Version July 2025
Note: Trials in neonatal patients were conducted using the product Avastin 25 mg/mL vial for injection of bevacizumab. Alymsys (bevacizumab-maly), Mvasi (bevacizumab-awwb), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) are biosimilars of Avastin; however, reported experience with biosimilars in neonatal patients is lacking. In adults, it is recommended to not administer bevacizumab products until at least 28 days after surgery and the wound is fully healed; refer to specific protocols.
Retinopathy of prematurity (ROP): Note: Systemic absorption following intravitreal bevacizumab has been described in neonates up to 8 weeks postinjection (Ref); evaluate the risks and benefits prior to use; closely monitor for adverse effects.
PMA ≥31 weeks and PNA ≥28 days: Limited data available; dosing regimens variable; dose not established:
Conventional dose: Intravitreal injection: 0.625 mg as a single dose in the affected eye(s) (Ref).
Low dose: Intravitreal injection: 0.0625 to 0.5 mg has been reported in the literature (Ref). In one retrospective study, patients receiving ultra-low dose (0.0625 mg) experienced significantly faster retinal vascularization compared to patients receiving conventional dose (0.625 mg) (97 ± 29 days vs 168 ± 65 days), but slower time to disappearance of plus sign (3.66 ± 2.46 days vs 2.45 ± 1.7 days) (Ref). Doses as low as 0.004 to 0.031 mg have been reported (Ref).
Note: Refer to individual protocols; details concerning dosing in combination regimens should also be consulted. Trials in pediatric patients were conducted using the product Avastin 25 mg/mL vial for injection of bevacizumab. Alymsys (bevacizumab-maly), Mvasi (bevacizumab-awwb), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) are biosimilars of Avastin; however, reported experience with the biosimilar product in pediatric oncology patients is lacking. In adults, it is recommended to not administer bevacizumab products until at least 28 days after surgery and the wound is fully healed; refer to specific protocols.
Primary CNS tumor; recurrent/refractory (high/low grade gliomas, medulloblastoma): Limited data available; efficacy results variable: Children and Adolescents: IV: 10 mg/kg/dose every 2 weeks (Ref) or days 1 and 15 of each 28-day cycle (Ref); mostly used in combination with irinotecan with/without temozolomide or 15 mg/kg/dose every 3 weeks has also been used (Ref). In general, when treating high-grade glioma, patients with contrast-enhancing disease showed greater response or remained stable, while patients with noncontrast-enhancing disease had disease progression (Ref); others have observed only minimal efficacy in patients with high grade glioma (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult oncology patients; specific recommendations for oncology pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.
|
Adverse Reaction |
Severity |
Bevacizumab Dosage Modification |
|---|---|---|
|
a No dose reductions for IV bevacizumab are recommended. | ||
|
Cardiovascular toxicity: Heart failure |
Any |
Discontinue bevacizumab. |
|
GI toxicity: Perforation or fistula |
GI perforation (any grade) |
Discontinue bevacizumab. |
|
Tracheoesophageal fistula (any grade) |
Discontinue bevacizumab. | |
|
Fistula (grade 4) |
Discontinue bevacizumab. | |
|
Fistula formation involving internal organ |
Discontinue bevacizumab. | |
|
Hemorrhage |
Hemoptysis (recent history of ≥2.5 mL) |
Withhold bevacizumab. |
|
Grade 3 or 4 |
Discontinue bevacizumab. | |
|
Hypertension |
Any |
Manage as appropriate with antihypertensive therapy. |
|
Severe hypertension (not controlled by medical management) |
Withhold bevacizumab; resume when hypertension is controlled. | |
|
Hypertensive crisis |
Discontinue bevacizumab. | |
|
Hypertensive encephalopathy |
Discontinue bevacizumab. | |
|
Infusion reaction |
Clinically insignificant (mild) |
Decrease bevacizumab infusion rate. |
|
Clinically significant |
Interrupt bevacizumab infusion; after symptoms resolve, resume at a decreased infusion rate. | |
|
Severe |
Discontinue bevacizumab and administer appropriate medical therapy (eg, epinephrine, corticosteroids, IV antihistamines, bronchodilators, oxygen). | |
|
Posterior reversible encephalopathy syndrome |
Any |
Discontinue bevacizumab. |
|
Thromboembolic events |
Arterial thromboembolism (severe) |
Discontinue bevacizumab. The safety of resuming bevacizumab after resolution of an arterial thromboembolism is unknown. |
|
Venous thromboembolism (grade 4) |
Discontinue bevacizumab. | |
|
Wound healing complications |
Any |
Withhold bevacizumab until adequate wound healing. The safety of resuming bevacizumab after resolution of wound healing complications is unknown. |
|
Necrotizing fasciitis |
Discontinue bevacizumab. | |
Baseline: There are no dosage adjustments provided in the manufacturer's labeling.
Renal toxicity during therapy: There are no pediatric-specific recommendations; in adult oncology patients, the following has been recommended:
Nephrotic syndrome: Discontinue bevacizumab.
Proteinuria ≥2 g per 24 hours in the absence of nephrotic syndrome: Withhold bevacizumab until proteinuria <2 g per 24 hours.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Bevacizumab (including biosimilars): Drug information")
Dosage guidance:
Safety: Withhold bevacizumab for at least 28 days prior to elective surgery. Do not administer bevacizumab products until at least 28 days after major surgery and until the wound is adequately healed.
Dosage form information: In the United States, Alymsys (bevacizumab-maly), Mvasi (bevacizumab-awwb), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab). In Canada, Abevmy, Aybintio, Bambevi, Mvasi, Vegzelma, and Zirabev are approved as biosimilars to Avastin (bevacizumab); refer to Canadian product monograph(s) for biosimilar-specific indication details.
Clinical considerations: Refer to the protocol or institutional guidance for additional details of off-label dosing.
Age-related macular degeneration (off-label use/route): Intravitreal: 1.25 mg (0.05 mL) monthly for 3 months, then may be given scheduled (monthly) or as needed based on monthly ophthalmologic assessment (Ref).
Breast cancer, metastatic (off-label use): IV: 10 mg/kg every 2 weeks (in combination with paclitaxel) (Ref).
Cervical cancer, persistent, recurrent, or metastatic (Avastin and bevacizumab biosimilars): IV: 15 mg/kg every 3 weeks (in combination with paclitaxel and either cisplatin or topotecan) until disease progression or unacceptable toxicity (Ref).
Off-label combinations: IV: 15 mg/kg every 3 weeks (in combination with pembrolizumab, paclitaxel [conventional], and either cisplatin or carboplatin); continue until disease progression or unacceptable toxicity (Ref) or 15 mg/kg every 3 weeks (in combination with atezolizumab, cisplatin or carboplatin, and paclitaxel [conventional]); continue until disease progression or unacceptable toxicity. Patients with a complete response following ≥6 cycles of treatment may discontinue chemotherapy and continue maintenance therapy with atezolizumab and bevacizumab (Ref).
Colorectal cancer, metastatic:
Colorectal cancer, metastatic, in combination with fluorouracil-based chemotherapy (Avastin and bevacizumab biosimilars), first- or second-line therapy: IV: 5 mg/kg every 2 weeks (in combination with bolus-IFL) or 10 mg/kg every 2 weeks (in combination with FOLFOX4).
Off-label combination for refractory disease: IV: 5 mg/kg every 2 weeks (in combination with trifluridine and tipiracil); continue until disease progression or unacceptable toxicity (Ref).
Colorectal cancer, metastatic, following first-line therapy containing bevacizumab (Avastin and bevacizumab biosimilars): IV: 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks (in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based regimen).
Diabetic macular edema (off-label use/route): Intravitreal: 1.25 mg (0.05 mL) initially; repeat every 4 weeks depending on ophthalmologic response (visual acuity or central subfield thickness assessment) (Ref); refer to protocol and supplementary materials for additional dosage and administration details.
Endometrial cancer, recurrent or persistent (off-label use): IV: 15 mg/kg every 3 weeks (as monotherapy) until disease progression or unacceptable toxicity (Ref).
Glioblastoma, recurrent (Avastin and bevacizumab biosimilars): IV: 10 mg/kg every 2 weeks as a single agent; continue until disease progression or unacceptable toxicity or (off-label combination) 10 mg/kg every 2 weeks (in combination with irinotecan); continue until disease progression or unacceptable toxicity (Ref) or (off-label dosing/combination) 15 mg/kg every 3 weeks (10 mg/kg every 2 weeks in patients with poor performance status), either as a single agent or in combination with chemotherapy; continue until disease progression or unacceptable toxicity (Ref).
Hepatocellular carcinoma, unresectable or metastatic (Avastin only): Note: Evaluate for esophageal varices within 6 months of bevacizumab initiation (Ref). Screening for and management of esophageal varices (when present) is recommended prior to bevacizumab initiation (Ref).
IV: 15 mg/kg once every 3 weeks (in combination with atezolizumab on the same day) until disease progression or unacceptable toxicity; may continue beyond disease progression if clinical benefit is demonstrated. If atezolizumab is discontinued due to unacceptable toxicity, may continue bevacizumab monotherapy (Ref).
Hereditary hemorrhagic telangiectasia (off-label use): IV: 5 mg/kg every 2 weeks for 6 doses (Ref) with variable maintenance doses up to 5 mg/kg every 1 to 3 months for 12 months, followed by longer dosing intervals; some patients may not require maintenance doses (Ref) or 5 mg/kg every 2 weeks for 4 doses, followed by 5 mg/kg once a month for 4 doses; additional doses (or dose modifications) may be administered if response is suboptimal (Ref).
Malignant pleural mesothelioma, unresectable (off-label use): IV: 15 mg/kg every 3 weeks (in combination with pemetrexed and cisplatin) for up to 6 cycles, followed by bevacizumab maintenance therapy at 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Ref).
Meningioma, recurrent or refractory (off-label use): IV: 10 mg/kg every 2 weeks for 6 months, followed by 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Ref).
Non–small cell lung cancer, nonsquamous histology, first-line therapy (Avastin and bevacizumab biosimilars): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and paclitaxel) for 6 cycles (Ref).
Off-label combinations: 15 mg/kg every 3 weeks (in combination with pemetrexed and carboplatin) for up to 4 cycles (Ref) or 7.5 mg/kg every 3 weeks (in combination with pemetrexed and cisplatin) for 4 cycles (Ref) or 15 mg/kg every 3 weeks (in combination with atezolizumab, paclitaxel, and carboplatin) for 4 to 6 cycles (Ref).
Maintenance therapy (off-label use): 15 mg/kg every 3 weeks as a single agent (after 6 cycles of induction therapy with bevacizumab, carboplatin and paclitaxel); continue maintenance therapy until disease progression or unacceptable toxicity (Ref) or 15 mg/kg (in combination with pemetrexed) every 3 weeks (following 4 cycles of induction therapy with bevacizumab, pemetrexed, and carboplatin); continue until disease progression or unacceptable toxicity (Ref) or 7.5 mg/kg (in combination with pemetrexed) every 3 weeks (following 4 cycles of induction therapy with bevacizumab, cisplatin and pemetrexed); continue until disease progression or unacceptable toxicity (Ref) or 15 mg/kg every 3 weeks, with or without maintenance atezolizumab (following 4 to 6 cycles of induction therapy with atezolizumab, paclitaxel and carboplatin); continue until disease progression or unacceptable toxicity (Ref).
Ovarian (epithelial), fallopian tube, or primary peritoneal cancer:
Ovarian (epithelial), fallopian tube, or primary peritoneal cancer: Stage III or IV disease following initial surgical resection (Avastin and bevacizumab biosimilars): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and paclitaxel) for up to 6 cycles, followed by bevacizumab 15 mg/kg every 3 weeks (monotherapy), for a total of up to 22 cycles or until disease progression (whichever occurs earlier); may delay bevacizumab to begin at cycle 2 to reduce the risk of wound healing complications (Ref).
First-line maintenance treatment (off-label combination): 15 mg/kg once every 3 weeks (in combination with olaparib) if complete or partial response is achieved following first-line, platinum-based chemotherapy (Ref). Bevacizumab should be administered for a total of 15 months (including when administered with chemotherapy as well as maintenance).
Ovarian (epithelial), fallopian tube, or primary peritoneal cancer: Platinum-resistant recurrent (Avastin and bevacizumab biosimilars): IV: 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks (in combination with paclitaxel, doxorubicin [liposomal], or topotecan) (Ref).
Ovarian (epithelial), fallopian tube, or primary peritoneal cancer: Platinum-sensitive recurrent (Avastin and bevacizumab biosimilars): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and gemcitabine for 6 to 10 cycles or with carboplatin and paclitaxel for 6 to 8 cycles) then continue with bevacizumab (monotherapy) until disease progression or unacceptable toxicity (Ref).
Renal cell cancer, metastatic (Avastin and bevacizumab biosimilars):
Note: Not a preferred treatment option; other contemporary therapies have replaced the use of bevacizumab in the treatment of renal cell carcinoma.
IV: 10 mg/kg every 2 weeks (in combination with interferon alfa) or (off-label dosing) 10 mg/kg every 2 weeks as monotherapy (Ref).
Soft tissue sarcoma, angiosarcoma, metastatic or locally advanced (off-label use; based on limited data): IV: 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Kidney impairment prior to treatment initiation:
IV, Intravitreal:
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).
Hemodialysis, intermittent (thrice weekly): Not dialyzable (Ref): No dosage adjustment necessary (Ref); use with caution due to lack of clinical experience (Ref).
Peritoneal dialysis: Not likely to be significantly dialyzable (large molecular weight): No dosage adjustment necessary; use with caution due to lack of clinical experience (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
Nephrotoxicity during treatment:
Nephrotic syndrome (proteinuria >3.5 g per 24 hours): Discontinue bevacizumab and refer to a kidney specialist, as bevacizumab has primarily been associated with renal thrombotic microangiopathy, but minimal change disease, focal segmental glomerulosclerosis, and IgA vasculitis have also been described (Ref).
Proteinuria ≥2 to ≤3.5 g per 24 hours: Withhold bevacizumab and resume therapy if and when urine protein levels are <2 g per 24 hours (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
Treatment with bevacizumab is associated with a two- to fourfold higher risk for the development of gastrointestinal perforation in patients with advanced cancer (Ref); GI perforation may be fatal. Perforation may be complicated by intraabdominal abscess, fistula formation, and the need for diverting ostomies. Serious fistulae, including tracheoesophageal fistula, bronchopleural fistula, fistula of the bile duct, vaginal fistula, renal fistula, and bladder fistula, have also occurred in patients treated with bevacizumab. GI-vaginal fistula formation may lead to bowel obstruction that requires surgical intervention and diverting ostomy. In a study of postoperative patients with colorectal cancer, a majority of fistulas were responsive to cessation of bevacizumab; average time to healing following cessation was 2 months (range: 1 to 5 months) (Ref).
Mechanism: Not clearly established; may be dose-related (Ref) and related to pharmacologic action (ie, vascular endothelial growth factor [VEGF] inhibition), resulting in regression of capillaries of intestinal villi (Ref). VEGF inhibition may also contribute to necrosis of adjacent bowel secondary to inhibition of tumor angiogenesis (Ref), ischemic perforation of normal bowel due to arterial microthromboembolism (Ref), induction of GI ulceration (Ref), and impaired GI mucosal repair mechanisms (Ref).
Onset: GI perforation: Varied; has been reported within 1 to 49 days of treatment (Ref). The majority of perforations occurred within 50 days of the first dose in clinical trials. Fistula: Varied; has been reported as early as 2 to 5 weeks following bevacizumab treatment (Ref). The majority of fistulae occurred within 6 months of the first dose in clinical trials.
Risk factors:
• Advanced age (Ref)
• Concomitant treatment with taxanes or oxaliplatin (Ref)
• Diverticular disease (Ref)
• Dose; risk may be increased with higher doses (ie, 5 mg/kg per week) (Ref)
• History of bowel resection (Ref)
• History of inflammatory bowel disease (Ref)
• Previous pelvic radiation (Ref)
• Tumor type (fistula formation): Cervical cancer
• Tumor type (GI perforation): Colorectal cancer (Ref); renal cell cancer (Ref); prostate cancer (Ref)
• Tumors involving the abdominal cavity (Ref)
Meta-analyses have demonstrated an increased risk of high-grade decreased left ventricular ejection fraction and high-grade heart failure with the use of bevacizumab (Ref). In a scientific statement from the American Heart Association, bevacizumab has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (Ref). Cardiovascular toxicities may be reversible upon withdrawal of bevacizumab and/or initiation of appropriate cardiovascular management; in some instances, bevacizumab may be safely resumed in patients with cardiovascular toxicity (Ref).
Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (ie, vascular endothelial growth factor inhibition) (Ref).
Onset: Delayed; in clinical trials, time to onset of left ventricular dysfunction or heart failure was 1 to 6 months after the first dose.
Risk factors:
• Prior exposure to or concurrent use with anthracycline chemotherapy
• Concurrent use with taxane chemotherapy (Ref)
• Dose; risk may be increased with higher doses (ie, 5 mg/kg per week) (Ref)
Bevacizumab may result in two distinct patterns of bleeding (minor and serious hemorrhage); hemorrhage was the leading cause of treatment-related mortality in a systematic review and meta-analysis (Ref). Severe or fatal hemorrhage (including hemoptysis, gastrointestinal hemorrhage, hematemesis, intracranial hemorrhage, epistaxis, and vaginal hemorrhage) occurred up to fivefold more frequently in patients receiving bevacizumab, compared to patients receiving chemotherapy alone (Ref). Among patients with fatal hemorrhage, the most common sites were the lung, CNS, and GI tract (Ref). Intracranial hemorrhage has been reported (Ref); risk does not appear to be increased in patients with CNS metastases (Ref). Intravitreal administration of vascular endothelial growth factor [VEGF] inhibitors does not appear to increase the risk of nonocular hemorrhage (Ref). Concurrent use of therapeutic anticoagulation does not appear to increase the risk of severe bleeding in patients treated with bevacizumab (Ref).
Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (VEGF inhibition). Possible mechanisms include direct vascular damage through tumor necrosis, loss of vascular integrity through impacts on endothelial cell function (eg, exposure of procoagulant phospholipids within the luminal membrane), inhibition of the coagulation cascade through VEGF effects on tissue factor, and thrombocytopenia with concurrent chemotherapy (Ref).
Risk factors:
• Aspirin use (Ref)
• Baseline lung cavitation (potential risk factor for severe pulmonary hemorrhage in non-small cell lung cancer (NSCLC) (Ref)
• Dose; risk for severe bleeding greater with higher doses (ie, 5 mg/kg per week) (Ref)
• GI Hemorrhage: History of bowel resection and inflammatory bowel disease (Ref)
• Squamous NSCLC: High-grade serious or fatal pulmonary hemorrhage
• Treatment duration ≤6 months (Ref)
In patients with advanced cancer, treatment with bevacizumab is associated with up to a fourfold higher risk for the development of hypertension (Ref). Intravitreal administration of bevacizumab may also be associated with the development of hypertension in all ages, although results are mixed (Ref). Hypertension appears to be reversible and usually resolves upon discontinuation of therapy (Ref).
Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (vascular endothelial growth factor [VEGF] inhibition). Multiple mechanisms have been proposed, including endothelial vasoconstriction and vascular resistance through reduction in nitric oxide and prostacyclin synthesis and increases in circulating endothelin-1 (Ref), interruption of survival signaling in endothelial cells and decreased angiogenesis, leading to cellular apoptosis, reduced microvascular density (rarefaction), and ultimately an increase in vascular resistance and regulation of endothelial cell function in the renal glomeruli (Ref).
Onset: Varied; in a prospective study in patients with newly diagnosed ovarian cancer, the majority of cases occurred within the first 6 months of therapy (median: 2.1 months [range: 0 to 28 months]) (Ref).
Risk factors:
• Advanced age (Ref)
• Dose; risk may be increased with higher doses (ie, 5 mg/kg per week) (Ref)
• Genetic polymorphisms of VEGF (Ref)
• Hyperlipidemia (Ref)
• Obesity (Ref)
• Preexisting hypertension or cardiovascular disease (Ref)
• Previous treatment with anthracycline (Ref)
Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bevacizumab and is characterized in oncology patients by nonhealing (persistence >8 weeks) exposed or necrotic bone in the maxillofacial region in patients with current or previous treatment with bone modifying agents or angiogenic inhibitors and no history of radiation or metastatic disease to the jaw (Ref). ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth/periodontal infection, toothache, or gingival ulceration/erosion. Cases of osteonecrosis and avascular necrosis of tibia, femur, and humerus have also been reported with bevacizumab with improvement or complete resolution upon discontinuation and surgical repair (Ref).
Osteonecrosis, including ONJ, has been associated with bevacizumab use alone or in combination with other chemotherapies, steroids, and bisphosphonates in pediatric patients. A report of three pediatric patients (ages: 10 years, 13 years, and 17 years) has also described cases of osteonecrosis of the wrist and knee (Ref).
Mechanism: Dose-related; related to pharmacologic action (vascular endothelial growth factor inhibition) resulting in wound healing impairment, and effects on bone remodeling (Ref).
Onset: Varied; time to onset of osteonecrosis has been reported from 1 to 55 weeks from initiation of bevacizumab therapy (Ref).
Risk factors:
• Concomitant exposure to antiresorptive therapy (eg, bisphosphonates, denosumab) (Ref)
• Ill-fitting dentures (Ref)
• Invasive dental procedures (Ref)
• Poor oral health (Ref)
• Tobacco use (Ref)
• Uncontrolled diabetes (Ref)
Bevacizumab is associated with proteinuria; grade 3 (urine dipstick 4+ or >3.5 g protein per 24 hours) and grade 4 proteinuria have occurred in clinical studies. The median time to resolution following discontinuation was ~6 months; proteinuria remained unresolved in 40% of patients after median follow-up of 11.2 months and required bevacizumab discontinuation in nearly one-third of patients. A pooled analysis from 7 studies found that 5% of patients receiving bevacizumab in combination with chemotherapy experienced grades 2 to 4 proteinuria (urine dipstick 2+ or >1 g protein per 24 hours or nephrotic syndrome), which resolved in nearly three-fourths of patients; bevacizumab was reinitiated in 42% of patients, although nearly half of patients who reinitiated bevacizumab experienced recurrent grades 2 to 4 proteinuria. Nephrotic syndrome has occurred in patients receiving bevacizumab, sometimes with fatal outcome. Kidney biopsy of patients with proteinuria demonstrated findings consistent with renal thrombotic microangiopathy (TMA), minimal change disease, and/or focal segmental glomerulonephritis (Ref). A large retrospective analysis comparing bevacizumab with chemotherapy to chemotherapy alone found higher rates of increased serum creatinine (1.5 to 1.9 times baseline) in patients who received bevacizumab; serum creatinine did not return to baseline in approximately one-third of patients who received bevacizumab. Reports of proteinuria, kidney function decline, and glomerular injury have also been reported with the use of intravitreal bevacizumab, although results are mixed (Ref).
Mechanism: Not clearly established; may be dose-related and related to pharmacologic action (vascular endothelial growth factor inhibition), resulting in renal podocyte dysfunction (Ref). Additional mechanisms have been proposed, including potential adaptive hyperfiltration response following nephrectomy (renal cell cancer) (Ref) and increased glomerular pressure caused by bevacizumab-induced hypertension, resulting in increased protein filtration (Ref).
Onset: Delayed; median time to onset in clinical trials: 5.6 months (range: 15 days to 37 months). Kidney dysfunction secondary to TMA may occur later than cases related to glomerulonephritis (Ref).
Risk factors:
• Concurrent use of nephrotoxic agents (Ref)
• Dose; risk may be increased with higher doses (ie, 5 mg/kg per week) (Ref)
• Females (TMA subset) (Ref)
• Preexisting kidney disease
• Tumor type: Renal cell cancer (Ref)
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported; common presenting symptoms include headache, altered alertness, behavioral changes, seizure, visual disturbances, nausea, and vomiting; coma may develop in severe cases (Ref). Symptoms typically resolve or improve within days to weeks after discontinuation and strict blood pressure control (Ref). The safety of resuming bevacizumab in patients developing RPLS is unknown.
Mechanism: Dose-related; exact mechanism is unknown, likely secondary to pharmacologic action (ie, vascular endothelial growth factor inhibition), resulting in alterations in blood pressure, resulting in cerebral vascular autoregulation and vasogenic edema and endothelial damage and secondary disruption of the blood-brain-barrier (Ref).
Onset: Varied; onset of symptoms in clinical trials: 16 hours up to 1 year after the first dose of bevacizumab (Ref).
Risk factors:
• Females (Ref)
Bevacizumab is associated with an increased risk of arterial thrombosis, including cerebral infarction, cerebrovascular accident, acute myocardial infarction, transient ischemic attacks, and angina pectoris, when used in combination with chemotherapy (Ref). Data on venous thromboembolism are conflicting (Ref); however, pulmonary embolism and deep vein thrombosis were observed in bevacizumab clinical trials. A meta-analysis suggested that bevacizumab significantly increased the risk of CNS ischemic events (Ref). In a clinical trial of patients with glioblastoma treated with bevacizumab combination therapy, the risk of arterial thrombosis was increased compared with placebo; however, the majority of events resolved (Ref). The safety of reinitiating bevacizumab after an arterial thrombotic event is resolved is unknown.
Mechanism: Not clearly established; likely dose-related and related to pharmacologic action (vascular endothelial growth factor inhibition) resulting in endothelial cell apoptosis creating a prothrombotic state (Ref), lack of endothelial cell renewal resulting in exposure of the extracellular matrix to circulating blood and platelet activation through exposure to collagen and von Willebrand factor (Ref), increased tissue factor expression, reduced nitric oxide and thrombomodulin expression, and direct platelet activation (Ref).
Risk factors:
• Arterial thromboembolic events (ATE):
- Age ≥65 years (Ref)
- Diabetes
- Dose; risk may be increased with higher doses (ie, 5 mg/kg per week) (Ref)
- History of ATE (Ref)
- Tumor type: Glioblastoma multiforme (Ref), renal cell cancer (Ref), colorectal cancer (Ref)
Vascular endothelial growth factor (VEGF) receptor inhibitors, including bevacizumab, are associated with impaired wound healing, including serious and fatal complications. In addition, necrotizing fasciitis, including fatal cases, have occurred secondary to wound healing complications in bevacizumab-treated patients. The safety of resuming bevacizumab after resolution of wound healing complications has not been established.
Mechanism: Not clearly established; likely dose-related and related to pharmacologic action (ie, VEGF inhibition), resulting in platelet dysfunction and decreased expression of endothelial tissue factor (Ref).
Onset: Intermediate; in a study of patients with breast cancer, wound healing complications typically occurred within 4 weeks of surgery (Ref).
Risk factors:
• Colon cancer in the perioperative setting (Ref)
• Initiation of bevacizumab within 7 days of vascular access device placement (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Percentages reported as monotherapy and as part of combination chemotherapy regimens. Some studies only reported hematologic toxicities grades ≥4 and nonhematologic toxicities grades ≥3.
>10%:
Cardiovascular: Hypertension (24% to 42%) (table 1), peripheral edema (15%), venous thromboembolism (grades 3/4: 11%) (table 2)
|
Drug (Bevacizumab) |
Comparator |
Bevacizumab Dose |
Indication |
Number of Patients (Bevacizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|
|
Bevacizumab with carboplatin and paclitaxel followed by bevacizumab alone: 32% |
Carboplatin and paclitaxel: 14% |
15 mg/kg every 3 weeks |
Epithelial ovarian, fallopian tube or primary peritoneal cancer |
608 |
602 |
|
Bevacizumab with carboplatin and paclitaxel: 24% |
Carboplatin and paclitaxel: 14% |
15 mg/kg every 3 weeks |
Epithelial ovarian, fallopian tube or primary peritoneal cancer |
607 |
602 |
|
Bevacizumab with interferon alfa: 28% |
Placebo with interferon alfa: 9% |
10 mg/kg every 2 weeks alfa |
Metastatic renal cell carcinoma |
337 |
304 |
|
Bevacizumab with chemotherapy: 29% |
Chemotherapy: 6% |
15 mg/kg every 3 weeks |
Persistent, recurrent, or metastatic cervical cancer |
218 |
222 |
|
Bevacizumab with carboplatin and gemcitabine: 42% |
Placebo with carboplatin and gemcitabine: 9% |
15 mg/kg every 3 weeks |
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer |
247 |
233 |
|
Drug (Bevacizumab) |
Comparator |
Bevacizumab Dose |
Indication |
Number of Patients (Bevacizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|
|
Bevacizumab with chemotherapy (grades 3/4): 11% |
Chemotherapy (grades 3/4): 5% |
15 mg/kg every 3 weeks |
Persistent, recurrent, or metastatic cervical cancer |
218 |
222 |
Dermatologic: Exfoliative dermatitis, xeroderma
Endocrine & metabolic: Hyperglycemia (26%), hypoalbuminemia (16%), hypomagnesemia (24%), hyponatremia (19%), weight loss (20% to 21%)
Gastrointestinal: Abdominal pain (grade 3/4: 8% to 12%), decreased appetite (34% to 36%), diarrhea (21% to 40%), dysgeusia, nausea (53% to 72%), stomatitis (15% to 25%)
Genitourinary: Ovarian failure (34%), pelvic pain (14%), proteinuria (10% to 20%) (table 3), urinary tract infection (22%)
|
Drug (Bevacizumab) |
Comparator |
Bevacizumab Dose |
Indication |
Number of Patients (Bevacizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|
|
Bevacizumab with interferon alfa: 20% |
Placebo with interferon alfa: 3% |
10 mg/kg every 2 weeks |
Metastatic renal cell carcinoma |
337 |
304 |
|
Bevacizumab with chemotherapy: 10% |
Chemotherapy: 3% |
15 mg/kg every 3 weeks |
Persistent, recurrent, or metastatic cervical cancer |
218 |
222 |
|
Bevacizumab with carboplatin and gemcitabine: 20% |
Placebo with carboplatin and gemcitabine: 3% |
15 mg/kg every 3 weeks |
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer |
247 |
233 |
Hematologic & oncologic: Bruise (17%), leukopenia (grades 3/4: 37% to 53%), lymphocytopenia (12%; grades 3/4: 6%), neutropenia (12%; grades 3/4: 8% to 21%), thrombocytopenia (58%; grades 3/4: 20% to 40%)
Nervous system: Anxiety (17%), dizziness (23%), dysarthria (8% to 12%), fatigue (33% to 82%), headache (22% to 49%), insomnia (21%), myasthenia (13% to 15%), voice disorder (5% to 13%)
Neuromuscular & skeletal: Arthralgia (28% to 41%), back pain (12% to 21%), limb pain (19% to 25%), myalgia (19%)
Ophthalmic: Disease of the lacrimal apparatus
Renal: Increased serum creatinine (16%) (table 4)
|
Drug (Bevacizumab) |
Comparator |
Bevacizumab Dose |
Indication |
Number of Patients (Bevacizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|
|
Bevacizumab with chemotherapy: 16% |
Chemotherapy: 10% |
15 mg/kg every 3 weeks |
Persistent, recurrent, or metastatic cervical cancer |
218 |
222 |
Respiratory: Cough (26%), dyspnea (26% to 30%), epistaxis (17% to 55%) (table 5), oropharyngeal pain (16%), pulmonary hemorrhage (4% to 31%), sinusitis (15%)
|
Drug (Bevacizumab) |
Comparator |
Bevacizumab Dose |
Indication |
Number of Patients (Bevacizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|
|
Bevacizumab with carboplatin and paclitaxel followed by bevacizumab alone: 31% |
Carboplatin and paclitaxel: 9% |
15 mg/kg every 3 weeks |
Epithelial ovarian, fallopian tube or primary peritoneal cancer |
608 |
602 |
|
Bevacizumab with carboplatin and paclitaxel: 30% |
Carboplatin and paclitaxel: 9% |
15 mg/kg every 3 weeks |
Epithelial ovarian, fallopian tube or primary peritoneal cancer |
607 |
602 |
|
Bevacizumab with interferon alfa: 27% |
Placebo with interferon alfa: 4% |
10 mg/kg every 2 weeks alfa |
Metastatic renal cell carcinoma |
337 |
304 |
|
Bevacizumab with chemotherapy: 17% |
Chemotherapy: 1% |
15 mg/kg every 3 weeks |
Persistent, recurrent, or metastatic cervical cancer |
218 |
222 |
|
Bevacizumab with carboplatin and gemcitabine: 55% |
Placebo with carboplatin and gemcitabine: 14% |
15 mg/kg every 3 weeks |
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer |
247 |
233 |
Miscellaneous: Postoperative wound complication (5% to 15%)
1% to 10%:
Cardiovascular: Arterial thrombosis (grades ≥3: 5%) (table 6), decreased left ventricular ejection fraction (10%) (table 7), deep vein thrombosis (grades 3/4: 9%) (table 8), intra-abdominal venous thrombosis (grades 3/4: 3%), left ventricular dysfunction (grades ≥3: 1%) (table 9), pulmonary embolism (1%), syncope (grades 3/4: 3%), thrombosis (10%)
|
Drug (Bevacizumab) |
Comparator |
|---|---|
|
Bevacizumab with chemotherapy (grades ≥3): 5% |
Chemotherapy (grades ≥3): ≤2% |
|
Drug (Bevacizumab) |
Comparator |
|---|---|
|
Bevacizumab with chemotherapy: 10% |
Chemotherapy: 5% |
|
Drug (Bevacizumab) |
Comparator |
Bevacizumab Dose |
Indication |
Number of Patients (Bevacizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|
|
Bevacizumab with IV fluorouracil-based chemotherapy (grades 3/4): 9% |
Placebo with IV fluorouracil-based chemotherapy (grades 3/4): 5% |
5 mg/kg every 2 weeks |
Metastatic colorectal cancer |
392 |
396 |
|
Drug (Bevacizumab) |
Comparator |
|---|---|
|
Bevacizumab with chemotherapy (grades ≥3): 1% |
Chemotherapy (grades ≥3): 0.6% |
Dermatologic: Acne vulgaris (1%), cellulitis (grades 3/4: 3%)
Endocrine & metabolic: Dehydration (grades 3/4: 4%), hypokalemia (grades 3/4: 7%)
Gastrointestinal: Constipation (grades 3/4: 4%), fistula of bile duct (≤2%), gastritis (1%), gastroesophageal reflux disease (2%), gastrointestinal fistula (≤2%), gastrointestinal perforation (≤3%), gingival hemorrhage (4% to 7%), gingival pain (1%), gingivitis (2%), hemorrhoids (8%), oral mucosa ulcer (2%), rectal fistula (6%), rectal pain (6%), tooth abscess (2%), tracheoesophageal fistula (≤2%)
Genitourinary: Bladder fistula (≤2%), vaginal fistula (≤2%)
Hematologic & oncologic: Hemorrhage (grades ≥3: 0.4% to 7%; including major hemorrhage) (table 10)
|
Drug (Bevacizumab) |
Comparator |
Bevacizumab Dose |
Indication |
Number of Patients (Bevacizumab) |
Number of Patients (Comparator) |
|---|---|---|---|---|---|
|
Grades ≥3: 0.4% to 7% |
N/A |
N/A |
Across clinical studies |
N/A |
N/A |
|
Bevacizumab with interferon alfa (grades ≥3): 3% |
Placebo with interferon alfa (grades ≥3): 0.3% |
10 mg/kg every 2 weeks |
Metastatic renal cell carcinoma |
337 |
304 |
Hypersensitivity: Infusion related reaction (<3%; severe infusion related reaction: <1%, including anaphylaxis, nonimmune anaphylaxis, hypertensive crisis)
Infection: Infection (10%)
Nervous system: Asthenia (grades 3/4: 10%), pain (grades 3/4: 8%)
Ophthalmic: Blurred vision (2%)
Otic: Deafness (1%), tinnitus (2%)
Renal: Renal fistula (≤2%)
Respiratory: Bronchopleural fistula (≤2%), nasal congestion (8%), nasal signs and symptoms (7% to 10%), rhinitis (≥3%), rhinorrhea (10%)
Miscellaneous: Fistula (≤2%)
<1%:
Immunologic: Antibody development
Nervous system: Reversible posterior leukoencephalopathy syndrome
Renal: Nephrotic syndrome
Frequency not defined:
Gastrointestinal: Hematemesis
Genitourinary: Vaginal hemorrhage
Hypersensitivity reaction: Hypersensitivity reaction
Nervous system: Cerebral infarction
Postmarketing:
Cardiovascular: Acute myocardial infarction (Ref), aneurysm (arterial), angina pectoris (Ref), aortic aneurysm, aortic dissection, coronary artery dissection, heart failure (Ref), mesenteric thrombosis, myocardial rupture (arterial rupture and aortic rupture)
Gastrointestinal: Gallbladder perforation (Ref), gastrointestinal anastomotic ulcer, gastrointestinal hemorrhage (Ref), gastrointestinal ulcer, intestinal necrosis
Hematologic & oncologic: Pancytopenia
Infection: Fulminant necrotizing fasciitis (Ref)
Nervous system: Cerebrovascular accident (Ref), intracranial hemorrhage (Ref), transient ischemic attacks (Ref)
Neuromuscular & skeletal: Osteonecrosis of the jaw (Ref)
Ophthalmic: Inflammation of anterior segment of eye (toxic anterior segment syndrome) (Ref)
Renal: Renal thrombotic microangiopathy (Ref)
Respiratory: Hemoptysis (Ref), nasal septum perforation (Ref), pulmonary hypertension (Ref)
Miscellaneous: Polyserositis
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to bevacizumab, any component of the formulation, Chinese hamster ovary cell products or other recombinant human or humanized antibodies; untreated CNS metastases
Concerns related to adverse effects:
• GI perforation/fistula: Serious and sometimes fatal GI perforation has occurred with bevacizumab. A higher incidence of GI perforation is associated with a history of prior pelvic radiation. Most cases of GI perforation occurred within 50 days of the first bevacizumab dose. Perforation may be complicated by intra-abdominal abscess, fistula formation, and/or diverting ostomy requirement. Serious fistulae (including tracheoesophageal, bronchopleural, biliary, vaginal, renal, and bladder fistulas) have been reported at a higher incidence in patients receiving bevacizumab products (compared to patients receiving chemotherapy), with the highest incidence occurring in patients with cervical cancer. Most fistulae occurred within 6 months of the first bevacizumab dose. Patients who develop GI vaginal fistula may also have bowel obstruction that requires surgical intervention and diverting ostomy. Avoid bevacizumab products in patients with ovarian cancer with evidence of recto-sigmoid involvement (by pelvic examination) or bowel involvement (on CT scan), or clinical symptoms of bowel obstruction.
• Heart failure: In a scientific statement from the American Heart Association (AHA), bevacizumab has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (AHA [Page 2016]). Bevacizumab is not indicated for use in combination with anthracycline-based chemotherapy. The incidence of grade ≥3 left ventricular dysfunction was higher in patients receiving bevacizumab with chemotherapy compared to patients who received chemotherapy alone (1% vs 0.6%). Among patients who received prior anthracycline therapy, the incidence of heart failure (HF) was higher in patients receiving bevacizumab with chemotherapy, compared to patients who received chemotherapy alone (4% vs 0.6%). In previously untreated patients with hematologic malignancy, the incidence of HF and left ventricular ejection fraction (LVEF) decline were increased in patients receiving bevacizumab with anthracycline-based chemotherapy (compared to patients receiving anthracycline-based chemotherapy alone). The proportion of patients with a LVEF decline (from baseline) of ≥20% or a decline from baseline of 10% to <50%, was higher in patients receiving bevacizumab with chemotherapy compared to patients receiving chemotherapy alone (10% vs 5%). Time to onset of left ventricular dysfunction or HF was 1 to 6 months after the first bevacizumab dose in most patients; HF resolved in nearly two-thirds of patients.
• Hemorrhage: Bevacizumab may result in 2 distinct bleeding patterns: minor hemorrhage (usually grade 1 epistaxis) or serious hemorrhage (which may be fatal). Severe or fatal hemorrhage (including hemoptysis, GI 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, grades 3, 4, or 5 hemorrhagic events have occurred in a small percentage of patients receiving bevacizumab. Serious or fatal pulmonary hemorrhage has been reported in nearly one-third of patients receiving bevacizumab plus chemotherapy for non-small cell lung cancer (NSCLC) with squamous cell histology (not an FDA-approved indication), as well as a small portion of NSCLC with nonsquamous histology; while no cases occurred in patients receiving chemotherapy alone. Patients with variceal bleeding within 6 months prior to treatment initiation, with untreated or incompletely treated varices with bleeding, or at high risk of bleeding were excluded from the HCC clinical trials (there are no data to support the safety of bevacizumab in these patients). Minor hemorrhages, including grade 1 epistaxis may commonly occur.
• Hypertension: Bevacizumab may cause and/or worsen hypertension. Severe hypertension occurred at a higher incidence in patients receiving bevacizumab products (compared to patients receiving chemotherapy alone).
• Infusion reactions: Infusion reactions (eg, hypertension, hypertensive crisis [associated with neurologic signs/symptoms], wheezing, oxygen desaturation, hypersensitivity [grade 3], chest pain, rigors, headache, diaphoresis) may occur with the first infusion (uncommon); severe reactions were rare.
• Mortality: Bevacizumab, in combination with chemotherapy (or biologic therapy), is associated with an increased risk of treatment-related mortality; a higher risk of fatal adverse events was identified in a meta-analysis of 16 trials in which bevacizumab was used for the treatment of various cancers (breast cancer, colorectal cancer, NSCLC, pancreatic cancer, prostate cancer, and renal cell cancer) and compared to chemotherapy alone (Ranpura 2011).
• Necrotizing fasciitis: Cases of necrotizing fasciitis, including fatalities, have been reported in patients receiving bevacizumab, usually secondary to wound healing complications, GI perforation, or fistula formation.
• Ocular adverse events: Serious eye infections and vision loss due to endophthalmitis have been reported from intravitreal administration (off-label use/route). Cases of bacterial endophthalmitis, retinal detachments (tractional and rhegmatogenous), uveitis, and vitreous hemorrhage have been reported (AAO [Flaxel 2020]).
• Osteonecrosis of the jaw: According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), medication-related osteonecrosis of the jaw (MRONJ) has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy. Antiangiogenic agents, when given concomitantly with antiresorptive agents, are associated with an increased risk of osteonecrosis of the jaw (ONJ). Other risk factors for MRONJ include dentoalveolar surgery (eg, tooth extraction, dental implants), preexisting inflammatory dental disease, and concomitant corticosteroid use. The AAOMS suggests that if medically permissible, initiation of antiangiogenic agents for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiangiogenesis therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once antiangiogenic therapy for oncologic disease is initiated, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). Cases of non-mandibular ONJ has also been reported in pediatric patients who have received bevacizumab (bevacizumab is not approved for use in pediatric patients).
• Posterior reversible encephalopathy syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) have been reported. Symptoms (which include headache, seizure, confusion, lethargy, blindness and/or other vision, or neurologic disturbances) may occur from 16 hours to 1 year after treatment initiation. PRES may also be associated with mild to severe hypertension. MRI is necessary for confirmation of PRES diagnosis. Resolution of symptoms usually occurs within days after discontinuation; however, neurologic sequelae may remain. The safety of treatment reinitiation after PRES is not known.
• Proteinuria/nephrotic syndrome:
- Bevacizumab products are associated with an increased incidence and severity of proteinuria. Grade 3 (urine dipstick 4+ or >3.5 g protein/24 hours) and grade 4 (nephrotic syndrome) proteinuria have occurred in clinical studies. The overall incidence of all grades of proteinuria in one study was 20%. The median onset of proteinuria was 5.6 months (range: 0.5 to 37 months) after bevacizumab initiation and the median time to resolution was ~6 months. Proteinuria remained unresolved in 40% of patients after median follow-up of 11.2 months and required bevacizumab discontinuation in nearly one-third of patients. A pooled analysis from 7 studies found that 5% of patients receiving bevacizumab products in combination with chemotherapy experienced grades 2 to 4 proteinuria (urine dipstick 2+ or >1 g protein/24 hours or nephrotic syndrome), which resolved in nearly three-fourths of patients; bevacizumab was reinitiated in 42% of patients, although nearly half of patients who reinitiated bevacizumab experienced recurrent grades 2 to 4 proteinuria.
- Nephrotic syndrome has occurred (rarely) in patients receiving bevacizumab, sometimes with fatal outcome. In some cases, kidney biopsy of patients with proteinuria demonstrated findings consistent with thrombotic microangiopathy. A large retrospective analysis comparing bevacizumab with chemotherapy to chemotherapy alone found higher rates of serum creatinine elevations (1.5 to 1.9 times baseline) in patients who received bevacizumab; serum creatinine did not return to baseline in approximately one-third of patients who received bevacizumab. Urine protein/creatinine ratio does not appear to correlate with 24-hour urine protein.
- A retrospective study suggested that intravitreal bevacizumab is not associated with deterioration of kidney function (Kameda 2018). However, glomerular injury with microangiopathy features, even after intravitreal injection, has been reported and monitoring is recommended (Ahmed 2021; Huang 2017; Touzani 2019).
• Thromboembolism: Bevacizumab products are associated with an increased incidence of arterial thromboembolic events (ATE), including cerebral infarction, stroke, myocardial infarction, transient ischemic attack, angina, and other ATEs, when used in combination with chemotherapy. The highest incidence of ATE occurred in patients with glioblastoma. History of ATE, diabetes, or ≥65 years of age may present an even greater risk. Although patients with cancer are already at risk for venous thromboembolism (VTE), a meta-analysis of 15 controlled trials has demonstrated an increased risk for VTE in patients who received bevacizumab (Nalluri 2008). Patients receiving bevacizumab plus chemotherapy had a higher incidence of grade 3 or higher VTE compared to those patients who received chemotherapy alone.
• Wound healing complications: In a controlled study in which bevacizumab was not administered within 28 days of major surgical procedures, the incidence of wound healing complications (including serious/fatal complications) was higher in patients with metastatic colorectal cancer who underwent surgery while receiving bevacizumab compared to patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent glioblastoma, the incidence of wound healing events was higher in patients who received bevacizumab compared to patients who did not receive bevacizumab. In a retrospective review of central venous access device placements (a minor procedure), a greater risk of wound dehiscence was observed when port placement and bevacizumab administration were separated by <14 days (Erinjeri 2011).
Disease-related concerns:
• Renal impairment: An increase in diastolic and systolic BPs were noted in a retrospective review of patients with renal insufficiency (CrCl ≤60 mL/minute) who received bevacizumab for renal cell cancer (Gupta 2011).
Special populations:
• Older adult: Patients ≥65 years of age have an increased incidence of arterial thrombotic events.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Systemic absorption following intravitreal administration with decreases in vascular endothelial growth factor (VEGF) serum concentration have been reported in neonates being treated for retinopathy of prematurity (ROP); bevacizumab concentrations were detected for up to 60 days and VEGF concentrations were suppressed up to 8 weeks postinjection (Sato 2012; Wu 2015). A retrospective study (n=64) reported 68% of patients were diagnosed with new-onset hypertension within 4 weeks of intravitreal administration for ROP; most patients (55%) presented with hypertension within the first week (Twitty 2021). Hypotension has also been reported in a preterm twin; hypotension was noted within 24 hours of intravitreal bevacizumab administration and resolved; there was no occurrence of hypotension in the other twin (Wu 2016). A possible case of posterior reversible encephalopathy syndrome (PRES) was reported in one former 25-week GA neonate who developed severe hypertension within 10 days of receipt of intravitreal bevacizumab (Twitty 2020). Literature regarding long-term neurodevelopmental safety of intravitreal bevacizumab is conflicting (Kaushal 2021; Morin 2016; Murakami 2021; Tsai 2021; Zayek 2021).
Avzivi (Bevacizumab tnjn): FDA approved December 2023; anticipated availability is currently unknown. Avzivi is approved as a biosimilar to Avastin. Consult the prescribing information for additional information.
Jobevne (Bevacizumab nwgd): FDA approved April 2025; anticipated availability is currently unknown. Jobevne is approved as a biosimilar to Avastin. Consult the prescribing information for additional information.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Vegzelma: Bevacizumab-adcd 100 mg/4 mL (4 mL); Bevacizumab-adcd 400 mg/16 mL (16 mL)
Solution, Intravenous [preservative free]:
Alymsys: Bevacizumab-maly 100 mg/4 mL (4 mL); Bevacizumab-maly 400 mg/16 mL (16 mL)
Avastin: 100 mg/4 mL (4 mL); 400 mg/16 mL (16 mL)
Mvasi: Bevacizumab-awwb 100 mg/4mL (4 mL); Bevacizumab-awwb 400 mg/16 mL (16 mL)
Zirabev: Bevacizumab-bvzr 100 mg/4 mL (4 mL); Bevacizumab-bvzr 400 mg/16 mL (16 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]
No
Solution (Alymsys Intravenous)
100 mg/4 mL (per mL): $215.58
400 mg/16 mL (per mL): $215.58
Solution (Avastin Intravenous)
100 mg/4 mL (per mL): $239.08
400 mg/16 mL (per mL): $239.08
Solution (Mvasi Intravenous)
100 mg/4 mL (per mL): $209.32
400 mg/16 mL (per mL): $209.32
Solution (Vegzelma Intravenous)
100 mg/4 mL (per mL): $203.22
400 mg/16 mL (per mL): $203.22
Solution (Zirabev Intravenous)
100 mg/4 mL (per mL): $184.02
400 mg/16 mL (per mL): $184.02
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Abevmy: 100 mg/4 mL (4 mL); 400 mg/16 mL (16 mL)
Avastin: 100 mg/4 mL (4 mL, 16 mL)
Aybintio: 100 mg/4 mL (4 mL); 400 mg/16 mL (16 mL)
Bambevi: 100 mg/4 mL (4 mL); 400 mg/16 mL (16 mL)
Mvasi: 100 mg/4 mL (4 mL); 400 mg/16 mL (16 mL)
Vegzelma: Bevacizumab-adcd 100 mg/4 mL (4 mL); Bevacizumab-adcd 400 mg/16 mL (16 mL)
Zirabev: 100 mg/4 mL (4 mL) [contains disodium edta, polysorbate 80]
Zirabev: 400 mg/16 mL (16 mL) [contains polysorbate 80]
Parenteral:
IV infusion: Infuse the initial dose over 90 minutes; second infusion may be shortened to 60 minutes if the initial infusion is well-tolerated. Third and subsequent infusions may be shortened to 30 minutes if the 60-minute infusion is well-tolerated. Monitor closely during the infusion for signs/symptoms of an infusion reaction. Do not administer IV push. Do not administer with dextrose solutions. Temporarily withhold bevacizumab for 4 weeks prior to elective surgery and for at least 4 weeks (and until the surgical incision is fully healed) after surgery.
Intravitreal injection: Note: Neonatal trials were conducted using Avastin 25 mg/mL vial for injection. Alymsys (bevacizumab-maly), Mvasi (bevacizumab-awwb), and Zirabev (bevacizumab-bvzr) are biosimilars of Avastin; however, reported experience with biosimilars in neonatal patients is lacking. Some dosage forms (eg, prefilled syringes) may not allow accurate measurement of neonatal doses; therefore, use should be avoided.
Prior to intravitreal bevacizumab administration, topical anesthetic is usually applied; the site is sterilized before and/or after administration (Ref). Inject undiluted or diluted bevacizumab solution. One trial for retinopathy of prematurity (ROP) used an insulin syringe (0.3 mL syringe with a 31-gauge, 5/16-inch needle) to accurately deliver the dose; each 1 unit on an insulin syringe is equivalent to 0.01 mL; conventional bevacizumab dose of 0.625 mg would equate to 2.5 units on an insulin syringe using a 25 mg/mL solution (Ref). Some experts are recommending the use of a 32-gauge, 4 mm needle to minimize complications from intravitreal injections (Ref). Following the procedure, a topical ophthalmic antibiotic drop is usually administered for 3 to 7 days (Ref).
IV: Infuse the initial dose over 90 minutes. The second infusion may be administered over 60 minutes if the initial infusion is well tolerated. The third and subsequent infusions may be administered over 30 minutes if the 60-minute infusion is well tolerated.
Off-label infusion rate : A rate of 0.5 mg/kg/minute has been described (Ref); refer to article for further information. In a study evaluating the safety of the 0.5 mg/kg/minute infusion rate of doses <10 mg/kg, proteinuria and hypertension incidences were not increased with the shorter infusion time (Ref).
Do not administer with dextrose solutions.
When administering in combination with atezolizumab, administer atezolizumab prior to bevacizumab (on the same day).
Monitor closely during the infusion for signs/symptoms of an infusion reaction. Decrease infusion rate for mild (clinically insignificant) infusion reaction; interrupt infusion for clinically significant infusion reaction (after symptoms resolve, resume at a decreased infusion rate); discontinue bevacizumab for severe infusion reaction.
Intravitreal injection (off-label use/route): Adequate local anesthesia and a topical broad-spectrum antimicrobial agent should be administered prior to the procedure.
Vials:
All products: Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Store in the original carton; protect from light. Do not shake.
Additional product-specific storage information: Aybintio [Canadian product]: Intact vial may also be stored at ≤30°C (86°F) for up to 35 days; protect from light. Must discard after 35 days even if returned to refrigerator.
Solutions diluted for infusion:
US labeling: Solutions diluted in NS are stable for up to 4 hours (Alymsys), 8 hours (Avastin, Mvasi), 24 hours (Vegzelma), or 16 days (Zirabev) under refrigeration or for up to 4 hours at room temperature (≤30°C [86°F]) (Vegzelma). Discard unused portion of vial.
Canadian labeling: All products: Solutions diluted in NS are stable for up to 24 hours under refrigeration; extended storage information under refrigeration or at room temperature may be available (refer to manufacturer's labeling for details).
Treatment of metastatic colorectal cancer; treatment of unresectable, locally advanced recurrent or metastatic nonsquamous, non-small cell lung cancer; treatment of recurrent glioblastoma; treatment of metastatic renal cell cancer; treatment of persistent, recurrent, or metastatic cervical cancer; treatment of ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-resistant recurrent); treatment of unresectable or metastatic hepatocellular carcinoma (in combination with atezolizumab) in patients who have not received prior systemic therapy (All indications: FDA approved in adults). Note: Alymsys (bevacizumab-maly), Mvasi (bevacizumab-awwb), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab); approved uses may vary (consult product labeling).
Has also been used in the treatment of pediatric refractory solid tumors and primary CNS tumors; has been used in neonates intravitreally for retinopathy of prematurity (Stage 3+).
Avastin may be confused with Astelin.
Bevacizumab may be confused with bezlotoxumab, brentuximab vedotin, broculizumab, caplacizumab, cetuximab, necitumumab, ranibizumab, riTUXimab.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
Avastin [US, Canada, and multiple international markets] may be confused with Avaxim, a brand name for hepatitis A vaccine [Canada and multiple international markets].
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
5-Aminosalicylic Acid Derivatives: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Androgens: Hypertension-Associated Agents may increase hypertensive effects of Androgens. Risk C: Monitor
Anthracyclines: Bevacizumab may increase cardiotoxic effects of Anthracyclines. Risk X: Avoid
Antithyroid Agents: Myelosuppressive Agents may increase neutropenic effects of Antithyroid Agents. Risk C: Monitor
BCG (Intravesical): Myelosuppressive Agents may decrease therapeutic effects of BCG (Intravesical). Myelosuppressive Agents may increase adverse/toxic effects of BCG (Intravesical). Risk X: Avoid
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may increase adverse/toxic effects of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor
Chloramphenicol (Ophthalmic): May increase adverse/toxic effects of Myelosuppressive Agents. Risk C: Monitor
Chloramphenicol (Systemic): Myelosuppressive Agents may increase myelosuppressive effects of Chloramphenicol (Systemic). Risk X: Avoid
Cladribine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk X: Avoid
CloZAPine: Myelosuppressive Agents may increase adverse/toxic effects of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor
Deferiprone: Myelosuppressive Agents may increase neutropenic effects of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider Therapy Modification
Efgartigimod Alfa: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Fexinidazole: Myelosuppressive Agents may increase myelosuppressive effects of Fexinidazole. Risk X: Avoid
Linezolid: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Naloxegol: Bevacizumab may increase adverse/toxic effects of Naloxegol. Specifically, the risk for gastrointestinal perforation may be increased. Risk C: Monitor
Nipocalimab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Olaparib: Myelosuppressive Agents may increase myelosuppressive effects of Olaparib. Risk C: Monitor
Promazine: May increase myelosuppressive effects of Myelosuppressive Agents. Risk C: Monitor
Ropeginterferon Alfa-2b: Myelosuppressive Agents may increase myelosuppressive effects of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider Therapy Modification
Rozanolixizumab: May decrease therapeutic effects of Fc Receptor-Binding Agents. Risk C: Monitor
Solriamfetol: May increase hypertensive effects of Hypertension-Associated Agents. Risk C: Monitor
SORAfenib: Bevacizumab may increase adverse/toxic effects of SORAfenib. Specifically, the risk for hand-foot skin reaction may be increased. Risk C: Monitor
SUNItinib: Bevacizumab may increase adverse/toxic effects of SUNItinib. Specifically, the risk for a specific form of anemia, microangiopathic hemolytic anemia (MAHA), may be increased. Bevacizumab may increase hypertensive effects of SUNItinib. Risk X: Avoid
Evaluate pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for 6 months following the last bevacizumab dose.
In premenopausal patients with solid tumors receiving adjuvant therapy, the incidence of ovarian failure was 34% for bevacizumab with chemotherapy versus 2% for chemotherapy alone. Recovery of ovarian function (resumption of menses, positive serum β-HCG pregnancy test, or follicle-stimulating hormone level <30 mIU/mL) at all time points in the post-treatment period after bevacizumab discontinuation was demonstrated in approximately 22% of patients who received bevacizumab. The long-term effects of bevacizumab on fertility are unknown. Patients who could become pregnant should be informed of the potential risk of ovarian failure prior to bevacizumab initiation.
Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor; VEGF is required to achieve and maintain normal pregnancies (Peracha 2016). Based on findings in animal reproduction studies and on the mechanism of action, bevacizumab may cause fetal harm if administered during pregnancy. Information from postmarketing reports following systemic exposure in pregnancy is limited.
Information following intravitreal bevacizumab use in pregnancy is also limited (Introini 2012; Kianersi 2016; Petrou 2010; Polizzi 2015a; Polizzi 2015b; Sarmad 2016; Sullivan 2014; Tarantola 2010; Wu 2010). Based on studies in nonpregnant adults, VEGF inhibitors can alter systemic concentrations of VEGF and placental growth factor following intravitreal administration (Peracha 2016; Zehetner 2015). Until additional information is available, intravitreal use during the first trimester should be avoided and use later in pregnancy should be based on patient specific risks versus benefits (Peracha 2016; Polizzi 2015b).
Systemic administration of bevacizumab was found to cause a preeclampsia-like syndrome in nonpregnant patients (Cross 2012). Preeclampsia was reported in a pregnant patient following intravitreal administration; however, this case also had a significant obstetric history which may have contributed to this finding (Sullivan 2014).
IV administration: Monitor for proteinuria/nephrotic syndrome (by serial dipstick urine analysis); collect 24-hour urine in patients with ≥2+ reading. Monitor BP every 2 to 3 weeks; more frequently if hypertension develops during therapy; continue to monitor BP after discontinuing due to bevacizumab-induced hypertension or worsening hypertension. Evaluate for varices within 6 months of treatment initiation (in patients with hepatocellular carcinoma). Evaluate pregnancy status prior to use (in females of reproductive potential). Monitor closely during the infusion for signs/symptoms of an infusion reaction. Monitor for signs/symptoms of GI perforation or fistula (including abdominal pain, constipation, vomiting, and fever), bleeding (including epistaxis, hemoptysis, GI, and/or CNS bleeding), posterior reversible encephalopathy syndrome, thromboembolism (arterial and venous), wound healing complications, and/or heart failure.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Intravitreal administration: Monitor BP, heart rate, respiratory rate, and oxygen saturation prior to, during, and after the procedure; monitor for signs and symptoms of infection or ocular inflammation; consider short- and long-term monitoring for sequelae of systemic absorption when used in neonates (Sato 2012)
Bevacizumab is a recombinant, humanized monoclonal antibody which binds to, and neutralizes, vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors, Flt-1 and KDR. VEGF binding initiates angiogenesis (endothelial proliferation and the formation of new blood vessels). The inhibition of microvascular growth is believed to retard the growth of all tissues (including metastatic tissue).
Distribution: CV% central volume: 2.9 (22%) L
Half-life elimination:
IV:
Pediatric patients (age: 1 to 21 years): Median: 11.8 days (range: 4.4 to 14.6 days) (Glade Bender 2008)
Adults: ~20 days (range: 11 to 50 days)
Intravitreal: ~5 to 10 days (Bakri 2007; Krohne 2008)
Excretion: Clearance (mean): Adults: 0.23 L/day
Sex: Males had a higher clearance and larger volume of distribution in the central compartment when compared with females (clearance: 0.26 L/day vs 0.21 L/day; distribution: 3.2 L vs 2.7 L).
Tumor burden: Patients with a higher tumor burden had a higher clearance of bevacizumab compared with patients who had a tumor burden below the median (0.25 L/day vs 0.2 L/day).
