Tykerb Special Precautions

Decreased Left Ventricular Ejection Fraction: TYKERB has been reported to decrease LVEF [see Clinical Trials Experience under Adverse Reactions]. 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 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 Dose Modification Guidelines under Dosage & Administration].
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 TYKERB should be discontinued and patients should not be retreated with TYKERB [see Clinical Trials Experience under Adverse Reactions].
Patients With Severe Hepatic Impairment: If TYKERB is to be administered to patients with severe preexisting hepatic impairment, dose reduction should be considered [see Dose Modification Guidelines under Dosage & Administration and Hepatic impairment as follows]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Hepatotoxicity as previously mentioned].
Diarrhea: Diarrhea has been reported during treatment with TYKERB [see Clinical Trials Experience under 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. TYKERB-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 antidiarrheal 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 Dose Modification Guidelines under Dosage & Administration].
Interstitial Lung Disease/Pneumonitis: TYKERB has been associated with interstitial lung disease (ILD) and pneumonitis in monotherapy or in combination with other chemotherapies [see Clinical Trials Experience under Adverse Reactions]. Patients should be monitored for pulmonary symptoms indicative of ILD or pneumonitis. TYKERB should be discontinued in patients who experience pulmonary symptoms indicative of ILD/pneumonitis, which are greater than or equal to Grade 3 (NCI CTCAE v3.0).
QT Prolongation: A concentration-dependent QT prolongation has been associated with TYKERB [see Pharmacology: Pharmacodynamics under Actions]. Monitor patients who have or may develop prolongation of QTc during treatment with TYKERB. 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, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to TYKERB 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.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animal studies, TYKERB 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 Pregnancy & Lactation and Pharmacology: Mechanism of Action under Actions]. Verify the pregnancy status of females of reproductive potential prior to initiation of TYKERB. Advise females of reproductive potential to use effective contraception during treatment with TYKERB and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TYKERB and for 1 week after the last dose [see Use in Pregnancy & Lactation].
Renal Impairment: 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.
Hepatic Impairment: The pharmacokinetics of lapatinib were examined in subjects with preexisting 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 preexisting 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 preexisting hepatic impairment [see Dose Modification Guidelines under Dosage & Administration]. In patients who develop severe hepatotoxicity while on therapy, TYKERB should be discontinued and patients should not be retreated with TYKERB [see Hepatoxicity as previously mentioned].
Use in Children: The safety and effectiveness of TYKERB in pediatric patients have not been established.
Use in the Elderly: 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.