Patients receiving Avastin plus chemotherapy, with a history of arterial thromboembolism or age greater than 65 years have an increased risk of developing arterial thromboembolic events during therapy. Caution should be taken when treating these patients with Avastin.

Therapy should be permanently discontinued in patients who develop arterial thromboembolic events.

Venous thromboembolism (see section 4.8)

Patients may be at risk of developing venous thromboembolic events, including pulmonary embolism under Avastin treatment. Avastin should be discontinued in patients with life-threatening (Grade 4) pulmonary embolism, patients with Grade 3 need to be closely monitored.

Haemorrhage

Patients treated with Avastin have an increased risk of haemorrhage, especially tumour-associated haemorrhage. Avastin should be discontinued permanently in patients who experience Grade 3 or 4 bleeding during Avastin therapy (see section 4.8).

Patients with untreated CNS metastases were routinely excluded from clinical trials with Avastin, based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patients has not been prospectively eva luated in randomised clinical trials (see section 4.8). Patients should be monitored for signs and symptoms of CNS bleeding, and Avastin treatment discontinued in cases of intracranial bleeding.

There is no information on the safety profile of Avastin in patients with congenital bleeding diathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting Avastin treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised before initiating therapy in these patients. However, patients who developed venous thrombosis while receiving therapy did not appear to have an increased rate of grade 3 or above bleeding when treated with a full dose of warfarin and Avastin concomitantly.

Pulmonary haemorrhage/haemoptysis

Patients with non-small cell lung cancer treated with Avastin may be at risk of serious, and in some cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/ haemoptysis (> 2.5 ml of red blood) should not be treated with Avastin.

Congestive heart failure (CHF) (see section 4.8)

Events consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic declines in left ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalisation. Caution should be exercised when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with Avastin.

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 group compared to the treatment with anthracyclines only. CHF grade 3 or higher events were somewhat more frequent among patients receiving bevacizumab in combin