brexpiprazole, Rexulti

 Indications

Treatment of schizophrenia. Adjunctive treatment of

major depressive disorder.

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

Effects: Decreased manifestations of schizophrenia

including excitable, paranoic, or withdrawn behavior.

Improvement in symptoms of depression with

increased sense of wellbeing.

Pharmacokinetics

Absorption: Well absorbed (95%) following oral

administration.

Distribution: Displays extravascular distribution.

Protein Binding: 99%.

Metabolism and Excretion: Metabolized by

CYP3A4 and CYP2D6; 25% excreted in urine (1% unchanged),

46% in feces (14% unchanged).

Half-life: 91 hr.

TIME/ACTION PROFILE (improvement in

symptoms)

ROUTE ONSET PEAK DURATION

PO (schizophrenia)

within 1–2 wk 4–6 wk unknown

PO (depression)

within 1 wk 5 wk unknown

Contraindications/Precautions

Contraindicated in: Hypersensitivity.

Use Cautiously in: History of seizures, concurrent

use of medications that maypseizure threshold; Preexisting

cardiovascular disease, dehydration, hypotension,

concurrent antihypertensives, diuretics, electrolyte

imbalance (qrisk of orthostatic hypotension,

correct deficits before treatment); Pre-existing low

WBC (mayqrisk of leukopenia/neutropenia; History of

diabetes, metabolic syndrome or dyslipidemia (may exacerbate);

Patients 24 yr (mayqsuicidal ideation/behaviors,

monitor carefully); Patients at risk for falls;

Poor CYP2D6 metabolizers (PM), doseprequired;

Geri: Elderly patients with dementia-induced psychoses

(qrisk of serious adverse cardiovascular reactions and

death), consider age, concurrent medical conditions

and medications, renal/hepatic/cardiac function; OB:

Safety not established; use during third trimester may

result in extrapyramidal/withdrawal symptoms in infant;

Lactation: Consider health benefits against risk of adverse

effects in infant; Pedi: Safety and effectiveness not

established (mayqsuicidal ideation/behaviors).

Adverse Reactions/Side Effects

CNS: SEIZURES, abnormal dreams, dizziness, drowsiness,

headache, restlessness. EENT: blurred vision.

CV: cerebrovascular adverse reactions (qin elderly

patients with dementia-related psychoses), orthostatic hypotension/syncope. GI: abdominal pain, constipation,

diarrhea, dry mouth, dysphagia, excess salivation,

flatulence. Hemat: agranulocytosis, leukopenia, neutropenia.

Metab:qappetite,qweight, hyperglycemia/

diabetes, dyslipidemia. Neuro: akathisia, dystonia, extrapyramidal

symptoms, tardive dyskinesia, tremor.

Misc: NEUROLEPTIC MALIGNANT SYNDROME, allergic reactions

including ANAPHYLAXIS, body temperature dysregulation.

Interactions

Drug-Drug: Concurrent use with strong CYP3A4 inhibitors

including clarithromycin, itraconazole or

ketoconazoleqblood levels, effects and risk of adverse

reactions;pdose of brexpiprazole required. Concurrent

use with strong CYP2D6 inhibitors including

fluoxetine, paroxetine, or quinidineqblood levels,

effects and risk of adverse reactions;pdose of brexpiprazole

required. 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  duloxetineq

blood levels, effects and risk of toxicity;pdose of brexpiprazole

required. Concurrent use of strong inducers

of CYP3A4 including rifampinpblood levels and

effectiveness;qdose of brexpiprazole required. Concurrent

use of antihypertensives or diuretics (qrisk

of hypotension). Concurrent use of medications that

maypseizure threshold (qrisk of seizures).

Drug-Natural Products: Concurrent use of St.

John’s wortpblood levels and effectiveness;qdose of

brexpiprazole required.

Route/Dosage

PO (Adults): Schizophrenia—1 mg once daily for

the 1st 4 days (Days 1–4), thenqto 2 mg once daily

for the next 3 days (Days 5–8), thenqto 4 mg once

daily on Day 8 (not to exceed 4 mg once daily); Major

depressive disorder—0.5 or 1 mg once daily initially,

may beqto 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.

Hepatic Impairment

PO (Adults): Moderate to severe hepatic impairment

[Child-Pugh score 7]—maximum daily dose

should not exceed 3 mg for schizophrenia or 2 mg for

major depressive disorder.

Renal Impairment

PO (Adults): Moderate/severe/end-stage renal impairment

[CCr 60 mL/min]—maximum daily dose

should not exceed 3 mg for schizophrenia or 2 mg for

major depressive disorder.

Availability

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