Tykerb

lapatinib

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

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. [See Warnings and Precautions (5.2).]

Indications and Usage for Tykerb

Tykerb® is indicated in combination with:

• capecitabine for the 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.


• 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.

Tykerb Dosage and Administration

Recommended Dosing

HER2 Positive Metastatic Breast Cancer: The recommended dose of Tykerb is 1,250 mg given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. Tykerb should be taken at least one hour before or one hour after a meal. The dose of Tykerb 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 Tykerb is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with Tykerb, 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. The dose of Tykerb should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)].

Dose Modification Guidelines

Cardiac Events: Tykerb 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) and in patients with an LVEF that drops below the institution’s lower limit of normal [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Tykerb 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 Tykerb 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.

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 Tykerb may be considered when patients develop ≥Grade 2 NCI CTCAE toxicity and can be restarted at 1,250 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then Tykerb 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.

Dosage Forms and Strengths

250 mg tablets — oval, biconvex, orange, film-coated with GS XJG debossed on one side.

Contraindications

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

Warnings and Precautions

Decreased Left Ventricular Ejection Fraction

Tykerb has been reported to decrease LVEF [see Adverse Reactions (6.1)]. In clinical trials, the majority (>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 Tykerb is 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 Tykerb 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 Tykerb to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration (2.2)].

Hepatotoxicity

Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal) has been observed in clinical trials (<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 Tykerb should be discontinued and patients should not be retreated with Tykerb [see Adverse Reactions (6.1)].

Patients with Severe Hepatic Impairment

If Tykerb is 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, Tykerb should be discontinued and patients should not be retreated with Tykerb [see Warnings and Precautions (5.2)].

Diarrhea

Diarrhea, including severe diarrhea, has been reported during treatment with Tykerb [see Adverse Reactions (6.1)]. Proactive management of diarrhea with anti-diarrheal agents is important. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with Tykerb.

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. Tykerb should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).

QT Prolongation

QT prolongation was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see Clinical Pharmacology (12.4)]. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration.

Use in Pregnancy

Tykerb can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Tykerb is expected to result in adverse reproductive effects. Lapatinib administered to rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth [see Use in Specific Populations (8.1)].

There are no adequate and well-controlled studies with Tykerb in pregnant women. Women should be advised not to become pregnant when taking Tykerb. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions

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 Tykerb has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of Tykerb 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 (>20%) during therapy with Tykerb 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 Grade 3 and 4 adverse reactions (NCI CTCAE v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.

Table 1. Adverse Reactions Occurring in ≥10% of Patients

	Tykerb 1,250 mg/day + Capecitabine 2,000 mg/m2/day			Capecitabine 2,500 mg/m2/day
	(N = 198)			(N = 191)
	All Gradesa	Grade 3	Grade 4	All Gradesa	Grade 3	Grade 4
Reactions	%	%	%	%	%	%
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

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

b Grade 3 dermatitis acneiform was reported in <1% of patients in Tykerb plus capecitabine group.

Table 2. Selected Laboratory Abnormalities

	Tykerb 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

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Hormone Receptor Positive, Metastatic Breast Cancer: In a randomized clinical trial of patients (N = 1,286) with hormone receptor positive, metastatic breast cancer, who had not received chemotherapy for their metastatic disease, patients received letrozole with or without Tykerb. In this trial, the safety profile of Tykerb was consistent with previously reported results from trials of Tykerb 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 ≥10% of Patients

	Tykerb 1,500 mg/day + Letrozole 2.5 mg/day			Letrozole 2.5 mg/day
	(N = 654)			(N = 624)
	All Gradesa	Grade 3	Grade 4	All Gradesa	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 administrative 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

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

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.

Table 4. Selected Laboratory Abnormalities

	Tykerb 1,500 mg/day + Letrozole 2.5 mg/day			Letrozole 2.5 mg/day
	All Gradesa	Grade 3	Grade 4	All Gradesa	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

a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

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 ≥Grade 3 (NCI CTCAE), or a ≥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 Tykerb/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3). [See Warnings and Precautions (5.1).] Among 654 patients who received Tykerb/letrozole combination treatment, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions.

Hepatotoxicity: Tykerb has been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)].

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Tykerb. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity reactions including anaphylaxis [see Contraindications (4)].

Skin and Subcutaneous Tissue Disorders: Nail disorders including paronychia.

Drug Interactions

Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems

Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be exercised and dose reduction of the concomitant substrate drug sho