Ezetimibe (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 x the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 x the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.

No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.

In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 x the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).

13.2 Animal Toxicology and/or 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 mcg/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 mcg/kg/day, respectively. These results are consistent with Ezetimibe Tablets 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 to 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 to 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 Ezetimibe Tablets 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, ethinyl 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 statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

Ezetimibe Tablets reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

Monotherapy

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, Ezetimibe Tablets significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (see Table6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

TABLE 6: Response to Ezetimibe Tablets in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)

Treatment Group N Total-C LDL-C Apo B Non-HDL-C TG* HDL-C
Study 1 Placebo 205 +1 +1 -1 +1 -1 -1
Ezetimibe 622 -12 -18 -15 -16 -7 +1
Study 2 Placebo 226 +1 +1 -1 +2 +2 -2
Ezetimibe 666 -12 -18 -16 -16 -9 +1
Pooled Data‡ (Studies 1 & 2) Placebo 431 0 +1 -2 +1 0 -2
Ezetimibe 1288 -13 -18 -16 -16 -8 +1

* For triglycerides, median % change from baseline

Baseline — on no lipid-lowering drug

Ezetimibe Tablets significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.

Combination with Statins

Ezetimibe Tablets Added to On-going Statin Therapy

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either Ezetimibe Tablets or placebo in addition to their on-going statin.

Ezetimibe Tablets, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe Tablets were generally consistent across all statins.

TABLE 7: Response to Addition of Ezetimibe Tablets to On-Going Statin Therapy* in Patients with Hyperlipidemia (Mean % Change from Treated Baseline)

Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG† HDL-C
On-going Statin + Placebo§ 390 -2 -4 -3 -3 -3 +1
On-going Statin + Ezetimibe Tablets§ 379 -17 -25 -19 -23 -14 +3

* Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin)

For triglycerides, median % change from baseline

Baseline — on a statin alone.

§ Ezetimibe Tablets + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to statin alone.

Ezetimibe Tablets Initiated Concurrently with a Statin

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe Tablets or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.

When all patients receiving Ezetimibe Tablets with a statin were compared to all those receiving the corresponding statin alone, Ezetimibe Tablets significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by Ezetimibe Tablets were generally consistent across all statins. (See footnote ‡, Tables 8 to 11.)

TABLE 8: Response to Ezetimibe Tablets and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG* HDL-C
Placebo 60 +4 +4 +3 +4 -6 +4
Ezetimibe Tablets 65 -14 -20 -15 -18 -5 +4
Atorvastatin 10 mg 60 -26 -37 -28 -34 -21 +6
Ezetimibe Tablets + Atorvastatin 10 mg 65 -38 -53 -43 -49 -31 +9
Atorvastatin 20 mg 60 -30 -42 -34 -39 -23 +4
Ezetimibe Tablets + Atorvastatin 20 mg 62 -39 -54 -44 -50 -30 +9
Atorvastatin 40 mg 66 -32 -45 -37 -41 -24 +4
Ezetimibe Tablets + Atorvastatin 40 mg 65 -42 -56 -45 -52 -34 +5
Atorvastatin 80 mg 62 -40 -54 -46 -51 -31 +3
Ezetimibe Tablets + Atorvastatin 80 mg 63 -46 -61 -50 -58 -40 +7
Pooled data (All Atorvastatin Doses) 248 -32 -44 -36 -41 -24 +4
Pooled data (All Ezetimibe Tablets + Atorvastatin Doses) 255 -41 -56 -45 -52 -33 +7

* For triglycerides, median % change from baseline

Baseline — on no lipid-lowering drug

Ezetimibe Tablets + all doses of atorvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg).

TABLE 9: Response to Ezetimibe Tablets and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG* HDL-C
Placebo 70 -1 -1 0 -1 +2 +1
Ezetimibe Tablets 61 -13 -19 -14 -17 -11 +5
Simvastatin 10 mg 70 -18 -27 -21 -25 -14 +8
Ezetimibe Tablets + Simvastatin 10 mg 67 -32 -46 -35 -42 -26 +9
Simvastatin 20 mg 61 -26 -36 -29 -33 -18 +6
Ezetimibe Tablets + Simvastatin 20 mg 69 -33 -46 -36 -42 -25 +9
Simvastatin 40 mg 65 -27 -38 -32 -35 -24 +6
Ezetimibe Tablets + Simvastatin 40 mg 73 -40 -56 -45 -51 -32 +11
Simvastatin 80 mg 67 -32 -45 -37 -41 -23 +8
Ezetimibe Tablets + Simvastatin 80 mg 65 -41 -58 -47 -53 -31 +8
Pooled data (All Simvastatin Doses) 263 -26 -36 -30 -34 -20 +7
Pooled data (All Ezetimibe Tablets + Simvastatin Doses) 274 -37 -51 -41 -47 -29 +9

* For triglycerides, median % change from baseline

Baseline — on no lipid-lowering drug

Ezetimibe Tablets + all doses of simvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10 to 80 mg).

TABLE 10: Response to Ezetimibe Tablets and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG* HDL-C
Placebo 65 0 -1 -2 0 -1 +2
Ezetimibe Tablets 64 -13 -20 -15 -17 -5 +4
Pravastatin 10 mg 66 -15 -21 -16 -20 -14 +6
Ezetimibe Tablets + Pravastatin 10 mg 71 -24 -34 -27 -32 -23 +8
Pravastatin 20 mg 69 -15 -23 -18 -20 -8 +8
Ezetimibe Tablets + Pravastatin 20 mg 66 -27 -40 -31 -36 -21 +8
Pravastatin 40 mg 70 -22 -31 -26 -28 -19 +6
Ezetimibe Tablets + Pravastatin 40 mg 67 -30 -42 -32 -39 -21 +8
Pooled data (All Pravastatin Doses) 205 -17 -25 -20 -23 -14 +7
Pooled data (All Ezetimibe Tablets + Pravastatin Doses)‡ 204 -27 -39 -30 -36 -21 +8

* For triglycerides, median % change from baseline

Baseline — on no lipid-lowering drug

Ezetimibe Tablets + all doses of pravastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10 to 40 mg).

TABLE 11: Response to Ezetimibe Tablets and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline)

Treatment (Daily Dose) N Total-C LDL-C Apo B Non-HDL-C TG* HDL-C
Placebo 64 +1 0 +1 +1 +6 0
Ezetimibe Tablets 72 -13 -19 -14 -16 -5 +3
Lovastatin 10 mg 73 -15 -20 -17 -19 -11 +5
Ezetimibe Tablets + Lovastatin 10 mg 65 -24 -34 -27 -31 -19 +8
Lovastatin 20 mg 74 -19 -26 -21 -24 -12 +3
Ezetimibe Tablets + Lovastatin 20 mg 62 -29 -41 -34 -39 -27 +9
Lovastatin 40 mg 73 -21 -30 -25 -27 -15 +5
Ezetimibe Tablets + Lovastatin 40 mg 65 -33 -46 -38 -43 -27 +9
Pooled data (All Lovastatin Doses) 220 -18 -25 -21 -23 -12 +4
Pooled data (All Ezetimibe Tablets + Lovastatin Doses) 192 -29 -40 -33 -38 -25 +9

* For triglycerides, median % change from baseline

Baseline — on no lipid-lowering drug

Ezetimibe Tablets + all doses of lovastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10 to 40 mg).

Combination with Fenofibrate

In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe Tablets alone, 160 mg fenofibrate alone, or Ezetimibe Tablets and 160 mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe Tablets co-administered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.

Ezetimibe Tablets co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe Tablets co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).

TABLE 12: Response to Ezetimibe Tablets and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean* % Change from Untreated Baseline† at 12 weeks)

Treatment (Daily Dose) N Total-C LDL-C Apo B TG* HDL-C Non-HDL-C
Placebo 63 0 0 -1 -9 +3 0
Ezetimibe Tablets 185 -12 -13 -11 -11 +4 -15
Fenofibrate 160 mg 188 -11 -6 -15 -43 +19 -16
Ezetimibe Tablets + Fenofibrate 160 mg 183 -22 -20 -26 -44 +19 -30

* For triglycerides, median % change from baseline

Baseline — on no lipid-lowering drug

The changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe Tablets co-administered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.

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