Lapatinib: Package Insert and Label Information

LAPATINIB — lapatinib ditosylate tablet
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

Lapatinib 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 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 have not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.

2 DOSAGE AND ADMINISTRATION

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/m² /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 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 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 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 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, rifapentin, phenobarbital, St. John’s Wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib 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 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 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.

3 DOSAGE FORMS AND STRENGTHS

250 mg tablets — Orange colored, oval shaped, film-coated tablets, debossed “NTL” on one side and plain on another side.

4 CONTRAINDICATIONS

Lapatinib tablets are contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components.

5 WARNINGS AND PRECAUTIONS

5.1 Decreased Left Ventricular Ejection Fraction

Lapatinib tablets have 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)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

HER2-Positive Metastatic Breast Cancer: The safety of lapatinib tablets has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of lapatinib tablets in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. [see Clinical Studies (14.1).] Adverse reactions, which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm, are shown in Table 1.

The most common adverse reactions (greater than or equal to 20%) during therapy with lapatinib tablets plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.

The most common Grades 3 and 4 adverse reactions (NCI CTCAE v3.0) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.Table 1: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients

a NCI CTCAE v3.0.b Grade 3 dermatitis acneiform was reported in less than 1% of patients in the group receiving lapatinib tablets plus capecitabine.
	Lapatinib Tablets 1,250 mg/day + Capecitabine 2,000 mg/m2 /day(N = 198)			Capecitabine 2,500 mg/m2 /day(N=191)
Reactions	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
	%	%	%	%	%	%
Gastrointestinal disorders
Diarrhea	65	13	1	40	10	0
Nausea	44	2	0	43	2	0
Vomiting	26	2	0	21	2	0
Stomatitis	14	0	0	11	<1	0
Dyspepsia	11	<1	0	3	0	0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia	53	12	0	51	14	0
Rashb	28	2	0	14	1	0
Dry skin	10	0	0	6	0	0
General disorders and administrative site conditions
Mucosal inflammation	15	0	0	12	2	0
Musculoskeletal and connective tissue disorders
Pain in extremity	12	1	0	7	<1	0
Back pain	11	1	0	6	<1	0
Respiratory, thoracic, and mediastinal disorders
Dyspnea	12	3	0	8	2	0
Psychiatric disorders
Insomnia	10	<1	0	6	0	0

Table 2: Selected Laboratory Abnormalities

Abbreviations: CI, confidence interval; PFS, progression-free survival.a NCI CTCAE v3.0.
	Lapatinib Tablets 1,250 mg/day + Capecitabine 2,000 mg/m2 /day			Capecitabine 2,500 mg/m2 /day
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Parameters	%	%	%	%	%	%
Hematologic
Hemoglobin	56	<1	0	53	1	0
Platelets	18	<1	0	17	<1	<1
Neutrophils	22	3	<1	31	2	1
Hepatic
Total Bilirubin	45	4	0	30	3	0
AST	49	2	<1	43	2	0
ALT	37	2	0	33	1	0

Hormone Receptor-Positive, Metastatic Breast Cancer: In a randomized, Phase 3 clinical trial of patients (N = 1286) with hormone receptor-positive, metastatic breast cancer, who had not received chemotherapy for their metastatic disease, patients received letrozole with or without lapatinib tablets. In this trial, the safety profile of lapatinib tablets was consistent with previously reported results from trials of lapatinib tablets in the advanced or metastatic breast cancer population. Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 3. Selected laboratory abnormalities are shown in Table 4.

Table 3: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients

a NCI CTCAE, v3.0. b In addition to the rash reported under “Skin and subcutaneous tissue disorders”, 3 additional subjects in each treatment arm had rash under “Infections and infestations”; none were Grade 3 or 4.
	Lapatinib Tablets 1,500 mg/day + Letrozole 2.5 mg/day (N = 654)			Letrozole 2.5 mg/day (N = 624)
	All Grades a	Grade 3	Grade 4	All Grades a	Grade 3	Grade 4
Reactions	%	%	%	%	%	%
Gastrointestinal disorders
Diarrhea	64	9	<1	20	<1	0
Nausea	31	<1	0	21	<1	0
Vomiting	17	1	<1	11	<1	<1
Anorexia	11	<1	0	9	<1	0
Skin and subcutaneous tissue disorders
Rashb	44	1	0	13	0	0
Dry skin	13	<1	0	4	0	0
Alopecia	13	<1	0	7	0	0
Pruritus	12	<1	0	9	<1	0
Nail disorder	11	<1	0	<1	0	0
General disorders and administration site conditions
Fatigue	20	2	0	17	<1	0
Asthenia	12	<1	0	11	<1	0
Nervous system disorders
Headache	14	<1	0	13	<1	0
Respiratory, thoracic, and mediastinal disorders
Epistaxis	11	<1	0	2	<1	0

Table 4: Selected Laboratory Abnormalities

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.a NCI CTCAE, v3.0.
	Lapatinib Tablets 1,500 mg/day + Letrozole 2.5 mg/day			Letrozole 2.5 mg/day
	All Grades a	Grade 3	Grade 4	All Grades a	Grade 3	Grade 4
Hepatic Parameters	%	%	%	%	%	%
AST	53	6	0	36	2	<1
ALT	46	5	<1	35	1	0
Total Bilirubin	22	<1	<1	11	1	<1

Hormone Receptor-Positive, HER2+ Metastatic Breast Cancer: In another randomized, Phase 3 clinical trial of postmenopausal patients (N = 355) with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) which had progressed after prior trastuzumab-containing chemotherapy and endocrine therapies, patients received lapatinib tablets with trastuzumab and an aromatase inhibitor (AI) (letrozole, exemestane, or anastrozole), lapatinib tablets with an AI, or trastuzumab with an AI. In this trial, the safety profile of the treatment groups was consistent with the known safety of these agents. The most frequent study treatment-related AEs (> 10%) in each of the lapatinib tablets -containing treatment arms were diarrhea, rash, paronychia, nausea, stomatitis, dermatitis acneiform, and decreased appetite, which were infrequent to absent in the trastuzumab treatment arm. The frequency of cardiac AEs (mostly decrease in ejection fraction) was 7% in the lapatinib tablets + trastuzumab + AI group, 2% in the lapatinib tablets + AI group and 3% in the trastuzumab + AI group. Adverse reactions which occurred in at least 10% of patients in the treatment arms are shown in Table 5.

Table 5: Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients

a NCI CTCAE v3.0 b Includes multiple adverse reaction terms for rash.
	Lapatinib Tablets (1,000 mg) + Trastuzumab + AI (N = 118)			Lapatinib Tablets (1,500 mg) +AI (N = 119)				Trastuzumab + AI (N = 116)
	All Grades a	Grade 3	Grade 4		All Grades a	Grade 3	Grade 4	All Grades a	Grade 3	Grade 4
Reactions	%	%	%		%	%	%	%	%	%
Gastrointestinal disorders
Diarrhea	69	13	0		51	6	0	9	0	0
Nausea	22	0	0		22	2	0	9	0	0
Stomatitis	17	0	0		13	<1	0	3	0	0
Vomiting	10	0	0		14	0	0	<1	<1	0
Skin and subcutaneous tissue disorders
Rashb	54	0	0		44	3	0	5	0	0
Palmar-plantar erythrodysesthesia	10	0	0		8	<1	0	<1	0	0
Alopecia	10	0	0		7	0	0	2	0	0
General disorders and administrative site conditions
Fatigue	12	<1	0		14	2	0	10	0	0
Musculoskeletal and connective tissue disorders
Arthralgia	13	<1	0		14	0	0	12	0	0
Pain in extremity	7	<1	0		10	0	0	3	0	0
Respiratory, thoracic, and mediastinal disorders
Cough	8	0	0		8	0	0	15	0	0
Metabolism and nutrition dis orders
Decreased appetite	18	0	0		13	0	0	3	0	0
Infections and infestations
Paronychia	30	0	0		15	2	0	0	0	0
Investigations
Alanine aminotransferaseincreased	7	0	0		15	3	<1	6	4	0
Aspartate aminotransferaseincreased	6	0	0		17	5	0	9	4	0
Nervous system disorders
Headache	5	0	0		16	2	0	10	<1	0

Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are greater than or equal to Grade 3 (NCI CTCAE v3.0), or a greater than or equal to 20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution’s lower limit of normal. Among 198 patients who received combination treatment with lapatinib tablets/capecitabine, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3.0). Among 654 patients who received combination treatment with lapatinib tablets/letrozole, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions [see Warnings and Precautions (5.1)].

Hepatotoxicity: Lapatinib tablets have been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)].

Interstitial Lung Disease/Pneumonitis: Lapatinib tablets have been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see Warnings and Precautions (5.5)].