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Bevacizumab

Medically reviewed on March 25, 2018

Pronunciation

(be vuh SIZ uh mab)

Index Terms

  • Anti-VEGF Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Bevacizumab, inj
  • Bevacizumab-awwb
  • Mvasi
  • rhuMAb-VEGF

Dosage Forms

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)

Brand Names: U.S.

  • Avastin

Pharmacologic Category

  • Antineoplastic Agent, Monoclonal Antibody
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor
  • Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

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 of distribution: 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)

Special Populations: Gender

Men had a higher clearance and larger volume of distribution in the central compartment when compared with women. There is no evidence that this difference decreases the efficacy of bevacizumab in men.

Special Populations Note

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. There is no evidence suggesting that this difference leads to decreased efficacy.

Use: Labeled Indications

Cervical cancer, persistent/recurrent/metastatic (Avastin [bevacizumab], Mvasi [bevacizumab-awwb; biosimilar]): Treatment of persistent, recurrent, or metastatic cervical cancer (in combination with paclitaxel and either cisplatin or topotecan).

Colorectal cancer, metastatic (Avastin, Mvasi): 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): Treatment of recurrent glioblastoma

Glioblastoma, progressive (Mvasi): Treatment of glioblastoma (as a single agent) in patients with progressive disease

Non-small cell lung cancer, nonsquamous (Avastin, Mvasi): First-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non-small cell lung cancer (NSCLC) (in combination with carboplatin and paclitaxel).

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-resistant recurrent) (Avastin): 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.

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-sensitive recurrent) (Avastin): 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, Mvasi): Treatment of metastatic renal cell carcinoma (RCC) (in combination with interferon alfa).

Off Label Uses

Age-related macular degeneration

Data from multicenter randomized, controlled trials support the use of intravitreal bevacizumab in the management of age-related macular edema (AMD). American Academy of Ophthalmology Preferred Practice Pattern guidelines recommend the use of vascular endothelial growth factor (VEGF) inhibitors, including intravitreal bevacizumab, in the treatment of neovascular AMD.

Breast cancer, metastatic

Data from a large randomized controlled phase III study of paclitaxel with or without bevacizumab supports the use of bevacizumab in the treatment of metastatic breast cancer, based on the primary endpoint of progression-free survival [Miller 2007].

Diabetic macular edema

Data from a multicenter, randomized phase III study supports the use of intravitreal bevacizumab in the treatment of center-involved diabetic macular edema [Wells 2015]. American Academy of Ophthalmology Preferred Practice Pattern guidelines recommend VEGF inhibitors, including intravitreal bevacizumab, as initial treatment of choice for management of center-involved diabetic macular edema [American Academy of Ophthalmology 2016].

Endometrial cancer, recurrent or persistent

Data from a phase II study supports the use of bevacizumab (as a single agent) in the treatment of recurrent or persistent endometrial cancer [Aghajanian 2011]. Additional trials may be necessary to further define the role of bevacizumab in this condition.

Gliomas (recurrent or progressive) (pediatrics)

Data from 3 small retrospective studies suggest that bevacizumab (in combination with irinotecan; with or without temozolomide) may provide benefit in the treatment of recurrent or progressive high-grade gliomas in pediatric patients [Kang 2008], [Narayana 2010], [Parekh 2011]. Data from a small retrospective study suggest that bevacizumab (in combination with irinotecan) may be of benefit in the management of recurrent low-grade gliomas in pediatric patients [Packer 2009]. Additional data may be necessary to further define the role of bevacizumab in this condition.

Hereditary hemorrhagic telangiectasia

Data from a small non-randomized phase II study supports the use of systemic bevacizumab in the management of hereditary hemorrhagic telangiectasia in patients with high cardiac output and severe liver involvement [Dupuis-Girod 2012]. Additional studies may be necessary to further define the role of bevacizumab in the management of this condition.

Malignant pleural mesothelioma (unresectable)

Data from a large randomized controlled multicenter phase III study supports the use of bevacizumab (in combination with cisplatin and pemetrexed) in the management of unresectable malignant pleural mesothelioma in patients under 75 years of age [Zalcman 2016].

Medulloblastoma (relapsed or refractory)

Data from a small retrospective review and case reports suggest that bevacizumab in combination with irinotecan (with or without temozolomide; with or without vincristine) may provide some benefit (partial response or stable disease) in pediatric patients with relapsed or refractory medulloblastoma [Aguilera 2011], [Aguilera 2013]. Additional data may be necessary to further define the role of bevacizumab in this condition.

Soft tissue sarcoma, angiosarcoma

Data from a phase II trial with a limited number of patients studied suggest that bevacizumab may be beneficial for the treatment of angiosarcoma [Agulnik 2013]. Additional data may be necessary to further define the role of bevacizumab in this condition.

Soft tissue sarcoma, hemangiopericytoma

Data from a small number of patients in a retrospective review suggest that bevacizumab (in combination with temozolomide) may be beneficial for the treatment of hemangiopericytoma [Park 2011]. Additional data may be necessary to further define the role of bevacizumab in this condition.

Solid tumors, refractory (pediatrics)

Data from a small retrospective study (compassionate use) suggests that bevacizumab may provide some benefit (partial response) in heavily pre-treated pediatric patients with refractory solid tumors [Benesch 2008]. Additional data may be necessary to further define the role of bevacizumab in this condition.

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

Dosing: Adult

Note: Do not administer bevacizumab products until at least 28 days after surgery and the wound is fully healed.

Cervical cancer, persistent/recurrent/metastatic (Avastin [bevacizumab], Mvasi [bevacizumab-awwb; biosimilar]): IV: 15 mg/kg every 3 weeks (in combination with paclitaxel and either cisplatin or topotecan) until disease progression or unacceptable toxicity (Tewari 2014)

Colorectal cancer, metastatic, in combination with fluorouracil-based chemotherapy (Avastin, Mvasi): 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, Mvasi): 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)

Glioblastoma, recurrent or progressive (Avastin, Mvasi): 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)

Non-small cell lung cancer (nonsquamous cell histology), first-line therapy (Avastin, Mvasi): 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 or 15 mg/kg every 3 weeks (in combination with cisplatin and gemcitabine) for up to 6 cycles (Reck 2009; Reck 2010) or 7.5 mg/kg every 3 weeks (in combination with pemetrexed and cisplatin) for 4 cycles (Barlesi 2013)

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)

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-resistant recurrent) (Avastin): IV: 10 mg/kg every 2 weeks (in combination with weekly paclitaxel, every 4 week doxorubicin [liposomal], or days 1, 8, and 15 topotecan) or 15 mg/kg every 3 weeks (in combination with every 3 week topotecan) (Pujade-Lauraine 2014)

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-sensitive recurrent) (Avastin): 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 2015).

Renal cell cancer, metastatic (Avastin, Mvasi): 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)

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)

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)

Hereditary hemorrhagic telangiectasia (off-label use): IV: 5 mg/kg every 2 weeks for 6 doses (Dupuis-Girod 2012). Additional data may be necessary to further define the role of bevacizumab in this condition.

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)

Soft tissue sarcoma, angiosarcoma, metastatic or locally advanced (off-label use): IV: 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity (Agulnik 2013). Additional data may be necessary to further define the role of bevacizumab in this condition.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Do not administer bevacizumab products until at least 28 days after surgery and the wound is fully healed.

Gliomas, recurrent or progressive (off-label use; based on limited data): Children and Adolescents: IV: 10 mg/kg every 2 weeks in combination with irinotecan (with or without temozolomide) (Kang 2008; Narayana 2010; Packer 2009; Parekh 2011). Additional data may be necessary to further define the role of bevacizumab in this condition.

Medulloblastoma, relapsed/refractory (off-label use; based on limited data): Children: IV: 10 mg/kg every 2 weeks in combination with irinotecan (with or without temozolomide; with or without vincristine) (Aguilera 2011; Aguilera 2013). Additional data may be necessary to further define the role of bevacizumab in this condition.

Solid tumors, refractory (off-label use; based on limited data): Children and Adolescents: IV: 5 to 10 mg/kg every 2 or 3 weeks (Benesch 2008). Additional data may be necessary to further define the role of bevacizumab in this condition.

Dosing: Renal Impairment

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.

Dosing: Hepatic Impairment

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

Dosing: Adjustment for Toxicity

IV administration (systemic): There are no recommended dosage reductions.

Fistula (grade 4), tracheoesophageal fistula (any grade), fistula formation involving any internal organ: Discontinue bevacizumab.

Gastrointestinal perforation (any grade): Discontinue bevacizumab.

Heart failure: Discontinue bevacizumab.

Hemorrhage:

Grade 3 or 4: Discontinue bevacizumab.

Hemoptysis (recent history of ≥2.5 mL): Withhold bevacizumab.

Hypertension:

Hypertensive crisis: Discontinue bevacizumab.

Hypertensive encephalopathy: Discontinue bevacizumab.

Severe hypertension: Withhold bevacizumab if not controlled with medical management; resume when hypertension is controlled.

Infusion reaction:

Clinically insignificant (mild): Decrease infusion rate.

Clinically significant: Interrupt infusion; after symptoms resolve, resume at a decreased infusion rate.

Severe: Discontinue bevacizumab.

Posterior reversible encephalopathy syndrome (PRES): Discontinue bevacizumab.

Thromboembolic events:

Arterial thromboembolism (severe): Discontinue bevacizumab.

Venous thromboembolism (grade 4): Discontinue bevacizumab.

Wound healing complications (requiring medical intervention or necrotizing fasciitis): Discontinue bevacizumab.

Reconstitution

Dilute in 100 mL NS prior to infusion (the manufacturer recommends a total volume of 100 mL). Incompatibilities with polyvinylchloride (PVC) or polyolefin bags have not been observed. Do not administer or mix with dextrose-containing solutions.

Administration

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. After tolerance at the 90-, 60-, and 30-minute infusion rates has been established, some institutions use an off-label 10-minute infusion rate (0.5 mg/kg/minute) in adults for bevacizumab dosed at 5 mg/kg (Reidy 2007). In a study evaluating the safety of the 0.5 mg/kg/minute infusion rate, proteinuria, and hypertension incidences were not increased with the shorter infusion time (Shah 2013). Do not administer with dextrose solutions.

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.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F) in original carton; do not freeze. Protect from light; do not shake. Solutions diluted in NS are stable for up to 8 hours under refrigeration. Discard unused portion of vial.

Drug Interactions

Anthracyclines: Bevacizumab may enhance the cardiotoxic effect of Anthracyclines. Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. 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. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

SORAfenib: Bevacizumab may enhance the adverse/toxic effect of SORAfenib. Specifically, the risk for hand-foot skin reaction may be increased. 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. Avoid combination

Adverse Reactions

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 (19% to 42%), venous thromboembolism (secondary: 21%; with oral anticoagulants), peripheral edema (15%), hypotension (7% to 15%), venous thromboembolism (8% to 14%), arterial thrombosis (6%)

Central nervous system: Fatigue (33% to 82%), pain (8% to 62%), headache (22% to 49%), dizziness (13% to 26%), insomnia (21%), taste disorder (14% to 21%), peripheral sensory neuropathy (17% to 18%), anxiety (17%), myasthenia (13%)

Dermatologic: Alopecia (6% to 32%), exfoliative dermatitis (23%), palmar-plantar erythrodysesthesia (11%), xeroderma (7%)

Endocrine & metabolic: Ovarian failure (34%), hyperglycemia (26% to 31%), hypomagnesemia (24% to 27%), weight loss (15% to 21%), hyponatremia (17% to 19%), hypoalbuminemia (11% to 16%), hypocalcemia (12%)

Gastrointestinal: Nausea (72%), abdominal pain (33% to 61%), vomiting (33% to 52%), anorexia (35% to 43%), constipation (40%), diarrhea (21% to 39%), decreased appetite (34% to 35%), stomatitis (15% to 33%), gastrointestinal hemorrhage (19% to 24%), dyspepsia (17% to 24%), mucosal inflammation (13% to 15%)

Genitourinary: Proteinuria (4% to 36%; median onset: 5.6 months; median time to resolution: 6.1 months), urinary tract infection (22%), pelvic pain (14%)

Hematologic & oncologic: Thrombocytopenia (5% to 58%; grade 3/4: 40%), hemorrhage (40%; grades 3/4: ≤7%), leukopenia (grades 3/4: 37%), pulmonary hemorrhage (4% to 31%), neutropenia (12%; grades ≥3: 8% to 27%, grade 4: 27%), bruise (17%), lymphocytopenia (12%; grades 3/4: 6%)

Infection: Infection (55%; serious: 7% to 14%; pneumonia, catheter infection, or wound infection)

Neuromuscular & skeletal: Arthralgia (28% to 45%), myalgia (19% to 29%), limb pain (25%), back pain (12% to 21%), dysarthria (8% to 14%)

Renal: Increased serum creatinine (13% to 16%)

Respiratory: Epistaxis (17% to 55%), upper respiratory tract infection (40% to 47%), cough (26% to 30%), dyspnea (25% to 30%), allergic rhinitis (17%), oropharyngeal pain (16%), sinusitis (7% to 15%), nasal sign & symptoms (mucosal disorder: 14%), rhinitis (3% to >10%)

Miscellaneous: Postoperative wound complication (including dehiscence, 1% to 15%)

1% to 10%:

Cardiovascular: Thrombosis (8% to 10%), deep vein thrombosis (6% to 9%), chest pain (8%), intra-abdominal thrombosis (venous, grades 3/4: 3%), syncope (grades 3/4: 3%), left ventricular dysfunction (grades 3/4: 1%), pulmonary embolism (1%)

Central nervous system: Voice disorder (5% to 13%)

Dermatologic: Nail disease (10%), dermal ulcer (6%), cellulitis (grades 3/4: 3%), acne vulgaris (1%)

Endocrine & metabolic: Dehydration (grades 3/4: 4% to 10%), hyperkalemia (9%), hypokalemia (grades 3/4: 7%)

Gastrointestinal: Hemorrhoids (8%), xerostomia (4% to 7%), gingival hemorrhage (minor, 2% to 7%), rectal pain (6%), colitis (1% to 6%), intestinal obstruction (grades 3/4: 4%), gastrointestinal perforation (≤3%), gastroesophageal reflux disease (2%), gingivitis (2%), oral mucosa ulcer (2%), gastrointestinal fistula (≤2%), gastritis (1%), gingival pain (1%)

Genitourinary: Vaginal hemorrhage (4%)

Hematologic & oncologic: Febrile neutropenia (5%), neutropenic infection (grades 3/4: 5%), hemorrhage (CNS; 5%)

Hepatic: Increased serum AST (15%)

Infection: Abscess (tooth, 2%)

Neuromuscular & skeletal: Weakness (grades 3/4: 10%), neck pain (9%)

Ophthalmic: Blurred vision (2%)

Otic: Tinnitus (2%), deafness (1%)

Respiratory: Rhinorrhea (10%), nasal congestion (8%), pneumonitis (grades 3/4: 5%)

Miscellaneous: Fistula (gastrointestinal-vaginal; 8%), fistula (anal; 6%), infusion related reaction (<3%), fistula (≤2%)

<1%, postmarketing, and/or case reports: Anaphylaxis, anastomotic ulcer, angina pectoris, antibody development (anti-bevacizumab and neutralizing), bladder fistula, bronchopleural fistula, cerebral infarction, conjunctival hemorrhage, endophthalmitis (infectious and sterile), eye discomfort, eye pain, fistula of bile duct, fulminant necrotizing fasciitis, gallbladder perforation, gastrointestinal ulcer, hemolytic anemia (microangiopathic; when used in combination with sunitinib), hemoptysis, hemorrhagic stroke, hypersensitivity, hypertensive crisis, hypertensive encephalopathy, increased intraocular pressure, inflammation of anterior segment of eye (toxic anterior segment syndrome) (Sato 2010), intestinal necrosis, intraocular inflammation (iritis, vitritis), mesenteric thrombosis, myocardial infarction, nasal septum perforation, nephrotic syndrome, ocular hyperemia, osteonecrosis of the jaw, pancytopenia, permanent vision loss, polyserositis, pulmonary hypertension, rectal fistula, renal failure, renal fistula, renal thrombotic microangiopathy, retinal detachment, retinal hemorrhage, reversible posterior leukoencephalopathy syndrome, sepsis, tracheoesophageal fistula, transient ischemic attacks, vaginal fistula, visual disturbance, vitreous hemorrhage, vitreous opacity

ALERT: U.S. Boxed Warning

GI perforations:

The incidence of GI perforations, some fatal, in patients receiving bevacizumab products ranges from 0.3% to 3%. Discontinue bevacizumab products in patients with GI perforation.

Surgery and wound healing complications:

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in patients receiving bevacizumab products. Discontinue bevacizumab products in patients who develop wound healing complications that require medical intervention. Withhold bevacizumab products at least 28 days prior to elective surgery. Do not administer bevacizumab products for at least 28 days after surgery and until the surgical wound is fully healed.

Hemorrhage:

Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurs up to 5-fold more frequently in patients receiving bevacizumab products. Do not administer bevacizumab products to patients with a recent history of hemoptysis. Discontinue in patients who develop grade 3 to 4 hemorrhage.

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal perforation/fistula: [US Boxed Warning]: GI perforation, (sometimes fatal) in patients receiving bevacizumab products ranges from 0.3% to 3%; discontinue bevacizumab products in patients with GI perforation. 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 gastrointestinal vaginal fistula may also have bowel obstruction which 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. Discontinue in patients who develop gastrointestinal perforation, tracheoesophageal fistula, any grade 4 fistula, or fistula formation involving any internal organ.

• Heart failure: In a scientific statement from the American Heart Association, bevacizumab has been determined to be an agent that may either cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: moderate/major) (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 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. Discontinue bevacizumab products in patients who develop HF.

• Hemorrhage: [US Boxed Warning]: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving bevacizumab products. Do not administer bevacizumab products to patients with a recent history of hemoptysis (≥2.5 mL blood). Discontinue in patients who develop grade 3 to 4 hemorrhage. 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. Minor hemorrhages, including grade 1 epistaxis may commonly occur.

• Hypertension: Bevacizumab may cause and/or worsen hypertension. The incidence of severe hypertension in increased with bevacizumab products. Manage hypertension with antihypertensive therapy. Monitor BP every 2 to 3 weeks during bevacizumab treatment and regularly after discontinuation if bevacizumab-induced hypertension occurs or worsens. Withhold bevacizumab treatment in patients with severe hypertension that is uncontrolled with medical management (resume bevacizumab after blood pressure is controlled). Discontinue bevacizumab products in patients who experience a hypertensive crisis or hypertensive encephalopathy.

• 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. Decrease the infusion rate for mild/clinically insignificant infusion reactions. Interrupt infusion for clinically significant infusion reactions and consider resuming at a slower rate following resolution. Discontinue bevacizumab for severe infusion reaction and administer appropriate medical therapy (eg, epinephrine, corticosteroids, IV antihistamines, bronchodilators, and/or oxygen).

• 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. Discontinue in patients who develop necrotizing fasciitis.

• Ocular adverse events: Serious eye infections and vision loss due to endophthalmitis have been reported from intravitreal administration (off-label use/route).

• Osteonecrosis of the jaw (ONJ): 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 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).

• Ovarian failure: In premenopausal women 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 FSH level <30 mIU/mL) at all time points in the post-treatment period after bevacizumab discontinuation was demonstrated in approximately one-fifth of females who received bevacizumab. The long-term effects of bevacizumab on fertility are unknown. Females of reproductive potential should be informed of the potential risk of ovarian failure prior to bevacizumab initiation.

• 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. Discontinue bevacizumab products in patients who develop PRES. 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 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. Monitor proteinuria (by serial dipstick urine analysis) for proteinuria development or worsening of proteinuria throughout bevacizumab therapy. Further assess with a 24-hour urine collection for ≥2+ urine dipstick readings. Withhold bevacizumab for proteinuria ≥2 g/24 hours; resume when <2 g/24 hours. Discontinue bevacizumab products in patients who develop nephrotic syndrome. Urine protein/creatinine ratio (UPCR) 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, MI, TIA, 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 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. Discontinue bevacizumab in patients with severe ATE or grade 4 VTE, including pulmonary embolism.

• Wound healing complications: [US Boxed Warning]: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in patients receiving bevacizumab products; discontinue in patients who develop wound healing complications that require medical intervention. Withhold bevacizumab products at least 28 days prior to elective surgery. Do not administer bevacizumab products for at least 28 days after surgery and until the surgical wound is fully healed. 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 mCRC 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 blood pressures were noted in a retrospective review of patients with renal insufficiency (CrCl ≤60 mL/minute) who received bevacizumab for renal cell cancer (Gupta 2011).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Patients ≥65 years of age have an increased incidence of arterial thrombotic events.

Monitoring Parameters

Monitor for proteinuria/nephrotic syndrome with urine dipstick; collect 24-hour urine in patients with ≥2+ reading. Monitor blood pressure every 2 to 3 weeks; more frequently if hypertension develops during therapy; continue to monitor blood pressure after discontinuing due to bevacizumab-induced hypertension. Monitor closely during the infusion for signs/symptoms of an infusion reaction. Monitor for signs/symptoms of gastrointestinal perforation or fistula (including abdominal pain, constipation, vomiting, and fever), bleeding (including epistaxis, hemoptysis, gastrointestinal, and/or CNS bleeding), and thromboembolism (arterial and venous).

AMD (off-label use): Monitor intraocular pressure and retinal artery perfusion. Monitor for signs/symptoms of infectious endophthalmitis and retinal detachment (AAO 2011).

Diabetic macular edema (off-label use): Monitor visual acuity, central subfield thickness, and intraocular pressure; 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.

Pregnancy Considerations

Based on findings in animal reproduction studies and on the mechanism of action, bevacizumab may cause fetal harm if administered to a pregnant woman. Information from postmarketing reports following exposure in pregnancy is limited. Women of reproductive potential should use effective contraception during therapy and for 6 months following the last bevacizumab dose. Bevacizumab treatment may also increase the risk of ovarian failure and impair fertility; long term effects on fertility are not known.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, muscle pain, joint pain, muscle weakness, neck pain, diarrhea, loss of strength and energy, lack of appetite, dry skin, nail changes, change in taste, weight loss, rhinorrhea, insomnia, tearing, or change in voice. Have patient report immediately to prescriber signs of infusion reaction, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of infection, signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), tachycardia, sweating a lot, burning or numbness feeling, anxiety, redness or irritation of palms or soles of feet, signs of necrotizing fasciitis (warm skin with red or purple areas of swelling that spread quickly; ulcers, blisters, black spots on the skin; or any other skin changes), signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), severe dizziness, passing out, vision changes, shortness of breath, excessive weight gain, swelling of arms or legs, severe headache, severe nausea, vomiting, severe constipation, severe abdominal pain, wound healing impairment, or mouth irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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