bevacizumab (Avastin)

Dosing and uses of Avastin (bevacizumab)

• Adult
• Pediatric

 

Adult dosage forms and strengths

injectable solution

• 25mg/mL

 

Metastatic Colorectal Cancer

Indicated for first-line and second-line treatment for metastatic colorectal carcinoma (in combination with 5-fluorouracil-based chemotherapy)

Fluorouracil based chemotherapy: 5-10 mg/kg IV q2Weeks

Administer 5 mg/kg when used in combination with bolus-IFL (ie, irinotecan, 5-FU, leucovorin)

Administer 10 mg/kg when used in combination with FOLFOX4 (ie, oxaliplatin, 5-FU, leucovorin)

Second-line continuation treatment with bevacizumaB

• Indicated for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen
• Use bevacizumab in combination with a fluoropyrimidine (eg, 5-FU, capecitabine) plus irinotecan or oxaliplatin-based chemotherapy
• 5 mg/kg IV q2Weeks or 7.5 mg/kg IV q3Weeks

 

Nonsmall Cell Lung Cancer

Indicated for unresectable, locally advanced, recurrent or metastatic, nonsquamous NSCLC in combination wtih carboplatin and paclitaxeL

15 mg/kg IV q3wk

 

Breast Cancer

Indication for metastatic breast cancer (HER2-negative) revoked by FDA in November 2011 due to failure to delay tumor growth or provide survival benefit

 

Renal Cell Carcinoma

Indicated for metastatic renal cell carcinoma (with interferon alfa-2a)

10 mg/kg IV q2Weeks (with interferon alfa-2a or as monotherapy)

 

Cervical Cancer

Indicated as part of a combination chemotherapy regimen for persistent, recurrent, or metastatic carcinoma of the cervix

15 mg/kg IV infusion q3wk

Administer in combination with 1 of the following chemotherapy regimens: paclitaxel and cisplatin, or paclitaxel and topotecan

 

Ovarian, Fallopian Tube, or Peritoneal Cancer

Indicated in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens

10 mg/kg IV q2Weeks in combination with 1 of the following IV chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly) Or

15 mg/kg IV q3Weeks in combination with topotecan (q3Weeks)

 

Glioblastoma

Indicated for glioblastoma as a single agent for patients with progressive disease following prior therapy

10 mg/kg IV q2wk

 

Exudative ARMD (Off-label)

Off-label indication for exudative age-related macular degeneration

Off-label: 1.25 mg (in 0.05mL of solution) administered by intravitreal injection once monthly

Reference: CATT Research Group, N Engl J Med 2011;364:1897-1908

The need to repackage the drug from the available size vial into a smaller doses increases risk for transmission of infection if improper aseptic technique occurrs

 

Dosing Considerations

Limitation of use (colorectal cancer): Not indicated for adjuvant treatment of colon cancer

 

Orphan Designations

Coadministration with platinum-based antineoplastic and fluorouracil or capecitabine for treatment of stomach cancer

Melanoma stages IIb-IV

Hereditary hemorrhagic telangiectasia

Pancreatic cancer

Mesothelioma

Coat disease

Sponsor

• Genentech, Inc; 1 DNA Way; South San Francisco, CA 94080-4990
• MicroSert, Ltd; Bar Yehuda Street; Nesher (Coat disease)

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Avastin (bevacizumab) adverse (side) effects

>10%

Weakness (73-74%)

Hypertension (23-67%; grades 3/4: 8-18%)

Pain (61-62%)

Abdominal pain (50-61%; grades 3/4: 8%)

Vomiting (47-52%, grades 3/4:6-11%)

URI (40-47%)

Constipation (29-40%)

Leukopenia (grades 3/4: 37%)

Proteinuria (36%, grades 3/4: 3%)

Epistaxis (32-35%)

Ovarian failure (with mFolfox) (34%)

Diarrhea (grades 3/4: 2-34%)

Stomatitis (30-32%)

Alopecia (6-32%)

Neutropenia (grades 3/4: 6-27%)

Headache (26%; grades 3/4: 2-4%)

Dyspnea (25-26%)

Dizziness (19-26%)

GI hemorrhage (19-24%)

Dyspepsia (17-24%)

Taste alteration (14-21%)

Dry skin (7-20%)

Exfoliative dermatitis (3-19%)

Fatigue (grades 3/4: 5-19%)

Flatulence (11-19%)

Lacrimation disorder (6-18%)

Neuropathy (grades 3/4: 1-17%)

Weight loss (15-16%)

Hypokalemia (12-16%)

Skin discoloration (2-16%)

Thromboembolic events (grades 3/4: 15%)

Myalgia (8-15%)

Hypotension (7-15%)

Nausea (grades 3/4: 4-12%)

Back pain (undefined)

 

1-10%

Dehydration (grades 3/4: 3-10%)

DVT (6-9%; grades 3/4: 9%)

Polyuria (3-6%)

Bilirubinemia (1-6%)

Colitis (1-6%)

Confusion (1-6%)

Neutropenia (5%)

Thrombocytopenia (5%)

Xerostomia (4-7%)

Ileus (grades 3/4: 4-5%)

Abnormal gait (1-5%)

Bone pain (grade 3/4: 4%)

Hyponatremia (grades 3/4: 4%)

GI perforations (<4%)

Arterial thrombosis (3-4%)

Intra-abdominal venous thrombosis (grades 3/4: 3%)

Rash desquamation (grades 3/4: 3%)

Syncope (grades 3/4: 3%)

Infusion reaction (<3%)

Cardio-cerebrovascular arterial thrombotic event (2-4%)

CHF (2%)

Wound dehiscence (1%)

 

Postmarketing Reports

Body as whole: Polyserositis

Cardiovascular: Pulmonary hypertension, RPLS, mesenteric venous occlusion

Osteonecrosis of the jaw

Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision, endophthalmitis (infectious and sterile), intraocular inflammation, retinal detachment, increased IOP, hemorrhage (including conjunctival, vitreous hemorrhage, or retinal hemorrhage), vitreous floaters, ocular hyperemia, ocular pain or discomfort

Gastrointestinal: Gastrointestinal ulcer, intestinal necrosis, anastomotic ulceration

Hemic and lymphatic: Pancytopenia

Hepatobiliary disorders: Gallbladder perforation

Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation

Musculoskeletal: Osteonecrosis of the jaw

Renal: Renal thrombotic microangiopathy

Respiratory: Nasal septum perforation

Dysphonia

Systemic events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, hypertension, gastrointestinal perforation, hemorrhage

Non-mandibular osteonecrosis and posterior reversible encephalopathy syndrome (PRES)

 

Warnings

Black box warnings

Gastrointestinal perforations

• Gastrointestinal (GI) perforation, fistula formation, and/or intra-abdominal abscess unrelated to therapy duration reported in patients with colorectal cancer as well as other types of cancers
• Typical presentation reported as abdominal pain associated with symptoms such as constipation and vomiting
• Include GI perforation in the differential diagnosis of patients presenting with abdominal pain
• Discontinue therapy permanently in patients with GI perforation

Surgery and wound healing complications

• Administration may result in the development of fatal wound dehiscence
• Discontinue therapy in patients with wound dehiscence requiring medical intervention
• Discontinue at least 28 days prior to elective surgery
• Do not initiate bevacizumab for at least 28 days after surgery and until the surgical wound is fully healed

Hemorrhage

• Severe or fatal hemorrhage, hemoptysis, gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding are increased in bevacizumab-treated patients
• Do not administer the drug to patients with serious hemorrhage or recent hemoptysis

 

Contraindications

None

 

Cautions

Impairs wound healing; discontinue before elected surgeries and do not initiate following surgery (see Black box warnings)

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE; discontinue bevacizumab for severe ATe

Increased risk of venous thromboembolic events (VTE) reported in patients treated with bevacizumab for cervical cancer; discontinue bevacizumab for life-threatening VTe

Monitor blood pressure and treat hypertension; increased risk for severe hypertension; temporarily suspend treatment; discontinue if hypertensive crisis or hypertensive encephalopathy

Increased relative risk for heart failure has been associated with therapy

Posterior reversible encephalopathy syndrome (PRES) reported (0.5%); discontinue if PRES develops

Proteinuria reported; temporarily suspend treatment for ≥2 g proteinuria/24 hr; discontinue if nephrotic syndrome occurs (incidence <1%)

Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the last dose

Infusion reactions may occur and include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis; stop infusion if severe and administer appropriate therapy

GI perforation and fistula formation

• Serious and sometimes fatal GI perforation occurs at a higher incidence in bevacizumab treated patients compared to controls; incidence of perforation ranged from 0.3 to 3.2% across clinical studies
• In a cervical cancer trial, the incidence of GI-vaginal fistulae was 8.2% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation
• In a platinum-resistant ovarian cancer trial, the incidence of GI perforation was 1.7%
• Serious and sometimes fatal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in bevacizumab-treated patients compared to controls
• From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer, 1.8% of bevacizumab-treated patients and 1.4% of control patients were reported to have had nongastrointestinal vaginal, vesical, or female genital tract fistulae

 

Pregnancy and lactation

Pregnancy category: C

Lactation: not known if excreted in breast milk; discontinuation of nursing advised during & for a prolonged period following use (due to the long half-life)

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Avastin (bevacizumab)

Mechanism of action

Recombinant humanized monoclonal antibody to VEGF; blocks the angiogenic molecule VEGF thereby inhibiting tumor angiogenesis, starving tumor of blood and nutrients

 

Pharmacokinetics

Half-Life: 20 days (range 11-50 days)

Metabolism: N/A

Excretion: N/A

 

Administration

IV Preparation

Aseptically withdraw necessary amount & dilute in a total volume of 100 mL Ns

Diluted solutions for infusion may be stored at 2-8°C for 8 hr

 

IV Administration

Do not administer as IV push or bolus; administer only as an IV infusion

Do not initiate until at least 28 days following major surgery; wait until the surgical incision has fully healed

Deliver first infusion over 90 min IV; if well-tolerated, second infusion may be administered over 60 min & each subsequent infusion, over 30 min if 60 min infusion tolerated

 

Storage

Refrigerate, do not freeze

Do not shake

Protect vials from light