For:
HR+, HER2+ Metastatic Breast Cancer (mBC)

Important Safety Information WARNING: 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.

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Indication TYKERB® (lapatinib) tablets is indicated in combination with 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 & ADMINISTRATION

Recommended Oral Dosing

TYKERB® (lapatinib) Tablets 1500-mg Daily Dose1

 

aTablets not shown at actual size.

Dose Administration

Directions for Taking TYKERB1-3

 

bStrong CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole.
cStrong CYP3A4 inducers: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St John's wort.

 

Modify dose for cardiac and other toxicities, severe hepatic impairment, diarrhea, and CYP3A4 drug interactions. TYKERB should be permanently discontinued in patients with diarrhea which is National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 4.

Dose Modification

Dose Modification Guidelines1

Modify dose for cardiac and other toxicities, severe hepatic impairment, diarrhea, and CYP3A4 drug interactions. TYKERB should be permanently discontinued in patients with diarrhea which is National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade 4. The concomitant use of strong CYP3A4 inhibitors and inducers should be avoided. Please see accompanying Prescribing Information

Cardiac Events: TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by NCI CTCAE v3 and in patients with an LVEF that drops below the institution's lower limit of normal. TYKERB 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 1,500 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 1,500 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.

Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (eg, 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.

Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (eg, 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. 

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 1,500 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then TYKERB 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.

References:

1.  Tykerb [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
2.  Femara [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.
3.  National Institutes of Health Senior Health Web site. http://nihseniorhealth.gov/takingmedicines/takingmedicinessafely/01.html. Accessed July 24, 2015.

INDICATION

TYKERB® (lapatinib) tablets is indicated in combination with 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.

IMPORTANT SAFETY INFORMATION

WARNING: 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.

Contraindication: TYKERB is contraindicated in patients with known severe hypersensitivity (eg, anaphylaxis) to this product or any of its components.

Decreased Left Ventricular Ejection Fraction (LVEF): TYKERB has been reported to decrease LVEF. In clinical trials, >57% of LVEF decreases occurred within the first 12 weeks of treatment. Use caution if administering to patients with conditions that could impair LVEF. Confirm normal LVEF before starting TYKERB, and continue evaluations during treatment.

Hepatotoxicity: Hepatotoxicity [alanine transaminase (ALT) or aspartate transaminase (AST) >3 times the upper limit of normal (ULN) and total bilirubin >2 times the ULN] 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.

Patients With Severe Hepatic Impairment: If TYKERB is to be administered to patients with severe preexisting hepatic impairment, dose reduction should be considered.

Diarrhea: Diarrhea has been reported during treatment with TYKERB. 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 grade 3 and 4 diarrhea occurring in <10% and <1% of patients, respectively. 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.

Interstitial Lung Disease/Pneumonitis: TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Discontinue TYKERB in patients who experience pulmonary symptoms indicative of greater than or equal to grade 3 interstitial lung disease/pneumonitis.

QT Prolongation: A concentration-dependent QT prolongation has been associated with TYKERB. During treatment with TYKERB, monitor patients who have or may develop QT prolongation, including patients with hypokalemia or hypomagnesemia, congenital long QT syndrome, patients taking cumulative high-dose anthracycline, antiarrhythmics, or other products with known risk for QT prolongation/Torsades de Pointes. Correct hypokalemia or hypomagnesemia prior to TYKERB administration.

Severe Cutaneous Reactions have been reported. Discontinue TYKERB if life-threatening reactions (eg, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis) are suspected.

Pregnancy: TYKERB can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Prior to the initiation of TYKERB, verify the pregnancy status of females of reproductive potential and advise them 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.

Adverse Reactions: The most common adverse reactions (≥10%) during therapy with TYKERB plus letrozole compared to letrozole were diarrhea (64%, 20%), rash (44%, 13%), nausea (31%, 21%), fatigue (20%, 17%), vomiting (17%, 11%), headache, (14%, 13%), dry skin (13%, 4%), alopecia (13%, 7%), pruritus (12%, 9%), asthenia (12%, 11%), nail disorder (11%, <1%), anorexia (11%, 9%) and epistaxis (11%, 2%).The most common (≥2%) grade 3 and 4 adverse reactions with TYKERB plus letrozole compared to letrozole were diarrhea (9%, <1%) and fatigue (2%, <1%).

Laboratory Abnormalities: Laboratory abnormalities during therapy with TYKERB plus letrozole compared to letrozole included increased AST (53%, 36%), increased ALT (46%, 35%), and increased total bilirubin (22%, 11%).

Please see accompanying full Prescribing Information, including Boxed WARNING.