| Duration | N | Design | Doses Studied | Control | Primary Endpoint |
| 6-Week | 751 | Fixed Dose | 1.5 mg/day + ADT; 3 mg/day + ADT |
Placebo + ADT | Mean change from baseline in MADRS total score at the end of Week 6 |
| 8-Week | 808 | Flexible Dose | 1-2 mg/day + ADT; 2-4.5 mg/day + ADT Mean VRAYLAR dose was 2.6 mg/day |
Placebo + ADT | Mean change from baseline in MADRS total score at the end of Week 8 |
Both adjunctive MDD studies were randomized, double-blind, placebo-controlled, and evaluated the efficacy and safety of VRAYLAR in adult patients (mean age of 45 years, range 18-65 years) who met DSM-IV-TR or DSM-5 criteria for MDD, with or without symptoms of anxiety, and had an inadequate response to 1 to 3 courses of prior antidepressant (ADT) therapy.§
In each study, the primary endpoint was mean change from baseline to Week 6 (fixed-dose study) or Week 8 (flexible-dose study) in the MADRS total score. Fixed-dose (N=751) was a 6-week trial involving 2 fixed doses of VRAYLAR (1.5 mg/day or 3 mg/day) + ADT vs placebo + ADT. Flexible-dose (N=808) was an 8-week trial involving flexible doses of VRAYLAR (1-2 mg/day or 2-4.5 mg/day) + ADT vs placebo + ADT, with a mean dose of 2.6 mg/day.
§Inadequate response during antidepressant treatment was defined as less than 50% improvement to antidepressant treatment of adequate dose and duration.
Most patients had moderate to severe depressive symptoms at baseline with ADT
Baseline mean MADRS total scores:
6-Week MDD Trial (pooled) = 32.5
VRAYLAR 1.5 mg/day + ADT = 32.8
VRAYLAR 3 mg/day + ADT = 32.7
Placebo + ADT = 31.9
8-Week MDD Flexible-Dose Trial
VRAYLAR 1-2 mg/day + ADT = 28.8
VRAYLAR 2-4.5 mg/day + ADT = 29.3
Placebo + ADT = 28.9
Across both MDD studies, about 70% of patients had inadequate response to their first antidepressant therapy in the current episode
In the 6-week fixed-dose MDD study, 83% of patients had anxiety symptoms at baselineII
Patients enrolled were taking the most commonly used antidepressants, including¶:
||Overall, 83% of patients had anxiety symptoms at baseline, defined as a score of ≥7 at baseline on the HAM-D anxiety/somatization factor. Anxiety/somatization factor comprises the following 6 items from the HAM-D; psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight.
¶These are not all of the ADTs patients were taking prior to and during the VRAYLAR MDD studies. Please see publications for complete list.2
ADT=antidepressant therapy; DSM=Diagnostic and Statistical Manual of Mental Disorders; LS= least squares; MADRS=Montgomery-Asberg Depression Rating Scale; MDD=major depressive disorder; NS= Not significant; TR=text revision.
Observed reduction in MADRS total score by nearly 50% for:
These analyses were not prespecified endpoints and were not adjusted for multiplicity. Therefore, treatment differences cannot be regarded as statistically significant.
A post-hoc analysis of data from 1 multicenter, randomized, placebo-controlled, double-blind study of adults with MDD who had an inadequate response to ADT alone (n=751). Patients in the mITT population (n=751) were either treated with placebo (n=249), VRAYLAR 1.5 mg/day + ADT, or VRAYLAR 3 mg/day + ADT (n=502). The primary efficacy parameter was change from baseline at 6 weeks in MADRS total score and was analyzed using an MMRM approach.
#This was a post-hoc analysis of the primary endpoint (MADRS change from baseline to Week 6) and was not adjusted for multiple comparisons.
**The primary endpoint was change from baseline to Week 6 in MADRS total score. Results of a representative, pivotal, multicenter, randomized, placebo-controlled 6-week trial in adults with MDD (N=751). Patients were randomized in 3 arms: cariprazine 1.5 mg, cariprazine 3 mg, or placebo + ongoing ADT.1,2
mITT=modified intent-to-treat; MMRM=mixed-effects model for repeated measures.
These analyses were not prespecified endpoints and were not adjusted for multiplicity. Therefore, treatment differences cannot be regarded as statistically significant.
A post-hoc analysis of data from 1 multicenter, randomized, placebo-controlled, double-blind study of adults with MDD who had an inadequate response to ADT alone (n=751). Patients in the mITT population (n=751) were either treated with placebo + ADT (n=249), VRAYLAR 1.5 mg/day + ADT, or VRAYLAR 3 mg/day + ADT (n=502). The primary efficacy parameter was change from baseline at 6 weeks in MADRS total score and was analyzed using an MMRM approach.
††This was a post-hoc analysis of the primary endpoint (MADRS change from baseline to Week 6) and was not adjusted for multiple comparisons.
‡‡The primary endpoint was change from baseline to Week 6 in MADRS total score. Results of a representative, pivotal, multicenter, randomized, placebo-controlled 6-week trial in adults with MDD (N=751). Patients were randomized in 3 arms: cariprazine 1.5 mg, cariprazine 3 mg, or placebo + ongoing ADT.1,2
These analyses did not assess the effect of treatment on symptoms of anxiety.
These analyses were not prespecified endpoints and were not adjusted for multiplicity. Therefore, treatment differences cannot be regarded as statistically significant.
A post-hoc analysis of data from 1 multicenter, randomized, placebo-controlled, double-blind study of adults with MDD who had an inadequate response to ADT alone (n=751). Patients in the mITT population (n=751) were either treated with placebo + ADT (n=249), VRAYLAR 1.5 mg/day + ADT, or VRAYLAR 3 mg/day + ADT (n=502). The primary efficacy parameter was change from baseline at 6 weeks in MADRS total score and was analyzed using an MMRM approach.
Overall, 83% of patients had anxiety symptoms at baseline, defined as a score of ≥7 at baseline on the HAM-D anxiety/somatization factor. Anxiety/somatization factor comprises the following 6 items from the HAM-D: psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight.
§§The primary endpoint was change from baseline to Week 6 in MADRS total score. Results of 1 pivotal, multicenter, randomized, placebo-controlled 6-week trial in adults with MDD (N=751). Patients were randomized in 3 arms: VRAYLAR 1.5 mg, VRAYLAR 3 mg, or placebo + ongoing ADT. This was a post-hoc analysis of the primary endpoint (MADRS change from baseline to Week 6) and was not adjusted for multiple comparisons.1,2
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.
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:
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 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 clinical trials ( 5% and at least twice the rate of placebo) are listed below:
US-VRA-220402
