brexpiprazole (Rx)

>10%

Akathisia (4-14%)

1-10%

Headache (4-9%)

Weight increased (3-8%)

Nasopharyngitis (1-7%)

Extrapyramidal symptoms, excluding akathisia (5-6%)

Somnolence (4-6%)

Dyspepsia (2-6%)

Constipation (1-6%)

Tremor (2-5%)

Fatigue/sedation (2-5%)

Dizziness (1-5%)

Increased CPK blood levels (2-4%)

Decreased cortisol levels (2-4%)

Anxiety (2-4%)

Restlessness (2-4%)

Increased appetite (2-3%)

Diarrhea (1-3%)

Frequency Unknown

Dystonia

Postmarketing Reports

Falls

Pathological gambling and other compulsive behaviors

Contraindications

Hypersensitivity; reactions have included rash, facial swelling, urticaria, and angioedema

Cautions

Increased mortality in elderly patients with dementia-related psychosis (see Black Box Warnings); 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 with placebo

Suicidal thoughts and behaviors reported in children, adolescents, and young adults who are taking antidepressant drugs (see Black Box Warnings)

Potentially fatal neuroleptic malignant syndrome (NMS) reported in association with administration of antipsychotic drugs; if NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring

Potentially irreversible, involuntary, dyskinetic movements (ie, tardive dyskinesia) reported with antipsychotic drugs; incidence highest in elderly persons, especially elderly women

Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus (including extreme cases associated with ketoacidosis or hyperosmolar coma or death), dyslipidemia, and body weight gain; assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment; before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment; monitor weight at baseline and frequently thereafter

May cause leukopenia, neutropenia, and agranulocytosis; monitor and discontinue if severe neutropenia (ANC <1000/mm³); 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

Orthostatic hypotension or syncope may occur (rare); generally, the risk is greatest during initial dose titration and when increasing the dose; orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medication, patients with known cardiovascular disease, and patients with cerebrovascular disease)

May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; perform complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy

Caution with a history of seizures or with conditions/drugs that potentially lower the seizure threshold

Body temperature dysregulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents

Dysphagia: Esophageal dysmotility and aspiration pneumonia reported

Sedation and hypersomnia reported that may cause impaired judgement, thinking, or motor skills

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and inability to control urges; consider dose reduction or stopping medication if a patient develops such urges

Pregnancy

Rexulti pregnancy exposure registry: Monitors pregnancy outcomes in women exposed to brexpiprazole during pregnancy; for more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancy

Adequate and well-controlled studies have not been conducted with brexpiprazole in pregnant women to inform drug-associated risks; however, neonates whose mothers are exposed to antipsychotic drugs, like brexpiprazole, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder)

Animal reproduction studies

• No teratogenicity was observed with oral administration of brexpiprazole to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, of maximum recommended human dose (MRHD) of 4 mg/day on a mg/m² basis
• However, when pregnant rats were administered brexpiprazole during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD

Lactation

Unknown if distributed in human breast milk

Present in rat milk

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Serotonin-dopamine activity modulator (SDAM) that acts as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors

Absorption

Absolute bioavailability: 95%

Peak plasma time: 4 hr

Steady-state concentration: 1-12 days

Distribution

Protein bound: >99% to serum albumin and alpha-1-acid glycoprotein; its protein binding is not affected by renal or hepatic impairment

Brexpiprazole protein binding is not affected by warfarin, diazepam, or digitoxin

Vd: 1.56 L/kg

Metabolism

Metabolized primarily by CYP2D6 and CYP3A4 isoenzymes

Elimination

Half-life: 91 hr

Clearance: 19.8 mL·hr/kg

Excretion: 25% urine; 46% feces

Instructions

May take with or without food