Posterior Reversible Encephalopathy Syndrome (PRES), (rare) (see also section 4.4)
 
Vascular disorders
 Renal thrombotic microangiopathy, which may be clinically manifested as proteinuria (not known) with or without concomitant sunitinib use. For further information on proteinuria see section 4.4 and Proteinuria in section 4.8.
 
Respiratory, thoracic and mediastinal disorders
 Nasal septum perforation (not known)

Pulmonary hypertension (not known)

Dysphonia (common)
 
Gastrointestinal disorders
 Gastrointestinal ulcer (not known)
 
Hepatobiliary disorders
 Gall bladder perforation (not known)
 
Musculoskeletal and connective tissue disorders
 Cases of Osteonecrosis of the Jaw (ONJ) have been reported in patients treated with Avastin, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4)
 
Cases of non-mandibular osteonecrosis have been observed in Avastin treated paediatric patients (see section 4.8, Paediatric population).
 
Congenital, familial, and genetic disorder
 Cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.6 )
 

* if specified, the frequency has been derived from clinical trial data

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail:medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose
The highest dose tested in humans (20 mg/kg of body weight, intravenous every 2 weeks) was associated with severe migraine in several patients.

5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents, other antineoplastic agents, monoclonal antibodies, ATC code: L01X C07

Mechanism of action

Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth.

Pharmacodynamic effects

Administration of bevacizum