Intravitreal use

Avastin is not formulated for intravitreal use.

Eye disorders

Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal use of Avastin compounded from vials approved for intravenous administration in cancer patients. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in various degrees of visual loss, including permanent blindness.

Systemic effects following intravitreal use

A reduction of circulating VEGF concentration has been demonstrated following intravitreal anti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors.

Ovarian failure/fertility

Avastin may impair female fertility (see sections 4.6 and 4.8). Therefore fertility preservation strategies should be discussed with women of child-bearing potential prior to starting treatment with Avastin.

4.5 Interaction with other medicinal products and other forms of interaction
Effect of antineoplastic agents on bevacizumab pharmacokinetics

No clinically relevant pharmacokinetic interaction of co-administered chemotherapy on Avastin pharmacokinetics has been observed based on the results of a population PK analysis. There was neither statistical significance nor clinically relevant difference in clearance of Avastin in patients receiving Avastin monotherapy compared to patients receiving Avastin in combination with interferon alfa-2a or other chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine).

Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents

Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN38.

Results from one trial in metastatic colorectal cancer patients demonstrated no significant effect of bevacizumab on the pharmacokinetics of capecitabine and its metabolites, and on the pharmacokinetics of oxaliplatin, as determined by measurement of free and total platinum.

Results from one trial in renal cancer patients demonstrated no significant effect of bevacizumab on the pharmacokinetics of interferon alfa-2a.

The potential effect of bevacizumab on the pharmacokinetics of cisplatin and gemcitabine was investigated in non-squamous NSCLC patients. Trial results demonstrated no significant effect of bevacizumab on the pharmacokinetics of cisplatin. Due to high inter-patient variability and limited sampling, the results from that trial do not allow firm conclusions to be drawn on the impact of bevacizumab on gemcitabine pharmacokinetics.

Combination of bevacizumab and sunitinib malate

In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/k