Excretion Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the and 60% in the faeces within 96 hours. The amount recovered in the faeces represents absorbed drug equivalents excreted in bile as well as unabsorbed drug. Following an intravenous injection of the -hydroxyacid metabolite an average of only 0.3% of the IV dose was excreted in urine as inhibitors. Characteristics in Special Populations Paediatric Patients Ezetimibe The absorption and metabolism of ezetimibe are similar between children and adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the paediatric population < 10 years of age are not available. Clinical experience in paediatric and adolescent patients (ages 9 to 17) has been limited to patients with HoFH or homozygous sitosterolaemia. (see PRECAUTIONS). Elderly Patients Ezetimibe Plasma concentrations for total ezetimibe are about 2fold higher in the elderly ( 65 years) than in the young (18 to 45 years). LDLC reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe (see PRECAUTIONS). Hepatic Insufficiency Ezetimibe a single 10mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7fold in patients with mild hepatic insufficiency (ChildPugh score 5 or 6), compared to healthy subjects. In a 14day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (ChildPugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (ChildPugh score > 9) hepatic insufficiency, ezetimibe is not recommended in these patients (see PRECAUTIONS).
† Mean absolute change from baseline are mmol/L for all parameters except Apo B, which is in g/L) a For triglycerides, median absolute change from baseline b Baseline on no lipid-lowering drug Table 1a Response to VYTORIN in Patients with Primary Hypercholesterolaemia (Meana Percent Change from Untreated Baselineb) Treatment (Daily Dose) N Total-C Pct† [Baseline‡] LDL-C Pct† [Baseline‡] B Pct† [Baseline‡] HDL-C Pct† [Baseline‡] TGa Pct† [Baseline‡] Non-HDL-C Pct† [Baseline‡] Pooled data (All VYTORIN doses)c 353 -38 [6.73] -53 [4.52] -42 [1.60] +8 [1.31] -28 [1.90] -49 [5.42] Pooled data (All simvastatin doses)c 349 -26 [6.70] -38 [4.52] -29 [1.59] +8 [1.28] -15 [1.89] -34 [5.42] Ezetimibe10 mg 92 -14 [6.79] -20 [4.55] -15 [1.58] +7 [1.32] -13 [1.85] -19 [5.46] Placebo 93 +2 [6.66] +3 [4.49] +3 [1.59] +2 [1.30] -2 [1.83] +2 [5.36] VYTORIN by dose
10/20 238 -2.52 [6.84] -2.36 [4.62] -0.67 [1.64] +0.08 [1.27] -0.42 [1.89] -2.60 [5.57] 10/40 238 -2.81 [6.85] -2.64 [4.60] -0.77 [1.66] +0.10 [1.27] -0.55 [1.94] -2.91 [5.58] 10/80 237 -2.90 [6.81] -2.68 [4.59] -0.80 [1.65] +0.08 [1.27] -0.60 [1.92] -2.98 [5.54] Atorvastatin by dose 10 mg 238 -1.82 [6.77] -1.67 [4.53] -0.51 [1.63] +0.07 [1.25] -0.41 [1.93] -1.89 [5.52] 20 mg 237 -2.23 [6.86] -2.03 [4.61] -0.61 [1.67] +0.05 [1.26] -0.46 [1.96] -2.28 [5.60] 40 mg 237 -2.46 [6.85] -2.25 [4.65] -0.67 [1.64] +0.04 [1.30] -0.41 [1.82] -2.49 [5.55] 80 mg 239 -2.78 [6.89] -2.49 [4.72] -0.74 [1.67] +0.10 [1.24] -0.59 [1.87] -2.79 [5.65] † Mean absolute change from baseline (units are mmol/L for all parameters except Apo B, which is in g/L) a For triglycerides, median absolute change from baseline b Baseline - on no lipid-lowering drug
10/80 237 -43d [6.81] -59 d [4.59] -48 d [1.65] +8 d [1.27] -31 [1.92] -54 d [5.54] Atorvastatin by dose 10 mg 238 -27 [6.77] -36 [4.53] -31 [1.63] +7 [1.25] -21 [1.93] -34 [5.52] 20 mg 237 -32 [6.86] -44 [4.61] -37 [1.67] +5 [1.26] -25 [1.96] -41 [5.60] 40 mg 237 -36 [6.85] -48 [4.65] -40 [1.64] +4 [1.30] -24 [1.82] -45 [5.55] 80 mg 239 -40 [6.89] -53 [4.72] -44 [1.67] +1 [1.24] -32 [1.87] -50 [5.65] † Mean percent change from baseline ‡ Baseline units are mmol/L for all parameters except Apo B, which is in g/L a For triglycerides, median % change from baseline b Baseline - on no drug c p<0.05 for difference with atorvastatin d p<0.05 for difference with atorvastatin at mg doses of the simvastatin component In a multicenter, double-blind, 24-week, forced titration study, 788 patients with primary hypercholesterolaemia, who had not met their NCEP ATP III target LDL-C goal, were randomised to receive co-administered ezetimibe and simvastatin equivalent to VYTORIN (10/10 and 10/20) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6week intervals to 80 mg. At each pre-specified dose comparison, VYTORIN