Lorlatinib


Generic Medicine Info
Indications and Dosage
Oral
Metastatic non-small cell lung carcinoma
Adult: In patients with ALK-positive tumours whose disease have progressed on crizotinib and ≥1 other ALK inhibitor, or alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy: 100 mg once daily, given continuously 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). Dose reductions are made in 25-mg steps. Discontinue permanently if the patient is unable to tolerate 50 mg once daily.
Special Patient Group
Patients taking concomitant strong CYP3A4 inhibitors: Initially, 75 mg once daily. If dose reduction to 75 mg once daily has been made to manage adverse effects, reduce further to 50 mg once daily.
Renal Impairment
Severe: Not recommended.
Hepatic Impairment
Moderate to severe: Not recommended.
Administration
Film-Coated Tab: May be taken with or without food. Preferably taken at the same time each day. Swallow whole, do not chew/crush/split.
Contraindications
Pregnancy and lactation. Concomitant use with strong CYP3A inducers.
Special Precautions
Moderate to severe hepatic and severe renal impairment. Patients taking concomitant strong CYP3A4 inhibitors and moderate CYP3A inducers.
Adverse Reactions
Significant: Anaemia, mild lymphopenia and thrombocytopenia, CNS effects (e.g. seizures, psychotic effects [e.g. hallucinations], changes in cognitive function, mood [including suicidal ideation, anxiety, depression], speech, mental status and sleep), AV block, PR interval prolongation, reduced LVEF, increased serum cholesterol, triglycerides, amylase and lipase.
Eye disorders: Diplopia, photophobia, photopsia, blurred vision, visual impairment, reduced visual acuity, vitreous floaters.
Gastrointestinal disorders: Diarrhoea, constipation, nausea.
General disorders and administration site conditions: Fatigue, asthenia.
Investigations: Increased weight.
Metabolism and nutrition disorders: Oedema.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
Nervous system disorders: Peripheral neuropathy, headache.
Skin and subcutaneous tissue disorders: Rash.
Potentially Fatal: Interstitial lung disease or pneumonitis.
Patient Counseling Information
This drug may cause CNS effects (e.g. seizures, hallucinations), if affected, do not drive or operate machinery.
Monitoring Parameters
Establish ALK positivity using a validated ALK assay and evaluate pregnancy status prior to initiation of therapy. Monitor serum cholesterol, triglycerides, ECG, AST/ALT, bilirubin, amylase and lipase elevations; signs and symptoms of CNS effects and interstitial lung disease/pneumonitis.
Drug Interactions
Decreased plasma concentrations with moderate CYP3A inducers. Increased plasma concentrations with strong CYP3A inhibitors (e.g. itraconazole, boceprevir, ritonavir, cobicistat, troleandomycin). Reduced plasma concentrations of CYP3A substrates with narrow therapeutic indices (e.g. fentanyl, ciclosporin, ergotamine, hormonal contraceptives, pimozide, quinidine, sirolimus) and P-glycoprotein substrates (e.g. digoxin, dabigatran).
Potentially Fatal: Increased AST/ALT with concomitant use of strong CYP3A inducers (e.g. rifampicin, phenytoin, carbamazepine, mitotane, enzalutamide) which may lead to severe hepatotoxicity.
Food Interaction
Reduced plasma concentrations with St. John’s wort; avoid concomitant use. Increased plasma concentrations with grapefruit products.
Action
Description: Lorlatinib is an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK) and c-rosoncogene-1 (ROS1), as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2 and ACK. It inhibits phosphorylation of ALK and ALK-mediated signal transduction, thus reducing cellular proliferation and survival in tumours which express these fusion proteins.
Pharmacokinetics:
Absorption: Rapidly absorbed. Bioavailability: 81%. Time to peak plasma concentration: Approx 0.5-4 hours.
Distribution: Crosses the blood-brain barrier. Plasma protein binding: 66%.
Metabolism: Metabolised mainly via oxidation by the CYP3A4 and via glucuronidation by the UDP-glucuronosyltransferase1A4 (UGT1A4), with minor contributions from CYP2C8, CYP2C19, CYP3A5 and UGT1A3.
Excretion: Via urine (48%, <1% as unchanged drug) and faeces (41%, approx 9% as unchanged drug). Elimination half-life: 24 hours.
Chemical Structure

Chemical Structure Image
Lorlatinib

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 71731823, Lorlatinib. https://pubchem.ncbi.nlm.nih.gov/compound/Lorlatinib. Accessed Mar. 25, 2021.

Storage
Store between 20-25°C. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01ED05 - lorlatinib ; Belongs to the class of anaplastic lymphoma kinase (ALK) inhibitors. Used in the treatment of cancer.
References
Anon. Lorlatinib. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 09/02/2020.

Anon. Lorlatinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 09/02/2020.

Buckingham R (ed). Lorlatinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/02/2020.

Joint Formulary Committee. Lorlatinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/02/2020.

Lorbrena Tablet, Film Coated (Pfizer Laboratories Div Pfizer Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 09/02/2020.

Lorbrena Tablets (Pfizer Inc). U.S. FDA. https://www.fda.gov. Accessed 09/02/2020.

Lorviqua 25 mg and 100 mg Film-Coated Tablets (Pfizer Europe MA EEIG). MHRA. https://products.mhra.gov.uk. Accessed 09/02/2020.

Disclaimer: This information is independently developed by MIMS based on Lorlatinib 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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