n of binimetinib in rats for up to 6 months was associated with soft tissue mineralisation, gastric mucosal lesions and reversible minimal to mild clinical pathology changes at 7 to 12.5 times human therapeutic exposures. In a gastric irritation study in rats, an increased incidence of superficial mucosal lesions and of hemorrhagic ulcers were observed. In cynomolgus monkeys, oral administration of binimetinib was associated with gastro-intestinal intolerance, moderate clinical pathology changes, bone marrow hypercellularity and microscopic findings of gastrointestinal inflammation, reversible at the lowest doses which were below human therapeutic exposures.
Carcinogenic potential of binimetinib was not eva luated. Standard genotixicity studies with binimetinib were negative.
The potential embryo-foetal effects of binimetinib were eva luated in rats and rabbits. In rats, lower gestational body weight gain and fetal body weights and a decreased number of ossified fetal sternebrae were noted. No effects were noted at 14-times the human therapeutic exposure .
In rabbits, mortality, maternal physical signs of toxicity, lower gestational body weight and abortion were noted. The number of viable foetuses and foetal body weights were reduced and post-implantation loss and resorptions were increased. An increased litter incidence of foetal ventricular septal defects and pulmonary trunk alterations was noted at the highest doses. No effects were observed at 3times the human therapeutic exposure.
Fertility studies were not conducted with binimetinib. In repeat-dose toxicity studies, no concern in terms of fertility was raised from pathological examination of reproductive organs in rats and monkeys.
Binimetinib has phototoxic potential in vitro.
A minimal risk for photosensitisation was shown in vivo at an oral dose providing 3.8-fold higher exposure than that achieved with the recommended dose in humans. These data indicate that there is minimal risk for phototoxicity with binimetinib at therapeutic doses in patients.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Lactose monohydrate
Cellulose microcrystalline (E460i)
Silica colloidal anhydrous (E551)
Croscarmellose sodium (E468)
Magnesium stearate (E470b)
Film-coating
Polyvinyl alcohol (E1203)
Macrogol 3350 (E1521)
Titanium dioxide (E171)
Talc (E533b)
Iron oxide yellow (E172)
Iron oxide black (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
PVC/PVDC/Alu blister containing 12 tablets. Each pack contains 84 tablets.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Pierre Fabre Medicament 45, place Abel Gance 92100 Boulogne-Billancourt France
8. Marketing authorisation number(s)
EU/1/18/1315/001
9. Date of first authorisation/renewal of the authorisation
20 September 2018
10. Date of revision of the text
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
