lapatinib 250 MG Oral Tablet

INDICATIONS AND USAGE Lapatinib tablets are kinase inhibitor indicated in combination with: ( 1 ) 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 lapatinib tablets in combination with capecetabine. 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. Lapatinib tablets in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer. Lapatinib tablet is a kinase inhibitor indicated in combination with: ( 1 ) 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 lapatinib tablets 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. Lapatinib tablets in combination with an aromatase inhibitor have not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.

DOSAGE AND ADMINISTRATION The recommended dosage of lapatinib tablets for advanced or metastatic breast cancer is 1,250 mg (5 tablets) given orally once daily on Days 1 to 21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1 to 14 in a repeating 21-day cycle. ( 2.1 ) The recommended dose of lapatinib tablets 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 lapatinib tablets are coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily. ( 2.1 ) Lapatinib tablets 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. ( 2.1 ) Lapatinib tablets should be taken once daily. Do not divide daily doses of lapatinib tablets. ( 2.1 , 12.3 ) Modify dose for cardiac and other toxicities, severe hepatic impairment, diarrhea, and CYP3A4 drug interactions. ( 2.2 ) 2.1 Recommended Dosing HER2-Positive Metastatic Breast Cancer : The recommended dose of lapatinib tablets is 1,250 mg given orally once daily on Days 1 to 21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1 to 14 in a repeating 21-day cycle. Lapatinib tablets should be taken at least one hour before or one hour after a meal. The dose of lapatinib tablets should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)] . Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs. Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer : The recommended dose of lapatinib tablets is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with lapatinib tablets, the recommended dose of letrozole is 2.5 mg once daily. Lapatinib tablets should be taken at least one hour before or one hour after a meal. The dose of lapatinib tablets should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)] . 2.2 Dose Modification Guidelines Cardiac Events : Lapatinib tablets should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0), and in patients with an LVEF that drops below the institution’s lower limit of normal (LLN) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] . Lapatinib tablets in combination with capecitabine may be restarted at a reduced dose (1,000 mg/day) and in combination with letrozole may be restarted at a reduced dose of 1,250 mg/day after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic. Hepatic Impairment : Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of lapatinib tablets reduced. A dose reduction from 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day to 1,000 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment. Diarrhea : Lapatinib tablets should be interrupted in patients with diarrhea which is NCI CTCAE Grade 3 or Grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting greater than or equal to NCI CTCAE Grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration). Lapatinib tablets may be reintroduced at a lower dose (reduced from 1,250 mg/day to 1,000 mg/day or from 1,500 mg/day to 1,250 mg/day) when diarrhea resolves to Grade 1 or less. Lapatinib tablets should be permanently discontinued in patients with diarrhea, which is NCI CTCAE Grade 4 [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)] . Concomitant Strong CYP3A4 Inhibitors : The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib tablets dose is adjusted upward to the indicated dose [see Drug Interactions (7.2)] . Concomitant Strong CYP3A4 Inducers : The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib tablets should be titrated gradually from 1,250 mg/day up to 4,500 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) based on tolerability. This dose of lapatinib tablets is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, the lapatinib tablets dose should be reduced to the indicated dose [see Drug Interactions (7.2)] . Other Toxicities : Discontinuation or interruption of dosing with lapatinib tablets may be considered when patients develop greater than or equal to Grade 2 NCI CTCAE toxicity, and can be restarted at the standard dose of 1,250 or 1,500 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then lapatinib tablets in combination with capecitabine should be restarted at a lower dose (1,000 mg/day) and in combination with letrozole should be restarted at a lower dose of 1,250 mg/day. See manufacturer’s prescribing information for the coadministered product dosage adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

WARNINGS AND PRECAUTIONS Decreases in left ventricular ejection fraction (LVEF) have been reported. Confirm normal LVEF before starting lapatinib tablets and continue evaluations during treatment. ( 5.1 ) Lapatinib 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 lapatinib tablets if patients experience severe changes in liver function tests. ( 5.2 ) Dose reduction in patients with severe hepatic impairment should be considered. ( 2.2 , 5.3 , 8.7 ) Diarrhea, including severe diarrhea, has been reported during treatment. Manage with antidiarrheal agents, and replace fluids and electrolytes if severe. ( 5.4 ) Lapatinib has been associated with interstitial lung disease and pneumonitis. Discontinue lapatinib tablets if patients experience severe pulmonary symptoms. ( 5.5 ) Lapatinib may prolong the QT interval in some patients. Consider electrocardiogram (ECG) and electrolyte monitoring. ( 5.6 , 12.2 ) Severe cutaneous reactions have been reported. Discontinue lapatinib tablets if life-threatening reactions are suspected. ( 5.7 ) Lapatinib tablets can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 ). 5.1 Decreased Left Ventricular Ejection Fraction Lapatinib tablets has been reported to decrease LVEF [see Adverse Reactions (6.1 ) ]. In clinical trials, the majority (greater than 57%) of LVEF decreases occurred within the first 12 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if lapatinib tablets are to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with lapatinib tablets to ensure that the patient has a baseline LVEF that is within the institution's normal limits. LVEF should continue to be evaluated during treatment with lapatinib tablets to ensure that LVEF does not decline below the institution's normal limits [see Dosage and Administration (2.2) ]. 5.2 Hepatotoxicity Hepatotoxicity [alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) and total bilirubin greater than 2 times the ULN] has been observed in clinical trials (less than 1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with lapatinib tablets should be discontinued and patients should not be retreated with lapatinib tablets [see Adverse Reactions (6.1 )]. 5.3 Patients with Severe Hepatic Impairment If lapatinib tablets are to be administered to patients with severe pre existing hepatic impairment, dose reduction should be considered [see Dosage and Administration (2.2) and Use in Specific Populations (8.7) ]. In patients who develop severe hepatotoxicity while on therapy, lapatinib tablets should be discontinued and patients should not be retreated with lapatinib tablets [see Warnings and Precautions (5.2)]. 5.4 Diarrhea Diarrhea has been reported during treatment with lapatinib [see Adverse Reactions(6.1)]. The diarrhea may be severe, and deaths have been reported. Diarrhea generally occurs early during treatment with lapatinib with almost half of those patients with diarrhea first experiencing it within 6 days. This usually lasts 4 to 5 days. Lapatinib-induced diarrhea is usually low-grade, with severe diarrhea of NCI CTCAE Grades 3 and 4 occurring in less than 10% and less than 1% of patients, respectively. Early identification and intervention is critical for the optimal management of diarrhea. Patients should be instructed to report any change in bowel patterns immediately. Prompt treatment of diarrhea with anti-diarrheal agents (such as loperamide) after the first unformed stool is recommended. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics, such as fluoroquinolones (especially if diarrhea is persistent beyond 24 hours, there is fever, or Grade 3 or 4 neutropenia), and interruption or discontinuation of therapy with lapatinib [see Dosage and Administration (2.2) ]. 5.5 Interstitial Lung Disease/Pneumonitis Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Adverse Reactions (6.1 )]. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib tablets should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis, which are greater than or equal to Grade 3 (NCI CTCAE v 3.0). 5.6 QT Prolongation A concentration-dependent QT prolongation has been associated with lapatinib tablets [see Clinical Pharmacology (12.2 )]. Monitor patients who have or may develop prolongation of QTc during treatment with lapatinib tablets. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products with known risk for QT prolongation/Torsades de Pointes (TdP), and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to lapatinib tablets administration. 5.7 Severe Cutaneous Reactions Severe cutaneous reactions have been reported with lapatinib tablets. If life-threatening reactions, such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (e.g., progressive skin rash often with blisters or mucosal lesions) are suspected, discontinue treatment with lapatinib tablets. 5.8 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animal studies, lapatinib tablets can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, administration of lapatinib to pregnant rats during the period of organogenesis and through lactation led to death of offspring within the first 4 days after birth at maternal exposures that were ≥ 3.3 times the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses (with maternal exposures approximately 6.4 and 0.2 times, respectively, the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine). Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1 ) and Clinical Pharmacology (12.1 )]. Verify the pregnancy status of females of reproductive potential prior to initiation of lapatinib tablets. Advise females of reproductive potential to use effective contraception during treatment with lapatinib tablets and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with lapatinib tablets and for 1 week after the last dose [see Use in Specific Populations (8.1 , 8.3 )].

CONTRAINDICATIONS Lapatinib tablets are 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. ( 4 )

Mechanism of Action 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 Ki 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 . These in vitro findings suggest non-cross-resistance between these two agents. Hormone receptor-positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that coexpress the HER2 tend to be resistant to established endocrine therapies. Similarly, hormone receptor-positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.