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)].

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*	Avastin with IFL (N=392)	Placebo with IFL (N=396)
* NCI-CTC version 3
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*	Avastin with Interferon Alfa (N=337)	Placebo with Interferon Alfa (N=304)
* NCI-CTC version 3
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*	Avastin with Chemotherapy (N=218)	Chemotherapy (N=222)
* NCI-CTC version 3
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*	Avastin with carboplatin and paclitaxel followed by Avastin alone† (N=608)	Avastin with carboplatin and paclitaxel‡ (N= 607)	Carboplatin and paclitaxel§ (N= 602)
* NCI-CTC version 3, † CPB15+, ‡ CPB15, § CPP
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*	Avastin with Chemotherapy (N=179)	Chemotherapy (N=181)
* NCI-CTC version 3
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*	Avastin with Carboplatin and Gemcitabine (N=247)	Placebo with Carboplatin and Gemcitabine (N=233)
* NCI-CTC version 3
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*	Avastin with Carboplatin and Paclitaxel (N=325)	Carboplatin and Paclitaxel (N=332)
* NCI-CTC version 3
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)
Adverse Reaction	All Grades* (%)	Grades 3–4* (%)	All Grades* (%)	Grades 3–4* (%)
2 Graded per NCI CTCAE v4.0
* Includes fatigue and asthenia
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)
Laboratory Abnormality	All Grades* (%)	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.
* Graded per NCI CTCAE v4.0
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