CARIPRAZINE- cariprazine_capsule

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 D 2 1A 2A in vitro Cariprazine acts as a partial agonist at the dopamine D 3 2 i 2L 2S 1A i 2B 2A i 1 i 2C 1A i 50 Effect on QTc Interval At a dose three-times the maximum recommended dose, cariprazine does not prolong the QTc interval to clinically relevant extent. Cariprazine 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 cariprazine, 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 days to 4 days for cariprazine, about 1 day to 2 days for DCAR and approximately 1 week 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. 6 After discontinuation of cariprazine capsules, 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 cariprazine, 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/day a a SE: standard error; TOTAL CAR: sum concentration of cariprazine, DCAR and DDCAR; CAR: cariprazine Absorption After single dose administration of cariprazine, the peak plasma cariprazine concentration occurred in approximately 3 hours to 6 hours. Administration of a single dose of 1. 5 mg cariprazine capsule with a high-fat meal did not significantly affect the C max 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, exposure (C max [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 in vitro Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), or 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 in vitro Based on in vitro In vivo studies CYP3A4 inhibitors Co-administration of ketoconazole (400 mg/day), a strong CYP3A4 inhibitor, with cariprazine (0. 5 mg/day) increased cariprazine C max 0-24h max 0-24h max 0-24h 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. Proton pump inhibitors Co-administration of pantoprazole (40 mg/day), a proton pump inhibitor, with cariprazine (6 mg/day) in patients with schizophrenia for 15 days did not affect cariprazine exposure at steady-state, based on C max 0-24 Image.

Cariprazine capsules are indicated for the: Treatment of schizophrenia in adults [see Clinical Studies ( 14. 1 Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults [see Clinical Studies ( 14. 2 Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults [see Clinical Studies ( 14. 3 Cariprazine is an atypical antipsychotic indicated for the: Treatment of schizophrenia in adults ( 1 Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults ( 1 Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults ( 1.

Administer cariprazine once daily with or without food ( 2 Starting Dose Recommended Dose Schizophrenia ( 2. 5 mg daily 1. 5 mg to 6 mg daily Bipolar Mania ( 2. 5 mg daily 3 mg to 6 mg daily Bipolar Depression ( 2. 5 mg or 3 mg daily Schizophrenia and Bipolar Mania: Dosages above 6 mg daily do not confer significant benefit but increase the risk of dose-related adverse reactions ( 2. 3 Bipolar Depression: The maximum recommended daily dosage is 3 mg ( 2. 4 Cariprazine 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 cariprazine and after each dosage change [see Warnings and Precautions ( 5. 3 The recommended dosage range is 1. 5 mg to 6 mg once daily. The starting dosage of cariprazine is 1. 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 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 The recommended dosage range is 3 mg to 6 mg once daily. The starting dose of cariprazine is 1. 5 mg and should be increased to 3 mg on Day 2. 2 The starting dose of cariprazine is 1. 5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. Maximum recommended dosage is 3 mg once daily. CYP3A4 is responsible for the formation and elimination of the major active metabolites of cariprazine. Dosage recommendation for patients initiating a strong CYP3A4 inhibitor while on a stable dose of cariprazine [see Drug Interactions ( 7. 1 Dosage recommendation for patients initiating cariprazine therapy while already on a strong CYP3A4 inhibitor: [see Drug Interactions ( 7. 1 Dosage recommendation for patients concomitantly taking cariprazine with CYP3A4 inducers: [see Dosage and Administration ( 2. 3 Following discontinuation of cariprazine, the decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients' clinical symptoms; the plasma concentration of cariprazine and its active metabolites will decline by 50% in ~1 week [see Clinical Pharmacology ( 12.

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 5. 1 Suicidal Thoughts and Behaviors [see Boxed Warning 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 (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 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 cariprazine consisting of 4,753 adult patients exposed to one or more doses of cariprazine for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 940. 3 patient-years. A total of 2,568 cariprazine-treated patients had at least 6 weeks and 296 cariprazine-treated patients had at least 48 weeks of exposure. Patients with Schizophrenia The following findings are based on four placebo-controlled, 6-week schizophrenia trials with cariprazine doses ranging from 1. 5 mg to 12 mg once daily. The maximum recommended dosage is 6 mg daily. Adverse Reactions Associated with Discontinuation of Treatment Common Adverse Reactions (>= 5% and at least twice the rate of placebo) Adverse Reactions with an incidence of >= 2% and greater than placebo, at any dose are shown in Table 5. Table 5 Adverse Reactions Occurring in >= 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials Note: Figures rounded to the nearest integer * a Tachycardia terms b Abdominal pain terms c Diarrhea terms d Fatigue terms e Hepatic enzyme increase terms f Extrapyramidal Symptoms terms g Headache terms h Somnolence terms i Insomnia terms j Hypertension terms circle System Organ Class / Preferred Term Placebo (N= 584) (%) Cariprazine * 1. 5 mg/day to 3 mg/day (N=539) (%) 4. 5 mg/day to 6 mg/day (N=575) (%) 9 mg/day to 12 mg/day circle (%) Cardiac Disorders 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 tract infection 1 1 < 1 2 Investigations Blood creatine phosphokinase increased 1 1 2 3 Hepatic enzyme increased e < 1 1 1 2 Weight increased 1 3 2 3 Metabolism and nutrition disorders Decreased appetite 2 1 3 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 1 2 1 2 Back pain 2 3 3 1 Pain in extremity 3 2 2 4 Nervous System Disorders Akathisia 4 9 13 14 Extrapyramidal Symptoms f 8 15 19 20 Headache g 13 9 11 18 Somnolence h 5 5 8 10 Dizziness 2 3 5 5 Psychiatric Disorders Agitation 4 3 5 3 Insomnia i 11 12 13 11 Restlessness 3 4 6 5 Anxiety 4 6 5 3 Respiratory, thoracic and mediastinal disorders Cough 2 1 2 4 Skin and subcutaneous disorders Rash 1 < 1 1 2 Vascular Disorders Hypertension j 1 2 3 6 Patients with Bipolar Mania The following findings are based on three placebo-controlled, 3-week bipolar mania trials with cariprazine doses ranging from 3 mg to 12 mg once daily. Adverse Reactions Associated with Discontinuation of Treatment Common Adverse Reactions (>= 5% and at least twice the rate of placebo) Adverse Reactions with an incidence of >= 2% and greater than placebo at any dose are shown in Table 6. Table 6 Adverse Reactions Occurring in >= 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials Note: Figures rounded to the nearest integer * a Tachycardia terms: b Abdominal pain terms: c Diarrhea: d Fatigue terms: e Pyrexia terms: f Hepatic enzymes increased terms: g Extrapyramidal Symptoms terms: h Headache terms: i Somnolence terms: j Insomnia terms: k Hypertension terms: ⸰ The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. System Organ Class / Preferred Term Placebo (N= 442) (%) Cariprazine * 3 mg/day to 6 mg/day (N=263) (%) 9 mg/day to 12 mg/day circle (%) Cardiac Disorders Tachycardia a 1 2 1 Eye Disorders Vision blurred 1 4 4 Gastrointestinal Disorders Nausea 7 13 11 Constipation 5 6 11 Vomiting 4 10 8 Dry mouth 2 3 2 Dyspepsia 4 7 9 Abdominal pain b 5 6 8 Diarrhea c 5 5 6 Toothache 2 4 3 General Disorders/Administration Site Conditions Fatigue d 2 4 5 Pyrexia e 2 1 4 Investigations Blood creatine phosphokinase increased 2 2 3 Hepatic enzymes increased f < 1 1 3 Weight increased 2 2 3 Metabolism and Nutrition Disorders Decreased appetite 3 3 4 Musculoskeletal and Connective Tissue Disorders Pain in extremity 2 4 2 Back pain 1 1 3 Nervous System Disorders Akathisia 5 20 21 Extrapyramidal Symptoms g 12 26 29 Headache h 13 14 13 Dizziness 4 7 6 Somnolence i 4 7 8 Psychiatric Disorders Insomnia j 7 9 8 Restlessness 2 7 7 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 2 1 3 Vascular Disorders Hypertension k 1 5 4 Patients with Bipolar Depression The following findings are based on three placebo-controlled, two 6-week and one 8-week bipolar depression trials with cariprazine doses of 1. 5 mg and 3 mg once daily. Adverse Reactions Associated with Discontinuation of Treatment C ommon Adverse Reactions (>= 5% and at least twice the rate of placebo) Adverse Reactions with an incidence of >= 2% and greater than placebo at 1. 5 mg or 3 mg doses are shown in Table 7. Table 7 Adverse Reactions Occurring in >= 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in two 6-week trials and one 8-week trial a Extrapyramidal symptoms terms: b Somnolence terms: c Fatigue terms: d Insomnia terms: Placebo (N=468) (%) Cariprazine 1. 5 mg/day (N=470) (%) 3 mg/day (N=469) (%) Restlessness 3 2 7 Akathisia 2 6 10 Extrapyramidal symptoms a 2 4 6 Dizziness 2 4 3 Somnolence b 4 7 6 Nausea 3 7 7 Increased appetite 1 3 3 Weight increase < 1 2 2 Fatigue c 2 4 3 Insomnia d 7 7 10 Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Extrapyramidal Symptoms (EPS) and Akathisia In schizophrenia, bipolar mania and bipolar depression trials, data were objectively collected using the Simpson Angus Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score <= 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Rating Scale (BARS) for treatment-emergent akathisia (BARS total score <= 2 at baseline and > 2 post-baseline). In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for cariprazine-treated patients versus 8% for placebo-treated patients. These events led to discontinuation in 0. 3% of cariprazine-treated patients versus 0. 2% of placebo-treated patients. The incidence of akathisia was 11% for cariprazine-treated patients versus 4% for placebo-treated patients. 5% of cariprazine-treated patients versus 0. The incidence of EPS is shown in Table 8. Table 8 Incidence of EPS Compared to Placebo in 6-Week Schizophrenia Studies Note: Figures rounded to the nearest integer * ** Dystonia includes adverse event terms: section Parkinsonism includes adverse event terms: circle Adverse Event Term Placebo (N= 584) (%) Cariprazine * 1. 5 mg/day to 6 mg/day (N=575) (%) 9 mg/day to 12 mg/day circle (N=203) (%) All EPS events 14 24 32 33 All EPS events, excluding Akathisia/Restlessness 8 15 19 20 Akathisia 4 9 13 14 Dystonia ** < 1 2 2 2 Parkinsonism section 7 13 16 18 Restlessness 3 4 6 5 Musculoskeletal stiffness 1 1 3 1 In 3-week bipolar mania trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for cariprazine-treated patients versus 12% for placebo-treated patients. These events led to a discontinuation in 1% of cariprazine-treated patients versus 0. The incidence of akathisia was 20% for cariprazine-treated patients versus 5% for placebo-treated patients. These events led to discontinuation in 2% of cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of EPS is provided in Table 9. Table 9 Incidence of EPS Compared to Placebo in 3-Week Bipolar Mania Trials Note: Figures rounded to the nearest integer * ** Dystonia includes adverse event terms: section Parkinsonism includes adverse event terms: circle Adverse Event Term Placebo (N= 442) (%) Cariprazine * 3 mg/day to 6 mg/day (N=263) (%) 9 mg/day to 12 mg/day circle (%) All EPS events 18 41 45 All EPS events, excluding Akathisia/Restlessness 12 26 29 Akathisia 5 20 21 Dystonia ** 1 5 3 Parkinsonism section 10 21 26 Restlessness 2 7 7 Musculoskeletal stiffness 1 2 2 In the two 6-week and one 8-week bipolar depression trials, the incidence of reported events related to EPS, excluding akathisia and restlessness was 4% for cariprazine-treated patients versus 2% for placebo-treated patients. 4% of cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of akathisia was 8% for cariprazine-treated patients versus 2% for placebo-treated patients. These events led to discontinuation in 1. 5% of cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of EPS is shown in Table 10. Table 10 Incidence of EPS Compared to Placebo in two 6-Week and one 8-Week Bipolar Depression Trials Note: Figures rounded to the nearest integer * Dystonia includes adverse event terms: section Parkinsonism includes adverse event terms: Adverse Event Term Placebo (N=468) (%) Cariprazine * 1. 5 mg/day (N=470) (%) 3 mg/day (N=469) (%) All EPS events 7 10 19 All EPS events, excluding Akathisia/Restlessness 2 4 6 Akathisia 2 6 10 Dystonia * < 1 < 1 < 1 Parkinsonism section 2 3 4 Restlessness 3 2 7 Musculoskeletal stiffness < 1 < 1 1 Tardive Dyskinesia 0 0 < 1 Cataracts In the long-term uncontrolled schizophrenia (48-week) and bipolar mania (16-week) trials, the incidence of cataracts was 0. 2%, respectively. The development of cataracts was observed in nonclinical studies [see Nonclinical Toxicology ( 13. 2 Vital Signs Changes There were no clinically meaningful differences between cariprazine-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 mg/day to 12 mg/day cariprazine-treated patients with schizophrenia. Pooled data from 6-week schizophrenia trials are shown in Table 11 and from 3-week bipolar mania trials are shown in Table 12. Table 11 Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials * circle Placebo (N=574) Cariprazine * 1. 5 mg/day to 3 mg/day (N=512) 4. 5 mg/day to 6 mg/day (N=570) 9 mg/day to 12 mg/day circle Supine Systolic Blood Pressure (mmHg) +0. 1 Supine Diastolic Blood Pressure (mmHg) +0. 4 Table 12 Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials * circle Placebo (N=439) Cariprazine * 3 mg/day to 6 mg/day (N=259) 9 mg/day to 12 mg/day circle (N=360) Supine Systolic Blood Pressure (mmHg) -0. 8 Supine Diastolic Blood Pressure (mmHg) +0. 9 In the two 6-week and one 8-week bipolar depression trials, there were no clinically meaningful differences between cariprazine-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine systolic and diastolic blood pressure. Pooled data from two 6-week and one 8-week bipolar depression trials are shown in Table 13. Table 13 Mean Change in Blood Pressure at Endpoint in two 6-Week and one 8-Week Bipolar Depression Trials Placebo (N=468) Cariprazine * 1. 5 mg/day (N=572) 3 mg/day (N=426) Supine Systolic Blood Pressure (mmHg) -0. 1 Supine Diastolic Blood Pressure (mmHg) 0. 3 Changes in Laboratory Tests The proportions of patients with transaminase elevations of >= 3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for cariprazine-treated patients, increasing with dose and was 1% for placebo-treated patients. The proportions of patients with transaminase elevations of >= 3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for cariprazine-treated patients depending on dose group administered and 2% for placebo-treated patients. The proportions of patients with transaminase elevations of >= 3 times the upper limits of the normal reference range in 6-week and 8-week bipolar depression trials ranged between 0% and 0. 5% for cariprazine-treated patients depending on dose group administered and 0. 4% for placebo-treated patients. The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1,000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for cariprazine-treated patients, increasing with dose and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1,000 U/L in 3-week bipolar mania trials was about 4% in cariprazine and placebo-treated patients. The proportions of patients with elevations of CPK greater than 1,000 U/L in 6-week and 8-week bipolar depression trials ranged between 0. 2% and 1% for cariprazine-treated patients versus 0. 2% for placebo-treated patients. Other Adverse Reactions Observed During the Pre-marketing Evaluation of Cariprazine Adverse reactions listed below were reported by patients treated with cariprazine at doses of >= 1. 5 mg once daily within the premarketing database of 3,988 cariprazine-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the cariprazine label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency, according to the following definition: those occurring in at least 1/100 patients (frequent) [only those not already listed in the tabulated results from placebo-controlled studies appear in this listing]; those occurring in 1/100 to 1/1,000 patients (infrequent); and those occurring in fewer than 1/1,000 patients (rare). Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis Hepatobiliary Disorders: Rare: hepatitis Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyponatremia Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Rare: ischemic stroke Psychiatric Disorders: Infrequent: suicide attempts, suicide ideation; Rare: completed suicide Renal and Urinary Disorders: Infrequent: pollakiuria Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis The following adverse reaction has been identified during post approval use of cariprazine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders.

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

Pregnancy: 8. 1 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cariprazine 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) [see Clinical Pharmacology ( 12. 3 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. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 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 mg/kg/day, 2. 5 mg/kg/day and 7. 5 mg/kg/day which are 0. 5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total cariprazine (i. 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. 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 mg/kg/day, 0. 3 mg/kg/day and 1 mg/kg/day which are 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 those of the first generation pups. Administration of cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0. 1 mg/kg/day, 1 mg/kg/day and 5 mg/kg/day, which are 0. 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. 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 cariprazine and any potential adverse effects on the breastfed infant from cariprazine or from the underlying maternal condition. Safety and effectiveness in pediatric patients have not been established. Pediatric studies of cariprazine have not been conducted. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning 5. 2 Clinical trials of cariprazine 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 cariprazine are at an increased risk of death compared to placebo. Cariprazine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning 5. 3 No dosage adjustment for cariprazine is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9) [see Clinical Pharmacology ( 12. 3 No dosage adjustment for cariprazine is required in patients with mild to moderate (CrCL >= 30 mL/minute) renal impairment [see Clinical Pharmacology ( 12. 3 Usage of cariprazine is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). Cariprazine has not been evaluated in this patient population. No dosage adjustment for cariprazine is needed for patients who smoke. Cariprazine is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of cariprazine. No dosage adjustment is required based on patient's age, sex, or race. These factors do not affect the pharmacokinetics of cariprazine [see Clinical Pharmacology ( 12.

RECENT MAJOR CHANGES
Boxed Warning 5/2019 Indications and Usage ( 1 5/2019 Dosage and Administration ( 2.4 5/2019 Warnings and Precautions ( 5.2 5.7 5/2019
DRUG INTERACTIONS
Strong CYP3A4 inhibitors: Reduce cariprazine dosage by half ( 2. 1 CYP3A4 inducers: Concomitant use is not recommended ( 2. 1 Table 14 Clinically Important Drug Interactions with Cariprazine Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of cariprazine with a strong CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of cariprazine alone [see Clinical Pharmacology ( 12. 3 Intervention: If cariprazine is used with a strong CYP3A4 inhibitor, reduce cariprazine dosage [see Dosage and Administration ( 2. 5 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 cariprazine has not been evaluated and the net effect is unclear [see Clinical Pharmacology ( 12. 3 Intervention: Concomitant use of cariprazine with a CYP3A4 inducer is not recommended [see Dosage and Administration ( 2. 5 Examples: rifampin, carbamazepine.

OVERDOSAGE
In pre-marketing clinical trials involving cariprazine in approximately 5,000 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. No specific antidotes for cariprazine 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis There was no increase in the incidence of tumors following daily oral administration of cariprazine to rats for 2 years and to Tg. rasH2 mice for 6 months at doses which are up to 4 and 19 times respectively, the MRHD of 6 mg/day based on AUC of total cariprazine, (i. sum of AUC values of cariprazine, DCAR and DDCAR). Rats were administered cariprazine at oral doses of 0. 5 (males)/1, 2. 5 mg/kg/day (females) which are 0. 8 (males)/ 0. 1 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. rasH2 mice were administered cariprazine at oral doses of 1, 5 and 15 (males)/5, 15 and 50 mg/kg/day (females) which are 0. 9 (males)/2. 6 to 19 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. Mutagenesis Cariprazine was not mutagenic in the in vitro in vitro in vivo in vitro in vitro in vitro Impairment of Fertility Cariprazine was administered orally to male and female rats before mating, through mating and up to day 7 of gestation at doses of 1 mg/kg/day, 3 mg/kg/day and 10 mg/kg/day which are 1. 6 to 16 times the MRHD of 6 mg/day based on mg/m 2 2 Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following oral daily administration for 13 weeks and/or 1 year and retinal degeneration/atrophy in the rat following oral daily administration for 2 years. Cataract in the dog was observed at 4 mg/kg/day which is 7. 1 (male) and 7. 7 (female) times the MRHD of 6 mg/day based on AUC of total cariprazine. The NOEL for cataract and retinal toxicity in the dog is 2 mg/kg/day which is 5 (males) to 3. 6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. Increased incidence and severity of retinal degeneration/atrophy in the rat occurred at all doses tested, including the low dose of 0. 75 mg/kg/day, at total cariprazine plasma levels less than clinical exposure (AUC) at the MRHD of 6 mg/day. Cataract was not observed in other repeat dose studies in pigmented mice or albino rats. Phospholipidosis was observed in the lungs of rats, dogs and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures (AUC) of total cariprazine. Phospholipidosis was not reversible at the end of the 1 month to 2 month drug-free periods. Inflammation was observed in the lungs of dogs dosed daily for 1 year with a NOEL of 1 mg/kg/day which is 2. 7 (males) and 1. 7 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine. No inflammation was observed at the end of 2-month drug free period following administration of 2 mg/kg/day which is 5 (males) and 3. 6 (females) times the MRHD of 6 mg/day based on AUC of total cariprazine; however, inflammation was still present at higher doses. Hypertrophy of the adrenal gland cortex was observed at clinically relevant total cariprazine plasma concentrations in rats (females only) and mice following daily oral administration of cariprazine for 2 years and 6 months, respectively. Reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed following daily oral administration of cariprazine to dogs for 1 year. The NOEL was 2 mg/kg/day which is 5 (males) and 3. The relevance of these findings to human risk is unknown.
CLINICAL STUDIES
The efficacy of cariprazine for the treatment of schizophrenia was established in three, 6-week, randomized, double-blind, placebo-controlled trials in patients (aged 18 years to 60 years) who met Diagnostic and Statistical Manual of Mental Disorders 4 th Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) rating scales were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items) and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). The PANSS total score may range from 30 to 210 with the higher score reflecting greater severity. The CGI-S is a validated clinician-related scale that measures the patient''s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was change from baseline in PANSS total score at the end of week 6. The change from baseline for cariprazine and active control groups was compared to placebo. The results of the trials are shown in Table 15. The time course of efficacy results of Study 2 is shown in Figure 2. Study 1: In a 6-week, placebo-controlled trial (N = 711) involving three fixed doses of cariprazine (1. 5 mg/day, 3 mg/day, or 4. 5 mg/day) and an active control (risperidone), all cariprazine doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 2: In a 6-week, placebo-controlled trial (N = 604) involving two fixed doses of cariprazine (3 mg/day or 6 mg/day) and an active control (aripiprazole), both cariprazine doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 3: In a 6-week, placebo-controlled trial (N = 439) involving two flexible-dose range groups of cariprazine (3 mg/day to 6 mg/day or 6 mg/day to 9 mg/day), both cariprazine groups were superior to placebo on the PANSS total score and the CGI-S. The efficacy of cariprazine was demonstrated at doses ranging from 1. 5 mg/day to 9 mg/day compared to placebo. There was, however, a dose-related increase in certain adverse reactions, particularly above 6 mg. Therefore, the maximum recommended dose is 6 mg/day. Examination of population subgroups based on age (there were few patients over 55), sex and race did not suggest any clear evidence of differential responsiveness. Table 15 Primary Analysis Results from Schizophrenia Trials ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval a * b Study Number Treatment Group (# ITT patients) Primary Efficacy Endpoint: PANSS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a Study 1 Cariprazine * 97. 6 Cariprazine * 97. 8 Cariprazine * 96. 4 Placebo 97. 5) -- Study 2 Cariprazine * 96. 5) -6 Cariprazine * 95. 8 Placebo 96. 5) -- Study 3 Cariprazine * 96. 8 Cariprazine *b 96. 3) Placebo 96. 6) -- Figure 2 Change from Baseline in PANSS total score by weekly visits (Study 2) The safety and efficacy of cariprazine as maintenance treatment in adults with schizophrenia were demonstrated in a randomized withdrawal trial that included 200 patients meeting DSM-IV criteria for schizophrenia who were clinically stable following 20 weeks of open-label cariprazine at doses of 3 mg/day to 9 mg/day. Patients were randomized to receive either placebo or cariprazine at the same dose for up to 72 weeks for observation of relapse. The primary endpoint was time to relapse. Relapse during the double-blind phase (DBP) was defined as meeting any one of the following criteria: hospitalization due to worsening of schizophrenia, increase in the PANSS total score by >= 30%, increase in CGI-S score by >= 2 points, deliberate self-injury, aggressive or violent behavior, clinically significant suicidal or homicidal ideation, or score > 4 on one or more of the following PANSS items: delusions (P1), conceptual disorganization (P2), hallucination (P3), suspiciousness or persecution (P6), hostility (P7), uncooperativeness (G8), or poor impulse control (G14). The efficacy of cariprazine was demonstrated at doses ranging from 3 mg/day to 9 mg/day compared to placebo. The Kaplan-Meier curves of the time to relapse during the double-blind, placebo-controlled, randomized withdrawal phase of the long-term trial are shown in Figure 3. Time to relapse was statistically significantly longer in the cariprazine-treated group compared to the placebo group. Figure 3 Kaplan-Meier Curves of Cumulative Rate of Relapse During the Double-Blind Treatment Period DB = double-blind * The efficacy of cariprazine in the acute treatment of bipolar mania was established in three, 3-week placebo-controlled trials in patients (mean age of 39 years, range 18 years to 65 years) who met DSM-IV-TR criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features. In all three trials, cariprazine was superior to placebo. Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity scale (CGI-S) were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: The YMRS is an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology. YMRS total score may range from 0 to 60 with a higher score reflecting greater severity. The CGI-S is validated clinician-related scale that measures the patient''s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was decrease from baseline in YMRS total score at the end of week 3. The change from baseline for each cariprazine dose group was compared to placebo. The results of the trials are shown in Table 16. The time course of efficacy results is shown in Figure 4. Study 4: In a 3-week, placebo-controlled trial (N = 492) involving two flexible-dose range groups of cariprazine (3 mg/day to 6 mg/day or 6 mg/day to 12 mg/day), both cariprazine dose groups were superior to placebo on the YMRS total score and the CGI-S. The 6 mg/day to 12 mg/day dose group showed no additional advantage. Study 5: In a 3-week, placebo-controlled trial (N = 235) involving a flexible-dose range of cariprazine (3 mg/day to 12 mg/day), cariprazine was superior to placebo on the YMRS total score and the CGI-S. Study 6: In a 3-week, placebo-controlled trial (N = 310) involving a flexible-dose range of cariprazine (3 mg/day to 12 mg/day), cariprazine was superior to placebo on the YMRS total score and the CGI-S. The efficacy of cariprazine was established at doses ranging from 3 mg/day to 12 mg/day. Doses above 6 mg did not appear to have additional benefit over lower doses (Table 16) and there was a dose-related increase in certain adverse reactions. Table 16 Primary Analysis Results from Manic or Mixed Episodes Associated with Bipolar I Disorder Trials ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval a * b Study Number Treatment Group (# ITT patients) Primary Efficacy Endpoint: YMRS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a Study 4 Cariprazine * 33. 1 Cariprazine *b 32. 9 Placebo 32. 8) -- Study 5 Cariprazine *b 30. 6 (5) -15 (1. 1 Placebo 30. 1) -- Study 6 Cariprazine *b 32. 3 Placebo 32. 9) -- Figure 4 Change from Baseline in YMRS total score by study visit (Study 4) * The efficacy of cariprazine in the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) was established in one 8-week and two 6-week placebo-controlled trials in patients (mean age of 41. 6 years, range 18 to 65 years) who met DSM-IV-TR or DSM-5 criteria for depressive episodes associated with bipolar I disorder. In each study, the primary endpoint was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of Week 6. The MADRS is a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The MADRS total score change from baseline for cariprazine compared to placebo is shown in Table 17. The time course of efficacy results of Study 8 is shown in Figure 5. In each study, the cariprazine 1. 5 mg dose demonstrated statistical significance over placebo. The secondary endpoint was change from baseline to Week 6 in CGIS. Study 7: In an 8-week, placebo-controlled trial (N = 571) involving three-fixed doses of cariprazine (0. 75 mg/day, 1. 5 mg/day and 3 mg/day), cariprazine 1. 5 mg was superior to placebo at end of Week 6 on the MADRS total score and the CGI-S. Study 8: In a 6-week, placebo-controlled trial (N = 474) involving two-fixed doses of cariprazine (1. 5 mg and 3 mg were superior to placebo at end of Week 6 on the MADRS total score. Study 9: In a 6-week, placebo-controlled trial (N = 478) involving two-fixed doses of cariprazine (1. Table 17 Primary Analysis Results from Bipolar Depression Trials ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval a * Study Number Treatment Group (# ITT patients) Primary Efficacy Endpoint: MADRS Total Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a Study 7 Cariprazine * 30. 8) -4 Cariprazine 30. 5 Placebo 30. 9) Study 8 Cariprazine * 30. 5 Cariprazine * 31 (4. 8) -3 Placebo 30. 8) Study 9 Cariprazine * 31. 5 Cariprazine 31. 8 Placebo 31. 8) Figure 5 LS Mean Change from Baseline in MADRS Total Score by Visits (Study 8) LS Mean: least-squares mean Image Image Image Image.

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