LAPATINIB

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 tablets are indicated in combination with: capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Limitations of Use : Patients should have disease progression on trastuzumab prior to initiation of treatment with lapatinib tablets 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 tablets in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer. Lapatinib tablets are a kinase inhibitor indicated in combination with: ( 1 ) capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal growth factor receptor 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Limitations of Use : Patients should have disease progression on trastuzumab prior to initiation of treatment with lapatinib tablets 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 tablets in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.

The recommended dosage of lapatinib tablets for advanced or metastatic breast cancer is 1,250 mg (5 tablets) given orally once daily on Days 1 to 21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1 to 14 in a repeating 21-day cycle. ( 2.1 ) 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. ( 2.1 ) 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. ( 2.1 ) Lapatinib tablets should be taken once daily. Do not divide daily doses of lapatinib tablets. ( 2.1 , 12.3 ) Modify dose for cardiac and other toxicities, severe hepatic impairment, diarrhea, and CYP3A4 drug interactions. ( 2.2 ) 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 1 to 21 continuously in combination with capecitabine 2,000 mg/m 2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1 to 14 in a repeating 21-day cycle. Lapatinib tablets should be taken at least one hour before or one hour after a meal. The dose of lapatinib tablets should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)] . Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs. Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer : The recommended dose of 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. Lapatinib tablets should be taken at least one hour before or one hour after a meal. The dose of lapatinib tablets should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended [see Clinical Pharmacology (12.3)] . 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) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] . 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. Hepatic Impairment : 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. Diarrhea : Lapatinib tablets 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 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 [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 tablets 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, 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 [see Drug Interactions (7.2)] . Other Toxicities : 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 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. ( 4 )

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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.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 [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 (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 3 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. Selected laboratory abnormalities are shown in 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. Selected Laboratory Abnormalities Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a NCI CTCAE v3.0. 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 2 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 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions [see Warnings and Precautions ( 5.1 )] . 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 )] . 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. Immune System Disorders : Hypersensitivity reactions, including anaphylaxis [see Contraindications ( 4 )] . Skin and Subcutaneous Tissue Disorders : Nail disorders, including paronychia. Severe cutaneous adverse reactions, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), skin fissures. Cardiac Disorders : Ventricular arrhythmias/Torsades de Pointes (TdP). Electrocardiogram (ECG) QT prolongation.

Lapatinib is likely to increase exposure to concomitantly administered drugs which are substrates of CYP3A4, CYP2C8, or P-glycoprotein (ABCB1). ( 7.1 ) Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction of lapatinib in patients coadministered a strong CYP3A4 inhibitor. ( 2.2 , 7.2 ) Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of lapatinib in patients coadministered a strong CYP3A4 inducer. ( 2.2 , 7.2 ) 7.1 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 greater than 1.2 ng/mL, the digoxin dose should be reduced by half. 7.2 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly (see Ketoconazole and Carbamazepine sections, below) . Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see Dosage and Administration ( 2.2 )] . Ketoconazole : In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control. Carbamazepine : In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%. 7.3 Drugs That Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If lapatinib is administered with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised. 7.4 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.