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BEVACIZUMAB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bevacizumab, a recombinant humanized monoclonal antibody, is a human vascular endothelial growth factor (VEGF) inhibitor.

Specific Substances

    1) BVC
    2) rhuMAb-VEGF
    3) CAS 216974-75-3

Available Forms Sources

    A) FORMS
    1) Bevacizumab is available as 100 mg and 400 mg in 4 mL and 16 mL single-use vials, respectively, for intravenous infusion (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) USES
    1) Bevacizumab is indicated for the following conditions (Prod Info AVASTIN(R) intravenous injection, 2015):
    a) First- or second-line therapy, in combination with intravenous 5-fluorouracil-based chemotherapy, for the treatment of metastatic colon or rectal cancer.
    b) Second-line therapy, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin-based chemotherapy for the treatment of metastatic colorectal cancer in patients who have progressed following first-line bevacizumab therapy.
    c) First-line therapy, in combination with carboplatin and paclitaxel, for the treatment of non-squamous, non-small lung cancer that is unresectable, locally advanced, recurrent, or metastatic.
    d) Single agent therapy for the treatment of glioblastoma in patients with progressive disease following prior therapy.
    e) In combination with interferon alfa for the treatment of metastatic renal cell carcinoma.
    f) In combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer.
    g) In combination with paclitaxel, pegylated liposomal doxorubicin or topotecan for the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Bevacizumab, a recombinant monoclonal antibody, is used to treat metastatic colorectal cancer, non-squamous non-small lung cancer, glioblastoma, metastatic renal cell carcinoma, cervical cancer, and epithelial ovarian, fallopian tube or primary peritoneal cancer.
    B) PHARMACOLOGY: Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), binding to and inhibiting the biologic activity of VEGF, as evidenced by in vitro and in vivo assay systems.
    C) TOXICOLOGY: Certain toxicities may be due to a class effect. VEGF is a stimulator of nitrous oxide, which acts as a vasodilator. Small amounts of nitrous oxide are continually released in order to overcome the natural tendency for a blood vessel to constrict. It is speculated that VEGF inhibition may decrease the availability of nitrous oxide, thereby resulting in more vasoconstriction, leading to hypertension. Inhibition of VEGF receptors may lead to endothelial cell apoptosis causing exposure of subendothelial cells and resulting in initiation of the coagulation cascade, leading to thromboembolism. VEGF is a primary regulator of renewal of the vascular endothelium. However, in response to trauma, VEGF inhibition may decrease the renewal capacity of the endothelium, thereby increasing the tendency to bleed.
    D) WITH THERAPEUTIC USE
    1) COMMON: Commonly reported adverse effects, with an incidence greater than 20%, include vomiting, stomatitis, diarrhea, anorexia, abdominal pain, constipation, gastrointestinal bleeding, hypertension, headache, alopecia, neutropenia, proteinuria, leukopenia, dizziness, asthenia, upper respiratory infection, dyspnea, and epistaxis.
    2) LESS FREQUENT: Adverse effects that were reported less frequently during clinical trials include deep vein thrombosis, arterial thromboembolism, congestive heart failure, impaired wound healing (including wound dehiscence), palmar-plantar erythrodysesthesia, hemorrhage (ie, hemoptysis, hematemesis, vaginal bleeding, and CNS and pulmonary hemorrhage), gastrointestinal perforation, altered taste sense, dehydration, hyponatremia, febrile neutropenia, thrombocytopenia, peripheral neuropathy, and fatigue.
    3) RARE: Hypertensive encephalopathy, nephrotic syndrome, tracheoesophageal fistulae, low-grade fever, and reversible posterior leukoencephalopathy syndrome (headache, seizure, lethargy, confusion, blindness, other visual disturbances, hypertension and fluid retention) have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Limited overdose data available. Overdose effects are expected to be an extension of adverse effects reported with therapeutic use. At 20 mg/kg IV (the highest dose tested), severe headache was reported.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Low-grade fever has been reported with bevacizumab therapy.
    0.2.20) REPRODUCTIVE
    A) Limited human postmarketing reports have observed fetal malformations during bevacizumab administration during pregnancy. Animal studies observed an increase in fetal resorptions, decreased maternal and fetal weight gain, meningocele, and multiple congenital malformations. Bevacizumab increases the risk of ovarian failure and may impair fertility. Because there is a potential for fetal harm and for serious adverse reactions to occur, breastfeeding is not recommended during bevacizumab therapy, and pregnant women should be advised of the potential risk to the fetus. Females of reproductive potential should use effective contraception during and for 6 months after bevacizumab therapy. A recent study found no evidence of the transfer of intravitreally administered bevacizumab into human breast milk, but breastfeeding should be avoided during IV bevacizumab therapy due to the potential for serious adverse reactions.

Laboratory Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    C) Monitor vital signs.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Evaluate patients for signs and symptoms of mucositis.
    G) Monitor urinalysis; proteinuria has been reported with therapeutic use.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives.
    C) INTRATHECAL INJECTION
    1) There are no reports of inadvertent intrathecal injection with bevacizumab. However, this drug has caused peripheral neuropathy following intravenous use in combination with other chemotherapeutic agents. Severe neurotoxicity may develop after intrathecal injection. The following recommendations are based on experience with antineoplastic agents. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Administered intravenously; ingestion is unlikely.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway or in patients with severe bleeding.
    F) ANTIDOTE
    1) None.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    K) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection.
    L) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    M) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    N) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking bevacizumab may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    O) PHARMACOKINETICS
    1) Central volume of distribution of bevacizumab was greater in males than in females (3.25 L vs. 2.66 L) in 491 patients who received 1 to 20 mg/kg weekly, every 2 weeks, or every 3 weeks. The estimated elimination half-life of bevacizumab was 20 days (range, 11 to 50 days) in a pharmacokinetic population analysis of 491 patients receiving 1 to 20 mg/kg weekly, every 2 weeks, or every 3 weeks.
    P) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been determined. The highest dose tested in humans was 20 mg/kg IV; headache was reported in 9 of 16 patients.
    B) THERAPEUTIC: ADULT: For treatment of metastatic colon or rectal cancer, 5 to 10 mg/kg as an IV infusion every 14 days. For non-squamous, non-small cell lung cancer, 15 mg/kg as an IV infusion every 3 weeks. For glioblastoma, 10 mg/kg IV every 2 weeks. PEDIATRIC: The safety and efficacy of bevacizumab in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Bevacizumab, a recombinant monoclonal antibody, is used to treat metastatic colorectal cancer, non-squamous non-small lung cancer, glioblastoma, metastatic renal cell carcinoma, cervical cancer, and epithelial ovarian, fallopian tube or primary peritoneal cancer.
    B) PHARMACOLOGY: Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), binding to and inhibiting the biologic activity of VEGF, as evidenced by in vitro and in vivo assay systems.
    C) TOXICOLOGY: Certain toxicities may be due to a class effect. VEGF is a stimulator of nitrous oxide, which acts as a vasodilator. Small amounts of nitrous oxide are continually released in order to overcome the natural tendency for a blood vessel to constrict. It is speculated that VEGF inhibition may decrease the availability of nitrous oxide, thereby resulting in more vasoconstriction, leading to hypertension. Inhibition of VEGF receptors may lead to endothelial cell apoptosis causing exposure of subendothelial cells and resulting in initiation of the coagulation cascade, leading to thromboembolism. VEGF is a primary regulator of renewal of the vascular endothelium. However, in response to trauma, VEGF inhibition may decrease the renewal capacity of the endothelium, thereby increasing the tendency to bleed.
    D) WITH THERAPEUTIC USE
    1) COMMON: Commonly reported adverse effects, with an incidence greater than 20%, include vomiting, stomatitis, diarrhea, anorexia, abdominal pain, constipation, gastrointestinal bleeding, hypertension, headache, alopecia, neutropenia, proteinuria, leukopenia, dizziness, asthenia, upper respiratory infection, dyspnea, and epistaxis.
    2) LESS FREQUENT: Adverse effects that were reported less frequently during clinical trials include deep vein thrombosis, arterial thromboembolism, congestive heart failure, impaired wound healing (including wound dehiscence), palmar-plantar erythrodysesthesia, hemorrhage (ie, hemoptysis, hematemesis, vaginal bleeding, and CNS and pulmonary hemorrhage), gastrointestinal perforation, altered taste sense, dehydration, hyponatremia, febrile neutropenia, thrombocytopenia, peripheral neuropathy, and fatigue.
    3) RARE: Hypertensive encephalopathy, nephrotic syndrome, tracheoesophageal fistulae, low-grade fever, and reversible posterior leukoencephalopathy syndrome (headache, seizure, lethargy, confusion, blindness, other visual disturbances, hypertension and fluid retention) have been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Limited overdose data available. Overdose effects are expected to be an extension of adverse effects reported with therapeutic use. At 20 mg/kg IV (the highest dose tested), severe headache was reported.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Low-grade fever has been reported with bevacizumab therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Low-grade fever has been reported with variable frequency during bevacizumab therapy (Gordon et al, 2001a; Chen et al, 2001; Rosen, 2002).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) In a retrospective case series, retinal pigment epithelial tears (RPE) occurred in 2.2% of patients with neovascular age-related macular degeneration treated with intravitreal bevacizumab. Included patients were identified by 9 retina specialists at 7 centers and had the presence or absence of pigment epithelial detachment (PED) and RPE tears confirmed by fundus photography, fluorescein angiography, and optical coherence tomography. Patients received intravitreal bevacizumab 1.25 mg/0.05 mL (n=14) or 2.5 mg/0.1 mL (n=8). Of 1064 eyes in 1038 patients receiving 2785 intravitreal bevacizumab injections (average injections per patient, 2.7; range, 1.4 to 5 injections), 1002 eyes had no preinjection RPE tears. At a median follow-up of 124.9 +/- 58.34 days (range, 42-240 days), 22 eyes (2.2%) in 22 patients (mean age, 80.2 +/- 7.4 years (yr); range, 65-93 yr) had post-bevacizumab injection RPE tears with 21 of those eyes also having a vascularized PED. The median time interval from bevacizumab injection to RPE tear was 37.3 +/- 28.7 days (range, 4-118 days) with 3 eyes (13.6%) developing a RPE tear within 1 week of a bevacizumab injection and 19 eyes (86.4%) developing a RPE tear greater than 1 week after a bevacizumab injection. RPE tears occurred more frequently after the first bevacizumab injection (n=16 (72.7%)) than after subsequent injections (second injection, n=5 (22.7%); third injection, n=1 (4.6%)). The mean subfoveal PED lesion size was significantly larger in eyes with RPE tears than in eyes without RPE tears (13.97 +/- 7.23 mm(2); range, 3.6-29.74 mm(2) verus 9.9 +/- 7.65 mm(2); range, 0.2-49.07 mm(2); p=0.01). Additionally, a multivariate logistical regression analysis demonstrated PED size to be a predictor for RPE tear after bevacizumab therapy (odds ratio (OR), 1.09; 95% confidence interval (CI), 1.01-1.18). The mean best-corrected Snellen visual acuity was not significantly different (p=0.48) for patients prior to bevacizumab injections (20/162) compared to patients having RPE tears after bevacizumab injections (20/160) and bevacizumab intravitreal therapy was continued in 27.3% of eyes after RPE tear development (Chan et al, 2007).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) EPISTAXIS
    a) In a randomized, double-blind clinical trial, epistaxis (grade 1 to 4) occurred in 35% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 32% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared to 10% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Across all clinical trials, severe hypertension was reported more often in bevacizumab-treated patients compared to controls, with 5% to 18% of patients experiencing grade 3 or 4 hypertension (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a randomized, double-blind, clinical trial, hypertension (grade 3 or 4) occurred in 12% of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab (n=392) compared with 2% of patients who received IFL plus placebo (n=396) (Prod Info AVASTIN(R) intravenous injection, 2015).
    c) In a double-blind, randomized placebo-controlled clinical trial, hypertension (grades 1 through 5) occurred in 28% of metastatic renal cell carcinoma patients receiving interferon-alpha plus bevacizumab (n=337) compared to 9% of patients receiving interferon-alpha plus placebo (n=304) (Prod Info AVASTIN(R) intravenous injection, 2015).
    d) In a multi-center, randomized trial, hypertension (grades 3 or 4) was reported in 11.5% of patients with persistent, recurrent, or metastatic carcinoma of the cervix receiving chemotherapy plus bevacizumab (n=218) compared to 0.5% of patients receiving only chemotherapy (n=222) (Prod Info AVASTIN(R) intravenous injection, 2015).
    e) A retrospective review of 154 patients who were treated with bevacizumab showed that 55 patients (35%) experienced hypertension, with 11 of the 55 patients (20%) developing new onset hypertension and 44 of the 55 patients (80%) experiencing an exacerbation of their pre-existing hypertension. Hypertension occurred at a median bevacizumab dose of 10 mg/kg, with median onset occurring 11 weeks (range, 3 to 33 weeks) after beginning bevacizumab therapy. Bevacizumab therapy was discontinued in 3 patients due to hypertensive complications, including chest tightness, a transient ischemic attack, and accelerated hypertension (Pande et al, 2007).
    B) HYPERTENSIVE ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) Hypertensive encephalopathy (with nephrotic syndrome) was reported in one breast cancer patient receiving bevacizumab 3 mg/kg every 2 weeks (Cobleigh et al, 2001).
    C) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure (grade 3 and 4 ) occurred in 2.2% of patients with metastatic breast cancer receiving bevacizumab plus paclitaxel compared with 0.3% of patients receiving paclitaxel alone (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) Congestive heart failure (CHF) occurred more frequently (10.9%) in previously untreated patients with diffuse large B-cell lymphoma (an unapproved use) who received bevacizumab plus R-CHOP (n=403; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for 6 to 8 cycles compared with 5% in placebo plus R-CHOP (n=379) for a relative risk of 2.2 (95% CI, 1.3 to 3.7). The onset of left-ventricular dysfunction or CHF was 1 to 6 months after initiation of therapy for at least 85% of the patients, which resolved in 62% of the CHF patients who received bevacizumab compared with 82% in the control arm (Prod Info AVASTIN(R) intravenous injection, 2015).
    D) ARTERIAL EMBOLUS AND THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Serious and sometimes fatal arterial thromboembolic events (ATE) (eg, cerebral infarction, transient ischemic attacks, myocardial infarction, angina) have been reported more often in patients who received bevacizumab plus chemotherapy compared with patients who received chemotherapy alone. Grade 3 or higher ATEs were reported in 2.6% of patients in the bevacizumab group compared with 0.8% of patients in the control group. The incidence of ATE was greater in patients who were 65 years and older (n=618; 35% of all patients) and who received bevacizumab plus chemotherapy than in those who received chemotherapy alone (8.5% vs 2.9%) compared with younger patients (2.1% vs 1.4%) (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a 2-arm randomized clinical trial that compared bevacizumab alone or bevacizumab with irinotecan for glioblastoma (n=163), bevacizumab-related grade 1 to 4 arterial thromboembolic events occurred in 6%, and grade 3 to 5 arterial thromboembolic events occurred in 3% of patients (Prod Info AVASTIN(R) intravenous injection, 2015).
    E) LEFT VENTRICULAR CARDIAC DYSFUNCTION
    1) WITH THERAPEUTIC USE
    a) Grade 3 or greater left ventricular dysfunction was reported in 1% of patients who received bevacizumab in clinical studies, compared with 0.6% incidence for subjects in the control arm, across the various indications (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) A decline in left-ventricular ejection fraction (LVEF) from baseline of 20% or more, or a decline from baseline of 10% or more to a LVEF value of less than 50% occurred more frequently (10.4%) in previously untreated patients with diffuse large B-cell lymphoma (an unapproved use) who received bevacizumab plus R-CHOP (n=403; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for 6 to 8 cycles compared with 5% in placebo plus R-CHOP (n=379), and was associated with congestive heart failure (CHF). The onset of LVEF or CHF was 1 to 6 months after initiation of therapy for at least 85% of the patients, and was resolved in 62% of the patients with CHF who received bevacizumab compared with 82% in the control arm (Prod Info AVASTIN(R) intravenous injection, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, 31% (4/13) of bevacizumab-treated patients with squamous cell non-small cell lung cancer and 4% (2/53) of patients with non-squamous non-small cell lung cancer experienced serious or fatal pulmonary hemorrhage compared with 0% (0/32) of patients receiving chemotherapy alone (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) HEMOPTYSIS
    1) WITH THERAPEUTIC USE
    a) Hemoptysis has been reported in patients with non-small cell lung cancer treated with bevacizumab and chemotherapy, with life-threatening or fatal hemoptysis occurring in 31% of patients with squamous histology and 2.3% of patients with non-squamous non-small cell lung cancer (Prod Info AVASTIN(R) IV injection, 2008).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, dyspnea (grade 1 to 4) occurred in 26% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 25% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 15% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    D) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, upper respiratory infection (grade 1 to 4) occurred in 47% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 40% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 39% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SENSORY NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label clinical trial, sensory neuropathy (grade 3 to 5) occurred in 17% (n=287) of patients with metastatic colorectal carcinoma receiving 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) plus bevacizumab compared with 9% (n=285) of patients receiving FOLFOX4 only (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a multicenter, randomized, open-label clinical trial, grade 2 to 4 peripheral sensory neuropathy was reported in 17.9% (n=179) of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer receiving chemotherapy plus bevacizumab compared to 7.2% (n=181) of patients receiving only chemotherapy (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
    1) WITH THERAPEUTIC USE
    a) Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in clinical trials (incidence less than 0.5%) and during postmarketing surveillance. Clinical presentation included headache, lethargy, seizures, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may also be present. Onset of symptoms has ranged from 16 hours to 1 year after initiation of bevacizumab. Although some patients have experienced ongoing neurologic sequelae, symptoms usually resolve or improve within days (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) CASE REPORT: A 59-year-old woman treated with bevacizumab for metastatic renal cancer experienced reversible posterior leukoencephalopathy 8 days after the last infusion (total of 7 infusions at 2-week intervals). She presented with severe lethargy and a blood pressure of 168/88 mm Hg. During bevacizumab treatment her blood pressure was approximately 100/70 mm Hg. She was hospitalized after experiencing a tonic-clonic seizure. Her blood pressure fluctuated between 156 mm Hg and 178 mm Hg systolic and between 70 mm Hg and 98 mm Hg diastolic. She also developed cortical blindness and extensor plantar responses. Extensive leukoencephalopathy was detected on magnetic resonance imaging (MRI) of the brain. An MRI 2 months before this event was normal. She subsequently had a small, left parieto-occipital hemorrhagic stroke. On hospital day 4, she was alert, able to read a newspaper, had normal blood pressure, and had normal plantar responses. An MRI 6 weeks later showed complete resolution (Glusker et al, 2006).
    C) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia, mild in severity, has been reported in up to 70% of patients during bevacizumab therapy (Pegram & Reese, 2002; Chen et al, 2001; Figg et al, 2002a; Gordon et al, 2001a; Cobleigh et al, 2001).
    b) In a randomized, double-blind clinical trial, asthenia (grade 3 and 4) occurred in 10% (n=392) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab compared with 7% (n=396) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache, usually mild in severity, has been reported in up to 50% of patients receiving bevacizumab (Pegram & Reese, 2002; Chen et al, 2001; Figg et al, 2002a; Gordon et al, 2001a). In one study of patients being treated with bevacizumab for breast cancer, headache, with nausea and vomiting, was dose-limiting with higher bevacizumab doses of 20 mg/kg every 2 weeks (Cobleigh et al, 2001).
    b) In a randomized, double-blind clinical trial, headache (grade 1 to 4) occurred in 26% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 26% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 19% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) At 20 mg/kg IV (the highest dose tested), headache was reported in 9 of 16 patients, and severe headache in 3 of 16 patients (Prod Info AVASTIN(R) intravenous injection, 2015).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind, clinical trial, dizziness (grade 1 to 4) occurred in 26% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 19% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 20% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    F) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label clinical trial, fatigue (grade 3 to 5) occurred in 19% (n=287) of patients with metastatic colorectal carcinoma receiving 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) plus bevacizumab compared with 13% (n=285) of patients receiving FOLFOX4 only (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a multicenter, randomized, open-label study, fatigue (grades 3 to 5) occurred in 16% (n=427) of patients with previously untreated locally advanced, metastatic or recurrent non-small cell lung cancer receiving paclitaxel and carboplatin (PC) plus bevacizumab compared to 13% (n=441) of patients receiving PC alone (Prod Info AVASTIN(R) intravenous injection, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, diarrhea (grade 3 and 4) occurred in 34% (n=392) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab compared with 25% (n=396) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a randomized, open-label clinical trial, diarrhea (grade 3 to 5) occurred in 18% (n=287) of patients with metastatic colorectal carcinoma receiving 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) plus bevacizumab compared with 13% (n=285) of patients receiving FOLFOX4 only (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In a randomized, open-label clinical trial, nausea and vomiting (grade 3 to 5) occurred in 12% and 11% of patients (n=287), respectively, with metastatic colorectal carcinoma receiving 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) plus bevacizumab compared with 5% and 4% of patients (n=285), respectively, receiving FOLFOX4 only (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a randomized, double-blind clinical trial, vomiting (grade 1 to 4) occurred in 52% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 47% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 47% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, constipation (grade 1 to 4) occurred in 40% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 29% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 29% (n=98) of patients who received IFL plus placebo. Grade 3 and 4 constipation were reported in 4% and 2% of patients in the bolus-IFL plus bevacizumab (n=392) and IFL plus placebo arms (n=396), respectively (Prod Info AVASTIN(R) intravenous injection, 2015).
    D) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, stomatitis (grade 1 to 4) occurred in 32% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 30% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 18% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    E) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, abdominal pain (grade 1 to 4) occurred in 61% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 50% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 55% (n=98) of patients who received IFL plus placebo. Grade 3 and 4 abdominal pain were reported in 8% and 5% of patients in the bolus-IFL plus bevacizumab (n=392) and IFL plus placebo arms (n=396), respectively (Prod Info AVASTIN(R) intravenous injection, 2015).
    F) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, gastrointestinal perforation was reported in 3.2% of bevacizumab-treated patients with persistent, recurrent, or metastatic cervical cancer, with fatalities occurring in less than 1% of the patients, and in 1.7% of bevacizumab-treated patients (n=179) with platinum-resistent ovarian cancer. Perforation may be associated with abdominal pain, nausea, emesis, constipation, and fever (Prod Info AVASTIN(R) intravenous injection, 2015).
    G) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, anorexia (grade 1 to 4) occurred in 43% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 35% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 30% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    H) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, taste disorder (grade 1 to 4) occurred in 14% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 21% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 9% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    I) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind, clinical trial, gastrointestinal hemorrhage (grade 1 to 4) occurred in 24% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 19% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 6% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    J) TRACHEOESOPHAGEAL FISTULA
    1) WITH THERAPEUTIC USE
    a) Two confirmed cases (1 fatal) and 1 suspected case (also fatal) of tracheoesophageal (TE) fistula were reported in the first 29 patients enrolled in a nonrandomized, single-arm phase II study of patients with limited-stage small cell lung cancer (SCLC). TE fistula occurred with persistent esophagitis while patients were receiving up to 6 months of bevacizumab maintenance, after having been given 4 cycles of concurrent irinotecan, carboplatin, bevacizumab, and radiation. TE fistula has also been reported in 6 patients during other lung and esophageal cancer studies of bevacizumab and chemotherapy alone or with concurrent radiation. The published literature contains limited data about TE fistula associated with limited-stage SCLC, but the incidence has been estimated to be less than 1% (Genentech, 2007).
    K) PNEUMATOSIS INTESTINALIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 54-year-old man, with a neuroendocrine tumor, presented with air in the small intestine while receiving chemotherapy that included bevacizumab. Constipation was the patient's only symptom. A CT scan revealed extensive pneumatosis of the small intestine. Approximately 6 weeks after cessation of bevacizumab therapy, the pneumatosis resolved (Asmis et al, 2008). The authors speculate that VEGF inhibition by bevacizumab may have caused damage to the microvasculature of the intestinal wall resulting in microperforations and leading to the development of pneumatosis intestinalis.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) In a multicenter, randomized, double-blind clinical trial, proteinuria (grades 1 through 5) occurred in 20% (n=337) of patients receiving interferon-alfa plus bevacizumab compared to 3% (n=304) of patients receiving interferon-alfa plus placebo. Median onset was 5.6 months (range, 15 days to 37 months) after initiation of therapy with bevacizumab. Median time to resolution was 6.1 months (range, 2.8 months to 11.3 months). In 40% of the bevacizumab-treated patients, the proteinuria did not resolve after 11.2 months, and 30% of the patients required permanent discontinuation of the bevacizumab (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) Grade 3 or 4 proteinuria occurred in 0.7% to 7.4% in bevacizumab-treated patients across several clinical studies (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) NEPHROTIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) In clinical studies, nephrotic syndrome occurred in less than 1% of patients receiving bevacizumab, with fatalities in some instances (Prod Info AVASTIN(R) intravenous injection, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Severe and fatal hemorrhages occurred up to 5 times more frequently in bevacizumab-treated patients compared with patients receiving chemotherapy alone. Grade 3 or greater hemorrhagic events occurred in 0.4% to 6.9% of patients across indications (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) Grade 3 or 4 bleeding occurred in 3.1% of patients receiving bolus-IFL (irinotecan, 5-fluorouracil/leucovorin) plus bevacizumab compared with 2.5% of patients receiving IFL/placebo in a phase III trial of patients with untreated metastatic colorectal cancer (Hurwitz et al, 2004).
    B) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia, including febrile neutropenia, has been reported more frequently in patients receiving bevacizumab plus chemotherapy compared to patients receiving chemotherapy alone (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a multicenter, randomized, open-label study (n=878), febrile neutropenia (grades 4 and 5) occurred in 5% (n=427) of patients with previously untreated locally advanced, metastatic, or recurrent non-small cell lung cancer receiving paclitaxel and carboplatin (PC) plus bevacizumab compared to 2% (n=441) of patients receiving PC alone. Additionally, the incidence of infection with grade 3 or 4 neutropenia was 4% and 2%, respectively, with 3 fatal cases in the PC plus bevacizumab arm. Infections which occurred more frequently during the first 6 cycles of treatment in the PC plus bevacizumab arm (13.6%) compared to the PC arm (6.6%) included pneumonia and catheter and wound infections (Prod Info AVASTIN(R) intravenous injection, 2015).
    C) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia has been reported more frequently in patients receiving bevacizumab plus chemotherapy compared to patients receiving chemotherapy alone (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a randomized, double-blind clinical trial, neutropenia (grade 3 and 4) occurred in 21% (n=392) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab compared with 14% (n=396) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    c) In a multicenter, randomized, open-label study, neutropenia (grades 4 and 5) occurred in 27% (n=427) of patients with previously untreated locally advanced, metastatic or recurrent non-small cell lung cancer receiving paclitaxel and carboplatin (PC) plus bevacizumab compared to 17% (n=441) of patients receiving PC alone; additionally, the incidence of infection with grade 3 or 4 neutropenia was 4% and 2%, respectively (Prod Info AVASTIN(R) intravenous injection, 2015).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind, clinical trial, leukopenia (grade 3 and 4) occurred in 37% (n=392) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab compared with 31% (n=396) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    E) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind, clinical trial, thrombocytopenia (grade 1 to 4) occurred in 5% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab compared with 0% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    F) THROMBOEMBOLISM OF VEIN
    1) WITH THERAPEUTIC USE
    a) In pooled data from 5 randomized, placebo-controlled, clinical trials in patients who did not have a recent history of clinically significant cardiovascular disease, the incidence of thromboembolic events was higher in patients receiving bevacizumab plus chemotherapy compared to patients receiving chemotherapy alone (Prod Info AVASTIN(R) IV injection, 2008).
    b) In a randomized, double-blind, clinical trial, grade 3 or 4 venous thromboembolic events (VTE) occurred in 15.1% (n=392) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab compared with 13.6% (n=396) of patients who received IFL plus placebo. In addition, deep vein thrombosis (9% vs 5%) and intra-abdominal venous thrombosis (3% vs 1%) were reported at a higher rate in the bolus-IFL plus bevacizumab arm compared with the IFL plus placebo arm. In patients who received full dose warfarin following a VTE, an additional VTE occurred in 21% (11/53) of patients in the IFL plus bevacizumab arm compared to 3% (1/30) of patients in the IFL plus placebo arm (Prod Info AVASTIN(R) intravenous injection, 2015).
    c) In a multicenter, randomized, open-label study, venous thromboembolic events (VTE) (grades 4 and 5) occurred in 5% (n=427) of patients with previously untreated locally advanced, metastatic or recurrent non-small cell lung cancer receiving paclitaxel and carboplatin (PC) plus bevacizumab compared to 3% (n=441) of patients receiving PC alone (Prod Info AVASTIN(R) intravenous injection, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind clinical trial, alopecia (grade 1 to 4) occurred in 32% (n=102) of patients with metastatic colorectal carcinoma receiving bolus-IFL (irinotecan/5-fluorouracil (5-FU)/leucovorin) plus bevacizumab and 6% (n=109) of patients receiving 5-FU/leucovorin plus bevacizumab compared with 26% (n=98) of patients who received IFL plus placebo (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) IMPAIRED WOUND HEALING
    1) WITH THERAPEUTIC USE
    a) Among patients requiring elective surgery within 60 days of receiving study treatment, impaired wound healing/bleeding complications were reported in 15% (6/39) of patients with metastatic colorectal cancer who received bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab compared with 4% (1/25) of patients who received bolus-IFL alone (Prod Info AVASTIN(R) intravenous injection, 2015).
    b) In a 2-arm randomized clinical trial that compared bevacizumab alone or bevacizumab with irinotecan for glioblastoma (n=163), bevacizumab-related wound-healing complications occurred in 6% (grade 1 to 4) and 3% (grade 3 to 5) of patients (Prod Info AVASTIN(R) intravenous injection, 2015).
    C) WOUND DEHISCENCE
    1) WITH THERAPEUTIC USE
    a) In clinical studies, wound dehiscence was reported in 0.8% (6/788) of patients receiving chemotherapy plus bevacizumab. Dehiscence has resulted in fatalities. The longest interval between the last dose of bevacizumab and dehiscence was 56 days which occurred in a patient who received bolus-IFL (irinotecan/5-fluorouracil/leucovorin) plus bevacizumab (Prod Info AVASTIN(R) IV injection, 2008).
    b) In a 2-arm randomized clinical trial that compared bevacizumab alone or bevacizumab with irinotecan for glioblastoma (n=163), postoperative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in 3 of 84 patients who received bevacizumab monotherapy and 1 of 79 patients who received bevacizumab plus irinotecan (Prod Info AVASTIN(R) intravenous injection, 2015).
    D) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rashes of the unspecified type have been described in some patients following bevacizumab infusion (Gordon et al, 2001a; Chen et al, 2001; Pegram & Reese, 2002).
    b) CASE REPORT: A 40-year-old man, with colorectal cancer, developed red papillary nodules on his chest, back, forehead, and around the eyes after beginning a chemotherapy regimen that included bevacizumab. The rash disappeared following cessation of bevacizumab therapy, but recurred each time bevacizumab was restarted (Gotlib et al, 2006).
    E) ACRAL ERYTHEMA DUE TO CYTOTOXIC THERAPY
    1) WITH THERAPEUTIC USE
    a) In a multicenter, open-label, randomized, 2-arm clinical trial, palmar-plantar erythrodysesthesia syndrome occurred in 10.6% (n=179) of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer receiving chemotherapy plus bevacizumab compared to 5% (n=181) of patients receiving only chemotherapy (Prod Info AVASTIN(R) intravenous injection, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) OSTEOARTHRITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 59-year-old woman with ovarian cancer and a 20-year history of intermittent osteoarthritis of the distal interphalangeal (DIP) joints of her hands bilaterally, responsive to naproxen therapy, developed acute onset of severe arthritis of the DIP joints and proximal interphalangeal joints bilaterally, preceded by a burning sensation and dermal desquamation of her hands and discoloration of her fingernails, approximately one month after beginning weekly therapy with bevacizumab (5 mg/kg) and paclitaxel. The arthritis was unresponsive to naproxen therapy, and hand and wrist x-rays revealed joint space narrowing, marginal osteophytes, and bony erosions of the DIP joints and interphalangeal joint of the thumb, indicative of erosive osteoarthritis. Following discontinuation of bevacizumab and paclitaxel therapy, her signs and symptoms significantly improved (Jaishuen et al, 2008).
    B) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 7-month-old child developed asymptomatic metaphyseal bone lesions after receiving 4 doses of bevacizumab, 10 mg/kg/dose, for treatment of cutaneovisceral angiomatosis with thrombocytopenia (CAT) syndrome. Initially, a chest radiograph revealed metaphyseal lesions of the proximal humeri, suggestive of rickets; however, subsequent laboratory analysis ruled out the presence of rickets. A complete skeletal survey also indicated metaphyseal lesions of the hip, knee, ankle, and wrist bones. Following discontinuation of bevacizumab therapy, a repeat skeletal survey, performed 2 months later, revealed complete resolution of the metaphyseal lesions (Smith et al, 2008). Based on animal studies that showed the development of physeal dysplasia of the distal femur following administration of VEGF inhibitors to monkeys with open growth plates, the authors hypothesize that the radiographic lesions of the patient were a result of administration of bevacizumab to a child with active epiphyseal growth plates.

Reproductive

    3.20.1) SUMMARY
    A) Limited human postmarketing reports have observed fetal malformations during bevacizumab administration during pregnancy. Animal studies observed an increase in fetal resorptions, decreased maternal and fetal weight gain, meningocele, and multiple congenital malformations. Bevacizumab increases the risk of ovarian failure and may impair fertility. Because there is a potential for fetal harm and for serious adverse reactions to occur, breastfeeding is not recommended during bevacizumab therapy, and pregnant women should be advised of the potential risk to the fetus. Females of reproductive potential should use effective contraception during and for 6 months after bevacizumab therapy. A recent study found no evidence of the transfer of intravitreally administered bevacizumab into human breast milk, but breastfeeding should be avoided during IV bevacizumab therapy due to the potential for serious adverse reactions.
    3.20.2) TERATOGENICITY
    A) FETAL MALFORMATIONS
    1) In humans, limited postmarketing reports have observed cases of fetal malformations when bevacizumab was administered during pregnancy (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) In animals, IV bevacizumab doses at least 1 times the clinical dose and administered every 3 days during the period of organogenesis produced multiple congenital malformations (eg, corneal opacities, abnormal ossification of the skull and skeleton including limb, phalangeal defects) as well as a decrease in fetal weight gain. Meningocele was observed at doses 10 times the clinical dose (Prod Info AVASTIN(R) intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Because bevacizumab can cause fetal harm, advise pregnant women of the potential risk to the fetus. Females of reproductive potential should use effective contraception during and for 6 months after bevacizumab therapy (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) In animals, IV bevacizumab doses at least 1 times the clinical dose and administered every 3 days during the period of organogenesis produced decreases in maternal weights and an increase in fetal resorptions (Prod Info AVASTIN(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) There are no data to assess the presence of IV administered bevacizumab in human milk, the effects on a breastfed infant, or the effects on milk production (Prod Info AVASTIN(R) intravenous injection, 2015).
    2) Advise women to avoid breastfeeding during bevacizumab therapy due to the potential for serious adverse effects in the nursing infant (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) LACK OF EFFECT
    1) An enzyme-linked immunosorbent assay sensitive to approximately 3 ng/mL detected no traces of bevacizumab in the breast milk of 2 women given monthly intravitreal injections of the drug over the course of up to 16 months. Western blot analysis of breast milk samples collected 1.5 and 7 hours after the injection of low levels of the drug revealed no detectable bevacizumab. These data suggest that intravitreally administered bevacizumab is not transferred into human breast milk at detectable levels (McFarland et al, 2015).
    3.20.5) FERTILITY
    A) OVARIAN FAILURE
    1) Although the long-term effects of bevacizumab on fertility are unknown, it increases the risk of ovarian failure and may impair fertility. In a human clinical trial, ovarian failure occurred in 34% of patients treated with chemotherapy plus bevacizumab vs 2% with chemotherapy alone. After treatment discontinuation, ovarian function was recovered in 22% of the bevacizumab-treated patients (Prod Info AVASTIN(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) MONKEYS: Dose-related decreases in ovarian and uterine weights, endometrial proliferation, number of menstrual cycles, and arrested follicular development or absent corpora lutea were observed in female cynomolgus monkeys treated with 0.4 to 20 times the recommended human dose of bevacizumab. Trends suggestive of reversibility were noted following a 4- to 12–week recovery period (Prod Info AVASTIN(R) intravenous injection, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    C) Monitor vital signs.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Evaluate patients for signs and symptoms of mucositis.
    G) Monitor urinalysis; proteinuria has been reported with therapeutic use.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    C) Monitor vital signs.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Evaluate patients for signs and symptoms of mucositis.
    G) Monitor urinalysis; proteinuria has been reported with therapeutic use.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is unlikely to be necessary because bevacizumab is administered parenterally.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been determined. The highest dose tested in humans was 20 mg/kg IV; headache was reported in 9 of 16 patients.
    B) THERAPEUTIC: ADULT: For treatment of metastatic colon or rectal cancer, 5 to 10 mg/kg as an IV infusion every 14 days. For non-squamous, non-small cell lung cancer, 15 mg/kg as an IV infusion every 3 weeks. For glioblastoma, 10 mg/kg IV every 2 weeks. PEDIATRIC: The safety and efficacy of bevacizumab in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) GLIOBLASTOMA
    1) The recommended dose of bevacizumab is 10 mg/kg IV over 90 minutes once every 2 weeks; if tolerated, the infusion may be given over 60 minutes for the second infusion and 30 minutes for subsequent infusions (Prod Info AVASTIN(R) intravenous injection solution, 2013).
    B) METASTATIC COLORECTAL CANCER
    1) The recommended dose of bevacizumab, given in combination with bolus-IFL (irinotecan, fluorouracil, leucovorin), is 5 mg/kg IV over 90 minutes once every 2 weeks. When given in combination with FOLFOX-4 (oxaliplatin plus leucovorin followed by a bolus and infusional 5-fluorouracil), the recommended dose of bevacizumab is 10 mg/kg IV once over 90 minutes every 2 weeks. When given in combination with fluoropyrimidine/irinotecan- or fluoropyrimidine/oxaliplatin-based chemotherapy in patients who have progressed on a first-line bevacizumab-containing regimen, the recommended dose of bevacizumab is 5 mg/kg IV once every 2 weeks or 7.5 mg/kg IV once every 3 weeks over 90 minutes. If tolerated, the infusions of bevacizumab may be given over 60 minutes for the second infusion and 30 minutes for subsequent infusions (Prod Info AVASTIN(R) intravenous injection solution, 2013).
    C) METASTATIC RENAL CELL CARCINOMA
    1) The recommended dose of bevacizumab is 10 mg/kg IV infusion over 90 minutes once every 2 weeks in combination with interferon alfa; if tolerated, the infusion may be given over 60 minutes for the second infusion and 30 minutes for subsequent infusions (Prod Info AVASTIN(R) intravenous injection solution, 2013).
    D) NON-SQUAMOUS, NON-SMALL CELL LUNG CANCER
    1) The recommended dose of bevacizumab is 15 mg/kg IV over 90 minutes once every 3 weeks in combination with paclitaxel and carboplatin; if tolerated, the infusion may be given over 60 minutes for the second infusion and 30 minutes for subsequent infusions (Prod Info AVASTIN(R) intravenous injection solution, 2013).
    E) PLATINUM-RESISTANT RECURRENT EPITHELIAL OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL CANCER
    1) The recommended dose of bevacizumab is 10 mg/kg IV over 90 minutes once every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan; or 15 mg/kg every 3 weeks in combination with topotecan; if tolerated, the infusion may be given over 60 minutes for the second infusion and 30 minutes for subsequent infusions (Prod Info AVASTIN(R) intravenous injection solution, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of bevacizumab in pediatric patients have not been established (Prod Info AVASTIN(R) intravenous injection solution, 2013).
    B) Bevacizumab was administered to a 7-month-old at a dose of 10 mg/kg/dose every 2 weeks; however the child developed metaphyseal bone lesions that were believed to be related to the bevacizumab, and it was discontinued (Smith et al, 2008).

Maximum Tolerated Exposure

    A) Headache was reported in 9 of 16 patients and severe headache occurred in 3 of 16 patients following an intravenous bevacizumab dose of 20 mg/kg (the highest dose tested) (Prod Info AVASTIN(R) intravenous injection, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). It is prepared by engineering VEGF-binding residues of a murine anti-VEGF monoclonal antibody into framework regions of human immunoglobulin-1 (IgG1) (Prod Info AVASTIN(R) intravenous injection, 2015; Figg et al, 2002; Gordon et al, 2001; Moore et al, 1999; Mordenti et al, 1999). Only 7% of the amino acid sequence is derived from the murine antibody, with 93% from IgG1 (Figg et al, 2002).
    B) Bevacizumab binds and neutralizes all human VEGF forms via recognition of binding sites for the two human VEGF receptor types (flt-1 and flk-1) (Gordon et al, 2001; Figg et al, 2002). In animal models, the antibody has been shown to stabilize established tumors or suppress tumor growth by inhibiting angiogenesis induced by VEGF (Gordon et al, 2001; Moore et al, 1999).

Toxicologic Mechanism

    A) Although specific mechanisms of action for bevacizumab-related toxicities have not been defined, certain toxicities may be due to a class effect (Saif & Mehra, 2006):
    1) HYPERTENSION: VEGF is a stimulator of nitrous oxide, which acts as a vasodilator. Small amounts of nitrous oxide are continually released in order to overcome the natural tendency for a blood vessel to constrict. It is speculated that VEGF inhibition may decrease the availability of nitrous oxide, thereby resulting in more vasoconstriction.
    2) THROMBOEMBOLISM: Inhibition of VEGF receptors may lead to endothelial cell apoptosis causing exposure of subendothelial cells and resulting in initiation of the coagulation cascade.
    3) HEMORRHAGE: VEGF is a primary regulator of renewal of the vascular endothelium. However, in response to trauma, VEGF inhibition may decrease the renewal capacity of the endothelium, thereby increasing the tendency to bleed.

Physicochemical

Physical Characteristics

    A) Bevacizumab is a clear to slightly opalescent, colorless to pale brown solution (Prod Info AVASTIN(R) intravenous injection solution, 2012).

Ph

    A) 6.2 (Prod Info AVASTIN(R) intravenous injection solution, 2012)

Molecular Weight

    A) 149 kilodaltons (Prod Info AVASTIN(R) intravenous injection solution, 2012)

References

General Bibliography

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