Dosing and uses of Tykerb (lapatinib)
Adult dosage forms and strengths
tablet
- 250mg
Breast Cancer
HER2-overexpressing metastatic breast cancer
- Indicated in combination with capecitabine for treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab
- 1250 mg PO qDay on Days 1-21 continuously in combination with capecitabine (2000 mg/m²/day PO divided q12hr) on Days 1-14 in a repeating 21-day cycle
Hormone-positive & HER2-positive advanced breast cancer
- Indicated in combination therapy with letrozole for treatment of postmenopausal women with hormone receptor-positive and HER2-positive breast cancer for whom hormonal therapy is indicated
- 1500 mg PO qDay administered continuously in combination with letrozole 2.5 mg PO qDay
Dosage modifications
- Discontinue with decreased LVEF ≥Grade 2 or an LVEF that drops below the institution’s lower limit of normal; lapatinib may be restarted at 1000 mg/day after recovery
- Other toxicities: Discontinue or interrupt dose should be considered when patients develop ≥Grade 2 NCI CTCAE toxicity; can be restarted at 1,250 mg/day when the toxicity improves to ≤Grade 1; if toxicity recurs, then lapatinib in combination with capecitabine should be restarted at a lower dose
- Severe hepatic impairment: Reduce dose (see Hepatic Impairment)
- Concomitant strong CYP3A4 inhibitors: Reduce dose to 500 mg/day
- Concomitant strong CYP3A4 inducers: Gradually titrate from 1250 mg/day up to 4500 mg/day (HER2 positive metastatic breast cancer) or from 1500 mg/day up to 5500 mg/day (Hormone receptor positive, HER2 positive breast cancer)
Gastric Cancer (Orphan)
Treatment of ErbB2 positive gastric cancer
Orphan indication sponsor
- GlaxoSmithKline; 1250 S. Collegeville Rd, P. O. Box 5089;Collegeville, PA 19426-0989
Esophageal Cancer (Orphan)
Treatment of ErbB2 positive esophageal cancer
Orphan indication sponsor
- GlaxoSmithKline; 1250 S. Collegeville Rd, P. O. Box 5089;Collegeville, PA 19426-0989
Hepatic Impairment
Severe (Child-Pugh Class C)
- HER2 positive metastatic breast cancer: Reduce dose from 1250 mg/day to 750 mg/day
- Hormone receptor positive, HER2 positive breast cancer: Reduce dose from 1500 mg/day to 1000 mg/day
Administration
Lapatinib should be taken at least 1 hour before or 1 hour after meals; however, capecitabine should be taken with food, or within 30 minutes after food
Modify dose for cardiac and other toxicities, severe hepatic impairment, and CYP3A4 interactions
Pediatric dosage forms and strengths
Safety and efficacy not established
Tykerb (lapatinib) adverse (side) effects
>10% (lapatinib+capecitabine vs capecitabine)
Diarrhea (65% vs 40%)
Anemia (56% vs 53%)
Hand-foot synd (53% vs 51%)
Increased LFTs (37-49% vs 30-43%)
Nausea (44% vs 43%)
Rash (28% vs 14%)
Vomiting (26% vs 21%)
Pain (23% vs 13%)
Neutropenia (22% vs 31%)
Thrombocytopenia (18% vs 17%)
Mucositis (15% vs 12%)
Stomatitis (14% vs 11%)
Dyspnea (12% vs 8%)
Dyspepsia (11% vs 3%)
Insomnia (10% vs 6%)
1-10%
Insomnia
LVEF decreased
Postmarketing Reports
Hypersensitivity reactions including anaphylaxis
Nail disorders including paronychia
Warnings
Black box warnings
AST or ALT >3 times the upper limit of normal (ULN) or bilirubin >1.5 times ULN reported and may be a severe toxicity and/or fatal; onset may occur within days to several months after initiating therapy
Contraindications
Hypersensitivity to any component
Cautions
Severe hepatic impairment
Concomitant QT-prolonging drugs; conditions that increase QT-prolongation risk
Risk of severe diarrhea
Substrate of & inhibits P-glycoprotein (ABCB1); caution if using concomitant ABCB1 substrates/inhibitors
Severe cutaneous reactions reported; discontinue therapy if life-threatening reactions are suspected
Decreases in left ventricular ejection fraction (LVEF) reported; confirm normal LVEF before initiating therapy and continue evaluations during treatment
Hepatotoxicity reported with therapy; monitor liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated; discontinue and do not restart therapy if patients experience severe changes in liver function tests
Consider dose reduction in patients with severe hepatic impairment
Linked to risk of interstitial lung disease & pneumonitis; monitor pulmonary symptoms
Increased risk of cardiac events with prior exposure to trastuzumab and anthracyclines.
Diarrhea
- Diarrhea reported and may be severe; deaths reported
- Generally occurs early during treatment with almost 50% first experiencing it within 6 days, and usually lasts 4-5 days
- Usually low-grade, with severe diarrhea of NCI CTCAE Grades 3 and 4 occurring in <10% and <1% of patients, respectively
- Early identification and intervention is critical for the optimal management of diarrhea
- Instruct patients to report any change in bowel patterns immediately
- Prompt treatment of diarrhea with anti-diarrheal agents (eg, loperamide) after the first unformed stool is recommended
- Severe cases may oral or IV electrolytes and fluids, antibiotics (eg, fluoroquinolones) if diarrhea persists beyond 24 hr, fever is present, or Grade 3-4 neutropenia
- If severe, interrupt or discontinue lapatinib
Pregnancy and lactation
Pregnancy category: d
Lactation: Do not nurse
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Tykerb (lapatinib)
Mechanism of action
Kinase inhibitor, blocks EGF-receptor HER2 kinase; tyrosing kinase inhibition possibly blocks angiogenesis and cellular proliferation
Absorption
Systemic absorption increased by food (AUC increase ~3-4 fold)
Peak Plasma Time: 4 hr
Peak Plasma Concentration: 2.43 mcg/mL (1.25 g dose)
Distribution
Protein Bound: 99%
Metabolism
Primarily metabolized by CYP3A4 and CYP3A5
Enzymes inhibited: CYP3A4 and CYP2C8
Eliminiation
Half-Life: 24 hr
Excretion: Feces
Pharmacogenomics
Mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2, and lacks effect on cells not overexpressing HER2
HER2 testing should be performed
Patients with breast cancers with intensive staining (3+) should definitely receive anti-HER2 therapy; the clinical relevance of 2+ staining is uncertain
Genetic testing laboratories
- The following companies currently offer IHC and/or FISH testing for HER2 overexpression
- Dako (https://www.dakousa.com/)
- Ventana Medical Systems (https://www.ventanamed.com/)
- Vysis/Abbott Molecular (https://www.abbottmolecular.com/)
- Invitrogen (https://www.invitrogen.com/)
