Fistulae (see section 4.8)

Patients may be at increased risk for the development of fistulae when treated with Avastin.

Permanently discontinue Avastin in patients with TE (tracheoesophageal) fistula or any grade 4 fistula.

Limited information is available on the continued use of Avastin in patients with other fistulae.

In cases of internal fistula not arising in the GI tract, discontinuation of Avastin should be considered.

Wound healing complications (see section 4.8)

Avastin may adversely affect the wound healing process. Therapy should not be initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing complications during therapy, treatment should be withheld until the wound is fully healed. Therapy should be withheld for elective surgery.

Hypertension (see section 4.8)

An increased incidence of hypertension was observed in Avastin-treated patients. Clinical safety data suggest that the incidence of hypertension is likely to be dose-dependent. Pre existing hypertension should be adequately controlled before starting Avastin treatment. There is no information on the effect of Avastin in patients with uncontrolled hypertension at the time of initiating therapy. Monitoring of blood pressure is generally recommended during therapy.

In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the individual situation of the affected patient. The use of diuretics to manage hypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Avastin should be permanently discontinued if medically significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensive encephalopathy.

Reversible posterior leukoencephalopathy syndrome (RPLS) (see section 4.8)

There have been rare reports of Avastin-treated patients developing signs and symptoms that are consistent with Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of RPLS requires confirmation by brain imaging. In patients developing RPLS, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of Avastin. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known.

Proteinuria (see section 4.8)

Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Avastin. There is evidence suggesting that all Grade [US National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 3.0] proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Therapy should be permanently discontinued in patients who develop Grade 4 proteinuria (nephrotic syndrome).

Arterial thromboembolism (see section 4.8)

In clinical trials, the incidence of arterial thromboembolic events including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was highe