KADCYLA

WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. ( 2.3 , 5.1 ) Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. ( 2.3 , 5.2 ) Embryo-Fetal Toxicity: Exposure to KADCYLA during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception. ( 5.3 , 8.1 , 8.3 ) WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning Hepatotoxicity, liver failure and death have occurred in KADCYLA-treated patients. Monitor hepatic function prior to initiation and prior to each dose. Institute dose modifications or permanently discontinue as appropriate. ( 2.3 , 5.1 ) KADCYLA may lead to reductions in left ventricular ejection fraction (LVEF). Assess LVEF prior to initiation. Monitor and withhold dosing or discontinue as appropriate. ( 2.3 , 5.2 ) Embryo-Fetal Toxicity: Exposure to KADCYLA during pregnancy can result in embryo-fetal harm. Advise patients of these risks and the need for effective contraception. ( 5.3 , 8.1 , 8.3 )

5 WARNINGS AND PRECAUTIONS Pulmonary Toxicity: Permanently discontinue KADCYLA in patients diagnosed with interstitial lung disease or pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, permanently discontinue KADCYLA for Grade ≥ 3 or for Grade 2 not responding to standard treatment. ( 2.2 , 5.4 ) Infusion-Related Reactions, Hypersensitivity Reactions: Monitor for signs and symptoms during and after infusion. If significant infusion-related reactions or hypersensitivity reactions occur, slow or interrupt the infusion and administer appropriate medical therapies. Permanently discontinue KADCYLA for life threatening infusion-related reaction. ( 2.1 , 2.2 , 5.5 ) Hemorrhage: Fatal cases of hemorrhage occurred in clinical trials among patients with no known identified risk factors, as well as among patients with thrombocytopenia and those receiving anti-coagulation and antiplatelet therapy. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary . ( 5.6 ) Thrombocytopenia: Monitor platelet counts prior to each KADCYLA dose. Institute dose modifications as appropriate. ( 2.2 , 5.7 ) Neurotoxicity: Monitor for signs or symptoms. Withhold dosing temporarily for patients experiencing Grade 3 or 4 peripheral neuropathy. ( 2.2 , 5.8 , 13.2 ) 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1) ] . Serious hepatotoxicity, including 3 fatal cases, has been observed in clinical trials (n=1624) with KADCYLA as single-agent. All fatal cases occurred in MBC clinical trials with KADCYLA, which included severe drug-induced liver injury and associated hepatic encephalopathy. Some of the patients experiencing hepatotoxicity had comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active liver disease (such as, hepatitis B virus or hepatitis C virus) were excluded from the EMILIA and KATHERINE studies [see Clinical Studies (14.1) ] . Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2) ] . Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 × ULN and concomitant total bilirubin > 2 × ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 × ULN or bilirubin > 1.5 × ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (5 cases out of 1624 treated patients, one of which was fatal). Two of these five cases of NRH were observed in EMILIA and two were observed in KATHERINE [see Adverse Reactions (6.1) ] . NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. Serious cases of heart failure, with no fatal cases, have been observed in clinical trials with KADCYLA. In EMILIA, left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group. In KATHERINE, left ventricular dysfunction occurred in 0.4% of patients in the KADCYLA-treated group and 0.6% of patients in the trastuzumab-treated group [see Adverse Reactions (6.1) ] . Based on limited data from a retrospective observational study, 22% (7 of 32) of patients with HER2-positive metastatic breast cancer (MBC) with a baseline LVEF of 40-49% treated with KADCYLA developed a congestive heart failure (CHF) or a > 10% reduction in LVEF [see Adverse Reactions (6.2) ]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution's normal limits. KADCYLA has not been studied in an adequately controlled study in patients with LVEF < 50%. For patients with MBC, if, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further. For patients with EBC, if, at routine monitoring, LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2) ] . Patients with a history of symptomatic CHF, serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from the EMILIA and KATHERINE studies [see Clinical Studies (14.1) ] . 5.3 Embryo-Fetal Toxicity KADCYLA can cause fetal harm when administered to a pregnant woman. Cases of oligohydramnios, and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death were observed in the post-marketing setting in patients treated with trastuzumab, the antibody component of KADCYLA. DM1, the cytotoxic component of KADCYLA, can cause embryo-fetal toxicity based on its mechanism of action. Verify the pregnancy status of females of reproductive potential prior to the initiation of KADCYLA. Advise pregnant women and females of reproductive potential that exposure to KADCYLA during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of KADCYLA [see Use in Specific Populations (8.1 , 8.3) ]. 5.4 Pulmonary Toxicity Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. Signs and symptoms include dyspnea, cough, fatigue, and pulmonary infiltrates. In patients with MBC, pneumonitis was reported at an incidence of 0.8% (7 out of 884 treated patients), with one case of Grade 3 pneumonitis. The overall incidence of pneumonitis was 1.2% in EMILIA. In KATHERINE, pneumonitis was reported at an incidence of 1.1% (8 out of 740 patients treated with KADCYLA), with one case of Grade 3 pneumonitis. Radiation pneumonitis was reported at an incidence of 1.8% (11 out of 623 patients treated with adjuvant radiotherapy and KADCYLA), with 2 cases of Grade 3 radiation pneumonitis [see Adverse Reactions (6.1) ] . Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. For patients with radiation pneumonitis in the adjuvant setting, KADCYLA should be permanently discontinued for Grade ≥ 3 or for Grade 2 not responding to standard treatment [see Dose Modifications (2.3) ] . Patients with dyspnea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary toxicity. 5.5 Infusion-Related Reactions, Hypersensitivity Reactions Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRRs) and/or hypersensitivity; treatment with KADCYLA is not recommended for these patients. Infusion-related reactions, characterized by one or more of the following symptoms − flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In EMILIA, the overall incidence of IRRs in patients treated with KADCYLA was 1.4%. In KATHERINE, the overall incidence of IRRs in patients treated with KADCYLA was 1.6% [see Adverse Reactions (6.1) ] . In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. KADCYLA treatment should be interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2) ] . Patients should be observed closely for IRR reactions, especially during the first infusion. One case of a serious, allergic/anaphylactic-like reaction has been observed in clinical trials of single-agent KADCYLA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. 5.6 Hemorrhage Cases of hemorrhagic events, including central nervous system, respiratory, and gastrointestinal hemorrhage, have been reported in clinical trials with KADCYLA. Some of these bleeding events resulted in fatal outcomes. In EMILIA, the overall incidence of hemorrhage was 32% in the KADCYLA-treated group and 16% in the lapatinib plus capecitabine-treated group. The incidence of Grade ≥ 3 hemorrhage was 1.8% in the KADCYLA-treated group and 0.8% in the lapatinib plus capecitabine-treated group. In KATHERINE, the overall incidence of hemorrhage was 29% in the KADCYLA-treated group and 10% in the trastuzumab-treated group. The incidence of Grade ≥ 3 hemorrhage was 0.4% in the KADCYLA-treated group, with one fatal case of intracranial hemorrhage, and 0.3% in the trastuzumab-treated group [see Adverse Reactions (6.1) ] . Although, in some of the observed cases the patients were also receiving anti-coagulation therapy, antiplatelet therapy, or had thrombocytopenia, in others there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary. 5.7 Thrombocytopenia Thrombocytopenia, or decreased platelet count, was reported in clinical trials of KADCYLA (145 of 1624 treated patients with Grade ≥ 3; 494 of 1624 treated patients with any Grade). The majority of these patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm 3 ) with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000/mm 3 ) by the next scheduled dose. In clinical trials of KADCYLA, the incidence and severity of thrombocytopenia were higher in Asian patients. In EMILIA, the overall incidence of thrombocytopenia was 31% in the KADCYLA-treated group and 3.3% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1) ] . The incidence of Grade ≥ 3 thrombocytopenia was 15% in the KADCYLA-treated group and 0.4% in the lapatinib plus capecitabine-treated group. In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 45% in the KADCYLA-treated group and 1.3% in the lapatinib plus capecitabine-treated group. In KATHERINE, the overall incidence of thrombocytopenia was 29% in the KADCYLA-treated group and 2.4% in the trastuzumab-treated group [see Adverse Reactions (6.1) ] . The incidence of Grade ≥ 3 thrombocytopenia was 6% in the KADCYLA-treated group and 0.3% in the trastuzumab-treated group. In Asian patients, the incidence of Grade ≥ 3 thrombocytopenia was 19% in the KADCYLA-treated group and 0% in the trastuzumab-treated group. The overall incidence of thrombocytopenia in the KADCYLA-treated group for Asian patients was 50%. Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose [see Dosage and Administration (2.2) ] . KADCYLA has not been studied in patients with platelet counts < 100,000/mm 3 prior to initiation of treatment. In the event of decreased platelet count to Grade ≥ 3 (< 50,000/mm 3 ) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm 3 ) [see Dosage and Administration (2.2) ] . Closely monitor patients with thrombocytopenia (< 100,000/mm 3 ) and patients on anti-coagulant treatment during treatment with KADCYLA. 5.8 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (26 of 1624 treated patients with Grade ≥ 3; 435 of 1624 treated patients with any Grade). In EMILIA, the overall incidence of peripheral neuropathy was 21% in the KADCYLA-treated group and 14% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1) ] . The incidence of Grade ≥ 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. In KATHERINE, the overall incidence of peripheral neuropathy was 32% in the KADCYLA-treated group and 17% in the trastuzumab-treated group. Peripheral neuropathy, including sensory and motor peripheral neuropathy, for KADCYLA treated patients 30% of cases were not resolved at the time of the primary IDFS analysis for KATHERINE. The incidence of Grade ≥ 3 peripheral neuropathy was 1.6% in the KADCYLA-treated group and 0.1% in the trastuzumab-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to Grade ≤ 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2) ] . 5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Hepatotoxicity [See Warnings and Precautions (5.1) ] Left Ventricular Dysfunction [See Warnings and Precautions (5.2) ] Embryo-Fetal Toxicity [See Warnings and Precautions (5.3) ] Pulmonary Toxicity [See Warnings and Precautions (5.4) ] Infusion-Related Reactions, Hypersensitivity Reactions [See Warnings and Precautions (5.5) ] Hemorrhage [See Warnings and Precautions (5.6) ] Thrombocytopenia [See Warnings and Precautions (5.7) ] Neurotoxicity [See Warnings and Precautions (5.8) ] Metastatic Breast Cancer The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis. ( 6.1 ) Early Breast Cancer The most common adverse reactions (≥ 25%) with KADCYLA were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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. The data in the WARNINGS AND PRECAUTIONS reflect exposure to KADCYLA as a single agent at 3.6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) in 1624 patients including 884 patients with HER2-positive metastatic breast cancer and 740 patients with HER2-positive early breast cancer (KATHERINE trial). Metastatic Breast Cancer In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (≥ 25%) adverse reactions were fatigue, nausea, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, increased transaminases, constipation and epistaxis. The adverse reactions described in Table 3 were identified in patients with HER2-positive metastatic breast cancer treated in the EMILIA trial [see Clinical Studies (14.1) ] . Patients were randomized to receive KADCYLA or lapatinib plus capecitabine. The median duration of study treatment was 7.6 months for patients in the KADCYLA-treated group and 5.5 months and 5.3 months for patients treated with lapatinib and capecitabine, respectively. In the EMILIA trial, 43% of patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 59% of patients in the lapatinib plus capecitabine-treated group. Dose adjustments for KADCYLA were permitted [see Dosage and Administration (2.2) ] . Thirty-two patients (7%) discontinued KADCYLA due to an adverse reaction, compared with 41 patients (8%) who discontinued lapatinib, and 51 patients (10%) who discontinued capecitabine due to an adverse reaction. The most common adverse reactions leading to KADCYLA discontinuation were thrombocytopenia and increased transaminases. Eighty patients (16%) treated with KADCYLA had adverse reactions leading to dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, and peripheral neuropathy. Adverse reactions that led to dose delays occurred in 116 (24%) of KADCYLA treated patients. The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, fatigue, increased transaminases and pyrexia. Table 3 reports the adverse reactions that occurred in patients in the KADCYLA-treated group (n=490) of the EMILIA trial. Selected laboratory abnormalities are shown in Table 4 . The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (frequency > 2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients on the KADCYLA Treatment Arm in the EMILIA Trial Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Abdominal pain: abdominal pain, abdominal pain upper Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Hypokalemia: hypokalemia, blood potassium decreased Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow). Adverse Reactions KADCYLA (3.6 mg/kg) n=490 Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) n=488 All Grades (%) Grade 3 – 4 (%) All Grades (%) Grade 3 – 4 (%) SMQ=standardized MedDRA queries Blood and Lymphatic System Disorders Thrombocytopenia 31 15 3.3 0.4 Anemia 14 4.1 11 2.5 Gastrointestinal Disorders Nausea 40 0.8 45 2.5 Constipation 27 0.4 11 0 Diarrhea 24 1.6 80 21 Vomiting 19 0.8 30 4.5 Abdominal pain 19 0.8 18 1.6 Dry Mouth 17 0 4.9 0.2 Stomatitis 14 0.2 33 2.5 General Disorders and Administration Fatigue 36 2.5 28 3.5 Pyrexia 19 0.2 8 0.4 Asthenia 18 0.4 18 1.6 Investigations Transaminases increased 29 8.0 14 2.5 Metabolism and Nutrition Disorders Hypokalemia 10 2.7 9 4.7 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 36 1.8 31 1.4 Arthralgia 19 0.6 8 0 Myalgia 14 0.6 3.7 0 Nervous System Disorders Headache 28 0.8 15 0.8 Peripheral neuropathy 21 2.2 14 0.2 Dizziness 10 0.4 11 0.2 Psychiatric Disorders Insomnia 12 0.4 9 0.2 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 23 0.2 8 0 Cough 18 0.2 13 0.2 Dyspnea 12 0.8 8 0.4 Skin and Subcutaneous Tissue Disorders Rash 12 0 28 1.8 Vascular Disorders Hemorrhage 32 1.8 16 0.8 The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in EMILIA: dyspepsia (9%), urinary tract infection (9%), chills (8%), dysgeusia (8%), neutropenia (7%), peripheral edema (7%), pruritus (6%), hypertension (5%), blood alkaline phosphatase increased (4.7%), vision blurred (4.5%), conjunctivitis (3.9%), dry eye (3.9%), lacrimation increased (3.3%), drug hypersensitivity (2.2%), left ventricular dysfunction (1.8%), infusion-related reaction (1.4%), pneumonitis (1.2%), nodular regenerative hyperplasia (0.4%), portal hypertension (0.4%). Table 4 Selected Laboratory Abnormalities (EMILIA) Parameter KADCYLA (3.6 mg/kg) Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) Chemistry Increased AST 98 7 0.5 65 3 0 Increased ALT 82 5 0.2 54 3 0 Decreased potassium 33 3 0 31 6 0.8 Increased bilirubin 17 0.6 0 57 2 0 Hematology Decreased platelet count 83 14 3 21 0.4 0.6 Decreased hemoglobin 60 4 1 64 3 0.2 Decreased neutrophils 39 3 0.6 38 6 2 Early Breast Cancer KADCYLA has been evaluated as a single-agent in 740 patients with HER2-positive early breast cancer. The adverse reactions described in Table 5 were identified in patients with HER2-positive early breast cancer treated in the KATHERINE trial [see Clinical Studies (14.2) ] . Patients were randomized to receive KADCYLA or trastuzumab. The median duration of study treatment was 10 months for patients in the KADCYLA-treated group and 10 months for patients treated with trastuzumab. One hundred and ninety (26%) patients experienced Grade ≥ 3 adverse reactions in the KADCYLA-treated group compared with 111 (15%) patients in the trastuzumab group. One hundred and thirty-three patients (18%) discontinued KADCYLA due to an adverse reaction, compared with 15 patients (2.1%) who discontinued trastuzumab due to an adverse reaction. The most common adverse reactions leading to KADCYLA discontinuation (in ≥ 1% of patients) were platelet count decreased, blood bilirubin increased, ejection fraction decreased, AST increased, ALT increased, and peripheral neuropathy. Dose adjustments for KADCYLA were permitted [see Dosage and Administration (2.2) ] . One hundred and six patients (14%) treated with KADCYLA had dose reductions. The most frequent adverse reactions leading to dose reduction of KADCYLA (in ≥ 1% of patients) included thrombocytopenia, increased transaminases, blood bilirubin and fatigue. Adverse reactions that led to dose delays occurred in 106 (14%) of KADCYLA treated patients. The most frequent adverse reactions leading to a dose delay of KADCYLA (in ≥ 1% of patients) were neutropenia, thrombocytopenia and AST increased. Selected laboratory abnormalities are shown in Table 6 . The most common adverse reactions seen with KADCYLA in the randomized trial (frequency > 25%) were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. The most common NCI–CTCAE (version 3) Grade ≥ 3 adverse reactions (> 2%) were thrombocytopenia and hypertension. Table 5 Adverse Reactions Occurring in ≥ 10% of Patients in the KATHERINE Trial Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Abdominal pain: abdominal pain, abdominal pain upper Urinary Tract Infection: urinary tract infection, cystitis Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow) Adverse Reactions KADCYLA n=740 Trastuzumab n=720 All grades (%) Grade 3 – 4 (%) All grades (%) Grade 3 – 4 (%) SMQ=standardized MedDRA queries Blood and Lymphatic System Disorders Thrombocytopenia 29 6 2.4 0.3 Anemia 10 1.1 9 0.1 Gastrointestinal Disorders Nausea 42 0.5 13 0.3 Constipation 17 0.1 8 0 Stomatitis 15 0.1 8 0.1 Vomiting 15 0.5 5 0.3 Dry Mouth 14 0.1 1.3 0 Diarrhea 12 0.8 13 0.3 Abdominal pain 11 0.4 7 0.3 General Disorders and Administration Fatigue 50 1.1 34 0.1 Pyrexia 10 0 4 0 Infections and Infestations Urinary tract infection 10 0.3 6 0.1 Investigations Transaminases increased 32 1.5 8 0.4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 30 0.7 29 0.7 Arthralgia 26 0.1 21 0 Myalgia 15 0.4 11 0 Nervous System Disorders Headache 28 0 17 0.1 Peripheral neuropathy 28 1.6 14 0.1 Dizziness 10 0.1 8 0.3 Psychiatric Disorders Insomnia 14 0 12 0.1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 22 0 3.5 0 Cough 14 0.1 12 0 Vascular Disorders Hemorrhage 29 0.4 Included one fatal hemorrhage. 10 0.3 The following clinically relevant adverse reactions were reported in < 10% of patients in the KADCYLA-treated group in KATHERINE: blood alkaline phosphatase increased (8%), dysgeusia (8%), dyspnea (8%), neutropenia (8%), blood bilirubin increased (7%), hypokalemia (7%), pruritus (7%), hypertension (6%), lacrimation increased (6%), chills (5%), dry eye (4.5%), dyspepsia (4.3%), peripheral edema (3.9%),vision blurred (3.9%), conjunctivitis (3.5%), left ventricular dysfunction (3.0%), drug hypersensitivity (2.7%), infusion-related reaction (1.6%), radiation pneumonitis (1.5%), pneumonitis (1.1%), rash (1.1%), asthenia (0.4%), nodular regenerative hyperplasia (0.3%). Table 6 Selected Laboratory Abnormalities (KATHERINE) Parameter KADCYLA n=740 Trastuzumab n=720 All Grade (%) Grade 3 (%) Grade 4 (%) All Grade (%) Grade 3 (%) Grade 4 (%) Chemistry Increased AST 79 0.8 0 21 0.1 0 Increased ALT 55 0.7 0 21 0.1 0 Decreased potassium 26 2 0.5 9 0.7 0.1 Increased bilirubin 12 0 0 4 0.7 0 Hematology Decreased platelet count 51 4 2 13 0.1 0.1 Decreased hemoglobin 31 1 0 29 0.3 0 Decreased neutrophils 24 1 0 19 0.6 0.6 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of KADCYLA. 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. Adverse Reactions from Observational Studies CHF and > 10% reduction in LVEF in patients with HER2-positive metastatic breast cancer with a baseline LVEF of 40-49% treated with KADCYLA [see Warnings and Precautions (5.2) ] . Adverse Reactions from Postmarketing Spontaneous Reports Tumor lysis syndrome (TLS) Skin/tissue necrosis after extravasation

<table width="75%" ID="Table3"><caption>Table 3 Adverse Reactions Occurring in &#x2265; 10% of Patients on the KADCYLA Treatment Arm in the EMILIA Trial<footnote ID="foot31">Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Abdominal pain: abdominal pain, abdominal pain upper Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Hypokalemia: hypokalemia, blood potassium decreased Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow).</footnote></caption><col width="40%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" align="center" valign="middle">Adverse Reactions</th><th styleCode="Rrule" colspan="2" valign="middle">KADCYLA (3.6 mg/kg) n=490</th><th styleCode="Rrule" colspan="2">Lapatinib (1250 mg) + Capecitabine (2000 mg/m²) n=488</th></tr><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 &#x2013; 4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 &#x2013; 4 (%)</th></tr></thead><tfoot><tr><td colspan="5" align="left">SMQ=standardized MedDRA queries</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Blood and Lymphatic System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">31</td><td styleCode="Rrule">15</td><td styleCode="Rrule">3.3</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">14</td><td styleCode="Rrule">4.1</td><td styleCode="Rrule">11</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">40</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">45</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">27</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">24</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">80</td><td styleCode="Rrule">21</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">30</td><td styleCode="Rrule">4.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry Mouth</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0</td><td styleCode="Rrule">4.9</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Stomatitis</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">33</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">General Disorders and Administration</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">36</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">28</td><td styleCode="Rrule">3.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">18</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Transaminases increased</td><td styleCode="Rrule">29</td><td styleCode="Rrule">8.0</td><td styleCode="Rrule">14</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2.7</td><td styleCode="Rrule">9</td><td styleCode="Rrule">4.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain</td><td styleCode="Rrule">36</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">31</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">3.7</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">28</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Peripheral neuropathy</td><td styleCode="Rrule">21</td><td styleCode="Rrule">2.2</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Respiratory, Thoracic, and Mediastinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">23</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">18</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td><td styleCode="Rrule">28</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Vascular Disorders</content></td></tr><tr><td styleCode="Lrule Rrule">Hemorrhage</td><td styleCode="Rrule">32</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">16</td><td styleCode="Rrule">0.8</td></tr></tbody></table>

<table width="75%" ID="Table4"><caption>Table 4 Selected Laboratory Abnormalities (EMILIA)</caption><col width="28%" align="left" valign="bottom"/><col width="12%" align="center" valign="bottom"/><col width="12%" align="center" valign="bottom"/><col width="12%" align="center" valign="bottom"/><col width="12%" align="center" valign="bottom"/><col width="12%" align="center" valign="bottom"/><col width="12%" align="center" valign="bottom"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" align="center">Parameter</th><th styleCode="Rrule" colspan="3">KADCYLA (3.6 mg/kg)</th><th styleCode="Rrule" colspan="3">Lapatinib (1250 mg) + Capecitabine (2000 mg/m²)</th></tr><tr><th styleCode="Rrule" align="center">All Grades (%)</th><th styleCode="Rrule">Grade 3 (%)</th><th styleCode="Rrule">Grade 4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 (%)</th><th styleCode="Rrule">Grade 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Chemistry</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased AST</td><td styleCode="Rrule">98</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">65</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased ALT</td><td styleCode="Rrule">82</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">54</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased potassium</td><td styleCode="Rrule">33</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td><td styleCode="Rrule">31</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased bilirubin</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">0</td><td styleCode="Rrule">57</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Hematology</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased platelet count</td><td styleCode="Rrule">83</td><td styleCode="Rrule">14</td><td styleCode="Rrule">3</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased hemoglobin</td><td styleCode="Rrule">60</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td><td styleCode="Rrule">64</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.2</td></tr><tr><td styleCode="Lrule Rrule">Decreased neutrophils</td><td styleCode="Rrule">39</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">38</td><td styleCode="Rrule">6</td><td styleCode="Rrule">2</td></tr></tbody></table>

<table width="90%" ID="Table5"><caption>Table 5 Adverse Reactions Occurring in &#x2265; 10% of Patients in the KATHERINE Trial<footnote ID="foot51">Grouped terms were used for the following Adverse Reactions: Thrombocytopenia: thrombocytopenia, platelet count decreased Anemia: anemia, hemoglobin decreased Stomatitis: stomatitis, mucosal inflammation, oropharyngeal pain Abdominal pain: abdominal pain, abdominal pain upper Urinary Tract Infection: urinary tract infection, cystitis Transaminases Increased: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased, liver function test abnormal, hepatic enzyme increased, hepatic function abnormal Musculoskeletal Pain: muscle spasms, musculoskeletal discomfort, musculoskeletal chest pain, back pain, pain in extremity, bone pain, musculoskeletal pain Peripheral neuropathy: neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia Hemorrhage: Hemorrhage terms (excl laboratory terms) (SMQ, wide), Hemorrhage laboratory terms (SMQ, narrow) </footnote></caption><col width="40%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" align="center" valign="middle">Adverse Reactions</th><th styleCode="Rrule" colspan="2">KADCYLA n=740</th><th styleCode="Rrule" colspan="2">Trastuzumab n=720</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">All grades (%)</th><th styleCode="Rrule">Grade 3 &#x2013; 4 (%)</th><th styleCode="Rrule">All grades (%)</th><th styleCode="Rrule">Grade 3 &#x2013; 4 (%)</th></tr></thead><tfoot><tr><td colspan="5" align="left">SMQ=standardized MedDRA queries</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Blood and Lymphatic System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">29</td><td styleCode="Rrule">6</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">42</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.1</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Stomatitis</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0.1</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry Mouth</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.1</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">General Disorders and Administration</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">50</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">34</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Infections and Infestations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.3</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Investigations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Transaminases increased</td><td styleCode="Rrule">32</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain</td><td styleCode="Rrule">30</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">29</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">26</td><td styleCode="Rrule">0.1</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">28</td><td styleCode="Rrule">0</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Peripheral neuropathy</td><td styleCode="Rrule">28</td><td styleCode="Rrule">1.6</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.1</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Respiratory, Thoracic, and Mediastinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">22</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.1</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Vascular Disorders</content></td></tr><tr><td styleCode="Lrule Rrule">Hemorrhage</td><td styleCode="Rrule">29</td><td styleCode="Rrule">0.4<footnote ID="foot52">Included one fatal hemorrhage.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.3</td></tr></tbody></table>