DRUG INTERACTIONS

• Strong CYP3A4 inhibitors: reduce VRAYLAR dosage by half 

• CYP3A4 inducers: do not recommend use with VRAYLAR 

ADVERSE REACTIONS

-­ Most common adverse reactions (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

WARNINGS AND PRECAUTIONS

­ • Cerebrovascular Adverse Reactions in Elderly Patients with DementiaRelated 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 halflife, monitor for adverse reactions and patient response for several weeks after starting VRAYLAR and with each dosage change 

• Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain ( 

• Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5

 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 

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 

Tardive Dyskinesia-                                                                                                Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur 

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  gain

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 

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 

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 

Heat Exposure and Dehydration -                                                                            Educate patients regarding appropriate care in avoiding overheating and dehydration [se

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  

Pregnancy-                                                                                                                    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 

Pregnancy Registry-                                                                                                 Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy 

Licensed from Gedeon Richter Plc. Manufactured by: Forest Laboratories Ireland Limited Dublin, IE. Distributed by: Allergan USA, Inc. Irvine, CA 92612 VRAYLAR® and it’s designs are trademarks of Forest Laboratories, LLC., an Allergan affiliate. 

. CLINICAL PHARMACOLOGY

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.

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).

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-                                                                                                         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 

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 

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.                                                                                                      

 USE IN SPECIFIC POPULATIONS

1. Pregnancy -                                                                                                           Pregnancy Exposure Registry-                                                                                There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy.

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

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

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.

3.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 

4.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 [s

5.Hepatic Impairment-                                                                                                    No dosage adjustment for VRAYLAR is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9) 

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 population.

6. Renal Impairment-                                                                                                       No dosage adjustment for VRAYLAR is required in patients with mild to moderate (CrCL = 30 mL/minute) renal impairment 

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.

7. 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.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 

9. DRUG ABUSE AND DEPENDENCE                                                                           .1 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 

 In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for upto-date guidance and advice.