etic and/or pharmacodynamic interactions following coadministration.
The coadministration of ezetimibe and atorvastatin in pregnant rats indicated that there was a test article-related increase in the skeletal variation “reduced ossification of the sternebrae” in the high dose (1000/108.6 mg/kg) ezetimibe/atorvastatin group. This may be related to the observed decrease in foetal body weights. In pregnant rabbits a low incidence of skeletal deformities (fused sternebrae, fused caudal vertebrae and asymmetrical sternebrae variation) were observed.
In a series of in vivo and in vitro assays, ezetimibe, given alone or coadministered with atorvastatin, exhibited no genotoxic potential.
Ezetimibe
Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic effects. In dogs treated for four weeks with ezetimibe (≥0.03 mg/kg/day) the cholesterol concentration in the cystic bile was increased by a factor of 2.5 to 3.5. However, in a one-year study on dogs given doses of up to 300 mg/kg/day no increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of ezetimibe cannot be ruled out.
Long-term carcinogenicity tests on ezetimibe were negative.
Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Ezetimibe crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1000 mg/kg/day.
Atorvastatin
Atorvastatin was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay. Atorvastatin was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC0-24h reached in humans at the highest recommended dose) showed hepatocellular adenomas in males and hepatocellular carcinomas in females. There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of embryos or fetuses. In rats, rabbits, and dogs atorvastatin had no effect on fertility and was not teratogenic, however, at maternally toxic doses foetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to high doses of atorvastatin. In rats, there is evidence of placental transfer. In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether atorvastatin or its metabolites are excreted in human milk.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipient(s)
Tablet core
Ezetimibe Layer
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Cellulose, microcrystalline
Povidone
Sodium laurilsulfate
Atorvastatin Layer
Cellulose, microcrystalline
Lactose monohydrate
Hydroxypropylcellulose
Croscarmellose sodium
Polysorbate 80
Calcium carbonate
Magnesium stearate
Silica, colloidal anhydrous
Film coating
Hypromellose
Macrogol 8000
Titanium dioxide (E171)
Talc
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 oxygen.
6.5 N
