es separated) †,# 40 mg, SD ↓80% ↓40%
Gemfibrozil 600 mg BID, 7 days† 40 mg, SD ↑35% ↓Less than 1%
Fenofibrate 160 mg QD, 7 days† 40 mg, SD ↑3% ↑2%
Boceprevir 800 mg TID, 7 days 40 mg, SD ↑2.30 fold ↑2.66 fold
Table 8: Effect of Atorvastatin on the Pharmacokinetics of Coadministered Drugs Atorvastatin Coadministered Drug and Dosing Regimen
Drug/Dose (mg) Change in AUC Change in Cmax
* See Drug Interactions (7) for clinical significance.
80 mg QD for 15 days Antipyrine, 600 mg SD ↑3% ↓11%
80 mg QD for 14 days Digoxin 0.25 mg QD, 20 days* ↑15% ↑20%
40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1 mg
- ethinyl estradiol 35 µg ↑28%
↑19% ↑23%
↑30%
10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change
10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓27% ↓18%
10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No animal carcinogenicity or fertility studies have been conducted with the combination of ezetimibe and atorvastatin. The combination of ezetimibe with atorvastatin did not show evidence of mutagenicity in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with ezetimibe and atorvastatin with or without metabolic activation. There was no evidence of genotoxicity at doses up to 250 mg/kg with the combination of ezetimibe and atorvastatin (1:1) in the in vivo mouse micronucleus test.
Ezetimibe
A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.
No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).
Atorvastatin
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC0-24hr value of approximately 16 times the mean human plasma drug exposure after an 80-mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in |
