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 ditosylate monohydrate has the following chemical structure:

Lapatinib is a yellow solid, and its solubility in water is 0.007 mg/mL and in 0.1N HCl is 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.

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.

Recommended Dosing

The recommended dose of TYKERB 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. TYKERB should be taken at least one hour before or one hour after a meal. The dose of TYKERB should be once daily; dividing the daily dose is not recommended [see CLINICAL PHARMACOLOGY].

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.

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 NCI 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 and ADVERSE REACTIONS]. TYKERB 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 to 750 mg/day 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 is 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]

Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 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 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.]

Other Toxicities: Discontinuation or interruption of dosing with TYKERB may be considered when patients develop ≥ Grade 2 NCI CTC 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 should be restarted at a lower dose (1,000 mg/day). TYKERB should be restarted at a lower dose (1,000 mg/day).

See manufacturer's prescribing information for capecitabine dosage adjustment guidelines in the event of toxicity.

Dosage Forms And Strengths

250 mg tablets - oval, biconvex, orange, film-coated with GS XJG debossed on one side.

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].

TYKERB is a registered trademark of GlaxoSmithKline. GlaxoSmithKline Research Triangle Park, NC 27709. FDA rev date: 07/07/08

Clinical Trials Experience

The safety of TYKERB has been evaluated in more than 3,500 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] 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.

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.

The most common adverse reactions ( > 20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar­plantar 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 CTC v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.

Table 1. Adverse Reactions Occurring in 10% of Patients

Table 2. Selected Laboratory Abnormalities

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 lapatinib/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0). [See WARNINGS and PRECAUTIONS]

Hepatotoxicity: Lapatinib has been associated with hepatoxicity [see Boxed Warning and WARNINGS and PRECAUTIONS].

Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see WARNINGS and PRECAUTIONS].

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 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 Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised.

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].

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%.

Drugs that Inhibit Drug Transport Systems

Lapatinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised.

Other Chemotherapy Agents

In a separate study, concomitant administration of lapatinib with capecitabine did not meaningfully alter the pharmacokinetics of either agent (or the metabolites of capecitabine).

Included as part of the PRECAUTIONS section.

Decreased Left Ventricular Ejection Fraction

TYKERB has been reported to decrease LVEF [see ADVERSE REACTIONS]. In the randomized clinical trial, the majority ( > 60%) of LVEF decreases occurred within the first 9 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].

Hepatotoxicity

Hepatotoxicity (ALT or AST > 3 times the upper limit of normal and total bilirubin > 1.5 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].

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 and Use in Specific Populations]. 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].

Diarrhea

Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB [see ADVERSE REACTIONS]. 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.

Interstitial Lung Disease/Pneumonitis

Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see ADVERSE REACTIONS]. 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).

QT Prolongation

QT prolongation measured by automated machine-read evaluation of ECG was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients [see CLINICAL PHARMACOLOGY]. 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. The prescriber should consider baseline and on-treatment electrocardiograms with QT measurement.

Pregnancy

Pregnancy Category D

TYKERB can cause fetal harm when administered to a pregnant woman. 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), 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). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.

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.

Patient Counseling Information

See FDA-approved patient labeling

Decreased Left Ventricular Ejection Fraction

Patients should be informed that TYKERB has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking TYKERB.

Diarrhea

Patients should be informed that TYKERB often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with TYKERB.

Drug Interactions

TYKERB may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.

Food

Patients should be informed of the importance of taking TYKERB at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food.

Divided Dosing

The dose of TYKERB should not be divided. Patients should be advised of the importance of taking TYKERB once daily, in contrast to capecitabine which is taken twice daily.

Nonclinical Toxicology

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, 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, respectively).

Use in Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS and PRECAUTIONS].

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.

Pediatric Use

The safety and effectiveness of TYKERB in pediatric patients have not been established.

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. No overall differences in safety or effectiveness of the combination of TYKERB and capecitabine were observed between these 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.

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 pharmacokinetics of lapatinib given that less than 2% (lapatinib and metabolites) of an administered dose is eliminated by the kidneys.

Hepatic Impairment

The pharmacokinetics of 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 increased approximately 14% and 63% in subjects with moderate and severe pre-existing hepatic impairment, 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]. 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].

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 plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.

None.

See manufacturer's prescribing information for capecitabine contraindications.

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 K_i^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-cross­resistance between these two agents.

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 (Pgp, 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 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 pharmacokinetics of lapatinib have not been performed.

QT Prolongation

The QT prolongation potential of lapatinib was assessed as part of an uncontrolled, open­label 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. Thirteen of the 81 subjects were found to have either QTcF (corrected QT by the Friedericia method) > 480 msec or an increase in QTcF > 60 msec by automated machine-read evaluation of ECG. Analysis of the data suggested a relationship between lapatinib concentration and the QTc interval.

Clinical Studies

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) over-expressing (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) 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 four months after the interim analysis are presented in Table 3, Figure 1, and Figure 2.

Table 3. Efficacy Results

Figure 1. Kaplan-Meier Estimates for Independent Review Panel-evaluated Time to Progression

Figure 2. Kaplan-Meier Estimates for Investigator Assessment Time to Progression

At the time of updated analysis, 30% of patients had died and the data for survival analysis are not mature. Fifty-five patients (28%) in the TYKERB plus capecitabine group and 64 subjects (32%) in the capecitabine group had died.

TYKERB
(TIE-curb)
(lapatinib) Tablets

Read this leaflet before you start taking TYKERB® and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

What is TYKERB?

TYKERB is used with the medicine capecitabine for the treatment of patients with advanced or metastatic breast cancer that is HER2 positive, and who have already had certain other breast cancer treatments.

Before you start taking TYKERB, tell your doctor about all of your medical conditions, including if you:

• have heart problems.
• have liver problems. You may need a lower dose of TYKERB.
• are pregnant or may become pregnant. TYKERB may harm an unborn baby. If you become pregnant during treatment with TYKERB, tell your doctor as soon as possible.
• are breastfeeding. It is not known if TYKERB passes into your breast milk or if it can harm your baby. If you are a woman who has or will have a baby, talk with your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines and herbal and dietary supplements. TYKERB and many other medicines may interact with each other. Your doctor needs to know what medicines you take so he or she can choose the right dose of TYKERB for you.

Especially tell your doctor if you take:

• antibiotics and anti-fungals (drugs used to treat infections)
• HIV (AIDS) treatments
• anticonvulsant drugs (drugs used to treat seizures)
• calcium channel blockers (drugs used to treat certain heart disorders or high blood pressure)
• antidepressants
• drugs used for stomach ulcers
• St. John's Wort or other herbal

Know the medicines you take. Keep a list of your medicines with you to show your doctor. Do not take other medicines during treatment with TYKERB without first checking with your doctor.

Because TYKERB is given with another drug called capecitabine, you should also discuss with your doctor or pharmacist any medicines that should be avoided when taking capecitabine.

How should I take TYKERB?

• Take TYKERB exactly as your doctor has told you. TYKERB and capecitabine are taken in 21 day cycles. The usual dose of TYKERB is 1,250 mg (5 tablets) taken by mouth, one time a day on days 1 to 21. Your doctor will tell you the dose of capecitabine you should take and when you should take it.
• TYKERB should be taken at least one hour before, or at least one hour after food.
• Do not eat or drink grapefruit products while taking TYKERB.
• Your doctor may adjust your dose of TYKERB depending on how you tolerate the treatment.
• If you forget to take your dose of TYKERB, take it as soon as you remember that day. If you miss a day, do not double your dose the next day. Just skip the missed dose.

What are the possible side effects of TYKERB?

Serious side effects include:

• heart problems
  • decreased pumping of blood from the heart
  • abnormal heartbeat
• liver problems, which may cause itching, yellow eyes or skin, dark urine, or pain or discomfort in the right upper area of the belly.
  • Your doctor should do blood tests to check your liver before you start taking TYKERB and during treatment.
• lung problems
• severe diarrhea, which may lead to you becoming dehydrated

Call your doctor right away if you have palpitations, persistent cough, shortness of breath, or severe diarrhea.

Common side effects of TYKERB in combination with capecitabine include:

• diarrhea
• red, painful hands and feet
• nausea
• rash
• vomiting
• tiredness
• mouth sores
• loss of appetite
• indigestion

Tell your doctor about any side effect that gets serious or that does not go away.

These are not all the side effects with TYKERB. Ask your doctor or pharmacist for more information.

You may also get side effects from capecitabine. Talk to your doctor about possible side effects with capecitabine.

How should I store TYKERB tablets?

• Store TYKERB tablets at room temperature between 59° and 86°F (15° to 30°C). Keep the container closed tightly.
• Do not keep medicine that is out of date or that you no longer need. Be sure that if you throw any medicine away, it is out of the reach of children.
• Keep TYKERB and all medicines out of the reach of children.

General information about TYKERB

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use TYKERB for any other condition for which it was not prescribed. Do not give TYKERB to other people, even if they have the same condition that you have. It may harm them.

This leaflet summarizes the most important information about TYKERB. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about TYKERB that is written for health professionals. For more information you can call toll-free 1­888-825-5249.

What are the ingredients in TYKERB?

Active Ingredient: Lapatinib.

Inactive Ingredients: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Orange film-coat: FD&C yellow #6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide.

TYKERB tablets are oval, biconvex, orange, film-coated with GS XJG printed on one side.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

LAPATINIB - ORAL

(la-PA-ti-nib)

COMMON BRAND NAME(S): Tykerb

USES: Lapatinib is used together with another medication (capecitabine) to treat a certain type of breast cancer (HER2-positive) that has not responded to the standard treatment. It works by slowing or stopping the growth of cancer cells.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using lapatinib and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth 1 hour before or 1 hour after a meal, usually once daily or as directed by your doctor. It is important that you do not take this medication more than once daily.

The dosage is based on your medical condition, response to treatment, and certain other drugs you may be taking.

Do not increase your dose or take this medication more often than prescribed. Your condition will not improve any faster, and the risk of serious side effects may be increased.

Avoid eating grapefruit or drinking grapefruit juice while being treated with this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of certain medications in your bloodstream. Consult your doctor or pharmacist for more details.

Since this drug can be absorbed through the skin and lungs, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets.

Follow your doctor's instructions on how to correctly take capecitabine with this medication.

SIDE EFFECTS: Nausea, vomiting, upset stomach, mouth sores, mild rash, dry skin, and trouble sleeping may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Diarrhea is a common side effect and may become severe. Tell your doctor immediately if diarrhea occurs or if you have signs of a severe loss of body water (dehydration) such as dizziness or decreased amount of urine. Your doctor should prescribe additional medication to help control your symptoms. If your diarrhea becomes severe, your doctor may need to stop or delay your lapatinib treatment.

Treatment with this drug may sometimes cause your hands/feet to develop a skin reaction called hand-foot syndrome (palmar-plantar erythrodysesthesia). Tell your doctor immediately if you experience swelling, pain, redness, peeling, blisters, or tingling/burning of the hands/feet. The symptoms can be made worse by heat/pressure on your hands/feet. Avoid prolonged sun exposure, tanning booths, and sunlamps, as well as unnecessary exposure to heat (e.g., hot dishwater, long hot baths). Use a sunscreen and wear protective clothing when outdoors. Avoid pressure on elbows, knees, and soles of feet (e.g., leaning on elbows, kneeling, taking long walks). Wear loose clothing and comfortable shoes. Depending on how severe your hand-foot syndrome is, your doctor may give you an additional medication to reduce the symptoms, or stop or delay your lapatinib treatment.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual tiredness, shortness of breath, swelling ankles/feet, fast/pounding/irregular heartbeat, dizziness, fainting, dark urine, yellowing skin/eyes.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking lapatinib, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart disease (e.g., heart failure, irregular heartbeat, long QT syndrome), liver disease, mineral imbalances (e.g., low potassium/magnesium).

This medication is not recommended for use during pregnancy. It may harm an unborn baby. Therefore, it is important to prevent pregnancy while taking this medication. Consult your doctor for more details and to discuss using at least 2 reliable forms of birth control (e.g., condoms, birth control pills) while taking this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs affecting liver enzymes that remove lapatinib from your body (such as dexamethasone, cimetidine, St. John's wort, azole antifungals including itraconazole/ketoconazole, macrolide antibiotics including erythromycin/clarithromycin, HIV protease inhibitors including ritonavir/saquinavir, rifamycins including rifabutin, certain anti-seizure medicines including carbamazepine/phenytoin).

This drug can slow down the removal of other drugs from your body by affecting certain liver enzymes. These affected drugs include certain "statin" cholesterol medications (simvastatin, lovastatin, atorvastatin), tacrolimus, trazodone, digoxin, and cyclosporine, among others. Tell your doctor if you also take any of these medications.

Other drugs besides lapatinib that may affect the heart rhythm (QTc prolongation in the EKG) include dofetilide, pimozide, procainamide, amiodarone, quinidine, and sotalol, among others. QTc prolongation can infrequently result in serious (rarely fatal) irregular heartbeat. Consult your doctor or pharmacist for more details and for instructions on how you may reduce your risk of this effect.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe diarrhea/vomiting.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., EKG, electrolyte levels, heart/liver function) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to take each scheduled dose of this medication as directed. If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.