Brigatinib


Concise Prescribing Info
Indications/Uses
ALK-positive metastatic non-small cell lung carcinoma previously treated with crizotinib.
Dosage/Direction for Use
Adult : PO Initial: 90 mg once daily for 7 days, if tolerated, may increase to 180 mg once daily. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Dosage Details
Oral
Metastatic non-small cell lung carcinoma
Adult: Patients with Anaplastic lymphoma kinase (ALK)-positive, previously treated with crizotinib: Initially, 90 mg once daily for 7 days, if tolerated, may increase to 180 mg once daily. Continue until disease progression or unacceptable toxicity occurs. If treatment is interrupted for 14 days or longer for reasons other than adverse effects, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose. Dose reduction, interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Special Patient Group
Patients taking strong CYP3A4 inhibitors: Reduce dose by approx 50%, resume to usual dose upon discontinuation of treatment.
Renal Impairment
Severe (eGFR <30 mL/min): 60 mg once daily for 7 days, then increased to 90 mg once daily.
Hepatic Impairment
Severe (Child-Pugh class C): 60 mg once daily for 7 days, then increased to 120 mg once daily.
Administration
Film-Coated Tab: May be taken with or without food. Swallow whole, do not chew/crush.
Contraindications
Pregnancy and lactation. Concomitant use with moderate and strong CYP3A4 inducers e.g. rifampicin, St. John’s wort, grapefruit or grapefruit juice.
Special Precautions
Concomitant use with strong CYP3A4 inhibitors. Renal and hepatic impairment.
Adverse Reactions
Significant: Cardiac effects (e.g. hypertension), visual disturbances (e.g. blurred vision, diplopia, reduced visual acuity, macular oedema, cataract), hyperglycaemia; elevations of CPK, pancreatic enzymes (e.g. lipase and amylase), hepatic enzymes (e.g. AST/ALT) and bilirubin.
Blood and lymphatic system disorders: Anaemia.
Cardiac disorders: Palpitations, tachycardia, chest discomfort.
Gastrointestinal disorders: Nausea, diarrhoea, vomiting, constipation, abdominal pain, dry mouth, dyspepsia, stomatitis, flatulence.
General disorders and admin site conditions: Fatigue, oedema, pyrexia, pain.
Infections and infestations: Pneumonia.
Investigations: ECG QT prolonged, weight decreased, increased alkaline phosphatase and blood lactate dehydrogenase, elevated blood creatinine, increased APTT, decreased neutrophil, lymphocyte, platelet, and WBC counts.
Metabolism and nutrition disorders: Decreased appetite, hypokalaemia, hyponatraemia, hypophosphataemia, hypomagnesaemia, hypercalcaemia, hyperinsulinaemia.
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia, pain in extremity.
Nervous system disorders: Headache, dizziness, dysgeusia, peripheral neuropathy, memory impairment.
Psychiatric disorders: Insomnia.
Respiratory, thoracic and mediastinal disorders: Cough, dyspnoea, non-cardiac chest pain, upper respiratory tract infection.
Skin and subcutaneous tissue disorders: Rash, pruritus, dry skin, photosensitivity.
Potentially Fatal: Pulmonary toxicity (e.g. interstitial lung disease or pneumonitis), bradycardia.
Patient Counseling Information
This drug may cause dizziness, visual disturbances or fatigue, if affected, do not drive or operate machinery.
MonitoringParameters
Establish ALK positivity. Monitor blood pressure and heart rate after 2 weeks and at least monthly thereafter; creatine phosphokinase (CPK) and amylase/lipase levels periodically during treatment; fasting serum glucose at baseline and periodically thereafter. Assess for signs/symptoms of interstitial lung disease (ILD) or pneumonitis, muscular symptoms of CPK elevations, and visual disturbances.
Drug Interactions
Decreased plasma concentration and efficacy with strong CYP3A4 inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), and moderate CYP3A4 inducers (e.g. efavirenz, modafinil, bosentan, etravine, nafcillin). Increased plasma concentration with strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, indinavir, nelfinavir, ritonavir, clarithromycin, telithromycin, troleandomycin, mibefradil, nefazodone). Increased risk of bradycardia with antihypertensive agents. May reduce plasma levels and efficacy of CYP3A substrates (e.g. alfentanil, fentanyl, quinidine, ciclosporin, tacrolimus, hormonal contraceptives). May increase plasma concentrations of transporter substrates (e.g. digoxin, dabigatran, colchicine, pravastatin, methotrexate, rosuvastatin, sulfasalazine).
Food Interaction
Avoid grapefruit or grapefruit juice as it may increase brigatinib plasma concentrations. Avoid St. John’s wort as it may decrease brigatinib plasma concentrations.
Action
Description: 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 inhibits the autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: Approx 1-4 hours.
Distribution: Volume of distribution: 153 L. Plasma protein binding: 91%.
Metabolism: Metabolised in the liver mainly via N-demethylation and cysteine conjugation by CYP2C8 and CYP3A4 isoenzymes to form its primary N-desmethyl brigatinib (AP26123) metabolite.
Excretion: Mainly via faeces (65%; 41% as unchanged drug); urine (25%; 86% as unchanged drug). Elimination half-life: 25 hours.
Chemical Structure

Chemical Structure Image
Brigatinib

Source: National Center for Biotechnology Information. PubChem Database. Brigatinib, CID=68165256, https://pubchem.ncbi.nlm.nih.gov/compound/Brigatinib (accessed on Jan. 21, 2020)

Storage
Store between 20-25°C. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01XE43 - brigatinib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
References
Alunbrig Tablet, Coated (Ariad Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 09/09/2019.

Anon. Brigatinib. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 09/09/2019.

Anon. Brigatinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 09/09/2019.

Buckingham R (ed). Brigatinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/09/2019.

Joint Formulary Committee. Brigatinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/09/2019.

Disclaimer: This information is independently developed by MIMS based on Brigatinib from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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