Lapatinib


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO HER2 overexpressing advanced or metastatic breast cancer Patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab: 1,250 mg once daily on days 1-21 w/ capecitabine 2,000 mg/m2/day in 2 divided doses approx 12 hr apart on days 1-14 of the cycle. HER2 overexpressing hormone receptor positive metastatic breast cancer Post-menopausal women whom hormonal therapy is indicated: 1,500 mg once daily continuously w/ letrozole 2.5 mg once daily.
Dosage Details
Oral
HER2-overexpressing advanced or metastatic breast cancer
Adult: Patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab: 1,250 mg once daily on days 1-21 in combination with capecitabine 2,000 mg/m2 daily in 2 divided doses approx 12 hr apart on days 1-14 of the cycle.

Oral
HER2-overexpressing hormone receptor positive metastatic breast cancer
Adult: Post-menopausal women whom hormonal therapy is indicated: 1,500 mg once daily continuously given in combination w/ letrozole 2.5 mg once daily.
Special Patient Group
HLA-DRB1*07:01 allele

Patient with 1 or 2 copies of HLA-DRB1*07:01 allele may have increased risk of hepatotoxicity manifested by increased ALT, when treated with lapatinib. However, other genetic and clinical factors may also influence the risk of lapatinib-induced hepatotoxicity. It is recommended to monitor liver functions in all patients treated with lapatinib regardless of genotype.

HLA-DQA1*02:01 allele

Patient with 1 or 2 copies of HLA-DQA1*02:01 allele may have increased risk of hepatotoxicity manifested by increased ALT, when treated with lapatinib. The prevalence of this allele has been estimated in 25% of white, 20% of African American, 20% of Hispanic, and 15% of Asian, but only 1% of Japanese. However, other genetic and clinical factors may also influence the risk of lapatinib-induced hepatotoxicity. It is recommended to monitor liver functions in all patients treated with lapatinib regardless of genotype.
Hepatic Impairment
HER2 overexpressing advanced or metastatic breast cancer:
Severe: 750 mg once daily.
HER2 overexpressing hormone receptor positive metastatic breast cancer:
Severe: 1 g once daily.
Administration
Should be taken on an empty stomach. Take at least 1 hr before or 1 hr after a meal. Do not eat/drink grapefruit products.
Special Precautions
Patient w/ hypokalaemia or hypomagnesaemia, congenital QT prolongation. Severe hepatic impairment. Pregnancy and lactation. Patient who are carriers of HLA-DRB1*07:01 and/or HLA-DQA1*02:01 alleles. Patient Counselling Advise patient to report any change in bowel patterns immediately. Monitoring Parameters Monitor LVEF prior to and periodically during treatment; ECG and electrolytes. LFT, including serum concentrations of transaminases, bilirubin, and alkaline phosphatase should be monitored before, and every 4-6 wk during treatment.
Adverse Reactions
GI disturbances, dermatological reactions (e.g. palmar-plantar erythrodysesthesia, rash), fatigue, decreases in LVEF, QT interval prolongation, stomatitis, mucosal inflammation, pain in extremities, back pain, dyspnoea, insomnia, epistaxis, alopecia, nail disorders (e.g. paronychia), interstitial lung disease, pneumonitis and hypersensitivity reactions including anaphylaxis.
Potentially Fatal: Hepatotoxicity, severe diarrhoea.
Patient Counseling Information
Advise patient to report any change in bowel patterns immediately.
MonitoringParameters
Monitor LVEF prior to and periodically during treatment; ECG and electrolytes. LFT, including serum concentrations of transaminases, bilirubin, and alkaline phosphatase should be monitored before, and every 4-6 wk during treatment.
Drug Interactions
May increase the serum levels of CYP3A4, CYP2C8 and P-glycoprotein substrates. Increased exposure w/ CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, atazanavir, ritonavir). CYP3A4 inducers (e.g. carbamazepine, rifampicin) may reduce exposure to lapatinib. Increased risk of QT prolongation w/ drugs known to prolong QT intervals (e.g. antiarrythmic agents, cumulative high-dose anthracycline therapy). May increase serum levels of digoxin.
Food Interaction
Increased lapatinib exposure w/ food. Plasma levels may be increased w/ grapefruit juice. St John's wort may decrease lapatinib systemic exposure.
Action
Description: Lapatinib is a 4-anilinoquinazoline tyrosine kinase inhibitor of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors. It blocks the phosphorylation and activation of downstream 2nd messengers (Erk1/2 and Akt) which regulate cellular proliferation and survival of ErbB- and ErbB2-expressing tumours.
Pharmacokinetics:
Absorption: Variable and incompletely absorbed. Systemic exposure is increased w/ food. Time to peak plasma concentration: Approx 4 hr.
Distribution: Plasma protein binding: >99% (albumin and α1 acid glycoprotein).
Metabolism: Undergoes extensive hepatic metabolism primarily via CYP3A4 and CYP3A5 isoenzymes, to a lesser extent via CYP2C19 and CYP2C8 isoenzymes.
Excretion: Via faeces approx 27% (parent lapatinib); approx 14% (metabolites). Terminal half-life: Approx 14 hr (single dose). Effective half-life: 24 hr (repeated dosing).
Storage
Store between 15-30°C.
References
Schaid DJ, Spraggs CF, McDonnell SK et al. Prospective Validation of HLA-DRB1*07:01 Allele Carriage As a Predictive Risk Factor for Lapatinib-Induced Liver Injury. Journal of Clinical Oncology. 2014 Aug;32(22):2296-2303. doi: 10.1200/JCO.2013.52.9867. Accessed 15/10/2018. PMID: 24687830

Spraggs CF, Budde LR, Briley L et al. HLA-DQA1*02:01 is a Major Risk Factor for Lapatinib-Induced Hepatotoxicity in Women With Advanced Breast Cancer. Journal of Clinical Oncology. 2011 Feb;29(6):667-673. doi: 10.1200/JCO.2010.31.3197. Accessed 15/10/2018. PMID: 21245432

Anon. Lapatinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 25/03/2014.

Buckingham R (ed). Lapatinib Tosilate. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 25/03/2014.

Clinical Annotation for HLA-DQA1*02:01 Related to Lapatinib- Toxicity (2B). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 15/10/2018.

Clinical Annotation for HLA-DRB1*07:01:01:01; Lapatinib; Toxic Liver Disease (Level 3 toxicity/ADR). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 20/09/2018.

McEvoy GK, Snow EK, Miller J et al (eds). Lapatinib Ditosylate. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 25/03/2014.

Tykerb (GlaxoSmithKline LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 25/03/2014.

Tykerb Tablets. U.S. FDA. https://www.fda.gov/. Accessed 25/03/2014.

Tyverb (Novartis Pharmaceuticals Corporation). U.S. FDA. https://www.fda.gov/. Accessed 21/09/2018.

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