Video: REXULTI® (brexpiprazole): Clinical Pharmacology Overview
Watch Dr. Jason Bermak discuss the clinical pharmacology and proposed MOA of REXULTI.
Dr. Bermak is a paid consultant of Otsuka America Pharmaceutical, Inc. and Lundbeck.
Hello, I’m Doctor Jason Bermak.
Welcome to: “REXULTI® (brexpiprazole): Clinical Pharmacology Overview."
REXULTI is indicated for:
Use as an adjunctive therapy to antidepressants in adults with major depressive disorder - or MDD - and for the treatment of schizophrenia in adults
REXULTI has the following BOXED WARNINGS:
INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS AND SUICIDAL THOUGHTS AND BEHAVIORS.
Now, let’s take a few moments to discuss the clinical pharmacology of REXULTI.
Let us begin with the mechanism of action of REXULTI.
While the mechanism of action of REXULTI is unknown, its efficacy 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.1
The pharmacodynamic profile of REXULTI includes its activity as an antagonist at noradrenergic alpha-1B and alpha-2C receptors.1,2
REXULTI is a distinct chemical entity. It is not an isomer or metabolite of any other compound.2
Here we see information on the pharmacologic profile of REXULTI.
REXULTI has a similar range of binding affinities for receptors across 3 neurotransmitter systems.2
As a reminder, the binding affinity - or (Ki) here - is expressed as a nanomolar concentration—where the lower value represents a higher binding affinity.2
REXULTI has subnanomolar binding affinities for key dopaminergic, serotonergic, and noradrenergic receptors, and has relatively low affinity to muscarinic and histaminergic receptors.1
The pharmacokinetic half-life of REXULTI is 91 hours.1
INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI® (brexpiprazole)
REXULTI is indicated for:
- Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
- Treatment of schizophrenia in adults
IMPORTANT SAFETY INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
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.
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Antidepressants increase the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients.
Contraindication: In patients with known hypersensitivity reaction to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria and anaphylaxis.
Cerebrovascular Adverse Events, Including Stroke: In clinical trials, elderly patients with dementia 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.
Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, intensive symptomatic treatment, and monitoring.
Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.
Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes including:
- Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment.
- 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.
- Weight Gain: Weight gain has been observed in patients treated with REXULTI. Monitor weight at baseline and frequently thereafter.
Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking REXULTI. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping REXULTI if such urges develop.
Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in this class. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue REXULTI at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.
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. Monitor in patients vulnerable to hypotension, and those with cardiovascular and cerebrovascular diseases.
Falls: Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.
Seizures: REXULTI may cause seizures and should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.
Body Temperature Dysregulation: Use REXULTI with caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics. including REXULTI, and should be used with caution in patients at risk for aspiration.
Potential for Cognitive and Motor Impairment: REXULTI has the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are reasonably certain REXULTI does not affect them adversely.
Concomitant Medication: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.
Most commonly observed adverse reactions: In clinical trials, the most common adverse reactions were:
- Major Depressive Disorder (MDD) (adjunctive treatment to antidepressant therapy; ≥5% incidence and at least twice the rate of placebo for REXULTI vs. placebo): akathisia and weight increase
- Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs. placebo): weight increased
Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.
Pregnancy: Adequate and well-controlled studies to assess the risks of REXULTI during pregnancy have not been conducted. REXULTI should be used during pregnancy only if the benefit justifies the risk to the fetus.
Lactation: It is not known if REXULTI is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at www.fda.gov/medwatch).or FDA at (
Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.
- REXULTI [prescribing information]. Tokyo, Japan: Otsuka Pharmaceutical Co, Ltd.
- Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350:589-604.
Dr. Jason Bermak, MD, PhD
Medical Director & Psychiatrist, SF-Care Inc.
Dr. Bermak is a paid
consultant of Otsuka
Inc. and Lundbeck.
REXULTI is a distinct chemical entity that is not an isomer or metabolite of any other compound1
The mechanism of action of brexpiprazole is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.2
REXULTI—an atypical antipsychotic with a similar range of binding affinities for receptors across 3 neurotransmitter systems1
Determined in vitro in cells overexpressing human receptors.
aDrugs are considered to have a high binding affinity for a receptor when the binding affinity (Ki) value is <1 nM.