Proven antidepressant efficacy for bipolar I depression1,14-16

Change in MADRS total score in bipolar I depression studies1,14-16

Charts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total scoreCharts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total scoreCharts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total score

Study 7 (N=431)1,2,14

Charts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total scoreCharts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total scoreCharts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total score

Study 8 (N=474)1,2,15

Charts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total scoreCharts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total scoreCharts of three pivotal bipolar I studies for VRAYLAR that show change in MADRS total score

Study 9 (N=478)1,2,16

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 6.1,14-16

VRAYLAR demonstrated efficacy in bipolar I depression, with no more than 2.8% of VRAYLAR patients experiencing treatment-emergent mania (vs 3.5% in placebo)2*

*Patients with nonmissing baseline and ≥1 postbaseline parameter assessment during the double-blind treatment period—Study 7: VRAYLAR 1.5 mg/day (n=4/145) and VRAYLAR 3 mg/day (n=4/145) compared to placebo (n=5/142); Study 8: VRAYLAR 1.5 mg/day (n=1/153) and VRAYLAR 3 mg/day (n=0/164) compared to placebo (n=2/157); Study 9: VRAYLAR 1.5 mg/day (n=2/162) and VRAYLAR 3 mg/day (n=0/154) compared to placebo (n=2/158).2
DSM=Diagnostic and Statistical Manual of Mental Disorders; LS=least squares; MADRS=Montgomery-Asberg Depression Rating Scale; MMRM=mixed-effects model for repeated measures; TR=text revision.

Post-hoc analysis of pooled data from VRAYLAR pivotal bipolar I depression studies17

Chart shows post-hoc analysis of pooled data from VRAYLAR pivotal bipolar I depression studiesChart shows post-hoc analysis of pooled data from VRAYLAR pivotal bipolar I depression studies

Observed reduction in all individual MADRS item scores at Week 617

MADRS ITEMS (SCORED 0-6)

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 was analyzed using an MMRM approach.17


ITT=intent-to-treat.

Change in functional outcomes

Additional efficacy endpoint in one pivotal bipolar I depression trial: Change in Functioning Assessment Short Test (FAST) total score at Week 82

Chart of additional efficacy endpoint in one pivotal bipolar I depression trial: Change in Functioning Assessment Short Test (FAST) total score at Week 8Chart of additional efficacy endpoint in one pivotal bipolar I depression trial: Change in Functioning Assessment Short Test (FAST) total score at Week 8Chart of additional efficacy endpoint in one pivotal bipolar I depression trial: Change in Functioning Assessment Short Test (FAST) total score at Week 8
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 6.2

The FAST evaluates functional impairment18

The FAST is a clinician-rated scale designed to assess functional impairment 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
SD=standard deviation; SE=standard error.
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. Safety and effectiveness of VRAYLAR have not been established in pediatric patients.

Contraindication: VRAYLAR is contraindicated in patients with known hypersensitivity. Reactions have included rash, pruritus, urticaria, and events suggestive of angioedema.

Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials with antipsychotic drugs, elderly subjects 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 events 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 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 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 CYP3A4 inhibitors increase VRAYLAR concentrations, so VRAYLAR dose reduction is recommended. Concomitant use with CYP3A4 inducers is not recommended.

Adverse Reactions: In clinical trials, the most common adverse reactions (≥5% and at least twice the rate of placebo) are listed below:

  • 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%).
  • 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%).
INDICATIONS AND USAGE

VRAYLAR (cariprazine) is indicated in adults for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression), the acute treatment of manic or mixed episodes associated with bipolar I disorder, and the treatment of schizophrenia.

Please also see full Prescribing Information, including Boxed Warnings.
SEE MORE +
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. Safety and effectiveness of VRAYLAR have not been established in pediatric patients.

Contraindication: VRAYLAR is contraindicated in patients with known hypersensitivity. Reactions have included rash, pruritus, urticaria, and events suggestive of angioedema.

Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials with antipsychotic drugs, elderly subjects 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 events 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 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 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 CYP3A4 inhibitors increase VRAYLAR concentrations, so VRAYLAR dose reduction is recommended. Concomitant use with CYP3A4 inducers is not recommended.

Adverse Reactions: In clinical trials, the most common adverse reactions (≥5% and at least twice the rate of placebo) are listed below:

  • 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%).
  • 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%).
INDICATIONS AND USAGE

VRAYLAR (cariprazine) is indicated in adults for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression), the acute treatment of manic or mixed episodes associated with bipolar I disorder, and the treatment of schizophrenia.

Please also see full Prescribing Information, including Boxed Warnings.