Lapatinib

5 WARNINGS AND PRECAUTIONS Decreases in left ventricular ejection fraction (LVEF) have been reported. Confirm normal LVEF before starting lapatinib 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 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 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 if life-threatening reactions are suspected. ( 5.7 ) Lapatinib 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 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 is to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with lapatinib to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue to be evaluated during treatment with lapatinib to ensure that LVEF does not decline below the institution’s normal limits [see Dosage and Administration ( 2.2 )] . 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 should be discontinued and patients should not be retreated with lapatinib [see Adverse Reactions ( 6.1 )] . 5.3 Patients With Severe Hepatic Impairment If lapatinib is to be administered to patients with severe preexisting hepatic impairment, dose reduction should be considered [see Dosage and Administration (2.2 ) and Use in Specific Populations ( 8.7 )] . In patients who develop severe hepatotoxicity while on therapy, lapatinib should be discontinued and patients should not be retreated with lapatinib [see Warnings and Precautions ( 5.2 )] . 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 antidiarrheal 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 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 v3.0). 5.6 QT Prolongation A concentration-dependent QT prolongation has been associated with lapatinib [see Clinical Pharmacology ( 12.2 )] . Monitor patients who have or may develop prolongation of QTc during treatment with lapatinib. 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 administration. 5.7 Severe Cutaneous Reactions Severe cutaneous reactions have been reported with lapatinib. If life-threatening reactions, such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (e.g., progressive skin rash often with blisters or mucosal lesions) are suspected, discontinue treatment with lapatinib. 5.8 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animal studies, lapatinib can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, administration of lapatinib to pregnant rats during the period of 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 (with maternal exposures approximately 6.4 and 0.2 times, respectively, the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine). Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1) and Clinical Pharmacology ( 12.1 )] . Verify the pregnancy status of females of reproductive potential prior to initiation of lapatinib. Advise females of reproductive potential to use effective contraception during treatment with lapatinib and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with lapatinib and for 1 week after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

6 ADVERSE REACTIONS 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 AvKARE at 1-855-361-3993 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 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. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS 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.

8 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 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, advise lactating women not to breastfeed during treatment with lapatinib 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. Contraception Females Based on findings in animal studies, lapatinib 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 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 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 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 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. 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 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 preexisting 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 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 )] . In patients who develop severe hepatotoxicity while on therapy, lapatinib should be discontinued and patients should not be retreated with lapatinib [see Warnings and Precautions ( 5.2 )] .

8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, lapatinib 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).