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WARNING
GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE
The incidence of gastrointestinal perforation, some fatal, in bevacizumab product-treated patients ranges from 0.3 to 3.2%. Discontinue MVASI in patients with gastrointestinal perforation [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in bevacizumab product-treated patients. Discontinue MVASI in patients with wound dehiscence. The appropriate interval between termination of bevacizumab products and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate MVASI for at least 28 days after surgery and until the surgical wound is fully healed [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five-fold more frequently in patients receiving bevacizumab products. Do not administer MVASI to patients with serious hemorrhage or recent hemoptysis [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
MVASI (bevacizumab-awwb) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab products contain human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. MVASI has an approximate molecular weight of 149 kD. MVASI is produced in a mammalian cell (Chinese Hamster Ovary) expression system.
MVASI is a colorless to pale yellow, sterile, pH 6.2 solution for intravenous infusion. MVASI is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of bevacizumab-awwb (25 mg/mL). The 100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.
The following clinically significant adverse reactions are described elsewhere in the labeling:
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 bevacizumab 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 another cancer, at the recommended dose and schedule for a median of 6 to 23 doses. The most common adverse reactions observed in patients receiving bevacizumab 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, bevacizumab was discontinued in 8% to 22% of patients because of adverse reactions [see Clinical Studies (14)].
In Combination with bolus-IFL
The safety of bevacizumab was evaluated in 392 patients who received at least one dose of bevacizumab in a double-blind, active-controlled study (AVF2107g), which compared bevacizumab (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, bevacizumab with bolus-IFL, or bevacizumab 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 Bevacizumab vs. Placebo in Study AVF2107g
| Adverse Reactiona | Bevacizumab 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% |
| a NCI-CTC version 3. | ||
In Combination with FOLFOX4
The safety of bevacizumab 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, bevacizumab (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1) with FOLFOX4, or bevacizumab alone (10 mg/kg every 2 weeks). Bevacizumab 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 bevacizumab 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.
The safety of bevacizumab was evaluated as first-line treatment in 422 patients with unresectable NSCLC who received at least one dose of bevacizumab 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 bevacizumab (15 mg/kg every 3 weeks). After completion or upon discontinuation of chemotherapy, patients randomized to receive bevacizumab continued to receive bevacizumab 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 bevacizumab 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%).
The safety of bevacizumab 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 bevacizumab and are considered safety evaluable [see Clinical Studies (14.4)]. Patients were randomized (2:1) to receive bevacizumab (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 bevacizumab with lomustine arm, 22% of patients discontinued treatment due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving bevacizumab with lomustine, the adverse reaction profile was similar to that observed in other approved indications.
The safety of bevacizumab was evaluated in 337 patients who received at least one dose of bevacizumab in a multicenter, double-blind study (BO17705) in patients with mRCC. Patients who had undergone a nephrectomy were randomized (1:1) to receive either bevacizumab (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 Bevacizumab vs. Placebo with Interferon-Alfa in Study BO17705
| Adverse Reactiona | Bevacizumab 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% |
| a NCI-CTC version 3. | ||
The following adverse reactions were reported at a 5-fold greater incidence in patients receiving bevacizumab 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).
The safety of bevacizumab was evaluated in 218 patients who received at least one dose of bevacizumab 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 bevacizumab (15 mg/kg every 3 weeks), or paclitaxel and topotecan with or without bevacizumab (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 bevacizumab 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
Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study GOG-0240
| Adverse Reactiona | Bevacizumab 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% | 0.0% |
| Reproductive system and breast | ||
| Pelvic pain | 14% | 8% |
| Hematology | ||
| Neutropenia | 12% | 6% |
| Lymphopenia | 12% | 5% |
| a NCI-CTC version 3. | ||
Stage III or IV Following Initial Surgical Resection
The safety of bevacizumab was evaluated in GOG-0218, a multicenter, randomized, double-blind, placebo controlled, three arm study, which evaluated the addition of bevacizumab 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 bevacizumab (CPP), carboplatin and paclitaxel with bevacizumab for up to six cycles (CPB15), or carboplatin and paclitaxel with bevacizumab for six cycles followed by bevacizumab as a single agent for up to 16 additional doses (CPB15+). Bevacizumab was given at 15 mg/kg every three weeks. On this trial, 1215 patients received at least one dose of bevacizumab. 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 bevacizumab 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 Bevacizumab
with Chemotherapy vs. Chemotherapy Alone in GOG-0218
| Adverse Reactiona | Bevacizumab with carboplatin and paclitaxel followed by bevacizumab alone* (N=608) |
Bevacizumab with carboplatin and paclitaxel** (N= 607) |
Carboplatin and paclitaxel*** (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% | 17% |
| Dyspnea | 26% | 28% | 20% |
| Nasal mucosal disorder | 10% | 7% | 4% |
| a NCI-CTC version 3, * CPB15+, ** CPB15, ***CPP | |||
Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
The safety of bevacizumab was evaluated in 179 patients who received at least one dose of bevacizumab in a multicenter, open-label study (MO22224) in which patients were randomized (1:1) to bevacizumab 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 bevacizumab 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 bevacizumab 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 bevacizumab 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
Bevacizumab with Chemotherapy vs. Chemotherapy Alone in Study MO22224
| Adverse Reactiona | Bevacizumab 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% |
| aNCI-CTC version 3 | ||
Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Study AVF4095g
The safety of bevacizumab was evaluated in 247 patients who received at least one dose of bevacizumab 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 bevacizumab (15 mg/kg) or placebo every 3 weeks with carboplatin and gemcitabine for 6 to 10 cycles followed by bevacizumab 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 bevacizumab 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 Bevacizumab
with Chemotherapy vs. Placebo with Chemotherapy in Study AVF4095g
| Adverse Reactiona | Bevacizumab 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% |
| a NCI-CTC version 3 | ||
Study GOG-0213
The safety of bevacizumab 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 bevacizumab (15 mg/kg every 3 weeks) with carboplatin and paclitaxel for 6 to 8 cycles followed by bevacizumab 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 bevacizumab 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 Bevacizumab
with Chemotherapy vs. Chemotherapy Alone in Study GOG-0213
| Adverse Reactiona | Bevacizumab 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 disorde | 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% |
| a NCI-CTC version 3 | ||
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 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.
The following adverse reactions have been identified during postapproval use of bevacizumab products. 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
No clinically meaningful effect on the pharmacokinetics of irinotecan or its active metabolite SN38, interferon-alfa, carboplatin or paclitaxel was observed when bevacizumab was administered in combination with these drugs; however, 3 of the 8 patients receiving bevacizumab 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.
Included as part of the PRECAUTIONS section.
Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving bevacizumab products 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 bevacizumab products 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 MVASI 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.
In a controlled clinical study in which bevacizumab 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 bevacizumab and 4% in patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound healing events was 5% in patients who received bevacizumab and 0.7% in patients who did not receive bevacizumab [see Adverse Reactions (6.1)].
In patients who experience wound healing complications during MVASI treatment, withhold MVASI 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 bevacizumab products after resolution of wound healing complications has not been established [see Dosage and Administration (2.7)].
Necrotizing fasciitis including fatal cases, has been reported in patients receiving bevacizumab, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue MVASI in patients who develop necrotizing fasciitis.
Bevacizumab products 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 bevacizumab 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 bevacizumab [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 bevacizumab with chemotherapy compared to none of the patients receiving chemotherapy alone.
Do not administer MVASI to patients with recent history of hemoptysis of 1/2 teaspoon or more of red blood. Discontinue in patients who develop a Grade 3-4 hemorrhage.
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 bevacizumab compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3-5 ATE was 5% in patients receiving bevacizumab 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 bevacizumab products after an ATE is resolved is not known.
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 bevacizumab 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 bevacizumab with chemotherapy compared to 2% in patients receiving chemotherapy alone.
Discontinue MVASI in patients with a Grade 4 VTE, including pulmonary embolism.
Severe hypertension occurred at a higher incidence in patients receiving bevacizumab products 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 MVASI. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with MVASI-induced or -exacerbated hypertension after discontinuing MVASI. Withhold MVASI 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.
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 MVASI in patients who develop PRES. Symptoms usually resolve or improve within days after discontinuing bevacizumab products, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating bevacizumab products in patients who developed PRES is not known.
The incidence and severity of proteinuria was higher in patients receiving bevacizumab 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 bevacizumab. 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 bevacizumab 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 bevacizumab 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. Bevacizumab was reinitiated in 42% of patients. Of the 113 patients who reinitiated bevacizumab, 48% experienced a second episode of Grades 2-4 proteinuria.
Nephrotic syndrome occurred in < 1% of patients receiving bevacizumab 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 bevacizumab 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 bevacizumab. Serum creatinine levels did not return to baseline in approximately one-third of patients who received bevacizumab.
Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during MVASI 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)].
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).
Based on its mechanism of action and findings from animal studies, bevacizumab products 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 MVASI and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving bevacizumab with chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After discontinuing bevacizumab, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% of women receiving bevacizumab. 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 bevacizumab products on fertility are unknown. Inform females of reproductive potential of the risk of ovarian failure prior to initiating MVASI [see Adverse Reactions (6.1), Use in Specific Populations (8.3)].
MVASI is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade ≥ 3 left ventricular dysfunction was 1% in patients receiving bevacizumab compared to 0.6% of patients receiving chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of congestive heart failure (CHF) was 4% for patients receiving bevacizumab 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 bevacizumab 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 bevacizumab 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 bevacizumab arm compared to 82% in the placebo arm. Discontinue MVASI in patients who develop CHF.
No studies have been conducted to assess potential of bevacizumab products for carcinogenicity or mutagenicity.
Bevacizumab products may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab exhibited arrested follicular development or absent corpora lutea as well as dose-related decreases in ovarian and uterine weights, endometrial proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point; however, decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained evident.
Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed time to wound closure.
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Bevacizumab products bind VEGF and prevent the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.
The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of bevacizumab every week, every 2 weeks, or every 3 weeks, bevacizumab pharmacokinetics are linear and the predicted time to reach more than 90% of steady state concentration is 84 days. The accumulation ratio following a dose of 10 mg/kg of bevacizumab once every 2 weeks is 2.8.
Population simulations of bevacizumab exposures provide a median trough concentration of 80.3 mcg/mL on Day 84 (10th, 90th percentile: 45, 128) following a dose of 5 mg/kg once every two weeks.
The mean (% coefficient of variation [CV%]) central volume of distribution is 2.9 (22%) L.
The mean (CV%) clearance is 0.23 (33) L/day. The estimated half-life is 20 days (11 to 50 days).
The clearance of bevacizumab varied by body weight, sex, and tumor burden. After correcting for body weight, males had a higher bevacizumab clearance (0.26 L/day vs. 0.21 L/day) and a larger central volume of distribution (3.2 L vs. 2.7 L) than females. Patients with higher tumor burden (at or above median value of tumor surface area) had a higher bevacizumab clearance (0.25 L/day vs. 0.20 L/day) than patients with tumor burdens below the median. In Study AVF2107g, there was no evidence of lesser efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated with bevacizumab as compared to females and patients with low tumor burden.
Bevacizumab products may increase the risk of developing gastrointestinal perforations and fistulae. Advise patients to immediately contact their health care provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, or vomiting [see Warnings and Precautions (5.1)].
Bevacizumab products can increase the risk of wound healing complications. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider [see Warnings and Precautions (5.2)].
Bevacizumab products can increase the risk of hemorrhage. Advise patients to immediately contact their health care provider for signs and symptoms of serious or unusual bleeding including coughing or spitting blood [see Warnings and Precautions (5.3)].
Bevacizumab products increase the risk of arterial and venous thromboembolic events. Advise patients to immediately contact their health care provider for signs and symptoms of arterial or venous thromboembolism [see Warnings and Precautions (5.4, 5.5)].
Bevacizumab products can increase blood pressure. Advise patients that they will undergo routine blood pressure monitoring and to contact their health care provider if they experience changes in blood pressure [see Warnings and Precautions (5.6)].
Posterior reversible encephalopathy syndrome (PRES) has been associated with bevacizumab products treatment. Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see Warnings and Precautions (5.7)].
Bevacizumab products increase the risk of proteinuria and renal injury, including nephrotic syndrome. Advise patients that treatment with MVASI requires regular monitoring of renal function and to contact their health care provider for proteinuria or signs and symptoms of nephrotic syndrome [see Warnings and Precautions (5.8)].
Bevacizumab products can cause infusion-related reactions. Advise patients to contact their health care provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.9)].
Bevacizumab products can increase the risk of developing congestive heart failure. Advise patients to contact their health care provider immediately for signs and symptoms of CHF [see Warnings and Precautions (5.12)].
Advise female patients that bevacizumab products may cause fetal harm and to inform their health care provider with a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with MVASI and for 6 months after the last dose [see Use in Specific Populations (8.3)].
Bevacizumab products may lead to ovarian failure. Advise patients of potential options for preservation of ova prior to starting treatment [see Warnings and Precautions (5.11)].
Advise women not to breastfeed during treatment with MVASI and for 6 months after the last dose [see Use in Specific Populations (8.2)].
