WARNINGS AND PRECAUTIONS
Decreased Left Ventricular Ejection Fraction
TYKERB has been reported to decrease LVEF [see Adverse Reactions]. In the randomized clinical trial, the majority (>60%) of LVEF decreases occurred within the first 9 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].
Patients with Severe Hepatic Impairment
If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered [see Dosage and Administration and Use in Specific Populations].
Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB [see Adverse Reactions]. 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]. 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 measured by automated machine-read evaluation of ECG was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see Clinical Pharmacology]. 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. The prescriber should consider baseline and on-treatment electrocardiograms with QT measurement.
Pregnancy Category D
TYKERB can cause fetal harm when administered to a pregnant woman. In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC).
Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.
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.
USE IN SPECIFIC POPULATIONS
Pregnancy Category D [see Warnings and Precautions].
It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TYKERB, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of TYKERB in pediatric patients have not been established.
Of the total number of metastatic breast cancer patients in clinical studies of TYKERB in combination with capecitabine (N = 198), 17% were 65 years of age and older, and 1% were 75 years of age and older. No overall differences in safety or effectiveness of the combination of TYKERB and capecitabine were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. There is no experience with TYKERB in patients with severe renal impairment. However, renal impairment is unlikely to affect the pharmacokinetics of lapatinib given that less than 2% (lapatinib and metabolites) of an administered dose is eliminated by the kidneys.
The pharmacokinetics of lapatinib were examined in subjects with moderate (n = 8) or severe (n = 4) hepatic impairment (Child-Pugh Class B/C, respectively) and in 8 healthy control subjects. Systemic exposure (AUC) to lapatinib after a single oral 100-mg dose increased approximately 14% and 63% in subjects with moderate and severe hepatic impairment, respectively. Administration of TYKERB in patients with severe hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction should be considered for patients with severe hepatic impairment [see Dosage and Administration] .