Cariprazine Capsules

Dosage Forms And Strengths

VRAYLAR (cariprazine) capsules are available in four strengths.

• 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”

VRAYLAR capsules are supplied as follows:

Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect 3 mg and 4.5 mg capsules from light to prevent potential color fading.

Manufactured by: Forest Laboratories Ireland Limited Dublin, IE. Distributed by: Allergan USA, Inc. Irvine, CA 92612. Revised: Feb 2017

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS]
• Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS]
• Late Occurring Adverse Reactions[see WARNINGS AND PRECAUTIONS]
• Metabolic Changes [see WARNINGS AND PRECAUTIONS]
• Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Orthostatic Hypotension and Syncope [see WARNINGS AND PRECAUTIONS]
• Falls [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS]
• Body Temperature Dysregulation [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The information below is derived from the clinical trial database for VRAYLAR, consisting of 1733 patients with schizophrenia (aged 18 to 65) and 1025 patients with manic or mixed episodes associated with bipolar I disorder (aged 18 to 65) exposed to one or more doses with a total experience of 566.5 patient-years. Of these patients, 1317 participated in placebo-controlled, 6-week schizophrenia trials with doses ranging from 1.5 mg to 12 mg/day and 623 participated in placebo-controlled, 3-week bipolar mania trials with doses ranging from 3 mg to 12 mg/day. A total of 364 VRAYLAR-treated patients had at least 24 weeks of exposure and 239 VRAYLAR-treated patients had at least 48 weeks of exposure.

The following findings are based on four placebo-controlled, 6-week schizophrenia trials with VRAYLAR doses ranging from 1.5 to 12 mg once daily.

Adverse Reactions Associated with Discontinuation of Treatment: There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo.

Common Adverse Reactions ( ≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms and akathisia.

Adverse Reactions with an incidence of ≥ 2% and greater than placebo, at any dose are shown in Table 3.

Table 3: Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials

The following findings are based on three placebo-controlled, 3-week bipolar mania trials with VRAYLAR doses ranging from 3 to 12 mg once daily.

Adverse Reactions Associated with Discontinuation of Treatment: The only adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received VRAYLAR discontinued treatment due to an adverse reaction, compared with 7% of placebo-treated patients in these trials.

Common Adverse Reactions ( ≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.

Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in Table 4.

Table 4: Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

In schizophrenia and bipolar mania trials, data were objectively collected using the Simpson Angus Rating Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score ≤ 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Scale (BARS) for treatment-emergent akathisia (BARS total score ≤ 2 at baseline and > 2 post-baseline).

In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for VRAYLAR-treated patients versus 8% for placebo-treated patients. These events led to discontinuation in 0.3% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These events led to discontinuation in 0.5% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of EPS is shown in Table 5.

Table 5: Incidence of EPS Compared to Placebo in 6-Week Schizophrenia Studies

In 3-week bipolar mania trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for VRAYLAR-treated patients versus 12% for placebo-treated patients. These events led to a discontinuation in 1% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for VRAYLAR-treated patients versus 5% for placebo-treated patients. These events led to discontinuation in 2% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of EPS is provided in Table 6.

Table 6: Incidence of EPS Compared to Placebo in 3-Week Bipolar Mania Trials

In the long-term uncontrolled schizophrenia (48-week) and bipolar mania (16-week) trials, the incidence of cataracts was 0.1% and 0.2%, respectively. The development of cataracts was observed in nonclinical studies [see Nonclinical Toxicology]. The possibility of lenticular changes or cataracts cannot be excluded at this time.

There were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 -12 mg/day VRAYLAR-treated schizophrenia patients.

Pooled data from 6-week schizophrenia and 3-week bipolar mania trials are shown in Tables 7 and 8.

Table 7:Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials

Table 8: Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials

The proportions of patients with transaminase elevations of ≥ 3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for VRAYLAR-treated patients, increasing with dose, and was 1% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥ 3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for VRAYLAR-treated patients depending on dose group administered and 2% for placebo-treated patients.

The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1000 U/L in 6week schizophrenia trials ranged between 4% and 6% for VRAYLAR-treated patients, increasing with dose, and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in cariprazine and placebo-treated patients.

Adverse reactions listed below were reported by patients treated with VRAYLAR at doses of ≥ 1.5 mg once daily within the database of 2758 VRAYLAR-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the VRAYLAR label are not included.

Reactions are further categorized by organ class and listed in order of decreasing frequency, according to the following definition: those occurring in at least 1/100 patients (frequent) [only those not already listed in the tabulated results from placebo-controlled studies appear in this listing]; those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).

Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis

Hepatobiliary Disorders: Rare: hepatitis

Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyponatremia

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Rare: ischemic stroke

Psychiatric Disorders: Infrequent: suicide attempts, suicide ideation; Rare: completed suicide

Renal and Urinary Disorders: Infrequent: pollakiuria

 Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis