Bevaas

Bevacizumab.

Active ingredient: Bevacizumab (humanised anti-VEGF monoclonal antibody).
BEVAAS Concentrate for solution for infusion 100 mg/4 mL: BEVAAS Concentrate for solution for infusion 100 mg/4 mL, each vial contains: Bevacizumab 100 mg.
BEVAAS Concentrate for solution for infusion 400 mg/16 mL: BEVAAS Concentrate for solution for infusion 400 mg/16 mL, each vial contains: Bevacizumab 400 mg.
BEVAAS is not formulated for intravitreal use (see General under PRECAUTIONS).
Excipients/Inactive Ingredients: α,α trehalose dehydrate, Dibasic sodium phosphate (Anhydrous), Monobasic sodium phosphate (monohydrate), polysorbate 20, water for injection.

Therapeutic/Pharmacologic Class of Drug: Anti-neoplastic agent. ATC Code: L01X C07.
Pharmacology: Mechanism of action: Bevacizumab 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 inhibits the binding of VEGF to its receptors, Flt-1 and KDR, on the surface of endothelial cells. Neutralising the biological activity of VEGF reduces the vascularisation of tumour, thereby inhibiting tumour growth.
Pharmacodynamics: Clinical/Efficacy Studies of Bevaas: A prospective, randomized, multiple-dose, multi-center, comparative, parallel clinical study was conducted to evaluate the efficacy, safety, immunogenicity and pharmacokinetics of an intravenous infusion of Test Product-Bevacizumab and Reference Product-Bevacizumab administered in combination with standard chemotherapy in patients of metastatic colorectal cancer.
Patients were screened for study eligibility up to 21 days followed by 24 weeks of treatment period [8 cycles with XELOX regimen (each cycle 3 weeks) or 12 cycles with FOLFOX-4 regimen (each cycle 2 weeks)].
All eligible patients were randomly assigned to receive either Hetero-Bevacizumab or Reference-Bevacizumab in 2:1 ratio either with XELOX or FOLFOX-4 chemotherapy regimen. The choice of the concomitant chemotherapy regimen was based on investigator's discretion. No dose adjustments were allowed for Bevacizumab.
Dose adjustments for other concomitant chemotherapeutic agents were permitted as per the prescribing information of the respective drugs/as per the institutional standards/PIs discretion.
First fifteen patients randomly assigned to Hetero-Bevacizumab (ten patients) and Reference Bevacizumab (five patients) treatment arms were evaluated for infusion related reactions (IRRs) after first dose. Data and Safety Monitoring Board (DSMB) reviewed the safety data of 1st 15 patients before further recruitment.
Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) scan was performed at baseline (screening), at the end of cycle 2, cycle 4, cycle 6, and End of Treatment (EOT) visit for XELOX regimen and baseline (screening), at the end of cycle 3, cycle 6, cycle 9 and EOT visit for FOLFOX-4 regimen.
Immunogenicity assessed by testing serum for the presence of anti-bevacizumab antibodies in Hetero-Bevacizumab or Reference-Bevacizumab groups at screening, end of cycle 4 and EOT visit in XELOX regimen and at screening, end of cycle 6, and EOT visit in FOLFOX-4 regimen. Blood samples for Vascular Endothelial Growth Factor (VEGF) levels were collected at screening, end of cycle 1, cycle 6 and EOT visit. VEGF levels were considered as pharmacodynamic marker of Bevacizumab.
Pharmacokinetic, pharmacodynamic and immunogenicity parameters were tested at Syngene Bioanalytical Laboratory as per the applicable regulatory guidelines and standard operating procedures.
Safety was evaluated by monitoring of adverse events (AE), significant clinical signs symptoms and laboratory abnormalities throughout the study.
Efficacy analysis included patients who have completed at least three cycles of FOLFOX-4 regimen or two cycles of XELOX regimen and have at least one post baseline radiological assessment.
Statistical analysis was performed on the efficacy, safety, pharmacokinetic and pharmacodynamic data by Cliantha Research Limited.
Overall Response Rate (CR+PR) according to RECIST 1.1 guidelines: ITT Population: Overall Response Rate (ORR) was 35.53%, 46.97%, 49.02% and 46.94% in Hetero Bevacizumab at week 6, week 12, week 18 and week 24 respectively compared to 16.22%, 32.35%, 37.04% and 33.33% in Roche-Bevacizumab. Hetero-Bevacizumab was comparable to Roche-Bevacizumab at week 6, week 12, week 18 and week 24 with significantly higher response at week 6. (See Table 1.)


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PP Population: Overall Response Rate (ORR) was 42.31%, 50%, 50% and 47.73% in Hetero-Bevacizumab at week 6, week 12, week 18 and week 24 respectively compared to 19.23%, 32%, 33.33% and 33.33% in Roche-Bevacizumab. Hetero-Bevacizumab was comparable to Roche Bevacizumab at week 6, week 12, week 18 and week 24 with significantly higher response at week 6. (See Table 2.)


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Pharmacokinetic study: This study was a double blind, randomized, balanced, pararell group Phase I study comparing the pharmacokinetics and safety of Bevacizumab.
The primary objective of this study was to evaluate the pharmacokinetic and safety profiles of Bevacizumab after administering the following products under investigation: A single IV dose containing 1 mg/kg of Local reference product; A single IV dose containing 1 mg/kg of Test Product 2.
The Test 2 Formulation, solution for intravenous infusion containing Bevacizumab 100 mg/4 ml showed a similar pharmacokinetic profile of Bevacizumab, in terms of the amount and speed of absorption with respect to the reference formulation. (See Tables 3, 4 and 5.)


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Pharmacodynamics Results - Vascular Endothelial Growth Factor (VEGF) Assessments: The VEGF levels were decreased from screening to week 2 (-393.32 pg/ml in Hetero Bevacizumab group and -214.01 pg/ml in Roche- Bevacizumab), week 12 (-330.19 pg/ml in Hetero-Bevacizumab and -179.99 pg/ml in Roche- Bevacizumab) and week 24 (-369.08 pg/ml in Hetero-Bevacizumab and -161.97 pg/ml in Roche- Bevacizumab). The reduction in VEGF levels from baseline to week 2, week 12 and week 24 were comparable between Hetero-Bevacizumab and Roche-Bevacizumab. (See Tables 6 and 7.)


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Conclusion: Overall Response Rate (ORR) was 35.53%, 46.97%, 49.02% and 46.94% in Hetero Bevacizumab at week 6, week 12, week 18 and week 24 respectively compared to 16.22%, 32.35%, 37.04% and 33.33% in Roche-Bevacizumab. Hetero-Bevacizumab was comparable to Roche-Bevacizumab at week 6, week 12, week 18 and week 24 with significantly higher response at week 6.
This data of ORR demonstrate that efficacy of Hetero-Bevacizumab is comparable with that of Roche-Bevacizumab in patients with Metastatic Colorectal cancer.
Both the treatment arms showed comparable safety profile in this study. No significant safety concerns were reported with the Hetero-Bevacizumab or Roche-Bevacizumab.
The decrease in VEGF levels were also comparable between the two groups. Improvement in quality of life data based on FACT-C questionnaire was also comparable between the two groups.
Pharmacokinetic results: The analysis of Bevacizumab bioavailable fraction of Test Product 2, solution for IV infusion containing Bevacizumab 100 mg/4 mL, in comparison with the Reference Product, solution for intravenous infusion containing Bevacizumab 100 mg/4 ml, shows that for: Ln Cmax: The point estimate μTest 2/μReference= 100.95% and the 90% CI (89.75 - 113.55) are within the 80 - 125% region.
Ln AUC0-t: The point estimate μTest 2/μReference= 94.87% and the 90% CI (84.91 - 105.99) are within the 80 - 125% region.
Ln AUC0-inf: The point estimate μTest 2/μReference= 95.02% and the 90% CI (84.80 - 106.49) are within the 80 - 125% region.
The Test 2 Formulation - Solution for intravenous containing Bevacizumab 100 mg/4 mL, showed a similar pharmacokinetic profile of Bevacizumab, in terms of the amount and speed of absorption with respect to the reference formulation.
Clinical/Efficacy Studies of Bevacizumab Innovator: Metastatic Colorectal Cancer (mCRC): The safety and efficacy of the recommended dose of Bevacizumab innovator (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 innovator was combined with two chemotherapy regimens: AVF2107g: A weekly schedule of irinotecan/bolus 5 fluorouracil/leucovorin (IFL regimen) for 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-fluoroacil/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.
Bevacizumab innovator in Combination with IFL Chemotherapy for First-Line Treatment of Metastatic Carcinoma of the Colon or Rectum (AVF2107g): This was a phase III randomized, double-blind, active-controlled clinical trial evaluating Bevacizumab innovator 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 (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus 5-FU/LV+Bevacizumab innovator (Arm 3). Enrollment in Arm 3 was discontinued, as pre-specified, once safety of Bevacizumab innovator with the IFL regimen was established and considered acceptable. All treatments were continued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an ECOG performance status of 0.43% had a value of 1 and 0.4% had a value of 2. 15.5% had received prior radiotherapy and 28.4% prior chemotherapy. (See Table 8.)


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The primary efficacy parameter of the trial was overall survival. The addition of Bevacizumab innovator to IFL resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see Table 9). The clinical benefit of Bevacizumab innovator, as measured by survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumour, number of organs involved, and duration of metastatic disease.
The efficacy results of Bevacizumab innovator in combination with IFL-chemotherapy are displayed in Table 9. (See Table 9.)


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Among the 110 patients randomized to Arm 3 (5-FU/FA+Bevacizumab innovator) prior to discontinuation of this arm, the median overall survival was 18.3 months, and the median progression free survival was 8.8 months.
Bevacizumab innovator in Combination with 5-FU/FA Chemotherapy for the First-Line Treatment of Metastatic Carcinoma of the Colon or Rectum in Patients Who Were Not Optimal Candidates for First-Line Irinotecan Treatment (AVF2192g): This was a phase II randomized, double-blind, active-controlled clinical trial evaluating the efficacy and safety of Bevacizumab innovator in combination with 5-FU/FA as first-line treatment for metastatic colorectal cancer in patients who were not optimal candidates for first-line irinotecan treatment.
Patients had to be either more susceptible to irinotecan toxicity (≥ 65 years, prior radiotherapy to pelvis or abdomen) or less likely to benefit from irinotecan treatment (PS ≥ 1, baseline albumin < 3.5 g/dL) in order to be eligible for enrollment. One hundred and five patients were randomized to 5-FU/FA + placebo arm and 104 patients to 5-FU/FA + Bevacizumab innovator (5 mg/kg every 2 weeks) arm.
All treatments were continued until disease progression. The overall mean age was 71 years; 28.2% of patients had a ECOG performance status of 0, 65.1% had a value of 1, and 6.7% had a value of 2.
The addition of Bevacizumab innovator 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective response rates, significantly longer progression-free survival, and a trend in longer survival, compared to 5-FU/FA chemotherapy alone (see Table 9). These efficacy data were consistent with the results observed in studies AVF2107g and AVF0780g.
Bevacizumab innovator in Combination with 5-FU/FA Chemotherapy for the First-Line Treatment of Metastatic Carcinoma of the Colon or Rectum (AVF0780g): This was a phase II randomized, active-controlled, open-labelled clinical trial investigating Bevacizumab innovator in combination with 5-FU/FA as first-line treatment of metastatic colorectal cancer. The median age was 64 years. 19% of the patients had received prior chemotherapy and 14% prior radiotherapy. Seventy-one patients were randomized to receive bolus 5-FU/FA or 5-FU/FA + Bevacizumab innovator (5 mg/kg every 2 weeks). A third group of 33 patients received bolus 5-FU/FA + Bevacizumab innovator (10 mg/kg every 2 weeks). Patients were treated until disease progression. The primary endpoints of the trial were objective response rate and progression-free survival. The addition of Bevacizumab innovator 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective response rates, longer progression-free survival, and a trend in longer survival, compared with 5-FU/FA chemotherapy alone (see Table 10). These efficacy data are consistent with the results from study AVF2107g.
The efficacy data from studies AVF0780g and AVF2192g investigating Bevacizumab innovator in combination with 5-FU/FA-chemotherapy are summarized in Table 10. (See Table 10.)


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Pharmacokinetics: The pharmacokinetics of Bevacizumab innovator were characterised in patients with various types of solid tumours. The doses tested were 0.1-10 mg/kg weekly in phase I; 3-20 mg/kg every two weeks (q2w) or every three weeks (q3w) in phase II; 5 mg/kg (q2w) or 15 mg/kg q3w in phase III. In all clinical trials, Bevacizumab innovator was administered as an IV infusion.
As observed with other antibodies, the pharmacokinetics of Bevacizumab innovator are well described by a two-compartment model. Overall, in all clinical trials, Bevacizumab innovator disposition was characterized by a low clearance, a limited volume of the central compartment (Vc), and a long elimination half-life. This enables target therapeutic Bevacizumab innovator serum levels to be maintained with a range of administration schedules (such as one administration every 2 or 3 weeks).
In a population pharmacokinetic meta-analysis there was no significant difference in the pharmacokinetics of Bevacizumab innovator in relation to race when body weight is taken into account, or in relation to age (no correlation between Bevacizumab innovator clearance and patient age [the median age was 59 year with 5^th and 95^th percentiles of 37 and 76 year]).
Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab innovator clearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster in subjects with higher tumour burden when compared with a typical patient with median values of albumin and tumour burden.
Absorption: No text.
Distribution: The typical value for central volume (Vc) was 2.73 L and 3.28 L for female and male subjects respectively, which is in the range that has been described for IgGs and other monoclonal antibodies. The typical value for peripheral volume (Vp) was 1.69 L and 2.35 L for female and male patients respectively, when Bevacizumab innovator is coadministered with anti-neoplastic agents.
After correcting for body weight, male subjects had a larger Vc (+ 20%) than females.
Metabolism: Assessment of Bevacizumab innovator metabolism in rabbits following a single IV dose of 125I-Bevacizumab innovator indicated that its metabolic profile was similar to that expected for a native IgG molecule which does not bind VEGF. The metabolism and elimination of Bevacizumab innovator is similar to endogenous IgG i.e. primarily via proteolytic catabolism throughout the body, including endothelial cells, and does not rely primarily on elimination through the kidneys and liver. Binding of the IgG to the FcRn receptor result in protection from cellular metabolism and the long terminal half-life.
Elimination: The pharmacokinetics of Bevacizumab innovator are linear at doses ranging from 1.5 to 10 mg/kg/wk. The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male patients, respectively. After correcting for body weight, male patients had a higher Bevacizumab innovator clearance (+ 17%) than females. According to the two-compartmental model, the elimination half-life is 18 days for a typical female patient and 20 days for a typical male patient.
Pharmacokinetics in Special Populations: The population pharmacokinetics of Bevacizumab innovator were analysed to evaluate the effects of demographic characteristics. In adults, the results showed no significant difference in the pharmacokinetics of Bevacizumab innovator in relation to age.
Pediatric Population: The pharmacokinetics of Bevacizumab innovator were evaluated in 152 patients (7 months to 21 years; 5.9 to 125 kg) across 4 clinical studies using a population pharmacokinetic model. The pharmacokinetic results show that the clearance and the volume of distribution of Bevacizumab innovator were comparable between pediatric and adult patients when normalized by bodyweight. Age was not associated with the pharmacokinetics of Bevacizumab innovator when body weight was taken into account.
Renal impairment: No studies have been conducted to investigate the pharmacokinetics of Bevacizumab innovator in renally impaired patients since the kidneys are not a major organ for Bevacizumab innovator metabolism or excretion.
Hepatic impairment: No studies have been conducted to investigate the pharmacokinetics of Bevacizumab innovator in patients with hepatic impairment since the liver is not a major organ for Bevacizumab innovator metabolism or excretion.
Toxicology: Non clinical safety: Carcinogenicity: Studies have not been performed to evaluate the carcinogenic potential of Bevacizumab.
Mutagenicity: Studies have not been performed to evaluate the mutagenic potential of Bevacizumab.
Impairment of Fertility: No specific studies in animals have been performed to evaluate the effect of Bevacizumab on fertility. No adverse effect on male reproductive organs was observed in repeat dose toxicity studies in cynomolgus monkeys.
Inhibition of ovarian function was characterised by decreases in ovarian and/or uterine weight and the number of corpora lutea, a reduction in endometrial proliferation and an inhibition of follicular maturation in cynomolgus monkeys treated with Bevacizumab for 13 or 26 weeks. The doses associated with this effect were ≥ 4 times the human therapeutic dose or ≥ 2-fold above the expected human exposure based on average serum concentrations in female monkeys. In rabbits, administration of 50 mg/kg resulted in a Bevacizumab significant decrease in ovarian weight and number of corpora lutea. The results in both monkeys and rabbits were reversible upon cessation of treatment. The inhibition of angiogenesis following administration of Bevacizumab is likely to result in an adverse effect on female fertility.
Reproductive Toxicity: Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased incidence of specific gross and skeletal foetal alterations. Adverse foetal outcomes were observed at all tested doses of 10 - 100 mg/kg. Information on foetal malformations observed in the post marketing setting are provided in Use in Pregnancy & Lactation and Post Marketing under Adverse Reactions.
Other: Physeal Development: In studies of up to 26 weeks duration in cynomolgus monkeys, Bevacizumab was associated with physeal dysplasia. Physeal dysplasia was characterised primarily by thickened growth plate cartilage, subchondral bony plate formation and inhibition of vascular invasion of the growth plate. This effect occurred at doses ≥ 0.8 times the human therapeutic dose and exposure levels slightly below the expected human clinical exposure, based on average serum concentrations. It should be noted, however, that physeal dysplasia occurred only in actively growing animals with open growth plates.
Wound Healing: In rabbits, the effects of Bevacizumab on circular wound healing were studied. Wound re-epithelialisation was delayed in rabbits following five doses of Bevacizumab, ranging from 2 - 50 mg/kg, over a 2-week period. A trend toward a dose-dependent relationship was observed. The magnitude of effect on wound healing was similar to that observed with corticosteroid administration. Upon treatment cessation with either 2 or 10 mg/kg Bevacizumab, the wounds closed completely. The lower dose of 2 mg/kg was approximately equivalent to the proposed clinical dose. A more sensitive linear wound healing model was also studied in rabbits. Three doses of Bevacizumab ranging from 0.5 - 2 mg/kg dose-dependently and significantly decreased the tensile strength of the wounds, consistently with delayed wound healing. The low dose of 0.5 mg/kg was 5-fold below the proposed clinical dose.
As effects on wound healing were observed in rabbits at doses below the proposed clinical dose, the capacity for Bevacizumab to adversely impact wound healing in human should be considered. In cynomolgus monkeys, the effects of Bevacizumab on the healing of a linear incision were highly variable and no dose-response relationship was evident.
Renal Function: In normal cynomolgus monkeys, Bevacizumab had no measurable effect on renal function treated once or twice weekly for up to 26 weeks, and did not accumulate in the kidney of rabbits following two doses up to 100 mg/kg (approximately 80-folds the proposed clinical dose).
Investigative toxicity studies in rabbits, using models of renal dysfunction, showed that Bevacizumab did not exacerbate renal glomerular injury induced by bovine serum albumin or renal tubular damage induced by Cisplatin.
Albumin: In male cynomolgus monkeys, Bevacizumab administered at doses of 10 mg/kg twice weekly or 50 mg/kg once weekly for 26 weeks was associated with a statistically significant decrease in albumin and albumin to globulin ratio and increase in globulin. These effects were reversible upon cessation of exposure. As the parameters remained within the normal reference range of values for these endpoints, these changes were not considered as clinically significant.
Hypertension: At doses up to 50 mg/kg twice weekly in cynomolgus monkeys, Bevacizumab showed no effects on blood pressure.
Haemostasis: Non-clinical toxicology studies of up to 26 weeks duration in cynomolgus monkeys did not find changes in haematology or coagulation parameters including platelet counts, prothrombin and activated partial thromboplastin time. A model of haemostasis in rabbits, used to investigate the effect of Bevacizumab on thrombus formation, did not show alteration in the rate of clot formation or any other haematological parameters compared to treatment with Bevacizumab vehicle.

Metastatic colorectal cancer (mCRC): BEVAAS in combination with Fluoropyrimidine-based chemotherapy is indicated for the treatment of patients with metastatic carcinoma of the colon or rectum.

General: BEVAAS should be prepared by a healthcare professional using aseptic technique.
The initial BEVAAS dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30-minutes.
Dose reduction of BEVAAS for adverse events is not recommended. If indicated, BEVAAS should either be permanently discontinued or temporarily suspended.
Metastatic colorectal cancer (mCRC): The recommended dose of BEVAAS, administered as an intravenous infusion, is either 5 mg/kg or 10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks. Dose reduction for adverse events is not recommended. If indicated, therapy should either permanently discontinued or temporarily suspended.
Special dosage instructions: Pediatric use: The safety and efficacy of Bevacizumab in patients under the age of 18 years have not been established.
Geriatric use: No dose adjustment is required in the patient ≥ 65 years of age.
Renal impairment: The safety and efficacy of Bevacizumab has not been studied in patients with renal impairment.
Hepatic impairment: The safety and efficacy of Bevacizumab have not been studied in patients with hepatic impairment.

The highest dose tested in humans (20 mg/kg of body weight every 2 weeks, intravenous) was associated with severe migraine in several patients.

BEVAAS is contraindicated in: Patients with known hypersensitivity to any components of the product.
Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
Pregnancy.
Patients with untreated Central Nervous System (CNS) metastases.

General: In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Gastrointestinal perforations: Patients may be at increased risk for the development of gastrointestinal perforation and gallbladder perforation when treated with Bevacizumab. Bevacizumab should be permanently discontinued in patients who develop gastrointestinal perforation.
Patients treated for persistent, recurrent, or metastatic cervical cancer with Bevacizumab may be at increased risk of fistula between the vagina and any part of the GI tract (Gastrointestinal vaginal fistula).
Intra-abdominal inflammatory process may be at risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients.
Non-GI Fistula: Patients may be increased risk for the development of fistula when treated with Bevacizumab.
Permanently discontinue Bevacizumab in patients with tracheoesophangeal (TE) fistula or any Grade 4 fistula. Limited information is available on the continued use of Bevacizumab in patients with other fistula. In cases of internal fistula not arising in the GI tract, discontinuation of Bevacizumab should be considered.
Haemorrhage: Patients treated with Bevacizumab have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Bevacizumab should be permanently discontinued in patients who experience grade 3 or 4 bleeding during Bevacizumab therapy.
Patients with untreated CNS metastases were routinely excluded from clinical trials with Bevacizumab innovator, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patient has not been prospectively evaluated. Patients should be monitored for signs and symptoms of CNS bleeding, and Bevacizumab innovator treatment discontinued in cases of intracranial bleeding.
There is no information on the safety profile of Bevacizumab in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting Bevacizumab treatment. Therefore, caution should be exercised before initiating Bevacizumab therapy in these patients. However, patients who develop venous thrombosis while receiving Bevacizumab therapy did not appear to have an increased rate of Grade 3 or above bleeding when treated with full dose of Warfarin and Bevacizumab innovator concomitantly.
Severe Eye Infections Following Compounding for Unapproved Intravitreal Use: Individual cases and clusters of serious ocular adverse events have been reported (including infectious endophthalmitis and other ocular inflammatory conditions) following unapproved intravitreal use of Bevacizumab compounded from vials approved for intravenous administration in cancer patients. Some of these events have resulted in various degrees of visual loss, including permanent blindness.
Pulmonary hemorrhage/hemoptysis: Patients with non-small cell lung cancer treated with Bevacizumab may be at risk for serious, and in some cases fatal, pulmonary hemorrhage/hemoptysis. Patients with recent pulmonary hemorrhage/hemoptysis (> ½ teaspoon red blood) should not be treated with Bevacizumab.
Hypertension: An increased incidence of hypertension was observed in patients treated with Bevacizumab. Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately controlled before starting Bevacizumab treatment. There is no information on the effect of Bevacizumab in patients with uncontrolled hypertension at the time of initiating Bevacizumab therapy. Monitoring of blood pressure is recommended during Bevacizumab therapy.
In most cases, hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient. The use of diuretics to manage hypertension is not advised in patients who receive a Cisplatin-based chemotherapy regimen. Bevacizumab should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if, the patient develops hypertensive crisis or hypertensive encephalopathy.
Posterior Reversible Encephalopathy Syndrome (PRES): There have been rare reports of Bevacizumab-treated patients developing signs and symptoms that are consistent with Posterior Reversible Encephalopathy Syndrome (PRES), a rare neurological disorder, which can present with the following signs and symptoms among others: Seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably Magnetic Resonance Imaging (MRI). In patients developing PRES, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of Bevacizumab. The safety of reinitiating Bevacizumab therapy in patients previously experiencing PRES is not known.
Arterial thromboembolism: In clinical trials, the incidence of arterial thromboembolism events including cerebrovascular accidents, transient ischaemic attack (TIA) and myocardial infarction (MI) was higher in patients receiving Bevacizumab innovator in combination with chemotherapy compared to those who received chemotherapy alone.
Bevacizumab should be permanently discontinued in patients who develop arterial thromboembolic events.
Patients receiving Bevacizumab plus chemotherapy with a history of arterial thromboembolism, diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolic events during Bevacizumab therapy. Caution should be taken when treating such patients with Bevacizumab.
Venous thromboembolism: Patients may be at risk of developing venous thromboembolic events, including pulmonary embolism under Bevacizumab treatment.
Patients treated for persistent, recurrent, or metastatic cervical cancer with Bevacizumab may be at increased risk of venous thromboembolic events.
Bevacizumab should be discontinued in patients with life-threatening (grade 4) venous thromboembolic events, including pulmonary embolism. Patients with thromboembolic events ≤ grade 3 need to be closely monitored.
Congestive heart failure: Event consistent with congestive heart failure (CHF) were reported. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalization.
Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with Bevacizumab.
Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with Anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present.
In patients in AVF3694g who received treatment with Anthracyclines and who had not received Anthracyclines before, no increased incidence of all grade CHF was observed in the Anthracycline + Bevacizumab innovator group compared to the treatment with anthracyclines only. In both AVF3694g and AVF3693g, CHF grade 3 or higher events were somewhat more frequent among patients receiving Bevacizumab innovator in combination with chemotherapy than in patient receiving chemotherapy alone. This is consistent with result in patients in other studies of metastatic breast cancer who did not receive concurrent Anthracycline treatment.
Neutropenia: Increased rates of severe neutropenia, febrile neutropenia, or infection with severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus Bevacizumab in comparison to chemotherapy alone.
Wound healing: Bevacizumab may adversely affect the wound healing process. Serious wound healing complications with a fatal outcome have been reported.
Bevacizumab therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experience wound healing complications during Bevacizumab treatment, Bevacizumab should be withheld until the wound is fully healed. Bevacizumab therapy should be withheld for elective surgery.
Necrotising fasciitis including fatal cases, has rarely been reported in patients treated with Bevacizumab; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Bevacizumab therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.
Proteinuria: In clinical trials, the incidence of proteinuria was higher in patients receiving Bevacizumab innovator in combination with chemotherapy compared to those who received chemotherapy alone. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% patients treated with Bevacizumab innovator. In the event of nephrotic syndrome, Bevacizumab should be permanently discontinued.
Hypersensitivity reactions, infusion reactions: Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation of the patient during and following the administration of Bevacizumab is recommended as expected for any infusion of a therapeutic humanized monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.
Ovarian Failure/Fertility: Bevacizumab may impair female fertility. Therefore, fertility preservation strategies should be discussed with women of childbearing potential prior to starting treatment with Bevacizumab.
Drug Abuse and Dependence: No information available.
Ability to drive and use machines: No studies on the effects on the ability to drive and use machine have been performed. However, there is no evidence that Bevacizumab treatment results in an increase in adverse events that might lead to impairment of the ability to drive or operate machinery or impairment of mental ability.
Renal impairment: The safety and efficacy of Bevacizumab has not been studied in patients with renal impairment.
Hepatic impairment: The safety and efficacy of Bevacizumab has not been studied in patients with hepatic impairment.
Use in Children: Bevacizumab is not approved for use in patients under the age of 18 years. The safety and efficacy of Bevacizumab in this population has not been established.
In published reports, cases of osteonecrosis at sites other than the jaw have been observed in patients under the age of 18 years exposed to Bevacizumab.
Use in the Elderly: Refer to Arterial Thromboembolism as previously mentioned.

Pregnancy: Angiogenesis has been shown to be critically important to fetal development. The inhibition of angiogenesis following administration of Bevacizumab could result in an adverse outcome of pregnancy.
There are no adequate and well-controlled studies in pregnant women. IgGs are known to cross the placental barrier, and Bevacizumab may inhibit angiogenesis in fetus. 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.
Therefore, Bevacizumab should not be used during pregnancy. In women with childbearing potential, appropriate contraceptive measures should be used during Bevacizumab therapy. Based on pharmacokinetic considerations, contraceptive measures should be used for at least 6 months following the last dose of Bevacizumab.
Fertility: Repeat dose safety studies in animals have shown that Bevacizumab may have an adverse effect on female fertility. A substudy with 295 premenopausal women has shown a higher incidence of new cases of ovarian failure in the Bevacizumab innovator 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 information available.
Lactation: It is not known whether Bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and Bevacizumab could harm infant growth and development, women should be advised to discontinue nursing during Bevacizumab therapy and not to breast feed for at least 6 months following the last dose of Bevacizumab.

See Table 11 as follows.


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Clinical Trials: Clinical trials have been conducted in patients with various malignancies treated with Bevacizumab innovator, predominantly in combination with chemotherapy. The safety profile from a clinical trial population of approximately 5500 patients is presented as follows. For post marketing experience see Post Marketing as follows. See Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions for details of major studies, including study design 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 therapy are likely to be dose-dependent.
The most frequently observed adverse drug reactions across clinical trials in patients receiving Bevacizumab were hypertension, fatigue or asthenia, diarrhea and abdominal pain.
Table 12 lists adverse drug reactions associated with the use of Bevacizumab innovator 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 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. (See Table 12.)


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Further information on selected, serious adverse drug reactions: The following adverse drug reactions, reported using NCI-CTC for assessment of toxicity, have been observed in patients treated with Bevacizumab.
Gastrointestinal Perforation and Fistula: Bevacizumab has been associated with serious cases of gastrointestinal perforation. Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with metastatic breast cancer or non-squamous non-small cell lung cancer, up to 2% in patients with metastatic renal cell cancer, or ovarian cancer, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer.
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI perforations (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation.
The occurrence of those events varied in type and severity, ranging from free air seen on the plain abdominal X-ray, which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases underlying intra-abdominal inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis or chemotherapy-associated colitis. A causal association of intra-abdominal inflammatory process and gastrointestinal perforation to Bevacizumab has not been established.
Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all Bevacizumab innovator treated patients. In Bevacizumab innovator clinical trials, gastrointestinal fistula (all grade) have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with other types of cancer.
In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistula was 8.3% in Bevacizumab innovator-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI-vaginal fistula may also have bowel obstructions and require surgical intervention as well as diverting ostomies.
Non-GI Fistula: Bevacizumab use has been associated with serious cases of fistula including events resulting in death.
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG- 240), 1.8% of Bevacizumab innovator-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistula.
Uncommon (≥ 0.1% to < 1%) reports of other types of fistula that involve areas of the body other than the gastrointestinal tract (e.g., bronchopleural, urogenital and biliary fistula) were observed across various indications. Fistula have also been reported in post marketing experience.
Events were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of Bevacizumab, with most events occurring within the first 6 months of therapy.
Haemorrhage: In clinical trials across all indications the overall incidence of NCI-CTC Grade 3 - 5 bleeding events ranged from 0.4% to 0.5% in Bevacizumab innovator-treated patients, compared to 0 to 2.9% of patients in chemotherapy control group. The haemorrhagic events that have been observed in Bevacizumab innovator clinical studies were predominantly tumour-associated haemorrhage (see as follows) and minor mucocutaneous haemorrhage (e.g. epistaxis).
Tumour-associated haemorrhage was observed in phase I and phase II studies. In patients with non-small cell lung cancer receiving Bevacizumab innovator, serious haemorrhage was observed in 9% (6% fatal) of treated patients.
Major or massive pulmonary haemorrhage/hemoptysis has been observed primarily in studies in patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment with antirheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior radiotherapy, Bevacizumab therapy, previous medical history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. The only variables that showed statistically significant correlations with bleeding were Bevacizumab therapy and squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent studies, while patients with unknown tumour histology were included.
In patients with NSCLC excluding predominant squamous histology, all Grade events were seen with a frequency of up to 9.3% when treated with Bevacizumab innovator plus chemotherapy compared with 5% in the patients treated with chemotherapy alone. Grade 3-5 events have been observed in up to 2.3% of patients treated with Bevacizumab innovator plus chemotherapy as compared with < 1% with chemotherapy alone. Major or massive pulmonary haemorrhage/haemoptysis can occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome.
Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectal patients, and have been assessed as tumour-associated haemorrhages.
Tumour-associated haemorrhages were also seen rarely in other tumour types and locations and included cases of central nervous system (CNS) bleeding in patients with hepatoma with CNS metastases and continuous oozing of blood from a thigh sarcoma with necrosis.
The incidence of CNS bleeding in patients untreated CNS metastases receiving Bevacizumab has not been prospectively evaluated in randomized clinical studies. In an exploratory retrospective analysis of data from 13 completed randomized trials in patients with various tumour types, 3 patients out of 91 (3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated with Bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to Bevacizumab.
Across all Bevacizumab innovator clinical trials, mucocutaneous haemorrhage were seen in up to 50% patients treated with Bevacizumab innovator. These were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes the Bevacizumab treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (e.g. epitaxis) may be dose-dependent.
There have also been less common events of minor mucocutaneous haemorrhage in other locations, such as gingival bleeding and vaginal bleeding.
Hypertension: In clinical trials, the overall incidence of hypertension (all grades) of up to 42.1% in the Bevacizumab innovator containing arms compared with up to 14% in the control arms. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving Bevacizumab innovator ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with Bevacizumab innovator compared to up to 0.2% patients treated with the same chemotherapy alone.
Hypertension was generally adequately controlled with oral-hypertensives such as angiotensin converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation (0.7% of Bevacizumab innovator-treated patients or hospitalisation, and resulted in hypertensive encephalopathy in one case (0.1%).
Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal. The risk of Bevacizumab-associated hypertension did not correlate with the patients' baseline characteristics, underlying disease or concomitant therapy.
Posterior Reversible Encephalopathy Syndrome: Two confirmed cases (0.8%) of PRES have been reported in one clinical study. Symptoms usually resolve or improve within days, although some patients have experienced neurologic sequelae.
Thromboembolism: Arterial thromboembolism: An increased incidence of arterial thromboembolic events was observed in patients treated with Bevacizumab across indications including cerebrovascular accidents, myocardial infarction, transient ischemic attacks, and other arterial thromboembolic events.
In clinical trials, the overall incidence ranged up to 3.8% in the Bevacizumab innovator containing arms compared up to 1.7% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving Bevacizumab innovator in combination with chemotherapy compared to 0.5% of patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) were reported in up to 2.7% of Bevacizumab innovator treated patients versus up to 0.5% of patients in the control group; myocardial infarction was reported in up to 1.4% Bevacizumab innovator treated versus up to 0.7% of patients in control groups.
In one clinical trial, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with Irinotecan were included. In this trial arterial thromboembolic events were observed in 11% (11/100) of Bevacizumab innovator patients compared to 5.8% (6/104) in the chemotherapy control group.
Venous thromboembolism: In clinical trials of metastatic carcinoma of the colon or rectum, venous thromboembolic events including deep venous thrombosis, pulmonary embolism and thrombophlebitis occurred in 9.0% - 16.6% of Bevacizumab innovator-treated patients compared to that of 13.5% - 15.2% in the controls. It could not be determined if these events were due to the patients' underlying cancer, their cytotoxic chemotherapy, Bevacizumab or other risk factors. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 venous thromboembolic events have been reported in up to 10.6% of patients treated with chemotherapy and Bevacizumab innovator compared with up to 5.4% in patients with chemotherapy alone.
Congestive Heart Failure: In clinical trials with Bevacizumab innovator, congestive heart failure (CHF) was observed in all cancer indications studied to date, but occurred predominantly in patients with metastatic breast cancer.
In five phase III studies (AVF2119g, E2100, BO17708, AVF3694g and AVF3693g) in patients with metastatic breast cancer CHF Grade 3 or higher was reported in up to 3.5% of patients treated with Bevacizumab innovator in combination with chemotherapy compared with up to 0.9% in the control arms. For patients in study AVF3694g who received Anthracyclines concomitantly with Bevacizumab, the incidences of grade 3 or higher CHF for the respective Bevacizumab and control arms were similar to those in the other studies in metastatic breast cancer: 2.9% in the Anthracycline + Bevacizumab arm and 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all grade CHF were similar between the Anthracycline + Bevacizumab (6.2%) and the Anthracycline + placebo arms (6.0%).
Most patients who developed CHF during mBC trials showed improved symptoms and/or left ventricular function following appropriate medical therapy.
In most clinical trials of Bevacizumab innovator, patients with pre-existing CHF of NYHA II-IV were excluded, therefore, no information is available on the risk of CHF in this population.
Prior Anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors for the development of CHF.
An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B-cell lymphoma when receiving Bevacizumab innovator with a cumulative Doxorubicin dose greater than 300 mg/m². This phase III clinical trial compared Rituximab/Cyclophosphamide/Doxorubicin/Vincristine/Prednisone (R-CHOP) plus Bevacizumab to R-CHOP without Bevacizumab. While the incidence of CHF was, in both arms, above that previously observed for Doxorubicin therapy, the rate was higher in the R-CHOP plus Bevacizumab arm.
Wound Healing: As Bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days prior to starting Bevacizumab innovator treatment were excluded from participation in phase III trials.
Across mCRC clinical trials there was no increased risk of post-operative bleeding or wound healing complications observed in patients who underwent major surgery between 28-60 days prior to starting Bevacizumab innovator therapy. An increased incidence of post-operative bleeding or wound healing complications occurring within 60 days of major surgery was observed, if the patient was being treated with Bevacizumab at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).
Cases of serious wound healing complications have been reported during Bevacizumab use, some of which had a fatal outcome.
In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications were observed in up to 1.1% of patients receiving Bevacizumab innovator compared with up to 0.9% patients in the control arms.
Proteinuria: In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients receiving Bevacizumab innovator. Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome. Grade 3 proteinuria was reported in up to <3.1% of treated patients: however, in up 7% of patients treated for advanced and/or metastatic renal cell carcinoma. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients.
The proteinuria was not associated with renal impairment and rarely required permanent discontinuation of Bevacizumab therapy.
In clinical trials of metastatic carcinoma of the colon or rectum, proteinuria was reported as an adverse event in 21.7% - 38.0% of Bevacizumab innovator-treated patients.
Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Bevacizumab. There is evidence suggesting that Grade 1 proteinuria may be related to Bevacizumab dose. Testing for proteinuria is recommended prior to start of Bevacizumab therapy. In most clinical studies urine protein levels of ≥ 2 g/24 hours led to the holding of Bevacizumab until recovery to < 2 g/24 hours.
Hypersensitivity, Infusion Reactions: In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving Bevacizumab in combination with chemotherapies than with chemotherapy alone. The incidence of these reactions in some clinical trials of Bevacizumab innovator is common (up to 5% in Bevacizumab innovator-treated patients).
Ovarian Failure/Fertility: The incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated. New cases of ovarian failure were reported more frequently in patients receiving Bevacizumab. After discontinuation of Bevacizumab treatment, ovarian function recovered in a majority of women. Long term effects of the treatment with Bevacizumab on fertility are unknown.
Elderly Patients: In age > 65 years was associated with an increased risk of developing arterial thromboembolic events including cerebrovascular accidents, transient ischaemic attacks (TIAs) and myocardial infarctions compared to those aged ≤ 65 years when treated with Bevacizumab. Other reaction with a higher frequency seen in patients over 65 were Grade 3 - 4 leucopenia, and thrombocytopenia; and all Grade neutropenia, diarrhea, nausea, headache and fatigue.
From a clinical trial in patients with metastatic colorectal cancer (study AVF2107), no increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, hypertension, proteinuria, congestive heart failure and haemorrhage, was observed in elderly patients (> 65 years) receiving Bevacizumab innovator as compared to those aged ≤ 65 years treated with Bevacizumab innovator.
In the phase III study in metastatic carcinoma of colon or rectum trial (AVF2107g), 114 out of the 392 patients who received Bevacizumab innovator were older than 65 years. Only Grade 3/4 leukopenia occurred at an incidence of ≥ 5% in the elderly patients (> 65 years) compared to those patients aged ≤ 65 years.
In the phase II study in metastatic carcinoma of colon or rectum trial (AVF2192g), the majority of the Bevacizumab innovator-treated patients was older than 65 years (83%). The overall safety profile of Bevacizumab innovator from this study was comparable to the overall safety profile observed in Study AVF2107g.
Laboratory abnormalities: Decreased neutrophil counts, decreased white blood cell count and presence of urine protein may be associated with Bevacizumab treatment.
Across clinical trials, the following grade 3 and 4 (NCI - CTCAE v.3) laboratory abnormalities were seen with an increased (≥ 2%) incidence in patients treated with Bevacizumab compared to those in the control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased PT (prothrombin time), normalized ratio.
Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 times baseline level), both with and without proteinuria, are associated with the use of Bevacizumab.
The observed increase in serum creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated with Bevacizumab.
Post Marketing: (See Tables 13 and 14.)


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Effect of neoplastic agents on Bevacizumab pharmacokinetics: No clinically relevant pharmacokinetics interaction of co-administered chemotherapy on Bevacizumab pharmacokinetics has been observed based on the results of a population pharmacokinetic analysis. There was neither statistical significance nor clinically relevant differences in Bevacizumab clearance in patients receiving Bevacizumab monotherapy compared to patients receiving Bevacizumab in combination with Interferon alpha 2a or chemotherapies (IFL, 5-FU/LV, Carboplatin-Paclitaxel, Capecitabine, Doxorubicin or Gemcitabine).
Effect of Bevacizumab on the pharmacokinetics of other antineoplastic agents: No clinically relevant interaction of Bevacizumab was observed on the pharmacokinetics of 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.
Radiotherapy: The safety and efficacy of concomitant administration of radiotherapy and Bevacizumab have not been established.

Special instructions for use, handling and disposal: Bevacizumab infusions should not be administered or mixed with Dextrose or Glucose solutions.
Do not administer as an intravenous push or bolus.
Bevacizumab should be prepared by a healthcare professional using aseptic technique. Use sterile needle and syringe to prepare Bevacizumab. 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 mg/mL - 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 is not formulated for intravitreal use.
Chemical and physical infusion stability has been demonstrated for 48 hours at 2°C - 8°C and at room temperature 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 - 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Incompatibilities: No incompatibilities between Bevacizumab and polyvinyl chloride or polyolefine bags have been observed. A concentration-dependent degradation profile of Bevacizumab 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 via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.

Store in a refrigerator (2°C - 8°C). Do not freeze or shake.
Keep the vial in the outer carton in order to protect from light.

Targeted Cancer Therapy

L01FG01 - bevacizumab ; Belongs to the class of VEGF/VEGFR (Vascular Endothelial Growth Factor) inhibitors. Used in the treatment of cancer.

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