Vraylar

Indications and Usage ( 1 ) 12/2025 Dosage and Administration ( 2.2 , 2.3 , 2.6 ) 12/2025 Warnings and Precautions, Metabolic Changes ( 5.7 ) 12/2025

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 …

3 . DOSAGE FORMS AND STRENGTHS VRAYLAR (cariprazine) capsules are available in six strengths. 0.5 mg capsules: Ivory to yellow cap and a grey to green body imprinted with “FL 0.5” 0.75 mg capsules: Grey to green cap and blue body imprinted with “FL 0.75” 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” Capsules: 0.5 mg, 0.75 mg, 1.5 mg, 3 mg, 4.5 mg, and 6 mg ( 3 )

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 )

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 …

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 USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 ) 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 un …

12.1 Mechanism of Action 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.

11 . DESCRIPTION The active ingredient of VRAYLAR is cariprazine, an atypical antipsychotic, in hydrochloride salt form. The chemical name is trans -N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride; its empirical formula is C 21 H 3 2 Cl 2 N 4 O•HCl and its molecular weight is 463.9 g/mol. The chemical structure is: VRAYLAR capsules are intended for oral administration only. Each hard gelatin capsule contains 0.5, 0.75, 1.5, 3, 4.5, or 6 mg of cariprazine base (equivalent to 0.545 mg, 0.818 mg, 1.635 mg , 3.27 mg, 4.905 mg, or 6.54 mg cariprazine HCl). In addition, capsules include the following inactive ingredients: gelatin, magnesium stearate, pregelatinized starch, shellac, and titanium dioxide. Colorants include black iron oxide (0.5, 0.75, 1.5, 3, and 6 mg), FD&C Blue 1 (0.5, 0.75, 3, 4.5, and 6 mg), FD&C Red 3 (6 mg), FD&C Red 40 (3 and 4.5 mg), or yellow iron oxide (0.5, 3, and 4.5 mg). The chemical structure for VRAYLAR is cariprazine HCl, an atypical antipsychotic. The chemical name is trans-N-{4-[2-[4-(2,3 dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride; its empirical formula is C21H33Cl3N4O and its molecular weight is 463.9 g/mol.

10 OVERDOSAGE 10.1 Human Experience In pre-marketing clinical trials involving VRAYLAR in approximately 5000 patients or healthy subjects, accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day. 10.2 Management of Overdosage No specific antidotes for VRAYLAR are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied VRAYLAR (cariprazine) capsules are supplied as follows: Capsule Strength Imprint Codes Capsule Color Package Configuration NDC Code 0.5 mg FL 0.5 Ivory to yellow cap and grey to green body Bottle of 30 61874-250-30 0.75 mg FL 0.75 Grey to green cap and blue body Bottle of 30 61874-275-30 1.5 mg FL 1.5 White cap and body Blister pack of 7 61874-115-17 Bottle of 30 61874-115-30 Bottle of 90 61874-115-90 Box of 20 (Hospital Unit Dose) 61874-115-20 3 mg FL 3 Green to blue-green cap and white body Bottle of 30 61874-130-30 Bottle of 90 61874-130-90 Box of 20 (Hospital Unit Dose) 61874-130-20 4.5 mg FL 4.5 Green to blue-green cap and body Bottle of 30 61874-145-30 Bottle of 90 61874-145-90 6 mg FL 6 Purple cap and white body Bottle of 30 61874-160-30 Bottle of 90 61874-160-90 (1) 1.5 mg, (6) 3 mg FL 1.5, FL 3 Mixed Blister pack of 7 61874-170-08 16.2 Storage and Handling Store at 20oC to 25°C (68oF 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.

16.1 How Supplied VRAYLAR (cariprazine) capsules are supplied as follows: Capsule Strength Imprint Codes Capsule Color Package Configuration NDC Code 0.5 mg FL 0.5 Ivory to yellow cap and grey to green body Bottle of 30 61874-250-30 0.75 mg FL 0.75 Grey to green cap and blue body Bottle of 30 61874-275-30 1.5 mg FL 1.5 White cap and body Blister pack of 7 61874-115-17 Bottle of 30 61874-115-30 Bottle of 90 61874-115-90 Box of 20 (Hospital Unit Dose) 61874-115-20 3 mg FL 3 Green to blue-green cap and white body Bottle of 30 61874-130-30 Bottle of 90 61874-130-90 Box of 20 (Hospital Unit Dose) 61874-130-20 4.5 mg FL 4.5 Green to blue-green cap and body Bottle of 30 61874-145-30 Bottle of 90 61874-145-90 6 mg FL 6 Purple cap and white body Bottle of 30 61874-160-30 Bottle of 90 61874-160-90 (1) 1.5 mg, (6) 3 mg FL 1.5, FL 3 Mixed Blister pack of 7 61874-170-08