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Renal Insufficiency After a single 10-mg dose of ezetimibe in patients with severe renal disease (n= 8; mean CrCl <30 mL/ min/ 1.73 m 2 ), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n= 9). Drug Interactions (See also PRECAUTIONS, Drug Interactions) Text Continues Below
ZETIA 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. Warfarin: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males.
Digoxin:
Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of digoxin and the ECG parameters (HR, PR, QT, and QTc intervals) in a study of twelve
healthy adult males. Gemfibrozil: In a study of twelve healthy adult males, concomitant administration of gemfibrozil (600 mg twice daily) significantly increased the oral bioavailability of total ezetimibe by a factor of 1.7.
Ezetimibe (10 mg once daily) did not significantly affect the bioavailability of gemfibrozil.
Oral Contraceptives: Co-administration of ezetimibe (10 mg once daily) with oral contraceptives had no significant effect on the bioavailability of ethinyl estradiol or levonorgestrel in a study of eighteen healthy adult females. Cimetidine: Multiple doses of cimetidine (400 mg twice daily) had no significant effect on the oral bioavailability of ezetimibe and total ezetimibe in a study of twelve healthy adults. Antacids: In a study of twelve healthy adults, a single dose of antacid (Supralox TM 20 mL) administration had no significant effect on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or ezetimibe based on AUC values. The Cmax value of total ezetimibe was decreased by 30%. Glipizide: In a study of twelve healthy adult males, steady-state levels of ezetimibe (10 mg once daily) had no significant effect on the pharmacokinetics and pharmacodynamics of glipizide. A single dose of glipizide (10 mg) had no significant effect on the exposure to total ezetimibe or ezetimibe. HMG-CoA reductase inhibitors: In studies of healthy hypercholesterolemic (LDL-C 130 mg/ dL) adult subjects, concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of either lovastatin, simvastatin, pravastatin, atorvastatin, or fluvastatin. No significant effect on the bioavailability of total ezetimibe and ezetimibe was demonstrated by either lovastatin (20 mg once daily), pravastatin (20 mg once daily), atorvastatin (10 mg once daily), or fluvastatin (20 mg once daily). Fenofibrate: In a study of thirty-two healthy hypercholesterolemic (LDL-C 130 mg/ dL) adult subjects, concomitant fenofibrate (200 mg once daily) administration increased the mean Cmax and AUC values of total ezetimibe approximately 64% and 48%, respectively. Pharmacokinetics of fenofibrate were not significantly affected by ezetimibe (10 mg once daily). Cholestyramine: In a study of forty healthy hypercholesterolemic (LDL-C 130 mg/ dL) adult subjects, concomitant cholestyramine (4 g twice daily) administration decreased the mean AUC values of total ezetimibe and ezetimibe approximately 55% and 80%, respectively. ANIMAL PHARMACOLOGY The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 µ g/ kg/ day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 µ g/ kg/ day, respectively. These results are consistent with ZETIA being a potent cholesterol absorption inhibitor. In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug. In 1-month studies in dogs given ezetimibe (0. 03-300 mg/ kg/ day), the concentration of cholesterol in gallbladder bile increased ~2-to 4-fold. However, a dose of 300 mg/ kg/ day administered to dogs for one
year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0. 3-5 mg/ kg/ day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively. A series of acute preclinical studies was performed to determine the selectivity of ZETIA for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14 C cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethyl estradiol, or the fat-soluble vitamins A and D. In 4-to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase inhibitors (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits. CLINICAL STUDIES Primary Hypercholesterolemia ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with hypercholesterolemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy. ZETIA is effective in patients with hypercholesterolemia, in men and women, in younger and older patients, alone or administered with an HMG-CoA reductase inhibitor. Experience in pediatric and adolescent patients (ages 9 to 17) has been limited to patients with homozygous familial hypercholesterolemia (HoFH) or sitosterolemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of ZETIA. Monotherapy In two, multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ZETIA significantly lowered total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to placebo (see Table 1). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C. Table 1
Response to ZETIA in Patients with Primary Hypercholesterolemia
(Mean a % Change from Untreated Baseline b ) Treatment
group N Total-C LDL-C Apo B TG a HDL-C Placebo 205 +1 +1 -1 -1 -1 Study 1 c
Ezetimibe 622 -12 -18 -15 -7 +1 Placebo 226 +1 +1 -1 +2 -2 Study 2 c
Ezetimibe 666 -12 -18 -16 -9 +1 Placebo 431 0 +1 -2 0 -2 Pooled Data c
(Studies 1 & 2) Ezetimibe 1288 -13 -18 -16 -8 +1 a For triglycerides, median % change from baseline
b Baseline -on no lipid-lowering drug
c ZETIA significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to placebo. Combination with HMG-CoA Reductase Inhibitors ZETIA Added to On-going HMG-CoA Reductase Inhibitor Therapy
In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hypercholesterolemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving HMG-CoA reductase inhibitor monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either ZETIA or placebo in addition to their on-going HMG-CoA reductase inhibitor therapy. ZETIA, added to on-going HMG-CoA reductase inhibitor therapy, significantly lowered total-C, LDL-C, Apo B, and TG, and increased HDL-C compared with an HMG-CoA reductase inhibitor administered alone (see Table 2). LDL-C reductions induced by ZETIA were generally consistent across all HMG-CoA reductase inhibitors. Table 2
Response to Addition of ZETIA to On-going HMG-CoA Reductase Inhibitor Therapy a in Patients with Hypercholesterolemia
(Mean b % Change from Treated Baseline c ) Treatment
(Daily Dose) N Total-C LDL-C Apo B TG b HDL-C On-going HMG-CoA reductase inhibitor +Placebo d 390 -2 -4 -3 -3 +1
On-going HMG-CoA reductase inhibitor +ZETIA d 379 -17 -25 -19 -14 +3
a Patients receiving each HMG-CoA reductase inhibitor: 40% atorvastatin, 31% simvastatin, 29% others
(pravastatin, fluvastatin, cerivastatin, lovastatin)
b For triglycerides, median % change from baseline
c Baseline -on an HMG-CoA reductase inhibitor alone.
d ZETIA + HMG-CoA reductase inhibitor significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to HMG-CoA reductase inhibitor alone. ZETIA Initiated Concurrently with an HMG-CoA Reductase Inhibitor
In four, multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hypercholesterolemic patients, ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin. When all patients receiving ZETIA with an HMG-CoA reductase inhibitor were compared to all those receiving the corresponding HMG-CoA reductase inhibitor alone, ZETIA significantly lowered total-C, LDL-C, Apo B, and TG, and, with the exception of pravastatin, increased HDL-C compared to the HMG-CoA reductase inhibitor administered alone. LDL-C reductions induced by ZETIA were generally consistent
across all HMG-CoA reductase inhibitors. (See footnote c, Tables 3 to 6.) Table 3
Response to ZETIA and Atorvastatin Initiated Concurrently
in Patients with Primary Hypercholesterolemia
(Mean a % Change from Untreated Baseline b ) Treatment
(Daily Dose) N Total-C LDL-C Apo B TG a HDL-C Placebo 60 +4 +4 +3 -6 +4
ZETIA 65 -14 -20 -15 -5 +4
Atorvastatin 10 mg 60 -26 -37 -28 -21 +6
ZETIA + Atorvastatin 10 mg 65 -38 -53 -43 -31 +9 Atorvastatin 20 mg 60 -30 -42 -34 -23 +4
ZETIA + Atorvastatin 20 mg 62 -39 -54 -44 -30 +9 Atorvastatin 40 mg 66 -32 -45 -37 -24 +4
ZETIA + Atorvastatin 40 mg 65 -42 -56 -45 -34 +5 Atorvastatin 80 mg 62 -40 -54 -46 -31 +3
ZETIA + Atorvastatin 80 mg 63 -46 -61 -50 -40 +7 Pooled data (All Atorvastatin Doses) c 248 -32 -44 -36 -24 +4
Pooled data (All ZETIA + Atorvastatin Doses) c 255 -41 -56 -45 -33 +7 a For triglycerides, median % change from baseline
b Baseline -on no lipid-lowering drug
c ZETIA + all doses of atorvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10-80 mg). Table 4
Response to ZETIA and Simvastatin Initiated Concurrently
in Patients with Primary Hypercholesterolemia
(Mean a % Change from Untreated Baseline b ) Treatment
(Daily Dose) N Total-C LDL-C Apo B TG a HDL-C Placebo 70 -1 -1 0 +2 +1
ZETIA 61 -13 -19 -14 -11 +5
Simvastatin 10 mg 70 -18 -27 -21 -14 +8
ZETIA + Simvastatin 10 mg 67 -32 -46 -35 -26 +9 Simvastatin 20 mg 61 -26 -36 -29 -18 +6
ZETIA + Simvastatin 20 mg 69 -33 -46 -36 -25 +9 Simvastatin 40 mg 65 -27 -38 -32 -24 +6
ZETIA + Simvastatin 40 mg 73 -40 -56 -45 -32 +11 Simvastatin 80 mg 67 -32 -45 -37 -23 +8
ZETIA + Simvastatin 80 mg 65 -41 -58 -47 -31 +8 Pooled data (All Simvastatin Doses) c 263 -26 -36 -30 -20 +7
Pooled data (All ZETIA + Simvastatin Doses) c 274 -37 -51 -41 -29 +9 a For triglycerides, median % change from baseline
b Baseline -on no lipid-lowering drug
c ZETIA + all doses of simvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all
doses of simvastatin pooled (10-80 mg). Table 5
Response to ZETIA and Pravastatin Initiated Concurrently
in Patients with Primary Hypercholesterolemia
(Mean a % Change from Untreated Baseline b ) Treatment
(Daily Dose) N Total-C LDL-C Apo B TG a HDL-C Placebo 65 0 -1 -2 -1 +2
ZETIA 64 -13 -20 -15 -5 +4
Pravastatin 10 mg 66 -15 -21 -16 -14 +6
ZETIA + Pravastatin 10 mg 71 -24 -34 -27 -23 +8 Pravastatin 20 mg 69 -15 -23 -18 -8 +8
ZETIA + Pravastatin 20 mg 66 -27 -40 -31 -21 +8 Pravastatin 40 mg 70 -22 -31 -26 -19 +6
ZETIA + Pravastatin 40 mg 67 -30 -42 -32 -21 +8 Pooled data (All Pravastatin Doses) c 205 -17 -25 -20 -14 +7
Pooled data (All ZETIA + Pravastatin Doses) c 204 -27 -39 -30 -21 +8 a For triglycerides, median % change from baseline
b Baseline -on no lipid-lowering drug
c ZETIA + all doses of pravastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and TG compared to all doses of pravastatin pooled (10-40 mg). Table 6
Response to ZETIA and Lovastatin Initiated Concurrently
in Patients with Primary Hypercholesterolemia
(Mean a % Change from Untreated Baseline b ) Treatment
(Daily Dose) N Total-C LDL-C Apo B TG a HDL-C Placebo 64 +1 0 +1 +6 0
ZETIA 72 -13 -19 -14 -5 +3
Lovastatin 10 mg 73 -15 -20 -17 -11 +5
ZETIA + Lovastatin 10 mg 65 -24 -34 -27 -19 +8 Lovastatin 20 mg 74 -19 -26 -21 -12 +3
ZETIA + Lovastatin 20 mg 62 -29 -41 -34 -27 +9 Lovastatin 40 mg 73 -21 -30 -25 -15 +5
ZETIA + Lovastatin 40 mg 65 -33 -46 -38 -27 +9 Pooled data (All Lovastatin Doses) c 220 -18 -25 -21 -12 +4
Pooled data (All ZETIA + Lovastatin Doses) c 192 -29 -40 -33 -25 +9 a For triglycerides, median % change from baseline
b Baseline -on no lipid-lowering drug
c ZETIA + all doses of lovastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10-40 mg). Homozygous Familial Hypercholesterolemia (HoFH) A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/ or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ZETIA administered with atorvastatin or simvastatin (40 mg), or ZETIA administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine (see PRECAUTIONS), ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/ dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/ dL in the group randomized to ZETIA plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. ZETIA, administered with atorvastatin or simvastatin (40 and 80 mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with ZETIA plus 80 mg atorvastatin or with ZETIA plus 80 mg simvastatin, LDL-C was reduced by 27%. Homozygous Sitosterolemia (Phytosterolemia) A study was conducted to assess the efficacy of ZETIA in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (> 5 mg/ dL) on their current therapeutic regimen (diet, bile-acid-binding resins, HMG-CoA reductase inhibitors, ileal bypass surgery and/ or LDL apheresis), were randomized to receive ZETIA (n= 30) or placebo (n= 7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine (see PRECAUTIONS), ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL-apheresis, ZETIA significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ZETIA, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established. Reductions in sitosterol and campesterol were consistent between patients taking ZETIA concomitantly with bile acid sequestrants (n= 8) and patients not on concomitant bile acid sequestrant therapy (n= 21). Page: << Prev | 1 | 2 | 3 | 4 | 5
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