Brexpiprazole

Oral
Schizophrenia

Oral
Major depressive disorder

Schizophrenia

Patients taking strong CYP2D6 inhibitor or strong CYP3A4 inhibitor: Reduce to half of the usual dose.

Patients taking moderate to strong CYP2D6 inhibitors in combination with moderate or strong CYP3A4 inhibitors: Reduce to 25% of the usual dose.

Patients taking strong CYP3A4 inducers: Double the usual dose over 1-2 weeks.

Pharmacogenomics:

Brexpiprazole is predominantly metabolised by CYP3A4 and CYP2D6 isoenzymes into inactive metabolite. Genetic polymorphism of CYP2D6 gene may affect the efficacy of brexpiprazole. The prevalence of CYP2D6 poor metabolisers is approx 8% in Caucasians and 3-8% in Black/African Americans.

CYP2D6 poor metabolisers
Patients may have higher brexpiprazole concentrations as compared to normal metabolisers and have increased risk for side effects.
Recommendation: Reduce brexpiprazole dose to 50% of the usual dose. Additionally, for those who are concomitantly taking strong or moderate CYP3A4 inhibitors, reduce the usual dose to 25%.

Schizophrenia:
Moderate, severe or ESRD

CrCl (mL/min)	Dosage
<60	Max: 3 mg once daily.

Major depressive disorder:
Moderate, severe or ESRD

CrCl (mL/min)	Dosage
<60	Max: 2 mg once daily.

Schizophrenia
Moderate to severe (Child-Pugh score ≥7): Max: 3 mg once daily.

Major depressive disorder
Moderate to severe (Child-Pugh score ≥7): Max: 2 mg once daily.

May be taken with or without food.

Patient with pre-existing low WBC count or absolute neutrophil count, history of drug-induced leucopenia or neutropenia; risk factors for aspiration pneumonia (e.g. Alzheimer’s disease); hypotension or conditions that may predispose to hypotension (e.g. hypovolaemia, dehydration, concomitant antihypertensive therapy); CV disease (e.g. history of MI, ischaemic heart disease, heart failure, conduction abnormalities); cerebrovascular disease, hypertension (including accelerated or malignant), family history of QT prolongation, electrolyte imbalance; history of seizure or conditions that lowers seizure threshold, Lewy body or Parkinson disease dementia, diabetes mellitus or risk factors for diabetes mellitus (e.g. family history, obesity), history of impulse control disorders, history of or risk factors for sleep apnoea. Patient subjected to strenuous exercise, extreme heat, and concomitant use of anticholinergic medications. CYP2D6 poor metabolisers. Avoid abrupt withdrawal. Moderate to severe renal and hepatic impairment. Elderly with dementia-related psychosis. Pregnancy and lactation.

Significant: Suicidal thoughts and behaviour, extrapyramidal symptoms (e.g. tardive dyskinesia, akathisia, parkinsonism), hyperglycaemia, dyslipidaemia, weight gain, blood dyscrasias (e.g. leucopenia, neutropenia, agranulocytosis), syncope, orthostatic hypotension, somnolence, motor and sensory instability leading to falls or fractures; seizure, impaired core body temperature regulation, oesophageal dysmotility and aspiration, venous thromboembolism. Rarely, impulse control disorders (e.g. pathological gambling, uncontrolled sexual urges, uncontrolled spending, binge or compulsive eating).
Eye disorders: Blurred vision.
Gastrointestinal disorders: Constipation, dyspepsia, diarrhoea, nausea, dry mouth, salivary hypersecretion, abdominal pain, flatulence.
General disorders and administration site conditions: Fatigue.
Investigations: Increased blood creatinine phosphokinase, serum prolactin; decreased blood cortisol.
Metabolism and nutrition disorders: Increased appetite.
Musculoskeletal and connective tissue disorders: Myalgia, back pain, pain in extremity.
Nervous system disorders: Akathisia, headache, tremor, sedation, dizziness, restlessness.
Psychiatric disorders: Anxiety, abnormal dreams, insomnia.
Renal and urinary disorders: UTI.
Respiratory, thoracic and mediastinal disorders: Nasopharyngitis.
Skin and subcutaneous tissue disorders: Hyperhidrosis.
Potentially Fatal: Neuroleptic malignant syndrome.

This drug may cause somnolence, if affected, do not drive or operate machinery.

Closely monitor for clinical worsening and suicidality particularly during the first 2 months of therapy and during dosage adjustments. Monitor vital signs, CBC as clinically indicated; blood pressure (at baseline, repeat after 3 months then annually); weight, height, BMI, waist circumference (at baseline, repeat at 4, 8 and 12 weeks then quarterly); electrolytes and liver function (annually and as clinically indicated); personal and family history of obesity, diabetes, dyslipidaemia, hypertension, CV disease (at baseline then annually); fasting plasma glucose level/HbA_1c (at baseline, repeat after 3 months then annually); fasting lipid panel (at baseline, repeat after 3 months then as clinically indicated). Monitor for changes in menstruation, libido, development of galactorrhoea, erectile and ejaculatory function, abnormal involuntary movements or parkinsonian signs, tardive dyskinesia, and fall risk. Perform ocular examination yearly in patients >40 years or every 2 years in younger patients.

Increased serum concentration with moderate to strong CYP3A4 inhibitors (e.g. itraconazole, ritonavir, clarithromycin, ketoconazole) or moderate to strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine). Decreased serum concentration with strong CYP3A4 inducers (e.g. rifampicin).

Decreased exposure with St. John’s wort. Increased sedative effect with alcohol.

Description:
Mechanism of Action: Brexpiprazole is an atypical antipsychotic that acts as a partial agonist at dopamine D₂ and serotonin 5-HT_1A receptors and as an antagonist at 5-HT_2A receptors. However, its exact mechanism of action in the treatment of major depressive disorder or schizophrenia is still unknown.
Pharmacokinetics:
Absorption: Bioavailability: 95%. Time to peak plasma concentrations: Within 4 hours.
Distribution: Volume of distribution: 1.56 L/kg (IV). Plasma protein binding: >99%, mainly to serum albumin and α₁-acid glycoprotein.
Metabolism: Metabolised in the liver mainly by CYP3A4 and CYP2D6 to its major inactive metabolite, DM-3411.
Excretion: Via faeces (46%; approx 14% as unchanged drug); urine (25%; <1% as unchanged drug). Elimination half-life: 91 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 11978813, Brexpiprazole. https://pubchem.ncbi.nlm.nih.gov/compound/Brexpiprazole. Accessed Oct. 27, 2020.

Store between 20-25°C.

Antipsychotics

N05AX16 - brexpiprazole ; Belongs to the class of other antipsychotics.

Annotation of DPWG Guideline for Brexpiprazole and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 10/07/2020.

Annotation of EMA Label for Brexpiprazole and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 10/07/2020.

Annotation of FDA Label for Brexpiprazole and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 10/07/2020.

Anon. Brexpiprazole. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 10/07/2020.

Anon. CYP2D6 - Brexpiprazole (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 10/07/2020.

Buckingham R (ed). Brexpiprazole. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 10/07/2020.

Rexulti Film-Coated Tablet (Otsuka [Philippines] Pharmaceutical Inc.). MIMS Philippines. http://www.mims.com/philippines. Accessed 10/07/2020.

Rexulti Tablet (Otsuka America Pharmaceutical, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 10/07/2020.

Rxulti Film-Coated Tablets (Otsuka Pharmaceutical Netherlands B.V.). European Medicines Agency [online]. Accessed 03/08/2020.