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Black Box Warning
WARNING
See full prescribing information for complete 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
Overview
Lapatinib is an antineoplastic agent that is FDA approved for the treatment of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Condition1
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.
Limitation 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.
Dosing Information
2.1 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)].
2.2 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 v3) 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.
Diarrhea: TYKERB 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 ≥NCI CTCAE Grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration). TYKERB 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. TYKERB 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 TYKERB may be considered when patients develop ≥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 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
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Dosing Information
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Dosing Information
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Dosing Information
Dosage
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Lapatinib in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lapatinib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Lapatinib in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Lapatinib in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lapatinib in pediatric patients.
Contraindications
TYKERB is contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components.
Warnings
WARNING
See full prescribing information for complete 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
5.1 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)].
5.2 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)].
5.3 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)].
5.4 Diarrhea
Diarrhea has been reported during treatment with TYKERB [see Adverse Reactions (6.1)]. The diarrhea may be severe, and deaths have been reported. Diarrhea generally occurs early during treatment with TYKERB, 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 <10% and <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 TYKERB [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. TYKERB should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).
5.6 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.
5.7 Severe Cutaneous Reactions
Severe cutaneous reactions have been reported with TYKERB. 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 TYKERB.
5.8 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.
Precautions
Description
Adverse Reactions
Clinical Trials Experience
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 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.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lapatinib in the drug label.
