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adverse reactions
6 ADVERSE REACTIONS 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. The most frequent study treatment-related AEs (> 10%) in each of the lapatinib tablets -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 tablets + trastuzumab + AI group, 2% in the lapatinib tablets + 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 Tablets (1,000 mg) + Trastuzumab + AI (N = 118) Lapatinib Tablets (1,500 mg) +AI (N = 119) Trastuzumab + AI (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 dis orders 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 tablets/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 tablets/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 tablets have been associated with hepatotoxicity [see Boxed Warning and Warnings and Precautions (5.2 )]. Interstitial Lung Disease/Pneumonitis : Lapatinib tablets 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 tablets. 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 reaction, 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.