Vraylar

VRAYLAR™ is indicated for the:

• Treatment of schizophrenia [see Clinical Studies]
• Acute treatment of manic or mixed episodes associated with bipolar I disorder [see Clinical Studies].

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

Dosage And Administration

Advise patients that VRAYLAR can be taken with or without food. Counsel them on the importance of following dosage escalation instructions [see DOSAGE AND ADMINISTRATION].

Neuroleptic Malignant Syndrome (NMS)

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

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see WARNINGS AND PRECAUTIONS].

Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see WARNINGS AND PRECAUTIONS].

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking VRAYLAR [see WARNINGS AND PRECAUTIONS].

Orthostatic Hypotension

Counsel patients on the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dose [see WARNINGS AND PRECAUTIONS].

Interference With Cognitive And Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that VRAYLAR therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS].

Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS].

Concomitant Medications

Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-thecounter drugs since there is a potential for interactions [see DRUG INTERACTIONS].

Pregnancy

Advise patients that third trimester use of VRAYLAR may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations].

Pregnancy Registry

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

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Vraylar crosses into human milk. It is also not known how Vraylar effects the breastfed infant or its effects on milk production. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Vraylar.

• Store at 20 C to 25 C (68 F to 77 F)
• Keep this medication and all other medications out of the reach of children.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• severe distress or agitation;

• a seizure (convulsions);

• uncontrolled muscle movements in your face (chewing, lip smacking, frowning, tongue movement, blinking or eye movement);

• trouble swallowing;

• a blood cell disorder--sudden weakness or ill feeling, fever, chills, sore throat, mouth sores, red or swollen gums, trouble swallowing, skin sores, cold or flu symptoms, cough, trouble breathing;

• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss; or

• severe nervous system reaction--very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.

Cariprazine can have long lasting effects on your body. Some side effects could occur for several weeks after you stop using this medicine. You may also have new side effects whenever your dose is changed.

Common side effects may include:

• muscle movements;

• upset stomach, vomiting;

• drowsiness; or

• feeling restless.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Taking cariprazine with other drugs that make you sleepy or slow your breathing can cause dangerous or life-threatening side effects. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Many drugs can interact with cariprazine. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with cariprazine. Give a list of all your medicines to any healthcare provider who treats you.

Absorption

Bioavailability

Peak plasma concentrations of cariprazine achieved within approximately 3–6 hours following oral administration.1

Mean steady-state concentrations of cariprazine and DCAR achieved within about 1–2 weeks.1 Mean steady-state concentration of DDCAR achieved within about 4–8 weeks; however, time varies and may take >12 weeks in some patients.1

The principal active metabolites, DCAR and DDCAR, are present at mean plasma concentrations approximately 30 and 400% of plasma cariprazine concentrations after 12 weeks, respectively.1

Food

High-fat meal did not substantially affect peak plasma concentration or AUC of cariprazine or DCAR.1

Special Populations

In patients with mild or moderate hepatic impairment, cariprazine exposure is approximately 25% higher and DCAR and DDCAR exposure is approximately 45% lower than in individuals with normal hepatic function.1

Distribution

Extent

Cariprazine distributes into milk in rats; not known if drug or metabolites distribute into human milk.1

Plasma Protein Binding

Cariprazine and its principal active metabolites: 91–97% bound.1

Elimination

Metabolism

Extensively metabolized by CYP3A4 and, to a lesser extent, CYP2D6 to DCAR and DDCAR, which are pharmacologically active with similar potency to cariprazine.1

DCAR metabolized by CYP3A4 and CYP2D6 to DDCAR.1

DDCAR metabolized by CYP3A4 to a hydroxylated metabolite.1

Elimination Route

Following chronic administration of cariprazine, approximately 21% of daily dose recovered in urine; approximately 1.2% of dose excreted in urine as unchanged cariprazine.1

Half-life

Cariprazine: 2–4 days.1

DDCAR: Approximately 1–3 weeks.1

Following discontinuance, mean plasma concentrations of cariprazine and DCAR decrease by about 50% in about 1 day and mean plasma concentrations of DDCAR decrease by about 50% after 1 week.1

Special Populations

Pharmacokinetic analyses indicate no substantial relationship between clearance of the drug and its metabolites and Clcr.1 Not studied in severe renal impairment.1

Age, gender, and race do not have clinically important effects on pharmacokinetics of cariprazine, DCAR, or DDCAR.1 CYP2D6 poor metabolizer status also does not appear to affect the pharmacokinetics of cariprazine and its metabolites.1

Cariprazine is used to treat symptoms of psychotic (mental) disorders, such as schizophrenia, mania, or bipolar disorder. This medicine should not be used to treat behavioral problems in older adults with dementia. It changes some of the chemicals in the brain that cause psychotic disorders.

This medicine is available only with your doctor's prescription.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking Vraylar as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Vraylar is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.2)].

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Vraylar is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, 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.

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.

There is no known treatment for tardive dyskinesia, although the syndrome 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.

Late-Occurring Adverse Reactions

Adverse events may first appear several weeks after the initiation of Vraylar treatment, probably 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 Dosage and Administration (2.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3)].

Monitor for adverse reactions, including 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.

Metabolic Changes

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.

Schizophrenia

In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion 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. In the long-term, open-label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥6.5%).

Bipolar Mania

In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportion 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. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥6.5%).

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.

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.

Bipolar Mania

In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, 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. Tables 1 and 2 show the change in body weight occurring from baseline to endpoint in 6-week schizophrenia and 3-week bipolar mania 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.

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including Vraylar. Agranulocytosis (including fatal cases) has been reported with other agents in the class.

Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Vraylar at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Vraylar in patients with absolute neutrophil count < 1000/mm3 and follow their WBC until recovery.

Orthostatic Hypotension and Syncope

Atypical antipsychotics cause orthostatic hypotension and syncope. 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 not observed.

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.

5.9 Falls

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.

Seizures

Like other antipsychotic drugs, Vraylar may cause seizures. This risk is greatest 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 older patients.

Potential for Cognitive and Motor Impairment

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

In 6-week schizophrenia trials, somnolence (hypersomnia, sedation, and somnolence) was reported in 7% of Vraylar-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of Vraylar-treated patients compared to 4% of placebo-treated patients.

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.

Body Temperature Dysregulation

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use Vraylar with caution in patient who may experience these conditions.

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.

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.2)]
• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)]
• Tardive Dyskinesia [see Warnings and Precautions (5.4)]
• Late Occurring Adverse Reactions[see Warnings and Precautions (5.5)]
• Metabolic Changes [see Warnings and Precautions (5.6)]
• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7)]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.8)]
• Falls [see Warnings and Precautions (5.9)]
• Seizures [see Warnings and Precautions (5.10)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.11)]
• Body Temperature Dysregulation [see Warnings and Precautions (5.12)]
• Dysphagia [see Warnings and Precautions (5.13)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The information below is derived from the clinical trial database for Vraylar, consisting of 1733 patients with schizophrenia (aged 18 to 65) and 1025 patients with manic or mixed episodes associated with bipolar I disorder (aged 18 to 65) exposed to one or more doses with a total experience of 566.5 patient-years. Of these patients, 1317 participated in placebo-controlled, 6-week schizophrenia trials with doses ranging from 1.5 mg to 12 mg/day and 623 participated in placebo-controlled, 3-week bipolar mania trials with doses ranging from 3 mg to 12 mg/day. A total of 364 Vraylar-treated patients had at least 24 weeks of exposure and 239 Vraylar-treated patients had at least 48 weeks of exposure.

Patients with Schizophrenia

The following findings are based on four placebo-controlled, 6-week schizophrenia trials with Vraylar doses ranging from 1.5 to 12 mg once daily.

Adverse Reactions Associated with Discontinuation of Treatment: There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in Vraylar-treated patients and at least twice the rate of placebo.

Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms and akathisia.

Adverse Reactions with an incidence of ≥ 2% and greater than placebo, at any dose are shown in Table 3.

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.

Adverse Reactions Associated with Discontinuation of Treatment: The only adverse reaction 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 reaction, compared with 7% of placebo-treated patients in these trials.

Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.

Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in Table 4.

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Extrapyramidal Symptoms (EPS) and Akathisia

In schizophrenia and bipolar mania trials, data were objectively collected using the Simpson Angus Rating Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score ≤ 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Scale (BARS) for treatment-emergent akathisia (BARS total score ≤ 2 at baseline and > 2 post-baseline).

In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for 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 incidence of EPS is shown in Table 5.

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 EPS is provided in Table 6.

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 Nonclinical Toxicology (13.2)]. The possibility of lenticular changes or cataracts cannot be excluded at this time.

Vital Signs Changes

There were no clinically meaningful differences between Vraylar-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 - 12 mg/day Vraylar-treated schizophrenia patients.

Pooled data from 6-week schizophrenia and 3-week bipolar mania trials are shown in Tables 7 and 8.

Changes in Laboratory Tests

The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for 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 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 proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in cariprazine and placebo-treated patients.

Other Adverse Reactions Observed During the Pre-marketing Evaluation of Vraylar

Adverse reactions listed below were reported by patients treated with Vraylar at doses of ≥ 1.5 mg once daily within the database of 2758 Vraylar-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the 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

Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyponatremia

Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis

Nervous System Disorders: Rare: ischemic stroke

Psychiatric Disorders: Infrequent: suicide attempts, suicide ideation; Rare: completed suicide

Renal and Urinary Disorders: Infrequent: pollakiuria

Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis

Avoid drinking alcohol. Dangerous side effects could occur.

Vraylar may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

While you are taking Vraylar, you may be more sensitive to temperature extremes such as very hot conditions. Avoid becoming overheated or dehydrated. Drink plenty of fluids, especially in hot weather and during exercise.

Applies to cariprazine: oral capsule

Along with its needed effects, cariprazine (the active ingredient contained in Vraylar) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking cariprazine:

• Blurred vision
• chills
• dizziness
• drooling
• fever
• headache
• inability to move the eyes
• inability to sit still
• increased blinking or spasms of the eyelid
• loss of balance control
• muscle trembling, jerking, or stiffness
• need to keep moving
• nervousness
• pounding in the ears
• restlessness
• shuffling walk
• slow or fast heartbeat
• sticking out of the tongue
• stiffness of the limbs
• trouble with breathing, speaking, or swallowing
• twisting movements of the body
• uncontrolled movements, especially of the face, neck, arms, or legs
• unusual facial expressions

• Bladder pain
• bloody or cloudy urine
• difficult, burning, or painful urination
• fast, pounding, or irregular heartbeat or pulse
• frequent urge to urinate
• lower back or side pain
• muscle aches
• sore throat
• stuffy or runny nose
• unusual tiredness or weakness

• Confusion
• convulsions
• double vision
• drooling
• high fever
• increased sweating
• lip smacking or puckering
• muscle trembling, jerking, or stiffness
• puffing of the cheeks
• rapid or worm-like movements of the tongue
• severe muscle stiffness
• uncontrolled chewing movements
• unusually pale skin

Some side effects of cariprazine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain
• diarrhea
• difficulty having a bowel movement (stool)
• nausea
• sleepiness or unusual drowsiness
• trouble sleeping

• Acid or sour stomach
• anxiety
• back pain
• belching
• cough
• decreased appetite
• difficulty with moving
• dry mouth
• heartburn
• indigestion
• irritability
• muscle pain or stiffness
• pain in the arms, joints, or legs
• rash
• shaking
• stomach discomfort or upset
• weight gain

Applies to cariprazine: oral capsule, oral kit

General

The most frequently reported adverse effects were extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.[Ref]

Nervous system

Very common (10% or more): Extrapyramidal symptoms (29%), akathisia (21%), headache (18%)
Common (1% to 10%): Dizziness, somnolence, dystonia, Parkinsonism
Rare (less than 0.1%): Ischemic stroke[Ref]

During 6 week schizophrenia placebo controlled trials, 17% of patients reported extrapyramidal symptoms, excluding akathisia and restlessness in the cariprazine group. This led to study discontinuation in 0.3% of patients. Akathisia occurred in 11% of patients, leading to study discontinuation of 0.5%.

In 3 week bipolar mania placebo controlled trials, 28% of cariprazine treated patients experienced extrapyramidal symptoms, excluding akathisia and restlessness. This led to study discontinuation in 1% of patients. Akathisia occurred in 20% of patients, leading to study discontinuation of 2%.[Ref]

Metabolic

Hyperglycemia/Diabetes Mellitus: In long-term, open label studies in patients with schizophrenia or bipolar disorder, 4% of patients with normal baseline hemoglobin A1c developed elevated levels (HbA1c 6.5% or higher). In short-term trials, the number of patients with shifts from normal fasting glucose (less than 100 mg/dL) to high (greater than 126 mg/dL) and borderline (100 to less than 126 mg/dL) levels were similar to placebo-treated patients.

Dyslipidemia: In the 3 week placebo controlled bipolar mania and 6 week placebo controlled schizophrenia trials, the shifts in fasting total cholesterol, LDL, HDL, and triglycerides were similar in treatment and placebo groups.

Weight gain: In the 6 week placebo controlled trial of patients with schizophrenia, a 7% weight increase or greater was observed in 8% of the patients receiving 1.5 mg to 3 mg of drug daily (n=512), 8% of patients receiving 4.5 mg to 6 mg daily (n=570), and 17% in the 9 mg to 12 mg once daily group (n=203). During a long term, uncontrolled trial in patients with schizophrenia, the mean change from baseline weight at 48 weeks was 2.5 kg.[Ref]

Common (1% to 10%): Decreased appetite, weight gain, increase in blood creatine phosphokinase, hyperglycemia
Infrequent: Hyponatremia, diabetes mellitus
Frequency not reported: Dyslipidemia[Ref]

Cardiovascular

In 3 placebo controlled trials, during a three week period of treating bipolar mania (n=1065), there was no clinically significant difference between cariprazine (the active ingredient contained in Vraylar) and placebo treated patients regarding changes from baseline to endpoint supine blood pressure parameters. There was however, an increase in supine diastolic blood pressure in the 9 to 12 mg orally once a day cariprazine treated patients.[Ref]

Common (1% to 10%): Tachycardia, hypertension
Uncommon (0.1% to 1%): Orthostatic hypotension[Ref]

Dermatologic

Common (1% to 10%): Rash
Infrequent: Hyperhidrosis[Ref]

Gastrointestinal

Very Common (10% or more): Nausea (11%)
Common (1% to 10%): Constipation, vomiting, dyspepsia, abdominal pain, diarrhea, dry mouth, toothache
Infrequent: Gastroesophageal reflux disease, gastritis
Frequency not reported: Dysphagia[Ref]

Psychiatric

Very common (10% or more): Insomnia (13%)
Common (1% to 10%): Restlessness, agitation, anxiety
Rare (less than 0.1%): Completed suicide
Infrequent: Suicide attempts, suicidal ideation[Ref]

Hematologic

Frequency not reported: Leukopenia, neutropenia, agranulocytosis[Ref]

Hepatic

Transaminase elevations 3 times the upper limit of normal or greater occurred in 1% to 2% of patients in the cariprazine (the active ingredient contained in Vraylar) group during 6 week schizophrenia trials; the incidence increased with dose. Elevations occurred in 2% to 4% of patients during 3 week bipolar mania trials.[Ref]

Uncommon (0.1% to 1%): Increase in hepatic enzymes
Rare (less than 0.1%): Hepatitis[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection
Infrequent: Pollakiuria[Ref]

Hypersensitivity

Frequency not reported: Rash, pruritus, urticaria, swollen lips/tongue, face and pharyngeal edema, swelling of the face[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, arthralgia, pain in extremities, stiffness
Rare (less than 0.1%): Rhabdomyolysis[Ref]

Respiratory

Common (1% to 10%): Cough, oropharyngeal pain
Uncommon (0.1% to 1%): Nasopharyngitis[Ref]

Ocular

Common (1% to 10%): Blurred vision
Uncommon (0.1% to 1%): Cataracts[Ref]

In long term uncontrolled schizophrenia (48 week) and bipolar mania (16 week) trials, cataracts occurred in 0.1% and 0.2% of participants respectively.[Ref]

Other

Common (1% to 10%): Fatigue, pyrexia[Ref]

Some side effects of Vraylar may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.