Brexpiprazole

Registered South African indications:

• Schizophrenia 

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients

Cautions 

• Pregnancy
• Breastfeeding
• Women of childbearing potential
• Moderate, severe and end-stage renal impairment 
• Moderate to severe hepatic impairment 
• Elderly
  - Dementia
  - Dementia-related psychosis
  - Women 
• Patients at high risk for suicide
• Diabetes mellitus
  - Risk factors for diabetes
  - Family history of diabetes
  - Obesity 
• Risk factors for leukopenia and neutropenia
  - Pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC)
  - History of drug-induced leukopenia or neutropenia
• Known cardiovascular disease
• Family history of QT prolongation
• Electrolyte imbalance
• Risk factors for venous thromboembolism
• Hypotension or risk factors thereof
  - Dehydration
  - Hypovolemia
  - Treatment with antihypertensive medicinal agents
  - History of cardiovascular disease (e.g., heart failure, myocardial infarction, ischaemia, or conduction abnormalities)
  - History of cerebrovascular disease
  - Antipsychotic-naïve
• High risk for falls
• History of seizures or conditions that potentially lower the seizure threshold
• Risk of aspiration pneumonia
  - Elderly, particularly with advanced Alzheimer’s dementia
• History of impulse control disorders
• Conditions which may contribute to elevation in core body temperature 
  - Strenuous exercise
  - Exposure to extreme heat
  - Dehydration
  - Coadministration with medicinal agents with anticholinergic activity
• Coadministration with medicinal agents that prolong the QT interval
• Galactose intolerance e.g. galactosaemia 
• Lapp lactase deficiency 
• Glucose-galactose malabsorption 
• May impair ability to drive and operate machinery 

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Schizophrenia 

• Oral (tab): Day 1-4: 1mg, dly; Day 5-7: 2mg, dly; Day 8 onwards: 4mg, dly without regard to food, based on the patient’s clinical response and tolerability; Maintenance: 2-4mg; Max: 4mg/24hrs

Periodically reassess to determine the continued need for maintenance treatment 

See additional prescribing points for dosing for CYP2D6 poor metabolizers and concomitant use with CYP inhibitors/inducers

Brexpiprazole is not approved for the treatment of dementia-related psychosis

Not established for use in children below 18 years 

Pregnancy 

• Caution; not recommended
• Safe use of brexpiprazole during pregnancy has not been established; brexpiprazole is not recommended during pregnancy
• Neonates exposed to antipsychotic medicines during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization
• The effect of brexpiprazole on labour and delivery in humans is unknown. Parturition in rats was not affected by brexpiprazole
• Women of childbearing potential should use effective contraception

Breastfeeding

• Caution; not recommended 
• Safe use of brexpiprazole during breastfeeding has not been established
• Brexpiprazole was excreted into the milk of rats during lactation
• Because of the potential for serious adverse reactions in breastfeeding infants, women taking brexpiprazole should not breastfeed their infants

Fertility 

• The effect of brexpiprazole on human fertility has not been evaluated. Studies in animals have shown decreased female fertility

Renal Impairment

• Mild (CrCl>60ml/min): No dose adjustment recommended 
• Moderate, severe and end-stage (CrCl<60ml/min): Caution; dose adjustment recommended 
  Max: 3mg/24hrs

Hepatic Impairment 

• Mild: No dose adjustment recommended
• Moderate to severe (Child-Pugh score ≥7): Caution; dose adjustment recommended 
  Max: 3mg/24hrs

Elderly

• Caution; no dose adjustment recommended 
  Clinical studies did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Akathisia
• Tremor
• Sedation 
• Extrapyramidal symptoms
• Tardive dyskinesia (See additional prescribing points) 
• Neuroleptic malignant syndrome (See additional prescribing points) 
• Suicidal thoughts and behaviours (children, adolescents and young children)
• Suicidal attempt
• Somnolence
• Orthostatic/ postural hypotension
  - Dizziness
  - Light headedness
  - Tachycardia
• Motor and sensory instability
  - Falls (and, consequently, fractures or other injuries)
• Syncope
• Seizures
• Impulse-control disorders
  - Gambling 
• Stroke

Cardiovascular Disorders

• Increased blood pressure 
• QT interval prolongation
• Venous thromboembolism

Respiratory Disorders

• Cough 
• Aspiration pneumonia

Gastrointestinal Disorders

• Diarrhoea
• Nausea
• Upper abdominal pain
• Dental caries
• Flatulence
• Dysphagia

Endocrine and Metabolic Disorders

• Increased weight
• Hyperglycaemia
  - Ketoacidosis
  - Hyperosmolar coma
  - Death
• Increased blood triglycerides
• Increased total cholesterol
• Increased LDL cholesterol
• Decreased HDL cholesterol
• Dyslipidaemia

Musculoskeletal Disorders

• Back pain
• Myalgia
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Rash

Immune, Blood and Lymphatic System Disorders

• Leukopenia
• Neutropenia
• Agranulocytosis
• Temperature regulation disorder
• Hypersensitivity reactions
  - Rash
  - Angioedema
  - Facial swelling
  - Anaphylaxis
  - Urticaria

Others

• Pain
  - Pain in extremity
• Death (increased in elderly patients)

• Strong CYP2D6 inhibitors
• Quinidine
• Strong CYP3A4 inhibitors
• Ketoconazole
• Strong CYP3A4 inducers
• Rifampicin

• Electrolytes
• Hepatic function
• Renal function
• Thyroid stimulating hormone
• Fasting blood glucose/ HbA1c
• Lipid profile
• Vital signs
• Weight
• Height
• Body mass index (BMI)

Specific cases may require

• Full blood count
• Prolactin
• Waist circumference

Additional observations

• Adherence
• Extrapyramidal symptoms
• Fall risk
• Mental status and alertness
• Metabolic syndrome history
  - Personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease
• Symptoms of hyperprolactinemia
  - Changes in menstruation
  - Libido
  - Gynaecomastia
  - Development of galactorrhoea
  - Erectile and ejaculatory function
• Tardive dyskinesia

Dosing modifications for CYP2D6 poor metabolizers and for concomitant use with CYP inhibitors/inducers

Neuroleptic malignant syndrome (NMS)

• NMS has been reported in association with administration of antipsychotic medicines including brexpiprazole
• Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia)
• Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines including brexpiprazole must be discontinued. If a patient requires treatment with antipsychotic medicines after recovery from NMS, the potential reintroduction of medicine should be carefully considered

Tardive dyskinesia

• A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic medicines
• Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome
• If signs and symptoms of tardive dyskinesia appear in a patient on brexpiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment

Brexpiprazole binds with high affinity to multiple serotonin, dopamine and noradrenergic receptors. While the precise mechanism of action of brexpiprazole in treating psychiatric conditions is unknown, the pharmacology of brexpiprazole is believed to be mediated by a combination of high binding affinity and functional activities at multiple monoaminergic receptors. It has modulatory activity at the serotonin and dopamine systems that combines partial agonist activity at serotonergic 5-HT_1A and at dopaminergic D₂ receptors with antagonist activity at serotonergic 5-HT_2A receptors, with similar high affinities at all of these receptors (Ki:0.1-0.5nM). Brexpiprazole also shows antagonist activity at noradrenergic α_1B/2C with affinity in the same sub-nanomolar Ki range (Ki:0.2-0.6nM). The 5 HT_1A/D2 receptor partial agonist activity in combination with 5-HT_2A and α_1B/2C receptors antagonism of brexpiprazole may contribute with antipsychotic and antidepressant efficacy. 

Tablet 0.5mg

• Rexulti (H. Lundbeck) originator

Tablet 1mg

• Rexulti (H. Lundbeck) originator

Tablet 2mg

• Rexulti (H. Lundbeck) originator

Tablet 3mg

• Rexulti (H. Lundbeck) originator

Tablet 4mg

• Rexulti (H. Lundbeck) originator