VRAYLAR® (cariprazine) Efficacy for Bipolar Depression Skip to Main Content Contact Medical Information Prescribing Information Patient Site Savings Cards Request Samples Speaker Program Request a Rep Indications Adjunctive MDD Overview Bipolar I Overview Schizophrenia Efficacy Adjunctive MDD Bipolar I Depression Bipolar I Acute Manic or Mixed Episodes Schizophrenia Tolerability & Safety Mechanism of Action Dosing Savings & Resources Access Savings Resources VRAYLAR Videos Speaker Program Request a Rep Proven effective in improving overall depressive symptoms of bipolar I 1-5 Primary endpoint Primary endpoint Anhedonia analysis Change in functional outcomes MADRS symptom analysis HAM-A analysis Study 7 Study 8 Study 9 Change in MADRS total score in bipolar I depression studies Study 7 (N=431) 1-3 Pinch to zoom Baseline Mean 30.4 Placebo (n=141) 30.3 VRAYLAR 1.5 mg/day (n=145) 30.6 VRAYLAR 3 mg/day (n=145) It is unknown if the statistically significant differences observed at time points earlier than Week 6 represent clinically relevant treatment effects. Study design Two 6-week and one 8-week randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of VRAYLAR in adult patients (18-65 years old) who met DSM-IV-TR and DSM-5 criteria for depressive episodes associated with bipolar I disorder. The primary statistical analyses were conducted using an MMRM approach. In each study, the primary endpoint was the LS mean change from baseline in MADRS total score at the end of Week 6. 1,3-5 Clinical trial patients VRAYLAR studies included the types of bipolar I depression patients that you may see in your practice Baseline characteristics across the 3 pivotal bipolar I depression studies VRAYLAR was evaluated as a monotherapy 1,3-5 Studies included bipolar I depression patients with or without manic symptoms 3-6§ ~8 out of 10 patients in the trials rated their current or most recent depressive episode associated with bipolar I as moderate 2 of VRAYLAR-treated patients were previously on antidepressants (n=527/939) 2 of VRAYLAR-treated patients were previously on mood stabilizers (n=493/939) 2 of patients had moderate to severe anhedonia symptoms (n=949/1383) 2|| of patients had anxiety symptoms (n=894/1383) 7¶ § Concurrent manic symptoms defined as a YMRS total score ≥4. Patients with a YMRS total score >10 (Study 7) or >12 (Studies 8 and 9) at baseline were excluded from these studies. 3-6 || Overall, 69% of patients had MADRS anhedonia subscale scores of ≥18. The MADRS anhedonia subscale is the sum of the following items: 1 (apparent sadness), 2 (reported sadness), 6 (concentration difficulties), 7 (lassitude), and 8 (inability to feel). 2 ¶ Overall, 65% of patients treated with cariprazine 1.5 mg/day or 3 mg/day had higher anxiety symptoms at baseline, defined as a HAM-D anxiety/somatization subscale score of ≥7. 7 Change in MADRS total score in bipolar I depression studies Study 8 (N=474) 1,2,4 Pinch to zoom Baseline Mean 30.2 Placebo (n=156) 30.7 VRAYLAR 1.5 mg/day (n=154) 31.0 VRAYLAR 3 mg/day (n=164) It is unknown if the statistically significant differences observed at time points earlier than Week 6 represent clinically relevant treatment effects. Study design Two 6-week and one 8-week randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of VRAYLAR in adult patients (18-65 years old) who met DSM-IV-TR and DSM-5 criteria for depressive episodes associated with bipolar I disorder. The primary statistical analyses were conducted using an MMRM approach. In each study, the primary endpoint was the LS mean change from baseline in MADRS total score at the end of Week 6. 1,3-5 Clinical trial patients VRAYLAR studies included the types of bipolar I depression patients that you may see in your practice Baseline characteristics across the 3 pivotal bipolar I depression studies VRAYLAR was evaluated as a monotherapy 1,3-5 Studies included bipolar I depression patients with or without manic symptoms 3-6§ ~8 out of 10 patients in the trials rated their current or most recent depressive episode associated with bipolar I as moderate 2 of VRAYLAR-treated patients were previously on antidepressants (n=527/939) 2 of VRAYLAR-treated patients were previously on mood stabilizers (n=493/939) 2 of patients had moderate to severe anhedonia symptoms (n=949/1383) 2|| of patients had anxiety symptoms (n=894/1383) 7¶ § Concurrent manic symptoms defined as a YMRS total score ≥4. Patients with a YMRS total score >10 (Study 7) or >12 (Studies 8 and 9) at baseline were excluded from these studies. 3-6 || Overall, 69% of patients had MADRS anhedonia subscale scores of ≥18. The MADRS anhedonia subscale is the sum of the following items: 1 (apparent sadness), 2 (reported sadness), 6 (concentration difficulties), 7 (lassitude), and 8 (inability to feel). 2 ¶ Overall, 65% of patients treated with cariprazine 1.5 mg/day or 3 mg/day had higher anxiety symptoms at baseline, defined as a HAM-D anxiety/somatization subscale score of ≥7. 7 Change in MADRS total score in bipolar I depression studies Study 9 (N=478) 1,2,5 Pinch to zoom Baseline Mean 31.4 Placebo (n=163) 31.5 VRAYLAR 1.5 mg/day (n=162) 31.5 VRAYLAR 3 mg/day (n=153) It is unknown if the statistically significant differences observed at time points earlier than Week 6 represent clinically relevant treatment effects. Study design Two 6-week and one 8-week randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of VRAYLAR in adult patients (18-65 years old) who met DSM-IV-TR and DSM-5 criteria for depressive episodes associated with bipolar I disorder. The primary statistical analyses were conducted using an MMRM approach. In each study, the primary endpoint was the LS mean change from baseline in MADRS total score at the end of Week 6. 1,3-5 Clinical trial patients VRAYLAR studies included the types of bipolar I depression patients that you may see in your practice Baseline characteristics across the 3 pivotal bipolar I depression studies VRAYLAR was evaluated as a monotherapy 1,3-5 Studies included bipolar I depression patients with or without manic symptoms 3-6§ ~8 out of 10 patients in the trials rated their current or most recent depressive episode associated with bipolar I as moderate 2 of VRAYLAR-treated patients were previously on antidepressants (n=527/939) 2 of VRAYLAR-treated patients were previously on mood stabilizers (n=493/939) 2 of patients had moderate to severe anhedonia symptoms (n=949/1383) 2|| of patients had anxiety symptoms (n=894/1383) 7¶ § Concurrent manic symptoms defined as a YMRS total score ≥4. Patients with a YMRS total score >10 (Study 7) or >12 (Studies 8 and 9) at baseline were excluded from these studies. 3-6 || Overall, 69% of patients had MADRS anhedonia subscale scores of ≥18. The MADRS anhedonia subscale is the sum of the following items: 1 (apparent sadness), 2 (reported sadness), 6 (concentration difficulties), 7 (lassitude), and 8 (inability to feel). 2 ¶ Overall, 65% of patients treated with cariprazine 1.5 mg/day or 3 mg/day had higher anxiety symptoms at baseline, defined as a HAM-D anxiety/somatization subscale score of ≥7. 7 Observed reduction in anhedonia subscale score in patients with bipolar I depression at Week 6 in a post-hoc analysis 2# ** Change from baseline in anhedonia (loss of interest or pleasure) subscale score Intent-to-treat population (N=1383) Pinch to zoom Baseline Mean Anhedonia Subscale Score 18.5 Placebo (n=460) 18.8 VRAYLAR 1.5 mg/day (n=461) 18.7 VRAYLAR 3 mg/day (n=462) These analyses were not prespecified endpoints and were not adjusted for multiplicity. Therefore, treatment differences cannot be regarded as statistically significant. MADRS anhedonia subscale is the sum of the following items: 1 (apparent sadness), 2 (reported sadness), 6 (concentration difficulties), 7 (lassitude), and 8 (inability to feel). 2 # This was a post-hoc analysis of the primary endpoint (MADRS change from baseline to Week 6) and was not adjusted for multiple comparisons. 2 **The primary endpoint was change from baseline to Week 6 in MADRS total score. Results of pooled data from two 6-week and one 8-week pivotal, multicenter, randomized, placebo-controlled trials in adults with bipolar I depression (N=1383). Patients were randomized in 3 arms: VRAYLAR 1.5 mg, VRAYLAR 3 mg, or placebo. 2-5 Study design 2-5 Results of pooled data from two 6-week and one 8-week pivotal, multicenter, randomized, placebo-controlled trials. Patients in the ITT population (N=1383) were treated with either placebo (n=460) or VRAYLAR (n=923). This was a post-hoc analysis of the primary endpoint (MADRS change from baseline to Week 6) and was not adjusted for multiple comparisons. MADRS anhedonia subscale 2 MADRS anhedonia subscale score components The MADRS anhedonia subscale score is composed of 5 items: Apparent sadness Reported sadness Concentration difficulties Lassitude, eg, lack of energy/motivation Inability to feel Change in functional outcomes across autonomy, occupational functioning, cognitive functioning, financial issues, relationships, and leisure time Additional efficacy endpoint in one pivotal bipolar I depression trial: Change in Functioning Assessment Short Test (FAST) total score at Week 8 2 Pinch to zoom Placebo (n=129) Baseline mean (SD): 38.8 (12.3) VRAYLAR 1.5 mg/day (n=134) Baseline mean (SD): 38.8 (13.5) VRAYLAR 3 mg/day (n=125) Baseline mean (SD): 38.8 (13.8) These analyses were not prespecified endpoints and were not adjusted for multiplicity. Therefore, treatment differences cannot be regarded as statistically significant. VRAYLAR was approved based on the primary endpoint, mean change in MADRS total score from baseline at Week 6 . 1 Study design This 8-week, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of VRAYLAR in adult patients (18-65 years old) who met DSM-IV-TR criteria for depressive episodes associated with bipolar I disorder. The primary statistical analysis was conducted using an MMRM approach. The primary endpoint was the LS mean change from baseline in MADRS total score at the end of Week 6. 1,3 FAST items The FAST evaluates functional impairment 8 The FAST is a clinician-rated scale designed to assess functional impairments in patients with bipolar I disorder. It consists of 24 items divided among 6 areas of functioning: Autonomy Capacity to do things alone and make their own decisions Occupational functioning Capacity to perform and succeed at work Cognitive functioning Capacity to concentrate, learn, and problem-solve Financial issues Capacity to manage and spend money responsibly Interpersonal relationships Capacity to maintain relationships and socialize Leisure time Capacity to pursue hobbies and other activities of leisure Items are rated using a 4-point scale: 0=no difficulty; 1=mild difficulty; 2=moderate difficulty; 3=severe difficulty. The total score is the sum of all 24 items. The higher the score, the more serious the difficulties are. Observed reduction in individual MADRS item scores at Week 6 in a post-hoc analysis 2,9 MADRS items (Scored 0-6) Pinch to zoom Placebo (n=460) VRAYLAR 1.5-3 mg/day (n=923) These analyses were not prespecified endpoints and were not adjusted for multiplicity. Therefore, treatment differences cannot be regarded as statistically significant. VRAYLAR was approved based on the primary endpoint, mean change in MADRS total score from baseline at Week 6. 1 Study design A post-hoc analysis of data pooled from 3 randomized, placebo-controlled, double-blind studies of adult patients with bipolar I disorder. Patients in the ITT population (N=1383) were treated with either placebo (n=460) or VRAYLAR (n=923). VRAYLAR doses 1.5-3 mg/day were pooled for analysis. Mean change from baseline at 6 weeks on individual MADRS items were analyzed using an MMRM approach. 9 Observed reduction in anxiety symptom score in patients with bipolar I depression at Week 6 4,5 Additional efficacy endpoint in 2 pivotal bipolar I depression trials: Mean change from baseline to Week 6 in Hamilton Anxiety Scale (HAM-A) Pinch to zoom VRAYLAR is indicated in adults for the treatment of bipolar I depression. VRAYLAR is not approved for the treatment of anxiety disorders. 1 HAM-A was an additional efficacy endpoint in two 6-week bipolar I depression trials. This prespecified endpoint was not adjusted for multiplicity, therefore, treatment differences cannot be regarded as statistically significant. 4,5 Study design Results from two phase 3 6-week randomized, double-blind, placebo-controlled, parallel-group, fixed-dose studies in adults with bipolar I depression. Patients were randomized in 3 arms: VRAYLAR 1.5 mg/day, VRAYLAR 3 mg/day, or placebo. This was an additional prespecified endpoint and was not adjusted for multiple comparisons. 4,5 HAM-A scale Hamilton Anxiety Rating Scale (HAM-A) components 10 The HAM-A scale measures the severity of anxiety symptoms and consists of the following 14 items: Anxious mood Tension Fears Insomnia Intellectual (cognitive) Depressed mood General somatic (muscular) General somatic (sensory) Cardiovascular symptoms Respiratory symptoms Gastrointestinal symptoms Genitourinary symptoms Autonomic symptoms Behavior at interview Each item is rated using a 4-point scale: 0 = not present; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe. The total score is the sum of all 14 items. Review tolerability & safety Review dosing DSM= Diagnostic and Statistical Manual of Mental Disorders; HAM-A=Hamilton Anxiety Rating Scale; HAM-D=Hamilton Depression Rating Scale; ITT=intent-to-treat; LS=least squares; MADRS=Montgomery-Asberg Depression Rating Scale; MMRM=mixed-effects model for repeated measures; SD=standard deviation; TR=text revision; YMRS=Young Mania Rating Scale. INDICATIONS AND USAGE VRAYLAR (cariprazine) is indicated in adults as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD), for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression), for the acute treatment of manic or mixed episodes associated with bipolar I disorder, and for the treatment of schizophrenia. IMPORTANT SAFETY INFORMATION WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for treatment of patients with dementia-related psychosis. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Contraindication: VRAYLAR is contraindicated in patients with known hypersensitivity. Reactions have included rash, pruritus, urticaria, and reactions suggestive of angioedema. Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials with antipsychotic drugs, elderly patients with dementia had a higher incidence of cerebrovascular adverse reactions, including fatalities, vs placebo. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with antipsychotic drugs. NMS may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and monitoring. Tardive Dyskinesia (TD): Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible may increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. If signs and symptoms of TD appear, drug discontinuation should be considered. Late-Occurring Adverse Reactions: Adverse reactions may first appear several weeks after initiation of VRAYLAR, 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 starting VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug. Metabolic Changes: Atypical antipsychotics, including VRAYLAR, have caused metabolic changes, such as: Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. Assess fasting glucose before or soon after initiation of treatment, and monitor periodically during long-term treatment. Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after starting an antipsychotic, obtain baseline fasting lipid profile and monitor periodically during treatment. Weight Gain: Weight gain has been observed with VRAYLAR. Monitor weight at baseline and frequently thereafter. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia have been reported with antipsychotics, including VRAYLAR. Agranulocytosis (including fatal cases) has been reported with other antipsychotics. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue VRAYLAR at the first sign of a clinically significant decline in WBC and in severely neutropenic patients. Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope, with the greatest risk during initial titration and with dose increases. Monitor orthostatic vital signs in patients predisposed to hypotension and in those with cardiovascular/cerebrovascular diseases. Falls: 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 antipsychotics and recurrently for patients on long-term therapy. Seizures: Use VRAYLAR with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment: Somnolence was reported with VRAYLAR. Caution patients about performing activities requiring mental alertness (eg, operating hazardous machinery or a motor vehicle). Body Temperature Dysregulation: Use VRAYLAR with caution in patients who may experience conditions that increase body temperature (eg, strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics). Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics. Antipsychotic drugs, including VRAYLAR, should be used cautiously in patients at risk for aspiration. Drug Interactions: Strong and moderate CYP3A4 inhibitors increase VRAYLAR concentrations, so VRAYLAR dose reduction is recommended. Concomitant use with CYP3A4 inducers is not recommended. Adverse Reactions: The most common adverse reactions in adult clinical trials (≥5% and at least twice the rate of placebo) are listed below: Adjunctive Treatment of Major Depressive Disorder: In 6-week, fixed-dose trials the incidences within the recommended doses (VRAYLAR 1.5 mg/day + antidepressant therapy [ADT] or 3 mg/day + ADT vs placebo + ADT) were akathisia (7%, 10% vs 2%), nausea (7%, 6% vs 3%), and insomnia (9%, 10% vs 5%). In one 8-week flexible-dose trial, incidences within the doses (VRAYLAR 1-2 mg/day + antidepressant therapy [ADT] or 2-4.5 mg/day + ADT vs placebo + ADT) were akathisia (8%, 23% vs 3%), restlessness (8%, 8% vs 3%), fatigue (7%, 10% vs 4%), constipation (2%, 5% vs 2%), nausea (7%, 13% vs 5%), increased appetite (2%, 5% vs 2%), dizziness (4%, 5% vs 2%), insomnia (14%, 16% vs 8%), and extrapyramidal symptoms (12%, 18% vs 5%). Bipolar Mania: The incidences within the recommended dose range (VRAYLAR 3–6 mg/day vs placebo) were EPS (26% vs 12%), akathisia (20% vs 5%), vomiting (10% vs 4%), dyspepsia (7% vs 4%), somnolence (7% vs 4%), and restlessness (7% vs 2%). Bipolar Depression: The incidences within the recommended doses (VRAYLAR 1.5 mg/day or 3 mg/day vs placebo) were nausea (7%, 7% vs 3%), akathisia (6%, 10% vs 2%), restlessness (2%, 7% vs 3%), and EPS (4%, 6% vs 2%). Schizophrenia: The incidences within the recommended dose range (VRAYLAR 1.5–3 mg/day and 4.5–6 mg/day vs placebo) were EPS (15%, 19% vs 8%) and akathisia (9%, 13% vs 4%). VRAYLAR is available in 0.5 mg, 0.75 mg, 1.5 mg, 3 mg, 4.5 mg, and 6 mg capsules. INDICATIONS AND USAGE VRAYLAR (cariprazine) is indicated for adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults, for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults, for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adult and pediatric patients 10 years of age and older, and for the treatment of schizophrenia in adult and pediatric patients 13 years of age and older. US-VRAA-250443 Please also see full Prescribing Information , including Boxed Warnings. References: VRAYLAR [package insert]. North Chicago, IL: AbbVie Inc; 2024. Data on file. AbbVie Inc. Durgam S, Earley W, Lipschitz A, et al. An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry . 2016;173(3):271-281. doi:10.1176/appi.ajp.2015.15020164 Earley W, Burgess MV, Rekeda L, et al. Cariprazine treatment of bipolar depression: a randomized double-blind placebo-controlled phase 3 study. Am J Psychiatry . 2019;176(6):439-448. doi:10.1176/appi.ajp.2018.18070824 Earley WR, Burgess MV, Khan B, et al. Efficacy and safety of cariprazine in bipolar I depression: a double-blind, placebo-controlled phase 3 study. Bipolar Disord . 2020;22(4):372-384. doi:10.1111/bdi.12852 McIntyre RS, Suppes T, Earley W, Patel M, Stahl SM. Cariprazine efficacy in bipolar 1 depression with and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-controlled studies. CNS Spectrums . 2020;25(4):502-510. doi:10.1017/S1092852919001287 Jain R, McIntyre RS, Cutler AJ, et al. Efficacy of cariprazine in patients with bipolar depression and higher or lower levels of baseline anxiety: a pooled post hoc analysis. Int Clin Psychopharmacol . 2024;39(2):82-92. doi:10.1097/YIC.0000000000000500 Rosa AR, Sánchez-Moreno J, Martínez-Aran A, et al. Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar disorder. Clin Pract Epidemiol Ment Health . 2007;3:5. doi:10.1186/1745-0179-3-5 Yatham LN, Vieta E, McIntyre RS, Jain R, Patel M, Earley W. Broad efficacy of cariprazine on depressive symptoms in bipolar disorder and the clinical implications. Prim Care Companion CNS Disord . 2020;22(5):20m02611. doi:10.4088/PCC.20m02611 Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol . 1959;32(1):50-55. doi:10.1111/j.2044-8341.1959.tb00467.x Important Safety Information Full Prescribing Information About AbbVie Site Map Accessibility Statement Contact Us Terms of Use Privacy Notice Cookies Settings Your Privacy Choices US-VRAA-240301 If you are a patient, and have any questions, please discuss them with your doctor or healthcare provider. For additional information about VRAYLAR ® , call AbbVie Medical Information toll-free at 1.800.678.1605 . Licensed from Gedeon Richter Plc. © 2025 AbbVie. All rights reserved. VRAYLAR ® and its design are trademarks of Allergan Pharmaceuticals International Limited, an AbbVie company. VRAYPAY SM is a service mark of Allergan Pharmaceuticals International Limited, an AbbVie company. You are about to enter a site that is for U.S. Healthcare Professionals only. By selecting "Yes" below, you certify that you are a Healthcare Professional and that you wish to proceed to the Healthcare Professionals Only section on the AbbVie Medical Information site. Products or treatments described on this site are available in the U.S. but may not be available in all other countries. I am a licensed Healthcare Professional and wish to proceed to the Healthcare Professionals Only AbbVie Medical Information Site. Yes No US-VRAA-240301 WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for treatment of patients with dementia-related psychosis. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for treatment of patients with dementia-related psychosis. WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for treatment of patients with dementia-related psychosis. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for treatment of patients with dementia-related psychosis. INDICATIONS AND USAGE VRAYLAR (cariprazine) is indicated in adults as adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD), for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression), for the acute treatment of manic or mixed episodes associated with bipolar I disorder, and for the treatment of schizophrenia. IMPORTANT SAFETY INFORMATION WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for treatment of patients with dementia-related psychosis. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Contraindication: VRAYLAR is contraindicated in patients with known hypersensitivity. Reactions have included rash, pruritus, urticaria, and reactions suggestive of angioedema. Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials with antipsychotic drugs, elderly patients with dementia had a higher incidence of cerebrovascular adverse reactions, including fatalities, vs placebo. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with antipsychotic drugs. NMS may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and monitoring. Tardive Dyskinesia (TD): Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible may increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. If signs and symptoms of TD appear, drug discontinuation should be considered. Late-Occurring Adverse Reactions: Adverse reactions may first appear several weeks after initiation of VRAYLAR, 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 starting VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug. Metabolic Changes: Atypical antipsychotics, including VRAYLAR, have caused metabolic changes, such as: Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. Assess fasting glucose before or soon after initiation of treatment, and monitor periodically during long-term treatment. Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after starting an antipsychotic, obtain baseline fasting lipid profile and monitor periodically during treatment. Weight Gain: Weight gain has been observed with VRAYLAR. Monitor weight at baseline and frequently thereafter. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia have been reported with antipsychotics, including VRAYLAR. Agranulocytosis (including fatal cases) has been reported with other antipsychotics. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue VRAYLAR at the first sign of a clinically significant decline in WBC and in severely neutropenic patients. Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope, with the greatest risk during initial titration and with dose increases. Monitor orthostatic vital signs in patients predisposed to hypotension and in those with cardiovascular/cerebrovascular diseases. Falls: 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 antipsychotics and recurrently for patients on long-term therapy. Seizures: Use VRAYLAR with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment: Somnolence was reported with VRAYLAR. Caution patients about performing activities requiring mental alertness (eg, operating hazardous machinery or a motor vehicle). Body Temperature Dysregulation: Use VRAYLAR with caution in patients who may experience conditions that increase body temperature (eg, strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics). Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics. Antipsychotic drugs, including VRAYLAR, should be used cautiously in patients at risk for aspiration. Drug Interactions: Strong and moderate CYP3A4 inhibitors increase VRAYLAR concentrations, so VRAYLAR dose reduction is recommended. Concomitant use with CYP3A4 inducers is not recommended. Adverse Reactions: The most common adverse reactions in adult clinical trials (≥5% and at least twice the rate of placebo) are listed below: Adjunctive Treatment of Major Depressive Disorder: In 6-week, fixed-dose trials the incidences within the recommended doses (VRAYLAR 1.5 mg/day + antidepressant therapy [ADT] or 3 mg/day + ADT vs placebo + ADT) were akathisia (7%, 10% vs 2%), nausea (7%, 6% vs 3%), and insomnia (9%, 10% vs 5%). In one 8-week flexible-dose trial, incidences within the doses (VRAYLAR 1-2 mg/day + antidepressant therapy [ADT] or 2-4.5 mg/day + ADT vs placebo + ADT) were akathisia (8%, 23% vs 3%), restlessness (8%, 8% vs 3%), fatigue (7%, 10% vs 4%), constipation (2%, 5% vs 2%), nausea (7%, 13% vs 5%), increased appetite (2%, 5% vs 2%), dizziness (4%, 5% vs 2%), insomnia (14%, 16% vs 8%), and extrapyramidal symptoms (12%, 18% vs 5%). Bipolar Mania: The incidences within the recommended dose range (VRAYLAR 3–6 mg/day vs placebo) were EPS (26% vs 12%), akathisia (20% vs 5%), vomiting (10% vs 4%), dyspepsia (7% vs 4%), somnolence (7% vs 4%), and restlessness (7% vs 2%). Bipolar Depression: The incidences within the recommended doses (VRAYLAR 1.5 mg/day or 3 mg/day vs placebo) were nausea (7%, 7% vs 3%), akathisia (6%, 10% vs 2%), restlessness (2%, 7% vs 3%), and EPS (4%, 6% vs 2%). Schizophrenia: The incidences within the recommended dose range (VRAYLAR 1.5–3 mg/day and 4.5–6 mg/day vs placebo) were EPS (15%, 19% vs 8%) and akathisia (9%, 13% vs 4%). VRAYLAR is available in 0.5 mg, 0.75 mg, 1.5 mg, 3 mg, 4.5 mg, and 6 mg capsules. INDICATIONS AND USAGE VRAYLAR (cariprazine) is indicated for adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults, for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults, for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adult and pediatric patients 10 years of age and older, and for the treatment of schizophrenia in adult and pediatric patients 13 years of age and older. US-VRAA-250443 Please also see full Prescribing Information , including Boxed Warnings.