Lapatinib

TYKERB ® is indicated in combination with: capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Limitations of Use: Patients should have disease progression on trastuzumab prior to initiation of treatment with TYKERB in combination with capecitabine. letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated. TYKERB in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated K i app values of 3nM and 13nM, respectively) with a dissociation half-life of greater than or equal to 300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models. An additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the active metabolite of capecitabine) were used in combination in the 4-tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro.

The recommended dosage of TYKERB for advanced or metastatic breast cancer is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. The recommended dose of TYKERB for hormone receptor-positive, HER2-positive metastatic breast cancer is 1,500 mg (6 tablets) given orally once daily continuously in combination with letrozole. When TYKERB is coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily. TYKERB should be taken at least one hour before or one hour after a meal. However, capecitabine should be taken with food or within 30 minutes after food. TYKERB should be taken once daily. Do not divide daily doses of TYKERB.

TYKERB is contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components.

Boxed warning (hepatotoxicity): Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. Decreases in left ventricular ejection fraction (LVEF) have been reported. Confirm normal LVEF before starting TYKERB and continue evaluations during treatment. TYKERB has been associated with hepatotoxicity. Monitor liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. Discontinue and do not restart TYKERB if patients experience severe changes in liver function tests. Dose reduction in patients with severe hepatic impairment should be considered. Diarrhea, including severe diarrhea, has been reported during treatment. Manage with antidiarrheal agents, and replace fluids and electrolytes if severe.

The most common (greater than 20%) adverse reactions during treatment with TYKERB plus capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, and fatigue. The most common (greater than or equal to 20%) adverse reactions during treatment with TYKERB plus letrozole were diarrhea, rash, nausea, and fatigue.

TYKERB is likely to increase exposure to concomitantly administered drugs which are substrates of CYP3A4, CYP2C8, or P-glycoprotein (ABCB1). Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction of TYKERB in patients coadministered a strong CYP3A4 inhibitor. Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of TYKERB in patients coadministered a strong CYP3A4 inducer.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F).