ZALTRAP

5 WARNINGS AND PRECAUTIONS Hemorrhage : Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in patients who have received ZALTRAP. Do not administer ZALTRAP to patients with severe hemorrhage. ( 5.1 ) Gastrointestinal Perforation : Discontinue ZALTRAP therapy in patients who experience GI perforation. ( 5.2 ) Impaired Wound Healing : Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer for at least 4 weeks following major surgery and until wounds have adequately healed. Discontinue ZALTRAP in patients with impaired wound healing. The safety of resumption of ZALTRAP after resolution of wound healing complications has not been established. ( 5.3 ) Fistula Formation : Discontinue ZALTRAP if fistula occurs. ( 2.2 , 5.4 ) Hypertension : Monitor blood pressure and treat hypertension. Temporarily suspend ZALTRAP if hypertension is not controlled. Discontinue ZALTRAP if hypertensive crisis develops. ( 2.2 , 5.5 ) Arterial Thromboembolic Events (ATE) : Discontinue ZALTRAP if ATE develops. ( 5.6 ) Proteinuria : Monitor urine protein. Suspend ZALTRAP for proteinuria of 2 grams per 24 hours or more. Discontinue ZALTRAP if nephrotic syndrome or thrombotic microangiopathy (TMA) develops. ( 2.2 , 5.7 ) Neutropenia and Neutropenic Complications : Delay administration of ZALTRAP/FOLFIRI until neutrophil count is 1.5 × 10 9 /L or higher. ( 5.8 ) Diarrhea and Dehydration : Incidence of severe diarrhea and dehydration is increased. Monitor elderly patients more closely. ( 5.9 , 8.5 ) Reversible Posterior Leukoencephalopathy Syndrome : Discontinue ZALTRAP. ( 5.10 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. ( 5.11 , 8.1 , 8.3 ) 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) was reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2) ] . 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo. Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2) ] . 5.3 Impaired Wound Healing Grade 3 impaired wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen. Withhold ZALTRAP for at least 4 weeks prior to elective surgery. Do not administer ZALTRAP for at least 4 weeks after major surgery and until wounds have adequately healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with impaired wound healing. The safety of resumption of ZALTRAP after resolution of wound healing complications has not been established [see Dosage and Administration (2.2) ] . 5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 patient treated with placebo (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2) ] . 5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing antihypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment. Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate antihypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled and permanently reduce the ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2) ] . 5.6 Arterial Thromboembolic Events ATE, including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2) ] . 5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC, proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1) ] . Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Patients with a dipstick of ≥2+ for protein or a UPCR greater than 1 should undergo a 24-hour urine collection. Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2) ] . 5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1) ] . Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 10 9 /L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1) ] . The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Use in Specific Populations (8.5) ] . Monitor elderly patients closely for diarrhea. 5.10 Reversible Posterior Leukoencephalopathy Syndrome RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm the diagnosis of RPLS with magnetic resonance imaging (MRI) and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2) ] . 5.11 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women. Administration of ziv-aflibercept during the period of organogenesis was embryotoxic and teratogenic in rabbits at exposure levels approximately 0.3 times the human exposure at the 4 mg per kg dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZALTRAP and for 3 months following the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions (5.1) ] Gastrointestinal Perforation [see Warnings and Precautions (5.2) ] Impaired Wound Healing [see Warnings and Precautions (5.3) ] Fistula Formation [see Warnings and Precautions (5.4) ] Hypertension [see Warnings and Precautions (5.5) ] Arterial Thromboembolic Events [see Warnings and Precautions (5.6) ] Proteinuria [see Warnings and Precautions (5.7) ] Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8) ] Diarrhea and Dehydration [see Warnings and Precautions (5.9) ] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10) ] Most common adverse reactions (≥20% incidence) were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 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 safety of ZALTRAP in combination with FOLFIRI was evaluated in VELOUR (EFC102621) [see Clinical Studies (14) ]. Patients received ZALTRAP 4 mg per kg (N=611) or placebo (N=605) intravenously every two weeks (one cycle) in combination with FOLFIRI. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI. The most common Grade 3–4 adverse reactions (≥5%) in the ZALTRAP/FOLFIRI arm were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia. The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria. The ZALTRAP dose was reduced and/or omitted in 17% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI. The most common adverse reactions (≥20%) in the ZALTRAP/FOLFIRI arm were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache. Adverse reactions and laboratory abnormalities that occurred in ≥5% (all grades) of patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients who received ZALTRAP/FOLFIRI compared to those who received placebo/FOLFIRI in VELOUR are shown in Table 1. VELOUR was not designed to demonstrate a statistically significant difference in adverse reaction rates for ZALTRAP/FOLFIRI as compared to placebo/FOLFIRI for any adverse reactions listed below. Table 1: Selected Adverse Reactions and Laboratory Findings in VELOUR Primary System Organ Class Preferred Term ZALTRAP/ FOLFIRI (N=611) Placebo/ FOLFIRI (N=605) All grades (%) Grades 3–4 (%) All grades (%) Grades 3–4 (%) Note: Adverse Reactions are reported using MedDRA version 13.1 and graded using NCI CTC version 3.0 Blood and lymphatic system disorders Leukopenia 78 16 72 12 Neutropenia 67 37 57 30 Thrombocytopenia 48 3 35 2 Gastrointestinal disorders Diarrhea 69 19 57 8 Stomatitis 50 13 33 5 Abdominal Pain 27 4 24 2 Abdominal Pain Upper 11 1 8 1 Hemorrhoids 6 0 2 0 Rectal Hemorrhage 5 0.7 2 0.5 Proctalgia 5 0.3 2 0.3 Investigations AST increased 62 3 54 2 ALT increased 50 3 39 2 Weight decreased 32 3 14 0.8 Renal and urinary disorders Proteinuria Compilation of clinical and laboratory data 62 8 41 1 Serum creatinine increased 23 0 19 0.5 General disorders and administration site conditions Fatigue 48 13 39 8 Asthenia 18 5 13 3 Vascular disorders Hypertension 41 19 11 1.5 Metabolism and nutrition disorders Decreased Appetite 32 3 24 2 Dehydration 9 4 3 1 Respiratory, thoracic and mediastinal disorders Epistaxis 28 0.2 7 0 Dysphonia 25 0.5 3 0 Dyspnea 12 0.8 9 0.8 Oropharyngeal Pain 8 0.2 3 0 Rhinorrhea 6 0 2 0 Nervous system disorders Headache 22 2 9 0.3 Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysesthesia Syndrome 11 3 4 0.5 Skin Hyperpigmentation 8 0 3 0 Infections Urinary Tract Infection 9 0.8 6 0.8 Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for antiproduct antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZALTRAP. 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. Musculoskeletal and connective tissue disorders : Osteonecrosis of the jaw Cardiac disorders : Cardiac failure, ejection fraction decreased Vascular disorders : Arterial (including aortic) aneurysms, dissections, and rupture

<table width="100%"><caption>Table 1: Selected Adverse Reactions and Laboratory Findings in VELOUR</caption><col width="40%" align="left" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Primary System Organ Class Preferred Term</th><th styleCode="Rrule" colspan="2">ZALTRAP/ FOLFIRI (N=611)</th><th styleCode="Rrule" colspan="2">Placebo/ FOLFIRI (N=605)</th></tr><tr><th styleCode="Rrule" align="center">All grades (%)</th><th styleCode="Rrule">Grades 3&#x2013;4 (%)</th><th styleCode="Rrule">All grades (%)</th><th styleCode="Rrule">Grades 3&#x2013;4 (%)</th></tr></thead><tfoot><tr><td colspan="5">Note: Adverse Reactions are reported using MedDRA version 13.1 and graded using NCI CTC version 3.0</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"> Leukopenia</td><td styleCode="Rrule">78</td><td styleCode="Rrule">16</td><td styleCode="Rrule">72</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">67</td><td styleCode="Rrule">37</td><td styleCode="Rrule">57</td><td styleCode="Rrule">30</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Thrombocytopenia</td><td styleCode="Rrule">48</td><td styleCode="Rrule">3</td><td styleCode="Rrule">35</td><td styleCode="Rrule">2</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"> Diarrhea</td><td styleCode="Rrule">69</td><td styleCode="Rrule">19</td><td styleCode="Rrule">57</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Stomatitis</td><td styleCode="Rrule">50</td><td styleCode="Rrule">13</td><td styleCode="Rrule">33</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal Pain</td><td styleCode="Rrule">27</td><td styleCode="Rrule">4</td><td styleCode="Rrule">24</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal Pain Upper</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1</td><td styleCode="Rrule">8</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hemorrhoids</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rectal Hemorrhage</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Proctalgia</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0.3</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0.3</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"> AST increased</td><td styleCode="Rrule">62</td><td styleCode="Rrule">3</td><td styleCode="Rrule">54</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> ALT increased</td><td styleCode="Rrule">50</td><td styleCode="Rrule">3</td><td styleCode="Rrule">39</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Weight decreased</td><td styleCode="Rrule">32</td><td styleCode="Rrule">3</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Renal and urinary disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Proteinuria<footnote>Compilation of clinical and laboratory data</footnote></td><td styleCode="Rrule">62</td><td styleCode="Rrule">8</td><td styleCode="Rrule">41</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Serum creatinine increased</td><td styleCode="Rrule">23</td><td styleCode="Rrule">0</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">48</td><td styleCode="Rrule">13</td><td styleCode="Rrule">39</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">18</td><td styleCode="Rrule">5</td><td styleCode="Rrule">13</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Vascular disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertension</td><td styleCode="Rrule">41</td><td styleCode="Rrule">19</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.5</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"> Decreased Appetite</td><td styleCode="Rrule">32</td><td styleCode="Rrule">3</td><td styleCode="Rrule">24</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dehydration</td><td styleCode="Rrule">9</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3</td><td styleCode="Rrule">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">28</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysphonia</td><td styleCode="Rrule">25</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</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">9</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Oropharyngeal Pain</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0.2</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rhinorrhea</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</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">22</td><td styleCode="Rrule">2</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.3</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"> Palmar-Plantar Erythrodysesthesia Syndrome</td><td styleCode="Rrule">11</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Skin Hyperpigmentation</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Infections</content></td></tr><tr><td styleCode="Lrule Rrule"> Urinary Tract Infection</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0.8</td></tr></tbody></table>