TYKERB (lapatinib) tablets
Initial U.S. Approval: 2007
FULL PRESCRIBING INFORMATION
WARNING: HEPATOTOXICITY 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® 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
2.1 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)].
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) and in patients with an LVEF that drops below the institution’s lower limit of normal [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 44 750 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.
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 lapatinib dose is
adjusted upward to the indicated dose. [See Drug Interactions
(7.2).]
Concomitant Strong CYP3A4 Inducers:
The concomitant use of strong CYP3A4 60 inducers should be
avoided (e.g., 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. [See Drug Interactions (7.2).]
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) 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 3 djustment
guidelines in the event of toxicity and other relevant safety information
or contraindications.
3 DOSAGE FORMS AND STRENGTHS
250 mg tablets — oval, biconvex, orange,
film-coated with GS XJG debossed on one side.
4 CONTRAINDICATIONS
TYKERB is contraindicated in patients with known severe
hypersensitivity (e.g., anaphylaxis) to this product or any of its
components.
5 WARNINGS AND PRECAUTIONS
5.1 Decreased Left Ventricular Ejection Fraction
TYKERB has been reported to decrease LVEF [see Adverse Reactions
(6.1)].
In clinical trials, the majority (>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 Dosage and
Administration (2.2)].
5.2 Hepatotoxicity
Hepatotoxicity (ALT or 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 and patients should not be retreated with TYKERB [see
Adverse Reactions (6.1)].
5.3 Patients with Severe Hepatic Impairment
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 Populations (8.7)]. In
patients who develop severe hepatotoxicity while on therapy, TYKERB
should be discontinued and patients should not be retreated with TYKERB [see
Warnings and Precautions (5.2)].
5.4 Diarrhea
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 important. Severe
cases of diarrhea may require administration of oral or intravenous
electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.
5.5 Interstitial Lung Disease/Pneumonitis
Lapatinib has been associated with interstitial lung disease and
pneumonitis in 116 monotherapy or in combination with other chemotherapies [see
Adverse Reactions (6.1)]. Patients should be monitored for pulmonary symptoms
indicative of interstitial lung disease or pneumonitis. TYKERB should be
discontinued in patients who experience pulmonary symptoms indicative of
interstitial lung disease/pneumonitis which are ≥Grade 3
(NCI CTCAE).
5.6 QT Prolongation
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 administered with caution to
patients who have or may develop prolongation of QTc. These conditions
include patients with hypokalemia or hypomagnesemia, with congenital long
QT syndrome, patients taking anti-arrhythmic medicines or other medicinal
products that lead to QT prolongation, and cumulative high-dose anthracycline
therapy. Hypokalemia or hypomagnesemia should be corrected prior to
lapatinib administration.
5.7 Use in Pregnancy
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 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)]. 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 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.
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 146 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.
patients (N = 1,286) with hormone receptor positive,
metastatic breast cancer, who had not received chemotherapy for their
metastatic disease, patients received letrozole with or without TYKERB. In
this trial, the safety profile of TYKERB was consistent with previously
reported results from trials of TYKERB in the advanced or metastatic breast
cancer population. 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 3. Selected laboratory abnormalities are shown in Table 4.
Decreases in Left Ventricular Ejection Fraction: Due to
potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in
clinical trials at approximately 8-week intervals. LVEF decreases were
defined as signs or symptoms of deterioration in left ventricular cardiac
function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative
to baseline which is below the institution's lower limit of normal. Among
198 patients who received TYKERB/capecitabine combination treatment, 3
experienced 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 treatment, 26 patients experienced Grade 1 or 2
and 6 patients had Grade 3 or 4 LVEF adverse reactions.
Hepatotoxicity: TYKERB has been associated with
hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)].
Interstitial Lung Disease/Pneumonitis: TYKERB has been
associated with interstitial lung disease and pneumonitis in monotherapy
or in combination with other chemotherapies [see Warnings and Precautions
(5.5)].
6.2 Postmarketing Experience
The following adverse reactions have been identified during
post-approval use of TYKERB. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Immune System Disorders: Hypersensitivity reactions including
anaphylaxis [see Contraindications (4)].
Skin and Subcutaneous Tissue Disorders: Nail disorders including
paronychia.
DRUG INTERACTIONS
7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug
Transport Systems Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at
clinically relevant concentrations. Caution should be exercised and dose
reduction of the concomitant substrate drug should be considered when dosing
lapatinib concurrently with medications with narrow therapeutic windows that
are substrates of CYP3A4 or CYP2C8. Lapatinib did not significantly inhibit the
9 following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and
CYP2D6 or UGT enzymes in vitro, however, the clinical significance is
unknown.
Lapatinib inhibits human P-glycoprotein. If TYKERB is
administered with drugs that are substrates of P-gp, increased concentrations
of the substrate drug are likely, and caution should be exercised.
Paclitaxel: In cancer patients receiving TYKERB and the CYP2C8
substrate paclitaxel, 24-hour systemic exposure (AUC) of paclitaxel was
increased 23%. This increase in paclitaxel exposure may have been
underestimated from the in vivo evaluation due to study design
limitations.
7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4
Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and
concomitant administration of strong inhibitors or inducers of CYP3A4
alter lapatinib concentrations significantly (see Ketoconazole and
Carbamazepine sections, below). Dose adjustment of lapatinib should be
considered for patients who must receive concomitant strong inhibitors or
concomitant strong inducers of CYP3A4 enzymes [see Dosage and Administration (2.2)].
Ketoconazole: In healthy subjects receiving ketoconazole,
a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC)
to lapatinib was increased to 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 100 mg twice daily for 3 days
and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was
decreased approximately 72%.
7.3 Drugs that Inhibit Drug Transport Systems
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 likely, and caution should
be exercised.
8 USE IN SPECIFIC POPULATIONS
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 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. In a study where pregnant rats were dosed with
lapatinib during organogenesis and through lactation, at a dose of 120
mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC
following 1,250 mg dose of lapatinib plus capecitabine), 91% of the pups
had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were
dead. The highest no-effect dose for this study was 20 mg/kg/day
(approximately equal to the human clinical exposure based on AUC).
Lapatinib was studied for effects on embryo-fetal development in pregnant rats
and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no
teratogenic effects; however, minor anomalies (left-sided umbilical
artery, cervical rib, and precocious ossification) occurred in rats at the
maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human
clinical exposure based on AUC following 1,250 mg dose of lapatinib plus
capecitabine). In rabbits, lapatinib was associated with maternal toxicity
at 60 and 120 mg/kg/day 258 (approximately 0.07 and 0.2 times the human
clinical exposure, respectively, based on AUC following 1,250 mg dose of
lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal
toxicity was associated with decreased fetal body weights and minor skeletal
variations.
8.3 Nursing Mothers
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 infants from TYKERB, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of TYKERB in pediatric patients
have not been established.
8.5 Geriatric Use
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. 8.6 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 harmacokinetics of lapatinib given that
less than 2% (lapatinib and metabolites) of an administered dose is
eliminated by the kidneys.
8.7 Hepatic Impairment
The pharmacokineticof lapatinib were examined in subjects
with pre-existing 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 11
airment, 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
pre-existing hepatic impairment [see Dosage and Administration (2.2)]. In
patients who develop severe hepatotoxicity while on therapy, TYKERB should be
discontinued and patients should not be retreated with TYKERB [see Warnings and
Precautions (5.2)].
10 OVERDOSAGE
There is no known antidote for overdoses of TYKERB. The maximum
oral doses of lapatinib that have been administered in clinical trials are
1,800 mg once daily. More frequent ingestion of TYKERB could result in
serum concentrations exceeding those observed in clinical trials and
could result in increased toxicity. Therefore, missed doses should not be
replaced and dosing should resume with the next scheduled daily
dose. There has been a report of one patient who took 3,000 mg of TYKERB
for 10 days. This patient had Grade 3 diarrhea and vomiting on Day 10. The
event resolved following IV hydration and interruption of treatment with TYKERB
and letrozole. Because lapatinib is not significantly renally excreted and
is highly bound to plasma6 proteins, hemodialysis would not be expected to be
an effective method to enhance the elimination of lapatinib
11 DESCRIPTION
Lapatinib is a small molecule and a member of the
4-anilinoquinazoline class of kinase inhibitors. It is present as the
monohydrate of the ditosylate salt, with chemical name N-(3
chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2
(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4
methylbenzenesulfonate) monohydrate. It has the molecular formula
C29H26ClFN4O4S (C7H8O3S)2 H2O and a molecular weight of 943.5.
Lapatinib is a yellow solid, and its solubility in water is
0.007 mg/mL and in 0.1N HCl is 318 0.001 mg/mL at 25°C
Each 250 mg tablet of TYKERB contains 405 mg of lapatinib
ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or
250 mg lapatinib free base. The inactive ingredients of TYKERB are:
Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone,
sodium starch glycolate. Coating: Orange film-coat: FD&C yellow No.
6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400,
polysorbate 80, titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the
intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor
(EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2])
receptors (estimated Ki app values of 3nM and 13nM, respectively) with a
dissociation half-life of ≥300 minutes. Lapatinib inhibits ErbB-driven
tumor cell growth in vitro and in various animal models. An additive effect was
demonstrated in an in vitro study when lapatinib and 5-FU (the active
metabolite of capecitabine) were used in combination in the 4 tumor cell lines
tested. The growth inhibitory effects of lapatinib were evaluated in
trastuzumab-conditioned cell lines. Lapatinib retained significant
activity against breast cancer cell lines selected for long-term growth in
trastuzumab-containing medium in vitro. These in vitro findings suggest
non-cross resistance between these two agents.
Hormone receptor positive breast cancer cells (with ER
[Estrogen Receptor] and/or PgR [Progesterone Receptor]) that coexpress
the HER2 tend to be resistant to established endocrine therapies.
Similarly, hormone receptor positive breast cancer cells that initially lack
EGFR or HER2 upregulate these receptor proteins as the tumor becomes
resistant to endocrine therapy.
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 hour). Peak plasma concentrations (Cmax) 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) values of
Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.hr/mL (23.4
to 56 mcg.hr/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 (Cmax approximately 2.5- and 3-fold higher) when
administered with a low fat (5% fat-500 calories) or with a high fat (50%
fat-1,000 calories) meal, respectively.
Distribution: Lapatinib is highly bound (>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 in vitro to
inhibit these efflux transporters, as well as the hepatic uptake
transporter OATP 1B1, at clinically relevant concentrations.
Metabolism: Lapatinib undergoes extensive metabolism, primarily
by CYP3A4 and 363 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 (<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 372 pharmacokinetics of lapatinib have not been
performed.
12.4 QT Prolongation The QT prolongation potential of
lapatinib was assessed as part of an uncontrolled, open label dose escalation
study in advanced cancer patients. Eighty-one patients received daily
doses of lapatinib ranging from 175 mg/day to 1,800 mg/day. Serial ECGs
were collected on Day 1 and Day 14 to evaluate the effect of lapatinib on
QT intervals. Analysis of the data suggested a consistent concentration-dependent
increase in QTc interval.
13 NONCLINICAL TOXICOLOGY
3.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year carcinogenicity studies with lapatinib are ongoing. Lapatinib was not
clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration
assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome
aberration assay or the in vivo rat bone marrow chromosome aberration assay at
single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to
4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and
in vivo assays.
There were no effects on male or female rat mating or fertility
at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males
(approximately 6.4 times and 2.6 times the expected human clinical
exposure based on AUC following 1,250 mg dose of lapatinib plus
capecitabine, respectively). The effect of lapatinib on human fertility is
unknown. However, when female rats were given oral doses of lapatinib
during breeding and through the first 6 days of gestation, a significant
decrease in the number of live fetuses was seen at 120 mg/kg/day and in
the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3
times the expected human clinical exposure based on AUC following 1,250 mg dose
of lapatinib plus capecitabine,respectively).
14 CLINICAL STUDIES
14.1 HER2 Positive Metastatic Breast Cancer The efficacy and
safety of TYKERB in combination with capecitabine in breast cancer were
evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had
HER2 (ErbB2) overexpressing (IHC 3+ or IHC 2+ confirmed by FISH), locally
advanced or metastatic breast cancer, progressing after prior treatment that
included anthracyclines, taxanes, and trastuzumab. Patients were
randomized to receive either TYKERB 1,250 mg once daily (continuously)4 plus
capecitabine 2,000 mg/m2 /day on Days 1-14 every 21 days, or to receive
capecitabine alone at a dose of 2,500 mg/m2 /day on Days 1-14 every 21
days. The endpoint was time to progression (TTP). TTP was defined as time
from randomization to tumor progression or death related to breast cancer.
Based on the results of a pre-specified interim analysis, further enrollment
was discontinued. Three hundred and ninety-nine (399) patients were
enrolled in this study. The median age was 53 years and 14% were older
than 65 years. Ninety-one percent (91%) were Caucasian. Ninety-seven
percent (97%) had stage IV breast cancer, 48% were estrogen receptor+
(ER+) or progesterone receptor+ (PR+), and 95% were ErbB2 IHC 3+ or IHC 2+ with
FISH confirmation. Approximately 95% of patients had prior treatment with
anthracyclines, taxanes, and trastuzumab. Efficacy analyses 4 months
after the interim analysis are presented in Table 5, Figure 1, and Figure
2.
16 HOW SUPPLIED/STORAGE AND
HANDLING
The 250 mg tablets of TYKERB are oval, biconvex, orange, and
film-coated with GS XJG debossed on one side and are available in:
Bottles of 150 tablets: NDC 0173-0752-00
Store at 25°C (77°F); excursions
permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
