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The most common serious drug side effects are: Gastrointestinal Perforation (see Precautions); Hemorrhage, including pulmonary hemorrhage/hemoptysis which is more common in NSCLC patients (see Precautions); Arterial thromboembolism (see Precautions).
The analysis of clinical safety data showed that the incidence of hypertension and proteinuria associated with bevacizumab treatment was dose dependent.
The most common adverse drug reaction during clinical trials in patients receiving bevacizumab was hypertension, fatigue or weakness, diarrhea, and abdominal pain.
Summary Table of Adverse Drug Reactions in Clinical studies: Table 23 lists adverse reactions associated with the use of bevacizumab in combination with a variety of chemotherapy regimens in multiple indications. Classified by MedDRA system organ class, the frequency of each symptom is categorized as follows: Very Common (≥1/10); Common (≥1/100 - <1/100); Rare (≥1/10,000 - <1/10,000); Extremely Rare (<1/10,000). These symptoms were at least 2% different from those of the control group (NCI-CTC (Common Toxicity Criteria) adverse events level 3-5) or at least 10% different from those of the control group (NCI-CTC adverse events level 1-5). This occurred in at least one pivotal trial, were we added adverse drug reactions to the most appropriate category according to the highest incidence in the key clinical studies. In each study group, the frequency of adverse drug reactions was shown in descending order of severity. Some resulting side effects are common effects of chemotherapy. However, when combine bevacizumab and chemotherapy, some side effects may be worsened, such as palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral neuropathy with paclitaxel or oxaliplatin, nails disorders or alopecia with paclitaxel, and pericarditis with erlotinib. (See Table 23.)
Click on icon to see table/diagram/imageDescription of selected adverse drug reactions from clinical trials: The following adverse drug reactions have been reported using the NCI-CTC to assess toxicity observed in patients administered bevacizumab: Gastrointestinal perforation and fistulae (see Precautions): Severe gastrointestinal perforations have been reported in association with bevacizumab. In clinical trials, the incidence of gastrointestinal perforation was less than 1% among patients with metastatic breast cancer or non-squamous non-small cell lung cancer. While patients with metastatic renal cancer, brain tumor (Glioblastoma), newly diagnosed cancer or ovarian cancer had their incidence up to 2%. On the other hand, patients with metastatic colorectal cancer the incidence observed was up to 2.7% (including gastrointestinal fistulae and abscess). Gastrointestinal perforation has also been reported in patients with relapsed glioblastoma.
In a clinical study in patients with persistent, recurrent, or metastatic cervical cancer (Study GOG-0240), GI perforations were reported. The average severity (all levels of severity) was 3.2% among patients with a history of pelvic radiation therapy.
The occurrence of those events varies in type and severity, 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 intraabdominal inflammation was present, either from gastric ulcer disease, tumor necrosis, diverticulitis, or chemotherapy-associated colitis. A casual 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 perforation, which represents between 0.2%-1% of all patients treated with bevacizumab.
In clinical trials of bevacizumab, the gastrointestinal fistulae (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.
The incidence of the GI-vagina fistulae was found in patients with persistent, recurrent, or metastatic cervical cancer, 8.3% in bevacizumab-treated patients and 0.9% in controls. These patients had a history of prior pelvic radiation. Patients who develop GI-vaginal fistulae may also have bowel obstruction and require surgical intervention as well as diverting ostomies.
Non-GI Fistulae (see Precautions): Bevacizumab use has been associated with serious cases of fistulae including events resulting in death.
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-0240) 1.8% of bevacizumab treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae.
Uncommon (≥0.1% to <1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract (e.g. bronchopleural, biliary fistulae) were observed across various indications. Fistulae have also been reported in post marketing experience.
Events were reported at various time point 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 treatment.
Hemorrhage: In clinical trials across all indications, the overall incidence of NCI-CTC Grade 3-5 bleeding events ranged from 0.4% to 6.9% in Bevacizumab treated-patients, compared with 0 to 4.5% in control patients receiving chemotherapy. The hemorrhage events that have been observed in clinical studies were predominantly tumor-associated hemorrhage (see as follows) and minor mucocutaneous hemorrhage (e.g. epistaxis).
Tumor-associated Hemorrhage: Major or massive pulmonary hemorrhage/hemoptysis has been observed primarily in studies in patient with non-small cell lung cancer (NSCLC). Possible risk factors included squamous cell lung cancer histology, treatment with anti-rheumatic/anti-inflammatory drug, treatment with anticoagulant, prior radiotherapy, Bevacizumab therapy, previous medical history of atherosclerosis central tumor location and cavitation of formation before or during treatment. The only variable that showed statistically significant correlations with bleeding were bevacizumab treatment and squamous cell histology. Patients with NSCLC of known squamous cell histology or mixed cell types with predominant squamous cell histology were excluded from subsequent studies, while patients with unknown tumor 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 plus chemotherapy compared with up to 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 in combination with chemotherapy as compared with less than 1% with chemotherapy alone. Major or massive pulmonary hemorrhage/hemoptysis can occur suddenly, and up to two-thirds of serious pulmonary hemorrhages resulted in a fatal outcome (see Precautions).
There have been reports of gastrointestinal hemorrhage, rectal hemorrhage, and melaena in patients with colorectal patients, and have been assessed as tumor-associated hemorrhages.
Tumor-associated hemorrhages were also seen rarely in other tumor types and locations and included cases of central nervous system (CNS) bleeding in patients with CNS metastases and in patients with glioblastoma.
The incidence of CNS bleeding in patients with 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 types of tumors, 3 out of 91 (3.3%) patients with brain metastases experienced CNS bleeding (all Grade) when treated with bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In two subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 CNS hemorrhage was reported.
Intracranial hemorrhage can occur in patients with relapsed glioblastoma. In AVF3708g trial, CNS hemorrhages was reported in 2.4% (2/84) of patients in the bevacizumab alone arm (Grade 1); and in 3.8% (3/79) of patients treated with bevacizumab and Irinotecan (Grade 1, 2 and 4).
Across all bevacizumab clinical trials, mucocutaneous hemorrhages were seen in up to 50% of patients treated with bevacizumab. These were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any change in the bevacizumab treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous hemorrhages (e.g., epistaxis) may be dose-dependent.
There have also been less common events of minor mucocutaneous hemorrhages in other locations, such as gingival bleeding or vaginal bleeding.
Hypertension (see Precautions): In clinical trials, with the exception of JO25567 study, the overall increased incidence of hypertension (all grades) ranged up to 42.1% in the bevacizumab-treated group compared with up to 14% in the control group. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (Hypertensive crisis) occurred in up to 1.0% of patients treated with bevacizumab compared to up to 0.2% patients treated with the same chemotherapy alone.
In JO25567 study, all grade hypertension was observed in 77.3% of patients who received bevacizumab in combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFT activating mutation, compared of 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60% in patients treated with bevacizumab and erlotinib compared to 11.7% in patients treated with erlotinib alone.
There were no grade 4 or 5 hypertension events.
Hypertension was generally adequately controlled with oral antihypertensive such as angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of bevacizumab treatment or hospitalization.
Very rare cases of hypertensive encephalopathy have been reported, some of which were (see Precautions). The risk of bevacizumab-associated hypertension did not correlate with the patients' baseline characteristics, underlying disease, or concomitant treatment.
Posterior Reversible Encephalopathy Syndrome (see Precautions): Two confirmed cases (0.8%) of PRES have been reported in one clinical trial. Symptoms usually resolve or improve within days, although some patients have experienced neurological 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 5.9% in the group treated with bevacizumab compared with up to 1.7% in the group treated with chemotherapy alone. Fatal outcome was reported in 0.8% of patients receiving bevacizumab plus chemotherapy compared to 0.5% of patients receiving the chemotherapy alone. Cerebrovascular accidents (including transient ischemic attacks) were reported in up to 2.7% of patient receiving bevacizumab versus up to 0.5% of patients in the control group; myocardial infarction was reported in up to 1.4% of bevacizumab treated versus up to 0.7% of patients in control group.
In one clinical trial, AVF2192, patients with metastatic colorectal cancer who were not candidates for irinotecan treatments were included. In this trial arterial thromboembolic events were observed in 11% (11/100) of bevacizumab patients compared to 5.8% (6/104) in the chemotherapy control group. In an uncontrolled clinical trial, AVF3708, in patients with relapsed glioblastoma, arterial thromboembolic events were observed in 6.3% (5/79) of patients receiving bevacizumab with irinotecan compared to up to 48% (4/84) of patients receiving bevacizumab alone.
Venous thromboembolism (see Precautions): In clinical trials across indications, the overall incidence of venous thromboembolic events ranged from 2.8% to 17.3% in the bevacizumab group alone, compared to 3.2% to 15.6% of the chemotherapy control group. Venous thromboembolic events include deep venous thrombosis and pulmonary embolism.
Grade 3-5 venous thromboembolic events have been reported in up to 7.8% of patients treated with chemotherapy in combination with bevacizumab compared with up to 4.9% in patients with chemotherapy alone. Patients who have experienced a venous thromboembolic event may be at higher risk for a recurrence if they treated with bevacizumab in combination with chemotherapy versus chemotherapy alone.
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-0240), grade 3-5 venous thromboembolic events have been reported in up to 10.6% of patients treated with bevacizumab in combination with chemotherapy compared with up to 5.4% in patients with chemotherapy alone.
The clinical trial, BO21990, Grade 3-5 venous thromboembolic events were observed in 7.6% of patients with newly diagnosed glioblastoma treated with bevacizumab in combination with chemotherapy and radiotherapy, compared to 8.0% of patients treated with chemotherapy and radiotherapy alone.
Congestive Heart failure: In clinical trials with bevacizumab, 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 in combination with chemotherapy compared with up to 0.9% in the control group. 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 anthracyclines + bevacizumab arm and 0% in the anthracyclines + placebo arm. Additionally, in study AVF3694g, the incidences of all grade CHF were similar between the anthracyclines + bevacizumab (6.2%) and the anthracyclines + placebo (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, 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 (see Precautions).
An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B-cell lymphoma when receiving bevacizumab with a cumulative doxorubicin dose greater than 300 mg/m2. This Phase III clinical trial compared rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (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 (see Precautions): As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days prior to the initiation of Bevacizumab 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 underwent major surgery between 28 - 60 days prior to starting bevacizumab 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) to 20% (3/15).
Cases of serious wound healing complications have been reported during the use of bevacizumab, some of which had a fatal outcome (see Precautions).
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, compared to 0.9% of patients in the control group.
In a study of patients with relapsed glioblastoma (AVF3708g study) the incidence of post-operative wound healing complications (including craniotomy site wound dehiscence and cerebrospinal fluid leak) was 3.6% in patients receiving bevacizumab alone, and 1.3% in patients receiving bevacizumab in combination with irinotecan.
In patients with newly diagnosed glioblastoma (BO21990 study), the incidence of Grade 3-5 post-operative wound healing complications (including complications following craniotomy) was 3.3% when treated with bevacizumab combined with chemotherapy and radiotherapy, compared with 1.6% when treated with chemotherapy and radiotherapy alone.
Proteinuria (see Precautions): Reports of proteinuria in clinical studies ranged from 0.7% - 54.7% of patients treated with bevacizumab. Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome. Grade 3 proteinuria was reported in up to 8.1% of treated patients, Grade 4 proteinuria (nephrotic syndrome) was seen in up 1.4% of 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 before starting of Bevacizumab treatment. In most clinical studies, urine protein level of ≥ 2g/24hrs led to the holding of bevacizumab until recovery to < 2g/24hrs.
Hypersensitivity, infusion reactions (see Precautions and Post marketing experience under Adverse Reactions): In some clinical trials, anaphylactic and anaphylactoid-type reactions were reported more frequently in patients who received bevacizumab in combination with chemotherapies than those who received chemotherapy alone. The incidence of these reactions in some clinical trials of bevacizumab is common (up to 5% in patients treated with Bevacizumab).
Ovarian Failure/Fertility (see Precautions and Female and Male of Reproductive Potential under Use in Pregnancy & Lactation): The incidence of new cases of ovarian failure, defined as amenorrhea lasting 3 or more months, FSH levels ≥ 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 treatment with bevacizumab, ovarian function recovered in a majority of women. Long-term effects of the treatment with Bevacizumab on fertility are unknown.
Infections (see Precautions): In clinical trial BO21990, a randomized, double-blind, placebo controlled, multicenter phase III study of bevacizumab in combination with chemotherapy and radiotherapy for the treatment of patients with newly diagnosed glioblastoma, the incidence of all Grade 3 - 5 infections was 54.4% and 12.8% in patients receiving Bevacizumab in combination with chemotherapy and radiotherapy arm versus 39.1% and 7.8%, respectively, in patients receiving chemotherapy and radiotherapy only arm.
Elderly Patients: In randomized clinical studies, age > 65 years was associated with an increased risk of developing arterial thromboembolic events, including cerebrovascular accidents, transient ischemic attacks and myocardial infarction as compared to patients aged ≤ 65 years when treated with Bevacizumab (see Precautions and Clinical Studies: Thromboembolism as previously mentioned). Other adverse reactions with higher frequency seen in patients over 65 years were Grade 3-4 leucopenia, thrombocytopenia; and all Grade neutropenia, diarrhea, nausea, headache, and fatigue.
From a clinical trials of patients with metastatic colorectal cancer (AVF2107 study), no increase in the incidences of other reactions, including gastrointestinal perforation, wound healing complications, congestive heart failure and hemorrhage, was observed in elderly patients (> 65 years) receiving bevacizumab compared to patients aged ≤ 65 years treated with bevacizumab.
Laboratory Abnormalities: Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with bevacizumab treatment.
Across clinical trials, the following Grade 3-4 laboratory abnormalities were seen with an increased (≥ 2%) incidence in patients treated with Bevacizumab compared to those in the control group: hyperglycemia, decreased hemoglobin, hypokalemia, hyponatremia, decreased white blood cell count, increased PT (prothrombin time), normalized ratios.
Clinical studies 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 increased in serum creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated with bevacizumab.
Post marketing experience: The following adverse drug reactions have been identified from post marketing experience with bevacizumab (Table 24). Based on spontaneous case reports and literature cases. Adverse drug reactions are listed according to system organ classes in MedDRA and the corresponding frequency category estimation for each adverse drug reaction is based on the following convention: Very Common (≥1/10); Common (≥1/100 to < 1/10); Uncommon (≥1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare (< 1/10,000). (See Table 24.)
Click on icon to see table/diagram/imageDescription of selected adverse drug reactions from post marketing experience: Eye disorders (Reported from unapproved intravitreal use): Infectious endophthalmitis4 (frequency is unknown; some cases leading to permanent blindness; one case reported extraocular extension of infection resulting in meningoencephalitis) Intraocular inflammation (some cases leading to permanent blindness; including a cluster of serious eye inflammation leading to blindness after compounding an anticancer chemotherapy product for intravenous administration) such as sterile endophthalmitis, Uveitis, Vitritis; Retinal detachment (frequency is unknown); Retinal Pigment Epithelial Tear (frequency is unknown); Intraocular pressure increased (frequency is unknown); Intraocular hemorrhage such as vitreous hemorrhage or retinal hemorrhage (frequency is unknown); Conjunctival hemorrhage (frequency is unknown).
An observational claims database study comparing unapproved intravitreal bevacizumab to an approved treatment1, which does not correspond to the approval indications, but in comparison with the approved treatments in patients with wet macular degeneration, it was possible to see that the risk of developing ophthalmic inflammation was increased in patients receiving Bevacizumab (adjusted HR: 1.82: 99% CI: 1.20, 2.76) (incidence of 0.46 events per 100 patients per year) as well as increasing the risk of cataract surgery (adjusted HR: 1.11: 99% CI: 1.01, 1.23) (incidence of 6.33 incidents per 100 patients per year; compared to an incidence of 5.64 per 100 patients per year).
Following variable and non-validated methods in compounding, storage, and handling of Bevacizumab5, serious ocular adverse events (including infectious endophthalmitis and other ocular inflammatory conditions) affecting multiple patients have been reported.
Systemic events (Reported from unapproved intravitreal use): An observational claims database study comparing unapproved intravitreal1 Bevacizumab to an approved treatment in patients treated for wet age-related macular degeneration has reported an increased risk of hemorrhagic stroke for Bevacizumab (adjusted HR 1.57; 99% CI 1.04, 2.37) (incidence 0.41 events per 100 patients per year; comparator 0.26 events per 100 patients per year), as well as increased risk for overall mortality (adjusted HR 1.11; 99% Cl; 1.01, 1.23) (Incidence 6.03 events per 100 patients per year; comparator 5.51 events per 100 patients per year).
A second observational study found similar results for all cause mortality. A randomized, controlled clinical trial comparing unapproved bevacizumab to an approved treatment for patients with wet age-related macular degeneration has reported an increased risk of serious systemic adverse events for bevacizumab, most of which resulted in hospitalization (adjusted risk ratio 1.29; 95% Cl 1.01, 1.66) (Incidence 24.1%; comparator 19.0%).
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