ation with chemotherapy than in patients receiving chemotherapy alone. This is consistent with results in patients in other studies of metastatic breast cancer who did not receive concurrent anthracycline treatment (see section 4.8).
Neutropenia and infections (see section 4.8)
Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus Avastin in comparison to chemotherapy alone. This has mainly been seen in combination with platinum- or taxane-based therapies in the treatment of NSCLC and mBC.
Hypersensitivity reactions/infusion reactions (see section 4.8)
Patients may be at risk of developing infusion/hypersensitivity reaction. Close observation of the patient during and following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanized monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies should be administered. A systematic premedication is not warranted.
Osteonecrosis of the jaw (see section 4.8)
Cases of ONJ have been reported in cancer patients treated with Avastin, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates, for which ONJ is an identified risk. Caution should be exercised when Avastin and i.v. bisphosphonates are administered simultaneously or sequentially.
Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry should be considered prior to starting the treatment with Avastin. In patients who have previously received or are receiving i.v. bisphosphonates invasive dental procedures should be avoided, if possible.
Eye disorders
Adverse reactions have been reported from unapproved intravitreal use. 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 appeared as serious adverse reactions.
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 bev
