Note: 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. In the United States, Mvasi (bevacizumab-awwb) and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab). In Canada, Bambevi, Mvasi, and Zirabev are approved as biosimilars to Avastin (bevacizumab); refer to Canadian product monograph(s) for biosimilar-specific indication details.
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 (Chakravarthy 2013; Martin 2012).
Breast cancer, metastatic (off-label use): IV: 10 mg/kg every 2 weeks (in combination with paclitaxel) (Miller 2007).
Cervical cancer, persistent/recurrent/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 (Tewari 2014; Tewari 2017).
Off-label combination: IV: 15 mg/kg every 3 weeks (in combination with pembrolizumab, paclitaxel [conventional], and either cisplatin or carboplatin) until disease progression or unacceptable toxicity; refer to protocol for further information (Colombo 2021).
Colorectal cancer, metastatic, in combination with fluorouracil-based chemotherapy (Avastin and bevacizumab biosimilars): IV: 5 mg/kg every 2 weeks (in combination with bolus-IFL) or 10 mg/kg every 2 weeks (in combination with FOLFOX4).
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) (Wells 2015); 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 (Aghajanian 2011).
Glioblastoma, recurrent (Avastin and bevacizumab biosimilars): IV: 10 mg/kg every 2 weeks as a single agent until disease progression or unacceptable toxicity or (off-label combination) 10 mg/kg every 2 weeks (in combination with irinotecan) until disease progression or unacceptable toxicity (Friedman 2009; Vredenburgh 2007).
Hepatocellular carcinoma, unresectable or metastatic (Avastin only): 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 (Finn 2020). Note: Evaluate for esophageal varices within 6 months of bevacizumab initiation. If present, esophageal varices should be managed prior to bevacizumab initiation (ASCO [Gordan 2020]).
Hereditary hemorrhagic telangiectasia (off-label use): IV: 5 mg/kg every 2 weeks for 6 doses (Dupuis-Girod 2012; Faughnan 2020) 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 (Faughnan 2020) 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 (refer to protocol for further details) (Iyer 2018).
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 (Zalcman 2016).
Non-small cell lung cancer (nonsquamous cell histology), first-line therapy (Avastin and bevacizumab biosimilars): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and paclitaxel) for 6 cycles (Sandler 2006).
Off-label combinations: 15 mg/kg every 3 weeks (in combination with pemetrexed and carboplatin) for up to 4 cycles (Patel 2013) or 7.5 mg/kg every 3 weeks (in combination with pemetrexed and cisplatin) for 4 cycles (Barlesi 2013) or 15 mg/kg every 3 weeks (in combination with atezolizumab, paclitaxel, and carboplatin) for 4 to 6 cycles (Socinski 2018).
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 (Sandler 2006) 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 (Patel 2013) 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 (Barlesi 2013) 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 (Socinski 2018).
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 (Burger 2011).
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 (Ray-Coquard 2019). 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) (Pujade-Lauraine 2014).
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 (Aghajanian 2012; Aghajanian 2015; Coleman 2017).
Renal cell cancer, metastatic (Avastin and bevacizumab biosimilars): IV: 10 mg/kg every 2 weeks (in combination with interferon alfa) or (off-label dosing) 10 mg/kg every 2 weeks as monotherapy (Yang 2003).
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 (Agulnik 2013).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Renal impairment prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling.
Renal toxicity during treatment:
Nephrotic syndrome: Discontinue bevacizumab.
Proteinuria ≥2 g/24 hours in the absence of nephrotic syndrome: Withhold bevacizumab until proteinuria <2 g/24 hours.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Bevacizumab (including biosimilars): Pediatric drug information")
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. Mvasi (bevacizumab-awwb) 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 (Aguilera 2011; Aguilera 2013; Packer 2009; Parekh 2011; Reismüller 2010) or days 1 and 15 of each 28-day cycle (Kang 2008); mostly used in combination with irinotecan with/without temozolomide or 15 mg/kg/dose every 3 weeks has also been used (Parekh 2011; Reismüller 2010). 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 (Parekh 2011); others have observed only minimal efficacy in patients with high grade glioma (Narayana 2010).
Refractory solid tumor: Limited data available: Children and Adolescents: IV: 5 to 15 mg/kg/dose every 2 weeks in a 28-day course (Glade Bender 2008) or 5 to 10 mg/kg every 2 to 3 weeks (Benesch 2008).
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.
Refer to adult dosing.
Adverse reaction |
Severity |
Bevacizumab dosage modification |
---|---|---|
aNo 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, and/or 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. |
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
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
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Avastin: 100 mg/4 mL (4 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)
Zirabev: 100 mg/4 mL (4 mL) [contains disodium edta, polysorbate 80]
Zirabev: 400 mg/16 mL (16 mL) [contains polysorbate 80]
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 (Reidy 2007); 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 (Shah 2013).
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.
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: Inject undiluted bevacizumab solution. The major clinical 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; typical bevacizumab dose of 0.625 mg would equate to 2.5 units on an insulin syringe using a 25 mg/mL solution. Note: Trials in neonatal patients were conducted using the product Avastin 25 mg/mL vial for injection of bevacizumab. Mvasi (bevacizumab-awwb) is a biosimilar of Avastin; however, reported experience with the biosimilar in neonatal patients is lacking. Some dosage forms (eg, prefilled syringes) may not allow accurate measurement of neonatal doses; therefore, use should be avoided.
In an ROP trial, the injection site was anesthetized with a drop of tetracaine hydrochloride 0.5% ophthalmic solution or proparacaine hydrochloride 0.5% ophthalmic solution prior to bevacizumab administration and sterilized before and after administration with a drop of povidone-iodine 5% ophthalmic solution. Following the procedure, a topical ophthalmic antibiotic drop was also administered every 6 hours for 7 days (Mintz-Hittner 2011).
Cervical cancer, persistent/recurrent/metastatic (Avastin and bevacizumab biosimilars): Treatment of persistent, recurrent, or metastatic cervical cancer (in combination with paclitaxel and either cisplatin or topotecan).
Colorectal cancer, metastatic (Avastin and bevacizumab biosimilars): First- or second-line treatment of metastatic colorectal cancer (CRC) (in combination with fluorouracil-based chemotherapy); second-line treatment of metastatic CRC (in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy) after progression on a first-line treatment containing bevacizumab.
Limitations of use: Not indicated for the adjuvant treatment of colon cancer.
Glioblastoma, recurrent (Avastin and bevacizumab biosimilars): Treatment of recurrent glioblastoma in adults.
Hepatocellular carcinoma, unresectable or metastatic (Avastin only): Treatment of unresectable or metastatic hepatocellular carcinoma (in combination with atezolizumab) in patients who have not received prior systemic therapy.
Non-small cell lung cancer, nonsquamous (Avastin and bevacizumab biosimilars): First-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer (in combination with carboplatin and paclitaxel).
Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (Avastin and bevacizumab biosimilars):
Stage III or IV disease, following initial surgical resection: Treatment of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection (in combination with carboplatin and paclitaxel, followed by single-agent bevacizumab).
Platinum-resistant recurrent: Treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (in combination with paclitaxel, doxorubicin [liposomal], or topotecan) in patients who received no more than 2 prior chemotherapy regimens.
Platinum-sensitive recurrent: Treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine and then followed by single-agent bevacizumab).
Renal cell carcinoma, metastatic (Avastin and bevacizumab biosimilars): Treatment of metastatic renal cell carcinoma (in combination with interferon alfa).
Note: In the United States, Mvasi (bevacizumab-awwb) and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab). In Canada, Bambevi, Mvasi, and Zirabev are approved as biosimilars to Avastin (bevacizumab); refer to Canadian product monograph(s) for biosimilar-specific indication details.
Age-related macular degeneration; Breast cancer, metastatic; Diabetic macular edema; Endometrial cancer, recurrent or persistent; Hereditary hemorrhagic telangiectasia; Malignant pleural mesothelioma (unresectable); Soft tissue sarcoma, angiosarcoma; Soft tissue sarcoma, hemangiopericytoma
Avastin may be confused with Astelin.
Bevacizumab may be confused with bezlotoxumab, brentuximab vedotin, broculizumab, caplacizumab, cetuximab, necitumumab, ranibizumab, riTUXimab.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Avastin [US, Canada, and multiple international markets] may be confused with Avaxim, a brand name for hepatitis A vaccine [Canada and multiple international markets].
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%), peripheral edema (15%), venous thromboembolism (grades 3/4: 5% to 11%)
Dermatologic: Exfoliative dermatitis, xeroderma
Endocrine & metabolic: Hyperglycemia (26%), hypoalbuminemia (16%), hypomagnesemia (24%), hyponatremia (19%), ovarian failure (34%), 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: Pelvic pain (14%), proteinuria (10% to 20%), urinary tract infection (22%)
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%), pulmonary hemorrhage (4% to 31%), thrombocytopenia (58%; grade 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%)
Respiratory: Cough (26%), dyspnea (26% to 30%), epistaxis (17% to 55%), oropharyngeal pain (16%), sinusitis (15%)
Miscellaneous: Postoperative wound complication (5% to 15%)
1% to 10%:
Cardiovascular: Arterial thrombosis (grades ≥3: 5%), decreased left ventricular ejection fraction (10%), deep vein thrombosis (grades 3/4: 9%), intra-abdominal venous thrombosis (grades 3/4: 3%), left ventricular dysfunction (grades 3/4: 1%), pulmonary embolism (1%), syncope (grades 3/4: 3%), thrombosis (10%)
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%), tracheoesophageal fistula (≤2%)
Genitourinary: Bladder fistula (≤2%), vaginal fistula (≤2%)
Hematologic & oncologic: Hemorrhage (grades ≥3: ≤7%; including major hemorrhage)
Infection: Infection (10%), tooth abscess (2%)
Nervous system: Pain (grades 3/4: 8%)
Neuromuscular & skeletal: Asthenia (grades 3/4: 10%)
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%), infusion related reaction (<3%; severe infusion related reaction: <1%, including hypertensive crisis)
<1%:
Genitourinary: Nephrotic syndrome
Immunologic: Antibody development
Nervous system: Reversible posterior leukoencephalopathy syndrome
Frequency not defined:
Cardiovascular: Acute myocardial infarction, angina pectoris, cerebral infarction, transient ischemic attacks
Gastrointestinal: Gastrointestinal hemorrhage, hematemesis
Genitourinary: Vaginal hemorrhage
Hypersensitivity reaction: Hypersensitivity reaction
Nervous system: Intracranial hemorrhage
Respiratory: Hemoptysis
Postmarketing:
Cardiovascular: Aneurysm (arterial), aortic aneurysm, aortic dissection, coronary artery dissection, mesenteric thrombosis, myocardial rupture (arterial rupture and aortic rupture)
Gastrointestinal: Gallbladder perforation, gastrointestinal anastomotic ulcer, gastrointestinal ulcer, intestinal necrosis
Hematologic & oncologic: Pancytopenia
Neuromuscular & skeletal: Fulminant necrotizing fasciitis, osteonecrosis of the jaw, polyserositis
Ophthalmic: Inflammation of anterior segment of eye (toxic anterior segment syndrome) (Sato 2010)
Renal: Renal thrombotic microangiopathy
Respiratory: Nasal septum perforation, pulmonary hypertension
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). Manage hypertension with antihypertensive therapy.
• 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.
• 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). If possible, it may be more appropriate to wait until at least 6 to 8 weeks after bevacizumab discontinuation for major surgical procedures (Cortes 2012; Gordon 2009).
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:
• Elderly: 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.
Some experts recommend caution regarding use in premature neonates for retinopathy of prematurity (ROP) outside of controlled, clinical trials (Quinn 2011); systemic absorption after intravitreal administration with decreases in VEGF serum concentration (as low as 9% of baseline systemic concentration) have been reported in a case series of 11 neonates (Sato 2012); short- and long-term implications of systemic exposure are unknown; monitoring is recommended. Osteonecrosis of the jaw has been associated with bevacizumab use alone or in combination with other chemotherapies, steroids, and bisphosphonates. 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 (Fangusaro 2013).
None known.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Anthracyclines: Bevacizumab may enhance the cardiotoxic effect of Anthracyclines. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect 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
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Naloxegol: Bevacizumab may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for gastrointestinal perforation may be increased. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect 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
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
SORAfenib: Bevacizumab may enhance the adverse/toxic effect of SORAfenib. Specifically, the risk for hand-foot skin reaction may be increased. Risk C: Monitor therapy
SUNItinib: May enhance the adverse/toxic effect of Bevacizumab. Specifically, the risk for a specific form of anemia, microangiopathic hemolytic anemia (MAHA), may be increased. Bevacizumab may enhance the hypertensive effect of SUNItinib. Risk X: Avoid combination
Evaluate pregnancy status prior to use in patients who may become pregnant. Patients who may 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 may 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 to a pregnant patient. 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).
It is not known if bevacizumab is present in breast milk.
Bevacizumab was found to influence concentrations of vascular endothelial growth factor (VEGF) in breast milk following intravitreal injection (Ehlken 2012). Bevacizumab was not detected in the breast milk of a lactating patient when tested 1 day before and 1 week after an intravitreal injection (McFarland 2015).
Immunoglobulins are excreted in breast milk and it is assumed that bevacizumab may appear in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during treatment and for 6 months following the last dose of bevacizumab.
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 patients who may become pregnant). 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.
Age-related macular degeneration (off-label use): Monitor intraocular pressure (IOP). Follow-up exam (including visual acuity, Amsler grid, and stereoscopic biomicroscopic fundus examination) ~4 weeks after intravitreal administration; then periodic biomicroscopic fundus examination. Monitor mononuclear near vision; monitor for signs/symptoms of infectious endophthalmitis (eg, eye pain/discomfort, worsening eye redness, blurred/decreased vision, increased light sensitivity, increased floaters), retinal detachment, and decreased vision (AAO [Flaxel 2020]).
Diabetic macular edema (off-label use): Monitor visual acuity, central subfield thickness, and IOP; monitor for signs/symptoms of infectious endophthalmitis, cataracts, and retinal detachment (AAO 2016).
Hereditary hemorrhagic telangiectasia (off-label use): Cardiac output measurements and liver radiologic response (via ultrasound and hepatic CT exams) prior to initial treatment and at 3 and 6 months following the first dose (Dupuis-Girod 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
Gender: 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).
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 (Zirabev Intravenous)
100 mg/4 mL (per mL): $184.02
400 mg/16 mL (per mL): $184.02
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