----------------------------DRUG INTERACTIONS------------------------------­ • Doses above 6 mg daily do not confer significant benefit but increased the • Strong CYP3A4 inhibitors: reduce VRAYLAR dosage by half (2.4, 7.1) risk of dose-related adverse reactions. • CYP3A4 inducers: do not recommend use with VRAYLAR (2.4, 7.1) -----------

Name of the drug-   VRAYLAR

Active ingriendents-    Cariprazine

FDA approved use-    To treat schizophrenia and bipolar disorder in adults

Date of Approval         9/17/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION -

WARNINGS AND PRECAUTIONS-

­ These highlights do not include all the information needed to use • Cerebrovascular Adverse Reactions in Elderly Patients with DementiaVRAYLAR safely and effectively. See full prescribing information for Related Psychosis: Increased incidence of cerebrovascular adverse VRAYLAR. reactions (e.g., stroke, transient ischemic attack)

5.2) • Neuroleptic Malignant Syndrome: Manage with immediate VRAYLAR™ (cariprazine) capsules, for oral use discontinuation and close monitoring (5.3) Initial U.S. Approval: XXXX • Tardive Dyskinesia: Discontinue if appropriate

(5.4) WARNING • Late-Occurring Adverse Reactions: Because of VRAYLAR’s long half- :

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA life, monitor for adverse reactions and patient response for several -RELATED PSYCHOSIS See full prescribing information for complete boxed warning. weeks after starting VRAYLAR and with each dosage change (5.5) ? Elderly patients with dementia • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, -related psychosis treated with antipsychotic drugs are at an increased risk of death. dyslipidemia and weight gain (5.6) ? VRAYLAR • Orthostatic Hypotension: Monitor heart rate and blood pressure and is not approved for the treatment of patients with warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.8) dementia-related psychosis. (5.1)

-------------------------------INDICATIONS AND USAGE--------------------------­ VRAYLAR --------

--------------------ADVERSE REACTIONS------------------------------­ is an atypical antipsychotic indicated for the: Most common adverse reactions (incidence = 5% and at least twice the rate • Treatment of schizophrenia (1) of placebo) were (6.1): • Acute treatment of manic or mixed episodes associated with bipolar I • Schizophrenia: extrapyramidal symptoms and akathisia disorder (1) • Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia,

-------------------------DOSAGE AND ADMINISTRATION----------------------- vomiting, somnolence, and restlessness • Administer VRAYLAR once daily with or without food (2) Starting Dose Recommended Dose Schizophrenia (2.2) 1.5 mg/day 1.5 mg to 6 mg/day Bipolar Mania (2.3) 1.5 mg/day 3 mg to 6 mg/day To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1­ 800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

----------------------------DRUG INTERACTIONS------------------------------­ • Doses above 6 mg daily do not confer significant benefit but increased the • Strong CYP3A4 inhibitors: reduce VRAYLAR dosage by half (2.4, 7.1) risk of dose-related adverse reactions. • CYP3A4 inducers: do not recommend use with VRAYLAR (2.4, 7.1) ---------------------

 SPEDOSAGE FORMS AND STRENGTHS---------------------- ----------------------USE INCIFIC POPULATIONS----------------------­ Capsules: 1.5 mg, 3 mg, 4.5 mg, and 6 mg

(3) • Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure

(8.1) -------------------------------CONTRAINDICATIONS-----------------------------­ Known hypersensitivity to VRAYLAR (4)

--------------------ADVERSE REACTIONS------------------------------­ is an atypical antipsychotic indicated for the: Most common adverse reactions (incidence = 5% and at least twice the rate • Treatment of schizophrenia (1) of placebo) were (6.1): • Acute treatment of manic or mixed episodes associated with bipolar I • Schizophrenia: extrapyramidal symptoms and akathisia disorder (1) • Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia,

(8.1) -------------------------------CONTRAINDICATIONS-----------------------------­ Known hypersensitivity to VRAYLAR (4)

-----------------------WARNINGS AND PRECAUTIONS---------------------­ These highlights do not include all the information needed to use • Cerebrovascular Adverse Reactions in Elderly Patients with DementiaVRAYLAR safely and effectively. See full prescribing information for Related Psychosis: Increased incidence of cerebrovascular adverse VRAYLAR. reactions (e.g., stroke, transient ischemic attack) (5.2) • Neuroleptic Malignant Syndrome: Manage with immediate VRAYLAR™ (cariprazine) capsules, for oral use discontinuation and close monitoring (5.3) Initial U.S. Approval: XXXX • Tardive Dyskinesia: Discontinue if appropriate (5.4) WARNING • Late-Occurring Adverse Reactions: Because of VRAYLAR’s long half- : INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA life, monitor for adverse reactions and patient response for several -RELATED PSYCHOSIS See full prescribing information for complete boxed warning. weeks after starting VRAYLAR and with each dosage change (5.5) ? Elderly patients with dementia • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, -related psychosis treated with antipsychotic drugs are at an increased risk of death. dyslipidemia and weight gain (5.6) ? VRAYLAR • Orthostatic Hypotension: Monitor heart rate and blood pressure and is not approved for the treatment of patients with warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.8) dementia-related psychosis. (5.1) -------------------------------INDICATIONS AND USAGE--------------------------­ VRAYLAR

----------------------------ADVERSE REACTIONS------------------------------­ is an atypical antipsychotic indicated for the: Most common adverse reactions (incidence = 5% and at least twice the rate • Treatment of schizophrenia (1) of placebo) were (6.1): • Acute treatment of manic or mixed episodes associated with bipolar I • Schizophrenia: extrapyramidal symptoms and akathisia disorder (1) • Bipolar mania: extrapyramidal symptoms, akathisia, dyspepsia,

-------------------------DOSAGE AND ADMINISTRATION----------------------- vomiting, somnolence, and restlessness • Administer VRAYLAR once daily with or without food (2) Starting Dose Recommended Dose Schizophrenia (2.2) 1.5 mg/day 1.5 mg to 6 mg/day Bipolar Mania (2.3) 1.5 mg/day 3 mg to 6 mg/day To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1­ 800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------DRUG INTERACTIONS------------------------------­ • Doses above 6 mg daily do not confer significant benefit but increased the • Strong CYP3A4 inhibitors: reduce VRAYLAR dosage by half (2.4, 7.1) risk of dose-related adverse reactions. • CYP3A4 inducers: do not recommend use with VRAYLAR (2.4, 7.1) ---------------------DOSAGE FORMS AND STRENGTHS---------------------- ----------------------USE IN SPECIFIC POPULATIONS----------------------­ Capsules: 1.5 mg, 3 mg, 4.5 mg, and 6 mg (3) • Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure (8.1) -------------------------------CONTRAINDICATIONS-----------------------------­ Known hypersensitivity to VRAYLAR (4) See 17 for PATIENT COUNSELING INFORMATION

DOSAGE FORMS AND STRENGTHS-

USE INCIFIC POPULATIONS----------------------­ Capsules: 1.5 mg, 3 mg, 4.5 mg, and 6 mg

-------------------------DOSAGE AND ADMINISTRATION----------------------- vomiting, somnolence, and restlessness • Administer VRAYLAR once daily with or without food (2) Starting Dose Recommended Dose Schizophrenia (2.2) 1.5 mg/day 1.5 mg to 6 mg/day Bipolar Mania (2.3) 1.5 mg/day 3 mg to 6 mg/day To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1­ 800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

PATIENT COUNSELING INFORMATION-

 Physicians are advised to discuss with patients for whom they prescribe VRAYLAR all relevant safety information including, but not limited to, the following: Dosage and

Administration Advise patients that VRAYLAR can be taken with or without food. Counsel them on the importance of following dosage escalation instructions [see Dosage and Administration (2)].

Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs [see Warnings and Precautions (5.3)].

Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.4)].

Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.7)].

Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking VRAYLAR [see Warnings and Precautions (5.8)].

Orthostatic Hypotension Counsel patients on the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions (5.9)].

Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that VRAYLAR therapy does not affect them adversely [see Warnings and Precautions (5.11)].

Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.12)].

Concomitant Medications Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-thecounter drugs since there is a potential for interactions [see Drug Interactions (7.1)].

Pregnancy VRAYLAR™ (cariprazine) Capsules - draft labeling text –redline Page 29 of 30 Reference ID: 3821760 Advise patients that third trimester use of VRAYLAR may cause extrapyramidal and/or withdrawal symptoms in a neonate.

Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy [see Use in Specific Populations (8.1)].

Licensed from Gedeon Richter Plc. Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA VRAYLAR™ is a trademark of Actavis, Inc. or its affiliates. © 20XX Actavis. All rights reserved.

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action The mechanism of action of cariprazine in schizophrenia and bipolar I disorder is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.

Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug. 12.2 Pharmacodynamics Cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors with high binding affinity (Ki values 0.085 nM, and 0.49 nM (D2L) and 0.69 nM (D2S), respectively) and at the serotonin 5-HT1A receptors (Ki value 2.6 nM)

. Cariprazine acts as an antagonist at 5-HT2B and 5-HT2A receptors with high and moderate binding affinity (Ki values 0.58 nM and 18.8 nM respectively) as well as it binds to the histamine H1 receptors (Ki value 23.2 nM). Cariprazine shows lower binding affinity to the serotonin 5­ HT2C and a1A- adrenergic receptors (Ki values 134 nM and 155 nM, respectively) and has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000 nM). Effect on QTc Interval At a dose three-times the maximum recommended dose, cariprazine does not prolong the QTc interval to clinically relevant extent.

12.3 Pharmacokinetics VRAYLAR activity is thought to be mediated by cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which are pharmacologically equipotent to cariprazine. After multiple dose administration of VRAYLAR, mean cariprazine and DCAR concentrations reached steady state at around Week 1 to Week 2 and mean DDCAR concentrations appeared to be approaching steady state at around Week 4 to Week 8 in a 12-week study (Figure 1). The half-lives based on time to reach steady state, estimated from the mean concentration-time curves, are 2 to 4 days for cariprazine, VRAYLAR™ (cariprazine) Capsules - draft labeling text –redline Page 19 of 30 Reference ID: 3821760 and approximately 1 to 3 weeks for DDCAR. The time to reach steady state for the major active metabolite DDCAR was variable across patients, with some patients not achieving steady state at the end of the 12 week treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.5)]. Mean concentrations of DCAR and DDCAR are approximately 30% and 400%, respectively, of cariprazine concentrations by the end of 12-week treatment. After discontinuation of VRAYLAR, cariprazine, DCAR, and DDCAR plasma concentrations declined in a multi-exponential manner. Mean plasma concentrations of DDCAR decreased by about 50%, 1 week after the last dose and mean cariprazine and DCAR concentration dropped by about 50% in about 1 day. There was an approximately 90% decline in plasma exposure within 1 week for cariprazine and DCAR, and at about 4 weeks for DDCAR. Following a single dose of 1 mg of cariprazine administration, DDCAR remained detectable 8 weeks post-dose. After multiple dosing of VRAYLAR, plasma exposure of cariprazine, DCAR, and DDCAR, increases approximately proportionally over the therapeutic dose range. Figure 1. Plasma Concentration (Mean ± SE)-Time Profile During and Following 12-weeks of Treatment with Cariprazine 6 mg/daya Plasma Concentration (nM) 140 120 100 80 60 40 20 0 TOTAL CAR DDCAR CAR DCAR 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (Weeks) a Trough concentrations shown during treatment with cariprazine 6 mg/day. SE: standard error; TOTAL CAR: sum concentration of cariprazine, DCAR and DDCAR; CAR: cariprazine Absorption After single dose administration of VRAYLAR, the peak plasma cariprazine concentration occurred in approximately 3-6 hours. Administration of a single dose of 1.5 mg VRAYLAR capsule with a high-fat meal did not significantly affect the Cmax and AUC of cariprazine or DCAR. Distribution VRAYLAR™ (cariprazine) Capsules - draft labeling text –redline Page 20 of 30 Reference ID: 3821760 Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins.

Elimination Metabolism Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite.

Excretion Following administration of 12.5 mg/day cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose was excreted in urine as unchanged cariprazine.

Studies in Specific Populations

Hepatic Impairment Compared to healthy subjects, patients with either mild or moderate hepatic impairment (Child-Pugh score between 5 and 9) had approximately 25% higher exposure (Cmax and AUC) for cariprazine and approximately 45% lower exposure for the major active metabolites, DCAR and DDCAR, following a single dose of 1 mg cariprazine or 0.5 mg cariprazine for 14 days [see Use in Specific Populations (8.6)]

Renal Impairment Cariprazine and its major active metabolites are minimally excreted in urine. Pharmacokinetic analyses indicated no significant relationship between plasma clearance and creatinine clearance [see Use in Specific Populations (8.7)].

CYP2D6 Poor Metabolizers CYP2D6 poor metabolizer status does not have clinically relevant effect on pharmacokinetics of cariprazine, DCAR, or DDCAR. Age, Sex, Race Age, sex, or race does not have clinically relevant effect on pharmacokinetics of cariprazine, DCAR, or DDCAR. Drug Interaction Studies In vitro studies Cariprazine and its major active metabolites did not induce CYP1A2 and CYP3A4 enzymes and were weak inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 in vitro. Cariprazine was also a weak inhibitor of CYP2C19, CYP2A6, and CYP2E1 in vitro. Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). Cariprazine and its major active metabolites were poor or non-inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro.

The major active metabolites were also poor or non-inhibitors of transporter P-gp VRAYLAR™ (cariprazine) Capsules - draft labeling text –redline Page 21 of 30 Reference ID: 3821760 although cariprazine was probably a P-gp inhibitor based on the theoretical GI concentrations at high doses in vitro. CYP 3A4 inhibitors Coadministration of ketoconazole (400 mg/day), a strong CYP3A4 inhibitor, with VRAYLAR (0.5 mg/day) increased cariprazine Cmax and AUC0-24h by about 3.5-fold and 4-fold, respectively; increased DDCAR Cmax and AUC0-24h by about 1.5-fold; and decreased DCAR Cmax and AUC0-24h by about onethird.

The impact of moderate CYP3A4 inhibitors has not been studied. CYP3A4 inducers CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the plasma exposure of cariprazine and its major active metabolites has not been evaluated, and the net effect is unclear. CYP2D6 inhibitors CYP2D6 inhibitors are not expected to influence pharmacokinetics of cariprazine, DCAR or DDCAR based on the observations in CYP2D6 poor metabolizers.

DRUG INTERACTIONS 7.1 Drugs Having Clinically Important Interactions with VRAYLAR Table 9: Clinically Important Drug Interactions with VRAYLAR Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of VRAYLAR with a strong 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 CYP3A4 inhibitor, reduce VRAYLAR dosage [see Dosage and Administration (2.3)]. Examples: itraconazole, ketoconazole 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)]. VRAYLAR™ (cariprazine) Capsules - draft labeling text –redline Page 15 of 30 Reference ID: 3821760 Intervention: Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended [see Dosage and Administration (2.1, 2.3)]. Examples: rifampin, carbamazepine 7.2 Drugs Having No Clinically Important Interactions with VRAYLAR Based on in vitro studies, VRAYLAR is unlikely to cause clinically significant pharmacokinetic drug interactions with substrates of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E, and CYP3A4, or OATP1B1, OATP1B3, BCRP, OCT2, OAT1 and OAT3 [see Clinical Pharmacology (12.3)].

8. USE IN SPECIFIC POPULATIONS

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-researchprograms/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.

There are no available data on VRAYLAR use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. 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 unknow

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 VRAYLAR™ (cariprazine) Capsules - draft labeling text –redline Page 16 of 30 Reference ID: 3821760 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/kg/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 to these of the first generation pups. Administration of cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs.

8.2 Lactation Risk Summary Lactation studies have not been conducted to assess the presence of cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for VRAYLAR and any potential adverse effects on the breastfed infant from VRAYLAR or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies of VRAYLAR have not been conducted. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery [see Use in Specific Populations (8.1)]

8.5 Geriatric Use Clinical trials of VRAYLAR in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Elderly patients with dementia-related psychosis treated with VRAYLAR are at an increased risk of death compared to placebo. VRAYLAR is not approved for the treatment of patients with dementiarelated psychosis [see Boxed Warning and Warnings and Precautions (5.1, 5.2)]. VRAYLAR™ (cariprazine) Capsules - draft labeling text –redline Page 17 of 30 Reference ID: 3821760

8.6 Hepatic Impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9) [see Clinical Pharmacology 12.3)]. Usage of VRAYLAR is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). VRAYLAR has not been evaluated in this patient populatio

8.7 Renal Impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate (CrCL = 30 mL/minute) renal impairment [see Clinical Pharmacology 12.3)]. Usage of VRAYLAR is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). VRAYLAR has not been evaluated in this patient population.

8.8 Smoking No dosage adjustment for VRAYLAR is needed for patients who smoke. VRAYLAR is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of VRAYLAR.

8.9 Other Specific Populations No dosage adjustment is required based on patient’s age, sex, or race. These factors do not affect the pharmacokinetics of VRAYLAR [see Clinical Pharmacology 12.3)]. 9.

DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance VRAYLAR is not a controlled substance. 9.2 Abuse VRAYLAR has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance. 9.3 Dependence VRAYLAR has not been systematically studied in animals or humans for its potential for physical dependence.

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 upto-date guidance and adv