Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: Immunoglobulin G 1 (human-mouse monoclonal rhuMAb-VEGF γ-chain anti-human vascular endothelial growth factor), disulfide with human-mouse monoclonal rhuMAb-VEGF light chain, dimer
Molecular Formula: C6638H10160N1720O2108S44
CAS Number: 216974-75-3
- GI Perforations
- Surgery and Wound Healing Complications
Increased incidence of surgical and wound healing complications; may be serious and fatal.1 Discontinue bevacizumab permanently if wound dehiscence and wound healing complications requiring medical intervention occur.1 (See Surgery and Wound Healing Complications under Cautions.)
Appropriate interval between discontinuance of bevacizumab and subsequent elective surgery required to decrease risk of wound healing complications not established.1 However, manufacturer recommends discontinuing therapy ≥28 days prior to elective surgery.1
Do not initiate therapy until ≥28 days following major surgery and after surgical incision has fully healed.1
Uses for Bevacizumab
Used in combination with IV fluorouracil-based chemotherapy for the first-line treatment of metastatic cancer of the colon or rectum.1 2 3 4 9 Analysis of pooled data suggests that use of bevacizumab in combination with fluorouracil and leucovorin is associated with prolonged survival.20
Used in combination with IV fluorouracil-based chemotherapy for the second-line treatment of previously treated metastatic cancer of the colon or rectum.1 Interim analysis of data from one study indicated bevacizumab monotherapy† was associated with decreased survival compared with combination regimen consisting of fluorouracil, leucovorin, and oxaliplatin.1
Investigated for use in combination with fluorouracil, leucovorin, and oxaliplatin (modified FOLFOX6)† as adjuvant therapy following surgery for early-stage (i.e., stage II or III)† colon cancer.28 Data from a randomized study demonstrated no improvement in disease-free survival; therefore, such use not recommended.53
Non-small Cell Lung Cancer
Used in combination with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC.1 10 Data from a randomized study suggest that use of bevacizumab in combination with carboplatin and paclitaxel is associated with prolonged survival; benefit less certain in women, patients ≥65 years of age, and those with ≥5% weight loss.1 11
Investigated for use in combination with cisplatin and gemcitabine† for first-line treatment of locally advanced, metastatic, or recurrent nonsquamous NSCLC.1 Data from a randomized study suggest that such use is associated with prolonged progression-free survival but not prolonged overall survival.1
Used as a single agent for treatment of glioblastoma in patients whose disease has progressed following radiation therapy and chemotherapy (i.e., temozolomide).1 Efficacy is based on increased objective response rate; currently, no data available that demonstrate prolonged overall survival or amelioration of disease-related symptoms.1 47 48
Renal Cell Carcinoma
Previously labeled for use in combination with paclitaxel for first-line treatment of metastatic HER2-negative breast cancer†.44 However, FDA concluded that such use has not been shown in postmarketing studies to prolong overall survival or provide sufficient clinical benefit (e.g., prolongation of progression-free survival, amelioration of disease-related symptoms, improvement in quality of life) to outweigh the risk of severe, potentially fatal, adverse effects (e.g., MI, CHF, severe hypertension, bleeding or hemorrhage, perforation and fistula/abscess formation,44 wound healing complications).65 66 68 Therefore, on November 18, 2011, FDA revoked approval of bevacizumab for this use;68 Health Canada, but not the European Medicines Agency (EMA), took similar action.65 69 The United Kingdom’s Institute for Health and Clinical Excellence (NICE) reached similar conclusions about the lack of evidence of clinical benefit and has not supported this use.65 70 The AHFS Oncology Expert Committee concluded that use of bevacizumab in combination with paclitaxel for first-line treatment of metastatic breast cancer currently is not fully established because of equivocal evidence.77
Patients currently receiving bevacizumab for breast cancer should consult their clinician about whether to continue bevacizumab therapy or consider other treatment options.67 Clinicians should use clinical judgment in deciding whether patients should continue receiving bevacizumab in combination with paclitaxel, receive paclitaxel monotherapy, or consider other treatment options.67
AHFS OncologyExpert Committee also concluded that use of bevacizumab in combination with chemotherapy (e.g., taxanes, capecitabine, gemcitabine, vinorelbine)14 75 for the treatment of metastatic breast cancer previously treated with cytotoxic chemotherapy† currently is not fully established because of equivocal evidence.78
Investigated for use in treatment of ovarian cancer†.26 Data from randomized studies suggest that use of bevacizumab in combination with carboplatin and paclitaxel is associated with prolonged progression-free survival, but not prolonged overall survival, and an increased risk of hypertension and GI perforation.71 72 Effects on overall survival not fully elucidated (i.e., no difference in overall survival reported in one study, final overall survival data not yet available for another study).71 72
Has been used by intravitreal injection† in treatment of neovascular age-related macular degeneration†.34 41 85 86 87 88 89 Appears to have similar efficacy as ranibizumab in improving visual acuity; however, conflicting data reported regarding relative risk of serious systemic adverse effects.41 87 88 Consider patient-specific factors, which may vary the level of risk, prior to intravitreal use.88 (See Ocular Effects under Cautions.)
Bevacizumab Dosage and Administration
Use alone or in combination with other chemotherapeutic agents.1 (See Dosage under Dosage and Administration.)
Do not initiate therapy until ≥28 days following major surgery and after surgical incision has fully healed.1 (See Surgery and Wound Healing Complications under Cautions.)
Discontinue therapy ≥28 days prior to elective surgery; do not resume until surgical incision has fully healed.1 (See Surgery and Wound Healing Complications under Cautions.)
For solution and drug compatibility information, see Compatibility under Stability.
Do not shake vial prior to dilution.1
Rate of Administration
Administer initial dose over 90 minutes.1 (See Infusion Reactions under Cautions.)
If well tolerated, administer second dose over 60 minutes.1
If second dose is well tolerated, administer subsequent doses over 30 minutes.1
Has been administered safely over shorter infusion times (0.5 mg/kg per minute).43
Consult respective manufacturers or published protocols for dosage, method of administration, and administration sequence of drugs in combination regimens.3
First-line Treatment of Metastatic Colorectal CancerIV
5 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1
Use in combination with IV fluorouracil-based chemotherapy.1 In clinical studies, bevacizumab was used in combination with the IFL regimen (irinotecan 125 mg/m2, fluorouracil 500 mg/m2, and leucovorin 20 mg/m2, administered by IV injection once weekly for 4 out of every 6 weeks)1 4 or the 5-FU/LV regimen (leucovorin 500 mg/m2 by IV infusion over 2 hours, then fluorouracil 500 mg/m2 by slow IV injection [1 hour after initiation of leucovorin] given once weekly for the first 6 weeks out of every 8-week cycle).1 2 3
Second-line Treatment of Metastatic Colorectal CancerIV
10 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1
Use in combination with IV fluorouracil-based chemotherapy.1 In clinical studies, bevacizumab was administered on day 1 of the treatment cycle prior to the FOLFOX4 regimen (oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 concurrently IV, then fluorouracil 400 mg/m2 by direct IV injection, followed by fluorouracil 600 mg/m2 by continuous IV infusion on day 1; and leucovorin 200 mg/m2 IV, then fluorouracil 400 mg/m2 by direct IV injection, followed by fluorouracil 600 mg/m2 by continuous IV infusion on day 2; treatment cycles repeated every 2 weeks).1
Non-small Cell Lung Cancer
Use in combination with IV paclitaxel and carboplatin (PC regimen).1 f In clinical studies, bevacizumab was administered 1 hour after the PC regimen (paclitaxel 200 mg/m2 by IV infusion over 3 hours, then carboplatin [at dose required to obtain AUC of 6 mg/mL per minute] by IV infusion over 15–30 minutes beginning 60 minutes after completion of paclitaxel; treatment cycles repeated every 3 weeks).1 11 d e f In these studies, patients received up to 6 cycles of bevacizumab in combination with the PC regimen, after which bevacizumab monotherapy (15 mg/kg every 3 weeks) was continued until disease progression or unacceptable toxicity occurred.1 11 d e f A median of 7 treatment cycles (including cycles of bevacizumab monotherapy) was administered.11
10 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1
Renal Cell Carcinoma
10 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1
Use in combination with interferon alfa (9 million units sub-Q 3 times weekly).1
First-line Treatment of Metastatic Breast Cancer†IV
10 mg/kg every 2 weeks; has been used in combination with IV paclitaxel (90 mg/m2 IV once weekly for 3 out of 4 weeks).64 However, this regimen has not been shown to prolong overall survival or provide sufficient clinical benefit to outweigh the risk of severe, potentially fatal, adverse effects.65 (See Breast Cancer under Uses.)
Dosage Modification for Toxicity
Discontinue therapy permanently if GI perforation (i.e., GI perforation, fistula formation in GI tract, intra-abdominal abscess), non-GI fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, severe hemorrhage requiring medical intervention, severe arterial thromboembolic event, nephrotic syndrome, hypertensive crisis, or hypertensive encephalopathy occurs.1 7
Discontinue therapy if reversible posterior leukoencephalopathy syndrome (RPLS) occurs.1 31 32 (See Reversible Posterior Leukoencephalopathy Syndrome [RPLS] under Cautions.) Risk of reinitiating therapy in patients previously experiencing RPLS not known.1 32
Discontinue therapy temporarily in patients with evidence of moderate to severe proteinuria pending further evaluation, in patients with severe hypertension not controlled by medical management, or in patients with severe infusion reactions.1 (See Cautions.)
No dosage adjustment required in geriatric patients.1
Cautions for Bevacizumab
Consider the usual cautions, precautions, and contraindications of any other antineoplastic agents included in the therapeutic regimen.3
Severe, sometimes fatal, GI perforation reported; generally manifested as abdominal pain, nausea, vomiting, constipation, and fever.1 Usually occurs within the first 50 days following initiation of bevacizumab.1
If GI perforation (GI perforation, fistula formation in GI tract, and/or intra-abdominal abscess) occurs, discontinue bevacizumab permanently.1
Surgery and Wound Healing Complications
Wound healing and bleeding complications (including wound dehiscence), sometimes fatal, reported.1
Do not initiate bevacizumab therapy until ≥28 days following major surgery and after surgical incision has fully healed.1
Discontinue bevacizumab ≥28 days prior to elective surgery.1 Appropriate interval between discontinuance of bevacizumab and subsequent elective surgery not established, but consider long half-life of bevacizumab.1 (See Half-life under Pharmacokinetics.) Manufacturer recommends resuming therapy only after surgical incision has fully healed.1
Discontinue bevacizumab permanently if wound dehiscence and wound healing complications requiring medical intervention occur.1 (See Boxed Warning.)
Severe, sometimes fatal, hemorrhagic events (e.g., hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, vaginal bleeding) reported.1 (See Boxed Warning.)
Risk of severe or fatal pulmonary hemorrhage in patients with non-small cell lung cancer.1 Serious or fatal pulmonary hemorrhage reported in 31% of patients with squamous cell histology and in 4% of patients with nonsquamous cell histology.1
Mild hemorrhagic events, most commonly grade 1 epistaxis, also reported.1
Infusion reactions (e.g., hypertension, hypertensive crisis associated with neurologic manifestations, wheezing, oxygen desaturation, grade 3 hypersensitivity, chest pain, headache, rigor, diaphoresis) reported.1
Infuse initial doses slowly, increasing rate of infusion as tolerated.1 (See Rate of Administration under Dosage and Administration.)
Non-GI Fistula Formation
Severe, sometimes fatal, non-GI fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, and bladder sites reported; usually occurs within first 6 months of treatment.1 If non-GI fistula formation involving an internal organ occurs, discontinue bevacizumab permanently.1
Serious, sometimes fatal, arterial thromboembolic events (e.g., cerebral infarction, TIA, MI, angina) reported.1 7 8 16 17 Increased risk in patients with a history of arterial thromboembolism or patients >65 years of age.1 7 Weigh risks against benefits of therapy.17 Discontinue therapy permanently if severe arterial thromboembolic event occurs;1 7 safety of resuming therapy after resolution of an arterial thromboembolic event not studied.1
Grade 3 or 4 venous thromboembolic events (e.g., DVT, intra-abdominal venous thrombosis) reported.1 Increased risk of developing second thromboembolic event reported in patients with metastatic colorectal cancer receiving bevacizumab with chemotherapy despite use of full-dose warfarin therapy following an initial venous thromboembolic event.1
Severe hypertension (grade 3 or 4) reported.1
Monitor BP every 2–3 weeks during therapy.1 If hypertension occurs, initiate appropriate antihypertensive therapy and monitor BP regularly.1 Temporarily discontinue therapy in patients with severe hypertension not controlled with medical management.1 Discontinue therapy permanently if hypertensive crisis or hypertensive encephalopathy occurs.1 If therapy is discontinued because of hypertension, monitor BP at regular intervals thereafter.1
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
RPLS (a brain-capillary leak syndrome) reported.1 29 30 32 May manifest with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances; mild to severe hypertension also may occur.1 32 Manifestations occurred from 16 hours to 1 year after initiation of bevacizumab.1 32 Magnetic resonance imaging (MRI) is necessary to confirm diagnosis of RPLS.1 32
Closely monitor and maintain strict control of BP during and following bevacizumab infusion.30 If RPLS develops, discontinue bevacizumab and initiate treatment of hypertension as clinically indicated.1 31 32 Symptoms usually lessen or resolve within days of drug discontinuance, but some patients have experienced ongoing neurologic sequelae.1 32 Risk of reinitiating bevacizumab in patients previously experiencing RPLS not known.1 32
Increased incidence and severity of proteinuria reported.1 Severity ranges from clinically silent to nephrotic syndrome.6 Proteinuria with findings of thrombotic microangiopathy on renal biopsy reported in patients receiving bevacizumab alone or in combination with other antineoplastic agents for various cancers.1 37
Monitor patients for development or worsening of proteinuria with serial urinalysis.1 Further assessment (e.g., 24-hour urine collection) recommended if ≥2+ urine dipstick reading occurs.1 Interrupt bevacizumab therapy for moderate proteinuria (≥2 g per 24 hours); resume therapy when proteinuria is <2 g per 24 hours.1 Safety of continuing therapy in patients with moderate to severe proteinuria not known.1
Discontinue bevacizumab permanently in patients with nephrotic syndrome.1
Ovarian failure reported in premenopausal women receiving bevacizumab in combination with chemotherapy (i.e., modified FOLFOX6)† for adjuvant treatment of colorectal cancer.1 Recovery of ovarian function occurred in 22% of patients following discontinuance of bevacizumab.1 Long-term effects on fertility unknown.1
Inform women of childbearing potential of risk of ovarian failure prior to initiating bevacizumab.1
Neutropenia and Infection
Severe (grade 3 or 4) neutropenia, febrile neutropenia, infection with severe neutropenia (sometimes fatal), and serious infections (e.g., pneumonia, catheter infections, wound infections) reported.1
CHF reported; higher risk in patients also receiving or who had previously received anthracyclines.1
Safety of continuation or resumption of bevacizumab in patients who develop cardiac dysfunction not studied.1
Microangiopathic Hemolytic Anemia
Microangiopathic hemolytic anemia reported in patients with solid tumors receiving bevacizumab and sunitinib†;35 36 cases were reversible within 3 weeks following discontinuance of both drugs without other interventions.35 36 Use of bevacizumab in combination with sunitinib is not recommended.35 36
Permanent loss of vision, endophthalmitis (infectious and sterile), intraocular inflammation, retinal detachment, increased IOP, hemorrhage (including conjunctival, vitreous, or retinal hemorrhage), vitreous floaters, ocular hyperemia, and ocular pain or discomfort reported in patients receiving intravitreal injection† of bevacizumab for treatment of various ocular disorders†.1
No difference in overall survival relative to younger adults observed in patients receiving bevacizumab and chemotherapy for metastatic colorectal cancer.1 However, possible increased risk of asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, MI, CHF, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, hyponatremia, nausea, vomiting, ileus, and fatigue.1
Increased incidence of arterial thromboembolic events in patients >66 years of age receiving bevacizumab with chemotherapy compared with younger adults.1 (See Thromboembolism under Cautions.)
Increased risk of proteinuria in patients ≥65 years of age receiving bevacizumab in combination with paclitaxel and carboplatin, compared with younger adults.1 (See Proteinuria under Cautions.)
Possible increased incidence of dyspepsia, GI hemorrhage, edema, epistaxis, increased cough, and voice alteration compared with younger adults.1
Common Adverse Effects
Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis.1
Interactions for Bevacizumab
No effect on carboplatin exposure1
No effect on interferon alfa exposure1
Possible decreased paclitaxel exposure after 4 treatment cycles of bevacizumab in combination with paclitaxel and carboplatin1
Relationship between bevacizumab exposure and clinical outcome not studied.1
Metabolized by reticuloendothelial system.3
Eliminated via reticuloendothelial system.3
Approximately 20 days (range: 11–50 days).1
Store diluted solution at 2–8°C for up to 8 hours.1
For information on systemic interactions resulting from concomitant use, see Interactions.
No incompatibilities with PVC or polyolefin bags.1
Sodium chloride 0.9%
Binds to human vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors (Flt-1, KDR) on the surface of endothelial cells.1 This may result in inhibition of angiogenesis, thus reducing microvascular growth of tumors and inhibiting metastatic disease progression.1 2 3 5
Advice to Patients
Importance of understanding potential risks associated with therapy, including severe hypertension, wound healing complications, arterial thromboembolic events, and ovarian failure.1
Importance of routine monitoring of BP; advise patients to inform clinician if BP is elevated.1
Importance of immediately informing clinician if unusual bleeding, high fever, rigors, sudden worsening of neurologic function, persistent or severe abdominal pain, severe constipation, or vomiting occurs.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
For injection, concentrate, for IV infusion
25 mg/mL (100 and 400 mg)
AHFS DI Essentials. © Copyright 2016, Selected Revisions June 30, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
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3. Genentech, South San Francisco, CA: Personal communication.
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