Lapatinib
Lapatinib 250mg Tablets

What is Lapatinib?

Lapatinib is used with the medicine capecitabine for the treatment of people with advanced or metastatic breast cancer that is HER2-positive (tumors that produce large amounts of a protein called human epidermal growth factor receptor-2), and who have already had certain other breast cancer treatments.

Lapatinib is also used with a type of medicine called letrozole for the treatment of postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.

It is not known if Lapatinib is safe and effective in children.

Who should not take Lapatinib?

Do not take Lapatinib if you are allergic to any of the ingredients in Lapatinib. See the end of this leaflet for a complete list of ingredients in Lapatinib.

What should I tell my doctor before taking Lapatinib?

Before you take Lapatinib, tell your doctor if you:

• have heart problems.
• have liver problems. You may need a lower dose of Lapatinib.
• have any other medical conditions.
• are pregnant or plan to become pregnant. Lapatinib can harm your unborn baby. You should not become pregnant while taking Lapatinib. Tell your doctor right away if you become pregnant during treatment with Lapatinib.
• are breastfeeding or plan to breastfeed. It is not known if Lapatinib passes into your breast milk. You and your doctor should decide if you will take Lapatinib or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Lapatinib may affect the way other medicines work, and other medicines may affect the way Lapatinib works.

Especially tell your doctor if you take:

• antibiotics and anti-fungal medicines (used to treat infections)
• HIV medicines
• medicines used to treat seizures
• medicines used to treat heart problems or high blood pressure
• antidepressants
• medicines that reduce stomach acid (antacids)
• St. John’s wort

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a new medicine. Do not take other medicines during treatment with Lapatinib without first talking with your doctor.

How should I take Lapatinib?

• Take Lapatinib exactly as your doctor tells you to take it. Your doctor may change your dose of Lapatinib if needed.
  • For people with advanced or metastatic breast cancer, Lapatinib and capecitabine are taken in 21-day cycles. The usual dose of Lapatinib is 1,250 mg (5 tablets) taken by mouth all at once, 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.
  • Take capecitabine with food or within 30 minutes after food.
  • For people with hormone receptor-positive, HER2-positive breast cancer, Lapatinib and letrozole are taken every day. The usual dose of Lapatinib is 1,500 mg (6 tablets) taken by mouth all at once, one time a day. Your doctor will tell you the dose of letrozole you should take and when you should take it.
• Lapatinib should be taken at least 1 hour before, or at least 1 hour after a meal.
• Do not eat or drink grapefruit products during treatment with Lapatinib.
• If you miss a dose of Lapatinib, take your next dose at your regular time the next day.
• If you take too much Lapatinib, call your doctor or go to the nearest hospital emergency room right away.

What are the possible side effects of Lapatinib?

Lapatinib may cause serious side effects, including:

• heart problems, including decreased pumping of blood from the heart and an abnormal heartbeat. Signs and symptoms of an abnormal heartbeat include:
  
  • feeling like your heart is pounding or racing
  • dizziness
  • tiredness
  • feeling lightheaded
  • shortness of breath
  
  Your doctor should check your heart function before you start taking Lapatinib and during treatment.
• liver problems. Liver problems can be severe and deaths have happened. Signs and symptoms of liver problems include:
  • itching
  • yellowing of your skin or the white part of your eyes
  • dark urine
  • pain or discomfort in the right upper stomach area
  
  Your doctor should do blood tests to check your liver before you start taking Lapatinib and during treatment.
• diarrhea. Diarrhea is common with Lapatinib and may sometimes be severe. Severe diarrhea can cause loss of body fluid (dehydration) and some deaths have happened. Call your doctor right away if you have a change in bowel pattern or if you have severe diarrhea. Follow your doctor’s instructions for what to do to help prevent or treat diarrhea.
• lung problems. Symptoms of a lung problem with Lapatinib include a cough that will not go away or shortness of breath.

Call your doctor right away if you have any of the signs or symptoms of the serious side effects listed above.

Common side effects of Lapatinib in combination with capecitabine or letrozole include:

• diarrhea
• red, painful hands and feet
• nausea
• rash
• vomiting
• tiredness or weakness
• mouth sores
• loss of appetite
• indigestion
• unusual hair loss or thinning
• nose bleeds
• headache
• dry skin
• itching
• nail disorders such as nail bed changes, nail pain, infection and swelling of the cuticles.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Lapatinib. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA.

You may also get side effects from the other medicines taken with Lapatinib. Talk to your doctor about possible side effects you may get during treatment.

How should I store Lapatinib Tablets?

• Store Lapatinib Tablets at room temperature between 68° and 77°F (20° and 25°C).
• Keep the container closed tightly.
• Do not keep medicine that is out of date or that you no longer need.

Keep Lapatinib and all medicines out of the reach of children.

General information about Lapatinib
Medicines are sometimes prescribed for purposes other than those listed in patient information leaflets. Do not use Lapatinib for a condition for which it was not prescribed. Do not give Lapatinib to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about Lapatinib. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Lapatinib that is written for health professionals.

What are the ingredients in Lapatinib?

Active ingredient: Lapatinib.

Inactive ingredients: 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.

Lapatinib
Lapatinib 250mg Tablets

INDICATIONS AND USAGE

Lapatinib is indicated in combination with:

• capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
  
  Limitation of Use: Patients should have disease progression on trastuzumab prior to initiation of treatment with Lapatinib in combination with capecitabine.
• letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.

Lapatinib 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

Recommended Dosing
HER2-Positive Metastatic Breast Cancer:
The recommended dose of Lapatinib 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. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended. 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 Lapatinib is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with Lapatinib, the recommended dose of letrozole is 2.5 mg once daily. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended.

Dose Modification Guidelines
Cardiac Events:
Lapatinib should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3) 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)]. Lapatinib 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 Lapatinib reduced. A dose reduction from 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day to 1,000 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment.

Diarrhea:
Lapatinib should be interrupted in patients with diarrhea which is NCI CTCAE Grade 3 or Grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting ≥NCI CTCAE Grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration). Lapatinib may be reintroduced at a lower dose (reduced from 1,250 mg/day to 1,000 mg/day or from 1,500 mg/day to 1,250 mg/day) when diarrhea resolves to Grade 1 or less. Lapatinib should be permanently discontinued in patients with diarrhea which is NCI CTCAE Grade 4 [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

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 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 Lapatinib may be considered when patients develop ≥Grade 2 NCI CTCAE toxicity and can be restarted at the standard dose of 1,250 or 1,500 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then Lapatinib in combination with capecitabine should be restarted at a lower dose (1,000 mg/day) and in combination with letrozole should be restarted at a lower dose of 1,250 mg/day.

See manufacturer’s prescribing information for the coadministered product dosage adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

Lapatinib is contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components.

WARNINGS AND PRECAUTIONS

Decreased Left Ventricular Ejection Fraction
Lapatinib 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 Lapatinib 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 Lapatinib 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 Lapatinib to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration (2.2)].

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 Lapatinib should be discontinued and patients should not be retreated with Lapatinib [see Adverse Reactions (6.1)].

Patients With Severe Hepatic Impairment
If Lapatinib 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, Lapatinib should be discontinued and patients should not be retreated with Lapatinib [see Warnings and Precautions (5.2)].

Diarrhea
Diarrhea has been reported during treatment with Lapatinib [see Adverse Reactions (6.1)]. The diarrhea may be severe, and deaths have been reported. Diarrhea generally occurs early during treatment with Lapatinib, with almost half of those patients with diarrhea first experiencing it within 6 days. This usually lasts 4 to 5 days. Lapatinib-induced diarrhea is usually low-grade, with severe diarrhea of NCI CTCAE Grades 3 and 4 occurring in <10% and <1% of patients, respectively. Early identification and intervention is critical for the optimal management of diarrhea. Patients should be instructed to report any change in bowel patterns immediately. Prompt treatment of diarrhea with anti-diarrheal agents (such as loperamide) after the first unformed stool is recommended. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhea is persistent beyond 24 hours, there is fever, or Grade 3 or 4 neutropenia), and interruption or discontinuation of therapy with Lapatinib [see Dosage and Administration (2.2)].

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 (6.1)]. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib 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 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.

Use in Pregnancy
Lapatinib can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Lapatinib 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 Lapatinib in pregnant women. Women should be advised not to become pregnant when taking Lapatinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE REACTIONS

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 Lapatinib has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of Lapatinib 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 Lapatinib 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.

Hormone Receptor-Positive, Metastatic Breast Cancer:
In a randomized clinical trial of 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 Lapatinib. In this trial, the safety profile of Lapatinib was consistent with previously reported results from trials of Lapatinib 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 combination treatment with Lapatinib/capecitabine, 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 combination treatment with Lapatinib/letrozole, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions.

Hepatotoxicity:
Lapatinib has been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2)].

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 (5.5)].

Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Lapatinib. 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

Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems
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 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, CYP2C8, or P-gp. 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.

Midazolam:
Following coadministration of Lapatinib and midazolam (CYP3A4 substrate), 24-hour systemic exposure (AUC) of orally administered midazolam increased 45%, while 24-hour AUC of intravenously administered midazolam increased 22%.

Paclitaxel:
In cancer patients receiving Lapatinib and paclitaxel (CYP2C8 and P-gp substrate), 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.

Digoxin:
Following coadministration of Lapatinib and digoxin (P-gp substrate), systemic AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations should be monitored prior to initiation of Lapatinib and throughout coadministration. If digoxin serum concentration is >1.2 ng/mL, the digoxin dose should be reduced by half.

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%.

Drugs That Inhibit Drug Transport Systems
Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Lapatinib is administered with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised.

Acid-Reducing Agents
The aqueous solubility of lapatinib is pH dependent, with higher pH resulting in lower solubility. However, esomeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 7 days, did not result in a clinically meaningful reduction in lapatinib steady-state exposure.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.7)].

Based on findings in animals, Lapatinib 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 Lapatinib in pregnant women. Women should be advised not to become pregnant when taking Lapatinib. 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 (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.

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 Lapatinib, 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 Lapatinib in pediatric patients have not been established.

Geriatric Use
Of the total number of metastatic breast cancer patients in clinical studies of Lapatinib 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 Lapatinib 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.

Renal Impairment
Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. There is no experience with Lapatinib 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 Lapatinib 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.

OVERDOSAGE

There is no known antidote for overdoses of Lapatinib. The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of Lapatinib 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.

Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily and where reported, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG), and/or mucosal inflammation.

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.

Treatment of overdose with Lapatinib should consist of general supportive measures.

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 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 Lapatinib contains 405 mg of lapatinib ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or 250 mg lapatinib free base.

The inactive ingredients of Lapatinib 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.

CLINICAL PHARMACOLOGY

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 Kiapp 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.

Pharmacokinetics
Absorption:
Absorption following oral administration of Lapatinib is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of Lapatinib 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.h/mL (23.4 to 56 mcg.h/mL).

Divided daily doses of Lapatinib 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 to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.

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

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

Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<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, 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.

Pharmacogenomics
The HLA alleles DQA1*02:01 and DRB1*07:01 were associated with hepatotoxicity reactions in a genetic substudy of a monotherapy trial with Lapatinib (n = 1,194). Severe liver injury (ALT >5 times the upper limit of normal, NCI CTCAE Grade 3) occurred in 2% of patients overall; the incidence of severe liver injury among DQA1*02:01 or DRBI*07:01 allele carriers was 8% versus 0.5% in non-carriers. These HLA alleles are present in approximately 15% to 25% of Caucasian, Asian, African, and Hispanic populations and 1% in Japanese populations. Liver function should be monitored in all patients receiving therapy with Lapatinib regardless of genotype.

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 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).

CLINICAL STUDIES

HER2-Positive Metastatic Breast Cancer
The efficacy and safety of Lapatinib 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 Lapatinib 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 4 months after the interim analysis are presented in Table 5, Figure 1, and Figure 2.

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 above efficacy analysis, the overall survival data were not mature (32% events). However, based on the TTP results, the study was unblinded and patients receiving capecitabine alone were allowed to cross over to treatment with Lapatinib plus capecitabine. The survival data were followed for an additional 2 years to be mature and the analysis is summarized in Table 6.

Clinical Studies Describing Limitation of Use: In two randomized trials, Lapatinib-based chemotherapy regimens have been shown to be less effective than trastuzumab-based chemotherapy regimens. The first randomized, open-label study compared the safety and efficacy of Lapatinib in combination with capecitabine relative to trastuzumab in combination with capecitabine in women with HER2-positive metastatic breast cancer (N = 540). The study was stopped early based on the findings of a pre-planned interim analysis showing a low incidence of CNS events (primary endpoint) and superior efficacy of the trastuzumab plus capecitabine. The median progression-free survival was 6.6 months in the group receiving Lapatinib in combination with capecitabine compared with 8.0 months in the group receiving the trastuzumab combination [HR = 1.30 (95% CI: 1.04, 1.64)]. Overall survival was analyzed when 26% of deaths occurred in the group receiving Lapatinib in combination with capecitabine and 22% in the group receiving the trastuzumab combination [HR = 1.34 (95% CI: 0.95, 1.92)].

The second randomized, open-label study compared the safety and efficacy of taxane-based chemotherapy plus Lapatinib to taxane-based chemotherapy plus trastuzumab as first-line therapy in women with HER2-positive, metastatic breast cancer (N = 652). The study was stopped early based on findings from a pre-planned interim analysis. The median progression-free survival was 11.3 months in the trastuzumab combination treatment arm compared to 9.0 months in patients treated with Lapatinib in the combination arm for the intent-to-treat population [HR = 1.37 (95% CI: 1.13, 1.65)].

Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer
The efficacy and safety of Lapatinib in combination with letrozole were evaluated in a double-blind, placebo-controlled, multi-center study. A total of 1,286 postmenopausal women with hormone receptor-positive (ER-positive and/or PgR-positive) metastatic breast cancer, who had not received prior therapy for metastatic disease, were randomly assigned to receive either Lapatinib (1,500 mg once daily) plus letrozole (2.5 mg once daily) (n = 642) or letrozole (2.5 mg once daily) alone (n = 644). Of all patients randomized to treatment, 219 (17%) patients had tumors overexpressing the HER2 receptor, defined as fluorescence in situ hybridization (FISH) (≥2 or 3+ immunohistochemistry (IHC). There were 952 (74%) patients who were HER2-negative and 115 (9%) patients did not have their HER2 receptor status confirmed. The primary objective was to evaluate and compare progression-free survival (PFS) in the HER2-positive population. Progression-free survival was defined as the interval of time between date of randomization and the earlier date of first documented sign of disease progression or death due to any cause.

The baseline demographic and disease characteristics were balanced between the two treatment arms. The median age was 63 years and 45% were 65 years of age or older. Eighty-four percent (84%) of the patients were white. Approximately 50% of the HER2-positive population had prior adjuvant/neo-adjuvant chemotherapy and 56% had prior hormonal therapy. Only 2 patients had prior trastuzumab.

In the HER2-positive subgroup (n = 219), the addition of Lapatinib to letrozole resulted in an improvement in PFS. In the HER2-negative subgroup, there was no improvement in PFS of the combination of Lapatinib plus letrozole compared to the letrozole plus placebo. Overall response rate (ORR) was also improved with the combination of Lapatinib plus letrozole. The overall survival (OS) data were not mature. Efficacy analyses for the hormone receptor-positive, HER2-positive and HER2-negative subgroups are presented in Table 7 and Figure 3.

Figure 3. Kaplan-Meier Estimates for Progression-Free Survival for the HER2-Positive Population

HOW SUPPLIED/STORAGE AND HANDLING

The 250 mg tablets of Lapatinib are oval, biconvex, orange, and film-coated with GS XJG debossed on one side and are available in:

Bottles of 150 tablets

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

Information for Patients
Patients should be informed of the following:

• Lapatinib 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 Lapatinib.
• Lapatinib 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 immediately if there is any change in bowel patterns or severe diarrhea occurs during treatment with Lapatinib.
• Lapatinib 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.
• Lapatinib may interact with grapefruit. Patients should not take Lapatinib with grapefruit products.
• Lapatinib should be taken 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.
• The dose of Lapatinib should be taken once daily. Dividing the daily dose is not recommended.