Vraylar

1 . INDICATIONS AND USAGE VRAYLAR ® is indicated for: • Treatment of schizophrenia in adult and pediatric patients 13 years of age and older [see Clinical Studies ( 14.1 )] • Acute treatment of manic or mixed episodes associated with bipolar I disorder in adult and pediatric patients 10 years of age and older [see Clinical Studies ( 14.2 )] • Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adult patients [see Clinical Studies ( 14.3 )] • Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adult patients [see Clinical Studies ( 14.4 )] VRAYLAR is an atypical antipsychotic indicated for: Treatment of schizophrenia in adults and pediatric patients 13 years of age and older ( 1 ) Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and pediatric patients 10 years of age and older ( 1 ) Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults ( 1 ) Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults ( 1 )

2 . DOSAGE AND ADMINISTRATION Administer VRAYLAR orally once daily with or without food ( 2 ) Starting Dose Recommended Dose Schizophrenia in Adults ( 2.2 ) 1.5 mg daily 1.5 mg to 6 mg daily Schizophrenia in Pediatric Patients (13-17 years) ( 2.2 ) 0.5 mg daily 1.5 mg to 4.5 mg daily Bipolar Mania in Adults ( 2.3 ) 1.5 mg daily 3 mg to 6 mg daily Bipolar Mania in Pediatric Patients (10-17 years) ( 2.3 ) 0.5 mg daily 3 mg or 4.5 mg daily Bipolar Depression in Adults ( 2.4 ) 1.5 mg daily 1.5 mg or 3 mg daily Adjunctive therapy to antidepressants for MDD in Adults ( 2.5 ) 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 ( 2.2 , 2.3 ) Pediatric patients with Schizophrenia and Bipolar Mania: Maximum recommended daily dosage is 4.5 mg. Adults with Bipolar Depression: Maximum recommended daily dosage is 3 mg ( 2.4 ) Adjunctive therapy for treatment of MDD in Adults: Maximum recommended daily dosage is 3 mg ( 2.5 ) 2.1 General Dosing Information VRAYLAR is given orally once daily and can be taken with or without food. Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Prescribers should monitor patients for adverse reactions and treatment response for several weeks after starting VRAYLAR and after each dosage change [see Warnings and Precautions ( 5.6 ) , Clinical Pharmacology ( 12.3 )] . 2.2 Recommended Dosage in Schizophrenia Adult Patients The starting dosage of VRAYLAR is 1.5 mg orally once daily. The recommended dosage range is 1.5 mg to 6 mg orally once daily. The dosage can be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg orally once daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )] . Pediatric Patients (13 to 17 years of age) The starting dosage of VRAYLAR is 0.5 mg orally once daily. The recommended dosage range is 1.5 mg to 4.5 mg orally once daily. Increase the dosage to 1.5 mg orally once daily on Day 3. Depending upon clinical response and tolerability, the dosage may be increased to 3 mg orally once daily starting on Day 5, and to 4.5 mg orally once daily starting on Day 8. The maximum recommended dosage is 4.5 mg orally once daily. 2.3 Recommended Dosage in Manic or M ixed E pisodes Associated with Bipolar I Disorder Adult Patients The starting dosage of VRAYLAR is 1.5 mg orally once daily. Increase the dosage to 3 mg orally once daily on Day 2. The recommended dosage range is 3 mg to 6 mg orally once daily. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. The maximum recommended dosage is 6 mg orally once daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions [ see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.2 ) ] . Pediatric Patients (10 to 17 years of age)​ The starting dosage of VRAYLAR is 0.5 mg orally once daily. The recommended dosage is 3 mg or 4.5 mg orally once daily. Increase the dosage to 1.5 mg orally once daily on Day 3 and to 3 mg orally once daily on Day 5. Depending upon clinical response and tolerability, the dosage may be increased to 4.5 mg orally once daily starting on Day 8. The maximum recommended dosage is 4.5 mg orally once daily. 2.4 Recommended Dosage in Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) in Adult Patients The starting dosage of VRAYLAR is 1.5 mg orally once daily. Depending upon clinical response and to…

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) ( 5.3 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.4 ) Tardive Dyskinesia : Discontinue if appropriate ( 5.5 ) 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 ( 5.6 ) Metabolic Changes : Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis : Perform complete blood counts (CBC) in patients with pre-existing low white blood cell counts (WBC) or history of leukopenia or neutropenia. Consider discontinuing VRAYLAR if a clinically significant decline in WBC occurs in absence of other causative factors ( 5.8 ) Orthostatic H ypotension and Syncope : Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.11 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery ( 5.12 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions ( 5.3 ) ] . 5.2 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 3. Table 3: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults…

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 ( 4 )

7 DRUG INTERACTIONS 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 [see Clinical Pharmacology ( 12.3 ) ]. Intervention: If VRAYLAR is used with a strong or moderate CYP3A4 inhibitor, reduce VRAYLAR dosage [see D osage and A dministration ( 2.6 ) ] . 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 [see Clinical Pharmacology ( 12.3 ) ]. Intervention: Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended [see Dosage and Administration ( 2.1 , 2.6 ) ] . Strong and Moderate CYP3A4 inhibitors: Reduce VRAYLAR dosage ( 2.6 , 7 ) CYP3A4 inducers: Concomitant use is not recommended ( 2.6 , 7 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). There are no available data on VRAYLAR use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. The major active metabolite of cariprazine, DDCAR, has been detected in adult patients up to 12 weeks after discontinuation of VRAYLAR [see Clinical Pharmacology ( 12.3 )]. Based on animal data, VRAYLAR may cause fetal harm. Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data Animal Data Administration of cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day, which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total cariprazine (i.e. sum of cariprazine, DCAR, and DDCAR), caused fetal developmental toxicity at all doses, which included reduced body weight, decreased male anogenital distance, and skeletal malformations of bent limb bones, scapula, and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5-times the MRHD of 6 mg/day based on AUC of total cariprazine. At these doses, cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. Administration of cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day, which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine, caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar…

6 ADVERSE REACTIONS 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 ( 5.1 )] Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions ( 5.2 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.3 )] Neuroleptic Malignant Syndrome [see Warnings and Precautions ( 5.4 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.5 )] Late Occurring Adverse Reactions [see Warnings and Precautions ( 5.6 )] Metabolic Changes [see Warnings and Precautions ( 5.7 )] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions ( 5.8 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.9 )] Falls [see Warnings and Precautions ( 5.10 )] Seizures [ see Warnings and Precautions ( 5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.12 )] Body Temperature Dysregulation [see Warnings and Precautions ( 5.13 )] Dysphagia [see Warnings and Precautions ( 5.14 )] Most common adverse reactions in adults (incidence ≥ 5% and at least twice the rate of placebo) were ( 6.1 ) : Schizophrenia: extrapyramidal symptoms and akathisia Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness Bipolar depression: nausea, akathisia, restlessness, and extrapyramidal symptoms Adjunctive treatment of MDD: akathisia, restlessness, fatigue, constipation, nausea, insomnia, increased appetite, dizziness, and extrapyramidal symptoms To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 an integrated clinical study database for VRAYLAR consisting of 6,722 adult patients exposed to one or more doses of VRAYLAR for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder, bipolar depression, and adjunctive treatment of major depressive disorder in placebo-controlled studies. This experience corresponds with a total experience of 1,182.8 patient-years. A total of 4,329 VRAYLAR-treated patients had at least 6 weeks and 296 VRAYLAR-treated patients had at least 48 weeks of exposure. Adult Patients with Schizophrenia 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. The maximum recommended dosage is 6 mg 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 8. Table 8. Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials VRAYLAR * System Organ Class / Preferred Term Placebo (N= 584) (%) 1.5 to 3 mg/day (N=539) (%) 4.5 to 6 mg/day (N=575) (%) 9 to 12 mg/day ⸰ (N=203) (%) Cardiac Disorder s Tachycardia a 1 2 2 3 Gastrointestinal Disorders Abdominal pain b 5 3 4 7 Constipation 5 6 7 10 Diarrhea c 3 1 4 5 Dry Mouth 2 1 2 3 Dyspepsia 4 4 5 5 Nausea 5 5 7 8 Toothache 4 3 3 6 Vomiting 3 4 5 5 General Disorders/Administration Site Conditions Fatigue d 1 1 3 2 Infections and Infestations Nasopharyngitis 1 1 1 2 Urinary tra…