Cariprazine

1. INDICATIONS AND USAGE 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.

The mechanism of action of cariprazine is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D 2 and serotonin 5-HT 1A receptors and antagonist activity at serotonin 5-HT 2A receptors. Cariprazine forms two major metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug.

2. DOSAGE AND ADMINISTRATION 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.

4. CONTRAINDICATIONS VRAYLAR is contraindicated in patients with history of a hypersensitivity reaction to cariprazine. Reactions have ranged from rash, pruritus, urticaria, and reactions suggestive of angioedema (e.g., swollen tongue, lip swelling, face edema, pharyngeal edema, and swelling face). Known hypersensitivity to VRAYLAR

Boxed warning: Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis. 5. WARNINGS AND PRECAUTIONS 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.

The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis Suicidal Thoughts and Behaviors Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Neuroleptic Malignant Syndrome Tardive Dyskinesia Late Occurring Adverse Reactions Metabolic Changes Leukopenia, Neutropenia, and Agranulocytosis Orthostatic Hypotension and Syncope Falls Seizures Potential for Cognitive and Motor Impairment Body Temperature Dysregulation Dysphagia Most common adverse reactions in adults (incidence ≥ 5% and at least twice the rate of placebo) were: Schizophrenia: extrapyramidal symptoms and akathisia Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness Bipolar depression: nausea, akathisia, restlessness…

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.

Store at 20ºC to 25°C (68ºF to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F).