"May 14, 2013 -- Actress and activist Angelina Jolie's recent decision to have a preventive double mastectomy highlights the difficult choices facing women who find out they have a high risk for breast cancer because of their genes.
Decreased Left Ventricular Ejection Fraction
TYKERB has been reported to decrease LVEF [see ADVERSE REACTIONS]. 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].
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].
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 and Use In Specific Populations]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Hepatotoxicity above].
Diarrhea has been reported during treatment with TYKERB [see ADVERSE REACTIONS]. 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].
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 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.
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.
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].
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Patients should be informed of the following:
- TYKERB has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking TYKERB.
- TYKERB often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician immediately if there is any change in bowel patterns or severe diarrhea occurs during treatment with TYKERB.
- TYKERB may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.
- TYKERB may interact with grapefruit. Patients should not take TYKERB with grapefruit products.
- TYKERB should be taken at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food.
- The dose of TYKERB should be taken once daily. Dividing the daily dose is not recommended.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In carcinogenicity studies, lapatinib was administered orally for up to 104 weeks at doses of 75 and 150 mg/kg/day in male mice and 75, 150, and 300 mg/kg/day in female mice (approximately 0.7 to 2 times the expected human clinical exposure based on AUC for a clinical dose of 1,250 mg/day) and 60, 120, 240 and 500 mg/kg/day (approximately 0.6 to 2.3 times the expected human clinical exposure based on AUC) in male rats, and 20, 60, and 180 mg/kg/day (approximately 1.4 to 10 times the expected human clinical exposure based on AUC) in female rats. There was no evidence of carcinogenicity in mice. In male rats, there was an increased incidence of whole body combined hemangiomas and hemangiosarcomas.
Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays.
There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥ 60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine, respectively).
Animal Toxicology And/Or Pharmacology
In 104-week repeat-dose studies in rodents, severe skin lesions that led to lethality were seen at the highest doses tested (300 mg/kg/day) in male mice and female rats. There was also an increase in renal infarcts and papillary necrosis in female rats at ≥ 60 mg/kg/day and ≥ 180 mg/kg/day, respectively (approximately 7 and 10 times the expected human clinical exposure based on AUC, respectively). The relevance of these findings for humans is uncertain.
Use In Specific Populations
Pregnancy Category D
[see WARNINGS AND PRECAUTIONS].
Based on findings in animals, TYKERB can cause fetal harm when administered to a pregnant woman. Lapatinib administered to rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses. 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.
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 following 1,250-mg dose of lapatinib plus capecitabine), 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 following 1,250-mg dose of lapatinib plus capecitabine). 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 following 1,250-mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.
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. Of the total number of hormone receptor-positive, HER2-positive metastatic breast cancer patients in clinical studies of TYKERB in combination with letrozole (N = 642), 44% were 65 years of age and older, and 12% were 75 years of age and older. No overall differences in safety or effectiveness were observed between elderly 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 pre-existing 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 pre-existing 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 pre-existing hepatic impairment [see DOSAGE AND ADMINISTRATION]. 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].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/21/2015
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