. The active ingredient of VRAYLAR is cariprazine, an atypical antipsychotic, in hydrochloride salt form. The chemical name is trans -N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride; its empirical formula is C 21 H 3 2 Cl 2 N 4 O•HCl and its molecular weight is 463.9 g/mol. The chemical structure is: VRAYLAR capsules are intended for oral administration only. Each hard gelatin capsule contains 0.5, 0.75, 1.5, 3, 4.5, or 6 mg of cariprazine base (equivalent to 0.545 mg, 0.818 mg, 1.635 mg , 3.27 mg, 4.905 mg, or 6.54 mg cariprazine HCl). In addition, capsules include the following inactive ingredients: gelatin, magnesium stearate, pregelatinized starch, shellac, and titanium dioxide. Colorants include black iron oxide (0.5, 0.75, 1.5, 3, and 6 mg), FD&C Blue 1 (0.5, 0.75, 3, 4.5, and 6 mg), FD&C Red 3 (6 mg), FD&C Red 40 (3 and 4.5 mg), or yellow iron oxide (0.5, 3, and 4.5 mg). The chemical structure for VRAYLAR is cariprazine HCl, an atypical antipsychotic. The chemical name is trans-N-{4-[2-[4-(2,3 dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride; its empirical formula is C21H33Cl3N4O and its molecular weight is 463.9 g/mol.

. VRAYLAR ® is indicated for: • Treatment of schizophrenia in adult and pediatric patients 13 years of age and older • Acute treatment of manic or mixed episodes associated with bipolar I disorder in adult and pediatric patients 10 years of age and older • Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adult patients • Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adult patients VRAYLAR is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults and pediatric patients 13 years of age and older Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and pediatric patients 10 years of age and older Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults

. VRAYLAR (cariprazine) capsules are available in six strengths

mg capsules: Ivory to yellow cap and a grey to green body imprinted with “FL 0.5” 0.75 mg capsules: Grey to green cap and blue body imprinted with “FL 0.75” 1.5 mg capsules: White cap and body imprinted with “FL 1.5” 3 mg capsules: Green to blue-green cap and white body imprinted with “FL 3” 4.5 mg capsules: Green to blue-green cap and body imprinted with “FL 4.5” 6 mg capsules: Purple cap and white body imprinted with “FL 6” Capsules: 0.5 mg, 0.75 mg, 1.5 mg, 3 mg, 4.5 mg, and 6 mg

. Administer VRAYLAR orally once daily with or without food Starting Dose Recommended Dose Schizophrenia in Adults 1.5 mg daily 1.5 mg to 6 mg daily Schizophrenia in Pediatric Patients (13-17 years) 0.5 mg daily 1.5 mg to 4.5 mg daily Bipolar Mania in Adults 1.5 mg daily 3 mg to 6 mg daily Bipolar Mania in Pediatric Patients (10-17 years) 0.5 mg daily 3 mg or 4.5 mg daily Bipolar Depression in Adults 1.5 mg daily 1.5 mg or 3 mg daily Adjunctive therapy to antidepressants for MDD in Adults 1.5 mg daily 1.5 mg or 3 mg daily Adults with Schizophrenia and Bipolar Mania: Maximum recommended daily dosage is 6 mg. Dosages above 6 mg daily do not confer significant benefit, but increase the risk of dose-related adverse reactions Pediatric patients with Schizophrenia and Bipolar Mania: Maximum recommended daily dosage is 4.5 mg. Adults with Bipolar Depression: Maximum recommended daily dosage is 3 mg Adjunctive therapy for treatment of MDD in Adults: Maximum recommended daily dosage is 3 mg 2.1 General Dosing Information VRAYLAR is given orally once daily and can be taken with or without food. Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Prescribers should monitor patients for adverse reactions and treatment response for several weeks after starting VRAYLAR and after each dosage change

Recommended Dosage in Schizophrenia Adult Patients The starting dosage of VRAYLAR is 1.5 mg orally once daily. The recommended dosage range is 1.5 mg to 6 mg orally once daily. The dosage can be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg orally once daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions . Pediatric Patients (13 to 17 years of age) The starting dosage of VRAYLAR is 0.5 mg orally once daily. The recommended dosage range is 1.5 mg to 4.5 mg orally once daily. Increase the dosage to 1.5 mg orally once daily on Day 3. Depending upon clinical response and tolerability, the dosage may be increased to 3 mg orally once daily starting on Day 5, and to 4.5 mg orally once daily starting on Day 8. The maximum recommended dosage is 4.5 mg orally once daily

Recommended Dosage in Manic or M ixed E pisodes Associated with Bipolar I Disorder Adult Patients The starting dosage of VRAYLAR is 1.5 mg orally once daily. Increase the dosage to 3 mg orally once daily on Day 2. The recommended dosage range is 3 mg to 6 mg orally once daily. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg orally once daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions [ see Adverse Reactions, Clinical Studies ] . Pediatric Patients (10 to 17 years of age)​ The starting dosage of VRAYLAR is 0.5 mg orally once daily. The recommended dosage is 3 mg or 4.5 mg orally once daily. Increase the dosage to 1.5 mg orally once daily on Day 3 and to 3 mg orally once daily on Day 5. Depending upon clinical response and tolerability, the dosage may be increased to 4.5 mg orally once daily starting on Day 8. The maximum recommended dosage is 4.5 mg orally once daily

Recommended Dosage in Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) in Adult Patients The starting dosage of VRAYLAR is 1.5 mg orally once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg orally once daily on Day 15. Maximum recommended dosage is 3 mg orally once daily

Recommended Dosage for Adjunctive Therapy to Antidepressants for the Treatment of Major Depressive Disorder in Adult Patients The starting dosage of VRAYLAR is 1.5 mg orally once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg orally once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions . Maximum recommended dosage is 3 mg orally once daily. 2. 6 Dosage Modifications for CYP3A4 Inhibitors and Inducers Initiating VRAYLAR While Taking a Strong or Moderate CYP3A4 Inhibitor Dosage modifications for the starting dosage of VRAYLAR in adult patients taking a strong or moderate CYP3A4 inhibitor are presented in Table 1: Table 1: Dosage Modifications for the Starting Dosage of VRAYLAR in Adult Patients Taking a Strong or Moderate CYP3A4 Inhibitor Adult Patients VRAYLAR Starting Dosage When Taking a Strong CYP3A4 Inhibitor When Taking a Moderate CYP3A4 Inhibitor Schizophrenia Start at 0.5 mg orally once daily; increase to 0.75 mg orally once daily, if needed* Start at 0.75 mg orally once daily; increase to 1.5 mg orally daily, if needed* Bipolar Mania Bipolar Depression 0.5 mg orally once daily 0.75 mg orally once daily Adjunctive therapy for treatment of MDD *Depending upon clinical response and tolerability. Initiating VRAYLAR is not recommended in pediatric patients while taking a strong or moderate CYP3A4 Inhibitor. Initiating a Strong or Moderate CYP3A4 Inhibitor While Taking a Stable Dosage of VRAYLAR Dosage recommendations for adult and pediatric patients initiating a strong or moderate CYP3A4 inhibitor while on a stable dose of VRAYLAR : Table 2: Dosage Modifications for VRAYLAR When Initiating a Strong or Moderate CYP3A4 Inhibitor and While Taking a Stable Dos ag e of VRAYLAR in Adult and Pediatric Patients Currently on VRAYLAR Dosage VRAYLAR Dosage When Initiating a Strong CYP3A4 Inhibitor VRAYLAR Dosage When Initiating a Moderate CYP3A4 Inhibitor 1.5 mg or 3 mg once daily 0.5 mg orally once daily 0.75 mg orally once daily 4.5 mg or 6 mg once daily 0.75 mg orally once daily 1.5 mg orally once daily When the strong or moderate CYP3A4 inhibitor is discontinued, the VRAYLAR dosage may need to be increased based on clinical response and tolerability . Dosage Modifications for Patients Concomitantly Taking VRAYLAR with CYP3A4 Inducers Concomitant use of VRAYLAR and a CYP3A4 inducer has not been evaluated and is not recommended . 2. 7 Treatment Discontinuation Following discontinuation of VRAYLAR, the decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients’ clinical symptoms; the plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week [ see Clinical Pharmacology] . There are no systematically collected data to specifically address switching patients from VRAYLAR to other antipsychotics or concerning concomitant administration with other antipsychotics.

. Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring Tardive Dyskinesia : Discontinue if appropriate 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 Metabolic Changes : Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain 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 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 Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold Potential for Cognitive and Motor Impairment: Use caution when operating machinery 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

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 . 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 . 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 <126 mg/dL) or from borderline to high were similar in patients treated with VRAYLAR and placebo. In a long-term, open-label adjunctive treatment of MDD study, 7% patients with normal hemoglobin A1c baseline values developed elevated levels (> 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 (<170 mg/dL) baseline total cholesterol to high (≥200 mg/dL), and 9.1% (1/11) of patients taking VRAYLAR experienced shifts from normal baseline HDL cholesterol (>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 (<170 mg/dL) baseline total cholesterol to high (≥200 mg/dL), and 10.6% (10/94) of patients taking VRAYLAR experienced shifts from normal baseline HDL cholesterol (>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.

Table 15 displays clinically significant drug interactions with VRAYLAR. Table 15. Clinically Significant Drug Interactions with VRAYLAR Strong or Moderate CYP3A4 Inhibitors Clinical Impact: Concomitant use of VRAYLAR with a strong or moderate CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of VRAYLAR alone . Intervention: If VRAYLAR is used with a strong or moderate CYP3A4 inhibitor, reduce VRAYLAR dosage . CYP3A4 Inducers Clinical Impact: CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of VRAYLAR has not been evaluated, and the net effect is unclear . Intervention: Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended . Strong and Moderate CYP3A4 inhibitors: Reduce VRAYLAR dosage ( 2.6 , 7 ) CYP3A4 inducers: Concomitant use is not recommended ( 2.6 , 7 )