Clinical Trials: Summary of the safety profile: The overall safety profile of Avastin Roche is based on data from over 5,200 patients with various malignancies, predominantly treated with Avastin Roche in combination with chemotherapy in clinical trials.
The most serious adverse reactions were: Gastrointestinal perforations (see Precautions, General).
Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients (see Precautions, General).
Arterial thromboembolism (see Precautions, General).
The most frequently observed adverse reactions across clinical trials in patients receiving Avastin Roche were hypertension, fatigue or asthenia, diarrhoea and abdominal pain.
Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with Avastin Roche therapy are likely to be dose-dependent.
Tabulated list of adverse reactions: The adverse reactions listed in this section fall into the following frequency categories: 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); not known (cannot be estimated from the available data).
Tables 23 and 24 list adverse reactions associated with the use of Avastin Roche in combination with different chemotherapy regimens in multiple indications.
Table 23 provides all adverse reactions by frequency that were determined to have a causal relationship with Avastin Roche through: comparative incidences noted between clinical trial treatment arms (with at least a 10% difference compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a 2% difference compared to the control arm for NCI-CTCAE Grade 3-5 reactions, post-authorisation safety studies, spontaneous reporting, epidemiological studies\non-interventional or observational studies, or through an evaluation of individual case reports.
Table 24 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Table 24 also includes adverse reactions which are considered by the MAH to be clinically significant or severe.
Post-marketing adverse reactions are included in both Tables 23 and 24, where applicable. Detailed information about these post-marketing reactions are provided in Table 25.
Adverse reactions are added to the appropriate frequency category in the tables as follows according to the highest incidence seen in any indication.
Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.
Some of the adverse reactions are reactions commonly seen with chemotherapy; however, Avastin Roche 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, and nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.
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Description of selected serious adverse reactions: Gastrointestinal (GI) Perforations and Fistulae (see Precautions, General): Avastin Roche 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 non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer receiving front-line treatment, 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.
Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all Avastin Roche treated patients.
In Avastin Roche clinical trials, 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.
GI-Vaginal Fistulae in Study GOG-0240: In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was 8.3% in Avastin Roche-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with Avastin Roche + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with recurrence outside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.
Non-GI Fistulae (see Precautions, General): Avastin Roche use has been associated with serious cases of fistulae including reactions resulting in death.
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-240), 1.8% of Avastin Roche-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 and biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience.
Reactions were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of Avastin Roche, with most reactions occurring within the first 6 months of therapy.
Wound Healing (see Precautions, General): As Avastin Roche may adversely impact wound healing, patients who had major surgery within the last 28 days were excluded from participation in phase III clinical trials.
In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of post-operative bleeding or wound healing complications observed in patients who underwent major surgery 28-60 days prior to starting Avastin Roche. An increased incidence of post-operative bleeding or wound healing complication occurring within 60 days of major surgery was observed if the patient was being treated with Avastin Roche at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).
Serious wound healing complications, including anastomotic complications, have been reported, 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 Avastin Roche compared with up to 0.9% of patients in the control arms (NCI-CTCAE v.3).
In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to 1.2% of patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3).
In the study of patients with relapsed glioblastoma (study AVF3708g), the incidence of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) was 3.6% in patients treated with single-agent Avastin Roche and 1.3% in patients treated with Avastin Roche plus irinotecan.
Hypertension (see Precautions, General): In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all Grades) ranged up to 42.1% in the Avastin Roche arms compared with up to 14% in the control arms . The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receiving Avastin Roche ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with Avastin Roche and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone.
In study JO25567, all grade hypertension was observed in 77.3% of the patients who received Avastin in combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activating mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60.0% in patients treated with Avastin in combination with 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 anti-hypertensives such as angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of Avastin Roche treatment or hospitalisation.
Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.
The risk of Avastin Roche-associated hypertension did not correlate with the patients' baseline characteristics, underlying disease or concomitant therapy.
Posterior Reversible Encephalopathy Syndrome (see Precautions, General): There have been rare reports of Avastin Roche-treated patients developing signs and symptoms that are consistent with PRES, a rare neurological disorder. Presentation may include seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. The clinical presentation of PRES is often nonspecific, and therefore the diagnosis of PRES requires confirmation by brain imaging, preferably MRI.
In patients developing PRES, early recognition of symptoms with prompt treatment of specific symptoms including control of hypertension (if associated with severe uncontrolled hypertension) is recommended in addition to discontinuation of bevacizumab therapy.
Symptoms usually resolve or improve within days after treatment discontinuation, although some patients have experienced some neurologic sequelae. The safety of reinitiating Avastin Roche therapy in patients previously experiencing PRES is not known.
Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not have radiological confirmation via MRI.
Proteinuria (see Precautions, General): In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patients receiving Avastin Roche.
Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 8.1% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Avastin Roche therapy. In most clinical trials urine protein levels of ≥2g/24 hrs led to the holding of Avastin Roche until recovery to <2g/24 hrs.
Haemorrhage (see Precautions, General): In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleeding reactions ranged from 0.4% to 6.9% in Avastin Roche treated patients, compared with up to 4.5% of patients in the chemotherapy control group.
From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 bleeding reactions have been reported in up to 8.3% of patients treated with Avastin Roche in combination with paclitaxel and topotecan compared with up to 4.6% of patients treated with paclitaxel and topotecan.
The haemorrhagic reactions that have been observed in clinical trials were predominantly tumour-associated haemorrhage (see as follows) and minor mucocutaneous haemorrhage (e.g. epistaxis).
Tumour-associated Haemorrhage (see Precautions, General): Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in patients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants, prior radiotherapy, Avastin Roche 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 Avastin Roche 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 phase III trials, while patients with unknown tumour histology were included.
In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seen with a frequency of up to 9% when treated with Avastin Roche plus chemotherapy compared with up to 5% in the patients treated with chemotherapy alone. Grade 3-5 reactions have been observed in up to 2.3% of patients treated with Avastin Roche plus chemotherapy as compared with <1% with chemotherapy alone (NCI-CTCAE v.3). 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 cancer patients, and have been assessed as tumour-associated haemorrhages.
Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including cases of central nervous system (CNS) bleeding in patients with CNS metastases (see Precautions, General).
The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not been prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysis of data from 13 completed randomised 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. In two subsequent studies in patients with treated brain metastases (which included around 800 patients), one case of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at the time of interim safety analysis (NCI-CTCAE v.3).
Intracranial haemorrhage can occur in patients with relapsed glioblastoma. In study AVF3708g, CNS haemorrhage was reported in 2.4% (2/84) of patients in the Avastin Roche alone arm (Grade 1); and in 3.8% (3/79) of patients treated with Avastin Roche and irinotecan (Grades 1, 2 and 4).
Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of Avastin Roche-treated patients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes in the Avastin Roche treatment regimen. Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent.
There have also been less common reactions of minor mucocutaneous haemorrhage in other locations, such as gingival bleeding or vaginal bleeding.
Thromboembolism (see Precautions, General): Arterial Thromboembolism: An increased incidence of arterial thromboembolic reactions was observed in patients treated with Avastin Roche across indications, including cerebrovascular accidents, myocardial infarction, transient ischaemic attacks, and other arterial thromboembolic reactions.
In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the Avastin Roche containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving Avastin Roche compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reported in up to 2.7% of patients treated with Avastin Roche in combination with chemotherapy compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% of patients treated with Avastin Roche in combination with chemotherapy compared to up to 0.7% of patients treated with chemotherapy alone.
In one clinical trial evaluating Avastin Roche in combination with 5-fluorouracil/folinic acid, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan were included. In this trial arterial thromboembolic reactions were observed in 11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group.
Venous Thromboembolism: The incidence of venous thromboembolic reactions in clinical trials was similar in patients receiving Avastin Roche in combination with chemotherapy compared to those receiving the control chemotherapy alone. Venous thromboembolic reactions include deep venous thrombosis, pulmonary embolism and thrombophlebitis.
In clinical trials across indications, the overall incidence of venous thromboembolic reactions ranged from 2.8% to 17.3% of Avastin Roche-treated patients compared with 3.2% to 15.6% in the control arms.
Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervical cancer).
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 15.6% of patients treated with Avastin Roche in combination with paclitaxel and cisplatin compared with up to 7.0% of patients treated with paclitaxel and cisplatin.
Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if they receive Avastin Roche in combination with chemotherapy versus chemotherapy alone.
Congestive Heart Failure (CHF): In clinical trials with Avastin Roche, congestive heart failure (CHF) was observed in all cancer indications studied to date, but occurred predominantly in patients with metastatic breast cancer. In four phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breast cancer CHF Grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated with Avastin Roche 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 + Avastin Roche (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 Avastin Roche, patients with pre-existing CHF of NYHA (New York Heart Association) 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 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. These results suggest that close clinical observation with appropriate cardiac assessments should be considered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m2 when combined with bevacizumab.
Hypersensitivity Reactions/Infusion Reactions (see Precautions, General and Post Marketing Experience as follows): In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving Avastin Roche in combination with chemotherapy than with chemotherapy alone. The incidence of these reactions in some clinical trials of Avastin Roche is common (up to 5% in bevacizumab-treated patients).
Infections: From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 infections have been reported in up to 24% of patients treated with Avastin Roche in combination with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxel and topotecan.
Ovarian Failure/Fertility (see Precautions, General and Fertility under Use in Pregnancy & Lactation): In NSABP C-08, a phase III trial of Avastin Roche in adjuvant treatment of patients with colon cancer, 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 in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown.
Laboratory Abnormalities: Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with Avastin Roche treatment.
Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated with Avastin Roche with at least a 2% difference compared to the corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR).
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 Avastin Roche. The observed increase in serum creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated with Avastin Roche.
Other special populations: Elderly Patients: In randomised clinical trials, age >65 years was associated with an increased risk of developing arterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were Grade 3-4 leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all Grade neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged ≤65 years when treated with Avastin Roche (see Precautions, General and Thromboembolism). In one clinical trial, the incidence of hypertension of grade ≥3 was two fold higher in patients aged >65 years than in the younger age group (<65 years). In a study of platinum-resistant recurrent ovarian cancer patients, alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension were also reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treated patients ≥65 years of age compared with bevacizumab-treated patients aged <65 years.
No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, congestive heart failure, and haemorrhage was observed in elderly patients (>65 years) receiving Avastin Roche as compared to those aged ≤65 years treated with Avastin Roche.
Paediatric Population: The safety of Avastin Roche in children and adolescents has not been established. Avastin Roche is not approved for use in patients under the age of 18 years. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years treated with Avastin Roche.
Post-Marketing Experience: See Table 25.
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