ration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Effects of Simvastatin on Other Drugs
CYP3A4 Inhibitors: 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.
Effects of Other Drugs on Simvastatin
Cyclosporine: Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
CYP3A4 Inhibitors: The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.2); Drug Interactions (7.1)].
Table 6 Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with / without coadministered drug)
No Effect = 1.00
AUC Cmax
*
Results based on a chemical assay except results with propranolol as indicated.
†
Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
‡
Simvastatin acid refers to the β-hydroxyacid of simvastatin.
§
The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
¶
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
#
Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
Þ
Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related [ see Warnings and Precautions (5.2); Drug Interactions (7.4)].
Contraindicated with JUVISYNC [see Contraindications (4); Warnings and Precautions (5.2)]
Telithromycin† 200 mg QD for 4 days 80 mg simvastatin acid‡
simvastatin 12
8.9 15
5.3
Nelfinavir† 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid‡
simvastatin
6
6.2
Itraconazole† 200 mg QD for 4 days 80 mg simvastatin acid‡
simvastatin 13.1
13.1
Posaconazole 100 mg (oral suspension)
QD for 13 days 40 mg s |
