Brigatinib

Registered South African indications:

• Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) of the adenocarcinoma cell type

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

Cautions

International manufacturer recommendations

• Pregnancy
  - Females of reproductive potential
• Breastfeeding
• Males of reproductive potential
• Severe renal impairment (eGFR <30ml/min/1.73m²)
• Severe hepatic impairment (Child-Pugh Class C)
• Elderly
• Less than 7 days between the last dose of crizotinib and the first dose of brigatinib
• History of interstitial lung disease or drug-induced pneumonitis
• Patients on antihyperglycaemic treatment
• Coadministration with strong CYP3A inhibitors 
• Coadministration with strong and moderate CYP3A inducers
• Coadministration with other agents known to cause bradycardia
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption 
• May affect ability to drive and operate machinery

South African manufacturer recommendations

• Females of reproductive potential
• Males of reproductive potential
• Severe renal impairment (eGFR <30ml/min/1.73m²)
• Severe hepatic impairment (Child-Pugh Class C)
• Elderly
• Less than 7 days between the last dose of crizotinib and the first dose of brigatinib
• History of interstitial lung disease or drug-induced pneumonitis
• Patients on antihyperglycaemic treatment
• Coadministration with strong CYP3A inhibitors
• Coadministration with strong and moderate CYP3A inducers
• Coadministration with other agents known to cause bradycardia
• Coadministration with live attenuated vaccines
• Galactose intolerance, e.g., galactosemia
• Total lactase deficiency
• Glucose-galactose malabsorption
• May affect ability to drive and operate machinery

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

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used in the treatment of

Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)
- As monotherapy for the treatment of patients previously not treated with an ALK inhibitor
- As monotherapy for the treatment of patients previously treated with crizotinib

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Consult a specialist for dosage and regimens

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ALK-positive NSCLC status should be known prior to initiation of therapy. A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised

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Consult a specialist for dosing interruption and/or dose reduction based on individual safety or tolerability, and dose modifications for adverse reactions

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South African manufacturer recommendations

Used in the treatment of 

Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) of the adenocarcinoma cell type 
- As monotherapy for the treatment of patients who have progressed on or are intolerant to crizotinib

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Consult a specialist for dosage and regimens

---

ALK-positive NSCLC status should be known prior to initiation of therapy. A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised

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Consult a specialist for dosing interruption and/or dose reduction based on individual safety or tolerability, and dose modifications for adverse reactions

Not established for use in children below 18 years

Pregnancy

International manufacturer recommendations

• Caution; not recommended
• Brigatinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity
• There are no clinical data on the use of brigatinib in pregnant women. Brigatinib should not be used during pregnancy unless the clinical condition of the mother requires treatment. If brigatinib is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to a foetus
• Women of childbearing age being treated with brigatinib should be advised not to become pregnant and men being treated with brigatinib should be advised not to father a child during treatment. Women of reproductive potential should be advised to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose
• Men with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib

South African manufacturer recommendations

• Contraindicated
• Brigatinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity
• There are no clinical data on the use of brigatinib in pregnant women. Brigatinib should not be used during pregnancy unless the clinical condition of the mother requires treatment. If brigatinib is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to a foetus
• Women of childbearing age being treated with brigatinib should be advised not to become pregnant and men being treated with brigatinib should be advised not to father a child during treatment. Women of reproductive potential should be advised to use effective non-hormonal contraception during treatment with brigatinib and for at least 4 months following the final dose
• Men with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 3 months after the last dose of brigatinib

Breastfeeding

International manufacturer recommendations

• Caution; not recommended
• It is unknown whether brigatinib is excreted in human milk. Available data cannot exclude potential excretion in human milk. Breastfeeding should be stopped during treatment with brigatinib

South African manufacturer recommendations

• Contraindicated
• Breastfeeding should be stopped during treatment with brigatinib

Fertility

International manufacturer recommendations

• No human data on the effect of brigatinib on fertility are available. Based on repeat-dose toxicity studies in male animals, brigatinib may cause reduced fertility in males. The clinical relevance of these findings to human fertility is unknown

South African manufacturer recommendations

• No human data on the effect of brigatinib on fertility are available. Based on repeat-dose toxicity studies in male animals, brigatinib may cause reduced fertility in males

Renal Impairment

• Mild to moderate (eGFR ≥30ml/min/1.73m²): No dose adjustment recommended
• Severe (eGFR <30ml/min/1.73m²): Caution; dose adjustment recommended
  Initial: 60mg, dly for the first 7 days; Then: 90mg, dly
  Closely monitor for new or worsening respiratory symptoms that may indicate ILD/ pneumonitis (e.g., dyspnoea, cough, etc.) particularly in the first week

Hepatic Impairment

• Mild to moderate (Child-Pugh Classes A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; dose adjustment recommended
  Initial: 60mg, dly for the first 7 days; Then: 120mg, dly

Elderly

• Caution; no dose adjustment recommended
  The limited data on the safety and efficacy of brigatinib in patients aged ≥65 years suggest that a dose adjustment is not required
  There are no available data on patients >85 years of age

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Headache
  - Sinus headache
  - Head discomfort
  - Migraine
  - Tension headache
• Peripheral neuropathy
  - Paraesthesia
  - Peripheral sensory neuropathy
  - Dysaesthesia
  - Hyperaesthesia
  - Hypoaesthesia
  - Neuralgia
  - Peripheral neuropathy
  - Neurotoxicity
  - Peripheral motor neuropathy
  - Polyneuropathy
  - Burning sensation
  - Post herpetic neuralgia
• Dizziness
• Memory impairment
• Dysgeusia
• Fatigue

Cardiovascular Disorders

• Bradycardia
  - Sinus bradycardia
• Prolonged Electrocardiogram QT
• Tachycardia
  - Sinus tachycardia
  - Atrial tachycardia
  - Increased heart rate
• Palpitations
• Hypertension
  - Increased blood pressure
  - Diastolic hypertension
  - Systolic hypertension

Respiratory Disorders

• Upper respiratory tract infection
• Pneumonia
  - Atypical pneumonia
  - Aspiration pneumonia
  - Cryptococcal pneumonia
  - Lower respiratory tract infection
  - Viral lower respiratory tract infection
  - Lung infection
• Cough
• Pneumonitis
  - Interstitial lung disease
• Dyspnoea
  - Exertional dyspnoea

Gastrointestinal Disorders

• Increased lipase
• Diarrhoea
• Increased amylase
• Nausea and vomiting
• Lower or upper abdominal pain
  - Abdominal discomfort
  - Abdominal distension
  - Epigastric discomfort
• Constipation
• Stomatitis
  - Aphthous stomatitis
  - Aphthous ulcer
  - Mouth ulceration
  - Oral mucosal blistering
• Dry mouth
• Dyspepsia
• Flatulence
• Pancreatitis

Hepatobiliary Disorders

• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased alkaline phosphatase
• Increased blood lactate dehydrogenase
• Hyperbilirubinaemia

Genitourinary Disorders

• Increased blood creatinine

Endocrine and Metabolic Disorders

• Hyperglycaemia
• Hyperinsulinaemia
• Hypophosphataemia
• Hypomagnesaemia
• Hypercalcaemia
• Hyponatraemia
• Hypokalaemia
• Increased blood cholesterol(hypercholesterolemia)
• Decreased appetite
• Decreased weight

Musculoskeletal Disorders

• Increased blood creatine phosphokinase
• Myalgia
  - Musculoskeletal pain
  - Muscle spasms
  - Muscle tightness
  - Muscle twitching
  - Musculoskeletal discomfort
• Arthralgia
• Musculoskeletal chest pain
• Pain in extremity
• Musculoskeletal stiffness

Skin and Subcutaneous Tissue Disorders

• Rash
  - Dermatitis acneiform
  - Erythema
  - Exfoliative rash
  - Erythematous rash
  - Macular rash
  - Maculopapular rash
  - Papular rash
  - Pruritic rash
  - Pustular rash
  - Dermatitis
  - Allergic dermatitis
  - Contact dermatitis
  - Generalised erythema
  - Follicular rash
  - Urticaria
  - Drug eruption
  - Toxic skin eruption
• Pruritus
  - Allergic pruritus
  - Generalised pruritus
  - Genital pruritus
  - Vulvovaginal pruritus
• Dry skin
• Photosensitivity reaction

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Increased activated partial thromboplastin time
• Decreased lymphocyte count
• Decreased white blood cell count
• Decreased neutrophil count
• Decreased platelet count
• Oedema
  - Eyelid oedema
  - Face oedema
  - Peripheral oedema
  - Periorbital oedema
  - Swelling face
  - Generalised oedema
  - Peripheral swelling
  - Angioedema
  - Lip swelling
  - Periorbital swelling
  - Skin swelling
  - Swelling of eyelid
• Fever

Sensory Disorders

• Visual disturbance
  - Altered visual depth perception
  - Cataract
  - Acquired colour blindness
  - Diplopia
  - Glaucoma
  - Increased intraocular pressure
  - Macular oedema
  - Photophobia
  - Photopsia
  - Retinal oedema
  - Blurred vision
  - Reduced visual acuity
  - Visual field defect
  - Visual impairment
  - Vitreous detachment
  - Vitreous floaters
  - Amaurosis fugax

Others

• Non-cardiac chest pain
• Chest discomfort

• Strong CYP3A inhibitors
• Itraconazole
• Antiviral agents
• Indinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• Macrolide antibiotics
• Clarithromycin
• Telithromycin
• Troleandomycin
• Antifungals
• Ketoconazole
• Voriconazole
• Nefazodone
• Moderate CYP3A inhibitors
• Diltiazem
• Verapamil
• Strong CYP2C8 inhibitors
• Gemfibrozil
• Strong CYP3A inducers
• Rifampicin
• Carbamazepine
• Phenytoin
• Rifabutin
• Phenobarbital
• Moderate CYP3A inducers
• Efavirenz
• Modafinil
• Bosentan
• Etravirine
• Nafcillin
• CYP3A substrates
• Alfentanil
• Fentanyl
• Quinidine
• Cyclosporine
• Sirolimus
• Tacrolimus
• CYP2C substrates
• P-glycoprotein substrates
• Digoxin
• Dabigatran
• Colchicine
• Pravastatin
• Breast cancer resistance protein substrates
• Methotrexate
• Rosuvastatin
• Sulfasalazine
• Organic cation transporter 1 substrates
• Multidrug and toxin extrusion protein 1 substrates
• Multidrug and toxin extrusion protein 2K substrates

Other Interactions

• Grapefruit or grapefruit juice
• St. John's wort

• Anaplastic lymphoma kinase (ALK) positivity
• Creatine phosphokinase (CPK)
• Amylase/ lipase levels
• Serum glucose  
• Heart rate
• Blood pressure

Some cases may require

• Pregnancy status
• Hepatitis B virus (HBV) screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen
• Renal function

Additional observations

• Signs and symptoms of
  - Interstitial lung disease (ILD)/ pneumonitis
  - Muscular symptoms of CPK elevations
  - Visual disturbances (ophthalmologic evaluation)

Method of administration

• Brigatinib tablets should be swallowed whole and with water. Brigatinib may be taken with or without food

Coadministration with strong CYP3A inhibitors and strong and moderate CYP3A inducers

• The concomitant use of brigatinib with strong CYP3A inhibitors should be avoided. If concomitant use of strong CYP3A inhibitors cannot be avoided, the dose of brigatinib should be reduced from 180mg to 90mg, or from 90mg to 60mg. After discontinuation of a strong CYP3A inhibitor, brigatinib should be resumed at the dose that was tolerated prior to the initiation of the strong CYP3A inhibitor
• The concomitant use of brigatinib with strong and moderate CYP3A inducers should be avoided

Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-like growth factor 1 receptor (IGF-1R). Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo assays.

Tablet 30mg

• Alunbrig 30mg (Takeda) originator

Tablet 90mg

• Alunbrig 90mg (Takeda) originator

Tablet 180mg

• Alunbrig 180mg (Takeda) originator