Post-marketing experience

Table 2 Adverse reactions reported in post-marketing setting

System organ class (SOC)
 Reactions (frequency*)
 
Nervous system disorders
 Hypertensive encephalopathy (very rare) (see also section 4.4 and Hypertension in section 4.8)

Reversible posterior leukoencephalopathy syndrome (rare) (see also section 4.4)
 
Vascular disorders
 Renal thrombotic microangiopathy, clinically manifested as proteinuria (not known). 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)
 
Immune system disorders
 Hypersensitivity reactions and infusion reactions (not known); with the following possible co-manifestations: dyspnoea/difficulty breathing, flushing/redness/rash, hypotension or hypertension, oxygen desaturation, chest pain, rigors and nausea/vomiting (see also section 4.4 and Hypersensitivity reactions/infusion reactions above)
 
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 i.v. bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4)

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

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: monoclonal antibody, 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 bevacizumab or its parental murine antibody to xenotransplant models of cancer in nude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast, pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeability was reduced.

Clinical efficacy

Metastatic carcinoma of the colon or rectum (mCRC)

The safety and efficacy of the recommended dose (5 mg/kg of body weight every two weeks) in metastatic carcinoma of the colon or rectum were studied in three randomised, active-controlled clinical trials in combination with fluoropyrimidine-based first-line chemotherapy. Avastin was combined with two chemotherapy regimens:

• AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/folinic acid (IFL) for a total of 4 weeks of each 6 week-cycle (Saltz regi