Drug: Avastin

Avastin (bevacizumab) 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 contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Avastin has an approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Avastin is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous infusion. Avastin is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Avastin (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 a,a-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.

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The following serious adverse reactions are discussed in greater detail in other sections of the label:
  • Gastrointestinal Perforations and Fistulae [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Non-Gastrointestinal Fistulae [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Surgery and Wound Healing Complications [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Hemorrhage [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Arterial Thromboembolic Events [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Venous Thromboembolic Events [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Hypertensive Crisis [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Posterior Reversible Encephalopathy Syndrome [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Proteinuria [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Infusion Reactions [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
  • Ovarian Failure [See WARNINGS AND PRECAUTIONS, Use in Specific Populations]
The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis Some of the adverse reactions are commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4996 patients with CRC, non-squamous NSCLC, glioblastoma, mRCC, or cervical cancer or platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer including controlled (Studies 1, 2, 4, 5, 8 9 and 10) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies] The population was aged 18-89 years (median 60 years), 42% male and 86% White. The population included 2184 first- and second-line mCRC patients who received a median of 10 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of Avastin, 218 cervical cancer patients who received a median of 6 doses of Avastin and 179 platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 1338 adjuvant CRC patients, including 669 female patients, who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone. In Study 6, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS] Venous Thromboembolic Events The overall incidence of Grade 3-4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone. In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%. Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5, 8 and 10. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re-initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re-initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See WARNINGS AND PRECAUTIONS] Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3-4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B-cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum P-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Avastin-treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum P-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Avastin exposure on fertility are unknown. [See WARNINGS AND PRECAUTIONS, Use In Specific Populations] Post-Treatment Vascular Events In an open-label, randomized, controlled trial of Avastin in adjuvant colorectal cancer, an indication for which Avastin is not approved, the overall incidence rate of post-treatment Grade ≥ 3 vascular events was 3.1% (41 of 1338) among patients receiving mFOLFOX6 plus Avastin, compared to 1.6% (21 of 1349) among patients receiving mFOLFOX6 alone. Post-treatment vascular events included arterial and venous thromboembolic events, ischemic events, and vascular aneurysms. Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3-4 adverse events and selected Grade 1-2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3-4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1. Table 1: NCI-CTC Grade 3-4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2%] Avastin vs. Control)
  Arm 1IFL + Placebo
(n = 396) Arm 2IFL + Avastin
(n = 392) NCI-CTC Grade 3-4 Events 74% 87% Body as a Whole   Asthenia 7% 10%   Abdominal Pain 5% 8%   Pain 5% 8% Cardiovascular   Hypertension 2% 12%   Deep Vein Thrombosis 5% 9%   Intra-Abdominal Thrombosis 1% 3%   Syncope 1% 3% Digestive   Diarrhea 25% 34%   Constipation 2% 4% Hemic/Lymphatic   Leukopenia 31% 37%   Neutropeniaa 14% 21% a Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. Grade 1-4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1-4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued. Table 2 : NCI-CTC Grade 1-4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 5%] in IFL+Avastin vs. IFL)
  Arm 1 IFL+ Placebo
(n = 98) Arm 2 IFL+ Avastin
(n = 102) Arm 3 5-FU/LV + Avastin
(n = 109) Body as a Whole   Pain 55% 61% 62%   Abdominal Pain 55% 61% 50%   Headache 19% 26% 26% Cardiovascular   Hypertension 14% 23% 34%   Hypotension 7% 15% 7%   Deep Vein Thrombosis 3% 9% 6% Digestive   Vomiting 47% 52% 47%   Anorexia 30% 43% 35%   Constipation 29% 40% 29%   Stomatitis 18% 32% 30%   Dyspepsia 15% 24% 17%   GI Hemorrhage 6% 24% 19%   Weight Loss 10% 15% 16%   Dry Mouth 2% 7% 4%   Colitis 1% 6% 1% Hemic/Lymphatic   Thrombocytopenia 0% 5% 5% Nervous   Dizziness 20% 26% 19% Respiratory   Upper Respiratory Infection 39% 47% 40%   Epistaxis 10% 35% 32%   Dyspnea 15% 26% 25%   Voice Alteration 2% 9% 6% Skin/Aroendases   Alopecia 26% 32% 6%   Skin Ulcer 1% 6% 6% Special Senses   Taste Disorder 9% 14% 21% Uroeenital   Proteinuria 24% 36% 36% Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving 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 used in Study 2. Avastin in Combination with Fluoropyrimidine-Irinotecan or Fluoropyrimidine-Oxaliplatin Based Chemotherapy in Second-line mCRC Patients who have Progressed on an Avastin Containing Regimen in First-line mCRC No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 5. Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events (occurring at a higher incidence ( ≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (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%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin-related adverse events (Grade 1-4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3-5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3-5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin compared to 304 patients receiving IFN-a plus placebo arm 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, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1-5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-a plus placebo arm are presented in Table 3. Table 3 : NCI-CTC Grades 1-5 Adverse Events in Study 8 (Occurring at Higher Incidence [ ≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo)
System Organ Class/
Preferred terma IFN-α + Placebo
(n = 304) IFN-α + Avastin
(n = 337) Gastrointestinal disorders   Diarrhea 16% 21% General disorders and administration site conditions   Fatigue 27% 33% Investigations   Weight decreased 15% 20% Metabolism and nutrition disorders   Anorexia 31% 36% Musculoskeletal and connective tissue disorders   Myalgia 14% 19%   Back pain 6% 12% Nervous system disorders   Headache  16% 24% Renal and urinary disorders   Proteinuria 3% 20% Respiratory, thoracic and mediastinal disorders   Epistaxis 4% 27%   Dysphonia 0% 5% Vascular disorders   Hypertension 9% 28% aAdverse events were encoded using MedDRA, Version 10.1. The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone 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 Carcinoma of the Cervix All grade adverse reactions were collected in Study 9. Grade 1-4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4. Table 4: NCI-CTC Grades 1-4 and 3-4 Adverse Reactions in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo + Avastin vs. Chemo Alone)
  Grade 1-4 reactions Grade 3-4 reactions Chemo Alone
(n=222) Chemo + Avastin
(n=218) Chemo Alone
(n=222) Chemo + Avastin
(n=218) Metabolism and Nutrition Disorders   Decreased Appetite 26% 34%       Hyperglycemia 19% 26%       Hypomagnesemia 15% 24%       Hyponatremia 10% 19%       Hypoalbuminemia 11% 16%     General Disorders and Administration Site Conditions   Fatigue 75% 80%       Edema Peripheral 22% 15%     Investigations   Weight Decreased 7% 21%       Blood Creatinine Increased 10% 16%     Infections and Infestations   Urinary Tract Infection 14% 22%       Infection 5% 10%     Vascular Disorders   Hypertension 6% 29% 0.5% 11.5%   Thrombosis 3% 10% 2.7% 8.3% Nervous System Disorders   Headache 13% 22%       Dysarthria 1% 8%     Gastrointestinal Disorders   Stomatitis 10% 15%       Proctalgia 1% 6%       Anal Fistula — 6%     Blood and Lymphatic System Disorders   Neutropenia 6% 12%       Lymphopenia 5% 12%       Psychiatric Disorders       Anxiety 10% 17%     Reproductive System and Breast Disorders   Pelvic Pain 8% 14%     Respiratory, Thoracic and Mediastinal Disorders   Epistaxis 1% 17%     Renal and Urinary Disorders   Proteinuria 3% 10%     Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥ 2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection (8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%). There were no Grade 5 adverse reactions occurring at a higher incidence ( ≥ 2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone. Platinum-Resistant Recurrent Epithelia Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded in this study. Grade 2-4 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone are presented in Table 5. Table 5: Grade 2-4 Adverse Events Occurring at Higher Incidence [ ≥ 5%] in Chemo + Avastin vs. Chemo Safety-Evaluable Patients
System Organ Class Preferred Term Chemo
(n=181) Chemo + Avastin
(n=179) Blood And Lymphatic System Disorders   Neutropenia 25.4% 30.7% General Disorders And Administration Site Conditions   Mucosal Inflammation 5.5% 12.8% Infections And Infestations   Infection 4.4% 10.6% Nervous System Disorders   Peripheral Sensory Neuropathy 7.2% 17.9% Renal And Urinary Disorders   Proteinuria 0.6% 12.3% Respiratory, Thoracic and Mediastinal Disorders   Epistaxis 0.0% 5.0% Skin And Subcutaneous Tissue Disorders   Palmar-Plantar Erythrodysaesthesia Syndrome 5.0% 10.6% Vascular Disorders   Hypertension 5.5% 19.0% Grade 3-4 adverse events occurring at a higher incidence ( ≥ 2%) in 179 patients receiving Avastin plus 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%). There were no Grade 5 events occurring at a higher incidence ( ≥ 2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone. Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment-emergent anti-bevacizumab antibodies 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-product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 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, PRES, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment o f various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment o f various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage Read the Avastin (bevacizumab) Side Effects Center for a complete guide to possible side effectsLearn More »

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Administration Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion.
  • Do not initiate Avastin until at least 28 days following major surgery. Administer Avastin after the surgical incision has fully healed.
  • 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 infusion over 60 minutes is tolerated.
Recommended Doses And Schedules Patients should continue treatment until disease progression or unacceptable toxicity. Metastatic Colorectal Cancer (mCRC) The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy.
  • Administer 5 mg/kg when used in combination with bolus-IFL.
  • Administer 10 mg/kg when used in combination with FOLFOX4.
  • Administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy regimen in patients who have progressed on a first-line Avastin-containing regimen.
Non-Squamous Non-Small Cell Lung Cancer (NSCLC) The recommended dose is 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel. Glioblastoma The recommended dose is 10 mg/kg every 2 weeks. Metastatic Renal Cell Carcinoma (mRCC) The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa. Cervical Cancer The recommended dose of Avastin is 15 mg/kg every 3 weeks as an intravenous infusion administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin, or paclitaxel and topotecan. Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer The recommended dose is 10mg/kg every 2 weeks in combination with one of the following intravenous chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); or 15 mg/kg every 3 weeks in combination with topotecan (every 3 weeks). Preparation For Administration Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Avastin and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives. DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. Dose Modifications There are no recommended dose reductions. Discontinue Avastin For
  • Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ [See BOXED WARNING, WARNINGS AND PRECAUTIONS]
  • Wound dehiscence and wound healing complications requiring medical intervention [See WARNINGS AND PRECAUTIONS]
  • Serious hemorrhage (i.e., requiring medical intervention) [See BOXED WARNING, WARNINGS AND PRECAUTIONS]
  • Severe arterial thromboembolic events [See WARNINGS AND PRECAUTIONS]
  • Life-threatening (Grade 4) venous thromboembolic events, including pulmonary embolism [See WARNINGS AND PRECAUTIONS]
  • Hypertensive crisis or hypertensive encephalopathy [See WARNINGS AND PRECAUTIONS]
  • Posterior Reversible Encephalopathy Syndrome (PRES) [See WARNINGS AND PRECAUTIONS]
  • Nephrotic syndrome [See WARNINGS AND PRECAUTIONS]
Temporarily Suspend Avastin For
  • At least 4 weeks prior to elective surgery [See WARNINGS AND PRECAUTIONS]
  • Severe hypertension not controlled with medical management [See WARNINGS AND PRECAUTIONS]
  • Moderate to severe proteinuria [See WARNINGS AND PRECAUTIONS]
  • Severe infusion reactions [See WARNINGS AND PRECAUTIONS]

Source: http://www.rxlist.com

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. Read the Avastin Drug Interactions Center for a complete guide to possible interactions Learn More »

Source: http://www.rxlist.com

Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil-based chemotherapy. 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] Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer in combination with carboplatin and paclitaxel. Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies] Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Persistent, Recurrent, Or Metastatic Carcinoma Of The Cervix Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies] Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer 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.

Source: http://www.rxlist.com

None. Last reviewed on RxList: 5/27/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Source: http://www.rxlist.com

Dosage Forms And Strengths 100 mg per 4 mL single-use vial
400 mg per 16 mL single-use vial Storage And Handling Avastin vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] are stable at 2-8°C (36-46°F). Avastin vials should be protected from light. Do not freeze or shake. Diluted Avastin solutions may be stored at 2-8°C (36-46°F) for up to 8 hours. Store in the original carton until time of use. No incompatibilities between Avastin and polyvinylchloride or polyolefin bags have been observed. Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990. Revised: May 2015 Last reviewed on RxList: 5/27/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Gastrointestinal Perforations And Fistulae Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See ADVERSE REACTIONS] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in < 1% of Avastin-treated patients. In a platinum-resistant ovarian cancer trial (Study 10), the incidence of GI perforation was 1.7% (3/179). In this trial, patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Avoid use of Avastin in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal-vaginal fistulae was 8.3% in Avastin-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See BOXED WARNING, DOSAGE AND ADMINISTRATION] Non-Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. Uncommon ( < 1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post-marketing experience. Most events occurred within the first 6 months of Avastin therapy. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin-treated patients and 1.4% of control patients were reported to have had nongastrointestinal vaginal, vesical, or female genital tract fistulae. Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See DOSAGE AND ADMINISTRATION] Surgery And Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See ADVERSE REACTIONS] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See BOXED WARNING, DOSAGE AND ADMINISTRATION] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See ADVERSE REACTIONS] Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See ADVERSE REACTIONS] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non-small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%-5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3-4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ ½ teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See BOXED WARNING, DOSAGE AND ADMINISTRATION] Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See DOSAGE AND ADMINISTRATION] Venous Thromboembolic Events Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life-threatening (Grade 4) VTE, including pulmonary embolism. [See DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS] Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See DOSAGE AND ADMINISTRATION] Posterior Reversible Encephalopathy Syndrome (PRES) PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. 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 (MRI) is necessary to confirm the diagnosis of PRES. Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See DOSAGE AND ADMINISTRATION] Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See ADVERSE REACTIONS] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See DOSAGE AND ADMINISTRATION] 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). [See Use in Specific Populations] Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon ( < 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See DOSAGE AND ADMINISTRATION] Embryo-fetal Toxicity Avastin may cause fetal harm based on the drug's mechanism of action and findings from animal studies. 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 VEGF Receptor 2 (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 and for 6 months after the last dose of Avastin. [See Use in Specific Populations, CLINICAL PHARMACOLOGY] Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See ADVERSE REACTIONS, Use in Specific Populations] Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility No carcinogenicity or mutagenicity studies of bevacizumab have been conducted. Bevacizumab 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. Use In Specific Populations Pregnancy Risk Summary Avastin may cause fetal harm based on findings from animal studies and the drug's mechanism of action. [See CLINICAL PHARMACOLOGY] 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 VEGF Receptor 2 (VEGFR2) 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 2-4% and 15-20%, respectively. Data Animal Data Pregnant rabbits dosed with 10 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 (42.1% for the 0 mg/kg dose, 76.5% for the 30 mg/kg dose, and 95% for the 100 mg/kg dose ) or fetal alterations (9.1% for the 0 mg/kg dose, 14.8% for the 30 mg/kg dose, and 61.2% 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. Lactation 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 a nursing woman that breastfeeding is not recommended during treatment with Avastin. Females And Males Of Reproductive Potential Contraception Females Avastin may cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective contraception during treatment with Avastin and for 6 months following the last dose of Avastin. [See Use In Specific Populations] 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 starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin-treated patients. [See WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS] Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. 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. Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See WARNINGS AND PRECAUTIONS] Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged > 65 years and 1127 patients < 65 years of age. 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 arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See WARNINGS AND PRECAUTIONS] Last reviewed on RxList: 5/27/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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