l safety data
Repeat dose toxicity
Major toxicity findings in mice and dogs following repeated dosing for up to 9 months were the gastrointestinal, haematopoietic, reproductive, skeletal and dental systems, with No Observed Adverse Effect Levels (NOAEL) approximately equivalent to or below expected human exposure at the recommended clinical starting dose (based on AUC levels).
Carcinogenicity
Carcinogenicity studies have not been performed with axitinib.
Genotoxicity
Axitinib was not mutagenic or clastogenic in conventional genotoxicity assays in vitro. A significant increase in polyploidy was observed in vitro at concentrations > 0.22 µg/mL, and an elevation in micronucleated polychromatic erythrocytes was observed in vivo with No Observed Effect Level (NOEL) 69-fold the expected human exposure. Genotoxicity findings are not considered clinically relevant at exposure levels observed in humans.
Reproduction toxicity
Axitinib-related findings in the testes and epididymis included decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, and reduced sperm density and count. These findings were observed in mice at exposure levels approximately 12-fold the expected human exposure, and in dogs at exposure levels below the expected human exposure. There was no effect on mating or fertility in male mice at exposure levels approximately 57-fold the expected human exposure. Findings in females included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at exposures approximately equivalent to the expected human exposure. Reduced fertility and embryonic viability were observed in female mice at all doses tested, with exposure levels at the lowest dose approximately 10-fold the expected human exposure.
Pregnant mice exposed to axitinib showed an increased occurrence of cleft palate malformations and skeletal variations, including delayed ossification, at exposure levels below the expected human exposure. Perinatal and postnatal developmental toxicity studies have not been conducted.
Toxicity findings in immature animals
Reversible physeal dysplasia was observed in mice and dogs given axitinib for at least 1 month at exposure levels approximately six-fold higher than the expected human exposure. Partially reversible dental caries were observed in mice treated for more than 1 month at exposure levels similar to the expected human exposure. Other toxicities of potential concern to paediatric patients have not been eva luated in juvenile animals.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Magnesium stearate
Tablet film-coating:
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate
Triacetin (E1518)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
1 mg, 3 mg, 5 mg, 7 mg film-coated tablets
Aluminium/aluminium blister containing 14 film-coated tablets. Each pack contains 28 or 56 film-coated tablets.
1 mg film-coated tablets
HDPE bottle with a silica gel desiccant and a polypropylene closure containing 180 film-coated |
