6-week and 8-week bipolar depression trials ranged between 0.2% and 1% for VRAYLAR-treated patients versus 0.2% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in two 6-week adjunctive treatment of major depressive disorder trials ranged between 0.6% and 0.8% for VRAYLAR-treated patients versus 0% for placebo-treated patients. Other Adverse Reactions Observed During the Pre – marketing Evaluation of VRAYLAR Adverse reactions listed below were reported by patients treated with VRAYLAR at doses of ≥ 1.5 mg once daily within the premarketing database of 5,763 VRAYLAR-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 VRAYLAR 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 1/1000 patients (infrequent); and those occurring in fewer than 1/1,000 patients (rare). Gastrointestinal D isorders: Infrequent : gastroesop hageal reflux disease, gastritis Hepatobiliary D isorders: Rare: hepatitis Metabolism and N utrition D isorders: Frequent : decreased appetite; Rare : hyponatremia Musculoskeletal and C onnective T issue D isorders: Rare : rhabdomyolysis Nervous S ystem D isorders: Rare : ischemic stroke Psychiatric D isorders: Infrequent: suicide ideation; Rare : completed suicide , suicide attempts Renal and U rinary D isorders: Infrequent : pollakiuria Skin and S ubcutaneous T issue D isorders: Infrequent: hyperhidrosis Pediatric Patients with Schizophrenia (13 to 17 years of age) or Bipolar Mania/Mixed Episodes (10 to 17 years of age) In a long-term open-label study, safety was assessed in 164 pediatric patients with schizophrenia or bipolar I disorder, of whom 72 received VRAYLAR for at least 6 months. Adverse reactions reported in clinical studies for this age group were generally similar to those observed in adult patients. 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of VRAYLAR. 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

8 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). There are no available data on VRAYLAR use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. The major active metabolite of cariprazine, DDCAR, has been detected in adult patients up to 12 weeks after discontinuation of VRAYLAR [see Clinical Pharmacology ( 12.3 )]. Based on animal data, VRAYLAR may cause fetal harm. Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Administration of cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day, which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total cariprazine (i.e. sum of cariprazine, DCAR, and DDCAR), caused fetal developmental toxicity at all doses, which included reduced body weight, decreased male anogenital distance, and skeletal malformations of bent limb bones, scapula, and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5-times the MRHD of 6 mg/day based on AUC of total cariprazine. At these doses, cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. Administration of cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day, which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine, caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar to those of the first generation pups. Administration of cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine, was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs. 8.2 Lactation Risk Summary Lactation studies have not been conducted to assess the presence of cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for VRAYLAR and any potential adverse effects on the breastfed infant from VRAYLAR or from the underlying maternal condition. 8.4 Pediatric Use Schizophrenia The safety and effectiveness of VRAYLAR for treatment of schizophrenia have been established in pediatric patients 13 years of age and older. Use of VRAYLAR in this population is supported by evidence from adequate and well-controlled studies in adults with schizophrenia, pharmacokinetic data from adults and pediatric patients, and safety data in pediatric patients 13 to 17 years of age [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . The safety and effectiveness of VRAYLAR for the treatment of schizophrenia have not been established in pediatric patients less than 13 years of age. Manic and Mixed Episodes Associated with Bipolar I Disorder The safety and effectiveness of VRAYLAR for treatment of manic and mixed episodes associated with bipolar I disorder have been established in pediatric patients 10 years of age and older. Use of VRAYLAR in this population is supported by evidence from adequate and well-controlled studies in adults with manic and mixed episodes associated with bipolar I disorder, pharmacokinetic data from adult and pediatric patients, and safety data in pediatric patients 10 to 17 years of age [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . The safety and effectiveness of VRAYLAR for the treatment of manic and mixed episodes associated with bipolar I disorder have not been established in pediatric patients less than 10 years of age. Bipolar Depression The safety and effectiveness of VRAYLAR for treatment of bipolar depression in pediatric patients have not been established. Adjunctive Therapy for Treatment of MDD The safety and effectiveness of VRAYLAR as adjunctive therapy for treatment of MDD in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions ( 5.2 )] . Irritability Associated with Autism Spectrum Disorder​ The safety and effectiveness of VRAYLAR for the treatment of irritability associated with autism spectrum disorder in pediatric patients have not been established. In a single, 8-week, double-blind, placebo-controlled, flexible-dose clinical study conducted in pediatric patients 5 to 17 years of age with irritability associated with autism spectrum disorder diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [DSM-5] criteria, a total of 161 patients were enrolled, of which 76 patients received cariprazine and 79 received placebo. In this study, patients 5 to 9 years of age who were randomized to active treatment received cariprazine oral solution, which is not an approved formulation. Somnolence, including sedation, occurred in 18% of cariprazine-treated compared to 1% of placebo-treated pediatric patients and was observed at a higher rate than reported in other VRAYLAR studies evaluating adult patients. The mean increase in age-and-sex adjusted body weight z-score from baseline to last visit was 0.2 for cariprazine-treated versus less than 0.1 for placebo-treated pediatric patients. Increases in age- and sex-adjusted body weight z-score of at least 0.5 SD from baseline was higher in cariprazine-treated versus placebo-treated pediatric patients (19% versus 1%). In a long term, open-label study in pediatric patients 5 to 17 years of age with irritability associated with autism spectrum disorder, the mean change in weight from baseline to last available visit was 5.3 kg; two patients discontinued due to increased weight. When body weight was adjusted for age and sex, the mean z-score change from baseline to last visit was 0.4 for cariprazine-treated patients, and 32% of patients had an increase in age- and sex-adjusted body weight z-score of at least 0.5 SD from baseline. Juvenile Animal Studies Juvenile rats were administered cariprazine at doses of 1, 3 and 10 mg/kg/day by oral gavage from days 28 to 90 of age, followed by an 8-week recovery (non-dosing) period. At 10 mg/kg/day, there were decreases in growth (decreased body weight and bone mass in both sexes and altered bone geometry and size in males), microscopic findings in the lung suggestive of phospholipidosis, and increased motor activity, which persisted following dose cessation. In addition, impaired learning and memory performance was observed during the dosing period, however, this effect did not persist following dose cessation. Microscopic findings in the mammary gland and/or reproductive tract (vagina, uterus and ovary) at ≥1 mg/kg/day and altered findings in the adrenal gland at doses ≥3 mg/kg/day were considered secondary to the increase in prolactin levels and were consistent with findings observed in adult rats. The no observed adverse effect level (NOAEL) was 3 mg/kg/day which is associated with systemic exposures approximately equal to clinical exposures produced at the maximum recommended pediatric dose of 4.5 mg/day based on AUC of total cariprazine. Juvenile dogs were administered cariprazine at doses of 1, 3 and 6 mg/kg/day by oral gavage from weeks 13 to 39 of age, followed by a 4-week recovery (non-dosing) period. At doses ≥1 mg/kg/day, CNS clinical signs of decreased activity, lack of coordination, and reduced food intake were observed. At doses ≥3 mg/kg/day reversible effects on growth and non-reversible lens opacities/lens degeneration, that were not associated with retinal changes, were observed. The NOAEL was 1 mg/kg/day which is associated with systemic exposures approximately equal to clinical exposures produced at the maximum recommended pediatric dose of 4.5 mg/day based on AUC of total cariprazine. 8.5 Geriatric Use Clinical trials of VRAYLAR did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warning s and Precautions ( 5.1 , 5.3 ) ] . 8.6 Hepatic Impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9) [ see C linical Pharmacology ( 12.3 ) ] . Usage of VRAYLAR is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). VRAYLAR has not been evaluated in this patient population. 8.7 Renal Impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate (CrCL ≥ 30 mL/minute) renal impairment [ see Clinical Pharmacology ( 12.3 ) ] . Usage of VRAYLAR is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). VRAYLAR has not been evaluated in this patient population. 8.8 Other Specific Populations No dosage adjustment is required based on patient’s age, sex, or race. These factors do not affect the pharmacokinetics of VRAYLAR [ see Clinical Pharmacology ( 12.3 ) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). There are no available data on VRAYLAR use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. The major active metabolite of cariprazine, DDCAR, has been detected in adult patients up to 12 weeks after discontinuation of VRAYLAR [see Clinical Pharmacology ( 12.3 )]. Based on animal data, VRAYLAR may cause fetal harm. Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Administration of cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day, which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total cariprazine (i.e. sum of cariprazine, DCAR, and DDCAR), caused fetal developmental toxicity at all doses, which included reduced body weight, decreased male anogenital distance, and skeletal malformations of bent limb bones, scapula, and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5-times the MRHD of 6 mg/day based on AUC of total cariprazine. At these doses, cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. Administration of cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day, which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine, caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar to those of the first generation pups. Administration of cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine, was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs.

8.4 Pediatric Use Schizophrenia The safety and effectiveness of VRAYLAR for treatment of schizophrenia have been established in pediatric patients 13 years of age and older. Use of VRAYLAR in this population is supported by evidence from adequate and well-controlled studies in adults with schizophrenia, pharmacokinetic data from adults and pediatric patients, and safety data in pediatric patients 13 to 17 years of age [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . The safety and effectiveness of VRAYLAR for the treatment of schizophrenia have not been established in pediatric patients less than 13 years of age. Manic and Mixed Episodes Associated with Bipolar I Disorder The safety and effectiveness of VRAYLAR for treatment of manic and mixed episodes associated with bipolar I disorder have been established in pediatric patients 10 years of age and older. Use of VRAYLAR in this population is supported by evidence from adequate and well-controlled studies in adults with manic and mixed episodes associated with bipolar I disorder, pharmacokinetic data from adult and pediatric patients, and safety data in pediatric patients 10 to 17 years of age [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . The safety and effectiveness of VRAYLAR for the treatment of manic and mixed episodes associated with bipolar I disorder have not been established in pediatric patients less than 10 years of age. Bipolar Depression The safety and effectiveness of VRAYLAR for treatment of bipolar depression in pediatric patients have not been established. Adjunctive Therapy for Treatment of MDD The safety and effectiveness of VRAYLAR as adjunctive therapy for treatment of MDD in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions ( 5.2 )] . Irritability Associated with Autism Spectrum Disorder​ The safety and effectiveness of VRAYLAR for the treatment of irritability associated with autism spectrum disorder in pediatric patients have not been established. In a single, 8-week, double-blind, placebo-controlled, flexible-dose clinical study conducted in pediatric patients 5 to 17 years of age with irritability associated with autism spectrum disorder diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [DSM-5] criteria, a total of 161 patients were enrolled, of which 76 patients received cariprazine and 79 received placebo. In this study, patients 5 to 9 years of age who were randomized to active treatment received cariprazine oral solution, which is not an approved formulation. Somnolence, including sedation, occurred in 18% of cariprazine-treated compared to 1% of placebo-treated pediatric patients and was observed at a higher rate than reported in other VRAYLAR studies evaluating adult patients. The mean increase in age-and-sex adjusted body weight z-score from baseline to last visit was 0.2 for cariprazine-treated versus less than 0.1 for placebo-treated pediatric patients. Increases in age- and sex-adjusted body weight z-score of at least 0.5 SD from baseline was higher in cariprazine-treated versus placebo-treated pediatric patients (19% versus 1%). In a long term, open-label study in pediatric patients 5 to 17 years of age with irritability associated with autism spectrum disorder, the mean change in weight from baseline to last available visit was 5.3 kg; two patients discontinued due to increased weight. When body weight was adjusted for age and sex, the mean z-score change from baseline to last visit was 0.4 for cariprazine-treated patients, and 32% of patients had an increase in age- and sex-adjusted body weight z-score of at least 0.5 SD from baseline. Juvenile Animal Studies Juvenile rats were administered cariprazine at doses of 1, 3 and 10 mg/kg/day by oral gavage from days 28 to 90 of age, followed by an 8-week recovery (non-dosing) period. At 10 mg/kg/day, there were decreases in growth (decreased body weight and bone mass in both sexes and altered bone geometry and size in males), microscopic findings in the lung suggestive of phospholipidosis, and increased motor activity, which persisted following dose cessation. In addition, impaired learning and memory performance was observed during the dosing period, however, this effect did not persist following dose cessation. Microscopic findings in the mammary gland and/or reproductive tract (vagina, uterus and ovary) at ≥1 mg/kg/day and altered findings in the adrenal gland at doses ≥3 mg/kg/day were considered secondary to the increase in prolactin levels and were consistent with findings observed in adult rats. The no observed adverse effect level (NOAEL) was 3 mg/kg/day which is associated with systemic exposures approximately equal to clinical exposures produced at the maximum recommended pediatric dose of 4.5 mg/day based on AUC of total cariprazine. Juvenile dogs were administered cariprazine at doses of 1, 3 and 6 mg/kg/day by oral gavage from weeks 13 to 39 of age, followed by a 4-week recovery (non-dosing) period. At doses ≥1 mg/kg/day, CNS clinical signs of decreased activity, lack of coordination, and reduced food intake were observed. At doses ≥3 mg/kg/day reversible effects on growth and non-reversible lens opacities/lens degeneration, that were not associated with retinal changes, were observed. The NOAEL was 1 mg/kg/day which is associated with systemic exposures approximately equal to clinical exposures produced at the maximum recommended pediatric dose of 4.5 mg/day based on AUC of total cariprazine.