Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab clearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster in subjects with higher tumour burden when compared with a typical patient with median values of albumin and tumour burden.
Pharmacokinetics in special populations

The population pharmacokinetics were analysed to eva luate the effects of demographic characteristics. The results showed no significant difference in the pharmacokinetics of bevacizumab in relation to age.

Renal impairment: No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally impaired patients since the kidneys are not a major organ for bevacizumab metabolism or excretion.

Hepatic impairment: No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients with hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion.

Paediatric population

The pharmacokinetics of bevacizumab have been studied in a limited number of paediatric patients. The resulting pharmacokinetic data suggest that the volume of distribution and clearance of bevacizumab were comparable to that in adults with solid tumours.

5.3 Preclinical safety data
 In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed in young animals with open growth plates, at bevacizumab average serum concentrations below the expected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown to inhibit wound healing at doses below the proposed clinical dose. Effects on wound healing were shown to be fully reversible.
Studies to eva luate the mutagenic and carcinogenic potential of bevacizumab have not been performed.
No specific studies in animals have been conducted to eva luate the effect on fertility. An adverse effect on female fertility can however be expected as repeat dose toxicity studies in animals have shown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and associated decrease in ovarian and uterus weight as well as a decrease in the number of menstrual cycles.
Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased incidence of specific gross and skeletal foetal malformations. Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted in average serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every 2 weeks.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

 Trehalose dihydrate

Sodium phosphate

Polysorbate 20

Water for injections

6.2 Incompatibilities

 This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

A concentration dependent degradation profile of bevacizumab was observed when diluted with glucose solutions (5%).

6.3 Shelf life

 2 years.

Chemical and physical in-use stability has been demonstrated for 48 hours at 2°C to 30°C in sodium chloride 9 mg/ml (0.9%) solution fo