PACLITAXEL PROTEIN BOUND PARTICLES ALBUMIN BOUND

WARNING: SEVERE MYELOSUPPRESSION Do not administer Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm 3 [see Contraindications ( 4 )]. Monitor for neutropenia, which may be severe and result in infection or sepsis [see Warnings and Precautions ( 5.1 , 5.3 )]. Perform frequent complete blood cell counts on all patients receiving Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.3 )]. WARNING: SEVERE MYELOSUPPRESSION See full prescribing information for complete boxed warning. Do not administer Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) therapy to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 . ( 4 ) Monitor for neutropenia, which may be severe and result in infection or sepsis. ( 5.1 , 5.3 ) Perform frequent complete blood cell counts on all patients receiving Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound). ( 5.1 , 5.3 )

5 WARNINGS AND PRECAUTIONS Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. ( 5.2 ) Sepsis occurred in patients with or without neutropenia who received protein bound paclitaxel in combination with gemcitabine; interrupt Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine until sepsis resolves, and if neutropenia, until neutrophils are at least 1500 cells/mm 3 , then resume treatment at reduced dose levels. ( 5.3 ) Pneumonitis occurred with the use of protein bound paclitaxel in combination with gemcitabine; permanently discontinue treatment with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine. ( 5.4 ) Severe hypersensitivity reactions with fatal outcome have been reported. Do not rechallenge with this drug. ( 4 , 5.5 ) Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, consider dose reduction and closely monitor patients with hepatic impairment. ( 2.5 , 5.6 ) Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) contains albumin derived from human blood, which has a theoretical risk of viral transmission. ( 5.7 ) Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 ) 5.1 Severe Myelosuppression Severe myelosuppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of protein bound paclitaxel. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for severe neutropenia and thrombocytopenia by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm 3 [see Contraindications ( 4 )] . In the case of severe neutropenia (<500 cells/mm 3 for seven days or more) during a course of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) therapy, reduce the dose of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) after ANC recovers to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm 3 and platelet count of at least 100,000 cells/mm 3 on Day 1 or to an ANC of at least 500 cells/mm 3 and platelet count of at least 50,000 cells/mm 3 on Days 8 or 15 of the cycle [see Dosage and Administration ( 2.6 )]. In patients with adenocarcinoma of the pancreas, withhold Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine if the ANC is less than 500 cells/mm 3 or platelets are less than 50,000 cells/mm 3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm 3 or platelet count is less than 100,000 cells/mm 3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration ( 2.6 )]. 5.2 Severe Neuropathy Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions ( 6.1 )] . If ≥ Grade 3 sensory neuropathy develops, withhold Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) [see Dosage and Administration ( 2.6 )] . 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received protein bound paclitaxel in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration ( 2.6 )] . 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving protein bound paclitaxel in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and gemcitabine. 5.5 Severe Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Do not rechallenge patients who experience a severe hypersensitivity reaction to Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) with this drug [see Contraindications ( 4 )] . Cross-hypersensitivity between protein bound paclitaxel and other taxane products has been reported and may include severe reactions such as anaphylaxis. Closely monitor patients with a previous history of hypersensitivity to other taxanes during initiation of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) therapy. 5.6 Use in Patients with Hepatic Impairment The exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment. Closely monitor patients with hepatic impairment for severe myelosuppression Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN). Reduce the starting dose for patients with moderate or severe hepatic impairment [see Dosage and Administration ( 2.5 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] . 5.7 Albumin (Human) Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Embryo-Fetal Toxicity Based on mechanism of action and findings in animals, Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of protein bound paclitaxel to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and for at least six months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ), Clinical Pharmacology ( 12.1 )]. Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) and for at least three months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ), Nonclinical Toxicology ( 13.1 )].

6 ADVERSE REACTIONS 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 most common adverse reactions (≥ 20%) with single-agent use of protein bound paclitaxel in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions ( 6.1 )] . The most common adverse reactions (≥ 20%) of protein bound paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions ( 6.1 )]. The most common serious adverse reactions of protein bound paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of protein bound paclitaxel are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of protein bound paclitaxel are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in protein bound paclitaxel dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of protein bound paclitaxel in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies ( 14.3 )] , the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of protein bound paclitaxel are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration [see Adverse Reactions ( 6.1 )] . The most common serious adverse reactions of protein bound paclitaxel (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of protein bound paclitaxel are peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of protein bound paclitaxel are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in protein bound paclitaxel dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%). The most common adverse reactions (≥ 20%) in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea. ( 6.1 ) The most common adverse reactions (≥ 20%) in NSCLC are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue. ( 6.1 ) The most common (≥ 20%) adverse reactions of protein bound paclitaxel in adenocarcinoma of the pancreas are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-888-532-7998 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Metastatic Breast Cancer Table 6 shows the frequency of important adverse reactions in the randomized comparative trial for the patients who received either single-agent protein bound paclitaxel or paclitaxel injection for the treatment of metastatic breast cancer. Table 6: Adverse Reactions in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients Protein-Bound Paclitaxel 260 mg/m 2 over 30 min (n=229) Paclitaxel Injection 175 mg/m 2 over 3 h a (n=225) a Paclitaxel injection patients received premedication. b Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. c Severe events are defined as at least Grade 3 toxicity. Bone Marrow Neutropenia < 2.0 x 10 9 /L < 0.5 x 10 9 /L 80 9 82 22 Thrombocytopenia < 100 x 10 9 /L < 50 x 10 9 /L 2 <1 3 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reaction b All 4 12 Severe c 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Events c 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptoms c 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptoms c 8 4 Asthenia Any Symptoms 47 39 Severe Symptoms c 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptoms c 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptoms c 3 <1 Vomiting Any Symptoms 18 10 Severe Symptoms c 4 1 Diarrhea Any Symptoms 27 15 Severe Symptoms c <1 1 Mucositis Any Symptoms 7 6 Severe Symptoms c <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 Other Adverse Reactions Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm 3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m 2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m 2 . Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with protein bound paclitaxel. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of protein bound paclitaxel administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of Paclitaxel Protein-Bound Particles for Injectable Suspension (Albumin-Bound) in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent protein bound paclitaxel occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with protein bound paclitaxel. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of protein bound paclitaxel discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with protein bound paclitaxel developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of protein bound paclitaxel and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with protein bound paclitaxel and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m 2 ). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after protein bound paclitaxel administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with protein bound paclitaxel and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 protein bound paclitaxel/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. Protein bound paclitaxel was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m 2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m 2 , following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of protein bound paclitaxel/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in protein bound paclitaxel plus carboplatin- treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the protein bound paclitaxel plus carboplatin treatment group). Table 7 provides the frequency and severity of laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between protein bound paclitaxel plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 7: Selected Hematologic Laboratory-Detected Abnormalities with a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups 1 508 patients assessed in protein bound paclitaxel/carboplatin-treated group. 2 514 patients assessed in paclitaxel injection/carboplatin-treated group. 3 513 patients assessed in paclitaxel injection/carboplatin-treated group. Protein Bound Paclitaxel (100 mg/m 2 weekly) plus carboplatin Paclitaxel Injection (200 mg/m 2 every 3 weeks) plus carboplatin Grades 1-4 (%) Grade 3-4 (%) Grades 1-4 (%) Grade 3-4 (%) Anemia 1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia 1,3 68 18 55 9 Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 protein bound paclitaxel plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin. Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). System Organ Class Adverse Reaction Protein Bound Paclitaxel (100 mg/m 2 weekly) + carboplatin (N=514) Paclitaxel Injection (200 mg/m 2 every 3 weeks) + carboplatin (N=524) Grade 1-4 Toxicity (%) Grade 3-4 Toxicity (%) Grades 1-4 Toxicity (%) Grade 3-4 Toxicity (%) Nervous system disorders Peripheral neuropathy a 48 3 64 12 General disorders and administration site conditions Edema peripheral 10 0 4 <1 Respiratory thoracic and mediastinal disorders Epistaxis 7 0 2 0 Musculoskeletal and connective Arthralgia 13 <1 25 2 tissue disorders Myalgia 10 <1 19 2 For the protein bound paclitaxel plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of protein bound paclitaxel. Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received protein bound paclitaxel plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the protein bound paclitaxel/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the protein bound paclitaxel /gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of protein bound paclitaxel was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1- 4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in protein bound paclitaxel plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the Protein Bound Paclitaxel/Gemcitabine Arm a 405 patients assessed in protein bound paclitaxel/gemcitabine-treated group. b 388 patients assessed in gemcitabine-treated group. c 404 patients assessed in protein bound paclitaxel/gemcitabine-treated group. d Neutrophil growth factors were administered to 26% of patients in the protein bound paclitaxel /gemcitabine group. Protein Bound Paclitaxel (125 mg/m 2 )/ Gemcitabine d Gemcitabine Grades 1-4 (%) Grade 3-4 (%) Grades 1-4 (%) Grade 3-4 (%) Neutropenia a,b 73 38 58 27 Thrombocytopenia b,c 74 13 70 9 Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the protein bound paclitaxel plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the Protein Bound Paclitaxel/Gemcitabine Arm System Organ Class Adverse Reaction Protein Bound Paclitaxel (125 mg/m 2 ) and gemcitabine (N=421) Gemcitabine (N=402) All Grades Grade 3 or Higher All Grades Grade 3 or Higher a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococcal. General disorders and administration site conditions Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) Peripheral edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) Gastrointestinal disorders Nausea 228 (54%) 27 (6%) 192 (48%) 14 (3%) Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Skin and subcutaneous tissue disorders Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathy a 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition disorders Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and mediastinal disorders Cough 72 (17%) 0 30 (7%) 0 Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infections b 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and connective tissue disorders Pain in extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received protein bound paclitaxel/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received protein bound paclitaxel/gemcitabine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the protein bound paclitaxel arm was 140 days. Upon suspension of protein bound paclitaxel dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of protein bound paclitaxel -treated patients with Grade 3 peripheral neuropathy, 44% resumed protein bound paclitaxel at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received protein bound paclitaxel/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received protein bound paclitaxel/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the protein bound paclitaxel arm with pneumonitis died. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of protein bound paclitaxel or with paclitaxel injection and may be expected to occur with protein bound paclitaxel. 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. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions. Cross-hypersensitivity between protein bound and other taxanes has been reported. Cardiovascular Congestive heart failure, left ventricular dysfunction, and atrioventricular block. Most patients were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory Pneumonitis, interstitial pneumonia, and pulmonary embolism . Radiation pneumonitis in patients receiving concurrent radiotherapy. Lung fibrosis has been reported with paclitaxel injection. Neurologic Cranial nerve palsies and vocal cord paresis, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reduced visual acuity due to cystoid macular edema (CME). After cessation of treatment, CME may improve, and visual acuity may return to baseline. Abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. Hepatic Hepatic necrosis and hepatic encephalopathy leading to death in patients treated with paclitaxel injection. Gastrointestinal (GI) Intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis. In patients treated with paclitaxel injection, neutropenic enterocolitis (typhlitis) despite the coadministration of G-CSF, alone and in combination with other chemotherapeutic agents. Injection Site Reaction Extravasation. Closely monitor the protein bound paclitaxel infusion site for possible infiltration during drug administration [see Dosage and Administration 2.1 )] . Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported with paclitaxel injection. In some cases, the onset of the injection site reaction occurred during a prolonged infusion or was delayed up to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site has been reported. Metabolic and Nutritional Disorders Tumor lysis syndrome. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus. Photosensitivity reactions, radiation recall phenomenon, scleroderma, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Conjunctivitis, cellulitis, and increased lacrimation have been reported with paclitaxel injection. Accidental Exposure Upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, tingling, burning, and redness have been reported.

<table><caption>Table 6: Adverse Reactions in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule </caption><col/><col/><col/><thead><tr><th valign="top" styleCode=" Botrule Toprule Lrule Rrule" rowspan="2"/><th align="center" valign="top" styleCode=" Botrule Toprule Rrule" colspan="2"><content styleCode="bold">Percent of Patients</content></th></tr><tr><th align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Protein-Bound Paclitaxel 260 mg/m</content><content styleCode="bold">²</content><content styleCode="bold">over 30 min (n=229)</content></th><th align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Paclitaxel Injection 175 mg/m</content><content styleCode="bold">²</content><content styleCode="bold">over 3 h</content><content styleCode="bold">^a</content> <content styleCode="bold">(n=225)</content></th></tr></thead><tfoot><tr><td valign="top" colspan="3"><paragraph>^a Paclitaxel injection patients received premedication. </paragraph></td></tr><tr><td valign="top" colspan="3"><paragraph>^b Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. </paragraph></td></tr><tr><td valign="top" colspan="3"><paragraph>^c Severe events are defined as at least Grade 3 toxicity. </paragraph></td></tr></tfoot><tbody><tr><td styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Bone Marrow</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" rowspan="2" styleCode=" Botrule Lrule Rrule">Neutropenia &lt; 2.0 x 10⁹/L &lt; 0.5 x 10⁹/L </td><td align="center" valign="top" styleCode=" Botrule Rrule"> </td><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td align="center" valign="top" styleCode=" Botrule Rrule">80 9 </td><td align="center" valign="top" styleCode=" Botrule Rrule">82 22 </td></tr><tr><td valign="top" rowspan="2" styleCode=" Botrule Lrule Rrule">Thrombocytopenia &lt; 100 x 10⁹/L &lt; 50 x 10⁹/L </td><td align="center" valign="top" styleCode=" Botrule Rrule"> </td><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td align="center" valign="top" styleCode=" Botrule Rrule">2 &lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">3 &lt;1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">Anemia </td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> &lt; 11 g/dL </td><td align="center" valign="top" styleCode=" Botrule Rrule">33 </td><td align="center" valign="top" styleCode=" Botrule Rrule">25 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> &lt; 8 g/dL </td><td align="center" valign="top" styleCode=" Botrule Rrule">1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Infections </td><td align="center" valign="top" styleCode=" Botrule Rrule">24 </td><td align="center" valign="top" styleCode=" Botrule Rrule">20 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Febrile Neutropenia </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td><td align="center" valign="top" styleCode=" Botrule Rrule">1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Neutropenic Sepsis </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Bleeding </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Hypersensitivity Reaction</content><content styleCode="bold">^b</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> All </td><td align="center" valign="top" styleCode=" Botrule Rrule">4 </td><td align="center" valign="top" styleCode=" Botrule Rrule">12 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">0 </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td></tr><tr><td styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Cardiovascular</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Vital Sign Changes During Administration </td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Bradycardia </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Hypotension </td><td align="center" valign="top" styleCode=" Botrule Rrule">5 </td><td align="center" valign="top" styleCode=" Botrule Rrule">5 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Cardiovascular Events^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">3 </td><td align="center" valign="top" styleCode=" Botrule Rrule">4 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Abnormal ECG</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> All Patients </td><td align="center" valign="top" styleCode=" Botrule Rrule">60 </td><td align="center" valign="top" styleCode=" Botrule Rrule">52 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Patients with Normal Baseline </td><td align="center" valign="top" styleCode=" Botrule Rrule">35 </td><td align="center" valign="top" styleCode=" Botrule Rrule">30 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Respiratory</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Cough </td><td align="center" valign="top" styleCode=" Botrule Rrule">7 </td><td align="center" valign="top" styleCode=" Botrule Rrule">6 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Dyspnea </td><td align="center" valign="top" styleCode=" Botrule Rrule">12 </td><td align="center" valign="top" styleCode=" Botrule Rrule">9 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Sensory Neuropathy</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">71 </td><td align="center" valign="top" styleCode=" Botrule Rrule">56 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">10 </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Myalgia / Arthralgia</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">44 </td><td align="center" valign="top" styleCode=" Botrule Rrule">49 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">8 </td><td align="center" valign="top" styleCode=" Botrule Rrule">4 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Asthenia</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">47 </td><td align="center" valign="top" styleCode=" Botrule Rrule">39 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">8 </td><td align="center" valign="top" styleCode=" Botrule Rrule">3 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Fluid Retention/Edema</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">10 </td><td align="center" valign="top" styleCode=" Botrule Rrule">8 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">0 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Nausea </td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">30 </td><td align="center" valign="top" styleCode=" Botrule Rrule">22 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">3 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Vomiting </td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">18 </td><td align="center" valign="top" styleCode=" Botrule Rrule">10 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">4 </td><td align="center" valign="top" styleCode=" Botrule Rrule">1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Diarrhea </td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">27 </td><td align="center" valign="top" styleCode=" Botrule Rrule">15 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Mucositis </td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Any Symptoms </td><td align="center" valign="top" styleCode=" Botrule Rrule">7 </td><td align="center" valign="top" styleCode=" Botrule Rrule">6 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Severe Symptoms^c</td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">0 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Alopecia</content></td><td align="center" valign="top" styleCode=" Botrule Rrule">90 </td><td align="center" valign="top" styleCode=" Botrule Rrule">94 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Hepatic</content> (Patients with Normal Baseline) </td><td align="center" valign="top" styleCode=" Botrule Rrule"/><td align="center" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Bilirubin Elevations </td><td align="center" valign="top" styleCode=" Botrule Rrule">7 </td><td align="center" valign="top" styleCode=" Botrule Rrule">7 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> Alkaline Phosphatase Elevations </td><td align="center" valign="top" styleCode=" Botrule Rrule">36 </td><td align="center" valign="top" styleCode=" Botrule Rrule">31 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"> AST (SGOT) Elevations </td><td align="center" valign="top" styleCode=" Botrule Rrule">39 </td><td align="center" valign="top" styleCode=" Botrule Rrule">32 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule"><content styleCode="bold">Injection Site Reaction</content></td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">1 </td></tr></tbody></table>

<table><caption>Table 7: Selected Hematologic Laboratory-Detected Abnormalities with a Difference of &#x2265; 5% for grades (1-4) or &#x2265; 2% for Grade 3-4 Toxicity Between Treatment Groups </caption><col/><col/><col/><col/><col/><tfoot><tr><td valign="top" colspan="5"><paragraph>¹ 508 patients assessed in protein bound paclitaxel/carboplatin-treated group. </paragraph></td></tr><tr><td valign="top" colspan="5"><paragraph>² 514 patients assessed in paclitaxel injection/carboplatin-treated group. </paragraph></td></tr><tr><td valign="top" colspan="5"><paragraph>³ 513 patients assessed in paclitaxel injection/carboplatin-treated group. </paragraph></td></tr></tfoot><tbody><tr><td valign="top" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"/><td align="center" valign="top" colspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Protein Bound Paclitaxel (100 mg/m</content><content styleCode="bold">²</content><content styleCode="bold">weekly) plus carboplatin</content></td><td align="center" colspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Paclitaxel Injection (200 mg/m</content><content styleCode="bold">²</content><content styleCode="bold">every 3 weeks) plus carboplatin</content></td></tr><tr><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grades 1-4 (%)</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grade 3-4 (%)</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grades 1-4 (%)</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grade 3-4 (%)</content></td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">Anemia^1,2</td><td align="center" valign="top" styleCode=" Botrule Rrule">98 </td><td align="center" valign="top" styleCode=" Botrule Rrule">28 </td><td align="center" valign="top" styleCode=" Botrule Rrule">91 </td><td align="center" valign="top" styleCode=" Botrule Rrule">7 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">Neutropenia^1,3</td><td align="center" valign="top" styleCode=" Botrule Rrule">85 </td><td align="center" valign="top" styleCode=" Botrule Rrule">47 </td><td align="center" valign="top" styleCode=" Botrule Rrule">83 </td><td align="center" valign="top" styleCode=" Botrule Rrule">58 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">Thrombocytopenia^1,3</td><td align="center" valign="top" styleCode=" Botrule Rrule">68 </td><td align="center" valign="top" styleCode=" Botrule Rrule">18 </td><td align="center" valign="top" styleCode=" Botrule Rrule">55 </td><td align="center" valign="top" styleCode=" Botrule Rrule">9 </td></tr></tbody></table>

<table><caption>Table 8: Selected Adverse Reactions with a Difference of &#x2265;5% for All Grade Toxicity or &#x2265;2% for Grade 3-4 Toxicity Between Treatment Groups </caption><col/><col/><col/><col/><col/><col/><tfoot><tr><td valign="top" colspan="6"><paragraph>^a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). </paragraph></td></tr></tfoot><tbody><tr><td valign="bottom" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">System Organ Class</content></td><td valign="bottom" rowspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Adverse Reaction</content> </td><td align="center" valign="top" colspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Protein Bound Paclitaxel (100 mg/m</content><content styleCode="bold">²</content><content styleCode="bold">weekly)</content> <content styleCode="bold">+ carboplatin (N=514)</content></td><td align="center" colspan="2" styleCode=" Botrule Toprule Rrule"><content styleCode="bold">Paclitaxel Injection (200 mg/m</content><content styleCode="bold">²</content><content styleCode="bold">every 3 weeks) + carboplatin (N=524)</content></td></tr><tr><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grade 1-4 Toxicity</content> <content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grade 3-4 Toxicity</content> <content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grades 1-4 Toxicity</content> <content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode=" Botrule Rrule"><content styleCode="bold">Grade 3-4 Toxicity</content> <content styleCode="bold">(%)</content></td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">Nervous system disorders </td><td valign="top" styleCode=" Botrule Rrule">Peripheral neuropathy<content styleCode="bold">^a</content></td><td align="center" valign="top" styleCode=" Botrule Rrule">48 </td><td align="center" valign="top" styleCode=" Botrule Rrule">3 </td><td align="center" valign="top" styleCode=" Botrule Rrule">64 </td><td align="center" valign="top" styleCode=" Botrule Rrule">12 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">General disorders and administration site conditions </td><td valign="top" styleCode=" Botrule Rrule">Edema peripheral </td><td align="center" valign="top" styleCode=" Botrule Rrule">10 </td><td align="center" valign="top" styleCode=" Botrule Rrule">0 </td><td align="center" valign="top" styleCode=" Botrule Rrule">4 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">Respiratory thoracic and mediastinal disorders </td><td valign="top" styleCode=" Botrule Rrule">Epistaxis </td><td align="center" valign="top" styleCode=" Botrule Rrule">7 </td><td align="center" valign="top" styleCode=" Botrule Rrule">0 </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td><td align="center" valign="top" styleCode=" Botrule Rrule">0 </td></tr><tr><td valign="top" styleCode=" Lrule Rrule">Musculoskeletal and connective </td><td valign="top" styleCode=" Botrule Rrule">Arthralgia </td><td align="center" valign="top" styleCode=" Botrule Rrule">13 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">25 </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td></tr><tr><td valign="top" styleCode=" Botrule Lrule Rrule">tissue disorders </td><td valign="top" styleCode=" Botrule Rrule">Myalgia </td><td align="center" valign="top" styleCode=" Botrule Rrule">10 </td><td align="center" valign="top" styleCode=" Botrule Rrule">&lt;1 </td><td align="center" valign="top" styleCode=" Botrule Rrule">19 </td><td align="center" valign="top" styleCode=" Botrule Rrule">2 </td></tr></tbody></table>