Bevaas Adverse Reactions

See Table 11 as follows.


Click on icon to see table/diagram/image


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.)


Click on icon to see table/diagram/image


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.)


Click on icon to see table/diagram/image




Click on icon to see table/diagram/image