Azacitidine

5 WARNINGS AND PRECAUTIONS Risks of Substitution with Other Azacitidine Products : Do not substitute Azacitidine for Injection for oral azacitidine ( 2.1 , 5.1 ). Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood counts (CBC) frequently ( 5.2 ). Hepatotoxicity : Patients with severe preexisting hepatic impairment are at higher risk for toxicity ( 5.3 ). Renal Toxicity : Monitor patients with renal impairment for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys ( 5.4 ). Tumor Lysis Syndrome : Azacitidine for Injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Assess baseline risk and monitor and treat as appropriate ( 5.5 ). Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.6 , 8.1 , 8.3 ). 5.1 Risks of Substitution with Other Azacitidine Products Due to substantial differences in the pharmacokinetic parameters [ see Clinical Pharmacology ( 12.3 )], the recommended dose and schedule for Azacitidine for Injection are different from those of oral azacitidine products. Treatment of patients using Azacitidine for Injection at the recommended dosage of oral azacitidine may result in a fatal adverse reaction. Treatment of patients using oral azacitidine at the doses recommended for Azacitidine for Injection may not be effective. Do not substitute Azacitidine for Injection for oral azacitidine [ see Dosage and Administration (2.1) ]. 5.2 Anemia, Neutropenia and Thrombocytopenia Azacitidine for Injection causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response [ see Dosage and Administration (2.4) ] . Pediatric use information is approved for Celgene Corporation’s Vidaza ® (azacitidine for injection). However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information. 5.3 Hepatic Toxicity in Patients with Severe Pre-existing Hepatic Impairment Because Azacitidine for Injection is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin less than 30 g/L. Azacitidine for Injection is contraindicated in patients with advanced malignant hepatic tumors [ see Contraindications (4) ] . Monitor liver chemistries prior to initiation of therapy and with each cycle. Safety and effectiveness of Azacitidine for Injection in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials. Pediatric use information is approved for Celgene Corporation’s Vidaza ® (azacitidine for injection). However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information. 5.4 Renal Toxicity Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to less than 20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium less than 3 mEq/L) developed in 5 patients with CML (an unapproved use) treated with azacitidine and etoposide. Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle. If unexplained reductions in serum bicarbonate less than 20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose [ see Dosage and Administration (2.5) ] . Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, monitor these patients closely for toxicity [see Dosage and Administration ( 2.5 , 2.6 )] . Patients with MDS and renal impairment were excluded from the clinical studies. Pediatric use information is approved for Celgene Corporation’s Vidaza ® (azacitidine for injection). However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information. 5.5 Tumor Lysis Syndrome Azacitidine for Injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate. 5.6 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman. In animal studies, azacitidine caused adverse developmental outcomes when administered to mice and rats at doses of 3 to 12 mg/m 2 and 6 mg/m 2 (approximately 4% to 16% and 8%) of the recommended human daily dose of 75 mg/m 2 , respectively. Advise pregnant women of the potential risk to a fetus . Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 3 months following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Anemia, Neutropenia and Thrombocytopenia [ see Warnings and Precautions (5.2) ] Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [ see Warnings and Precautions (5.3) ] Renal Toxicity [ see Warnings and Precautions (5.4) ] Tumor Lysis Syndrome [ see Warnings and Precautions (5.5) ] Most common adverse reactions (> 30%) in adult patients with MDS by subcutaneous route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia and ecchymosis. Most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-888-838-2872 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 data described below reflect exposure to azacitidine in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration) [ see Clinical Studies (14) ] . In Studies 1, 2 and 3, a total of 268 patients were exposed to azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m 2 . In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily azacitidine doses of 75 mg/m 2 . Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route) in Adult Patients with MDS : nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia. Adverse Reactions Most Frequently (Greater Than 2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route) in Adult Patients with MDS : Discontinuation : leukopenia, thrombocytopenia, neutropenia. Dose Held : leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced : leukopenia, neutropenia, thrombocytopenia. Table 1 presents adverse reactions occurring in at least 5% of patients treated with azacitidine (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the azacitidine-treated group than for the observation group; patients received azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months. Table 1: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in All Subcutaneous Azacitidine-Treated Patients; Studies 1 and 2) Number (%) of Patients Body System Adverse Reaction a All Azacitidine b Observation c (N=220) (N=92) a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. b Includes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine. Blood and lymphatic system disorders Anemia 153 (70) 59 (64) Anemia aggravated 12 (6) 5 (5) Febrile neutropenia 36 (16) 4 (4) Leukopenia 106 (48) 27 (29) Neutropenia 71 (32) 10 (11) Thrombocytopenia 144 (66) 42 (46) Gastrointestinal disorders Abdominal tenderness 26 (12) 1 (1) Constipation 74 (34) 6 (7) Diarrhea 80 (36) 13 (14) Gingival bleeding 21 (10) 4 (4) Loose stools 12 (6) 0 Mouth hemorrhage 11 (5) 1 (1) Nausea 155 (71) 16 (17) Stomatitis 17 (8) 0 Vomiting 119 (54) 5 (5) General disorders and administration site conditions Chest pain 36 (16) 5 (5) Injection site bruising 31 (14) 0 Injection site erythema 77 (35) 0 Injection site granuloma 11 (5) 0 Injection site pain 50 (23) 0 Injection site pigmentation changes 11 (5) 0 Injection site pruritus 15 (7) 0 Injection site reaction 30 (14) 0 Injection site swelling 11 (5) 0 Lethargy 17 (8) 2 (2) Malaise 24 (11) 1 (1) Pyrexia 114 (52) 28 (30) Infections and infestations Nasopharyngitis 32 (15) 3 (3) Pneumonia 24 (11) 5 (5) Upper respiratory tract infection 28 (13) 4 (4) Injury, poisoning, and procedural complications Post procedural hemorrhage 13 (6) 1 (1) Metabolism and nutrition disorders Anorexia 45 (21) 6 (7) Musculoskeletal and connective tissue disorders Arthralgia 49 (22) 3 (3) Chest wall pain 11 (5) 0 Myalgia 35 (16) 2 (2) Nervous system disorders Dizziness 41 (19) 5 (5) Headache 48 (22) 10 (11) Psychiatric disorders Anxiety 29 (13) 3 (3) Insomnia 24 (11) 4 (4) Respiratory, thoracic and mediastinal disorders Dyspnea 64 (29) 11 (12) Skin and subcutaneous tissue disorders Dry skin 11 (5) 1 (1) Ecchymosis 67 (31) 14 (15) Erythema 37 (17) 4 (4) Rash 31 (14) 9 (10) Skin nodule 11 (5) 1 (1) Urticaria 13 (6) 1 (1) Vascular disorders Hematoma 19 (9) 0 Hypotension 15 (7) 2 (2) Petechiae 52 (24) 8 (9) Table 2 presents adverse reactions occurring in at least 5% of patients treated with azacitidine in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with azacitidine was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). Table 2: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in the Azacitidine -Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4) Number (%) of Patients Any Grade Grade 3/4 Body System Adverse Reactions a Azacitidine (N=175) Best Supportive Care Only (N= 102) Azacitidine (N=175) Best Supportive Care Only (N= 102) a Multiple reports of the same preferred term from a patient were only counted once within each treatment. Blood and lymphatic system disorders Anemia 90 (51) 45 (44) 24 (14) 9 (9) Febrile neutropenia 24 (14) 10 (10) 22 (13) 7 (7) Leukopenia 32 (18) 2 (2) 26 (15) 1 (1) Neutropenia 115 (66) 29 (28) 107 (61) 22 (22) Thrombocytopenia 122 (70) 35 (34) 102 (58) 29 (28) Gastrointestinal disorders Abdominal pain 22 (13) 7 (7) 7 (4) 0 Constipation 88 (50) 8 (8) 2 (1) 0 Dyspepsia 10 (6) 2 (2) 0 0 Nausea 84 (48) 12 (12) 3 (2) 0 Vomiting 47 (27) 7 (7) 0 0 General disorders and administration site conditions Fatigue 42 (24) 12 (12) 6 (3) 2 (2) Injection site bruising 9 (5) 0 0 0 Injection site erythema 75 (43) 0 0 0 Injection site hematoma 11 (6) 0 0 0 Injection site induration 9 (5) 0 0 0 Injection site pain 33 (19) 0 0 0 Injection site rash 10 (6) 0 0 0 Injection site reaction 51 (29) 0 1 (1) 0 Pyrexia 53 (30) 18 (18) 8 (5) 1 (1) Infections and infestations Rhinitis 10 (6) 1 (1) 0 0 Upper respiratory tract infection 16 (9) 4 (4) 3 (2) 0 Urinary tract infection 15 (9) 3 (3) 3 (2) 0 Investigations Weight decreased 14 (8) 0 1 (1) 0 Metabolism and nutrition disorders Hypokalemia 11 (6) 3 (3) 3 (2) 3 (3) Nervous system disorders Lethargy 13 (7) 2 (2) 0 1 (1) Psychiatric disorders Anxiety 9 (5) 1 (1) 0 0 Insomnia 15 (9) 3 (3) 0 0 Renal and urinary disorders Hematuria 11 (6) 2 (2) 4 (2) 1 (1) Respiratory, thoracic and mediastinal disorders Dyspnea 26 (15) 5 (5) 6 (3) 2 (2) Dyspnea exertional 9 (5) 1 (1) 0 0 Pharyngolaryngeal pain 11 (6) 3 (3) 0 0 Skin and subcutaneous tissue disorders Erythema 13 (7) 3 (3) 0 0 Petechiae 20 (11) 4 (4) 2 (1) 0 Pruritus 21 (12) 2 (2) 0 0 Rash 18 (10) 1 (1) 0 0 Vascular disorders Hypertension 15 (9) 4 (4) 2 (1) 2 (2) In Studies 1, 2 and 4 with subcutaneous administration of azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of azacitidine. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of subcutaneous treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment. Overall, adverse reactions were qualitatively similar between the intravenous and subcutaneous studies. Adverse reactions that appeared to be specifically associated with the intravenous route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage). In clinical studies of either subcutaneous or intravenous azacitidine, the following serious adverse reactions occurring at a rate of less than 5% (and not described in Tables 1 or 2) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy. Eye disorders: eye hemorrhage Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome. Hepatobiliary disorders: cholecystitis. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified: leukemia cutis. Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage. Renal and urinary disorders: loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension. Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of azacitidine. 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. Interstitial lung disease Tumor lysis syndrome Injection site necrosis Sweet’s syndrome (acute febrile neutrophilic dermatosis) Necrotizing fasciitis (including fatal cases) Differentiation syndrome Pericardial effusion Pericarditis Cutaneous vasculitis

<table ID="_RefID0EFKAE" width="97.5%"><caption>Table 1: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in All Subcutaneous Azacitidine-Treated Patients; Studies 1 and 2)</caption><col width="47%"/><col width="22%"/><col width="30%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Number (%) of Patients</content></th></tr><tr><th align="left" styleCode="Rrule Lrule " valign="top"><content styleCode="bold">Body System Adverse Reaction ^a</content></th><th align="center" styleCode="Rrule Lrule " valign="top"><content styleCode="bold">All Azacitidine ^b</content></th><th align="center" styleCode="Rrule Lrule " valign="top"><content styleCode="bold">Observation ^c</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"/><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">(N=220)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">(N=92)</content></th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top">^aMultiple terms of the same preferred terms for a patient are only counted once within each treatment group. </td></tr><tr><td align="left" colspan="3" valign="top">^bIncludes adverse reactions from all patients exposed to azacitidine, including patients after crossing over from observations. </td></tr><tr><td align="left" colspan="3" valign="top">^cIncludes adverse reactions from observation period only; excludes any adverse events after crossover to azacitidine. </td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and lymphatic system disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>153 (70)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>59 (64)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anemia aggravated</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36 (16)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>106 (48)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>27 (29)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>71 (32)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (11)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Thrombocytopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>144 (66)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42 (46)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abdominal tenderness</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26 (12)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>74 (34)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>80 (36)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (14)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gingival bleeding</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21 (10)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Loose stools</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mouth hemorrhage</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>155 (71)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16 (17)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Stomatitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17 (8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>119 (54)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (5)</paragraph></td></tr><tr><td colspan="2" styleCode="Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General disorders and administration site conditions</content></paragraph></td><td styleCode="Rrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Chest pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>36 (16)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site bruising</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31 (14)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site erythema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>77 (35)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site granuloma</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>50 (23)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site pigmentation changes</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site pruritus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reaction</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>30 (14)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site swelling</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lethargy</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>17 (8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Malaise</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24 (11)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>114 (52)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28 (30)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infections and infestations</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nasopharyngitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32 (15)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pneumonia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24 (11)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper respiratory tract infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>28 (13)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Injury, poisoning, and procedural complications</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Post procedural hemorrhage</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and nutrition disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anorexia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45 (21)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Arthralgia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>49 (22)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Chest wall pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Myalgia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35 (16)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>41 (19)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>48 (22)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (11)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Psychiatric disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anxiety</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (13)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24 (11)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>64 (29)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (12)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dry skin</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Ecchymosis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>67 (31)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14 (15)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Erythema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>37 (17)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>31 (14)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (10)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Skin nodule</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urticaria</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hematoma</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19 (9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypotension</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Petechiae</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>52 (24)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>8 (9)</paragraph></td></tr></tbody></table>

<table ID="_RefID0EMEAG" width="100%"><caption>Table 2: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in the Azacitidine -Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)</caption><col width="35%"/><col width="14%"/><col width="21%"/><col width="14%"/><col width="17%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Number (%) of Patients</content></th></tr><tr><th align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><content styleCode="bold">Any Grade</content></th><th align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><content styleCode="bold">Grade 3/4</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Body System Adverse Reactions ^a</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Azacitidine</content> <content styleCode="bold">(N=175)</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Best</content> <content styleCode="bold">Supportive</content> <content styleCode="bold">Care Only</content> <content styleCode="bold">(N= 102)</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Azacitidine</content> <content styleCode="bold">(N=175)</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><content styleCode="bold">Best</content> <content styleCode="bold">Supportive</content> <content styleCode="bold">Care Only</content> <content styleCode="bold">(N= 102)</content></th></tr></thead><tfoot><tr><td align="left" colspan="5" valign="top">^aMultiple reports of the same preferred term from a patient were only counted once within each treatment. </td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and lymphatic system disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>90 (51)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>45 (44)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24 (14)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24 (14)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (10)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22 (13)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>32 (18)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26 (15)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>115 (66)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (28)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>107 (61)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22 (22)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Thrombocytopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>122 (70)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>35 (34)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>102 (58)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>29 (28)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abdominal pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>22 (13)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>88 (50)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>84 (48)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (12)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>47 (27)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General disorders and administration site conditions</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>42 (24)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 (12)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site bruising</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site erythema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>75 (43)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site hematoma</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site induration</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>33 (19)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site rash</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reaction</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>51 (29)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>53 (30)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18 (18)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infections and infestations</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rhinitis</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>10 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper respiratory tract infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16 (9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urinary tract infection</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15 (9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Investigations</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Weight decreased</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14 (8)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and nutrition disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lethargy</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Psychiatric disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anxiety</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15 (9)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Renal and urinary disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hematuria</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26 (15)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspnea exertional</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9 (5)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pharyngolaryngeal pain</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>11 (6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Erythema</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Petechiae</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20 (11)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4 (4)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pruritus</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>21 (12)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18 (10)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 (1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular disorders</content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Hypertension</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>15 (9)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>4 (4)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2 (1)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2 (2)</paragraph></td></tr></tbody></table>