1.77 1.56

1.47
  Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6-9 simvastatin acid

simvastatin 2.26

1.86 2.28

1.75
Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience 
  Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid

simvastatin 1.7

2 1.6

2
  Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid

simvastatin 1.4

1.6 1.4

1.7
No dosing adjustments required for the following:
  Fenofibrate 160 mg QD X 14 days 80 mg QD on Days 8-14 simvastatin acid
simvastatin 0.64
0.89 0.89
0.83
  Niacin
extended-releaseÞ 2 g single dose 20 mg single dose simvastatin acid
simvastatin 1.6
1.4 1.84
1.08
  Propranolol 80 mg single dose 80 mg single dose total inhibitor

active inhibitor 0.79

0.79 ↓ from 33.6 to 21.1 ng∙eq/mL
↓ from 7.0 to 4.7 ng∙eq/mL
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.

Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityIn a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC).

In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produce