Tykerb

TYKERB^® is indicated in combination with:

• capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab.
  
  
  
  
  Limitations of Use
  : Patients should have disease progression on trastuzumab prior to initiation of treatment with TYKERB in combination with capecitabine.
  
  
  
  
• 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.

The recommended dosage of TYKERB for advanced or metastatic breast cancer is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m²/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. (

The recommended dose of TYKERB for hormone receptor-positive, HER2-positive metastatic breast cancer is 1,500 mg (6 tablets) given orally once daily continuously in combination with letrozole. When TYKERB is coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily. (

• TYKERB should be taken at least one hour before or one hour after a meal. However, capecitabine should be taken with food or within 30 minutes after food. (
  2.1     Recommended Dosing

  HER2-Positive Metastatic Breast Cancer

  : The recommended dose of TYKERB is 1,250 mg given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m²/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended

  [see Clinical Pharmacology (12.3)]

  . Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.

  Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer

  : The recommended dose of TYKERB is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with TYKERB, the recommended dose of letrozole is 2.5 mg once daily. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended

  [see Clinical Pharmacology (12.3)]

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• TYKERB should be taken once daily. Do not divide daily doses of TYKERB. (
  2.1     Recommended Dosing

  HER2-Positive Metastatic Breast Cancer

  : The recommended dose of TYKERB is 1,250 mg given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m²/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended

  [see Clinical Pharmacology (12.3)]

  . Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.

  Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer

  : The recommended dose of TYKERB is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with TYKERB, the recommended dose of letrozole is 2.5 mg once daily. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended

  [see Clinical Pharmacology (12.3)]

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  12.3     Pharmacokinetics

  Absorption

  : Absorption following oral administration of TYKERB is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (C_max) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of TYKERB results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours.

  At the dose of 1,250 mg daily, steady-state geometric mean [95% confidence interval (CI)] values of C_maxwere 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.h/mL (23.4 to 56 mcg.h/mL).

  Divided daily doses of TYKERB resulted in approximately 2-fold higher exposure at steady state (steady-state AUC) compared to the same total dose administered once daily.

  Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (C_maxapproximately 2.5- and 3-fold higher) when administered with a low-fat (5% fat-500 calories) or with a high-fat (50% fat-1000 calories) meal, respectively.

  Distribution

  : Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.

  Metabolism

  : Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.

  Elimination

  : At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours.

  Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (less than 2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.

  Effects of Age, Gender, or Race

  : Studies of the effects of age, gender, or race on the pharmacokinetics of lapatinib have not been performed.
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• Modify dose for cardiac and other toxicities, severe hepatic impairment, diarrhea, and CYP3A4 drug interactions. (
  2.2     Dose Modification Guidelines

  Cardiac Events

  : TYKERB should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0), and in patients with an LVEF that drops below the institution’s lower limit of normal (LLN)

  [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]

  . TYKERB in combination with capecitabine may be restarted at a reduced dose (1,000 mg/day) and 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 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer indication) or 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 greater than or equal to 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 or 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

  [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]

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  Concomitant Strong CYP3A4 Inhibitors

  : The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., 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 TYKERB dose is adjusted upward to the indicated dose

  [see Drug Interactions (7.2)]

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  Concomitant Strong CYP3A4 Inducers

  : The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of TYKERB 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 TYKERB 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 TYKERB dose should be reduced to the indicated dose

  [see Drug Interactions (7.2)]

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  Other Toxicities

  : Discontinuation or interruption of dosing with TYKERB may be considered when patients develop greater than or equal to Grade 2 NCI CTCAE toxicity, and can be restarted at the standard dose of 1,250 or 1,500 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) and 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.
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250 mg tablets — oval, biconvex, orange, film-coated with ‘GS XJG’ debossed on one side.

• Lactation: Advise not to breastfeed. (
  8.2     Lactation

  Risk Summary

  There are no data on the presence of lapatinib in human milk, or its effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in a breastfed child from TYKERB, advise lactating women not to breastfeed during treatment with TYKERB and for 1 week after the last dose.
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• Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of TYKERB. (
  8.3     Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to the initiation of TYKERB.

  Contraception

  Females

  Based on findings in animal studies, TYKERB can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  . Advise females of reproductive potential to use effective contraception during treatment with TYKERB and for 1 week after the last dose.

  Males

  Based on findings in animal reproduction studies, 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 Specific Populations (8.1)]

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