Brexpiprazole

Introduction Overview

Generic Name

brexpiprazole

Brand Name

Rexulti

Dosage Form

oral tablet (0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg)

Drug Class

Atypical antipsychotics

Pharmacokinetics

Absorption:
Brexpiprazole is administered orally and exhibits efficient absorption from the gastrointestinal tract. Peak plasma concentrations are typically reached within 4 hours post-dose. The drug can be taken with or without food, as food intake does not significantly affect its bioavailability. The absolute bioavailability has not been explicitly reported, but clinical studies suggest consistent and reliable oral absorption. Factors such as gastric pH and motility have limited impact on absorption, ensuring predictable plasma levels in diverse patient populations.

Distribution:
Brexpiprazole exhibits extensive distribution throughout the body tissues, with a volume of distribution estimated to be approximately 2.1 L/kg. The drug is highly protein-bound, approximately 99%, primarily to albumin and alpha-1-acid glycoprotein, which influences its plasma free concentration. Due to this high protein binding, displacement by other highly bound drugs can potentially alter its free levels. Brexpiprazole crosses the blood-brain barrier effectively, facilitating its central nervous system activity which is crucial for its antipsychotic and antidepressant effects.

Metabolism:
Brexpiprazole undergoes extensive hepatic metabolism primarily via the cytochrome P450 enzymes CYP3A4 and CYP2D6. The metabolic pathways involve oxidation and dealkylation to form pharmacologically active and inactive metabolites. Polymorphisms in CYP2D6 can affect the metabolism rate and plasma levels of brexpiprazole, necessitating dosage adjustments in poor metabolizers. Co-administration of strong CYP3A4 or CYP2D6 inhibitors or inducers significantly impacts brexpiprazole metabolism, thereby affecting drug exposure and therapeutic outcomes.

Elimination:
The elimination half-life of brexpiprazole is approximately 91 hours, allowing once-daily dosing. It is eliminated primarily via hepatic metabolism, followed by renal and fecal excretion of metabolites. Less than 1% of the unchanged drug is excreted in the urine. Steady-state plasma concentrations are typically achieved within 10 to 12 days of repeated dosing. Due to its prolonged half-life, dosage adjustments should consider the accumulation potential and clinical response, especially when modifying therapy or discontinuing the drug.

Dosage Forms

Available Dosage Forms:
Rexulti is available exclusively as oral tablets with the following strengths: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. Tablets are film-coated and intended for oral administration without regard to meals.

Dosages for Adults and Adolescents:
- Major Depressive Disorder (Adults): Starting dose of 0.5 to 1 mg once daily, titrated to a target dose of 2 mg once daily, with a maximum recommended dose of 3 mg daily.
- Schizophrenia (Adults): Initiated at 1 mg once daily, with a target dose between 2 to 4 mg once daily and a maximum dose of 4 mg daily.
- Schizophrenia (Adolescents 13 to 17 years old): Starting at 0.5 mg once daily, titrated to 2 to 4 mg once daily, with a maximum of 4 mg daily.
- Agitation associated with dementia due to Alzheimer’s disease: Starting dose 0.5 mg once daily, titrated to a target dose of 2 mg daily, with a maximum dose of 3 mg daily.

Specific Patient Populations:
- Hepatic Impairment: Dosage adjustments are recommended in moderate to severe liver disease due to altered metabolism; close monitoring is prudent.
- Renal Impairment: Dose adjustments are advised for patients with moderate to severe renal impairment to mitigate accumulation.
- Elderly: Caution is recommended due to risks associated with dementia-related psychosis and the general vulnerability to side effects such as orthostatic hypotension and sedation.
- Poor Metabolizers of CYP2D6: Require dosage reduction approximately to one-half or one-quarter standard doses when used concomitantly with CYP3A4 inhibitors.
- Interacting Medications: Adjustments are necessary when combined with strong/moderate CYP3A4 or CYP2D6 inhibitors or inducers, with dosing reduction or increase as clinically indicated.

Mechanism Of Action

Brexpiprazole, the active ingredient in Rexulti, functions as a serotonin-dopamine activity modulator (SDAM), belonging to the class of atypical antipsychotics. Its pharmacologic action stems primarily from its partial agonist activity at dopamine D2 receptors and serotonin 5-HT1A receptors, along with antagonist activity at serotonin 5-HT2A receptors. This unique receptor modulation balances dopamine and serotonin neurotransmission, which is implicated in the pathophysiology of schizophrenia, depression, and agitation associated with dementia.

At the molecular level, brexpiprazole exhibits high affinity and partial agonism at dopamine D2 receptors, which helps regulate dopaminergic activity by preventing excessive dopamine receptor stimulation yet maintaining sufficient dopaminergic tone. Concurrent partial agonism at 5-HT1A receptors contributes to anxiolytic and antidepressant effects by enhancing serotonergic neurotransmission. Antagonism at the 5-HT2A receptors inhibits excitatory serotonin signaling, reducing psychotic symptoms and minimizing extrapyramidal side effects compared to typical antipsychotics.

This receptor profile differs subtly from that of other atypical antipsychotics such as aripiprazole by possessing lower intrinsic activity at D2 receptors, potentially accounting for a better side effect profile with reduced akathisia and restlessness. Brexpiprazole’s activity at other receptors, including alpha-1 adrenergic and histamine H1 receptors, also influences its clinical effects and adverse event profile, such as sedation and orthostatic hypotension.

Clinically, this mechanism translates to efficacy in reducing psychotic symptoms in schizophrenia, augmenting antidepressant therapy in major depressive disorder, and alleviating agitation related to dementia. Its receptor modulation restores neurotransmitter imbalances in brain regions linked to mood, cognition, and behavior, improving clinical outcomes with tolerability superior to some older antipsychotics. Ongoing research continues to elucidate brexpiprazole's receptor interactions and clinical benefits across psychiatric disorders.

Pharmacological Actions

Partial agonist activity at dopamine D2 receptors modulating dopaminergic neurotransmission.
Partial agonist activity at serotonin 5-HT1A receptors contributing to anxiolytic and antidepressant effects.
Antagonist activity at serotonin 5-HT2A receptors reducing psychotic symptoms and extrapyramidal side effects.
Modulation of alpha-1 adrenergic receptors causing vasodilation and potential orthostatic hypotension.
Low to moderate affinity antagonism at histamine H1 receptors contributing to sedation and weight gain.
Regulation of neurotransmitter imbalances implicated in schizophrenia, major depressive disorder, and dementia-related agitation.
Activity distinct from first-generation antipsychotics, offering improved tolerability and reduced motor side effects.
Influences cognitive and mood pathways through combined serotonergic and dopaminergic receptor activity.
Minimal anticholinergic effects compared to older antipsychotic agents.
Neurotransmitter modulation leading to decreased agitation and improved mood stabilization.
Potential to improve negative and cognitive symptoms of schizophrenia via receptor profile.
Synergistic action with antidepressants enhancing therapeutic effects in major depressive disorder.

Therapeutic Or Clinical Uses

Treatment of schizophrenia in adults and adolescents aged 13 years and older.
Adjunctive therapy for major depressive disorder in adults when used with antidepressants.
Management of agitation associated with dementia due to Alzheimer's disease.
Indicated for patients who have inadequate response to other antipsychotic or antidepressant therapies.
Use in reducing psychotic episodes and preventing relapse in chronic schizophrenia.
Alleviation of depressive symptoms through serotonin-dopamine modulation.
Treatment option with a potentially lower risk of extrapyramidal symptoms and restlessness.
Utilized in patients who require oral maintenance therapy for schizophrenia or mood disorders.
Approved for agitation in dementia related to Alzheimer's, although not for dementia-related psychosis without agitation.
Can be beneficial in managing behavioral disturbances in older adults with dementia.
Option for patients intolerant or unresponsive to other atypical antipsychotics.
Reduction of suicidal ideation risk through mood stabilization in depressive disorders.
Applicable in clinical settings where once-daily oral administration is preferred for compliance.

Side Or Adverse Effects

Weight gain, commonly observed and possibly related to metabolic effects and increased appetite.
Somnolence or sleepiness leading to decreased alertness in some patients.
Dizziness, potentially related to orthostatic hypotension or CNS effects.
Akathisia or restlessness presenting as an urge to move or inability to stay still.
Common cold-like symptoms such as nasopharyngitis, a mild but frequent adverse event.
Orthostatic hypotension causing lightheadedness or fainting, especially on abrupt standing.
Increased blood sugar levels (hyperglycemia) and potential risk of new-onset diabetes mellitus.
Elevations in cholesterol and triglycerides necessitating periodic lipid monitoring.
Potential for tardive dyskinesia—uncontrolled involuntary movements typically in the face or tongue.
Neuroleptic malignant syndrome, a rare but life-threatening reaction characterized by hyperthermia and muscle rigidity.
Seizures or convulsions reported, requiring caution in susceptible individuals.
Compulsive behaviors including gambling, shopping, or hypersexuality induced by dopaminergic modulation.
Potential for falls due to sedation, orthostatic hypotension, and impaired coordination.
Difficulty swallowing (dysphagia) increasing risk for aspiration pneumonia.
Possible leukopenia or low white blood cell count requiring periodic hematologic monitoring.

Precautions

Caution in elderly patients with dementia-related psychosis due to increased mortality risk.
Monitor for emergence or worsening of suicidal thoughts, particularly in patients under 24 years of age.
Regular monitoring of blood glucose and lipid profiles due to metabolic risks.
Assess blood pressure to mitigate risk of orthostatic hypotension and related falls.
Consider gradual dose titration to minimize side effects such as dizziness, sedation, and akathisia.
Use caution in patients with a history of seizures or conditions predisposing to convulsions.
Monitor for signs of neuroleptic malignant syndrome, and discontinue drug if symptoms appear.
Be vigilant for unusual compulsive behaviors and discuss with patients and caregivers.
Avoid abrupt discontinuation to prevent withdrawal or relapse of psychiatric symptoms.
Evaluate for potential drug interactions affecting CYP3A4 and CYP2D6 metabolic pathways.
Use with caution in patients with hepatic or renal impairment due to altered drug clearance.
Pregnancy risk assessment and counseling due to potential harm to unborn fetus.
Consider risk-benefit in breastfeeding women due to unknown levels in breast milk.
Ensure patient adherence and proper follow-up to monitor therapeutic response and side effects.
Advise patients to avoid activities requiring mental alertness, such as driving, until effects are known.

Warnings

Boxed warning for increased risk of death in elderly patients with dementia-related psychosis.
Increased risk of suicidal thoughts and behaviors in patients aged 24 years and younger.
Potential for cerebrovascular events including stroke in elderly with dementia-related psychosis.
Risk of neuroleptic malignant syndrome, requiring emergent medical attention if suspected.
Possible irreversible tardive dyskinesia even after discontinuation of Rexulti.
Warning for metabolic changes including hyperglycemia, diabetes, dyslipidemia, and weight gain.
Risk of orthostatic hypotension and syncope, particularly during treatment initiation or dosage increases.
Potential for sedation and drowsiness impacting ability to operate machinery or drive.
Compulsive behaviors necessitate careful monitoring and patient/family education.
Precaution regarding increased risk of falls in elderly patients due to pharmacodynamic effects.
Use caution during pregnancy as Rexulti may cause neonatal withdrawal or extrapyramidal symptoms.
Potential for drug interactions impacting drug levels and increasing adverse effects.
Risk of seizures may be increased in patients predisposed to convulsions.
Warn about difficulty swallowing and aspiration risk in vulnerable populations.
Discontinue administration upon development of severe allergic or hypersensitivity reactions.

Contraindication

Hypersensitivity to brexpiprazole or any inactive components of the formulation.
Use in elderly patients with dementia-related psychosis to treat psychosis due to increased mortality risk.
Known hypersensitivity reactions including anaphylaxis to Rexulti or its excipients.
In patients under 13 years of age for schizophrenia due to lack of established safety and efficacy.
Not indicated or approved for use as monotherapy treatment of depression.
Contraindicated in patients with known history of neuroleptic malignant syndrome when considering rechallenge.
Avoid use in patients with uncontrolled epilepsy without appropriate seizure prophylaxis.
Contraindicated as an as-needed treatment for acute agitation associated with dementia.
Patients with severe hepatic impairment should generally avoid use unless benefit outweighs risk.
Use contraindicated with concomitant medications causing significant CYP3A4 or CYP2D6 inhibition without dosage adjustments.
Patients with history of hypersensitivity to other atypical antipsychotics should be evaluated carefully before use.
Caution or avoidance in patients with uncompensated cardiovascular disease prone to orthostatic hypotension.

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) increase brexpiprazole levels; dosage reduction recommended.
Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) increase plasma concentration requiring dose adjustments.
Concomitant use with strong/moderate CYP2D6 and CYP3A4 inhibitors necessitates dosage reduction to one-quarter of usual dose.
CYP3A4 inducers (e.g., rifampicin, phenytoin, St. John’s Wort) reduce brexpiprazole levels; dosage increase may be required.
Potential additive CNS depressant effects with other sedatives, alcohol, or CNS-active medications.
Drugs causing QT prolongation should be used cautiously, monitoring ECG due to additive risk.
Concurrent use with other dopamine antagonists may alter therapeutic and adverse effects.
Interactions with antihypertensive drugs may exacerbate orthostatic hypotension.
Medications that affect blood glucose or lipid metabolism may have additive metabolic effects.
Potential interaction with anticonvulsants altering plasma concentrations of brexpiprazole.
Co-administration with certain antidepressants may require careful monitoring of side effects and therapeutic response.
Drugs altering gastric pH unlikely to affect absorption significantly but should be monitored clinically.
No significant interactions with over-the-counter medications reported, but caution advised.
Adjustment of doses and close monitoring advised during initiation, discontinuation, or dose changes of interacting drugs.

Preparations Of The Drug

Oral tablets available in strengths of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg for flexible dosing.
Tablets are film-coated to aid in swallowing and protect drug stability.
Supplied in blister packs or bottles for outpatient prescription dispensing.
Storage recommended at controlled room temperature between 20°C to 25°C (68°F to 77°F).
Inactive ingredients include lactose monohydrate, corn starch, microcrystalline cellulose, and others, ensuring tablet integrity.
Color additives include titanium dioxide, iron oxide, and ferrosoferric oxide to distinguish dosage strengths.
Formulations are designed for once-daily administration to promote adherence.
Rexulti is available as a branded drug and also as generic brexpiprazole for major indications.
No parenteral or alternative dosage forms (e.g., liquid, injectable) are currently marketed.
Packaging instructions advise keeping tablets out of reach of children to prevent accidental ingestion.
Tablets are non-hygroscopic; however, storage in a dry environment is recommended to maintain potency.
Instructions advise not to crush or break tablets without healthcare provider approval to ensure proper dosing.
Prescriptions typically start with lower strengths with titration to higher doses based on clinical response.
Manufactured by Otsuka Pharmaceutical in partnership with Lundbeck, ensuring quality control standards.