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Indications/Uses
In combination w/ fluoropyrimidine-based chemotherapy as treatment for metastatic carcinoma of the colon or rectum. First line treatment of unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer in addition to platinum-based chemotherapy; w/ epidermal growth factor receptor activating mutations in combination w/ erlotinib. In combination w/ interferon α-2a as 1st-line treatment of advanced &/or metastatic renal cell cancer. In combination w/ radiotherapy & temozolomide for adult patients w/ newly diagnosed glioblastoma. As a single agent or in combination w/ irinotecan for glioblastoma after relapse or disease progression. In combination w/ carboplatin & paclitaxel as front-line treatment of epithelial ovarian, fallopian tube or primary peritoneal cancer. In combination w/ carboplatin & gemcitabine or in combination w/ carboplatin & paclitaxel for recurrent, platinum-sensitive, epithelial ovarian, fallopian tube or primary peritoneal cancer. In combination w/ paclitaxel, topotecan or pegylated liposomal doxorubicin for patients w/ recurrent, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens. In combination w/ paclitaxel & cisplatin, or paclitaxel & topotecan for persistent, recurrent, or metastatic cervical cancer.
Dosage/Direction for Use
IV infusion Initial dose should be delivered over 90 min. If well tolerated, 2nd infusion may be administered over 60 min. Subsequent infusions may be administered over 30 min, if 60 min infusion is well tolerated. MCRC 1st-line treatment: 5 mg/kg once every 2 wk or 7.5 mg/kg once every 3 wk. 2nd-line treatment: 5 mg/kg or 10 mg/kg once every 2 wk, or 7.5 mg/kg or 15 mg/kg once every 3 wk. Continue treatment until progression of underlying disease. Patients previously treated w/ Avastin can continue w/ treatment following 1st progression. Advanced, recurrent metastatic or recurrent NSCLC 1st-line treatment in combination w/ platinum-based chemotherapy: 7.5 mg/kg once every 3 wk in addition to cisplatin-based chemotherapy, or 15 mg/kg once every 3 wk in addition to carboplatin-based chemotherapy. 1st-line treatment w/ EGFR activating mutations in combination w/ erlotinib: 15 mg/kg once every 3 wk continued until disease progression. Advanced &/or mRCC 10 mg/kg once every 2 wk until progression of the underlying disease. Glioblastoma [malignant glioma (WHO grade IV)] Newly diagnosed: 10 mg/kg once every 2 wk in combination w/ temozolomide & radiotherapy for 6 wk. Following a 4-wk treatment break, re-initiate (10 mg/kg once every 2 wk) in combination w/ temozolomide for up to 6 cycles of 4-wk duration. After administration of up to 6 cycles of combined Avastin & temozolomide, Avastin (15 mg/kg once every 3 wk) is continued as single agent until progression of underlying disease. Treatment of recurrent disease: 10 mg/kg once every 2 wk or 15 mg/kg once every 3 wk. Treatment can be continued until progression of underlying disease. Epithelial ovarian, fallopian tube & primary peritoneal cancer Front-line treatment: 15 mg/kg once every 3 wk in addition to carboplatin & paclitaxel for up to 6 cycles followed by continued use of Avastin as single agent for 15 mth or until disease progression. Treatment of recurrent disease: Platinum-sensitive: 15 mg/kg once every 3 wk in combination w/ carboplatin & paclitaxel for 6 cycles & up to 8 cycles or alternatively, 15 mg/kg every 3 wk in combination w/ carboplatin & gemcitabine for 6 cycles & up to 10 cycles, followed by continued use of Avastin as single agent until disease progression. Platinum-resistant: 10 mg/kg once every 2 wk in combination w/ one of the following agents: Paclitaxel, topotecan (given wkly) or pegylated liposomal doxorubicin. Alternatively, 15 mg/kg every 3 wk in combination w/ topotecan on days 1-5 every 3 wk. Treatment is continued until disease progression. Cervical cancer In combination w/ paclitaxel & cisplatin or topotecan: 15 mg/kg once every 3 wk as IV infusion. Treatment is continued until disease progression.
Overdosage
The highest dose tested in humans (20 mg/kg of body weight, intravenous) was associated with severe migraine in several patients.
Contraindications
Bevacizumab (Avastin) is contraindicated in patients with known hypersensitivity to: Any components of the product; Chinese hamster ovary cell products or other recombinant human or humanised antibodies.
Special Precautions
Hypersensitivity or infusion reactions. Increased risk of GI & gallbladder perforation & fistulae; hemorrhage especially tumour-associated hemorrhage, venous thromboembolic events including pulmonary embolism. Permanently discontinue if GI perforation, tracheoesophageal fistula or any Grade 4 fistula; Grade 3 or 4 bleeding during therapy; arterial thromboembolic events & life-threatening Grade 4 venous thromboembolic event; intracranial bleeding develops or occurs. Monitor for signs & symptoms of CNS bleeding. Patients w/ congenital bleeding diathesis, acquired coagulopathy or receiving full dose of anticoagulants prior to initial treatment. Severe eye infections following compounding for unapproved intravitreal use. Do not treat patients w/ recent pulmonary hemorrhage/hemoptysis. Adequately control preexisting HTN prior to initial treatment. Monitor BP during treatment. Posterior reversible encephalopathy syndrome (PRES). Increased risk of arterial thromboembolic events in patients w/ a history of arterial thromboembolism, diabetes or age >65 yr; venous thromboembolism. Closely monitor patients w/ thromboembolic events ≤Grade 3. Preexisting CV disease eg, preexisting CAD or CHF; neutropenia, proteinuria. Do not initiate for at least 28 days following major surgery or until surgical wound is fully healed. Withhold therapy for elective surgery. Discontinue & promptly initiate appropriate treatment in patients who develop necrotising fasciitis. Fertility preservation strategies should be discussed in women of child-bearing potential prior to initial treatment. Not to be used during pregnancy & lactation. Not to be used in childn <18 yr.
Use In Pregnancy & Lactation
Pregnancy: Angiogenesis has been shown to be critically important to foetal development. The inhibition of angiogenesis following administration of Bevacizumab (Avastin) could result in an adverse outcome of pregnancy.
There are no adequate and well-controlled studies in pregnant women (see Pharmacology: Toxicology: Preclinical safety data: Teratogenicity under Actions). IgGs are known to cross the placental barrier, and Bevacizumab (Avastin) may inhibit angiogenesis in the foetus. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see Post Marketing under Adverse Reactions).
Therefore, Bevacizumab (Avastin) should not be used during pregnancy. In women with childbearing potential, appropriate contraceptive measures should be used during Bevacizumab (Avastin) therapy. Based on pharmacokinetic considerations, contraceptive measures should be used for at least 6 months following the last dose of Bevacizumab (Avastin).
Fertility: (see General under Precautions and Clinical Trials under Adverse Reactions).
Repeat dose safety studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see Pharmacology: Toxicology: Preclinical Safety under Actions). A substudy with 295 premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab on fertility are unknown.
Labour and Delivery: No text.
Nursing Mothers: It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and Avastin could harm infant growth and development, women should be advised to discontinue nursing during Bevacizumab (Avastin) therapy and not to breast feed for at least 6 months following the last dose of Bevacizumab (Avastin).
There are no adequate and well-controlled studies in pregnant women (see Pharmacology: Toxicology: Preclinical safety data: Teratogenicity under Actions). IgGs are known to cross the placental barrier, and Bevacizumab (Avastin) may inhibit angiogenesis in the foetus. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see Post Marketing under Adverse Reactions).
Therefore, Bevacizumab (Avastin) should not be used during pregnancy. In women with childbearing potential, appropriate contraceptive measures should be used during Bevacizumab (Avastin) therapy. Based on pharmacokinetic considerations, contraceptive measures should be used for at least 6 months following the last dose of Bevacizumab (Avastin).
Fertility: (see General under Precautions and Clinical Trials under Adverse Reactions).
Repeat dose safety studies in animals have shown that bevacizumab may have an adverse effect on female fertility (see Pharmacology: Toxicology: Preclinical Safety under Actions). A substudy with 295 premenopausal women has shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of the treatment with bevacizumab on fertility are unknown.
Labour and Delivery: No text.
Nursing Mothers: It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and Avastin could harm infant growth and development, women should be advised to discontinue nursing during Bevacizumab (Avastin) therapy and not to breast feed for at least 6 months following the last dose of Bevacizumab (Avastin).
Adverse Reactions
Clinical Trials:Clinical trials have been conducted in patients with various malignancies treated with Bevacizumab (Avastin), predominantly in combination with chemotherapy. The safety profile from a clinical trial population of approximately 5,500 patients is presented in this section. For post marketing experience see Post Marketing as follows. See Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions for details of major studies, including study designs and major efficacy results.
The most serious adverse drug reactions were: Gastrointestinal Perforations (see General under Precautions); Haemorrhage including pulmonary haemorrhage/haemoptysis, which is more common in NSCLC patients (see General under Precautions); Arterial Thromboembolism (see General under Precautions).
Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Bevacizumab (Avastin) therapy are likely to be dose-dependent.
The most frequently observed adverse drug reactions across clinical trials in patients receiving Bevacizumab (Avastin) were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.
Adverse drug reactions associated with the use of Bevacizumab (Avastin) in combination with different chemotherapy regimens in multiple indications. These reactions had occurred either with at least a 2% difference compared to the control arm (NCI-CTC Grade 3-5 reactions) or with at least a 10% difference compared to the control arm (NCI-CTC Grade 1-5 reactions), in at least one of the major clinical trials. The adverse drug reactions listed in this table fall into the following categories (Very Common (≥ 10%) and Common (≥ 1% - < 10%)). Adverse drug reactions are added to the appropriate category in the table as follows according to the highest incidence seen in any of the major clinical trials. Within each frequency grouping adverse drug reactions are presented in order of decreasing seriousness. Some of the adverse reactions are reactions commonly seen with chemotherapy, however, Bevacizumab (Avastin) may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.
The most serious adverse drug reactions were: Gastrointestinal Perforations (see General under Precautions); Haemorrhage including pulmonary haemorrhage/haemoptysis, which is more common in NSCLC patients (see General under Precautions); Arterial Thromboembolism (see General under Precautions).
Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Bevacizumab (Avastin) therapy are likely to be dose-dependent.
The most frequently observed adverse drug reactions across clinical trials in patients receiving Bevacizumab (Avastin) were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.
Adverse drug reactions associated with the use of Bevacizumab (Avastin) in combination with different chemotherapy regimens in multiple indications. These reactions had occurred either with at least a 2% difference compared to the control arm (NCI-CTC Grade 3-5 reactions) or with at least a 10% difference compared to the control arm (NCI-CTC Grade 1-5 reactions), in at least one of the major clinical trials. The adverse drug reactions listed in this table fall into the following categories (Very Common (≥ 10%) and Common (≥ 1% - < 10%)). Adverse drug reactions are added to the appropriate category in the table as follows according to the highest incidence seen in any of the major clinical trials. Within each frequency grouping adverse drug reactions are presented in order of decreasing seriousness. Some of the adverse reactions are reactions commonly seen with chemotherapy, however, Bevacizumab (Avastin) may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.
Drug Interactions
Effect of antineoplastic agents on bevacizumab pharmacokinetics: No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokinetics was observed based on the results of population pharmacokinetic analyses. There was neither statistical significance nor clinically relevant differences in bevacizumab clearance in patients receiving Bevacizumab (Avastin) monotherapy compared to patients receiving Bevacizumab (Avastin) in combination with interferon alpha 2a, erlotinib or chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin, or cisplatin/gemcitabine).
Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents: No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co-administered interferon alpha 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn.
Combination of bevacizumab and sunitinib malate: In two clinical studies of metastatic renal cell carcinoma, microangiopathic hemolytic anemia (MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib malate (50 mg daily) combination.
MAHA is a hemolytic disorder which can present with red cell fragmentation, anemia, and thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed in some of these patients. All of these findings were reversible upon discontinuation of bevacizumab and sunitinib malate (see General: Hypertension, Proteinuria and Posterior Reversible Encephalopathy (PRES) under Precautions)
Radiotherapy: The safety and efficacy of concomitant administration of chemotherapy (temozolomide), radiotherapy and Bevacizumab (Avastin) was evaluated in study BO21990, a Phase III, randomized, double blind, placebo controlled study of 921 patients with newly diagnosed glioblastoma. No new adverse events associated with Bevacizumab (Avastin) were reported in this study.
The safety and efficacy of concomitant administration of radiotherapy and Bevacizumab (Avastin) has not been established in other indications.
Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents: No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co-administered interferon alpha 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn.
Combination of bevacizumab and sunitinib malate: In two clinical studies of metastatic renal cell carcinoma, microangiopathic hemolytic anemia (MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib malate (50 mg daily) combination.
MAHA is a hemolytic disorder which can present with red cell fragmentation, anemia, and thrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed in some of these patients. All of these findings were reversible upon discontinuation of bevacizumab and sunitinib malate (see General: Hypertension, Proteinuria and Posterior Reversible Encephalopathy (PRES) under Precautions)
Radiotherapy: The safety and efficacy of concomitant administration of chemotherapy (temozolomide), radiotherapy and Bevacizumab (Avastin) was evaluated in study BO21990, a Phase III, randomized, double blind, placebo controlled study of 921 patients with newly diagnosed glioblastoma. No new adverse events associated with Bevacizumab (Avastin) were reported in this study.
The safety and efficacy of concomitant administration of radiotherapy and Bevacizumab (Avastin) has not been established in other indications.
Caution For Usage
Special instructions for use, handling and disposal: Bevacizumab (Avastin) infusions should not be administered or mixed with dextrose or glucose solutions (see Incompatibilities as follows).
Do not administer as an intravenous push or bolus.
Bevacizumab (Avastin) should be prepared by a healthcare professional using aseptic technique. Withdraw the necessary amount of bevacizumab and dilute to the required administration volume with 0.9% sodium chloride solution. The concentration of the final bevacizumab solution should be kept within the range of 1.4 - 16.5 mg/ml.
Discard any unused portion left in a vial, as the product contains no preservatives. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Bevacizumab (Avastin) is not formulated for intravitreal use.
Incompatibilities: No incompatibilities between Bevacizumab (Avastin) and polyvinyl chloride or polyolefin bags have been observed. A concentration-dependent degradation profile of Bevacizumab (Avastin) was observed when diluted with dextrose solutions (5%).
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
Do not administer as an intravenous push or bolus.
Bevacizumab (Avastin) should be prepared by a healthcare professional using aseptic technique. Withdraw the necessary amount of bevacizumab and dilute to the required administration volume with 0.9% sodium chloride solution. The concentration of the final bevacizumab solution should be kept within the range of 1.4 - 16.5 mg/ml.
Discard any unused portion left in a vial, as the product contains no preservatives. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Bevacizumab (Avastin) is not formulated for intravitreal use.
Incompatibilities: No incompatibilities between Bevacizumab (Avastin) and polyvinyl chloride or polyolefin bags have been observed. A concentration-dependent degradation profile of Bevacizumab (Avastin) was observed when diluted with dextrose solutions (5%).
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
Storage
Store vials in a refrigerator at 2°C-8°C.
Keep vial in the outer carton in order to protect from light.
DO NOT FREEZE. DO NOT SHAKE.
Bevacizumab (Avastin) does not contain any antimicrobial preservative; therefore, care must be taken to ensure the sterility of the prepared solution.
Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C-30°C in 0.9% sodium chloride solution. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Keep vial in the outer carton in order to protect from light.
DO NOT FREEZE. DO NOT SHAKE.
Bevacizumab (Avastin) does not contain any antimicrobial preservative; therefore, care must be taken to ensure the sterility of the prepared solution.
Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C-30°C in 0.9% sodium chloride solution. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Action
Pharmacotherapeutic Group: Antineoplastic agent. ATC Code: L01XC07.
Pharmacology: Pharmacodynamics: Mechanism of Action: Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab contains human framework regions with antigen binding regions of a humanized murine antibody that binds to VEGF. Bevacizumab is produced by recombinant DNA technology in a Chinese Hamster ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin and is purified by a process that includes specific viral inactivation and removal steps. Gentamicin is detectable in the final product at ≤0.35 ppm. Bevacizumab consists of 214 amino acids and has a molecular weight of approximately 149,000 daltons.
Bevacizumab (Avastin) inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralizing the biologic activity of VEGF reduces the vascularization of tumors, thereby inhibiting tumor growth. Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in nude mice resulted in extensive anti-tumor activity in human cancers, including colon, breast, pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeability was reduced.
Clinical/Efficacy Studies: Metastatic Colorectal Cancer (mCRC): The safety and efficacy of the recommended dose of Bevacizumab (Avastin) (5 mg/kg of body weight every two weeks) in metastatic carcinoma of the colon or rectum were studied in three randomized, active-controlled clinical trials in combination with fluoropyrimidine-based first-line chemotherapy. Bevacizumab (Avastin) was combined with two chemotherapy regimens: AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/leucovorin (IFL regimen) for a total of 4 weeks of each 6 week cycle.
AVF0780g: In combination with bolus 5-fluorouracil/leucovorin (5-FU/LV) for a total of 6 weeks of each 8 week cycle (Roswell Park regimen).
AVF2192g: In combination with bolus 5-fluorouracil/leucovorin (5-FU/LV) for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecan treatment.
Three additional studies with Bevacizumab (Avastin) have been conducted in mCRC patients: first-line (NO16966), second-line with no previous Bevacizumab (Avastin) treatment (E3200), and second-line with previous Bevacizumab (Avastin) treatment following disease progression in first-line (ML18147). In these studies, Bevacizumab (Avastin) was administered at the following dosing regimens, in combination with FOLFOX-4 (5FU/LV/oxaliplatin), XELOX (capecitabine/oxaliplatin), and fluoroprymidine/irinotecan and fluoroprymidine/oxaliplatin: NO16966: Bevacizumab (Avastin) 7.5 mg/kg of body weight every 3 weeks in combination with oral capecitabine and intravenous oxaliplatin (XELOX) or Bevacizumab (Avastin) 5 mg/kg every 2 weeks in combination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4).
E3200: Bevacizumab (Avastin) 10 mg/kg of body weight every 2 weeks in combination with leucovorin and 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4) in Bevacizumab (Avastin) naïve patients.
ML18147: Bevacizumab (Avastin) 5.0 mg/kg of body weight every 2 weeks or Bevacizumab (Avastin) 7.5 mg/kg of body weight every 3 weeks in combination with fluoropyrimidine/irinotecan or fluoropyrimidine/oxaliplatin in patients with disease progression following first-line treatment with Bevacizumab (Avastin). Use of irinotecan- or oxaliplatin-containing regimen was switched depending on first-line usage of either oxaliplatin or irinotecan.
AVF2107g: This was a phase III randomized, double-blind, active-controlled clinical trial evaluating Bevacizumab (Avastin) in combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum. Eight hundred and thirteen patients were randomized to receive IFL + placebo (Arm 1) or IFL + Bevacizumab (Avastin) (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus 5-FU/LV + Bevacizumab (Avastin) (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safety of Bevacizumab (Avastin) with the IFL regimen was established and considered acceptable.
The primary efficacy parameter of the trial was overall survival. The addition of Bevacizumab (Avastin) to IFL resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see Table 1 for details). The clinical benefit of Bevacizumab (Avastin), as measured by survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumor, number of organs involved, and duration of metastatic disease.
Pharmacology: Pharmacodynamics: Mechanism of Action: Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab contains human framework regions with antigen binding regions of a humanized murine antibody that binds to VEGF. Bevacizumab is produced by recombinant DNA technology in a Chinese Hamster ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin and is purified by a process that includes specific viral inactivation and removal steps. Gentamicin is detectable in the final product at ≤0.35 ppm. Bevacizumab consists of 214 amino acids and has a molecular weight of approximately 149,000 daltons.
Bevacizumab (Avastin) inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralizing the biologic activity of VEGF reduces the vascularization of tumors, thereby inhibiting tumor growth. Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in nude mice resulted in extensive anti-tumor activity in human cancers, including colon, breast, pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeability was reduced.
Clinical/Efficacy Studies: Metastatic Colorectal Cancer (mCRC): The safety and efficacy of the recommended dose of Bevacizumab (Avastin) (5 mg/kg of body weight every two weeks) in metastatic carcinoma of the colon or rectum were studied in three randomized, active-controlled clinical trials in combination with fluoropyrimidine-based first-line chemotherapy. Bevacizumab (Avastin) was combined with two chemotherapy regimens: AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/leucovorin (IFL regimen) for a total of 4 weeks of each 6 week cycle.
AVF0780g: In combination with bolus 5-fluorouracil/leucovorin (5-FU/LV) for a total of 6 weeks of each 8 week cycle (Roswell Park regimen).
AVF2192g: In combination with bolus 5-fluorouracil/leucovorin (5-FU/LV) for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecan treatment.
Three additional studies with Bevacizumab (Avastin) have been conducted in mCRC patients: first-line (NO16966), second-line with no previous Bevacizumab (Avastin) treatment (E3200), and second-line with previous Bevacizumab (Avastin) treatment following disease progression in first-line (ML18147). In these studies, Bevacizumab (Avastin) was administered at the following dosing regimens, in combination with FOLFOX-4 (5FU/LV/oxaliplatin), XELOX (capecitabine/oxaliplatin), and fluoroprymidine/irinotecan and fluoroprymidine/oxaliplatin: NO16966: Bevacizumab (Avastin) 7.5 mg/kg of body weight every 3 weeks in combination with oral capecitabine and intravenous oxaliplatin (XELOX) or Bevacizumab (Avastin) 5 mg/kg every 2 weeks in combination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4).
E3200: Bevacizumab (Avastin) 10 mg/kg of body weight every 2 weeks in combination with leucovorin and 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4) in Bevacizumab (Avastin) naïve patients.
ML18147: Bevacizumab (Avastin) 5.0 mg/kg of body weight every 2 weeks or Bevacizumab (Avastin) 7.5 mg/kg of body weight every 3 weeks in combination with fluoropyrimidine/irinotecan or fluoropyrimidine/oxaliplatin in patients with disease progression following first-line treatment with Bevacizumab (Avastin). Use of irinotecan- or oxaliplatin-containing regimen was switched depending on first-line usage of either oxaliplatin or irinotecan.
AVF2107g: This was a phase III randomized, double-blind, active-controlled clinical trial evaluating Bevacizumab (Avastin) in combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum. Eight hundred and thirteen patients were randomized to receive IFL + placebo (Arm 1) or IFL + Bevacizumab (Avastin) (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus 5-FU/LV + Bevacizumab (Avastin) (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safety of Bevacizumab (Avastin) with the IFL regimen was established and considered acceptable.
The primary efficacy parameter of the trial was overall survival. The addition of Bevacizumab (Avastin) to IFL resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see Table 1 for details). The clinical benefit of Bevacizumab (Avastin), as measured by survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumor, number of organs involved, and duration of metastatic disease.
MedsGo Class
Targeted Cancer Therapy
Features
Dosage
400 mg / 16 ml (25 mg / ml)
Ingredients
- Bevacizumab
Packaging
Concentrate for Infusion (I.V.) 16ml
Generic Name
Bevacizumab
Registration Number
BR-969
Classification
Prescription Drug (RX)
Product Questions
Questions
