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Bevacizumab (including biosimilars): Drug information

Bevacizumab (including biosimilars): Drug information
(For additional information see "Bevacizumab (including biosimilars): Patient drug information" and see "Bevacizumab (including biosimilars): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Alymsys;
  • Avastin;
  • Mvasi;
  • Zirabev
Brand Names: Canada
  • Abevmy;
  • Avastin;
  • Aybintio;
  • Bambevi;
  • Mvasi;
  • Zirabev
Pharmacologic Category
  • Antineoplastic Agent, Monoclonal Antibody;
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor;
  • Vascular Endothelial Growth Factor (VEGF) Inhibitor
Dosing: Adult

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, Alymsys (bevacizumab-maly), Mvasi (bevacizumab-awwb), and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab). In Canada, Abevmy, Aybintio, 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

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

Breast cancer, metastatic (off-label use): IV: 10 mg/kg every 2 weeks (in combination with paclitaxel) (Miller 2007).

Cervical cancer, persistent/recurrent/metastatic

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

Colorectal cancer, metastatic:

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).

Off-label combination: IV: 5 mg/kg every 2 weeks (in combination with trifluridine and tipiracil); continue until disease progression or unacceptable toxicity (Pfieffer 2020; Satake 2020).

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

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

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

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

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

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

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 histology, first-line therapy

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 (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, fallopian tube, or primary peritoneal cancer

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 (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

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 (Yang 2003).

Soft tissue sarcoma, angiosarcoma, metastatic or locally advanced

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.

Dosing: Kidney Impairment: Adult

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 (Meibohm 2012; expert opinion).

Hemodialysis, intermittent (thrice weekly): Not dialyzable (Garnier-Viougeat 2007): No dosage adjustment necessary (Funasaka 2019; Garnier-Viougeat 2007; Klajer 2020; Morales 2012; Syrios 2013); use with caution due to lack of clinical experience (expert opinion).

Peritoneal dialysis: Not likely to be significantly dialyzable (large molecular weight): No dosage adjustment necessary; use with caution due to lack of clinical experience (expert opinion).

CRRT: No dosage adjustment necessary (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (expert opinion).

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 (Brandes 2015; Endo 2019; Hanna 2016; Uy 2009).

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 (Brandes 2015; manufacturer's labeling)

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Pediatric

(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. Alymsys (bevacizumab-maly), 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

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

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.

Bevacizumab IV Dosage Modification for Adverse Reactionsa

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.

Dosing: Kidney Impairment: Pediatric

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.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Obesity: Adult

American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2: The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status. If dose reduction for toxicity is recommended in the prescribing information, the dose should be increased back to the initial or previously tolerated dose only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (ASCO [Griggs 2021]).

Dosing: Adjustment for Toxicity: Adult
Bevacizumab IV Dosage Modification for Adverse Reactionsa

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 at least 28 days after major surgery and until adequate wound healing; the safety of resuming bevacizumab after resolution of wound healing complications is unknown (manufacturer’s labeling). 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).

Necrotizing fasciitis

Discontinue bevacizumab.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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]

Generic Equivalent Available: US

No

Dosage Forms: Canada

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)

Zirabev: 100 mg/4 mL (4 mL) [contains disodium edta, polysorbate 80]

Zirabev: 400 mg/16 mL (16 mL) [contains polysorbate 80]

Product Availability

Vegzelma (bevacizumab-adcd): FDA approved September 2022; anticipated availability currently unknown. Vegzelma is approved as a biosimilar to Avastin.

Administration: Adult

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.

Administration: Pediatric

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 (Beck 2020; Çömez 2021; Mintz-Hittner 2011; Shafiq 2020). 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 (Mintz-Hittner 2011). Some experts are recommending the use of a 32-gauge, 4 mm needle to minimize complications from intravitreal injections (Beck 2020). Following the procedure, a topical ophthalmic antibiotic drop is usually administered for 3 to 7 days (Çömez 2021; Fouzdar Jain 2018; Harder 2013; Mintz-Hittner 2011).

Use: Labeled Indications

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).

Guideline recommendations: American Society of Clinical Oncology:

Based on the American Society of Clinical Oncology management and care of patients with invasive cervical cancer resource-stratified clinical practice guideline rapid communication update, bevacizumab (in combination with pembrolizumab, paclitaxel [conventional], and either cisplatin or carboplatin) may be offered as upfront therapy for eligible patients with persistent, recurrent, or metastatic cervical carcinoma (± individualized radiation therapy and/or palliative care) in enhanced and maximal resource settings (ASCO [Chuang 2022]).

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, Alymsys (bevacizumab-maly), Mvasi (bevacizumab-awwb) and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab). In Canada, Abevmy, Aybintio, Bambevi, Mvasi, and Zirabev are approved as biosimilars to Avastin (bevacizumab); refer to Canadian product monograph(s) for biosimilar-specific indication details.

Use: Off-Label: Adult

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

Medication Safety Issues
Sound-alike/look-alike issues:

Avastin may be confused with Astelin.

Bevacizumab may be confused with bezlotoxumab, brentuximab vedotin, broculizumab, caplacizumab, cetuximab, necitumumab, ranibizumab, riTUXimab.

High alert medication:

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.

International issues:

Avastin [US, Canada, and multiple international markets] may be confused with Avaxim, a brand name for hepatitis A vaccine [Canada and multiple international markets].

Adverse Reactions

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%), 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%), 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%), 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%)

Respiratory: Cough (26%), dyspnea (26% to 30%), epistaxis (17% to 55%), oropharyngeal pain (16%), pulmonary hemorrhage (4% to 31%), 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%), tooth abscess (2%), tracheoesophageal fistula (≤2%)

Genitourinary: Bladder fistula (≤2%), vaginal fistula (≤2%)

Hematologic & oncologic: Hemorrhage (grades ≥3: ≤7%; including major hemorrhage)

Hypersensitivity: Infusion related reaction (<3%; severe infusion related reaction: <1%, including anaphylaxis, nonimmune anaphylaxis, and 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:

Cardiovascular: Acute myocardial infarction, angina pectoris

Gastrointestinal: Gastrointestinal hemorrhage, hematemesis

Genitourinary: Vaginal hemorrhage

Hypersensitivity reaction: Hypersensitivity reaction

Nervous system: Cerebral infarction, intracranial hemorrhage, transient ischemic attacks

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

Infection: Fulminant necrotizing fasciitis

Neuromuscular & skeletal: Osteonecrosis of the jaw

Ophthalmic: Inflammation of anterior segment of eye (toxic anterior segment syndrome) (Sato 2010)

Renal: Renal thrombotic microangiopathy

Respiratory: Nasal septum perforation, pulmonary hypertension

Miscellaneous: Polyserositis

Contraindications

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

Warnings/Precautions

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.

Warnings: Additional Pediatric Considerations

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. 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).

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).

Metabolism/Transport Effects

None known.

Drug Interactions

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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. 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

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. 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

Reproductive Considerations

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.

Pregnancy Considerations

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).

Breastfeeding Considerations

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.

Monitoring Parameters

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 could 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).

Mechanism of Action

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).

Pharmacokinetics

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

Pharmacokinetics: Additional Considerations

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).

Pricing: US

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 (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.

Brand Names: International
  • Avastin (AE, AR, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CR, CU, CY, CZ, DE, DK, DO, EC, EE, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, IE, IL, IN, IS, IT, JO, JP, KR, KW, LB, LK, LT, LU, LV, MX, MY, NI, NL, NO, NZ, PA, PE, PH, PL, PT, PY, QA, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TW, UA, UY, VN, ZA, ZW);
  • Bevastim (BD);
  • Bevax (AR, CO);
  • Bivastin (BD);
  • Lumiere (CO);
  • Mvasi (HU, LT, LV, NL, PT, SK);
  • MVASI (TW);
  • Zirabev (AT, CZ, DK, EE, HR, HU, LT, LV, NL, PT, SK, TW)


For country code abbreviations (show table)
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  3. Aghajanian C, Goff B, Nycum LR, Wang YV, Husain A, Blank SV. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2015;139(1):10-16. [PubMed 26271155]
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  6. Aguilera D, Mazewskli C, Fangusaro J, et al. Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience. Childs Nerv Syst. 2013;29:589-596. doi:10.1007/s00381-012-2013-4 [PubMed 23296323]
  7. Agulnik M, Yarber JL, Okuno SH, et al. An Open-Label, Multicenter, Phase II Study of Bevacizumab for the Treatment of Angiosarcoma and Epithelioid Hemangioendotheliomas. Ann Oncol. 2013;24(1):257-263. [PubMed 22910841]
  8. Ahmed M, Alouch N, Ahmed A, Jagadesh SK. Worsening of renal function and uncontrolled hypertension from intravitreal bevacizumab injections. Proc (Bayl Univ Med Cent). 2021;34(4):527-529. doi:10.1080/08998280.2021.1885285 [PubMed 34219948]
  9. Al-Samkari H, Kasthuri RS, Parambil JG, et al. An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica. 2021;106(8):2161-2169. doi:10.3324/haematol.2020.261859 [PubMed 32675221]
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  11. Allegra CJ, Yothers G, O'Connell MJ, et al. Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer. J Clin Oncol. 2009;27(20):3385-3390. [PubMed 19414665]
  12. Alymsys (bevacizumab) [prescribing information]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; April 2022.
  13. American Academy of Ophthalmology. Diabetic Retinopathy. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2016. Accessed November 14, 2017.
  14. Avastin (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech Inc; December 2020.
  15. Avastin (bevacizumab) [product monograph]. Mississauga, Ontario, Canada: Hoffmann-La Roche Limited; April 2022.
  16. Avastin (bevacizumab) [prescribing information]. South San Francisco, California: Genentech, Inc; September 2022.
  17. Aybintio (bevacizumab) [product monograph]. Kirkland, Quebec, Canada: Organon Canada Inc; November 2021.
  18. Azad NS, Aragon-Ching JB, Dahut WL, et al. Hand-Foot Skin Reaction Increases With Cumulative Sorafenib Dose and With Combination Anti-Vascular Endothelial Growth Factor Therapy. Clin Cancer Res. 2009;15(4):1411-1416. [PubMed 19228742]
  19. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology, 2007;114(5):855-859. [PubMed 17467524]
  20. Bansal N and Hoffman M. Bladder Perforation in a Patient With Recurrent Epithelial Ovarian Cancer After Treatment With Bevacizumab. Gynecol Oncol. 2011;120(2):313-314. [PubMed 21055796]
  21. Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013;31(24):3004-3011. [PubMed 23835708]
  22. Beck KD, Rahman EZ, Ells A, Mireskandari K, Berrocal AM, Harper CA 3rd. SAFER-ROP: Updated protocol for anti-VEGF injections for retinopathy of prematurity. Ophthalmic Surg Lasers Imaging Retina. 2020;51(7):402-406. doi:10.3928/23258160-20200702-05 [PubMed 32706898]
  23. Benesch M, Windelberg M, Sauseng W, et al. Compassionate use of bevacizumab (Avastin) in children and young adults with refractory or recurrent solid tumors. Ann Oncol. 2008;19(4):807-813. doi:10.1093/annonc/mdm510 [PubMed 18056650]
  24. Bracarda S, Bellmunt J, Melichar B, et al. Overall Survival in Patients With Metastatic Renal Cell Carcinoma Initially Treated With Bevacizumab Plus Interferon-α2a and Subsequent Therapy With Tyrosine Kinase Inhibitors: A Retrospective Analysis of the Phase III AVOREN Trial. BJU Int. 2011;107(2):214-219. [PubMed 20942831]
  25. Brandes AA, Bartolotti M, Tosoni A, Poggi R, Franceschi E. Practical management of bevacizumab-related toxicities in glioblastoma. Oncologist. 2015;20(2):166-175. doi:10.1634/theoncologist.2014-0330 [PubMed 25568148]
  26. Burger RA, Brady MF, Bookman MA, et al. Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer. N Engl J Med. 2011;365(26):2473-2483. [PubMed 22204724]
  27. Burger RA, Sill MW, Monk BJ, et al. Phase II Trial of Bevacizumab in Persistent or Recurrent Epithelial Ovarian Cancer or Primary Peritoneal Cancer: A Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(33):5165-5171. [PubMed 18024863]
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