ry arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans.
Increased liver weight and hepatocellular hypertrophy were observed in mice, rats and dogs after treatment with macitentan. These changes were largely reversible and considered non-adverse adaptations of the liver to increased metabolic demand.
Macitentan induced minimal to slight mucosal hyperplasia and inflammatory infiltration in the submucosa of the nasal cavity in the mouse carcinogenicity study at all doses. No nasal cavity findings were noted in the 3-month mouse toxicity study or in rat and dog studies.
Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays. Macitentan was not phototoxic in vivo after single dose at exposures of up to 24-fold the human exposure.
Carcinogenicity studies of 2 years' duration did not reveal a carcinogenic potential at exposures 18-fold and 116-fold the human exposure in rats and mice, respectively.
Testicular tubular dilatation was observed in chronic toxicity studies with male rats and dogs with safety margins of 11.6 and 5.8, respectively. Tubular dilatation was fully reversible. After 2 years of treatment, testicular tubular atrophy was seen in rats at 4-fold the human exposure. Hypospermatogenesis was observed in the life-long carcinogenicity study in rats and in the repeat-dose toxicity studies in dogs at exposures that provide safety margins of 9.7 in rats and 23 in dogs. The safety margins for fertility were 18 for male and 44 for female rats. No testicular findings were noted in mice after treatment up to 2 years. The effect of macitentan on human male fertility is not known (section 4.6).
Macitentan was teratogenic in rabbits and rats at all doses tested. In both species there were cardiovascular and mandibular arch fusion abnormalities.
Administration of macitentan to female rats from late pregnancy through lactation at maternal exposures 5-fold the human exposure, caused reduced pup survival and impairment of the reproductive capability of the offspring, which was exposed to macitentan during late intrauterine life and via the milk during the suckling period.
Treatment of juvenile rats from postnatal Day 4 to Day 114 caused reduced body weight gain leading to secondary effects on development (slight delay of descensus testis, reversible reduction of long-bone length, prolonged estrous cycle). Slightly increased pre- and post-implantation loss, decreased mean number of pups, and decreased testis and epididymis weights, were observed at exposures 7-fold the human exposure. Testicular tubular atrophy, and minimal effects on reproductive variables and sperm morphology were recorded at exposures 3.8-fold the human exposure.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Lactose monohydrate
Microcrystalline cellulose (E460i)
Sodium starch glycolate Type A
Povidone
Magnesium stearate (E572)
Polysorbate 80 (E433)
Film coat
Polyvinyl alcohol (E1203)
Titanium dioxide (E171)
Talc (E553b)
Lecithin, soybean (E322)
Xanthan gum (E415)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
Do not store above 30 °C.
6.5 Nature and contents of container
White, opaque PVC/PE/PVdC/Aluminium foil blisters in cartons containing 15 or 30 film-coated tablets.
White hig |
