FDA label 3989c607-12c7-4bdd-abed-a582ca09abdc

WARNING: CAPILLARY LEAK SYNDROME (CLS), NEUROLOGIC TOXICITIES and SERIOUS INFECTIONS Capillary leak syndrome (CLS), including life threatening or fatal reactions, has occurred in patients treated with Proleukin. Do not administer Proleukin to patients with significant cardiac, pulmonary, renal, and hepatic impairment. Administer Proleukin in a hospital setting with an intensive care facility. Withhold or discontinue Proleukin as recommended [see Dosage and Administration ( 2.4 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . Neurologic toxicities, which may be life-threatening or result in coma or permanent neurological deficits, have occurred in patients treated with Proleukin. Withhold or discontinue Proleukin as recommended [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.2 )] . Serious Infections including sepsis and bacterial endocarditis have occurred in patients treated with Proleukin. Treat pre-existing bacterial infections prior to initiation of Proleukin therapy and withhold Proleukin as recommended [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.3 )] . WARNING: CAPILLARY LEAK SYNDROME (CLS), NEUROLOGIC TOXICITY, AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Capillary Leak Syndrome (CLS) including life-threatening or fatal reactions, has occurred in patients treated with Proleukin. Administer Proleukin in a hospital setting with an intensive care unit. Withhold or discontinue Proleukin as recommended. ( 2.4 , 4 , 5.1 ) Neurologic toxicities, which may be life-threatening or result in coma or permanent neurological deficits, have occurred in patients treated with Proleukin. Withhold or discontinue Proleukin as recommended. ( 2.4 , 5.2 ) Serious infections including sepsis and bacterial endocarditis have occurred in patients treated with Proleukin. Treat preexisting bacterial infections prior to initiating Proleukin and withhold Proleukin as recommended. ( 2.4 , 5.3 )

5 WARNINGS AND PRECAUTIONS Renal Toxicity: Monitor renal function at baseline and throughout treatment. Withhold Proleukin or permanently discontinue, based on severity. ( 2.4 , 5.4 ) Immune-mediated Adverse Reactions: Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders can occur in any system or tissue. Proleukin may increase the risk of allograft rejection in transplant patients. Monitor patients and treat as indicated. ( 5.5 ) Severe Hypersensitivity Reaction: Permanently discontinue Proleukin for severe hypersensitivity reactions. ( 4 , 5.9 ) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Capillary Leak Syndrome Severe and life-threatening capillary leak syndrome (CLS) characterized by hypotension, dyspnea, edema, and hypoalbuminemia can occur with Proleukin, and can result in end organ toxicity including cardiac, respiratory, renal, hepatic toxicity, or death. Do not administer Proleukin to patients with significant cardiac, pulmonary, renal, or hepatic impairment. Avoid concomitant use of Proleukin with other products known to cause hypotension including antihypertensive drugs, those that cause renal toxicity, or hepatotoxicity. CLS may begin immediately after Proleukin treatment is initiated. Monitor for signs and symptoms of CLS including assessments of vital signs, weight, fluid intake, albumin levels and urine output. Withhold or discontinue Proleukin for failure to maintain organ perfusion as demonstrated by altered mental status, reduced urine output, oxygen saturation <90%, a fall in the systolic blood pressure below 90 mm Hg, or onset of cardiac arrhythmias. Initiate standard management for CLS, which may include intensive care [see Dosage and Administration ( 2.4 ), Use in Specific Populations ( 8.1 )] . 5.2 Neurologic Toxicity Proleukin can cause neurologic toxicities including mental status changes, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, demyelinating polyneuropathy, and coma. Alterations in mental status may progress for several days before recovery begins. Permanent neurologic deficits have occurred. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. One case of possible cerebral vasculitis has been reported. Monitor patients for signs and symptoms of neurological toxicity during Proleukin treatment. Withhold Proleukin in patients developing moderate to severe lethargy or somnolence; continued administration may result in coma. Permanently discontinue Proleukin for coma or toxic psychosis lasting >48 hours or for repetitive or difficult to control seizures [see Dosage and Administration ( 2.4 )]. Evaluate and treat CNS metastases prior to initiation of Proleukin. If possible, avoid concomitant use of Proleukin with other product(s) with a known potential to cause neurotoxicity, and avoid Proleukin in patients with seizure disorders or abnormal intracranial imaging [see Contraindications ( 4 ), Adverse Reactions ( 6.1 , 6.2 )] . Concomitant use of Proleukin with other products that cause neurotoxicity may result in a greater risk of severe neurotoxicity. 5.3 Serious Infections Including Sepsis Proleukin can cause impaired neutrophil function (reduced chemotaxis) and an increased risk of disseminated infection, including sepsis and bacterial endocarditis. Treat pre-existing bacterial infections prior to initiating Proleukin. Consider antibiotic prophylaxis in patients with indwelling central lines. Monitor patients for the development of signs and symptoms of infection during treatment and withhold Proleukin based on severity [see Dosage and Administration ( 2.4 )]. 5.4 Renal Toxicity Serious renal toxicity, including oliguria and renal failure can occur with Proleukin [see Adverse Reactions ( 6.1 , 6.2 )] . Pre-existing renal impairment or coadministration of Proleukin with other products known to cause renal toxicity may increase this risk. If possible, avoid concomitant use of Proleukin with other product(s) with a known potential to cause renal toxicity. Serum creatinine should be ≤1.5 mg/dL before beginning Proleukin. Monitor serum creatinine at baseline and daily throughout each course of therapy. Withhold Proleukin, or permanently discontinue, based on severity [see Dosage and Administration ( 2.4 )] . 5.5 Immune-mediated Adverse Reactions Exacerbation of pre-existing autoimmune disease or initial presentation of autoimmune and inflammatory disorders has been reported following treatment with Proleukin. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. These have included exacerbation of Crohn’s disease, colitis, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome, bullous pemphigoid, myocarditis, myositis, and neuritis including optic neuritis resulting in blindness [see Adverse Reactions ( 6.2 )] . Proleukin may increase the risk of allograft rejection in transplant patients [see Contraindications ( 4 )] . Hypothyroidism, sometimes preceded by hyperthyroidism, has been reported following Proleukin treatment. Evaluate thyroid function at baseline and periodically during treatment and initiate thyroid replacement therapy as clinically indicated. Hyperglycemia and/or diabetes mellitus has been reported during Proleukin therapy. Monitor patients for hyperglycemia and initiate treatment with insulin as clinically indicated. 5.6 Embryo-Fetal Toxicity Based on findings in an animal study and its mechanism of action, Proleukin may cause fetal harm or loss of pregnancy when administered to a pregnant woman. In pregnant rats, aldesleukin has been shown to have embryolethal effects at doses 27 times and maternal toxicities at doses 2.1 times the human exposure at the recommended clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with Proleukin [see Use in Specific Populations ( 8.1 , 8.3 )]. 5.7 Serious Manifestations of Eosinophilia Serious manifestations of eosinophilia involving eosinophilic infiltration of cardiac and pulmonary tissues can occur following Proleukin. 5.8 Delayed Adverse Reactions to Iodinated Contrast Media A review of the literature revealed that 12.6% (range 11-28%) of 501 patients treated with various interleukin-2-containing regimens who were subsequently administered radiographic iodinated contrast media experienced acute, atypical adverse reactions. The onset of symptoms usually occurred within hours (most commonly 1 to 4 hours) following the administration of contrast media. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. These reactions may resemble the immediate side effects caused by interleukin-2 administration. Most events were reported to occur when contrast media was given within 4 weeks after the last dose of interleukin-2. These events were also reported to occur when contrast media was given several months after interleukin-2 treatment [see Adverse Reactions ( 6.2 )] . 5.9 Severe Hypersensitivity Reactions Proleukin can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue Proleukin in patients who experience a severe hypersensitivity reaction [see Contraindications ( 4 ), Adverse Reactions ( 6.2 )]. 5.10 Infusion-Related Reactions Proleukin can cause fevers, chills, or rigors. Premedicate patients with an antipyretic prior to beginning Proleukin and continue during treatment as needed for fever [see Adverse Reactions ( 6.2 ) and Dosage and Administration ( 2.3 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Capillary Leak Syndrome [see Warnings and Precautions ( 5.1 )]. Neurotoxicity [see Warnings and Precautions ( 5.2 )]. Serious Infections Including Sepsis [see Warnings and Precautions ( 5.3 )]. Renal Toxicity [see Warnings and Precautions ( 5.4 )]. Immune-Mediated Adverse Reactions [see Warnings and Precautions ( 5.5 )]. Serious Manifestations of Eosinophilia [see Warnings and Precautions ( 5.7 )]. Severe Hypersensitivity Reactions [see Warnings and Precautions ( 5.9 )]. Infusion-Related Reactions [see Warnings and Precautions ( 5.10 )] . Most common (≥ 30%) adverse reactions including laboratory abnormalities are hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state and increased creatinine. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Clinigen, Inc. at 1-877-776-5385 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Proleukin was evaluated in a series of single and multicenter, controlled studies enrolling a total of 525 patients with metastatic renal cell carcinoma (mRCC studies) or metastatic melanoma (metastatic melanoma studies) [see Clinical Studies ( 14.1 , 14.2 )] . In patients who received Proleukin in these studies, fatal adverse reactions occurred in 4% (11/255) of the patients with metastatic RCC, and 2% (6/270) of the patients with metastatic melanoma. In these studies, >90% of patients had doses withheld for adverse reactions [see Dosage and Administration ( 2.4 )]. The most common (≥30%) adverse reactions were hypotension, hyperbilirubinemia, dyspnea, rash, diarrhea, oliguria, chills, vomiting, thrombocytopenia, nausea, confusional state, and increased creatinine. Table 4 summarizes adverse reactions that occurred in these studies. Table 4: Adverse Reactions (≥10% all grades or ≥1% Grade 4) in Patients with Metastatic Renal Cell Carcinoma or Metastatic Melanoma (n=525) receiving Proleukin a Cardiovascular disorder: Electrocardiogram abnormal, cardiac failure congestive. b Lung disorder: Pulmonary congestion, rales, rhonchi. c Respiratory disorder: Acute respiratory distress syndrome, lung infiltration, lung disorder, respiratory failure, endotracheal intubation. Adverse Reaction Proleukin N = 525 All Grades (%) Grade 4 (%) General disorders Chills 52 0 Pyrexia 29 1 Edema peripheral 28 0 Malaise 27 0 Asthenia 23 0 Edema 15 0 Pain 12 0 Cardiac disorders Hypotension 71 3 Blood pressure fluctuation Not documented 1 Tachycardia 23 0 Dilated veins 13 0 Supraventricular tachycardia 12 1 Ventricular tachycardia <10 1 Cardiovascular disorder a 11 0 Myocardial infarction <10 1 Arrhythmia 10 0 Cardiac arrest <10 1 Gastrointestinal disorders Diarrhea 67 2 Vomiting 50 0 Nausea 35 0 Stomatitis 22 <1 Decreased appetite 20 0 Abdominal pain 11 0 Abdominal distention 10 0 Blood and lymphatic system disorders Thrombocytopenia 37 1 Anemia 29 0 Leukopenia 16 0 Disseminated intravascular coagulation <10 1 Infections Infections 13 1 Sepsis <10 1 Hepatobiliary disorders Hyperbilirubinemia 40 2 Aspartate aminotransferase increased 23 1 Metabolic and nutritional disorders Weight increased 16 0 Acidosis 12 1 Hypomagnesemia 12 0 Hypocalcemia 11 <1 Blood alkaline phosphatase increased 10 0 Nervous system disorders Confusional state 34 1 Stupor <10 1 Coma <10 2 Psychotic disorder <10 1 Somnolence 22 0 Anxiety 12 0 Dizziness 11 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 43 1 Lung disorder b 24 0 Respiratory disorder c 11 3 Apnea <10 1 Cough 11 0 Rhinitis 10 0 Skin and subcutaneous tissue disorders Rash 42 0 Pruritis 24 0 Dermatitis exfoliative 18 0 Renal and urinary disorders Oliguria 63 6 Blood creatinine increased 33 1 Anuria <10 5 Acute kidney injury <10 1 Additional life-threatening adverse reactions (Grade 4) were reported by <1% of the 525 patients: Cardiac disorders: bradycardia, pericardial effusion, ventricular extrasystoles, myocardial ischemia, arrhythmia supraventricular, coronary artery disease, atrioventricular block second degree, endocarditis Eye disorders: mydriasis, pupillary disorder Gastrointestinal disorders: intestinal perforation, gastrointestinal hemorrhage, hematemesis, pancreatitis, diarrhea hemorrhagic General disorders and administration site conditions: hypothermia Infections and infestations: gangrene Metabolism and nutrition disorders: hyperuricemia Nervous system disorders: syncope, neuropathy peripheral, seizure, generalized tonic-clonic seizure Investigations: liver function tests abnormal, blood urea increased Psychiatric disorders: agitation, paranoia Renal and urinary disorders: renal failure, renal tubular necrosis Respiratory, thoracic and mediastinal disorders: respiratory acidosis, asthma, pulmonary edema, hyperventilation, hypoxia, hemoptysis, hypoventilation, pneumothorax Vascular disorders: shock, hemorrhage, phlebitis, thrombosis Other Clinical Trial Experience The following serious adverse reactions were reported in patients with RCC, melanoma, or other cancers treated with Proleukin-based regimens (n >1800 patients) using dosages other than the recommended dosage: Cardiovascular disorders: transient ischemic attacks, pericarditis Gastrointestinal disorders: duodenal ulcer; gastrointestinal necrosis, tracheo-esophageal fistula Nervous system disorders: meningitis, brain edema Renal and urinary disorders: nephritis (allergic) In the same clinical population, the following fatal events each occurred with a frequency of <1%: hyperthermia malignant; cardiac arrest; myocardial infarction; pulmonary embolism; cerebrovascular accident; intestinal perforation; hepatic failure or renal failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; respiratory failure. Patients with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events. 6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of Proleukin. 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: neutropenia, febrile neutropenia, eosinophilia, lymphopenia Cardiac disorders: cardiomyopathy, cardiac tamponade Endocrine disorders: hyperthyroidism Gastrointestinal disorders: gastritis, intestinal obstruction General disorders and administration site conditions: injection site necrosis Hepatobiliary disorders: hepatitis, hepatosplenomegaly, cholecystitis Immune system disorders: anaphylactic reaction, angioedema, urticaria Infections and infestations: pneumonia (bacterial, fungal, viral), endocarditis, cellulitis Metabolism and nutrition disorders: hyponatremia, hypophosphatemia Musculoskeletal and connective tissue disorders: myopathy, rhabdomyolysis Nervous system disorders: encephalopathy, extrapyramidal disorder, neuralgia Psychiatric disorders: insomnia Vascular disorders: hypertension, subdural hemorrhage, subarachnoid hemorrhage, cerebral hemorrhage, retroperitoneal hemorrhage

<table ID="t4" width="700px"><caption>Table 4: Adverse Reactions (&#x2265;10% all grades or &#x2265;1% Grade 4) in Patients with Metastatic Renal Cell Carcinoma or Metastatic Melanoma (n=525) receiving Proleukin</caption><colgroup><col width="460"/><col width="270"/><col width="270"/></colgroup><tfoot><tr styleCode="First Last"><td colspan="3" align="left"><paragraph styleCode="First Text">^a Cardiovascular disorder: Electrocardiogram abnormal, cardiac failure congestive.</paragraph><paragraph styleCode="Text">^b Lung disorder: Pulmonary congestion, rales, rhonchi.</paragraph><paragraph styleCode="Text">^c Respiratory disorder: Acute respiratory distress syndrome, lung infiltration, lung disorder, respiratory failure, endotracheal intubation.</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Rrule Toprule" rowspan="2" valign="middle"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td styleCode="Lrule Rrule Toprule" colspan="2" align="center" valign="top"><paragraph><content styleCode="bold">Proleukin</content></paragraph><paragraph><content styleCode="bold">N = 525</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">All Grades (%)</content></paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">Grade 4 (%)</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">General disorders </content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Chills</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>52</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Pyrexia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>29</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Edema peripheral</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>28</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Malaise</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>27</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Asthenia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>23</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Edema</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>15</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Pain</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>12</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Cardiac disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Hypotension</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>71</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Blood pressure fluctuation</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Not documented</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Tachycardia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>23</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Dilated veins</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>13</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Supraventricular tachycardia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>12</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Ventricular tachycardia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Cardiovascular disorder^a</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>11</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Myocardial infarction</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Arrhythmia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Cardiac arrest</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Diarrhea</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>67</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Vomiting</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>50</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Nausea</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>35</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Stomatitis</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>22</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Decreased appetite</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>20</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Abdominal pain</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>11</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Abdominal distention</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Blood and lymphatic system disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Thrombocytopenia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>37</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Anemia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>29</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Leukopenia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>16</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Disseminated intravascular coagulation</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Infections</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Infections</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>13</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Sepsis</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Hepatobiliary disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Hyperbilirubinemia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>40</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Aspartate aminotransferase increased</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>23</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Metabolic and nutritional disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Weight increased</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>16</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Acidosis</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>12</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Hypomagnesemia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>12</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Hypocalcemia</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>11</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Blood alkaline phosphatase increased</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Confusional state</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>34</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Stupor</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Coma</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Psychotic disorder</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Somnolence</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>22</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Anxiety</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>12</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Dizziness</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>11</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Dyspnea</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>43</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Lung disorder^b</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>24</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Respiratory disorder^c</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>11</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Apnea</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Cough</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>11</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Rhinitis</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Rash</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>42</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Pruritis</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>24</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Dermatitis exfoliative</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>18</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" colspan="3" valign="top"><paragraph><content styleCode="bold">Renal and urinary disorders</content></paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Oliguria</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>63</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Blood creatinine increased</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>33</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Anuria</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>Acute kidney injury</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>&lt;10</paragraph></td><td styleCode="Lrule Rrule Toprule" valign="top"><paragraph>1</paragraph></td></tr></tbody></table>