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. Information on foetal malformations observed in the post marketing setting are provided in section 4.6 Fertility, Pregnancy and Lactation and 4.8 Undesirable Effects.

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
Vial (unopened)

2 years.

Diluted medicinal product

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 for injection. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container
4 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 100 mg of bevacizumab.

16 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 400 mg of bevacizumab.

Pack of 1 vial.

6.6 Special precautions for disposal and other handling
Avastin should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared solution.

The necessary amount of bevacizumab should be withdrawn and diluted to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution for in