Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE Avastin is a vascular endothelial growth factor directed antibody indicated for the treatment of: Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment. (1.1) Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen. (1.1) Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. (1.1) Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first-line treatment. (1.2) Recurrent glioblastoma in adults. (1.3) Metastatic renal cell carcinoma in combination with interferon alfa. (1.4) Persistent, recurrent, or metastatic cervical cancer, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan. (1.5) Epithelial ovarian, fallopian tube, or primary peritoneal cancer: in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection (1.6) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than 2 prior chemotherapy regimens (1.6) in combination with carboplatin and paclitaxel or carboplatin and gemcitabine, followed by Avastin as a single agent, for platinum-sensitive recurrent diesase (1.6) 1.1 Metastatic Colorectal Cancer (mCRC) Avastin, in combination with intravenous 5-fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer [see Clinical Studies (14.2)]. 1.2 First-Line Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer. 1.3 Recurrent Glioblastoma (GBM) Avastin is indicated for the treatment of recurrent glioblastoma in adults. 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma. 1.5 Persistent, Recurrent, or Metastatic Cervical Cancer Avastin, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer. 1.6 Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection. Avastin, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens. Avastin, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

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contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of 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 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, rectal 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 Trial 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 most common adverse reactions observed in patients receiving Avastin as a single agent or in combination with chemotherapy at a rate > 10%, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. The safety data below reflect exposure to Avastin in 4134 patients with mCRC, non-squamous NSCLC, glioblastoma, mRCC, cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer, including controlled studies (AVF2107g, E3200, E4599, EORTC 26101, BO17705, GOG-0240, MO22224, AVF4095, GOG-0213, and GOG-0218) at the recommended dose and schedule for a median of 6 to 23 doses. Across clinical studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14)]. Stage III or IV Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer Following Initial Surgical Resection GOG-0218 was a multicenter, randomized, double-blind, placebo controlled, three arm study evaluating 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. Patients were randomized (1:1:1) to be treated with 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. Adverse reactions are presented in Table 2. Table 2: Grade 1-5 Adverse Reactions Occuring at Higher Incidence ( ≥5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0218 Adverse reactionNCI-CTC version 3, Avastin with carboplatin and paclitaxel followed by Avastin aloneCPB15+, (N=608) Avastin with carboplatin and paclitaxelCPB15, (N= 607) Carboplatin and paclitaxelCPP (N= 602) Gastrointestinal disorders Diarrhea 38% 40% 34% Nausea 58% 53% 51% Stomatitis 25% 19% 14% General disorders and administration site conditions Fatigue 80% 72% 73% Musculoskeletal and connective tissue disorders Arthralgia 41% 33% 35% Muscular weakness 15% 13% 9% Pain in extremity 25% 19% 17% Nervous system disorders Dysarthria 12% 10% 2% Headache 34% 26% 21% Respiratory, thoracic and mediastinal disorders Dyspnea 26% 28% 20% Epistaxis 31% 30% 9% Nasal mucosal disorder 10% 7% 4% Vascular disorders Hypertension 32% 24% 14% Grade 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%), platelet count decreased (CPB15+ - 21%, CPB15 - 20%, CPP - 15%) and white blood cell count decreased (CPB15+ - 51%, CPB15 - 53%, CPP - 50%). 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. 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. Adverse reactions are presented in Table 3. Table 3: Grade 2−4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study MO22224 Adverse ReactionNCI-CTC version 3 Avastin with Chemotherapy (N=179) Chemotherapy (N=181) Blood and lymphatic system disorders Neutropenia 31% 25% General disorders Mucosal inflammation 13% 6% Infections Infection 11% 4% Nervous system disorders Peripheral sensory neuropathy 18% 7% Renal and urinary disorders Proteinuria 12% 0.6% Respiratory, thoracic and mediastinal disorders Epistaxis 5% 0% Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia 11% 5% Vascular disorders Hypertension 19% 6% Grade 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%). Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 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. 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. Adverse reactions are presented in Table 4. Table 4: Grade 1−5 Adverse Reactions Occurring at a Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g Adverse ReactionNCI-CTC version 3 Avastin with Carboplatin and Gemcitabine (N=247) Placebo with Carboplatin and Gemcitabine (N=233) Blood and lymphatic system disorders Thrombocytopenia 58% 51% Gastrointestinal disorders Nausea 72% 66% Diarrhea 38% 29% Stomatitis 15% 7% Hemorrhoids 8% 3% Gingival bleeding 7% 0% General disorders Fatigue 82% 75% Mucosal inflammation 15% 10% Infections Sinusitis 15% 9% Injury and procedural complications Contusion 17% 9% Musculoskeletal and connective tissue disorders Arthralgia 28% 19% Back pain 21% 13% Nervous system disorders Headache 49% 30% Dizziness 23% 17% Psychiatric disorders Insomnia 21% 15% Renal and urinary disorders Proteinuria 20% 3% Respiratory, thoracic and mediastinal disorders Epistaxis 55% 14% Dyspnea 30% 24% Cough 26% 18% Oropharyngeal pain 16% 10% Dysphonia 13% 3% Rhinorrhea 10% 4% Sinus congestion 8% 2% Vascular disorders Hypertension 42% 9% Grade 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%). 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. 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. Adverse reactions are presented in Table 5. Table 5: Grade 1−5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213 Adverse ReactionNCI-CTC version 3 Avastin with Carboplatin and Paclitaxel (N=325) Carboplatin and Paclitaxel (N=332) Gastrointestinal disorders Diarrhea 39% 32% Abdominal pain 33% 28% Vomiting 33% 25% Stomatitis 33% 16% Metabolism and nutrition disorders Decreased appetite 35% 25% Hyperglycemia 31% 24% Hypomagnesemia 27% 17% Hyponatremia 17% 6% Weight decreased 15% 4% Hypocalcemia 12% 5% Hypoalbuminemia 11% 6% Hyperkalemia 9% 3% Musculoskeletal and connective tissue disorders Arthralgia 45% 30% Myalgia 29% 18% Pain in extremity 25% 14% Back pain 17% 10% Muscular weakness 13% 8% Neck pain 9% 0% Respiratory, thoracic and mediastinal disorders Epistaxis 33% 2% Dyspnea 30% 25% Cough 30% 17% Rhinitis allergic 17% 4% Nasal mucosal disorder 14% 3% Nervous system disorders Headache 38% 20% Dysarthria 14% 2% Dizziness 13% 8% Hepatic Disorders Aspartate aminotransferase increased 15% 9% Skin and subcutaneous tissue disorders Exfoliative rash 23% 16% Nail disorder 10% 2% Dry skin 7% 2% Vascular disorders Hypertension 42% 3% Renal and urinary disorders Proteinuria 17% 1% Blood creatinine increased 13% 5% General disorders Chest pain 8% 2% Infections Sinusitis 7% 2% Grade 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%). Metastatic Renal Cell Carcinoma (mRCC) 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 metastatic renal cell carcinoma. 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. Patients were treated until disease progression or unacceptable toxicity. The demographics of the safety population were similar to the demographics of the efficacy population. Grade 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 6. Table 6: Grades 1-5 Adverse Reactions Occurring at Higher Incidence (≥ 5%) of Patients Receiving Avastin vs. Placebo with Interferon Alfa in Study BO17705 Adverse ReactionNCI-CTC version 3 Avastin with Interferon Alfa (N=337) Placebo with Interferon Alfa (N=304) Gastrointestinal disorders Diarrhea 21% 16% General disorders and administration site conditions Fatigue 33% 27% Metabolism and nutrition disorders Decreased appetite 36% 31% Weight decreased 20% 15% Musculoskeletal and connective tissue disorders Myalgia 19% 14% Back pain 12% 6% Nervous system disorders Headache 24% 16% Renal and urinary disorders Proteinuria 20% 3% Respiratory, thoracic and mediastinal disorders Epistaxis 27% 4% Dysphonia 5% 0% Vascular disorders Hypertension 28% 9% 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 4: 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. 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. Adverse reactions are presented in Table 7. Table 7: Grades 1-4 Adverse Reactions Occurring at Higher Incidence (≥ 5%) in Patients Receiving Avastin with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240 Adverse ReactionNCI-CTC version 3 Avastin with Chemotherapy (N=218) Chemotherapy (N=222) Metabolism and nutrition disorders Decreased appetite 34% 26% Hyperglycemia 26% 19% Hypomagnesemia 24% 15% Weight Decreased 21% 7% Hyponatremia 19% 10% Hypoalbuminemia 16% 11% General disorders Fatigue 80% 75% Edema Peripheral 15% 22% Infections and infestations Urinary Tract Infection 22% 14% Infection 10% 5% Vascular disorders Hypertension 29% 6% Thrombosis 10% 3% Nervous system disorders Headache 22% 13% Dysarthria 8% 1% Gastrointestinal disorders Stomatitis 15% 10% Proctalgia 6% 1% Anal fistula 6% 0.0% Blood and lymphatic system disorders Neutropenia 12% 6% Lymphopenia 12% 5% Psychiatric disorders Anxiety 17% 10% Reproductive system and breast disorders Pelvic pain 14% 8% Respiratory, thoracic and mediastinal disorders Epistaxis 17% 1% Renal and urinary disorders Blood Creatinine Increased 16% 10% Proteinuria 10% 3% Grade 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%). Metastatic Colorectal Cancer (mCRC) 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. Patients were randomized (1:1:1) to placebo with bolus IFL, Avastin with bolus IFL, or Avastin with 5 fluorouracil and leucovorin. The demographics of the safety population were similar to the demographics of the efficacy population. All Grade 3–4 adverse reactions and selected Grade 1–2 adverse reactions (i.e., hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Adverse reactions are presented in Table 8. Table 8: Grade 3–4 Adverse Reactions Occurring at Higher Incidence (≥ 2%) in Patients Receiving Avastin vs. Placebo in Study AVF2107g Adverse ReactionNCI-CTC version 3 Avastin with IFL (N=392) Placebo with IFL (N=396) General disorders Asthenia 10% 7% Pain 8% 5% Vascular disorders Hypertension 12% 2% Deep Vein Thrombosis 9% 5% Intra-Abdominal Thrombosis 3% 1% Syncope 3% 1% Gastrointestinal disorders Diarrhea 34% 25% Abdominal Pain 8% 5% Constipation 4% 2% Blood and lymphatic disorders Leukopenia 37% 31% Neutropenia 21% 14% The safety of Avastin was evaluated in 521 patients in an open-label, active-controlled study (E3200). Patients who were previously treated with irinotecan and fluorouracil for initial therapy for metastatic colorectal cancer. 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. The most frequent adverse reactions (selected Grade 3–5 non-hematologic and Grade 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 event rates due to the reporting mechanisms. First-Line Non Squamous Non Small Cell Lung Cancer (NSCLC) 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). 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 Grade 3-5 non hematologic and Grade 4-5 hematologic adverse reactions were collected. Grade 3-5 non hematologic and Grade 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 EORTC 26101 was a multicenter, randomized, open-label study 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. 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. 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 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 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 post-approval 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. Body as a Whole: 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

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Dosing and administration
2 DOSAGE AND ADMINISTRATION Do not administer Avastin for 28 days following major surgery and until surgical wound is fully healed. (2.1) Metastatic colorectal cancer (2.2) 5 mg/kg every 2 weeks with bolus-IFL 10 mg/kg every 2 weeks with FOLFOX4 5 mg/ kg every 2 weeks or 7.5 mg/kg every 3 weeks with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy after progression on a first-line Avastin containing regimen First-Line Non–squamous non–small cell lung cancer (2.3) 15 mg/kg every 3 weeks with carboplatin and paclitaxel Recurrent glioblastoma (2.4) 10 mg/kg every 2 weeks Metastatic renal cell cancer ( 2.5) 10 mg/kg every 2 weeks with interferon alfa Persistent, recurrent, or metastatic cervical cancer (2.6) 15 mg/kg every 3 weeks with paclitaxel and cisplatin, or paclitaxel and topotecan Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection (2.7) 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (2.7) 10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or topotecan given every week 15 mg/kg every 3 weeks with topotecan given every 3 weeks Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (2.7) 15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6-8 cycles, followed by 15 mg/kg every 3 weeks as a single agent 15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6-10 cycles, followed by 15 mg/kg every 3 weeks as a single agent Administer as an intravenous infusion. (2.9) 2.1 Important Administration Information Do not administer Avastin until at least 28 days following surgery and the wound is fully healed. 2.2 Metastatic Colorectal Cancer (mCRC) The recommended dose when Avastin is administered in combination with intravenous 5-fluorouracil-based chemotherapy is: 5 mg/kg every 2 weeks intravenously in combination with bolus-IFL. 10 mg/kg every 2 weeks intravenously in combination with FOLFOX4. 5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line Avastin-containing regimen. 2.3 First-Line Non-Squamous Non-Small Cell Lung Cancer (NSCLC) The recommended dose is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel. 2.4 Recurrent Glioblastoma (GBM) The recommended dose is 10 mg/kg intravenously every 2 weeks. 2.5 Metastatic Renal Cell Carcinoma (mRCC) The recommended dose is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa. 2.6 Persistent, Recurrent, or Metastatic Cervical Cancer The recommended dose of Avastin is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan. 2.7 Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer Treatment of Stage III or IV Disease Following Initial Surgical Resection: The recommended dose is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles or until disease progression, whichever occurs earlier. Treatment of Recurrent Disease: Platinum Resistant The recommended dose is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan (every week). The recommended dose is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3 weeks). Platinum Sensitive The recommended dose is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for 6 to 8 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease progression. The recommended dose is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and gemcitabine for 6 to 10 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease progression. 2.8 Dose Modifications for Adverse Reactions Table 1 describes dose modifications for specific adverse reactions [see Warnings and Precautions (5)]. No dose reductions for Avastin are recommended. Table 1: Dose Modifications for Adverse Reactions Adverse Reaction Severity Dose Modification Gastrointestinal Perforation and fistulae [see Warnings and Precautions (5.1)]. Gastrointestinal perforation, any grade Tracheoesophageal fistula, any grade Fistula, Grade 4 Fistula formation involving any internal organ Discontinue Avastin Wound Healing Complications [see Warnings and Precautions (5.2)]. Wound healing complications requiring medical intervention Necrotizing fasciitis Discontinue Avastin Hemorrhage [see Warnings and Precautions (5.3)]. Grade 3 or 4 Discontinue Avastin Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more Withhold Avastin Thromboembolic Events [see Warnings and Precautions (5.4, 5.5)]. Arterial thromboembolism, severe Discontinue Avastin Venous thromboembolism, Grade 4 Discontinue Avastin Hypertension [see Warnings and Precautions (5.6)]. Hypertensive crisis Hypertensive encephalopathy Discontinue Avastin Hypertension, severe Withhold Avastin if not controlled with medical management; resume once controlled Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.7)]. Any Discontinue Avastin Renal Toxicity and Proteinuria [see Warnings and Precautions (5.8)]. Nephrotic syndrome Discontinue Avastin Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome Withhold Avastin until proteinuria less than 2 grams per 24 hours Infusion Reaction [see Warnings and Precautions (5.10)]. Severe infusion reaction Discontinue Avastin Clinically significant Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve Mild, clinically insignificant Decrease infusion rate Congestive Heart Failure [see Warnings and Precautions (5.12)]. Any Discontinue Avastin 2.9 Preparation and Administration Administration Administer as an intravenous infusion. First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated. Administer all subsequent infusions over 30 minutes if second infusion over 60 minutes is tolerated. Preparation Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Withdraw necessary amount of Avastin and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. Discard any unused portion left in a vial, as the product contains no preservatives. Store diluted Avastin solution at 2–8°C (36–46°F) for up to 8 hours. No incompatibilities between Avastin and polyvinylchloride or polyolefin bags have been observed.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breast feed. (8.2) 8.1 Pregnancy Risk Summary Avastin may cause fetal harm based on findings from animal studies and its mechanism of action. [see Clinical Pharmacology (12.1)]. Limited postmarketing reports describe cases of fetal malformations with use of Avastin in pregnancy; however, these reports are insufficient to determine drug associated risks. In animal reproduction studies, intravenous administration of bevacizumab to pregnant rabbits every 3 days during organogenesis at doses approximately 1 to 10 times the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight gain and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects [see Data]. Furthermore, animal models link angiogenesis and VEGF and VEGFR-2 to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Pregnant rabbits dosed with 10 mg/kg to 100 mg/kg bevacizumab (approximately 1 to 10 times the clinical dose of 10 mg/kg) every three days during the period of organogenesis (gestation day 6–18) exhibited decreases in maternal and fetal body weights and increased number of fetal resorptions. There were dose-related increases in the number of litters containing fetuses with any type of malformation (42% for the 0 mg/kg dose, 76% for the 30 mg/kg dose, and 95% for the 100 mg/kg dose) or fetal alterations (9% for the 0 mg/kg dose, 15% for the 30 mg/kg dose, and 61% for the 100 mg/kg dose). Skeletal deformities were observed at all dose levels, with some abnormalities including meningocele observed only at the 100 mg/kg dose level. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges. 8.2 Lactation Risk Summary No data are available regarding the presence of bevacizumab in human milk, the effects on the breast fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential for serious adverse reactions in breastfed infants from bevacizumab, advise women not to breastfeed during treatment with Avastin and for 6 months following the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Avastin may cause fetal harm when administered to a pregnant woman. [see Use in Specific Populations (8.1).] Advise female of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin. Infertility Females Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to the first-dose of Avastin. Long-term effects of Avastin on fertility are not known. In a clinical study of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in patients who received Avastin with chemotherapy (34%) compared patients who received chemotherapy alone (2%). After discontinuing Avastin with chemotherapy, recovery of ovarian function occurred in 22% of these patients. [see Warnings and Precautions (5.11), Adverse Reactions (6.1) .] 8.4 Pediatric Use The safety and effectiveness of Avastin in pediatric patients have not been established. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who have received Avastin. Avastin is not approved for use in patients under the age of 18 years. Antitumor activity was not observed among eight pediatric patients with relapsed glioblastoma receiving bevacizumab and irinotecan. Addition of Avastin to standard of care did not result in improved event-free survival in pediatric patients enrolled in two randomized clinical trials, one in high grade glioma (n= 121) and one in metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma (n= 154). Based on the population pharmacokinetics analysis of data from 152 pediatric patients with cancer (7 months to 21 years of age), clearance normalized by body weight in pediatrics was comparable to that in adults. Animal Data Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In an exploratory, pooled analysis of 1745 patients from five randomized, controlled studies, 35% patients were ≥ 65 years old. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age; however, the increase in the incidence of ATE was greater in patients ≥ 65 years (8% vs. 3%) as compared to patients < 65 years (2% vs. 1%) [see Warnings and Precautions (5.4)].

Interactions

7 DRUG INTERACTIONS No clinically meaningful effect on the pharmacokinetics of irinotecan or its active metabolite SN38, interferon alfa, carboplatin or paclitaxel was observed when Avastin was administered in combination with these drugs; however, 3 of the 8 patients receiving Avastin with paclitaxel and carboplatin had lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel and carboplatin alone had a greater paclitaxel exposure at Day 63 than at Day 0.

More information

Category Value
Authorisation number BLA125085
Agency product number 2S9ZZM9Q9V
Orphan designation No
Product NDC 50242-061,50242-060
Date First Approved 26-02-2004
Date Last Revised 19-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1657074
Storage and handling Store refrigerated at 2–8°C (36–46°F) in the original carton until time of use to protect from light. Do not freeze or shake the vial.
Marketing authorisation holder Genentech, Inc.
Warnings WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE See full prescribing information for complete boxed warning. Gastrointestinal Perforations: Discontinue for gastrointestinal perforation. (5.1) Surgery and Wound Healing Complications: Discontinue in patients who develop wound healing complications that require medical intervention. Withhold for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed. (5.2) Hemorrhage: Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3-4 hemorrhage (5.3) Gastrointestinal Perforations: The incidence of gastrointestinal perforation, some fatal, in patients receiving Avastin ranges from 0.3% to 3%. Discontinue Avastin in patients who develop gastrointestinal perforation [see Warnings and Precautions (5.1)]. Surgery and Wound Healing Complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in patients receiving Avastin. Discontinue Avastin in patients who develop wound healing complications that require medical intervention. Withhold Avastin at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery, and until the wound is fully healed [see Warnings and Precautions (5.2)]. Hemorrhages: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with a recent history of hemoptysis. Discontinue in patients who develop Grade 3-4 hemorrhage [see Warnings and Precautions (5.3)].