Bevixa IV Infusion

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in-vitro and in-vivo assay systems. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab has an approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous infusion.

Patients should continue treatment until disease progression or unacceptable toxicity.

Metastatic Colorectal Cancer (mCRC): The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy.

• Administer 5 mg/kg when used in combination with bolus-IFL.
• Administer 10 mg/kg when used in combination with FOLFOX4.
• Administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy regimen in patients who have progressed on a first-line Bevacizumab-containing regimen.

Non-Squamous Non-Small Cell Lung Cancer: (NSNSCLC): The recommended dose is 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel.

Glioblastoma: The recommended dose is 10 mg/kg every 2 weeks.

Metastatic Renal Cell Carcinoma (mRCC): The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa.

Cervical Cancer: The recommended dose of Bevacizumab is 15 mg/kg every 3 weeks as an intravenous infusion administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin, or paclitaxel and topotecan.

Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer: The recommended dose is 10mg/kg every 2 weeks in combination with one of the following intravenous chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); or 15 mg/kg every 3 weeks in combination with topotecan (every 3 weeks).

Platinum-Sensitive Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: The recommended dose is 15 mg/kg every 3 weeks when administered in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Bevacizumab 15 mg/kg every 3 weeks as a single agent until disease progression. Alternatively, 15 mg/kg every 3 weeks when administrated in combination with carboplatin and gemcitabine for 6 cycles and up to 10 cycles, followed by continued use of Bevacizumab 15 mg/kg every 3 weeks as a single agent until disease progression.

Do not administer as an IV push or bolus. Do not initiate Bevacizumab for 28 days following major surgery (until surgical wound is fully healed).

First infusion: Administer infusion over 90 minutes.
Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated.

Preparation for Administration: Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw the necessary amount of Bevacizumab and dilute in a total volume of 100 ml of 0.9% Sodium Chloride injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives.

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI
regimen with or without Bevixa. The results demonstrated no significant effect of Bevixa on the pharmacokinetics of irinotecan or its active metabolite SN38.

There are no contraindications listed in the manufacturer’s labeling.

Most common adverse reactions (incidence >10% and at least twice the control arm rate) are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Pregnancy: Bevacizumab may cause fetal harm based on findings from animal studies and the drug’s mechanism of action.

Lactation: No data are available regarding 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 from bevacizumab, advise a nursing woman that breastfeeding is not recommended during treatment with Bevacizumab.

Perforation or Fistula: Discontinue Bevixa if perforation or fistula occurs.

Arterial Thromboembolic Events or ATE (e.g., myocardial infarction, cerebral infarction): Discontinue Bevixa for severe ATE.

Venous Thromboembolic Events or VTE: Discontinue Bevixa for lifethreatening VTE.

Hypertension: Monitor blood pressure and treat hypertension. Temporarily suspend Bevixa if not medically controlled. Discontinue Bevixa for hypertensive crisis or hypertensive encephalopathy.

Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue Bevixa.

Proteinuria: Monitor urine protein. Discontinue Bevixa for nephrotic syndrome. Temporarily suspend Bevixa for moderate proteinuria.

Infusion Reactions: Stop Bevixa for severe infusion reactions.

Embryo-fetal Toxicity: Advise females of potential risk to a fetus and the need for use of effective contraception.

Ovarian Failure: Advise females of the potential risk.

Pediatric Use: The safety, effectiveness and pharmacokinetic profile of Bevixa in pediatric patients have not been established. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years who have received Bevixa. Bevixa is not approved for use in patients under the age of 18 years. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with Bevixa and irinotecan. There is insufficient information to determine the safety and efficacy of Bevixa in children with glioblastoma. Animal Data Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

Geriatric Use In Study: Severe adverse events that occurred at a higher incidence (≥2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Bevixa on overall survival was similar in elderly patients as compared to younger patients.

The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine out of 16 patients and with severe headache in three out of 16 patients.

Targeted Cancer Therapy

Store the Bevixa vial in a refrigerator at 2-8°C. Keep the vial in the outer carton due to light sensitivity. Do not freeze. Keep out of reach of children.