Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if they receive Avastin in combination with chemotherapy versus chemotherapy alone.

Congestive heart failure (CHF)

In clinical trials with Avastin, 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 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 (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, 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 section 4.4 and Post-marketing experience below)

In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients receiving Avastin in combination with chemotherapy than with chemotherapy alone. The incidence of these reactions in some clinical trials of Avastin 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 in combination with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxel and topotecan.

Ovarian failure/fertility (see sections 4.4 and 4.6)

In NSABP C-08, a phase III trial of Avastin in adjuvant treatment of patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or