Events were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of Avastin, with most events occurring within the first 6 months of therapy.

Wound healing (see section 4.4)

As Avastin 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. 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 at the time of surgery. The incidence varied between 10% (4/40) and 20% (3/15).

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 compared with up to 0.9% of patients in the control arms.

Hypertension (see section 4.4)

An increased incidence of hypertension (all grades) of up to 34% has been observed in Avastin-treated patients in clinical trials compared with up to 14% in those treated with comparator. Grade 3 and 4 hypertension (requiring oral anti-hypertensive medicines) in patients receiving Avastin ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with Avastin and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone.

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 treatment or hospitalisation.

Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.

The risk of Avastin-associated hypertension did not correlate with the patients' baseline characteristics, underlying disease or concomitant therapy.

Proteinuria (see section 4.4)

In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients receiving Avastin.

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria. Grade 3 proteinuria was reported in < 3% of treated patients: however, in patients treated for advanced and/or metastatic renal cell carcinoma this was up to 7% in patients having minimal to no proteinuria at baseline. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. The proteinuria seen in clinical trials was not associated with renal dysfunction and rarely required permanent discontinuation of therapy. Testing for proteinuria is recommended prior to start of Avastin therapy. In most clinical trials urine protein levels of  2g/24 hrs led to the holding of Avastin until recovery to < 2g/24 hrs.

Haemorrhage (see section 4.4)

In clinical trials across all indications the overall incidence of NCI-CTC Grade 3-5 bleeding events ranged from 0.4% to 5% in Avastin treated patients, compared with up to 2.9% of patients in the chemo