ted to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Drug Interactions [See also Drug Interactions (7).]
No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with atorvastatin. Specific pharmacokinetic drug interaction studies with LIPTRUZET have not been performed.
Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.
Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of LIPTRUZET with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of the atorvastatin component of LIPTRUZET. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.
Ezetimibe
Table 5: Effect of Coadministered Drugs on Total Ezetimibe Coadministered Drug and Dosing Regimen Total Ezetimibe*
Change in AUC Change in Cmax
* Based on 10-mg dose of ezetimibe † Post-renal transplant patients with mild impaired or normal renal function. In a different study, a renal transplant patient with severe renal impairment (creatinine clearance of 13.2 mL/min/1.73 m 2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. ‡ See Drug Interactions (7) § Supralox ®, 20 mL
Cyclosporine-stable dose required (75-150 mg BID)†,‡ ↑240% ↑290%
Fenofibrate, 200 mg QD, 14 days‡ ↑48% ↑64%
Gemfibrozil, 600 mg BID, 7 days‡ ↑64% ↑91%
Cholestyramine, 4 g BID, 14 days‡ ↓55% ↓4%
Aluminum & magnesium hydroxide combination antacid, single dose§ ↓4% ↓30%
Cimetidine, 400 mg BID, 7 days ↑6% ↑22%
Glipizide, 10 mg, single dose ↑4% ↓8%
Statins
Lovastatin 20 mg QD, 7 days ↑9% ↑3%
Pravastatin 20 mg QD, 14 days ↑7% ↑23%
Atorvastatin 10 mg QD, 14 days ↓2% ↑12%
Rosuvastatin 10 mg QD, 14 days ↑13% ↑18%
Fluvastatin 20 mg QD, 14 days ↓19% ↑7%
Table 6: Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs Coadministered Drug and its Dosage Regimen Ezetimibe Dosage Regimen Change in AUC
of Coadministered Drug Change in Cmax
of Coadministered Drug
* See Drug Interactions (7)
Warfarin, 25 mg single dose on Day 7 10 mg QD, 11 days ↓2% (R-warfarin)
↓4% (S-warfarin) ↑3% (R-warfarin)
↑1% (S-warfarin)
Digoxin, 0.5 mg single dose 10 mg QD, 8 days ↑2% ↓7%
Gemfibrozil, 600 mg BID, 7 days* 10 mg QD, 7 days ↓1% ↓11%
Ethinyl estradiol & Levonorgestrel, QD, 21 days 10 mg QD, Days 8-14 of 21 d oral contraceptive cycle Ethinyl estradiol
0%
Levonorgestrel
0% Ethinyl estradiol
↓9%
Levonorgestrel
↓5%
Glipizide, 10 mg on Days 1 and 9 10 mg QD, Days 2-9 ↓3% ↓5%
Fenofibrate, 200 mg QD, |
