1 INDICATIONS AND USAGE Sunitinib malate capsule is a kinase inhibitor indicated for: treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.

( 1.1 ) treatment of adult patients with advanced renal cell carcinoma (RCC).

( 1.2 ) adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.

( 1.3 ) treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.

( 1.4 ) 1.1 Gastrointestinal Stromal Tumor Sunitinib malate capsules are indicated for the treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.

1.2 Advanced Renal Cell Carcinoma Sunitinib malate capsules are indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC).

1.3 Adjuvant Treatment of Renal Cell Carcinoma Sunitinib malate capsules are indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.

1.4 Advanced Pancreatic Neuroendocrine Tumors Sunitinib malate capsules are indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling.

Hepatotoxicity [ see Warnings and Precautions (5.1) ] Cardiovascular Events [ see Warnings and Precautions (5.2) ] QT Interval Prolongation and Torsade de Pointes [ see Warnings and Precautions (5.3) ] Hypertension [ see Warnings and Precautions (5.4) ] Hemorrhagic Events [ see Warnings and Precautions (5.5) ] Tumor Lysis Syndrome [ see Warnings and Precautions (5.6) ] Thrombotic Microangiopathy [ see Warnings and Precautions (5.7) ] Proteinuria [ see Warnings and Precautions (5.8) ] Dermatologic Toxicities [ see Warnings and Precautions (5.9) ] Reversible Posterior Leukoencephalopathy Syndrome [ see Warnings and Precautions (5.10) ] Thyroid Dysfunction [ see Warnings and Precautions (5.11) ] Hypoglycemia [ see Warnings and Precautions (5.12) ] Osteonecrosis of the Jaw [ see Warnings and Precautions (5.13) ] Impaired Wound Healing [ see Warnings and Precautions (5.14) ] The most common adverse reactions (≥25%) are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the Warnings and Precautions reflect exposure to sunitinib malate in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET.

In this pooled safety population, the most common adverse reactions (≥25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.

Gastrointestinal Stromal Tumor The safety of sunitinib malate was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate 50 mg daily on Schedule 4/2 (n=202) or placebo (n=102).

Median duration of blinded study treatment was 2 cycles for patients on sunitinib malate (mean: 3.0; range: 1-9) and 1 cycle (mean; 1.8; range: 1-6) for patients on placebo at the time of the interim analysis.

Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the sunitinib malate arm.

Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate.

Table 3 summarizes the adverse reactions for Study 1.

Table 3.

Adverse Reactions Reported in ≥10% of GIST Patients Who Received Sunitinib Malate in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo* in Study 1 Adverse Reaction GIST Sunitinib malate (N=202) Placebo (N=102) All Grades % Grade 3-4 % All Grades % Grade 3-4 % Any Adverse Reaction 94 56 97 51 Gastrointestinal Diarrhea Mucositis/stomatitis Constipation 40 29 20 4 1 0 27 18 14 0 2 2 Metabolism/Nutrition Anorexia a Asthenia 33 22 1 5 29 11 5 3 Dermatology Skin discoloration Rash Hand-foot syndrome 30 14 14 0 1 4 23 9 10 0 0 3 Neurology Altered taste 21 0 12 0 Cardiac Hypertension 15 4 11 0 Musculoskeletal Myalgia/limb pain 14 1 9 1 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients.

a Includes decreased appetite.

Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received sunitinib malate.

Table 4 summarizes the laboratory abnormalities in Study 1.

Table 4.

Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received Sunitinib Malate or Placebo in the Double-Blind Treatment Phase* in Study 1 Laboratory Abnormality GIST Sunitinib malate (N=202) Placebo (N=102) All Grades* % Grade 3-4* ,a % All Grades* % Grade 3-4* ,b % Any Laboratory Abnormality 34 22 Hematology Neutrophils decreased Lymphocytes decreased Platelets decreased Hemoglobin decreased 53 38 38 26 10 0 5 3 4 16 4 22 0 0 0 2 Gastrointestinal AST/ALT increased Lipase increased Alkaline phosphatase increased Amylase increased Total bilirubin increased Indirect bilirubin increased 39 25 24 17 16 10 2 10 4 5 1 0 23 17 21 12 8 4 1 7 4 3 0 0 Renal/Metabolic Creatinine increased Potassium decreased Sodium increased 12 12 10 1 1 0 7 4 4 0 0 1 Cardiac Decreased LVEF 11 1 3 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; GIST=gastrointestinal stromal tumor; LVEF=left ventricular ejection fraction; N=number of patients.

a Grade 4 laboratory abnormalities in patients on sunitinib malate included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%).

b Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).

After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate [ see Clinical Studies (14.1) ].

For 241 patients randomized to the sunitinib malate arm, including 139 who received sunitinib malate in both the double-blind and open-label phases, the median duration of sunitinib malate treatment was 6 cycles (mean: 8.5; range: 1–44).

For the 255 patients who ultimately received open-label sunitinib malate treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1–37) from the time of the unblinding.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib malate.

Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate.

The most common Grade 3 or 4 adverse reactions in patients who received sunitinib malate in the open-label phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

Advanced Renal Cell Carcinoma The safety of sunitinib malate was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib malate 50 mg daily on Schedule 4/2 (n=375) or interferon alfa 9 million International Units (MIU) (n=360).

The median duration of treatment was 11.1 months (range: 0.4 to 46.1) for sunitinib malate treatment and 4.1 months (range: 0.1 to 45.6) for interferon alfa treatment.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the sunitinib malate arm.

Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate.

Table 5 summarizes the adverse reactions for Study 3.

Table 5.

Adverse Reactions Reported in ≥10% of Patients With RCC Who Received Sunitinib Malate or Interferon Alfa* in Study 3 Adverse Reaction Treatment-Naïve RCC Sunitinib malate (N=375) Interferon Alfa (N=360) All Grades % Grade 3-4 a % All Grades % Grade 3-4 b % Any Adverse Reaction 99 77 99 55 Gastrointestinal Diarrhea Nausea Mucositis/stomatitis Vomiting Dyspepsia Abdominal pain c Constipation Dry mouth Oral pain Flatulence GERD/reflux esophagitis Glossodynia Hemorrhoids 66 58 47 39 34 30 23 13 14 14 12 11 10 10 6 3 5 2 5 1 0 <1 0 <1 0 0 21 41 5 17 4 12 14 7 1 2 1 1 2 <1 2 <1 1 0 1 <1 <1 0 0 0 0 0 Constitutional Fatigue Asthenia Fever Weight decreased Chills Chest Pain Influenza like illness 62 26 22 16 14 13 5 15 11 1 <1 1 2 0 56 22 37 17 31 7 15 15 6 <1 1 0 1 <1 Metabolism/Nutrition Anorexia d 48 3 42 2 Neurology Altered taste e Headache Dizziness 47 23 11 <1 1 <1 15 19 14 0 0 1 Hemorrhage/Bleeding Bleeding, all sites 37 4 f 10 1 Cardiac Hypertension Edema peripheral Ejection fraction decreased 34 24 16 13 2 3 4 5 5 <1 1 2 Dermatology Rash Hand-foot syndrome Skin discoloration/yellow skin Dry skin Hair color changes Alopecia Erythema Pruritus 29 29 25 23 20 14 12 12 2 8 <1 <1 0 0 <1 <1 11 1 0 7 <1 9 1 7 <1 0 0 0 0 0 0 <1 Musculoskeletal Pain in extremity/limb discomfort Arthralgia Back pain 40 30 28 5 3 5 30 19 14 2 1 2 Respiratory Cough Dyspnea Nasopharyngitis Oropharyngeal pain Upper respiratory tract infection 27 26 14 14 11 1 6 0 <1 <1 14 20 2 2 2 <1 4 0 0 0 Endocrine Hypothyroidism 16 2 1 0 Psychiatric Insomnia Depression g 15 11 <1 0 10 14 0 1 *Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.

a Grade 4 ARs in patients on sunitinib malate included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%).

b Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%).

c Includes flank pain.

d Includes decreased appetite.

e Includes ageusia, hypogeusia, and dysgeusia.

f Includes 1 patient with Grade 5 gastric hemorrhage.

g Includes depressed mood.

Table 6 summarizes the laboratory abnormalities in Study 3.

Table 6.

Laboratory Abnormalities Reported in ≥10% of RCC Patients Who Received Sunitinib Malate or Interferon Alfa in Study 3 Laboratory Abnormality Treatment-Naïve RCC Sunitinib malate (N=375) Interferon Alfa ( N=360) All Grades* % Grade 3-4* ,a % All Grades* % Grade 3-4* ,b % Hematology Hemoglobin decreased Neutrophils decreased Platelets decreased Lymphocytes decreased 79 77 68 68 8 17 9 18 69 49 24 68 5 9 1 26 Renal/Metabolic Creatinine increased Creatine kinase increased Uric acid increased Calcium increased Phosphorus decreased Albumin decreased Glucose increased Sodium decreased Glucose decreased Potassium increased Calcium increased Potassium decreased Sodium increased 70 49 46 42 31 28 23 20 17 16 13 13 13 <1 2 14 1 6 1 6 8 0 3 <1 1 0 51 11 33 40 24 20 15 15 12 17 10 2 10 <1 1 8 1 6 0 6 4 <1 4 1 <1 0 Gastrointestinal AST increased Lipase increased ALT increased Alkaline phosphatase increased Amylase increased Total bilirubin increased Indirect bilirubin increased 56 56 51 46 35 20 13 2 18 3 2 6 1 1 38 46 40 37 32 2 1 2 8 2 2 3 0 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; RCC=renal cell carcinoma.

a Grade 4 laboratory abnormalities in patients on sunitinib malate included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%).

b Grade 4 laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%).

Long-Term Safety in RCC The long-term safety of sunitinib malate in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings.The analysis included 5739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years.

Prolonged treatment with sunitinib malate did not appear to be associated with new types of adverse reactions.There appeared to be no increase in the yearly incidence of adverse reactions at later time points.

Hypothyroidism increased during the second year of treatment with new cases reported up to year 4.

Adjuvant Treatment of RCC The safety of sunitinib malate was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received sunitinib malate 50 mg daily on Schedule 4/2 (n=306) or placebo (n=304).The median duration of treatment was 12.4 months (range: 0.13 to 14.9) for sunitinib malate and 12.4 months (range: 0.03 to 13.7) for placebo.

Permanent discontinuation due to an adverse reaction occurred in 28% of patients in the sunitinib malate arm.

Adverse reactions leading to permanent discontinuation in >2% of patients include hand-foot syndrome and fatigue/asthenia.

Dosing interruptions occurred in 54% and dose reductions occurred in 46% of patients who received sunitinib malate.

Table 7 summarizes the adverse reactions in S-TRAC.

Table 7.

Adverse Reactions Reported in ≥10% of Patients With RCC Who Received Sunitinib Malate and More Commonly Than in Patients Given Placebo* in S-TRAC Adverse Reaction Adjuvant Treatment of RCC Sunitinib malate (N=306) Placebo (N=304) All Grades % Grade 3-4 % All Grades % Grade 3-4 % Any Adverse Reaction 99 60 88 15 Gastrointestinal Mucositis/Stomatitis a Diarrhea Nausea Dyspepsia Abdominal pain b Vomiting Constipation 61 57 34 27 25 19 12 6 4 2 1 2 2 0 15 22 15 7 9 7 11 0 <1 0 0 <1 0 0 Constitutional Fatigue/Asthenia Localized edema c Pyrexia 57 18 12 8 <1 <1 34 <1 6 2 0 0 Dermatology Hand-foot syndrome Rash d Hair color changes Skin discoloration/Yellow skin Dry skin 50 24 22 18 14 16 2 0 0 0 10 12 2 1 6 <1 0 0 0 0 Cardiac Hypertension e Edema/Peripheral edema 39 10 8 <1 14 7 1 0 Neurology Altered taste f Headache 38 19 <1 <1 6 12 0 0 Endocrine Hypothyroidism/TSH increased 24 <1 4 0 Hemorrhage /Bleeding Bleeding events, all sites g 24 <1 5 <1 Metabolism/Nutrition Anorexia/Decreased appetite 19 <1 5 0 Musculoskeletal Pain in extremity Arthralgia 15 11 <1 <1 7 10 0 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.

a Includes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain.

b Includes abdominal pain, abdominal pain lower, and abdominal pain upper.

c Includes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema.

d Includes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic.

e Includes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis.

f Includes ageusia, hypogeusia, and dysgeusia.

g Includes epistaxis, gingiva lbleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria.

Grade 4 adverse reactions in patients on sunitinib malate included hand-foot syndrome (1%), fatigue (<1%), abdominal pain (< 1%), stomatitis (<1%), and pyrexia (< 1%).

Grade 3-4 laboratory abnormalities that occurred in ≥2% of patients receiving sunitinib malate include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).

Advanced Pancreatic Neuroendocrine Tumors The safety of sunitinib malate was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received sunitinib malate 37.5 mg once daily (n=83) or placebo (n=82).

The median number of days on treatment was 139 days (range: 13-532 days) for patients on sunitinib malate and 113 days (range: 1-614 days) for patients on placebo.

Nineteen patients (23%) on sunitinib malate and 4 patients (5%) on placebo were on study for >1 year.

Permanent discontinuation due to an adverse reaction occurred in 22% in the sunitinib malate arm.

Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received sunitinib malate.

Table 8 summarizes the adverse reactions in Study 6.

Table 8.

Adverse Reactions Reported in ≥10% of Patients With pNET Who Received Sunitinib Malate and More Commonly Than in Patients Given Placebo* in Study 6 Adverse Reaction pNET Sunitinib malate (N=83) Placebo (N=82) All Grades % Grade 3-4 a % All Grades % Grade 3-4 % Any Adverse Reaction 99 54 95 50 Gastrointestinal Diarrhea Stomatitis/oral syndromes b Nausea Abdominal pain c Vomiting Dyspepsia 59 48 45 39 34 15 5 6 1 5 0 0 39 18 29 34 31 6 2 0 1 10 2 0 Constitutional Asthenia Fatigue Weight decreased 34 33 16 5 5 1 27 27 11 4 9 0 Dermatology Hair color changes Hand-foot syndrome Rash Dry skin 29 23 18 15 1 6 0 0 1 2 5 11 0 0 0 0 Cardiac Hypertension 27 10 5 1 Hemorrhage /Bleeding Bleeding events d Epistaxis 22 21 0 1 10 5 4 0 Neurology Dysgeusia Headache 21 18 0 0 5 13 0 1 Psychiatric Insomnia 18 0 12 0 Musculoskeletal Arthralgia 15 0 6 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: N=number of patients; pNET=pancreatic neuroendocrine tumors.

a Grade 4 adverse reactions in patients on sunitinib malate included fatigue (1%).

b Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth.

c Includes abdominal discomfort, abdominal pain, and abdominal pain upper.

d Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.

Table 9 summarizes the laboratory abnormalities in Study 6.

Table 9.

Laboratory Abnormalities Reported in ≥10% of Patients With pNET Who Received Sunitinib Malate in Study 6 Laboratory Abnormality pNET Sunitinib malate Placebo All Grades* % Grade 3-4* ,a % All Grades* % Grade 3-4* ,b % Gastrointestinal AST increased Alkaline phosphatase increased ALT increased Total bilirubin increased Amylase increased Lipase increased 72 63 61 37 20 17 5 10 4 1 4 5 70 70 55 28 10 11 3 11 3 4 1 4 Hematology Neutrophils decreased Hemoglobin decreased Platelets decreased Lymphocytes decreased 71 65 60 56 16 0 5 7 16 55 15 35 0 1 0 4 Renal/Metabolic Glucose increased Albumin decreased Phosphorus decreased Calcium decreased Sodium decreased Creatinine increased Glucose decreased Potassium decreased Magnesium decreased Potassium increased 71 41 36 34 29 27 22 21 19 18 12 1 7 0 2 5 2 4 0 1 78 37 22 19 34 28 15 14 10 11 18 1 5 0 3 5 4 0 0 1 * The denominator used to calculate the rate varied from 52 to 82 for sunitinib malate and 39 to 80 for Placebo based on the number of patients with a baseline value and at least one post-treatment value.

Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; pNET=pancreatic neuroendocrine tumors.

a Grade 4 laboratory abnormalities in patients on sunitinib malate included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%), and total bilirubin (1%).

b Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%).

Venous Thromboembolic Events In pooled safety population, 3.5% of patients experienced a venous thromboembolic event, including Grade 3-4 in 2.2% of patients.

Pancreatic Function Pancreatitis was observed in 1 patient (1%) in the pNET study, 5 patients (1%) in the treatment-naïve RCC study, and 1 patient (<1%) in the adjuvant treatment for RCC study on sunitinib malate.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sunitinib malate.

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.

Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia*.

Gastrointestinal disorders: esophagitis.

Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis.

Immune system disorders: hypersensitivity reactions, including angioedema.

Infections and infestations: serious infection (with or without neutropenia)*.

The infections most commonly observed with sunitinib malate include respiratory, urinary tract, skin infections, and sepsis/septic shock.

Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression*; myopathy and/or rhabdomyolysis with or without acute renal failure*.

Renal and urinary disorders: renal impairment and/or failure*.

Respiratory disorders: pulmonary embolism*, pleural effusion*.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive de-challenges.

Vascular disorders: arterial (including aortic) aneurysms, dissections*, and rupture*; arterial thromboembolic events*.

The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction.

General disorders and administration site conditions: impaired wound healing.

*including some fatalities