IXEMPRA

WARNING: TOXICITY IN PATIENTS WITH HEPATIC IMPAIRMENT IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )]. WARNING: TOXICITY IN PATIENTS WITH HEPATIC IMPAIRMENT See full prescribing information for complete boxed warning. IXEMPRA ® in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity and neutropenia-related death. ( 4 , 5.3 )

5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Monitor for symptoms of neuropathy (sensory and motor neuropathy).) Withhold, reduce, or discontinue IXEMPRA depending on severity. ( 2.3 , 5.1 ). Myelosuppression: Neutropenia, febrile neutropenia, and infections have occurred. Monitor blood cell counts before and during treatment with IXEMPRA. Withhold, reduce, or discontinue IXEMPRA depending on severity ( 2.3 , 5.2 ). Increased Toxicity in Patients with Hepatic Impairment: Grade 4 neutropenia, febrile neutropenia, and serious adverse reactions may occur in patients with hepatic impairment during treatment with IXEMPRA. Reduce dose depending on severity. ( 2.3 , 5.3 , 6.1 ). Hypersensitivity Reactions: Severe hypersensitivity reactions (including anaphylaxis) have occurred. Premedicate all patients before treatment with IXEMPRA. Withhold, reduce, or discontinue IXEMPRA depending on severity ( 2.1 , 2.3 , 5.4 ). Cardiac Adverse Reactions: Myocardial ischemia and ventricular dysfunction have occurred. Closely monitor patients with a history of cardiac disease during treatment with IXEMPRA. Consider discontinuation of IXEMPRA in patients who develop cardiac ischemia or impaired cardiac function ( 2.3 , 5.5 ). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception ( 5.6 , 8.1 , 8.3) Alcohol Content: The alcohol content in a dose of IXEMPRA may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. ( 5.7 ). 5.2 Myelosuppression Severe, life-threatening, or fatal myelosuppression can occur in patients treated with IXEMPRA. Myelosuppression is dose-dependent and primarily manifests as neutropenia. In clinical studies, grade 4 neutropenia (<500 cells/mm 3 ) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with single agent IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as a single agent, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN [see Boxed Warning, Contraindications ( 4 ), and Warnings and Precautions ( 5.3 )] . Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as a single agent. No neutropenia-related deaths were reported in 24 patients with AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN treated with IXEMPRA as a single agent. IXEMPRA is contraindicated for use in patients with a neutrophil count of <1500 cells/mm 3 . [see Contraindications ( 4 )] . Monitor patients receiving IXEMPRA for myelosuppression with frequent peripheral blood cell counts. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of myelosuppression [see Dosage and Administration ( 2.3 )] . 5.1 Peripheral Neuropathy Peripheral neuropathy (sensory and motor neuropathy) occurred in patients treated with IXEMPRA in combination with capecitabine and in patients treated with single agent IXEMPRA as shown in Table (see Table 3 ). Table 3: Peripheral Neuropathy a Sensory and motor neuropathy combined. b 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1). IXEMPRA IXEMPRA as with capecitabine Single Agent Study 046 Study 081 Peripheral neuropathy (all grades) a,b 67% 63% Peripheral neuropathy (grades 3/4) a,b 23% 14% Discontinuation due to neuropathy 21% 6% Median number of cycles to onset of grade 3/4 neuropathy 4 4 Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1 6.0 weeks 4.6 weeks In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3 or 4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset. A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Monitor patients for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of peripheral neuropathy [ see Dosage and Administration ( 2.3 ) ]. 5.3 Increased Toxicities in Patients with Hepatic Impairment Patients with baseline AST or ALT >2.5 x ULN or bilirubin >1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m 2 in combination with capecitabine or as single agent in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was increased oin patients with hepatic impairment. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN due to increased risk of toxicity- and neutropenia-related death [see Boxed Warning , Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )]. With IXEMPRA single agent therapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reatcitons were increased in patients with hepatic impairment [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 ). Reduce the dose IXEMPRA based in the degree of hepatic impairment. Avoid use in patients with AST or ALT >10 x ULN or bilirubin >3 x ULN [see Dosage and Administration ( 2.4 )] 5.4 Hypersensitivity Reactions IXEMPRA is contraindicated in patients with a history of a severe hypersensitivity reaction to agents containing Cremophor ® EL or its derivatives (eg, polyoxyethylated castor oil) [ see Contraindications ( 4 )] . Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1 %) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H 1 and H 2 antagonists, and extension of the infusion time should be considered [see Dosage and Administration ( 2.3 ) and Contraindications ( 4 )] Administer an H 1 and H 2 antagonist approximately 1 hour before IXEMPRA infusion and observe patients for hypersensitivity reaction occur, stop the infusion of IXEMPRA provide supportive treatment as clinically indicated (e.g.. epinephrine, corticosteriods). 5.5 Cardiac Adverse Reactions Cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) occurred in patients receiving IXEMPRA in combination with capecitabine (1.9%) and as a single agent (0.3%). Supraventricular arrhythmias were observed in the combination arm (0.5%). Closely monitor patients with a history of cardiac disease during treatment with IXEMPRA. Consider discontinuation of IXEMPRA in patients who develop cardiac ischemia or impaired cardiac function [see Dosage and Administration ( 2.3 )]. 5.6 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC. Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )]. 5.7 Alcohol Content The alcohol content in a dose of IXEMPRA may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in IXEMPRA on the ability to drive or use machines immediately after the infusion. Each administration of IXEMPRA at the recommended dosage of 40 mg/m 2 delivers approximately 8.4 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver approximately 16.8 grams of ethanol [see Description ( 11 )].

<table width="100%" ID="t3"><caption>Table 3: Peripheral Neuropathy</caption><colgroup><col align="left" width="70.200%"/><col align="left" width="16.933%"/><col align="left" width="12.867%"/></colgroup><tfoot><tr><td align="left" colspan="3" styleCode="Toprule" valign="top"><paragraph>^a Sensory and motor neuropathy combined. </paragraph></td></tr><tr><td align="left" colspan="3" styleCode="Botrule" valign="top"><paragraph>^b 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1). </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule" valign="bottom"/><td align="left" styleCode="Toprule Botrule" valign="top"/><td align="left" styleCode="Toprule Botrule" valign="top"/></tr><tr><td align="left" valign="top"/><td align="center" valign="top"><content styleCode="bold">IXEMPRA</content></td><td align="center" valign="top"><content styleCode="bold">IXEMPRA as</content></td></tr><tr><td align="left" valign="top"/><td align="center" valign="bottom"><content styleCode="bold">with capecitabine</content></td><td align="center" valign="bottom"><content styleCode="bold">Single Agent</content></td></tr><tr><td align="left" styleCode="Botrule" valign="top"/><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">Study 046</content></td><td align="center" styleCode="Botrule" valign="top"><content styleCode="bold">Study 081</content></td></tr><tr><td align="left" valign="bottom">Peripheral neuropathy (all grades) ^a,b</td><td align="left" valign="bottom">67%</td><td align="left" valign="bottom">63%</td></tr><tr><td align="left" valign="top">Peripheral neuropathy (grades 3/4) ^a,b</td><td align="left" valign="top">23%</td><td align="left" valign="top">14%</td></tr><tr><td align="left" valign="top">Discontinuation due to neuropathy</td><td align="left" valign="top">21%</td><td align="left" valign="top">6%</td></tr><tr><td align="left" valign="top">Median number of cycles to onset of grade 3/4 neuropathy</td><td align="left" valign="top">4</td><td align="left" valign="top">4</td></tr><tr><td align="left" styleCode="Botrule" valign="top">Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1</td><td align="left" styleCode="Botrule" valign="top">6.0 weeks</td><td align="left" styleCode="Botrule" valign="top"><paragraph/><paragraph>4.6 weeks</paragraph></td></tr></tbody></table>

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections. Peripheral neuropathy [see Warnings and Precautions ( 5.1 )] Myelosuppression [see Warnings and Precautions ( 5.2 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] Cardiac Adverse reactions [see Warnings and Precautions ( 5.5) ] The most common adverse reactions (≥20%) are peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. Additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, and constipation ( 6 ). Hematologic laboratory abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact R-Pharm US at 1-844-586-8953 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, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m 2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as a single agent (n=368) in this study received 1250 mg/m twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 40 mg/m 2 administered intravenously over 3 hours every 3 weeks. The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculo­skeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia. Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5. Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5 . b A composite of multiple terms. c Three patients (1 %) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions ( 5.2 )]. d No grade 4 reports. e Peripheral sensory neuropathy was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1 -3 severity scale in Study 046. Study 046 Study 081 IXEMPRA with capecitabine n=369 Capecitabine n=368 IXEMPRA Single Agent n=126 Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Preferred Term (%) (%) (%) (%) (%) (%) Infections and Infestations Upper respiratory tract infection 4 0 3 0 6 0 Blood and Lymphatic System Disorders 1 d 3 d Febrile neutropenia 5 4 c 1 3 Immune System Disorders 1 d Hypersensitivity b 2 1 d 0 0 5 Metabolism and Nutrition Disorders Anorexia b 34 3 d 15 1 d 19 2 d Dehydration b 5 2 2 <1 d 2 1 d Psychiatric Disorders Insomnia b 9 <1 d 2 0 5 0 Nervous System Disorders Peripheral neuropathy Sensory neuropathy b 65 21 16 0 62 14 Motor neuropathy b 16 5 d <1 0 10 1 d Headache 8 <1 d 3 0 11 0 Taste disorder b 12 0 4 0 6 0 Dizziness 8 1 d 5 1 d 7 0 Eye Disorders Lacrimation increased 5 0 4 <1 d 4 0 Vascular Disorders Hot flush b 5 0 2 0 6 0 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea b 7 1 4 1 9 1 d Cough b 6 0 2 0 2 0 Gastrointestinal Disorders Nausea 53 3 d 40 2 d 42 2 d Vomiting b 39 4 d 24 2 29 1 d Stomatitis/mucositis b 31 4 20 3 d 29 6 Diarrhea b 44 6 d 39 9 22 1 d Constipation 22 0 6 <1 d 16 2 d Abdominal pain b 24 2 d 14 1 d 13 2 d Gastroesophageal reflux disease b 7 1 d 8 0 6 0 Skin and Subcutaneous Tissue Disorders Alopecia b 31 0 3 0 48 0 Skin rash b 17 1 d 7 0 9 2 d Nail disorder b 24 2 d 10 <1 d 9 0 Palmar-plantar erythrodysesthesia syndrome b 64 18 d 63 17 d 8 2 d Pruritus 5 0 2 0 6 1 d Skin exfoliation b 5 <1 d 3 0 2 0 Skin hyperpigmentation b 11 0 14 0 2 0 Musculoskeletal, Connective Tissue, and Bone Disorders Myalgia/arthralgia b 39 8 d 5 <1 d 49 8 d Musculoskeletal pain b 23 2 d 5 0 20 3 d General Disorders and Administration Site Conditions Fatigue/asthenia b 60 16 29 4 56 13 Edema b 8 0 5 <1 d 9 1 d Pyrexia 10 1 d 4 0 8 1 d Pain b 9 1 d 2 0 8 3 d Chest pain b 4 1 d <1 0 5 1 d Investigations Weight decreased 11 0 3 0 6 0 Table 5: Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA a G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received IXEMPRA in Study 046 and Study 081, respectively. Study 046 Study 081 IXEMPRA with capecitabine n=369 Capecitabine n=368 IXEMPRA single agent n=126 Hematology Parameter Grade 3 (%) Grade 4 (%) Grade 3 (%) Grade 4 (%) Grade 3 (%) Grade 4 (%) Neutropenia a 32 36 9 2 31 23 Leukopenia (WBC) 41 16 5 1 36 13 Anemia (Hgb) 8 2 4 1 6 2 Thrombocytopenia 5 3 2 2 5 2 The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as single agent or in combination with other therapies in clinical studies. Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection Blood and Lymphatic System Disorders: coagulopathy, lymphopenia Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage Hepatobiliary Disorders: acute hepatic failure, jaundice Skin and Subcutaneous Tissue Disorders: erythema multiforme Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus Renal and Urinary Disorders: nephrolithiasis, renal failure General Disorders and Administration Site Conditions: chills Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase 6.2 Postmarketing Experience The following adverse reaction has been identified during postapproval use of IXEMPRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Procedural Complications: Radiation recall

<table width="100%" ID="t4"><colgroup><col align="left" width="52.800%"/><col align="left" width="12.100%"/><col align="left" width="7.857%"/><col align="left" width="7.257%"/><col align="left" width="7.257%"/><col align="left" width="4.643%"/><col align="left" width="8.086%"/></colgroup><tfoot><tr><td align="left" colspan="7" valign="top"><paragraph>^b A composite of multiple terms. </paragraph></td></tr><tr><td align="left" colspan="7" valign="top"><paragraph>^c Three patients (1 %) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s21">5.2</linkHtml>)]. </content></paragraph></td></tr><tr><td align="left" colspan="7" valign="top"><paragraph>^d No grade 4 reports. </paragraph></td></tr><tr><td align="left" colspan="7" valign="top"><paragraph>^e Peripheral sensory neuropathy was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy. </paragraph></td></tr><tr><td align="left" colspan="7" styleCode="Botrule" valign="top"><paragraph>^fPalmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1 -3 severity scale in Study 046. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule" valign="top"/><td align="left" styleCode="Toprule Botrule" valign="top"/><td align="left" styleCode="Toprule Botrule" valign="top"/><td align="left" styleCode="Toprule Botrule" valign="bottom"><content styleCode="bold">Study 046</content></td><td align="left" styleCode="Toprule Botrule Rrule" valign="top"/><td align="left" colspan="2" styleCode="Toprule Botrule" valign="bottom"><content styleCode="bold">Study 081</content></td></tr><tr><td align="left" styleCode="Botrule" valign="top"/><td align="center" colspan="2" styleCode="Botrule" valign="bottom"><content styleCode="bold">IXEMPRA with capecitabine n=369</content></td><td align="center" colspan="2" styleCode="Botrule" valign="bottom"><content styleCode="bold">Capecitabine</content> <content styleCode="bold">n=368</content></td><td align="center" colspan="2" styleCode="Botrule Lrule" valign="bottom"><content styleCode="bold">IXEMPRA</content> Single Agent <content styleCode="bold">n=126</content></td></tr><tr><td align="left" valign="bottom">Adverse Reaction</td><td align="left" valign="bottom"><content styleCode="bold">All Grades</content></td><td align="left" valign="bottom"><content styleCode="bold">Grade 3/4</content></td><td align="left" valign="bottom"><content styleCode="bold">All Grades</content></td><td align="left" styleCode="Rrule" valign="bottom"><content styleCode="bold">Grade 3/4</content></td><td align="left" valign="bottom"><content styleCode="bold">All Grades</content></td><td align="left" valign="bottom"><content styleCode="bold">Grade 3/4</content></td></tr><tr><td align="left" styleCode="Botrule" valign="middle"><content styleCode="bold">Preferred Term</content></td><td align="left" styleCode="Botrule" valign="middle">(%)</td><td align="left" styleCode="Botrule" valign="middle">(%)</td><td align="left" styleCode="Botrule" valign="middle">(%)</td><td align="left" styleCode="Botrule Rrule" valign="middle">(%)</td><td align="left" styleCode="Botrule" valign="middle">(%)</td><td align="left" styleCode="Botrule" valign="middle">(%)</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Infections and Infestations</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Upper respiratory tract infection</td><td align="left" valign="top">4</td><td align="left" valign="bottom">0</td><td align="left" valign="top">3</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">6</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Blood and Lymphatic System Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" rowspan="2" styleCode="Rrule" valign="bottom">1 ^d</td><td align="left" valign="top"/><td align="left" rowspan="2" valign="bottom">3 ^d</td></tr><tr><td align="left" valign="top">Febrile neutropenia</td><td align="left" valign="top">5</td><td align="left" valign="top">4 ^c</td><td align="left" valign="bottom">1</td><td align="left" valign="top">3</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Immune System Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" rowspan="2" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="top">Hypersensitivity ^b</td><td align="left" valign="bottom">2</td><td align="left" valign="bottom">1 ^d</td><td align="left" valign="bottom">0</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="top">5</td></tr><tr><td align="left" valign="top"><content styleCode="bold"><content styleCode="italics">Metabolism and Nutrition Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="bottom">Anorexia ^b</td><td align="left" valign="bottom">34</td><td align="left" valign="bottom">3 ^d</td><td align="left" valign="bottom">15</td><td align="left" styleCode="Rrule" valign="bottom">1 ^d</td><td align="left" valign="bottom">19</td><td align="left" valign="bottom">2 ^d</td></tr><tr><td align="left" valign="bottom">Dehydration ^b</td><td align="left" valign="middle">5</td><td align="left" valign="bottom">2</td><td align="left" valign="bottom">2</td><td align="left" styleCode="Rrule" valign="middle">&lt;1 ^d</td><td align="left" valign="bottom">2</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Psychiatric Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Insomnia ^b</td><td align="left" valign="top">9</td><td align="left" valign="top">&lt;1 ^d</td><td align="left" valign="bottom">2</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="top">5</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Nervous System Disorders</content></content> Peripheral neuropathy </td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Sensory neuropathy ^b</td><td align="left" valign="top">65</td><td align="left" valign="bottom">21</td><td align="left" valign="bottom">16</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">62</td><td align="left" valign="top">14</td></tr><tr><td align="left" valign="bottom">Motor neuropathy ^b</td><td align="left" valign="bottom">16</td><td align="left" valign="middle">5 ^d</td><td align="left" valign="middle">&lt;1</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">10</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="middle">Headache</td><td align="left" valign="bottom">8</td><td align="left" valign="middle">&lt;1 ^d</td><td align="left" valign="middle">3</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">11</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="middle">Taste disorder ^b</td><td align="left" valign="bottom">12</td><td align="left" valign="bottom">0</td><td align="left" valign="middle">4</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">6</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="bottom">Dizziness</td><td align="left" valign="bottom">8</td><td align="left" valign="bottom">1 ^d</td><td align="left" valign="bottom">5</td><td align="left" styleCode="Rrule" valign="bottom">1 ^d</td><td align="left" valign="bottom">7</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Eye Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Lacrimation increased</td><td align="left" valign="top">5</td><td align="left" valign="bottom">0</td><td align="left" valign="top">4</td><td align="left" styleCode="Rrule" valign="top">&lt;1 ^d</td><td align="left" valign="top">4</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Vascular Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="middle">Hot flush ^b</td><td align="left" valign="middle">5</td><td align="left" valign="bottom">0</td><td align="left" valign="bottom">2</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">6</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="top"><content styleCode="bold"><content styleCode="italics">Respiratory, Thoracic, and Mediastinal Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Dyspnea ^b</td><td align="left" valign="top">7</td><td align="left" valign="bottom">1</td><td align="left" valign="top">4</td><td align="left" styleCode="Rrule" valign="bottom">1</td><td align="left" valign="top">9</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="top">Cough ^b</td><td align="left" valign="bottom">6</td><td align="left" valign="bottom">0</td><td align="left" valign="bottom">2</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">2</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="top"><content styleCode="bold"><content styleCode="italics">Gastrointestinal Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="bottom">Nausea</td><td align="left" valign="bottom">53</td><td align="left" valign="bottom">3 ^d</td><td align="left" valign="bottom">40</td><td align="left" styleCode="Rrule" valign="bottom">2 ^d</td><td align="left" valign="bottom">42</td><td align="left" valign="bottom">2 ^d</td></tr><tr><td align="left" valign="top">Vomiting ^b</td><td align="left" valign="top">39</td><td align="left" valign="top">4 ^d</td><td align="left" valign="top">24</td><td align="left" styleCode="Rrule" valign="bottom">2</td><td align="left" valign="top">29</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="bottom">Stomatitis/mucositis ^b</td><td align="left" valign="bottom">31</td><td align="left" valign="bottom">4</td><td align="left" valign="bottom">20</td><td align="left" styleCode="Rrule" valign="bottom">3 ^d</td><td align="left" valign="bottom">29</td><td align="left" valign="bottom">6</td></tr><tr><td align="left" valign="bottom">Diarrhea ^b</td><td align="left" valign="bottom">44</td><td align="left" valign="bottom">6 ^d</td><td align="left" valign="bottom">39</td><td align="left" styleCode="Rrule" valign="bottom">9</td><td align="left" valign="bottom">22</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="bottom">Constipation</td><td align="left" valign="bottom">22</td><td align="left" valign="bottom">0</td><td align="left" valign="bottom">6</td><td align="left" styleCode="Rrule" valign="bottom">&lt;1 ^d</td><td align="left" valign="bottom">16</td><td align="left" valign="bottom">2 ^d</td></tr><tr><td align="left" valign="top">Abdominal pain ^b</td><td align="left" valign="top">24</td><td align="left" valign="bottom">2 ^d</td><td align="left" valign="top">14</td><td align="left" styleCode="Rrule" valign="bottom">1 ^d</td><td align="left" valign="top">13</td><td align="left" valign="bottom">2 ^d</td></tr><tr><td align="left" valign="bottom">Gastroesophageal reflux disease ^b</td><td align="left" valign="middle">7</td><td align="left" valign="bottom">1 ^d</td><td align="left" valign="bottom">8</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">6</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="top"><content styleCode="bold"><content styleCode="italics">Skin and Subcutaneous Tissue Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Alopecia ^b</td><td align="left" valign="top">31</td><td align="left" valign="bottom">0</td><td align="left" valign="top">3</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="top">48</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="top">Skin rash ^b</td><td align="left" valign="top">17</td><td align="left" valign="bottom">1 ^d</td><td align="left" valign="top">7</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="top">9</td><td align="left" valign="bottom">2 ^d</td></tr><tr><td align="left" valign="bottom">Nail disorder ^b</td><td align="left" valign="bottom">24</td><td align="left" valign="bottom">2 ^d</td><td align="left" valign="bottom">10</td><td align="left" styleCode="Rrule" valign="bottom">&lt;1 ^d</td><td align="left" valign="bottom">9</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="top">Palmar-plantar erythrodysesthesia syndrome ^b</td><td align="left" valign="top">64</td><td align="left" valign="bottom">18 ^d</td><td align="left" valign="top">63</td><td align="left" styleCode="Rrule" valign="top">17 ^d</td><td align="left" valign="bottom">8</td><td align="left" valign="bottom">2 ^d</td></tr><tr><td align="left" valign="middle">Pruritus</td><td align="left" valign="middle">5</td><td align="left" valign="bottom">0</td><td align="left" valign="bottom">2</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">6</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="bottom">Skin exfoliation ^b</td><td align="left" valign="bottom">5</td><td align="left" valign="bottom">&lt;1 ^d</td><td align="left" valign="bottom">3</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">2</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="bottom">Skin hyperpigmentation ^b</td><td align="left" valign="bottom">11</td><td align="left" valign="bottom">0</td><td align="left" valign="top">14</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">2</td><td align="left" valign="bottom">0</td></tr><tr><td align="left" valign="top"><content styleCode="bold"><content styleCode="italics">Musculoskeletal, Connective Tissue, and Bone Disorders</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Myalgia/arthralgia ^b</td><td align="left" valign="top">39</td><td align="left" valign="bottom">8 ^d</td><td align="left" valign="top">5</td><td align="left" styleCode="Rrule" valign="top">&lt;1 ^d</td><td align="left" valign="top">49</td><td align="left" valign="bottom">8 ^d</td></tr><tr><td align="left" valign="top">Musculoskeletal pain ^b</td><td align="left" valign="top">23</td><td align="left" valign="bottom">2 ^d</td><td align="left" valign="top">5</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">20</td><td align="left" valign="top">3 ^d</td></tr><tr><td align="left" valign="top"><content styleCode="bold"><content styleCode="italics">General Disorders and Administration Site Conditions</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" valign="top">Fatigue/asthenia ^b</td><td align="left" valign="bottom">60</td><td align="left" valign="bottom">16</td><td align="left" valign="top">29</td><td align="left" styleCode="Rrule" valign="top">4</td><td align="left" valign="top">56</td><td align="left" valign="top">13</td></tr><tr><td align="left" valign="bottom">Edema ^b</td><td align="left" valign="bottom">8</td><td align="left" valign="bottom">0</td><td align="left" valign="bottom">5</td><td align="left" styleCode="Rrule" valign="bottom">&lt;1 ^d</td><td align="left" valign="bottom">9</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="middle">Pyrexia</td><td align="left" valign="bottom">10</td><td align="left" valign="bottom">1 ^d</td><td align="left" valign="middle">4</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">8</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="top">Pain ^b</td><td align="left" valign="top">9</td><td align="left" valign="bottom">1 ^d</td><td align="left" valign="bottom">2</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">8</td><td align="left" valign="top">3 ^d</td></tr><tr><td align="left" valign="bottom">Chest pain ^b</td><td align="left" valign="bottom">4</td><td align="left" valign="bottom">1 ^d</td><td align="left" valign="bottom">&lt;1</td><td align="left" styleCode="Rrule" valign="bottom">0</td><td align="left" valign="bottom">5</td><td align="left" valign="bottom">1 ^d</td></tr><tr><td align="left" valign="bottom"><content styleCode="bold"><content styleCode="italics">Investigations</content></content></td><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/><td align="left" styleCode="Rrule" valign="top"/><td align="left" valign="top"/><td align="left" valign="top"/></tr><tr><td align="left" styleCode="Botrule" valign="top">Weight decreased</td><td align="left" styleCode="Botrule" valign="bottom">11</td><td align="left" styleCode="Botrule" valign="bottom">0</td><td align="left" styleCode="Botrule" valign="top">3</td><td align="left" styleCode="Botrule Rrule" valign="bottom">0</td><td align="left" styleCode="Botrule" valign="bottom">6</td><td align="left" styleCode="Botrule" valign="bottom">0</td></tr></tbody></table>

<table width="100%" ID="t5"><caption>Table 5: Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA</caption><colgroup><col align="left" width="24.039%"/><col align="left" width="12.670%"/><col align="left" width="12.670%"/><col align="left" width="12.655%"/><col align="left" width="12.655%"/><col align="left" width="12.655%"/><col align="left" width="12.655%"/></colgroup><tfoot><tr><td align="left" colspan="7" styleCode="Toprule Botrule" valign="top"><paragraph>^aG-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received IXEMPRA in Study 046 and Study 081, respectively. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Botrule" valign="top"/><td align="center" colspan="4" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Study 046</content></td><td align="center" colspan="2" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Study 081</content></td></tr><tr><td align="left" styleCode="Botrule" valign="top"/><td align="center" colspan="2" styleCode="Botrule" valign="top"><content styleCode="bold">IXEMPRA with capecitabine n=369 </content></td><td align="center" colspan="2" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Capecitabine n=368 </content></td><td align="center" colspan="2" styleCode="Botrule Lrule" valign="top"><content styleCode="bold">IXEMPRA single agent n=126 </content></td></tr><tr><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Hematology Parameter</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Grade 3 (%)</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Grade 4 (%)</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Grade 3 (%)</content></td><td align="left" styleCode="Botrule Rrule" valign="top"><content styleCode="bold">Grade 4 (%)</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Grade 3 (%)</content></td><td align="left" styleCode="Botrule" valign="top"><content styleCode="bold">Grade 4 (%)</content></td></tr><tr><td align="left" styleCode="Botrule" valign="top">Neutropenia ^a</td><td align="left" styleCode="Botrule" valign="top">32</td><td align="left" styleCode="Botrule" valign="top">36</td><td align="left" styleCode="Botrule" valign="top">9</td><td align="left" styleCode="Botrule Rrule" valign="top">2</td><td align="left" styleCode="Botrule" valign="top">31</td><td align="left" styleCode="Botrule" valign="top">23</td></tr><tr><td align="left" styleCode="Botrule" valign="top">Leukopenia (WBC)</td><td align="left" styleCode="Botrule" valign="top">41</td><td align="left" styleCode="Botrule" valign="top">16</td><td align="left" styleCode="Botrule" valign="top">5</td><td align="left" styleCode="Botrule Rrule" valign="top">1</td><td align="left" styleCode="Botrule" valign="top">36</td><td align="left" styleCode="Botrule" valign="top">13</td></tr><tr><td align="left" styleCode="Botrule" valign="top">Anemia (Hgb)</td><td align="left" styleCode="Botrule" valign="top">8</td><td align="left" styleCode="Botrule" valign="top">2</td><td align="left" styleCode="Botrule" valign="top">4</td><td align="left" styleCode="Botrule Rrule" valign="top">1</td><td align="left" styleCode="Botrule" valign="top">6</td><td align="left" styleCode="Botrule" valign="top">2</td></tr><tr><td align="left" styleCode="Botrule" valign="top">Thrombocytopenia</td><td align="left" styleCode="Botrule" valign="top">5</td><td align="left" styleCode="Botrule" valign="top">3</td><td align="left" styleCode="Botrule" valign="top">2</td><td align="left" styleCode="Botrule Rrule" valign="top">2</td><td align="left" styleCode="Botrule" valign="top">5</td><td align="left" styleCode="Botrule" valign="top">2</td></tr></tbody></table>