Avastin

5 WARNINGS AND PRECAUTIONS Gastrointestinal Perforations and Fistula : Discontinue for gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any organ ( 5.1 ) Surgery and Wound Healing Complications : In patients who experience wound healing complications during Avastin treatment, withhold Avastin until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days following a major surgery, and until adequate wound healing. The safety of resumption of AVASTIN after resolution of wound healing complication has not been established. Discontinue for wound healing complication of necrotizing fasciitis. ( 5.2 ) Hemorrhage: Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3-4 hemorrhage ( 5.3 ) Arterial Thromboembolic Events (ATE) : Discontinue for severe ATE. ( 5.4 ) Venous Thromboembolic Events (VTE) : Discontinue for Grade 4 VTE. ( 5.5 ) Hypertension : Monitor blood pressure and treat hypertension. Withhold if not medically controlled; resume once controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. ( 5.6 ) Posterior Reversible Encephalopathy Syndrome (PRES ) : Discontinue. ( 5.7 ) Renal Injury and Proteinuria : Monitor urine protein. Discontinue for nephrotic syndrome. Withhold until less than 2 grams of protein in urine. ( 5.8 ) Infusion-Related Reactions : Decrease rate for infusion-related reactions. Discontinue for severe infusion-related reactions and administer medical therapy. ( 5.9 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. ( 5.10 , 8.1 , 8.3 ) Ovarian Failure : Advise females of the potential risk. ( 5.11 , 8.3 ) Congestive Heart Failure (CHF) : Discontinue Avastin in patients who develop CHF. ( 5.12 ) 5.1 Gastrointestinal Perforations and Fistulae Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical studies, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of perforations occurred within 50 days of the first dose [see Adverse Reactions (6.1) ] . Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites) occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The incidence ranged from < 1% to 1.8% across clinical studies, with the highest incidence in patients with cervical cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a diverting ostomy. Avoid Avastin in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Discontinue in patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue in patients with fistula formation involving any internal organ . 5.2 Surgery and Wound Healing Complications In a controlled clinical study in which Avastin was not administered within 28 days of major surgical procedures, the incidence of wound healing complications, including serious and fatal complications, was 15% in patients with mCRC who underwent surgery while receiving Avastin and 4% in patients who did not receive Avastin. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received Avastin and 0.7% in patients who did not receive Avastin [see Adverse Reactions (6.1) ]. In patients who experience wound healing complications during Avastin treatment, withhold Avastin until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days following major surgery and until adequate wound healing. The safety of resumption of AVASTIN after resolution of wound healing complications has not been established [see Dosage and Administration (2.9) ] . Necrotizing fasciitis including fatal cases, has been reported in patients receiving Avastin, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin in patients who develop necrotizing fasciitis . 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, which is most commonly Grade 1 epistaxis, and serious hemorrhage, which in some cases has been fatal. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-5 hemorrhagic events ranged from 0.4% to 7% in patients receiving Avastin [see Adverse Reactions (6.1) ]. Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC and 4% of patients with non-squamous NSCLC receiving Avastin with chemotherapy compared to none of the patients receiving chemotherapy alone. An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC. There is lack of clinical data to support the safety of Avastin in patients with variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding because these patients were excluded from clinical trials of Avastin in HCC [see Clinical Studies (14.10) ] . Do not administer Avastin to patients with recent history of hemoptysis of 1/2 teaspoon or more of red blood. Discontinue in patients who develop a Grades 3-4 hemorrhage. 5.4 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3-5 ATE was 5% in patients receiving Avastin with chemotherapy compared to ≤2% in patients receiving chemotherapy alone; the highest incidence occurred in patients with GBM. The risk of developing ATE was increased in patients with a history of arterial thromboembolism, diabetes, or >65 years [see Use in Specific Populations (8.5) ]. Discontinue in patients who develop a severe ATE. The safety of reinitiating Avastin after an ATE is resolved is not known. 5.5 Venous Thromboembolic Events An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see Adverse Reactions (6.1) ] . In Study GOG-0240, Grades 3-4 VTE occurred in 11% of patients receiving Avastin with chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of Grades 3-4 VTE was 5% in patients receiving Avastin with chemotherapy compared to 2% in patients receiving chemotherapy alone. Discontinue Avastin in patients with a Grade 4 VTE, including pulmonary embolism . 5.6 Hypertension Severe hypertension occurred at a higher incidence in patients receiving Avastin as compared to patients receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-4 hypertension ranged from 5% to 18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuing Avastin. Withhold Avastin in patients with severe hypertension that is not controlled with medical management; resume once controlled with medical management. Discontinue in patients who develop hypertensive crisis or hypertensive encephalopathy. 5.7 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) was reported in < 0.5% of patients across clinical studies. The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. Discontinue Avastin in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing Avastin, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin in patients who developed PRES is not known. 5.8 Renal Injury and Proteinuria The incidence and severity of proteinuria was higher in patients receiving Avastin as compared to patients receiving chemotherapy. Grade 3 (defined as urine dipstick 4+ or > 3.5 grams of protein per 24 hours) to Grade 4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies. The overall incidence of proteinuria (all grades) was only adequately assessed in Study BO17705, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (15 days to 37 months) after initiating Avastin. Median time to resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required discontinuation of Avastin in 30% of the patients who developed proteinuria [see Adverse Reactions (6.1) ] . In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving Avastin with chemotherapy experienced Grades 2-4 (defined as urine dipstick 2+ or greater or > 1 gram of protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2-4 proteinuria resolved in 74% of patients. Avastin was reinitiated in 42% of patients. Of the 113 patients who reinitiated Avastin, 48% experienced a second episode of Grades 2-4 proteinuria. Nephrotic syndrome occurred in < 1% of patients receiving Avastin across clinical studies, in some instances with fatal outcome. In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who received Avastin with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of elevated serum creatinine levels (between 1.5 to 1.9 times baseline levels) in patients who received Avastin. Serum creatinine levels did not return to baseline in approximately one-third of patients who received Avastin. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Withhold for proteinuria greater than or equal to 2 grams per 24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24-hour urine protein [Pearson Correlation 0.39 (95% CI: 0.17, 0.57)] . 5.9 Infusion-Related Reactions Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions with the first dose occurred in < 3% of patients and severe reactions occurred in 0.4% of patients. Decrease the rate of infusion for mild, clinically insignificant infusion-related reactions. Interrupt the infusion in patients with clinically significant infusion-related reactions and consider resuming at a slower rate following resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriate medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen). 5.10 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, Avastin may cause fetal harm when administered to pregnant women. Congenital malformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ]. 5.11 Ovarian Failure The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After discontinuing Avastin, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% of women receiving Avastin. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or an FSH level < 30 mIU/mL during the post-treatment period. Long-term effects of Avastin on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to initiating Avastin [see Adverse Reactions (6.1) , Use in Specific Populations (8.3) ]. 5.12 Congestive Heart Failure (CHF) Avastin is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥ 3 left ventricular dysfunction was 1% in patients receiving Avastin compared to 0.6% of patients receiving chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of CHF was 4% for patients receiving Avastin with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone. In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left ventricular ejection fraction (LVEF) were increased in patients receiving Avastin with anthracycline-based chemotherapy compared to patients receiving placebo with the same chemotherapy regimen. The proportion of patients with a decline in LVEF from baseline of ≥ 20% or a decline from baseline of 10% to < 50%, was 10% in patients receiving Avastin with chemotherapy compared to 5% in patients receiving chemotherapy alone. Time to onset of left-ventricular dysfunction or CHF was 1 to 6 months after the first dose in at least 85% of the patients and was resolved in 62% of the patients who developed CHF in the Avastin arm compared to 82% in the placebo arm. Discontinue Avastin in patients who develop CHF.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1) ] . Surgery and Wound Healing Complications [see Warnings and Precautions (5.2) ]. Hemorrhage [see Warnings and Precautions (5.3) ]. Arterial Thromboembolic Events [see Warnings and Precautions (5.4) ]. Venous Thromboembolic Events [see Warnings and Precautions (5.5) ]. Hypertension [see Warnings and Precautions (5.6) ]. Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.7) ]. Renal Injury and Proteinuria [see Warnings and Precautions (5.8) ]. Infusion-Related Reactions [see Warnings and Precautions (5.9) ]. Ovarian Failure [see Warnings and Precautions (5.11) ]. Congestive Heart Failure [see Warnings and Precautions (5.12) ]. Most common adverse reactions incidence (incidence > 10%) are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech, Inc. at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety data in Warnings and Precautions and described below reflect exposure to Avastin in 4463 patients including those with mCRC (AVF2107g, E3200), non-squamous NSCLC (E4599), GBM (EORTC 26101), mRCC (BO17705), cervical cancer (GOG-0240), epithelial ovarian, fallopian tube, or primary peritoneal cancer (MO22224, AVF4095, GOG-0213, and GOG-0218), or HCC (IMbrave150) at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving Avastin as a single agent or in combination with other anti-cancer therapies at a rate > 10% were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across clinical studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14) ]. Metastatic Colorectal Cancer In Combination with bolus-IFL The safety of Avastin was evaluated in 392 patients who received at least one dose of Avastin in a double-blind, active-controlled study (AVF2107g), which compared Avastin (5 mg/kg every 2 weeks) with bolus-IFL to placebo with bolus-IFL in patients with mCRC [see Clinical Studies (14.1) ] . Patients were randomized (1:1:1) to placebo with bolus-IFL, Avastin with bolus-IFL, or Avastin with fluorouracil and leucovorin. The demographics of the safety population were similar to the demographics of the efficacy population. All Grades 3–4 adverse reactions and selected Grades 1–2 adverse reactions (i.e., hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 2 . Table 2: Grades 3-4 Adverse Reactions Occurring at Higher Incidence (≥2%) in Patients Receiving Avastin vs. Placebo in Study AVF2107g Adverse Reaction NCI-CTC version 3 Avastin with IFL (N=392) Placebo with IFL (N=396) Hematology Leukopenia 37% 31% Neutropenia 21% 14% Gastrointestinal Diarrhea 34% 25% Abdominal pain 8% 5% Constipation 4% 2% Vascular Hypertension 12% 2% Deep vein thrombosis 9% 5% Intra-abdominal thrombosis 3% 1% Syncope 3% 1% General Asthenia 10% 7% Pain 8% 5% In Combination with FOLFOX4 The safety of Avastin was evaluated in 521 patients in an open-label, active-controlled study (E3200) in patients who were previously treated with irinotecan and fluorouracil for initial therapy for mCRC. Patients were randomized (1:1:1) to FOLFOX4, Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4, or Avastin alone (10 mg/kg every 2 weeks). Avastin was continued until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Selected Grades 3–5 non-hematologic and Grades 4–5 hematologic occurring at a higher incidence (≥ 2%) in patients receiving Avastin with FOLFOX4 compared to FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse reaction rates due to the reporting mechanisms. First-Line Non Squamous Non-Small Cell Lung Cancer The safety of Avastin was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of Avastin in an active-controlled, open-label, multicenter trial (E4599) [see Clinical Studies (14.3) ] . Chemotherapy naïve patients with locally advanced, metastatic or recurrent non–squamous NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel and carboplatin with or without Avastin (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients randomized to receive Avastin continued to receive Avastin alone until disease progression or until unacceptable toxicity. The trial excluded patients with predominant squamous histology (mixed cell type tumors only), CNS metastasis, gross hemoptysis (1/2 teaspoon or more of red blood), unstable angina, or receiving therapeutic anticoagulation. The demographics of the safety population were similar to the demographics of the efficacy population. Only Grades 3-5 non-hematologic and Grades 4-5 hematologic adverse reactions were collected. Grades 3-5 non-hematologic and Grades 4-5 hematologic adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving Avastin with paclitaxel and carboplatin compared with patients receiving chemotherapy alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thromboembolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Recurrent Glioblastoma The safety of Avastin was evaluated in a multicenter, randomized, open-label study (EORTC 26101) in patients with recurrent GBM following radiotherapy and temozolomide of whom 278 patients received at least one dose of Avastin and are considered safety evaluable [see Clinical Studies (14.4) ] . Patients were randomized (2:1) to receive Avastin (10 mg/kg every 2 weeks) with lomustine or lomustine alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. In the Avastin with lomustine arm, 22% of patients discontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving Avastin with lomustine, the adverse reaction profile was similar to that observed in other approved indications. Metastatic Renal Cell Carcinoma The safety of Avastin was evaluated in 337 patients who received at least one dose of Avastin in a multicenter, double-blind study (BO17705) in patients with mRCC. Patients who had undergone a nephrectomy were randomized (1:1) to receive either Avastin (10 mg/kg every 2 weeks) or placebo with interferon alfa [see Clinical Studies (14.5) ] . Patients were treated until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-5 adverse reactions occurring at a higher incidence ( >2%) were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Adverse reactions are presented in Table 3 . Table 3: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (≥5%) of Patients Receiving Avastin vs. Placebo with Interferon Alfa in Study BO17705 Adverse Reaction NCI-CTC version 3 Avastin with Interferon Alfa (N=337) Placebo with Interferon Alfa (N=304) Metabolism and nutrition Decreased appetite 36% 31% Weight loss 20% 15% General Fatigue 33% 27% Vascular Hypertension 28% 9% Respiratory, thoracic and mediastinal Epistaxis 27% 4% Dysphonia 5% 0% Nervous system Headache 24% 16% Gastrointestinal Diarrhea 21% 16% Renal and urinary Proteinuria 20% 3% Musculoskeletal and connective tissue Myalgia 19% 14% Back pain 12% 6% The following adverse reactions were reported at a 5-fold greater incidence in patients receiving Avastin with interferon-alfa compared to patients receiving placebo with interferon-alfa and not represented in Table 3 : gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs. 0); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs. 1); tinnitus (7 vs. 1); tooth abscess (7 vs. 0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). Persistent, Recurrent, or Metastatic Cervical Cancer The safety of Avastin was evaluated in 218 patients who received at least one dose of Avastin in a multicenter study (GOG-0240) in patients with persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.6) ] . Patients were randomized (1:1:1:1) to receive paclitaxel and cisplatin with or without Avastin (15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without Avastin (15 mg/kg every 3 weeks). The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in 218 patients receiving Avastin with chemotherapy compared to 222 patients receiving chemotherapy alone were abdominal pain (12% vs. 10%), hypertension (11% vs. 0.5%), thrombosis (8% vs. 3%), diarrhea (6% vs. 3%), anal fistula (4% vs. 0%), proctalgia (3% vs. 0%), urinary tract infection (8% vs. 6%), cellulitis (3% vs. 0.5%), fatigue (14% vs. 10%), hypokalemia (7% vs. 4%), hyponatremia (4% vs. 1%), dehydration (4% vs. 0.5%), neutropenia (8% vs. 4%), lymphopenia (6% vs. 3%), back pain (6% vs. 3%), and pelvic pain (6% vs. 1%). Adverse reactions are presented in Table 4 . Table 4: Grades 1-4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240 Adverse Reaction NCI-CTC version 3 Avastin with Chemotherapy (N=218) Chemotherapy (N=222) General Fatigue 80% 75% Peripheral edema 15% 22% Metabolism and nutrition Decreased appetite 34% 26% Hyperglycemia 26% 19% Hypomagnesemia 24% 15% Weight loss 21% 7% Hyponatremia 19% 10% Hypoalbuminemia 16% 11% Vascular Hypertension 29% 6% Thrombosis 10% 3% Infections Urinary tract infection 22% 14% Infection 10% 5% Nervous system Headache 22% 13% Dysarthria 8% 1% Psychiatric Anxiety 17% 10% Respiratory, thoracic and mediastinal Epistaxis 17% 1% Renal and urinary Increased blood creatinine 16% 10% Proteinuria 10% 3% Gastrointestinal Stomatitis 15% 10% Proctalgia 6% 1% Anal fistula 6% 0% Reproductive system and breast Pelvic pain 14% 8% Hematology Neutropenia 12% 6% Lymphopenia 12% 5% Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer Stage III or IV Following Initial Surgical Resection The safety of Avastin was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo controlled, three arm study, which evaluated the addition of Avastin to carboplatin and paclitaxel for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection [see Clinical Studies (14.7) ] . Patients were randomized (1:1:1) to carboplatin and paclitaxel without Avastin (CPP), carboplatin and paclitaxel with Avastin for up to six cycles (CPB15), or carboplatin and paclitaxel with Avastin for six cycles followed by Avastin as a single agent for up to 16 additional doses (CPB15+). Avastin was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of Avastin. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥2%) in either of the Avastin arms versus the control arm were fatigue (CPB15+ - 9%, CPB15 - 6%, CPP - 6%), hypertension (CPB15+ - 10%, CPB15 - 6%, CPP - 2%), thrombocytopenia (CPB15+ - 21%, CPB15 - 20%, CPP - 15%) and leukopenia (CPB15+ - 51%, CPB15 - 53%, CPP - 50%). Adverse reactions are presented in Table 5 . Table 5: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in GOG-0218 Adverse Reaction NCI-CTC version 3, Avastin with carboplatin and paclitaxel followed by Avastin alone CPB15+, (N=608) Avastin with carboplatin and paclitaxel CPB15, (N= 607) Carboplatin and paclitaxel CPP (N= 602) General Fatigue 80% 72% 73% Gastrointestinal Nausea 58% 53% 51% Diarrhea 38% 40% 34% Stomatitis 25% 19% 14% Musculoskeletal and connective tissue Arthralgia 41% 33% 35% Pain in extremity 25% 19% 17% Muscular weakness 15% 13% 9% Nervous system Headache 34% 26% 21% Dysarthria 12% 10% 2% Vascular Hypertension 32% 24% 14% Respiratory, thoracic and mediastinal Epistaxis 31% 30% 9% Dyspnea 26% 28% 20% Nasal mucosal disorder 10% 7% 4% Platinum - Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer The safety of Avastin was evaluated in 179 patients who received at least one dose of Avastin in a multicenter, open-label study (MO22224) in which patients were randomized (1:1) to Avastin with chemotherapy or chemotherapy alone in patients with platinum resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within < 6 months from the most recent platinum based therapy [see Clinical Studies (14.8) ] . Patients were randomized to receive Avastin 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks. Patients had received no more than 2 prior chemotherapy regimens. The trial excluded patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Patients were treated until disease progression or unacceptable toxicity. Forty percent of patients on the chemotherapy alone arm received Avastin alone upon progression. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence ( ≥ 2%) in 179 patients receiving Avastin with chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs. 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%). Adverse reactions are presented in Table 6 . Table 6: Grades 2–4 Adverse Reactions Occurring at Higher Incidence ( ≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study MO22224 Adverse Reaction NCI-CTC version 3 Avastin with Chemotherapy (N=179) Chemotherapy (N=181) Hematology Neutropenia 31% 25% Vascular Hypertension 19% 6% Nervous system Peripheral sensory neuropathy 18% 7% General Mucosal inflammation 13% 6% Renal and urinary Proteinuria 12% 0.6% Skin and subcutaneous tissue Palmar-plantar erythrodysaesthesia 11% 5% Infections Infection 11% 4% Respiratory, thoracic and mediastinal Epistaxis 5% 0% Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Study AVF4095g The safety of Avastin was evaluated in 247 patients who received at least one dose of Avastin in a double-blind study (AVF4095g) in patients with platinum sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer [see Clinical Studies (14.9 ] . Patients were randomized (1:1) to receive Avastin (15 mg/kg) or placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by Avastin or placebo alone until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving Avastin with chemotherapy compared to placebo with chemotherapy were: thrombocytopenia (40% vs. 34%), nausea (4% vs. 1.3%), fatigue (6% vs. 4%), headache (4% vs. 0.9%), proteinuria (10% vs. 0.4%), dyspnea (4% vs. 1.7%), epistaxis (5% vs. 0.4%), and hypertension (17% vs. 0.9%). Adverse reactions are presented in Table 7 . Table 7: Grades 1–5 Adverse Reactions Occurring at a Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g Adverse Reaction NCI-CTC version 3 Avastin with Carboplatin and Gemcitabine (N=247) Placebo with Carboplatin and Gemcitabine (N=233) General Fatigue 82% 75% Mucosal inflammation 15% 10% Gastrointestinal Nausea 72% 66% Diarrhea 38% 29% Stomatitis 15% 7% Hemorrhoids 8% 3% Gingival bleeding 7% 0% Hematology Thrombocytopenia 58% 51% Respiratory, thoracic and mediastinal Epistaxis 55% 14% Dyspnea 30% 24% Cough 26% 18% Oropharyngeal pain 16% 10% Dysphonia 13% 3% Rhinorrhea 10% 4% Sinus congestion 8% 2% Nervous system Headache 49% 30% Dizziness 23% 17% Vascular Hypertension 42% 9% Musculoskeletal and connective tissue Arthralgia 28% 19% Back pain 21% 13% Psychiatric Insomnia 21% 15% Renal and urinary Proteinuria 20% 3% Injury and procedural Contusion 17% 9% Infections Sinusitis 15% 9% Study GOG-0213 The safety of Avastin was evaluated in an open-label, controlled study (GOG-0213) in 325 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have not received more than one previous regimen of chemotherapy [see Clinical Studies (14.9) ] . Patients were randomized (1:1) to receive carboplatin and paclitaxel for 6 to 8 cycles or Avastin (15 mg/kg every 3 weeks) with carboplatin and paclitaxel for 6 to 8 cycles followed by Avastin as a single agent until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Grades 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in patients receiving Avastin with chemotherapy compared to chemotherapy alone were: hypertension (11% vs. 0.6%), fatigue (8% vs. 3%), febrile neutropenia (6% vs. 3%), proteinuria (8% vs. 0%), abdominal pain (6% vs. 0.9%), hyponatremia (4% vs. 0.9%), headache (3% vs. 0.9%), and pain in extremity (3% vs. 0%). Adverse reactions are presented in Table 8 . Table 8: Grades 1–5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213 Adverse Reaction NCI-CTC version 3 Avastin with Carboplatin and Paclitaxel (N=325) Carboplatin and Paclitaxel (N=332) Musculoskeletal and connective tissue Arthralgia 45% 30% Myalgia 29% 18% Pain in extremity 25% 14% Back pain 17% 10% Muscular weakness 13% 8% Neck pain 9% 0% Vascular Hypertension 42% 3% Gastrointestinal Diarrhea 39% 32% Abdominal pain 33% 28% Vomiting 33% 25% Stomatitis 33% 16% Nervous system Headache 38% 20% Dysarthria 14% 2% Dizziness 13% 8% Metabolism and nutrition Decreased appetite 35% 25% Hyperglycemia 31% 24% Hypomagnesemia 27% 17% Hyponatremia 17% 6% Weight loss 15% 4% Hypocalcemia 12% 5% Hypoalbuminemia 11% 6% Hyperkalemia 9% 3% Respiratory, thoracic and mediastinal Epistaxis 33% 2% Dyspnea 30% 25% Cough 30% 17% Rhinitis allergic 17% 4% Nasal mucosal disorder 14% 3% Skin and subcutaneous tissue Exfoliative rash 23% 16% Nail disorder 10% 2% Dry skin 7% 2% Renal and urinary Proteinuria 17% 1% Increased blood creatinine 13% 5% Hepatic Increased aspartate aminotransferase 15% 9% General Chest pain 8% 2% Infections Sinusitis 7% 2% Hepatocellular Carcinoma (HCC) The safety of Avastin in combination with atezolizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment [see Clinical Studies (14.10) ] . Patients received 1,200 mg of atezolizumab intravenously followed by 15 mg/kg Avastin (n=329) every 3 weeks, or 400 mg of sorafenib (n=156) given orally twice daily, until disease progression or unacceptable toxicity. The median duration of exposure to Avastin was 6.9 months (range: 0-16 months) and to atezolizumab was 7.4 months (range: 0-16 months). Fatal adverse reactions occurred in 4.6% of patients in the Avastin and atezolizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%). Serious adverse reactions occurred in 38% of patients in the Avastin and atezolizumab arm. The most frequent serious adverse reactions (≥ 2%) were gastrointestinal hemorrhage (7%), infections (6%), and pyrexia (2.1%). Adverse reactions leading to discontinuation of Avastin occurred in 15% of patients in the Avastin and atezolizumab arm. The most common adverse reactions leading to Avastin discontinuation were hemorrhages (4.9%), including bleeding varicose vein, hemorrhage and gastrointestinal, subarachnoid, and pulmonary hemorrhages; and increased transaminases or bilirubin (0.9%). Adverse reactions leading to interruption of Avastin occurred in 46% of patients in the Avastin and atezolizumab arm; the most common (≥ 2%) were proteinuria (6%); infections (6%); hypertension (6%); liver function laboratory abnormalities including increased transaminases, bilirubin, or alkaline phosphatase (4.6%); gastrointestinal hemorrhages (3%); thrombocytopenia/decreased platelet count (4.3%); and pyrexia (2.4%). Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received Avastin and atezolizumab in IMbrave150. Table 9: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving Avastin in IMbrave150 Adverse Reaction Avastin in combination with atezolizumab (n = 329) Sorafenib (n=156) All Grades Includes fatigue and asthenia (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) 2 Graded per NCI CTCAE v4.0 Vascular Disorders Hypertension 30 15 24 12 General Disorders and Administration Site Conditions Fatigue/asthenia 26 2 32 6 Pyrexia 18 0 10 0 Renal and Urinary Disorders Proteinuria 20 3 7 0.6 Investigations Weight Decreased 11 0 10 0 Skin and Subcutaneous Tissue Disorders Pruritus 19 0 10 0 Rash 12 0 17 2.6 Gastrointestinal Disorders Diarrhea 19 1.8 49 5 Constipation 13 0 14 0 Abdominal Pain 12 0 17 0 Nausea 12 0 16 0 Vomiting 10 0 8 0 Metabolism and Nutrition Disorders Decreased Appetite 18 1.2 24 3.8 Respiratory, Thoracic and Mediastinal Disorders Cough 12 0 10 0 Epistaxis 10 0 4.5 0 Injury, Poisoning and Procedural Complications Infusion Related Reaction 11 2.4 0 0 Table 10: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients with HCC Receiving Avastin in IMbrave150 Laboratory Abnormality Avastin in combination with atezolizumab (n=329) Sorafenib (n=156) All Grades Graded per NCI CTCAE v4.0 (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Avastin plus atezolizumab (222-323) and sorafenib (90-153) NA = Not applicable. Chemistry Increased AST 86 16 90 16 Increased Alkaline Phosphatase 70 4 76 4.6 Increased ALT 62 8 70 4.6 Decreased Albumin 60 1.5 54 0.7 Decreased Sodium 54 13 49 9 Increased Glucose 48 9 43 4.6 Decreased Calcium 30 0.3 35 1.3 Decreased Phosphorus 26 4.7 58 16 Increased Potassium 23 1.9 16 2 Hypomagnesemia 22 0 22 0 Hematology Decreased Platelet 68 7 63 4.6 Decreased Lymphocytes 62 13 58 11 Decreased Hemoglobin 58 3.1 62 3.9 Increased Bilirubin 57 8 59 14 Decreased Leukocyte 32 3.4 29 1.3 Decreased Neutrophil 23 2.3 16 1.1 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bevacizumab in the studies described below with the incidence of antibodies in other studies or to other bevacizumab products may be misleading. In clinical studies for adjuvant treatment of a solid tumor, 0.6% (14/2233) of patients tested positive for treatment-emergent anti-bevacizumab antibodies as detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-bevacizumab antibodies is not known. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Avastin. 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. General: Polyserositis Cardiovascular: Pulmonary hypertension, Mesenteric venous occlusion Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal and Connective Tissue Disorders: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

<table width="75%" ID="table2"><caption>Table 2: Grades 3-4 Adverse Reactions Occurring at Higher Incidence (&#x2265;2%) in Patients Receiving Avastin vs. Placebo in Study AVF2107g</caption><col width="34%" align="left" valign="middle"/><col width="33%" align="center" valign="middle"/><col width="33%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="middle">Adverse Reaction<footnote>NCI-CTC version 3</footnote></th><th styleCode="Rrule">Avastin with IFL (N=392)</th><th styleCode="Rrule">Placebo with IFL (N=396)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Leukopenia</td><td styleCode="Rrule">37%</td><td styleCode="Rrule">31%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">21%</td><td styleCode="Rrule">14%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">34%</td><td styleCode="Rrule">25%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Vascular</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertension</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Deep vein thrombosis</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Intra-abdominal thrombosis</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Syncope</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Asthenia</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">7%</td></tr><tr><td styleCode="Lrule Rrule"> Pain</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">5%</td></tr></tbody></table>

<table width="75%" ID="table3"><caption>Table 3: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (&#x2265;5%) of Patients Receiving Avastin vs. Placebo with Interferon Alfa in Study BO17705</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction<footnote>NCI-CTC version 3</footnote></th><th styleCode="Rrule">Avastin with Interferon Alfa (N=337)</th><th styleCode="Rrule">Placebo with Interferon Alfa (N=304)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and nutrition</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">36%</td><td styleCode="Rrule">31%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Weight loss</td><td styleCode="Rrule">20%</td><td styleCode="Rrule">15%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">33%</td><td styleCode="Rrule">27%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Vascular</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertension</td><td styleCode="Rrule">28%</td><td styleCode="Rrule">9%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory, thoracic and mediastinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Epistaxis</td><td styleCode="Rrule">27%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysphonia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Nervous system</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">24%</td><td styleCode="Rrule">16%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">21%</td><td styleCode="Rrule">16%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Renal and urinary</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Proteinuria</td><td styleCode="Rrule">20%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Musculoskeletal and connective tissue </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Myalgia</td><td styleCode="Rrule">19%</td><td styleCode="Rrule">14%</td></tr><tr><td styleCode="Lrule Rrule"> Back pain</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">6%</td></tr></tbody></table>

<table width="75%" ID="table4"><caption>Table 4: Grades 1-4 Adverse Reactions Occurring at Higher Incidence (&#x2265; 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction<footnote>NCI-CTC version 3</footnote></th><th styleCode="Rrule">Avastin with Chemotherapy (N=218)</th><th styleCode="Rrule">Chemotherapy (N=222)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">80%</td><td styleCode="Rrule">75%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral edema</td><td styleCode="Rrule">15%</td><td styleCode="Rrule">22%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and nutrition</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">34%</td><td styleCode="Rrule">26%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hyperglycemia</td><td styleCode="Rrule">26%</td><td styleCode="Rrule">19%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypomagnesemia</td><td styleCode="Rrule">24%</td><td styleCode="Rrule">15%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Weight loss</td><td styleCode="Rrule">21%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hyponatremia</td><td styleCode="Rrule">19%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypoalbuminemia</td><td styleCode="Rrule">16%</td><td styleCode="Rrule">11%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Vascular</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertension</td><td styleCode="Rrule">29%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Thrombosis</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Urinary tract infection</td><td styleCode="Rrule">22%</td><td styleCode="Rrule">14%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Infection</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Nervous system</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">22%</td><td styleCode="Rrule">13%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysarthria</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Psychiatric</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anxiety</td><td styleCode="Rrule">17%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory, thoracic and mediastinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Epistaxis</td><td styleCode="Rrule">17%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Renal and urinary</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased blood creatinine</td><td styleCode="Rrule">16%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Proteinuria</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Stomatitis</td><td styleCode="Rrule">15%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Proctalgia</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anal fistula</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Reproductive system and breast</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pelvic pain</td><td styleCode="Rrule">14%</td><td styleCode="Rrule">8%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutropenia</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">6%</td></tr><tr><td styleCode="Lrule Rrule"> Lymphopenia</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">5%</td></tr></tbody></table>