Bevacizumab
Vascular Endothelial Growth Factor Inhibitor [EPC]
What it is used for
of: Metastatic colorectal cancer, in combination with intravenous 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 bevacizumab product-containing regimen. ( 1.1 ) Limitations of Use : MVASI 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 MVASI 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 MVASI as a single agent, for platinum-sensitive recurrent disease ( 1.6 ) 1.1 Metastatic Colorectal Cancer MVASI, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer (mCRC). MVASI, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product-containing regimen. Limitations of Use : MVASI 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 MVASI, 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 (NSCLC). 1.3 Recurrent Glioblastoma MVASI is indicated for the treatment of recurrent glioblastoma (GBM) in adults. 1.4 Metastatic Renal Cell Carcinoma MVASI, in combination with interferon-alfa, is indicated for the treatment of metastatic renal cell carcinoma (mRCC). 1.5 Persistent, Recurrent, or Metastatic Cervical Cancer MVASI, 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 MVASI, in combination with carboplatin and paclitaxel, followed by MVASI 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. MVASI, 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. MVASI, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by MVASI as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Warnings
5 WARNINGS AND PRECAUTIONS Gastrointestinal Perforations and Fistula : Discontinue for gastrointestinal perforations, tracheoesophageal fistula, Grade 4 fistula, or fistula formation involving any organ. ( 5.1 ) Surgery and Wound Healing Complications : In patients who experience wound healing complications during MVASI treatment, withhold MVASI until adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer MVASI for at least 28 days following a major surgery, and until adequate wound healing. The safety of resumption of bevacizumab products after resolution of wound healing complication has not been established. Discontinue for wound healing complication of necrotizing fasciitis. ( 5.2 ) Hemorrhage : Severe or fatal hemorrhages have occurred. Do not administer for recent hemoptysis. Discontinue for Grade 3-4 hemorrhage. ( 5.3 ) Arterial Thromboembolic Events (ATE) : Discontinue for severe ATE. ( 5.4 ) Venous Thromboembolic Events (VTE) : Discontinue for Grade 4 VTE. ( 5.5 ) Hypertension : Monitor blood pressure and treat hypertension. Withhold if not medically controlled; resume once controlled. Discontinue for hypertensive crisis or hypertensive encephalopathy. ( 5.6 ) Posterior Reversible Encephalopathy Syndrome (PRES) : Discontinue. ( 5.7 ) Renal Injury and Proteinuria : Monitor urine protein. Discontinue for nephrotic syndrome. Withhold until less than 2 grams of protein in urine. ( 5.8 ) Infusion-Related Reactions : Decrease rate for infusion-related reactions. Discontinue for severe infusion-related reactions and administer medical therapy. ( 5.9 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception. ( 5.10 , 8.1 , 8.3 ) Ovarian Failure : Advise females of the potential risk. ( 5.11 , 8.3 ) Congestive Heart Failure (CHF) : Discontinue MVASI in patients who develop CHF. ( 5.12 ) 5.1 Gastrointestinal Perforations and Fistulae Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving 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. 5.2 Surgery and Wound Healing Complications 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. 5.3 Hemorrhage 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. 5.4 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina occurred at a higher incidence in patients receiving 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. 5.5 Venous Thromboembolic Events An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see Adverse Reactions (6.1) ] . In Study GOG-0240, Grades 3-4 VTE occurred in 11% of patients receiving 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. 5.6 Hypertension 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. 5.7 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) was reported in < 0.5% of patients across clinical studies. The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. Discontinue 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. 5.8 Renal Injury and Proteinuria 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)]. 5.9 Infusion-Related Reactions Infusion-related reactions reported across clinical studies and postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, anaphylactoid/anaphylactic reactions, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion-related reactions with the first dose occurred in < 3% of patients and severe reactions occurred in 0.4% of patients. Decrease the rate of infusion for mild, clinically insignifi
Possible side effects
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Gastrointestinal Perforations and Fistulae [see Warnings and Precautions (5.1) ] . Surgery and Wound Healing Complications [see Warnings and Precautions (5.2) ] . Hemorrhage [see Warnings and Precautions (5.3) ] . Arterial Thromboembolic Events [see Warnings and Precautions (5.4) ] . Venous Thromboembolic Events [see Warnings and Precautions (5.5) ] . Hypertension [see Warnings and Precautions (5.6) ] . Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.7) ] . Renal Injury and Proteinuria [see Warnings and Precautions (5.8) ] . Infusion-Related Reactions [see Warnings and Precautions (5.9) ] . Ovarian Failure [see Warnings and Precautions (5.11) ] . Congestive Heart Failure [see Warnings and Precautions (5.12) ] . Most common adverse reactions incidence (incidence > 10%) are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety data in Warnings and Precautions and described below reflect exposure to 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) ] . Metastatic Colorectal Cancer 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 Reaction NCI-CTC version 3. 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% 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. First-Line Non-Squamous Non-Small Cell Lung Cancer 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%). Recurrent Glioblastoma 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. Metastatic Renal Cell Carcinoma 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 Reaction NCI-CTC version 3. 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% 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). Persistent, Recurrent, or Metastatic Cervical Cancer 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 Reaction NCI-CTC version 3. 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
Storage
16 HOW SUPPLIED/STORAGE AND HANDLING MVASI (bevacizumab-awwb) injection is a clear to slightly opalescent, colorless to pale yellow, sterile solution for intravenous infusion supplied as single-dose vials in the following strengths: 100 mg/4 mL (25 mg/mL) (NDC 55513-206-01, 55513-206-21) and 400 mg/16 mL (25 mg/mL) (NDC 55513-207-01, 55513-207-21). Each carton contains one vial. Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton until time of use to protect from light. Do not freeze or shake the vial or carton.
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