Paediatric population

No studies have been conducted to investigate the pharmacokinetics of vemurafenib in paediatric patients.

5.3 Preclinical safety data
 The preclinical safety profile of vemurafenib was assessed in rats, dogs, and rabbits.

Repeat-dose toxicology studies identified the liver and bone marrow as target organs in the dog. Reversible toxic effects (hepatocellular necrosis and degeneration) in the liver at exposures below the anticipated clinical exposure (based on AUC comparisons) were noted in the 13-week dog study. Focal bone marrow necrosis was noted in one dog in a prematurely terminated 39-week BID dog study at exposures similar to the anticipated clinical exposure (based on AUC comparisons). In an in vitro bone marrow cytotoxicity study, slight cytotoxicity was observed in some lympho-haematopoietic cell populations of rat, dog and human at clinically relevant concentrations.

Vemurafenib was shown to be phototoxic, in vitro, on cultured murine fibroblasts after UVA irradiation, but not in vivo in a rat study at doses up to 450 mg/kg/day (at exposures below the anticipated clinical exposure (based on AUC comparison). No specific studies with vemurafenib have been conducted in animals to eva luate the effect on fertility. However, in repeat-dose toxicity studies, no histopathological findings were noted on reproductive organs in males and females in rats and dogs at doses up to 450 mg/kg/day (at exposures below the anticipated clinical exposure based on AUC comparison). No teratogenicity was observed in embryofoetal development studies in rats and rabbits at doses up to respectively 250 mg/kg/day and 450 mg/kg/day leading to exposures below the anticipated clinical exposure (based on AUC comparison). However, exposures in the embryofoetal development studies were below the clinical exposure based on AUC comparison, it is therefore difficult to define to what extent these results can be extrapolated to humans. Therefore an effect of vemurafenib on the foetus cannot be excluded. No studies were performed regarding pre- and postnatal development.

No signs of genotoxicity were identified in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) nor in the in vivo rat bone marrow micronucleus test conducted with vemurafenib.

Carcinogenicity studies have not been conducted with vemurafenib.

6. Pharmaceutical particulars
  
6.1 List of excipients
 Core

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Hydroxypropylcellulose

Film-coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide red (E172)

6.2 Incompatibilities
 Not applicable.

6.3 Shelf life
 2 years.

6.4 Special precautions for storage
 Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
 Aluminium / Aluminium perforated unit dose blisters

Pack-size: 56 x 1 film-coated tablets (7 blisters of 8 x 1 tablet)
6.6 Special precautions for disposal and other handling
 Any unused medicinal product or waste material should be disposed of in accordance wit