Bevacizumab

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)

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 disodium dihydrate, polysorbate 80]

Pharmacology

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/Pharmacodynamics

Distribution

CV% central volume of distribution: 2.9 (22%) L

Excretion

Clearance (mean): Adults: 0.23 L/day

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)

Use in Specific Populations

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 and bevacizumab biosimilars): Treatment of persistent, recurrent, or metastatic cervical cancer (in combination with paclitaxel and either cisplatin or topotecan).

Colorectal cancer, metastatic (Avastin and bevacizumab biosimilars): First- or second-line treatment of metastatic colorectal cancer (CRC) (in combination with fluorouracil-based chemotherapy); second-line treatment of metastatic CRC (in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy) after progression on a first-line treatment containing bevacizumab.

Limitations of use: Not indicated for the adjuvant treatment of colon cancer.

Glioblastoma, recurrent (Avastin and bevacizumab biosimilars): Treatment of recurrent glioblastoma in adults.

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 only):

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: Mvasi (bevacizumab-awwb) and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab).

Use: Off Label

Age-related macular degenerationayes

Data from multicenter, randomized, controlled trials support the use of intravitreal bevacizumab in the management of age-related macular degeneration (AMD) Chakravarthy 2013, Martin 2011, Martin 2012.

American Academy of Ophthalmology (AAO) Preferred Practice Pattern guidelines recommend the use of vascular endothelial growth factor (VEGF) inhibitors, including intravitreal bevacizumab, as first-line therapy for the treatment of neovascular AMD

Breast cancer, metastaticb

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

Diabetic macular edemaayes

Data from a multicenter, randomized phase III study support the use of intravitreal bevacizumab in the treatment of center-involved diabetic macular edema Wells 2015. AAO Preferred Practice Pattern guidelines recommend vascular endothelial growth factor inhibitors, including intravitreal bevacizumab, as initial treatment of choice for management of center-involved diabetic macular edema AAO 2016.

Endometrial cancer, recurrent or persistentb

Data from a phase II study support the use of bevacizumab (as a single agent) in the treatment of recurrent or persistent endometrial cancer Aghajanian 2011.

Hereditary hemorrhagic telangiectasiac

Data from a small non-randomized phase II study support 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. Data from a retrospective study in patients with refractory hereditary hemorrhagic telangiectasia also support the use of bevacizumab for management of related severe GI bleeding and/or epistaxis Iyer 2018.

Malignant pleural mesothelioma (unresectable)a

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

Soft tissue sarcoma, angiosarcomac

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.

Soft tissue sarcoma, hemangiopericytomac

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.

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

Dosage and Administration

Dosing: Adult

Note: Do not administer bevacizumab products until at least 28 days after surgery and the wound is fully healed. Mvasi (bevacizumab-awwb) and Zirabev (bevacizumab-bvzr) are approved as biosimilars to Avastin (bevacizumab).

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).

Colorectal cancer, metastatic, in combination with fluorouracil-based chemotherapy (Avastin and bevacizumab biosimilars): IV: 5 mg/kg every 2 weeks (in combination with bolus-IFL) or 10 mg/kg every 2 weeks (in combination with FOLFOX4).

Colorectal cancer, metastatic, following first-line therapy containing bevacizumab (Avastin and bevacizumab biosimilars): IV: 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks (in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based regimen).

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).

Non-small cell lung cancer (nonsquamous cell histology), first-line therapy (Avastin and bevacizumab biosimilars): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and paclitaxel) for 6 cycles (Sandler 2006).

Off-label combinations: 15 mg/kg every 3 weeks (in combination with pemetrexed and carboplatin) for up to 4 cycles (Patel 2013) or 7.5 mg/kg every 3 weeks (in combination with pemetrexed and cisplatin) for 4 cycles (Barlesi 2013) or 15 mg/kg every 3 weeks (in combination with atezolizumab, paclitaxel, and carboplatin) for 4 to 6 cycles (Socinski 2018).

Maintenance therapy (off-label use): 15 mg/kg every 3 weeks as a single agent (after 6 cycles of induction therapy with bevacizumab, carboplatin and paclitaxel); continue maintenance therapy until disease progression or unacceptable toxicity (Sandler 2006) or 15 mg/kg (in combination with pemetrexed) every 3 weeks (following 4 cycles of induction therapy with bevacizumab, pemetrexed, and carboplatin); continue until disease progression or unacceptable toxicity (Patel 2013) or 7.5 mg/kg (in combination with pemetrexed) every 3 weeks (following 4 cycles of induction therapy with bevacizumab, cisplatin and pemetrexed); continue until disease progression or unacceptable toxicity (Barlesi 2013) or 15 mg/kg every 3 weeks, with or without maintenance atezolizumab (following 4 to 6 cycles of induction therapy with atezolizumab, paclitaxel and carboplatin); continue until disease progression or unacceptable toxicity (Socinski 2018).

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (stage III or IV disease following initial surgical resection) (Avastin only): 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).

Ovarian (epithelial), fallopian tube, or primary peritoneal cancer (platinum-resistant recurrent) (Avastin only): 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 only): IV: 15 mg/kg every 3 weeks (in combination with carboplatin and gemcitabine for 6 to 10 cycles or with carboplatin and paclitaxel for 6 to 8 cycles) then continue with bevacizumab (monotherapy) until disease progression or unacceptable toxicity (Aghajanian 2012; Aghajanian 2015; Coleman 2017).

Renal cell cancer, metastatic (Avastin and bevacizumab biosimilars): IV: 10 mg/kg every 2 weeks (in combination with interferon alfa) or (off-label dosing) 10 mg/kg every 2 weeks as monotherapy (Yang 2003).

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; based on limited data): IV: 5 mg/kg every 2 weeks for 6 doses (Dupuis-Girod 2012) or 5 mg/kg every 2 weeks for 4 doses, followed by 5 mg/kg once a month for 4 doses; additional doses (or dose modifications) may be administered if response is suboptimal (refer to protocol for further details) (Iyer 2018).

Malignant pleural mesothelioma, unresectable (off-label use): IV: 15 mg/kg every 3 weeks (in combination with pemetrexed and cisplatin) for up to 6 cycles, followed by bevacizumab maintenance therapy at 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity (Zalcman 2016).

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).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Refer to individual protocols; details concerning dosing in combination regimens should also be consulted. Trials in pediatric patients were conducted using the product Avastin 25 mg/mL vial for injection of bevacizumab. Mvasi (bevacizumab-awwb) is a biosimilar of Avastin; however, reported experience with the biosimilar product in pediatric oncology patients is lacking.

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)

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)

Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult oncology patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.

Adult: IV administration (systemic): There are no recommended dosage reductions. Temporary suspension is recommended for severe infusion reactions, at least 4 weeks prior to (and after) elective surgery, in moderate to severe proteinuria (in most studies, treatment was withheld for ≥2 g proteinuria/24 hours), or in patients with severe hypertension which is not controlled with medical management. Permanent discontinuation is recommended (by the manufacturer) in patients who develop wound dehiscence and wound healing complications requiring intervention, necrotizing fasciitis, fistula (gastrointestinal and nongastrointestinal), gastrointestinal perforation, intra-abdominal abscess, hypertensive crisis, hypertensive encephalopathy, serious bleeding/hemorrhage, severe arterial thromboembolic event, life-threatening (grade 4) venous thromboembolic events (including pulmonary embolism), nephrotic syndrome, or PRES.

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 manufacturers recommend a total volume of 100 mL). Do not use (and discard) if solution in vial appears cloudy, discolored, or contains particulate matter. 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.

Off-label infusion rate: 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 patients 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); do not freeze. Store in the original carton; 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

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

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

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. 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. Consider therapy modification

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

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

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 (24% to 42%), peripheral edema (15%), venous thromboembolism (grades 3/4: 5% to 11%)

Central nervous system: Fatigue (33% to 82%), headache (22% to 49%), dizziness (23%), insomnia (21%), anxiety (17%), myasthenia (13% to 15%), voice disorder (5% to 13%), dysarthria (8% to 12%), taste disorder

Dermatologic: Exfoliative dermatitis, xeroderma

Endocrine & metabolic: Ovarian failure (34%), hyperglycemia (26%), hypomagnesemia (24%), weight loss (20% to 21%), hyponatremia (19%), hypoalbuminemia (16%)

Gastrointestinal: Nausea (53% to 72%), diarrhea (21% to 40%), decreased appetite (34% to 36%), stomatitis (15% to 25%), abdominal pain (grade 3/4: 8% to 12%)

Genitourinary: Urinary tract infection (22%), proteinuria (5% to 20%), pelvic pain (14%)

Hematologic & oncologic: Thrombocytopenia (58%; grade 3/4: 20% to 40%), leukopenia (grades 3/4: 37% to 53%), pulmonary hemorrhage (4% to 31%), neutropenia (12%; grades ≥3: 8% to 21%), bruise (17%), lymphocytopenia (12%; grades 3/4: 6%), rectal hemorrhage

Neuromuscular & skeletal: Arthralgia (28% to 41%), limb pain (19% to 25%), back pain (12% to 21%), myalgia (19%)

Ophthalmic: Disease of the lacrimal apparatus

Renal: Increased serum creatinine (16%)

Respiratory: Epistaxis (17% to 55%), dyspnea (26% to 30%), cough (26%), oropharyngeal pain (16%), sinusitis (15%)

Miscellaneous: Postoperative wound complication (5% to 15%)

1% to 10%:

Cardiovascular: Decreased left ventricular ejection fraction (10%), thrombosis (10%), deep vein thrombosis (grades 3/4: 9%), arterial thrombosis (grades ≥3: 5%), intra-abdominal venous thrombosis (grades 3/4: 3%), syncope (grades 3/4: 3%), left ventricular dysfunction (grades 3/4: 1%), pulmonary embolism (1%)

Central nervous system: Pain (grades 3/4: 8%)

Dermatologic: Cellulitis (grades 3/4: 3%), acne vulgaris (1%)

Endocrine & metabolic: Hypokalemia (grades 3/4: 7%), dehydration (grades 3/4: 4%)

Gastrointestinal: Hemorrhoids (8%), gingival hemorrhage (4% to 7%), rectal pain (6%), constipation (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%)

Hematologic & oncologic: Hemorrhage (grades ≥3: ≤7%)

Infection: Infection (10%), tooth abscess (2%)

Neuromuscular & skeletal: Asthenia (grades 3/4: 10%)

Ophthalmic: Blurred vision (2%)

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

Respiratory: Rhinorrhea (10%), nasal signs and symptoms (7% to 10%), nasal congestion (8%), rhinitis (≥3%)

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

<1%: Antibody development, cerebral infarction, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome

Frequency not defined:

Cardiovascular: Acute myocardial infarction, angina pectoris, cerebral infarction, intracranial hemorrhage, transient ischemic attacks

Gastrointestinal: Fistula of bile duct, gastrointestinal hemorrhage, hematemesis, tracheoesophageal fistula

Genitourinary: Bladder fistula, vaginal fistula, vaginal hemorrhage

Renal: Renal fistula

Respiratory: Bronchopleural fistula, hemoptysis

Postmarketing: Fulminant necrotizing fasciitis, gallbladder perforation, gastrointestinal anastomotic ulcer, gastrointestinal ulcer, hypersensitivity reaction, hypertensive crisis, inflammation of anterior segment of eye (toxic anterior segment syndrome) (Sato 2010), intestinal necrosis, mesenteric thrombosis, nasal septum perforation, osteonecrosis of the jaw, pancytopenia, polyserositis, pulmonary hypertension, renal thrombotic microangiopathy

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. Discontinue in patients who develop GI 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 (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. Discontinue bevacizumab products in patients who develop HF.
• 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. Minor hemorrhages, including grade 1 epistaxis may commonly occur. Do not administer bevacizumab to patients with a recent history of hemoptysis (≥2.5 mL red blood). Discontinue bevacizumab in patients who develop grade 3 or 4 hemorrhage.
• Hypertension: Bevacizumab may cause and/or worsen hypertension. Severe hypertension occurred at a higher incidence in patients receiving bevacizumab products (compared to patients receiving chemotherapy alone). Manage hypertension with antihypertensive therapy. Monitor blood pressure (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 BP 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 bevacizumab 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: 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).
• 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 follicle-stimulating hormone 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 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. 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 does not appear to correlate with 24-hour urine protein.
• Thromboembolism: Bevacizumab products are associated with an increased incidence of arterial thromboembolic events (ATE), including cerebral infarction, stroke, myocardial infarction, transient ischemic attack, angina, and other ATEs, when used in combination with chemotherapy. The highest incidence of ATE occurred in patients with glioblastoma. History of ATE, diabetes, or ≥65 years of age may present an even greater risk. Although patients with cancer are already at risk for venous thromboembolism (VTE), a meta-analysis of 15 controlled trials has demonstrated an increased risk for VTE in patients who received bevacizumab (Nalluri 2008). Patients receiving bevacizumab plus chemotherapy had a higher incidence of grade 3 or higher VTE compared to those patients who received chemotherapy alone. Discontinue bevacizumab in patients with severe ATE or grade 4 VTE, including pulmonary embolism (the safety of re-initiating bevacizumab following ATE is unknown).
• Wound healing complications: Discontinue bevacizumab in patients with wound healing complications requiring medical intervention. Withhold bevacizumab for at least 28 days prior to elective surgery. Do not administer bevacizumab for at least 28 days following surgery and until the 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 metastatic colorectal cancer who underwent surgery while receiving bevacizumab compared to patients who did not receive bevacizumab. In a controlled clinical study in patients with relapsed or recurrent glioblastoma, the incidence of wound healing events was higher in patients who received bevacizumab compared to patients who did not receive bevacizumab. In a retrospective review of central venous access device placements (a minor procedure), a greater risk of wound dehiscence was observed when port placement and bevacizumab administration were separated by <14 days (Erinjeri 2011). If possible, it may be more appropriate to wait until at least 6 to 8 weeks after bevacizumab discontinuation for major surgical procedures (Cortes 2012; Gordon 2009).

Disease-related concerns:

• Renal impairment: An increase in diastolic and systolic BPs were noted in a retrospective review of patients with renal insufficiency (CrCl ≤60 mL/minute) who received bevacizumab for renal cell cancer (Gupta 2011).

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.

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.

Monitoring Parameters

Monitor for proteinuria/nephrotic syndrome with urine dipstick; collect 24-hour urine in patients with ≥2+ reading. Monitor blood pressure (BP) every 2 to 3 weeks; more frequently if hypertension develops during therapy; continue to monitor BP after discontinuing due to bevacizumab-induced hypertension. 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), thromboembolism (arterial and venous), wound healing complications, and heart failure.

AMD (off-label use): Monitor intraocular pressure (IOP) 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 (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).

Pregnancy

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 to a pregnant woman. 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 females (Cross 2012). Preeclampsia was reported in a pregnant female following intravitreal administration; however, this case also had a significant obstetric history which may have contributed to this finding (Sullivan 2014).

Evaluate pregnancy status prior to use in females of reproductive potential. Women of reproductive potential should use effective contraception during therapy and for 6 months following the last bevacizumab dose. When used systemically, bevacizumab may increase the risk of ovarian failure and impair fertility; ovarian function may recover in a subset of patients; however, long-term effects on fertility are not known.

Patient Education

What is this drug used for?

• It is used to treat cancer.
• It may be given to you for other reasons. Talk with the doctor.

Children:

• This drug is not approved for use in children. However, the doctor may decide the benefits of taking this drug outweigh the risks. If your child has been given this drug, ask the doctor for information about the benefits and risks. Talk with the doctor if you have questions about giving this drug to your child.

Frequently reported side effects of this drug

• Back pain
• Muscle pain
• Joint pain
• Nausea
• Vomiting
• Neck pain
• Diarrhea
• Loss of strength and energy
• Lack of appetite
• Dry skin
• Nail changes
• Change in taste
• Weight loss
• Runny nose
• Trouble sleeping
• Tearing
• Change in voice

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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.
• Infection
• Blood clots like 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; chest pain; shortness of breath; fast heartbeat; or coughing up blood.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Sweating a lot
• Burning or numbness feeling
• Anxiety
• Redness or irritation of palms or soles of feet
• Necrotizing fasciitis like warm skin with red or purple areas of swelling that spread quickly; ulcers, blisters, black spots on the skin; or any other skin changes.
• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache.
• Severe cerebrovascular disease like 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 constipation
• Severe abdominal pain
• Wound healing impairment
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.