NITAPAL

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

C 29 H 26 ClFN 4 O 4 S (C 7 H 8 O 3 S) 2 H 2 O and a molecular weight of 943.5 g/mol.

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 tablets are as follows: iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3350, polyvinyl alcohol (part hydrolyzed), povidone, sodium starch glycolate Type A, talc, and titanium dioxide. chemical structure.

Lapatinib is prescribed with other breast cancer treatments.

Carefully used under the supervision of a doctor in the following cases: heart disease and hypertension; irregular levels of potassium and magnesium in blood; problems with pancreas; liver and diabetes.

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 greater than or equal to 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. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of lapatinib on the QT-interval was evaluated in a single-blind, placebo-controlled, single sequence (placebo and active treatment) crossover study in patients with advanced solid tumors (N = 58).

During the 4.

• day treatment period, three doses of matching placebo were administered 12 hours apart in the morning and evening on Day and in the morning on Day 2.

This was followed by three doses of lapatinib 2,000 mg (1.3 to 1.6 times the recommended dosage) administered in the same way.

Measurements, including ECGs and pharmacokinetic samples were done at baseline and at the same time points on Day and Day 4.

In the evaluable population of subjects who had complete dosing and ECG assessments (N = 37), the maximum mean ∆∆QTcF (90% CI) of 8.75 ms was observed 10 hours after ingestion of the third dose of lapatinib 2,000 mg. The ∆∆QTcF exceeded the 5 ms threshold and the upper bound 90% CIs exceeded the 10 ms threshold at multiple time points.

There was a concentration-dependent increase in

QTcF effects. 12.3 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 to 1.5 hours).

Peak plasma concentrations (C max ) of lapatinib are achieved approximately 4 hours after administration.

Daily dosing of lapatinib results in achievement of steady state within to 7 days, indicating an effective half-life of 24 hours.

At the dose of 1,250 mg daily, steady-state geometric mean [95% confidence interval (CI)] values of C max 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.

AUC values were approximately 3.

• and 4-fold higher (C max 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.

Lapatinib is highly bound (greater than 99%) to albumin and alpha-1 acid glycoprotein.

In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1).

Lapatinib has also been shown to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.

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.

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

Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (less than 2%) renal excretion.

Recovery of parent lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.

Effects of

Age, Gender, or Race: Studies of the effects of age, gender, or race on the pharmacokinetics of lapatinib have not been performed. 12.5 Pharmacogenomics The HLA alleles DQA102:01 and DRB107:01 were associated with hepatotoxicity reactions in a genetic substudy of a monotherapy trial with lapatinib (n = 1,194).

Severe liver injury (ALT greater than 5 times the upper limit of normal, NCI CTCAE Grade 3) occurred in 2% of patients overall; the incidence of severe liver injury among DQA102:01 or DRBI07:01 allele carriers was 8% versus 0.5% in non-carriers.

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.

An anticancer drug belongs to the Tyrozine Keynes family, which interferes with the growth and spread of cancer cells in the body.

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The most common (greater than 20%) adverse reactions during treatment with lapatinib plus capecitabine were diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, and fatigue.

The most common (greater than or equal to 20%) adverse reactions during treatment with lapatinib plus letrozole were diarrhea, rash, nausea, and fatigue.fda.gov/medwatch. 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 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.

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 (greater than 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

Grades and 4 adverse reactions (NCI CTCAE v3.0) were diarrhea and palmar-plantar erythrodysesthesia.

Selected laboratory abnormalities are shown in

Table 2.

Table 1.

Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients a NCI CTCAE v3.0. b Grade 3 dermatitis acneiform was reported in less than 1% of patients in the group receiving lapatinib plus capecitabine.

Lapatinib 1,250 mg/day + Capecitabine 2,000 mg/m 2 /day Capecitabine 2,500 mg/m 2 /day (N = 198) (N = 191) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Reactions % % % % % % Gastrointestinal disorders Diarrhea 65 13 1 40 10 0 Nausea 44 2 0 43 2 0 Vomiting 26 2 0 21 2 0 Stomatitis 14 0 0 11 < 1 0 Dyspepsia 11 < 1 0 3 0 0 Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia 53 12 0 51 14 0 Rash b 28 2 0 14 1 0 Dry skin 10 0 0 6 0 0 General disorders and administration site conditions Mucosal inflammation 15 0 0 12 2 0 Musculoskeletal and connective tissue disorders Pain in extremity 12 1 0 7 < 1 0 Back pain 11 1 0 6 < 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 12 3 0 8 2 0 Psychiatric disorders Insomnia 10 < 1 0 6 0 0 Table 2.

Selected Laboratory Abnormalities Abbreviations

ALT, alanine aminotransferase; AST, aspartate aminotransferase. a NCI CTCAE v3.0.

Lapatinib 1,250 mg/day + Capecitabine 2,000 mg/m 2 /day Capecitabine 2,500 mg/m 2 /day All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Parameters % % % % % % Hematologic Hemoglobin 56 < 1 0 53 1 0 Platelets 18 < 1 0 17 < 1 < 1 Neutrophils 22 3 < 1 31 2 1 Hepatic Total Bilirubin 45 4 0 30 3 0 AST 49 2 < 1 43 2 0 ALT 37 2 0 33 1 0 Hormone Receptor-Positive, Metastatic Breast Cancer: In a randomized, Phase 3 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.

Table 4.

Table 3.

Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients a NCI CTCAE v3.0. b In addition to the rash reported under "Skin and subcutaneous tissue disorders", 3 additional subjects in each treatment arm had rash under "Infections and infestations"; none were Grade 3 or 4.

Lapatinib 1,500 mg/day + Letrozole 2.5 mg/day Letrozole 2.5 mg/day (N = 654) (N = 624) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Reactions % % % % % % Gastrointestinal disorders Diarrhea 64 9 < 1 20 < 1 0 Nausea 31 < 1 0 21 < 1 0 Vomiting 17 1 < 1 11 < 1 < 1 Anorexia 11 < 1 0 9 < 1 0 Skin and subcutaneous tissue disorders Rash b 44 1 0 13 0 0 Dry skin 13 < 1 0 4 0 0 Alopecia 13 < 1 0 7 0 0 Pruritus 12 < 1 0 9 < 1 0 Nail disorder 11 < 1 0 < 1 0 0 General disorders and administration site conditions Fatigue 20 2 0 17 < 1 0 Asthenia 12 < 1 0 11 < 1 0 Nervous system disorders Headache 14 < 1 0 13 < 1 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 11 < 1 0 2 < 1 0 Table 4.

Lapatinib 1,500 mg/day + Letrozole 2.5 mg/day Letrozole 2.5 mg/day All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Hepatic Parameters % % % % % % AST 53 6 0 36 2 < 1 ALT 46 5 < 1 35 1 0 Total Bilirubin 22 < 1 < 1 11 1 < 1 Hormone Receptor-Positive, HER2+ Metastatic Breast Cancer: In another randomized, Phase 3 clinical trial of postmenopausal patients (N = 355) with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) which had progressed after prior trastuzumab-containing chemotherapy and endocrine therapies, patients received lapatinib with trastuzumab and an aromatase inhibitor (AI) (letrozole, exemestane, or anastrozole), lapatinib with an AI, or trastuzumab with an AI.

In this trial, the safety profile of the treatment groups was consistent with the known safety of these agents.

The most frequent study treatment-related

AEs (> 10%) in each of the lapatinib-containing treatment arms were diarrhea, rash, paronychia, nausea, stomatitis, dermatitis acneiform, and decreased appetite, which were infrequent to absent in the trastuzumab treatment arm.

The frequency of cardiac

AEs (mostly decrease in ejection fraction) was 7% in the lapatinib+trastuzumab+AI group, 2% in the lapatinib+AI group and 3% in the trastuzumab+AI group.

Adverse reactions which occurred in at least 10% of patients in the treatment arms are shown in Table 5.

Table 5.

Adverse Reactions Occurring in Greater Than or Equal to 10% of Patients a NCI CTCAE v3.0. b Includes multiple adverse reaction terms for rash.

Lapatinib (1,000 mg) + Trastuzumab + AI Lapatinib (1,500 mg) + AI Trastuzumab + AI (N = 118) (N = 119) (N = 116) All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 Reactions (%) (%) (%) (%) (%) (%) (%) (%) (%) Gastrointestinal disorders Diarrhea 69 13 0 51 6 0 9 0 0 Nausea 22 0 0 22 2 0 9 0 0 Stomatitis 17 0 0 13 < 1 0 3 0 0 Vomiting 10 0 0 14 0 0 < 1 < 1 0 Skin and subcutaneous tissue disorders Rash b 54 0 0 44 3 0 5 0 0 Palmar-plantar erythrodysesthesia 10 0 0 8 < 1 0 < 1 0 0 Alopecia 10 0 0 7 0 0 2 0 0 General disorders and administration site conditions Fatigue 12 < 1 0 14 2 0 10 0 0 Musculoskeletal and connective tissue disorders Arthralgia 13 < 1 0 14 0 0 12 0 0 Pain in extremity 7 < 1 0 10 0 0 3 0 0 Respiratory, thoracic, and mediastinal disorders Cough 8 0 0 8 0 0 15 0 0 Metabolism and nutrition disorders Decreased appetite 18 0 0 13 0 0 3 0 0.

Infections and infestations Paronychia 30 0 0 15 2 0 0 0 0.

Investigations Alanine aminotransferase increased 7 0 0 15 3 < 1 6 4 0 Aspartate aminotransferase increased 6 0 0 17 5 0 9 4 0 Nervous system disorders Headache 5 0 0 16 2 0 10 < 1 0 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 greater than or equal to Grade 3 (NCI CTCAE v3.0), or a greater than or equal to 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 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3.0).

Among 654 patients who received combination treatment with lapatinib/letrozole, 26 patients experienced Grade 1 or and 6 patients had Grade 3 or 4 LVEF adverse reactions.

Lapatinib has been associated with hepatotoxicity.

Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies. 6.2 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.

Disorders : Hypersensitivity reactions, including anaphylaxis.

Disorders : Nail disorders, including paronychia.

Severe cutaneous adverse reactions, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), skin fissures.

Disorders : Ventricular arrhythmias/Torsades de Pointes (TdP).

Electrocardiogram (ECG) QT prolongation.fda.gov/medwatch.

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 to 9,000 mg daily and where reported, the duration varied between 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.

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

Known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components.

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

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

When lapatinib tablets are coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily.

Lapatinib tablets should be taken at least one hour before or one hour after a meal.

However, capecitabine should be taken with food or within 30 minutes after food.

Lapatinib tablets should be taken once daily.

Do not divide daily doses of lapatinib tablets.

Modify dose for cardiac and other toxicities, severe hepatic impairment, diarrhea, and CYP3A4 drug interactions. 2.1 Recommended Dosing HER2-Positive Metastatic Breast Cancer: The recommended dose of lapatinib tablets is 1,250 mg given orally once daily on Days to 21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days to 14 in a repeating 21-day cycle.

The dose of lapatinib tablets 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.

Receptor-Positive, HER2-Positive Metastatic Breast Cancer: The recommended dose of lapatinib tablets is 1,500 mg given orally once daily continuously in combination with letrozole.

When coadministered with lapatinib tablets, the recommended dose of letrozole is 2.5 mg once daily.

The dose of lapatinib tablets should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended. 2.2 Dose Modification Guidelines Cardiac Events: Lapatinib tablets should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0), and in patients with an LVEF that drops below the institution’s lower limit of normal (LLN) .

Lapatinib tablets 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.

Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of lapatinib tablets 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.

Lapatinib tablets should be interrupted in patients with diarrhea which is NCI CTCAE Grade 3 or Grade 1 or with complicating features (moderate to severe abdominal cramping, nausea or vomiting greater than or equal to NCI CTCAE Grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration).

Lapatinib tablets 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 tablets should be permanently discontinued in patients with diarrhea, which is NCI CTCAE Grade 4.

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 tablets dose is adjusted upward to the indicated dose.

CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s wort).

If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib tablets 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 tablets 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 tablets dose should be reduced to the indicated dose.

Discontinuation or interruption of dosing with lapatinib tablets may be considered when patients develop greater than or equal to Grade 2 NCI CTCAE toxicity, and can be restarted at the standard dose of 1,250 or 1,500 mg/day when the toxicity improves to Grade 1 or less.

If the toxicity recurs, then lapatinib tablets 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.

Lapatinib tablets are available as follows: 250 mg.

• Each yellow, oval, film-coated tablet, debossed with “L250” on one side and “TV” on the other side contains 398 mg lapatinib ditosylate equivalent to 250 mg of lapatinib.

Tablets are available in bottles of 150 (NDC 42291-035-15).

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) .

Keep this and all medications out of the reach of children.

Based on findings in animal studies and its mechanism of action, lapatinib can cause fetal harm when administered to a pregnant woman.

There are no available human data to inform of the drug-associated risks.

In an animal reproduction study, administration of lapatinib to pregnant rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth at maternal exposures that were ≥ 3.3 times the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine.

When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of lapatinib at 30, 60, and 120 mg/kg/day during the period of organogenesis.

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 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.

In a pre.

• and post-natal development study, rats were given oral doses of 20, 60, and 120 mg/kg/day during gestation through lactation up to weaning.

In rats, doses of and 120 mg/kg/day (approximately 3.3 and 6.4 times the human clinical exposure, respectively, based on AUC following 1,250 mg dose of lapatinib plus capecitabine) led to decrease in F1 postnatal survival (91% and 34% of the pups died by the fourth day after birth, at and 120 mg/kg/day, respectively).

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

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.