Bevacizumab

Indications

Bevacizumab is used for: Colo-rectal cancer, Lung cancers, Renal cancers, Ovarian cancers, Breast cancers, glioblastoma multiforme of the brain, Exudative ARMD

Adult Dose

General: Bevacizumab should be prepared by a healthcare professional using aseptic technique. The initial Bevacizumab dose should be delivered over 90 min as an IV infusion. If the 1st infusion is well tolerated, the 2nd infusion may be administered over 60 min. If the 60-min infusion is well tolerated, all subsequent infusions may be administered over 30 min. Dose reduction of Bevacizumab for adverse events is not recommended. If indicated, Bevacizumab should either be permanently discontinued or temporarily suspended. Metastatic Colorectal Cancer (mCRC): The recommended dose of Bevacizumab, administered as an IV infusion, is as follows: First-line Treatment: 5 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg of body weight given once every 3 weeks. Second-line Treatment: 10 mg/kg of body weight given every 2 weeks or 15 mg/kg of body weight given once every 3 weeks. It is recommended that Bevacizumab treatment be continued until progression of the underlying disease. Locally Recurrent or Metastatic Breast Cancer (mBC): The recommended dose of Bevacizumab is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of body weight given once every 3 weeks as an IV infusion. Clinical benefit in mBC patients has also been demonstrated at a dose of 7.5 mg/kg of body weight given once every 3 weeks as an IV infusion. It is recommended that Bevacizumab treatment be continued until progression of the underlying disease. Advanced, Metastatic or Recurrent Non-Small Cell Lung Cancer (NSCLC): Bevacizumab is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Bevacizumab as a single agent until disease progression. The recommended dose when used in addition to cisplatin-based chemotherapy is 7.5 mg/kg of body weight given once every 3 weeks as an IV infusion. The recommended dose when used in addition to carboplatin-based chemotherapy is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. Advanced and/or Metastatic Renal Cell Cancer (mRCC): The recommended dose is 10 mg/kg of body weight given once every 2 weeks as an IV infusion. It is recommended that treatment be continued until progression of the underlying disease. Malignant Glioma (WHO Grade IV)-Glioblastoma: The recommended dose of Bevacizumab is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of body weight given once every 3 weeks as an IV infusion. Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer: The recommended dose is 15 mg/kg of body weight given once every 3 weeks. Exudative age-related macular degeneration 1.25 mg (in 0.05mL of solution) administered by intravitreal injection once monthly

Child Dose

Renal Dose

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

Contra Indications

Hypersensitivity to any component Recent hemoptysis

Precautions

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 Wound healing complications Administration may result in the development of fatal wound dehiscence Discontinue therapy in patients with wound dehiscence requiring medical intervention Hemorrhage Fatal pulmonary hemorrhage can occur in patients with non-small cell lung cancer treated with chemotherapy and bevacizumab Do not administer the drug to patients with recent hemoptysis (at least 2.5 mL of red blood) 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-Lactation

Pregnancy Based on findings from animal studies and its mechanism of action, drug may cause fetal harm in pregnant women Limited postmarketing reports describe cases of fetal malformations with bevacizumab use in pregnancy; however, these reports are insufficient to determine drug associated risks Animal data In animal reproduction studies, IV administration of bevacizumab to pregnant rabbits every 3 days during organogenesis at doses ~1-10 times the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight gain and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects Animal models link angiogenesis and VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development Contraception Advise pregnant women of the potential risk to a fetus Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of bevacizumab Infertility Inform females of reproductive potential of the risk of ovarian failure prior to starting; long term effects of bevacizumab exposure on fertility are unknown Lactation No data available on the presence of bevacizumab in human milk, the effects on the breast fed infant, or the effects on milk production Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for 6 months after last dose

Interactions

Irinotecan/5–fluorouracil/leucovorin The incidence of epistaxis and grade 1 or 2 hemorrhage (including GI hemorrhage, minor gum bleeding, vaginal hemorrhage) was greater in patients receiving bevacizumab plus irinotecan/5-fluorouracil/leucovorin compared with patients receiving irinotecan/5-fluorouracil/leucovorin plus placebo. Closely monitor the patient during coadministration. Live vaccines The administration of live vaccines to patients receiving bevacizumab may result in a reduced immune response. Avoid coadministration. Paclitaxel Decreased paclitaxel exposure was seen when paclitaxel/carboplatin was given in combination with bevacizumab. Closely monitor the patient during coadministration. Sunitinib Coadministration of bevacizumab and sunitinib has been reported to cause unexpected severe toxicity (eg, microangiopathic hemolytic anemia). Coadministration of sunitinib and bevacizumab is not recommended.

Adverse Effects

Side effects of Bevacizumab : >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%)

Mechanism of Action

Bevacizumab binds to VEGF, the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF reduces the vascularisation of tumours, normalises remaining tumour vasculature and inhibits the formation of new tumour vasculature thereby inhibiting tumour growth.