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. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Warnings, Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis as follows].
Suicidal Thoughts and Behaviors: The possibility of a suicide attempt is inherent in psychotic illnesses. Close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.
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 cerebrovascular adverse reactions (stroke and transient ischemic attacks), including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Warnings, Increased Mortality in Elderly Patients with Dementia-Related Psychosis as previously mentioned].
QT Prolongation: QT prolongation can develop in patients treated with antipsychotics. In clinical trials, only a few, non-serious, QT prolongations have been reported with brexpiprazole. Caution should be exercised when brexpiprazole is prescribed in patients with known cardiovascular disease, family history of QT prolongation, electrolyte imbalance or in concomitant use with other medicinal products thought to prolong the QT interval.
Venous Thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotics. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with brexpiprazole and preventive measures undertaken.
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, 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
If NMS is suspected, immediately discontinue REXULTI and provide intensive symptomatic treatment and monitoring.
Tardive Dyskinesia: Tardive dyskinesia, a syndrome 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 not possible to predict which patients are likely to 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 increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment.
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.
Given these considerations, REXULTI 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 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 on REXULTI, dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. However, some patients may require treatment with REXULTI despite the presence of the syndrome.
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 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 REXULTI [see Clinical Trials Experience under Adverse Reactions]. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.
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 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 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.
Patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.
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.
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 REXULTI- and placebo-treated patients. Table 3 shows the proportions of patients with changes in fasting triglycerides. (See Table 3.)
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 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, including REXULTI. Monitor weight at baseline and frequently thereafter.
Table 4 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 4.)
Click on icon to see table/diagram/imageIn the long-term, open-label schizophrenia studies, 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.
Pathological Gambling and Other Compulsive Behaviors: Post-marketing case reports suggest that patients can experience intensive 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. Patients with a prior history of impulse-control disorders may be at increased risk and should be monitored carefully. 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. Consider dose reduction or stopping the medication if a patient develops such urges.
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/mm3 and follow their WBC until recovery.
Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Adverse reactions related to orthostatic hypotension can include dizziness, lightheadedness and tachycardia. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the short-term, placebo-controlled clinical studies of REXULTI in patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo patents included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%).
Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, (e.g., elderly patients, patients w/ dehydration, hypovolemia, concomitant treatment w/ antihypertensive medication), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs. REXULTI 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.
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 therapy.
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: 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: 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: REXULTI, like other antipsychotics, has minor to moderate influence on ability to drive and use machines, impair judgement, or thinking due to potential nervous system effects, such as sedation and dizziness that are common adverse drug reactions. In 6-week, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients.
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that REXULTI therapy does not affect them adversely.
Lactose: REXULTI film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 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 REXULTI-associated adverse reactions [see Dosage Adjustments for Renal Impairment under Dosage & Administration].
Other Specific Populations: No dosage adjustment for 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: REXULTI is not a controlled substance.
Abuse: Animals given access to REXULTI did not self-administer the drug, suggesting that REXULTI does not have rewarding properties.
Dependence: Humans and animals that received chronic REXULTI administration did not demonstrate any withdrawal signs upon drug discontinuation. This suggests that REXULTI does not produce physical dependence.
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Use in Elderly: Clinical studies of the efficacy of REXULTI did not include any patients aged 65 or older to determine whether they respond differently from younger patients. The safety and efficacy of brexpiprazole in the treatment of schizophrenia in patients aged 65 years and older have not been established. It is not possible to advise on a minimum effective/safe dose in this population.
Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Warnings, Increased Mortality in Elderly Patients with Dementia-Related Psychosis ].
