-------------------------------CONTRAINDICATIONS------------------------
`Known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its
`
`components. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------
`
`
`• Decreases in left ventricular ejection fraction have been reported. Confirm
`normal LVEF before starting TYKERB and continue evaluations during
`treatment. (5.1)
`
`• Lapatinib has been associated with hepatotoxicity. Monitor liver function
`tests before initiation of treatment, every 4 to 6 weeks during treatment,
`and as clinically indicated. Discontinue and do not restart TYKERB if
`
`patients experience severe changes in liver function tests. (5.2)
`
`• Dose reduction in patients with severe hepatic impairment should be
`
`considered. (2.2, 5.3, 8.7)
`
`
`• Diarrhea, including severe diarrhea, has been reported during treatment.
`
`Manage with anti-diarrheal agents, and replace fluids and electrolytes if
`severe. (5.4)
`
`• Lapatinib has been associated with interstitial lung disease and
`
`pneumonitis. Discontinue TYKERB if patients experience severe
`
`
`pulmonary symptoms. (5.5)
`
`• Lapatinib may prolong the QT interval in some patients. Consider ECG
`
`and electrolyte monitoring. (5.6, 12.4)
`
`
`• Fetal harm can occur when administered to a pregnant woman. Women
`should be advised not to become pregnant when taking TYKERB. (5.7)
`
`------------------------------ ADVERSE REACTIONS -----------------------
`The most common (>20%) adverse reactions during treatment with TYKERB
`
`
`plus capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea,
`
`rash, vomiting, and fatigue. The most common (≥20%) adverse reactions
`
`
`during treatment with TYKERB plus letrozole were diarrhea, rash, nausea,
`
`
`and fatigue. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`-------------------------------DRUG INTERACTIONS------------------------
`• TYKERB is likely to increase exposure to concomitantly administered
`drugs which are substrates of CYP3A4, CYP2C8, or P-glycoprotein
`(ABCB1). (7.1)
`
`• Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction
`
`of TYKERB in patients coadministered a strong CYP3A4 inhibitor.
`(2.2, 7.2)
`
`
`• Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose
`increase of TYKERB in patients coadministered a strong CYP3A4
`
`inducer. (2.2, 7.2)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`
`
`Revised: XX/YEAR
`
`
`
` 
` 
`Nursing Mothers
`8.3
` 
` 
`Pediatric Use
`8.4
` 
` 
`Geriatric Use
`8.5
` 
` 
`Renal Impairment
`8.6
` 
` 
`Hepatic Impairment
`8.7
` 
` 
`10 OVERDOSAGE
` 
` 
`11 DESCRIPTION
` 
` 
`12 CLINICAL PHARMACOLOGY
` 
` 
`12.1 Mechanism of Action
` 
` 
`12.3
`Pharmacokinetics
` 
` 
`12.4 QT Prolongation
` 
` 
`13 NONCLINICAL TOXICOLOGY
` 
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 
` 
`14 CLINICAL STUDIES
` 
` 
`14.1 HER2 Positive Metastatic Breast Cancer
` 
`14.2 Hormone Receptor Positive, HER2 Positive Metastatic
` 
`Breast Cancer
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`17 PATIENT COUNSELING INFORMATION
`
` 
` 
`Information for Patients
`17.1
` 
` 
`17.2
`FDA-Approved Patient Labeling
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use TYKERB
`safely and effectively. See full prescribing information for TYKERB.
`TYKERB (lapatinib) tablets
`
`Initial U.S. Approval: 2007
`WARNING: HEPATOTOXICITY
`See full prescribing information for complete boxed 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. [See Warnings and
`Precautions (5.2).]
`
`----------------------------INDICATIONS AND USAGE---------------------
`TYKERB, a kinase inhibitor, is indicated in combination with: (1)
`
`• 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.
`
`
`• 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.
`----------------------- DOSAGE AND ADMINISTRATION ----------------
`
`
`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. (2.1)
`The recommended dose of TYKERB for hormone receptor positive, HER2
`
`positive metastatic breast cancer is 1500 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. (2.1)
`
`• 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)
`
`• TYKERB should be taken once daily. Do not divide daily doses of
`
`TYKERB. (2.1, 12.3)
`
`• Modify dose for cardiac and other toxicities, severe hepatic impairment,
`and CYP3A4 drug interactions. (2.2)
`--------------------- DOSAGE FORMS AND STRENGTHS --------------
`
`250 mg tablets (3)
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
` 
`FULL PRESCRIBING INFORMATION
` 
`WARNING: HEPATOTOXICITY
` 
` 
`INDICATIONS AND USAGE
`1
` 
` 
`2
`DOSAGE AND ADMINISTRATION
`
` 
` 
`Recommended Dosing
`2.1
` 
` 
`2.2
`Dose Modification Guidelines
` 
` 
`DOSAGE FORMS AND STRENGTHS
`3
` 
` 
`CONTRAINDICATIONS
`4
` 
` 
`5 WARNINGS AND PRECAUTIONS
` 
` 
`Decreased Left Ventricular Ejection Fraction
`5.1
` 
` 
`5.2
`Hepatotoxicity
` 
` 
`5.3
`Patients with Severe Hepatic Impairment
` 
` 
`5.4
`Diarrhea
` 
` 
`5.5
`Interstitial Lung Disease/Pneumonitis
` 
` 
`5.6
`QT Prolongation
` 
` 
`5.7
`Use in Pregnancy
` 
`ADVERSE REACTIONS
` 
` 
`Clinical Trials Experience
`6.1
` 
` 
`6.2
`Postmarketing Experience
` 
`DRUG INTERACTIONS
` 
`Effects of Lapatinib on Drug Metabolizing Enzymes and
`7.1
` 
`Drug Transport Systems
` 
` 
`Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes
`7.2
` 
` 
`7.3
`Drugs that Inhibit Drug Transport Systems
` 
`USE IN SPECIFIC POPULATIONS
` 
` 
`8.1
`Pregnancy
`
` 
`6
`
` 
`7
`
` 
`8
`
`
`
`Reference ID: 2999707
`
`1
`
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`IPR2014-00676
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`

`
`______________________________________________________________________
`
`1
`
`FULL PRESCRIBING INFORMATION
`
`2 WARNING: HEPATOTOXICITY
`Hepatotoxicity has been observed in clinical trials and postmarketing experience.
`
`3
`4 The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is
`
` uncertain. [See Warnings and Precautions (5.2).]
`5
`
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`
`INDICATIONS AND USAGE
`1
`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.
`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.
`
`
`•
`
`DOSAGE AND ADMINISTRATION
`2
`16
`2.1 Recommended Dosing
`17
`HER2 Positive Metastatic Breast Cancer: The recommended dose of TYKERB is
`18
`
`1,250 mg given orally once daily on Days 1-21 continuously in combination with capecitabine
`19
`2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in
`20
`a repeating 21 day cycle. TYKERB should be taken at least one hour before or one hour after a
`21
`22 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
`23
`24
`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
`25
`26
`unacceptable toxicity occurs.
`Hormone Receptor Positive, HER2 Positive Metastatic Breast Cancer: The
`27
`
`recommended dose of TYKERB is 1,500 mg given orally once daily continuously in
`28
`29
`combination with letrozole. When coadministered with TYKERB, the recommended dose of
`30
`letrozole is 2.5 mg once daily. TYKERB should be taken at least one hour before or one hour
`31
`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)].
`32
`2.2 Dose Modification Guidelines
`33
`Cardiac Events: TYKERB should be discontinued in patients with a decreased left
`
`34
`35
`ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute
`
`Reference ID: 2999707
`
`
`2
`
`
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`
`36 Common Terminology Criteria for Adverse Events (NCI CTCAE) and in patients with an LVEF
`that drops below the institution’s lower limit of normal [see Warnings and Precautions (5.1) and
`37
`Adverse Reactions (6.1)]. TYKERB in combination with capecitabine may be restarted at a
`38
`39
`reduced dose (1,000 mg/day) and in combination with letrozole may be restarted at a reduced
`40
`dose of 1,250 mg/day after a minimum of 2 weeks if the LVEF recovers to normal and the
`
`41
` patient is asymptomatic.
`Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh Class C)
`
`42
`should have their dose of TYKERB reduced. A dose reduction from 1,250 mg/day to
`43
`44
`750 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day to
`45
`1,000 mg/day (hormone receptor positive, HER2 positive breast cancer indication) in patients
`46 with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the
`47
`normal range and should be considered. However, there are no clinical data with this dose
`48
`adjustment in patients with severe hepatic impairment.
`Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4
`
`49
`inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
`50
`51
`indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit
`52 may also increase plasma concentrations of lapatinib and should be avoided. If patients must be
`53
`coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction
`54
`to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without
`55
`inhibitors and should be considered. However, there are no clinical data with this dose
`56
`adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is
`57
`discontinued, a washout period of approximately 1 week should be allowed before the lapatinib
`dose is adjusted upward to the indicated dose. [See Drug Interactions (7.2).]
`58
`
`Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4
`59
`
`inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
`60
`61
`rifapentin, phenobarbital, St. John’s Wort). If patients must be coadministered a strong CYP3A4
`62
`inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually
`63
`from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or
`64
`from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer
`65
`indication) based on tolerability. This dose of lapatinib is predicted to adjust the lapatinib AUC
`66
`to the range observed without inducers and should be considered. However, there are no clinical
`67
`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. [See Drug
`68
`Interactions (7.2).]
`69
`
`Other Toxicities: Discontinuation or interruption of dosing with TYKERB may be
`70
`
`considered when patients develop ≥Grade 2 NCI CTCAE toxicity and can be restarted at
`71
`72
`1,250 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then
`73
`TYKERB in combination with capecitabine should be restarted at a lower dose (1,000 mg/day)
`74
`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
`
`75
`
`Reference ID: 2999707
`
`
`
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`
`76
`77
`
`78
`79
`80
`
`81
`82
`83
`
`adjustment guidelines in the event of toxicity and other relevant safety information or
`contraindications.
`
`DOSAGE FORMS AND STRENGTHS
`250 mg tablets — oval, biconvex, orange, film-coated with GS XJG debossed on one
`
`3
`
`side.
`
`CONTRAINDICATIONS
`4
`TYKERB is contraindicated in patients with known severe hypersensitivity (e.g.,
`
`anaphylaxis) to this product or any of its components.
`
`WARNINGS AND PRECAUTIONS
`5
`84
`5.1 Decreased Left Ventricular Ejection Fraction
`85
`TYKERB has been reported to decrease LVEF [see Adverse Reactions (6.1)]. In clinical
`
`86
`trials, the majority (>57%) of LVEF decreases occurred within the first 12 weeks of treatment;
`87
`however, data on long-term exposure are limited. Caution should be taken if TYKERB is to be
`88
`administered to patients with conditions that could impair left ventricular function. LVEF should
`89
`be evaluated in all patients prior to initiation of treatment with TYKERB to ensure that the
`90
`patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue
`91
`to be evaluated during treatment with TYKERB to ensure that LVEF does not decline below the
`92
`institution’s normal limits [see Dosage and Administration (2.2)].
`93
`5.2 Hepatotoxicity
`
`94
`Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin
`95
`
`>2 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and
`96
`postmarketing experience. The hepatotoxicity may be severe and deaths have been reported.
`97
`98 Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after
`99
`initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase)
`100
`should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as
`101
`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 (6.1)].
`102
`5.3 Patients with Severe Hepatic Impairment
`103
`104
`If TYKERB is to be administered to patients with severe pre-existing hepatic impairment,
`
`dose reduction should be considered [see Dosage and Administration (2.2) and Use in Specific
`105
`Populations (8.7)]. In patients who develop severe hepatotoxicity while on therapy, TYKERB
`106
`should be discontinued and patients should not be retreated with TYKERB [see Warnings and
`107
`Precautions (5.2)].
`108
`5.4 Diarrhea
`109
`110
`Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB
`
`[see Adverse Reactions (6.1)]. Proactive management of diarrhea with anti-diarrheal agents is
`111
`112
`important. Severe cases of diarrhea may require administration of oral or intravenous electrolytes
`113
`and fluids, and interruption or discontinuation of therapy with TYKERB.
`
`Reference ID: 2999707
`
`
`
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`
`Interstitial Lung Disease/Pneumonitis
`5.5
`114
`Lapatinib has been associated with interstitial lung disease and pneumonitis in
`115
`
`116 monotherapy or in combination with other chemotherapies [see Adverse Reactions (6.1)].
`117
`Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or
`118
`pneumonitis. TYKERB should be discontinued in patients who experience pulmonary symptoms
`119
`indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).
`5.6 QT Prolongation
`120
`
`121
`QT prolongation was observed in an uncontrolled, open-label dose escalation study of
`lapatinib in advanced cancer patients [see Clinical Pharmacology (12.4)]. Lapatinib should be
`122
`123
`administered with caution to patients who have or may develop prolongation of QTc. These
`124
`conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT
`125
`syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT
`126
`prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or
`127
`hypomagnesemia should be corrected prior to lapatinib administration.
`5.7 Use in Pregnancy
`128
`129
`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
`130
`131
`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 (8.1)].
`132
`133
`There are no adequate and well-controlled studies with TYKERB in pregnant women.
`
`134 Women should be advised not to become pregnant when taking TYKERB. If this drug is used
`135
`during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
`136
`apprised of the potential hazard to the fetus.
`
`137
`138
`139
`140
`141
`142
`143
`144
`145
`146
`147
`148
`149
`150
`151
`152
`
`6
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`
`rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
`
`trials of another drug and may not reflect the rates observed in practice.
`HER2 Positive Metastatic Breast Cancer: The safety of TYKERB has been evaluated
`
`in more than 12,000 patients in clinical trials. The efficacy and safety of TYKERB in
`combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized,
`Phase 3 trial. [See Clinical Studies (14.1).] Adverse reactions which occurred in at least 10% of
`patients in either treatment arm and were higher in the combination arm are shown in Table 1.
`The most common adverse reactions (>20%) during therapy with TYKERB plus
`
`capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar­
`plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse
`reaction resulting in discontinuation of study medication.
`The most common Grade 3 and 4 adverse reactions (NCI CTCAE v3) were diarrhea and
`
`palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.
`
`Reference ID: 2999707
`
`
`
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`153
`154 Table 1. Adverse Reactions Occurring in ≥10% of Patients
`TYKERB 1,250 mg/day +
`Capecitabine
`2,000 mg/m2/day
`
`
` (N = 198)
`Grade
`3
`%
`
`13
`2
`2
`0
`<1
`
`
`Capecitabine
`2,500 mg/m2/day
`
`
` (N = 191)
`Grade
`3
`%
`
`10
`2
`2
`<1
`0
`
`
`
`
`All
` Gradesa
`%
`
`40
`43
`21
`11
`3
`
`
`Grade
`4
`%
`
`0
`0
`0
`0
`0
`
`
`Grade
`4
`%
`
`1
`0
`0
`0
`0
`
`
`
`
`53
`28
`10
`
`
`15
`
`
`12
`11
`
`
`12
`2
`0
`
`
`0
`
`
`1
`1
`
`
`0
`0
`0
`
`
`0
`
`
`0
`0
`
`
`51
`14
`6
`
`
`12
`
`
`7
`6
`
`
`14
`1
`0
`
`
`2
`
`
`<1
`<1
`
`
`0
`0
`0
`
`
`0
`
`
`0
`0
`
`
`0
`
`0
`
`
`
`
`
`155
`156
`157
`158
`
`
`Reference ID: 2999707
`
`
`
`6
`
`
`
`
`All
` Gradesa
`%
`
`65
`44
`26
`14
`11
`
`
`
`
`
`
`
`
`
`Reactions
`Gastrointestinal disorders
`
`Diarrhea
`Nausea
`Vomiting
` Stomatitis
`Dyspepsia
`Skin and subcutaneous tissue
`disorders
`
`Palmar-plantar erythrodysesthesia
`
`Rashb
`
`Dry skin
`
`General disorders and
` administrative site conditions
`
`Mucosal inflammation
`Musculoskeletal and connective
`tissue disorders
`
`Pain in extremity
` Back pain
`Respiratory, thoracic, and
`mediastinal disorders
`
`
`2
`8
`0
`3
`12
`Dyspnea
`Psychiatric disorders
`
`
`
`
`
`
`0
`6
`0
`<1
`10
`Insomnia
`a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
`
`b Grade 3 dermatitis acneiform was reported in <1% of patients in TYKERB plus capecitabine
`
`group.
`
`
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`
`159 Table 2. Selected Laboratory Abnormalities
`TYKERB 1,250 mg/day +
`Capecitabine 2,000 mg/m2/day
`Capecitabine 2,500 mg/m2/day
`
` All Gradesa
`Grade 3 Grade 4 All Gradesa Grade 3 Grade 4
`
`%
`%
`%
`%
`%
`%
`Parameters
`Hematologic
`
`
`
`
`
`
`56
`<1
`0
`53
`1
`0
`
`Hemoglobin
`18
`<1
`0
`17
`<1
`<1
`Platelets
`22
`3
`<1
`31
`2
`1
`Neutrophils
`Hepatic
`
`
`
`
`
`
`45
`4
`0
`30
`3
`0
`Total Bilirubin
`49
`2
`<1
`43
`2
`0
`AST
`37
`2
`0
`33
`1
`0
`ALT
`
` a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
`
`
`
`
`
`160
`161
`Hormone Receptor Positive, Metastatic Breast Cancer: In a randomized clinical
`162
`trial of patients (N = 1,286) with hormone receptor positive, metastatic breast cancer, who had
`163
`not received chemotherapy for their metastatic disease, patients received letrozole with or
`164
`165 without TYKERB. In this trial, the safety profile of TYKERB was consistent with previously
`166
`reported results from trials of TYKERB in the advanced or metastatic breast cancer population.
`167 Adverse reactions which occurred in at least 10% of patients in either treatment arm and were
`168
`higher in the combination arm are shown in Table 3. Selected laboratory abnormalities are
`169
`shown in Table 4.
`170
`
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`171 Table 3. Adverse Reactions Occurring in ≥10% of Patients
`TYKERB 1,500 mg/day +
`Letrozole 2.5 mg/day
`(N = 654)
`
`
`Grade
`3
`%
`
`9
`<1
`1
`<1
`
`
`Letrozole 2.5 mg/day
`(N = 624)
`
`
`Grade
`3
`%
`
`<1
`<1
`<1
`<1
`
`
`
`
`All
` Gradesa
`%
`
`20
`21
`11
`9
`
`
`Grade
`4
`%
`
`0
`0
`<1
`0
`
`
`Grade
`4
`%
`
`<1
`0
`<1
`0
`
`
`Reactions
`
`Gastrointestinal disorders
` Diarrhea
`Nausea
` Vomiting
`Anorexia
`Skin and subcutaneous tissue
`disorders
`
` Rashb
`
`Dry skin
`Alopecia
`Pruritus
` Nail Disorder
`General disorders and
`administrative site conditions
` Fatigue
`Asthenia
`
`Nervous system disorders
`
`Headache
`
`Respiratory, thoracic, and
`mediastinal disorders
`
`<1
`2
`0
`<1
`11
`Epistaxis
`a
`National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
`In addition to the rash reported under "Skin and subcutaneous tissue disorders", 3 additional
`subjects in each treatment arm had rash under "Infections and infestations"; none were Grade
`3 or 4.
`
`
`
`
`
`All
` Gradesa
`%
`
`64
`31
`17
`11
`
`
`
`
`
`
`
`
`44
`13
`13
`12
`11
`
`
`20
`12
`
`14
`
`
`1
`<1
`<1
`<1
`<1
`
`
`2
`<1
`
`<1
`
`
`0
`0
`0
`0
`0
`
`
`0
`0
`
`0
`
`
`13
`4
`7
`9
`<1
`
`
`17
`11
`
`13
`
`
`0
`0
`0
`<1
`0
`
`
`<1
`<1
`
`<1
`
`
`0
`0
`0
`0
`0
`
`
`0
`0
`
`0
`
`
`0
`
`
`
`
`
`
`
`b
`
`
`
`172
`173
`174
`175
`176
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`177 Table 4. Selected Laboratory Abnormalities
`TYKERB 1,500 mg/day +
`Letrozole 2.5 mg/day
`Letrozole 2.5 mg/day
`All Gradesa Grade 3 Grade 4 All Gradesa Grade 3 Grade 4
`
`
`%
`%
`%
`%
`%
`%
` Hepatic Parameters
`
`53
`6
`0
`36
`2
`<1
`
`AST
`46
`5
`<1
`35
`1
`0
`ALT
`22
`<1
`<1
`11
`1
`<1
` Total Bilirubin
`
` a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
`
`
`
`
`
`178
`179
`Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity
`180
`181 with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week
`182
`intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular
`183
`cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac
`184
`ejection fraction relative to baseline which is below the institution's lower limit of normal.
`185 Among 198 patients who received TYKERB/capecitabine combination treatment, 3 experienced
`186 Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3). [See Warnings and
`Precautions (5.1).] Among 654 patients who received TYKERB/letrozole combination
`187
`188
`treatment, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse
`189
`reactions.
`Hepatotoxicity: TYKERB has been associated with hepatotoxicity [see Boxed Warning
`190
`and Warnings and Precautions (5.2)].
`191
`Interstitial Lung Disease/Pneumonitis: TYKERB has been associated with interstitial
`192
`lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see
`
`193
`
`194 Warnings and Precautions (5.5)].
`6.2 Postmarketing Experience
`195
`The following adverse reactions have been identified during post-approval use of
`196
`
`TYKERB. Because these reactions are reported voluntarily from a population of uncertain size,
`197
`
`it is not always possible to reliably estimate their frequency or establish a causal relationship to
`198
`199
`drug exposure.
`Immune System Disorders: Hypersensitivity reactions including anaphylaxis [see
`200
`201 Contraindications (4)].
`Skin and Subcutaneous Tissue Disorders: Nail disorders including paronychia.
`202
`
`
`
`
`
`
`
`DRUG INTERACTIONS
`7
`203
`7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport
`204
`205 Systems
`
`206
`Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at
`clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be
`207
`208
`exercised and dose reduction of the concomitant substrate drug should be considered when
`209
`dosing TYKERB concurrently with medications with narrow therapeutic windows that are
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`substrates of CYP3A4, CYP2C8, or P-gp. Lapatinib did not significantly inhibit the following
`210
`enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT
`211
`enzymes in vitro, however, the clinical significance is unknown.
`212
`
`Midazolam: Following coadministration of TYKERB and midazolam (CYP3A4
`213
`substrate), 24-hour systemic exposure (AUC) of orally administered midazolam increased 45%,
`214
`215 while 24-hour AUC of intravenously administered midazolam increased 22%.
`
`Paclitaxel: In cancer patients receiving TYKERB and paclitaxel (CYP2C8 and P-gp
`216
`substrate), 24-hour systemic exposure (AUC) of paclitaxel was increased 23%. This increase in
`217
`218
`paclitaxel exposure may have been underestimated from the in vivo evaluation due to study
`219
`design limitations.
`
`Digoxin: Following coadministration of TYKERB and digoxin (P-gp substrate), systemic
`220
`221 AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations
`222
`should be monitored prior to initiation of TYKERB and throughout coadministration. If digoxin
`223
`serum concentration is >1.2 ng/mL, the digoxin dose should be reduced by half.
`7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes
`224
`225
`Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration
`
`of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see
`226
`227 Ketoconazole and Carbamazepine sections, below). Dose adjustment of lapatinib should be
`228
`considered for patients who must receive concomitant strong inhibitors or concomitant strong
`inducers of CYP3A4 enzymes [see Dosage and Administration (2.2)].
`229
`Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at
`230
`
`200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to
`231
`232
`approximately 3.6-fold of control and half-life increased to 1.7-fold of control.
`Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at
`233
`
`100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to
`234
`235
`lapatinib was decreased approximately 72%.
`7.3 Drugs that Inhibit Drug Transport Systems
`236
`237
`Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If
`
`TYKERB is administered with drugs that inhibit P-gp, increased concentrations of lapatinib are
`238
`239
`likely, and caution should be exercised.
`
`240
`241
`242
`243
`244
`245
`246
`247
`248
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Pregnancy Category D [see Warnings and Precautions (5.7)].
`
`
`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
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`this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the
`249
`
` patient should be apprised of the potential hazard to the fetus.
`250
`In a study where pregnant rats were dosed with lapatinib during organogenesis and
`
`251
`through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical
`252
`exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine), 91% of the
`253
`pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The
`254
`highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human
`255
`clinical exposure based on AUC).
`256
`
`Lapatinib was studied for effects on embryo-fetal development in pregnant rats and
`257
`rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects;
`258
`however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification)
`259
`occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the
`260
`human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine).
`261
`In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day
`262
`(approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC
`263
`following 1,250 mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day.
`264
`265 Maternal toxicity was associated with decreased fetal body weights and minor skeletal
`266
`variations.
`8.3 Nursing Mothers
`267
`
`268
`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
`269
`270
`infants from TYKERB, a decision should be made whether to discontinue nursing or to
`271
`discontinue the drug, taking into account the importance of the drug to the mother.
`8.4 Pediatric Use
`272
`273
`The safety and effectiveness of TYKERB in pediatric patients have not been established.
`8.5 Geriatric Use
`274
`275
`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
`276
`277
`75 years of age and older. Of the total number of hormone receptor positive, HER2 positive
`278 metastatic breast cancer patients in clinical studies of TYKERB in combination with letrozole
`279
`(N = 642), 44% were 65 years of age and older, and 12%