brexpiprazole

General

**BEERS Drug**

Genetic Implications: Genetic Implications

Pronunciation:
brex-pip-ra-zole


Trade Name(s)

  • Rexulti

Ther. Class.

antipsychotics

antidepressants

Pharm. Class.

serotonin-dopamine activity modulators (SDAM)

Indications

  • Schizophrenia.
  • Adjunctive treatment of major depressive disorder.
  • Agitation associated with dementia due to Alzheimer's disease.

Action

Psychotropic activity may be due to partial agonist activity at dopamine D2  and serotonin 5-HT1A  receptors and antagonist activity at the 5-HT2A  receptor.

Therapeutic Effect(s):

  • Decreased manifestations of schizophrenia, including excitable, paranoic, or withdrawn behavior.
  • Improvement in symptoms of depression with increased sense of well-being.
  • Decreased agitation associated with dementia due to Alzheimer's disease.

Pharmacokinetics

Absorption: Well absorbed (95%) following oral administration.

Distribution: Displays extravascular distribution.

Protein Binding: >99%.

Metabolism and Excretion: Primarily metabolized by the liver via the CYP3A4 and CYP2D6 isoenzymes; Genetic implication the CYP2D6 enzyme system exhibits genetic polymorphism (~7% of population may be poor metabolizers and may have significantly ↑ brexpiprazole concentrations and an ↑ risk of adverse effects). 25% excreted in urine (<1% unchanged), 46% in feces (14% unchanged).

Half-life: 91 hr.

TIME/ACTION PROFILE (improvement in symptoms)

ROUTEONSETPEAKDURATION
PO (schizophrenia)within 1–2 wk4–6 wkunknown
PO (depression)within 1 wk5 wkunknown

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity.

Use Cautiously in:

  • History of seizures or concurrent use of medications that may ↓ seizure threshold;
  • Pre-existing cardiovascular disease, dehydration, hypotension, concurrent antihypertensives, diuretics, electrolyte imbalance (↑ risk of orthostatic hypotension, correct deficits before treatment);
  • Pre-existing low WBC (may ↑ risk of leukopenia/neutropenia);
  • History of diabetes, metabolic syndrome, or dyslipidemia (may exacerbate);
  • Patients <24 yr (may ↑ suicidal ideation/behaviors, monitor carefully);
  • Patients at risk for falls;
  • Genetic implication Poor CYP2D6 metabolizers (PM), dose ↓ required;
  • OB:  Use during third trimester may result in extrapyramidal/withdrawal symptoms in infant; use during pregnancy only if potential maternal benefit justifies potential fetal risk;
  • Lactation: Safety not established during breastfeeding;
  • Pedi:  Antidepressants may ↑ risk of suicidal ideation/behaviors in children; safety and effectiveness not established in children <18 yr (major depressive disorder) or <13 yr (schizophrenia);
  • Geri:  Appears on Beers list. ↑ risk of stroke, cognitive decline, and mortality in older adults with dementia. Avoid use in older adults, except for schizophrenia, adjunctive treatment of major depressive disorder, or agitation associated with dementia due to Alzheimer's disease.

Adverse Reactions/Side Effects

CV: cerebrovascular adverse reactions (↑ in elderly patients with dementia-related psychoses), orthostatic hypotension/syncope

EENT: blurred vision

Endo: hyperglycemia/diabetes

GI: abdominal pain, constipation, diarrhea, dry mouth, dysphagia, excess salivation, flatulence

Hemat: agranulocytosis, leukopenia, neutropenia

Metabolic: ↑ weight, ↑ appetite, dyslipidemia

Neuro: akathisia, abnormal dreams, cognitive impairment, dizziness, drowsiness, dystonia, extrapyramidal symptoms, headache, NEUROLEPTIC MALIGNANT SYNDROME, restlessness, sedation, SEIZURES, tardive dyskinesia, tremor, urges (eating, gambling, sexual, shopping)

Misc: body temperature dysregulation, HYPERSENSITIVITY REACTIONS (including anaphylaxis)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Strong CYP3A4 inhibitors, including  clarithromycin,  itraconazole  or  ketoconazole, may ↑ levels and risk of toxicity; ↓ brexpiprazole dose.
  •  Strong CYP2D6 inhibitors, including  fluoxetine,  paroxetine, or  quinidine, may ↑ levels and risk of toxicity; ↓ brexpiprazole dose.
  • Combined use of  strong or moderate CYP3A4 inhibitors with strong or moderate CYP2D6 inhibitors  in addition to brexpiprazole, including the following combinations:  itraconazole + quinidine,  fluconazole + paroxetine,  itraconazole + duloxetine  or  fluconazole + duloxetine, may ↑ levels and risk of toxicity; ↓ brexpiprazole dose.
  •  Strong CYP3A4 inducers, including  rifampin, may ↓ levels and effectiveness; ↑ brexpiprazole dose.
  • Concurrent use of  antihypertensives  or  diuretics  may ↑ the risk of hypotension.
  • Concurrent use of  medications that may ↓ seizure threshold  may ↑ the risk of seizures.

Drug-Natural Products:

 St. John's wort  may ↓ levels and effectiveness; ↑ brexpiprazole dose.

Route/Dosage

Schizophrenia

PO (Adults): 1 mg once daily on Days 1–4; then ↑ to 2 mg once daily on Days 5–7; then ↑ to 4 mg once daily on Day 8 (not to exceed 4 mg once daily).  Known CYP2D6 poor metabolizers:  use 50% of the usual dose.  Concurrent use of strong CYP2D6 inhibitors (schizophrenia only) or CYP3A4 inhibitors:  use 50% of the usual dose;  Concurrent use of strong/moderate CYP2D6 inhibitors AND strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Known CYP2D6 poor metabolizer taking concurrent strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Concurrent use of strong CYP3A4 inducers:  double usual dose over 1–2 wk; titrate by clinical response.

PO (Children 13–17 yr): 0.5 mg once daily on Days 1–4; then ↑ to 1 mg once daily on Days 5–7; then ↑ to 2 mg once daily on Day 8. May ↑ dose by 1 mg/day on weekly basis (not to exceed 4 mg once daily).  Known CYP2D6 poor metabolizers:  use 50% of the usual dose.  Concurrent use of strong CYP2D6 inhibitors (schizophrenia only) or CYP3A4 inhibitors:  use 50% of the usual dose;  Concurrent use of strong/moderate CYP2D6 inhibitors AND strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Known CYP2D6 poor metabolizer taking concurrent strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Concurrent use of strong CYP3A4 inducers:  double usual dose over 1–2 wk; titrate by clinical response.

Renal Impairment 
PO (Adults and Children 13–17 yr): Moderate/severe/end-stage renal impairment [CCr <60 mL/min]:  maximum daily dose should not exceed 3 mg.

Hepatic Impairment 
(Adults and Children 13–17 yr): Moderate to severe hepatic impairment [Child-Pugh score ≥7]:  maximum daily dose should not exceed 3 mg.

Major Depressive Disorder

PO (Adults): 0.5 or 1 mg once daily initially; may be ↑ to 2 mg once daily (not to exceed 3 mg once daily);  Known CYP2D6 poor metabolizers:  use 50% of the usual dose.  Concurrent use of strong CYP2D6 inhibitors (schizophrenia only) or CYP3A4 inhibitors:  use 50% of the usual dose;  Concurrent use of strong/moderate CYP2D6 inhibitors AND strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Known CYP2D6 poor metabolizer taking concurrent strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Concurrent use of strong CYP3A4 inducers:  double usual dose over 1–2 wk; titrate by clinical response.

Renal Impairment 
PO (Adults): Moderate/severe/end-stage renal impairment [CCr <60 mL/min]:  maximum daily dose should not exceed 2 mg.

Hepatic Impairment 
PO (Adults): Moderate to severe hepatic impairment [Child-Pugh score ≥7]:  maximum daily dose should not exceed 2 mg.

Agitation Associated with Dementia Due to Alzheimer's Disease

PO (Adults): 0.5 mg once daily on Days 1–7; then ↑ to 1 mg once daily on Days 8–14;, then ↑ to 2 mg once daily on Day 15. May ↑ to 3 mg once daily after ≥14 days based on clinical response and tolerability.  Known CYP2D6 poor metabolizers:  use 50% of the usual dose.  Concurrent use of strong CYP2D6 inhibitors (schizophrenia only) or CYP3A4 inhibitors:  use 50% of the usual dose;  Concurrent use of strong/moderate CYP2D6 inhibitors AND strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Known CYP2D6 poor metabolizer taking concurrent strong/moderate CYP3A4 inhibitors:  use 25% of the usual dose;  Concurrent use of strong CYP3A4 inducers:  double usual dose over 1–2 wk; titrate by clinical response.

Renal Impairment 
PO (Adults): Moderate/severe/end-stage renal impairment [CCr <60 mL/min]:  maximum daily dose should not exceed 2 mg.

Hepatic Impairment 
PO (Adults): Moderate to severe hepatic impairment [Child-Pugh score ≥7]:  maximum daily dose should not exceed 2 mg.

Availability (generic available)

Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg

Assessment

  • Assess mental status (orientation, mood, behavior) before and periodically during therapy. Assess for suicidal tendencies, especially during early therapy for depression. Restrict amount of drug available to patient. Risk may be increased in children, adolescents, and adults ≤24 yr.
  • Assess weight and BMI initially and throughout therapy.
  • Obtain fasting blood glucose and cholesterol levels initially and periodically during therapy.
  • Monitor BP (sitting, standing, lying), pulse, and respiratory rate before and periodically during therapy.
  • Observe patient carefully when administering medication to ensure that medication is actually taken and not hoarded or cheeked.
  • Monitor patient for onset of akathisia (restlessness or desire to keep moving) and extrapyramidal side effects ( parkinsonian:  difficulty speaking or swallowing, loss of balance control, pill rolling of hands, masklike face, shuffling gait, rigidity, tremors; and  dystonic:  muscle spasms, twisting motions, twitching, inability to move eyes, weakness of arms or legs) periodically during therapy. Report these symptoms.
  • Monitor for tardive dyskinesia (uncontrolled rhythmic movement of mouth, face, and extremities; lip smacking or puckering; puffing of cheeks; uncontrolled chewing; rapid or worm-like movements of tongue). Notify health care professional immediately if these symptoms occur; symptoms may partially or completely resolve, but may be irreversible.
  • Monitor for development of neuroleptic malignant syndrome (fever, muscle rigidity, altered mental status, respiratory distress, tachycardia, seizures, diaphoresis, hypertension or hypotension, pallor, tiredness, loss of bladder control, elevated CK, myoglobinuria/rhabdomyolysis, acute renal failure). Notify health care professional immediately if these symptoms occur.
  • Assess for fall risk. Drowsiness, orthostatic hypotension, and motor and sensory instability ↑ risk. Institute prevention if indicated.

Lab Test Considerations:

Monitor CBC frequently during initial mo of therapy in patients with pre-existing or history of low WBC. May cause leukopenia, neutropenia, or agranulocytosis. Discontinue therapy if severe neutropenia (ANC <1000 mm3  occurs).

  • Monitor blood glucose and cholesterol levels initially and periodically during therapy.

Implementation

  • Brexpiprazole is not indicated as an as-needed ("prn") treatment for agitation associated with dementia due to Alzheimer's disease.
  • PO Administer once daily without regard to meals.

Patient/Family Teaching

  • Advise patient to take medication as directed and not to skip doses or double up on missed doses. Take missed doses as soon as remembered unless almost time for the next dose. Do not stop taking brexpiprazole without consulting health care professional. Advise patient to read  Medication Guide  before starting and with each Rx refill in case of changes.
  • Inform patient of possibility of extrapyramidal symptoms and tardive dyskinesia. Instruct patient to report these symptoms immediately.
  • Advise patient to make position changes slowly to minimize orthostatic hypotension. Protect from falls.
  • Medication may cause drowsiness and light-headedness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
  • Advise patient and family to notify health care professional if thoughts about suicide or dying, attempts to commit suicide, new or worse depression, new or worse anxiety, feeling very agitated or restless, panic attacks, trouble sleeping, new or worse irritability, acting aggressive, being angry or violent, acting on dangerous impulses, an extreme increase in activity and talking, or other unusual changes in behavior or mood occur or if signs and symptoms of high blood sugar (feel very thirsty, urinating more than usual, feel very hungry, feel weak or tired, nausea, confusion, breath smells fruity) occur.
  • Inform patient that brexipiprazole may cause weight gain. Advise patient to monitor weight periodically. Notify health care professional of significant weight gain.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any new medications. Caution patient to avoid taking alcohol or other CNS depressants concurrently with this medication.
  • Advise patient that extremes in temperature should be avoided because this drug impairs body temperature regulation.
  • Advise patient to notify health care professional if new or ↑ eating/binge eating or gambling, sexual, shopping, or other impulse control disorders occur.
  • Advise patient to notify health care professional of medication regimen prior to treatment or surgery.
  • Rep:  May cause fetal harm. Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy. May cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates whose mothers were exposed to antipsychotic drugs during third trimester of pregnancy. Symptoms vary in severity. Some neonates recover within hr or days without specific treatment; others require prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Encourage pregnant patients to enroll in registry by contacting National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi....
  • Emphasize the importance of routine follow-up exams and continued participation in psychotherapy as indicated.

Evaluation/Desired Outcomes

  • Decrease in excitable, paranoic, or withdrawn behavior.
  • Increased sense of wellbeing in patients with depression.
  • Decreased agitation associated with dementia due to Alzheimer's disease.