Lapatinib
Tablet, Film Coated · Oral
Uses
Lapatinib tablets are 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 capecetabine. 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 tablet is 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 have not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.
Dosage and administration
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 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 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, rifapentine, 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.
Dosage forms and strengths
250 mg tablets — orange colored, oval shaped, film-coated tablets, debossed “NTL” on one side and plain on another side. 250 mg tablets ( 3 )
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 )
Warnings and precautions
Decreases in left ventricular ejection fraction (LVEF) have been reported. Confirm normal LVEF before starting lapatinib tablets and continue evaluations during treatment. ( 5.1 ) Lapatinib has been associated with hepatotoxicity. Monitor liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. Discontinue and do not restart lapatinib tablets if patients experience severe changes in liver function tests. ( 5.2 ) Dose reduction in patients with severe hepatic impairment should be considered. ( 2.2 , 5.3 , 8.7 ) Diarrhea, including severe diarrhea, has been reported during treatment. Manage with antidiarrheal agents, and replace fluids and electrolytes if severe. ( 5.4 ) Lapatinib has been associated with interstitial lung disease and pneumonitis. Discontinue lapatinib tablets if patients experience severe pulmonary symptoms. ( 5.5 ) Lapatinib may prolong the QT interval in some patients. Consider electrocardiogram (ECG) and electrolyte monitoring. ( 5.6 , 12.2 ) Severe cutaneous reactions have been reported. Discontinue lapatinib tablets if life-threatening reactions are suspected. ( 5.7 ) Lapatinib tablets can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 ). 5.1 Decreased Left Ventricular Ejection Fraction Lapatinib tablets has been reported to decrease LVEF [see Adverse Reactions (6.1 ) ]. In clinical trials, the majority (greater than 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 tablets are 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 tablets 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 tablets to ensure that LVEF does not decline below the institution's normal limits [see Dosage and Administration (2.2) ]. 5.2 Hepatotoxicity Hepatotoxicity [alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) and total bilirubin greater than 2 times the ULN] has been observed in clinical trials (less than 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 tablets should be discontinued and patients should not be retreated with lapatinib tablets [see Adverse Reactions (6.1 )]. 5.3 Patients with Severe Hepatic Impairment If lapatinib tablets are 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 tablets should be discontinued and patients should not be retreated with lapatinib tablets [see Warnings and Precautions (5.2)]. 5.4 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 less than 10% and less than 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) ]. 5.5 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 tablets should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis, which are greater than or equal to Grade 3 (NCI CTCAE v 3.0). 5.6 QT Prolongation A concentration-dependent QT prolongation has been associated with lapatinib tablets [see Clinical Pharmacology (12.2 )]. Monitor patients who have or may develop prolongation of QTc during treatment with lapatinib tablets. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products with known risk for QT prolongation/Torsades de Pointes (TdP), and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to lapatinib tablets administration. 5.7 Severe Cutaneous Reactions Severe cutaneous reactions have been reported with lapatinib tablets.
Side effects
The most common (greater than 20%) adverse reactions during treatment with lapatinib tablets 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 tablets plus letrozole were diarrhea, rash, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 tablets has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of lapatinib tablets 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 or equal to 20%) during therapy with lapatinib tablets 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 tablets plus capecitabine. Lapatinib Tablets 1,250 mg/day + Capecitabine 2,000 mg/m 2 /day (N = 198) Capecitabine 2,500 mg/m 2 /day (N=191) Reactions All Grades a Grade 3 Grade 4 All Grades a Grade 3 Grade 4 % % % % % % 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 Tablets 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 = 1286) with hormone receptor-positive, metastatic breast cancer, who had not received chemotherapy for their metastatic disease, patients received letrozole with or without lapatinib tablets. In this trial, the safety profile of lapatinib tablets was consistent with previously reported results from trials of lapatinib tablets 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 Tablets 1,500 mg/day + Letrozole 2.5 mg/day (N = 654) Letrozole 2.5 mg/day (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 Tablets 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 tablets with trastuzumab and an aromatase inhibitor (AI) (letrozole, exemestane, or anastrozole), lapatinib tablets 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.
Drug interactions
Lapatinib tablets are 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 tablets in patients coadministered a strong CYP3A4 inhibitor. (2.2, 7.2) Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of lapatinib tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets are 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.
Use in specific populations
Lactation: Advise not to breastfeed. ( 8.2 ) Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of lapatinib tablets. ( 8.3 ) 8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, lapatinib tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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. (see Data). 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. Data Animal Data 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 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. 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 60 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 60 and 120 mg/kg/day, respectively). 8.2 Lactation Risk Summary There are no data on the presence of lapatinib in human milk, or its effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in a breastfed child from lapatinib tablets, advise lactating women not to breastfeed during treatment with lapatinib tablets and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of lapatinib tablets. Contraception Females Based on findings in animal studies, lapatinib tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during treatment with lapatinib tablets and for 1 week after the last dose. Males Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with lapatinib tablets and for 1 week after the last dose [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use The safety and effectiveness of lapatinib tablets in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of metastatic breast cancer patients in clinical studies of lapatinib tablets 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 tablets in combination with letrozole (N = 642), 44% were 65 years of age and older, and 12% were 75 years of age and older. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Lapatinib pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. There is no experience with lapatinib tablets 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. 8.7 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 preexisting hepatic impairment, respectively. Administration of lapatinib tablets 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 preexisting hepatic impairment [see Dosage and Administration (2.2)] .
Pregnancy
8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, lapatinib tablets can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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. (see Data). 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. Data Animal Data 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 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. 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 60 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 60 and 120 mg/kg/day, respectively).
Pediatric use
8.4 Pediatric Use The safety and effectiveness of lapatinib tablets in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use Of the total number of metastatic breast cancer patients in clinical studies of lapatinib tablets 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 tablets 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.
Overdosage
There is no known antidote for overdoses of lapatinib tablets. The maximum oral doses of lapatinib that have been administered in clinical trials are 1,800 mg once daily. More frequent ingestion of lapatinib tablets 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 [see Adverse Reactions (6.1) ] 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 tablets 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 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). It has the molecular formula C 29 H 26 ClFN 4 O 4 S (C 7 H 8 O 3 S) 2 and a molecular weight of 925.48 g/mol. Lapatinib ditosylate 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 lapatinib film coated tablet contains 398 mg lapatinib ditosylate equivalent to 250 mg lapatinib free base. The inactive ingredients of lapatinib tablets are: FD & C Yellow # 6/Sunset yellow FCF Aluminum lake, hypromellose, lecithin (soy), magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, polyvinyl alcohol, povidone, sodium starch glycolate, talc, titanium dioxide, xanthan gum. lapatinib chemical structure
Mechanism of action
12.1 Mechanism of Action Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated K i 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.
How supplied
Lapatinib tablets 250 mg are orange colored, oval shaped, film-coated tablets, debossed “NTL” on one side and plain on another side and are available in: Bottles of 150 tablets: NDC 68180-801-36 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients of the following: Decreased Left Ventricular Ejection Fraction (LVEF) Lapatinib tablets have been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue [see Warnings and Precautions (5.1 ) ]. Advise patients to inform their healthcare provider if they develop these symptoms while taking lapatinib tablets. Hepatotoxicity and Hepatic Impairment Periodic laboratory testing will be performed while taking lapatinib tablets. Advise patients to report signs and symptoms of liver dysfunction to their healthcare provider right away [see Warnings and Precautions (5.2 )]. Diarrhea Lapatinib tablets often causes diarrhea which may be severe in some cases [see Warnings and Precautions (5.4) ]. Instruct patients on how to manage and/or prevent diarrhea and to inform their healthcare provider immediately if there is any change in bowel patterns or severe diarrhea occurs during treatment with lapatinib tablets. Interstitial Lung Disease/Pneumonitis Advise patients to report pulmonary signs or symptoms indicative of ILD or pneumonitis [see Warnings and Precautions (5.5 )] Severe Cutaneous Reactions Advise patients to report severe cutaneous reactions to their healthcare provider if they develop these symptoms while taking lapatinib tablets [see Warnings and Precautions (5.7 )]. Drug and Food Interactions Lapatinib tablets may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products [see Drug Interactions (7 )]. Lapatinib tablets may interact with grapefruit. Advise patients not to take lapatinib tablets with grapefruit products [see Dosage and Administration (2.2 ), Drug Interactions (7.2 )]. Dosing Administration Lapatinib tablets 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 tablets should be taken once daily. Dividing the daily dose is not recommended [see Dosage and Administration (2.1 )]. Embryo-Fetal Toxicity Inform female patients of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider if they are pregnant or become pregnant [see Use in Specific Populations (8.1 )]. Advise females of reproductive potential to use effective contraception during treatment with Lapatinib tablets and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week following the last dose [see Warning and Precautions (5.8 ) and Use in Specific Populations (8.1 , 8.3 )]. Lactation Advise patients not to breastfeed during treatment and for 1 week after the last dose of lapatinib tablets [see Use in Specific Populations (8.2 )] Manufactured by: Natco Pharma Limited India Distributed by: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States. Rev.: 06/2025 Medication Guide PATIENT INFORMATION LAPATINIB (la-PA-ti-nib) tablets What are lapatinib tablets? Lapatinib tablets are prescription medicine used: with the medicine capecitabine to treat people with breast cancer that is advanced or that has spread to other parts of the body (metastatic), and: 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 Before taking lapatinib tablets with capecitabine, your breast cancer should have gotten worse (progressed) with the medicine trastuzumab. with the medicine letrozole to treat women who: have gone through the change of life (postmenopausal), and who have metastatic breast cancer that is hormone receptor-positive, HER2-positive, and hormonal therapy is a treatment option for them. It is not known if lapatinib tablets are safe and effective in children. Do not take lapatinib tablets if you are allergic to any of the ingredients in lapatinib tablets. A complete list of ingredients in lapatinib tablets can be found at the end of this Patient Information. Before you take lapatinib tablets, tell your healthcare provider about all of your medical conditions, including if you: have heart problems have liver problems. You may need a lower dose of lapatinib tablets. For females, tell your healthcare provider if you: are pregnant or plan to become pregnant. Lapatinib tablets can harm your unborn baby. Your healthcare provider should check to see if you are pregnant before you start taking lapatinib tablets. You should use effective birth control (contraception) during treatment with lapatinib tablets and for 1 week after the last dose of lapatinib tablets. Tell your healthcare provider right away if you become pregnant during treatment with lapatinib tablets. are breastfeeding or plan to breastfeed. It is not known if lapatinib passes into your breast milk. You should not breastfeed during treatment with lapatinib tablets and for 1 week after the last dose of lapatinib tablets. Talk to your healthcare provider about the best way to feed your baby if you breastfeed. For males with female partners who are able to become pregnant: use effective contraception during treatment with lapatinib tablets and for 1 week after the last dose. if your female partner becomes pregnant during treatment with lapatinib tablets, tell your healthcare provider right away. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Lapatinib tablets may affect the way other medicines work, and other medicines may affect the way lapatinib tablets works. Know the medicines you take.
Label text from the FDA structured product label by Lupin Pharmaceuticals, Inc. (revised Jun 10, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Lapatinib Ditosylate in 3 products
Lapatinib NDC products (3)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 42291-035 | Lapatinib Ditosylate 250 mg/1 Tablet, Film Coated | AvKARE | ANDA |
| 68180-801 | Lapatinib Ditosylate 250 mg/1 Tablet | Lupin Pharmaceuticals, Inc. | ANDA |
| 0480-3237 | Lapatinib Ditosylate 250 mg/1 Tablet, Film Coated | Teva Pharmaceuticals, Inc. | ANDA |
Frequently asked questions
What is Lapatinib used for?
Lapatinib tablets are 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…
What are the side effects of Lapatinib?
The most common (greater than 20%) adverse reactions during treatment with lapatinib tablets 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 tablets plus letrozole were diarrhea, rash, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE… See the full label for the complete list.
Who makes Lapatinib?
Lapatinib is listed by 3 labelers in the FDA NDC directory, including AvKARE, Lupin Pharmaceuticals, Inc., Teva Pharmaceuticals, Inc..