imvastatin acid
simvastatin 7.3
10.3 9.2
9.4
200 mg (oral suspension)
QD for 13 days 40 mg simvastatin acid
simvastatin 8.5
10.6 9.5
11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid
simvastatin 2.85
1.35 2.18
0.91
Avoid >1 quart of grapefruit juice [see Warnings and Precautions 5.2)]
Grapefruit Juice§
(high dose) 200 mL of double-strength TID¶ 60 mg single dose simvastatin acid
simvastatin 7
16
Grapefruit Juice§
(low dose) 8 oz (about 237 mL) of single-strength# 20 mg single dose simvastatin acid
simvastatin 1.3
1.9
Avoid taking with >100 mg/10 mg JUVISYNC, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.2)]
Verapamil SR 240 mg QD Days 1-7 then 240 mg BID on Days 8-10 80 mg on Day 10 simvastatin acid
simvastatin 2.3
2.5 2.4
2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid
simvastatin 2.69
3.10 2.69
2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Avoid taking with >100 mg/20 mg JUVISYNC, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.2)]
Amlodipine 10 mg QD for 10 days 80 mg on Day 10 simvastatin acid
simvastatin 1.58
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
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 Simvastatin acid
Simvastatin 1.75
1.76 1.72
1.79
No dosing adjustments required for the following:
Fenofibrate 160 mg QD for 14 days 80 mg QD on Days 8-14 simvastatin acid
simvastatin 0.64
0.89 0.89
0.83
Niacin extended-release Þ 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
0.79
↓ from 33.6 to 21.1 ng∙eq/mL
active inhibitor 0.79 ↓ from 7.0 to 4.7 ng∙eq/mL
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Sitagliptin
A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.
In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, |
