General: Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing REXULTI for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).
Falls: 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.
Cardiovascular: Orthostatic Hypotension: In the short-term, placebo-controlled clinical studies of REXULTI in subjects with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo subjects included: dizziness (2.3% versus 1.4%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%). In the short-term, placebo-controlled clinical studies of REXULTI + ADT in subjects with MDD, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated subjects compared to placebo + ADT subjects included: dizziness (2.6% versus 1.6%), dizziness postural (0.1% versus 0.4%), orthostatic hypotension (0.1% versus 0%), and syncope (0.1% versus 0.4%).
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.
Patients with a recent history of myocardial infarction or unstable cardiovascular disease were excluded from clinical trials.
QT Interval: The effects of REXULTI on the QT/QTc interval were evaluated in a dedicated ECG study (see Pharmacology: Pharmacodynamics: Cardiac Electrophysiology under Actions). The trial involved administration of REXULTI at a therapeutic dose of 4 mg/day or a supratherapeutic dose of 12 mg/day for 11 days in 147 clinically stable patients with schizophrenia. On day 11, the maximum placebo-adjusted mean change from baseline in the QTcI interval was 8.3 ms (90% CI 3.7, 12.9) at 6 h post-dosing in the brexpiprazole 4 mg/day group (N=62) and 3.1 ms (90% CI -1.7, 8.0) at 4 h post-dosing in the brexpiprazole 12 mg/day group (N=53).
QTc prolongation may lead to an increased risk of ventricular arrhythmias including torsade de pointes. Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
Particular care should be exercised when administering REXULTI to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug (see Overview under Interactions).
Risk factors for torsade de pointes in the general population include, but are not limited to, the following: female gender; age ≥65 years; baseline prolongation of the QT/QTc interval; presence of genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndromes; family history of sudden cardiac death at <50 years of age; cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, cardiomyopathy, conduction system disease); history of arrhythmias; electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) or conditions leading to electrolyte disturbances (e.g., persistent vomiting, eating disorders); bradycardia; acute neurological events (e.g., intracranial or subarachnoid haemorrhage, stroke, intracranial trauma); diabetes mellitus; and autonomic neuropathy.
When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug. Patients should be advised to contact their healthcare provider immediately to report any new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, or changes in or new use of other medications.
Dependence/Tolerance: Brexpiprazole has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. In drug dependence studies in animals, no withdrawal symptoms were observed upon abrupt cessation of dosing in rats and monkeys, and no frequent self-administration of brexpiprazole was observed in monkeys. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of REXULTI misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).
Endocrine and Metabolism: Hyperglycemia and Diabetes Mellitus: In both short-term placebo-controlled trials and long-term open-label trials with REXULTI, there have been reports of hyperglycemia in subjects treated with REXULTI. Diabetic ketoacidosis has occurred in patients with no reported history of hyperglycemia. Therefore, patients should have baseline and periodic monitoring of blood glucose and body weight.
Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies which did not include REXULTI, suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotics. Because REXULTI was not marketed at the time these studies were performed, it is not known if brexpiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients should have baseline and periodic monitoring of blood glucose and body weight. Any patient treated with atypical antipsychotics should also be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.
Weight Gain: Antipsychotic drugs have been associated with metabolic changes, including weight gain. Clinical monitoring of weight is recommended (see Selected Adverse Events: Weight Gain under Adverse Reactions).
Dyslipidemia: Undesirable alterations in lipids have been observed in subjects treated with atypical antipsychotics. Therefore, patients should have baseline and periodic monitoring of fasting lipid profile (see Abnormal Hematologic and Clinical Chemistry Findings: Fasting Lipids under Adverse Reactions).
Hyperprolactinemia: Like other antipsychotics, REXULTI can elevate prolactin levels. Elevations associated with REXULTI treatment are generally mild and may decline during administration, however, in some infrequent cases the effect may persist during chronic administration (see Abnormal Hematologic and Clinical Chemistry Findings: Prolactin under Adverse Reactions).
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male patients.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a REXULTI carcinogenicity study conducted in mice (see Pharmacology: Toxicology: Carcinogenesis under Actions). The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear. To date, neither clinical nor epidemiological studies have shown an association between chronic administration of these drugs and mammary tumorigenesis.
Genitourinary: Although no cases of priapism were reported in clinical trials with REXULTI, rare cases of priapism have been reported with antipsychotic use. With other psychotropic drugs, this adverse reaction did not appear to be dose-dependent and did not correlate with the duration of treatment.
Hematologic: In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis has also been reported. Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting REXULTI and then periodically throughout treatment.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of REXULTI should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue REXULTI in patients with severe neutropenia (absolute neutrophil count <1x109/L) and follow their WBC counts until recovery.
Venous thromboembolism: Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs including REXULTI, in case reports and/or observational studies. When prescribing REXULTI all potential risk factors for VTE should be identified and preventative measures undertaken.
Immune: Hypersensitivity: Spontaneous post-market reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema and facial swelling, rash and urticaria, have been reported with REXULTI (see Contraindications; Post-Market Adverse Drug Reactions: Immune system disorders under Adverse Reactions).
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Post-market cases of DRESS have been reported in association with atypical antipsychotic drugs similar to brexpiprazole.
Neurologic: Neuroleptic Malignant Syndrome (NMS): Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with 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 creatine phosphokinase (CPK), myoglobinuria (rhabdomyolysis), and acute renal failure.
In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, 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 all antipsychotic drugs including REXULTI and other drugs not essential to 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 for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of therapy should be very carefully considered. The patient should be carefully monitored, since recurrence of NMS has 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 is 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 increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increases. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
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, 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 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 such 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 REXULTI, drug discontinuation should be considered. However, some patients may require treatment with REXULTI despite the presence of the syndrome.
Seizure/Convulsion: As with other antipsychotic drugs, REXULTI should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Post-marketing cases of seizures have been reported with REXULTI. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. (See Post-Market Adverse Drug Reactions: Neurological under Adverse Reactions.)
Potential for Cognitive and Motor Impairment: Like other antipsychotics drugs, REXULTI has the potential to impair judgment, thinking, or motor skills. Because REXULTI may cause somnolence and impair motor skills, patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that REXULTI therapy does not affect them adversely.
Psychiatric: Suicide: Completed suicide, attempted suicide, suicidal behavior and suicidal ideation have been reported during post-market use of REXULTI. The possibility of a suicide attempt is inherent in psychotic illnesses and major depressive disorder (MDD). In addition, depression may be co-morbid with schizophrenia. The risk of suicide-related events during a depressive episode may persist until remission occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Close supervision and appropriate clinical management of high-risk patients should accompany drug therapy. Prescriptions for REXULTI should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. (See Post-Market Adverse Drug Reactions: Psychiatric disorders under Adverse Reactions.)
Impulse-Control Disorders/Compulsive Behaviors: Post-marketing reports of impulse-control disorders including pathological gambling and compulsive shopping, binge eating, and hypersexuality and other compulsive behaviors have been reported very rarely in patients treated with brexpiprazole. Patients with a prior history of impulse-control disorder 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. Consider dose reduction or stopping the medication if a patient develops such urges while taking brexpiprazole.
Labor and Delivery: The effect of REXULTI on labor and delivery in humans is unknown. Parturition in rats was not affected by brexpiprazole.
Use in Patients with Hepatic Impairment: For patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), the maximum recommended dosage is 1.25 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Hepatic Insufficiency under Actions; Dosing Considerations: Hepatic Impairment under Dosage & Administration).
Use in Patients with Renal Impairment: For patients with moderate, severe or end-stage renal impairment (creatinine clearance CLcr<60 mL/minute), the maximum recommended dosage is 1.25 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Renal Insufficiency under Actions; Dosing Considerations: Renal Impairment under Dosage & Administration).
CYP2D6 Poor Metabolizers: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: CYP2D6 poor metabolism status under Actions; Dosing Considerations: CYP isozymes under Dosage & Administration).
Lactose: REXULTI tablets contain lactose. This should be considered when prescribing to patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
Use in Pregnancy: Teratogenic effects: There are no adequate and well-controlled studies of REXULTI in pregnant women. It is not known whether REXULTI can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.
In animal studies, brexpiprazole was not teratogenic and did not cause adverse developmental effects when administered during pregnancy at doses up to 24-fold in rats and 49-fold in rabbits, of the maximum recommended human dose (MRHD) of 4 mg/day on a mg/m2 body surface area for a 60-kg patient (see Pharmacology: Toxicology: Reproductive Toxicity under Actions). In a pregnant and lactating rat study, there was an increase in stillbirths and deaths of offspring at doses ≥ 10 mg/kg/day (24-fold MRHD on a mg/m2 basis).
Non-teratogenic effects: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
REXULTI should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus.
Use in Lactation: REXULTI was excreted in milk of rats during lactation. It is not known whether REXULTI or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended that women receiving REXULTI should not breast-feed.
Use in Children: The safety and effectiveness of REXULTI in patients under the age of 18 years have not been established and its use is not recommended.
Weight gain has been observed with atypical antipsychotic use in pediatric and adolescent patient populations. Independent of any drug-specific effects, weight gain can be associated with adverse changes in other metabolic parameters (e.g., glucose and lipid metabolism). Abnormal childhood weight and metabolic status can have adverse effects on cardiovascular outcomes in adulthood. Weight gain and adverse effects on other metabolic parameters associated with atypical antipsychotics can be more frequent or severe in pediatric and adolescent patients than in the adult patients.
The long-term safety, including cardiometabolic effects and effects on growth, maturation and behavioural development in patients under 18 years of age has not been systematically evaluated.
Use in the Elderly: Geriatrics (> 65 years of age): Clinical studies of REXULTI did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Geriatrics under Actions; Increased Mortality in Elderly Patients with Dementia under Warnings).
Use in Elderly Patients with Dementia: Overall Mortality: Elderly patients with dementia treated with atypical antipsychotic drugs showed increased mortality compared to placebo in a meta-analysis of 13 placebo-controlled trials of various atypical antipsychotic drugs. REXULTI is not indicated for the treatment of patients with dementia (e.g. dementia-related psychosis) (see Increased Mortality in Elderly Patients with Dementia under Warnings).
Cerebrovascular Adverse Events, Including Stroke in Elderly Patients with Dementia: In placebo-controlled trials with some atypical antipsychotics, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. There are insufficient data with REXULTI to know if there is an increased risk of cerebrovascular events associated with REXULTI. REXULTI is not indicated for the treatment of patients with dementia (e.g. dementia-related psychosis) (see also Increased Mortality in Elderly Patients with Dementia under Warnings).
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including REXULTI. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. REXULTI and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.