Vraylar Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................. 2

TABLE OF CONTENTS ............................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................................... 4

1 INDICATIONS ................................................................................................................ 4

1.1 Pediatrics ................................................................................................................. 4

1.2 Geriatrics ................................................................................................................. 4

2 CONTRAINDICATIONS .................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................. 5

4 DOSAGE AND ADMINISTRATION .................................................................................. 5

4.1 Dosing Considerations ............................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ........................................................ 6

4.4 Administration ......................................................................................................... 8

4.5 Missed Dose ............................................................................................................ 8

5 OVERDOSAGE ............................................................................................................... 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .................................. 8

7 WARNINGS AND PRECAUTIONS ................................................................................... 9

7.1 Special Populations................................................................................................ 16

7.1.1 Pregnant Women ................................................................................................... 16

7.1.2 Breastfeeding ......................................................................................................... 17

7.1.3 Pediatrics ................................................................................................................ 17

7.1.4 Geriatrics ................................................................................................................ 17

8 ADVERSE REACTIONS ................................................................................................. 17

8.1 Adverse Reaction Overview ................................................................................... 17

8.2 Clinical Trial Adverse Reactions ............................................................................. 18

8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 28

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 29

8.5 Post-Market Adverse Reactions ............................................................................ 29

9 DRUG INTERACTIONS ................................................................................................. 30

9.1 Serious Drug Interactions ...................................................................................... 30

9.2 Drug Interactions Overview ................................................................................... 30

9.3 Drug-Behavioural Interactions ............................................................................... 30

9.4 Drug-Drug Interactions .......................................................................................... 31

9.5 Drug-Food Interactions .......................................................................................... 32

9.6 Drug-Herb Interactions .......................................................................................... 33

9.7 Drug-Laboratory Test Interactions ......................................................................... 33

10 CLINICAL PHARMACOLOGY ........................................................................................ 33

10.1 Mechanism of Action ....................................................................................... 33

10.2 Pharmacodynamics ......................................................................................... 33

10.3 Pharmacokinetics ............................................................................................ 34

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 37

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 37

PART II: SCIENTIFIC INFORMATION ........................................................................................ 38

13 PHARMACEUTICAL INFORMATION ............................................................................. 38

14 CLINICAL TRIALS ......................................................................................................... 39

14.1 Clinical Trials by Indication .............................................................................. 39

Schizophrenia .................................................................................................................. 39

Bipolar Mania .................................................................................................................. 44

Bipolar Depression .......................................................................................................... 46

15 MICROBIOLOGY ......................................................................................................... 48

16 NON-CLINICAL TOXICOLOGY ...................................................................................... 48

PATIENT MEDICATION INFORMATION ................................................................................... 52

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Schizophrenia

VRAYLAR (cariprazine) is indicated for:

• the treatment of schizophrenia in adults.

In controlled clinical trials, VRAYLAR was found to improve both positive and negative symptoms.

Bipolar I disorder

VRAYLAR is indicated as monotherapy for:

• Bipolar Mania: acute management of manic or mixed episodes associated with bipolar I disorder in adults, and
• Bipolar Depression: acute management of depressive episodes associated with bipolar I disorder in adults.

The efficacy of VRAYLAR for long-term use has not been systematically evaluated in controlled studies for bipolar mania and depression (See 14 CLINICAL TRIALS). The physician who elects to use VRAYLAR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics: VRAYLAR is not indicated in elderly patients with dementia. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX. The safety and efficacy of VRAYLAR have not been systematically evaluated in patients 65 years of age or older. Caution should be used when treating geriatric patients. See 7.1.4 Geriatrics and 10.3 Pharmacokinetics.

2 CONTRAINDICATIONS

VRAYLAR is contraindicated:

• in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• With concomitant use of strong and moderate CYP3A4 inhibitors. See 9.4 Drug-Drug Interactions and 9.5 Drug-Food Interactions. Due to the slow elimination of cariprazine and its metabolites, treatment with strong and moderate CYP3A4 inhibitors must be initiated at least 2 weeks after VRAYLAR discontinuation.
• With concomitant use of strong and moderate CYP3A4 inducers. See 9.4 Drug-Drug Interactions and 9.6 Drug-Herb Interactions.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

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 7 WARNINGS AND PRECAUTIONS and 10.3 Pharmacokinetics.

Prior to initiating treatment with VRAYLAR, the following assessments should be done to guide patient selection and treatment.

Cardiac effects:

• Patients with pre-existing hypertension and other cardiovascular disease should be treated and stabilized before starting therapy with VRAYLAR. Blood pressure should be monitored. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular.

Hematologic effects:

• Complete blood count (CBC) should be tested in patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia. See 7 WARNINGS AND PRECAUTIONS, Hematologic.

Endocrine and metabolic effects:

• Baseline blood glucose, lipid profile and weight should be measured. See 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism.

Hepatic effects:

• Transaminase and total bilirubin should be measured in patients with known or suspected abnormal hepatic function. See 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; 8.2 Clinical Trial Adverse Reactions; 8.3 Less Common Clinical Trial Adverse Reactions; 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data.

Ophthalmologic effects:

• Patients should undergo ophthalmologic examination prior to or shortly after initiating treatment with VRAYLAR. See 7 WARNINGS AND PRECAUTIONS, Ophthalmologic.

Women of childbearing potential:

• Women of childbearing potential must be advised to use highly effective contraceptive methods to avoid pregnancy while treated with VRAYLAR and for at least 12 weeks following treatment discontinuation. See 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential and 7.1.1 Pregnant Women.

4.2 Recommended Dose and Dosage Adjustment

• Schizophrenia

The starting dosage of VRAYLAR is 1.5 mg daily. The recommended target dosage for VRAYLAR is 1.5 mg to 6 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased gradually in 1.5 mg increments. The maximum recommended dosage is 6 mg daily. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability. Periodically reassess to determine the continued need and appropriate dosage for treatment.

In short-term controlled clinical trials, dosages above 6 mg/day did not confer increased efficacy to outweigh the dose-related treatment emergent adverse events.

• Bipolar Mania (manic or mixed episodes associated with bipolar I disorder)

The recommended dosage range is 1.5 mg to 6 mg once daily. The starting dose of VRAYLAR is 1.5 mg and can be increased thereafter by 1.5 mg increments, based on clinical response and tolerability. The lowest effective dose should be used. The maximum recommended dosage is 6 mg daily.

• Bipolar Depression (depressive episodes associated with bipolar I disorder)

The recommended dose of VRAYLAR 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. The lowest effective dose should be used. Maximum recommended dosage is 3 mg once daily.

See also 4.2 Recommended Dose and Dosage Adjustment, Special Populations.

• Special Populations
• Pediatrics (< 18 years of age):

No data are available to Health Canada: therefore, Health Canada has not authorized an indication for pediatric use.

• Geriatrics (> 65 years of age):

VRAYLAR is not indicated in elderly patients with dementia. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and 7.1.4 Geriatrics.

The safety and efficacy of VRAYLAR in patients 65 years of age or older has not been established. 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 (see 10.3 Pharmacokinetics).

• Patients with Hepatic Impairment:

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

VRAYLAR should be used with caution in patients with moderate hepatic impairment.

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. See 10.3 Pharmacokinetics.

• Patients with Renal Impairment:

No dosage adjustment for VRAYLAR is required in patients with mild to moderate renal impairment (CrCL ≥ 30 mL/minute). 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.

• Concomitant use of CYP3A4 Inhibitors and Inducers:

CYP3A4 is responsible for the formation and elimination of the major active metabolites of cariprazine.

Concomitant use with strong and moderate CYP3A4 inhibitors and strong and moderate CYP3A4 inducers is contraindicated. See 2 CONTRAINDICATIONS; 9.4 Drug-Drug Interactions; 9.5 Drug-Food Interactions; 9.6 Drug-Herb interactions.

Use VRAYLAR with caution in patients concomitantly taking weak CYP3A4 inhibitors (See 9.4 Drug-Drug Interactions).

• Other Specific Populations:

Dose adjustments are not necessary on the basis of race; however, use caution with doses higher than 4.5 mg in patients with low body weight (≤ 63 kg). See 10.3 Pharmacokinetics.

• Smoking:

No dosage adjustment for VRAYLAR is needed for patients who smoke. See 9.3 Drug-Behavioural Interactions.

• Treatment Discontinuation

There are no systematically collected data to specifically address switching patients from VRAYLAR to other antipsychotics, switching to VRAYLAR from another antipsychotic, or concerning concomitant administration with other antipsychotics.

When switching from another antipsychotic to VRAYLAR, gradual cross-titration should be considered, with gradual discontinuation of the previous treatment while VRAYLAR is initiated.

When switching to another antipsychotic from VRAYLAR, the new antipsychotic should be initiated at its lowest dose while cariprazine is discontinued. Following discontinuation of VRAYLAR, 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 10.3 Pharmacokinetics.

In all cases the period of overlapping antipsychotic administration should be minimized.

4.4 Administration

VRAYLAR is given orally once daily and can be taken with or without food (see 9.5 Drug-Food Interactions).

4.5 Missed Dose

If a patient misses a dose by a few hours, the patient should be advised to take their dose as soon as he/she remembers. If most of the day has passed, he/she should be advised to wait until the next scheduled dose. Patients should be advised to not take 2 doses of VRAYLAR at once.

5 OVERDOSAGE

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.

Management of Overdosage

No specific antidotes for VRAYLAR are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and continuous electrocardiogram monitoring. The possibility of multiple drug involvement should be considered.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 Dosage Forms, Strengths, Composition and Packaging

Each hard gelatin capsule contains a white to off-white powder of cariprazine HCl, which is equivalent to 1.5, 3, 4.5, or 6 mg of cariprazine base.

1.5 mg capsule: Size # “4” white opaque capsule with a black “FL 1.5” imprint on the body of the capsule with a rectified radial orientation.

3 mg capsule: Size # “4” white opaque body and green to blue green opaque cap with a black “FL 3” imprint on the body of the capsule with a rectified radial orientation.

4.5 mg capsule: Size # “4” green to blue-green opaque capsule with a white “FL 4.5” imprint on the body of the capsule with a rectified radial orientation.

6 mg capsule: Size # “3” capsule with a white opaque body and a purple opaque cap with a black “FL 6” imprint on the body of the capsule with a rectified radial orientation.

Packaging: VRAYLAR will be supplied in following configurations:

Bottles of 30 capsules: 1.5 mg, 3 mg, 4.5 mg and 6 mg

Physician’s Sample available as a blister of 7 capsules: 1.5 mg, 3 mg, 4.5 mg and 6 mg

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Body Temperature Regulation:

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing VRAYLAR for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

Falls:

Atypical antipsychotics, including VRAYLAR, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Late-Occurring Adverse Reactions:

Adverse events may first appear several weeks after the initiation of VRAYLAR treatment, likely because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. See 4.1 Dosing Considerations and 10.3 Pharmacokinetics.

Monitor for adverse reactions, including extrapyramidal symptoms (EPS) or akathisia, and patient response for several weeks after a patient has begun VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug.

Carcinogenesis and Mutagenesis

For animal data, see 16 NON-CLINICAL TOXICOLOGY.

Cardiovascular

Hypertension and Tachycardia:

Cariprazine can cause hypertension and tachycardia. See 8.2 Clinical Trial Adverse Reactions; 10.2 Pharmacodynamics, Cardiac Electrophysiology and Hemodynamics.

Blood pressure should be measured prior to initiating treatment and periodically throughout treatment with VRAYLAR. Pre-existing hypertension and other cardiovascular disease should be treated and stabilized before starting therapy with VRAYLAR.

Orthostatic Hypotension and Syncope:

Atypical antipsychotics can cause orthostatic hypotension and syncope. Symptoms associated with orthostatic hypotension can include dizziness, light-headedness and tachycardia. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of VRAYLAR and was not more frequent on VRAYLAR than placebo. Syncope was reported infrequently.

Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. VRAYLAR has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials.

ECG changes:

QT prolongation can develop in patients treated with antipsychotics.

With cariprazine, no QTc interval prolongation was detected compared to placebo-risperidone in a clinical trial designed to assess QT prolongation. See 10.2 Pharmacodynamics, Cardiac Electrophysiology and Hemodynamics.

In clinical trials, infrequent non-serious QT prolongations were reported with cariprazine.

Cariprazine should be used cautiously in patients with known cardiovascular disease or in patients with a family history of QT prolongation and in patients treated with medicinal products that might cause QT prolongation.

Dependence/Tolerance

VRAYLAR has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence.

While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of VRAYLAR misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Driving and Operating Machinery

VRAYLAR, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills.

In the placebo-controlled clinical trials in patients with schizophrenia, bipolar mania and bipolar depression, somnolence (somnolence, sedation, hypersomnia) was a common treatment emergent adverse event that was reported more frequently in patients treated with VRAYLAR compared to patients that received placebo. See 8.2 Clinical Trial Adverse Reactions.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with VRAYLAR does not affect them adversely.

Endocrine and Metabolism

Atypical antipsychotic drugs, including VRAYLAR, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus:

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies, which did not include VRAYLAR, suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because VRAYLAR was not marketed at the time these studies were performed, it is not known if VRAYLAR is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients should have baseline and periodic monitoring of blood glucose and body weight. See 4.1 Dosing Considerations and 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Schizophrenia

In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (< 100 mg/dL) to high (≥ 126 mg/dL) and borderline (≥ 100 and < 126 mg/dL) to high were similar in patients treated with VRAYLAR and placebo. A shift from normal to high fasting glucose was reported for 7% of patients on placebo and 8% of patients on VRAYLAR and a shift from borderline to high was reported for 24% of patients on placebo and 16% of patients on VRAYLAR. The proportions of patients with shifts in fasting glucose increased over time during the longer-term open-label studies. At 48 weeks, 14% of patients had a shift from normal (< 100 mg/dL) to high (≥ 126 mg/dL) and 58% of patients had a shift from borderline (≥ 100 and < 126 mg/dL) to high. In the long-term, open-label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%).

Bipolar Disorder

In three placebo-controlled 3-week bipolar mania trials there was a low-level imbalance in the percentage of patients with shifts from normal (< 100 mg/dL) to high (≥ 126 mg/dL) fasting glucose. No dose response was observed. In the 16-week open-label study, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥ 6.5%).

In three placebo-controlled 6- to 8-week bipolar depression trials, the proportion of patients with shifts in fasting glucose from normal (< 100 mg/dL) to high (≥ 126 mg/dL), borderline (≥ 100 and < 126 mg/dL) to high and normal/impaired (< 126 mg/dL) to high were similar in patients treated with VRAYLAR and placebo.

Dyslipidemia:

Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. See 4.1 Dosing Considerations and 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests.

Schizophrenia

In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with VRAYLAR and placebo. During longer-term open-label treatment with VRAYLAR, the proportions of patients with shifts in fasting and non-fasting HDL and fasting triglycerides increased over time and showed a marked increase relative to what was observed in the 6-week controlled trials. A shift in fasting and non-fasting HDL from normal (≥ 40 mg/dL) to low (< 40 mg/dL) was reported in 4.7% of patients on placebo and 3.8% on VRAYLAR in the 6-week trials and in 44% of patients treated with VRAYLAR for 48 weeks in longer-term open-label trials. A shift in fasting triglycerides from normal (< 150 mg/dL) to high (≥ 200 mg/dL) was reported in 8.3% of patients on placebo and 7.6% of patients treated with VRAYLAR in the 6-week trials and in 29% of patients that received open-label treatment with VRAYLAR for 48 weeks.

Bipolar Disorder

In three placebo-controlled 3-week bipolar mania trials and in three placebo-controlled 6- to 8-week bipolar depression trials in adults, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with VRAYLAR and placebo.

Weight Gain:

Weight gain has been observed with use of atypical antipsychotics, including VRAYLAR. Monitor weight at baseline and frequently thereafter. See 8.2 Clinical Trial Adverse Reactions .

Genitourinary

Rare cases of priapism have been reported with antipsychotic use. This adverse reaction is generally not found to be dose-dependent or correlated with the duration of treatment.

Hematologic

Leukopenia, Neutropenia, and Agranulocytosis:

In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis has also been reported. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting VRAYLAR and then periodically throughout treatment.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of VRAYLAR should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue VRAYLAR in patients with severe neutropenia (absolute neutrophil count < 1x10⁹/L) and follow their WBC counts until recovery.

Thromboembolism:

Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including VRAYLAR, in case reports and/or observational studies. When prescribing VRAYLAR, all potential risk factors for VTE should be identified and preventative measures undertaken.

Hepatic/Biliary/Pancreatic

See 8.2 Clinical Trial Adverse Reactions; 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Findings.

Monitoring and Laboratory Tests

The following assessments should be done before and periodically during treatment with VRAYLAR.

• Monitor blood pressure. See 4.1 Dosing Considerations; 7 WARNINGS AND PRECAUTIONS, Cardiovascular.
• Monitor complete blood count (CBC). See 4.1 Dosing Considerations; 7 WARNINGS AND PRECAUTIONS, Hematologic.
• Monitor blood glucose, lipid profile and weight. See 4.1 Dosing Considerations; 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism.
• Monitor transaminase and bilirubin levels in patients with known or suspected abnormal hepatic function. See 4.1 Dosing Considerations; 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic; 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Findings.
• Ophthalmologic examination in patients who develop changes in vision during treatment See 4.1 Dosing Considerations; 7 WARNINGS AND PRECAUTIONS, Ophthalmologic.

Neurologic

Neuroleptic Malignant Syndrome (NMS):

Neuroleptic Malignant Syndrome (NMS) is a potentially fatal symptom complex that has been reported in association with administration of antipsychotic drugs, including VRAYLAR.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue VRAYLAR and provide intensive symptomatic treatment and monitoring.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of all antipsychotic drugs, including VRAYLAR, and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

Extrapyramidal Symptoms (EPS)/Akathisia/Restlessness:

Akathisia and restlessness are frequently occurring adverse reactions of antipsychotics. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion, as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot, and crossing and uncrossing the legs while sitting. As cariprazine causes akathisia and restlessness, it should be used cautiously in patients who are prone to or already exhibit symptoms of akathisia. Akathisia develops early in treatment. Therefore, close monitoring in the first phase of treatment is important. Prevention includes slow up-titration; treatment measures include slight down-titration of cariprazine or anti-EPS medication. The dose can be modified based on individual response and tolerability. See 4.2. Recommended dose and dosage adjustment; 8.2 Clinical Trial Adverse Reactions.

Tardive Dyskinesia:

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including VRAYLAR. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.

Given these considerations, VRAYLAR should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on VRAYLAR, drug discontinuation should be considered. However, some patients may require treatment with VRAYLAR despite the presence of the syndrome.

Seizures:

Like other atypical antipsychotic drugs, VRAYLAR may cause seizures and should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Ophthalmologic

The development of cataracts and retinal toxicity was observed in association with cariprazine treatment in chronic dog studies at approximately 4 times the maximum recommended human dose (MRHD) of 6 mg/day. Lens changes and cataracts have also been observed in patients during long-term VRAYLAR treatment, but a causal relationship to VRAYLAR use has not been established. The possibility of lenticular changes during long-term use of VRAYLAR in human, thus cannot be excluded at this time. An ophthalmologic examination prior to or shortly after initiating treatment with VRAYLAR is recommended. Patients who develop symptoms such as blurred vision or other changes in vision during treatment should undergo an ophthalmologic examination. If clinically significant ocular changes associated with VRAYLAR use are observed, discontinuation of VRAYLAR should be considered.

Psychiatric

Suicide/ suicidal thoughts or clinical worsening:

Depressive episodes are associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission of depression occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. In addition to depressive episodes associated with bipolar disorder, depression may be co-morbid with schizophrenia.

Schizophrenia as well as manic episodes associated with bipolar disorder, can also be associated with an increased risk of suicide-related events, and thus close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.

Patients with a history of suicide-related events are also known to be at a greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.

Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare professional. Consider changing the therapeutic regimen, including possibly discontinuing VRAYLAR, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Prescriptions for VRAYLAR should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Reproductive Health: Female and Male Potential

Women of childbearing potential/contraception:

Women of childbearing potential must be advised to avoid pregnancy while treated with VRAYLAR. See 7.1.1 Pregnant Women. Female patients of childbearing potential must use highly effective contraceptive methods during treatment and for at least 12 weeks following treatment discontinuation.

Respiratory

Dysphagia:

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with VRAYLAR. VRAYLAR and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.

Skin

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life-threatening adverse drug reactions that have been reported with atypical antipsychotic exposure. SCARs commonly present as a combination of the following symptoms: malaise, mucosal ulceration, extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy and possible eosinophilia. Discontinue VRAYLAR if severe cutaneous adverse reactions occur. See 8.5 Post-Market Adverse Reactions.

7.1 Special Populations

7.1.1 Pregnant Women

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 10.3 Pharmacokinetics.

Teratogenic effects

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 16 NON-CLINICAL TOXICOLOGY.

Non-teratogenic effects Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Women of childbearing potential must be advised to avoid pregnancy while being treated with VRAYLAR. See 7 WARNINGS AND PRECAUTIONS, Reproductive Health: Female and Male Potential.

The use of VRAYLAR during pregnancy is not recommended unless the expected benefits outweigh the potential risks to the fetus. Patients should be advised to notify their physician if they become pregnant during treatment with VRAYLAR.

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/research/pregnancyregistry/atypicalantipsychotic/.

7.1.2 Breastfeeding

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. See 16 NON-CLINICAL TOXICOLOGY, Lactational Transfer. 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.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of VRAYLAR have not been established in patients less than 18 years of age.

7.1.4 Geriatrics

Clinical trials of VRAYLAR in the treatment of schizophrenia and bipolar mania did not include enough patients aged 65 and older to determine whether the safety and efficacy of VRAYLAR are different in elderly patients compared to 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 dementia related psychosis. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Use in Geriatric Patients with Dementia

Overall Mortality: Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. VRAYLAR is not indicated in elderly patients with dementia (e.g., dementia-related psychosis). See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Cerebrovascular Adverse Events, including Stroke: In placebo-controlled trials with some atypical antipsychotics in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. VRAYLAR is not approved for the treatment of patients with dementia (e.g., dementia-related psychosis). See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including VRAYLAR. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. VRAYLAR is not indicated for the treatment of dementia-related psychosis and should not be used in patients at risk for aspiration pneumonia.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The information below is derived from an integrated clinical study database for VRAYLAR consisting of 4753 adult patients exposed to one or more doses of VRAYLAR 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 2568

VRAYLAR-treated patients had at least 6 weeks and 296 VRAYLAR-treated patients had at least 48 weeks of exposure.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

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.

Treatment Emergent Adverse Events Associated with Discontinuation of Treatment: A total of 9% (118/1317) of patients treated with VRAYLAR (1.5 mg/day to 12 mg/day) and 12% (71/584) of patients that received placebo in 6-week clinical trials discontinued due to adverse events. 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. Akathisia, insomnia, restlessness, aggression, headache and hypertension were the only treatment emergent adverse events that led to discontinuation of treatment for > 2 patients treated with VRAYLAR and more frequently than in patients that received placebo.

Most common treatment emergent adverse events: The most common treatment emergent adverse events, reported in ≥ 5% of patients treated with VRAYLAR and at least twice the rate of placebo in the 6-week schizophrenia clinical trials were extrapyramidal symptoms and akathisia.

Treatment emergent adverse events with an incidence of ≥ 2% and greater than placebo, at any dose are shown below in Table 2.

Table 2 Treatment Emergent Adverse Events Occurring in ≥ 2% of VRAYLAR-treated Patients and Placebo-treated Adult Patients in 6-Week Schizophrenia Trials

Patients with Bipolar Mania

The following findings are based on three placebo-controlled, 3-week bipolar mania trials with VRAYLAR doses ranging from 3 to 12 mg once daily. The maximum recommended dosage is 6 mg daily.

Treatment Emergent Adverse Events Associated with Discontinuation of Treatment: The adverse events leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received VRAYLAR discontinued treatment due to an adverse event, compared with 7% of placebo-treated patients in these trials.

Most common treatment emergent adverse events (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.

Treatment emergent adverse events with an incidence of ≥ 2% and greater than placebo at any dose are shown below in Table 3.

Table 3 Treatment Emergent Adverse Events Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials

Patients with Bipolar Depression

The following findings are based on three placebo-controlled, two 6-week and one 8-week bipolar depression trials with VRAYLAR doses of 1.5 mg, and 3 mg once daily.

Treatment Emergent Adverse Events Associated with Discontinuation of Treatment: There were no adverse events leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo. Overall, 7% of the patients who received VRAYLAR discontinued treatment due to an adverse event, compared with 5% of placebo-treated patients in these trials.

Most common treatment emergent adverse events (≥ 5% and at least twice the rate of placebo): nausea, akathisia, restlessness, and extrapyramidal symptoms.

Treatment emergent adverse events with an incidence of ≥ 2% and greater than placebo at 1.5 mg or 3 mg doses are shown in Table 4.

Table 4 Treatment Emergent Adverse Events Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in two 6-week trials and one 8-week trial Bipolar Depression Trials

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).

Schizophrenia:

In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for VRAYLAR-treated patients versus 8% for placebo-treated patients. These events led to discontinuation in 0.3% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for VRAYLAR treated patients versus 4% for placebo-treated patients. These events led to discontinuation in 0.5% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The majority (97.7%) of akathisia and EPS AEs were mild or moderate in severity and less than 1% led to discontinuation. The incidence of EPS based on Adverse

Events is shown in Table 5. The incidences of parkinsonism and akathisia based on the SAS and BARS, respectively, are shown in Table 6.

Table 5 Incidence of Treatment Emergent EPS Adverse Events Compared to Placebo in 6-Week Schizophrenia Studies

In the long-term study, the rate of new cases of akathisia did not continue to escalate over time. Akathisia was manageable; 99.7% events were mild to moderate in severity and approximately 1% led to discontinuation.

Table 6 Incidence of Parkinsonism and Akathisia Compared to Placebo in 6-Week Schizophrenia Studies Based on Shifts from Baseline in SAS or BARS Scores

Bipolar Mania:

In 3-week bipolar mania trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for VRAYLAR-treated patients versus 12% for placebo-treated patients. These events led to a discontinuation in 1% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for VRAYLAR treated patients versus 5% for placebo-treated patients. These events led to discontinuation in 2% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of akathisia and extrapyramidal disorder was lower in patients who received a modal dose of 3 to 6 mg VRAYLAR compared to patients who received a modal dose of 9 to 12 mg VRAYLAR. The majority (93.6%) of akathisia and extrapyramidal symptoms AEs were mild or moderate severity. The incidence of EPS is provided in Table 7. The incidences of parkinsonism and akathisia based on the SAS and BARS, respectively, are shown in Table 8.

Table 7 Incidence of EPS Compared to Placebo in 3-Week Bipolar Mania Trials

The onset of akathisia and EPS events occurred mostly during the initial 2-weeks of treatment and then the number of new cases decreased thereafter. This pattern was also observed in the 16 week study.

Table 8 Incidence of Parkinsonism and Akathisia Compared to Placebo in three 3-Week Bipolar Mania Trials Based on Shifts from Baseline in SAS or BARS Scores

Bipolar Depression:

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 VRAYLAR-treated patients versus 2% for placebo-treated patients. These events led to discontinuation in 0.4% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of akathisia was 8% for VRAYLAR-treated patients versus 2% for placebo-treated patients. These events led to discontinuation in 1.5% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The majority (97.2%) of akathisia AEs were mild or moderate in severity. The overall rate of akathisia was lower in bipolar depression studies compared with other indications, possibly due to the slower titration schemes and lower doses used in the bipolar depression studies. The incidence of EPS is shown in Table 9. The incidences of parkinsonism and akathisia based on the SAS and BARS, respectively, are shown in Table 10.

Table 9 Incidence of EPS Compared to Placebo in two 6-Week and one 8-Week Bipolar Depression Trials

Table 10 Incidence of Parkinsonism and Akathisia Compared to Placebo in two 6-Week and one 8-Week Bipolar Depression Trials Based on Shifts from Baseline in SAS or BARS Scores

Additional Safety Evaluations:

Cataracts

In the long-term uncontrolled schizophrenia (48-week) and bipolar mania (16-week) trials, the incidence of cataracts was 0.1% and 0.2%, respectively. The development of cataracts was observed in nonclinical studies. See 16 NON-CLINICAL TOXICOLOGY. The possibility of lenticular changes or cataracts cannot be excluded at this time.

Vital Signs Changes

In general, at the recommended doses for VRAYLAR, there were no clinically meaningful differences between VRAYLAR-treated patients and patients on placebo in mean change from baseline to endpoint in supine blood pressure parameters in the short-term schizophrenia, bipolar mania or bipolar depression clinical trials. However, increases in blood pressure and heart rate were observed with VRAYLAR in the ECG assessment study. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 10.2 Pharmacodynamics, Cardiac Electrophysiology and Hemodynamics.

Weight

Weight gain has been observed with use of atypical antipsychotics, including VRAYLAR. Monitor weight at baseline and frequently thereafter. Table 11, Table 12 and Table 13 show the change in body weight occurring from baseline to endpoint in 6-week schizophrenia, 3-week bipolar mania, and 6-week and 8-week bipolar depression trials, respectively.

Schizophrenia:

Table 11 shows the change in body weight occurring from baseline to endpoint in 6-week schizophrenia trials.

Table 11 Change in Body Weight (kg) in 6-Week Schizophrenia Trials

In long-term, uncontrolled trials with VRAYLAR in schizophrenia, the mean changes from baseline in weight at 12, 24, and 48 weeks were 1.2 kg, 1.7 kg, and 2.5 kg, respectively.

Bipolar Mania

Table 12 show the change in body weight occurring from baseline to endpoint in 3-week bipolar mania trials.

Table 12 Change in Body Weight (kg) in 3-Week Bipolar Mania Trials

There was a slight difference in mean weight gain between VRAYLAR and placebo patients (+0.5 kg vs. 0.2 kg, respectively).

Bipolar Depression

Table 13 shows the change in body weight occurring from baseline to endpoint in the two 6-week and one 8-week bipolar depression trials.

Table 13 Change in Body Weight (kg) in two 6-Week and one 8-Week Bipolar Depression Trials

There was a slight difference in mean weight gain between VRAYLAR and placebo patients (+0.6 kg vs. -0.1 kg, respectively).

8.3 Less Common Clinical Trial Adverse Reactions

Adverse events listed below were reported by patients treated with VRAYLAR at doses of ≥ 1.5 mg once daily within the premarketing database of 3988 VRAYLAR-treated patients. The events listed are those that could be of clinical importance, as well as those that are plausibly drug-related on pharmacologic or other grounds. Adverse events that appear elsewhere in the VRAYLAR 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 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).

Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis

Hepatobiliary Disorders: Rare: hepatitis

Investigations: Infrequent: blood triglycerides increased; blood glucose increased

Metabolism and Nutrition Disorders: Infrequent: hyponatremia; hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Infrequent: dysarthria; 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

Vascular Disorders: Infrequent: orthostatic hypotension

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

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 VRAYLAR-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 VRAYLAR-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 VRAYLAR-treated patients depending on dose group administered and 0.4% for placebo-treated patients. Most cases of transaminase elevation were asymptomatic, and the majority of cases had confounds such as, recent prior or concomitant medications, history of transaminase elevation, mild baseline elevations or positive baseline serology for hepatitis, history of alcohol use/abuse. See 4.1 Dosing Considerations; 7 WARNINGS AND PRECAUTIONS Monitoring and Laboratory Tests.

The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for VRAYLAR-treated patients, increasing with dose, and was 4% for placebo-treated patients. The proportion of patients with elevations of CPK greater than 1000 U/L in the long-term open-label 48-week studies was 8.7%. The proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in VRAYLAR and placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 6-week and 8- week bipolar depression trials ranged between 0.2% and 1% for VRAYLAR-treated patients versus 0.2% for placebo-treated patients.

8.5 Post-Market Adverse Reactions

The following adverse reaction has been identified during post approval use of VRAYLAR.

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: Stevens-Johnson syndrome.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

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

Based on in vitro results, cariprazine has the potential to act as a CYP3A4/3A5 inducer at the intestinal level. At clinically relevant concentrations, cariprazine and its metabolites, DCAR and DDCAR, are not expected to induce hepatic CYP3A4/3A5, CYP1A2 and CYP2B6 or to inhibit the activity of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/3A5.

Based on in vitro results, cariprazine has the potential to act as a weak P-glycoprotein (P-gp) inhibitor at the intestinal level. At clinically relevant concentrations, cariprazine and its metabolites, DCAR and DDCAR, are not expected to inhibit the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), breast cancer resistance protein (BCRP), organic cation transporter 2 (OCT2), and organic anion transporter 1 and 3 (OAT1 and OAT3).

In vitro results showed that cariprazine and its metabolites, DCAR and DDCAR, are not substrates of P-gp, OATP1B1, OATP1B3 and BCRP. Therefore, no interaction is expected between VRAYLAR and inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP.

9.3 Drug-Behavioural Interactions

Alcohol / CNS Drugs

Given the primary central nervous system effects of cariprazine, VRAYLAR should be used with caution in combination with other centrally acting medicinal products and alcohol.

Smoking

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

9.4 Drug-Drug Interactions

Table 14 Established or Potential Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

CYP2D6 inhibitors:

In vitro results showed that the CYP2D6-mediated pathway plays a minor role in cariprazine metabolism. Therefore, CYP2D6 inhibitors are not expected to influence pharmacokinetics of cariprazine, DCAR or DDCAR.

9.5 Drug-Food Interactions

In clinical studies, VRAYLAR was administered without regard to food.

A dedicated drug-food interaction study demonstrated that food had no significant effect on C_max or AUCT. However, administration of 1.5 mg VRAYLAR with a high-fat, high-calorie meal delayed median (minimum-maximum) time to C_max (T_max) to 9.0 (2.0-12.0) hours from 4.0 (3.0-9.0) hours following administration of 1.5 mg VRAYLAR under fasting conditions.

Grapefruit is a known CYP3A4 inhibitor. Co-administration of VRAYLAR with strong and moderate CYP3A4 inhibitors is contraindicated. See 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions.

Patients must be instructed to avoid consumption of grapefruit or grapefruit-containing products while being treated with VRAYLAR and for at least 2 weeks after treatment discontinuation.

9.6 Drug-Herb Interactions

St John’s Wort is a known CYP3A4 inducer. Co-administration of VRAYLAR with strong and moderate CYP3A4 inducers is contraindicated. See 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The mechanism of action of cariprazine in schizophrenia and bipolar I disorder is unknown. However, the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at central dopamine D₃, D₂ and serotonin 5-HT_1A receptors and antagonist activity at 5-HT_2A receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding and functional activity profiles similar to the parent drug.

10.2 Pharmacodynamics

Cariprazine acts as a dopamine D₃/D₂ receptor partial agonist with high in vitro binding affinity at the dopamine D₃ (K_i = 0.085-0.3 nM), and D₂ receptors (K_i values, D_2L= 0.49-0.71 nM and D_2S = 0.69). Cariprazine acts as a partial agonist at the serotonin 5-HT_1A receptor with high in vitro binding affinity (K_i = 1.4- 2.6 nM) and acts as an antagonist at 5-HT_2B and 5-HT_2A receptors as well as histamine H₁ receptors with high to moderate binding affinities (Ki values, 5-HT_2B =0.58 -1.1 nM; 5-HT_2A = 18.8 nM; H₁ = 23.2 nM respectively). Cariprazine shows lower binding affinity to 5-HT_2C and α_1A- adrenergic receptors (K_i values, 5HT_2C = 134 nM and α_1A = 155 nM, respectively) and has no appreciable binding affinity for cholinergic muscarinic receptors (IC₅₀>1000 nM).

Cardiac Electrophysiology and Hemodynamics

In a double-blind, placebo- and positive-controlled, parallel group ECG assessment study, patients with schizophrenia or schizoaffective disorder were randomized to receive supratherapeutic doses of cariprazine 9 mg/day and 18 mg/day (n = 63) or placebo-risperidone (n = 66). To attain cariprazine, DCAR and DDCAR plasma concentrations with the supratherapeutic doses that would be similar to steady-state concentrations at the maximum recommended dose of 6 mg/day within a short timeframe, patients in the cariprazine group received placebo from days 1-5, were upward titrated from 1.5 mg/day to 6 mg/day from days 6-9, received 9 mg/day from days 10-20, were upward titrated from 12 mg/day to 15 mg/day from days 21-24, and received 18 mg/day from days 25-35. The mean C_max values for CAR (22.8 ng/mL) and DCAR (4.8 ng/mL) reported for the supratherapeutic 9 mg/day dose on day 20 were similar to those reported for the therapeutic 6 mg/day dose at steady-state in other trials, whilst the mean C_max for DDCAR (23.1 ng/mL) was lower. The mean C_max values achieved with the supratherapeutic 18 mg/day dose on day 34 were twice those achieved with the therapeutic 6 mg/day dose at steady-state in other trials.

In the placebo-risperidone group, patients received placebo from days 1-5, risperidone 4 mg/day from days 7-15, placebo from days 16-20, risperidone 4 mg/day from days 21-29, and placebo from days 30-34. A positive control or placebo was administered on days 6 and 35, according to a nested crossover design.

ECG assessments were performed on day 20 and day 34 and compared with day 5 baseline. Blood pressure was measured daily.

Blood Pressure:

Cariprazine caused increases in systolic and diastolic blood pressure.

On day 20, the mean change from baseline in systolic blood pressure ranged from -3.7 mmHg to - 2.9 mmHg for placebo-risperidone and from 5.3 mmHg to 5.4 mmHg for cariprazine 9 mg/day, whilst the mean change from baseline in diastolic blood pressure ranged from -2.6 mmHg to -0.8 mmHg for placebo-risperidone and from 4.9 mmHg to 5.2 mmHg for cariprazine 9 mg/day.

On day 34, the mean change from baseline in systolic blood pressure ranged from -3.8 mmHg to - 3.3 mmHg for placebo-risperidone and from 5.2 mmHg to 5.4 mmHg for cariprazine 18 mg/day, whilst the mean change from baseline in diastolic blood pressure ranged from -2.3 mmHg to -1.4 mmHg for placebo-risperidone and from 4.3 mmHg to 5.8 mmHg for cariprazine 18 mg/day.

Heart Rate:

Cariprazine was associated with an increase in heart rate. The maximum difference from placebo-risperidone in mean change from baseline heart rate was 7.2 bpm (90% CI 4.1, 10.4) on day 20 during treatment with cariprazine 9 mg/day and 8.2 bpm (90% CI 4.8, 11.6) on day 34 during treatment with cariprazine 18 mg/day.

QTc Interval:

Risperidone and its active metabolite, paliperidone, cause QTc prolongation. On day 20, the mean change from baseline QTcF ranged from 6.2 ms to 10.4 ms in the placebo-risperidone group and from 1.7 ms to 5.6 ms in the cariprazine group during treatment with the 9 mg/day dose. On day 34, the mean change from baseline QTcF ranged from 4.5 ms to 8.3 ms in the placebo-risperidone group and from 1.0 ms to 5.3 ms in the cariprazine group during treatment with the 18 mg/day dose.

According to a concentration-response model of the relationship between mean change from baseline QTcF and total cariprazine (the combination of the parent compound and its two major active metabolites, DCAR and DDCAR), no meaningful effect on the QTcF interval was predicted for total cariprazine concentrations up to 200 nmol/L. The mean C_max for total cariprazine at steady-state during treatment with the 6 mg/day maximum recommended therapeutic dose is expected to be approximately 100-150 nmol/L.

Because of the upward titration design, comparisons between the 9 mg/day and 18 mg/day doses are not controlled for time and sequence effects.

10.3 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 functional half-lives based on time to reach 90% steady state, estimated from the mean concentration-time curves, are 2 to 4 days for cariprazine, about 1 to 2 days for DCAR, 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 4.1 Dosing Considerations and 7 WARNINGS AND PRECAUTIONS, Late-Occurring Adverse Reactions. 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.

Based on a population pharmacokinetic analysis, terminal elimination half-lives (mean ± SD) are 10.1 ± 0.66 days for cariprazine, 5.9 ± 2.8 days for DCAR, 19.1 ± 9.25 days for DDCAR, and 8.9 ± 9.19 days for total CAR.

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/day^a,b

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

b. The presented plasma-concentration vs. time profile was based on the Study A002-A11. Cariprazine tablets were orally administered once a day for 12 weeks to Japanese schizophrenia patients (n = 16) starting with an initial dose of 1.5 mg/day on Day 1, followed by daily up-titration dosages for 1 to 4 days to a fixed final dose of 6 mg/day for 12 weeks (See Special Populations and Conditions).

Absorption

After single dose administration of VRAYLAR, the peak plasma cariprazine concentration occurred in approximately 3-6 hours. See 9.5 Drug-Food Interactions.

Distribution

Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins.

Metabolism

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

Elimination

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.

Special Populations and Conditions

• Pediatrics

VRAYLAR is not approved for use in pediatric patients.

• Geriatrics

In a population pharmacokinetic analysis, age did not significantly affect the pharmacokinetics of cariprazine, DCAR, or DDCAR in patients aged 18 to 65 years. Dose adjustments are not necessary on the basis of age for adults 18 to 65 years of age. The effect of age for elderly patients (> 65 years of age) on cariprazine pharmacokinetics, efficacy and safety was not evaluated. Caution should be used when treating geriatric patients. See 1.2 Geriatrics; 4.1 Dosing Considerations; 7.1.4 Geriatrics.

• Sex

In a population pharmacokinetic analysis, gender did not have clinically relevant effects on the pharmacokinetics of cariprazine, DCAR, or DDCAR. Dose adjustments are not necessary on the basis of gender.

• Genetic Polymorphism

Based on the final population PK analysis, there were no statistically significant differences in cariprazine, DCAR, DDCAR, and TOTAL cariprazine exposures between extensive and poor metabolizers of CYP2D6.

• Ethnic Origin

Based on a population pharmacokinetic analysis (n = 2036), total cariprazine AUC was 45% higher in Asian patients (n = 312) and 24% lower in Black patients (n = 689) compared to that in Caucasian patients (n = 961). These differences were due to the combined effect of race and weight on cariprazine PK. The subjects with lower body weight (33-63 kg) had 36% higher total cariprazine AUC compared to the reference group with weight ranging from 74 to 82 kg. Dose adjustments are not necessary on the basis of race, however, use caution for dose increase higher than 4.5 mg in patients with low body weight (≤ 63 kg).

• Hepatic Insufficiency

Compared to healthy subjects, total cariprazine exposure (C_max and AUC) in subjects with either mild or moderate hepatic impairment (Child-Pugh score between 5 and 9) was decreased by 16 to 20% and by 11 to 14%, respectively, following daily doses of 0.5 mg cariprazine (a subtherapeutic dose) for 14 days. In this study, no subject was exposed to therapeutic doses of cariprazine and full effect on cariprazine exposure could not be determined as one of the metabolites, DDCAR, had not reached steady-state.

In a population pharmacokinetic analysis (n = 2036), no clinically significant differences in the PK of cariprazine and its metabolites were observed in patients with mild hepatic impairment (n = 290), whereas the effect of moderate hepatic impairment remains unclear due to the very small sample size (n = 4) and other confounding variables. VRAYLAR should therefore be used with caution in patients with moderate hepatic impairment.

The effect of severe hepatic impairment on the pharmacokinetics of cariprazine and its metabolites has not been evaluated. Therefore, the use of VRAYLAR in patients with severe hepatic impairment is not recommended.

• Renal Insufficiency

Cariprazine and its major active metabolites are minimally excreted in urine. Pharmacokinetic analyses indicated no significant relationship between plasma clearance and creatinine clearance. Based on a population pharmacokinetic analysis (n = 2036), no clinically significant differences in the PK of cariprazine and its metabolites were observed in subjects with mild (n = 353) and moderate (n = 20) renal impairment. The effect of severe renal impairment on pharmacokinetics of cariprazine and its metabolites has not been evaluated. Therefore, the use of VRAYLAR in patients with severe renal impairment is not recommended.

11 STORAGE, STABILITY AND DISPOSAL

Store between 15 and 30°C. Protect 3 mg and 4.5 mg capsules from light to prevent potential color fading.

Keep out of reach and sight of children.

Disposal of VRAYLAR capsules should be in keeping with recommendations governing the disposal of pharmaceutical biohazardous waste.

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Common name: cariprazine HCl

Chemical name: trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride;

Molecular formula and: C21H33Cl3N4O

molecular mass: 463.9 g/mol

Structural formula:

Physicochemical properties: White to almost white crystalline powder. The polymorph Form I of cariprazine HCl is the most stable and relevant form which can be unequivocally differentiated from the polymorph Form III by FT-IR.

Practically insoluble in Isopropanol and N,N-Dimethylformamide

Very slightly soluble in Acetone, Acetonitrile, and Water

Slightly soluble in Dichloromethane and Ethanol

Freely soluble in Methanol

Cariprazine HCl exhibits maximum solubility at approximately pH 3

The following table provides the solubilities over the physiological pH range (1.2-6.8) for the drug substance Cariprazine HCl.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Schizophrenia

The efficacy of VRAYLAR for the treatment of schizophrenia was established in three, 6-week, randomized, double-blind, placebo-controlled trials and one longer-term randomized withdrawal trial. All trials included patients (aged 18 to 60 years) who met Diagnostic and Statistical Manual of Mental Disorders 4^th edition, Text Revision (DSM-IV-TR) criteria for schizophrenia who were experiencing an acute exacerbation of psychotic symptoms. Details of study designs and patient demographics are provided in Table 15 for the short-term trials and in Table 17 for the randomized withdrawal trial. Results are presented in Table 16 for the short-term trials and Table 18 for the randomized withdrawal trial.

Trial Design and Study Demographics in 6-week Trials for Schizophrenia

Studies RGH-MD-16 and RGH-MD-04 used a fixed-dose regimen to compare VRAYLAR 1.5 mg/day, 3 mg/day or 4.5 mg/day to placebo (Study RGH-MD-16) and VRAYLAR 3 mg/day and 6 mg/day to placebo (Study RGH-MD-04). Both studies included an active control arm (risperidone or aripiprazole) to assess assay sensitivity. In both trials, patients who were randomized to VRAYLAR initiated treatment at 1.5 mg/day and in Study RGH-MD-16, one treatment group received VRAYLAR 1.5 mg/day for the duration of the study. For patients assigned to dosages above 1.5 mg/day, the dosage was increased by 1.5 mg increments each day. On Day 2 the dosage increased to 3 mg for patients assigned to 3 mg/day or higher; on Day 3 the dosage increased to 4.5 mg for patients assigned to 4.5 mg/day or higher; and, on Day 4 the dosage increased to 6 mg for patients assigned to 6 mg/day. Once assigned dosages were reached, patients remained on these doses for the duration of the trial.

Study RGH-MD-05 used a fixed-flexible dose regimen, comparing VRAYLAR 3 to 6 mg/day (low dose group) and 6 to 9 mg/day (high dose group) to placebo. All patients who were randomized to VRAYLAR initiated treatment at 1.5 mg/day. The dosage was increased to 3 mg/day on Day 2 for all patients in both VRAYLAR dose groups and maintained at 3 mg/day for the first 2 weeks in the low dose group. In the high dose group the dosage was increased to 4.5 mg/day on Day 3, to 6 mg/day starting on Day 4 and maintained at 6 mg/day for the first 2 weeks in this group. On Day 14 patients in either VRAYLAR group with an inadequate response, defined as < 20% improvement in Positive and Negative Syndrome Scale (PANSS) total score from baseline to end of Week 2 and a Clinical Global Impressions-Severity (CGI-S) score > 4, and who did not have significant tolerability issues had the dose increased by 1.5 mg increments. In the low dose group, the dosage was increased to 4.5 mg/day for Days 14 and 15, and to 6 mg/day thereafter. In the high dose group, the dosage was increased to 7.5 mg/day for Days 14 and 15, and to 9 mg/day thereafter. Dosages were fixed from the end of Week 3 to Week 6.

The 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 VRAYLAR and active control groups was compared to placebo.

Table 15 Summary of patient demographics in 6-week clinical trials in Schizophrenia (Intent-to-Treat Population)

Results of 6-week trials for Schizophrenia

Study RGH-MD-16: In a 6-week, placebo-controlled trial (n = 711) using three fixed doses of VRAYLAR (1.5, 3, or 4.5 mg/day) and an active control (risperidone), improvements in PANSS total score and CGI-S score from baseline to study endpoint were statistically significant with all VRAYLAR doses and the active control compared to placebo.

The active reference confirmed the assay sensitivity of the study.

Study RGH-MD-04: In a 6-week, placebo-controlled trial (n = 604) using two fixed doses of VRAYLAR (3 or 6 mg/day) and an active control (aripiprazole), improvements in PANSS total score and CGI-S score from baseline to study endpoint were statistically significant with both VRAYLAR doses and the active control compared to placebo. Adjusted p-values for the primary and secondary endpoints were based on matched parallel gatekeeping procedure.

The active reference confirmed the assay sensitivity of the study.

Study RGH-MD-05: In a 6-week, placebo-controlled trial (n = 439) using two flexible-dose ranges of VRAYLAR (3 to 6 mg/day or 6 to 9 mg/day), improvements in PANSS total score and CGI-S score from baseline to study endpoint were statistically significant with both VRAYLAR dose ranges compared to placebo. Adjusted p-values for the primary and secondary endpoints were based on matched parallel gatekeeping procedure.

Results are summarized in Table 16. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Therefore, the maximum recommended dose is 6 mg/day.

Table 16 Primary Analysis Results of 6-week trials for Schizophrenia

Trial Design and Study Demographics in Longer-term trial (up to 92 weeks) for Schizophrenia (RGH-MD-06)

Study RGH-MD-06 was a randomized withdrawal, double-blind, placebo-controlled trial to evaluate the efficacy, safety and tolerability of VRAYLAR in adults with schizophrenia. The trial included patients meeting DSM-IV-TR criteria for schizophrenia who were experiencing an acute exacerbation of psychotic symptoms at study entry. Patients who completed 20 weeks of open-label treatment with cariprazine and met criteria for stability could be randomized to either cariprazine or placebo for observation of relapse, for up to 72 weeks during the double-blind phase of the study.

A total of 751 patients entered the study and received open-label treatment with VRAYLAR at doses of 3 to 9 mg/day for 20 weeks. During the open-label phase all patients received VRAYLAR 1.5 mg on Day 1 and had an increase in dosage to 3 mg/day on Day 2. The dosage could have been increased based on response and tolerability to 4.5 mg/day (Day 4), 6 mg/day (Day 6) or to a maximum dose of 9 mg/day (Day 10). For the first 6 weeks of open-label treatment dose adjustments were allowed; thereafter, patients remained on a stable dose within the range of 3 to 9 mg/day. Patients who did not tolerate VRAYLAR 3 mg/day were discontinued from the study. A total of 200 patients who completed 20 weeks of open-label treatment on a stable dose of VRAYLAR (3 to 9 mg/day) and met protocol-defined criteria for stability were randomized to receive either placebo or cariprazine (1:1) at the same dose for observation of relapse during the double-blind phase of the study. The total study duration was 92 weeks. Details on patient demographics are provided in Table 17.

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).

Table 17 Summary of patient demographics in longer-term Schizophrenia Trial

Results of Longer-term trial (up to 92 weeks), Schizophrenia (Study RGH-MD-06)

After 20-weeks of open-label treatment with VRAYLAR, patients who were clinically stable and continued to receive VRAYLAR 3 to 9 mg/day had a statistically significant longer time to relapse than patients who were randomized to placebo (p=0.0010).

Table 18 Primary Efficacy Analysis: Survival Analysis Summary of Time to First Relapse During the Double-blind Treatment Period (Double-blind Intent-to-Treat Population) in Study RGH-MD-06

Bipolar Mania

Bipolar Mania Trial Design and Study Demographics

Summary of patient demographics for clinical trials in Manic or Mixed Episodes Associated with Bipolar I Disorder (Bipolar Mania)

The efficacy of VRAYLAR in the acute management of bipolar mania was established in three, 3-week placebo-controlled trials in patients (mean age of 39 years, range 18 to 65 years) who met DSM-IV-TR criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features. Details on patient demographics are provided in Table 19. In all three trials, VRAYLAR was statistically 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.

In each study, the primary endpoint was change from baseline in YMRS total score at the end of week 3. The change from baseline for each VRAYLAR dose group was compared to placebo. The results of the trials are shown in Table 20.

Table 19 Summary of patient demographics for clinical trials in patients with Manic or Mixed Episodes Associated with Bipolar I Disorder Trials (Bipolar Mania) (Intent-to-Treat Population)

Study Results

Results of studies 31, 32 and 33 in patients with Manic or Mixed Episodes Associated with Bipolar I Disorder (Bipolar Mania)

Study RGH-MD-31: In a 3-week, placebo-controlled trial (n = 235) involving a flexible-dose range of VRAYLAR (3 to 12 mg/day), VRAYLAR was statistically superior to placebo on the YMRS total score and CGI-S.

Study RGH-MD-32: In a 3-week, placebo-controlled trial (n = 310) involving a flexible-dose range of VRAYLAR (3 to 12 mg/day), VRAYLAR was statistically superior to placebo on the YMRS total score and CGI-S.

Study RGH-MD-33: In a 3-week, placebo-controlled trial (n = 492) involving two flexible-dose range groups of VRAYLAR (3 to 6 mg/day or 6 to 12 mg/day), both VRAYLAR dose groups were statistically superior to placebo on the YMRS total score and the CGI-S. The 6 to 12 mg/day dose group showed no additional advantage.

The efficacy of VRAYLAR was established at doses ranging from 3 to 12 mg/day. Doses above 6 mg did not confer additional benefit over lower doses (Table 20) while there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 6 mg/day.

Table 20 Primary Analysis Results from Manic or Mixed Episodes Associated with Bipolar I Disorder Trials (Bipolar Mania)

Bipolar Depression

Trial Design and Study Demographics in clinical trials in Depressive Episodes Associated with Bipolar I Disorder

The efficacy of VRAYLAR in the management 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. Details on patient demographics is provided in Table 21.

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 VRAYLAR compared to placebo is shown in Table 22.

The secondary endpoint was change from baseline to Week 6 in CGI-S. 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.

Table 21 Summary of patient demographics for clinical trials in Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) (Intent-to-Treat Population)

Results of Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression)

Study RGH-MD-53: In a 6-week, placebo-controlled trial (n = 478) involving two-fixed doses of VRAYLAR (1.5 mg/day and 3 mg/day), VRAYLAR 1.5 mg was superior to placebo at end of Week 6 on the MADRS total score and the CGI-S. VRAYLAR 3 mg was not statistically superior to placebo for the primary and secondary endpoints.

Study RGH-MD-54: In a 6-week, placebo-controlled trial (n = 474) involving two-fixed doses of VRAYLAR (1.5 mg/day and 3 mg/day), VRAYLAR 1.5 mg and 3 mg were superior to placebo at end of Week 6 on the MADRS total score but not on the CGI-S score.

Study RGH-MD-56: In an 8-week, placebo-controlled trial (n = 571) involving three-fixed doses of VRAYLAR (0.75 mg/day, 1.5 mg/day, and 3 mg/day), VRAYLAR 1.5 mg was superior to placebo at end of Week 6 on the MADRS total score and the CGI-S. VRAYLAR 0.75 mg and 3 mg were not statistically superior to placebo for the primary and secondary endpoints.

Table 22 Primary Analysis Results for clinical trials in Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression)

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Cariprazine is metabolized to the major human metabolites DCAR and DDCAR in rats, mice, rabbits, and dogs. Comparisons of systemic exposure at adverse effect dose levels, no effect dose levels (NOEL), and no adverse effect dose levels (NOAEL) in animals to that at the maximal recommended human dose (MRHD) are on the basis of total cariprazine (cariprazine + DCAR + DDCAR). In patients, total cariprazine exposure based on AUC_0-24h was 1273 ng·h/mL at the 6 mg MRHD.

Neurological and behavioral clinical signs attributed to the pharmacological effects of cariprazine were noted in dogs, rats, and mice. Clinical signs decreased in incidence and severity with repeated dosing. In dogs, decreased spontaneous motor activity, tremor, staring into space, vocalization, and/or disorientation were noted with dose related increases in frequency and severity.

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 3 mg/kg/day in a 13 week study and 4 mg/kg/day in the 52 week study. At 3 mg/kg/day in the dog, AUC of total cariprazine was 10.2 (male) and 6.0 (female) times that of patients at the MRHD. In the dog, electroretinography (ERG) evaluations conducted in a 13-week study did not indicate any cariprazine related functional effects on the outer retina at doses up to 8 mg/kg/day. The NOEL for cataract and retinal toxicity in the dog is 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. Increased incidence and severity of retinal degeneration/atrophy in the rat occurred at all doses tested (≥ 0.75 mg/kg/day and thus, at total cariprazine exposures less than that at the MRHD. Cataract was not observed in other repeat dose studies in pigmented mice or albino rats and retinal degeneration in the 2-year rat study appeared to be exacerbation of an age-related process.

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 1-2 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 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 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 3.6 (females) times the MRHD based on AUC of total cariprazine. The relevance of these findings to patients is unknown.

Cariprazine-related changes indicative of pseudopregnancy were observed in the female mammary gland at all dose levels of all studies conducted in mice and rats and in the reproductive organs in all mouse studies and shorter term rat studies. These findings are known class effects of antipsychotics that cause increases in circulating prolactin. Cariprazine oral doses of 0.1 and 1 mg/kg/day given for 14 days to female rats resulted in increases in serum prolactin of 87- and 256-fold, respectively, compared to controls. The female mammary gland and reproductive organ findings observed in the rodent were not observed in the dog. They are considered rodent specific and, thus, unlikely to be relevant for patients.

Genotoxicity:

Cariprazine was not mutagenic in the in vitro bacterial reverse mutation assay, nor clastogenic in the in vitro human lymphocyte chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay. However, cariprazine increased the mutation frequency in the in vitro mouse lymphoma assay under conditions of metabolic activation. The major human metabolite DDCAR was not mutagenic in the in vitro bacterial reverse mutation assay, however, it was clastogenic and induced structural chromosomal aberration in the in vitro human lymphocyte chromosomal aberration assay.

Carcinogenicity:

There was no treatment-related 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.

Rats were administered cariprazine at oral doses of 0.25, 0.75, and 2.5 (males)/1, 2.5, and 7.5 mg/kg/day (females) which resulted in exposures that were 0.2 to 1.8 (males)/ 0.8 to 4.1 (females) times that at the MRHD based on the AUC of total cariprazine.

Tg.rasH2 mice were administered cariprazine at oral doses of 1, 5, and 15 (males)/5, 15, and 50 mg/kg/day (females) which resulted in exposures that were 0.2 to 7.9 (males)/2.6 to 19 (females) times the MRHD based on AUC of total cariprazine.

Reproductive and Developmental Toxicology:

• Fertility and early embryonic development

Cariprazine was administered orally to male and female rats before mating, through mating and up to day 7 of gestation at doses of 1, 3, and 10 mg/kg/day which are 1.6 to 16 times the MRHD of 6 mg/day based on mg/m². In female rats, lower fertility and conception indices were observed at all dose levels which are equal to or higher than 1.6 times the MRHD of 6 mg/day based on mg/m² while at 10 mg/kg/day, numbers of delivered pups and implantation sites were reduced with concomitant decreases in live litter size. The NOAEL for female reproductive toxicity was < 1 mg/kg/day and the NOAEL for F1 developmental toxicity was 3 mg/kg/day. No effects on male fertility were noted at any dose up to 4.3 times the MRHD of 6 mg/day based on AUC of total cariprazine.

Embryo fetal development

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 AUC of total cariprazine at the MRHD caused fetal developmental toxicity at all doses. Reduced fetal body weight and decreased male anogenital distance were noted at all doses, and external and skeletal malformations as well as increased incidences of visceral and skeletal variations were seen at 2.5 and 7.5 mg/kg/day. 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 based on AUC of total cariprazine. At these doses, cariprazine caused fetal external malformations (localized fetal thoracic edema), skeletal malformations (bent limb bones, scapular and humerus), 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.

Cariprazine was not teratogenic in pregnant rabbits after administration of oral doses of 0.1, 1, and 5 mg/kg/day during the period of organogenesis, which are 0.02 to 4.6 times the MRHD based on AUC of total cariprazine. Maternal body weight and food consumption were decreased at mg/kg/day; however, no adverse effects were observed on pregnancy parameters or reproductive organs.

• Perinatal and postnatal reproductive toxicity

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 based on AUC of total cariprazine, did not cause maternal toxicity. Reduced postnatal survival and body weights occurred throughout the pre-weaning and post-weaning periods of first generation pups at 1 mg/kg/day. 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.

• Lactational Transfer

Cariprazine was administered to pregnant rats during pregnancy and lactation at 0.1, 0.3, and 1 mg/kg/day. Cariprazine concentrations in dams at 2 h post-dose on lactation day 10 increased proportionally with dose and decreased approximately 1.5-fold by 4 h post-dose. Cariprazine milk concentrations determined 2 h post-dose increased with dose and were between 1.6- and 2.9-fold higher than plasma concentrations. Plasma analysis in F1 pups showed little to no exposure to cariprazine, and no detectable exposure to cariprazine metabolites DCAR and DDCAR.