Get your patient on Rexulti (Brexpiprazole)

REXULTI is indicated for:

• Adjunctive treatment to antidepressants for major depressive disorder (MDD) in adults
• Treatment of schizophrenia in adults and pediatric patients ages 13 years and older
• Treatment of agitation associated with dementia due to Alzheimer's disease

REXULTI is not indicated as an as needed ("prn") treatment for agitation associated with dementia due to Alzheimer's disease [see

Advise patients that REXULTI can be taken with or without food. Advise patients regarding importance of following dosage escalation instructions

REXULTI tablets are available in 6 strengths:

• 0.25 mg tablets are light brown, round, shallow convex, bevel-edged body with "BRX" and "0.25" imprinted on one side.
• 0.5 mg tablets: are light orange, round, shallow convex, bevel-edged body with "BRX" and "0.5" imprinted on one side.
• 1 mg tablets are light yellow, round, shallow convex, bevel-edged body with "BRX" and "1" imprinted on one side.
• 2 mg tablets are light green, round, shallow convex, bevel-edged body with "BRX" and "2" imprinted on one side.
• 3 mg tablets are light purple, round, shallow convex, bevel-edged body with "BRX" and "3" imprinted on one side.
• 4 mg tablets are white, round, shallow convex, bevel-edged body with "BRX" and "4" imprinted on one side.

REXULTI is contraindicated in patients with a known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swelling, urticaria, and anaphylaxis.

• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis:
  [Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) 5.3]

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

  In placebo-controlled trials in elderly patients with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease

  [see

  Boxed Warning,Warnings and Precautions (5.1)].
• Neuroleptic Malignant Syndrome:
  [Manage with immediate discontinuation and close monitoring. 5.4]

  5.4 Neuroleptic Malignant Syndrome (NMS)

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

  Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

  If NMS is suspected, immediately discontinue REXULTI and provide intensive symptomatic treatment and monitoring.
• Tardive Dyskinesia:
  [Discontinue if clinically appropriate. 5.5]

  5.5 Tardive Dyskinesia

  Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown.

  The risk of tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the cumulative dose increases. The syndrome can develop after relatively brief treatment periods, 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 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, REXULTI should be prescribed in a manner most likely to reduce the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs and 2) for whom alternative, equally 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 needed to produce a satisfactory clinical response. Periodically reassess the need for continued treatment.

  If signs and symptoms of tardive dyskinesia appear in a patient treated with REXULTI, drug discontinuation should be considered. However, some patients may require treatment with REXULTI despite the presence of the syndrome.
• Metabolic Changes:
  [Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. 5.6]

  5.6 Metabolic Changes

  Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes including hyperglycemia, diabetes mellitus, dyslipidemia, and body 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/Diabetes Mellitus

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

  Adjunctive Treatment of Major Depressive Disorder

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with MDD, 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 REXULTI and placebo. In the long-term, open-label depression studies, 5% of adult patients with normal baseline fasting glucose experienced a shift to high while taking REXULTI plus an antidepressant (ADT); 25% of patients with borderline fasting glucose experienced shifts to high. Combined, 9% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term depression studies.

  Schizophrenia (Adults)

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo. In the long-term, open-label schizophrenia studies, 8% of adult patients with normal baseline fasting glucose experienced a shift from normal to high while taking REXULTI; 17% of patients with borderline fasting glucose experienced shifts from borderline to high. Combined, 10% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies.

  Schizophrenia Pediatric Patients (13 to 17 years of age)

  In a 6-week, placebo-controlled study in pediatric patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo. In this study, 1.1% of pediatric patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) while taking REXULTI.

  In the long-term, open-label study in pediatric patients with schizophrenia, 2.7% of pediatric patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) while taking REXULTI.

  Agitation Associated with Dementia Due to Alzheimer's Disease

  In the 12-week placebo-controlled, fixed-dose studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or impaired (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI (14%) and patients treated with placebo (16%).

  Of the patients who were previously treated with REXULTI for 12-weeks and continued into a 12-week, active-treatment extension study, 15% of patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) fasting glucose while taking REXULTI; 30% of patients with impaired fasting glucose experienced shifts from impaired fasting glucose (≥100 and <126 mg/dL) to high fasting glucose. Combined, 20% of patients with normal or impaired fasting glucose experienced shifts to high fasting glucose.

  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.

  Adjunctive Treatment of Major Depressive Disorder

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 3 shows the proportions of patients with changes in fasting triglycerides.

  Table 3 Change in Fasting Triglycerides in the 6-Week Placebo-Controlled, Fixed-Dose MDD Studies

  Proportion of Patients with Shifts Baseline to Post-Baseline
  Triglycerides	Placebo	1 mg/day	2 mg/day	3 mg/day
  Normal to High (<150 mg/dL to ≥200 and <500 mg/dL)	6% (15/257)denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with shift	5% (7/145)	13% (15/115)	9% (13/150)
  Normal/Borderline to Very High (<200 mg/dL to ≥500 mg/dL)	0% (0/309)	0% (0/177)	0.7% (1/143)	0% (0/179)

  In the long-term, open-label depression studies, shifts in baseline fasting cholesterol from normal to high were reported in 9% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 14% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 17% experienced shifts to high, and 0.2% experienced shifts to very high. Combined, 0.6% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term depression studies.

  Schizophrenia (Adults)

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 4 shows the proportions of patients with changes in fasting triglycerides.

  Table 4 Change in Fasting Triglycerides in the 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients

  Proportion of Patients with Shifts Baseline to Post-Baseline
  Triglycerides	Placebo	1 mg/day	2 mg/day	4 mg/day
  Normal to High (<150 mg/dL to ≥200 and <500 mg/dL)	6% (15/253)denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with shift	10% (7/72)	8% (19/232)	10% (22/226)
  Normal/Borderline to Very High (<200 mg/dL to ≥500 mg/dL)	0% (0/303)	0% (0/94)	0% (0/283)	0.4% (1/283)

  In the long-term, open-label schizophrenia studies in adult patients, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 2% (LDL cholesterol), and shifts in baseline from normal to low were reported in 17% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 13% experienced shifts to high, and 0.4% experienced shifts to very high triglycerides. Combined, 0.6% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies.

  Schizophrenia [Pediatric Patients (13 to 17 years of age)]

  The safety and efficacy of REXULTI have not been established in patients under the age of 13 years. In a 6-week, placebo-controlled study in pediatric patients with schizophrenia, no clinically meaningful changes in fasting cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were observed between the REXULTI and placebo groups.

  In the long-term, open-label study in pediatric patients with schizophrenia, shifts in baseline fasting total cholesterol from normal to high (<170 to ≥200 mg/dL) were reported in 7% of patients taking REXULTI, and shifts in baseline HDL cholesterol from normal to low (>45 to <40 mg/dL) were reported in 10%% of patients taking REXULTI. Of patients with normal baseline triglycerides, 15% experienced shifts from normal to high (<90 to ≥130 mg/dL).

  Agitation Associated with Dementia Due to Alzheimer's Disease

  In the 12-week placebo-controlled, fixed-dose clinical studies in patients (55 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, changes in total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients.

  Table 5 shows the proportions of patients with changes in fasting triglycerides in REXULTI- and placebo-treated patients.

  Table 5 Change in Fasting Triglycerides in the 12-Week Placebo-Controlled, Fixed-Dose Agitation Associated with Dementia Due to Alzheimer's Disease Studies

  Proportion of Patients with Shifts Baseline to Post-Baseline
  Triglycerides	Placebo	1 mg/day	2 mg/day	3 mg/day
  Normal to High (<150 and 200 to <500 mg/dL)	6% (10/157)denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with shift	9% (9/99)	13% (17/133)	6% (6/94)
  Borderline to High (150 and <200mg/dL to 200 and <500 mg/dL)	12% (3/26)	33% (2/6)	28% (7/25)	26% (6/23)
  Normal/Borderline to High (<200 mg/dL to 200 and <500 mg/dL)	7% (13/183)	11% (11/105)	15% (24/158)	10% (12/117)

  Of the patients who were previously treated with REXULTI for 12 weeks and continued into a 12-week, active-treatment extension study, 9% of patients taking REXULTI showed shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL), and 16% of patients taking REXULTI showed shifts in baseline HDL cholesterol from normal to low (≥40 to <40 mg/dL). Of the patients with normal baseline triglycerides, 18% experienced shifts from normal (<150 mg/dL) to high (200 to <500 mg/dL).

  Weight Gain

  Weight gain has been observed in patients treated with atypical antipsychotics, including REXULTI. Monitor weight at baseline and frequently thereafter.

  Adjunctive Treatment of Major Depressive Disorder: Table 6 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week placebo-controlled, fixed-dose clinical studies in patients with MDD.

  Table 6 Increases in Body Weight in the 6-Week Placebo-Controlled, Fixed-Dose MDD Studies

  	Placebo	1 mg/day	2 mg/day	3 mg/day
  	n=407	n=225	n=187	n=228
  Mean Change from Baseline (kg) at Last Visit
  All Patients	+0.3	+1.3	+1.6	+1.6
  Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (n/NN=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with a shift ≥7%)
  	2%	5%	5%	2%
  	(8/407)	(11/225)	(9/187)	(5/228)

  In the long-term, open-label depression studies, 4% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 2.9 kg at Week 26 and 3.1 kg at Week 52. In the long-term, open-label depression studies, 30% of patients demonstrated a ≥7% increase in body weight, and 4% demonstrated a ≥7% decrease in body weight.

  Schizophrenia

  (

  Adults)

  Table 7 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia.

  Table 7 Increases in Body Weight in the 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients

  	Placebo	1 mg/day	2 mg/day	4 mg/day
  	n=362	n=120	n=362	n=362
  Mean Change from Baseline (kg) at Last Visit
  All Patients	+0.2	+1.0	+1.2	+1.2
  Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with a shift ≥7%n/N)
  	4%	10%	11%	10%
  	(15/362)	(12/120)	(38/362)	(37/362)

  In the long-term, open-label schizophrenia studies in adult patients, 0.6% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 1.3 kg at Week 26 and 2.0 kg at Week 52. In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥7% increase in body weight, and 10% demonstrated a ≥7% decrease in body weight.

  Schizophrenia [Pediatric Patients (13 to 17 years of age)]

  In a 6-week, placebo-controlled study in pediatric patients with schizophrenia, no patients discontinued due to weight increase. The mean increase in weight from baseline to last visit was 0.8 kg in the REXULTI group and no changes were seen in the placebo groups. The percentage of pediatric patients demonstrating a ≥7% increase in body weight was 8.2% in the REXULTI group and 4.9% in the placebo group.

  In the long-term, open label study in pediatric patients with schizophrenia, 0.5% of patients discontinued due to weight increase. The mean increase in weight from the open-label study baseline to last visit was 3.8 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents by comparisons to age- and gender- matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this study, the mean change in z-score from open-label baseline to last visit was 0.10 SD for body weight, while 20% of patients had an increase in age-and-gender-adjusted body weight z-score of at least 0.5 SD from baseline. When treating pediatric, weight gain should be monitored and assessed against that expected for normal growth.

  Agitation Associated with Dementia Due to Alzheimer's Disease

  In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportion of the patients with a ≥7% increase in body weight (kg) at any visit were 2% in REXULTI compared to 0% in placebo group.

  In patients who were previously treated with REXULTI for 12 weeks and who continued into a 12-week, active-treatment extension study, there was no mean change in weight (kg) from baseline to last visit in association with REXULTI. In this extension study, 4% of patients demonstrated ≥7% increase in body weight, and 5% demonstrated a ≥7% decrease in body weight from baseline to last visit.
• Pathological Gambling and Other Compulsive Behaviors:
  [Consider dose reduction or discontinuation. 5.7]

  5.7 Pathological Gambling and Other Compulsive Behaviors

  Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking REXULTI. Other compulsive urges, reported less frequently, include sexual urges, shopping, eating, or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with REXULTI. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
• Leukopenia, Neutropenia, and Agranulocytosis:
  [Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing REXULTI if a clinically significant decline in WBC occurs in absence of other causative factors. 5.8]

  5.8 Leukopenia, Neutropenia, and Agranulocytosis

  Leukopenia and neutropenia have been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this 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 REXULTI 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 REXULTI in patients with absolute neutrophil count <1000/mm³and follow their WBC until recovery.
• Orthostatic Hypotension and Syncope:
  [Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope. 5.9]

  5.9 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. In the short-term, placebo-controlled clinical studies of REXULTI plus ADT in adult patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in REXULTI plus ADT-treated patients compared to placebo plus ADT-treated patients included: dizziness (2% versus 2%) and orthostatic hypotension (0.1% versus 0%). In the short-term, placebo-controlled clinical studies of REXULTI in adult patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo patients included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%). In 12-week, placebo-controlled clinical studies of REXULTI in patients with agitation associated with dementia due to Alzheimer's disease, the incidence of orthostatic hypotension-related adverse reactions in patients treated with REXULTI compared to patients treated with placebo included: dizziness (3% versus 3%), orthostatic hypotension (1% versus 1%), and syncope (0.2% versus 0.8%).

  Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medication), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. REXULTI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from the premarketing clinical studies.
• Seizures:
  [Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. 5.11]

  5.11 Seizures

  Like other antipsychotic drugs, REXULTI 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:
  [Use caution when operating machinery. 5.14]

  5.14 Potential for Cognitive and Motor Impairment

  REXULTI, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, or motor skills. In the 6-week placebo-controlled clinical studies in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% of REXULTI plus ADT-treated patients compared to 1% of placebo plus ADT-treated patients.

  In the 6-week placebo-controlled clinical studies in adult patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients.

  In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, somnolence (including sedation) was reported in 3% of patients treated with REXULTI compared to 1% of patients treated with placebo.

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

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]

  WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS

  WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS

  See full prescribing information for complete boxed warning.

  • [Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease. 5.1]

    5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

    Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in the drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

    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. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease

    [see

    [Boxed Warning] ,Warnings and Precautions (5.3)]
  • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Safety and effectiveness of REXULTI have not been established in pediatric patients with MDD. (5.2,8.4)

  Increased Mortality in Elderly Patients with Dementia-Related Psychosis

  Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease

  [see Warnings and Precautions (5.1)]

  Suicidal Thoughts and Behaviors

  Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors

  [see Warnings and Precautions (5.2)]

  The safety and effectiveness of REXULTI have not been established in pediatric patients with MDD

  [see Warnings and Precautions (5.2)] ,[Use in Specific Populations (8.4)]

  ,[Warnings and Precautions (5.1)]
• Suicidal Thoughts and Behaviors in Adolescents and Young Adults
  [see Boxed Warning] ,[Warnings and Precautions (5.2)]
• Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis
  [see Warnings and Precautions (5.3)]
• Neuroleptic Malignant Syndrome (NMS)
  [see Warnings and Precautions (5.4)]

  5.4 Neuroleptic Malignant Syndrome (NMS)

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

  Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

  If NMS is suspected, immediately discontinue REXULTI and provide intensive symptomatic treatment and monitoring.
• Tardive Dyskinesia
  [see Warnings and Precautions (5.5)]

  5.5 Tardive Dyskinesia

  Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown.

  The risk of tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the cumulative dose increases. The syndrome can develop after relatively brief treatment periods, 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 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, REXULTI should be prescribed in a manner most likely to reduce the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs and 2) for whom alternative, equally 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 needed to produce a satisfactory clinical response. Periodically reassess the need for continued treatment.

  If signs and symptoms of tardive dyskinesia appear in a patient treated with REXULTI, drug discontinuation should be considered. However, some patients may require treatment with REXULTI despite the presence of the syndrome.
• Metabolic Changes
  [see Warnings and Precautions (5.6)]

  5.6 Metabolic Changes

  Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes including hyperglycemia, diabetes mellitus, dyslipidemia, and body 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/Diabetes Mellitus

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

  Adjunctive Treatment of Major Depressive Disorder

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with MDD, 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 REXULTI and placebo. In the long-term, open-label depression studies, 5% of adult patients with normal baseline fasting glucose experienced a shift to high while taking REXULTI plus an antidepressant (ADT); 25% of patients with borderline fasting glucose experienced shifts to high. Combined, 9% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term depression studies.

  Schizophrenia (Adults)

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo. In the long-term, open-label schizophrenia studies, 8% of adult patients with normal baseline fasting glucose experienced a shift from normal to high while taking REXULTI; 17% of patients with borderline fasting glucose experienced shifts from borderline to high. Combined, 10% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies.

  Schizophrenia Pediatric Patients (13 to 17 years of age)

  In a 6-week, placebo-controlled study in pediatric patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo. In this study, 1.1% of pediatric patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) while taking REXULTI.

  In the long-term, open-label study in pediatric patients with schizophrenia, 2.7% of pediatric patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) while taking REXULTI.

  Agitation Associated with Dementia Due to Alzheimer's Disease

  In the 12-week placebo-controlled, fixed-dose studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or impaired (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI (14%) and patients treated with placebo (16%).

  Of the patients who were previously treated with REXULTI for 12-weeks and continued into a 12-week, active-treatment extension study, 15% of patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) fasting glucose while taking REXULTI; 30% of patients with impaired fasting glucose experienced shifts from impaired fasting glucose (≥100 and <126 mg/dL) to high fasting glucose. Combined, 20% of patients with normal or impaired fasting glucose experienced shifts to high fasting glucose.

  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.

  Adjunctive Treatment of Major Depressive Disorder

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 3 shows the proportions of patients with changes in fasting triglycerides.

  Table 3 Change in Fasting Triglycerides in the 6-Week Placebo-Controlled, Fixed-Dose MDD Studies

  Proportion of Patients with Shifts Baseline to Post-Baseline
  Triglycerides	Placebo	1 mg/day	2 mg/day	3 mg/day
  Normal to High (<150 mg/dL to ≥200 and <500 mg/dL)	6% (15/257)denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with shift	5% (7/145)	13% (15/115)	9% (13/150)
  Normal/Borderline to Very High (<200 mg/dL to ≥500 mg/dL)	0% (0/309)	0% (0/177)	0.7% (1/143)	0% (0/179)

  In the long-term, open-label depression studies, shifts in baseline fasting cholesterol from normal to high were reported in 9% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 14% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 17% experienced shifts to high, and 0.2% experienced shifts to very high. Combined, 0.6% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term depression studies.

  Schizophrenia (Adults)

  In the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 4 shows the proportions of patients with changes in fasting triglycerides.

  Table 4 Change in Fasting Triglycerides in the 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients

  Proportion of Patients with Shifts Baseline to Post-Baseline
  Triglycerides	Placebo	1 mg/day	2 mg/day	4 mg/day
  Normal to High (<150 mg/dL to ≥200 and <500 mg/dL)	6% (15/253)denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with shift	10% (7/72)	8% (19/232)	10% (22/226)
  Normal/Borderline to Very High (<200 mg/dL to ≥500 mg/dL)	0% (0/303)	0% (0/94)	0% (0/283)	0.4% (1/283)

  In the long-term, open-label schizophrenia studies in adult patients, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 2% (LDL cholesterol), and shifts in baseline from normal to low were reported in 17% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 13% experienced shifts to high, and 0.4% experienced shifts to very high triglycerides. Combined, 0.6% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies.

  Schizophrenia [Pediatric Patients (13 to 17 years of age)]

  The safety and efficacy of REXULTI have not been established in patients under the age of 13 years. In a 6-week, placebo-controlled study in pediatric patients with schizophrenia, no clinically meaningful changes in fasting cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were observed between the REXULTI and placebo groups.

  In the long-term, open-label study in pediatric patients with schizophrenia, shifts in baseline fasting total cholesterol from normal to high (<170 to ≥200 mg/dL) were reported in 7% of patients taking REXULTI, and shifts in baseline HDL cholesterol from normal to low (>45 to <40 mg/dL) were reported in 10%% of patients taking REXULTI. Of patients with normal baseline triglycerides, 15% experienced shifts from normal to high (<90 to ≥130 mg/dL).

  Agitation Associated with Dementia Due to Alzheimer's Disease

  In the 12-week placebo-controlled, fixed-dose clinical studies in patients (55 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, changes in total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients.

  Table 5 shows the proportions of patients with changes in fasting triglycerides in REXULTI- and placebo-treated patients.

  Table 5 Change in Fasting Triglycerides in the 12-Week Placebo-Controlled, Fixed-Dose Agitation Associated with Dementia Due to Alzheimer's Disease Studies

  Proportion of Patients with Shifts Baseline to Post-Baseline
  Triglycerides	Placebo	1 mg/day	2 mg/day	3 mg/day
  Normal to High (<150 and 200 to <500 mg/dL)	6% (10/157)denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with shift	9% (9/99)	13% (17/133)	6% (6/94)
  Borderline to High (150 and <200mg/dL to 200 and <500 mg/dL)	12% (3/26)	33% (2/6)	28% (7/25)	26% (6/23)
  Normal/Borderline to High (<200 mg/dL to 200 and <500 mg/dL)	7% (13/183)	11% (11/105)	15% (24/158)	10% (12/117)

  Of the patients who were previously treated with REXULTI for 12 weeks and continued into a 12-week, active-treatment extension study, 9% of patients taking REXULTI showed shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL), and 16% of patients taking REXULTI showed shifts in baseline HDL cholesterol from normal to low (≥40 to <40 mg/dL). Of the patients with normal baseline triglycerides, 18% experienced shifts from normal (<150 mg/dL) to high (200 to <500 mg/dL).

  Weight Gain

  Weight gain has been observed in patients treated with atypical antipsychotics, including REXULTI. Monitor weight at baseline and frequently thereafter.

  Adjunctive Treatment of Major Depressive Disorder: Table 6 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week placebo-controlled, fixed-dose clinical studies in patients with MDD.

  Table 6 Increases in Body Weight in the 6-Week Placebo-Controlled, Fixed-Dose MDD Studies

  	Placebo	1 mg/day	2 mg/day	3 mg/day
  	n=407	n=225	n=187	n=228
  Mean Change from Baseline (kg) at Last Visit
  All Patients	+0.3	+1.3	+1.6	+1.6
  Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (n/NN=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with a shift ≥7%)
  	2%	5%	5%	2%
  	(8/407)	(11/225)	(9/187)	(5/228)

  In the long-term, open-label depression studies, 4% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 2.9 kg at Week 26 and 3.1 kg at Week 52. In the long-term, open-label depression studies, 30% of patients demonstrated a ≥7% increase in body weight, and 4% demonstrated a ≥7% decrease in body weight.

  Schizophrenia

  (

  Adults)

  Table 7 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia.

  Table 7 Increases in Body Weight in the 6-Week Placebo-Controlled, Fixed-Dose Schizophrenia Studies in Adult Patients

  	Placebo	1 mg/day	2 mg/day	4 mg/day
  	n=362	n=120	n=362	n=362
  Mean Change from Baseline (kg) at Last Visit
  All Patients	+0.2	+1.0	+1.2	+1.2
  Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (denotes n/N where N=the total number of patients who had a measurement at baseline and at least one post-baseline result;n=the number of patients with a shift ≥7%n/N)
  	4%	10%	11%	10%
  	(15/362)	(12/120)	(38/362)	(37/362)

  In the long-term, open-label schizophrenia studies in adult patients, 0.6% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 1.3 kg at Week 26 and 2.0 kg at Week 52. In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥7% increase in body weight, and 10% demonstrated a ≥7% decrease in body weight.

  Schizophrenia [Pediatric Patients (13 to 17 years of age)]

  In a 6-week, placebo-controlled study in pediatric patients with schizophrenia, no patients discontinued due to weight increase. The mean increase in weight from baseline to last visit was 0.8 kg in the REXULTI group and no changes were seen in the placebo groups. The percentage of pediatric patients demonstrating a ≥7% increase in body weight was 8.2% in the REXULTI group and 4.9% in the placebo group.

  In the long-term, open label study in pediatric patients with schizophrenia, 0.5% of patients discontinued due to weight increase. The mean increase in weight from the open-label study baseline to last visit was 3.8 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents by comparisons to age- and gender- matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this study, the mean change in z-score from open-label baseline to last visit was 0.10 SD for body weight, while 20% of patients had an increase in age-and-gender-adjusted body weight z-score of at least 0.5 SD from baseline. When treating pediatric, weight gain should be monitored and assessed against that expected for normal growth.

  Agitation Associated with Dementia Due to Alzheimer's Disease

  In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportion of the patients with a ≥7% increase in body weight (kg) at any visit were 2% in REXULTI compared to 0% in placebo group.

  In patients who were previously treated with REXULTI for 12 weeks and who continued into a 12-week, active-treatment extension study, there was no mean change in weight (kg) from baseline to last visit in association with REXULTI. In this extension study, 4% of patients demonstrated ≥7% increase in body weight, and 5% demonstrated a ≥7% decrease in body weight from baseline to last visit.
• Pathological Gambling and Other Compulsive Behaviors
  [see Warnings and Precautions (5.7)]

  5.7 Pathological Gambling and Other Compulsive Behaviors

  Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking REXULTI. Other compulsive urges, reported less frequently, include sexual urges, shopping, eating, or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with REXULTI. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
• Leukopenia, Neutropenia, and Agranulocytosis
  [see Warnings and Precautions (5.8)]

  5.8 Leukopenia, Neutropenia, and Agranulocytosis

  Leukopenia and neutropenia have been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this 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 REXULTI 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 REXULTI in patients with absolute neutrophil count <1000/mm³and follow their WBC until recovery.
• Orthostatic Hypotension and Syncope
  [see Warnings and Precautions (5.9)]

  5.9 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. In the short-term, placebo-controlled clinical studies of REXULTI plus ADT in adult patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in REXULTI plus ADT-treated patients compared to placebo plus ADT-treated patients included: dizziness (2% versus 2%) and orthostatic hypotension (0.1% versus 0%). In the short-term, placebo-controlled clinical studies of REXULTI in adult patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo patients included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%). In 12-week, placebo-controlled clinical studies of REXULTI in patients with agitation associated with dementia due to Alzheimer's disease, the incidence of orthostatic hypotension-related adverse reactions in patients treated with REXULTI compared to patients treated with placebo included: dizziness (3% versus 3%), orthostatic hypotension (1% versus 1%), and syncope (0.2% versus 0.8%).

  Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medication), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. REXULTI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from the premarketing clinical studies.
• Falls
  [see Warnings and Precautions (5.10)]

  5.10 Falls

  Antipsychotics, including REXULTI, 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 treatment.
• Seizures
  [see Warnings and Precautions (5.11)]

  5.11 Seizures

  Like other antipsychotic drugs, REXULTI 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.
• Body Temperature Dysregulation
  [see Warnings and Precautions (5.12)]

  5.12 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 REXULTI with caution in patients who may experience these conditions.
• Dysphagia
  [see Warnings and Precautions (5.13)]

  5.13 Dysphagia

  Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including REXULTI, should be used cautiously in patients at risk for aspiration.
• Potential for Cognitive and Motor Impairment
  [see Warnings and Precautions (5.14)]

  5.14 Potential for Cognitive and Motor Impairment

  REXULTI, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, or motor skills. In the 6-week placebo-controlled clinical studies in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% of REXULTI plus ADT-treated patients compared to 1% of placebo plus ADT-treated patients.

  In the 6-week placebo-controlled clinical studies in adult patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients.

  In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, somnolence (including sedation) was reported in 3% of patients treated with REXULTI compared to 1% of patients treated with placebo.

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

Brexpiprazole, an atypical antipsychotic, is available as REXULTI^® (brexpiprazole) tablets. Brexpiprazole is 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1

REXULTI tablets are for oral administration and are available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg strengths. Inactive ingredients include lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc. Colorants include titanium dioxide, iron oxide, and ferrosoferric oxide.

The mechanism of action of REXULTI in the adjunctive treatment of major depressive disorder, treatment of agitation associated with dementia due to Alzheimer's disease, or treatment of schizophrenia is unknown. However, the efficacy of REXULTI may be mediated through a combination of partial agonist activity at serotonin 5-HT_1A and dopamine D₂ receptors, and antagonist activity at serotonin 5-HT_2A receptors.

Lifetime carcinogenicity studies were conducted in ICR mice and Sprague Dawley rats. Brexpiprazole was administered orally for two years to male and female mice at doses of 0.75, 2, and 5 mg/kg/day (0.9 to 6.1 times the oral MRHD of 4 mg/day based on mg/m² body surface area) and to male and female rats at doses of 1, 3, and 10 mg/kg and 3, 10, and 30 mg/kg/day, respectively (2.4 to 24 and 7.3 to 73 times the oral MRHD, males and females). In female mice, the incidence of mammary gland adenocarcinoma was increased at all doses, and the incidence of adenosquamous carcinoma was increased at 2.4 and 6.1 times the MRHD. No increase in the incidence of tumors was observed in male mice. In the rat study, brexpiprazole was not carcinogenic in either sex at doses up to 73 times the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The potential for increasing serum prolactin level of brexpiprazole was shown in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.

The efficacy of REXULTI in the adjunctive treatment of major depressive disorder (MDD) was evaluated in two 6-week double-blind, placebo-controlled, fixed-dose studies of adult patients meeting DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, who had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant treatment (with escitalopram, fluoxetine, paroxetine controlled-release, sertraline, duloxetine delayed release, or venlafaxine extended release). Inadequate response during the prospective antidepressant treatment phase was defined as having persistent symptoms without substantial improvement throughout the course of treatment.

Patients in Study 1 (NCT01360645) were randomized to REXULTI 2 mg once a day or placebo. Patients in Study 2 (NCT01360632) were randomized to REXULTI 1 or 3 mg once a day or placebo. For patients randomized to REXULTI, all patients initiated treatment at 0.5 mg once daily during Week 1. At Week 2, the REXULTI dosage was increased to 1 mg in all treatment groups, and either maintained at 1 mg or increased to 2 mg or 3 mg once daily, based on treatment assignment, from Week 3 onwards. The dosages were then maintained for the 4 remaining weeks.

The primary endpoint was change from baseline to Week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-related scale used to assess the degree of depressive symptomatology, with 0 representing no symptoms and 60 representing worst symptoms.

At randomization, the mean MADRS total score was 27. In Studies 1 and 2, REXULTI (plus ADT) 2 mg once daily and 3 mg once daily were superior to placebo plus ADT in reducing mean MADRS total scores. Results from the primary efficacy parameters for both fixed dose studies are shown below in Table 13. Figure 4 below shows the time course of response based on the primary efficacy measure (MADRS) in Study 1.

An examination of population subgroups did not suggest differential response based on age, gender, race, or choice of prospective antidepressant.

REXULTI (brexpiprazole) tablets have markings on one side and are available in the following strengths and package configurations (see below):

• 0.25 mg tablets are light brown, round, shallow convex, bevel-edged body with "BRX" and "0.25" imprinted on one side

  NDC 59148-035-13

  Bottles of 30

• 0.5 mg tablets: are light orange, round, shallow convex, bevel-edged body with "BRX" and "0.5" imprinted on one side

  NDC 59148-036-13

  Bottles of 30

• 1 mg tablets are light yellow, round, shallow convex, bevel-edged body with "BRX" and "1" imprinted on one side

  NDC 59148-037-13

  Bottles of 30

• 2 mg tablets are light green, round, shallow convex, bevel-edged body with "BRX" and "2" imprinted on one side

  NDC 59148-038-13

  Bottles of 30

• 3 mg tablets are light purple, round, shallow convex, bevel-edged body with "BRX" and "3" imprinted on one side

  NDC 59148-039-13

  Bottles of 30

• 4 mg tablets are white, round, shallow convex, bevel-edged body with "BRX" and "4" imprinted on one side

  NDC 59148-040-13

  Bottles of 30