Sign Out
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. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Brexpiprazole (Rexulti) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis as follows].
Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults: In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 5.
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. (See Table 5.)
Click on icon to see table/diagram/imageIt is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Brexpiprazole (Rexulti), in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. Brexpiprazole (Rexulti) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Increased Mortality in Elderly Patients with Dementia-Related Psychosis previously].
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs.
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.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, Brexpiprazole (Rexulti) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to 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, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on Brexpiprazole (Rexulti), drug discontinuation should be considered. However, some patients may require treatment with Brexpiprazole (Rexulti) despite the presence of the syndrome.
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class 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. There have been reports of hyperglycemia in patients treated with Brexpiprazole (Rexulti) [see Clinical Trials Experience under Adverse Reactions]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the atypical antipsychotic drug.
Major Depressive Disorder: In the 6 week, placebo-controlled, fixed-dose clinical trials in 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 Brexpiprazole (Rexulti) and placebo.
In the long-term, open-label depression studies, 5% of patients with normal baseline fasting glucose experienced a shift to high while taking Brexpiprazole (Rexulti)+Antidepressant (ADT); 25% of subjects with borderline fasting glucose experienced shifts to high. Combined, 9% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term depression studies.
Schizophrenia: In the 6-week, placebo-controlled, fixed-dose clinical trials in 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 Brexpiprazole (Rexulti) and placebo.
In the long-term, open-label schizophrenia studies, 8% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking Brexpiprazole (Rexulti), 17% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 10% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies.
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Major Depressive Disorder: In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in Brexpiprazole (Rexulti)- and placebo-treated patients. Table 6 shows the proportions of patients with changes in fasting triglycerides. (See Table 6.)
Click on icon to see table/diagram/imageIn 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 Brexpiprazole (Rexulti). Of patients with normal baseline triglycerides, 17% experienced shifts to high, and 0.2% experienced shifts to very high. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term depression studies.
Schizophrenia: In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in Brexpiprazole (Rexulti)- and placebo-treated patients. Table 7 shows the proportions of patients with changes in fasting triglycerides. (See Table 7.)
Click on icon to see table/diagram/imageIn the long-term, open-label schizophrenia studies, 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 Brexpiprazole (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 subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies.
Weight Gain: Weight gain has been observed in patients treated with atypical antipsychotics. Clinical monitoring of weight is recommended.
Major Depressive Disorder: Table 8 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. (See Table 8.)
Click on icon to see table/diagram/imageIn the long-term, open-label depression studies, 4% of patients discontinued due to weight increase. Brexpiprazole (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: Table 9 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 schizophrenia. (See Table 9.)
Click on icon to see table/diagram/imageIn the long-term, open-label schizophrenia studies, 0.6% of patients discontinued due to weight increase. Brexpiprazole (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.
Leukopenia, Neutropenia, and Agranulocytosis: In clinical trial and/or post-marketing experience, leukopenia and neutropenia have been reported temporally related to atypical antipsychotic agents. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Brexpiprazole (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 Brexpiprazole (Rexulti) in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.
Orthostatic Hypotension and Syncope: In the short-term, placebo-controlled clinical studies of Brexpiprazole (Rexulti)+ADT in patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in Brexpiprazole (Rexulti)+ADT-treated patients compared to placebo+ADT patients included: dizziness (2% vs. 2%) and orthostatic hypotension (0.1% vs. 0%). In the short-term, placebo-controlled clinical studies of Brexpiprazole (Rexulti) in patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in Brexpiprazole (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%).
Adverse reactions associated with orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dosage and slower titration, and monitor orthostatic vital signs.
Seizures: As with other antipsychotic drugs, Brexpiprazole (Rexulti) should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.
Body Temperature Dysregulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Brexpiprazole (Rexulti) for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including Brexpiprazole (Rexulti), should be used cautiously in patients at risk for aspiration pneumonia.
Potential for Cognitive and Motor Impairment: In the short-term, placebo-controlled clinical trials in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% for Brexpiprazole (Rexulti)+ADT-treated patients compared to 1% of placebo+ADT patients.
In the short-term, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of Brexpiprazole (Rexulti)-treated patients compared to 3% of placebo-treated patients.
As with other antipsychotics that have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery including motor vehicles until they are certain that Brexpiprazole (Rexulti) therapy does not affect them adversely.
Impulse-Control Disorders/Compulsive Behaviors: Post-marketing reports of impulse-control disorders including gambling have been reported very rarely in patients treated with brexpiprazole and other antipsychotics with partial agonist activity at dopamine receptors. Patients with a prior history of impulse-control disorders may be at increased risk and should be monitored carefully. 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 increased impulse-control disorders or other compulsive behaviors while being treated with brexpiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. Compulsive behaviors may result in harm to the patient and others if not recognized.
CYP2D6 Poor Metabolizers: Dosage adjustment is recommended in known CYP2D6 poor metabolizers, because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant use with CYP Inhibitors or Inducers under Dosage & Administration, Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: Reduce the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7). Patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) generally had higher exposure to brexpiprazole than patients with normal hepatic function [see Pharmacology: Pharmacokinetics under Actions]. Greater exposure may increase the risk of Brexpiprazole (Rexulti)-associated adverse reactions [see Dosage Adjustments for Hepatic Impairment under Dosage & Administration].
Renal Impairment: Reduce the maximum recommended dosage in patients with moderate, severe, or end-stage renal impairment (CLcr<60 mL/minute). Patients with impaired renal function (CLcr<60 mL/minute) had higher exposure to brexpiprazole than patients with normal renal function [see Pharmacology: Pharmacokinetics under Actions]. Greater exposure may increase the risk of Brexpiprazole (Rexulti)-associated adverse reactions [see Dosage Adjustments for Renal Impairment under Dosage & Administration].
Other Specific Populations: No dosage adjustment for Brexpiprazole (Rexulti) is required on the basis of a patient's sex, race, or smoking status [see Pharmacology: Pharmacokinetics under Actions].
Drug Abuse and Dependence: Controlled Substance: Brexpiprazole (Rexulti) is not a controlled substance.
Abuse: Animals given access to Brexpiprazole (Rexulti) did not self-administer the drug, suggesting that Brexpiprazole (Rexulti) does not have rewarding properties.
Dependence: Humans and animals that received chronic Brexpiprazole (Rexulti) administration did not demonstrate any withdrawal signs upon drug discontinuation. This suggests that Brexpiprazole (Rexulti) does not produce physical dependence.
Use in Children: Safety and effectiveness in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults previously].
Use in Elderly: Clinical studies of the efficacy of Brexpiprazole (Rexulti) did not include any patients aged 65 or older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
Based on the results of a safety, tolerability and pharmacokinetics trial, the pharmacokinetics of once daily oral administration of brexpiprazole (up to 3 mg/day for 14 days) as an adjunct therapy in the treatment of elderly subjects (70 to 85 years old, N=11) with MDD were comparable to those observed in adults subjects with MDD.
Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. Brexpiprazole (Rexulti) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Increased Mortality in Elderly Patients with Dementia-Related Psychosis previously].
