Bevacizumab

Trade Names:Avastin- Injection, solution, concentrate 25 mg/mL

Pharmacology

Binds to vascular endothelial growth factor, interfering with endothelial cell proliferation.

Pharmacokinetics

Absorption

Time to reach steady state is predicted to be 100 days.

Elimination

Estimated half-life is approximately 20 days.

Special Populations

Pharmacokinetic profile in children has not been established.

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

Patients with a higher tumor burden had a higher Cl of bevacizumab compared with patients who had a tumor burden below the median. There is no evidence suggesting that this difference leads to a decreased efficacy.

Indications and Usage

In combination with IV 5–fluorouracil (5–FU)–based chemotherapy as first- or second-line treatment of metastatic carcinoma of the colon or rectum; in combination with carboplatin and paclitaxel as first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non–small cell lung cancer; in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic human epidermal growth factor receptor 2 (HER2)–negative breast cancer; as single-agent therapy for glioblastoma with progressive disease following prior therapy; in combination with interferon alfa for the treatment of metastatic renal cell carcinoma.

Unlabeled Uses

In combination with erlotinib to treat metastatic renal cell carcinoma.

Contraindications

None well documented.

Dosage and Administration

IV infusion 10 mg/kg every 14 days.

IV infusion 10 mg/kg every 14 days in combination with paclitaxel.

IV infusion 5 or 10 mg/kg every 14 days in combination with IV 5-fluorouracil–based chemotherapy. The recommended dosage is 5 mg/kg every 14 days when administered with irinotecan/5-fluorouracil/leucovorin, and 10 mg/kg every 14 days when administered with 5-fluorouracil/leucovorin/oxaliplatin.

IV infusion 10 mg/kg every 14 days in combination with interferon alfa.

IV infusion 15 mg/kg every 21 days in combination with carboplatin and paclitaxel.

General Advice

• For IV infusion only. Do not administer as an IV push or bolus.
• Patients should continue treatment until disease progression or unacceptable toxicity.
• Do not administer or mix bevacizumab with dextrose solutions.
• Administer first dose via IV infusion over 90 min following chemotherapy. If first infusion is well tolerated, second infusion may be administered over 60 min. If the 60–min infusion is well tolerated, subsequent infusions may be administered over 30 min.
• Discard any unused solution. Do not save for future administration.

Storage/Stability

Store vials in refrigerator (36° to 46°F) in original carton until time of use. Protect from light and freezing. Do not shake vials. Diluted solution for infusion may be refrigerated (36° to 46°F) for up to 8 h.

Drug Interactions

Incidence of adverse events including hemorrhage, neutropenia and febrile neutropenia, venous thrombolic events, postoperative wound healing, or bleeding complications may be increased. Closely monitor the patient during coadministration.

Decreased paclitaxel exposure was seen when paclitaxel/carboplatin was given in combination with bevacizumab. Closely monitor the patient during coadministration.

Coadministration of bevacizumab and sunitinib has been reported to cause unexpected severe toxicity (eg, microangiopathic hemolytic anemia with the development of thrombocytopenia, anemia, reticulocytosis, decreased serum haptoglobin, and the presence of schistocytes). Coadministration of sunitinib and bevacizumab is not recommended.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions were reported with combined use of bevacizumab and 5-FU/leucovorin–, 5-FU/irinotecan/leucovorin–, 5-FU/leucovorin/oxaliplatin–, capecitabine–, irinotecan–, paclitaxel–, or carboplatin/paclitaxel–based regimens.

Cardiovascular

Hypertension (34%); hypotension (15%); deep vein thrombosis (9%); venous thrombolic event (8%); arterial thrombolic event (6%); CNS hemorrhage, venous thrombus/embolism (5%); cerebrovascular ischemia, intra-abdominal thrombosis, syncope (3%); fatal MI.

CNS

Asthenia (57%); fatigue (45%); headache (37%); dizziness (26%); sensory neuropathy (24%); neurologic disorders (5%).

Dermatologic

Exfoliative dermatitis (84%); alopecia (32%); skin ulcer, wound healing complications (6%); rash/desquamation (3%).

EENT

Nasal septum perforation (postmarketing).

GI

Abdominal pain (61%); vomiting (52%); anorexia (43%); constipation (40%); diarrhea (34%); stomatitis (32%); dyspepsia, GI hemorrhage (24%); taste disorder (21%); nausea (12%); dry mouth (7%); colitis (6%); ileus (4%); GI perforation (2%); anastomotic ulceration, intestinal necrosis, mesenteric venous occlusion (postmarketing); death caused by GI perforation.

Genitourinary

Proteinuria (36%); albuminuria (22%); renal thrombotic microangiopathy (manifested as severe proteinuria) (postmarketing).

Hematologic-Lymphatic

Bleeding/hemorrhage (40%); leukopenia (37%); neutropenia (27%); neutrophils (6%); febrile neutropenia, thrombocytopenia (5%); infection with grade 3 or 4 neutropenia (4%); pancytopenia (postmarketing).

Metabolic-Nutritional

Weight loss (20%); dehydration (10%); hyponatremia (4%).

Musculoskeletal

Myalgia (19%); back pain (12%); bone pain (4%).

Respiratory

Upper respiratory tract infection (47%); epistaxis (35%); dyspnea (27%); voice alteration (9%); dysphonia, pneumonitis/pulmonary infiltrates (5%); pulmonary hypertension (postmarketing).

Miscellaneous

Pain (62%); infection without neutropenia (9%); infection with unknown absolute neutrophil count (3%); polyserositis, reversible posterior leukoencephalopathy syndrome (postmarketing); death associated with combined abdominal pain, diarrhea, hypotension, and weakness.

Precautions

Pregnancy

Category C .

Lactation

Undetermined, but human immunoglobulin G is excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Several studies indicate that patients 65 yr of age and older may have a greater relative risk for adverse reactions (eg, emesis, ileus, nausea, proteinuria) compared with younger patients.

Arterial thrombotic events

Serious, sometimes fatal, arterial thrombotic events, including cerebral infarction, transient ischemic attacks, MI, and angina, have occurred. Permanently discontinue therapy in patients who experience a severe arterial thromboembolic event during therapy.

CHF

Risk of developing CHF may be increased compared with administration of other chemotherapy alone. The safety of continuation or resumption of bevacizumab in patients with cardiac dysfunction has not been studied.

Elective surgery

Temporarily suspend treatment at least 4 wk prior to elective surgery.

Hypertension

Temporarily suspend therapy in patients who develop severe hypertension (more than 200/110 mm Hg) that is not controlled with medical management. Permanently discontinue therapy in patients who develop hypertensive crisis or hypertensive encephalopathy.

Immunogenicity

May occur.

Infusion reactions

Interrupt therapy in cases of severe infusion reactions (eg, chest pain, hypertensive crisis).

Nephrotic syndrome

May occur. Discontinue bevacizumab in patients with nephrotic syndrome.

Neutropenia and infection

Incidence of neutropenia, febrile neutropenia, and infection were greater in patients receiving bevacizumab plus chemotherapy compared with chemotherapy alone.

Non-GI fistula formation

Biliary, bladder, bronchopleural, tracheoesophageal, and vaginal fistula formation has been reported. Discontinue bevacizumab in patients with fistula formation involving an internal organ.

Proteinuria

Risk of developing proteinuria may be increased compared with administration of 5–fluorouracil alone. Temporarily suspend therapy in patient who develops moderate to severe proteinuria, pending further evaluation.

Reversible posterior leukoencephalopathy syndrome

Has been reported and can present as blindness (and other visual disturbances), confusion, headache, lethargy, neurologic disturbances, and seizures.

Venous thromboembolic events

Incidence of venous thromboembolic events and fatal arterial thromboembolic events was greater in patients receiving bevacizumab plus chemotherapy compared with chemotherapy alone.

Overdosage

Symptoms

Severe headache.

Patient Information

• Advise patient or caregiver that medication will be prepared and administered by a health care provider in a health care setting.
• Advise patient or caregiver that medication will be administered in combination with other chemotherapy medications.
• Advise family or caregiver to report any of the following to health care provider: black or bloody stools; coughing up blood; injection-site reaction; problems with wound healing; rash, itching, or hives; severe nosebleeds; stomach pain in association with constipation and/or vomiting; swelling of the face, lips, eyes, or tongue; wheezing, shortness of breath, or difficulty breathing; any other unusual or unexplained feelings or symptoms.
• Advise patient to have routine BP monitoring and contact their health care provider if BP is elevated.
• Advise women of childbearing potential to use effective contraception during and for at least 6 mo following treatment.

Copyright © 2009 Wolters Kluwer Health.