Pronunciation (be vuh SIZ uh mab)

U.S. Brand Names AvastinTM Synonyms rhuMAb-VEGF

Therapeutic Category
Antineoplastic Agent, Monoclonal Antibody
Vaccine, Recombinant
Use Treatment of metastatic colorectal cancer as a component of multidrug therapy

Pregnancy Risk Factor C

Pregnancy Implications There are no adequate or well-controlled studies in pregnant women, however bevacizumab is teratogenic in animal models. Angiogenesis is of critical importance to fetal development, and bevacizumab is likely to have adverse consequences in terms of fetal development. Adequate contraception during therapy is recommended. The risk and benefit of treatment should be evaluated in pregnant women. Patients should also be counseled regarding prolonged exposure following discontinuation of therapy due to the long half-life of bevacizumab.
Based on animal studies, bevacizumab may disrupt normal menstrual cycles and impair fertility by several effects, including reduced endometrial proliferation and follicular developmental arrest. Some parameters do not recover completely, or recover very slowly following discontinuation.

Contraindications Hypersensitivity to bevacizumab, murine products, or any component of the formulation

Warnings/Precautions Gastrointestinal perforation, intra-abdominal abscess, and wound dehiscence have been reported in patients receiving bevacizumab; monitor patients for signs/symptoms of abdominal pain, constipation or vomiting. Permanent discontinuation is recommended in patients who develop these complications. The appropriate intervals between administration of bevacizumab and surgical procedures to avoid impairment in wound healing has not been established. Do not initiate therapy within 28 days of major surgery and only following complete healing of the incision. Bevacizumab should be discontinued prior to elective surgery and the estimated half-life (20 days) should be considered.

Avoid use in patients with recent hemoptysis; significant pulmonary bleeding has been reported in patients receiving bevacizumab (primarily in patients with nonsmall cell lung cancer). Avoid use in patients with CNS metastases; patients with CNS metastases were excluded from clinical trials due to concerns for bleeding. Other serious bleeding events may occur, but with a lower frequency; discontinuation of treatment is recommended in all patients with serious hemorrhage.

May cause CHF and/or potentiate cardiotoxic effects of anthracyclines. Use with caution in patients with cardiovascular disease; patients with significant cardiovascular disease were excluded from clinical trials. Bevacizumab may cause and/or worsen hypertension; use caution in patients with pre-existing hypertension and monitor BP closely in all patients. Permanent discontinuation is recommended in patients who experience a hypertensive crisis. Proteinuria and/or nephrotic syndrome has been associated with bevacizumab; discontinuation of therapy is recommended in patients with nephrotic syndrome. Interrupt therapy in patients experiencing severe infusion reactions; there are no data to address reinstitution of therapy in patients who experience CHF and/or severe infusion reactions. Safety and efficacy in pediatric patients have not been established.

Adverse Reactions Note: No data available concerning the frequency of adverse reactions which may be attributed to bevacizumab alone. Where noted, the frequency in combination with irinotecan, fluorouracil, and leucovorin (IFL) is compared to placebo-containing arm from a controlled clinical trial.

>10%:Cardiovascular: Hypertension (23% vs 14%, severe/life-threatening 12% vs 2%); hypotension (15% versus 7%); thromboembolism (18% vs 15%)
Central nervous system: Pain (62% vs 55%, severe/life-threatening 8% vs 5%); headache (26% vs 19%); dizziness (26% vs 20%)
Dermatologic: Alopecia (32% vs 25%)
Endocrine & metabolic: Weight loss (15% vs 10%), hypokalemia (12% vs 10%)
Gastrointestinal: Gastrointestinal hemorrhage (24% vs 6%); abdominal pain (61% vs 55%, severe/life-threatening 8% vs 5%); diarrhea (severe/life-threatening 34% vs 25%); vomiting (52% vs 47%); anorexia (43% vs 30%); constipation (40% vs 29%, severe/life-threatening 4% vs 2%); stomatitis (32% vs 18%); dyspepsia (24% vs 15%)
Hematologic: Leukopenia (severe/life-threatening 37% vs 31%), neutropenia (severe/life-threatening 21% vs 14%)
Neuromuscular & skeletal: Weakness (74% vs 70%, severe/life-threatening 10% vs 7%); myalgia (15% vs 7%)
Renal: Proteinuria (36% vs 24%, including nephrotic syndrome in some patients); urinary frequency (3% vs 1%)
Respiratory: Upper respiratory infection (47% vs 39%), dyspnea (26% vs 15%), epistaxis (35% vs 10%)

1% to 10%:Cardiovascular: DVT (9% vs 3%), intra-arterial thrombosis (severe/life-threatening 3% vs 1%)
Central nervous system: Confusion (6% vs 1%), syncope (severe/life-threatening 3% vs 1%), abnormal gait (5% vs 0%)
Dermatologic: Skin ulcer (6% vs 1%)
Gastrointestinal: Flatulence, dry mouth, colitis, taste disorder (10% vs 9%), dry mouth (7% vs 2%), colitis (6% vs 1%)
Hematologic: Thrombocytopenia (5% vs 0%)
Hepatic: Bilirubinemia (1% vs 0)
Neuromuscular & skeletal: Myalgia (8% vs 7%)
Ocular: Tearing increased (6% vs 2%)?
Respiratory: Voice alteration (9% vs 2%)

<1% (Limited to important or life-threatening): Anastomotic ulceration, hyponatremia, intestinal obstruction, intestinal necrosis, mesenteric venous occlusion, pancytopenia, polyserositis, ureteral stricture

Drug Interactions

Anthracyclines: Bevacizumab may potentiate the cardiotoxic effects of anthracyclines.

Irinotecan: Serum concentrations of irinotecan’s active metabolite may be increased by bevacizumab; an approximate 33% increase has been observed.

Mechanism of Action Bevacizumab is a recombinant, humanized monoclonal antibody which binds to vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors. 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 metastatic tissue.

Pharmacodynamics/Kinetics

Half-life elimination: 20 days (range: 11-50 days)

Usual Dosage I.V.: Adults: Colorectal cancer: 5 mg/kg every 14 days until disease progression is detected

Dosage adjustment for toxicity: Temporary suspension is recommended in moderate-to-severe proteinuria or in patients with severe hypertension which is not controlled with medical management. Permanent discontinuation is recommended in patients who develop wound dehiscence requiring intervention, gastrointestinal perforation, hypertensive crisis, serious bleeding, or nephrotic syndrome.

Administration Do not administer as an I.V. bolus. Infuse the initial dose over 90 minutes (administer following chemotherapy). Infusion may be shortened to 60 minutes if the initial infusion is well tolerated. The third and subsequent infusions may be shortened to 30 minutes if the 60 minute infusion is well tolerated. Monitor closely during the infusion for signs/symptoms of an infusion reaction.

Monitoring Parameters Monitor closely during the infusion for signs/symptoms of an infusion reaction. Monitor CBC with differential; signs/symptoms of gastrointestinal perforation or abscess (including abdominal pain, constipation and vomiting); signs/symptoms of bleeding, including hemoptysis, gastrointestinal, and/or CNS bleeding, and/or epistaxis. Monitor blood pressure every 2-3 weeks. Monitor for proteinuria/nephrotic syndrome with serial urinalysis.

Dosage Forms Injection, solution [preservative free]: 25 mg/mL (4 mL, 16 mL)