Brigatinib

Oral
Anaplastic lymphoma kinase-positive advanced non-small cell lung cancer

Patients taking moderate CYP3A4 inhibitors: Reduce dose by approx 40%. Refer to detailed product guideline.

Patients taking strong CYP3A4 inhibitors: Reduce dose by approx 50%. Refer to detailed product guideline.

Patients taking moderate CYP3A4 inducers: Increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose as tolerated, up to Max of twice the dose. Refer to detailed product guideline.

CrCl (mL/min)	Dosage
15-29	Reduce dose by approx 50% (i.e. from 180 mg once daily to 90 mg once daily, or from 90 mg once daily to 60 mg once daily). Refer to detailed product guideline.

Severe (Child-Pugh class C): Reduce dose by approx 40% (i.e. from 180 mg once daily to 120 mg once daily, from 120 mg once daily to 90 mg once daily, or from 90 mg once daily to 60 mg once daily). Refer to detailed product guideline.

film-coated tab: May be taken with or without food. Swallow whole, do not chew/crush.

Lactation.

Patient taking strong or moderate CYP3A4 inhibitors or CYP3A4 inducers. Severe renal (CrCl 15-29 mL/min) and hepatic (Child-Pugh class C) impairment. Pregnancy.

Significant: Cardiac effects (e.g. hypertension, bradycardia), visual disturbances (e.g. blurred vision, diplopia, photophobia, photopsia, reduced visual acuity, macular oedema, cataract), photosensitivity; elevated creatine phosphokinase (CPK); elevated amylase and lipase, increased ALT, AST or bilirubin; new-onset or worsening hyperglycaemia.
Blood and lymphatic system disorders: Anaemia.
Cardiac disorders: Palpitations, tachycardia, chest discomfort.
Gastrointestinal disorders: Nausea, vomiting, dry mouth, dysgeusia, dyspepsia, constipation, flatulence, diarrhoea, abdominal pain, stomatitis.
General disorders and administration site conditions: Fatigue, oedema, pyrexia.
Investigations: Weight decreased, ECG QT prolonged, increased alkaline phosphatase, increased blood LDH, increased blood creatinine, increased blood cholesterol, increased aPTT; decreased lymphocyte, neutrophil, platelet or WBC count.
Metabolism and nutrition disorders: Decreased appetite, hyperinsulinaemia, hypophosphataemia, hypomagnesaemia, hypercalcaemia, hyponatraemia, hypokalaemia.
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia, pain in extremity, musculoskeletal stiffness, musculoskeletal chest pain.
Nervous system disorders: Headache, dizziness, memory impairment, peripheral neuropathy.
Psychiatric disorders: Insomnia.
Respiratory, thoracic and mediastinal disorders: Cough, dyspnoea, URTI, pneumonia.
Skin and subcutaneous tissue disorders: Rash, pruritus, dry skin.
Potentially Fatal: Pulmonary toxicity (e.g. ILD or pneumonitis).

This drug may cause dizziness, visual disturbances or fatigue; if affected, do not drive or operate machinery. Avoid prolonged sun exposure during treatment and for at least 5 days after stopping the treatment; apply broad-spectrum ultraviolet A (UVA) or ultraviolet B (UVB) sunscreen, lip balm with sun protection factor (SPF) of ≥30 or wear protective clothing when going outdoors. Women of childbearing potential and men with partners who could become pregnant must use proven birth control methods during therapy and for at least 4 months (in women) or at least 3 months (in men) after stopping the treatment.

Obtain pregnancy test prior to treatment initiation. Confirm ALK-positive status before therapy. Monitor LFTs (e.g. ALT, AST, total bilirubin), CPK, amylase or lipase levels, fasting serum glucose; heart rate, blood pressure. Assess for signs and symptoms of ILD or pneumonitis, muscular symptoms of CPK elevations and visual disturbances.

Increased serum concentration with moderate CYP3A4 inhibitors (e.g. diltiazem, verapamil) and strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, troleandomycin, nefazodone). Decreased serum concentration with moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil, nafcillin) and strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbital, rifampicin, rifabutin). May reduce serum concentration and efficacy of CYP3A4 substrates with narrow therapeutic index (e.g. alfentanil, fentanyl, quinidine, ciclosporin, sirolimus, tacrolimus). May increase plasma concentration of P-glycoprotein (P-gp) substrates (e.g. colchicine, dabigatran, digoxin, pravastatin), BCRP substrates (e.g. methotrexate, rosuvastatin, sulfasalazine).

Increased serum concentration with grapefruit or grapefruit juice. Decreased serum concentration with St. John's wort.

Description:
Mechanism of Action: Brigatinib is a multiple tyrosine kinases inhibitor with activity against anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), insulin-like growth factor-1 receptor (IGF-1R), fms-like tyrosine kinase 3 (FLT-3) and epidermal growth factor receptor (EGFR) deletion and point mutations. It blocks ALK autophosphorylation and ALK-mediated phosphorylation of the downstream signalling proteins signal transducer and activator of transcription 3 (STAT3), AKT serine or threonine kinase, extracellular signal-regulated kinase (ERK) 1/2 and ribosomal protein S6 in in vitro and in vivo assays.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: 1-4 hours.
Distribution: Plasma protein binding: 91%.
Metabolism: Metabolised in the liver via N-demethylation and cysteine conjugation by CYP2C8 and CYP3A4 isoenzymes.
Excretion: Via faeces (65%; 41% as unchanged drug); urine (25%; 86% as unchanged drug). Elimination half-life: 25 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 68165256, Brigatinib. https://pubchem.ncbi.nlm.nih.gov/compound/Brigatinib. Accessed Nov. 22, 2023.

Store between 15-30°C. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.

Targeted Cancer Therapy

L01ED04 - brigatinib ; Belongs to the class of anaplastic lymphoma kinase (ALK) inhibitors. Used in the treatment of cancer.

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