for:

HER2+ Advanced or Metastatic Breast Cancer (aBC or mBC)

Important Safety Information, including Boxed WARNING
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) 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.1

Limitation of use: Patients should have disease progression on trastuzumab prior to initiation of treatment with TYKERB in combination with capecitabine.1

DOSING & ADMINISTRATION

Recommended Oral Dosing

TYKERB 1250-mg Daily Dose1

aA treatment cycle is 21 days. TYKERB plus capecitabine is taken on days 1 to 14. TYKERB alone is taken on days 15 to 21. At the end of the 21 days, the treatment cycle should be repeated until disease progression or unacceptable toxicity occurs.
bTablets not shown at actual size.

 

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

Dose Administration

Directions for Taking TYKERB1,2


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

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 capecitabine may be restarted at a reduced dose (1,000 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) 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) 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 1,250 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).

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; 2015.
2.  National Institutes of Health Senior Health Web site. http://nihseniorhealth.gov/takingmedicines/takingmedicinessafely/01.html. Accessed July 24, 2015.

INDICATION

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.

 

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 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.

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: TYKERB prolongs the QT interval in some patients and should be administered with caution in 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 that lead to QT prolongation. Hypokalemia and hypomagnesemia should be corrected prior to administration, and electrocardiogram and electrolyte monitoring should be considered.

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. 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.

Adverse Reactions: The most common adverse reactions (≥10%) during therapy with TYKERB plus capecitabine vs capecitabine were diarrhea (65%, 40%), palmar-plantar erythrodysesthesia (53%, 51%), nausea (44%, 43%), rash (28%, 14%), vomiting (26%, 21%), fatigue (23%, 25%), mucosal inflammation (15%, 12%), stomatitis (14%, 11%), pain in extremity (12%, 7%), dyspnea (12%, 8%), back pain (11%, 6%), dyspepsia (11%, 3%), dry skin (10%, 6%), and insomnia (10%, 6%). The most common grade 3 and 4 adverse reactions with TYKERB plus capecitabine compared to capecitabine were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).

Laboratory Abnormalities: Laboratory abnormalities during therapy with TYKERB plus capecitabine vs capecitabine included increased AST (49%, 43%), increased ALT (37%, 33%), and increased total bilirubin (45%, 30%).

 Please see accompanying full Prescribing Information.