Entrectinib


Generic Medicine Info
Indications and Dosage
Oral
Locally advanced non-small cell lung carcinoma, Metastatic non-small cell lung carcinoma
Adult: In patients with ROS1-positive tumour not previously treated with ROS1 inhibitors: 600 mg once daily until disease progression or unacceptable toxicity. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).

Oral
Solid tumours
Adult: In patients with neurotrophic tyrosine receptor kinase [NTRK] gene fusion tumour who have locally advanced or metastatic disease or where surgical resection is likely to result in severe morbidity, have not received a prior NTRK inhibitor, or have no satisfactory treatment options: 600 mg once daily until disease progression or unacceptable toxicity. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).
Child: ≥12 years BSA 0.91-1.1 m2: 400 mg once daily; BSA 1.11-1.5 m2: 500 mg once daily; BSA >1.5 m2: 600 mg once daily. Doses are given until disease progression or unacceptable toxicity. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability. Dosage recommendations may vary among countries or individual products. Refer to specific product guidelines.
Special Patient Group
Patients taking strong CYP3A inhibitors: 100 mg once daily.

Patients taking moderate CYP3A inhibitors: 200 mg once daily.
Administration
May be taken with or without food. Swallow whole, do not open/chew/crush/dissolve.
Contraindications
Congenital long QT syndrome or QT interval >450 milliseconds. Pregnancy and lactation. Concomitant use with strong or moderate CYP3A inducers or other agents that prolong QT/QTc interval.
Special Precautions
Patient with susceptibility to QT-interval prolongation, electrolyte imbalance, significant cardiac disease (e.g. MI, CHF, or risk factors for CHF). Patients taking strong or moderate CYP3A inhibitors.
Adverse Reactions
Significant: QT interval prolongation, CHF, cognitive impairment (e.g. cognitive disorders, confusion, attention disturbance, memory impairment, amnesia, aphasia, mental status changes, hallucinations, delirium), mood disorders (e.g. anxiety, depression, agitation), dizziness, sleep disturbance (e.g. insomnia, somnolence, hypersomnia, sleep disorder), fractures, increased AST/ALT, hyperuricaemia, visual disorders (e.g. blurred vision, photophobia, diplopia, visual impairment, photopsia, cataract, vitreous floaters). Rarely, myocarditis.
Blood and lymphatic system disorders: Anaemia, neutropenia.
Gastrointestinal disorders: Constipation, diarrhoea, abdominal pain, dysphagia nausea, vomiting, dysgeusia.
General disorders and administration site conditions: Fatigue, pain, pyrexia.
Investigations: Increased weight, increased blood creatinine.
Metabolism and nutrition disorders: Oedema, decreased appetite, dehydration.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, muscle weakness.
Nervous system disorders: Dizziness, dysaesthesia, ataxia, headache, peripheral sensory neuropathy.
Renal and urinary disorders: UTI, urinary retention.
Respiratory, thoracic and mediastinal disorders: Cough, lung infection, pleural effusion.
Skin and subcutaneous tissue disorders: Rash, photosensitivity.
Vascular disorders: Syncope, hypotension.
Potentially Fatal: Pneumonia, dyspnoea, tumour lysis syndrome.
Patient Counseling Information
This drug may cause syncope, blurred vision, or dizziness, if affected, do not drive or operate machinery.
Monitoring Parameters
Assess NTRK gene fusion status or ROS1 rearrangements and perform pregnancy and hepatitis B virus screening prior to treatment initiation. Monitor LFT, serum uric acid level, LVEF, QT interval and electrolytes at baseline, periodically throughout therapy, and as clinically indicated; signs and symptoms of heart failure, CNS adverse effects, fractures, tumour lysis syndrome and visual changes.
Drug Interactions
Increased plasma concentrations with strong or moderate CYP3A inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, saquinavir).
Potentially Fatal: Decreased plasma concentrations with strong or moderate CYP3A inducers. (e.g. carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin). Increased risk of QTc interval prolongation with agents known to prolong QT/QTc interval.
Food Interaction
Increased plasma levels with grapefruit juice and decreased plasma levels with St. John’s wort; avoid concomitant use.
Action
Description: Entrectinib is a potent inhibitor of tropomyosin tyrosine receptor kinases (TRK) TRKA, TRKB, and TRKC. TRKA, TRKB and TRKC are encoded by neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Entrectinib also inhibits proto-oncogenic tyrosine-protein kinase c-ros oncogene-1 (ROS1) and anaplastic lymphoma kinase (ALK). Fusion proteins that include TRK, ROS1 or ALK kinase domains act as oncogenic drivers to promote hyperactivation of downstream signalling pathways, resulting in unchecked cell proliferation.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: 4-6 hours.
Distribution: Volume of distribution: 551 L (entrectinib); 81.1 L (M5 active metabolite). Plasma protein binding: >99%.
Metabolism: Metabolised in the liver mainly by CYP3A4 to form the active metabolite, M5.
Excretion: Mainly via faeces (83%; 36% as unchanged drug and 22% as M5); urine (3%). Elimination half-life: Entrectinib: 20 hours; M5 (active metabolite): 40 hours.
Chemical Structure

Chemical Structure Image
Entrectinib

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 25141092, Entrectinib. https://pubchem.ncbi.nlm.nih.gov/compound/Entrectinib. Accessed Apr. 27, 2021.

Storage
Store below 30°C.
This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01EX14 - entrectinib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.
References
Anon. Entrectinib. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 02/03/2021.

Anon. Entrectinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 02/03/2021.

Joint Formulary Committee. Entrectinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 02/03/2021.

Roche Products (New Zealand) Limited. Rozlytrek 100 mg and 200 mg Hard Capsules data sheet 03 July 2020. Medsafe. http://www.medsafe.govt.nz. Accessed 02/03/2021.

Rozlytrek 100 mg Hard Capsules (Roche Products Limited). MHRA. https://products.mhra.gov.uk. Accessed 02/03/2021.

Rozlytrek Capsule (Genentech Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 02/03/2021.

Disclaimer: This information is independently developed by MIMS based on Entrectinib 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 © 2021 MIMS. All rights reserved. Powered by MIMS.com
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