Nerlynx

5 WARNINGS AND PRECAUTIONS Diarrhea: Manage diarrhea through either NERLYNX dose escalation or loperamide prophylaxis ( 2.1 , 2.2 ). If diarrhea occurs despite recommended prophylaxis, treat with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥2 diarrhea that occurs after maximal dose reduction. ( 2.3 , 5.1 ) Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities. ( 2.3 , 5.2 ) Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Diarrhea Severe diarrhea and sequelae, such as dehydration, hypotension, and renal failure occurred during treatment with NERLYNX. Diarrhea was reported in 95% of NERLYNX-treated patients in ExteNET, a randomized placebo-controlled trial in the extended adjuvant setting who were not required to receive antidiarrheal prophylaxis. In the NERLYNX arm, Grade 3 diarrhea occurred in 40% and Grade 4 diarrhea occurred in 0.1% of patients. The majority of patients (93%) had diarrhea in the first month of treatment, the median time to first onset of Grade ≥3 diarrhea was 8 days (range, 1–350), and the median cumulative duration of Grade ≥3 diarrhea was 5 days (range, 1–139) [see Adverse Reactions ( 6.1 )] . Diarrhea was reported in 83% of NERLYNX plus capecitabine treated patients in NALA, a randomized placebo-controlled trial in the metastatic breast cancer setting who were required to receive anti-diarrheal prophylaxis in the first 21-day cycle. The majority of patients (70%) had diarrhea in the first 21 days of treatment, the median time to first onset of Grade ≥3 diarrhea was 11 days (range, 2–728) and the median cumulative duration of Grade ≥3 diarrhea was 3 days (range, 1–21). In the NERLYNX plus capecitabine arm, Grade 3 diarrhea occurred in 24% of patients [see Adverse Reactions ( 6.1 )] . Antidiarrheal prophylaxis has been shown to lower the incidence and severity of diarrhea. Instruct patients to initiate antidiarrheal prophylaxis with loperamide along with the first dose of NERLYNX and continue during the first 56 days of treatment; after day 56, titrate dose to achieve 1–2 bowel movements per day and not to exceed 16 mg loperamide per day [see Dosage and Administration ( 2.1 )] . Consider adding other agents to loperamide as clinically indicated [see Adverse Reactions ( 6.1 )] . Alternatively, a 2-week NERLYNX dose escalation approach prior to initiation of the recommended treatment regimen with NERLYNX can also be considered for diarrhea management [see Dosage and Administration ( 2.2 )]. For patients who used NERLYNX dose escalation, the median time to first onset of Grade ≥3 diarrhea was 45 days (range, 15–132) and the median cumulative duration of Grade ≥3 diarrhea was 2.5 days (range, 1–6). Grade 3 diarrhea occurred in 13% of patients who used NERLYNX dose escalation [see Adverse Reactions ( 6.1 )]. Monitor patients for diarrhea and treat with additional antidiarrheals as needed. When severe diarrhea with dehydration occurs, administer fluid and electrolytes as needed, interrupt NERLYNX, and reduce subsequent doses [see Dosage and Administration ( 2.3 )] . Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia). 5.2 Hepatotoxicity NERLYNX has been associated with hepatotoxicity characterized by increased liver enzymes. In ExteNET, 10% of patients experienced an alanine aminotransferase (ALT) increase ≥2× ULN, 5% of patients experienced an aspartate aminotransferase (AST) increase ≥2× ULN, and 1.7% of patients experienced an AST or ALT increase >5× ULN (≥Grade 3). Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of NERLYNX-treated patients. In the NALA study, in NERLYNX and capecitabine-treated patients, 7% experienced an ALT or AST increase >3× ULN, 2% experienced an ALT or AST increase >5× ULN, 7% experienced a bilirubin increase >1.5× ULN, and 1.3% experienced a bilirubin increase >3× ULN. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 0.3% of NERLYNX and capecitabine-treated patients. Total bilirubin, AST, ALT, and alkaline phosphatase should be measured prior to starting treatment with NERLYNX monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. These tests should also be performed in patients experiencing Grade 3 diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia [see Dosage and Administration ( 2.3 ) and Adverse Reactions ( 6.1 )] . 5.3 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, NERLYNX can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis caused abortions, embryo-fetal death, and fetal abnormalities in rabbits at maternal AUCs approximately 0.2 times the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Diarrhea [see Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (reported in ≥5% of patients) were: NERLYNX as a single agent: diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection. ( 6 ) NERLYNX in combination with capecitabine: diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) 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. Extended Adjuvant Treatment of Early-Stage Breast Cancer ExteNET The data described below reflect the safety data of NERLYNX as a single agent in ExteNET, a multicenter, randomized, double-blind, placebo-controlled study of NERLYNX within 2 years after completion of adjuvant treatment with trastuzumab-based therapy in women with HER2-positive early-stage breast cancer. Patients who received NERLYNX in this trial were not required to receive any prophylaxis with antidiarrheal agents to prevent the NERLYNX-related diarrhea. Patients were treated with 240 mg of NERLYNX given orally once daily with food, continuously until disease recurrence or for up to one year. The median duration of treatment was 11.6 months in the NERLYNX arm and 11.8 months in the placebo arm. The median age was 52 years (60% were ≥50 years old, 12% were ≥65 years old); 81% were Caucasian, 3% Black or African American, 14% Asian, and 3% other. A total of 1408 patients were treated with NERLYNX. NERLYNX dose reduction due to an adverse reaction of any grade occurred in 31% of patients receiving NERLYNX compared to 2.6% of patients receiving placebo. Permanent discontinuation due to any adverse reaction was reported in 28% of NERLYNX-treated patients. The most common adverse reaction leading to discontinuation was diarrhea, accounting for 17% of NERLYNX-treated patients. The most common adverse reactions (≥5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, vomiting, nausea, and abdominal pain. Serious adverse reactions in the NERLYNX arm included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), ALT increased (0.3%), AST increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%). Table 7 summarizes the adverse reactions in ExteNET. Table 7: Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in ExteNET * Includes abdominal pain, abdominal pain upper, and abdominal pain lower † Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, mucosal inflammation, oropharyngeal pain, oral pain, glossodynia, glossitis, and cheilitis ‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash pruritic, rash pustular, rash maculo-papular, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption § Includes nail disorder, paronychia, onychoclasis, nail discoloration, nail toxicity, nail growth abnormal, and nail dystrophy System Organ Class (Preferred Term) NERLYNX n=1408 Placebo n=1408 All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Gastrointestinal Disorders Diarrhea 95 40 0.1 35 2 0 Nausea 43 2 0 22 0.1 0 Abdominal pain * 36 2 0 15 0.4 0 Vomiting 26 3 0 8 0.4 0 Stomatitis † 14 0.6 0 6 0.1 0 Dyspepsia 10 0.4 0 4 0 0 Abdominal distension 5 0.3 0 3 0 0 Dry mouth 3 0.1 0 2 0 0 General Disorders and Administration Site Conditions Fatigue 27 2 0 20 0.4 0 Hepatobiliary Disorders Alanine aminotransferase increased 9 1 0.2 3 0.2 0 Aspartate aminotransferase increased 7 0.5 0.2 3 0.3 0 Infections and Infestations Urinary tract infection 5 0.1 0 2 0 0 Investigations Weight decreased 5 0.1 0 0.5 0 0 Metabolism and Nutrition Disorders Decreased appetite 12 0.2 0 3 0 0 Dehydration 4 0.9 0.1 0.4 0.1 0 Musculoskeletal and Connective Tissue Disorders Muscle spasms 11 0.1 0 3 0.1 0 Respiratory, Thoracic and Mediastinal Disorders Epistaxis 5 0 0 1 0.1 0 Skin and Subcutaneous Tissue Disorders Rash ‡ 18 0.6 0 9 0 0 Dry skin 6 0 0 2 0 0 Nail disorder § 8 0.3 0 2 0 0 Skin fissures 2 0.1 0 0.1 0 0 Advanced or Metastatic Breast Cancer NALA The data described below reflect the safety data of NERLYNX plus capecitabine in NALA, a randomized, multicenter, multinational, open-label, active-controlled study of HER2-positive metastatic breast cancer in patients, with or without brain metastases, who have received two or more prior anti HER2-based regimens in the metastatic setting. Patients were treated with NERLYNX 240 mg orally once daily Days 1–21 of a 21-day cycle in combination with capecitabine (750 mg/m 2 given orally twice daily) Days 1–14 of a 21-day cycle, or lapatinib 1250 mg orally once daily Days 1–21 of a 21-day cycle in combination with capecitabine (1000 mg/m 2 given orally twice daily) Days 1–14 of a 21-day cycle until disease progression. The median duration of treatment was 5.7 months in the NERLYNX plus capecitabine arm and 4.4 months in the lapatinib plus capecitabine arm. NERLYNX dose reduction due to an adverse reaction of any grade occurred in 10% of patients receiving NERLYNX plus capecitabine. Permanent discontinuation due to any adverse reaction was reported in 14% of NERLYNX plus capecitabine treated patients. The most common adverse reactions leading to discontinuation were vomiting (3.6%), diarrhea (2.6%), nausea (2.6%), and palmar-plantar erythrodysaesthesia syndrome (2.3%) of NERLYNX plus capecitabine-treated patients. The most common adverse reactions of any grade (≥5%) in the NERLYNX plus capecitabine arm were diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, nausea, vomiting, fatigue, and decreased appetite. Serious adverse reactions ≥2% in the NERLYNX plus capecitabine arm included diarrhea (7%), vomiting (3%), nausea (2.3%), and acute kidney injury (2.3%). Table 8 summarizes the adverse reactions in NALA. Table 8: Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in Combination with Capecitabine in NALA * Renal impairment includes acute kidney injury, blood creatinine increased, renal failure, and renal impairment. System Organ Class (Preferred Term) NERLYNX + Capecitabine n=303 Lapatinib + Capecitabine n=311 All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Gastrointestinal Disorders Diarrhea 83 25 0 66 13 0 Nausea 53 4.3 0 42 2.9 0 Vomiting 46 4 0 31 1.9 0 Constipation 31 1 0 13 0 0 Abdominal distension 8 0.3 0 3.2 0.6 0 General Disorders and Administration Site Conditions Fatigue/asthenia 45 6 0 40 4.5 0 Malaise 4.3 0 0 2.3 0.3 0 Influenza like illness 4 0 0 1.3 0 0 Infections and Infestations Urinary tract infection 9 0.7 0 4.2 0.6 0 Upper respiratory tract infection 8 0.3 0 4.5 0.3 0 Investigations Weight decreased 20 0.3 0 13 0.6 0 Metabolism and Nutrition Disorders Decreased appetite 35 2.6 0 22 2.3 0 Musculoskeletal and Connective Tissue Disorders Back pain 10 0.3 0 8 0.3 0 Arthralgia 10 0 0 6 1 0 Muscle spasms 5 0 0 1.9 0 0 Nervous System Disorder Dizziness 14 0.3 0 10 0.6 0 Renal and urinary disorders Renal impairment* 7 2 0.3 1 0 0.3 Dysuria 4.6 0 0 1.9 0 0 Management of Diarrhea CONTROL The CONTROL (NCT02400476) study was a multicenter, open-label, multi-cohort trial evaluating patients with early-stage HER2-positive breast cancer treated with NERLYNX 240 mg daily for up to one year receiving loperamide prophylaxis with additional anti-diarrheal treatment as needed or NERLYNX dose escalation with loperamide as needed. All patients in the prophylaxis cohort received loperamide 4 mg loading dose, followed by 4 mg three times a day from days 1-14, followed by 4 mg twice a day on days 15-56, followed by loperamide as needed through 1 year of treatment with NERLYNX [see Dosage and Administration ( 2.1 )]. All patients in the dose escalation cohort received NERLYNX 120 mg for Week 1, followed by NERLYNX 160 mg for Week 2, followed by NERLYNX 240 mg for Week 3 and thereafter [see Dosage and Administration ( 2.2 )] . Table 9 summarizes the diarrhea adverse reactions for NERLYNX with loperamide prophylaxis and NERLYNX dose escalation. Table 9: Diarrhea in Patients Treated with NERLYNX with Antidiarrheal Prophylaxis or Dose Escalation Loperamide Prophylaxis n=109 NERLYNX Dose Escalation n=60 Duration of Treatment, months Median 11.8 12.0 Range 0.1, 12.8 0.2, 12.4 Dose Intensity, mg per day Median 234 230 Range 46, 240 32, 236 Incidence of Diarrhea, % Any Grade 78 98 Grade 2 25 45 Grade 3 32 13 Action Taken, % Discontinuation due to diarrhea 18 3.3

<table ID="t7" width="100%"><caption>Table 7: Adverse Reactions Reported in &#x2265;2% of NERLYNX-Treated Patients in ExteNET</caption><col width="24.586%" align="left"/><col width="14.586%" align="left"/><col width="12.100%" align="left"/><col width="12.100%" align="left"/><col width="14.057%" align="left"/><col width="11.186%" align="left"/><col width="11.386%" align="left"/><tfoot><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote">* Includes abdominal pain, abdominal pain upper, and abdominal pain lower</paragraph></td></tr><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote">&#x2020; Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, mucosal inflammation, oropharyngeal pain, oral pain, glossodynia, glossitis, and cheilitis</paragraph></td></tr><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote">&#x2021; Includes rash, rash erythematous, rash follicular, rash generalized, rash pruritic, rash pustular, rash maculo-papular, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption</paragraph></td></tr><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote">&#xA7; Includes nail disorder, paronychia, onychoclasis, nail discoloration, nail toxicity, nail growth abnormal, and nail dystrophy</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="center" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">System Organ Class (Preferred Term) </content></td><td colspan="3" align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">NERLYNX</content><content styleCode="bold"><sup/></content> <content styleCode="bold">n=1408</content></td><td colspan="3" align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo n=1408 </content></td></tr><tr><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">All Grades (%) </content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 3 (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 4 (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">All Grades (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 3 (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 4 (%)</content></td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Diarrhea</td><td align="center" styleCode="Botrule Rrule" valign="top">95</td><td align="center" styleCode="Botrule Rrule" valign="top">40</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">35</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Nausea</td><td align="center" styleCode="Botrule Rrule" valign="top">43</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">22</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Abdominal pain ^*</td><td align="center" styleCode="Botrule Rrule" valign="top">36</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">15</td><td align="center" styleCode="Botrule Rrule" valign="top">0.4</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Vomiting</td><td align="center" styleCode="Botrule Rrule" valign="top">26</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">8</td><td align="center" styleCode="Botrule Rrule" valign="top">0.4</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Stomatitis ^&#x2020;</td><td align="center" styleCode="Botrule Rrule" valign="top">14</td><td align="center" styleCode="Botrule Rrule" valign="top">0.6</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">6</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Dyspepsia</td><td align="center" styleCode="Botrule Rrule" valign="top">10</td><td align="center" styleCode="Botrule Rrule" valign="top">0.4</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">4</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Abdominal distension</td><td align="center" styleCode="Botrule Rrule" valign="top">5</td><td align="center" styleCode="Botrule Rrule" valign="top">0.3</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Dry mouth</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Fatigue</td><td align="center" styleCode="Botrule Rrule" valign="top">27</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">20</td><td align="center" styleCode="Botrule Rrule" valign="top">0.4</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Hepatobiliary Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Alanine aminotransferase increased</td><td align="center" styleCode="Botrule Rrule" valign="top">9</td><td align="center" styleCode="Botrule Rrule" valign="top">1</td><td align="center" styleCode="Botrule Rrule" valign="top">0.2</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">0.2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Aspartate aminotransferase increased</td><td align="center" styleCode="Botrule Rrule" valign="top">7</td><td align="center" styleCode="Botrule Rrule" valign="top">0.5</td><td align="center" styleCode="Botrule Rrule" valign="top">0.2</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">0.3</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Infections and Infestations</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Urinary tract infection</td><td align="center" styleCode="Botrule Rrule" valign="top">5</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Investigations</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Weight decreased</td><td align="center" styleCode="Botrule Rrule" valign="top">5</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0.5</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Decreased appetite</td><td align="center" styleCode="Botrule Rrule" valign="top">12</td><td align="center" styleCode="Botrule Rrule" valign="top">0.2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Dehydration</td><td align="center" styleCode="Botrule Rrule" valign="top">4</td><td align="center" styleCode="Botrule Rrule" valign="top">0.9</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0.4</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Muscle spasms</td><td align="center" styleCode="Botrule Rrule" valign="top">11</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Epistaxis</td><td align="center" styleCode="Botrule Rrule" valign="top">5</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">1</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Rash ^&#x2021;</td><td align="center" styleCode="Botrule Rrule" valign="top">18</td><td align="center" styleCode="Botrule Rrule" valign="top">0.6</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">9</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Dry skin</td><td align="center" styleCode="Botrule Rrule" valign="top">6</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Nail disorder ^&#xA7;</td><td align="center" styleCode="Botrule Rrule" valign="top">8</td><td align="center" styleCode="Botrule Rrule" valign="top">0.3</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Skin fissures</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td><td align="center" styleCode="Botrule Rrule" valign="top">0</td></tr></tbody></table>

<table ID="t8" width="100%"><caption>Table 8: Adverse Reactions Reported in &#x2265;2% of NERLYNX-Treated Patients in Combination with Capecitabine in NALA</caption><col width="25.396%" align="left"/><col width="14.427%" align="left"/><col width="11.970%" align="left"/><col width="11.984%" align="left"/><col width="13.912%" align="left"/><col width="11.056%" align="left"/><col width="11.256%" align="left"/><tfoot><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote">* Renal impairment includes acute kidney injury, blood creatinine increased, renal failure, and renal impairment.</paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="center" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">System Organ Class (Preferred Term) </content></td><td colspan="3" align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">NERLYNX + Capecitabine</content><content styleCode="bold"><sup/></content> <content styleCode="bold">n=303</content></td><td colspan="3" align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Lapatinib + Capecitabine n=311 </content></td></tr><tr><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">All Grades (%) </content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 3 (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 4 (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">All Grades (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 3 (%)</content></td><td align="center" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 4 (%)</content></td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Diarrhea</td><td align="center" styleCode="Botrule Rrule" valign="middle">83</td><td align="center" styleCode="Botrule Rrule" valign="middle">25</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">66</td><td align="center" styleCode="Botrule Rrule" valign="middle">13</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Nausea</td><td align="center" styleCode="Botrule Rrule" valign="middle">53</td><td align="center" styleCode="Botrule Rrule" valign="middle">4.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">42</td><td align="center" styleCode="Botrule Rrule" valign="middle">2.9</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Vomiting</td><td align="center" styleCode="Botrule Rrule" valign="middle">46</td><td align="center" styleCode="Botrule Rrule" valign="middle">4</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">31</td><td align="center" styleCode="Botrule Rrule" valign="middle">1.9</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Constipation</td><td align="center" styleCode="Botrule Rrule" valign="middle">31</td><td align="center" styleCode="Botrule Rrule" valign="middle">1</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">13</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Abdominal distension</td><td align="center" styleCode="Botrule Rrule" valign="middle">8</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">3.2</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.6</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Fatigue/asthenia</td><td align="center" styleCode="Botrule Rrule" valign="middle">45</td><td align="center" styleCode="Botrule Rrule" valign="middle">6</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">40</td><td align="center" styleCode="Botrule Rrule" valign="middle">4.5</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Malaise</td><td align="center" styleCode="Botrule Rrule" valign="middle">4.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">2.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Influenza like illness</td><td align="center" styleCode="Botrule Rrule" valign="middle">4</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">1.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Infections and Infestations</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Urinary tract infection</td><td align="center" styleCode="Botrule Rrule" valign="middle">9</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.7</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">4.2</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.6</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Upper respiratory tract infection</td><td align="center" styleCode="Botrule Rrule" valign="middle">8</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">4.5</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Investigations</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Weight decreased</td><td align="center" styleCode="Botrule Rrule" valign="middle">20</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">13</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.6</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Decreased appetite</td><td align="center" styleCode="Botrule Rrule" valign="middle">35</td><td align="center" styleCode="Botrule Rrule" valign="middle">2.6</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">22</td><td align="center" styleCode="Botrule Rrule" valign="middle">2.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Back pain</td><td align="center" styleCode="Botrule Rrule" valign="middle">10</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">8</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Arthralgia</td><td align="center" styleCode="Botrule Rrule" valign="middle">10</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">6</td><td align="center" styleCode="Botrule Rrule" valign="middle">1</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Muscle spasms</td><td align="center" styleCode="Botrule Rrule" valign="middle">5</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">1.9</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Nervous System Disorder</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Dizziness</td><td align="center" styleCode="Botrule Rrule" valign="middle">14</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">10</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.6</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr><tr><td colspan="7" align="left" styleCode="Botrule Lrule Rrule" valign="middle"><content styleCode="bold">Renal and urinary disorders</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Renal impairment*</td><td align="center" styleCode="Botrule Rrule" valign="middle">7</td><td align="center" styleCode="Botrule Rrule" valign="middle">2</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td><td align="center" styleCode="Botrule Rrule" valign="middle">1</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0.3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="middle">Dysuria</td><td align="center" styleCode="Botrule Rrule" valign="middle">4.6</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">1.9</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td><td align="center" styleCode="Botrule Rrule" valign="middle">0</td></tr></tbody></table>

<table ID="t9" width="100%"><caption>Table 9: Diarrhea in Patients Treated with NERLYNX with Antidiarrheal Prophylaxis or Dose Escalation</caption><col width="34.867%" align="left"/><col width="33.133%" align="left"/><col width="32.000%" align="left"/><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"/><td align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">Loperamide Prophylaxis n=109 </content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="top"><content styleCode="bold">NERLYNX Dose Escalation</content> <content styleCode="bold">n=60</content></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Duration of Treatment, months</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Median</td><td align="center" styleCode="Botrule Rrule" valign="top">11.8</td><td align="center" styleCode="Botrule Rrule" valign="top">12.0</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Range</td><td align="center" styleCode="Botrule Rrule" valign="top">0.1, 12.8</td><td align="center" styleCode="Botrule Rrule" valign="top">0.2, 12.4</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Dose Intensity, mg per day</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Median</td><td align="center" styleCode="Botrule Rrule" valign="top">234</td><td align="center" styleCode="Botrule Rrule" valign="top">230</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Range</td><td align="center" styleCode="Botrule Rrule" valign="top">46, 240</td><td align="center" styleCode="Botrule Rrule" valign="top">32, 236</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Incidence of Diarrhea, %</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Any Grade</td><td align="center" styleCode="Botrule Rrule" valign="top">78</td><td align="center" styleCode="Botrule Rrule" valign="top">98</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Grade 2</td><td align="center" styleCode="Botrule Rrule" valign="top">25</td><td align="center" styleCode="Botrule Rrule" valign="top">45</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Grade 3</td><td align="center" styleCode="Botrule Rrule" valign="top">32</td><td align="center" styleCode="Botrule Rrule" valign="top">13</td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Action Taken, %</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Discontinuation due to diarrhea</td><td align="center" styleCode="Botrule Rrule" valign="top">18</td><td align="center" styleCode="Botrule Rrule" valign="top">3.3</td></tr></tbody></table>